Property fj Compliments fcT MODERN CLINICAL MEDICINE DISEASES OF METABOLISM AND OF THE BLOOD ANIMAL PARASITES TOXICOLOGY EDITED BY RICHARD C. CABOT, M.D. INSTRUCTOR IN CLINICAL MEDICINE IN THE MEDICAL SCHOOL OF HARVARD UNIVERSITY AN AUTHORIZED TRANSLATION FROM "DIE DEUTSCHE KLINIK1 UNDER THE GENERAL EDITORIAL SUPERVISION OF JULIUS L. SALINGER, M.D. WITH ONE COLORED PLATE AND FIFTY-EIGHT ILLUSTRATIONS IN THE TEXT NEW YORK AND LONDON D. APPLETON AND COMPANY 1911 Copyright, 1906, 1909, 1910, by D. APPLETON AND COMPANY PRINTED AT THE APPLETON PRESS NEW YORK, U. S. A. He INTRODUCTION Although the statement of Prof. Hoppe-Seyler that " The process of life of the organism is, in the main, a complete mystery" is still true, much has been accomplished by the researches of modern physiologists and clinicians who have endeavored to find the key to this enigma. Perhaps in no realm of medicine has labor fructified so richly as in the recent study of metabolism. This has been of value not only in diagnosis but, even more so, from the standpoint of treatment. It may be confidently stated that the treatment of some diseases of metabolism, such as diabetes mellitus, gout, and obesity, now rests on a scientific basis. This advance is almost exclu- sively due to the labors of the modern German school of physiologists and internal clinicians. What is true of the pathology of metabolism may also be asserted of diseases of the blood. The study of maladies whose etiology and pathology were formerly obscure has now been simplified, their relations classified, and the whole arranged in exact scientific order. The processes of blood forma- tion and blood degeneration, while not yet forming an open book, have in part been clearly portrayed. That therapy has not kept pace with this ad- vance affords an opportunity for the physician of the twentieth century, but much has already been accomplished, and many problems have been solved. For this progress also the medical world is indebted to modern research. The object of this volume is to present a picture of diseases which were formerly designated as of "obscure causation/' and to outline their treat- ment. Each article is the work of a master in his special field of labor. In the translation an endeavor has been made to adhere as closely as possible to the individual style of each contributor without the subserviency of clearness in the text. iv INTRODUCTION I am indebted for much, valuable service in the preparation of this volume to my secretary, Miss M. A. Clarke. In anticipation of the fact that many points in regard to these affec- tions will be searched for by the reader, and to facilitate this, an endeavor has been made to add a comprehensive and full general index. Julius L. Salinger. 1729 North 42nd Street, Philadelphia. EDITOR'S PREFACE We have in English no discussion of the Constitutional Diseases which treats with any fulness the problems arising when we consider the reasons for what occurs in these- diseases. The rationale of the symptomatology, the rationale of treatment (i. e., in diabetes) is here admirably set forth by clinicians each of whom speaks with authority. The writers have wisely confined themselves for the most part to thorough discussions of certain points in each of the diseases considered — making no fatuous attempt to compress a huge subject into narrow limits. They have brought their subjects up to date and given very frankly their personal views on the points at issue. For the manner and for the matter of their work, therefore, we are in- debted to our Teutonic brethren, and we are glad that the book will now find a large circle of readers. Eichard 0. Cabot. 190 Marlborough Street, Boston, Mass. LIST OF CONTEIBUTIONS The Quantitative Analysis of Disturbances of Metabolism in the Clinic. By W. Weintraud, Wiesbaden. Over-nutrition and Under-nutrition. By C. v. Noorden, Frankfort-on-Main. Diabetes Mellitus. By B. Naunyn, Strassburg. Diabetes Insipidus. By D. Gerhardt, Strassburg. Gout. By W. Ebstein, Gottingen. Obesity. By W. Ebstein, Gottingen. Myxedema with Special Reference to Organotherapy. By C. A. Ewald, Berlin. Addison's Disease. By L. Keiss, Berlin. Acromegalia. By C. Bend a, Berlin. Chronic Articular Rheumatism. By W. His, Basel. Pentosuria. By F. Blumenthal, Berlin. Blood and Blood Examination. By A. Lazarus, Charlottenburg (Berlin). The Anemias. By P. Ehrlich, Frankfort-on-Main, and A. Lazarus, Char- lottenburg (Berlin). Chlorosis. By E. Grawitz, Charlottenburg (Berlin). Leukemia. By W. von Leube, Wurzburg. Pseudo-leukemia (Hodgkin's Disease and Banti's Disease). By H. Senator, Berlin. The Hemorrhagic Diatheses. By M. Litten, Berlin. The Animal Parasites of Man. By E. Peeper, Greifswald. Important Poisons and Their Treatment. By E. v. Jaksch, Prague. CONTENTS PAGE The Quantitative Analysis of Disturbances op Metabolism in the Clinic . 1 Introduction 1 Consumption of Food in the Healthy 4 A. The Laws of Nutrition 4 Energy Metabolism per Square Meter of Body Surface . . ., ' 5 B. The Methods for Estimating the Calory Requirement of the Body . 6 C. The Energy Requirement of the Healthy 9 D. The Albumin Minimum 13 E. The Requirements for Albumin Deposition 15 The Food Requirement of the Sick . # 21 The Degree of Oxidation 22 The Maintenance Diet and the Proteid Requirement of the Sick ... 37 Disturbances in the Absorption of Food . 43 Concluding Remarks 49 Over-Nutrition and Under-Nutrition 54 1. Conception of the "Condition of Nutrition'! 54 2. Increase of Flesh and Increase of Fat 55 3. Occurrence and Consequences of Under-Nutrition 59 4. Occurrence and Consequences of Over-Nutrition 61 5. Indications for Hypernutrition and Hyponutrition 62 A. Over-Nutrition 63 B. Under-Nutrition 67 6. Remarks Regarding the Technic of Over-Nutrition and Under-Nutrition . 69 A. The Technic of Forced Feeding 70 B. The Technic of Antifat Cures 72 Diabetes Mellitus 77 I. Glycosuria and Diabetes 77 II. The Various Forms of Diabetes; Diabetic Predisposition .... 80 III. Mild and Severe Forms of Diabetes; Course, Symptomatology and Com- plications 83 IV. The Theory of the Treatment of Diabetes 87 V. Practical Therapy 92 VI. Tables 103 Short Popular Dietetic Rules for Diabetics 108 X CONTENTS PAGE Diabetes Insipidus . « . > 110 Symptoms and Clinical Course . . . . . » . . . . .112 Diagnosis ........ 121 Treatment 122 Gout 125 The Pathogenesis of Gout 126 Symptomatology 132 Course and Prognosis 145 Diagnosis 146 Treatment 146 Obesity 151 Etiology 133 Symptomatology 155 Diagnosis 159 Treatment . 160 Myxedema with Special Reference to Organotherapy 179 History 179 Etiology .180 Symptoms ' 180 Pathology * 186 Therapy 188 Addison's Disease 199 Clinical Picture of Addison's Disease 200 Grosser Pathologico- Anatomical Lesions in Addison's Disease 202 Anatomy and Physiology of the Adrenals 204 Pathologico- Anatomical Changes of the Nervous System in Addison's Disease 215 Diagnosis 222 Therapy 223 Acromegalia 229 Etiology 230 Symptoms . . ' . . . .' . . . . . . . . . 231 Pathology 234 Pathological Anatomy 237 Treatment 242 Chronic Articular Rheumatism 243 Pathology 248 Clinical Symptoms 250 Treatment 257 Literature 259 Pentosuria 262 Blood and Blood Examination 275 I. Hemoglobin 277 II. Counting the Blood-Corpuscles 281 CONTENTS xi PAGE III. Counting the Leukocytes 283 IV. Specific Gravity 284 V. Alkalinity . 286 VI. Volume of Red Cells 287 VII. Spectroscopic Examination 287 VIII. Agglutinative Reactions 288 IX. Bacteriological Examination 290 The Anemias 304 Simple Anemia 305 Progressive Pernicious Anemia 310 The Course of the Disease 317 Therapy . ...... 318 Chlorosis 320 Symptoms . 320 The Blood 325 Pathological Anatomy 329 Frequency of Chlorosis with Regard to Sex, Age and Locality .... 330 Predisposing Influences 331 The Genesis of Chlorosis 333 Diagnosis 336 Course of the Disease 337 Prognosis 339 Treatment 339 Prophylaxis 343 Leukemia * 344 Composition of the Blood . 344 Symptoms and Blood-Changes 348 Diagnosis 364 Leukocytosis 364 Prognosis 367 Treatment 367 Pseudo-Leukemia (Hodgkin's Disease and Banti's Disease) ..... 370 Hodgkin's Disease 371 Diagnosis 375 Etiology 377 Course, Duration and Result ........... 378 Therapy 378 Banti's Disease 381 The Hemorrhagic Diatheses 388 Scurvy 388 History 388 Etiology 393 Pathological Anatomy . 399 xii CONTENTS PAGE Symptomatology . 401 Diagnosis d o • • • . . . 409 Prognosis „ 410 Prophylaxis and Treatment „ 410 Hemophilia (Bleeder's Disease) 413 Pathological Anatomy . 430 Symptomatology and Course 434 Local Hemorrhages upon a Hemophilic Basis ...... 442 Prognosis . 451 Treatment 452 Morbus Maculosus Werlhofii (Purpura) (Purpura Simplex, Hemorrhagica, Rheumatica seu Peliosis, Rheumatica Schoenleinii) 457 Definition 457 Etiology 458 General Clinical Picture 469 Pathological Anatomy 487 Special Symptomatology 490 Treatment 496 The Animal Parasites op Man . . . . ....... 501 Protozoa 505 Trematodes 508 Cestodes 514 Prognosis 524 Therapy ................ 525 Echinococcus Disease 5?g Symptoms 532 Treatment 533 Echinococci of Various Organs . 534 Nematoda, Thread-Worms 544 Ankylostomiasis — Uncinariasis 560 Arthropoda . 565 Fly Larvae (Maggots) 573 Important Poisons and Their Treatment 579 LIST OF ILLUSTRATIONS FIG. PAGE 1. Incipient Myxedema ...... 181 2. Advanced Myxedema 182 3. Myxedema in the stage of recovery .......... 183 4. Rontgen picture showing Heberden's nodes ........ 247 5. Metatarso-phalangeal' articulation with beginning chronic arthritis . . . . 249 6. Subcutaneous nodules upon dorsal tendon sheaths in chronic exudative polyar- thritis 252 7. Patellar cartilage after an attack of gout 253 8. Radiograph of hand of a gouty patient ......... 254 9. Hemometer. (After v. Fleischl-Miescher) 278 10. Hemometer. (After Sahli) 279 11. Hemometer. (After Sahli) 279 12-13. Hemophotograph. (After Gaertner) 280 14. Hemocytometer. (After Thoma) 282 15. Microscopic picture with blood-corpuscles. (After Landois) .... 282 16. Absorption spectra of hemoglobin. (After Landois) 288 17. Relapsing Fever spirilli. (After v. Jaksch) 291 18. Use of forceps in blood examination 294 19. Small copper kettle for staining solutions 294 20. Ehrlich's eye-piece with iris diaphragm 301 21. Case of Hodgkin's disease 373 22. Genealogical tree of the bleeder family Mampel. (After Lossen) .... 416 23. Genealogical tree of a bleeder family. (After H. Gocht) 417 24. Genealogical tree of a family showing Daltonism. (After Horner) .... 419 25. Genealogical tree of a hemeralopic family. (After E. Ammann) . . . 420 26-28. Leydenia Gemmipara. (After von Leyden-Schaudinn) 505 29. Trichomonas Vaginalis. (After Kunstler) 507 30. Balantidium Minutum. (After Schaudinn) 508 31. Nyctotherus Faba. (After Schaudinn) 508 32. Distomum Hepaticum, Linne 509 33. Distomum Westermanni and ovum. (After Katsurada) 510 34. Distomum Spathulatum and ovum. (After Katsurada) ..... 510 35. Ova of Distomum Haematobium „ 512 36. Ova of Tenia Solium ........ ^15 xiv LIST OF ILLUSTRATIONS FIG. PAGE 37. Ova of Tenia Saginata 515 38-42. Tenia Confusa, Ward. (After Guyer) 517 43. Tenia Africana. (After v. Linstow) 518 44. Tenia Asiatica. (After v. Linstow) . . . .519 45. Cercocyst from Cyprinotus Incongruens, 1900 519 46. Hymenolepis Lanceolata, Bloch 520 47. Head of Hymenolepis Lanceolata, greatly enlarged 520 48. Proglottid of Hymenolepis 520 49. Bothriocephalus Grandis. Proglottid and ovum. (After Ijima and Kurimoto) 521 50. Tenia Echinococcus 527 51. Head of Tenia Echinococcus 527 52. Expectorated Echinococcus membrane 538 53. Filaria Embryos 547 54. Ankylostoma Duodenale .561 55. Ova of Ankylostoma Duodenale 561 56. Larva of Ankylostoma Duodenale 561 57-58. Sarcopsylla Penetrans, Sand-flea 573 COLORED PLATE Blood Cells Facing 302 DISEASES OF METABOLISM THE QUANTITATIVE ANALYSIS OF DISTURBANCES OF METABOLISM IN THE CLINIC By W. WEINTRAUD, Wiesbaden Contents: Introduction. — Normal metabolism: A. The laws of nutrition; B. The methods for estimating the calory requirement of man; 0. The normal energy requirement ; D. The albumin minimum; B. The require- ments for storing up albumin. — The food requirement of the sick: The degree of oxidation; maintenance diet and albumin requirement; dis- turbances of absorption of food. — Concluding remarks. INTRODUCTION During the past decade the scientific researches of internal medicine have been made chiefly in the clinico-chemical laboratory. Prepared and developed by physiology, the pathology of metabolism offered a fruitful field for study, hence it was not surprising that numerous young investigators soon found here their sphere of activity. A flood of researches in metabolism was the result. Clinical literature of the latest epoch bears the lasting impress of these workers. Many interesting questions concerning the laws of metabolism can be regarded as decided, chiefly by the theoretic conclusions based on these clinical studies, but an eminently practical issue has also been attained : Based upon these fundamental laws, a rational therapy of nutrition has been evolved which affords an extraordinarily fruitful field for professional usefulness. It is interesting to recount, in extenso, the valuable discoveries which have come from the clinico-chemical laboratories, and have brilliantly justified their raison d'etre. The problems which arose for solution, as soon as investigation passed beyond the mere examination of urine for albumin and sugar, were manifold. Often they led into the realm of physiology, and thus it happened that many obscure points in the physiology of digestion and metabolism were brilliantly illuminated by the labors of clinicians, and experimental investigation in the. clinical laboratory has especially enriched our knowledge of the physiology of metabolism. With energy and thoroughness, therefore, researches into the pathology of metabolism were pursued clinically. The wards of the hospitals offered rich material and abundant opportunity for observing the course of metabolic processes under abnormal conditions, and the desire to study physiological questions at the bedside was as much promoted by stimulus from the physio- logic laboratories of Hoppe-Seyler, Ludwig, Voit, Pfliiger, Salkowski, and 2 1 2 ANALYSIS OF DISTURBANCES OF METABOLISM Baumann as by the desire to find a key to the comprehension of pathologic processes. The practical result of these labors may be noted in the extraordinary interest manifested everywhere to-day in modern dietotherapy. For this rea- son it is worth while to cast a retrospective glance over the long road which has led to this satisfactory result. The scientific study of metabolism began when Lavoisier, in 1780, desig- nated chemical processes in the animal economy as the source of heat accom- panying all processes of life. He taught us that the food products in the body utilized the oxygen breathed in with the inspired air and decomposed, producing carbonic acid; that this process is therefore analogous to the combustion of organic substances outside of the body, and is an oxidation process which is the most important source of animal heat. A long time elapsed before the discovery of the law of conservation of energy also permitted new conceptions in the realm of biology (R. Meyer). In opposition to the view that, besides combustion, still other independent sources of heat were present in the circulation of the blood (friction, etc.), the opin- ion became general that all expressions of force which are recognized in the living organism (i. e., production of heat and capacity for work) were sus- ceptible of a uniform explanation. They originate from the energy which is furnished the body by the food. By tireless and long-continued original researches, Rubner proved conclusively that the law of the conservation of energy, the correctness of which R. Meyer and Helmholtz proved in the realm of physics, deserves proper recognition also in biology. The supply of energy contained in the food passes through the animal body without diminution. Thus the law of the permutation of forces, which had its origin in Lavoi- sier's discovery of combustion as the source of energy for the organism, was conclusively demonstrated by Rubner. It was an important epoch in the development of the laws of metabolism when Justus von Liebig demonstrated the identity of the proteids of the ani- mal and vegetable organisms in their chemical properties, and explained the relations of the albumin products of the food to the nitrogenous products of decomposition in the urine. We owe to him the knowledge that it is albumin, fat, and carbohydrates which are the basis of metabolic processes. He was the first to emphasize the fact of the unequal importance of the products neces- sary for structural formation in the animal organism. He assumed that the albumin introduced with the food alone reconstructs that which has been destroyed by the activity of the body, and called albumin the plastic (tissue- forming) food product, contrasting with it the N-free products (fat and carbohydrates) as respiratory products. These alone, he supposed, were attacked directly by the oxygen in the air, and by their combustion protected the plastic products, the albumin, from oxidation. But this theory of a division of all food products into two opposite groups could not be maintained, and the theory of Liebig that the oxygen taken up in respiration caused the disintegration of the food products, and that its amount decided the degree of metabolism was also later proven to be unten- INTRODUCTION 3 able. We know to-day that the causal relation between oxygen intake and food consumption as accepted by Liebig does not exist, but that in the living protoplasm of the cell exists the cause of the decomposition going on in the organism. Food decomposition does not take place in the blood and fluids, as was assumed at that time, but in the tissues, where the decomposition is produced by the chemical activity of the cells.1 The type and rate of metabolism are determined neither by the presence nor by the absence of oxygen, but only the energies dormant in the protoplasm of the cells — energies whose multiplicity the investigations of our own times are constantly impressing upon us. The amount of decomposition which takes place in the cell is decided alone by the energy requirement of the entire organism, so that the total consump- tion of the body is made up of the metabolism of all the cells. These cells, however, show a wonderful adjustment to the requirements of the organism, not only quantitatively but, on account of their specific properties, qualita- tively as well. It is not the oxygen that by its affinity to the individual constituents of the body dominates the chemical processes that occur there. If oxygen ruled, the readily oxidizable substances, such as uric acid, could not be so uniformly present in unaltered form in the excretions, while substances which are only oxidized with difficulty, such as the fats, are completely burned. It is the specific force contained in the protoplasm of the cells which causes the meta- bolic processes in the animal economy. Among these processes the splitting up of complex chemical bodies into simpler bodies, while oxygen is at the same time taken up, plays an important role. But besides mere splitting up, and splitting up with absorption of water (bydrolytic dissociation), other processes of reduction and synthesis are largely active, and occasionally all are combined in a single cell. Hence, as Eubner maintained, life cannot be described under the general idea of a process of combustion ; we must rather say that while life exists there is constantly an employment of energy and a transference of the same into other forms (activity and heat). Physiologic and pathologic chemistry will aid us still further in analyzing the chemical changes which occur during the processes of metabolism. The evolution of the individual protein substances contained in the cell, and the disclosure of their composition by the production of split-products, constitute the one method which has been followed with success in solving the problems here involved. But the protoplasm of the living cell and the proteid which we have produced from it by the aid of our chemical methods are quite differ- ent things. So also the products of decomposition which arise in the destruc- tion of the cell protoplasm in the body are quite different from those which we make by splitting up albuminous substance in a test tube. In the one case dead albumin, in the other living albumin is decomposed, and as we appre- ciate this great difference we seem to drift yet further from the solution of the i Eofmeister, " Chemie der lebenden Zelle," Vortrag, 1901. 4 ANALYSIS OF DISTURBANCES OF METABOLISM problem of life. Yet even here the ingenuity of our scientists has found a way to probe more deeply into the cause of things, and, though still in the first stages, the most recent investigations upon organs kept alive outside the body (saturated with blood, autolysis) have been followed by important results which permit us to expect more surprising conclusions in the future. On the other hand, it must be emphasized that although our knowledge of the chemical processes of metabolism is still comparatively primitive, the laws of metabolism have, been decidedly advanced by a more physical consid- eration of the processes. The dynamic conception of the transition of food products, thought out by Eubner, furnished a basis for labors in the clinical pathology of metabolism upon which a superstructure might be raised with ease and certainty ^ and upon this the imposing structure of modern laws of metabolism in the diseased body was soon erected. If we take this as our actual theme, we note that in the clinical study of metabolism in the last few decades quantitative investigations take precedence. The history of this begins with the publication of E. BischofF s book, "Urea as the Measure of Metabolism" (1853). The method of estimating the amount of urea by titration, first employed by J. v. Liebig, enabled Bischoff and Voit to undertake numerous investigations by which they determined the laws of nutrition in the carnivora.1 Chossat had previously, by careful experiments with starving pigeons, demonstrated the daily loss of weight and the amount of the excretions; and Bidder and Schmidt in their book, " The Digestive Fluids and Metabolism " (1852), described minutely the valuable results of their investigations regard- ing the metabolism of carnivora (cat) under the most varied conditions of nutrition. They were the first to relate in detail, after an investigation in which all requirements were fulfilled, how to find in the urine and the feces the nitrogen ingested in food in the form of meat, and upon this they founded the law of nitrogen equilibrium. With the aid of the elementary analysis of urine and feces, and the care- ful estimation of the factors of respiratory metabolism which were made pos- sible by the help of v. Pettenkofer, the study of the quantitative analysis of metabolism in Voit's physiologic laboratory in Munich soon attained great technical exactness. With this came the facilities for studying the alterations of decomposition under most varying circumstances, and particularly with food of different nature and quantity, and thus it became possible to deter- mine the laws of the total animal economy. CONSUMPTION OF FOOD IN THE HEALTHY A. THE LAWS OF NUTRITION The estimation of the amount of food required by the healthy human organ- ism to maintain its equilibrium has been the subject of many experiments by Voit and his pupils. i Bischoff u. Voit, " Die Gesetze der Erniihrung des Fleischfressers," 1880. COMSUMPTION OF FOOD IN THE HEALTHY 5 The more complete the technic, and the more ingenious the investi- gation, the more certainly the results show that metabolism is determined by the activities of the body (heat production and force). Then by excluding all external factors which could increase metabolism, it is shown that the " resting-energy " x of metabolism is equivalent in its potential value to the amount of heat produced. This has unquestionably been proven by Eubner's calorimetric investigations. In rest, the dissipation of heat is the only avenue for loss of force. Dis- sipation of heat, however, is a function of the surface of the body. If it determines the ratio of metabolism in rest, this metabolism must in turn be dependent upon the surface of the body (law of the development of the sur- face, Kubner). There can be no doubt that this biologic law also exists in pathology. Where conspicuous differences in the amount of the resting-energy per kilo- gram of body-weight exists, an attempt should be made to explain it by the variation in the amount of surface before we accept the view that a special protoplasm, characterized by a more active or sluggish metabolism, plays a role (in nurslings, in obesity, etc.). Table I ENERGY METABOLISM PER SQUARE METER OF BODY SURFACE Atrophic child (cow's milk). Atrophic child (infant milk) Breast-fed child. Normal child (cow's milk). . Boy, thin Boy, fat Man Man Man Man Man Weight in kilograms. Calories per twenty-four hours in one square meter. 3 1090 3 1036 5 1006 8 1143 26 1290 41 1279 493 11804 583 10304 673 10664 713 1116* 993 973* The metabolism which takes place normally in the body of a mammal when in absolute rest, for the purpose of maintaining life, is always the same, with- out regard to the source whence it obtains the organic material to fulfil its needs — whether from albumin, fat, or carbohydrates. For the maintenance of life the organic food products compensate accord- ing to their specific energy of tension (law of iso dynamics) . The amount of energy which the individual food products contribute to the processes of i German : Ruhewerth. 2 Rubner, Beitrage zur " Ernahrung im Knabenalter," Berlin, 1902, p. 62. s Weight with clothing. 4 Calculated from the carbonic acid values, 6 ANALYSIS OF DISTURBANCES OF METABOLISM metabolism that arise from them, and by their combustion in metabolism becomes living force, Rubner has calculated at 4.1 calories for one gram of albumin, 9.3 calories for one gram of fat, 4.1 calories for one gram of carbo- hydrate. These are the figures which are utilized as standards in all clinical inves- tigations in metabolism (the correspondence of the value for albumin and carbohydrate is quite accidental). In these values force is expressed in units of the heat which is generated in the organism when by combustion of the individual food products their end products in metabolism are produced. The loss which occurs in the intestines by insufficient absorption of the food is not considered here. They are, there- fore, gross values (large calories). To convert them into pure calories, Rub- ner has calculated a subtraction of 8 per cent, from the average heat value of the feces on a mixed diet. His latest investigations, by means of the direct calorimetry in man, have shown that the calculation obtained from chemical analysis of the standard figures in derived heat corresponds almost perfectly with the amount of heat in calories taken directly from the calorimeter. The method commonly used in the clinic to calculate the energy transference from the calory value of the food introduced is therefore accurate, if no severe disturbances in absorption are present. B. THE METHODS FOR ESTIMATING THE CALORY REQUIREMENT OF THE BODY The method in use in Voit's laboratory for determining the degree of metabolism in a healthy individual under various conditions of nutrition is by the comparison of intake and output in a trial period of twenty-four hours. This presupposes that the body within this time rids itself of the total end products of metabolism that have arisen from the decomposition of organic substances. This supposition is quite correct for excretion in the respired air and in the urine. To estimate the contents of the feces (the discharges usu- ally occurring later here), we need to mark in some way the beginning of the experimental period. This is usually accomplished without difficulty and with sufficient exactness by the administration of from 10 to 15 grams of powdered charcoal or 0.3 gram of carmin at the beginning and at the end of the metabolism investigation. This method in its high technical completion was the sine qua non for the quantitative investigation of metabolism at the bedside. An accurate estimate of the food ingested during the period of trial and of the carriers of energy contained in it (albumin, fat and carbohydrates) is necessary. The excretions, i. e., the urine, the feces and the expired air, are measured with exactness, and analyzed as to the amount of nitrogen and car- bonic acid which they contain. From a comparison of ingesta and excreta the balance is obtained. I shall quote an example of one of Voit's experiments : A workman weigh- ing 69.5 kilograms took in the form of meat, egg, albumin, milk, bread, lard, butter, flour and sugar a total of 137 grams of albumin, 117 grams of fat, and CONSUMPTION OF FOOD IN THE HEALTHY 7 352 grams of carbohydrate, containing 19.5 grams of N and 315.5 grams of C, besides 2,016 grams of water. He excreted in complete rest: In the urine 17.4 grams N., 12.7 grams C, 1,279 grams water. In the feces 2.1 " N., 14.5 " C, 83 " water. In the respiration 248.6 " C, 828 " water. Total 19.5 " N., 275.8 " C, 2,190 " water. The body was, therefore, in N-equilibrium ; excreted 174 grams of water and retained 39.8 grams of carbon, which corresponds to a deposition of 52 grams of fat. This method gives us knowledge of the body-albumin during the investiga- tion. This is estimated by means of the nitrogen balance, a method which, since that time, has come into general use. One hundred grams of albumin contain 16 grams of 1ST. If the entire amount of N" due to the decomposition of albumin during the trial period were excreted in the urine, the N figure of the urine need only be multiplied by 6.25 to determine the amount of albumin metabolism. The other N losses of the body are slight. A small portion appears in the feces as a residue of the intestinal secretions and this is sufficiently large to be calculated in each investigation. The other N" losses of the body (loss of hair, scales of the epidermis and sweat) are so insignificant that they may be ignored in a trial period lasting twenty-four hours. Nitrogen equilibrium is then shown when the food-N = urinary-N" -f- fecal-N. Voit's quantitative method of estimating metabolism also permits us to recognize from the carbon balance whether the body's need of N-free sub- stance has been fulfilled by the food given during the trial period or not. The organism has its very definite calory requirement. With an insufficient administration of nourishment, the body takes a supply of energy from its own material component parts. When, in a body previously in equilibrium, carbon is retained or more excreted than is ingested, a corresponding accumu- lation or loss of fat is indicated. In the form of carbohydrates (glycogen) the body does not accumulate any great supply of energy. In the quantitative estimation of metabolism in the clinic it has been necessary as a rule to proceed without determining the carbon balance. This require - the estimation of the total C02 excretion in the respired air, which can only be accomplished by means of a large respiratory apparatus such as that of Pettenkofer. Such an apparatus is expensive and very difficult to adjust. As many hours are required to make the experiment, it is incon- venient to employ this apparatus at the bedside. To compensate for this, the condition of the body-weight has been em- ployed as a control to determine whether, besides the proteid requirement, a sufficient energy supply for the needs of the organism is present in the food. If there is little variation in the material constituents of the body (albumin, fat and water), this is permissible, especially if the experimental period is not too brief. Instead of trials of twenty-four hours, therefore, trial periods of three to four days are usual in metabolism analyses of this type. 8 ANALYSIS OP DISTURBANCES OF METABOLISM If the test is made for still longer periods, the weight of the body alone, with minute estimation of the energy value of the food, may enable us to recognize the calory requirement. Forster demonstrated in persons living under ordinary conditions the food values just sufficient to maintain weight and to enable them to follow their usual occupations. In numerous investigations with larger groups of men (in barracks, in prisons and in almshouses) by an analysis of the food ingested, valuable standards have been established for the amount of food required by healthy persons. If the individual continues as vigorous as usual and his body-weight remains unchanged while on a prescribed diet, the con- clusion is justifiable that the amount of energy contained in the allotment of food is sufficient for the requirements of the body. As the metabolism of the body depends upon the needs of all the cells in the body, and represents essentially a process of combustion, it is obvious that the intake of oxygen should also be considered in estimating metabolism in the body. But the estimation of oxygen consumption is not an accurate measure of the total metabolism, because the same amount of oxygen, accord- ing to whether it is utilized for the oxidation of albumin, fat or carbohy- drates, corresponds to different quantities of heat; also because one gram of expired carbonic acid, according as it has been formed by combustion of one or another food stuff, corresponds to very different degrees of heat. Therefore, only when the nature of the food-materials decomposed in the body remains the same are consumption of oxygen and excretion of car- bonic acid a measure for changes in the entire consumption of products. By means of the large respiratory apparatus of Hoppe-Seyler-Tigerstedt, the direct estimation of all the factors of the respiratory metabolism of gases is possible. The apparatus is difficult to manage, however, and the necessarily long stay in the chamber of the person experimented upon makes its use inconvenient; therefore;, in the sick but few observations have been made on this plan. It is much easier to estimate the absorption of oxygen and the production of carbonic acid with the apparatus of Zuntz and Geppert. In brief experi- ments, trials are usually made by means of a mouth-piece for only five to ten minutes, at most for one hour; the 0, and C02 in the expired and inspired air and the amount of 0, intake and C02 excretion per minute are calculated from this. To calculate the total 02 consumption for an entire day from these figures would lead to error, on account of the great variation in the respiratory interchange of gases from hour to hour. Their reciprocal relation, however, furnishes the respiratory quotient, which gives valuable information regarding the nature of the material de- composed at the time. It approaches the value of 1.0 in carbohydrate com- bustion, while during the combustion of albumin alone it amounts to 0.73, and in combustion of fat to 0.7. For the quantitative estimation of the interchanges, the enormous amount of material gathered by Zuntz and his pupils in numerous healthy and sick persons contributes valuable points. In absolute rest of the body, and in the CONSUMPTION OF FOOD IN THE HEALTHY 9 intervals of intestinal inactivity, which occur from six to eight hours after meals, the values for the intake of 02 and the excretion of C02 per minute are quite constant for any healthy individual, and in different healthy indi- viduals they vary only within certain limits. In these " fasting values " we have standards, variation from which in one or the other direction denotes pathologic change. In conclusion, direct calorimetry must be considered as the exact method by which to determine the entire transference of energy in the resting body. This coincides, as already mentioned, with the total loss of heat, the coinci- dence of which with the heat-equivalent of the food stuffs consumed have been determined by Eubner in animals by masterly experiments. In man, and especially in the sick, direct calorimetric estimations to determine the quantity of the total metabolism have been carried out only in isolated cases (see below). C. THE ENERGY REQUIREMENT OF THE HEALTHY The quantity of food required by a workman while performing " moderate " labor Voit stated to be 118 grams of albumin, 50 grams of fat, and 500 grams of carbohydrates. This was based upon many experiences taken from daily life, and corresponds with the results of numerous exact analyses of metab- olism carried out, according to the method described above, in Voit's labora- tory (comparison of the intake and output). For a long time Voit's princi- ples existed almost as a dogma. Later the total calory value to which this diet corresponds (3,055 calories), as well as the large amount of albumin contained in it, became the subject of lively discussion, in which the clinical investigators took a prominent part. If the performance of muscular work increases the energy requirement of the body above that of rest (and, in fact, it multiplies several times the heat equivalent to the work done), the calory requirement of the "workman" cannot be estimated otherwise than by considering the amount of work to be performed. The rich statistical material which is now at hand confirms the requirement of Voit for about 43 calories (which is the amount contained in the above quantity of food per kilogram of body- weight) for persons doing active muscular work. From many observations Eubner calculates as the medium amount for a twenty-four-hour metabolism in the healthy adult, of average body size, and weighing 70 kilograms : Pure Calory per calories. kilogram. At rest 2,303 = 32.9 With slight muscular work 2,445 = 34.9 With moderate muscular work 2,868 = 41.0 With exhausting muscular work 3,362 = 48.0 With a deduction of 8 per cent, from the 3,055 large calories which are contained in Voit's amount of food, this corresponds exactly with Eubner's calculations. 10 ANALYSIS OF DISTURBANCES OF METABOLISM With more justice, Voifs requirement of 118 grams of albumin has been the subject of dispute. In the discussion regarding this amount there has been much difference of opinion. In their conception of the main point in dispute, the views of different authors were diametrically opposed; and the conflicting opinions which arose in consequence of this have kept the discus- sion alive to the present time. In the food of man, which consists of albumin, fat and carbohydrates, the albumin bodies grouped in contrast to N-free substances are especially important. While the latter may be compensated for to a great extent by each other and also by albumin, according to the measure of their energy value, a certain quantity of albumin in the daily food is irreplaceable and indispensable if the proteids of the body are to be maintained intact. To determine this indispensable amount of albumin, the minimum which the body requires to maintain the living substance in a functioning condition has been the subject of much discussion. For a time it was believed (Bidder and Schmidt) that this albumin mini- mum corresponded with the albumin-metabolism of persons kept in a state of starvation, i. e., that the nitrogen excretion in starvation furnishes a stand- ard for the nitrogenous metabolism necessary to maintain life, that is, the actual albumin requirement of the body. All the albumin absorbed from the intestine in excess of this was to be considered " luxury/' and was supposed, like the N-free substances, to undergo prompt combustion in the blood without becoming organized at all. Among clinicians, no less a one than Frerichs upheld this theory of " lux- ury combustion," propounded by C. Gr. Lehmann. Voit opposed the " luxury " theory. In his " Handbook of the Physiology of Total Metabolism " (page 269) he devotes a special chapter to contradicting this, and furnishes convincing proofs. According to experiments made in the dog, which of course are to be inter- preted somewhat differently from human experiments and which in their general application to man have been attacked by some investigators, the smallest quantity of albumin which will maintain the nitrogenous equilibrium of the body (on a mixed diet with N-free food substances) is usually 2| to 3 times larger than the nitrogenous metabolism in starvation. In their com- prehensive experiments E. Voit and Korkunoff 1 still found the minimum albumin-requirement to be 111 per cent, greater than the nitrogenous metab- olism in starvation (and even with very large amounts of starch in the food). It may therefore be considered as proved that if we give a dog only the amount of proteid which is decomposed in a state of starvation, this amount is not sufficient to maintain the nitrogenous equilibrium of the body. In man the same appears to be true. With sufficient food, the excretion of urea is increased decidedly above the starvation figures. From this experi- ence, and upon the basis of investigations on the nutrition of a large number of workmen, Voit computed as a standard for any sufficient diet the above- i E. Voit and KorJcunoff, " Die geringste zur Erhaltung des Stickstoffgleichgewichtes nothige Menge von Eiweiss." Zeitschr. f. Biol., xxxii, p. 58. CONSUMPTION OF FOOD IN THE HEALTHY 11 mentioned high requirement (hygienic albumin minimum in contrast to the physiologic albumin minimum). It appears, however, that proteid metabolism during starvation, even in the same individual, has no constant height, at least not during the first days of fasting. Here it apparently depends upon the composition of the food which has preceded the experiment and on the food products retained in the body. It is high if, in the days preceding the fast, a large amount of albumin has been ingested, and decidedly smaller if for a long time prior to the starvation period the ingestion of albumin has been slight. Only after from one to three days will the nitrogen excretion in the urine, varying in the same individual, show constant figures. This constant figure apparently depends on the composition of the body, i. e., its albumin and fat condition. From this, during starvation, it must make up its losses. The source of the albumin which is so rapidly decomposed during the first days of starvation is not, according to Yoit, the albumin of the organs, but the much more easily decomposed and soluble albumin of the fluids, the " cir- culating albumin." This quantity, which is increased by a diet rich in albu- min, also determines the proteid metabolism in the first days of starvation. A deficiency of albumin in the food diminishes the amount of " circulating albumin," and as this is dependent upon the fixed or organic albumin it indi- rectly works mischief upon the organs. A superfluous intake of albumin, on the other hand, increases the amount of the readily destroyed circulating albumin in the fluids, and hence propor- tional with the introduction of albumin there is an increased albumin decom- position which is dependent upon the amount of circulating albumin and the N-excretion in the urine. The amount of albumin consumed in a unit of time in the animal body is dependent to an astonishing degree upon the amount of the albumin ingested. The capacity of the normal adult organism to maintain its equilibrium with any amount of albumin — exceeding the minimum — is hardly limited (in so far as the body's capacity to take up albumin permits investigation). If the energy-requirement of the organism is met by the food, the proteid of food decomposes completely and with extraordinary rapidity. Scarcely absorbed in the fluids, it is soon destroyed, and in the briefest time its nitrogenous cleav- age products appear in the urine for excretion in quantities corresponding exactly with the increased albumin intake. This fact forms one of the most important points in Voit's whole theory of nutrition; important both for pathology and for physiology. Hence it became at once the spur for many clinical investigations in metabolism. Many endeavors have been made to explain these facts. They contradict completely the otherwise applicable law that the amount of decomposition in the animal body is equivalent to its requirement of energy. For Voit has shown that with a sufficient amount of food any additional amount of albu- min, no matter how large, is at once decomposed, so that metabolism (trans- ference of energy) is greatly increased. The changes in the total metabolism by variation of the intake other than those referred to above are slight. The introduction of amounts of 12 ANALYSIS OF DISTURBANCES OF METABOLISM food whose heat-equivalent is not decidedly above the interchange of forces in the starving organism does not increase the total metabolism, and with a diet beyond the amount required by the needs of the body the introduction of extra N-free material (fat and carbohydrates), no matter how great, in- creases the interchange of energy only to a certain percentage of the excess of food. If the surplus is introduced in the form of fat, only 10.7 per cent, of it undergoes combustion; therefore almost 90 per cent, is deposited as fat in the body. If superfluous carbohydrates are introduced, only 15.9 per cent, goes to increase the total metabolism; 84.1 per cent, is accumulated in the body and is utilized for fat formation, since the body's capacity to increase its carbohydrate material (glycogen deposit) is a limited one.1 Since the amount of metabolism is relatively independent of variations in the ingestion of nourishment, we have the conditions which make possible a deposition of fat. With an abundant introduction of albumin, however, proteid decomposi- tion increases in exact ratio to the superfluous amount of albumin ingested. The entire superfluous supply is taken up in metabolism, and the N-excretion in the urine shows a height corresponding to the increased administration. In reality it is, of course, only the N-containing complex in albumin which is excreted, and these products of excretion are at once thrown off. Of the non-nitrogenous components which remain after excretion, as well as also the superfluous fat and carbohydrates introduced, only a portion is subjected to decomposition, if the organism does not require thern to meet its energy requirements, while a considerable remainder (69.1 per cent.) is stored up in the body (fat formation from albumin). Only the elimination of nitrogen is complete. For this reason albumin occupies an exceptional position among food sub- stances; the organism requires it for its simple material maintenance. It is, therefore, difficult to understand why the organism should waste so much of, and so soon eliminate, this most valuable food product. A number of explanations for this apparent waste have been offered. It has been assumed that owing to the circulation of albumin products in the fluids after albumin nutrition, the individual food stuffs take part in the total metabolism. On the other hand, a special chemical affinity of the cell substance for the individual food products has been assumed owing to the fact that the albumin is most readily absorbed, less speedily the carbohydrates, and last of all the fats. Eubner 2 has lately assumed that the divisibility of the individual food stuffs explains the different share taken by each in the processes of metabo- lism. These differences in divisibility have not been sufficiently considered until now : " A measure of these differences is the size of the molecules. In the case of fat this amounts to 870, in grape sugar, to only 180. In what i This increase in metabolism by introduction of food was formerly explained by an increase of intestinal activity. Lately the correctness of this view has been doubted. 2 Jiubncr, " Handbuch der Ernahrungstherapie," Bd. i, p. 78. CONSUMPTION OF FOOD IN THE HEALTHY 13 form the albumin products circulate is not known. Nevertheless, the view that albumin and allied substances are always bodies of high atomic weight, has suffered a setback. The albumoses have a molecular weight of from 1,200 to 2,100; the peptones, however, of only about 200, similar to that of sugar. In a molecule of fat there are 8,170 calories, in a molecule of grape sugar only 674. The peptones vary very slightly from the latter value. The vari- eties of sugar and albumin, therefore, viewed from this standpoint, might predominate in decomposition without special forces coming into play." Gruber x looks upon the prompt splitting up of the albumin of food as a very necessary process, in fact as an arrangement which is quite indispensable to rid the organism as soon as possible of the great bulk of soluble albumin bodies which are unnecessary for its normal condition and which cannot be utilized. A further increase in the size of the organs in the adult animal is possible only to a slight degree after the body has reached the limit of growth fixed by its hereditary germinal predisposition (increase' of the size of muscles as the result of body exercise). To replace the amount of organic albumin daily destroyed a small portion of the food proteid is sufficient. As the accu- mulation of the balance in the body would alter the function of the organs, its immediate decomposition is absolutely necessary in order to keep the com- position and concentration of the body fluids unchanged in spite of any varia- tion in the composition of the food. The prompt splitting up of the food albumin is believed by Gruber to be the effect of the action of enzymes with which the cells of the adult healthy organism are richly supplied. This view has much to commend it. We can thus readily explain the enormous albumin accumulation which occurs in convalescence from severe diseases, after prolonged starvation, etc., and is almost independent of the administration of albumin. The absence of the albumin-splitting enzyme in body cells that have been damaged in their proteid constituents by disease explains the absence of that rapid splitting and excretion of proteids which occurs in health. D. THE ALBUMIN MINIMUM We have seen that Voit's requirement of 118 grams of albumin in the daily food of an adult performing moderate labor is a practical proposition for rational nutrition, and does not represent the physiologic albumin mini- mum which the mature body absolutely requires to supply its functioning organs. Incorrectly viewed, this stimulated a great number of researches in which the starting point was the question (although it can have only the- oretic interest), How far may the albumin metabolism be decreased without the body suffering in any of its albumin constituents? And yet every new investigator in the solution of this question attempts to establish a standard and to proclaim a still lower value as the " albumin minimum." That man may exist with smaller quantities of albumin, and be capable of work, Voit himself readily determined in the analysis of metabolism in a vegetarian who i Gruber, " Einige Bemerkungen zum Eiweissstoffwechsel." Zeitschr. f. Biol., xlii, p. 407. 14 ANALYSIS OF DISTURBANCES OF METABOLISM weighed 57 kilograms. Choosing his diet freely this person consumed, year in, year out, only 54.2 grams of albumin (with 32.4 grams of pure albumin), 22 grams of fat and 557 grams of carbohydrates, and maintained the same body-weight. The investigations in metabolism of Hirschfeld, Klemperer, Peschel, Kumagawa, Breisacher, and lately also of Siven and Albu, give even smaller values as the albumin minimum. The following table is a comparative com- pilation of the food values with which individual persons experimented upon were able to maintain their N-equilibrium. Table II Author. Body weight. Albumin. Albumin per kgm. Large calories per kgm. Duration of trial. 73.0 63.0 65.0 79.5 48.0 57.0 57.0 58.9 37.5 35.4 25.1 26.6 34.2 37.8 32.4 51.4 28.3 43.13 0.485 0.400 0.41 0.43 0.788 0.570 0.900 0.48 0.90 47.4 80.0 77.2 47.1 51.6 47.5 50.3 41.4 37.32 8 days 8 " Klemperer II 8 " 8 " 9 " Voit Usual diet 30 days 1 day 5 days Albu The albumin interchange in the professional fasters, Cetti and Breithaupt (calculated from the N-figures of the urine by multiplying by 6.25), gave on the other hand : x Cetti. Breithaupt. First day of s Second " tarvation 95.3 79.3 82.7 78.1 67.4 63.6 68.6 56.1 68.2 59.7 sjrams al bumin ft a it a « u a it it 63.1 grams albumin 62.5 " < c ( ( ( ( c c Third " M 83.7 " " Fourth " « 80.5 " " Fifth " « 68.9 " " Sixth " a 62.2 " " Seventh " « Eighth " Ninth " (( u Tenth " u Therefore, it is evident from the table that with a sufficient calory admin- istration in food products free of nitrogen the albumin requirement may fall far below 118 grams, and even below the metabolism under complete with- drawal of food. Theoretically this fact, determined by such numerous, painstaking inves- tigations, is of the greatest scientific interest. But caution has been quite properly enjoined upon us not to draw far-reaching conclusions from such i " Untersuchungen an zwei hungernden Menschen." Suppl.-Heft, pp. 21 u. 68. Virchotv's Arch., vol. cxxxi, CONSUMPTION OF FOOD IN THE HEALTHY 15 brief investigations of the practical laws of nutrition. We need not, with Prliiger, assign to albumin a pre-eminent importance " as the only and imme- diate source of muscular power," but, for the permanent nutrition of the healthy and the sick, we must still insist upon greater amounts of albumin than proved sufficient to maintain the albumin condition of the body in the experiments above cited. In fact it is hardly possible to transfer the conditions of an experiment to practice, and to find a diet that will give a sufficient degree of energy to the body, that will agree, that will continuously be palatable and can be digested, yet will contain such slight amounts of albumin as were, for exam- ple, present in the experiments of Siven. This, however, may be seen from all of the previously mentioned experi- ments— that the IST-equilibrium can only be maintained on such a low proteid diet when we have a sufficient calory supply. In most experiments the calory value of the food reaches the amount which Voit requires for the " medium worker" (with nine to ten hours' daily labor), although the persons experi- mented upon did not perform very laborious work; in a few experiments it decidedly exceeds this amount. Therefore, only with a superfluous calory administration can the albumin metabolism be diminished to such slight values. The calory carriers, carbohydrates and fat, are therefore albumin savers, and for practical nutrition this is perhaps the most important conclusion of these investigations regarding the albumin minimum. E. THE REQUIREMENTS FOR ALBUMIN DEPOSITION According to Voit's law, the addition of albumin to a diet already suffi- cient increases albumin metabolism to such an extent that after a few days IST-equilibrium is again reached, yet no decided accumulation of albumin occurs. But we should note here in the increase of the energy value of the food by the addition of fats and carbohydrates a process to diminish albumin metabolism, so that when albumin administration remains the same, albumin deposition must be the consequence. This gives us reason to hope to increase the body albumin by forced feeding. Unfortunately the energy supply contained in the superfluous food which is utilized in albumin deposition is not very great, as is shown by Voit's investigations in the dog. With the addition of carbohydrates upon an aver- age 91.5 per cent., and with the addition of fats upon an average 95 per cent, of the superfluous potential energy accumulates in the form of fat, and only 8.5 (or in fact only 5 per cent.) in the form of albumin. In man according to the investigations of v. ISToorden,1 at most 10 per cent, of the superfluous energy supply is utilized to store up albumin in the body. The experiments of Krug 2 upon himself, under v. Noorden's direction, i v. Noorden, " Verhandlung. der physiol. Geselschaft," im Arch. f. Anat. u. Physi- ologic, 1893. 2 Krug, " Leber Fleischmast beim Menschen." v. Noorden's Beitrage z. " Lehre vom Stoffwechsel," Heft 2. 16 ANALYSIS OF DISTURBANCES OF METABOLISM have shown, however, that a slight accumulation of albumin day by day can be attained by giving a food of high calory value for a long time. With food which differed from that of the prior period (when he was in N-equilibrium) by an increase of 1,710 calories, albumin remaining the same, Krug retained decided N-amounts (a total of about 50 grams in fifteen days) and, what is remarkable, the gain during the last of the fifteen days of forced feeding equalled that of the first days. Liithje 1 has lately obtained still larger IST-retention in his forced feeding experiments in which he increased the total energy administration of the food, like Krug, and also raised the quantity of albumin decidedly above the requirement (albumin administration up to 380 grams with 6,035 calories). The total retention in twenty-six days amounted to 149.61 grams of 1ST. This decided IST-retention within a short time, even more than the small values formerly obtained, raised doubts as to whether the 1ST retained in the body actually indicated a gain in " flesh." Voit has never regarded the IST-retention obtained by forced feeding as an increase of " organic albumin " ; he held the view that the albumin saved under the influence of nutrition remained in the circulation until it was changed into organic albumin by the slow production of new tissue. As, however, under the influence of hypernutrition, the plasma of blood and lymph does not, so far as we know, become richer in albumin, v. Koorden proposed the hypothesis that the albumin which is saved, and not yet utilized for the structure of new tissue, is retained as a dead mass in the living proto- plasm of the cells, analogous to the superfluous glycogen and fat, remaining there as " reserve albumin," though with decidedly different conditions of de- composition than are present in organic albumin. Correspondingly, he draws a sharp distinction between increase of " reserve albumin " and in- crease of muscle (by which he understands the increase of living cell albumin). He believes the latter to be a result of the specific growth energy Of the cells, a function of cellular labor, and not a result of extra nutrition since, as we have seen, hypernutrition increases only the reserve albumin. This hypothesis of v. Noorden's is not in agreement with Pfliiger' s 2 view regarding the meaning of the reserved and deposited albumin. In the latter's numerous publications on the subject, he maintained that the accumulated albumin is soon deposited as cell substance in the body of the animal, and therefore at once takes a prominent part in the total metabolism. Pfliiger does not regard it as a dead cell inclusion, but as a " working mass," and he also thus explains the increase of albumin metabolism which occurs after proteid administration as an increase of the "working cell substance," upon the amount of which, in his opinion, the total metabolism is directky de- pendent. i Liithje, Beitriige zur " Kenntniss des Eiweissstoffwechsels." Zeitschr. f. klin. Med., xliv, p. 21. 2 Pfliiger. Arch. f. d. ges. Phys., Bd. lii, p. 1. " Ueber einige Gesetze des Eiweiss- stoffwechsels," Bd. liv, p. 333. " Ueber den Einfluss, welchen Menge und Art der Nalmmg auf die Grosse des Stoffwechsels und der Leistungsflihigkeit ausiiben." Pfliigcr,s Arch., Bd. lxxvii, p. 425. CONSUMPTION OF FOOD IN THE HEALTHY 17 But the enormous amount of N-retention in the forced feeding investi- gations of Liithje makes us hesitate to believe that the total amount of nitrogen retained is really deposited as " albumin," especially as we should be forced to assume at the same time that the reserved albumin is deposited together with a quantity of water, such as corresponds to the usual relation between albumin and water in the cellular elements of the body (one gram of N = 6.25 grams, albumin = 29.4 grams of flesh). According to this we should have to suppose that the N-retention of 149.61 grams N, which was attained by Liithje within twenty-six days, corre- sponded to an albumin deposition of 935.06 grams of albumin, or a flesh deposition of 4,398.53 grams. The increase in the body-weight of the person experimented on amounted to 6,070 grams during this time. If we estimate the flesh accumulation from the N-retention, more than two-thirds of the increase in body- weight (4,398 grams) must have been due to flesh deposi- tion. The considerable calory excess contained in the administration of food in the days in question certainly must have resulted in a deposition of fat. The amount of this Liithje calculates in the usual manner; from the total calory excess during the entire period (29.656 calories) he deducts the calory value of the albumin which has accumulated (935.06 X 4.1), i.e., in round number 3,838 calories, and the remainder, amounting to 25.818 calo- ries, is ascribed to fat accumulation. Twenty-seven hundred and seventy-six grams of fat correspond to this energy value. The flesh accumulation of 4,398 grams, and a simultaneous fat deposition of 2,776 grams coincide very imperfectly with an increase in weight of only 6,070 grams. This may, however, be readily explained by the assumption that the body during the masting period lost a weight of water, corresponding to the difference (1,104 grams). In the feeding experiments of Krug, the same difference was noted. With an increase in weight of only 3,100 grams, the albumin accumulation of 1,455 grams calculated from the retained K, and the fat accumulation from the calory excess after deducting the albumin calory, amounted to 2,254 grams. Krug assumed without more ado that the body lost 609 grams of water. This assumption is certainly justifiable, and a decrease in water during forced feeding appears quite plausible if we remember that each increase of the albumin metabolism (for example, by a large albumin meal) is soon fol- lowed by a decided excretion of water. In my opinion the assumption of so large a loss of water is, however, unnec- essary. In the previously mentioned calculations, we have always proceeded on the assumption that the total calory excess of the food not used to store up albumin must be utilized in fat formation. It has, however, not been con- sidered that 'an excess of food also invariably increases the total metabolism, and, it may now be supposed, increases this out of proportion to the intestinal labor. A true luxury consumption of non-nitrogenous food substances takes place. Only a portion of the superfluous food energy is utilized in accumu- lation; in man another portion, probably showing individual variation, under- goes combustion, and is utilized in heat production, the organism replying 3 18 ANALYSIS OF DISTURBANCES OF METABOLISM to this increase by an increased excretion of vapor. In the investigations in forced feeding, the fat accumulation, which can only be controlled by an accurate estimation of the carbon balance, may also be less than authors have assumed, judging by the caloric excess in the food. In such a profuse N-retention, the supposition that the accumulation of nitrogen-containing end products of albumin metabolism may play a role appears to be quite unwarranted for the reason that there are no sufficient proofs that N-containing products of intermediary albumin metabolism re- main as such in large quantities in the body of the healthy. The view is much more likely that the N is retained as albumin, and that this albumin (as a native molecule, however, and without a corresponding participation of water) enters the cell. As evidence of this Liithje points to the observation that in certain snails albumin is found included in the cells in a crystalline form. It seems to me, however, that there is one phenomenon — which appears, so far as I am aware, in all investigations regarding albumin accumulation if the analyses in question are carried out — and which goes to show that the albu- min accumulated in the protoplasm of the cells increases and rejuvenates it while assimilating itself with the general cell albumin. I refer to the simul- taneous retention of phosphorus when N is retained, and its increased excre- tion (as P205) during albumin decrease. This is shown in the investigations of Kayser, and of Jacob and Bergell. It may be recognized also in Luthje's metabolism figures, and only lately Kaufmann has called attention to the decided phosphorus retention which he observed during albumin accumulation in feeding with egg albumin. The fact that any phosphorus containing albu- min body especially favors albumin accumulation (as was shown by Eohmann and his pupils, and also by Zuntz and Caspari) favors this view. Quite an analogous N-retention (which probably no one will doubt means an albumin accumulation) Post * has observed in his metabolism control experiments in growing animals. The amounts of nitrogen of the food which were not excreted in the urine and feces of three young dogs were decidedly greater than could be accounted for by the increase of body-weight, if the N-accumulation were reckoned in the formation of muscle albumin. Therefore, as in the investigations of Liithje, either a loss of water occurred or the retained nitrogen was utilized to build up a cell protoplasm with higher nitrogen contents than are found in muscular substance. When it became necessary, in forced feeding experiments in animals with meat free of fat, to promulgate a formula for the N-accumulation (Pfluger, Cremer) certain difficulties naturally arose. The amount of carbon retained in the organs was greater in comparison with the nitrogen than would corre- spond to the composition of albumin. If, with Pfluger, we reject the possibility of a fat formation from albu- min, although accepted by Voit's adherents, we must be content with assum- i Rost, " Zur Kenntniss des Stoffwechsels wachsender Hunde." Veroffentlichungen des kaiserl. Gesundheitsamtes, Bd. xviii, p. 206. CONSUMPTION OF FOOD IN THE HEALTHY 19 ing an " unknown tissue-building substance," and refer the N-retention to its accumulation. No matter in what form the nitrogen accumulates in the body in forced feeding, all authors seem to be unanimous in the opinion that the organism receives a valuable addition. For this reason, we shall enumerate again the methods which lead to an increase of the body albumin. We see N-retention without any increase in the administration of nitrogenous foods when we give a calory excess of N-free substances (Krug), and a still more decided N-accumulation when the food contains both an excessive calory value and an excess of albumin (Liithje). That an excess of albumin alone in an adult healthy person without de- cided increase of the albumin-saving fats and carbohydrates could bring about an albumin accumulation (apart from the slight N-retention in the first days, until N-equilibrium is attained) has been looked upon as impossible, according to Voit's principles. Only special circumstances (growth, con- valescence, diminution in body albumin from preceding starvation) would make it possible permanently to accumulate albumin in this way. Bornstein,1 however, lately showed in an experiment on himself that it is possible in man by an increased administration of albumin alone to produce a limited increase of the albumin contents of the body. By adding to his diet 50 grams of nutrose daily he accumulated in fourteen days 16 grams of N = 100 grams of albumin, just as, in Pniiger's experiments in feeding adult animals (dog and cat) with fat-free meat, a decided increase in weight was produced by flesh deposition. And as Pfliiger looks upon the increase of the albumin mass of the body as an increase of power, so Bornstein looks upon the N-accumulation as a sign of a previously sub-standard value of his mus- cular and albumin apparatus, which was then improved by a deposition of albumin. It is an interesting fact that stock raisers 2 to-day also believe it possible to bring about a production of flesh, in a restricted sense of the word and under certain circumstances, in adult animals to a more decided extent than was formerly thought possible. They regard an increased accumulation of albumin in the body of the adult animal as decidedly improving the quality of the meat — an improvement which does not depend upon an increase in muscle bulk or new formation of muscle fibers, but is due to an increase of the juices in which the muscular fibers are bathed. For the physician these views regarding muscle food are very interesting, inasmuch as it is often necessary for him to treat persons below par in their muscular activity. In cases in which a further accumulation of fat is never desirable (anemia, neurasthenia, etc.), Bornstein's advice to adopt forced feeding with a decided addition of albumin is certainly worthy of considera- i Bornstein, " Ueber die MSglichkeit der Eiweissmast." Berliner klin. Wochenschr., 1898, vol. ix, p. 791. 2 Henneberg und Pfeiffer, Journal f. Landwirthschaft , Bd. xxxviii. 20 ANALYSIS OF DISTURBANCES OF METABOLISM tion. It increases the albumin contents of the body, and also the albumin decomposition. We know that a man called on to perform work beyond the usual amount always prefers a diet rich in albumin (the average albumin metabolism in athletes is about 200 grams of albumin) x and this coincides perfectly with the views of Pfliiger that, " increased albumin decomposition is combined with that increased vitality which in the struggle for existence gains the victory." 2 More exact and recent investigations in metabolism show that the general tendency of working organs to attract albumin and to retain it for their growth is seen in the highest degree in the muscles. Caspari 3 studied a dog that, with a certain diet, was in N-eqiiilibrium, yet, with precisely the same food, continuous N-accumulation occurred when the dog was daily subjected to considerable muscular exertion. Bornstein 4 was able to show that the accumulation of albumin attained by him with the addition of a larger amount of albumin to an already sufficient diet could even be increased by daily muscular exercise in moderation (without work about 16 per cent, of what is ingested is accumulated; with moderate labor about 22 per cent.). He therefore speaks of a true labor hypertrophy of the muscles, and the investi- gations in metabolism carried out upon a large scale by Atwater and Bene- dict 5 confirm this view. Without increasing the nitrogenous food of their experimental persons during the period of labor, they produced an accumu- lation in albumin (in contrast to an N-loss in the period of rest), although in the period of labor the additional calories were given wholly in the form of carbohydrates without any additional albumin. It is of course obvious that this labor hypertrophy has its limits. Even with continuous muscular work, an increase of albumin in the food, which is also limited by the person's digestive capacity, will not force a continuous accumulation of muscle. A condition of equilibrium is attained in which, however, the body now controls more organic working albumin than formerly, and possesses increased vitality. For the treatment of the cases (constantly multiplying in our time) in which diminished capacity for work is one of the most prominent symptoms, these new studies in metabolism contain the most valuable hints. For who will maintain that every patient who comes to us with a body-weight corre- sponding to his age and his size controls an amount of the organic substances used in metabolism which corresponds to his maximum or even to his optimum ? With the recognition that we can build flesh by the simple addition of albumin to the food (a point on which Pfluger's views and Voit's teachings i Lichtenfeldt, " Ueber d. Nahrstoffbedarf b. Training." Pfluger's Arch., Bd. lxxxvi, p. 177. 2 Pfluger's Arch. f. d. ges. Physiol., Bd. li, p. 319. 3 Caspari, " Ueber Eiweissumsatz und Ansatz bei Muskelarbeit." Pfluger's Arch., Bd. lxxxiii, p. 6509. * Bornstein, " Eiweissmast und Muskelarbeit." Pfluger's Arch., Bd. lxxxv, iii, p. 540. 5 Atwater and Benedict, " Experiments on the metabolism of matter and energy in the human body." Washington, 1899. Quoted by Caspari, loc. cit., p. 539. THE FOOD REQUIREMENT OF THE SICK 21 are sharply contrasted), the saving of albumin by a superfluous calory addi- tion is not divested of its therapeutic importance. Where a simultaneous accumulation of fat is not undesirable, this high calory diet will, as a rule, be the easiest way of accumulating albumin. But here we should always remember that muscular work is an important auxiliary means of fixing the retained albumin in the organs of the body, and that a simultaneous high- proteid diet is not superfluous or even unnecessary. (See the considerable albumin accumulation in the investigations of Luthje.) That it is not immaterial in saving albumin whether the calory surplus is brought about by fat or carbohydrates in the food was shown long ago by the investigations of Voit and Rubner. Clinical researches in metabolism have confirmed this. In Kayser's x researches albumin was lost when he replaced the carbohydrates by an isodynamic amount of fat, and Tallquist 2 also demonstrated that the carbohydrates were capable in a higher degree than fat of protecting the albumin of the body from loss. To understand these differences, which apparently cannot be reconciled with the laws of isodynamics, it is well to remember the experiments of Eubner, according to which the different food stuffs (in equal excess) increase the interchange of energy very differently because they are utilized in quite vary- ing amounts, the fats undergoing combustion in metabolism, less so than the carbohydrates. In the practical therapy of nutrition this preponderance of the carbo- hydrates in comparison with the fats as albumin savers must not permit us to abstain from the plentiful use of fat for the purpose of saving albumin, especially in those cases in which carbohydrates are not allowed, i. e., in diabetes. And since we see here that with an exclusive albumin fat diet (without immoderate excess of albumin) diabetics are able to preserve their albumin condition with a relatively slight administration of fat calories, we might almost believe that the fats under certain circumstances may almost equal the carbohydrates in their albumin-saving effect. In the very plentiful use made of fat in modern dietetics we see further evidence of this. THE FOOD REQUIREMENT OF THE SICK For all physicians a fair comprehension of the total food requirement of the diseased organism is the best foundation in prescribing a suitable diet. Modern nutritive therapy no longer limits itself to the prohibition of this or that food. It expresses positive opinions in ordering the diet, both as regards the nature and the quantity of the food. Only in diseases which run a rapid course may the amount of food con- sumed be for the time disregarded. Here real starvation may be necessary on i Kayser, " Ueber die Beziehungen von Fett und Kohlehydraten zum Eiweissumsatz des Menschen." Diss., Berlin, 1893. 2 Tallquist, " Zur Frage des Einflusses von Fett und Kohlehydraten auf den Eiweiss- umsatz des Menschen." Arch. f. Hygiene, Bd. xli, p. 177. 22 ANALYSIS OF DISTURBANCES OF METABOLISM account of the altered functions of the stomach and intestines, and we may make up our minds regarding the quantity and choice of the food, quite inde- pendently of the actual food requirements of the body. In convalescence from such maladies and in all protracted diseases, how- ever, the quantity of the food is important. A proper appreciation of this in the dietetic treatment of chronic diseases will give the physician his best results. The appetite which normally regulates the quantity of nourishment in- gested, so that metabolism is always exactly covered in spite of all variations in regard to amount, is no measure for the amount of food required by the sick. Appetite is no guide when wasting diseases increase the food require- ment of the body; appetite is equally deceptive when excessive corpulence makes it imperative to bring about a reduction of the body-weight. Only an exact knowledge of the amount of total energy metabolism, the sum of the energy which the body requires and utilizes in the special case, is a guide to the physician for his dietetic orders in respect to quantity. THE DEGREE OF OXIDATION Eegarding the degree of metabolism in disease, clinical researches in the last few decades have given us definite figures. Without a knowledge of the amount of nourishment consumed, and with- out a proper consideration of the energy values contained in it, mere observa- tion at the bedside, and the analysis of the excretions in the urine exclusively, have frequently led to entirely erroneous conclusions. French literature re- garding azoturia, and the writings of Bouchard regarding the slowing of metabolism, contain numerous examples of this fallacy. Increase or slowing of metabolism had been frequently assumed in cases in which later control experiments in metabolism proved the contrary. When the exact methods of the German physiological schools (Voit, Pfliiger, Zuntz) were employed in the analysis of the processes of metabolism in the diseased organism the for- mer conclusions were reversed. In spite of this, we cannot yet claim clear insight into many pathologic conditions, but we may nevertheless say that many deeply rooted errors have been corrected by the methodic quantitative labors of our clinics. Metabolism in the normal human adult, in complete rest, amounts to about one calory per kilogram of body- weight and per hour; therefore with a weight of 70 kilograms, in twenty-four hours it is 1,680 calories (=21 calories per kilogram). Even with the ordinary exertion of daily life a decided increase occurs (from about 2,450 to 3,000 calories, i. e., 35 to 42 calories per kilogram). Increased ingestion of food, bodily exercise (muscu- lar labor) and the unavoidable giving off of heat while exercising are the factors to which this increase of transference may be attributed. The amount, the time limits and duration of the increase of metabolism resulting from exercise in healthy persons have been for this reason closely studied. The hope that differences in the rate of interchange of force in the well and the sick while at rest could be measured by the estimated intensity of THE FOOD REQUIREMENT OF THE SICK 23 oxidation (02 decomposition and C02 excretion) which characterizes individ- ual pathologic conditions has only been fulfilled to a slight degree. On the other hand, later researches have furnished proofs that the healthy and the sick differ in the reaction of their organism to influences that increase metab- olism (administration of food, work performed, and the amount of heat given off). To appreciate these differences, the physiology of metabolism must be briefly considered. The increase of the processes of oxidation and of heat production, under the influence of the intake of nourishment, which may be subjectively noted in a certain feeling of warmth, has been directly measured by calorimetry. The factors of the respiratory metabolism have also been indirectly con- trolled. If a dog's food is increased upon three different days to 55 per cent, above its previously determined calory requirement by administering iso- dynamic amounts of "albumin, fat and carbohydrates, its elimination of heat upon the albumin day rises 19.7 per cent., upon the fat day 6.8 per cent,, and upon the carbohydrate day 10.2 per cent. (Rubner). This coincides exactly with the figures which Magnus-Levy 2 obtained in his numerous analyses of the interchange of gases after the administration of particular foods; he has referred to these in his valuable dissertation on the influence of nourishment upon respiratory metabolism. He also deter- mined that the three principal food products increase C02 excretion and 02 consumption in very different degrees. The proteids again take the first place; they increase the intensity of oxidation from 50 to 60 per cent.; then follow the carbohydrates, after the administration of which the interchange of gases is only increased 35 per cent, above the point reached when the stom- ach is empty; finally the fats, which, if administered in amounts that do not exceed the normal requirement, scarcely increase the consumption of 02 in man at all, and in the dog increase it only about 10 per cent. Investigations in man with a freely chosen diet make the increase of metabolism after a meal very apparent. In the first four hours after break- fast the 0, intake, in comparison to that in a condition of rest, is increased 21, 37, 22 and 10 per cent. ; in the first five hours after the midday meal 36£, 30, 20, 18 and 18 per cent., and in the first three hours after the evening meal 33, 31 and 18 per cent. According to this, the increase of the inter- change of gases for a whole day, in consequence of the administration of food, amounts to 13 per cent, of the 02 intake, and 19f per cent, of the C02 excretion. Hosslin found similar figures which are the basis of Voit's investigations in metabolism, and if the body's requirement does not decidedly exceed the intake of nourishment, we are generally right in counting about 10 per cent, as the increase of the oxidation processes due to this cause (Zuntz). That this increase of oxidation is due principally to the increased labor i Magnus-Levy, " Ueber die Grosse des respiratorischen Stoffwechsels unter dem Einflusse der Nahrungsaufnahme." Pfliiger's Arch., Bd. Iv, p. 1. 24 ANALYSIS OF DISTURBANCES OF METABOLISM of digestion, and that with a superabundant nourishment these increases in metabolism can be pushed still further, was for a long time the predominant view (Zuntz and v. Mering). Yet lately authors have come more and more to the conclusion that the increase in the labor of the digestive organs is not sufficient to explain the heat production after intake of nourishment. Inves- tigations on this point have been carried on in patients, and have shown that the increase in metabolism produced by the administration of food is very much greater in some individuals than in others. These results have increased our doubts regarding the correctness of this prevalent opinion (see below) . Physiologists have determined the increase of metabolism after physical exertion even more minutely than that following the introduction of food. The promptness and delicacy of the changes in the amount of oxidation after muscular labor are almost astonishing. Increase in the peristalsis of the smooth musculature of the intestine after the introduction of mineral salts and after the administration of food, changes of the mechanism of respiration, unconscious muscular effort in strained positions of the body or when the temperature of the skin is reduced, all of these factors influence very notably the interchange of gases. Of course a much more striking variation becomes apparent in tests with muscular activ- ity of a type which can be mechanically measured. Kegarding the degree to which the process of oxidation may be increased, when the amount of work is increased, Zuntz and Katzenstein have given us exact figures. It is an absolute law that 02 consumption and CO, formation increase with the amount of muscular labor. Accordingly, the interchange of gases is greater when the individual is standing than when he is in the recumbent posture. The increase is slight if the person is standing in a com- fortable position ; it amounts to about 20 per cent, of the " rest value " if the person is standing erect as in military drill. In walking the consumption of products becomes from 2 to 4 times as great, according to the rapidity of the pace; in rapid hill climbing it is 5 times as great as the normal, and even more. Proportionally to the interchange of gases the heat production is increased by work (in comparison to rest values), as Atwater and Benedict have deter- mined by direct calorimetry. About two-thirds of the energy set free by increased decomposition is utilized in heat production, and under ordinary circumstances only one-third in mechanical work. (Under the influence of practice the utilization of energy for the performance of labor may increase just as it diminishes under the influence of exhaustion.) These are the values which have been estimated in the healthy. As to the way in which labor increases the total metabolism in disease, and how much useful energy in the shape of chemical activity the diseased body gets from the increased decomposition and from the utilization of its own muscles, only very isolated reports are at hand. From the reply to these questions, conclusions in regard to pathologic metabolism will inevitably result. THE FOOD REQUIREMENT OF THE SICK 25 The question most discussed has been whether the effects of cold and heat decidedly increase the processes of combustion in the body. That remain- ing in a cold atmosphere produces a great loss of heat will scarcely be doubted, and in the endeavor of the body to maintain its own temperature a decided loss in heat in consequence of cooling cannot be prevented, at any rate not without an increased consumption of its combustible material. The ques- tion to be chiefly considered is, whether the irritation of cold upon the sur- face of the body produces chemical changes in the interior, and thus directly increases the intensity of combustion. Speck disputes this, and considers that some physical regulation is responsible for the preservation of body tem- perature by limiting the loss of heat to the slightest amount. In his opinion, the involuntary muscular contractions which result as the effect of cold are the cause of the increase in the interchange of gases which has been observed. As a matter of fact, Loewy,1 in his investigations of the influence of cold upon the respiratory metabolism, was unable to determine an increase of 02 consumption in all cases of intelligent persons who understood their bodily functions and who maintained completely flaccid muscles during the investi- gations. This corresponds with the experience of Wolpert, which is of prac- tical importance, that " the temperature of the air of the work-room, during work within the limits of 5° C. and 25° C, exerts no especial influence upon the degree of C02 excretion, either during rest or during strenuous corporeal labor." (In contrast to this are the views of Liebermeister, according to whom the heat loss from the effect of cold causes directly an increase of heat production.) Eegarding the increase of oxidation processes which are generated by the action of heat upon the body, when the conduction of heat by evaporation is prevented, we have some interesting figures obtained in the experiments on the respiratory metabolism which v. Mering had performed in his clinic by Winternitz,2 Lohse,3 and others. In contrast to the decided increase of oxida- tion produced by the hot-water bath, as shown by these investigations, the effect of a hot-air bath upon metabolism is quite insignificant in consequence of a prompt physical regulation (sweating) (Salomon).4 According to the few researches at hand ( Schattenf roh,5 Wolpert6) we may assume that the influence of heat and cold in the metabolism of the sick is quite different from that in the healthy. In the obese, for example, at least i A. Loewy, " Ueber den Einfluss der Abkuhlung auf den Gaswechsel des Menschen." Pfliiger's Arch., Bd. xlvi, p. 189. 2 H. Winternitz, " Ueber den Einfluss heisser Bader auf den respiratorischen Stoff- wechsel." Klin. Jahrbuch, 1899, Bd. vii. — " Ueber die Wirkung verschiedener Bader auf den Gaswecbsel." Hab.-Schrift, 1902, Nauenburg. 3 Lohse, " Ein Beitrag zur Lehre von der Einwirkung des heissen Bades auf den mensehlichen Stoffwechsel." Diss., Halle, 1900. 4 Salomon, " Ueber die Wirkung der Heissluftbader und elektrischen Lichtbader." Zeitschr. f. diut. u. physik. Therap., Bd. v, Heft 3. 5 S chat ten f roh, " Respirationsversuche an einer fetten Versuchsperson." Arch. f. Hyg., Bd. xxxviii, p. 93. 6 Wolpert und Broden, " Respiratorische Arbeitsversuche bei wechselnder Luft- feuchtigkeit an einer fetten Versuchsperson." Arch. f. Hyg., Bd. xxxix, p. 298. 26 ANALYSIS OF DISTURBANCES OF METABOLISM under certain circumstances, the regulation is quite different from that in the lean person. In the latter, the greatly increased heat produced by hard physical exercise may be completely removed by radiation and conduction; in other words, by increasing the temperature of the skin, and this is attained by increased activity of the circulation of the blood. In the obese this method is unavailing, and the secretion of sweat must vicariously take the place of the insufficiently active blood-current. Even in rest and in sleep, the obese person, particularly in a very warm atmosphere, throws off more moisture in a humid atmosphere than in a dry one. As regards the endurance of high temperatures the person with great deposits of adipose tissue is easily over- come, even in rest, and especially so on exertion. Besides the insensible per- spiration which must be counted in heat regulation, the obese loses greatly by the sensible perspiration which exudes from the skin, and there is no doubt that as a result of this his metabolism (through changes in the blood com- position) is very different from that of the lean individual when exposed to changes of temperature. The numerous and practical methods given us by physiology for estimat- ing the degree of oxidation in health make it obvious that pathologic condi- tions should be studied and classified from the same point of view: Is the intensity of the processes of combustion increased or diminished, or unaltered ? It is well known that Bouchard x has described an important group of diseases (diabetes, obesity, gout) as the consequence of a " slowing of metabo- lism," and lately has extended the scope of this disturbance of metabolism still further so as to include in this group other pathological conditions. Formerly such facts as the increased excretion in the urine of incomplete products of combustion (uric acid, oxalic acid), maintenance of life on a lessened amount of food, the deposition of fat with a normal intake of food, decrease of body temperature at rest, etc., led him to ascribe the condition to a slowing of metabolism. To-day he attributes to a " slowing of metabo- lism " any disease which is shown by statistics to occur frequently in asso- ciation with diabetes, obesity, or gout, or which he supposes to have a genetic relationship with these diseases. Such a division, justified perhaps from the standpoint of clinical inves- tigation, has absolutely no foundation in exact quantitative analyses of metabo- lism. Where exact analyses have been carried out we find diseases grouped in an entirely different manner. In quite a number of pathological conditions which are to be considered here, we have exact analytic data concerning the intensity of the processes of oxidation and it will be interesting to consider the results from this standpoint. i Bouchard, " Troubles prealables de la nutrition in Traite de Pathologie gengrale," Tome iii, p. 179. THE FOOD REQUIREMENT OF THE SICK 27 In the following table, the "rest values" for 02 consumption and CO\ excretion, in various diseases, have been compiled. Disease. per min. c.c. CO, per min. c.c. Respir. Quotient. 3.27 2.38 4.41 3.47 3.38 2.31 5.21 3.64 3.68 3.18 4.40 3.68 3.89 2.98 0.766 6.64 5.45 .821 5.31 4.25 .799 4.33 3.4 .783 6.80 4.68 .687 6.89 5.82 .845 5.55 4.65 .838 6.43 4.84 .754 5.24 4.09 .783 5.76 4.56 .79 5.41 3.81 .70 2.31 1.74 .75 2.70 1.98 .73 3.82 3.20 .82 4.63 3.66 .79 2.9 2.5 .86 5.4 3.8 .74 4.85 3.82 .786 4.59 3.6 .784 6.25 5.07 .812 5.27 4.84 .919 6.0 3.6 4.7 3.2 5.5 4.0 7.3 4.4 6.8 4.7 5.9 3.8 5.9 3.0 4.6 3.1 5.5 3.8 6.2 5.3 5.9 4.9 1.40 1.04 .753 4.90 3.92 .8 5.86 5.69 .97 4.28 4.22 .987 5.05 4.3 .84 4.33 3.68 .85 Author. Fasting and Rest Value : Healthy Individuals j £im> ' ' Healthy Individuals j , j- ' " " Healthy Individuals j £im" ' ' Healthy Man (average from ) 41 trials) J Graves' Disease Very severe case Acute case Graves' Disease, 26 years (4 trials) . Graves' Disease, 24 years Before Thyreoid-Gland Feed- ) ing, 124 kilograms f During Thyreoid-Gland Feeding. Before Thyreoid-Gland Feeding. , During Thyreoid-Gland Feeding. Myxedema After Thyreoid-Gland Feeding. Fever: long-continued I Second Week of Enteric Fever. . . Pneumonia (inc.) Enteric Fever : 3. X. 39.6° 4.X. 39.6° Erysipelas, Fac. : 6. II. 39.8° 7. II. 39.8° , Phthisis, Pulm. : 9. V. 39.2° 20. VI. 39.2° Enteric Fever : 14. IX. 36.6° , 18.IX.36.6 Pneumonia: 28. VIII. 36.1° Tub. Pulm. : 20. VIII. 37.2° 22. VIII. 37.2° Enteric Fever Convalescence : 4th Day of Convalescence 13th Day of Convalescence 30th Day of Convalescence Enteric Fever Convalescence : 13th Day of Convalescence 35th Day of Convalescence Pneumonia-Convalescence : 13th Day ) Qeppert, Arch. f. exp. J Pathol., Bd. xxii, p. 367. \_ Ka tz en stein, Pfliiger's ) Arch., Bd. xlix. I Kraus, Zeitschr. f. klin. S Med., Bd. xviii, p. 21. \ Magnus - Levy, Pfliiger's "j Arch., Bd. lv, p. 23. Magnus-Levy, Zeitschr. f. klin. Med., xxxiii, p. 294. SStuve, Arb. aus. d. st. Kran- kenhaus Frankfurt a. M., 1896, p. 47. ) Thiele u. Nehring, Zeitschr. J f. klin. Med., xxx, p. 47. [■ Stuve, lot. cit., p. 45. ! Magnus-Levy, D e u t s c h . med. Wochenschr., 1896, p. 492. Fall 5 ) Kraus, Zeitschr. f. klin. Fall 6 1 Med., xviii, p. 177. Fall 2. Fall 3. - Riethus, p. 240. Svenson, Zeitschr. f. klin. Med., xxxvi, p. 94. 28 ANALYSIS OF DISTURBANCES OF METABOLISM Disease. o2 per min. c.c. C03 per min. c.c. Respir. Quotient. 4.06 3.14 .77 4.54 2.97 .66 3.99 2.71 .68 3.05 2.66 .73 3.04 2.31 .76 3.51 2.73 .78 3.96 2.93 .74 6.23 4.425 .7 5.164 3.795 .617 5.744 3.65 .64 4.53 3.22 .71 5.11 3.7 .72 5.48 4.0 .727 4.58 3.45 .75 3.47 2.96 .85 3.15 2.92 .92 3.38 3.29 .975 4.18 3.58 .86 4.15 2.94 .70 4.26 3.6 3.83 3.35 2.71 1.95 3.33 2.34 3.45 2.77 .804 2.48 1.87 .756 2.94 2.39 .812 3.74 2.39 .637 2.40 1.85 .771 2.88 2.31 .802 2.12 1.52 .719 3.22 2.42 .750 3.48 2.83 .814 2.82 2.04 .721 2.83 2.32 .821 2.41 1.87 .777 2.82 2.37 .840 2.7 1.98 .74 2.8 2.26 .81 4.25 3.36 .768 3.16 2.55 .807 3.42 2.70 .79 2.61 2.61 .725 9.76 8.16 .84 7.42 6.04 .81 3.56 2.90 .82 Diabetes : 1. Severe ease 2. Very severe case 3. Very severe case 4. Mild case 5. Mild case 6. Mild case Diabetes Severe case Severe case (Nine -hour investigation with ~ Hoppe-Seyler's respiration-ap- paratus with simultaneous ad- ministration of food during the investigation.) Anemia, pernic. progress Chlorosis Chlorosis Secondary Anemia after hemor- rhage from hemorrhoids Chlorosis Chlorosis Chlorosis Secondary Anemia Pernicious Anemia Severe Anemia Same patient with continued im- provement Obesity : Dr. Dr. Gew., 94 kilograms Frl. N., 70 kilograms Fr. Mai., 69.5 kilograms Fr. St., 76 kilograms Frl. E. Kr., 77 kilograms Fr. Kr., 88 kilograms Frl. Bu., 107 kilograms Fr. Ha., 111.4 kilograms Fr. Schu., 133.3 kilograms Hr. A. S., 80.2 kilograms Hr. Mar., 80 kilograms.. Hr. Stab., 91.5 kilograms Hr. Dr. Da., 92.7 kilograms Hr. Ha., 96 kilograms Hr. D. 0., 109 kilograms Fr. Eckmann D. P Aged : Fr. Kr., 75 years Fr. Kl., 71 years Hr. A. Kr., 71 years Hr. J. K., 78 years Youth: Boy, 2| years, 11.5 kilograms. . . Girl, 6| years, 18.2 kilograms. . . Girl, 20 years, 61 kilograms. . . . Leo, Zeitschr. 1 klin. Med., " Bd. xix, p. 117. iStuve, loc. cit., p. 49. Weintraud und Laves, Zeit- schr. f. phys. Chem., Bd. xix, Heft 6*. 1 [ Fr. Kraus, Zeitschr. f . klin. Med., xxii, p. 49. Thiele u. Nehring, Zeitschr., f. klin. Med., Bd. xxx, p. 56. Thiele u. Nehring, loc. cit., \ p. 59. 1 Magnus-Levy, Berliner klin. Wochschr., 1895, p. 351. ) v. Noorden, Lehrbuch, p. \ 448. , Magnus-Levy, Zeitschrift f. klin. Med., xxxiii, p. 302. Thiele u. Nehring, loc. cit. Stuve, loc. cit., p. 46. I Magnus-Levy, Zeitschrift f . | klin. Med., xxxiii, p. 266. / Magnus-Levy, Berlin, klin. f Wochschr., 1895, p. 652. Among pathological conditions in which investigation of the respiratory metabolism has invariably shown an increase, Graves' disease occupies the first place. THE FOOD REQUIREMENT OF THE SICK 29 Magnus-Levy,1 by his many valuable physiological researches in this realm, was the first to attempt to estimate the factors of respiratory metabolism in Graves' disease (Basedow's disease). He found the 02 intake and the C02 excretion decidedly greater, even 50 per cent, greater, than the rest values of healthy individuals. At the same time his results showed that the admin- istration of thyreoid extract in normal persons resulted in the same increase of the interchange of gases. These investigations also furnished the first experimental proof that there are toxins in metabolism which cause increased activity in the cells of the body during rest, and this discovery furnished a clue for the understanding of the disturbance in metabolism observed in Graves' disease (emaciation, sweat- ing, sensations of heat) as well as the clinical symptoms after thyreoid gland feeding, which are in many points similar. A year before this practical use had been made of the effects of metabolism thus elucidated, when Leichtenstern 2 determined the actual loss in weight of obese persons after thyreoid gland administration, and with this inaugurated a medical treatment for obesity. The quantitative investigations in metabolism which followed the clinical advice of Leichtenstern, the loss of weight after thyreoid administration, and the attempts to analyze the constituents of this loss first demonstrated that there is a decided loss in proteids and water. But some of the investigators 3 soon observed that, even when N-equilibrium was completely maintained, there was decided loss in weight which could only be explained by loss of water and fat. Analysis of the respiratory metabolism showed an enormous increase in the intensity of the processes of oxidation, and thus confirmed the clinical observation that in the losses of weight which are observed during thyreoid feeding it is particularly the body fat which is subject to increased oxidation. But it is certainly not on the body fat alone that the overflooding of metabolism with thyreoid secretions exerts its deleterious action in severe cases of Graves' disease. Even if we take the largest increase over " rest metabolism " which has ever been observed in Graves' disease (about 50 per cent, or 1,800 calories), an additional consumption of 900 calories or about 100 grams of fat in the daily food would cover the loss. Yet as a matter of fact exact quantitative investigations in metabolism have shown that we are not always successful in maintaining the equilibrium of body- weight (Fr. Miiller),4 even by a very profuse administration of nourishment, and only in mild cases, when condi- tions are favorable for a profuse intake of nourishment (good appetite), can the proteid constituents of the body be preserved (Scholz).5 The etiologic relations and the clinical contrasts between Graves' disease i Magnus-Levy. Berl. klin. Wochenschr., 1895, Nr. 30. 2 Leichtenstern, " Ueber Myxodem und iiber Entfettungscuren mit Schilddrusenfiit- terung." Deutsche med. Wochenschr., 1894, Nr. 50. 3 Grawitz, Miinchener med. Wochenschr., 1896, Nr. 14. 4 Fr. Miiller, Arch. f. Jclin. Med., vol. li, p. 36. 5 Scholz, Centralbl. f. inn. Med., 1895, Nr. 43. 30 ANALYSIS OF DISTURBANCES OF METABOLISM and myxedema (or sporadic cretinism) make it advisable to include these diseases here. They are the only ones in which a diminution of the normal oxidation has been proven with certainty to be intimately connected with disease. The values which Magnus-Levy x obtained in a case of sporadic cretinism (for 02 intake 2.8 to 3.0 c.c, for C02 excretion 2.4 to 2.5 c.c., per kilogram and per minute) are near the lowest normal limits, and when taken in connection with the clinical symptoms (low temperature, diminished formation of sweat, inactivity of the muscles) the few analyses of metabolism which have been made justify the conclusion that in this instance a diminution of metabolism was actually present, and was due to the nature of the disease. In no other diseases in which up to the present time the interchange of gases has been determined is the explanation of the results obtained so simple and clear as it is in Graves' disease and in myxedema. Nevertheless, the figures obtained have considerably modified the prevailing views regarding the intensity of the processes of combustion in special diseases, and by this means have broadened our insight into their pathogenesis, and have furnished us much help regarding their treatment. For a long time it was supposed that in fevee the processes of oxidation were increased. Nothing was more obvious than to connect the higher tem- perature of the body with an increased use of carbon-containing material in the body. Eegarding the degree of the increase of oxidation in the fever of human beings experimental investigations in animals could only give us imperfect standards (May2). Researches which Kraus 3 carried out in febrile human beings have, however, shown that fever is possible without decided increase of the oxidation processes (measured according to Zuntz's method which shows the relation of the factors of metabolism). This is particularly true of such individuals as have had fever for a long time — those suffering from inanition (Eobin et Binet4). In acute infectious fevers, the 02 consumption amounts to scarcely more than 20 per cent, above the normal. Previous to this, higher values have frequently been obtained for the increase in oxidation, but this has been due to accidental factors such as greater muscular activity owing to dyspnea, increased musouLar tonus in the chill of fever, etc. The amount of increase in the interchange of gases, which Kraus and Eiethus5 have shown to be attributable to some febrile infections, is suffi- i Magnus-Levy, Deutsche med. Wochenschr., 1896, p. 491. 2 May, " Der Stoffwechsel im Fieber," " Experimentalle Untersuchungen." Zeit- schrift f. Biol., vol. xxx, p. 1. 3 Kraus, " Ueber den respiratorischen Gasaustausch im Fieber." Zeitschr. f. klin. Med., vol. xviii, p. 160. * Robin et Binet, " Etudes cliniques sur le cbemisme respiratoire." Arch. g£n6r. de mid., 1896, Juin et Octobre. 6 Riethus, " Beobachtungen iiber den Gaswechsel kranker Menschen und den Einfluss antipyretischer Medicamente auf denselben." Arch. f. exp. Path. u. Pharm., vol. xliv, p. 239. THE FOOD REQUIREMENT OF THE SICK 31 ciently explained by the increase in proteid decomposition which forms part of every febrile process and, as it appears, bears a much more intimate rela- tion to febrile processes than the increase in oxidation (Traube, Naunyn1). The investigations which are constantly multiplying make it obvious that there is no constant and direct relation between the height of the temperature and the degree of the increase of oxidation. Febrile conditions occasionally show a conspicuously low consumption of oxygen, and afebrile cases con- spicuously high. The indications to be derived from this, in regard to the regulation of nutrition in fever patients, are obvious. It is not the absolute height of the fever which endangers the metabolism of the body, and for this reason it should not be our only care to study minutely the diet of our patients. On the contrary, it is the toxins produced by infection which prove injurious to the nutritive condition of the body, and in all cases in which the physician recognizes these deleterious consequences, he must arrange the dietary accord- ingly. Remembering this he will not disregard the dietetic indications of many afebrile infectious diseases (some forms of pulmonary tuberculosis). In contrast with fever, in which the increased combustion causes much less difficulty than the toxogenous proteid decomposition (see below) is the nutrition of convalescents. Here these difficulties are usually slight. Analysis of the diet, under which debilitated patients after long-continued under-nutrition are able to increase in weight, has frequently shown aston- ishingly low energy values. Fr. Miiller 2 in a case of stenosis of the esophagus after intoxication from caustic potash studied a fearfully emaciated patient, who gained 3.5 kilograms in three weeks, under a diet of only 24.7 to 30 calories per kilogram. Among GL Klemperer's 3 patients there were some who throve very well on a diet containing only 13.5 to 18 calories per kilo- gram. A patient of Nebelthau's 4 who was greatly emaciated in consequence of stubborn vomiting, accumulated very considerable amounts of albumin despite a quite insufficient proteid and calory administration after she had remained for four days without any food. Without doubt the processes of oxidation are here decreased to a certain degree. The metabolism is diminished to the minimum which is absolutely necessary to maintain life. Correspondingly, the formation of heat is slight (tendency to chilliness), and the power of bodily activity is limited. There is no objection to our assuming that this diminution of metabolism in chronic under-nutrition is a true slowing of metabolism. This makes it possible to maintain life even under very unfavorable external conditions, and is apparently produced gradually by adaptation and habit. Sudden withdrawal of nourishment does not diminish the total metabolism i Naunyn, Berliner klin. Wochenschr., 1869, Nr. 4. 2 Fried. Miiller, " Stoffwechseluntersuchungen von Krebskranken." Zeitschr. f. klin. Med., vol. xvi, p. 496. 3 G. Klemperer, " Ueber Stoffwechsel und Ernahrung in Krankheiten." Zeitschr. f. klin. Med., vol. xvi, p. 550. * Nebelthau, " Ein Beitrag zur Kenntniss der Acetonurie." Centralbl. f. inn. Med., 1897, p. 977. 32 ANALYSIS OP DISTURBANCES OF METABOLISM to anything like the same degree. In the estimations which Zuntz and Leh- mann x carried out in the professional faster Cetti, the " rest-values " for 02 consumption and C02 excretion during the days of starvation (on the average 4.78 and 3.34 c.c.) were but little lower than during the days pre- ceding the fast (5.35 c.c. 02, and 3.90 c.c. C02). In investigations in the case of the faster Breithaupt, the average values prior to the fast and after it had begun were almost exactly the same. Whether the ease with which patients convalescent from acute febrile disease compensate for their loss in weight depends upon the same capacity to economize in metabolism which enables patients in a state of chronic under- nutrition to gain weight even on a diet of low calory value is a mooted ques- tion. Svenson 2 has recently thrown light upon this question by investiga- tions of metabolism in convalescence from pneumonia and from enteric fever. His figures (see Table on page 27) do not show a tendency to economy in the processes of combustion. On the contrary, in the first afebrile days after a severe enteric fever, he found a slight diminution of the respiratory values; true convalescence with increase in weight was being characterized by high values, and metabolism was therefore increased. Hence the increase in weight cannot be explained by assuming a diminution of consumption. On the contrary, the balance is positive because the intake of nourishment with the usual increased appetite of convalescence is decidedly greater than the energy value of the average food of maintenance (60 to 90 calories per kilo- gram). The " rest- value " for metabolism in convalescence then is in any case increased and this is particularly true of the metabolism after work, as was shown by Svenson's further researches. The convalescent is able to utilize in muscular work only a small portion of the energy set free by the processes of combustion, and therefore has a higher C02 consumption per kilogram meter than the healthy man. There is no economy of metabolism here. Diabetes mellitus was for a long time looked upon as a disease in which metabolism was increased. The enormous ingestion of food which, because unsuitable, is often insufficient (in spite of its great energy value) to satisfy the appetite which accompanies diabetes mellitus, and to maintain nutrition, naturally led to this view, at a period when a deeper insight into the econ- omy of metabolism of the diabetic was not yet possible. The quantitative analyses of metabolism which, because of therapeutic ex- periments in diet, were carried out especially often in diabetics, soon showed, however, that with suitable food, the usual calory intake was sufficient to maintain the equilibrium of metabolism even in severe diabetes. The diabetic perversion of metabolism cannot be due to an increased inter- change of products since it is possible with a diet which contains only 25 i Zuntz und Lehmomn, Yirchow's Arch., vol. oxxxi ; Suppl.-Heft, pp. 50 und 91. 2 Svenson, " Stoffwechselversuche an Reconvalescenten." Zeitschr. f. klin. Med., vol. xliii, p. 86. THE FOOD REQUIREMENT OF THE SICK 33 calories per kilogram to maintain the patient for weeks in an active con- dition.1 On the contrary, observation proves that metabolism in the diabetic may occasionally be abnormally slow, and the experience accumulated by many careful investigations of the nutrition of diabetics demonstrates that, in many cases, it is in fact slower than the metabolism of a healthy person. I say in many cases, for this is by no means true of all. A pathologic diminution of the nutritive requirement is by no means the rule in diabetes. If, however, we give for a long time a diet which is apparently superfluous but, in reality, quite insufficient — because improper — under the influence of this chronic under-nutrition the same diminution in metabolism may . occur that also occurs in other persons who are under-nourished (see above). Hence it becomes possible to support life on less food than is necessary for healthy people and to increase the diabetic's weight with a diet which is only just sufficient for the needs of a normal person. Correspondingly, the rest values for 02 consumption and C02 excretion that have been determined in diabetes neither exceed nor fall below the limits which we have come to recognize in the normal individual (Voit and Petten- kofer, Leo,2 Weintraud and Laves,3 Strive4). The same is proven by the investigations of Magnus-Levy in gout, which Bouchard, as is well known, includes with diabetes among diseases character- ized by decreased metabolism. In the various forms of anemia (chlorosis, secondary and pernicious anemia) we might expect diminution of 02 intake, in view of the more or less marked diminution of the oxygen carriers in the blood, especially if we remember the fatty degeneration of organs, which is frequently observed in anemia. Experimental investigation, however, has decided against this view. In- deed the values determined for 02 intake and C02 output have been shown to be near the upper physiological limits. In those cases of pernicious anemia which are characterized by increased proteid decomposition, this limit has even been several times exceeded (Meyer,5 Magnus-Levy).6 A diminution of metabolism due to impoverished blood cannot therefore oe assumed (Kraus,7 Thiele and Nehring).8 i Weintraud, " Untersuchungen uber den Stoffwechsel im Diabetes melitus." Bibl. med., Cassel, 1893. 2 Leo, " Ueber den respiratoriscben Stoffwechsel und Diabetes." Zeitschr. f. klin. Med., vol. xix. 3 Weintraud und Laves, " Ueber den respiratorischen Stoffwechsel im Diabetes." Zeitschr. f. phys. Chemie, vol. xix. 4 Stiive, Arbeiten aus dem stadt. Krankenhaus Frankfurt a. M., 1896, p. 49. 5 R. Meyer, " Ueber 02 Verbrauch und C02 Ausscheidung bei Anamien." Dissert., Bonn, 1892. e Magnus-Levy, Berliner klin. Wochenschr., 1895, p. 351. 7 Kraus, " Ueber den Einfiuss von Krankheiten, besonders von anamischen Zustan- den, auf den respiratorischen Gasweehsel." Zeitschr. f. klin. Med., vol. xxii, p. 449. 8 Thiele und Nehring, Zeitschr. f. klin. Med., vol. xxx. 4 34 ANALYSIS OF DISTURBANCES OF METABOLISM It is remarkable that in certain forms of obesity no diminution of the physiologic processes of combustion can be determined. Clinicians have noted two classes of cases, (a) those in which overeating and deficiency of muscular labor were the obvious causes of the accumulation of fat, and (6) those in which even a normal amount of food resulted in accumulation of fat, and even with a decided diminution of nourishment it was impossible to bring about a reduction in weight. v. Noorden 1 reports the case of a man weighing 102 kilograms who — in spite of the fact that his food during three months did not exceed 1,720 calories per day, and that as an inspector of a country district he had every day plenty of exercise — lost only a kilogram of weight in three months. In a lady weighing 86 kilograms he failed to produce the slightest diminution in weight in the course of six weeks, though he reduced the food to 900 to 1,000 calories. In a woman weighing 145 kilograms, Stadelmann 2 reports that with a diet containing but 1,500 calories per day she not only throve but even gained one kilogram per week in weight. Only when nutrition was reduced to 1,000 calories did she begin to lose weight, while on 1,200 calories she gained in weight for a time. (Compare the criticisms of these reports in Eubner.)3 In the light of these observations the question constantly arises, whether the tissue elements of obese persons do not require a slighter amount of mate- rial to perform their normal functions, and whether the very ready accumula- tion of fat is not due to the fact that the organs function more economically than under normal conditions, v. Noorden was the first to study this ques- tion by exact experimental investigation, and in his excellent text-book, The Pathology of Metabolism, which stimulated so many later researches in metab- olism, he worked out in two cases of obesity the first figures representing the consumption of oxygen and the excretion of carbonic acid. (See Table.) Eesearches by Magnus-Levy followed these (Table). All the "minute- kilo-values " taken with an empty stomach are low, in fact near the lowest limit of the normal standard figures. " But they are not so low that a dimin- ished oxidation energy of the cells must be assumed, especially if we consider that the values per kilogram as calculated in the obese become lower the more fat the body accumulates. But in metabolism during quiet respiration this factor is not operative. In studies regarding the intensity of the process of combustion fat cannot be looked upon as of the same value as flesh and gland substance" (Magnus-Levy). Thus when it appeared that analysis of the respiratory metabolism (according to the Zuntz-Geppert method) would yield no support for the belief that there is a diminution of the processes of com- bustion in the obese, new researches by Jaquet 4 suggested the method by which in the corpulent an economy of the food material introduced produces the gradual deposition of fat. if. Noorden, "Die Fettsucht," in Nothnagel's Handbuch, p. 31. 2 Stadelmann, Berliner klin. Wochenschr., 1001, Nr. 25. 3 Rubner, Beitriige zur " Erniihrung im Kindesalter," Berlin, 1002, p. 31. 4 Jaquet und Svenson, " Zur Kenntniss des Stoffwechsels fettsuchtiger Personen." Zeitschr. f. klin. Med., Bd. xli, p. 375. THE FOOD REQUIREMENT OF THE SICK 35 According to a diagram proposed by Magnus-Levy 1 the total metabolism of an individual may be considered to be composed of three factors : 1. The entire metabolism in rest and with an empty stomach. 2. The metabolism which is necessary to sustain the work (glandular and intestinal) that results in the assimilation of food introduced. 3. The metabolism which is necessary for useful or useless movements of the body. Metabolism thus estimated amounts : For 1 „ to 1,600 calories. For 2 to 240 For 3 to 860 " Total 2,700 In fact it is unlikely that an obese person requires less energy than a healthy person for the maintenance of his vital functions, for normal activity of the heart and respiration, for the rest metabolism of the glandular activity and for the maintenance of body heat. v. Koorden mentioned the possibility that for 3 he saves something, because the development of heat which accom- panies physical exercise per kilogram of working protoplasm and per kilo- gram-meter of physical exercise is less in him than in the average person, but Magnus-Levy expressed his doubts of this. It was therefore particularly in- teresting that Jaquet found the value for 2 diminished in his corpulent patient. The increase of the products of combustion due to ingestion of nourishment was decidedly less and of shorter duration in his three obese patients than in normal persons. It was shown that during a period of digestion reckoned as fourteen hours, the obese require 21.84 liters 02 less than a normal person under similar circumstances. With this amount of 02, 11 grams of fat can be burned, and a daily saving of 11 grams of fat corresponds to an accumula- tion of 4 kilograms of fat a year. Thus the analysis of respiratory metabolism opens a path for the understanding of the pathogenesis of constitutional obesity. Practical rules for the nutrition of the sick cannot be immediately deduced from these clinical studies regarding the amount of respiratory metabolism in the diseases which have been mentioned, valuable as they are for our knowl- edge of disturbances of metabolism. The knowledge of 02 consumption and C02 excretion, conveyed to us in the clinical investigations which are almost exclusively carried out by Zuntz's method, with simultaneous estimation of albumin metabolism (by N-estima- tion in the urine) can give at most but approximate conclusions regarding the part played by individual food substances in combustion. The respiratory quotient gives us some information but the absolute value of the transference of energy in a unit of time cannot be calculated from the "minute-values" for 02 and C02, because, as was mentioned above (page 8), the same amounts of carbonic acid and oxygen correspond to entirely different degrees of heat, i Magnus-Levy, Zeitschr. f. klin. Med., Bd. xxxiii, p. 299. 36 ANALYSIS OF DISTURBANCES OF METABOLISM according as we are dealing with combustion of albumin, of fat, or of carbo- hydrates. A complete, correct calculation of force-transference and heat-transfer- ence is only possible if the excretion of carbon and of nitrogen is minutely investigated for a considerable period of time, and then from both of these the implication of proteids and of fat is estimated in metabolism. Prom the hour or minute values, fixed conclusions cannot be drawn regarding the total calory requirement ; they are therefore not final. We may hope, however, that prolonged investigations of the interchange of gases (with Pettenkofer's or, even better, with Hoppe-Seyler's apparatus) will give us more valuable con- clusions for pathology, and decidedly broaden our knowledge regarding total metabolism. The cases in which the entire interchange of forces in pathologic condi- tions has been determined by sufficiently exact .technical investigations are up to the present time very few. We owe them mostly to the labors of Eubner. In his researches in artificial nutrition carried on with Heubner 1 in a normal and in an atrophic nursling, intake and output were directly estimated in every way, and by calorimetric analysis it was possible to determine the actual figures for the interchange of forces. It was shown that there is no abnormal form of decomposition (force-transference) in the atrophic child. The diet necessary for maintenance in the atrophic child and in the healthy nursling correspond very well if we make allowance for small differences in. digestion and in the temperament of the children (influence of body rest, motion and sleep). If they are given an excess of food, both utilize about the same percentage for heat production, and about the same percentage is de- posited in the tissues. The only peculiarity of the atrophic child is a lessened power of intestinal absorption, and hence a more profuse production of feces. In a technically complete investigation of metabolism in an obese child, Eubner 2 was unable to determine any diminution of interchange of forces. Despite his pathologic predisposition, the boy required no less food than a healthy boy of the same weight tested by Camerer. On the other hand characteristic differences in the processes of decompo- sition were found by Sonden and Tigerstedt 3 in their investigations of metab- olism in men of various ages. They conclude from these that there is a greater life energy during youth, in contrast to the metabolism of the aged, in which a lessened consumption may be recognized. The heat production amounted : In boys of 35.2 kilos weight to 1,322 calories In men of 67.8 kilos weight to 1,016 " In an aged man of 62.3 kilos weight to 924 " i Rubner und Heubner, " Die natiirliche Ernahrung eines Siiuglings." Zeitschr. f. Biol., Bd. xxxvi, p. 1. " Die kiinstl. Ernahrung eines normalen und eines atrophischen Sauglings." Zeitschr. f. Biol., Bd. xxxviii, p. 315. 2 Rubner, Beitrjige zur " Ernahrung im Knabenalter mit besonderer Beriicksichtigung der Fettsucht," Berlin, 1902. 3 Sonden and Tigerstedt, " Untersuehungen iiber die Respiration und den Gesammt- stoffwechsel des Menschen." Skand. Arch. f. Physiol., 1895, Bd. vi. THE FOOD REQUIREMENT OF THE SICK 37 In view of the criticisms which Camerer and Bubner have devoted to these investigations we shall, however, withhold acceptance from the conclusions which Sonden and Tigerstedt have drawn from their researches in regard to the varying intensity of the processes of metabolism in the young and in the aged. (See Table.) THE MAINTENANCE DIET AND THE PROTEID REQUIREMENT OF THE SICK Besides the complete technic and investigations which can be carried on by means of complicated apparatus, we can use at the bedside a simpler method to determine the total metabolism, viz. : the calculation of the tension power, based upon the food which has been consumed. The demonstration in Rub- ners studies that to supply suitable energy the food of man must be adapted to his condition of life permits the conclusion that if the individual, although ill, maintains his body-weight, the supply of force present in his food corre- sponds with his metabolism (interchange of force). The calculation of the energy value of food from the standard figures given by Rubner is simple, and is in general use to-day. The only question that arises is whether the control of the body-weight and the frequent com- putation of the N-balance is sufficient to indicate all important changes in the material condition of the body. But for the clinical pathology of metabolism this is certainly sufficient, and with the proviso that this assumption is justifiable, the quantitative anal- yses of metabolism in patients, now coming into common use, give us valuable points for the administration of food suitable for the maintenance of the organism in special diseases, either hypernutrition or hyponutrition. A few of these investigations have been mentioned. It would extend this article too much if I were to enumerate them all; and some of them will be referred to later. (See absorption investigations.) v. Noorden's systematic tests of the energy value of food and his methods of producing a rapid increase in weight, will be described explicitly. In eight women who were confined to their beds weight began to increase when the food reached the following values: 26, 26.5, 19, 32, 33, 36, 36, 38.5, 39 calories per kilogram and per day. Upon the average 32 calories per kilo- gram. In five women who were out of bed for two to three hours during the day, increase in weight began when the value of the food reached 28, 31.5, 34, 36.5, 36.5, 40 calories per kilogram and per day. Upon the average 34 calories. In four women who spent most of the day out of bed, and occasionally walked about in the garden, increase in weight began when the value of food reached 32, 37, 37, 41 calories. Upon the average 37 calories per kilogram. Although these figures demonstrate that increase of weight occasionally occurs even when the calory value of the food is very slight (27 calories), never- theless v. Noorden cautions us that food in which the calory value is less than 30 calories per kilogram should not be used. The increase in weight with small calory values is usually limited to patients in whom prolonged under- nutrition has led to a decided diminution of the amount of water in the body, 38 ANALYSIS OF DISTURBANCES OF METABOLISM so that the increase in weight observed may be referred more to a satiation of the demand of the tissues for water than to an actual gain in substance.1 Yet it cannot be doubted, in view of these experiments, that, in emaciated individuals, administration of food of very slight calory value may compen- sate completely for the food requirement and the interchange of force, and may even permit an increase in weight. For if, in spite of a slight calory administration, ISF-equilibrium has been maintained for a long time and albu- min actually accumulated, there cannot be a calory deficit for any length of time. Later investigations in metabolism show that the N~-balance is to a great extent independent of the calory supply. The stimulation of albumin accumulation which results from muscular exertion as well as from growth makes possible an N-retention even with an insufficient calory supply and an actual loss in weight (Caspari 2). But there are many observations showing that after prolonged under- nutrition, such as occurs in disease, the body may, up to a certain point, adapt itself to a smaller amount of food. It limits itself to the functions absolutely necessary to maintain life, and under these conditions the slightest increase in food soon brings about an increase in weight as well as a retardation of the pathological processes, under the action of which the body has become so reduced. The lessening of body-weight, upon whose maintenance, according to Pfliiger, the energy of metabolism is dependent, becomes here the direct cause of a diminished rate of metabolism. The emaciation which is the invariable consequence of many diseases finds its chief expression in the decrease of body-weight, so that frequent weighings of the body in chronic diseases are, as Gerhardt says, almost as valuable as the temperature record in acute diseases. The variations may, however, be due to various causes. When patients suffering from gastric disease are emaciated this is often due wholly to the poverty of the calory value of their food, as was first emphat- ically stated and clearly proven by v. Noorden. The fear of pain, or a false estimation of the nutritive value of individual foods, may have aided in bring- ing this about. If food of normal calory value be given, the loss in weight ceases. Other patients (Graves' disease), as we have noted, lose weight, in spite of a calory intake sufficient for the healthy, because the intensity of the process of combustion is decidedly increased. If the capacity for taking food is great, as in many afebrile tubercular patients and in many cases of Base- dow's disease, the calory contents of their food need only be increased beyond the usual needs of the healthy, and they will not only attain their N-equi- librium, but will very soon begin to accumulate fat. This, however, does not succeed in all cases. Fr. Muller 3 was the first i v. Noorden, " Stoffverbrauch und Nahrungsbedarf in Krankheiten." Arbeiten aus dem stadt. Krankenhaus zu Frankfurt a. M., 1896, p. 3. 2 Caspari, " Ueber Eiweissumsatz und Ansatz bei der Muskelarbeit." Pfliiger's Arch., Bd. lxxxiii, p. 509. s Fr. Muller, " Stoffwechsel bei Krebskranken." Zeitschr. f. klin. Med., Bd. xvi, p. 496. THE FOOD REQUIREMENT OF THE SICK 39 to note in his cancer patients that in malignant cachexia, even with a plenti- ful calory supply (with sufficient albumin elements in the food), it was often impossible to attain JST-equilibrium. Gartig 1 confirmed these reports. Here a toxin damages the protoplasm of the cells, and the albuminous debris of cells, decidedly beyond the requirements of the pathologic organism for albumin, enters the circulation, there to suffer complete destruction. In fever patients, in whom the extraordinarily high urea figures obtained by former investigators (Traube and Naunyn) were for a long time empha- sized, we now have numerous analyses of metabolism some of which show that the destruction of tissue in acute cases of fever cannot be entirely pre- vented by any mode of nutrition (v. Ley den and Klemperer 2 ) . The same is also true of certain severe forms of anemia. Yet the increased decomposition of albumin does not always occur in impoverished conditions of the blood. We know this from the researches of v. Noorden, who conducted exact analyses in metabolism in severe chlorosis, which prove beyond doubt that such patients, with the ordinary calory supply and without particularly large amounts of albumin, are able to maintain their N-equilibrium (Lip- mann-AYulff 3 ) . On the other hand, there are certain clinical cases character- ized by a severe course, the so-called pernicious anemias, some of which are to-day explained by the presence of intestinal parasites; in these the proteid metabolism is pathologically increased. Even the first clinical observers of the disease (Striimpell, Eichhorst) found in these patients high urea values, though of course these figures, without simultaneous observation and analysis of the food, did not prove anything. Exact analyses of metabolism which Eosenquist 4 lately carried out in patients with bothriocephalus-anemia have determined with certainty that, at any rate in this form of pernicious anemia, there is an increased decomposition of albumin. These researches constitute conclusive proof of the law of so-called toxogenous decomposition of albumin, for they illustrate how, shortly after the expulsion of the parasites (five to six. days later), an accumulation of albumin, formerly impossible, was attained. As the blood changes here depend upon toxic action, after the removal of which normal regenerative changes take place, so also the pathologic decom- position of albumin may be readily stopped by expelling the parasites. The indications for preventing the threatening tissue destruction in febrile and cachectic patients are much more obscure. Yet this is often of para- mount importance in dietotherapeutic endeavors. Practical experience shows that the two methods which improve the albu- min balance in the healthy are also applicable here. By the administration of a liberal albumin diet, the N-loss may be diminished during fever (Bauer and Kiinstle) ; the same result can be obtained by giving a profuse calory supply of N-free substances. For both processes excellent methods are found i E. Gartig, " Untersuchungen iiber den Stoffwechsel in einem Fall von Care. (Esoph- agi." Diss., Berlin, 1890. 2 v. Leyden und G. Klemperer, " Ernahrungst.herapie in aeuten Fieberkrankheiten." " Handbuch d. Emahrungsther.," Bd. ii, p. 408. 3 Lipmann-Wulff, " Ueber Eiweisszersetzung bei Chlorose." Diss., Berlin, 1891. * Bosenquist, Berl. klin. Wochenschr., 1901, p. 666. 40 ANALYSIS OF DISTURBANCES OF METABOLISM in the tables of v. Leyden and Klemperer (loc. tit.). That the carbohydrates in themselves are superior to the fats as albumin savers (see page 21) and that they are especially valuable in the diet of fever and cancer patients as compared with albumin and fat (the administration of which is frequently limited by an unconquerable repugnance and by difficulty in digestion), is clearly shown by experience at the bedside as well as by experimental study. In fever artificially produced May x found a limitation of the combustion of albumin as a result of the profuse intake of carbohydrates. In spite of the pathologically increased toxogenous decomposition of albu- min the laws which normally control the metabolism of albumin are still active in wasting diseases. This fact should always be borne in mind, and measures based upon it should be employed in the dietetic treatment of such cases. Hirschf eld 2 succeeded by forced feeding in attaining an K-accumu- lation in tuberculous febrile cases, v. ISToorden, in his text-book, mentions quite a number of patients with temperatures of over 101.3° F. in the late weeks of typhoid cases running a slow course, also patients with sepsis and pulmonary tuberculosis, who on a diet rich in albumin but not of particularly high calory value were able, at least for two weeks, to maintain their body- weight. Whether nitrogen-equilibrium actually existed in these cases cannot be determined from the figures given. There is a great difference as regards the IST-balances in febrile and those in non-febrile convalescents for, with the same calory supply, we can produce in afebrile cases a decided gain in albu- min while in febrile cases we can scarcely maintain the nitrogen-equilibrium. The " intoxication necrosis " of the tissues which occurs in febrile dis- eases as well as from under-nutrition, and the deleterious effects of which cannot be prevented by any known means, is followed in convalescence by a remarkable endeavor of the enfeebled cells to recuperate. They attempt to gorge themselves with albumin, and the balance of metabolism which termi- nated in a nitrogen deficit suddenly begins to show an IST-retention (Diinsch- mann, v. Leyden and Klemperer, loc. cit.). The great rapidity with which this IST-retention may occur despite a nor- mal calory supply and normal proteid supply has been noted in numerous studies of metabolism.3 In this connection Luthje's 4 latest experiments in forced feeding have shown what can be done by means of abundant food dur- ing convalescence. In his studies of convalescents from enteric fever, IST-reten- tion of from 10, 12 to even 14 grams of N per day, corresponding almost to 100 grams of albumin within twenty-four hours, was repeatedly observed. This K-addition is all the more remarkable because, in my opinion, we must assume that the retained nitrogen is utilized for the production of living protoplasm, and therefore is utilized in the total metabolism. i May, " Der Stoffweehsel im Fieber." Zeitschr. f. Biologie, Bd. xxx, p. 41. 2 Hirschf eld, Deutsch. Arch. f. Jclin. Med., 1882, Bd. xxx, p. 28. 3 Albu, " Ueber den Eiweissstoffwechsel bei chronischer Unterernahrung." Zeitschr. f. klin. Med., Bd. xxxviii, p. 250; here also the other literature. * Liithje, Beitrage zur " Kenntniss des Eiweissstoffwechsel." Zeitschr. f. klin, Med., Bd. xliv, p. 22. THE FOOD REQUIREMENT OF THE SICK 41 With such an amount of N-retention there is no possibility that we are producing only a temporary retention of N-containing products of metabo- lism (proteid destruction). Further such an enormous increase cannot take wholly the form of circulating albumin (in Voit's sense). Neither can we call it "reserve albumin" (v. Noorden), if this term is meant to imply that the albumin accumulated during convalescence is a different kind of albu- min from, and subject to other laws of destruction than, ihe ordinary albumin of the organs. In the perbon experimented upon by Liithje, whose diet for twenty days averaged 62.5 grams of N,1 after a reduction to 16.7 grams N, K-equilibrium was attained, not at once indeed, but within three or four days ; and even after eight days, when the research was stopped, but small losses of nitrogen were shown.2 In view of the obvious tendency toward N-equilibrium in this case there is no reason to assume that, in the subsequent period, all the nitrogen (166.78 grams) which had accumulated during twenty days of the albumin period was again lost. At any rate, there was no loss in weight, although the patient after leaving the clinic and while living on a freely chosen diet probably did not consume a very large quantity of albumin. Apparently then the amount of his living cell substance probably remained large. Consequently, in later investigations in the same person larger quan- tities of albumin were required to bring about a large N-retention, a phe- nomenon quite in accord with the views of Pfliiger, according to which the degree of the albumin metabolism is dependent upon the amount of living cell substance of the body. We are, therefore, justified in holding the view that the N-retention in convalescents is not due to the retention of N-containing urinary products of metabolism, but to an actual accumulation of albumin which is equivalent to an increase of living protoplasm and, in a certain sense, to an increase in the activity of the body. Moreover, we must not always consider the muscles of the body alone, and for this reason the designation, " muscle-food," had better be avoided. Eichness in albumin (increase of the juices of the flesh) is only the necessary pre-requisite for great power in the musculature, and it is exercise and only exercise which increases power, on. which capacity for work is directly dependent. On the other hand a decided retention of nitrogen, which does not mean an accumulation of albumin (or an increase of living protoplasm), is fre- quently met with in renal diseases. Disturbance of the nitrogen-equilibrium is usual in these affections. It is evident without further elucidation that in nephritis which is a con- sequence of disease of the excretory organs urinary substances are prone to remain in the body, and we are therefore not far wrong, when we find rela- tively small amounts of nitrogen in the urine (in comparison with the i Corresponding to the enormous administration of 390 grams of albumin per day. 2 For which the further decrease of N-administration to 15.6 grams N is to be made partly responsible. 42 ANALYSIS OF DISTURBANCES OF METABOLISM amount of nitrogen administered in the food), in concluding that the cause is deficient excretion of nitrogenous products of albumin metabolism (Fleischer/ v. Noorden and Kitter 2 ) . Because of this fact, as well as because days with increased N-excretion often follow these periods of decided N"-retention, the K-elimination in nephri- tis is in a very " unaccountable and bizarre state which, according to v. Noor- den, characterizes the metabolism of renal patients." But we are here dealing wholly with disturbances of excretion; there are no changes in the amount of albumin metabolism (no toxogenous albumin decomposition). In investigations of the metabolism of gouty patients we are often con- fronted with irregularities in the excretion of urea, apparently in consequence of functional insufficiency of the organs of excretion, which is natural if we remember that renal disease often complicates gout (Vogel,3 Schmoll4). It is interesting to note that Rosemann 5 lately found in a healthy, or appar- ently healthy, young man during a long investigation in metabolism carried out for a different purpose, a decided IST-retention with subsequent increased excretion of urea. In this case there were no sufficient grounds for the assump- tion of any renal disease. On the other hand, the person experimented upon had suffered for years from a cutaneous affection (occasional attacks of urti- caria), and it is conceivable that, in consequence of this, the excretion of water through the kidneys had in the course of years become diminished in favor of that through the skin; and that, therefore, the N-elimination by means of the urine had suffered. However, the excretion of water in the urine during the period of N-retention was never so slight in this case that the urine could not have excreted more nitrogen. Rosemann, therefore, expressed the opinion that a prolonged ingestion of iodin was responsible for the dis- turbance of N-excretion (the person experimented upon had suffered from a cutaneous affection for years, and up to within fourteen days of the test had taken potassium iodid), but at the present time proofs are wanting that the secretory activity of the kidneys can be thus influenced by the use of iodin, even for a long time. 1 believe that every one who has made many quantitative researches in metabolism has occasionally met with healthy persons in whom, in spite of the most careful regulation of the amount of the food, it was impossible to attain N"-equilibrium. In such persons the daily N-excretion constantly varies up and down when we are attempting to get at the average figures. Oc- casionally there are periods of relatively low excretion lasting several days i Fleischer, Klinische und pathologisch-chemische Beitrage zmr " Lehre von den Nierenkrankheiten." Deutsches Archiv f. klin. Med., vol. xxix, p. 129. 2 v. Noorden und Ritter, " Untersuchungen fiber den Stoffwechsel Nierenkranker." Zeitschr. f. klin. Med., vol. xix, p. 197. 3 Vogel, v. Noorden's Beitrage zur "Lehre vom Stoffwechsel," 1894, Heft 2, p. 113. * Schmoll, " Stoffwechselversuche an einem Gichtkranken." Zeitschr. f. klin. Med., vol. xxix, p. 510. s Rosemann, " Ueber die Retention von Harnbestandtheilen im Korper." Pfliiger's Archiv, vol. lxxii, p. 467. THE FOOD REQUIREMENT OF THE SICK 43 followed by similar periods of increased N-excretion. This phenomenon is particularly frequent and familiar when the subject is on a regime rich in albumin (more than 20 grams of N in the daily food). In contrast with these irregularities of the excretion of nitrogen in the urine which occasionally occur in the healthy, and more frequently in renal disease and in gout, we have the N-retention which is observed in cachectic patients during the formation of transudates and edemas. Concerning this quite a number of investigations have been made, par- ticularly in patients with hepatic cirrhosis. Several times during the reac- cumulation of an ascites (after paracentesis) the nitrogen balance has been estimated (Schubert,1 Marischler and Ozarkiewicz -). That the N-retention which is noted in these cases does not indicate an actual albumin accumulation is clear. The retained nitrogen is not utilized as albumin to build up tissue but goes to form edema or ascites. Authors have therefore often spoken of a " pathological " jST-retention, and explained it by the hypothesis that while the organism normally possesses the faculty of destroying albumin and digest- ing it, this function is now lost. Most probably, however, purely mechanical disturbances of absorption here play a role in causing the retention of N. These disturbances depend upon changes in the amount of mineral salts in the fluids of the body, the osmotic changes being dependent upon variations in the concentration of these salts which cooperate with the active properties of the endothelia to govern absorption. There is no considerable interest in the often-discussed question whether the albumin in these re-accumulating transudates (ascites) comes from the albumin of the food, or whether the body albumin is utilized. The question becomes meaningless if we discard Voit's differentiation of two varieties of albumin in the body (organic albumin and circulating albumin). This deci- sion cannot be arrived at by analysis of the mineral metabolism in such cases, for the albumin of the food has been absorbed, taken up into the fluids of the body, and thence also into the cell protoplasm; thence together with the organic albumin it issues in the fluids of pathological transudates. DISTURBANCES IN THE ABSORPTION OF FOOD In determining the food requirement of a patient, we must consider (a) changes in the amount of oxidation due to the disease, (b) consumption of albumin due to toxic influences, and (c) other factors, important among which are the losses of energy which the body suffers by giving off food sub- stances which it should retain. These losses are so manifold and so various that it is impossible to place them side by side as equivalents. Some of these losses are not susceptible to quantitative estimation; on the other hand, in so far as they are due to i Schubert, " Ueber den N- und Cl-Umsatz wahrend der Bildung und nach der Punk- tion des Ascites bei Lebercirrhose." Dissert., Breslau, 1895. 2 Marischler und Ozarkieicicz, " Stoffwechsel bei abnehmendem und zunebmendem Ascites." Arch. f. VerdauungskranJch., vol. v, p. 222. 44 ANALYSIS OF DISTURBANCES OF METABOLISM faulty absorption of food — and this is to be especially discussed here — they can be well controlled and have in fact been thoroughly investigated. The loss in material which the body suffers from profuse sweating is rela- tively slight. But the heat equivalent that corresponds to the evaporation of one liter of sweat amounts to no less than 580 calories. We are justified, therefore, in speaking of " exhausting sweats." The food requirement of the patient is decidedly increased by muscular work. We know that even simple muscular tension, without any accompany- ing effort, is expressed in an increase of the respiratory metabolism. It is not essential, therefore, that there should be a pathologic tendency to movement which constantly keeps the entire musculature in action, as in many insane patients, or that severe convulsions should produce such shock. On the con- trary, even the restlessness of a patient in bed with increased respiration and cardiac action and mild tremor, as frequently occurs in the susceptible patient, will bring about an increase of oxidation. The degree of such in- crease in metabolism cannot, however, be determined quantitatively. The conditions are still more difficult if we attempt to estimate the loss of substance which the diseased body suffers in the discharge of transudates, in suppurating wounds, in profuse expectoration, in severe albuminuria, in long-continued hemorrhage, and the like. There can be no doubt that, in all cases in which there is loss of the body albumin, the diet must be arranged to compensate for it if loss of weight is to be prevented. The conditions are much plainer when, in consequence of qualitative dis- turbances of metabolism, the affected organism suffers loss because the food products are not oxidized to their normal end products, and, in consequence, material which is still capable of oxidation is present in the blood, and is excreted unoxidized or imperfectly oxidized in the urine. The sugar which the diabetic excretes in the urine is lost to the body as a source of power. If we fail to take account of this we overestimate the actual food-requirement and energy- interchange of the diabetic. With a suitable diet, in fact with a diet of the same calory values, we can produce equilibrium of metabolism in the diabetic as in the healthy. Only the food must be given to him in such a form that he can utilize it. By other products also, which, in disturbances of metabolism, are found in the urine (acetone, aceto-acetic acid, /3-oxybutyric acid, cystin, homogen- tisic acid, etc.) energy is occasionally lost to the body. The organism always loses energy when there is insufficient assimilation of food in the intestines. This occurs in the healthy, but is frequently and decidedly increased in the sick. Its amount may be accurately deter- mined. In the healthy estimation of the calory value of feces such as are dis- charged by those on a mixed diet has led Rubner to assume a reduction of 8 per cent, from the raw calory value of the ingested food as the average amount of energy thus lost. This calculation, however, is valid only under conditions in which the feces are made up chiefly of the unabsorbed residue THE FOOD REQUIREMENT OF THE SICK 45 of intestinal secretions, and do not contain remnants of food. These condi- tions are realized only when absorption is normal and the food is suitable. This assumption, however, is not true in health if the diet contains sub- stances in a form difficult of absorption. In the sick, in whom the mechan- ism of digestion as well as the mechanism of absorption is disturbed, the estimation of the food lost in the feces is absolutely necessary, for we cannot estimate it by simple subtraction. The analysis of feces is therefore very important in all quantitative clin- ical investigations of metabolism. The results, compared with an exact esti- mation of the food ingested, give a clear idea of the amount of food assim- ilated in the intestinal canal. Voit demonstrated in his laboratory the energy-value of the food of healthy persons by thus estimating the part which remained undigested in the intes- tine and in the feces when the subject was given various diets, simple or mixed. This forced us to investigate the manifold pathologic conditions which com- plicate the mechanism of digestion and the processes of absorption and to study the absorption of and utilization of food in these conditions. The researches undertaken in this direction are extremely numerous, and only their most important results can be summarized here. In by far the majority of these studies we have limited ourselves to esti- mating accurately the nitrogen and the fat during the period of investigation. In view of the fact that the disappearance of carbohydrates during their pas- sage through the intestinal canal is accomplished not only by absorption through the intestinal mucous membrane, but also by decomposition (fer- mentation), and hence that the residue of carbohydrates found in the feces does not give a reliable measure of the actual amount used, carbohydrate esti- mation in feces has been quite commonly neglected in these investigations. Only lately A. Schmidt x has minutely investigated this question, and in his " fermentation test " has given a method for determining accurately those portions of the undissolved carbohydrates which are susceptible to the fluids of digestion, yet have escaped absorption. His proposition to utilize always the same trial meal (qualitative and quantitative) for the quantitative estima- tion of the absorption of albumin and fat in disease deserves the fullest consideration. The investigation of the absorption of food in pathologic conditions, in so far as technic and quantitative estimation are concerned, has now reached a high degree of perfection. Comparatively few of the numerous researches in metabolism have given noteworthy and positive results concerning the assimilation of food. The researches of Fr. Muller 2 in the metabolism in jaundice, which are the earlier quantitative investigations at the bedside, should be mentioned first, since they determine a very important decrease in fat absorption in cases of occlusion of bile from the intestine. il. Schmidt, Dentsches Arch. f. klin. Med., Bd. lxi, pp. 280 und 545; Verh. gr. f. inn'ere Med., 1898 und 1899. 2 Fr. Muller, " Untersuchungen iiber Ikterus." Zeitschr. f. klin. Med., Bd. xii, p. 45. 46 ANALYSIS OF DISTURBANCES OF METABOLISM But also the negative results of many investigations which showed nor- mal or almost normal absorption in such pathologic states — conditions in which with a certain degree of justice it might have been supposed that more serious disturbances were present — have given a basis of support for the dietetic treatment of such cases, and have shown the fallacy of many diet lists based upon erroneous ideas. 1 refer to the excellent monograph of Ad. Schmidt and J. Strassburger,1 in which the results of their researches in this subject are compiled, and I shall limit myself to mentioning a few researches. The mal-assimilation of food which Fr. Miiller found in patients with stasis of bile is limited almost exclusively to fat. Miiller found in the feces of his patients fat amounting to 87.4 per cent, (against 22 per cent, in the healthy). The loss in fat often amounted to 50 to 70 per cent, of the fat administered as food. The same decided decrease of fat absorption was afterward observed in occlusion of the pancreatic juice from the intestine without complications (Deucher).2 In a case of carcinoma of the head of the pancreas, in which no stasis of bile was present, only 17 per cent, of the fat introduced was absorbed; therefore, the simultaneous action of pancreatic juice and bile is necessary for a sufficient absorption of fat in man. On the other hand, it appears from the reports of investigations that neither bile nor pancreatic juice is necessary for the complete splitting up of fats in the intestinal canal. Not only the fatty stools of the jaundiced patient (Pr. Miiller), but also (according to Deucher) the feces in occlusion of the pancreatic duct contain fat which is chiefly in a split-up form (up to 80 per cent.) ; therefore, Deucher teaches that we cannot eount upon the absence of free fatty acids in the feces as evidence of disturbances in the pancreatic function. Predominance of free fatty acids, naturally, not at the cost of the neutral fats, but, on the contrary, at the expense of the soaps (Deucher), means pre- sumably a decrease or absence of the pancreatic juice secretion. By others 3 in individual cases, a lessened fat splitting has also been ob- served in connection with occlusion of the pancreatic juice from the intes- tine. Volhard 4 has shown that, although the decomposition of neutral fats is primarily the function of the pancreas, in cases of occlusion of the pan- creatic juice, fat splitting occurs not only through the action of bacteria, but also through the action of the gastric juice which also contains a fat splitting ferment. There is need of further investigations with due consideration of this factor. i Ad. Schmidt und J. Strassburger, " Die Faces des Menschen," Bonn, 1901. 2 Deucher, " Stoffwechseluntersuchungen bei Verschluss des Ductus pancreaticus." Correspondenzbl. f. Schweitzer Aerzte, 1898, Nr. 11. 3 Fr. Miiller, loc. cit., Weintraud, " Die Bedeutung des quantitative!) Stoffwechsel- versuches fiir die Diagnostik innerer Krankheiten, insbesondcre von Pankreaserkrank- ungen." Die Eeillcunde, 1898, Heft 2. ' 4 Volhard, " Ueber das fettspaltende Ferment des Magens." Zeitschr. f. hlin. Med., 1901, Bd. xliii, p. 397. THE FOOD REQUIREMENT OF THE SICK 47 Except in the cases just mentioned a decided diminution in the absorption of fat, e. g., as a result of disturbance of the gastric chemism, has not yet been observed. With insufficient or increased HC1 in the gastric juice, and also in complete achylia (apepsia), the fat appearing in the feces does not amount to more, or to but very little more, than the usual percentage. On the other hand, unusually large amounts of fat are found in the dis- charges in disease of the intestine (amyloid degeneration,1 tabes mesenterica,2 chronic intestinal tuberculosis with chronic tubercular peritonitis,3 fatty diar- rhea [Biedert4]). Regarding the laws of albumin absorption in the sick, v. ISToorden 5 has demonstrated the surprising fact that the absence of HC1 in the gastric juice, in spite of its great importance for the peptonizing of the albumin bodies which is necessary for their absorption, nowise influences the assimilation of the latter. Patients with disease of the stomach, with anacidity and with hyperacidity, showed a quite normal power of albumin absorption in the intestine. But later, in cases of apepsia gastrica 6 and of pernicious anemia 7 in which not only HC1 but also the digestive ferments of the gastric juice were absent, slight diminution in the absorption of albumin was observed. It must, however, be remembered that in these conditions there is often not only independent disease of the mucous membrane of the stomach, but (as the anatomical findings in individual cases have also shown) actual atrophy of the glands in the intestinal mucous membrane. Hence it is easily understood how, in the absence of any peptic effect upon the albumin in the stomach, the vicarious intestinal digestion which ordinarily occurs does not produce complete absorption. The slight albumin losses in the feces, which amount to from 11 per cent, to 15 per cent., instead of 7 per cent, as in health, in these cases and also in complete occlusion of bile from the intestinal canal, are in sharp contrast with the great losses which occur in occlusion of the pancreatic juice (Deucher, Weintraud, loc. cit.). In extensive disease of the intestinal mucous membrane (as in an atrophic nursling) ,8 in intestinal amyloid disease,9 in extensive intestinal tuberculosis 10 great losses of nitrogen have been observed in the feces. i Fr. Midler, loc. cit. 2 Ad. Schmidt, loc. cit. 3 Weintraud, loc. cit. 4 Biedert, Jahrbuch der Kinderheilkunde, Bd. xxviii, p. 21. s v. Noorden, " Die Ausniitzung der Nahrung bei Magenkranken." Zeitschr. f. klin. Med., Xr. 17, p. 137. s Strauss, " Untersuchungen iiber die Resorption und den Stoffwechsel bei Apepsia gastrica." Zeitschr. f. klin. Med., Bd. xli, p. 280. 7 Eroen und Steyskal, " Klinisch-chemische Studien." Zeitschr. f. klin. Med., Bd. xl, p. 165. — Morazeivski, " Stoffwechselversuche bei schweren Aniimien." Virchow's Archiv, Bd. clix, Heft 2. 8 Rubner und Eeubner, " Die kiinstliehe Erniihrung eines normalen und eines atro- phischen Sauglings." Zeitschr. f. Biologie, Bd. xxxviii, p. 315. 9 Miiller, loc. cit. 10 Weintraud, loc. cit. 48 ANALYSIS OF DISTURBANCES OF METABOLISM Conditions of stasis, as in disease of the heart, do not cause decided loss in albumin absorption (Grassmann1) neither are diarrheas of mild grade combined with a decrease in the assimilation of albumin in the intestine (v. Hosslin).2 We know from the researches of v. Mering that the absorption of carbo- hydrates in the intestinal canal (in the form of sugar) does not take place so much by the chyle tracts as by means of the circulation, and that they are introduced through the roots of the portal vein into the general circula- tion. We might expect that circulatory disturbances in consequence of stasis of the portal vein and in uncompensated valvular disease would seriously interfere with the absorption of albumin. The investigations of Grassmann in persons with valvular disease did not show any such influence from disturbance upon the circulation, and many later studies of assimilation have not demonstrated a decided decrease in carbohydrate absorption. Even in Deucher's investigations in patients with occlusion of the pancreatic juice from the intestines, the absorption of carbo- hydrates is complete. Nevertheless, the pancreatic juice contains the most active saccharifying ferment known. The negative results obtained probably depend in part upon the unreli- ability of the method previously in use. It was therefore a matter of great importance when A. Schmidt with a uniform diet (test diet), and by means of a new method (fermentation test), taught us to discern the finer disturb- ances in the absorption of carbohydrates. In numerous investigations undertaken in association with Strassburger 3 he succeeded in recognizing a pathological condition (in which the clinical symptoms were not very pronounced, but, nevertheless, were sufficiently char- acterized by an incomplete digestion of starch) as a not uncommon disturb- ance of function of the small intestine (in a broader " sense, including the pancreas and the upper large intestine). Only by a quantitative study of metabolism can a positive diagnosis be made (intestinal fermentative dys- pepsia). In conclusion we must refer to the great importance of quantitative clin- ical researches in absorption, in the healthy and in the sick, as helping us to decide upon the merits of the nutritive preparations with which chemical in- dustry has flooded the market during the last ten years. The new albumin preparations, in particular, have thus instigated researches in the clinic, and the studies in metabolism upon which the employment of neutrose, eucasin, tropon, plasmon, and roborat are based are certainly not few. The degree of absorption as shown by quantitative investigations in metabolism, together with practical experience at the bedside, will always be the best measures of the actual value of such food preparations. i Grassmann, " Die Resorption der Nahrung bei Herzkranken." Zeitschr. f. klin. Med., Bd. xv, p. 183. 2 v. Hosslin, Experimentelle Beitriige zur " Frage der Erniihrung fiebernder Kranker." Virchoio's Archiv, Bd. Ixxxix, p. 95. s Schmidt und Strassburger, Deutsches Arch. f. Jclin. Med., Bd. lxix, p. 570. CONCLUDING REMARKS 49 CONCLUDING REMARKS In the pursuit of knowledge regarding metabolism in pathological condi- tions, also in the nutrition of the sick, in the last twenty years, it would be unjust to ignore the importance of the dynamic point of view in the inves- tigation of the processes of metabolism, which to-day dominates pathology as well as physiology. On the other hand, however, we cannot be too careful — when relying upon a law based upon the combustion value of individual food products — in con- sidering the quantitative exclusively, or even to such an extent as has been the custom of the average student of metabolism in the last few years. Primarily it is practical experience at the bedside which should dictate the diet, and not theoretical knowledge of food requirement, however well founded. The patient cannot be nourished with calories alone, and it would certainly restrict the further progress of our knowledge of the laws of nutri- tion if we should consider the caloric value of the individual foods more, and the individual digestibility and tolerance, the manner of preparation, etc., of foods less. All honor to the calory reckoning of the food — it is of inestimable value in the treatment of chronic diseases — but we must beware of carrying it too far. In practice we have a sufficiently well-founded dietetic treatment, espe- cially in acute disease, without calory reckonings. But apart from this limitation of its value in practical dietetics, which is not to be misunderstood, the purely dynamic conception of processes of metab- olism has not always influenced our scientific understanding and research in these problems in a fortunate way. Upon one of the first pages of Hoppe-Seyler's Physiologic Chemistry, these words are italicized : " The process of life of the organism is, in the main, a complete mystery." When we read, however, in modern clinical researches in metabolism, that in the form of albumin, fat or carbohydrates only such and such calories are to be allowed in the diet, or are to be eliminated from the diet, in order to increase or to diminish the proteids or fat of the body, or definitely to influ- ence the activity of the organism in this or that direction, we might almost believe that the veil had long been lifted from the mystery, while in reality we are as far from a solution as we were in the period in which Hoppe-Seyler wrote the foregoing words. In the modern pathology of metabolism the view is constantly becoming more prominent that the calory carriers of the introduced food are simply decomposed in the daily metabolism of the body without having oecome an integral constituent of the organism. This prevents us from studying the great problem of life, and the investigator gets his inspiration not from the hope of a speedy solution of the problem but purely in the exhilaration of steady work and steady progress upon the path already trodden; still the goal itself must never be lost sight of. This, however, is the case if the view is accepted as final that the mystery 50 ANALYSIS OF DISTURBANCES OF METABOLISM of life was long ago solved by the hypothesis that the organism is a machine in which the food products undergo combustion somewhat as in an oven, thereby becoming a source for the production of heat and force. This is what Liebig assumed for the IST-free foods (carbohydrates and fats), which he therefore designated as respiratory materials; because they undergo combustion without taking part in the structure of the body he did not consider them true foods. In true metabolism, in the decomposition of products, in labor and in the regeneration of tissue destroyed thereby, they have no part according to his conception. And when Voit explained the decided increase of albumin decomposition upon adding albumin to an already sufficient diet by an increase of " circulating albumin/' and (in place of the " luxury consumption " of albumin, which was the current theory) showed the special conditions of decomposition of circulating albumin, making it responsible for the increase in albumin decomposition, then it was proclaimed that albumin also may be decomposed without being taken up into the organic parts of the body. Thus the opinion became more deeply rooted, favored by the purely dynamic conception of the food products as carriers of energy, that without any entrance of the food into the tissue of the living cells, the condition of the body could be influenced by the food in the circulation, where the nutritive products were supposed to be built up by transference into higher stages of oxidation. In this manner the organism was supposed to be able to utilize its food and the energy resulting to cover its losses in heat and mechan- ical labor. This conception found decided support in the demonstration by Voit that muscular labor does not go hand in hand with an increased albumin decom- position. Many objections may be raised, however, to such a conception of the processes of nutrition. Since this conception occurs particularly in the arti- cles on metabolism written by clinical pathologists it is probably to be ex- plained by the historical development of the pathology of metabolism on the basis of Voit's law of metabolism and nutrition. Certainly much would have been otherwise if the principles which Pfliiger advocated in his numerous publications had been accepted. In many clinical researches of metabolism the subject of investigation can only be comprehended after considering its historical development. I shall only refer to the question, still mooted,1 whether alcohol is a nutrient and an albumin saver. As a carrier of energy alcohol is of even greater importance than the carbohydrates, the recognized albumin savers (one gram of alcohol = 7 calories, one gram of carbohydrates = 4.1 calo- ries). How could this question have been so long disputed if alcohol, following the dynamic laws, simply undergoes combustion in the body, and in this manner offers its energy value to the organism? And why, in the numerous clinical investigations of metabolism in regard to the albumin-saving action i R. Rosemann, " Ueber die angebliehe eiweisssparende Wirkung des Alkohols." Pfliiger's Arch., Bd. lxxvii, p. 405; here also the other literature. CONCLUDING REMARKS 51 of alcohol, does it so constantly strike us that the results of research are con- flicting and permit different explanations? Because the whole process is without doubt quite different from our ordi- nary dynamic conception of it. Alcohol, after absorption, is not only decom- posed into carbonic acid and water, and thus converted into a definite amount of heat, but, moreover, it enters the protoplasm of the cells where all oxida- tion takes place, and there modifies the destruction of the protoplasm. For the same reason the carbohydrates and fats do not act isodynamically in regard to albumin saving, as would be the case if the supply of heat repre- sented by them became free in the circulation. In fact the carbohydrates are more active than the fats in the physiologic experiments. By the appearance of acetone bodies after the complete withdrawal of carbohydrates, pathology indicates that not only quantitatively, but also quali- tatively, the destruction of the cell protoplasm occurs in different ways, accord- ing to whether the carbohydrate molecule or the fat molecule is found in the cell which dominates the processes of decomposition. It has already been mentioned that the newer facts regarding the condi- tions and the occurrence of the accumulation of albumin are very difficult to reconcile with Voit's laws of albumin metabolism. The fact that gelatin, and as Mann 1 has lately shown, also elastin, even although they are inferior to fat as calory carriers, are far superior as albu- min savers, certifies beyond doubt that the nitrogen-containing food mole- cule of the bod}r-cell in which decomposition takes place brings with it something else than the calories — something which influences metabolism, independently of the calories which it brings. Analogous with this is the remarkable observation of Loewi,2 who fed a dog with IST-free starch and cane sugar as the sole carriers of nitrogen and with soluble products of continuous pancreas digestion until the complete disappearance of the biuret reaction. Thus he managed to produce nitrogen equilibrium. Therefore, the dog must have formed albumin synthetically from the nitrogen carriers in solution (from amido acids, ammonia, purin bases and hexon bases). This proof was necessary to throw light upon many physiologic and patho- logic processes of metabolism. I shall mention only one more : According to the dominant teaching, it was formerly very difficult to answers questions which arose as to the origin of muscular power. Voit was the first to show that increased muscular labor is not expressed by a decided increase of albumin decomposition (in the balance of metabolism), and, in opposition to the views of Liebig who believed albumin decomposition to be inseparably combined with the activity of the organs, regarded the nitrogen- free food products as the source of energy from which the organs, without suffering in their substance, derived energy for their functions. Now the newer investigations of Caspari actually show an accumulation i Mann, " Ueber das Verhalten des Elastins im Stoffwechsel des Menschen." Arch, f. Hygiene, Bd. xxxvi, p. 166. 2 Loewi, " Ueber Eiweisssyntbese im Thierkorper." Centralbl. f. Physiol., Bd. xv, p. 590. 52 ANALYSIS OF DISTURBANCES OF METABOLISM of albumin (nitrogen retention) during forced muscular labor. Is it possi- ble that the muscular machine acts so wonderfully that it is not subject to wear and tear, but actually develops during this condition, while it transfers the energy supplied by the carbohydrates into living force? Or are the con- ditions in reality quite different, and are nitrogen-free substances really burned in the muscle during its work, or, on the contrary, does it decompose the specific albuminous protoplasm of the muscle cell so that the nitrogen also at once decomposes like the albumin of the muscle, and is utilized for the reconstruction of muscular albumin ? Verworn assumes that in muscular activity the biogen molecule which represents living albumin decomposes into atom groups containing nitrogen and non-nitrogenous atoms, of which only the latter are excreted in metabolism, whereas the former regenerate to com- plete biogens. That we must recognize synthetic processes if we are to make such an assumption, cannot be thought remarkable after what has been said. For does not the animal organism evolve from inorganic iron such a highly complicated molecule as is represented by hemoglobin? It produces syn- thetically nuclear albumin from its components, etc. If we dismiss the view that each molecule of food which is absorbed, and is required by the organism to maintain its vital functions, is at once in all its constituents decomposed into end-products of metabolism and quantita- tively excreted, then many other points in the pathology of metabolism for- merly difficult to understand will be made clear. When nuclein decomposition occurs in the body, the phosphoric acid ex- cretion is frequently not uniform with the excretion of alloxur bodies ; appar- ently because phosphorus is retained for the purpose of nuclein synthesis, for the regeneration of the nuclein which has been lost. After complete withdrawal of carbohydrates, the amount of sugar excreted in severe cases of diabetes (as has lately been frequently observed) may exceed the quantity which may be assumed to be formed from albumin. Be- fore we speak of a sugar formation from fat, we should think of a renegera- tion of the K-containing part of the albumin molecule after splitting off the carbohydrate group, perhaps with the aid of the atom groups taken from the fat molecule. This is, however, quite different from a direct sugar forma- tion from fat expressed in chemical equation. It is simultaneous splitting and synthesis, a work of the living cell, whose effort toward regeneration becomes greater the more its protoplasm is involved in decomposition. In the study of the pathology of metabolism, we must escape from the narrow confines of views which, in the discipline of student days, were of certain value to us, but which must no longer be a barrier to development. The opinion must probably be discarded that the amount of decomposi- tion of animal protoplasm (living substance), that is, the amount of metabo- lism necessary to maintain life, is equal in all individuals and at all times. Of course the common estimation of the amount of total energy consump- tion in clinical metabolism investigations is not decisive in judging this question. Slight, and even scarcely noticeable differences in the activity of different individuals (greater muscular exertion, etc.) may produce vary- ing degrees. Hence the difference of two values obtained under similar con- CONCLUDING REMARKS 53 ditions of research should not have too great importance attached to it, as the identity of the conditions is only apparent. Nevertheless the low nutritive values which are sufficient to maintain life after prolonged under-nutrition and in some cases of diabetes are of no importance. That in some obese persons an extreme diminution of the calory supply is actually necessary before they begin to lose weight also makes it likely that here a fundamental property of the living cells is changed, so that the degree of their energy of decomposition has been diminished. And the contrary experience that, in some perfectly healthy persons, even with a food very rich in calories, it is impossible to produce an increase in weight, makes us doubt whether in this case the amount of food is really the decisive factor in the interchange of energy. On the contrary, cases of this kind make it more likely that there is an increased energy of the cells and so an actual " luxury consumption." In practice these individuals do not always present such conspicuous exter- nal signs of a lively temperament that the increase in metabolism can be ex- plained by an increased activity of the muscles ; and we are the more inclined to search for an individual anomaly of protoplasmatic activity, if such an assumption can be in consonance with the dominant teaching. The dynamic theory, which has been of inestimable value in making us recognize in biology the force of the law of conservation of energy, naturally lays particular stress only upon the intake and output of the organism. But this theory does not exclude intermediary metabolism from consideration in the future. The importance of inorganic salts will then appear in its proper light; they are indispensable in the food; nevertheless, because they do not bring tension power (calories) into the organism they have no part assigned to them in the dynamic conception of the processes, of metabolism and nutrition. Again we must remember that in the animal organism we have not only ten- sion energy consumed, but sources of energy newly formed (ferments). Although researches in the realm of the pathology of metabolism will be- come much more complicated, when all these facts are borne in mind the desirable result will be attained that clinical pathology of metabolism will become deeper but less expansive. OVER-NUTRITION AND UNDER-NUTRITION By C. v. NOORDEN, Frankfort-on-Main In modern therapy, dietetic cures are becoming more important from year to year, particularly those which are intended to influence the entire nutritive condition. Originally confined to the domain of internal diseases, they have become familiar to the surgeon and gynecologist, and no less valu- able to them than to the specialist in clinical medicine. It is well worth while to consider the salient features of these cures, without expecting that much that is new will be promulgated. For the fundamental laws are well known, though their application to practice is eternally new. When the indi- viduality of each patient has to be considered, the rules lose their supposed uniformity and their diagrammatic aspect. Uniform and self-evident as the method is when formulated in theory, in practice each particular dietetic treatment brings with it new difficulties, new demands, and when the art of the physician has succeeded, he invariably experiences the gratification of an' artistic triumph. 1. CONCEPTION OF THE "CONDITION OF NUTRITION" "When we speak of a person's " condition of nutrition " we mean, in the first place, his development of adipose tissue; but not only this is to be con- sidered, for the state of the muscles is of no less importance. Their devel- opment is not always proportionate to the amount of fat. There are many persons who are deficient in fat and weak in muscle, and many who are rich in fat and strong in muscle. But there is a third class who are of strong muscular power and deficient in fat, and a fourth who are lacking in muscle and rich in fat. Of most importance, of course, is the condition of the muscles, all the more so since with powerful muscles we expect a normal composition of the blood and of the most important glandular organs. In every treatment by which we hope to influence the " condition of nutrition " the protection of the muscles must be kept in mind, or, stated more generally — the living and func- tioning protoplasm of the body must be protected, and if possible improved, so that the maximum of its development may be attained. How great is the amount of fat on the body — leaving out of considera- tion pathologic leanness, pathologic obesity and special instances (see below) — is of less significance. There is no generally accepted standard for a nor- mal amount of fat. Between emaciation on the one hand and obesity on the 54 INCREASE OF FLESH AND INCREASE OF FAT 55 other hand, there is a wide space for the conception of a " medium state of nutrition." Although this conception permits no positive statement as to the amount of superfluous fat, no definite body-weight, no distinct relation between weight and size, age and sex, that can be called normal, it must, nevertheless, be maintained that, for each individual, there is a definite stand- ard for the condition of nutrition, particularly with regard to the amount of fat. To recognize this optimum is the duty of the physician, and presup- poses much thought and experience. Good judgment will take into considera- tion the state of health, the competency of all the organs, and the entire mode of life. A few examples will illustrate this. Experience teaches us that persons who are predisposed to tuberculosis are endangered by leanness, and that a certain degree of corpulence protects them. Neurasthenics, as a rule, feel better if they have a large amount of adipose tissue. For patients suffer- ing from disease of the heart, Bright' s disease, and emphysema the slightest amount of superfluous fat is an evil, and in diseases that affect the organs of motion, obesity is, at least, the cause of great annoyance. Persons who perform hard labor continue in better health and are more capable of working if their adipose tissue is not too greatly developed. Those who have passed the prime of life, and are no longer compelled to work hard, bear a certain development of corpulency better than those just beginning the struggle for existence. These points will be amplified in the description of the indica- tions for over-nutrition -and under-nutrition. It follows from what has been said that in all treatment by which we attempt to influence nutrition, we must first of all try to maintain and improve the muscles; in certain cases, however, we attempt nutritive cures in which increase or diminution of adipose tissue represents the sole aim of the treatment. Even in these, however, the state of the muscles must not be lost sight of. The importance of this must be emphasized, for very frequently it is forgotten. We sometimes see patients with weak muscles who in the process of " strengthening " are fattened by various means, and when the cure is done we find obese subjects with feeble muscles. Again we see corpu- lent persons subjected to such irrational antifat cures that not only the fat but also the muscles and blood are depleted, and the activity of their func- tions permanently injured. Our theme will be the question: How far can and should the general condition of nutrition, i. e., of muscle and fat, be influenced by dietetic treat- ment? 2. INCREASE OF FLESH AND INCREASE OF FAT To accomplish the most important point, the accumulation of muscle, dietetic treatment has, unfortunately, but limited powers. Theoretically it appears to be most difficult to maintain the musculature of the body in anti- fat cures. The animal experiments of physiologists have invariably shown that with under-nourishment fat disappears from the body, but that albumin also decreases. To this loss of body albumin, that is to say, waste of muscle, we owe the serious consequences which frequently surprise those who carry out a too rapid antifat cure. Discussions regarding the admixture and 56 OVER-NUTRITION AND UNDER-NUTRITION amount of nourishment which will most surely produce a loss of fat without impairing the muscular condition have been carried on for years, and reached their acme in the debates at the Congress of Internal Medicine in the year 1885, and in the literary war waged between Ebstein and Oertel. The views were based rather upon theory than upon practical experience. Investigations regarding metabolism during antifat cures had not yet been attempted. A few years later when, independently of one another, F. Hirschfeld and v. Noorden-Dapper worked out this problem experimentally, contradictions at first resulted. The former found it almost impossible to produce a loss of fatty tissue without a simultaneous decrease of the body albumin. The other two authors proved by numerous investigations that this goal may be reached, and even without special difficulty, provided the leap from a plentiful diet to one of abstinence is not too sudden. All the authors who later devoted them- selves to similar researches have confirmed this. The satisfactory result of these studies of metabolism has had, it appears to me, great influence upon the practical work of physicians, and has encouraged them — certainly not to the detriment of the patient — to attempt careful antifat cures, where pre- viously they refrained from them because in every antifat cure — even if only transiently — the supply of body albumin was jeopardized. According to other investigations in metabolism as well as in my own, and also according to later researches of Dapper and myself, careful planning of the ingestion of nour- ishment so that the albumin supply of the body will not be decreased may obviate this danger, but by no means removes all other difficulties. For, in numerous cases, it is evident that the muscular power of the patient must not only be maintained but increased. This end also may be practically achieved, and will crown the success of a thoughtfully carried out antifat cure. It pre- supposes that the patient must become accustomed, from the beginning of the treatment, to an increasing amount of bodily exercise. We must utilize the well-known physiological fact that, if we exercise a muscle, it gains not only in strength but also in bulk. It is true that investigations of metabo- lism in which the combustion of albumin has been tested during dietetic antifat cures with and without systematic, muscular exercise have not yet been carried out; but we hardly require them, for clinical experience demon- strates how readily strength and size of muscles may be increased during dietetic antifat cures. Formerly (in opposition to the facts) we regarded the preservation of the stability of the organic albumin in antifat cures as difficult, even impos- sible. Yet, at the same time, it was not doubted that by forced feeding it was very easy to accelerate not only the formation of adipose tissue but also of the animate protoplasm of the body, and particularly to strengthen the muscles. The proposition, however, is by no means so simple as it appears. That albumin metabolism is diminished and IST-containing material accumu- lates in the body on over-feeding with albuminates, particularly with fat, and to a still greater degree with carbohydrates, had been long known from animal experiments by Bischoff and C. v. Voit and their pupils. Investigations in man— especially the researches of Bleibtreu and Krug— have confirmed this, and Bornstein and Liithje in their latest studies in metabolism have demon- INCREASE OF FLESH AND INCREASE OF FAT 57 strated the surprising fact that the amounts of nitrogen which remain in the body in over-nutrition may be raised in an astonishing degree. There can be no doubt, therefore, that an increase in the body nitrogen may be secured by the quality and quantity of food. In all probability we may go further and say that this increase of nitrogen means increase of albumin, i. e., the N" which remains accumulates in the body in the form of albumin. Here our knowl- edge for the present ceases. C. v. Yoit has called attention to the fact that, in an adult animal, the albumin accumulated by excessive nutrition is stored up in a form readily decomposed and must therefore be differentiated from true organic albumin. Hence he proposed the name " circulating albumin," Since it is, however, extremely unlikely that this albumin actually " circu- lates," i. e., that it is present in the circulating fluids, and as it is very much more probable that it is deposited in the cells, I have suggested the term "reserve albumin.'" This term has now been generally accepted. It is meant to imply that the albumin, like the fat globules and glycogen granules, is absorbed into the body of the cell, and is deposited there for a time (as reserve material) without becoming an integral constituent of the cell protoplasm. According to this, in the investigations conducted with me by Krug, and in my Text-Book of the Pathology of Metabolism, I have regarded it as unproven and improbable that the increase of body-albumin which may readily be attained is synonymous with increase of muscle. Increase of muscle should mean the increase of living cell-albumin. But the mass of blood-cells and gland-cells unquestionably is but little influenced, and this is especially true of muscle. With few exceptions (prominent among them E. Pfliiger and Bornstein) later authors have accepted this view, and in a recent excellent and instructive, as well as critical, dissertation by Liithje, who has produced by far the greatest increase of body-albumin, we find the same opinions ex- pressed. If increase of albumin (so readily attained) were synonymous with increase of true muscle tissue weaklings could without great difficulty be transformed into robust, muscular people. But this is of course impossible. Every one knows that over-nutrition will produce corpulent persons, but not athletes. Increase of muscle is a function of the specific growth energy of the cells, i. e., of cellular activity rather than of excessive nourishment. Hence we see plentiful and permanent increase of muscle : 1. In every growing body. 2. In the fully grown body when it is gradually accustoming itself to increased labor (work hypertrophy of the muscles). 3. When, from previously insufficient nourishment or from disease, the muscular tissue of the body has been diminished, and subsequently profuse nourishment makes up this loss. It is a fundamental error to look for the primary cause of this variety of muscle accumulation in food ; it is an expres- sion of the regenerative energy of the cells. This is a mighty power. It shows itself, as investigations in the metabolism of convalescence have demonstrated, even when there is no question of forced feeding, and indeed when the calory supply is so slight that fat must certainly be lost in the body, and even a healthy person would lose body albumin. 58 OVER-NUTRITION AND UNDER-NUTRITION Of course, under circumstances otherwise favorable for the accumulation of albumin, muscular development takes place more certainly and more rap- idly with very profuse nourishment than with scant food. Usually, however, in adults otherwise healthy — provided we consider long periods of time and not brief intervals — muscle-increase is independent of an excess of food. Muscle growth is dependent on food supply only because the body is better supplied by over-nutrition with reserve products (glycogen, fat, reserve albu- min), and because better food and the somatic and psychical stimulation resulting from it produce greater capacity for work. To this greater capacity of the muscles and secreting glands for work and the stimulus for blood for- mation which arises thereby, the body owes its power of accumulating proto- plasm as well as fat, and — what is more important — of permanently retain- ing it. From this point of view, it appears that under special conditions (after wasting disease or after prolonged periods of hunger and under-nutrition) we may hope by over-alimentation to promote the formation of new protoplasm, and particularly of muscular substance. The natural regenerative endeavor of the organism will aid us. If, however, we are treating persons who, although weak, are sufficiently well nourished, the chances for increased mus- cular development are much more uncertain. In such debilitated individuals, especially in convalescents, the accumula- tion of flesh will be greatly favored, if from the onset, or as soon as the strength at all permits it, forced feeding is combined with muscular exercise. This, however, contradicts a widely prevalent custom; for, in the original methods of Playfair-Mitchell, most patients who were to undergo forced feeding were advised either to go to bed or to keep as quiet as possible. In certain cases, for example, in very irritable nervous persons, this may be fully justified. Generally, however, it appears to me after years of experience that early and sufficient activity of the muscles is much more beneficial when we desire to nourish our patient. The increase in weight is not less than in rest cures, and it is gratifying to note that the patients gain in muscular strength and activity at the same time that they increase in weight and size. There is very little danger that, in consequence of muscular exercise, much of the fat which has been acquired with difficulty may be again lost, since the in- crease of appetite induced by muscular exercise easily makes good the material used up. In view of what has been said it is obvious that in forced feeding, as well as in carefully and wisely conducted antifat cures (for obesity), the increase and strengthening of the muscles is almost independent of the loss or accumu- lation of fat. Insufficient nourishment in obesity favors the loss of muscle; superfluous nourishment both in normal nutrition and when it is below par favors the accumulation of muscle. But muscle-loss and muscle-increase are not in immediate dependence upon, or in exact proportion to, the quantity of food. An individual factor always intervenes ; an elective property of the organism rather than the bulk of food produces muscle-accumulation. The conditions are quite different in losses and accumulations of fat. Here the law may be definitely stated. When the supply of nourishment is OCCURRENCE AND CONSEQUENCES OF UNDER-NUTRITION 59 less than the requirement for maintenance;, fat is always lost; when it is greater than the requirement for maintenance fat is always accumulated. In the former case we speak of under -nutrition, in the latter case of over- nutrition. Although I shall be repeating what is known to most readers, it is neces- sary to devote a few lines to the definitions of food necessary for maintenance, of over-nutrition, and of under-nutrition. In proportion to the requirement of the cells, according to the amount of work required of them externally and internally in heat production, etc., the body arranges the use of material for combustion. When the combustion value of the food is equal to the demand, the equilibrium of metabolism in the body is preserved. The amount of food which is necessary for this we call "food necessary for maintenance." Most normal persons, if left to them- selves and following their own inclinations, usually take neither more nor less food than is necessary for maintenance; variations in this balance of nutrition may occur, "but the deficiency of one day is made up the next. Con- sequently it is the rule that normal adults remain for years and decades at about the same weight. . The proportion of food which is necessary for the equilibrium of metabolism, calculated per day and for each kilo of the body- weight, must have a combustion value of from thirty to thirty-five calories in complete rest (in bed), thirty-five to forty calories with light exercise, forty to forty-five calories with moderate exercise, and forty-five to sixty calories in exhausting muscular labor. For children these figures are to be raised about one-third, for the aged they are to be lowered about one-fourth. There are no decided differences between males and females. These figures relate to a " moderate condition of nutrition " ; in the obese they are from twenty to twenty-five per cent, lower, in very thin persons they are just as much higher, for while fat in- creases the body-weight it takes no part in metabolism. This ratio will enable us to calculate the amount of food necessary in the individual case with suffi- cient exactness for practical purposes. 3. OCCURRENCE AND CONSEQUENCES OF UNDER-NUTRITION As soon as the supply of food (i. e., its combustion value) falls below that required for maintenance we have a state of Jiyponutrition. The under-nour- ished body does not accommodate its combustion processes to a lower scale — except perhaps in the most extreme marasmus and in the death agony. When the supply is less than the requirement, it lives upon its own body substance. In the obese, as we have seen, this process may be limited to the adipose tissue while the albumin, that is, the muscle, is preserved. In normal and mal-nutrition, however, apart from exceptional cases (in convalescence after acute diseases, or after periods of hunger), the supply of albumin in the body may also be slowly consumed, and the person not only loses fat but becomes weaker in muscle. We rarely resort to systematic under-nutrition except in the treatment of obesity. Whether or not treatment for obesity is indicated does not depend wholly upon the degree of corpulence, but also upon many 60 OVER-NUTRITION AND UNDER-NTJTRTTION other conditions, particularly upon the healthy state of certain organs, for ex- ample the heart and the kidneys. To this we shall refer later. But very often, without our interference and against our will, our food produces the character- istics of hyponutrition. This occurs in many diseases. We are unable to main- tain the balance of nutrition either because patients refuse to take a sufficient supply, or because diseases of certain organs (for example, the stomach) necessitate a limitation. In acute diseases which run a rapid course the dan- ger is not great, for what has been lost is rapidly regained in convalescence. But in chronic diseases the body is often more weakened and damaged by con- tinued under-nutrition than by the disease itself. It then becomes one of the most important duties of the physician to increase the amount of food at least to the point of maintenance, and, if possible, to make up what has been lost by forced feeding. He will then often have the pleasure of noting that not only does the state of nutrition improve, but that this improvement acts favorably in the cure of the disease. In some maladies, for instance, in not too far advanced tuberculosis of the lungs, this is the rule. At least as frequently as in actual disease we meet persons who are really not ill but under-nourished. This results from caprices of appetite, from unfounded fear of injury from this or that food (for example, fat substances), from disturbances of appetite which are slight or which are taken too seri- ously, from poverty, etc. Thus they have become accustomed to a too slight ingestion of nourishment. Sometimes this is habitual from youth, and such persons if left to themselves never attain the acme of nutrition (muscular and fatty tissue) of which they seem capable, judging from their constitution and build. Adipose tissue is scant, and the muscles, no matter how suscep- tible of development, and no matter what efforts are made to strengthen them by exercise, continue weak, for everything that is attempted is frustrated by the oxidation-processes of the body. Others first manifest the symptoms of chronic under-nutrition after they have reached adult life. These are mostly persons in whom there is a neuro- pathic taint, and in whom the various forms of nervous dyspepsia develop. Still others have become neurasthenic and hysterical only in the struggle for existence against adverse circumstances. Organic causes which would pre- vent a sufficient ingestion of food are not present, but manifold nervous dis- turbances interrupt the distinctive connection between actual food-require- ments (tissue hunger) and appetite (gastric hunger). Gradual loss of weight, disappearance of adipose and muscular tissues, lessening of the bodily and mental powers, are the inevitable consequences. These patients, to the detri- ment of their health, often seek a cure by unsuitable means, by gymnastic exercises and sports, by mountain climbing, by exhausting cold-water cures (frequently in so-called nature-cure institutions), where they hope to build up their nervous system. This acts at first like a whip, apparently increasing and stimulating their activities. But the oats are lacking, and in a short time tbere is a relapse to the former condition. The treatment is all the more harmful because the food, during the time spent in these exhausting cures, is weakening rather than strengthening. The patients and their "Natural- Healer " proceed from the view that a too p/ofuse animal diet has disordered OCCURRENCE AND CONSEQUENCES OF OVER-NUTRITION 61 the nervous system. Meat and eggs are withdrawn and the patients are put upon a vegetable diet. To this no special objection can be raised, provided it is carefully chosen; but too frequently it is lacking in nourishment. This has been so abundantly proven as to need no further consideration at this point. 4. OCCURRENCE AND CONSEQUENCES OF OVER-NUTRITION If the food (i. e., its combustion value) exceeds what is necessary for maintenance we have the condition of hypcrnutrition. In over-nutrition the organism does not increase its processes of combustion, or, at least, does so to a very slight extent. Perhaps the increase of oxidation which arises from over-nutrition has been for a time underestimated, as the latest investiga- tions of Fr. Miiller appear to prove. Theoretically this increase is interest- ing, but it is too slight to be of practical importance. The increase of oxidation is not due to a stimulation of the cells to a greater katabolic activity, in other words, to a greater rapidity of metabolism, but only to the greater labor which is put forth by the mechanism of mastication, the stomach and intestines, the digestive glands, the organs of circulation and respiration, etc., in order to work up and utilize the greater mass of food. After deducting the slight amounts spent upon the increased labor of diges- tion, etc. (about 7 per cent, to 20 per cent, of the energy supplied by the food), a large residue from the superfluous food remains, which accumulates as reserve material, and serves to increase the body mass. We call this " food surplus " (— the difference between food ingested and food used up in metab- olism). Aside from slight differences it is of no importance to the processes of metabolism whether the surplus of food occurs from excess of albuminates or of N-free food, or whether the increased supply comes from one source only (the albumin or the fat or the carbohydrates). A surplus of carbohydrate nourishment favors almost exclusively the production of adipose tissue, pro- vided special circumstances do not promote the increase of protoplasm (see above). In an especial case (B. Krug's experiment upon himself carried out under my direction) the following calculations were made: Dr. Krug (perfectly well and in a moderately good state of nutrition), after a period in which he had been abundantly nourished, took for fifteen days in addition to his ordinary food a daily total of 1,710 calories, consisting of fat and carbohvdrates. This sum represented " surplus nourishment " ; for the fifteen days it amounted to 25,650 calories. Of these 23,051 calories were utilized by the body. 1,720 calories = 7.46 per cent, albumin accumulation, and 21,331 calories = 92.54 per cent, accumulation of fat. Whether the production of albumin was equivalent to accumulation of flesh could not be decided. It follows from the preceding statements that after the ingestion of a surplus amount of food only an accumulation of fat can certainly be counted 62 OVER-NUTRITION AND UNDER-NUTRITION upon. It is quite uncertain whether an accumulation of muscle will take place; with an equal amount of surplus nourishment the gain in muscle varies from case to case. It is sometimes lacking, in other cases it occurs to a greater or less extent. But it may be prophesied with mathematical cer- tainty that in over-nutrition fat will accumulate. How much is dependent upon the amount of food, and how much upon the amount of work performed by the body? A disproportion between the supply of food and the assimila- tion of food, to which the accumulation of fat (and ultimately obesity) owes its origin, can be brought about : 1. By an increase of the food above an average normal consumption; 2. By diminution of exertion (muscle laziness) with an average normal amount of food ; 3. By a combination of superfluous food and diminished exertion. We frequently meet with cases of over-nutrition, but we are not so often called upon professionally to combat this condition as we are to treat under- nutrition. Occasionally, however, we are called to deal either with obesity or with persons who, by continuing their present mode of life, are in danger of be- coming too fat. Every corpulent person has behind him a period of over-nutri- tion ; not, perhaps, because he has eaten more than others who have not become fat, but he has eaten more than his individual constitution and bodily func- tions enabled him to utilize. It is immaterial whether this superfluous inges- tion of food has arisen in consequence of a preference for albumin, for fat, for carbohydrates, or for alcohol; we meet with obesity among decided meat- and-fat eaters as well as among those who prefer starchy foods, sweets, and beer. We observe it among those who perform hard manual labor, but who more than compensate for their great metabolism and output of energy by a profuse intake of food ; we observe it also in those who, although they eat little, consume an amount of food out of proportion to their slight physical activity, slight metabolism and slight output of strength. To elaborate this in indi- vidual instances would be to consider the etiology and pathogenesis of obesity, which is not the purpose of this article (the reader is referred to my mono- graph on obesity in Nothnagel's Handbuch der speciellen Pathologie und Therapie). Whether in the development of corpulence there is an increase of the mus- cles depends, as we observe daily, upon external conditions. The rule holds good that only those obese persons who utilize and, in spite of their corpu- lence, exercise their muscles have strong and firm muscles. In such people we see the picture of the so-called " plethoric obesity." Those who live much indoors have flabby and weak muscles, often so weak that serious consequences may be the result. Distressing yet convincing proofs are thus furnished to show how loose is the connection between over-nutrition and increase of muscle. 5. INDICATIONS FOR HYPERNUTRITION AND HYPONTJTRITION Having explained the changes of metabolism which occur in the organ- ism in under-nutrition and over-nutrition, we must briefly discuss the indi- cations for forced feeding and for antifat cures. INDICATIONS FOR HYPERNUTRITION AND HYPONUTRITION 63 A. OVER-NUTRITION Group 1. In chronic wasting diseases. — Considered historically, over- nutrition in pulmonary tuberculosis, or rather in tuberculosis of any type, is to be placed in the front rank. Even the old custom of administering cod liver oil in " scrofula " and tuberculosis belongs to this category. We have gradually been forced to acknowledge that its action is not specific but due to the fat which it contains, that is, to its high nutritive value. Brehmer was the first, and Dettweiler the next, systematically to employ over-nutrition in tuberculosis. The success of this method is surprising, as any one can see in his daily experience. By over-nutrition, as now carried out in all institutions for the cure of pulmonary tuberculosis, in hospitals, in the homes of the patients, or wherever it may be attempted, we do not attain a cure for tuber- culosis, but the favorable results which have been attained up to now in treat- ing tuberculosis are inseparably associated with over-nutrition. Here, better than anywhere else, it" may be noted how beneficially the improvement in the general nutrition acts upon the resistance of the tissues. I have already alluded to this elsewhere, and, after further experience, I wish to reiterate that the modern treatment of pulmonary tuberculosis by over-nutrition is in danger of accomplishing too much. Pulmonary patients who had formerly been emaciated sometimes after treatment become corpulent; this is not to be regarded as desirable, but as a disadvantage. For obesity always throws in- creased work upon the respiratory and circulatory organs, and in this way makes demands upon the diseased organ which it should be spared. But apart from these extreme cases, over-nutrition in pulmonary tuberculosis may be designated as one of the most valuable agents in the realm of dietetic therapy. Over-nutrition as a prophylactic measure produces even more favorable results than in tuberculosis that has already developed. It is especially valu- able in children and adolescents who have suffered from a previous tubercu- lous disease of the glands, joints and bones — and hence are liable to a later " pulmonary tuberculosis " — as well as in those who without such preceding affections are likely to become tuberculous on account of general weakness and hereditary predisposition. The majority of consumptives attacked in the second or third decades of life have been, as Brehmer once correctly re- marked, small eaters from youth. Under circumstances such as these the early resort to forced feeding, combined with exercises to harden the mus- cles and properly develop the body, is one of the most beneficent and grateful tasks of the family physician, all the more grateful if this method be insti- tuted early in life when the body is still in the stage of growth and the accumulation of muscular tissue takes place more readily than in later, years. Cures based on forced feeding practically play a less important role in all other chronic wasting diseases than in tuberculosis. Most important, per- haps, is over-nutrition in syphilis, a disease which frequently, and especially in its early stages, markedly influences nutrition, and in its subsequent course (in the so-called tertiary forms) almost invariably produces extensive tissue- disintegration. The old custom, originating centuries ago, and not yet rooted out, was to place these patients upon a scant, meager diet, and to weaken them 64 OVER-NUTRITION AND UNDER-NUTRITION by laxative drinks. In contrast to these old usages, an excessive or forced administration of nourishment has shown itself to be much more efficacious. Many protracted cases of tertiary syphilis can be cured only when the body has been thus strengthened by over-nutrition. Diabetes mellitus may also be counted among the chronic wasting diseases, naturally within certain limitations, as there are numerous cases of diabetes mellitus in which, vice versa, definite relations to obesity exist. Where this is not the case (as in the severe forms of diabetes, particularly that occurring in youth), emaciation is combined with the disease, partly as the result of losses in sugar, and partly as the result of peculiarities of the diet. To inter- fere, to replace by over-nutrition not only what has been lost and if possible to raise the patient's state of nutrition above the average, is important, for experience teaches that a good state of nutrition will often avert many of the dangers of the disease. Diabetes insipidus must also be mentioned. Unfortunately, we know little regarding the pathogenesis and the minute disturbances of metabolism which take place in this disease. The most conspicuous symptom in all severe cases is the decided emaciation and loss of strength, which cannot be reason- ably explained from the loss of water by the body. If we leave out of con- sideration the gradual restriction of the intake of water, and a few purely symptomatic drug indications, the especial and systematic improvement of the nutrition by a long-continued, forced diet is the only measure which promises success. In view of the rarity of these cases, I shall briefly report a case under treatment by me three years ago for diabetes insipidus. The disease occurred in a man aged fifty, and was credibly reported to have fol- lowed a severe shock sustained in a railway accident; it had existed for about fifteen months. The patient's previously normal state of nutrition had suf- fered acutely during this time, the loss in weight amounting to more than 25 kilograms. The daily amount of urine varied between 9 and 13 liters. In this case, by a plentiful addition of cream and butter to his diet (between 250 and 300 grams of milk fat daily), weight was increased 20 kilograms within four months. After the first six weeks, the urine had already diminished to between 5 and 6 liters, and, after two months more, to 3 to 4 liters. The once markedly debilitated patient had, in the meantime, become strong again and fully capable of working. He continued strong until attacked the following winter by pneumonia to which he succumbed. According to the statements of his relatives there had been no increase in the amount of urine. Finally, among the chronic wasting diseases, we must mention exoph- thalmic goiter (Basedow's disease). Probably from a thyreogenous auto- intoxication (Mobius, Fr. Miiller, A. Magnus-Levy) an increase of the proc- ess of metabolism occurs, i. e., an increase both in the assimilation of albumin and in the combustion of fat. In consequence of this, if the patients take only the amount of food which is the average for normal persons, this proves insufficient, and they therefore consume their own body substance (protoplasm and fat). Only by over-nutrition can we safeguard them from this. By over- nutrition it is possible at least to conserve the fat, or we may even hope to increase it. According to the researches of Fr. Miiller, we cannot count on INDICATIONS FOR HYPERNUTRITION AND HYPONUTRITION 65 maintaining and developing the muscular tissue even by forced feeding so long as the disease progresses. Nevertheless, forced feeding carried on per- sistently is remarkably successful; the patients accumulate valuable reserve material, and experience shows that they are much better than when exposed to progressive emaciation by dietetic negligence. But though it is necessary to promote the nutrition of the patient, it is not to be supposed that a very energetic and rapid forced feeding is here indicated. Great care is neces- sary; for patients who present severe forms of Graves' disease, and whose nutritive condition has been correspondingly damaged, suffer also from car- diac weakness. To maintain their balance of nutrition, they require upon the average from 15 to 20 per cent, more food than a person in normal health of the same weight and build, and of course if we are to attain an increase in weight, still more food is necessary. But according to my experience, the cardiac difficulties frequently increase if we proceed too rapidly with forced feeding. Indeed the cardiac weakness which results may be dangerous. Last year an able author reported a case in which, in a short time, an increase of weight of 22 pounds was brought about by over-nutrition. In spite of this desirable result, collapse occurred in which the patient succumbed. I believe it cannot be doubted that this too rapid over-nutrition was responsible for the unfavorable outcome. I have, myself, not seen such serious results from over-nutrition in Basedow's disease, but I have observed exacerbations which made me fear collapse. Hence, there is need of proceeding slowly in all severe cases; we must be satisfied if at first only the rapid loss of weight is stopped. When this has been accomplished, and the weight maintained for several weeks, forced feeding should be again resorted to, but an increase of about a pound a week should not be exceeded. Group 2. In functional nervous diseases. — We are indebted to S. Weir Mitchell for having pointed out the deleterious effects in neurasthenic and hys- terical persons of a poor state of nutrition — whether this dated from the onset or developed in the course of the disease. He still further demonstrated, by innumerable and convincing examples, that with systematic over-nutrition (forced feeding) not only the state of the nutrition but also the activity of the nervous system could be restored. Nearly twenty years have passed since the publication of these views by S. Weir Mitchell and since that time forced feeding in the treatment of neuras- thenia and hysteria has become the common method of nearly all physicians. The results thus attained are the foundation and the corner stone of the reputation which numerous clinics and sanatoria have acquired in the treat- ment of these cases. Retrospectively speaking, this therapeutic accomplish- ment which we owe to S. Weir Mitchell is of the highest significance. The treatment of Weir Mitchell and Playfair, the latter of whom did a great deal to popularize the method, consists of several factors : 1. Isolation of the patient. 2. Eest in bed, lasting according to the circumstances of the case from one to several weeks. 3. Over-nutrition; beginning with small amounts of food, and gradually increasing to high values. 6 QQ OVER-NUTRITION AND UNDER-NUTRITION 4. Massage and faradization of the muscles during the rest in bed ; careful hydrotherapy to stimulate the circulation. For numerous cases, especially those in which excessive irritability of the nervous system is prominent among the clinical symptoms, no more valuable treatment can be outlined to-day than the Weir Mitchell-Playfair plan. But it has been demonstrated that the diversity of the cases necessitates numerous modifications. The other factors associated with hypernutrition (especially isolation, rest in bed, massage, etc.) are frequently not only unnecessary, but actually a hindrance to success. The diet which Weir Mitchell proposed may be modified as occasion requires. Any one conversant with the laws of nutri- tion and with general therapy may with ease select what is suitable for each individual case. My experience leads me to state that I frequently employ only limited isolation, i. e., the removal of the patient from his usual surroundings and activities, but rarely insist on prolonged rest in bed. In my opinion, the latter should be avoided whenever possible, for reasons previously men- tioned. The indications for forced feeding, according to the experiences of the last twenty years, are present in functional neuroses combined with mal- nutrition, whether the poor state of nutrition is to be looked upon as the cause of the neurosis, or whether the neurosis by its influence on the intake of nourishment and digestive processes produces secondarily a damage to the nutrition of the body. In the former case, we can well hope to remove all of the pathologic phenomena together with their cause. In the latter case we are at least combating a symptom from which the disease constantly receives new stimulus. Here also, as in the case of exophthalmic goiter — although not for the same reasons — I must caution against immoderation. Many neurasthenics are easily fattened, and, after six to seven weeks, may show a gain of 30 or 40 pounds in weight. But during such rapid augmentation of body-weight new disturbances not infrequently appear which, in themselves unimportant, are over-estimated and exaggerated by the suspicious neurasthenic and hysterical patient. -For this reason, I limit the acquisition of weight desired to about 20 pounds, which, according to the individual case, may take from four to five weeks. Then a halt must be called, and after an interval, forced feeding, if necessary, may be begun again. Group 3. In all individuals with a poor condition of nutrition it is im- portant to determine whether this faulty nutrition has been the hindrance to the full development of their power, to the natural building up of their bodies (in children and young persons), to recuperation after excessive bodily and mental labor, or to convalescence after diseases. The guide for the physi- cian must be not only the present, but the thought of what the future may bring. The various special indications cannot be individually described with- out entering into the wide realm of general pathology. I should like to repeat (see above) that for every person there is a different optimum of nutrition. Only experience will enable the physician to estimate and recog- nize this optimum in individual cases. He who trains himself from this point INDICATIONS FOR HYPERNUTRITION AND HYPONUTRITION 67 of view possesses weapons against disease (existing and threatening) than which there are none more effective. Of course in all of these cases, even more than in G-roups 1 and 2, the development of the muscles must be considered, for by the accumulation of fat alone nothing is gained. Therefore, systematic muscular exercise must be added to forced feeding. The form which this exercise takes is of minor importance. I prefer exercise in the open air (walking, mountain climbing, gymnastic exercises, games, bicycling, etc.), provided we are certain of not overdoing, to massage or indoor gymnastics. Gymnastics with apparatus deserve consideration only when exercise in the open air is contra-indicated for special reasons, or when development of special muscle groups is desirable. As a rule, it is wise to regulate forced feeding and muscular exercise in this third group of cases, so that only a gradual increase of weight results. "We are then much more certain of a permanent and substantial gain. In cases belonging to the first and second group, increases in weight of about 12 to 15 pounds within four weeks — with certain exceptions (see above): — are worth striving for, and sometimes, as in neurasthenics, particularly rapid results are important as suggestive curative agents. But in cases of the third group it is better to have this increase in weight distributed over months instead of weeks. From this it may be further concluded that these persons, who need not so much an instant recovery from a morbid condition as a general strengthening of the body, should not be treated in hospitals or sanatoriums, or only temporarily. Few can bear removal from the ordinary routine of daily life for so long a time, for the air of the sanatorium is rich in psychical con- tagion. The treatment, and especially the regulations for forced feeding and slow increase of the body-weight, must therefore be planned according to the patient's circumstances, occupation, habits, and position in life. With strict regulations we are less likely to reach our goal than if the constraint of an institution is abolished. Of course a complete change from the previous mode of life which led to the unsatisfactory condition is the first step. Then we can easily learn whether a simple increase of food without any special regula- tion of its quality, quantity or distribution is sufficient, or whether any par- ticular food must be added to the diet to make the success certain, and, lastly, whether this addition should come from the albumin group, from fats or from carbohydrates. B. UNDER-NUTRITION Antifat cures are undertaken almost exclusively in obese persons; rarely, if ever, in persons normally or insufficiently nourished. What rule is to guide the plrysician in the important problem : Is an antifat cure to be begun or not? I desire to refute the opinion so frequently expressed that antifat cures always belong to the so-called " weakening cures." The popular views in regard to this are very exaggerated. I maintain positively that an anti- fat cure begun for proper reasons — and provided that the choice of the method, the rapidity with which it is carried out, and the loss of weight are adjusted to the individual condition — never deserves the name of a " weaken- ing cure/' but may always be conducted without injury to the patient, and gg OVER-NUTRITION AND UNDER-NUTRITION will always be beneficial to the whole body. It will be noted that this favorable opinion is based upon a number of provisos which, although apparently sim- ple, require careful consideration and good judgment. I shall mention only the most important of the indications as these have been elsewhere extensively discussed.1 1. Simple obesity in otherwise healthy persons. — (a) Extreme obesity is almost always an indication for an antifat cure. The dangers which may result from a further gain of fat are great, and we must endeavor to prevent them. Certain modifications are required by the age of the patient. In chil- dren and in adolescents up to about the twentieth year, we should be content with preventing an extreme development of obesity, and only from time to time, during short periods of from four to five weeks, should an effort be made to reduce the superfluous fat (intermittent antifat cures). In the aged antifat cures are prohibited, as almost invariably there is a rapid loss of strength. (b) Moderate obesity (body-weight about 15 to 25 kilograms above the average for the age, sex and height) is most frequent and at the same time best suited for treatment. In most cases it can be let alone without any great danger to health, but it cannot be denied that corpulence brings many evils in its train; for if any acute disease occurs (infections, diseases of the heart, of the lungs, of the kidneys, the joints, etc.) or after unusual exertion (such as over-strain of the heart) the obesity may become dangerous. Here, also, the rule holds that in the aged this treatment must not be attempted, and in childhood and in youth only in slow tempo and with the greatest caution. (c) Slight obesity (body-weight upon the average 5 to 15 kilograms above the normal) in healthy persons never necessitates an antifat cure, but, if the corpulence steadily increases, measures may be taken to check its further development. Nevertheless, very often, particularly in women, the aid of a physician is sought because of a desire to reduce weight and to attain slen- derness. In many cases the physician will all the more willingly comply with the wishes of his patients as he may thus gain control of their entire mode of life, in which usually much should be amended. Although in the effort to reduce early obesity, and in the timely regulation of detrimental habits, vanity rather than bodily ill is sometimes the motive power, we as physicians should not criticise this. It may amuse us, but it must be wel- comed as a therapeutic opportunity. Care is always necessary. Many a woman, as the result of a too rapid and too far reaching antifat cure, acquires in exchange for her moderate corpulence various derangements of the abdominal organs, such as constipation, ruptures, gastrectasis, movable kidney, sometimes also of the uterus; or, after the dis- appearance of fat, the liver and gall-bladder are more exposed to the pressure of the corset, the flow of bile is impeded, and gall-stones result. All these evils are much more frequent in slight corpulence than when it is marked. In the latter the antifat treatment is rarely carried to such an extent that decided pressure changes occur in the abdominal cavity; enough fat always remains to protect the viscera and preserve them from injury. i V. Noorden, " Sammlung klinischer Abhandlungen," Heft 1, Berlin, 1900. THE TECHNIC OF OVER-NUTRITION AND UNDER-NUTRITION 69 It may be said in general that slight obesity, does not especially demand slow and careful reduction of weight, although, to prevent excessive corpulence and for many other reasons, this is often very desirable. 2. Indications for antifat cures when obesity is complicated by other diseases. — Diseases of various kinds, from slight functional disturbances of vital organs to severe anatomical changes, may influence the physician in his decision of the antifat question. More frequently than otherwise, it is the complicating conditions that we meet which lead us to combat obesity. Such complications may lead us to undertake an antifat cure when if we found a normal condition of all the organs there would be no indication for treatment. Among the disturbances whose course and prognosis are influenced by obesity, and which for this reason may necessitate the reduction of moderate and even slight corpulence are the following : Disturbances of the organs of circulation, such as valvular diseases, myo- carditis, myocardiac degeneration of the heart, fatty heart, or better, cardiac weakness in obesity, arteriosclerosis, aortic aneurism, etc. Eenal diseases, particularly contracted kidney, on account of the implica- tion of the heart and the arteries which is always associated with it. Certain chronic diseases of the respiratory organs, such as chronic bron- chitis, pulmonary emphysema, extensive bronchiectases, bronchial asthma, adhesive pleurisy; kyphoscoliosis also may be here included. Chronic articular rheumatism. Gout in all severe forms. Other diseases characterized by loss or difficulty of motion or locomotion, for example, hemiplegias, chronic diseases of the spinal cord, some cases of peripheral paralysis, many surgical affections of the bones and joints, large varices, chronic ulcer formation upon the leg, deformities of the lower extremities, etc. Diseases of the nervous system. That neurasthenics and hysterical per- sons in general are in better condition when their fat is somewhat profusely developed has already been mentioned; therefore these are the patients who frequently require forced feeding (see above). But as these neuroses do not always disappear under forced feeding, neither does corpulence always pre- vent their appearance. Where the neurosis is combined with corpulence, care- ful antifat treatment and the re-establishment of the normal nutritive con- dition may be indicated, and may be as potent in relieving the neurosis as forced feeding is in thin, poorly nourished persons. 6. REMARKS REGARDING THE TECHNIC OF OVER-NUTRITION AND UNDER-NUTRITION It is an old axiom which constantly demonstrates itself anew that dietetic cures originating with this or that author, and advised for this or that disease, degenerate in practice into mere formulae. The " cure," the method, is forced upon the patient, instead of the method being adjusted to the patient and its main principles applied to the unending variety of cases. Routine precludes 70 OVER-NUTRITION AND UNDER-NUTRITION success in this field, and frequently does more harm than good. There is no single "best method" of over-nutrition, and no single best method for the removal of fat, but there is for each individual case one and only one best method. It must be constructed by the physician upon the scientific laws of nutrition, whether a celebrated name is attached to the method or not. Hard and fast dietetic rules are most widely developed in the realm of antif at cures. There are obesity cures according to Harvey-Banting, Oertel, Ebstein, Hirsch- feld, Schweninger, Kisch, Pastor Kneipp, etc. I do not intend either in over-nutrition or in under-nutrition to dwell upon the individualities of the methods, but I shall emphasize the main points. A. THE TECHNIC OF FORCED FEEDING Over-nutrition presupposes that the ingestion of food is to be greater than the requirement. How great the surplus of food is to be depends upon the rapidity with which the process is to be carried out. Apart from particu- lar indications (for example, in Graves' disease, see above) the capacity of the digestive organs should decide this question. How the requirements of the patient can be approximately determined from the body-weight has been related. According to the calculations which I made in a large number of cases treated by forced feeding I obtained the following results (I must admit in this connection that the figures had not been theoretically determined prior to beginning forced feeding, but were gained empirically during the treat- ment) : With a daily excess of food of about 500 to 800 calories, we get an increase of weight of from 600 to 1,000 grams in a week; with a daily in- crease in food of 800 to 1,200 calories, weight increases from 800 to 1,200 grams per week; with a daily excess of food of from 1,200 to 1,800 calories, weight increases from 1,200 to 2,000 grams per week. Quite properly the question arises, not only how many calories should the food contain, but also how much albumin and N-free substances are included in it. The albumin bodies theoretically considered have no great value in in- creasing weight. The average albumin content of ordinary diet (100 to 110 grams) may be somewhat increased in forced feeding, but hardly more than 50 grams. Still larger quantities of albumin can be utilized only in excep- tional cases as the bulk of the food becomes too great, and also because all albuminous foods produce satiety to a marked extent. Even the preparation of purified albumin products (casein, nutrose, tropon, plasmon, rooorat, aleu- ronat, ergon, etc.) has not changed this. From 20 to 30 grams during the day are useful ; larger quantities, if their use be prolonged, as a rule spoil the appetite, whether we administer them in milk, soups, sauces, pap, in the form of pastry or otherwise. No matter to what form we add the 50 grams of albu- min, which I have designated as the most that can be used, it is certain that for increase of weight little is gained by this; it only furnishes about 205 calories. I hold that in general, allowing for exceptions, the daily administration of from 120 to 130 grams of albumin is quite sufficient. My best results were arrived at by keeping within these limits. Nevertheless, it must be THE TECHNIC OF OVER-NUTRITION AND UNDER-NUTRITION 71 emphasized that occasionally the mere increase of the amount of albumin is beneficial; for example, in preparation for true forced feeding, or, if there is repugnance to great quantities of N-free food, during a " vacation period " of from eight to fourteen days which the patient may have to take in his forced feeding treatment. Under these conditions temporary forcing of the albumin- intake at the expense of the N-free substances renders the body more receptive to the later action of the true forced feeding. For these purposes the purified albumin preparations, such as plasmon, etc., are more suitable than meat. From 50 to 60 grams of plasmon may be given with advantage during the day. There is no difficulty in administering this amount, as, in this period, we no longer increase the N-free substance. During longer periods, however, little can be expected from such an exclusive increase of the albuminates. Among the substances free from nitrogen we may choose between the administration of fats or of carbohydrates, or may administer both in almost equal proportions. In principle it is immaterial, as fat and carbohydrates compensate for one another according to the law of isodynamics. One hun- dred grams of fat are equal to 224 grams of carbohydrates, and vice versa. As a rule the marked increase of carbohydrates is preferable, provided always that they are better tolerated than fats. In some patients this is unquestion- ably true, but in the majority certainly not. If we desire to add about 1,200 calories of N-free substances, we require either 129 grams of fat or 300 grams of carbohydrates ; many other mixtures may be used ; for example, 200 grams of carbohydrates and 40 grams of fat, or 100 grams of carbohydrates and 85 grams of fat. For more than ten years I have preferred to increase the administration of fat, for I have found that a larger amount of carbohydrates — 300 to 400 grams a day — is not well borne for any length of time. When, under the constraint of treatment in an institution, the patient is forced to take the large amounts of food which are necessary if we use the carbohydrates alone, we see only too frequently, after the restraint is removed, a period of anorexia during which much of the body-weight gained with so much difficulty is lost. Accordingly, the composition of the nourishment during forced feeding should be about as follows : 120 to 130 grams of albumin (490 to 530 calories). 300 to 350 grams of carbohydrate (1,230 to 1,435 calories). This nourishment (720 to 1,965 calories) forms the basis to which as much fat may be added as is necessary to make the proposed calory total : i.e., from 200 to 300 grams of fat (1,860 to 2,730 calories) or even more. Frequently a portion of the required calory excess may be given in the form of alcohol, whereby certain amounts of fat are protected from oxidation and preserved for the organism (9.3 grams of alcohol protect about 7 grams of fat from oxidation). The amount of water to be added, provided special indications do not necessitate exact regulation, may be according to the desire of the patient. As a rule, if much carbohydrate is given the amount is greater than if much fat is administered. 72 OVER-NUTRITION AND UNDER-NUTRITION B. THE TECHNIC OF ANTIFAT CURES In antifat cures the intake of nourishment must be smaller than the demand, and in the obese this cannot be estimated very readily. The practi- cal need will be satisfied if for an obese person the average normal require- ment, amounting to about 2,500 calories, is given and is combined with slight or moderate bodily exertion. On this basis I have proposed the following scale in antifat cures : * First grade of antifat diet. — To this belong antifat cures in which the diet may be reduced to about four-fifths of the normal requirement, i. e., to about 2,000 calories. Success follows this only when we are treating robust persons who are able to take sufficient bodily exercise. The action is usually slow ; we must not count in the beginning upon losing more than from three to four pounds, and later two to three pounds, of weight per month. Second grade of antifat diet. — In this category the antifat cures belong in which the diet is reduced to three-fifths of the usual requirement, there- fore, to about 1,400 to 1,500 calories. This diet may very readily be adapted to the mode of life of most patients, so that they can follow their occupations without hindrance. The rapidity of cure depends upon the amount of physical exercise they can take. If exercise is difficult or impossible (as in many women, in very lazy persons, in certain diseases, particularly in paralysis and with threatening signs of cardiac weakness), the action of diet alone is quite slow (about two to three pounds a month). In vigorous persons who, besides pursuing their daily occupations, can devote an hour to an hour and a half daily to mountain climbing, bicycling, rowing, exercise in the gymnasium, etc., at first losses in weight of four to six pounds, later of two to four pounds, a month are the result. For a time, as for instance during a vacation in the mountains, these losses may without excessive exertion be increased to 11 pounds a month or more. Third grade of antifat diet. — To this belong antifat cures in which the diet is less than three-fifths, or even only two-fifths of the usual requirement, i. e., about 1,000 to 1,400 calories. In this class belong the well-known diet- aries calculated to produce decided and rapid action, those of Banting-Harvey, Oertel, Ebstein, and others, as is shown by the following tables : Diet Scheme according to Albumin. Carbo- hydrates. Fat. 172 81 8 170 120 45 156 75 25 102 47 85 139 67 65 100 50 41 160 80 11 200 100 12 155 112 28 Calories. Maximum. Minimum . Banting Oertel Ebstein Hirschfeld J Maximum j Minimum Kisch | Plethoric obesity. { Anemic obesity . . v. Noorden . 1,100 1,600 1,180 1,300 1,400 1,000 1,086 1,116 1,366 i v. Noorden, " Die Fettsucht " in Nothnagel's " Handbuch der speciellen Pathologie und Therapie," Wien, 1900, p. 110. THE TECHNIC OF OVER-NUTRITION AND UNDER-NUTRITION 73 A diminution of food to about two-fifths of the usual requirement is looked upon as the utmost that may be wisely attempted in the obese patient. The amount and rapidity of the loss of weight depend in the main on the accompanying conditions. If the patient is inactive, the loss in weight amounts to from 6^ to 13 pounds in a month. The greater reductions are noted in the medium, the slighter decreases in the most marked grades of obesity. If auxiliary measures, such as systematic muscular exercise, hydro- therapeutic agents, mineral spring cures, etc., are utilized, the loss in weight may readily be increased to 22 to 33 pounds in a month. The following table showing the success which Dapper attained in his sanatorium at Kissingen, in which the diet scheme was based upon that pro- posed by me, is instructive : Number. Men. Women. Weight at the onset in kilograms. Duration of the treatment in weeks. Loss of weight during the time in kilograms. 1 M. W. M. M. M. W. M. M. W. M. W. M. M. W. M. W. M. M. W. M. M. W. W. M. M. 129.5 104.5 99.5 114.5 104.5 112.0 104.5 111.0 74.0 101.0 97.0 97.0 112.0 107.0 116.0 74.7 96.0 110.0 128. 107.0 106.7 113.5 133.7 114.0 105.8 5 2 4 5 5 3 u 5 5 4 2 4i 4 4 4 8* 4 4i 4 4 5 5 5 U 17.75 2 9.5 3 4.5 4 15.0 5 11.5 6 10.75 7 5.5 8 11. 9 7.5 10 10.0 11 9.5 12 4.5 13 10.0 14 9.0 15 10.75 16 5.0 17 8.0 18 9.5 19 10.5 20 11.5 21 9.5 22 10.5 23 13.0 24 13.5 25 10.0 In what proportions the main constituents of the food, albumin, fat, and carbohydrates, are to be arranged in the antifat diet of milder and medium grades is of minor importance. The restriction of food is not so complete that danger from uniformity of the diet is to be feared. On the other hand, the question as to how we are to act in antifat cures of the third degree has been much discussed. It cannot be considered of vital importance, for prac- tical experience has sufficiently demonstrated that with a high intake of albu- min (Banting, Oertel, Kisch, v. Noorden) as well as with a low intake of albumin (Ebstein, Hirschfeld) satisfactory results have been attained. The investigations in metabolism of the last few years are in accord with this. I regard the question as one of technic rather than of theory or principle. 74 OVER-NUTRITION AND UNDER-NUTRITION Experience appears to prove that in numerous patients the administration of large amounts of meat — equivalent to a high intake of albumin — is much better than small ones. Meat is not only the most important food for most persons, but also the one most desired. Nevertheless, there are many corpulent persons, especially women, who dislike large amounts of meat, and in whom any antifat diet that consists largely of meat will certainly suffer shipwreck. Nothing can be more unwise than, for the sake of theory, to force the admin- istration of albumin up to a certain height ; the requirements of the individual case and nothing else should be considered. But we must insist on not less than the minimum of about 100 grams of albumin. Above this, theoretically, the limit cannot be definite. In practice, about 180 grams of albumin per day should rarely be exceeded. No less warm than the question of the administration of albumin is the discussion, whether, among the substances free from nitrogen, more fat or more carbohydrate should be given. The important point is, that the total of these, according to their calory values, must be diminished so that the total amount of food reaches the degree aimed at in the antifat diet. But both the fat and the carbohydrates must be reduced below the average amount if the administration of nourishment is to be limited to two-fifths or three- fifths of the average requirement (see above). If only the one or the other is forbidden or limited — whether it be the fats or the carbohydrates — sufficient of the other remains in the diet to render the result dubious. Whether in the simultaneous limitation a little more fat (Ebstein, Hirschfeld) or a little more carbohydrate (Banting, Oertel, Kisch, v. Noorden) remains is of subordinate importance. Only the calory total of both, not the chemical constitution — whether fat or carbohydrates — is of significance. I regard it as only a question of technic how far the limitation of one or of the other is to be carried. The wishes, the manner of life, and the peculiarities of the patients, not the principles of treatment, are the determining factors. But from my own experience I should like to emphasize the fact that, as a rule, we attain better results if the fats are limited as much as possible, and somewhat more of carbohydrates are permitted in the food; for the carbohydrates furnish a larger volume, satisfy more readily, and permit a much greater variation in the diet. Alcohol, of course, must not be given with a free hand in antifat cures. As already remarked, it saves fat and in this manner favors its accumulation. Many persons owe their excessive adipose tissue, primarily, to the immoderate use of alcohol. Nevertheless, almost all authors have ascribed to alcohol a subordinate place in antifat cures — and quite properly so, since in practice its stimulating effect cannot always be dispensed with. But where it is possi- ble— particularly in young, robust people — it is wise to exclude alcohol on account of its high calory value. In antifat cures the question of the allowance of water is usually discussed. Among laymen, and also among physicians, the opinion prevails that the intake of fluids favors the accumulation of fat. This is unquestionably incor- rect. How easy and cheap would it be for the farmer if the administration of water favored fattening! On the other hand, the statement that antifat THE TECHNIC OF OVER-NUTRITION AND UNDER-NUTRITION 75 treatment is favored by limiting the amount of water cannot be pronounced unqualifiedly incorrect. We must be quite clear that this fact has no bearing on the relation between the administration of water and decomposition of fat — as taught by Oertel and Schweninger — but that water has its effect by influencing the intake of food. Many persons eat decidedly less when forbid- den to take as much fluid as they have been accustomed to doing. They cer- tainly eat less if the simultaneous ingestion of fluid and solid food is for- bidden. The lessened ingestion of food will then promote the disappearance of body fat. But this result cannot always be counted upon, for among the obese we meet many whose appetite is not influenced in the least by limiting the intake of fluid. They naturally remain fat, or even deposit more fat, no matter how much they are tormented by the thirst cure. I have formulated the present status of the question in the following state- ments : * 1. A limitation of the intake of fluid, according to Oertel and Schwen- inger, has not the slightest influence upon the decrease of body fat or upon the increase of fat metabolism. 2. The primary effect of limitation of fluid upon body-weight depends upon the losses of water from the blood and the tissues. This may be utilized therapeutically : (a) To improve the circulatory conditions in endangered failure of the heart (in cases of valvular disease, disease of the heart muscle, arteriosclero- sis, contracted kidney) ; (b) In patients with a tendency to immoderate production of sweat, and for the purpose of combating hydrorrhea ; (c) In some patients it is a valuable auxiliary remedy through suggestion. 3. The influence of the limitation of water upon fat metabolism, particu- larly in decreasing the amount of fat, is only indirect, and comes into ques- tion only under special conditions, namely: (a) If, by decreasing the fluid intake, the circulatory disturbances pres- ent are to be compensated; there may be then a possibility of favoring the combustion of fat by muscular exercise. (&) When, by decreasing the fluid intake, the appetite of the person for fat-producing foods is diminished. This result may appear in a marked degree, more frequently in slighter degree, or not at all. 4. When no special indications are present the intake of water is not to be limited in the obese, as, without this, we attain the same end and the limitation of water in such cases is only an unnecessary hardship for the patient. That, in antifat cures, under-nutrition is not the only agent to be em- ployed, but that this is to be assisted by systematic muscular exercise, has been reiterated. I shall not enter into individual points, but will only refer to other chapters of this book in which the treatment of obesity has been explic- itly described. Here it is only necessary to indicate the important points that should i Therapie der Gegenwart, April, 1900. 76 OVER-NUTRITION AND UNDER-NUTRITION be remembered in all curative methods in which over-nutrition and under- nutrition come into play. The better the physician understands the general laws of these cures, the more readily will he be able to meet the indications of the individual case. The successes of dietetic therapy may only too readily become matters of routine. Many practitioners adhere too closely to definite diet schemes which have been proposed by this or that celebrated author, or they even hand to the patients a so-called diet list which refers only to the disease, and not to the patient, and which means the annihilation of indi- vidual dietetic therapy. Only the intimate union of practical experience with a comprehensive understanding of fundamental theoretic laws will enable the physician to choose rightly in every case. He must always bear in mind that, although there are many methods of securing over-nutrition and under- nutrition, for the special case there is but one best method. DIET TABLE1 Diet List, Showing the Nutritive Value per Ounce of Various Foodstuffs Expressed in Calories, the Weight Required for a "Portion" of 100 Calories Each, and the Number of Calories of Each Food Principle in an Ordinary Serving of Food. °l Food. Calories Per Ounce. 8 oO Calories Served. 3i 5£ 6 3h 3" If 3V 3* 6 3^ 4f 3i 3i 3 2i 1* 2* 1 1 3 3| 5 4| 4| 1 "2" 3 2 2 2 2 2 2 45. 4| 4| Almonds Apples, Baked Apples, Fresh Apple Juice Apple Sauce Apricots Asparagus (cooked) .... Bananas Bananas, Baked Barley Gruel Barley, Pearl Bean Broth Beans, Baked Beans, Baked (canned) . Beet Greens (cooked) . . . Beets (cooked) Biscuit, Beaten Biscuit, Cream Biscuit, Gluten Biscuit, Rice Blackberries Blanc Mange (Chocolate) Blood Oranges Bouillon, Tomato Bouillon, Vegetable Brazil Nuts Bread Custard Pudding . Bread, Corn Bread, Gluten Bread, Graham Bread, Rye Bread, White Bread, Whole Wheat. . . Broth, Bean Broth (Mock Chicken) . . Broth (Vegetable) Butter (Dairy) 146.4 1.3 7.15 0 .8 0 8.8 1.6 4.73 .7 .87 3.2 12.5 6.6 9.1 .3 47.3 27.5 2.8 .9 2.6 22.86 .5 7.98 4.3 178.1 46.08 12.3 3.7 4.8 1.6 3.7 2.4 3.16 3.3 0 226.6 20.2 28.4 91.3 17 20.65 15.6 2.6 25.7 32.37 10.2 27.24 11.6 33.6 22.9 3.7 8.6 79.2 49.6 56.1 96.6 12.7 16.25 13.5 4.77 7 8.2 191.1 30.3 101.1 17 21.78 16.9 13.9 28.8 40.3 12.4 31.08 19.1 56 37.5 15.4 11.6 134.9 87.5 107.4 106 16.8 42.52 14.9 16.37 18.3 206.1 67.24 122.07 52 58.1 60.8 62.1 63.4 58 11.58 4.7 .5 0 72.8 72.6 76 74.2 76.4 71.7 19.13 11.7 3.3 227.8 .52 3.3 .98 5.8 4.6 6 7.1 3.47 2.5 8.1 3.2 5.2 1.7 2.6 6.5 8.6 .75 1.1 .93 .94 6 2.35 6.7 6.1 5.5 .48 .81 1.3 1.4 1.3 1.3 1.3 1.4 5.2 16 30.3 .4 7 2 2 0 1 4 5 5 8 9 9 22 32 27 8 5 10 24 45 7 4 12 4 17 29 9 23 17 18 20 21 18 24 22 14 13. 1 38 4 7 0 3 0 15 6 11 4 3 16 38 22 30 1 61 64 3 1 8 81 2 36 18 87 133 25 70 9 3 7 5 16 16 0 99 5 94 91 100 71 46 5 89 81 62 88 62 105 76 12 19 104 112 52 92 38 57 69 22 28 4 194 108 112 121 126 125 121 62 20 2.4 0 i 1 1 a 4 1 1 If H i X 4 A4 2 1 1 i 1* 1 3£ 1* 2 H H 1* l* 1 * 1 From the diet list of the Battle Creek Sanitarium, Battle Creek, Michigan, J. H. Kellogg, Medical Superintendent. 76 A DIET TABLE— Continued Calories Per Ounce. Calories Served. ,M Food. "c3 O H d _o . 0 OQ °§~ _d 13 A* °l o a '8 o Ph -^ O ■g o _d '3 0 e3 0 >> rd O ■a O £ m a O 6 Buttermilk 3.5 .8 7.6 12.4 .7 2.01 1 1.3 19.9 1.2 6.6 13.9 10.8 3.6 11.7 .2 2.9 .9 1.8 5.7 2.8 2.5 6.63 16.3 5.9 3.3 19.4 2.6 .5 18.2 0 48.5 .5 .9 0 1.16 1.48 .8 1.3 2.35 2.6 .5 1.2 3.3 8.5 5 10.8 0 2.8 6.87 1.3 6.1 40.9 14.2 '7*5 6.2 .3 12.4 2.2 134.9 28.8 1.4 2.9 25.1 .7 49.3 .5 i3" 2.7 7.5 26.43 32 23 1 169.2 .8 8 174.1 198 2.8 " .5 0 3.2 .7 .4 1.4 10.79 .5 5.6 ' .3 3.86 15.88 0 .4 67.1 5.6 1.9 66.8 94.2 10.9 10.3 .3 3.9 5.1 19.5 32.5 52.8 91.3 22 86.1 47.8 5.3 3.6 14.9 12.5 12.5 91.5 37.9 9" 4.93 18.2 18 86.6 15.2 2.85 56.1 18.9 11.8 23.8 16.6 10.2 6.8 5.8 17.63 20.7 94.7 90.1 6.3 14.2 22.9 17.16 17.85 96.6 48.7 2.85 10.4 8.8 114.6 120.8 11.6 19.8 10.2 5.5 37.3 22.8 174 95.6 103.5 28.5 122.9 48.7 57.5 5 16.7 31.2 18 101.5 71 48.3 38 9.3 206.8 21.4 92.4 207.5 200.9 107.4 19.4 13.2 23.8 20.9 12.39 8 8.5 30.7 23.8 95.2 91.3 15.2 14.2 31.7 26 44.5 96.6 51.9 76.8 9.6 11.3 87 .8 8.6 5.05 9.8 18.1 2.6 4.4 .6 1 .97 3.5 .8 2.1 1.7 20 6 3 5.4 1 1.4 2.1 2.6 10.7 .48 4.7 1.1 .48 .5 .9 5.15 7.6 4.2 4.7 8.07 12.5 11.7 3.25 4.2 1.05 1.09 6.6 7 3.1 3.8 2.2 1.1 1.9 1.3 25 3 15 20 5 7 3 1 40 3 132 42 7 10 12 1 6 2 5 18 8 3 8 26 46 9 9 9.1 1 9 0 45 1 3 0 5 9 5 7 7 11 1 1 16.5 25 '5 15 30 0 6 9 10 19 80 23 29 15 25' 5 269.8 90 1 7 25 2 107 1 0 42 8 12 38 42 183 3 82 2.8 16 84 99 3 2 0 16 4 3 8 36 2 2S "'9 11 45 0 1 88 40 5 130 157 70 39 7 5 10 42 65 168 67 58 88 147 12 7 45 40 34 160 54 '7i' 13 9 63 173.2 7 1 52 49 45 150 79 62 42 35 57 S7 149 99 31.5 75 68.7 49 50 100 118 3 3. 4 2 1 i 2+ n 2 6| 3. Q3 3 1 Carrots, Creamed Cauliflower, Steamed. . . Celery 3 4 1 4 2 2t Cherries 1 3 3* 3 Corn Cake 3 3 Corn Flakes 3. 94 Corn, Green, Sweet (cooked) 3. 1 3 Crackers, Graham Cranberries (cooked)... . Cream H 2 _L 3 Currants, Red 1 3i Custard, Plain 1 3 Dandelion Greens (cooked) * H Dates It H Egg Plant 1 1i Eggs, Poached -A 8 Eggnog, Milk 3 3 Endive i i 3* English Walnuts Farina 1 f 2 i 2 1 2 1 91 3f Figs Filberts French Salad Dressing . . Gluten Biscuit, 40%. .. Gooseberries, Stewed . . . Grape Fruit 2 1 1 1 4 4 H 1 3. 4 4 4 1 6 5 6 6i 6 3i Grape Juice Grapes (Atwater) Gruel, Barley Gruel, Corn Meal Gruel, Oatmeal Hash, Potatoes, and Onions 4i Hominy 1 1$ Honey 14 1 1 1 Jelly, Currant 5 jlvumyss 1 i 1 t H 1 5i 3 3 2:1 1 Lemonade Lentils (cooked) j Macaroni and Tomato . . Macaroni an Gratin Maple Sugar 2£ Marmalade, Lip; j Mayonnaise, Cooked.. . . 14 1 70 B DIET TABLE— Continued O.S Food. Calories Per Ounce. Milk, Skimmed Milk, Whole Nuts, Almonds Nuts, Hickory Oatmeal (Cooked) Olive Oil Olives, Ripe (7) Omelet Onions, Boiled Orange Juice Oranges Parsnips, Mashed ...... Patties, Rice Peaches, Fresh Peanuts Pears Peas, Green Pie, Apple Pie, Mince Pie, Pumpkin Pineapple, Fresh Plums Popped Corn Potatoes, Baked Prunes (Cooked) Pudding, Baked Indian . Pudding, Apple Tapioca Radishes Raisins Raspberries, Fresh Black Raspberries, Fresh Red . Rice, Boiled Salad, String Bean Salad, Vegetable Soup, Bean Soup, Clear Tomato. . . . Soup, Split Pea Spinach Squash, Baked Strawberries, Fresh Sugar (Granulated) Sweet Potatoes (Cooked) Toast, Breakfast Toast, Cream Tomatoes, Sliced Turnips, Mashed Watercress Watermelon Wheat, Cracked Whey Whole-wheat Wafers or Crackers Zwieback 4 3.8 24.5 IS 3.3 0 2 14 1.13 0 .9 1.7 14.9 .9 30.1 .7 7.S 7.5 15.09 3.25 .5 1.2 12.5 3.4 .8 4.8 4.5 1.5 3 2 1.2 3.3 .7 4.3 9.4 3.1 7.18 3.3 1.6 1.2 0 3.5 11.4 4.15 1 .6 1.4 .5 3.3 1.2 11.4 11.4 11 146.4 179.7 1.3 264.1 69.1 59 4.29 0 .5 5.9 39.04 .3 102.9 1.3 9.1 IS 22.2 7.26 .8 13.3 .4 .3 21.8 17.58 .3 2.6 "3 51.7 4.8 4 7 1.85 1 2. 1 0 5. 27. 29.9 1.1 2.8 26 26.4 o 6 5.8 20.2 13.3 13.4 0 5 1 5.1 15.1 13.5 9.5 77.24 11.6 8.5 16.5 17.5 37.2 35.1 24.88 11.3 23.5 91.8 28.9 26.4 20 26.44 6.7 14 14 28. 2 9. 24. 8. IS. 4. 16 8. 116. 49. 86. 13. 4. 2. 3. 7. 22 5. 84.5 85.8 10. S 20.6 191.1 211 IS 264.1 76.1 74 10.52 15.1 14.9 17.1 131.2 12.8 161.5 18.5 34.4 62.7 72.39 35.4 12.6 24.7 117.6 32.7 27.5 46.6 48.5 8.5 100.6 19.3 15.9 32.1 54.7 18.3 38.1 19 27.1 9.3 19.8 11.4 116.6 58.2 125 . 1 47.65 6.7 6.1 5.6 8.8 26.3 7.8 122.7 123.6 a> of 0*S 9.3 4.9 .52 47 5.6 .4 1.3 1.4 9.5 6.6 6.7 5.8 .76 7.8 .6 5.4 3 1.59 1.3 2.8 8 4 .85 3 3.65 2.1 2.07 11.7 1 5.2 6.3 3.1 1.8 5.5 2.6 5.2 3.6 10.7 5 8.5 .9 1.7 .8 2.1 16 16.4 17.8 11.4 3.8 12.8 .81 .8 Calories Served. 26 22.8 7 9 14 0 2 56 3 0 4 5 37 3 22.5 3 23 33 73 30 2 5 5 11 3 13 12 1 3 5.2 66 38 89.8 5 100 91 236 10 0 2 17 97 1 77.1 5 26 80 108 71 3 5' 1 1 58 45 o 10 "i" 93 6 15 36 8 3 6 7 0 19 12 143 4 12 1 4 6 5.6 27 13 2 6 25 17 34 9 4 5 0 12 4 18 4 2 2 4 18 8.4 12 11.4 26 39 34.8 5 6.6 56 0 7 4 12 75 69 28 191 46 6.3 67 51 162 169 168 45 95 40 88 96 54 68 5 57 46 111 5 13 65 47 83 13 40 38 25 169 34 64 17 11 7 67 126 40.6 86 85.8 ~76~cT h 1 3 i 1 1 3 1 1 U H l 11 Li l X i 1 1 li 2i FLESH FOODS. eg «£: §2 3 03 O => ^ tn 3* 2* 2i 6 3i 31 5 2f 3 2 3* 3 2 2i 1 2i 3 21 2i If H 2^ Food. Calories per Ounce. S^2 o Calories Served. § o 03 £l o3 - - 03 -3 O 19 6 0 48 352 0 90 10 0 23 1 1 79 21 0 28 4 18 95 5 0 48 252 0 61 39 0 48 152 0 80 120 0 61 39 0 39 10 1 70 30 0 24 12 14 12 188 0 56 144 0 54 246 0 45 105 0 46 54 0 40 10 0 29 71 0 73 27 0 Beef Juice Beef, Roasted (Fat) Beef, Round (Boiled, Lean).. Bouillon Chicken (Broilers) Clams Cod Fish Goose Halibut (Steak). Lamb Chops (Boiled) Lamb (Leg, Roast) Liver (Veal) Lobsters Mutton (Leg, Boiled) Oysters Pork (Bacon, Medium Fat) Pork (Ham, Boiled) Pork (Loin, Chops) Salmon (California) Shad Trout (Brook) Turkey Veal (Leg, Boiled) 5.42 18.14 40.9 2.3 24.6 7.5 19.3 18.1 21.78 25.3 22.2 21.78 19 29.1 7.2 11.3 25.4 18.5 20.4 21.9 22.2 24.1 30.4 1.71 136.85 4.54 .3 6.56 1.08 1.02 95.4 13.9 79.7 33.3 13.9 4.8 54.1 3.23 177.3 65.4 84.5 46.6 25.71 55.5 59.1 11.2 7.13 155.26 45.6 3 31.16 8.58 20.32 113.5 35.68 105 55.5 35.68 23.82 83.2 10.43 188.6 90.3 103 66.6 47.61 77.7 83.2 41.6 14 .65 2.2 33 3.2 11.6 4.9 .88 2.8 .96 1.8 2.8 4.1 1.2 6.8 .53 1.1 .97 1.5 2.1 3.6 1.2 2.4 4 1 i 4 1 i 1 3 1 2 2 1 \ 1 \ 2 2 3 H l 4 l l FOOD UNITS OR CALORIES PER OUNCE OF UNCOOKED FOODSTUFFS. None served in the uncooked state. Value given only for the purpose of comparison. Food Asparagus Barley, Pearled. . Beans (dried) .... Beans, Butter (green) Beans, Lima (dried) Beets Beans, String .... Cabbage Carrots Cauliflower Cocoa Corn, Green Cornmeal Cornstarch Cranberries Egg Plant Flour, Corn Flour, Graham. . . Flour, Rye Flour, Wheat (En- tire Wheat).. . . Flour, Wheat (Fine White)... Hour, Wheat (Pat.) 76 D Pro- teins. 2.1 9.9 26.3 11 21.1 1.9 2.7 1.9 1.3 2.1 25.2 3.6 10.7 ".6 1.4 8.3 15.5 7.9 16.1 9.2 12.6 Fats. .5 2.9 4.8 1.6 4 .3 1.1 1.3 77.1 2.9 5.1 l.Q .8 3.5 5.9 2.4 5.1 3.7 2.9 Car- bohy- drates. 3.9 90.8 69.5 34 76.9 11.3 8.6 6.5 10.9 5.5 44 23 87.9 105 11.5 6 91.5 83.3 91.8 83.8 89.1 87.7 Total. 6.5 103.6 100.6 46.6 102 13.5 12.1 9.2 13.3 8.9 146.3 29.5 103.7 105 13 7 8.2 103.3 104.7 102.1 105 102 103.2 Food. Gluten Meal (20 per cent.) Hominy Lentils Macaroni Mushrooms Oatmeal Onions Parsnips Peanuts Peas (dried) Peas, Green Potatoes Prunes Pumpkin Radishes Rice Spinach Squash Sweet Potatoes. . Turnips Vegetable Oys- ters or Salsify . Wheat, Cracked . Pro- teins. Fats. Car- bohy- drates. 18.4 1.7 83.6 9.7 1.6 92.2 30 2.7 69.1 3.5 4 18.4 4.1 1.1 7.9 18.8 19.2 78.8 1.9 .8 11.6 1.9 1.3 15.8 22.8 77.6 21.6 28.7 2.7 72.3 8.2 1.3 19.7 2.6 .3 21.5 2.5 0 85.8 1.2 .3 6.1 1.5 .3 6.8 9 .8 92 2.5 .8 3.7 1.6 1.3 10.5 2.1 1.9 32 1.5 .5 9.5 1 5.3 4.1 13 4.5 88.1 Total. 103.7 103.5 101.8 25.9 13.1 116.8 14.3 19 122 100.7 29.2 24.4 88 7.6 8.6 101.8 7 13.4 36 11.5 10.4 105.6 DIABETES MELLITUS By B. NAUNYN, Strassburg Contents: I. Glycosuria and Diabetes. II. The Various Forms of Dia- betes; Predisposition. III. Mild and Severe Forms of Diabetes; Course, Symptoms and Complications. IV. Theory and Treatment. V. Prac- tical Management. VI. Tables; Diet Lists; Scheme of Food Values; Dietetic Rules for Diabetics. I. GLYCOSURIA AND DIABETES Glycosuria, Levulosuria, Lactosuria and Pentosuria. Physiologic and Alimentary Glycosuria. Alimentary Glycosuria e saccharo; Non-Diabetic and Diabetic Forms. Spontaneous Non-Diabetic Glycosurias. By the term " glycosuria " we mean the appearance in the urine of true grape-sugar (dextrose, glucose), which is dextrorotary. We also speak of " levulosuria," when we mean the excretion of levulose, a fruit sugar which is levorotary. "Lactosuria" means the excretion of milk-sugar (lactose). A sugar containing five atoms of carbon, in its molecular composition known as pentose, may also appear, hence the term " pentosuria." Lactosuria may occur during pregnancy and in nurslings, and has nothing in common with diabetes. Pentose may be found in the urine after the inges- tion of cherries, plums and beer, and occasionally also in diabetic urine, but its role in diabetes is quite obscure. On the other hand, there are cases of diabetes mellitus in which levu- losuria takes the place of dextrosuria and levulose plays the part in the disease which ordinarily is assumed by dextrose. Such cases are, however, very rare, not more than half a dozen being known. Glycosuria (dextrosuria) is the cardinal symptom of diabetes mellitus, but not every case of glycosuria is of a diabetic nature. There is a so-called physiologic glycosuria; in other words, a normal individual may excrete dex- trose in his urine, but the quantity is always extremely small. Disregarding for the present so-called alimentary glycosuria, the percentage of sugar in the urine of healthy individuals is seldom more than 0.05 per cent., although it may reach 0.1 per cent, or even 0.2 per cent. It is fortunate that the amount of sugar in normal urine does not react to the ordinary tests. Trommer's (or Fehling's) and also Fischer's test only give a positive reaction in urine when the amount of sugar present is abnor- 7 77 78 DIABETES MELLITUS mally high; i. e., over. 0.1 per cent., and only when this quantity of sugar is present can it be quantitatively estimated. If on boiling urine in an alkaline solution of copper sulphate (Trommer's test) we immediately, not subse- quently, obtain a red or reddish-yellow precipitate, or if on warming the urine with phenylhydrazin and acetic acid on a water-bath for half an hour, a distinct crystalline sediment is deposited, we may be sure that the glycosuria is not physiologic. As possible sources of error there may be mentioned the presence in the urine of lactose, pentose, and combinations of glycuronic acid (after the administration of chloral, chloralamid, etc.). Lactose and pentose as well as combinations of glycuronic acid have a considerable power of reduction, but we may readily distinguish them from dextrose by the fermentation test and by polarization. In diabetes, then, we are concerned only with hyperglycosuria, or, in other words, with cases in which the sugar exists in such quantities as to react readily to the above mentioned tests. But hyperglycosuria may exist independently of diabetes. The so-called alimentary glycosuria is a case in point: a person whose urine does not contain sugar partakes of sugar or sugar forming substances (starchy material, dextrin) in sweetened foods and liquids, beer, bread or potatoes, etc. ; if sugar then appears in the urine so that it may be detected by means of any of the ordinary quantitative tests, this condition is designated alimentary glycosuria. In diabetics whose urine is temporarily free from sugar, this is of quite regular occurrence. It also takes place in non-diabetics, but with this differ- ence, that in the diabetic the sugar producers in the food — the flour in bread, etc. — if consumed in large amounts give rise to glycosuria almost as surely as the sugar itself, while this condition only occurs in the non-diabetic from sugar and not from starchy substances. Therefore, glycosuria after the ingestion of sugar need not be diabetic, but may be produced in normal persons even up to several per cent., provided the sugar (grape-sugar, milk-sugar, or cane-sugar) is given upon an empty stomach in amounts of 100 grams and over. If such a glycosuria occur after the consumption of 100 grams of sugar (usually grape-sugar is used) when the stomach is no longer empty, we are dealing with abnormal glycosuria, i. e., alimentary glycosuria e saccharo. This may indicate diabetes or be the first sign of the development of the disease; in other words, the person in question may develop diabetes sooner or later, but not necessarily; the indi- vidual need not be a diabetic, nor even become one. Taking as a criterion the nature of the processes concerned, let us now attempt to differentiate between diabetic and non-diabetic glycosuria. In the diabetic, the organs which are concerned in the consumption of sugar have suffered damage and are incapacitated for work ; they fail to extract the sugar from the blood which is brought to them, or they return it to the circulation, as they are incapable of utilizing it. Thus a hyperglycemia and consequent glycosuria arises, provided the amount of sugar in the blood is more than 0.2 per cent.-0.3 per cent., and this is a diabetic hyperglycemia and glycosuria. The condition depends upon obstruction to the normal drain- age of sugar from the blood by the organs of sugar metabolism, and it is for GLYCOSURIA AND DIABETES 79 this reason that sugar is excreted by the kidneys. But the organs whose function it is to burn sugar cannot take up from the blood and consume an unlimited amount of sugar, even if they and all the other organs are per- fectly sound and function normally. It is true that a flooding of the blood with sugar can hardly occur in health through the ingestion of starches, even in the largest amounts, as these are absorbed too slowly, but it may readily occur after ingestion of large quantities of readily absorbable sugar solu- tions. That alimentary glycosuria (e saccharo) may be explained in this manner is evident from the fact that in most of these cases the sugar (for example, milk-sugar or levulose) is excreted in the same form in which it is introduced. This explanation is also favored by the circumstance that alimentary glycosuria occurs more readily when the stomach is empty, for, as is well known, absorption is then more rapid. This pathologic but non- diabetic alimentary glycosuria (e saccharo) is probably due, therefore, to an abnormally hastened absorption of the sugar solution. Finally, non-diabetic glycosuria, i. e., glycosuria despite a normal condi- tion of the sugar-consuming organs, may occur when the renal secretion has become so increased that sugar and other solids are drawn out of the blood in abnormally large quantities and excreted with the urine. Perhaps it may be possible to explain in this way the fact that, after the ingestion, of much beer or champagne, sugar (even several per cent.) is occasionally found in the urine. It is possible, however, that in these " beer glycosurias " the damaging influence of the alcoholic beverage upon the liver is also a factor; the possi- bility is obvious enough, since, in cirrhosis of the liver, alimentary glycosuria is frequent. In these cases we are then concerned with diabetic glycosuria, i. e., with the complication of cirrhosis of the liver and diabetes mellitus. This example shows how difficult it is to separate alimentary glycosuria from the diabetic form, and there are many other illustrations of this diffi- culty. Thus, in traumatic neuroses true diabetes may occur. On the other hand, alimentary glycosuria (e saccharo) is a particularly frequent symptom in traumatic neuroses. And one cannot look upon this sign, in all cases, as indicating diabetes — at any rate in the overwhelming majority of cases such a condition does not arise. In exophthalmic goiter the same state of affairs exists. Taken all in all, in every alimentary glycosuria, including the " e saccharo " variety, it is necessary to observe great caution in deciding whether this is a sign of diabetes or not. Alimentary glycosuria following the ingestion of starch must always be looked upon as a sign of true diabetes. " Experimental " glycosuria in the human being does not play a great role, although it occasionally occurs — for example, glycosuria after poison- ing with coal gas, or with phloridzin for purposes of malingering. These conditions must be understood in order to recognize that they are not cases of diabetes. In all cases of spontaneous glycosuria (non-alimentary) the greatest care is necessary before deciding whether they are to be looked upon as signs of diabetes or not. "We must be sure that pentose or glycuronic acid in the urine is not mistaken for glycosuria; when lactosuria occurs in pregnancy or in 80 DIABETES MELLITUS the puerperal state, we must know that this has nothing to do with diabetes. As an example of true glycosuria appearing spontaneously in man, yet not the expression of diabetes, I can only mention the form occurring in cholera asiatica and cholera nostras. All other forms (unless proofs are present to the contrary) should be looked upon as diabetic ; but we need to know what is meant by diabetes, i. e., the disease of this name as it occurs in the human subject. II. THE VARIOUS FORMS OF DIABETES; DIABETIC PREDISPOSITION Acute Diabetes, the Acute Form Terminating Fatally and the Acute Form Resulting in Recovery — Transitory, Nervous (Cerebral Trauma), and Pancreatic Glycosuria Representing the Shortest Course of Acute Diabetes Mellitus Terminating in Recovery. Chronic Diabetes Mellitus as an Expression of an Hereditary Predisposition. Its Three Varieties: (a) The Pure Form, (b) Diabetes of the Aged, and (c) Organic Diabetes Mellitus. Etiology of Diabetes Mellitus and the Possibility of its Cure in the Light of Hereditary Predisposition — the Heredity of Diabetes Mellitus. One Form or Several Forms of Diabetes? Diabetes is generally considered a chronic affection, but it may take an acute course and be either rapidly fatal or readily curable. Well studied cases with an acutely fatal course have been reported; for instance, Wallach reports the case of a chemist who was accustomed to make weekly examinations of his own urine. The urine was always free from sugar until suddenly a severe glycosuria appeared, and within five weeks the man died in diabetic coma. The question of acute cases that terminate in recovery is less simple. Schmitz reports the case of a four-year-old child of a diabetic mother. The anxious mother had the urine of the child examined frequently, and it was always free from sugar up to November 22, 1871. On November 26th, the child was attacked by a gastric fever, and on the 27th the sugar contained in the urine amounted to 5.8 per cent. The child was put upon strict diet, and on the 13th of December the urine was again free from sugar. Although the patient gradually returned to the usual saccharine and amylaceous diet the urine remained normal for twenty years. Whether it is correct to say that the diabetes had already been cured upon the 13th of December is at least very questionable, for at that time, and for a long period afterward, the child lived upon a very strict diet, which later was even more restricted, so that very little was expected from its carbohydrate metabolism. On Decem- ber 13th, the recovery was probably only relative. Zinn observed a child attacked by diabetes mellitus after scarlatina; the patient, after ten weeks, even upon "mixed diet" showed no sugar in the urine; unfortunately the observations in regard to the recovery were only continued for a few months. Similar conditions may be observed in all cases of true diabetes in which recovery takes place. Diabetes after cerebral injuries also occurs as an acute disease which may THE VARIOUS FORMS OF DIABETES 81 terminate in recovery. As a result of trauma of the brain we note cases of diabetes that are severe, even very severe; then there are cases which run a milder course similar to those of Schmitz and Zinn mentioned above; finally, there are cases after cerebral injuries, in which transitory glycosuria, without any further consequences, occurs and lasts but a few days. What right have we to deny that these transitory glycosurias represent the mildest forms of dia- betes mellitus ? The same lessons which are taught us by the study of diabetes after cerebral injury in the human subject are paralleled as regards pancreatic diabetes by experiments upon animals; extirpation of the pancreas produces the most severe forms of chronic diabetes; transitory lesions of the organ produce mild ephemeral glycosuria. In my opinion we must admit that diabetes may occur as an acute affec- tion, and this conclusion has some practical importance; spontaneous, true, acute diabetes is certainly very rare, but transitory, spontaneous (?) gly- cosuria may be explained in this manner : Although the course of the disease is for the most part chronic, the con- ditions are not accurately designated if we call diabetes " a chronic disease " ; in the majority of cases there is an innate hereditary predisposition, a weak- ness of sugar metabolism, which, sooner or later, in combination with other causes, or even without such, may lead to insufficiency of sugar metabolism and thus give rise to the disease. According to this, three forms of the disease may be differentiated: 1. Diabetes mellitus of young individuals (those between thirty and forty years of age) ("pure diabetes"). In this form the hereditary weakness of sugar metabolism, without the association of any special disease of an organ, progresses to insufficiency. This occurs at an early period of life, owing to a particular severity of the pathologic predisposition, and, in keeping with this, the cases are for the most part serious.. 2. Diabetes of the aged, the usual mild diabetes of old persons; the saying that " the age of an individual depends upon the condition of his arteries " is also true in these cases; usually, arteriosclerosis is the underlying condi- tion and with this all factors are operative which favor its development; lux- urious living and, above all, the use of alcohol. It is readily seen that the least severely predisposed cases are the ones in which this form of diabetes is most likely to appear; perhaps this accounts for its relatively mild course. 3. Organic diabetes; this refers to cases in which disease of a particular organ is the immediate cause of the affection. As examples, there may be mentioned: (a) among the diseases of the liver, cirrhosis and, rarely, chronic cholelithiasis; (b) among diseases of the nervous system, apoplexy, chronic encephalomalacia, cerebral syphilis, dementia paralytica, tabes dorsalis, cere- bral trauma of all kinds, the various functional neuroses, particularly the trau- matic ones, and paralysis agitans; (c) diseases of the thyreoid gland (Graves' disease), and (d) diseases of the pancreas. Experimental evidence would seem to show that the pancreas takes the first position among the organs which cause diabetes, since by extirpation or 32 DIABETES MELLITUS by a more or less extensive resection, true diabetes may be produced. Our investigations in man, however, only correspond with this in so far as extir- pation of the pancreas and disease of the pancreas also cause diabetes in the human subject. On the other hand, diseases of the pancreas have only in rare instances been determined with certainty as the cause of diabetes; these affections are pancreatic calculi, pancreatic cirrhosis, neoplasms and cysts. If we have disease in an organ which is very influential in sugar metabo- lism, as, for instance, the nervous system or pancreas, this suffices to produce diabetes, even without a previous predisposition; if, however, a predisposi- tion exists, disease of one of the vital organs is not absolutely necessary. Slight general disturbances are sufficient to bring about an insufficiency in sugar metabolism. Thus the varying etiology of diabetes mellitus becomes comprehensible, and we learn to recognize as causes not only the above men- tioned organic diseases, but also many severe or mild general affections: influenza, enteric fever, scarlatina, erysipelas, phlegmons, syphilis, and, finally, the most manifold forms of trauma, surgical operations, psychical dis- turbances, bodily or mental over-exertion, indigestion and excesses of all kinds; all of these are occasionally of etiological significance in diabetes mellitus. This conception of diabetes mellitus as an expression of an hereditary weakness of metabolism makes clear at once what we can expect as regards the cure of diabetes. One can speak of actual cure only in those cases in which the disease appears as the result of an affection of one of the principal organs; if an affection of the organs in question improves, then diabetes may actually be " cured." That this occurs is certain (in man) in the case of diabetes as the result of brain injuries. If, however, as in most cases, the cause of diabetes must be referred to hereditary predisposition, we must at once assume a skeptical attitude in regard to the cure, all the more so if the predisposition is the only causal factor. Where other causes are associated with this, e. g., cirrhosis of the liver, infectious diseases, especially syphilis (we may remark in passing that syphi- lis plays but a very slight role in the etiology of diabetes), arterio-sclerotic circulatory disturbances, we have more reason to hope that, by treatment or by cure of the causes simultaneously present, sugar metabolism may again become sufficient, but the predisposition remains, and with it the danger that any fresh damage may bring about a relapse. Many cases may be explained in this way; for example, an elderly person who may have suffered many years ago with diabetes, is apparently cured ; i. e., he returns to his usual mode of living without paying much attention to his " cured " diabetes. The urine is free from sugar ; he is then attacked with influenza, or undergoes some marked psychical disturbance, and the glycosuria at once returns quite severely; or he has to submit to an operation, and after the operation a coma ensues, coma diabeticum, the urine containing many per cent, of sugar. We are justified in assuming (as we have) an hereditary predisposition for many cases of diabetes, apart from what has already been said, by the fact of the heredity of the disease. In most cases of diabetes, heredity is a factor ; MILD AND SEVERE FORMS OF DIABETES 83 it has been proven in more than 30 per cent, of my cases, and becomes more frequent the more closely I investigate. This hereditary predisposition is true of all three varieties, and can be demonstrated in a like number of cases of the organic form, in diabetes of the aged, and in " pure diabetes." The hereditary factor in diabetes is related to the neuropathic taint and to the pre- disposition to gout and obesity. In many families gout or some variety of neurosis or psychosis occurs alternately with diabetes, and if, in such diabetic families, one of the members is conspicuously fat, this is very suspicious of diabetes. These are, incidentally, the cases for which the improperly used term " diabetes of the obese " should be reserved, the cases, namely, in which obesity points to diabetes. It is often said that as the cases of diabetes are quite different, and as these etiologic differences correspond with differences in the course and the symp- tomatology, diabetes should no longer be looked upon as a single disease. We should no longer speak of "diabetes mellitus," but of "various forms" of diabetes mellitus. But in answer to this we must again emphasize in all forms of diabetes the hereditary predisposition. This is the common bond which holds these various forms together; it is operative in each of the varieties which are to be differentiated etiologically. In every type of the disease, in nervous diabetes, as well as in liver diabetes, in diabetes after infections, in diabetes of the aged, and in "pure" diabetes, 30 per cent, (or more) are hereditary cases. Further, we do not know at present whether the pathogenesis of glycosuria, i. e., the disturbance in metabolism which causes it in the different cases, is as multiform as the etiology; on the contrary, the glycosuria which occurs in all the various types of diabetes mellitus (so far as this point has been inves- tigated) is hyperglycemic in origin, i. e., the condition is due to an increase in the amount of sugar in the blood. This is only true, however, of diabetes mellitus as it occurs in man ; we can produce in animals and in man an experi- mental glycosuria which is not hyperglycemic, i. e., the form due to phloridzin. In animals even the most marked phloridzin glycosuria produces no note- worthy increase of sugar in the blood. We cannot, therefore, see any sufficient reason for speaking of " various forms " of diabetes, but we do distinguish a mild and a severe form of the disease. This distinction will be observed throughout the following descrip- tion of the symptomatology and it will also be seen that we have taken full account of the differences in etiology between different groups of diabetic cases. III. MILD AND SEVERE FORMS OF DIABETES; COURSE, SYMPTOMATOLOGY AND COMPLICATIONS Mild and severe forms of diabetes mellitus. The importance of complicating organic disease in the symptomatology of the mild cases. Differentiation of the various symp- toms according to whether they are due to the organic disease or to diabetes mellitus. Hyperglycemia as a cause of the latter. The albuminuria of the diabetic. In practice we cannot avoid differentiating between mild and severe cases, or the mild and severe forms of diabetes mellitus. It is true that this is only 84 DIABETES MELLITUS a difference of degree; the nature of the affection depends upon the same process in the mild and in the severe cases, and transitional forms are by no means rare. Well developed cases of the mild and of the severe variety resemble one another as little as an epileptic migraine resembles typical severe epilepsy, or even less. When, in a severe case of diabetes, 4 to 15 or more liters of urine are passed with a specific gravity of 1.025 to 1.040, or even 1.060, and a per- centage of sugar from 5 per cent, to 12 per cent, daily (200 to 1,500 grams of sugar daily), it is obvious that there must be an enormously increased intake of nourishment; yet it is easy to understand that in spite of this the patient emaciates, becomes debilitated, and soon perishes. The course of the disease in such cases is necessarily brief. Often within a few weeks the body- weight falls to 60 kilograms in a man or 50 kilograms in a woman, and in spite of all endeavors to prevent this, the patient's condition becomes pro- gressively worse; in from one and a half to three years increasing cachexia, diabetic coma, or pulmonary tuberculosis, terminates life. Mild cases of diabetes may exist undiscovered for years, even decades, until a complication or an accident leads to the discovery of the glycosuria; so vague may this condition be. In such cases only 10, 30 or 50 grams of sugar are excreted daily, with a normal or slightly increased amount of urine in twenty-four hours, and this state of things may go on indefinitely, although the patient before, as well as after, the discovery of the sugar pays but slight attention to his condition. If he limits the amount of beer, bread and starchy food and gives up sugar and potatoes entirely, this will suffice to keep his glycosuria within the limits above mentioned, whereas, in a severe case, even the strictest diet only brings about an amelioration, and the patient's whole life becomes a combat with glycosuria, a battle for existence. If glycosuria is a symptom in a mild case of diabetes, in a severe case it is the disease, the fatal disease itself. The loss of sugar in the urine, the impossibility of com- pensating for it by an increased nourishment, and the consequences, among which coma is common, are the conditions from which the patient suffers and to which he finally succumbs. In the severe cases glycosuria itself is, in a certain sense, the main disease, since usually in cases of " pure " diabetes no disease of any special organ can be found. It is not necessary to discuss the question whether in these cases of " pure " diabetes we are justified in looking upon a disease of some special organ — generally the pancreas — as the cause of the disturbances of metabolism. On account of my own position in regard to pancreatic diabetes I have par- ticularly interested myself in this question; but it is impossible to prove in these severe cases, either from the symptoms and signs present during the life of the patient, or at the autopsy, anything which points to disease of the pancreas or of any other organ. There are, as has already been mentioned, cases of diabetes due to disease of the pancreas, pancreatic calculi, cirrhosis of the pancreas, etc., but they are rare. The mild cases rarely belong to the type classified as "pure" diabetes; more frequently the symptoms point to hepatic diabetes, to nervous diabetes, or to diabetes of the aged ( arteriosclerotic diabetes). Nevertheless, "pure" MILD AND SEVERE FORMS OF DIABETES 85 diabetes may occasionally run a mild course, and cases of the other form may sometimes be severe ; this latter course is most frequently seen in the diabetes which occurs after trauma of the brain. Not infrequently the symptoms of the accompanying disease (hepatic, nervous, or arteriosclerotic ) are much more prominent than the slight gly- cosuria, and so it happens that the cirrhosis, or the tabes, in spite of the com- plicating diabetes, runs the same course which it would have assumed without the associated condition. In arterio-sclerotic diabetes, as the disease develops, the arterio-sclerosis may become more and more prominent, presenting circu- latory disturbances, cardiac asthma, angina pectoris, dropsy, congested liver and albuminuria; in all of these cases we may note that, as they progress, the glycosuria decreases and finally disappears. Although in many of these cases the glycosuria does not become promi- nent, nevertheless, the diabetes and the diabetic disturbances of metabolism usually do not fail to produce evil consequences; on the contrary, there is quite an array of complications and symptoms which appear frequently in mild cases; pruritus pudendorum, vaginitis, vulvitis, balanitis, phimosis, ure- thritis, impotence, fermentation of the urine in the bladder (with pneuma- turia), and as a consequence of this, cystitis and pyelonephritis; itching of the skin, urticaria, eczema, the most manifold ulcerating dermatoses, furun- culosis, carbuncle, lymphangitis, boils, intermittent claudication, gangrene of the toes, necrosis of internal organs, pulmonary gangrene, pulmonary tubercu- losis; also a host of nervous diseases; encephalomalacia, column degeneration of the spinal cord, neuritis, polyneuritis, neuralgia, peripheral paralyses (par- ticularly paralysis of the facial nerve), malperforant, very frequently loss of the patella reflex which occasionally ushers in the remarkable picture of pseudo-tabes diabetica. It is impossible to bring this confused array into any systematic arrange- ment; any one of these symptoms, or complications, may appear alone as the first sign of a diabetes, latent up to them ; each of these conditions may remain the only one, or be succeeded in any order by any of the others. For some of these conditions diabetes alone cannot be held responsible; thus arterio-sclerosis is the true cause of gangrene of the extremities with its occasional prodrome, claudicatio intermittens, perhaps also of malperforant. This is true, even though these lesions occur during the course of a case of diabetes. In the peripheral paralyses and neuralgias, the neuropathic predis- position doubtless often plays a part, and the diabetics that suffer from poly- neuritis are, as far as I know, all alcoholics. Naturally the question next arises whether diabetes has any influence at all in the production of these lesions; for example, in cardiac asthma or in angina pectoris of the diabetic; take the case of an old diabetic, with a glycosuria of from 3 per cent, to 4 per cent., from 50 to 60 grams of sugar per day, suffering from cardiac asthma or angina pectoris; there is slight venous stasis of the liver, occasionally slight albuminuria; nothing abnormal can be detected in the heart. Nevertheless, there is a well-grounded suspicion that a beginning cardiac insufficiency, perhaps due to myocardiac degenera- tion and perhaps to arterio-sclerosis, is present. Kemoval of the glycosuria 86 DIABETES MELLITUS helps but little; digitalis, however, soon brings relief. We must not be too certain that, in these complications of diabetes, glycosuria does not play a part, and we should never fail to attempt to remove the glycosuria, for there are cases, like the one just described, in which no result can be obtained with- out this method of treatment. It should remain a rule that wherever there is even a possibility that the symptom present is of a diabetic nature, the attempt must be made to reduce the glycosuria. We are compelled, then, seriously to consider glycosuria as the cause of these symptoms. Glycosuria may produce symptoms in two ways: First, by the loss of sugar; of this we have already spoken and shall have to refer to it again frequently; in mild diabetes the loss of sugar is not important, and glycosuria as such is only to be considered as the cause of urinary fermenta- tion and its consequences, such as pneumaturia, cystitis, pyelonephritis, pruritus pudendorum, balanitis, vaginitis, etc. In mild diabetes it is the hyperglycemia that we hold responsible for symptoms. As long as the diabetic excretes sugar, the sugar contents of his blood is increased above the normal and there is hyperglycemia. In marked glycosuria (above 1 per cent.) the hyperglycemia amounts to over 0.2 per cent, and in the severe grades of glycosuria it may amount to 0.7 per cent. ; if the gly- cosuria is slight (^ per cent, to 1 per cent.), or if the urine of the patient is free from sugar, the hyperglycemia is very slight, scarcely amounting to more than 0.1 per cent, (which is almost normal), and then the condition is not serious.' Diabetic hyperglycemia may certainly be held responsible for the loss of resistance of the diabetic — even of the mild cases — toward infections ; at least it has been experimentally proven that many of the pathogenic microbes flour- ish better in the tissues which contain sugar. I shall include, besides this, the cutaneous affections and the neuralgias as among the complications de- pendent upon the hyperglycemia, basing my opinion upon the results of the therapeutic removal of glycosuria. Removal, perhaps, implies too much; it would be more correct to say reduction, for to render the hyperglycemia innocuous, it is almost always sufficient to reduce the glycosuria to the limit mentioned above. Regarding the symptomatology and complications of diabetes, I must limit myself to what has been previously mentioned. The other important symp- toms not yet enumerated, for instance, coma, will be spoken of elsewhere; only in regard to albuminuria I should like to add a few words. Albuminuria has one significance in mild and another in severe cases; in mild cases, the albuminuria is the expression of a renal affection inde- pendent of the diabetes, although in some cases arteriosclerosis or hepatic cirrhosis may represent a connection between these diseases and the diabetes. In severe diabetes, the albuminuria may be referred directly to the diabetes ; it is the consequence of the excessive functional irritation from which the kidney suffers owing to the continued polyuria. Perhaps the abnormal constituents of diabetic urine, possibly the sugar itself, may irritate the renal elements. But this diabetic albuminuria is not nephritic in origin, i. e., it does not denote nephritis ; and we should err THE THEORY OF THE TREATMENT OF DIABETES 87 greatly if we were to diagnosticate nephritis on this account. What is found at the autopsy is the large, slightly hyperemic " diabetic kidney " which shows none of the changes that we expect to find in nephritis. The transition of diabetes into nephritis, which is frequently mentioned, is, therefore, very questionable ; the true diabetic albuminuria of severe cases is not nephritic, and the albuminuria of the mild cases is not diabetic, but frequently due to an independent nephritis. It is true that a genuine nephritic albuminuria not infrequently takes the place of glycosuria; for when the arterio-sclerotic or other form of chronic nephritis which may appear becomes really severe, the albuminuria becomes more pronounced, whereas the sugar disappears from the urine. IV. THE THEORY OF THE TREATMENT OF DIABETES Diabetic glycosuria has a tendency to increase during a decrease in the patient's tolerance, whereas during sugar-free periods the tolerance usually increases. Hyper- compensatory hyperglycemia. Dietetic aglycosuria as a theoretic postulate. The rela- tive importance of carbohydrates, albumin, fat, and alcohol for the diabetic. Difficulties in supplying sufficient nutrition ; temporary under-nutrition not always avoidable. Acidosis diabetica with acetonuria and diaceturia. The secondary increase of albumin waste and the secondary decrease of the powers of oxidation in diabetics. Acidosis an expression of the disproportion between over-abundant tissue-destruction and the less- ened powers of oxidation. Acidosis as a cause of the diabetic (dyspneic) coma. The only method of treatment of real value in diabetes is the dietetic. (We shall refer later to the medical treatment.) The foundation for the dietetic treatment in diabetes was laid one hundred years ago by an English physician, Eollo, but it is only of late years that this method of treatment has become general. Eollo discovered the correct method empirically, but, as is frequently the case, the theoretic foundation had to be worked out before his treatment obtained general recognition, and it required great labor to establish this theoretic foundation. But it is not for this reason that I intend to enter somewhat more minutely into these theoretic considera- tions of the treatment of diabetes, but because we cannot otherwise obtain such clear ideas of diabetes as are required for the practice of medicine. The first fundamental principle in the treatment of diabetes to which I refer is this : Diabetic glycosuria usually increases with time, while the tolerance of the patient decreases. The tolerance of the diabetic depends upon the relation between the amount of sugar excreted and the quantity of sugar and sugar producers (par- ticularly the carbohydrates) ingested. In the following example, for the sake of simplicity, I shall estimate the entire amount of the carbohydrates in the food as bread. A patient receives 500 grams of meat, 3 eggs, 400 grams of vegetables deficient in carbohydrates (salad, spinach, etc.), 100 grams of fat (cheese, sausage), in which there is some albumin which need not be taken into account, butter and fat in the food, 100 grams of wheat bread, 100 grams of cream and the necessary wine, coffee and water. He excretes two and a half liters of urine, with 3.5 per cent, sugar, that is, on the average, gg DIABETES MELLITUS 88 grams of sugar per day. If he lives for months, with this glycosuria, it is to be expected that with the same nourishment he will excrete more sugar; for example, 4 per cent., that is, upon an average, 100 grams per day; in other words, his tolerance (for carbohydrates) has decreased. This lessening of tolerance, due to the glycosuria, may not take place if the glycosuria is very slight and does not amount to more than from ten to twenty grams in a day; but in cases in which the glycosuria shows such an increase as in the example just quoted, the patient's tolerance is bound to diminish within a short time. The second fundamental peinciple which is a necessary complement to that mentioned above is as follows : When the diabetic is free from sugar, his tolerance usually increases. For example, a diabetic on the diet previously mentioned excretes 88 grams of sugar. To diminish the glycosuria his allowance of bread is reduced ; this decrease in food, however, is not sufficient; bread must be withdrawn entirely to render the patient free from sugar; as soon as even ten grams of bread are allowed he begins to excrete sugar again, although only from six to eight grams per day. Next the patient remains for four weeks without bread and his urine becomes free from sugar. After this, if the physician is careful, from twenty to thirty or forty grams of bread may gradually be given without being followed by an excretion of sugar; the patient's tolerance, during the sugar-free period of four weeks, has been materially improved. How may both these conditions be explained ? The improvement of toler- ance during the sugar-free period exemplifies Hoffmann's law that " by lessen- ing the work of any diseased function the latter may be improved," which law, however, if we are honest, is, in the case of diabetics, little more than a lengthy statement of the facts which are to be explained. There is more hope of success in the attempt to explain the aggravation of the patient's intolerance of carbohydrates during every decided glycosuria. The amount of sugar in the blood, as is well known, is quite constant in man, at least it never falls below a certain point (about 0.8 per cent.) ; if, for exam- ple, after severe muscular exertion, sugar almost disappears from the blood, a fresh supply is sent from the carbohydrate storehouse (the liver) ; this may be called a process of compensation. If now, after severe sugar losses, it is desirable that a great amount of sugar be quickly brought to the blood, it appears (according to some facts the explanation of which I shall not give at this point) that a hyper compensation occurs. Hence arises the paradoxical conception that loss of sugar produces hyperglycemia ! If this seeming para- dox is really true, and if it holds good even for the diabetic with an already existing hyperglycemia, then a spontaneous increase of diabetic hyperglycemia by hypercompensation becomes comprehensible. Therefore, as long as sugar is lost by the urine, a steady increase of hyperglycemia leading to a still greater glycosuria is to be expected. Whether these attempts at explanation are correct or not, the two laws themselves to which they refer are as near the truth, I think, as can be deter- mined to-day. And as the aim of the therapy of diabetes they show us this: to render the patient free from sugar and to Iceep him aglycosuric. This conclusion is identical with that arrived at in the end of the last chap- THE THEORY OF THE TREATMENT OF DIABETES 89 ter regarding the meaning of diabetic hyperglycemia. We there said that hyperglycemia is the cause of most of the complications and many of the dangers of diabetes mellitus, and the patient is safe only when he is excreting little or no sugar. Therefore, there can be no question that in every case of diabetes the therapeutic indication is to render the patient aglycosuric, or sugar-free. It is obvious that the treatment is to be begun as soon as possible, so that little time may remain in which the disease may unfold its tendency to develop ad pejus. If there is any theoretical law as regards treatment which is found to succeed in practice it is this. The chances for successful treatment are, ceteris paribus, very much better in recent cases. It is just as important to insist that the treatment is an obvious necessity in the later course of the disease, and should also be attempted from the beginning of symptoms by means of dietetic treatment. For it has been determined only as regards the dietetic treatment, and not as regards the aglycosuria brought about by drug treatment, that it increases the tolerance of the diabetic. There are no theoretic contra-indications (i. e., such as might be derived from our knowledge of the diabetic disturbances of metabolism) against carrying out this requirement, although the practical difficulties are fre- quently great. The dietetic treatment of the diabetic gains its end by forbidding the use of sugar and sugar-producing foods as far as possible. The sugar-producing foods are the carbohydrates and albumin. Even from albumin sugar is pro- duced in animal metabolism, and in no small quantity, as from 100 grams of albumin (which amounts to about 400 grams of raw meat) about 50 grams of sugar, or even more, may be formed. It is important to note that the organ- ism also produces sugar from those varieties of albumin which contain no preformed sugar, i. e., those from which it is impossible to extract sugar by chemical means. An example of such an albumin containing no preformed sugar is casein, and from this substance the diabetic produces sugar in large amounts. Sugar production from fat does not play such an important role as to influence diabetic glycosuria to any notable extent. For this reason, and on account of its high calory value, fat is the most valuable food substance for the diabetic. According to the very latest investigations (Bjierre) it may be looked upon as settled that alcohol has nutritive value (indeed, 1 gram of alcohol upon oxidation furnishes as much as 7 calories) and the diabetic does not form sugar from this. But its utilization as food is limited, for if it is admin- istered in large amounts it acts as a poison to protoplasm, increasing albumin decomposition. It is believed that this toxic action of alcohol is to be feared when more than 50 grams of alcohol are taken per day. That the patient must be sufficiently nourished, no matter how strict the diabetic treatment, is a well-known rule, but by this we do not mean to say that, temporarily, the patient may not be subjected to hyponutrition ; I have already spoken of this. Under some circumstances, as we shall see, it is even then permissible for the patient to abstain completely from food for twenty- 90 DIABETES MELLITUS four hours in order that his urine may become free from sugar. Just so, it is occasionally necessary to give for a few days so little food that some of the patient's body substance is utilized. At the beginning of strict dietetic cures, it is often very difficult to overcome this consumption of tissue in dia- betics who have previously lived upon a mixed diet and have excreted much sugar. Let me again illustrate. Imagine, for example, a man weighing 65 kilograms, who, on a mixed diet, has been excreting 600 grams of sugar daily. He is put upon a diet not absolutely free from carbohydrates. According to Rubner, a man requires for his , maintenance about 35 calories per kilogram, so that this man ought to have sufficient food to produce 35 X 65, or, in round numbers, 2,300 calories daily. 80 grams wheat bread contain 50 grams starch = 200 calories. 500 " boiled or fried meat, medium fat (5 per cent.) =750 " ... '200 " cream (30 per cent, fat) =600 " , 200 " milk =120 " 100 " fat, in butter, cheese, fat sausage, bacon, etc. = 900 " 2,570 calories. Besides this we will add about 300 to 400 grams of green vegetables, whose calory value, like that of the albumin partaken of in fat foods ( bacon, cheese, fat sausage, etc. ) , may be disregarded. According to this our patient would be plentifully fed, if he were free from sugar, for a diabetic who excretes no sugar does not emaciate, and consequently does not need any more food than a healthy person. Unfortunately, our patient continues on this diet to excrete his full 100 grams of sugar per day. The calory value of these 100 grams ( 400 calories ) must be subtracted from the total calory value of the food he is ingesting ; 2,570 calories — 400 calories = 2,170 calories, which is 130 calories less than the patient requires, according to Rubner. In some cases, under favorable circumstances, it is possible to supply these missing 130 calories by the further addition of fat, but by no means always; at least, under ordinary circumstances, it is often quite difficult to make the patient take the 500 grams of meat, 200 grams of cream and 100 grams of fat mentioned in the dietary above; and we must always avoid throwing too great a burden upon the metabolism of the diabetic. In short, as a choice of evils, we must often allow our patient to remain underfed and lose weight, until his excretion of sugar decreases appreciably. Only when the glycosuria becomes so slight that the net calory value of the ingested food approaches the gross calory value, can we expect to avoid the evil of under-nutrition. We must risk under-nutrition quite often, in severe cases, e. g., when, in order to abolish the glycosuria, we forbid all bread, and reduce the albuminous (meat) food considerably. I know of no successful treatment of severe cases without temporary under- nutrition, but the physician must be very careful during these periods. We should be especially cautious in regard to long-continued hyponutrition, such as entails a loss of weight of more than two kilograms in subjects who have already reached the minimum weight of 130 pounds in men and 110 pounds in women, for this loss is difficult to regain. In the consideration of the theory of treatment in diabetes, some mention of diabetic acidosis will not be out of place. By this term I mean the forma- THR THEORY OF THE TREATMENT OF DIABETES 91 tion of /3-oxybutyric acid in the processes of metabolism. It never fails to occur in serious cases, and even in mild cases it appears quite often. Acetonuria and diaceturia are part of acidosis, for both substances, acetone as well as acetoacetic acid (diacetic acid), originate from oxybutyria acid. I must insist upon this view which has many evidences in its favor, among them the fact that acetonuria and diaceturia only occur when oxybutyric acid is also found in the urine. I know very well that some prominent chemists have maintained the direct opposite, but I also know that very prominent chemists may be mistaken in their reports; for in the very cases in which they found no oxybutyric acid in spite of the presence of acetone and acetoacetic acid, and in the specimens which they kindly sent to me for examination in my laboratory, I succeeded in demonstrating oxybutyric acid in the urine. Therefore, acidosis, including acetonuria and diaceturia, plays an impor- tant role in diabetes. In twenty-four hours oxybutyric acid may be excreted in amounts above 100 grams, and acetone -f- diacetic acid up to 15 grams. As these substances are easily oxidized, their excretion in such large amounts shows a deficiency in the power of oxidation possessed by the tissues in these cases of diabetes mellitus. As regards this decrease in the power of oxidation in the diabetic, the conditions are very similar to those involved in the in- creased decomposition of albumin. Neither is primarily due to the diabetic disturbances of metabolism, but since the albuminoid decomposition is only increased when sugar is wasted and passes out unutilized in the urine, this weakness of oxidation may be referred to the lack of oxidation of sugar. The oxidation of sugar, however, does not fail because the general power of oxidation is diminished, but vice versa. Since for other reasons the sugar is not oxidized, the general power of oxidation becomes lessened; of all the products which are consumed in the organism, sugar is the most readily com- bustible, and in the fire which thus arises in normal metabolism, other less readily oxidizable substances are consumed, a process designated by physiolo- gists as secondary oxidation. Owing to the facts just mentioned, the same substances which produce acidosis may occur in other conditions — in non- diabetic persons whenever carbohydrates and sugars are withheld entirely. In the diabetic, too, they usually appear when the carbohydrates are excluded from the food. They may be excreted, however, in severe diabetes, with marked glycosuria, even when carbohydrates are eaten in large amounts. Here acidosis indicates that the sugar metabolism of the body has fallen so low that in spite of the plentiful ingestion of carbohydrate food, very little of it is consumed. The fire which lights the secondary oxidation processes is almost extinguished, and thus the total power of oxidation of the organism is dam- aged. It must be remembered that this condition is due to the disproportion between the products ready for oxidation in metabolism and the power of oxidation. In diabetic patients tissue decomposition goes on too rapidly for their power of oxidation ; their nourishment is both improper and too profuse, yet by limitation of their metabolism and careful diet it is often possible to restore to par the power of oxidation, and thus cause the acidosis to disappear. It has been necessary to discuss acidosis quite in detail because of its role in diabetic coma. Acidosis is the only certainly known cause of this coma 92 DIABETES MELLITUS (that is, of many cases of it). We now recognize that it is oxybutyric acid which produces true dyspneic coma; that is, an acid coma, i. e., a coma which is an expression of an over-acid condition of the blood, and this hyperacidity is due to the presence of a large amount of oxybutyric acid (100 grams or more), which is formed and which enters the blood within twenty-four hours. This fact, and also the danger that by a too rapid withdrawal of carbohydrates one may cause acidosis, as well as coma, renders it necessary for the physician to be familiar with this process. V. PRACTICAL THERAPY Every therapeutic measure is to be used, but after the dietetic treatment mineral waters alone are of much service. Prophylaxis ; obesity and diabetes mellitus. From the point of view of dietetic treatment, three forms of diabetes are to be distinguished: the medium severe, the mild, and the severe. The medium severe cases, their diagnosis and their importance in practice. The aim of treatment, in cases of each form. For the proper dietetic treatment of every case a quantitative and qualitative estimate of the entire dietary is necessary. Preliminaries of treatment: Quantitative regulation without limitation ; its result. Further steps toward the abolition of glycosuria and improve- ment of tolerance, maximal reduction of albuminous food and the twenty-four-hour fast. Diet lists for the diabetic; there are no foods absolutely permissible. Carbohydrate nutrition : Bread, cereals, vegetables, fruits ; calculation of their relative advantages and dangers. Meat, fish, and eggs. Fatty foods. Sausage, cheese, bacon, butter, oil, cream. Drinks : Milk, wine, beer, whiskey, tea, coffee. Artificial foods. Hospital treat- ment. Dispensary treatment and " bath-cures." Disturbances and dangers arising during the treatment of diabetes. I wish to speak first and chiefly of the dietetic treatment of diabetes, but of course every other therapeutic measure is to be welcomed and utilized. It should not be forgotten that since almost any disturbance of a diabetic's gen- eral health tends to aggravate the underlying disease, common sense teaches us to treat as carefully as we can any minor ailment from which the patient may suffer from time to time. If he is syphilitic, carefully planned specific treatment should be used, as also quinin in malaria, digitalis in circulatory disturbances, and appropriate treatment for nervous affections. By such treat- ment we may succeed in improving but, unfortunately, very rarely in curing the diabetes — that is to say, the glycosuria and the other symptoms which may be dependent on it. It is just as evident that the treatment of diabetes must always be a treatment of the entire organism, i. e., that the mode of life of the patient must be properly arranged in all respects. From this standpoint, there are two factors to be considered — mental and emotional rest, and sufficient muscular exercise; I say sufficient muscular exercise, but no more, for too much readily increases the glycosuria. The main point, however, the alpha and omega in the care of the diabetic, is the dietetic treatment; besides this, mineral water cures (Carlsbad, Neue- nahr, Vichy) also play a role, but not drugs. There is scarcely a physician familiar with diabetes who will resort to drugs to diminish the glycosuria. It is true there are many remedies which bring this about, and among them some which produce this effect without diminishing the demand for food or PRACTICAL THERAPY 93 the actual intake of nourishment. But — they act only in those cases in which the dietetic treatment alone would suffice, and in which they are, therefore, superfluous. During the administration of drugs (if we do use them) the dietetic treatment should never be forgotten, else the case will fail to do well in the long run. For a U'\v weeks, perhaps, here and there, by the adminis- tration of opium, occasionally also by the use of antipyrin and other nervines, the glycosuria may be limited or even removed. Then the action of these drugs ceases and glycosuria returns to its former height, sometimes even exceeding it. It appears, as I have already indicated, that the tolerance of the diabetic is not improved by a drug diminution of glycosuria; and even in an agly- cosuric condition, in case this is brovglit about by drugs, the patient's toler- ance does not improve as it does under diet. That we shall ever find a specific remedy for diabetes, must be regarded as quite unlikely, especially by those who, like myself, look upon the disease as an expression of hereditary weakness of metabolism; at present we cer- tainly do not possess such a remedy. We shall now proceed to the discussion of the dietetic treatment in detail. This method of treatment has its place not only in the care of confirmed, true diabetes mellitus, but also in prophylaxis. In families in whom this disease is hereditary there should be great mod- eration in the use of carbohydrates in any form, i. e., limitation of the sugar metabolism should be made an unalterable law. But there should also be moderation in eating and drinking in general. There can be no doubt that habitual hypernutrition favors the outbreak of diabetes if the predisposition to it exists. The cases of diabetes mellitus complicating obesity (even in full-blooded individuals with arteriosclerosis) are almost all to be included in this category. Alcoholism, at least that form that goes hand in hand with over-nutrition, also plays a part in the etiology of diabetes. In individuals with a hereditary predisposition and marked obesity due to over-nutrition, diabetes should always be watched for, and an occasional exam- ination be made of the urine voided four hours after a breakfast in which at least 100 grams of bread and about 30 grams of sugar have been consumed; or, for greater certainty, a test for glycosuria alimentaria e saccharo should be made, and the case should then be judged with the necessary reserve. In confirmed diabetes, dietetic therapy has for its object the elimination of glycosuria if possible. This occurs very readily in some cases, in others it is difficult, and in some it may be impossible; even when it may be accom- plished, although with difficulty, there are, unfortunately, many cases in which the results scarcely compensate the physician and patient for the required trouble. The amount of energy that should be put into the treatment varies in different cases, and much labor will be saved the physician and the patient if this fact is recognized from the onset; on this account it is convenient to divide diabetics into three groups, a method which I proposed ten years ago. 1. The moderately severe cases. 2. The mild cases. 3. The severe or very severe cases. 8 94 DIABETES MELLITUS We have already learned to differentiate between mild and severe cases, but in gauging the case from a therapeutic standpoint we need to recognize also a group of moderately severe cases. The mild cases are so benign that they offer a splendid prospect for therapy and usually require, but little treat- ment. The severe and very severe cases, on the other hand, are so malignant that even after the most energetic therapy the results obtained are slight and unsatisfactory because incomplete or transitory. In the group of moderately severe cases are included a great many which occupy a middle position, being by no means so benign that they do not require continued observation and proper treatment, but by no means so malignant that they should be left to their fate; by a more or less strict plan of treatment, they may be preserved in fair health and moderate activity for many years. Among the cases which at the beginning of treatment must be included in this intermediate group, there are not a few which prove to belong to the mild form, but which, on account of unfavorable influences, have passed temporarily into the moder- ately severe form. In this group we also find some which belong to the severe or very severe forms, but have not yet reached the full development of the disease. Let us illustrate : A man aged fifty, with an inherited predisposition to diabetes. Ten days previously, he undertook a lengthy and fatiguing excursion in the Black Forest, ate and drank more than usual, and was thoroughly drenched by a heavy rain. Since that time, he has had a voracious appetite, extreme thirst, marked diuresis, and has lost much weight. His urine contained 8 per cent, of sugar ( ! ) . His daily dietary was restricted quantitatively to about one pound of meat, several eggs, coffee with rich cream but no sugar, green vegetables ( no potatoes or beets ) , no cereals, 80 grams only of wheat bread, his meals to be prepared without flour; one bottle of wine was allowed. Within a few days his glycosuria had disappeared. The case has continued to run a mild course up to the present time ( twelve years subsequently ) . Since the acute attack, the patient's diet, for the most part, has been restricted as above, although at times it has been relaxed to the extent of allowing sweet champagne ; the sugar in the urine has never risen above 0.5 per cent. At the beginning of treatment this case appeared very desperate, but it soon became a clear example of the mild form of diabetes. To illustrate again : A peasant, thirty-three years of age and of a diabetic family. For five weeks following an accident he complained of hunger, thirst, loss of flesh, lassitude, and cramps in the calves of his legs. Patellar reflexes present; no complications; weight 48 kilograms; internal organs sound. After eight days on regulated diet including fat meat, with 150 grams of milk, and 20 grams of wheat bread, the sugar in his urine was still 4 per cent. — 5 per cent. (75 to 100 grams of sugar a day). Only after the complete withdrawal of bread and increase of milk to 200 grams did the urine gradually become free from sugar. After this on a diet with 200 grams of milk and 50 grams of bread he remained aglyco- suric for several months, but even then he had to rigidly conform to rules in order to prevent the reappearance of glycosuria. In this fashion he has now lived for years. His weight is 56 kilograms. This is a typical case of the medium severe form; severe at its onset but under continuous, moderately strict dietetic treatment taking a rather favor- able course. PRACTICAL THERAPY 95 The following is another typical example of this group : A bookbinder, seventeen years old. No family history of diabetes. For five weeks, without apparent cause, he was continually hungry, he lost weight, was extremely weak, and had a non-gonorrhea] urethritis. Organs sound; knee-jerk normal; weight 45 kilo- grams. On a diet of '220 to 300 grams of meat, green vegetables, 250 grams of milk and 300 grams of bread, there was a glycosuria of 6 per cent. = 150 to 200 grams of sugar a day. Only upon complete withdrawal of bread while still taking 25 grams of milk, did he become free from sugar. After a sugar-free period of one month, he could take more milk and a small quantity of bread without excreting sugar. He gradually became accustomed to a larger allowance of bread and milk, being careful never to take enough to produce glycosuria.' This tolerance gradually increased until he could ingest 170 grams of bread and 100 grams of milk without sugar appearing in the urine. The patient remained in this condition, outside the hospital, for two years. After this (probably because he did not adhere to the same diet) sugar was again excreted, and did not disappear on very strict diet — so that the case became severe. The object in quoting these examples is to show clearly the existence of a moderately severe form of the disease. At the outset, cases like those just quoted may readily be looked upon as extreme, and thus great harm may result. Among the points on which the recognition of medium severe cases rests the most important is this, that after partial withdrawal of carbohydrates (for example, 200 grams of milk and 50 grams of bread), no matter how marked the glycosuria has previously been, it immediately and decidedly decreases, usually falling below 100 grams. Besides, in these cases of medium severity, the amount of acidosis as determined by the ferric-chlorid and ace- tone reaction is slight, and the amount of urine is not great (4 and, at most, 5 liters per day) . All these conditions may also exist in severe cases. After determining to which group a given case belongs, the physician must outline the method of treatment as follows : 1. Mild cases are to be made aglycosuric, and maintained in this condition until continuous observation for at least six months has demonstrated that the disease shows no tendency to progress. Later, a permanent increase of glycosuria above 0.5 per cent, should not be permitted. Such a transitory increase need cause no anxiety, but as soon as it becomes greater the case is to be treated as at first by strict limitation of the diet. 2. Cases of the medium severe form are to be made aglycosuric by strict treatment if this is necessary. Then, in case they do not prove to be mild cases, they are to be permanently maintained in this condition. Even a mild glycosuria is not to be permitted, and anything causing a transitory increase of glycosuria is to be absolutely avoided, as it threatens the already greatly endangered tolerance. It is possible that there are individual cases which at the onset belong to the medium severe group, but which may be rendered mild, and then the indulgences possible for cases of the mild forms may be permitted; but such cases are certainly not frequent. 3. The nature of the severe and very severe cases becomes manifest when on the first attempt to produce aglycosuria the feebleness of their tolerance appears. In these cases, our primary object is to bring the patient to the point at which life can be maintained without a deficit; but this can rarely be brought about, unless we can limit, and that decidedly, the loss of sugar in 96 DIABETES MELLITUS the urine. We must make an attempt to diminish the glycosuria, and see how far we are successful. Now and then, we can accomplish more than we had hoped, and a better tolerance may follow a regulation of the diet and a reduc- tion of the glycosuria, so that we may succeed in maintaining the patient's equilibrium of metabolism with a very slight glycosuria and with a fair con- dition of health for years, even after all hope had seemed to be gone. This is the chief task of the physician, easy in some cases, more difficult in others, and in many almost impossible. Although the treatment of the different groups of cases varies, one general rule applies to all. We should determine the exact quantitative and qualitative diet for every diabetic who comes under treatment. Prout exaggerated when he stated (1820) that the quantity of the food, that is, the quantitative restriction, is more important for the diabetic than its quality ; but his maxim that all of the diabetic's food (including meat) is to be determined quantitatively, holds good, because noth- ing more unfortunate can befall a diabetic than the overtaxing of his general powers of metabolism. I consider the restriction of labor of the whole metab- olism to be an important advance in the therapy of diabetes. There are no foods which the diabetic can be allowed to eat in unrestricted amount; the quantity of each must be measured. We must see that he does not get too much carbohydrate food, or too much animal food, and that he has just enough fat, neither too much nor too little. I am proceeding on the supposition that the patient is to be treated not in a hospital but in his own home. First of all, we must determine quantita- tively for several days the amount of each food ingested. For this purpose it is only necessary to know the amount of each carbohydrate (flour, bread, sugar and milk) used in the preparation of his meals. If this plan is carried out, there is no difficulty later. Each variety of food should be served on a separate plate, and the amount weighed. Sauces are riot considered, and bread is weighed separately. If the patient cannot afford this, or if he is unwilling to do it, he should either go to a hospital where others will look after his food, or we must relinquish the attempt to regulate the waole diet quantitatively. We may be able to get along without weighing the food in very mild cases in which a moderate reduction of the carbohydrates is sufficient to control the disease. Still, most patients, even those in limited circumstances, can arrange to weigh their food. Usually a simple quantitative regulation of the diet, with liberal allowance for the wishes and inclination of the patient, and without too strict limitation, may be followed by good, even remarkably good results ; at any rate, we may thus ascertain the maximum of the glycosuria on a given diet and thus establish the necessary basis for further dietary regulations. An example will best serve to make this intelligible. A woman, forty years of age, no hereditary history obtainable, has suffered for four months from extreme hunger and thirst; there is copious diuresis; loss of weight 20 kilograms. Present weight 58 kilograms; no organic disturbances or complications; no acidosis; reflexes normal. The patient asserts that she has been on a diet, that is, that she has eaten but little bread, etc. During the first three days of treatment, she ate as before and was found to be excreting 2i to 3 liters of urine with 6 per cent, to 7 per cent. (=150 to 200 grams) of sugar per day. Then the diet was regulated quantitatively, PRACTICAL THERAPY 97 taking the wishes of the patient into consideration. She received, daily 500 grams of milk, 100 grams of bread, 200 grams of meat, 4 eggs, 200 grams of vegetables with ten per cent, of fat, 50 grams of butter, and 75 grams of fatty cheese or sausage, etc., with tea, coffee, and water ad libitum, and a half liter of wine. This diet was abundant, and gave the patient 35 calories per kilo of body- weight. She remarked that she had not eaten much more before treatment, not even of bread. During the following days she excreted li to 2 liters of urine, and 3.5 per cent. (=50-70 grams) of sugar daily. At the 'same time she felt stronger and improved each day. No acidosis. This is, in itself, a truly remarkable result of quantitative regulation of the diet. Of course, there was some restriction, but the patient hardly noticed it. In this case, the milk and the bread must be still further reduced until the sugar has disappeared entirely. Our patient preferred not to have the milk in her diet reduced. The bread was there- fore reduced to 40 grams, but after four days upon a diet containing 60 grams of bread she still excreted sugar, but when the milk was reduced to 300 grams and the bread to 40 grams there was no glycosuria. On this diet she remained aglycosuric, so that after fourteen days it was deemed possible to increase her food. For the sake of precaution, 100 grams of milk were withdrawn, but 10 grams of bread were added. She remained free from sugar. After three days 100 grams of milk were added, and the patient continued free from sugar; again after three days 10 grams of bread were added, and 100 grams of milk withdrawn. Thus she continued upon a diet of 500 grams of milk and 100 grams of bread for six weeks, when she was aglycosuric and in apparent full health, having attained a weight of 62 kilograms. She remained under observation. Occasionally, as the result of an indiscretion in diet, a slight, transitory glycosuria occurred, and then the patient would live on 50 grams of bread for a few days, or would desist altogether from eating bread for a whole day, then return to 50 grams of bread for a few days, until finally she became perfectly aglycosuric on a diet of 100 grams of bread. The removal of glycosuria is by no means always so easy and simple. Very often more stringent methods must be employed; carbohydrates, flour foods, and even milk, must be wholly excluded before the patient becomes entirely free from sugar, and frequently even this is insufficient and nothing remains but the reduction of albuminous food. The albumin nutrition may then be restricted to 200 grams, even to 150 grams of cooked meat (reckoning albumin as meat), so that the patient does not receive more than 40 to 50 grams of albumin. In the severe cases this limitation of the albumin nour- ishment is one of the most important points. Its effect is often much greater than can be explained by the withdrawal of the sugar formed from the albu- min. For example: With 100 grams of albumin (besides the necessary fat) 40 grams of sugar are excreted; after a reduction to 60 grams of albumin, sugar disappears in a few days. That 40 grams of sugar are formed from 40 grams of albumin is hardly possible ; therefore, the aglycosuria cannot be due to the limitation of sugar intake (in albumin). I have long been convinced that it is the limitation of food and the resulting disencumbrance of the entire metabolism which brings about this favorable result. The metabolism of the diabetic is not deficient in only one respect, namely, that with which we are concerned, the working up of the sugar molecule and its preparation for oxidation. His metabolism is deficient as a whole — witness the weakness of the powers of oxidation as expressed unmistakably in the acidosis. 98 DIABETES MELLITUS In the severe cases which we are now considering it is almost always neces- sary to limit the entire amount of food (albumin and fat included) so that its total calory value will be lowered, even below the minimum required by Eubner (35 calories per kilo of body- weight). Under-nutrition need not be feared; my diabetics, at least those who are treated in the hospital, get along with 30 calories, and even less, per kilo, without losing body- weight. When the excretion of sugar has fallen to the minimum, about 0.5 per cent., and not more than 10 grams of sugar per day are excreted, aglycosuria may finally be brought about by giving the patient no food for twenty-four hours. He may be allowed water ad libitum, for it is unnecessary in this con- dition that the patient should suffer from thirst. This procedure — a twenty- four-hour fast — was introduced by Cantani. Both the reduction of the albuminous foods and the twenty-four-hour fast seem cruel, or at least drastic, measures, but they really are not so; at least the author has never had the least difficulty in enforcing them. More diffi- culty in the strict dietetic treatment of diabetes is encountered in other direc- tions. We shall speak of this later on. After glycosuria has been abolished, if we expect to increase the tolerance, we must maintain aglycosuria for at least two weeks before we can appreciably add to the food. After the patient has been finally brought to the daily allow- ance of food which is sufficient for him he must remain upon this diet and be under observation. It is also advisable at times to institute once a week a twenty-four-hour fast for carbohydrates, during which period the patient receives no bread. Keeping the patient for a month or longer without bread, starchy foods or milk rarely succeeds, but the author knows of several diabetics who have lived for years on a strict albumin-fat diet with the addition daily of 200 to 400 grams of green vegetables (deficient in carbohydrates), and they have been able to attend to their business without taking unusual care of them- selves. One, a man about forty years of age, held the responsible position of professor at a university. We must, then, exert all our efforts and all our art properly to regulate the diet! In what follows, I shall only mention briefly some of the main rules, the observance of which will enable the physician judiciously to handle his dia- betics. We shall see, however, that in order to prescribe a diet, he must be familiar with the composition of the most common foods as regards fat and carbohydrates. All recent books on diabetes contain detailed data on this subject, and the most essential figures in this respect will be given at the conclusion of this article. I shall attempt no distinction between what is absolutely (in any quan- tity) allowable for a diabetic, and what is absolutely forbidden. I consider such a distinction wrong and dangerous. No diabetic should be permitted the unrestricted use of any food; everything must be ordered him quantita- tively. The amount of carbohydrates permitted is best considered in terms of wheat bread; and most patients prefer to take the amount of carbohydrates PRACTICAL THERAPY 99 permitted them in the form of good wheat bread. Some, however, would rather have it as flour-cakes, and there is no objection to their having it in the form of any simple carbohydrate that they prefer. If the patients take their carbohydrates partly as wheat bread and partly in some other way, then we must subtract the latter amount from the total that is permissible. Sup- pose, for instance, that the patient is allowed 100 grams of wheat bread = about 60 grams of starch. He prefers to take part of his starch in another form, for instance, as oatmeal or rice, in soup, 10 grams being sufficient to make a large dish of ^ of a liter ; or he takes balls of oatmeal, or 25 grams of oatmeal alone. Oatmeal and rice contain about 75 per cent, of starch. We can consider the 10 grams of oatmeal as equivalent to wheat bread, and there- fore we must subtract 10 grams (or to be quite accurate 12 grams) from the daily allowance (100 grams) of wheat bread. Twenty-five grams of grits or rice are equal to about 30 grams of wheat bread. Of course, the patient may have other forms of bread instead of wheat bread. Eolls are useful for this purpose, the amount of starch being almost the same as in wheat bread. The rolls may be cut into small slices and spread with butter. Eye bread is also serviceable; it contains 15 per cent, less of starch, but is heavier and more compact. Aleuronat bread contains only about half as much starch as wheat bread, but there are few diabetics who like this bread, although among all the varieties of so-called " diabetic bread," this has the most agreeable taste. Among vegetables the diabetic should eat only those in which the amount of carbolrydrates does not exceed 5 per cent, (compare the tables), and even this slight amount of carbohydrates must not be ignored in those cases in which the removal of glycosuria is difficult. With 300 grams of vegetables per day, it may amount to as much as 15 grams. Fruits should be permitted the diabetic if possible. There are plenty of fruits whose carbohydrates do not exceed 6 per cent, (sugar -j- pectin). They must be well cooked and sweetened with saccharin. Almost any kind of fruit may be given, even such as contain sugar in large amounts, but the amount of carbohydrates they contain must be deducted from the amount of bread which is permitted. Only grapes and dried fruits, on account of their high sugar-contents, are to be excluded. The fact that the sugar contained in fruit is levulose modifies the case but little, for after prolonged use levulose becomes almost as injurious as dextrose. Many so-called " fruits for diabetics " are to be found on the market ; they contain about 2 per cent, to 4 per cent, of sugar, therefore less than the fresh fruits, even those poor in sugar, but, unfortu- nately, many diabetics grow tired of them after a time. In meat, besides the albumin, we must take into account the fat it con- tains. Considering only the percentage of albumin (25 per cent.), the calory value of stewed or broiled meat is only 1. When the ordinary amount of fat is present (10 per cent.) the calory value becomes 2, but we must remember that in the cooking of meat (broiling, stewing) part of the fat is lost ; in fact, most of the fat is lost in cooking. Excluding the fat, all kinds of meat are of the same calory value. Liver is strictly forbidden; of other " glands " sweetbreads and brain, though not strictly meat, are of equal value on account of their high percentage of fat. Naturally, fat meat is always preferable for 100 DIABETES MELLITUS a diabetic; some fat meats and fat fish contain 20 per cent, of fat or more (see diet lists). As a working principle, let us say that a diabetic should not eat more than, 500 grams of meat (weighed after cooking), for most patients lose their appe- tite if they eat more; diabetics who are under close medical supervision may be permitted more, but it is usually of no benefit. Eggs are very useful. On account of the large amount of fat in the yolk, each egg has a value of 75 calories. If we allow more than two eggs, we should subtract 50 grams for each egg from the amount of meat allowed. Fat foods are of the greatest value, for fat, as a rule, does not increase glycosuria and has the enormous nutritive value of 9 calories, while starch and albumin have only 4. In good sausage (poor sausage often contains flour and but little fat!) there is 30 per cent, to 40 per cent, of fat; in good cheese from 20 per cent, to 30 per cent.; poor cheese contains but little fat. Butter contains 85 per cent, of fat; lard (butter or fat melted), bone marrow, and vegetable oils almost 100 per cent. Bacon varies greatly in regard to the amount of fat it contains ; it averages about 92 per cent. An enormous calory value may be obtained in the following foods: 100 grams of Holland cheese (30 per cent, fat) gives 270 calories, without including the albumin; 100 grams of good butter, 720 calories. Fat and butter may be mixed with vege- tables so as to make them contain 10 per cent., even 15 per cent, of fat; bacon and oil in salad, up to 20 per cent, to 40 per cent. Cheese may be pulverized and added to soups and sauces, and also may be made into cheese cakes, cheese puddings, etc. Cream contains 25 per cent, of fat, and is, therefore, very valuable; the slight amount of sugar it contains (3 per cent, milk-sugar) need scarcely be regarded. Some cream contains even more fat than this (up to 40 per cent,). If it is dairied in a very cleanly manner, it is at first very grate- ful to the taste, but after prolonged administration patients often do not like it. Milk is in general use, and, even in the most severe cases, of great value. But it must not be supposed that the milk-sugar is " harmless " to the dia- betic, for it is not much less so than dextrose and cane sugar; but milk con- tains very little sugar, only about 3 per cent. Its carbohydrate contents must be reckoned, but it also contains 4 per cent, to 5 per cent, of fat. There are several manufactured preparations of milk which contain a larger amount of fat, and in which the sugar is decreased; there are even artificial milks free from sugar — but my patients soon become tired of these preparations. Other fluids are to be estimated according to their carbohydrate value; among wines only the southern wines and champagne contain more than 3 per cent,; these contain 12 per cent. In beer the carbohydrate value is rarely under 6 per cent. Beer is more harmful than this percentage would lead us to suppose, as it contains the greater part of its carbohydrates as maltose; this at once decomposes in the intestines into dextrose, and, for this reason, the diabetic ingests in beer the most dangerous, most readily absorbable form of carbohydrate food. Among alcoholic liquors only rum, cognac, whiskey, etc., are to be con- PRACTICAL THERAPY 101 sidered ! No liqueurs ! These, and often the so-called " bitters/' contain enor- mous quantities of sugar. Coffee and tea may be looked upon as harmless for the diabetic. Cocoa contains (without admixture) 15 per cent, of starch, and must be estimated accordingly. If it is desirable to increase the menu still further, manufacturing chem- ists have placed many preparations on the market for the diabetic. The physi- cian should assist the diabetic to make his life as comfortable as possible, yet the medical adviser must never allow the reins to be taken out of his hands ; unfortunately, this often occurs. Which diabetics are to be treated at a hospital (of course, one well appointed with reference to diabetic treatment), which may be treated at home, and which should be sent to Carlsbad, Vichy, Neuenahr, etc. ? The very mild cases, in which only sugar, potatoes and beer must be restricted in order to make the urine free from sugar, do not need hospital treatment, though it is advisable for them to undergo each year, or at least from time to time, a course of treatment at any one of the previously men- tioned bath cures. Frequently these cases occur in elderly persons, in whom a cure of this sort is indicated on account of complicating arteriosclerosis, disease of the liver, or gout. It is often wise in such cases, after sugar has been discovered, to send them at once to Carlsbad; they return free from sugar, and with a greater docility and willingness to carry out further dietetic treatment. If the case is severe, so that it is necessary to reduce to a minimum the allowance of bread in order to free the urine from sugar, the question whether the patient should be treated at home or in a hospital must be settled by the individual circumstances. If the patient is sensible, reliable, and in easy circumstances, treatment at home should be tried, but we must not be too optimistic as to results ; as soon as signs of unreliability on the patient's part are detected, hospital treatment should be urged. If, under treatment at home, the sugar has been considerably reduced (to about 20-30 grams a day), we may send the patient to Carlsbad, whence he often returns sugar-free, and he may then more easily than before be kept aglycosuric ; but this applies only to the mild cases. Every diabetic whose case is not very mild, or who is not reliable or well- to-do, as well as every moderately severe and every severe case (that is, every patient from whose diet carbohydrates must be largely or wholly eliminated, if only for a time), must, to begin with, have hospital treatment. In a hos- pital we find out how much can be attained, and we determine the diet on which the patient will become sugar-free, or will have, at least, only a gly- cosuria of definite and known intensity. After this he must remain under supervision, and if the glycosuria again shows a progressive tendency he should return to the hospital. Poor patients with severe diabetes need hospital treat- ment at least every year, of six or eight weeks' duration the first year, and reduced, if necessary, to four weeks the next year. In the author's experience, " bath cures " rarely benefit these patients, and often do harm. 102 DIABETES MELLITUS DISTURBANCES AND DANGERS OCCURRING IN THE DIETETIC TREATMENT OF DIABETES That disturbances of digestion often occur during dietetic treatment has been known ever since the disease has been treated by a restriction of food. The more violent disturbances, such as used to occur when our knowledge was less, for instance, diarrhea, sometimes combined with vomiting, should now be prevented entirely. They may be avoided in trustworthy patients if the whole amount of food ingested is quantitatively determined, if too large a portion of meat is not allowed, and if we bear in mind the sensitiveness of the patient as regards fat and fatty foods. Some patients lose their appetite from the beginning, or as soon as carbohydrate food, especially bread, is re- stricted. This anorexia may be avoided by giving them fruits. If the patient likes the fruits prepared for diabetics he is very fortunate; otherwise cooked or uncooked fruits that contain but little sugar may be used. I am loath to forbid fruits altogether, and even in the severe cases I usually allow as much as 100 to 200 grams. Milk, also, is very valuable; -J to 1 liter of milk a day with a restricted fat-albumin diet often helps the patient over the period of anorexia without increasing the glycosuria to any extent, and without mak- ing the patient lose weight. With these precautions, we are not compelled to break off the dietetic treatment as soon as it is begun, but may go on with it cautiously as soon as the appetite has improved. Every disturbance of appetite, however, must be seriously considered, for, on the whole, cases with anorexia are the most difficult to deal with. In some of these cases, psychic depression plays a certain part, and if their disease is not too pronounced, they often get along much better at Carlsbad or Neuenahr than if they stay at home, or go to a hospital. In acidosis we have an especially formidable hindrance to strict dietetic treatment. In many of the moderately severe cases it appears as soon as the diet is restricted, or, if already present, it becomes more marked when the carbohydrates are limited. Then the patient is at once in danger, because acidosis may lead to coma. Formerly, this often happened when the diet was restricted too suddenly, and even to-day cases with acidosis are always in danger if severe gastric disturbances occur. In the absence of gastric irritabil- ity this danger may be averted by the administration of sodium bicarbonate. Enough should be given to make the urine feebly alkaline, and 50 or more grams in twenty-four hours may be necessary. With this precaution we may endeavor to reduce glycosuria by strict diet even where decided acidosis already exists. Of course all food and its calory value must be determined with quan- titative exactness, for, to repeat, it is the disproportion between the quantity of the products prepared in metabolism for oxidation and the power of oxida- tion itself which finds its expression in acidosis. In cases with acidosis we must not think of withdrawing carbohydrates entirely, but should allow 60 to 80 grams of bread, £ a liter of milk, and as much as 200 grams of fruit. The latter is here particularly important in order to prevent indigestion. We may counl with certainty on the fact that if the acetone reaction he- comes marked at the onset, the cause is simply the urinary sodium, that is, the TABLES 103 alkalinity of the urine. Sometimes the diacetic acid (ferric chlorid) reaction also becomes marked; but this should not be allowed to occur after the first few days. In case the reaction becomes still more intense, so that the urine blackens on the addition of ferric chlorid, milk should be cautiously added to the diet, and its calory value subtracted from that of the meat, which should be correspondingly reduced. Otherwise, if the general condition of the patient remains good, we may maintain an expectant attitude until the ferric chlorid reaction becomes less marked, which usually occurs in eight to four- teen days, sometimes earlier or later. When this diminution of acidosis begins the danger from this source is over; acidosis gradually disappears and will not cause trouble, even should a further restriction of the carbohydrates be necessary. Of course, if symptoms of coma appear we must increase the dose of sodium bicarbonate until the urine is alkaline. Sometimes 100 grams or more of sodium bicarbonate must be given in twenty-four hours. In almost every case of this kind, it is milk which answers our purpose best. VI. TABLES Tables of foods: different kinds of meat, fish, eggs, sausages, meat-preserves, and various kinds of cheese, arranged according to the amount of fat they contain. — Fat, butter and varieties of milk, with percentages of fat and carbohydrates. — Bread, flour and vegetables, with percentages of carbohydrates. — Fruits and their carbohydrate (sugar + pectin) contents. — Beer, wine and spirits, with their amounts of alcohol and carbohydrates. — Plan for calculating the food-value of the diet in calories. — Short popular dietary instructions for diabetics. MEAT WITH PERCENTAGE OF FAT 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. Percentage of Fat. Fat pork 37.34 Very fat mutton 36.39 River eel 28.37 Fat beef (from ox) 26.38 River lamprey (smoked or pickled) 25.59 Salt herring 16.89 Sprat 15.94 Very fat horseflesh 15.64 Salt mackerel 14 . 10 Salmon (smoked or salted) 11.86 Mackerel (fresh) 10.10 Rabbit (fat) 9.76 Chicken (fat) 9.34 Bloater 8.51 Bleak 8.13 Fat cow's meat. . , 7. 70 Fat veal 7.41 Fresh herring 7.11 Swedish anchovy (salt) 7.05 Lean pork 6.81 Salmon 6.42 Swedish anchovy (fresh) 5.87 Half fat mutton 5.77 Medium fat beef (ox) 5.19 Sea eel 5.02 Duck (wild) 3.11 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. Percentage of Fat. Groundling 2 . 68 Medium fat horseflesh 2 . 55 Anchovy 2.21 Roe (deer) 1.92 Plaice 0 . 25-1 . 80 Lean cow's meat 1 . 78 Fieldfare. Lean beef (ox) Partridge Chicken (lean) Hare Carp Pigeon Veal (lean) Stock-fish Gadus Pike Very lean horseflesh (minimum) . Roach Perch Codfish Oysters , Crab , Haddock , Torek 77 50 43 42 13 1.09 1.00 .82 .78 .70 .51 .50 .47 .44 .39 .37 .35 .30 .20 104 DIABETES MELLITUS EGGS Percentage of Fat. 1. Hens' eggs (average weight, 53 grams) 12.11 2. Duck eggs 15.49 Percentage of Fat. 3. Lapwing eggs 11.66 4. Carp roe 6.00 5. Caviar 15.70 SAUSAGES AND PRESERVED MEATS Percentage of Fat. 1. Clean, well-smoked, meat-free bacon 92.20 2. Westphalia sausage 39 . 88 3. Cervelat sausage 39 . 76 4. Frankfurters 39.61 5. Westphalia ham 36 . 48 6. Smoked beef-tongue 31 .61 Percentage of Fat. 7. Pomerania goose-breast 31 .49 8. Smoked beef 15.35 9. Tinned meat 12.63 10. Blood-sausage 11 .48 11. Hard smoked sausage 11.40 12. Dried beef 5.24 CHEESE Percentage of Fat. 1. Neufchatel 40.80 2. Stilton cheese 34.55 3. Stracchino cheese 33 . 67 4. Roquefort cheese 33 .44 5. Brick cheese 32.78 6. Cheddar cheese 32.37 7. Edam cheese 30.26 8. Gervais cheese 29.75 9. Emmenthal cheese 29.67 10. Gloucester cheese 28 . 08 11. Gruyere cheese 28.04 Percentage of Fat. 12. Cheshire cheese 27.46 13. Holland cheese 26.70 14. Artificial oleomargarin 25 . 95 15. Swiss cheese (ordinary) . . . . 23.54 16. Artificial fat cheese 21 . 70 17. Romadour 20.66 18. Camembert 21.00 19. Brie 20.27 20. Parmesan cheese 19.52 21. Swiss caraway cheese 12. 11 22. Meager cheese 6 . 84 DIFFERENT FATTY FOODS AND VARIETIES OF MILK {Arranged according to their fat and carbohydrate — sugar — contents.) Fat. Carbohy. 1. Plant-oil 100.00 2. Bone-marrow 100.00 3. Artificial butter 87. 76 4. Butter 83.27 5. Lard 100.00 6. Cream 26.75 7. Condensed cow's milk without addition of cane-sugar 13.19 0.8-0.58 3.52 15.38 Fat. Carbohy. 8. Sheep's milk 6.83 4.73 9. Goat's milk 3.94 4.39 10. Cow's milk 3.65 4.81 11. Ass'smilk 1.64 5.99 12. Buttermilk 93 3.73 13. Kumiss from cow's milk 85 3.10 14. Skimmed milk 74 4.75 15. Whey .23 4.70 The liver of fattened geese (Strassburg liver) should by no means be excluded from the diet on account of its supposedly high percentage of glycogen, for, in fact, this is slight, and does not amount to more than from 0.96 per cent, to 2.8 per cent, (of the fresh liver). I am unable to find any quantitative reports of the percentage of fat in these livers, but it may safely be assumed to be about 30 per cent. BREAD, FLOUR AND VEGETABLES {According to their percentage of carbohydrates.) Per cent. Fine flours (arrowroot, sago, maize, etc.) 83.31 Potato flour 80.83 Biscuit flour for children 77.30 Noodles 76.77 Rice 76^52 Per cent. Oatmeal 75.95 Cakes 73.30 Wheat rusks 72.00 Wheat for rolls 72.00 10. Barley flour 71.74 11. Rye flour 69.66 6. !). TABLES 105 BREAD, FLOUR AND VEGETABLES {continued) Per cent. 12. Barley bread 69.06 13. Coarse wheat flour, including bran for Graham bread 65.00 14. Oatmeal gruel 64. 73 15. Oat bread 64.21 16. Leguminose 64.05 17. Rolls 63.00 18. Coarse wheat bread 53 . 00 19. Rve bread 49.25 20. Soldiers' bread 49.00 21. Pumpernickel 47.00 22. So-called Graham bread 39.00 23. Aleuronat bread (Strassburg make) 34 . 30 24. Aleuronat bread (after Ebsfein) .. . 27.50 25. Peas (dry) 52.36 26. Beans (drv) 49.01 27. Lentils(d'ry) 53.46 28. Bishop's-cap 43.31 29. Truffles (air drv) 37.40 30. Soja beans. 29.99 31. Mushrooms (air dry) 28 . 99 32. Garlic 26.31 33. Onions (white) 25.69 34. Potatoes 20.69 35. Horseradish 15.89 36. Black salsify1 15.00 37. Sweet potato (topinambur) 14 . 00 38. Green garden peas 12 .00 39. Celery 11.80 40. Sugar beets 11 .72 41. Green cabbage 11 . 63 42. Pepperwort 11 . 61 43. Pale red onions (the tuber) 10.82 44. Truffles (fresh) 10.73 45. Red beets 9.56 59. 60. 61. 62. 63. 69. 70. 71. 72. 73. 46. Other-wort 47. Carrots (large) , 48. Beet- root 49. Scallion 50. Radish , 51. Kohlrabi, underground (tuber).. 52. Carrots (small) 53. Parsley 54. Dill , 55. Green horse beans , 56. Pumpkin , 57. Turnip leaves 58. Watermelon French beans 1 Leek (bulb and root) Red cabbage , Brussels sprouts Cabbage (Savoy) 64. Kohlrabi 65. White cabbage 66. Cauliflower 67. Leek (leaves) Spinach " Sugar loaf " Tomato Radish (small) Roman salad (lettuce) Sorrel 74. Mushrooms (fresh) 75. Prickly lettuce 76. Asparagus 77. Endive 78. Cucumbers 79. Headed lettuce Per cent. . . 9.46 .. 9.35 .. 9.26 .. 9.08 .. 8.43 8.18 8.18 7.44 7.43 7.35 7.33 7.28 7.14 6.60 6.53 6.25 6.22 6.02 4.00 4.87 4.55 4.55 4.44 4.29 4.07 3.79 3.55 3.43 2.91 2.73 2.63 2.58 2.28 2.19 Dates. PERCENTAGE OF CARBOHYDRATES IN DIFFERENT FRUITS, ETC (Sum of sugar and non-nitrogenous [sugar-producing'] extracts [pectin].) Sugar. N.-free extracts. S Dextrin 3.4 ) \ Sugar 58.00 \ Locust-bean ■p. . -, ( Cane-sugar 0.22 ) Dried prunes j Grape-sugar 44.19 \ Raisins 54.56 Dried apples 42.83 Dried figs 49 . 79 Dried nears (Grape-sugar 24.14 Vued pears -j Cane.sugar 4 99 Dried cherries 31 . 22 Bananas Chestnuts (genuine) Sunflower seed Poppy seed Wine grapes 14 . 36 Total. 13.00 74.40 67.67 67.67 17.69 62.10 7.48 62.04 11.40 54.23 49.79 19.34 48.47 14.19 45.51 23.05 23.05 38.34 38.34 20.03 20.03 18.74 18.74 1.96 16.32 1 Ripe black salsify and sweet potato (topinambur) contain levulose almost exclu- sively. The unripe roots contain much dextrose, the proportion between levulose and dextrose in both is inconstant and variable, as the roots are not always quite ripe. In French beans (55), the substance given as being a carbohydrate is inosite, which is not a genuine carbohydrate, and is entirely harmless. 106 DIABETES MELLITUS PERCENTAGE OF CARBOHYDRATES IN DIFFERENT FRUITS (continued) Sugar. N.-free extracts. Total. 14. Green gages 3.16 11.46 14.62 15. Mirabelle plums 3.9? 10.07 14.14 Hi. Apples 7.23 5.81 13.03 17. Cherries 10.24 1.76 12.00 18. Mulberries 9.19 2.03 11.22 19. Pears 8.26 3.54 11.80 2). Peaches 4.48 7.17 11.65 21. Prunes 6.15 4.02 11.07 22. Apricots 4.69 6.35 11.04 2:5. Hazelnuts 9.03 9.03 24. Gooseberries 7.03 1.40 8.43 25. Plums 3.56 4.68 8.24 26. Cocoanut 8.06 8.06 27. Walnuts 7.89 7.89 28. Currants 6.38 0.90 7.28 29. Almonds 7.23 7.23 30. Strawberries 6.28 0.48 6.76 81. Whortleberries 5.02 0.87 5.89 32. Candlenuts (bankulnut) 5.88 5.88 33. Blackberries 4.14 1.44 5.88 34. Oranges 4.59 0.95 5.54 35. Raspberries 3.86 1.44 5.30 36. Peanuts 1.85 1.85 37. Cranberries 1.53 1.53 DIFFERENT KINDS OF BEER (According to their alcohol and carbohydrate contents.) Carbo- Alcohol, hydrates. vol. per cent. 1. Braunschweiger Mumme „ 52.29 2.96 2. Wheat beer from Celle 10.45 0.70 3. Porter.... 7.55 5.35 4. Bock beer (Marzen, Saloon, double beer, etc.) 7.20 4.74 5. Ricebeer 6.83 4.02 6. Export beer 6.48 4.31 7. Ale 6.03 4.89 8. Lager or summer beer. . 5 . 78 3 . 95 9. Swedish beer 5.68 3.89 10. English beer 5.65 5.55 11. Lighter beer varieties (usual yeast and winter beers) 5.49 3.46 12. Berlin weiss beer (1878) 4.28 3.33 13. Belgian beer 3.84 6.08 AND SPIRITS PERCENTAGE OF CARBOHYDRATES (SUGAR + "EXTRACT") IN WINES Carbohydrates (sugar + "extract"). 0.8 1. Russian Dorvy- vodka. 2. Arrack 3. American whiskey... 4. French cognac 5. Rum 6. English whiskey. Alcohol, vol. per cent. 62.00 60.05 60.00 55.00 51.40 49.40 7. Ordinary brandy (s. schnaps) 45 .00 8. Sherry 9. Port ..'...*...".".*."..!'.".. 10. Madeira 11. Swedish punch 12. Muscatel 13. Greek wine 14. Tokay 15. Ruster Ausbrueh. 20.89 20.00 19.20 18.90 16.05 15.40 j 14.89 14.72 3.53 6.99 5.28 33.20 18.60 Max.... 41.00 Min.... 2.65 72.4 8.8 TABLES 107 PERCENTAGE OP CARBOHYDRATES IK WINES AND SPIRITS Alcohol, vol. per cent. 16. Malaga 14.22 17. Italian wine 13.86 18. Tyrolese wine 12.57 19. Bohemian white wine 12.09 20. Moselle and Saar wine 12.06 21. Palatinate wine 11.55 22. Rhine wine. ... 11.45 23. Bohemian red wine 11.16 24. Rhine-Hessian white wine 11.07 25. Baden wine 11 . 07 26. French champagne 10.35 27. French wine 10.34 28. French white wine 10.30 29. Alsatian wine 10.14 30. Rheingau wine (red wine) 11 .08 31. Alsatian fine wine . . 9 . 938 32. Aar wine 9.90 33. Hungarian wine 9 . 78 34. Hessian wine 9.67 35. Vorarlberg wine 9 . 66 36. Swiss wine 9.56 37. Red Rhine wine 9.55 38. Austrian red wine 9.49 39. Rhine wine mousseux 9.44 40. French red wine 9 . 40 41. Wiirttemberg wine 7. 85 42. Fruit wine 4.28-5.65 (continued) Carbohydrates (sugar + " extract "). 17.27 3.63 3.67 1.99 1.804 2.4 2.3 2.2 2.0 7 0 1.8 2.5 2.265 1.2 1.4 1.972 3.06 2.7 10.70 2.3 2 2 2.75^4.75 FOR CALCULATING THE NUTRITION AND CALORY VALUE OF THE DIET Food. Albumin. Fat. Carboh. Calories. Amount. Per cent. Amount. Per cent. Amount. Per cent. Amount. Per cent. Amount. 1. Meat 22.0 15.5 6.0 3.1 7.5 6.25 22.0 25.0 28.1 0.63 0.63 4.0 48.0 5.5 3.0 1.0 48.0 30.0 8.0 0.10 3-20 87.00 100.00 100.00 Gran 4.5 65. 55. 22. 1.3 0.85 is. 125. 500. 75. 59. 295. 250. 627. 375. 150. 30-200 800. 900. 900. 700. Calories 2. Sausage 4. Milk 5. Rolls 6. Wheat bread 7. D-sticks (Rademann) 8. Fat cheese 10. Bouillon 12, Butter 13. Lard 14. Oil 15. Alcohol (per cent, in ) Fat 108 DIABETES MELLITUS SHORT POPULAR DIETETIC RULES FOR DIABETICS No food is to be given to a diabetic in unrestricted amount! The follow- ing rules are not, therefore, to be understood as permitting any food in indis- criminate quantity. The physician must decide in the beginning how much of each food may be eaten, and the patient must comply with his orders. These tables are, therefore, subject to variation. 1. Meats: bouillon or meat broth; meat of any kind, stewed, grilled, smoked or preserved. The addition of flour or bread in the preparation of meat is to be avoided; hence, Wiener schnitzel, stuffing of meat, stuffing of chicken, etc., are forbidden. The kind of meat is of little importance except for the amount of fat it contains; the patient may take beef, pork, mutton, veal, goat, game, venison, birds, etc. The part of the body used for food is also of little account ; muscle, kidney, pancreas, brain, giblets, are all allowed. On account of the glycogen it contains, liver forms an exception and is forbidden. Flour and bread should not be used in the preparation of sauces. 2. Fish of any kind are allowed. Still, as they do not contain the same percentage of fat, they are of different values. The fattest are the eel, river lamprey and herring; most others are lean. Lobster and crab have the same value as lean fish. The same rules apply to their preparation as to that of meat. Shell-fish, oysters and snails are not advisable on account of their high percentage of glycogen. 3. Eggs and fat-foods. Eggs of any kind and preparation (without flour) are allowed; also good sausage (except liver sausage), ham, bacon, caviar, Strassburg goose-liver, sardines, fat, cheese, butter, oil, etc. 4. Milk preparations. Small quantities of not too sweet cream are allowed, also sour milk from which the milk-sugar has at least partially disappeared through fermentation. Eegarding milk, special orders from the physician must be obtained. 5. Vegetables and starchy foods. Of vegetables we allow spinach, cauli- flower, French beans, asparagus, lettuce, cucumbers, small quantities of celery and of crisp cabbage, mushrooms and other edible fungi (except truffles) and sauerkraut, as much fermented and as old as possible. Prohibited are flour, rice, cereals, sago, tapioca, potatoes, peas, lentils, dried beans, green peas, yellow, white and red beets, horseradish, arrow-root, and corn-starch. The orders of the physician must be strictly followed as to the amount of bread to be taken in twenty-four hours. Gluten bread, Graham bread, aleuronat bread, which are recommended as substitutes for ordinary wheat and rye bread, are, on account of the larger or smaller amount of flour they contain, to be used only after consulting the physician. 6. Fruits, etc. Advisable are mandarins, oranges, currants, raspberries, gooseberries and strawberries, but especially cranberries; also nuts and almonds. 7. Beverages: Allowed are water, mineral water, coffee, tea, red wine TABLES 109 which is not too sweet, or white wine, cognac, cherry brandy, and pure rye whiskey. Prohibited are cocoa, chocolate, sweet wine, champagne, and also beer and liqueurs. 8. Spices. Pepper, also red pepper, and small quantities of English mus- tard are harmless. Saccharin or crystallose is allowed in small quantities (0.1 gram per diem) to sweeten the food. Sugar, also levulose, is forbidden in any form, as well as honey. Every diabetic should be advised to eat as much fat and butter as he can without disturbing the appetite; hence, fat gravies, fat meat, vegetables, and salads prepared with considerable oil are recommended. DIABETES INSIPIDUS By D. GERHARDT, Strassburg Diabetes insipidus belongs to those diseases which are of great interest to physicians, less because of the frequency of their occurrence than on account of the peculiarities of the pathological disturbances, and their definite analogy to physiological experiment. Strictly speaking the disease has but one symptom : decided increase in the excretion of urine. Everything else that is mentioned among the symp- toms is either a consequence of this disturbance or is only an inconstant accom- panying symptom. Increase of the excretion of urine occurs in quite a number of pathological conditions as a more or less regular symptom ; thus, particularly in contracted kidney, in the convalescence of febrile diseases, and during the absorption of fluids from the cellular tissues or serous cavities. But we speak of diabetes insipidus only when none of these conditions is present. This rare disease occurs at all ages, most frequently between the tenth and fortieth years of life. The male sex is about twice as frequently affected as the female. There are great variations in the severity of the clinical picture in differ- ent cases. In many persons the disease lasts for decades, and even for a life- time; and beyond the inconvenience of frequent urination and the corre- sponding thirst, there are no disturbances of the general health. In others nutrition suffers greatly, and there is a lessening in the capacity for work yet without any influence on the duration of life. In still other cases it is a severe disease which soon terminates in death. This great difference in the severity of the symptoms makes it likely that there is no single disease corresponding to the name "diabetes insipidus," but that a number of different diseases in which the most conspicuous symp- tom is the profuse production of urine, are grouped under this name. We know that an increase of urinary excretion may be artificially pro- duced by increasing the intake of fluid, by raising blood-pressure, by irritation of certain areas of the central nervous system, by direct irritation of the kid- neys with certain pharmacological remedies, and finally, by the introduction of so-called diuretics, which in their excretion through the kidneys carry with them profuse quantities of water. It is probable that in the genesis of the clinical pictures which have been included under the name of diabetes insipidus, several of these factors and 110 DIABETES INSIPIDUS 111 perhaps all of them have played a part, and it is possible that upon the basis of such difference in the manner of production a separation of the varying clinical pictures into individual groups may be made. In such an attempt, however, we can hope for nothing more than partial success. One group of cases in which clinical observation or an anatomical finding shows organic disease of the brain can be sharpty denned. Since Claude Ber- nard's celebrated experiments have shown that by injuring an area in the floor of the fourth ventricle (close to the glycogenic center) simple polyuria may be produced, many cases of this type of diabetes insipidus have been col- lected, and it has been determined that in the majority of these cases there has been a definite change in the posterior cerebral areas, particularly in the region of the sinus rhomboidalis. These cases are in harmony with the teachings of physiology; they form a well-defined, genetically connected group, and though we may be in doubt whether certain cases belong in this category or not, this doubt is due to the fact that in these instances the alterations attributed to the brain are indefinite. Only a small proportion of all cases belongs to this group. Among the remainder, a group may be separated in which the increased excretion of urine is simply the result of an increased ingestion of fluid. In a number of cases it has been found that by limiting the ingestion of water, gradually or suddenly, we produce a short period of discomfort followed by cure of the disease. Here the obvious explanation is that the cause of the trouble is sim- ply an increased ingestion of fluid whether due to an unexplained thirst or to habit; in short that polydipsia is the trouble. Eegarding many other cases it must remain questionable whether they should be included in this group, partly because some symptoms are opposed to this idea, partly because the decisive test of limiting the ingestion of fluid cannot be carried out. Still other cases are proved by special characteristics in the clinical pic- ture to depend upon an increased excretion of water by the kidneys, inde- pendent of the ingestion of fluid. The facts which justify this explanation are : First, a diminished excretion of water by the skin and lungs in spite of the great natural afflux of water to these parts and, as a more easily recognized expression of this condition, an excessive amount of urine as compared with the amount of fluid ingested ; naturally the implied diminution of the amount of water normally ingested is at the expense of the water consumed with solid food. Secondly, we note the independence of the excretion of urine upon the ingestion of water, so that, for example, after a sudden stoppage of the intake of fluid, the production of urine continues unchanged, at any rate during the next few hours. These conditions, polydipsia and true polyuria, are in practice very diffi- cult to separate, and, in spite of much labor which some authors have bestowed upon this point during the last decades of the preceding century, the sepa- ration of these forms has not gained general acceptance. So it is with the attempt made by Schapiro and others to distinguish a form of diabetes insipidus due to disease of the abdominal sympathetic and to characterize it clinically ; it is not convincing. 112 DIABETES INSIPIDUS To gain a comprehensive grasp of the manifold clinical phenomena of the disease, it is still most convenient to group the cases according to their appar- ent etiology. Thus the following forms may be described : 1. Diabetes insipidus in cerebral diseases, 2. Diabetes insipidus in functional neuroses, 3. Diabetes insipidus, idiopathic form. Further description will show that under each of these divisions several very different clinical pictures are grouped together. SYMPTOMS AND CLINICAL COURSE The essential symptom is the large quantity of urine. The daily excre- tion is increased to 5, 10, even 20 liters, and in the severest cases it amounts to even more than this; cases have been reported in which the weight of the daily quantity of urine was as great as the body- weight. These cases occurred* in children weighing 20^ and 27^ pounds; a patient of Trousseau voided 43 liters daily. Of course the urine is greatly diluted, almost colorless, and feebly acid; its specific gravity is low, usually under 1.010, and it may even fall nearly to that of water. As a rule the normal solids of the urine show no deviation from their ordi- nary amounts. It is true that the daily amounts of urea and sodium chlorid have been found abnormally large or abnormally small in a number of cases, but it is extremely probable that this was in consequence of a profuse or scanty ingestion of albumin and sodium chlorid in the food; diabetes insipidus in itself does not influence these values. Uric acid and hreatinin are found in the usual amounts; special importance has been attached to the occurrence of inosite in urine free from sugar; but according to the investigations of Strauss and Ktilz it is only the result of profuse excretion of urine such as may occur in the healthy after abundant ingestion of water. The manner in which the urine is discharged varies in individual patients ; in most, the number, in others, only the quantity, of the individual evacua- tions is increased. Many patients excrete more urine during the night than during the day, as in cases of contracted kidney; others do not show this peculiarity. The "morning flood of urine" (Quincke), that is, the produc- tion of a large amount of urine as soon as the patient wakens in the morning even when he stays in bed and takes no fluid, is quite similar to what occurs in the case of healthy persons. Further, as regards the influence of increased body warmth, the excretion of urine in diabetes insipidus appears to conform to the condition of health, i. e., in fever whether produced naturally or arti- ficially (by injections of albumoses) it is decreased. In the main the kidney functions more independently of the ingestion of water than in the healthy individual; after the ingestion of a large amount of fluid the amount of urine does not increase so rapidly as in health (though even to this peculiarity there are many exceptions). After a decreased inges- tion of water it is true the urine decreases, but not so rapidly nor so markedly as in health. SYMPTOMS AND CLINICAL COURSE 113 The kidneys apparently endeavor to excrete more water; they withdraw fluid from the body approximately at a uniform rate; if water is not supplied in plentiful amounts, inspissation of the blood occurs more readily than in healthy individuals. Thus, in a case studied by Strubell, in a patient whose thirst was unrelieved by water for several hours, the specific gravity of the blood rose from 1.055 to 1.071. Similarly to the condition in contracted kidney (though here the secretion of urine is increased from other causes) we find in cases of diabetes insipidus a diminution of the excretion of water through the skin and lungs. We are not prone to attribute this condition to disturbance of the functions of the skin and lungs but are rather disposed to assume that most of the water has been discharged through the kidneys, and hence there is not enough left for the skin and the lungs. Only after the disease has lasted a long time does the diminution in the activity of the skin attain a certain independence in the clinical picture, as it does in nephritis. Insensible perspiration, as well as sweat formation, is diminished, and the fact that no sweating occurs in great summer heat has been noted in a number of clinical histories. Stoermer states that one of his patients showed a rise in temperature to 102.9° F. on very hot days; on account of his inability to sweat, the patient apparently was unable to cool his body in opposition to the high external heat. Naturally the increased excretion of water also requires an increased intake of water, and accordingly the normal desire for water is decidedly increased in all cases of diabetes insipidus. Decided thirst may be the first and most troublesome symptom of the disease, but the physician (in typical cases) sees in it only a result of the diabetes. How far a primary and pathological thirst with secondary increase in the amount of urine must be assumed in certain cases will be considered further on. That the condition of nutrition in many cases is not influenced, and in other suffers more or less severely, has been already mentioned. This varia- tion in the condition of the general health bears no direct relation to the amount of the urinary secretion. As thirst is uniformly present so also the appetite is often enormous. Ehrhardt relates the case of a patient who consumed 12 beefsteaks for break- fast and 11 portions of meat at his midday meal. It is self-evident that in these individuals the composition of the urine will deviate from the ordinary in that the amount of the dissolved constituents will be decidedly greater than the normal. French authors describe diabete azoturique as an inde- pendent affection differing from the ordinary diabetes by an increase of IST-excretion. It is very probable that a large number of cases included in this group represent really such cases of diabetes insipidus as were blessed with an appetite of the variety just mentioned. At any rate, in recent times, when pathology has not only considered excretion but also metabolism as a whole, no cases of diabetes insipidus have been reported in which albumin decompo- sition was decidedly greater than the albumin intake. Frequently with an improvement in the general condition, the abnor- mally great appetite also disappears. 114 DIABETES INSIPIDUS In contrast to these cases, there are others in which the amount of nour- ishment consumed is very slight, and in which nevertheless the body-weight is maintained. Quite a number of observations have been recorded which show that adults can maintain their N-equilibrium upon a diet containing remarkably small quantities of albumin (35 grams in a person weighing 55 kilograms). In most cases, however, the quantity of nutriment is about the normal amount. Quite frequently in patients suffering from diabetes insipidus, the tem- perature is found to be conspicuously low. Whether this is simply to be re- garded as the result of a profuse ingestion of cool drink cannot be decided. In view of the diminished metabolism which may be observed in some of the patients, we must consider the possibility that the diminution in the body warmth is to be referred to a lessened oxidation, such as occurs in old people. In contrast with this, an enormously increased body-weight has been re- ported in isolated cases. Disturbances on the part of the organs of circulation, such as cardiac hypertrophy, apparently do not occur; on the other hand, the digestive appa- ratus is sometimes damaged by the profuse ingestion of fluids. Gastric catarrh, especially, develops not infrequently; true gastrectasis is only noted exceptionally. The psychic functions do not appear to suffer serious disturbance, although hypochondriacal and melancholic attacks are frequently met with. In the cases which run their course with decided implication of the somatic condi- tion, these psychic disturbances are the rule. Occasionally, in diabetes in- sipidus occurring in youth, a general retardation of mental development is observed. Of other nervous disturbances, only sciatica is to be mentioned as a com- paratively frequent complication of diabetes insipidus. In the main, the diabetic does not appear more predisposed to general or organic disease than are healthy individuals. The reports that he is particu- larly susceptible to all sorts of infectious diseases, and that he is very liable to be attacked by tuberculosis, have not been confirmed by the study of more complete statistics. Only with one disease is there a close connection which must be somewhat more minutely considered; I mean diabetes mellitus. This may be in vari- ous ways. The connection is clearest in the cases of diabetes due to disease of the brain. A number of cases are on record in which, after trauma to the head, true diabetes mellitus with an increased urinary flow first appeared, the sugar, however, disappearing after a few weeks, and then for a long period, some- times for years, a simple polyuria persisted. We know from' Claude Bernard's experiments that the region, injury to which gives rise to polyuria, is situated only a few millimeters above the glycogenic area ; later investigations by Eck- hard have shown that in rabbits by lesions in the region of the sinus rhom- boidalis, sometimes glycosuria, sometimes polyuria, may be produced. It is SYMPTOMS AND CLINICAL COURSE 115 therefore quite plain that this cerebral form of diabetes insipidus is intimately related to diabetes mellitus. But even in the non-cerebral cases of diabetes insipidus we can often recog- nize a relationship to saccharin diabetes, especially when we note the transi- tion from the one disease to the other, and the occurrence of both diseases in members of the same family. Typical examples of such occurrence have been collected, particularly by Senator, and to these he has added cases observed by himself. It is quite probable that in these instances the neuropathic constitu- tion represents the connecting link. The results of animal experiments also suggest the possibility of a rela- tion between diabetes insipidus and diabetes mellitus. During increased (ex- periment) diuresis, no matter whether it is due to drugs or to a simple injec- tion of water, sugar is often found in the urine. Probably the sugar is simply swept along with the current, In man no well-attested examples of this purely secondary appearance of sugar in permanent polyuria have been observed, and the attempts to produce alimentary glycosuria in diabetes insipidus by an increased ingestion of sugar do not favor the view that such a washing out of sugar occurs readily in this disease. As we go on from this sketch of the disease to the special varieties of the malady and their course, simple polyuria in cerebral diseases must be first considered. This combination is not frequent; about 80 cases may be collected from literature. They are connected most often with injuries to the head; secondly with brain tumors, then with softening, while the rest are divided among various other cerebral affections, hemorrhage, encephalitis, meningitis, etc. In the overwhelming majority of cases, the lesion is found to be in the posterior parts of the brain, mostly in the region of the pons or the fourth ventricle, i. e., especially in, or at least in the vicinity of, the area in which Claude Bernard and Eckhard were able, by experimental lesions, to produce in animals transitory, and Kahler permanent, polyuria. Kahler collected from literature 25 cases after trauma to the head, and 21 following other cere- bral diseases, and added one of each variety from his own observations ; among the 22 cases of the second group, 4 occurred in disease of the pons, 2 from compression of the pons, 2 from compression of the sinus rhomboidalis by tumor, 3 in diffuse disease of the medulla oblongata; 1 was probably due to a lesion of the medulla oblongata, 1 to a cerebellar tumor, 2 to syphilis of the brain, and 7 to disease of the corpora quadrigemina. Less frequently, in cases of trauma to the head, the region of the sinus rhomboidalis is found to be the seat of the lesion ; the description in the few necropsies is not clear. On the other hand, in all of these eight cases there occurred other cerebral symptoms (particularly paralysis of the abducens) which point with great likelihood to a lesion in the pons. Hence, although diabetes insipidus is found especially in those cerebral diseases which affect the medulla oblongata, the pons, or the middle brain, nevertheless, upon accurate investigation of the individual observations, we find no single area in the brain which has been uniformly affected, and, on 116 DIABETES INSIPIDUS the other hand, a great number of observations show that every one of the previously mentioned areas may be affected without polyuria appearing. We must, therefore, .admit that although we can find cases which are in accord with Claude Bernard's celebrated experiments, and although the cases of diabetes mellitus occurring in connection with cerebral disease have turned out to be associated with a lesion of the very area in the floor of the fourth ventricle which was discovered in Bernard's experiments, nevertheless we cannot speak of diabetes insipidus in the same sense that we do of aphasia as a focal symptom, meaning that it occurs invariably in lesions of this area. In the majority of cases, diabetes insipidus first appears at a relatively advanced stage of the cerebral disease, i. e., after other cerebral symptoms have developed. In some cases, on the other hand, polyuria has been the only symptom for months. This has been observed several times in tubercular meningitis, in tumors of the brain, and in cerebral softening. A similar polyuria has been noted after trauma to the head, usually asso- ciated with other cerebral symptoms. Almost always the injuries are severe and are followed by complete loss of consciousness for several days. The in- crease of urine usually appeared for the first time after consciousness had returned ; comparatively often the signs that the seat of the cranial lesion was in the posterior brain were paralyses of the muscles of the eye. Such a polyuria arising after injuries to the head sometimes disappears with the other cere- bral symptoms, while in other cases it persists as the only morbid phenomenon for a varying period of time, even for many years. The form of diabetes insipidus which occurs in connection with cerebral affections usually leads only to a moderate increase in the amount of the urine. In the traumatic cases the daily excretion of urine amounts to from 5 to 20 liters; in the form occurring in non-traumatic cranial disease, from 5 to 10 liters are excreted. There are no peculiarities in the behavior of the polyuria which distinguish these cerebral cases from other types of polyuria. Variations in the intensity of the urinary disturbances occur, but are for the most part slight ; it is but little influenced by drugs or other therapeutic measures. The general health appears but slightly affected by the polyuria itself, apart from the influence of the cerebral disease. There is only one peculiarity of the cerebral form, and this is its relation to diabetes mellitus, which, as we have already mentioned, is apparently more distinctive than in other forms of the affection. Among the functional neuroses in which diabetes insipidus is frequently observed, two are of importance : epilepsy and hysteria. In epilepsy, polyuria usually develops gradually, after the underlying dis- ease has existed for years; more rarely it appears suddenly in connection with the attack. Usually it reaches but a moderate grade, and as a rule it is more susceptible to treatment than the cerebral form. The marmer in which epilepsy develops and its different stages are without any discernible influence on the polyuria. That diabetes insipidus occurs in connection with a particular form of epilepsy (e. g., one suspected to depend SYMPTOMS AND CLINICAL COURSE 117 on an organic cerebral affection) lias not been determined by any reliable evidence up to date. The cases associated with epilepsy are not very frequent. In contrast to this, those combined with hysteria form a very large group. It is true that there are great differences of opinion in regard to our right to associate many of these cases with hysteria. The earlier writings on this subject were based on a careful collection of cases from literature, and a few cases were described in detail as a proof of the possibility of a combination of hysteria and diabetes insipidus ; lately, with a number of authors, there is rather a tendency to class the bulk of such cases under hysteria, and we even read that practically all cases not due to organic cerebral lesions are of a hysterical nature. The latter view seems too extreme; but it is really difficult to draw the line correctly. We know that " normal " diabetes insipidus leads invariably to various psy- chical anomalies, slight in themselves (nervous irritation, hypochondriacal conditions and melancholia ) . Hence it may be difficult subsequently to deter- mine how far symptoms of this kind should be referred to diabetes insipidus, and how far they should be ascribed to an hysteria which has existed for some time. Diabetes insipidus develops in the course of hysteria either gradually or quite suddenly after nervous irritation, fright, or worry, or sometimes directly after a severe hysterical attack. In the latter cases it must be remembered that the hysterical attack is always followed by the profuse discharge of clear urine, typical urina spastica, that, therefore, a certain tendency to polyuria accompanies any such attack and is included in the conception of hysteria. Some cases of diabetes insipidus occur in profoundly hysterical individuals whose disease has existed for years, and who exhibit severe spasms, paralyses, and similar symptoms. Examples of this form have been particularly de- scribed by French authors; curiously it is more often seen in men than in women. More frequently, at least in Germany, polyuria appears in persons in whose previous history slight signs of hysteria are found, or in those in whom exami- nation reveals hysterical stigmata, such as anesthesia, hyperalgesia of the skin, mucous membranes, or ovaries, limitation of the fields of vision, and increased reflexes. That we are not dealing in such cases with a mere coincidence of two dis- eases entirely independent of one another, and that the diabetes insipidus may be a real symptom of the hysteria, has been demonstrated several times very clearly by the influence of hypnosis. By this means polyuria has been made to disappear suddenly, and later to reappear as before. Matthieu mentions a very significant case which was cured by the administration of powders con- taining nothing but sodium chlorid, but which later relapsed when the patient discovered the deception. In most of the hysterical cases, we are dealing apparently with pure poly- dipsia, as has already been mentioned, and in fact the majority of cases of polydipsia appear to belong to this group, viz. : to hysterical diabetes. But the reverse of this statement is not correct; cases of pure primary polyuria may also be caused by hysteria. Hg DIABETES INSIPIDUS Hysterical polyuria occurs most frequently in adults between the third and fourth decades of life. It is rare in adolescents and children, but, neverthe- less, Terrier reports two undoubted instances in children aged one and a half and two and a half years respectively. In this hysterical polyuria, as in the other forms, the patient is much more inconvenienced by constant thirst and the frequent desire to urinate than by actual pathologic symptoms ; but there are exceptions to this rule. Some per- sons in whom the further course of the disease justifies the diagnosis " hys- terical polyuria" emaciate decidedly as long as the diabetes exists. This is, however, unusual. As a rule, nutrition and the general well-being are not disturbed. Variations in the degree of polyuria are frequent ; often the course of the polyuria is parallel with the severity of the other hysterical phenomena. Hysterical polyuria may be cured, and sometimes with surprising rapid- ity. Occasionally this occurs spontaneously, more frequently after the employ- ment of various drugs (valerian, antipyrin, etc.), by suggestion, under true hypnosis, or by means of powders of sodium chlorid and similar placebos. Indeed, it is often this rapid cessation of the malady after such slight external causes that stamps the condition with certainty as hysteria. But by no means all cases of hysterical diabetes terminate so promptly. Many cases are protracted over long periods of time. In quite a number the history states only that at the time of the patient's discharge the diabetes con- tinued unimproved. In such cases the disease appears to last for decades. In another series it disappears gradually in the course of a few weeks under appropriate antihysteric treatment, or more rarely it ceases spontaneously. Diabetes insipidus in hysterical subjects shows very varying behavior. In some, the symptoms point decidedly to a primary increase of renal activity. This is especially shown by the dryness of the skin and the slight tendency to sweating. In other patients, on the contrary, perspiration is profuse, occa- sionally so free that they complain of it. If we are still in doubt, in such instances, whether the decided excretion of water through the skin can be explained by a primary renal insufficiency or whether the increased excretion of water is a phenomenon coordinate with the increased activity of the kid- neys, the study of a further group of cases distinctly proves that this hysterical polyuria is really the consequence of an increased ingestion of water, i. e., a condition of primary polydipsia. A number of such cases are susceptible of cure by a more or less compulsory limitation of the intake of water, without the patients undergoing any great hardship. Sometimes we have only to quiet the thirst with simple remedies, such as stewed prunes or small quantities of lemonade, in order to control the polyuria. Such cases appear to represent scarcely more than a bad habit, and the number of these cases may in reality be much greater than can be determined from the clinical histories in litera- ture because proof (i. e., the therapeutic test) cannot be obtained. As the third main group the idiopathic form of diabetes insipidus will next be considered, i. e., that form in which no other organic or functional dis- turbance can be found as a cause for the polyuria. According to its mode of origin we may subdivide this group into: SYMPTOMS AND CLINICAL COURSE 119 (a) A hereditary group, (&) A group occurring in connection with acute diseases, (c) The group of cases which appear after psychical irritation, (d) A group of cases in which the causes are various or quite un- known. The hereditary form has been observed only in isolated instances, but a few times in an extraordinarily striking way. The most remarkable series of observations we owe to Weil. He found 23 diabetics among 91 members of a family which embraced 4 generations, namely, the ancestor, 3 children, 7 grandchildren, and 12 great-grandchildren; the heredity was always a direct one, never skipping a generation; men and women were affected to a similar extent. Undue thirst was noted in some of these individuals even as nurs- lings ; besides the breast-milk, it was necessary to administer water ; in others the condition first arose between the second and fourth years of life. Almost all members of the family possessed a good constitution and enjoyed good health ; many reached extreme old age. There are also other records of the occurrence of diabetes insipidus in three or four successive generations, the individuals remaining mentally and phys- ically healthy, apart from the anomaly in question. With comparative frequency, i. e., in about 10 per cent, of all cases, dia- betes insipidus appears after acute infectious diseases (scarlatina, measles, diphtheria, malaria, rheumatic fever, etc.) ; most of these cases (like those just discussed) appeared to cause but slight disturbance of health. They are of theoretic interest from the fact that convalescence in these same infectious diseases is quite commonly associated with an increase in the excretion of urine. It appears therefore that permanent polyuria may arise from a nor- mal transitory polyuria, just as it does in hysterical individuals who have paroxysms with urina spastica. Similarly, permanent polyuria may appear after the temporary employment of diuretic remedies which cause a powerful diuresis. In a number of cases diabetes insipidus has occurred as a sequel of vari- ous deleterious factors; extreme cold or heat and sunstroke are mentioned as causes. More frequently alcoholic excesses, bodily injuries (excluding head injuries), and psychical trauma are mentioned. We include this entire group with the idiopathic form of diabetes. But in many cases doubt may arise whether they might not be grouped as well, or better, with hysteria. Even if none of the definite stigmata of hysteria is found, and if the course of the affection does not decidedly favor this diag- nosis, we often meet with striking proofs that the patients belong to the category of neuropathic individuals. They react in this peculiar way to rela- tively feeble irritations which in the normal individual would be without effect, and, when once produced, the abnormal activity of the kidneys continues for a long time. We often succeed in discovering from the history that certain abnormalities have preceded these pathological reactions. G-riffouilleres points to the fact that in youth enuresis nocturna has often preceded the condition. Numerous therapeutic experiments lead us to suspect that the neuropathic element plays a prominent role in the etiology of these forms of diabetes. 120 DIABETES INSIPIDUS Hence, even if we do not consider this type of diabetes as belonging to hys- teria, we must look upon it as closely related. In this category we also include the cases in which diabetes insipidus occurs in pregnancy. A typical example of this kind is reported by Janzen from v. Mering's clinic, in which a woman in three successive pregnancies was attacked by a severe form of diabetes insipidus (passing 15 liters of urine, whereas she ordinarily voided but 2 to 3 liters). The belief that such cases are closely related to the hysterical group is not simply a matter of theoretic classification but has an important influence on the choice of treatment to be employed and the energy with which it is to be carried out. A number of cases remain in which none of the previously mentioned fac- tors comes into question, and in which the malady progresses slowly, frequently becomes very severe, and comparatively often leads to decided loss of strength and to emaciation. These forms have mostly been looked upon as typical cases of diabetes insipidus. In the majority of these, observations regarding metab- olism and the influence of varying quantities of fluid ingested have been made. For the most part such cases are serious; as a rule, attempts at cure are unavailing or have only a transitory effect. Nevertheless, life is preserved and the nutrition, which at first suffers severely, improves again without, how- ever, reaching the normal. Occasionally, decided permanent impairment of health has been observed, but marasmus increasing in severity until the disease terminates in death is rare. Earlier literature contains more frequent reports of an unfavorable out- come. Indeed, Trousseau believed diabetes insipidus to be almost invariably fatal. During the last decades, however, it seems that no instances of the kind have been published ; perhaps a case reported by Strubell belongs to this group. As a rule, in these severe cases of diabetes insipidus the constitutional con- dition appears to go hand in hand with the psychical. Permanent psychical depression, hypochondriacal and melancholic conditions, are frequent and almost constantly accompanying phenomena. We may even be impelled to ask whether a psychical anomaly is not the fundamental condition, and the diabetes insipidus only a symptom. Nevertheless, such severe cases are rare; the majority of idiopathic cases lead a fairly comfortable life for years. The cases of diabetes insipidus developing from syphilis appear to occupy a position quite apart. A number of instances of this kind are known in which, besides the diabetes, there were various symptoms pointing to organic disease of the brain, and in some of these the necropsy showed the presence of gummata or of meningitis. In addition to these, there are cases in which diabetes insipidus develops during the course of syphilis, sometimes many years after infection has taken place and without any other cerebral symptoms. By antisyphilitic treatment this form of the affection has several times boon made to disappear promptly. It is therefore scarcely questionable that it was DIAGNOSIS 121 due to syphilis. Whether we are to assume in these cases a gumma of the brain (the simultaneous existence of destructive gummata of the skin in one of these patients appears to favor this view), or whether we are to assume a disturbance in the function of the kidney due to syphilis, is very difficult to determine at present. The practically important point is this, that in the course of syphilis, with or without cerebral symptoms, simple polyuria may occur, and that antiluetic treatment in both instances mav bring about a cure of the diabetes insipidus. DIAGNOSIS The diagnosis of diabetes insipidus is usually easy; the important symp- tom, polyuria, can be readily determined, care being taken not to confound the disease with other conditions in which polyuria also occurs. Diabetes mellitus may easily be excluded by an examination for sugar. The question whether or not contracted kidney is present is not always so promptly solved. Cases of chronic nephritis in which the urine is at times free from albumin are not very rare; but the examination of the heart, and particularly the hardness of the pulse, will generally lead to a correct diagnosis. It is note- worthy that in diabetes insipidus, in spite of the fact that plethora serosa occurs frequently, hypertrophy of the heart and changes in the tension of the pulse never result. Difficulties in the exclusion of nephritis may, however, arise in an oppo- site direction, namely, from the presence of slight quantities of albumin in the urine in diabetes insipidus. A number of clinical histories which describe otherwise typical cases of diabetes insipidus, some of the hysterical type, con- tain the statement that periodially small quantities of albumin could be detected in the urine. It is difficult to exclude nephritis in these cases as they have not come to autopsy; nevertheless the fact remains, that cases which in their course and especially in their uniform benignity do not differ from the ordinary picture of simple potyuria may from time to time show traces of albumin in the urine. Amyloid kidney, less often than contracted kidney, may lead to confu- sion; although occasionally albuminuria is absent here, the general condition, the enlargement of the liver and spleen, make the diagnosis clear. Arteriosclerosis more often leads to diagnostic difficulties, as it tends decidedly to increase the amount of the urine ; but here also the action of the heart and pulse is conclusive. Chronic pyelitis must also be considered in the differential diagnosis; in some few cases of diabetes insipidus described in literature, one cannot help suspecting that the writers were really portraying cases of pyelitis. The reports that the urine always contained slight traces of albumin and a puru- lent sediment are significant. Finally, the possibility that diabetes insipidus may be mistaken for the results of a simple increase of the intake of fluid must be considered. As a matter of fact this differentiation, at least for a time, may be simply impossible ; the limits vary and are partially arbitrary. If after simply dimin- 122 DIABETES INSIPIDUS ishing the amount of fluid ingested, the polyuria ceases, and never recurs, as is sometimes the case in the hysterical form of diabetes insipidus, it depends ultimately upon the option of the observer whether the case is classed as one of bad habit, or as diabetes insipidus; for diabetes is so comprehensive an entity that such cases as the above can be included under it. In fact, literature contains quite a numbe^ of such examples. TREATMENT Treatment may be carried out in various ways. Where possible, we should search for the underlying condition which results in polyuria, and an attempt should be made to remove this. In diabetes due to cerebral causes, such treatment is practicable only in isolated instances. Nevertheless, a case is on record in which, during the course of an apparently mild pulmonary tuberculosis, acute polyuria appeared, later followed by pain and stiffness in the cervical vertebrae, then paralysis of both arms and legs; here the diabetes was cured, simultaneously with the paralysis, by treatment with G-lisson's suspension. Otherwise, among the cerebral cases of diabetes insipidus, apart from the traumatic which not infrequently get well without treatment, only those depending upon cerebral syphilis are to be considered; in these cases and all others complicated by syphilis (whether a definite cerebral lesion exists or not), a cure may be effected by the use of iodin and mercury, as has been previously mentioned. Somewhat more uncertain are the cases occurring in the course of hys- teria. The fact that hypnotism sometimes brings about a prompt cure is a proof of the purely functional nature of these cases, and of the possibility of an " etiologic therapy " by purely psychical treatment. Whether or not in every hysterical case, or in every case that is suspected of being hysterical, hypnotism is to be employed, is a question that must be answered according to the confidence of the physician in the harmlessness of this remedial agent. In point of fact, in Germany no reports of cures of this kind have been made. On the other hand a number of measures of a more innocent nature directed against the general nervous condition have often been quite success- ful. Among these are, first, general dietetic measures, sufficient exercise in the open air, and proper employment; occasionally, change of climate has been successful; often diabetes has been seen to disappear or become less marked in the course of hydr other apeutic treatment. Regulated cold ablu- tions, douches, baths, in the milder cases can be carried out at the patient's own home, in the severe cases in hydropathic institutes ; lukewarm baths appear to have a similar effect. Among drugs which seem to be of use in a similar way, antipyrin (3 grams daily) and valerian are the favorites; the latter, given up to 20 grams of the powdered root, is sometimes decidedly beneficial; also potassium bromid, assafetida, and camphor, employed from the same point of view, have occa- sionally been very useful. The remedies just mentioned are, a priori, most useful in the cases in TREATMENT 123 which diabetes insipidus occurs in hysterical individuals. Regarding the prompt action of valerian, as well as of quite a number of remedies to be mentioned later on, the success of which is reported in the journals every year, it is unquestioned that diabetes insipidus is very often only a symptom of hys- teria which, like other hysterical symptoms, may disappear after the use of the most varied remedies; as, for instance, after the employment of powders of simple sodium chlorid, provided only that simultaneously the necessary psychic influence is exerted. Many cases, perhaps most of those that come under treatment at all, occur in individuals whose malady cannot positively be included in the category of hysteria, yet is closely related to this group of affections, and these people are known as " nervous persons " in the ordi- nary sense of the term. In them, as well as in frankly hysterical cases, success comparatively often follows the use of the previously mentioned remedies. Other drugs have been employed with the hope of influencing the circula- tion in the kidneys; the amount of urine in the main depends upon the height of the blood-pressure in the glomeruli, and the more contracted the small renal arteries are the less is the amount of blood which reaches the glomeruli. As the principal representative of such artery-constricting remedies, ergotin has frequently been administered in diabetes insipidus, particularly in the last few years, as its action has been much praised. Lead acetate and tannin are less useful. Atropin and other belladonna preparations, which are supposed to act more directly upon the secretion of the kidneys, have also an inhibiting secretory influence upon most of the other glands. This influence, unfortunately, is more obvious in the salivary glands than in the kidneys; at least, increased dryness of the mouth and correspondingly great thirst have been observed more often than decrease in the amount of the urine. Electricity has been employed for the sake of its (supposedly) direct influ- ence upon the renal function. As irritation of the cervical cord diminishes renal secretion in animal experiments (on account of its powerful contraction of the vasa afferentia) the attempt has been made to diminish the amount of urine in man by galvanization of the cervical cord. More recently we have attempted to make the current act directly upon the kidneys (both electrodes in the renal region). Whether the electrical current thus applied has any real action is very difficult to decide ; it is, however, a fact that this treatment is often quite successful. Another method by which we have tried to diminish renal secretion is by stimulating the excretion of water oy the skin. It has been frequently noted that the steam bath is conspicuously grateful to the diabetic, although it diminishes the secretion of urine; other patients report that they feel much better during the hot season than during the cold. Among the remedies which stimulate secretion by the skin, sweat haths and pilocarpin are to be consid- ered ; the former certainly have transitorily an ameliorating effect. Permanent and complete cure has not been observed; but decrease in subjective discom- fort and diminution in the daily amount of urine have been noted. The same is true of pilocarpin, polyuria decidedly decreasing with its employment (in- jections of from 0.01 to 0.015 on two successive days). It is true that in other 124 DIABETES INSIPIDUS cases the remedy has been ineffectual, and of course it will always be futile in persons who readily perspire. Finally, that method of treatment must be considered which perhaps appears to be the most obvious, the limitation of the intake of fluid. This has often been tried by the patients themselves, but, as regards the propriety and success of such attempts at cure, the views of different authors are dia- metrically opposed. In some cases withdrawal of water, strictly adhered to, acts with great rapidity; the patients are better almost from the first day, and after a few days may be looked upon as permanently cured. These are the cases which we have designated, upon the basis of this sort of improvement, as primary poly- dipsia. Very characteristic is a case described by Westphal : primarily for the purpose of studying her condition, the intake of fluid was limited, and at the conclusion of the experiment the disease was cured. In other cases the same result has been attained by a gradual diminution of drink. However, it is only with a small number of diabetics that we so readily reach the goal. Most patients cannot endure the tormenting thirst, and with or without the knowledge of the physician they will drink water. In such patients, this method of treatment can be carried out, and with it sometimes an actual cure attained, by isolation and observation. Geigel reports such a case of diabetes insipidus in which during the first few days of treatment severe disturbances appeared, but the withdrawal of water was persisted in, and after a short time the case could be looked upon as almost cured. For the cases of diabetes insipidus, sensu strictiori, in which the polyuria actually depends upon increased renal secretion, such attempts at cure by the withdrawal of water are rarely successful. Indeed there is reason to fear that we do harm by a dangerous inspissation of the blood. Unfortunately it is often difficult in practice to decide between the two forms, and this is true of the majority of cases, i. e., of those that are symptomatic of hysteria or at least have some connection with it. Despite this difficulty, and in order to achieve success wherever possible, it is advisable to attempt with all patients of this type a methodical and cautious withdrawal of water. Of course this can hardly be carried out except in thoroughly organized hospitals. GOUT By W. EBSTEIN, Gottingen The words " Gicht " and " Zipperlein " are genuine German words. The former is the equivalent of the old English masculine " ghida" which means " bodily pain in general." Zipperlein is the diminutive of " Zipper," formed from the verb " zippern," which in German means " jerking, restless, trip- ping." The term "Zipperlein" has been used in German for " Gicht" since the fifteenth century. It was invented by sufferers from this disease in a sort of grim humor. It is quite certain that the word " Gicht " is not, as was sup- posed, in etymological relation with the English word " gout," or with words of the same derivation in the Romanic languages (the French " goutte," the Italian " gotta," the Spanish " gota"). These designations cannot be re- jected, as they have become established by usage, but that they are not to be looked upon as appropriate every one must admit. They are based upon the old pathological conception that gout was caused by a peculiar humor distilled from the blood, which, drop by drop, was exuded into the joints, a view for the support of which no proof of any kind can be adduced. The designation " Zipperlein " for gout has quite properly been excluded from scientific nomenclature, as, in a symptomatologic connection, a uniform meaning is not attached to it. Among the ancients, the pathologic term u gout " was em- braced in the collective term " arthritis," under which every form of arthritic inflammation was included. The term " arthritis " for " gout " embraces so much more than the purely symptomatologic conception that it includes a very important and active constituent of gout, namely, the " inflammation " of a joint. The words podagra, chiragra, gonagra, omagra, ischiagra and rachisagra, were applied by the ancients to joint pains in different regions of the body, and pains chiefly due to gouty and rheumatic affections were thus designated. Certainly to-day, when we speak of podagra, we mean only a gouty affec- tion of the foot. The word " arthritis " of the ancients alone discloses noth- ing as to the etiology of the joint inflammation. Later an attempt was made to separate the various arthritic inflammations according to their cause, and after we had demonstrated the causal relation of uric acid and its combina- tion with alkalies to gout, the term arthritis urica, or uratica was given to gouty joint inflammations. As, however, there are still differences of opin- ion on this point, it would perhaps be wiser to speak only of gouty joint inflammations, or, for one who is fond of foreign designations, of gouty arthritis. 10 125 126 GOUT The name gout has the advantage that it indicates nothing more than the pain which always plays a prominent role in gouty affections. It must be remembered, however, that in gout we are not dealing with pain that is restricted to the joints, but with a general pain which is well described by Trousseau, " totum corpus est podagra." We shall refer to this more minutely when we consider the clinical aspect of gout. Gout is certainly a disease of antiquity. It is not my intention here to discuss in detail the historical aspect of the disease. A. Delpech has recently written quite a voluminous work (678 pages) on the history of gout and of rheumatism, in which he dwells upon the antiquity of the disease, and brings it down to the time of Thomas Sydenham (1624-1689). In the study of the clinical history of gout, we, as a rule, only go back to the time of Sydenham, and, it appears to me, quite properly so. Sydenham's description is an account of his own illness, for, when he wrote his dissertation, he had already been suffering from gout for thirty-four years. All that had been written prior to Sydenham's time regarding the symptomatology of gout was of little value compared with what Sydenham communicated to us. The elucidation of the cause and the cure of gout Sydenham bequeathed to posterity. THE PATHOGENESIS OF GOUT The pathogenesis of gout has been studied from many points, and is now by preference our subject of investigation. It was the theme which occupied the attention of the Section on Internal Medicine of the Xlllth Medical Con- gress in Paris. I was unable to perform the task allotted to me, and give a synopsis of this subject at the Congress; but, at Easter-tide, 1900, I sent to the Secretary of the Section of Internal Medicine a compilation setting forth my views, and it may not now be out of place briefly to discuss the present standing of the question as set forth in this thesis. The views expressed by me were as follows : 1. Gout is a more or less chronic disease which develops upon the basis of a pathologic predisposition which is hereditary and generally congenital, and is usually designated the uric acid diathesis. 2. Eegarding the ultimate cause of the uric acid diathesis, merely hypotheses can be at this time proposed. The intimate relations existing between the nucleins and uric acid make it appear likely that in the uric acid diathesis there is an abnormal composition of the cell nucleus ; that is, of the protoplasm in the person in question. It is quite evident that an individual predisposition which may assert itself through entire families and races is a prominent factor in the uric acid diathesis. 3. Various circumstances appear to show that true gout develops from the uric acid diathesis. Eegarding these circumstances the following may be mentioned : (a) The more pronounced the uric acid diathesis in a person, the earlier, that is, the more decidedly, ceteris paribus, will gout develop in him. (b) There are habits which favor the appearance of gout; among these are indolence and high living, especially the combination of these, and, of THE PATHOGENESIS OF GOUT 127 prime importance, the use of alcohol. In the main, the periodic variations which have heeii reported as to the frequency of gout may be referred to this. (c) There are acute and chronic intoxications as well as infections, which, in combination with the uric acid diathesis, favor the development of gout, and in which bacterial toxins also may play a part. I shall first mention the relations of gout to rheumatism, to syphilis, and to lead intoxication. Influ- enza, also, appears to predispose to gout. (d) Contagion, as was first asserted by no less an authority than Boer- haave, does not seem to play any part in gout. (e) Climatic conditions apparently have no influence upon the develop- ment of gout. 4. The poison which causes gout, the actual materia peccans, appears to be uric acid. Whether, besides this, other products of metabolism of the group of alloxur and nuclein bases are operative, or, as some authors assume, a poison the nature of which is unknown, is still an open question. It is likely that only the endogenous nuclein substances of the human body, and not the uric acid originating from the nucleins of the food, have a direct influence upon the pathogenesis of gout. Whether an increased formation of uric acid occurs in gout has not been proven with certainty, nor do I believe this proof to be absolutely necessary. Nevertheless, I consider such increase to be prob- able. That an increased production of uric acid (which we assume from an increased excretion) does not alone give rise to gout is taught by the study of leukemia. In some cases of this disease, as is well known, more uric acid is excreted than in any cases of gout. 5. Uric acid is a chemical, but not a septic, poison. Its action is not uni- form in all species of animals, at different ages in the same animal, nor in their different organs. Uric acid produces inflammation and necrotic changes in the affected tissues, and finally causes complete death of the tissue (necro- sis). Only after the tissue is wholly necrotic does a deposit of crystalline uric acid take place in the form of acid sodium urate (monosodium urate, Tollens, sodium biurate, Eoberts). According to Tollens, uric acid also circu- lates in the blood and in the alkaline juices of the tissue in the same alkaline combination, and not, as Eoberts has assumed, as sodium-quadriurate, a com- bination which Tollens more technically designates as hemisodium-urate. It is admitted at once that monosodium-urate, Tollens (sodium-biurate, Eoberts), under otherwise similar conditions may also be deposited as crystals in tissues, where not uric acid itself but another poison has caused necrosis. 6. To understand the pathogenesis of the different symptoms of gout, we must distinguish between (a) primary arthritic gout and (&) primary renal gout. The first is by far the more frequent, and the sufferers from this often reach extreme old age. Primary arthritic gout first develops under the influ- ence of a localized uric acid stasis, i. e., it is limited to one or more parts of the human body. In primary renal gout we have from the onset a generalized uric acid stasis, which, therefore, affects all parts of the body, and is invariably due to a primary and severe disease of the kidney. It is evident from the Transactions of the Section of Internal Medicine of the XHIth International Medical Congress, that the opinions of the two 128 GOUT reviews differed decidedly from my own, just mentioned, as I think I suffi- ciently emphasized in my theses; yet, as the subject is a very difficult one, this diversity of views is not to be wondered at, Nevertheless, our views have so much in common that we may hope, sooner or later, to come to some agree- ment regarding the most important points in the pathogenesis of gout. I base my remarks upon the review in the " Semaine med.icale," No. 30, 1900, pp. 202, 203, which reports the address of the reviewer, Dr. Le Gendre, and of the co-reviewer, Sir Dyce Duckworth. Of course, if Sir Dyce Duckworth believes that the kidney is the only organ in which the synthesis of uric acid is carried out, i. e., in which uric acid is formed — in which opinion he and his countryman Luff occupy quite an isolated position not only among pathologists but also among physiologists — unanimity in regard to the most important question in the pathogenesis of gout is not to be arrived at. Sir Dyce Duckworth maintains, with Garrod, that uric acid is the materia peccans in gout and that the latter results from a hindrance to the excretion of uric acid through a faulty action of the kid- ney which can by no means be demonstrated from anatomically determinable changes. Sir Dyce Duckworth, therefore, in all cases of gout, assumes a uricemia from a faulty excretion of uric acid. Le Gendre laid great stress in his paper upon the influence of functional disturbances of the kidney in the production of gout and also referred to the functional disturbances of the nervous system; these result in nutritive changes in the tissue and cells, and thereby cause irregularity -in the formation, that is, in the excretion, of toxic products of metabolism from the influence of which gout develops. In regard to these doubtful points in the pathogenesis, it appears to me advisable to wait for the publication of Le Gendre's complete paper. On the other hand, there are a number of factors which may be designated as occasional causes of gout, particularly family predisposition and the influence of the mode of life, etc., concerning which there is complete unanimity. Instead of voluminous descriptions, it will best serve our purpose to cite a few cases from practice. Observation I. — Dr. X., from H., a physician about thirty-nine years of age, con- sulted me June 22, 1900, on account of gout. About fifteen years before, while he was a medical student, I had repeatedly treated him for this. As a jolly fraternity student, he probably drank more beer than was good for him, and had acquired a decided embon- point at too early an age. In addition to a plentiful use of alcohol, he ate a great deal, and took very little exercise. In spite of these facts he was by no means dissipated, but passed a very good examination, and is now an extremely busy practitioner. The patient's family has a predisposition to gout; although his parents did not suffer from it, his maternal grandfather late in life had a severe form of gout, and two of his maternal uncles also suffered from it. As early as between his sixteenth and eighteenth years, the patient had repeated attacks of cramps in the calves, and he is inclined to regard as " gouty " an attack of " stiff knee " which appeared in his boyhood after a salt-water bath, and was accompanied by very severe pain. The first typical attack occurred in his twenty-first year, in the metatarsal phalangeal joint of the right great toe. The attacks recurred twice in the next year; the fourth attack, in June, 1885, which was accompanied with fever, was more severe than the preceding ones. The fifth attack, in September, 1885, which appeared three days after " turning " the left foot, was localized in the first metatarsal THE PATHOGENESIS OF GOUT 129 phalangeal joint. This ran its course within three days, was mild, and accompanied with only slight redness and swelling of the affected joint and no disturbance of his general health. After the patient began the practice of medicine he had no attack of gout for years. He lost his excessive weight, and when I met him in consultation a number of years ago I was astonished to find him rather thin. He followed minutely my dietetic regulations, and under this treatment only " premonitions " of his old trouble occurred. His constantly increasing, very extensive and exhausting practice now made it impossible for him to live in accordance with the rules previously followed. The attacks of gout recurred, and in the winter of 1899-1900 he suffered almost every two months from severe typical attacks, with violent onset, and constantly accompanied with fever. But while these formerly lasted for a few weeks, they now disappeared in a few days. These paroxysms were always associated with large effusions into the joints, and the seat of the attacks was in the toe and the talocrural joint upon both sides. The attacks were cured by the use of wine of colchicum seed, potassium iodid and sodium bicarbonate. Pain in the right shoulder joint, however, which had troubled him off and on for some time, now became chronic. The influence of trauma in the occurrence of typical gout was shown when, upon April 30, 1900, the patient fell from his bicycle, causing a contusion of the right talocrural and of the left knee joint. As early as the next day, in both of the- previously mentioned joints, a typical attack of gout developed which affected the patient greatly. He never had venereal disease; he smokes much — according to reports S mild cigars daily — and consumes a bottle of light wine daily, but no beer. The patient considers the wine necessary, as, without it, he has inter- mittent heart action. Appetite and digestion are good. His maximum weight was in 1883, when he weighed 209 pounds; now he weighs 176 pounds. During the attacks the urine is said to be scant and dark in color, but returns to the normal after the paroxysm has passed off. Albumin and sugar have never been present. The patient, when I examined him, had a pulse of 64, cardiac dulness was not increased, the second aortic sound was loud but not quite clear. Organic changes were not evident. The patient was very much enfeebled, and as he desired to undergo a bath and mineral spring treatment, I advised him to go first to the Allgan Alps at Obersdorf. On the 2d of August, 1900, the patient wrote me from the " Nebelhornhaus " (2,251 meters high), stating that he felt very well there and that without much trouble he could climb quite high mountains. Besides the observance of a strict dietetic regime, absti- nence from alcohol and a decided limitation of smoking were required. The case just cited is in many respects interesting, and I shall take oppor- tunity to revert to it later. At this time, only the factors which bear upon the pathogenesis of gout are to be considered. We note that the family predis- position of the patient was only in the ancestral line of the mother, the latter herself remaining free from the affection. The maternal grandfather and two of the maternal uncles, on the other hand, had gout. As the clinical history shows, the patient "was inclined to date the beginning of his disease from his youth. It is evident that gout may come on early in life. A very skilful physician who had suffered from gout, but who died of- a severe diabetes mel- litus complicated by nephritis, told me that even in his ninth year he had seizures of so-called rheumatism in the ball of the great toe of his left foot. In children, attacks of gout frequently follow trauma, and it has been main- tained that gout is the consequence of trauma. As a matter of fact, I have seen gout in adolescents, but always in boys, an observation which is confirmed by medical literature. The cramps in the calves with which my patient was affected between his sixteenth and eighteenth years may, in consideration of the course which the disease took, be regarded as premonitory gouty symptoms. From this, however, and also from numerous other experiences "at hand, it 130 GOUT cannot be doubted that the abuse of alcohol during his student days, as well as the previously mentioned obesity, conduced to the development of the gouty paroxysms. But it must be emphasized that, in my patient, the later disap- pearance of his corpulence aid not lead to the cessation of the gout. Obesity is, therefore, not a prerequisite for the production of gout, although they may occasionally occur in combination, sometimes with diabetes mellitus as well. Of further interest in my patient's history is the fact, that in proportion as he deviated from the mode of life advised by me, the latent gout, i. e., the gouty diathesis, asserted itself by the appearance of repeated paroxysms, and that the last attack of this kind occurred after a fall from a bicycle whereby he sustained a contusion of the left knee-joint and of the right talocrural. I do not consider this occurrence of a gouty paroxysm after trauma as by any means accidental. Opposed to its being a mere coincidence is the frequency with which this combination appears. My patient is a physician in easy circum- stances. We know that the wealthy minority, the so-called " upper ten thou- sand," are most frequently the subjects of gout. Among our hospital patients who, for the most part, belong to the poorer classes of the population, gout has heretofore been looked upon as a rare affection. I saw a poor tailor in the Hospital of the Home for Incurables in Breslau, who showed extensive, partly ruptured gouty tophi. Yet when I review the cases of gout accumulated dur- ing my long professional service in the Hospital, the number of the poor is quite small when compared with those in better circumstances whom I have seen in consultation and in my private hospital. In this connection, there has lately been a remarkable change in Germany, and one which is food for thought. Albert Fraenkel, in the Eeport of the Medical Division of the Hospital Urban in Berlin, from the year 1896 to 1897, and among 1,706 male patients, has observed 24 cases of arthritis uratica. In the hospitals of Eng- land, previous to this, the number of gouty patients was a striking one. In the years 1874 to 1876, in the Medical Division of St. George's Hospital in London, among 4,695 patients, not less than 97 cases of gout were present, while, in the same period of time, in the Munich Medical Clinic, among 4,670 patients, there were only 11 cases of gout. We might say, it is true, that in this coincidence plays a leading role. But it must be observed that in the same period of time, and in nearly the same number of patients, in a London Hospital, there were almost nine times as many cases of gout as in the Munich Hospital. If it is true that in Munich, upon the average, more than 200 liters of beer per capita of the population are yearly consumed, the conclusion must be drawn that the influence attributed to Munich beer in the development of uric acid gout must be regarded as erroneous during the period just men- tioned. The reports of His, Jr., and Magnus-Levy favor the increase of gout among the poorer population of Germany. Among the poor people of Leipsic the former not infrequently saw gout. The latter, in the Out-Patient Medical Clinic in Strassburg, made the same observation. Nevertheless, the social posi- tion, that is, the wealth or poverty of the individual — hence his mode of life — has no fundamental influence upon the development of gout. The special disposition of the person which is noted in other members of the same family, even in entire races, and which may be hereditary, is the important point. It THE PATHOGENESIS OF GOUT 131 is evident that the presence of so-called predisposing, favoring factors is not alone sufficient for the development of gout. In this connection, Thomas Oliver alludes in his valuable book, " Lead Poisoning," to an investigation regarding the workmen in the large lead works at Newcastle-on-Tyne, and this is very characteristic. As is well known, lead is a predisposing factor in the development of gout. Yet such of the workers in lead at Newcastle-on-Tyne as come from the north of England are only rarely attacked by gout, even when their kidneys are diseased, for in that por- tion of the population the predisposition to gout is absent; while those who come from the south of England, where the gouty predisposition is widely distributed, are frequently attacked with gout when employed in the pre- viously mentioned lead works in the north of England. One problem referred to by me in the above named theses on the pathogenesis of gout requires further discussion: in what does the predisposition to gout consist, and how is the so-called gouty predisposition, the uric acid diathesis, to be conceived ? The principal role is played by a faulty composition, not of the "humors/' the juices of the human body, but of the protoplasm including the nuclei of the cells, in consequence of which uric acid, and perhaps still other bodies of the group of the alloxur and nuclein bases, are either formed in increased amounts or in an unusual region. I believe it to be very likely that the simul- taneous occurrence of both these anomalies is the rule. The organs richest in nuclein play the most important part in this process, and I believe we may assume from the clinical history of gout that bone marrow and the great mus- cular masses of the human body, especially those of the extremities, are in- volved in this anomaly of uric acid formation. It is quite possible that in these tissues, already rich in nuclein substance, an increased formation of alloxur or nuclein bases, that is, of uric acid, takes place. My investigations have shown that uric acid is a chemical poison, and hence, until the same has been proven of the other previously named substances, and until the question has been answered whether there is a specific " gout poison," as is believed by some authors, uric acid may be looked upon as the materia peccans in gout. The uric acid, loosely combined with an alkali formed in the muscles and bone marrow, is dissolved, flows through the lymph and blood channels, and is for the most part excreted by the kidneys, unless other processes of decomposition take place during its course. If this process of excretion occurs smoothly and without hindrance, and if the gouty predisposition is not too decided, the con- sequences of the existing anomaly of metabolism will show themselves only after a certain time by a number of pathological phenomena, mild or severe, subjective and objective. But as soon as any intercurrent cause produces stasis of the juices rich in uric acid in the affected area — naturally at first in the peripheral parts, particularly in the lower extremities, in which stasis is especially prone to happen — engorgement will occur which, in consequence of this local stasis, also primo loco, in the affected parts of the body, will become more or less noticeable as a typical attack of gout. I call these cases primary arthritic gout. In Observation I, we have a case of primary arthritic gout which should more correctly be designated primary extremity gout, since not only the joints were implicated, but also the muscles, and especially the skin. 132 GOUT Besides the extremities, in this form of gout the most distant parts of the body, i. e., those situated at the actual periphery, are implicated, as, for in- stance, the concha auris. For the explanation of these phenomena in primary extremity (arthritic) gout, an insufficiency of the kidneys which causes gen- eral uric acid stasis is by no means necessary. Following Garrod's reasoning, this is still frequently assumed, although the reasons mentioned by him have been shown to be incorrect. We shall revert to this later. Besides this pri- mary extremity (arthritic) gout there is also a primary renal gout. Here, in consequence of a primary severe renal affection, most likely based upon a gouty predisposition, there is an incapacity on the part of the kidneys to ex- crete the waste of metabolism, i. e., the uric acid. Consequently a generalized uric acid stasis develops which affects all the parts of the body. The patients frequently die before a typical attack of gout occurs. They succumb, there- fore, to the renal affection, usually while still young, whereas in primary extremity (arthritic) gout they will live to old age. In primary arthritic gout the kidneys suffer as well as all the other organs ; but there are numerous cases of primary arthritic gout in which the patients die from intercurrent diseases, and in which the kidneys show absolutely nothing abnormal. Primary arthritic gout is fortunately by far the most frequent form of the disease, and the one we shall first consider. Formerly it was thought absolutely necessary to differentiate various forms of gout. I do not think it expedient to dilate upon this point, and will only mention that to-day designations are not infrequently used for some of these varieties, between which no important differences exist : thus we hear of latent gout, larval gout, pseudo-localized gout, retrocedent gout, etc. Yet I have not been satisfied with Garrod's differentiation of a regular and an irregular form; even in professional practice it does not sim- plify the condition. SYMPTOMATOLOGY We will now discuss the symptomatology of primary arthritic gout, and in order to make the condition clear I shall include the necessary pathologico- anatomical data. I shall retain the designation primary arthritic gout, as in the great majority of cases the joint symptoms are still the most prominent, and as I do not desire, by another designation, further to complicate a subject which is already rich in superfluous names. To avoid prolixity, in enumerating the possible limitations in the pathogenesis of gout, among the noxa which produce it I shall refer exclusively to uric acid as the materia peccans. This materia peccans which produces the disturbances, the totality of which, there- fore, forms the gouty symptom-complex, is in part a purely functional dis- turbance, for which up to the present no constant pathologico-anatomical material lesion is known ; in part, however, a disturbance for which the mate- rial substratum has been discovered. The latter depends in some degree upon inflammatory, also upon degenerative, changes in the organs and tissues. Suppurative processes are not produced by uric acid; it is not a septic, but chiefly a chemical, poison. The degenerative changes in gout from the influ- ence of uric acid show nothing characteristic of gout until necrosis of the SYMPTOMATOLOGY 133 affected tissue occurs. If tissue necrosis has taken place, then acid sodium urate is deposited in the form of crystalline needles. That necrosis of the tissue is the primary condition is shown from the fact that the necrosed area is larger than the urate deposits. Around the necrotic areas, more or less round cell infiltration is often found. I have proven that such gout foci, i. e., necroses with crystalline urates (completely analogous processes), may be experimentally produced in birds. In these experiments urate deposits also occur to a greater or less extent in normal tissue, i. e., in tissue which has not become necrotic. Of course, this has absolutely no connection with gout, but merely explains the post mortem finding that, with cessation of life, the tissues are saturated with urates, and these are excreted in a crystalline form. The symptoms of primary gout are as follows: In primary arthritic gout the first phenomena are the manifestations of the gouty predisposition. They may be designated as the premonitory or initial symptoms and they precede the first attack. It is possible that where the predisposition is not very great, and especially where an exciting cause is lacking, these so-called premonitory symptoms of gout may remain the only ones, so that a true gouty paroxysm does not develop at all. Generally, however, this is not the case. Under any circumstances, however, these premonitory symptoms may make it difficult properly to interpret the underlying condition. Not infrequently these pro- dromal symptoms, previously quite unintelligible to the physician, are at once explained by the sudden appearance of an attack of gout. Similar to these premonitory symptoms are the pathologic phenomena which have been desig- nated by me as intermediate symptoms. They occur in the intervals between the attacks of gout, show remarkable similarity to the premonitory symptoms, but are much more difficult to explain, as the preceding gouty paroxysms have closed the path to their proper recognition. We shall later consider more minutely these premonitory and intermediate symptoms. It appears expedient first to direct attention to the typical condition in primary arthritic gout, namely, to the acute paroxysm of gout, the typical attack. The clinical history of the physician suffering from primary arthritic gout (Observation I) shows that the first attack of gout may occur in very early life. I shall later demonstrate that this is also true of the appearance of extensive gouty tophi. As a rule, however, this is not the case. The first typical attack of gout usually occurs shortly before or after the fortieth year of life. The gouty attacks frequently recur at certain seasons of the year, especially at the beginning of spring and at the beginning of winter. Besides certain premonitory symptoms, the true attack may be preceded by prodromes in the part of the body that is to be the seat of the paroxysm, such as drawing pains, of slightly disagreeable sensations to which the patient pays no atten- tion, and of which we only learn by careful questioning. Much more fre- quently the attacks begin suddenly, often coming like a thief in the night, and surprising the calm sleeper. As a rule, the first attacks are prone to be localized in the most peripherally situated parts of the body, and especially in the joints of the lower extremities. The joints of the feet, chiefly the first metatarsophalangeal joints, are most frequently attacked. The typical attack of gout is a more or less severe process characterized by an inflamma- 134 GOUT tory but aseptic course, which is strikingly similar to an erysipelatous inflam- mation. Corresponding to the intensity of the inflammatory process, there is as a rule extraordinarily severe pain. Most patients declare it to be as though the affected parts of the body were tightly screwed in a vise. The skin is intensely red (purplish red or bluish red), sometimes even permeated by small hemorrhages ; it appears as though suppuration were developing, and is tender on pressure, glistening, and swollen. The swelling is the consequence of edema; upon pressure there is pitting of the skin which only very slowly disappears when the pressure is relaxed. In the most severe cases active motion is impossible, and upon attempting passive movement of the painful joints, the patients resist. Under these circumstances, the patient is early confined to his bed. Apart from these local pathologic phenomena, we also observe in acute paroxysms of gout disturbances of the general constitution. Especially note- worthy are the fever and the symptoms dependent upon this. In the milder attacks, fever may be absent. We note from Observation I that, in the same individual, it was present in some attacks and absent in others. Occasionally there is a slight rise of temperature only in the first days, so that if the patient, for instance, comes under observation only upon the third day of the attack there may be no fever. Usually, the fever is moderate, a rise above 102.2° F. being rarely reached at the height of the paroxysm. During the exacerbations so frequently observed in attacks of gout, the temperature rarely exceeds 101.3° F., and when remission occurs, as a rule it at once falls to normal. The age of the patient seems to have some influence upon the temperature curve during the paroxysm, as, under otherwise similar conditions, the highest temperatures occur in young robust patients. Nevertheless, in the aged, dur- ing acute attacks, rises in temperature are by no means absent. The further course of the gouty inflammation in the affected part of the body is generally typical. After the para-articular phlegmons have existed for a few days, or several weeks and longer with remissions and exacerbations, the latter being sometimes so severe that an extensive joint suppuration seems imminent, the inflammatory symptoms ameliorate, the pain usually subsides, and the affected joint in many cases returns apparently to its normal condi- tion. As in erysipelas, the skin becomes pale and desquamates. Neverthe- less, decided sensitiveness to pressure may be noted in the affected joints, and this increases upon active and passive movement. As a rule, the first attacks of gout are limited to one or several small joints of an extremity; rarely, for example, is the knee-joint implicated in the first attack of gout, Effusions, which are not at all rare in the gouty paroxysm, localize usually in the joints, and often they last for a long time. This causes the condition so frequently noted in the later course of the gouty process, in which two or more joints are attacked, one after the other, and thus the par- oxysm is decidedly prolonged. An illustration of this and of the fact that in the course of gout numerous joints are always implicated may here be given. Observation IT. — X., a lawyer from P»., forty-six years of age, consulted me on the Gth of July, 1890, on account of gout. His father — now over eighty years of age — and his younger brother are both said to have had an attack of gout. His mother died at SYMPTOMATOLOGY 135 the age of fifty-six of diabetes mellitus. Tlie patient previously had two attacks of pyorrhea. He admits prior and occasional marked abuse of alcohol; since practising his profession he drinks moderately. He has always been a great eater, and takes but little exercise. At the age of twenty-one or twenty-two he bad a sligbt attack of gout in a joint. The attack came on suddenly at five o'clock in tbe afternoon while in his office. In the following June the first severe attack occurred, and confined him for almost three months to his room. Remedies — external and internal — were ineffectual until finally the American remedy ( ?) — potassium iodid, colchicum and colocynthitin — brought relief. The attack was in the left foot, and localized especially to the great toe. The paroxysms now recurred yearly, and the right foot also became implicated. In the year 1888, after a prolonged, exhausting ride upon the tricycle, an attack of gout occurred which was localized in the left knee-joint. In November, 1895, a severe attack of gout came on after drinking a somewhat larger quantity than usual of cognac with which the patient hoped to abort an attack of influenza. At first both feet and the knee-joints were implicated; the patient was compelled for almost five months to remain uninterruptedly in the recumbent posture. Relapses constantly occurred in which also the right elbow-joint was involved. He reports that, when free from attacks, the urine was dark and frequently contained sediment. The patient was under observation in my private hospital from the- 6th to the 13th of July. He had tophi in the concha auris. The daily excretion of urine upon a mixed diet amounted to 0.6-0.8 gram in twenty- four hours with an excretion of urea of about 40 grams and a phosphate excretion of from 3.1-2.3 grams. I regulated the diet and advised him to spend his summer in the Tyrol or in Switzerland. He did the latter. In the main, the patient apparently fol- lowed directions. That he rigidly adhered to the diet, and absolutely avoided alcohol, cannot, however, be asserted. The best proof of this is furnished by the reappearance of gouty paroxysms. In the first year during which he adhered to the dietetic regime, he had no attacks. I cannot enter into details here; the following fact will suffice. When the patient celebrated his fiftieth birthday, he thought he could not do without champagne. I know not how much he drank, but this I do know, that the patient had a very severe paroxysm of gout upon the following day. The following case also is instructive. It proves that persons with a gouty predisposition can, by a proper mode of life, keep the disease in check. If they fail to do it, not only may severe attacks of gout appear in rapid sequence, but it is occasionally observed that the paroxysms soon attack a greater number of joints. Obseevatiox III. — The Commercial Councilor and City Councilman, X, aged forty- nine, a very busy man, whose grandfather suffered greatly from gout, states that he comes from a family in the main very healthy. Toward the end of the sixth decade of the last century, he had Asiatic cholera in Vienna; as a young man he had a severe attack of gonorrhea. The patient was under observation in my private hospital from the 11th to the 14th of August, 1899. Regarding his gout the patient wrote for me the following history : " About six years ago I was attacked with gouty pains in the great toe, which appeared every six months and very rapidly passed away. I went to Kissingen every year, which benefited me greatly. Last year (1898) I had a very painful attack of gout in the foot, particularly in the small joints, and in September, 1898, I went to Wiesbaden. At the beginning of February of the following year (1899) another and also very severe attack of gout occurred, mainly in the right knee, but also in the small joints of the right foot, which kept me confined to bed for about three weeks. In May, 1899, I went to Aix-la-Chapelle, where I took the bath cure for four weeks, and used douches. Shortly after my return, gouty pains recurred, but disappeared in a few days. At the present time, upon prolonged sitting, slight pains occur in the joints of the right foot but soon pass away." This closes the report. The patient had gouty tophi in the right ear. The urine showed a trace of albumin. The intestines appeared to be filled with feces. The gouty joints were sensitive to pressure. The patient relates that the 136 GOUT attacks constantly appear, and so suddenly and so decidedly that even ten minutes after the onset of an attack he is unable to walk. Lately the patient has suffered from cramps in the calves. His nutrition is good. He is extremely excitable, and lives in constant dread of the appearance of a sudden attack. The patient tells me that the liqueur Laville helps him, and purges him decidedly. I ordered the observance of purely dietetic rules, and upon the 7th of March, 1900, he wrote to me that he was adhering to my regulations, and since that time he has had no attack of gout. Nevertheless, I have reason to believe that the patient will not long continue this mode of life, although it is beneficial to him. In regard to the gouty paroxysms and the relative frequency with which the individual joints are attacked by the gouty process, what has already been stated may be amplified by the following account. The joints of the knee, elbow, and vertebra are far less frequently attacked than the joints of the toes and the tarsal joint, but among these rarer localizations that of the knee- joint is perhaps the most frequent. I once saw in a patient aged fifty-four, after all the peripheral joints had been attacked by gouty paroxysms, an acute gouty inflammation of the left sternoclavicular joint. Any joint may be attacked by gout; even the small joints of the larynx have been found in- volved. This much is evidently certain, that gouty changes in the joints of the legs are not only earlier but also far more common than in the joints of the upper extremities. The joints of the hand and of the elbow are as a -rule simultaneously involved. The premonitory as well as intermediate symptoms, to be discussed later, may become aggravated with the appearance of an acute paroxysm of gout. In connection with this description of an acute attack of gout it appears necessary to say a few words in regard to the composition of the urine, espe- cially as to the excretion of uric acid. Garrod assumed that during the acute attack the amount of uric acid excreted was diminished. He considered this to be due to a functional disturbance of renal activity, apparently because he was unable to find material changes in the kidneys. This diminished excre- tion of uric acid led Garrod, as already stated, to believe the gouty attack due to a retention of uric acid in the body, i. e., a generalized uric acid stasis. Garrod' s view is vulnerable from more than one point. It must be first stated that a product of metabolism which may be still further decomposed in the body may, during this further decomposition, appear in diminished amounts in the urine; hence it cannot be concluded from its lessened excre- tion in the urine that it is also produced in diminished amount in the organism. Furthermore, if the view of Garrod were actually correct, it is incomprehensible why — as in the majority of cases — the attack of gout should be localized in the metatarsophalangeal joint of the great toe. Now, however, since the old, quite untrustworthy methods of estimating uric acid in the urine have been replaced by reliable ones, it has been demonstrated not only that the amount of uric acid excreted during an attack of gout is not decreased but that it is either normal or decidedly increased. It is by no means necessary that uric acid sediment or urate sediments should be found in the urine. An increased excretion of uric acid during an attack of gout is in the main due only to the attack itself. It has been shown to be independent of the nature of the food and of the total albumin metabolism. Thus the view expressed SYMPTOMATOLOGY 137 above gains support from the fact that, in the gouty process, an increased production of uric acid occurs, and plays an important role. In the cases of gout complicated with severe renal inflammation the complete retention of the excretory function of the kidney for uric acid is proven beyond doubt by the fact that, on the administration of food rich in nuclein, the amount of uric acid in the urine of such persons may be increased. Associated with typical attacks of gout and occasionally without such attacks having preceded, in a certain proportion of gouty patients deposits of crystals which consist of acid sodium urate take place in the tissues. These prove that we are dealing with gout. Most frequently they are found in the joints in which one or more attacks of gout have occurred, and most commonly in the first metatarsophalangeal joint, in which the first and the most fre- quent paroxysms of gout are localized. However, it sometimes happens that these deposits are absent even when many typical attacks of gout have pre- ceded. A prerequisite for the production of such urate deposits is tissue necrosis in the affected parts of the body. If the deposit of urate in the tissue occurs in a nodular form, gout nodules (tophi) are spoken of. The number of these in the same individual may be quite large. The size of the tophi varies decidedly ; small at the beginning, they may attain the size of a chestnut or even become larger. The analysis of two gouty nodules in the laboratory of my clinic shows that the first consisted mainly of uric acid (59.7 per cent.) and alkalies which formed urates with it (nearly 70 per cent.). These urates are to be looked upon as monosodium urates (Tollens), though Eoberts desig- nates them as 'biurates. There is also about 28 per cent, of animal matter present. Phosphoric acid, calcium and magnesium — all three in combination — were present only in traces. The analysis of the second gouty tophus showed in the main analogous conditions. Here also uric acid made up the highest percentage (61.27 per cent.) • sodium oxid gave 12.28 per cent., and animal matter 26.45 per cent. For the practitioner, of course, these gouty tophi which are easily found and unquestionable are of chief interest from their diagnostic value. No error in diagnosis can be made in the case of a gouty patient with tophi in the ear, where they not infrequently develop in great numbers. Gouty tophi may, however, develop at very different parts of the body. The bursas mucosa which are usually implicated in primary arthritic gout, and which are very frequently filled with urate containing material, be- come the seat of such tophi. Every fresh gouty inflammation which is localized there, as a rule, produces a paroxysmal increase of the tophus. The bursa over the olecranon process appears to be the preferred seat of such gouty con- cretions. Here in some patients the first gouty tophus develops. These uratic deposits sometimes form without pain. There is at first swelling from which, upon puncture, a white cream-like fluid consisting of acid sodium urate exudes. Later these tophi become hard and firm. They may disintegrate, and form gouty ulcers, the base of which is the previously mentioned urates. The ulcers are slow in healing and may, according to their localization, etc., lead to seri- ous consequences when suppuration develops. Even when the urate masses sep- arate and the ulcers finally heal, they show a constant tendency to again form. To illustrate the clinical history of gouty tophi some cases may be quoted : 138 GOUT Observation IV. — This record shows what I have already emphatically stated that, in comparatively young persons who are attacked by primary arthritic gout, an extensive tophus formation may occur. This patient was a merchant, aged twenty-five, from Cleveland ( Ohio ) , who was evidently always a great eater, whereas he took scarcely any alcohol, nor was there any family predisposition. Even in his tenth year the patient suffered from decided cramps in the calves, and in his sixteenth year he had an attack of gout in the first left metatarsophalangeal joint. These attacks recurred frequently, and as time passed the intervals became shorter. In these paroxysms not only the various small but also the large joints, occasionally several simultaneously, were involved. The severest attacks always occurred in spring and late autumn. About a year and a half after the first attack — in the patient's eighteenth year — the first gouty tophi appeared in the left ear. The paroxysms almost always came on suddenly; only rarely were drawing pains in the joints present as prodromes, and in these joints the attack was usually localized. Psychical disturbance was said to favor the appearance of the attacks. I saw the patient for the first time upon September 29, 1885. He weighed 124 pounds. His weight is said to have never been greater than this. He was a pale, medium- sized man and had a large number of gouty tophi in both ears. The third phalanx of the little finger of the left hand was thickened to more than double its size in conse- quence of gouty deposits. Gouty swellings were also found in several of the other joints of the finger. Between the first and second phalanges of the middle finger there was an extensor tendon with a movable, indolent gouty nodule. A somewhat smaller one was situated upon the radial side of the left index finger. Tophi were absent upon the right hand. Upon the third toe of the right foot a tophus about the size of a hazelnut was present. Upon the left foot there were two nodules which had ruptured. One of these gouty ulcers was situated upon the nail phalanx of the great toe, the other at the heel. The skin surrounding these ulcers was inflamed. Where these gout tophi had ruptured, white, chalky, urate masses exuded. About fourteen days after the rupture of the tophus at the heel, almost all of the urate masses had been discharged. In the large joints no tophi were to be seen, nor were any deformities noted. The appetite of the patient continued good; the bowels were regular. About September 20, 1885, nine days before the patient came under my observation, he had an acute attack, running an afebrile course, not accompanied by disturbance of the appetite nor of the general system and localized in the left heel, the fingers of the right hand, and the right elbow-joint; amelioration began upon the 6th of October. The internal organs of the patient were normal and he was by no means cachectic. The urine did not contain albumin nor sugar. The daily excretion of urea at the height of the last mentioned attack varied between 23.3 and 27.1 grams in twenty- four hours. The uric acid estimations, at that time made by Heintz's method, can no longer be utilized. The examination of the sweat of the patient by means of the murexid test for uric acid gave a brown color with nitric acid, which upon the addition of ammonium changed to a yellowish brown. In the following winter, in Abbazia, the patient had an attack of gout which lasted for two weeks. In connection with this a gouty tophus developed upon the flexor side of the second phalanx of the ring finger of the right hand which the patient showed to me when he consulted me in the following May. After a stay in Abbazia, he also went to other places in Italy, and although he had no further attacks of gout he felt by no means well. We see in this observation a case of primary arthritic gout which began early in life; paroxysms rapidly succeeded each other and very soon led to quite extensive tophus formation. Gout shows a varying course. In regard to the paroxysm, it must be emphasized here that with a slight gouty predisposition combined with a suit- able manner of life, the typical attacks occur only rarely and pursue a short and mild course. Attacks of gout which are of rare occurrence may assume a definite periodic type. I knew an army officer of high rank who lived to be over eighty years of age, and who, up to the time of his death, had each SYMPTOMATOLOGY 139 year an attack of gout. People with slight gouty predisposition, in whom gout develops under the influence of one or more favoring factors, may keep the disease in check provided these predisposing factors are removed. Thus, for example, if the patient modifies his mode of life he may conquer the existing pathological predisposition which would otherwise enslave him. If such persons have been exempt from gout for a longer period than usual, they flatter themselves that they have been permanently cured of gout, although the physician may have frequently cautioned them to the contrary; but they learn only too soon, if they return to their former manner of life, that this is by no means the case. A single excess is sufficient to reawaken the slumber- ing predisposition to the disease. We now turn to the description of the premonitory and intermediate symptoms by which, as already remarked, I desire to have understood those symptoms which precede the individual paroxysms or are present between the attacks. When the individual attacks of gout have passed off, and during the period free from attacks, gouty patients are often troubled with a number of ailments. I shall here exclude entirely those symptoms which are due to the implication of the internal organs, and also others which not rarely com- plicate the pathological process; of these I shall speak later. In the period free from attacks, there is often more or less decided discomfort, referred particularly to the joints which have been affected, but also to those not attacked in the paroxysms; these disturbances often affect the muscles and bones of the surrounding areas. We must especially mention here that there is sometimes marked sensitiveness to pressure in the periosteum; this is elicited by pressure of the skin covering the bones, particularly the superficial bones such as the shin, but also the sternum, and more often the ribs. More troublesome, because often acute and ushered in with great severity, are the muscular s}rmptoms, especially the painful cramps in the legs which recur fre- quently; no less unpleasant are the so-called rheumatic pains in the lumbar region called by the Germans " Hexenscliuss" popularly known in English as " crick in the hack." To this may be added vague, wandering, muscular pains and a sensation of extreme fatigue which have a particularly depressing effect upon the patient. Although these muscular symptoms are by no means pathognomonic of gout — for we observe analogous symptoms occasionally also in diabetes — they have, notwithstanding, a certain diagnostic value. Between gout, diabetes mellitus and obesity, there are intimate relationships. I have included these three diseases in a pathologic group as " general diseases of the protoplasm with a hereditary predisposition." 1 Similar to the intermediate symptoms are those which precede the attacks. These may exist for years before the outbreak of a paroxysm. According to my experience, such symptoms may be present in persons with slight gouty predisposition who are of active habits and live temperately; they remain the only indication of the affection and a gouty paroxysm never appears. It is obvious that premonitory and intermediate symptoms may also occur, i Deutsche med. Wochenschr., 1898, Xr. 44, und Yerhandlungen der deutschen Natur- forscher und Aerzte, 70; Versammlung, 2. Halfte, Leipzig, 1899, p. 73. 140 GOUT soon or late, in consequence of implication of the internal organs in the gouty- process, for, in primary arthritic gout, as already explained, the entire organ- ism is more or less damaged in the course of time. These deleterious effects will show themselves earliest in persons whose gouty predisposition is severest and in those who are most exposed to the exciting causes of the disease. The acutest cases, however, are those in which several auxiliary causes become active in combination with a decidedly gouty predisposition. Under such circum- stances it may rapidly become apparent that, as is true also in primary arthritic gout, " Totum corpus est podagra" This leads us to the discussion of so-called visceral gout. This indicates nothing else than the implication of various other tissues and organs in the gouty process. In gout there is a decided tendency to catarrhal inflammation of the mucous membrane, and perhaps of the digestive canal, while even with- out this, many gouty patients throw too much labor upon their digestive organs, by immoderate eating and drinking, thus exposing them to inflamma- tory affections of this nature. We may mention, in passing, the frequent catarrhal affections of the mouth and pharynx in gout. The tongue, too, often takes part in this. Among the etiological factors in so-called psoriasis linguae, gout must be included. Worthy of note in the gouty is the loosening of the teeth which is often observed, and terminates in their premature falling out; an alveolar periostitis is looked upon as the essential cause of this very dis- agreeable symptom. Naturally the stomach is early implicated in gout, and it has been quite properly said that the stomach is in gout what the heart is in rheumatism. The gastric dyspepsias of the gouty play a great role in the symptomatology, even in those cases in which special dietetic errors cannot be proven. The causes of these dyspepsias are manifold as has been demonstrated by recent investigations. In the paroxysms of gout a decreased motility of the stomach and a decided diminution of the degree of acidity of the gastric juice has been observed; a deficiency in HC1 is said to be especially common. It is certainly true that in gouty patients dyspeptic symptoms of all kinds, among which anorexia is perhaps in the front rank, are wont to appear. Just as frequent in gout are intestinal dyspepsias. Often in this condition we observe very troublesome and obstinate constipation, by the removal of which, after treatment of the stomach has been quite ineffectual, in many cases the gastric dyspeptic symptoms entirely disappear and even the symptoms of gout in the extremities are decidedly improved. To the symptoms in primary arthritic gout referred to the digestive canal, we may add that in this condition also functional disturbances of the activity of the liver are noted. That inti- mate co-relation exists between gout and the liver can hardly be doubted. Charcot and others have even looked upon gout as the result of a functional disturbance of the liver. However, it is not the purpose of this article to enter upon the discussion of these complicated and theoretic questions. On the other hand, the practical and important point in treatment is to be empha- sized, that primary arthritic gout and cholelithiasis occur simultaneously with comparative frequency. Among other factors, the predisposition in gout of the mucous membrane of the biliary passages to inflammatory processes analo- gous to that of other mucous membranes may represent an important link in SYMPTOMATOLOGY 141 the chain connecting these pathologic processes. It may be here mentioned that in the etiology of the so-called hypertrophic hepatic cirrhosis gont appar- ently plays a part; indeed the liver appears to be implicated in primary arthritic gout, and even more frequently than is usually assumed. However, the heart and the vascular system play a far more important role in gout than the liver, at least from the standpoint of the practitioner. In regard to the heart, it may be remarked that in primary arthritic gout functional disturbances occur frequently; such are palpitation, intermittent beats, arrhythmia, and other irregularities of the heart's action, decided pain in the precordia, etc. These occur mostly as prodromal or intermediate symp- toms, and as a rule diminish with the development of the gouty paroxysm. In general, they are not of serious import, and are often mild and transitory ; nevertheless, they are frequently distressing to the patient. I have often observed such prodromal symptoms in gouty patients combined with stubborn intestinal disturbances, principally obstinate constipation, and have seen the cardiac symptoms disappear with a proper evacuation of the bowels after large enemata of oil. These functional cardiac disturbances which develop in pri- mary arthritic gout are usually observed in persons under fifty years of age. In older persons, especially in such as have had a number of severe attacks of gout, we should bear in mind that these symptoms are caused by organic changes in the circulatory apparatus, even though by physical examination no gross disturbance can be determined. I am very careful not to say in such cases " The heart is normal," but content myself with the expression : " I can find nothing abnormal in the heart." Particularly serious in such cases are attacks of angina pectoris, although I know quite a number of gouty patients who, in spite of this, have lived for a long time. In the case of older gouty patients, especially those who suffer from attacks of angina pectoris, there is often disease of the coronary arteries. In fact we see, as the result of gout, all the different parts of the heart (myocardium, endocardium, valves, peri- cardium?) attacked, sometimes singly, sometimes in combination. Occasion- ally, deposits of urates have been found in the excrescences of the cardiac valves and in so-called ossification of the aorta. Apart from these cardiac disturb- ances, there is also gouty renal inflammation which occurs in primary arthritic gout after a longer or shorter time, and I shall revert to this later. There are no specific cardiac symptoms of gout ; nevertheless, when investigating the etiology of attacks of angina pectoris, we should in the first place think of gout. How a cardiac affection can arise upon a gouty basis may perhaps be understood from the etiology. We can readily understand that, in the course of primary arthritic gout, the heart as well as the vascular system must become damaged because the organs of circulation are overwhelmed with blood laden with urates which do them injury. In the arteries, under these circumstances, there is developed a chronic inflammatory process, atheroma or an endarteritis ; and phlebectases must also be explained in the same manner, at least in part. Frequently disease of the urinary organs develops in the course of primary arthritic gout. I refer in the first place to the complication of gout with nephrolithiasis. This latter association has been denied by some, but incor- rectly; by others it is declared to be a mere coincidence. But here, in my 11 / 142 GOUT opinion, there may be a causal relation as well as in the not infrequent occur- rence of gall-stones in gouty patients (see above) with or without simultaneous urolithiasis. (See my article, " Einige Bemerkungen fiber die Beziehungen zwischen der Gicht und den Steinkrankheiten," Aerztliche Praxis, 1901, Nr. 4, where I have discussed these questions at length.) I shall now consider the condition of the kidneys in primary arthritic gout. At the autopsy of those who have suffered from this disease, the kidneys may be found quite sound and normal, even in the cases in which decided gouty changes in the joints had taken place. In other cases, the kidneys are variously altered by the morbid process. We find chronic interstitial changes with especial frequency, usually the picture of genuine contracted kidney. With this, amyloid degeneration of the kidney is often found. Deposits of urates may be entirely absent in the kidney and in such cases we are unable to recognize the etiology from the anatomical changes. In other cases besides a more or less advanced nephritis, urate crystals are found in the uriniferous tubules. Even this condition I do not believe to be characteristic of gout. Finally, we may note in the degenerated kidneys typical foci of necrosis with urate deposits which closely resemble gouty tophi, both consisting of mono- sodium urate (Tollens). Nephritis due to gout, in the main, shows the same symptom-complex as when due to other etiologic factors. So-called gouty gonorrhea has been much discussed; it is certainly a rare affection, in which, in so far as I have been able to form an opinion, we are principally concerned with a catarrh of the excretory ducts of the prostate. Inflammation of the mucous membranes of the respiratory organs is by no means rare in gout, and this is not remarkable in view of what has been stated regarding gouty disease of the mucous membranes. No further expla- nation is required concerning the way in which gout produces this complica- tion, nor why in this disease there is a predisposition to nutritive disturbance of the lungs themselves, which favors the development of pulmonary emphy- sema. It is also evident that gout by no means excludes the development of pulmonary tuberculosis and other affections of the lungs. Pulmonary tuber- culosis and gout not infrequently occur in combination. In the larynx specific gouty processes also occasionally take place. The symptoms on the part of the nervous system are of special interest. As is well known, many celebrated clinicians have maintained the opinion, to which some still adhere, that gout is essentially a trophoneurosis, or a disturb- ance of the nutritive function. This need not be here discussed. Certainly disturbances in all parts of the nervous system often accompany gout, but many of the usual cerebral affections are due to vascular changes produced in the course of the malady. Diseases of the cerebral vessels have frequently been proven to be the cause of severe diseases of the brain, for example, of cerebral hemorrhage. Often, however, in primary arthritic gout, so-called general neuroses are observed, i. e., those affections of the central nervous system for which no constant material substratum can be found. Among these I must first men- tion the severe neurasthenic conditions which sometimes reach the highest degree of hypochondriac depression, and which in some cases may even SYMPTOMATOLOGY 143 occur in paroxysms. In this group also belongs vertigo, which, however, as experience has taught me, may also be due to disease of the audi- tory apparatus in connection with gout. Here we must also mention migraine so commonly associated with gout, but which apparently develops under vary- ing conditions. Gouty paralyses and neuralgias, among which we find the visceral form, are in many cases due to neuritis. The gouty affections of the organs of special sense,m which, perhaps, those of the eye fill a prominent place, require description by a specialist. It need only here be remarked that glau- coma, so far as I am able to understand the condition, is usually due to gout. That gout plays a prominent role in the etiology of cutaneous affections cannot Be doubted. We have already described the gouty inflammation of the skin in the paroxysms ; to these also belong the so-called copper nose which is not always due to gout, but arises so frequently in gouty patients that a causal relation between them may be looked upon as very likely. This appearance of " rhinagra," which usually runs a chronic course in this prominent portion of the human countenance, must be considered analogous to the gouty processes in the ear. However, within the limits of my experience, necrotic processes of the skin rarely occur in the nose, and, therefore, gouty tophi are absent there. In regard to gouty concretions in the skin and in the subcutaneous connective tissue of the various regions of the body, it is unnecessary to speak further. Occasionally lymphangitis is seen as a consequence of gout. This condition does not give rise to difficulties according to the views which I have formed of the pathogenesis of primary arthritic gout. Gouty eczema and gouty psoriasis are frequently mentioned. It is at once evident that in the development of the former the irritation of the skin in gout, like the gouty inflammation of the mucous membranes, forms a predisposing factor. In psoriasis, of the cause of which we know so little, I have not succeeded in deducing any reliable connection between it and gout; I do not, however, by any means desire to deny the existence of such a connection, particularly as psoriasis and gout so often occur side by side. The same is also true of cer- tain cutaneous affections which may be referred to vasomotor disturbance, among which I desire primarily to call attention to urticaria, which often appears as a chronic affection in gouty women. That these cutaneous affec- tions are invariably due to gout I naturally do not believe. Finally, it may here be mentioned that alopecia is sometimes found associated with gout, although in these cases quite a number of other etiologic factors may bring about the condition. At this place only a review of the more frequent symptoms in so-called vis- ceral gout can be given. In the consideration of the diseases which occasion- ally accompany gout, the question will and must occur whether there is actually a causal connection between them. If we reflect that in gout all the organs are subject to a certain tissue irritation, we shall be inclined to regard many diseases as due to gout. The fact is of interest that celebrated French inves- tigators, such as Bazin and Ch. Bouchard, are of the opinion that cancer is the result of gout. The former has even said that gouty patients are par- ticularlv apt to succumb to cancer, especially to cancer of the rectum or of the bladder. I shall not enter into this in detail. On the other hand, the 144 GOUT fact must be expressly pointed out that gout, obesity and diabetes mellitus are intimately related, which is evident from the circumstance that two of these diseases, or not infrequently all three, simultaneously occur in the same person. There is an extensive literature regarding the connection between obesity and gout. Some look upon obesity and gout as inseparable accom- paniments of one another. Still I must emphatically state here that gouty patients are by no means all fat. Many are so, but even these may emaciate after they have become cachectic as the result of gout. Certainly there are, as has been stated, many fat gouty patients, and I may here refer to my arti- cle upon obesity, in which I mentioned such a case occurring in my practice, and took occasion to discuss the relation between gout and obesity somewhat more in detail. This observation is specially interesting because it concerns a lady who had well developed typical attacks of gout, which are by no means so rare as is usually supposed, but, on the contrary, in my experience, are fre- quent enough in women suffering from obesity. In discussing obesity, I re- ferred to the development of flat-foot which we occasionally observe with in- creasing corpulence, particularly in persons with a hereditary predisposition to obesity and gout ; these are mostly young individuals of either sex. The rela- tions between gout and diabetes mellitus need not be here considered. But it may be noted that gouty and diabetic symptoms not infrequently alternate with one another, a fact which causes the diabetes to assume a somewhat intermittent character. The excretion of sugar is then slight, as a rule, and the so-called diabetes arthriticus frequently shows a course similar to that described by Johann Peter Prank as diabetes decipiens. A. Gilbert and Emil Weil attrib- ute this form of diabetes mellitus to an insufficient or entirely absent function of the liver. Alimentary and rapidly disappearing, so-called simple, glyco- surias, which I always look upon with suspicion, are not so rare in gout. We must now consider the relation between gout and rheumatism. What is to be understood by this? Pirst, there are a number of so-called cases of chronic arthritic rheumatism which should be considered as gout. When per- sons about fifty years of age, who have previously never suffered from any disease resembling acute articular rheumatism, are attacked by an afebrile disease which particularly implicates or almost exclusively affects the small joints, which is accompanied by inflammatory symptoms, and which runs its course with acute exacerbations, gout should first be thought of. This is also true of the cases in which the joints show a certain deformity, and in which we usually recognize the presence of so-called deforming articular rheumatism, a disease which probably has no uniform etiology. An investigation of the family history certainly plays an important role in the diagnosis of such cases. Further, in considering the relation of rheumatism to gout it must be remem- bered that rheumatism, like all morbid processes that damage the joints, when combined with the gouty predisposition, furthers the development of gout, for anything that limits the free circulation of the fluids in the extremities favors the development of gout in persons who are predisposed. Rheumatism not only attacks the joints but all their component parts, i. e., the muscles as well, and must be looked upon as a more or less active occa- sional cause of gout. In a similar manner connecting links of relationship may COURSE AND PROGNOSIS 145 be found between gout and a number of other pathologic processes. From such points of view we may explain the well-known relations of syphilis to gout, which diseases frequently occur simultaneously. I believe that the explanation of this association may be that syphilis in a person predisposed to gout frequently precipitates an outbreak. It is a fact that in the beginning of the secondary stage in syphilitics the limbs, and particularly the joints, small and large, are especially implicated. Any one who fails sufficiently to consider this in treatment misses a very important curative guide. It is cer- tainly difficult, from the nature of the changes in the joints, and when gouty tophi are not present, to say that this is a case of true gout and that is one of rheumatism. These difficulties at once disappear if we consider the history of the so-called Heberden's nodes. By this term we understand the thicken- ing of the joints of the middle and end phalanges of the three-jointed fingers. Some authorities consider these joint deformities a* gouty; others look upon them as of rheumatic origin. In my experience such processes certainly may arise from a gouty basis; upon the other hand, we can by no means always prove that gout is the cause of these joint thickenings. We are not justi- fied in concluding from the same external .manifestation of a pathologic change a similarit}*- in the cause of the disease. A case in point is the con- tracture of the aponeurosis palmaris which has been named, after the cele- brated surgeon Dupuytren, Dupuytren's contracture. It was incorrectly main- tained that this by no means rare affection was always due to gout. This may be the case : it is not, however, necessarily so. At all events such obscure combinations in practice are not to be underestimated, since diversity of symp- toms always awakens interest, and for the affected patient, that is, for his etio- logic treatment, the elucidation of such questions is of the greatest importance. COURSE AND PROGNOSIS The course of gout, as shown by the previous description, is subject to many variations, the majority of which may be understood by supposing that in individual cases there is a varying intensity in the predisposition to the disease, as well as in the influence exerted by manifold occasional causes in producing the condition. Gout is a disease of extremely chronic course. The earlier the vital organs, such as the heart, the vascular system, and the kid- neys, are implicated the sooner does a fatal result ensue. So long as gout remains limited to the extremities, it is a comparatively harmless although very irksome disease. As it is often caused by the fault of the patient, it frequently makes him the sport of his associates and so irritates him. For this reason, the gouty patient with his " Weh und Ach so tausendf ach " and his " Zippern " is rarely the recipient of sympathy. People forget entirely that even an apparently mild attack of gout may be very serious, either be- cause it may throw itself upon the " internal parts," as the laity say, or, to use a more scientific expression, when it becomes retrocedent, because com- plications ensue or because the patients become cachectic. Nevertheless a gouty patient, in spite of periodically recurring attacks of moderate intensity, may reach very old age provided no intercurrent affections arise. 146 GOUT DIAGNOSIS The diagnosis of primary gout depends upon the presence of two symp- toms, namely, the typical attack and the gouty tophi. Either of these, pro- vided that it has been determined with absolute certainty, may in itself be looked upon as proof positive. It is not necessary to. repeat here by what means we may determine beyond doubt the presence of these two symptoms. I have endeavored in the description of the symptomatology to mention these factors briefly, but to characterize them definitely. Neither the joint phe- nomena, nor skiagraphy of the affected joints, are by any means such positive proof as to deserve the confidence of the physician in the diagnosis of primary arthritic gout. The same is true of the uric acid contents of the blood, of the serum from blisters, which is used in Garrod's so-called thread test, as well as of the uric acid contents of the urine. Such findings are by no means to be undervalued; but the data gained in this way cannot as yet well be utilized in practice. They do not increase our diagnostic certainty. On the other hand the recognition of a family predisposition, as well as the history of the patient in other respects, is of inestimable value. There are certain symptoms the consideration of which is important, par- ticularly those which we have learned to recognize as premonitory or inter- mediate. These, too, are by no means positive, yet they often as pathfinders lead us to success. This is true, for example, of lumbago, especially if it occurs frequently without other determinable etiologic factor, and is quite persistent. It is likewise true of the frequently recurring severe cramps in the calves, and of neurasthenia. I have always laid stress upon the fact that a great number of neurasthenics owe their neurasthenia to a gouty predispo- sition which acts by limiting their energy. Special difficulty in diagnosis is often met with in women, when no typical well-developed attacks of gout occur. Here the characteristic gouty tophi are sometimes absent, but, on the other hand, we may find the Heberden nodes. I have previously mentioned that in women true typical gouty paroxysms occasionally occur even although they do not have the same acuteness and intensity as the gouty attacks of men. In such cases the investigation of the etiology is important. It must also be maintained that not infrequently gouty paroxysms can be recognized as consequences of trauma. To the category of these belong a number of joint affections which are called " sprain of the ankle," " stretching of the tendons," etc. Such errors are especially prone to happen in dealing with children as gout is usually not looked for in them. These mistakes may be explained by the fact that, as a rule, a slight trauma precedes the gouty attacks, and this is just as predisposing for the onset of the gouty attacks as the other etiologic factors that have been enumerated. TREATMENT For all practical purposes the treatment of primary arthritic gout may be divided into two parts. First, we will consider the treatment of gout as a whole, including the treatment of the gouty predisposition, and secondly, the TREATMENT 147 treatment of the so-called acute gout, the typical gouty attack or the gouty paroxysm. In the treatment of the gouty process as a whole, prophylaxis plays a most important part. The latter appears simple enough, provided we are correct in assuming that gout depends for its development and existence upon a manner of life which deviates from the normal. Seneca, the celebrated Stoic philosopher, who lived in the first century, a.d., lamented that, in his age, the women who were living in the same opulent manner as the men showed the same tendency to gout as the men, while in the age of Hippocrates women were almost exempt from gout. In general this is true, for Hippocrates says expressly that women do not suffer from gout except when their menses cease. There is, therefore, some truth in the words of Seneca, and since that time moderation has been continuously taught. I will quote the advice of Thomas Sydenham in regard to the treatment of gout. He says (Medical Works, Translated by J. J. Marstaler, Vienna, 1787, ii, p. 312) : "In the first place, then, moderation must be observed in meat and drink, so that the stomach will receive no more" food than it can digest, and no fresh fuel be added to the disease. The other extreme, however, as I have found in my own person, is equally injurious. Abstinence weakens the parts by withholding their due proportion of that aliment which is necessary for supporting their strength and vigor." In regard to the diet of gouty patients and of those persons who have a family predisposition to gout, the same rules are to be observed as in the nutri- tion of the obese. The view formerly maintained that the use of fat increases the formation of uric acid has been shown to be entirely erroneous by investi- gations carried out in regard to the ingestion of fat. The amount of albumin permitted to gouty patients must not be deficient. Everything that weakens the body and diminishes the activity of the gouty patient influences the gouty process unfavorably. On the other hand, the administration of large quanti- ties of meat, as experience has shown, is decidedly deleterious to the gouty. I believe it, therefore, in the nutrition of gouty patients, to be not only advisable but even necessary to employ vegetable albumin in the manner mentioned by me in the treatment of obesity. I am even willing to maintain that for gouty patients a vegetarian diet with the necessary amount of vegetable albumin forms the most suitable plan of nutrition. Milk and milk products may fur- nish the variety which is grateful to the patient. Eggs also, if taken in mod- eration, may be permitted. White meat is looked upon as better than dark. Alcohol, no matter what its form, is poison for the gouty patient and for all those who are predisposed to the affection. Only when the physician for defi- nite reasons declares it to be necessary, is the amount prescribed by him to be employed. The most suitable drink for gouty patients is ordinary good drinking-water or mild alkaline waters. I frequently order that from the Offenbach Kaiser Friedrich Spring, which in my opinion is preferable to all other alkaline mineral waters on account of its slight amount of alkali. For this reason, drugs containing vegetable acids that are excreted in the urine in the form of carbonates should be used in the treatment of gout. The cherry cure and the strawberry cure are not improperly named. These fruits contain alkalies rich in vegetable acid. On the other hand, much harm is 148 GOUT done by the so-called lemon cure. Patients eat so much of this fruit that frequently troublesome dyspeptic symptoms arise. Neither do the grape cures bring about what was formerly expected of them. Sometimes they are fol- lowed by annoying gastric symptoms and even serious digestive disturbances. Moderation in eating and drinking is the first duty of the patient, but, not- withstanding this, the avoidance of all antifat cures, i. e., all measures liable to produce inanition, should be a guiding principle. In this connection the immoderate use of alkalies which are so frequently advised, chiefly on account of their uric acid solvent properties, is injudicious. Mineral spring cures and bath cures are frequently resorted to in gout, and the thermal baths enjoy a great reputation. I usually advise them for patients who cannot take necessary muscular exercise such as gymnastics, mountain tours, etc. The same is true of baths as of the employment of mineral water and bath cures in obesity, which, as we have seen, often accompanies gout. The thermal baths are, in general, to be reserved for (a) such cases of gout as occur in decrepit persons, (&) for old persons for whom energetic muscular activity is no longer possible, (c) for cases of gout in which exudates have formed in the joints and in which resorption is to be brought about, and (d) for cases in which complications make such a treatment necessary. From this point of view peat baths and mud baths are in many cases very serviceable. The sulphur mud baths in Pistyan in Upper Hungary as well as the mud baths in Germany are highly recommended. In many such cases of gout it is noted that, when all other remedies fail, sweat baths in the Grotto of Monsum- mano or in the Grotto of Bormio give very excellent results. Carlsbad, Wies- baden, Aix-la-Chapelle, Vichy, Wildbad and many other resorts are visited by gouty patients, but often without success unless they are assisted by suitable dietetic measures. It is of greater importance successfully to combat the morbid processes which in persons predisposed to gout form active auxiliary causes in its development, and decidedly favor its advance. Among these may be mentioned rheumatic affections and especially syphilis. In beginning a treatment of gout, it should always be determined whether syphilis has pre- ceded it or not. There are quite a number of so-called specific remedies for gout. Those which diminish uric acid formation, that is, which render the urates more soluble, play an important role. Of these remedies lithium has been for a long time in the van. It can only be administered as lithium carbonate, not as lithium chlorid. I have been unable to convince myself of the value of this remedy. Urotropin, introduced into practice by A. Nicolaier (twice daily a dose of 0.5 gram, 7-| grains, each tablet dissolved in a quarter of a liter of a slightly alkaline water), is better. But further investigations concerning its use are necessary. I have heard it praised by a number of old gouty patients who had tried almost everything. Piperazin (about 1 to 2 grams daily in an alkaline water) has proven useful, particularly for the " rheumatic " pains in chronic arthritic gout. The importance of treating the very defective intes- tinal function in the course of gout (constipation) is not to be underestimated. This disturbance of intestinal digestion must be relieved, and, as a rule, I employ large enemata of oil. That plentiful exercise is beneficial and neces- TREATMENT 149 sary to the gouty patient, requires no further explanation. As long as his strength permits this must be kept up. I have already stated that in these cases I prefer muscular exercise to all other methods. If the gouty paroxysms do not occur so suddenly and are not so severe that the patient must go to bed, he should remain as long as possible upon his feet. When, however, the patient cannot walk, and the affected member cannot be moved, " patience and cotton," as many old gouty persons say, are the best remedies; others praise the Laville liqueur, which is probably beneficial on account of the colcliicum which it contains. Colchicum is also administered as a tincture, or in combina- tion with opium, purgatives, and potassium iodid. Pure crystalline colchicin has lately been recommended in doses of one milligram. Such powerful reme- dies should naturalty only be taken under the advice and supervision of the physician. But only too frequently persons subject to gouty attacks refuse professional aid and attempt to cure themselves. The so-called antirheumat- ics, e. g., the salicylates, are also valuable occasionally for the relief of pain, although in the present status of our knowledge, they cannot be advised as a rational remedy for gout. The various symptoms and complications of gout should be treated accord- ing to special indications. Here we will only consider the treatment of the numerous nervous symptoms, especially the therapy of gouty neuralgia with its related conditions, and the functional cardiac disturbances which so fre- quently occur in the gouty. Where there is chronic constipation, the treat- ment previously mentioned for the evacuation of the intestine filled with feces is of paramount importance. Even if chronic constipation is not present a useful auxiliary remedy in intestinal treatment is the employment of arsenic and iron, preferably in the form of iron waters containing arsenic. In general it is advisable to begin with the mildest water of the Levico-Vetriolo in the Valsugana (South Tyrol). A residence in this region, which is easily acces- sible, is to be preferred to the use of the arsenic-containing mineral water at home, for the place is luxuriously furnished with all curative agents that are effective in gout, and is also advisable on account of its climate. There are many cases of so-called " larval " gout, which cannot readily be diagnosticated, yet are particularly benefited by such cures. Cures of this kind are also very suitable, mutatis mutandis, for such gouty patients as are already decrepit and have reached the so-called cachectic stage of gout. The many curative agents which nature and science there furnish, may be adapted in various ways by expert physicians to the individual needs of the patients. In these decrepit gouty patients no kind of so-called specific treatment is to be used, and col- chicum especially is badly borne. Only tonic treatment — adjusted to the con- dition— is advisable. In the surgical treatment of gouty tophi, all the precau- tions of antiseptic surgery are of course to be observed. A few words must be devoted to the consideration of primary renal gout, by which we mean the most serious form of gout, in which a generalized uric acid engorgement arises as the result of a severe renal affection and usually consists in a chronic and, particularly, in an interstitial inflammation of the kidneys. In this renal inflammation, the gout itself is an important patho- genetic factor. At all events, in primary renal gout the renal symptoms are 150 GOUT the earliest ones, and the joint symptoms are secondary. "When the latter de- velop, the nephritic process is usually so far advanced that the gouty nature of the affection can only be determined at autopsy, partly from the gouty changes in the kidney, partly from the gouty changes in the individual joints, particularly the first metatarsophalangeal joint. Fortunately this form of gout is not very frequent. The diagnosis during life is only possible when the conditions just described are recognized in the affected person. If the diag- nosis of primary renal gout has been made, the prognosis is grave, as in all severe interstitial renal inflammations, since the renal parenchyma is destroyed. The therapy should be directed to the renal affection, for which diaphoresis and the dietetic treatment mentioned in primary arthritic gout are first to be tried. OBESITY By W. EBSTEIN, Gottingen We understand by obesity an excessive infiltration of fat into the con- nective tissue in areas of the body where, also in healthy individuals, fat is found in varying quantities. The chief points of deposit of fat are the sub- cutaneous connective tissue and the mesentery. Special parts of the subcu- taneous connective tissue are particularly involved, chiefly the abdomen. In the region of the breasts the deposit of fat may also reach enormous grades. The female breast has been known to attain a weight of 33 pounds. The high- est grades of corpulence we designate obesity. In this condition fat also col- lects in regions where under normal conditions fat can hardly be perceived. Larrey, who accompanied Napoleon I as chief surgeon in all of his campaigns, saw in the Arabs in Syria scrota which attained, owing to fat formation, the size of a bulging cow's udder though under the skin of the normal scrotum only a very scanty loose connective tissue is found. Fat may, therefore, appear even in this region and in great quantity. In regard to the words in common use to designate obesity something may be added in the way of definition. Adipositas is a term often used and this designation is quite clear. A more general term is obesity; x the French speak of obesite. The word is derived from " ob " and " edere," and means literally " to eat up quickly." In Eng- lish the term corpulence is generally employed — a term which is also used by the Germans, but not to indicate the most marked grades of obesity. In the excellent book of William Osier: The Principles and Practice of Medi- cine, third edition (New York and London), 1898, page 439, the disease is described under the name of obesity, and it is mentioned that Lord Byron who was himself quite fat, as is well known, defined the condition — " oily dropsy." The designations " pimelosis " and " physconia " are but little em- ployed. Like the other terms just discussed, pimelosis refers directly to the main factor of the disease, being derived from the Greek word " rj TrifieXrj" i According to the Latin dictionary of Forcellinus, the word " obesitas " occurs in the writings of Columella (a contemporary of Celsus and Seneca), about the middle of the first century a.d., and in Suetonius (according to TeuffeVs History of Roman Literature, about 65 a.d. to 160 a.d.) . The former, in his " de re rustica " 6, 24, writes: " Ne steriles eas reddat, nimia corporis obesitas." The latter mentions in his biography of Domitian (18), that he was disfigured by a bald head as well as by " obesitate ventris." Further, Suetonius in his history of the life of Claudius (41) tells us that laughter was provoked " defractis compluribus subselliis obesitate cujusdam." In the Historia Naturalis, Pliny the dicier (born 23 a.d.) mentions (17, 27) that certain trees also " laborant obesitate." 151 152 OBESITY (= fat). Hyrtl (Text-Book of Human Anatomy, 20th edition, Vienna, 1889, p. 114) holds that the word constructed by pathologists, " pimelosis," is quite superfluous, since the Greek physicians already had a word for this disease, namely irtor^s. Physconia, from "6 i/^o-k^i/," big-bellied, is the nickname of Ptolemy the Eighth, Energetes the Second (170 b. c), the classic prede- cessor of Banting. Occasionally polysarcia adiposa (tfo-dpg, flesh) is used as a synonym for obesity. Strictly speaking, polysarcia should only be used for that stage of obesity in which the fat patient still retains his muscular power, as is occasionally observed at the beginning of the disease. But frequently such persons suffer from muscular weakness at the very onset of obesity. Among many other designations for obesity, lipomatosis universalis may be mentioned — a term which is used as a synonym for the highest grades of obesity. The fat which is normally present about the epicardium attains decided development, and, for example, in lipomatosis cordis, or true fatty heart, we note that the myocardium almost completely disappears before the proliferating fat which permeates it. That fat people have existed since the coming of man is in itself probable, but this is also proven by the oldest records. In the Book of Judges, 3, 21, we read that Ehud (a left-handed man whom Jahve had raised up to deliver the Israelites from the bondage of Eglon king of Moab), in obedience to God's command put forth his left hand, and took the dagger from his right thigh, and thrust it into Eglon' s belly, and the haft also went in after the blade, and the fat closed upon the blade, so that he could not draw the dagger out of his belly; for Eglon was a very fat man. In Psalms 73, 7, there is written, " Their eyes stand out with fatness : they have more than heart could wish," and, finally, in the Book of Job, 15, 27, we read: "Because he covereth his face with his fatness, and maketh collops of fat on his flanks." x Whether obesity was a matter for professional treatment among the Israelites cannot be determined from Biblical records; we shall revert to this later. In the Hippocratic writings we find the earliest rules regarding the treatment of obesity — rules which hold good even to-day. In the art of the Greek mythol- ogy, Silenus is usually represented as a bald-headed old man with a pug nose, small pig ears, and pot-bellied, a typical representation of obesity in the stage which I have designated as the " ludicrous." Eubens, in one of his pictures has graphically portrayed the plump, drunken Silenus, supported by a negro who walks behind him. That obesity during the time of the Eoman Emperors excited ridicule is proven by the previously mentioned quotation from Sue- tonius, and Columella alludes delicately to the prohibitive influence of obesity upon feminine fertility. Pliny the Elder, who was almost contemporaneous with Columella, formulated rules for the treatment of obesity which later were generally accepted. These ancient views have lately been brought forth by some authors as the result of their individual investigations. I shall subse- quently revert to this again. Obesity is a very common disease. Indeed L. Traube considers that a certain amount of stoutness (which the French and sometimes the Germans i W. Ebstein, " Die Medicin im Alten Testament," Stuttgart, 1900, pp. 10 and 150. ETIOLOGY 153 refer to as "embonpoint") is normal. Healthy, strong children are usually plump when the}r are born. This fat which the child brings into the world normally increases during its early life, but later it decreases. We see from this that a certain amount of adipose tissue is to be looked upon as normal in the child at birth and for the first few years after birth; indeed not only is it normal but its absence indicates something abnormal. An excessive amount of body fat, however, is morbid and an evil. What produces such an excessive formation of body fat? ETIOLOGY The causes of obesity can be best understood if we consider for a moment the process of fattening animals, which forms an important chapter in the science of farming. The stock raiser, whenever he is raising animals for slaughter, endeavors to increase fat as well as to produce meat. Many experi- ences with animals have shown that fodder deficient in fat as well as that rich in fat will, under some circumstances, produce a profuse accumulation of fat. Naturally, this presupposes that the food introduced exceeds the amount required to maintain the animal, and that albumin products are also present in the food in plentiful amounts. It is true that animals can be fattened with fat alone without the administration of any albumin, but in this case the animal is fed to death. Such experiments are made under conditions which do not come into question in the ordinary fattening of animals, or in the nutrition of the human subject. Apart from their fodder, the manner of life of the animals has a great influence upon the accumulation of fat, and espe- cially the prevention of too great activity. It has been determined by numer- ous and careful experiments that sheep and oxen which have been fattened may be kept very fat for several months on a comparatively small amount of fodder if they are prevented from active body movements and protected from cold. But we should by no means infer from this evidence that in the devel- opment of human obesity too little muscular activity is the only important factor, even if we suppose that the fattening of animals may be regarded as parallel with the development of obesity in man, of which however there can be no doubt. Of course we know that active muscular labor counteracts a too profuse accumulation of fat. Bunge believes that it is quite healthful and normal for man to eat everything that he likes and in any quantity that he pleases, and that in an otherwise normal mode of life this never leads to obesity. Bunge even declares it to be a portentous error to look for the cause of obesity in an over-profuse intake of nourishment or even in unsuitable food, i. e., in the too profuse intake of carbohydrates and fat. But his ideas by no means correspond with the facts. Bunge, it is true, does not deny that differ- ent persons are predisposed to obesity from different causes. This well-known fact need not even here be discussed in detail. But the familiar family pre- disposition to obesity cannot be adduced as a proof of Bunge's assertions. The objection is too obvious that laziness and an indisposition to take sufficient muscular exercise are also family traits, and also hereditary, and these may be more important than any predisposition to a too profuse fat deposit. An 154 OBESITY incontestable proof that a predisposition to obesity exists may be seen in the fact that there are many persons who eat whatever and as much as they wish, and nevertheless do not become obese. In what this predisposition to obesity consists is very difficult to say. I look upon obesity, gout, and diabetes mel- litus as well, as forming a single group of interrelated diseases whose basis I designate as "a general disease of protoplasm resting on a hereditary pre- disposition." The epithet " hereditary " is not to be strictly construed. The predisposition may, but need not, be hereditary. By protoplasm I understand not only the cell body but also the cell nucleus, therefore the cell in toto. One may readily conceive that in the production of each of the three diseases just mentioned cell body and cell nucleus are implicated in different ways, but I shall not follow these hypotheses any further at present. The investi- gations so far published regarding the respiratory interchange of gases in the obese do not justify any definite and certain opinions, but we may assume that the consumption of fat in a person predisposed to obesity is slighter than in one not so predisposed provided both live under the same conditions. Fur- ther investigations into the respiratory interchange of gases in the obese made with the large Pettenkofer respiratory apparatus, and lasting longer than twenty-four hours, are much needed. Experiments of shorter duration do not justify us in forming any opinion. The predisposition to obesity may become apparent at any time in the patient's life, and the manifestations vary much in intensity. Bunge believes that there is no predisposition to obesity which cannot be overcome by muscu- lar activity. Whether this assumption be correct can, of course, never be proven with certainty. In my opinion there are cases which cannot be cured by exercise unless there is also a limitation of the ingestion of nourishment. The predisposition to obesity rarely shows itself in childhood to any unbecom- ing degree. I have already mentioned that even in utero and in the first years of life there is normally a certain plumpness which rarely increases so as to exceed physiologic limits. I have, however, seen several exceptions to this rule. Occasionally children with a monstrous development of fat are exhibited in shows. What I have s.een of these makes me believe that in cases of this kind there is an excessive development of the whole body, a sort of gigantism, rather than a pure lipomatosis universalis, although the latter is favored by their very unnatural mode of life, for they pass their time almost exclusively in a sitting posture, and eat especially such food as decidedly pro- motes the accumulation of fat. Evidently this so-called polypionia infantum (which, in many cases at least, is associated with the condition described by Schonlein, called chlorosis gigantea) is quite rare. More frequent is an abnormal accumulation of fat in adolescents, especially in women at the period of puberty and in combination with various disturbances of menstrua- tion. In boys also, when the normal development of the sexual organs at the time of puberty is retarded, an increased development of the body fat is not infrequently noted. That eunuchs are fatter than normal beings, although often maintained, appears to me to be insufficiently proven. In animals, how- ever, castration favors fattening. On the other hand, there can be no doubt that women who were previously thin, after several .labors, very frequently SYMPTOMATOLOGY 155 even after their first child, acquire a decided increase of their panniculus adiposis. The same also occurs at the menopause, and during the period of involution in woman. In some men we note that the body fat may increase enormously even during vigorous adult life. There can be no doubt that at this period an improper mode of life decidedly favors the accumulation of fat. Any one who goes to Munich, and watches the inhabitants, will be able to confirm this. Of special interest is the previously mentioned obesity of women in the involution period, which, however, is by no means an invariable occurrence, but is observed in only about one woman in four during the menopause. Xevertheless, the obesity of women at this age has almost become proverbial. One speaks of " matronly proportions," and the Germans have a yet more significant phrase, " fat as an old woman." It is often asserted that this accumulation of fat is due to the cessation of menstruation, to the absence of function of the sexual glands which causes a decidedly diminished consump- tion of oxygen, and also that the decreased interchange of gases can be restored to normal and more than normal in a comparatively brief space of time by the use of oophorin, which compensates for the absence of ovarian activity. Fur- ther investigations will show whether, and how far, this teaching is justified. At any rate this much is certain, that a decided increase of body fat above the normal is often observed without lesions of any special organ showing a decidedly determinable influence. Thus, for example, obesity may occur after recovery from severe illness, and is then usually explained by the long rest in bed during convalescence, and by the increase of nourishment above the normal after a long period of semi-starvation. We know that not infre- quently, after recovery from severe enteric fever, the patient becomes quite stout, and that the corpulence acquired in this way is often permanent. A factor of importance in the pathogenesis of obesity is the use of alcohol. I have already referred to the immoderate use of beer in Munich, and it is not necessary to quote further examples. Bunge also declares alcohol to be conducive to the accumulation of fat, and in the main explains this by suppos- ing that alcohol, by its paralyzing action upon the brain, makes people lazy and unwilling to exert themselves. SYMPTOMATOLOGY In discussing the symptomatology of obesity I shall follow the division of obesity into three stages as proposed by me; if not pushed to a pedantic ex- treme, this plan simplifies matters very much. For practical purposes this division into three stages has shown itself to be very serviceable. In the first stage the obese man is an enviable person, in the second a ludicrous one, and in the third a pitiable one. The first stage may be identified with polysarcia. The flesh, the mus- cles, increase in due proportion to the fatty tissue. This is the type of obesity which conveys a majestic impression. The body becomes fuller, the figure fills out, the person reaches a proper embonpoint. This type is usually found in young persons whose youth is full of activity. In this stage obesity does 156 OBESITY not give rise to any inconvenience, and so long as the affected individuals maintain good muscular power no attempt should be made to remove or reduce the accumulation of fat. A certain amount of fat is a good reserve fund in time of need, for, not infrequently, even in this stage of corpulence, such unwelcome complications as gout and diabetes mellitus appear. Therefore, in this stage of obesity the condition is not to be combated, but any increase of it must be prevented. The conditions are naturally different when the obese individual becomes a ludicrous figure. Such persons suffer from the ridicule of their companions, and form an excellent subject for the gibes of artists and poets. The portly Silenus has already been mentioned. The fat Falstaff, the popular repre- sentative of low comedy, has been glorified and immortalized by no less a one than Shakespeare. Not equal to bodily exercise on account of their great weight, obese persons in this second stage have difficulty in dragging them- selves along even upon a level, and upon the slightest bodily exertion they not only sweat profusely, but, as a rule, they must soon moderate or altogether give up their exercise on account of dyspnea. So far, however, the dyspnea, though it occurs upon slight bodily movement, is usually still of the " functional " type, i. e., it is not due to irreparable changes of the thoracic organs or to other gross organic lesions. The difficulty in breathing is due rather to dispro- portionate development of the abdominal cavity in which the enormous dis- tention of the intestines by feces and gases due to atony of the bowel plays no insignificant role. Owing to this abdominal distention the thoracic space is decidedly narrowed. The diaphragm is forced up and its free excursion hin- dered, while the thoracic organs suffer a more or less decided compression lim- iting their function. Such obese persons, despite their difficulty in moving, show considerable fondness for all kinds of sport (hunting, horseback riding, etc.), particularly as they hope thereby to regain their health. But their motions and their whole appearance, which has so frequently been described and put into song, are so ludicrous that they provoke laughter. Yet we must not forget that even at this stage the complications and results of the immod- erate accumulation of body fat often become alarming. In the third stage of obesity all the severe sequelae develop which make the patient pitiable, and, in fact, he is commiserated. At this stage we meet especially the symptoms of severe disease of the heart, which I have just referred to, as a frequent accompaniment of obesity. This gives rise to dysp- nea due to severe anatomical changes in the heart, and thus differing from the functional form above described. Besides this, a constant accompaniment of every case of marked obesity is a steadily increasing anemia. Prominent observers have contrasted the anemic form of obesity with a plethoric variety, but appearances are deceptive. I need only mention the obese chlorotics from the country with their very red cheeks. Even if we admit the possibility of plethora vera sen sanguinea (which in fact is a greatly disputed condition), we must specifically deny that any plethora occurs in well-developed obesity. Plethora could only happen in those forms of corpulence which belong to the first stage of the disease, i. e., that in which the muscular system is still in a normal condition. In general, anemia with all of its symptoms SYMPTOMATOLOGY 157 and consequences is typical of advanced obesity, especially of lipomatosis universalis. We have already said that the other general "diseases of protoplasm based on hereditary predisposition " (gout and diabetes mellitus), frequently com- plicate the earlier stages of obesity, the enviable and the ludicrous stages. These unfortunate complications should not be regarded as direct sequelae of obesity, but as diseases developed as the result of a pathologic condition of the body cells. The three diseases need not accompany or follow one another, but may arise independently. Hence we must infer that in each of them a sepa- rate abnormality of protoplasm exists. That uratic calculi often occur in the form of obesity which is commonly seen in combination with gout, and that the stones are caused by the gout, has been taught me often enough by my own experience. These stones rarely reach such a size that they cannot be spontaneously voided with the urine. Atheromatous degeneration of the arteries, which is not infrequently noted in combination with obesity, I should not so much refer to the obesity as to the often coexisting gout, that is, to the uric acid diathesis. The obese, as a rule, enjoy an excellent appetite. Almost invariably they eat more than nor- mal persons under otherwise similar conditions. Special stress is to be laid upon this in estimating the quantity of food which a corpulent individual consumes. Naturally we must not depend upon his own reports. In my experience obese individuals who are recognized as notorious gourmands, will, if questioned, deny that they consume an immoderate amount of food. They usually only say that their food agrees with them very well. Fat people often have, as I have already pointed out, a tendency to obstinate constipation. Hemorrhoids exist, or at least develop, very often. Upon the basis of the composition of the urine, A. Kobin has differentiated two forms of obesity. In the one form there is profuse, in the other very slight, excretion of urea and phosphates. Eobin believes that in the former group obesity is the result of increased, in the latter case of decreased, assimilation. He holds that this division is of great importance, especially in measuring the amount of fluid allowed in the dietetic treatment. That with the previously mentioned com- plications the urine shows corresponding changes, need only be indicated here. In advanced obesity there is usually a tendency to catarrhal conditions, espe- cially of the pharynx and of the bronchial tree. Obesity, if left to itself (or improperly treated), and when no conditions arise which produce emaciation — as, for example, severe acute or chronic affections — becomes a protracted disease which, as a rule, shows a tendency to progress. Yet I have not infrequently known persons who have become fat in middle age to lose their fat as they grew older without an apparent reason. Usually this is not the case. As regards longevity, obesity is a factor gener- ally considered to shorten life. On this point we are indebted to the life insurance companies for valuable conclusions. Especially worthy of note, it appears to me, is what A. Hagler says in his book " On the Factors of Eesist- ance and the Prognosis of the Duration of Life in Normal Individuals " (Basel, 1896, page 47 et seq.) regarding the prognosis of obesity. All cases are by no means to be judged by the same scale. Age, heredity, manner 12 158 OBESITY of life and occupation must be carefully considered. Moreover, we should ascertain the patient's power of reaction against external influences, especially mountain climbing and other bodily exercise. Hagler requires that obese persons with an apoplectic or a diabetic family predisposition, with irregular pulse, with decided bradycardia, those who live in an improper manner, and those who are addicted to the use of alcohol, should be excluded from life insurance. No absolute norm for a maximal or minimal body-weight exists, but the rules laid down by Hagler are nevertheless noteworthy : " The insur- ance company at Basel is very cautious in its dealing with individuals of less than 340 grams, or more than 530 grams of weight per centimeter of body- height, and such are usually rejected. We have, however, reached the con- clusion that in certain regions, especially among the very large, often giant- sized, land owners and farmers of East Friesland, a higher body-weight is compatible with a normal duration of life." In my professional activity I have come across such persons, and in general may confirm this statement. But however true this may be, the risk of the obese person is to be estimated with caution. Even the enviable stage of obesity I look upon with suspicion, for it happens now and then that, without the ludicrous intervening, the pitiable stage arises, and this is especially frequent, in my experience, in the cases in which obesity is associated with diabetes mellitus. Primary arthritic gout, even when it runs a severe course, produces, as I have seen, far less dele- terious effects. Frequently the obese are threatened by lesions of the heart and the vascular system. In the heart itself in consequence of fatty deposits dilatation at first develops; sooner or later, when compensation for the dam- age to the cardiac muscle is no longer possible, the symptoms of muscular insufficiency supervene. The vascular disturbances are scarcely dependent upon obesity, but are to be referred to the uric acid diathesis, usually a factor in such cases. The arterial diseases of the obese usually cause effusions of blood into the brain, to which many fat persons succumb. It is of great practical importance in prognosis that persons who suffer from obesity, as is proved by experience, readily succumb to any infectious disease that attacks them. Among other factors which render the prognosis more serious in obesity, I must particularly emphasize the fact that as it progresses it makes the affected individual more and more sedentary, a habit to which the foot affections arising as the result of obesity also furnish their share. Flat-foot very often develops in the young, particularly in individuals hereditarily pre- disposed to obesity, when the body-weight increases. This usually affects those belonging to the higher classes of society, men as well as women. I should like to add here that I have observed such cases of flat-foot, mostly in those with a gouty predisposition. This is particularly worthy of note because such a deformity of the foot cannot be cured without considering gout as an etiologic factor. A sufficient amount of active muscular exercise is quite impossible on account of the affection of the joints of the foot and the result- ing pain. But if the superfluous fat is removed by suitable dietetic regimen, with the slighter weight the diseased feet will also show a corresponding improvement. At this point some remarks on the influence of increasing obesity upon DIAGNOSIS 159 the psychical life of the patient may be in order. It is commonly believed that fat persons have a more phlegmatic, and, associated with this, an espe- cially good-natured disposition. That there is a necessary connection between obesity and a special temperament characterized by indifference and apathy is certainly not true. I wish to issue a warning against the adoption of this very common assumption as correct. [That this is the general view, not only among the laity but even among philosophers and poets, is well illustrated by the familiar quotation from Julius Caesar, Act 1, Scene II, lines 192, et seq. : Let me have men about me that are fat, Sleek-headed men, and such as sleep o' nights: Yon Cassius has a lean and hungry look; He thinks too much: such men are dangerous. (J. L. S.)] It is true, however, that the obese individual is usually distinguished by a less irritable nervous system. It is often declared that obesity hinders the development of great mental power. With necessary limitations, we must admit the truth of this assumption as regards the extreme types of obesity. One who has a great burden of body fat to carry about with him can hardly be expected to develop mental powers equal to those of persons not limited in this way. So long as obesity is not excessive, strong, energetic, and talented natures will be able to adjust themselves to the increase of their body fat and the resulting restriction of their bodily movements without suffering any con- siderable limitation of their mental functions. DIAGNOSIS The diagnosis of obesity is, as a rule, made correctly by the laity, for the condition is obvious, and may be determined whenever one finds an immoderate development of fat in the subcutaneous connective tissue. More perplexing is the decision whether the superfluous fat development has proven detrimental to other structures, for example, to the muscular tissue, as we should assume in all of the more marked grades of obesity. But for the physician this offers no great difficulty. Whether too much fat is formed and deposited in the areas of the subcutaneous connective tissue which are most accessible to exami- nation is readily learned in most cases by observation of those parts of the body not covered by clothing, particularly the face. The cheeks, and espe- cially the region of the chin, appear more massive than normal. The " double chin " is a familiar feature. Yet there are fat individuals in whose faces the fat does not reach decided proportions. The nude body, as a rule, shows accu- rately to what extent fat is accumulated in the' subcutaneous connective tissue. All the landmarks of the body are displaced in obesity ; they appear as if they had been forced downward or pushed laterally. There is great accumulation of fat in the subcutaneous tissue of the mammary region, not only in fat women but also in fat men; in the latter we often see the subcutaneous fat heap up until it produces masses that in point of size are not much less than the well-developed female mamma. Upon the abdominal walls thick trans- verse rolls of fat may often be seen. Upon the lower portions of the thorax, 160 OBESITY and particularly over the crests of the ilium, great collops of fat stand out. An enormous size is often attained by the buttocks which are thickly cushioned with fat. These, however, do not appear rounded but assume a somewhat triangular form since the masses of fat hang downward and deviate laterally. Over the fold of the buttocks there is, therefore, a thick, shapeless mass formed by the superficial subcutaneous fatty tissue, which projects considerably beyond the lateral line of the thighs. In other cases the fat accumulates particularly in the sacral and lumbar regions. The remarkably great development at the fold of the buttock continues downward into the upper portion of the thigh, where the subcutaneous fatty tissue shows an increase that is scarcely less con- spicuous. In very corpulent persons the subcutaneous fatty tissue upon the legs also forms prominent tumors. Of course, it is only at the autopsy of the obese that we can recognize the full extent of the enormous masses of fat which pack the internal cavities of the body, the mediastinal fat, the fat upon the pleura, the great accumulations of epicardial fat, the often excessive accu- mulation of fat in the omentum and mesentery, as well in the folds of the synovial membranes, etc. J. P. Frank mentions a man observed by Boerhaave who, as the result of over-indulgence in food and drink, became so fat that the abdomen had to be carried in a sling which reached down from the shoulders, and the table at which he was accustomed to sit had to be cut away in a semicircle. His mesentery alone weighed 33 pounds. Such fat people are generally looked upon as unsightly. Among the Moors, however, obesity in women is regarded as a great mark of beauty, and among the Kelowi in Central Africa a faultless odalisk must have the weight and circumference of a young camel, a circumference which she attempts to secure by a fattening process carried out with great perseverance. De gustibus non est disputandum ! I have already mentioned the conclusions of the Basel Life Insurance Company in regard to the proportion between size and body-weight as a factor in prognosis. In the diagnosis, however, we must determine not only that the individual in question is obese but also the degree of his obesity ; we must recognize probable complications and the patient's capacity for work ; we must decide to what extent he is anemic, etc. All these questions ' must be accu- rately determined before treatment is begun, and careful examination of the urine must be made in every case if gross errors are to be avoided. TREATMENT The treatment by which a patient is freed from his fat is often designated antifat treatment. Of course, the individual is not to be rid of all his fat and reduced to absolute leanness, but he is to have the surplus fat removed. In such an antifat treatment, it must never be forgotten that adipose tissue is a normal constituent of the body, and that its complete absence is not only unbecoming but a decided menace to the health of the person in question. There are people whose occupation necessitates that they be thin and remain so, guarding themselves against the over-accumulation of fat from any cause. TREATMENT 161 This is attained by a process of training, so called, which consists in systematic and gradually increased exercise combined with a suitable diet. In this man- ner such persons fit themselves for various feats of strength. There is special training for riding, for marching, for swimming, for rowing, etc. We are all f amilia,r with the training of race horses ; by a special kind of treatment, by feeding and systematic muscular exercise, they are prepared for their task. By the same means men may prevent an increase of obesity, and eventually even become rid of it. In the well known processes of training, therefore, the first principles of the treatment of obesity are embodied. Nevertheless the detailed application of the latter is decidedly different, in that such tests of strength as are used in training are not suitable in the treatment of obesity, and, as a rule, would be dangerous in a corpulent person. Nothing is easier than to make a person lean. Debove at a meeting of the Academie de Medecine at Paris on the 6th of March, 1900, showed a patient who had just passed through an emaciation cure (cure d'amaigrissement) . To explain this method I will quote briefly a review of Debove's treatment published in the Semaine Medicate, No. 10, 1900, showing what this physician advises in the treatment of obesity. I must remark at the outset that obesity cures and emaciation cures are by no means to be looked upon as synonymous. In the former only the super- fluous fat is to be removed, while in the latter both fat and muscle are to be diminished. Leanness is attained by hunger ; a treatment to produce lean- ness and a hunger cure are identical. Debove's obese patient, who suffered from urinary gravel, weighed before treatment (which lasted less than a year), 147 kilograms; after treatment he weighed only 94 kilograms. The patient, therefore, in less than a year lost 53 kilograms of body-weight. How was this attained? The patient was put upon a pure milk diet. He received daily for one month %\ liters of milk, during the second month only 2 liters, and in the third month only one liter per day. The patient, who was unable to leave his bed, lost in the first two months of this treatment 15, and in the third month 5, kilograms of body-weight. After the first three months he weighed only 127 kilograms. During the next four months the patient re- ceived daily only one liter of milk. At the end of seven months from the begin- ning of the treatment he weighed only 105 kilograms. He then ceased to emaciate. But after a change of diet which permitted the patient to take cooked vegetables, salad and fruit in any quantity that he desired, he lost 12 kilograms more, so that he then weighed only 94 kilograms. As the result of this treatment Debove reports that the man not only was re- duced in flesh but that he regained his health and his physical and moral capacity. Debove hopes that the good effects of this treatment will be maintained. This case demonstrates that occasionally, by means of a starvation cure, we may obtain good results. In this case there was certainly a considerable degree of malnutrition, for 2.5 liters of milk per day, the amount which the patient received for the first month, is decidedly insufficient for nutrition, to say nothing of the fact that he had to content himself for months with one liter a day. Now it is certainly strange that, in this patient, loss of weight ceased 162 OBESITY after seven months in spite of continued insufficient nourishment. On the other hand, upon administration of a purely vegetable diet, especially after partaking of fruit in unlimited quantity, loss of weight again took place. I can only explain these facts by supposing that the patient, after the first seven months, became so hydremic that a further loss of weight was no longer possible. Subsequently, a decrease in weight could only be brought about when, by the diuretic influence of the vegetable acid salts resulting from the ingestion of large quantities of fruit, depletion of the fluids of the body occurred. In obesity cures nowadays we naturally do not wish to use any method of treatment which brings about inanition. It is true that in every obesity cure, however rationally it is carried out, there must always be depletion of some kind. This depletion, however, must not go so far that muscle as well as fat is lost. A withdrawal of fat without loss of muscle can be brought about by a suitable change in the diet . or by increased muscular activity, or — best of all — by a combination of both methods. By a diminution of the nourishment which has previously been taken in excess, and by an increase of muscular exercise which has previously been insufficient, the superfluous body fat will gradually be consumed. I do not doubt for a moment, and I have often em- phatically said, that this goal may be reached by very simple means. Typical in this respect is the quaint tale of Johann Peter Hebel, which many an indo- lent, fat carouser may take as an example. This story is told of a rich, fat Amsterdamer, whose physician, living a hundred hours' journe}r from him — and this was no less a personage than the celebrated physician Boerhaave, of Leyden — insisted that the patient visit him, and that he come on foot. He impressed upon him the necessity of a regular mode of life in order to crush the dragon which he carried around in his abdomen. The patient became an expert pedestrian, and then learned to saw wood; he restricted himself to the food that hunger required, became as healthy as a fish in water, and reached the age of eighty-seven years, four months and eighteen days. These effective means of preventing an excessive increase of body fat, or of causing superflu- ous fat to disappear, have met with little favor, though obviously they are so easy to carry out. We see that celebrated physicians like Johann Peter Frank almost maintain an attitude of hopelessness as regards measures for the re- moval of obesity. Frank joins in the old complaint of a Leipsic physician of his time that " a few succeed, by the aid of very strict diet, in wholly ridding themselves of their superfluous fat; as soon, however, as they have accom- plished this (not without great loss of power), and attempt to recuperate by a less severe nutrition and mode of life, they regain their previous amount of fat, or, in its place are attacked by a pitiable condition of dropsical accumu- lation." It is obvious from this that J. P. Frank had starvation cures in mind, and that he was so daunted by these unfortunate experiences that he did not further pursue his endeavors. He mentions no special dietetic rules for the relief of obesity. It seems to me best to present in chronological order a comprehensive review of the methods of treatment which have been employed in our time, and I desire expressly to state that much that has been claimed by individual TREATMENT 163 authors, with great self-laudation, as the product of their own ingenuity, may be referred to very ancient sources. First, then, as the earliest of the modern methods of treatment of obesity, the " no-fat cure " must be mentioned. This treatment prohibits the eating of fat, on the principle that under all circumstances fat will produce fat. The type of this is the so-called " Banting cure." Banting, a very corpulent Eng- lishman, Avho lost his fat by this method under the treatment of his physician, Harvey, has made himself and his cure widely celebrated. Certainly it is to his credit that he described his disease and his treatment in a very charming manner. This made obesity cures popular for the first time, but they were in practice long before Banting's time. A Parisian physician, Dr. Leon, in the year 1839, was the first to translate and annotate the work of the English physician, Wadd. This book treated of corpulence and its cure, and at the same time emphasized the fact that fat people must learn to endure thirst as much as possible. Leon appropriated the ancient teaching of Pliny, to which I shall revert later. " His views, however, did not appear to meet with general approval. Much greater publicity was attained by the methods of the Eng- lish physician, Thomas K. Chambers. He prohibited most strictly the use of fats and sugar as well as starch in the form of potatoes; he limited decid- edly the eating of bread, and permitted only very small quantities of fluids. I shall here quote two of Chambers's diet-tables; it is obvious that the first is much more strict than the second. The conclusion may be drawn from these tables that the enforcement of such strict rules met with great opposition on the part of the patient. Perhaps, too, Chambers himself found that too great a limitation of N-free foods is not well borne by patients. 1. Thos. K. Chambers, " Corpulence or Excess of Fat in the Human Body," London, 1850, p. 12G. Breakfast: Dry, toasted bread, or, better, ship biscuit; if severe muscular exercise is contemplated, a small piece of lean meat is also permitted. Midday meal (one o'clock) : Some meat (without fat) ; with this stale bread or crack- ers, or a small quantity of maccaroni ( cooked soft with some French mustard or stewed fruit ) , or some cracker pudding. Fluids may only be taken one-half hour after a meal. Later in the day if a sensation of weakness appear, a piece of biscuit and a glass of water, otherwise no solid food is permitted; before going to bed a cup of gruel or a baked apple is allowed. Chambers believes ten ounces (=300 grams) of solid food to be sufficient, but prescribes a small quantity of malt-extract at meal-time more effectually to quiet hunger. 2. Chambers, "Lectures on Corpulence," London, 1864, p. 542. Breakfast (to be taken early) : Two lamb chops carefully freed from fat, broiled or stewed, and ship biscuit. By way of variation a pigeon, game, or fish in corresponding amount. As fluid: Soda water, or, even better, ordinary water, perhaps a cup of tea without milk made in the Russian style with a thick slice of lemon. Lunch (second breakfast) : The same solid foods. Fluid: a glass of claret and Burgundy, half and half, with water. Dinner (best about six o'clock) : Soup and fish are to be avoided. Boiled lamb and beef are to form the principal constituents of diet. With this some biscuit with vegeta- bles rich in chlorophyl and starch, such as cabbage, lettuce, spinach, beans, and celery in small amounts; no potatoes. Sweets, eggs, and beer are to be avoided like poison. Next to water, claret is the best drink. Champagne is the worst. Evening: A cup of tea in the Russian style, or a glass of ice-water, or, better, a glass of soda water or ordinary water. 164 OBESITY Banting's diet list is as follows: Breakfast: 120 to 150 grams of beef or lamb, kidneys, fried fish, ham, or any cold meat (only pork being absolutely prohibited), a large cup of tea without milk or sugar, some rusks, or 30 grams of toast without butter (total of 150 to 180 grams of solids and 240 grams of fluid). Besides, Banting first took a swallow of " Balsam of Life " — probably a kind of bitter-tonic. Midday meal: 150 to 180 grams of fish (except salmon), or meat (no pork), or any kind of poultry or game, all sorts of vegetables (except potatoes), 30 grams of toasted bread or stewed fruit. Two to three glasses of red wine, sherry or Medoc (champagne, Port wine and beer are prohibited) ; total of 240 grams each of fluids and solids. Afternoon: A cup of tea (without milk or sugar), 60 to 90 grams of fruit, one or two large biscuits ; total of 60 grams of solid and 240 grams of fluid. Supper: 90 to 220 grams of meat or fish (same varieties as at the midday meal), and one or two glasses of red wine; total 90 to 120 grams of solids and 180 grams of fluid. As a drink just before going to bed some grog (consisting of red wine or rum without sugar) or one or two glasses of red wine. In this compilation it appears that Banting (who in respect to quantities did not exactly conform to this scheme) was allowed by his physician about 600 to 650 grams of solids and 500 to 1,000 grams of fluid per day. In Banting's letter describing his cure I cannot find the statement that he allowed an unlimited supply of water to persons predisposed to obesity — as Immer- mann and Cantani report. The following rules of Bobin may also be arranged among the antifat cures. Albert Bobin {Revue de therap. med.-chir., 1897, No. 24, quoted from the Correspondenzblatt fur Scliweizer Aerzte, 1898, page 96, No. 3) permits five meals daily. 1. Eight o'clock in the morning: A soft boiled egg, 20 grams of fish or lean meat taken cold without any addition, 10 grams of bread, a cup of weak tea as hot as possible and without sugar. 2. Ten o'clock: Two soft boiled eggs, 5 grams of bread, 160 c.c. of wine with water, or tea without sugar. 3. Twelve o'clock (midday meal) : Cold meat according to choice but without bread; as a substitute for bread, lettuce or water-cress with a little salt ; if absolutely necessary at most 30 grams of bread. Exclusively green vegetables, particularly boiled lettuce (100 to 150 grams). The same quantity of raw fruit for dessert; as fluid one or two glasses of red wine with water. A quarter of an hour after the meal a cup of weak tea without sugar. 4. Four o'clock p.m. : A cup of weak tea without sugar. 5. Evening, seven o'clock (supper) : Same as in the morning at eight o'clock with the addition of hot meat with or without fish, at most 100 grams. After every meal a walk lasting for one-half to three-quarters of an hour; besides, general hygienic measures, hydrotherapy with friction, steam baths and general massage are advised. Seven hours of sleep for adults, eight hours for children. No sleep dur- ing the day. Regarding Robin's advice as to the amount of fluid, mention will be made later. Bobin's diet regulations require much greater self-denial on the part of the obese than those of the English authors previously mentioned. I think it quite likely that Bobin reckoned first of all with the manner of life and the dietetic peculiarities of his French compatriots. Cantani is more strict with TREATMENT 165 his obese patients. He absolutely prohibits not only all fat, but also all foods made of flour, and also all sugar-containing materials. Cantani probably realized that the dietary formulas which he published could scarcely be followed by the obese, or only endured for a brief while. In some of his patients, partly on account of the unconquerable aversion con- sequent upon consuming such great amounts of meat, partly on account of the incapacity of the stomach to digest so much animal food, and partly because of the great muscular debility which appeared after following his dietary rules, Cantani himself combined his rules with Harvey-Banting formulas in which a certain quantity of carbohydrates and fat were permitted. How- ever, even the so-called Banting cure is by no means harmless. The large quantity of albumin required by it on the one hand, and the too great limita- tion of N-free foods (fat and carbohydrates) on the other hand, are very badly tolerated by the patient, and, as professional experience has shown, not infre- quently are productive of serious harm. We know, for example, to mention but one point, that no-fat cures of this kind may produce severe organic dis- ease of the kidneys. The danger of such cures would be yet greater if the " lean meat " did not contain a certain proportion of fat ; even lean beef con- tains about 2 per cent, of fat. Nevertheless, the amount of carbohydrates allowed by these tables is still insufficient. Cheese, of course, cannot be taken in a no-fat cure — it is expressly forbidden by Cantani — as there is no kind of cheese that is free from fat. By this no-fat method of treatment, quite insupportable conditions are produced which even a very strong-willed person can at most endure for only a brief while. Yet these methods were those most commonly employed up to the beginning of the eighth decade of the nineteenth century. Since then, however, the " no-fat " method has more and more fallen into disuse. Of course, it must be admitted that the treatment by the withdrawal of fat is effectual and even to a certain degree rational, i. e., by such a system of nutri- tion a loss of fat may be brought about without damage to the muscle; but great care must be exercised. In the most favorable cases the method can be pursued only for a period of a few weeks, or at most a few months, provided all goes well. Further, this method can only be risked in obese patients who are still in good muscular condition; for only very strong constitutions can endure such a diet for any length of time. On account of this limited applica- tion, the " no-fat " cures do not fulfil the requirements which a truly rational cure of obesity calls for. In such a method, for instance, it is desirable that the patient should, without danger to his health and without too great priva- tion, be able to continue the diet permanently after the result has been ob- tained, though perhaps with slight modifications. Such modifications have, however, not been proposed by any of the exponents of these methods if we except the advice of Cantani that, in case his dietary regulations prove impracticable, the Banting cure, i. e., the regime of Thomas K. Chambers, is to be substituted. I do not believe that such modifications of antifat cures are possible without violating and completely overthrowing their principle. In such a modification the amount of albumin which is to be consumed must be lessened, and either fat or carbohydrates substituted in a corresponding 166 OBESITY amount. Of course, under such circumstances, the diet loses its significance, which, after all, consists in the large amount of albumin which the patient is supposed to consume. The shortcomings of the " no-fat " cures, especially the fact that at best they admit of but temporary employment, caused me to propose in the year 1882 a method for the treatment of obesity which is free from the objection- able features of those previously mentioned, and which, without losing its distinguishing characteristics, may be variously modified from time to time according to whatever conditions may arise. My method, which is by no means a modification of the Banting cure, permits a manner of life which differs but little from that of other plain and sensible persons. My plan can be continued indefinitely by the person in question without the exercise of too great self-denial. By this means alone is it possible to retain perma- nently what has once been achieved. The treatment of obesity is a rational one only when we endeavor to bring about a lasting cure, and not only a rapid transitory result. We can never succeed permanently with any method of treatment if the patient follows it only for a certain length of time and then returns to his former mode of life; that which has shown itself as curative must form a permanent and integral constituent of his future manner of life. The conceptions which led me to propose for obese persons a diet which should be curative, and, in its main principles, could be maintained during life were chiefly the following: It is sufficiently proven by experience that even in fat persons the ingestion of a measured quantity of fat under certain circumstances fails to produce any accumulation of fat, and that the person in question may even rid himself of his superfluous fat provided that the carbohydrates are properly limited and that his manner of living is otherwise normal and in accordance with the fundamental laws of the modern phys- iology of nutrition. I have, therefore, abjured the fat-depletion cures and assigned to fat the place which it should occupy in the diet of the obese. The prohibition of fat is entirely opposed to the physiological laws of normal nutri- tion. Fat is a necessary food. No less prominent a physiologist than Don- ders refers to this as follows : " Too little fat undermines the organism, and lays a foundation for faulty nutrition, a poor admixture of the nutritive juices and of the tissues." That this law is not operative for the obese can neither be proven by scientific reasoning nor inferred from professional experience. Even Hippocrates advised for the obese the ingestion of foods prepared with fat, as, in this manner, the appetite was most rapidly satisfied. This obser- vation of Hippocrates is perfectly correct. It is, therefore, an ancient law of experience that by the addition of a cer- tain amount of fat to the food the sensation of hunger is more lastingly re- moved than by food very deficient in fat, or by an equivalent amount of carbo- hydrates or of albumin. Fatty foods act in this way not because they spoil the appetite nor (as has been maintained by some) because- they produce dys- peptic symptoms. On the contrary we see that dyspeptic symptoms appear frequently after the ingestion of too large quantities of meat. That one may eat enormously of meat without a sensation of satiety is well known. Quite TREATMENT 167 similar are the experiences in regard to carbohydrates. The question why fat satiates its most rapidly may be very easily explained by the observations of M. Matthes and E. Marquardsen (Verhandl. d. Congr. fur inner e Med., 1898, XVI, p. 358 u. fig.). These observers have shown that fats remain in the stomach for a long time, and that large amounts of fat necessitate a very large expenditure of the regulatory powers of the stomach, and produce a decided encumbrance of the same. As in my diet regulations too great amounts of fat are not permitted the obese, the deleterious effects arising there- from are not to be feared. Further, the inclusion of fat is by no means a cure by means of nausea, as has been stated by one author. It is in fact not a cure but a mode of living whereby fat simply assumes its proper function as a food. To attain this purpose, no larger amount of fat is necessary than is per- mitted to non-obese persons, even to those who are subjected to the hardest labor. In the nutrition of the obese the limitation in the amount of carbo- hydrates is the chief point. Of course, this does not mean that an intolerable limitation of vegetable food is necessary. On the contrary, in the nutrition of fat persons a plentiful use is to be made of green vegetables rich in water and poor in carbohydrates, since their pre-eminent qualifications as satiating foods and fat carriers make them especially suitable. Only vegetables rich in starch, such as turnips, potatoes, etc., are. to be avoided. By this method fat is administered to the patient in such wise as to cause no repugnance, and the carbohydrates may be limited by giving a bread richer in albumin than is usually taken — a point to which I called attention a number of years ago. Our ordinary bread contains only about 6 to 7 per cent, of albumin, and its nutritive product is almost exclusively starch. The starch may be decidedly reduced if the albumin contents of the bread are increased by the addition of vegetable albumin. In this manner it is easy to prepare, even at home, a very palatable bread which will contain from 20 to 30 per cent, of albumin. I have repeatedly published the formulas necessary for this purpose, last in the article by Schwalbe and myself on Diabetes Mellitus in the " Handbuch der praktischen Medicin," Stuttgart, 1901. For the preparation of such a bread we require pure vegetable albumin, which may be obtained from a num- ber of plants. Vegetable albumin is easily digested, readily utilized by the human organism, and is not only very much cheaper than meat but, for many other reasons, is even preferable. Up to very recent times but two such pure vegetable albumins were at our disposal, one of which was discovered by Dr. Johannes Hundhausen of Hamm i. W., and manufactured from gluten, a patent albumin which the inventor calls "■ aleuronat." In addition to small quantities of salts (0.78 per cent.) and cellulose (0.45 per cent.) aleuronat contains at least 80 per cent, of albumin, about 7 per cent, of carbohydrates, and about 9 per cent, of water. The second vegetable albumin, placed at our disposal later than aleuronat, is the rice albumin "ergon" which is manu- factured by Dr. Hensel & Co., in the chemical laboratory at Lesum near Bremen. This is not the place at which to enumerate the varied uses we may make of vegetable albumin in the nutrition of patients with diabetes mellitus. In 168 OBESITY obesity as well as in gout we utilize vegetable albumin almost exclusively for the preparation of a bread rich in albumin, by which we may satisfy a greater albumin requirement in the individual than is possible by means of our ordi- nary bread. In this manner larger amounts of bread may be permitted than would otherwise be allowable, which is very acceptable to the patient. By the aid of these vegetable albumins we may produce a bread which is entirely unobjectionable ; frequently, however, such a bread is distasteful. This is due to the fact that the necessary care has not been observed in its preparation. It therefore appears to me worth while to give some directions and a few recipes for the preparation of these breads rich in albumin, such breads as are useful in the dietetic treatment of obesity and gout. To ensure a faultless bread, absolutely necessary prerequisites are: 1. Scrupulous cleanliness of all uten- sils and purity of all ingredients; 2. A pure, starch- free, compressed yeast (common, so-called baker's yeast may be adulterated with starch flour up to 50 per cent.) with good fermenting power — for the preparation of good aleu- ronat or ergon bread requires a larger quantity of yeast than other breads; 3. An exact following of the recipes in regard to the amount of fluid. 1. RECIPE FOR THE PREPARATION OF WHEAT BREAD WHICH CONTAINS A.BOUT 27.5 PER CENT. OF ALBUMIN {Before the addition of any liquids.) 600 grams of wheat flour, 150 grams of aleuronat or ergon, 10 grams of yeast, i liter of milk, 5-J- grams of common salt, About one gram of sugar (i. e., as much as the yeast requires for fermentation). Proportion of aleuronat or ergon to wheat flour as 1 : 4. The flour and aleuronat are to be well mixed in a pan previously warmed to about 30° C. A small portion of the milk is warmed to about the same temperature, and after one gram of sugar has been dissolved in it the mixture is poured upon the crumbled yeast, and the whole set in a warm place at not over 30° C, and allowed to stand until it ferments. This mixture is then poured into the center of the flour and aleuronat (or ergon) mixture in such a way that the outer borders of the flour are not moistened. Next the remainder of the warm (30° C.) milk and the salt are stirred in with a spoon, still keeping the outer portions of the dough dry. The vessel must then stand in a warm place (30° C. ) covered with a cloth until the dough rises; then it is to be mixed, first with a spoon and then lightly with the hands (firm kneading is to be avoided), with the dry flour still remaining at the edges until a soft dough is formed from the entire mass. It is then made into small loaves which are allowed to rise in a baking pan slightly warmed (30° C), greased with butter. After they have risen, the loaves are glossed over with melted butter and baked for one-half or three-quarters of an hour. Brushing the surface of the loaves with cold water before they are taken from the oven gives them greater luster. These loaves may be eaten on the day of baking, or even a day or two later, but are better if placed in the oven and re-baked. Bread containing fat, and very palatable, may be made by adding butter to the mixture of warm milk and table salt in a proportion of about 50 grams of butter to about one pound of dough. This bread also is to be smeared with butter, and baked in a pan. TREATMENT 169 2. RECIPE FOR THE PREPARATION OP RYE BREAD WHICH CONTAINS ABOUT 27.5 PER CENT. OP ALBUMIN {Before the addition of liquids.) 1,200 grams of rye flour, 300 grams of aleuronat, 30 grams of sour dough,1 About 12 grams of table salt, About 1.5 liters of lukewarm water, and lastly, some caraway seed (if desired). Proportion of aleuronat to rye flour as 1 : 4. On the evening before baking, flour and aleuronat (or ergon) having been previously warmed are thoroughly mixed in a vessel warmed to 30° C. To this mixed flour add the sour dough which has been previously mixed with some of the lukewarm water, and is now poured into a hollow in the center of the mass of flour, the outer borders of the flour remaining dry and untouched. Now the dry aleuronat (or ergon) mixture at the edges is mixed with the watery mixture of sour dough in the center while we gradually add the rest- of the water, stirring from the center to the periphery. After this is done, the entire mass in the vessel is sprinkled with the aleuronat (ergon) flour mixture, and the dough prepared in this manner is allowed to stand over night (about twelve hours), well covered and kept warm at about 30° C. In the morning salt and caraway seed are added, and the mass is kneaded at once. If the dough is too stiff it may be made more spongy by the addition of lukewarm water, and if it is too sticky flour and aleuronat (or ergon), 1 to 1, may be kneaded in. Then the dough is placed in a shallow iron pan, covered with a linen cloth, and set in a warm place at about 30° C. for 2 to 2J hours, to rise. When light the loaves are brushed with melted butter, and baked for about 2 to 2£ hours. To test whether the bread is done, a splinter of wood may be introduced into a loaf, and if, on withdrawing it, no moist dough adheres to it the bread is thoroughly baked. It is advisable during the last part of the baking to turn the loaves in the pan. This bread should not be cut until the next day. It should be kept in a cool place, and in the summer in the refrigerator. Of course, bread containing less aleuronat or ergon may be made either with wheat flour, or with rye flour. Thus, for example, we can make bread which contains one and a half times as much or double the amount of albumin (in dry substance) contained in ordinary bread, which, as is well known, contains about ten per cent, of albumin (dry). To make bread containing about fifteen per cent, of albumin in the dried condition, add one part of aleuronat or ergon to about twenty parts of flour; to make bread containing about twenty per cent, of albumin (dry), add about one part of aleuronat or ergon to eight parts of flour. The smaller the amount of aleuronat or ergon the easier it is to make aleuronat or ergon bread. It is therefore advisable for an amateur in bread baking to begin with one of the weaker aleuronat or ergon breads according to the recipes just given. The breads containing larger quantities of albumin can then be made with greater certainty and ease. Eecently the number of vegetable-albumin preparations, has greatly in- creased. Among these may be mentioned the product of Niemoller in GHitersloh i. W. from grain, and called " rob or at" For baking purposes this is exceedingly useful. Further experiences will have to be gathered in regard to these preparations, whose number will probably increase still further. A formidable rival to these vegetable-albumin preparations is fresh casein. The investigations undertaken in my clinic by E. Schreiber (Centralbl. f. Stoffwechsel- und V erdoMungslcranklieiten, 1901, ISTr. 5) have shown that there ( i Rye flour dough from a previous baking, which has been set aside for several days, and has turned sour. [J. L. S.]) 170 OBESITY is no cheaper, and at the same time more palatable, albumin for these pur- poses. Bread produced from fresh casein (casein bread) may of course be also utilized in the nutrition of gouty patients, for casein does not produce an increase in uric acid excretion. The bread made with this casein can be readily baked by any baker. I have often used it with advantage in the nutrition of the obese, of gouty patients, and particularly also in diabetes mellitus. It is obvious that within certain limits leguminous vegetables may also be utilized in the nutrition of the obese. Besides a plentiful amount of albu- min these vegetables contain much carbohydrate, but with a corresponding limitation of the other carbohydrates of the diet, they may be used with advan- tage. The discreet use of fruit not too sweet, and of stewed fruit without the addition of sugar, is permitted. Sugar, puddings, and starchy foods of other kinds, as well as potatoes and all dishes made from them, are absolutely prohibited for the obese. A small quantity of wine deficient in sugar and containing small amounts of alcohol may be given, provided the patient can- not get along without it. Beer I prohibit. This is generally one of the most severe trials which the obese patient is called upon to undergo. Brillat-Savarin is, however, quite correct when he says to the obese : " Avoid beer as you would the pest." But with regard to tobacco, provided there is no contra- indication on account of the heart, I permit a moderate indulgence — two or three mild cigars a day. Finally, regarding the proper quantity of albumin for corpulent individ- uals, of course all superfluous proteid must be reduced according to the indi- vidual requirements, as in the antifat methods of treatment. Certainly custom permits entirely too much latitude in this direction, and often the patients take far too much albumin. We have seen that by including vegetable -albu- min in the diet, a considerable amount of the albumin needed by the body is provided. On the other hand, I must emphasize that, in such a diet, the patients have all the variety necessary for those who live under normal condi- tions, and who do not perform excessive bodily labor. With this diet, wherein the fatty foods fill their proper place, we find that hunger is more easily satis- fied than with an antifat diet, and that the thirst which occurs in all antifat cures is also avoided. If thirst were not a constant feature in " antifat cures " it would be unnecessary to make such statements as that the patients " must learn to endure thirst/' The effect of fat in diminishing thirst has been observed and dwelt upon by so many competent authorities that it is unneces- sary for me to enter more minutely into this subject. If the method of treat- ment proposed by me, or, let us say, the " proper manner of life for the obese," is maintained (controlled, of course, by an expert), eventually the superfluous fat, and only this, will gradually disappear. A too rapid loss of weight is injurious. Loss of fat should always occur slowly, and must be brought about with great care. The method must never be allowed to fall into a rigid routine, but must be arranged according to the individual conditions of each case; and it must also be so arranged that the patient may pursue his ordinary occupation without detriment. A few examples will serve to illustrate briefly the manner of life advised TREATMENT 171 by me. No hard and fast rules can be given because, as I have several times stated, the method should never become a routine affair. For example, in the first case (see below) if instead of the ordinary rye and wheat bread, a bread richer in albumin is chosen, the ration of bread must naturally be in- creased and the daily quantity of meat correspondingly diminished, etc. Three meals a day I believe to he the best rule. Yet even here some modification might become necessary. In spite of many slight, but important, variations the general principles remain the same. Observation I. — A man, forty-four years of age, moderately muscular, suffered from increasing corpulence though he was otherwise healthy and had formerly been thin. He led an active life, but limited his exercise to that in the house. He was of very temperate habits, especially in the use of alcohol. The obesity had evidently developed as the result of a very profuse ingestion of albuminous food, with the careful avoidance of fat, but with a fondness for carbohydrates, particularly for sweets. The diet which I had the patient follow was about as follows : 1. Breakfast (in summer at six or half-past six o'clock) : A large cup — about 250 c.c. — of strong tea without milk or sugar; 50 grams of bread (wheat or rye bread), toasted, with 20 or 30 grams of butter. 2. Midday meal (between two and half -past two o'clock) : Meat broth, frequently with bone marrow in a solid form (the bone should be cooked for an hour to an hour and a half so that the marrow does not melt) or with an egg, or other suitable addition; 120 to 180 grams of boiled or broiled meat, preferably fat meat if it agrees with him; vegetables as mentioned above, preferably peas, lentils or beans. For dessert, some fresh fruit if obtainable, particularly strawberries, cherries, and, best of all, apples. A salad, according to the season ; also apple-sauce freshly cooked or, if unobtainable, stewed dried or preserved fruit, always, however, without sugar. As fluid: Two to three glasses of a light Rhine wine. Soon after this meal a large cup (about 250 c.c.) of strong tea without sugar. 3. Supper (between seven and a half and eight o'clock) : In winter almost invariably, in summer occasionally, a cup of tea as in the morning and after the midday meal ; an egg or roast meat, preferably fat, or some ham with fat, or Cervelat sausage, or fish, smoked or fresh; a total of 75 to 80 grams of meat, about 30 grams of wheat bread, and 15 to 20 grams of fat, this depending on the amount of fat in the meat, with more or less butter. Occasionally a small quantity of cheese and some fresh fruit or stewed dried fruit. This diet was combined with moderate exercise in the open air; on Sundays he took walks usually lasting several hours, and these were continued during the summer holi- days when a residence of several weeks at the seashore or in the Alps interrupted his ordinary Avork. The effect on the patient's bodily health and mental activity was very good. The diet agreed excellently. A second breakfast was never taken, but he was always hungry for the midday meal. There was a remarkable decrease in the previously extreme thirst. In the evening the craving for food was not very great, and was easily satisfied. In the course of six months he lost 22 pounds, gradually but steadily, as is desirable in all such cases, and in about nine months his waist measurement decreased 16 cm. This diet, in the main, has been continued. As time passed the ingestion of fluid was still further decreased. Instead of a large cup of tea three times daily, he now took a small cup only in the morning, and in the evening coffee, which formerly had not been well borne; the daily use of wine had been stopped for years. Only at the beginning of the regulation of the diet was it necessary to weigh the allowance of the individual foods. He soon learned to estimate them very readily. After the use of aleuronat became known, it was employed by this patient very largely. Observation II. — While in the first observation we were dealing with a case of uncomplicated obesity, this one concerns a lady who suffered from obesity complicated by gout. The patient is thirty-seven years of age, the wife of an officer from K. The patient had no special family predisposition to obesity or gout. In her youth she was 172 OBESITY painfully thin, and began to menstruate at eleven years of age. She was apparently anemic, but otherwise strong and without any symptoms of importance. She married at nineteen, aborted after eight weeks, and within a few months became stout and remained so for almost nine months. During this time her husband died. As a widow she again became as thin as when she was a girl and remained so during her widowhood (seven years), during which time she was occasionally very ane- mic. After her second marriage, the patient soon became pregnant. After the birth of a girl (autumn, 1890) the patient became very stout, again lost some flesh in the next few years, but in 1893, after a serious miscarriage, she again became very stout and under the influence of an injudicious mode of life she remained so up to March, 1898, when she consulted me for the first time. After this miscarriage an exudate formed in the pelvis, and she has since then suffered from obstinate constipation ; it was on this account that she desired treatment. Besides this, the patient suffered from gout which had appeared for the first time in 1886, and was localized in the fingers, being diagnosticated by Professor Liicke in Strassburg. On this account Professor Liicke ordered a course of Vichy water at the Springs. At this time a difficulty in hearing appeared for the first time and gradually increased. In January, 1898, an acute attack of gout occurred in the great toe of the right foot, and lasted eight days. For some years cramps had occurred in the calves and feet, mostly at night when the patient went to bed, but also during the night, and they recurred almost every night, especially in the right leg. Early in March, 1898, severe pains were suddenly felt in the great toe of the right foot. The toe swelled somewhat and became red. In about ten days, during which period the patient was unable to stand upon the foot for several days, the attack subsided. From the 14th to the 25th of April, 1898, the patient suffered from an attack of influenza, during the course of which the temperature rose to 102.2° F., and she was much debilitated. About the 9th of May of the same year, suddenly and during her menstrual period, an attack of gout supervened. This was localized in the little finger of the left hand, and ran a typical course in a very short time. Upon the 12th of the same month, the redness of the affected area had disappeared. At the begin- ning of June the patient complained of decided gouty pains in the feet. The first metatarsophalangeal joints of both feet were very sensitive to pressure. No typical attack developed, however. When the patient stopped treatment upon the 23d of June, she was able to walk quite a distance without difficulty. In this case the treatment was first directed against the obesity, gout, and also particularly the stubborn constipation. For evacuation of the bowels, large enemata of oil were used with good effect. A diet was instituted according to the principles laid down by me, and, in so far as gout permitted, walking was ordered for active bodily exercise, which was supplemented by massage of the body. As a drug, the prolonged use of 0.5 (7i grains) urotropin in a quarter of a liter of alkaline water to be taken twice daily was prescribed. Her weight fell during this time from 199 pounds to 187 pounds. This success was evidently not due to the diet alone, which under the circum- stances could not be strictly carried out. During this time a severe influenza occurred from which the patient slowly recovered, also quite severe gout which of course also decreased the body-weight. When I saw the patient again in October of the same year, the constipation had been relieved by the continuance of the enemata, the gouty diffi- culties had not recurred, but there was a decided psychical depression which was increased by various external conditions. The weight had again risen to 194.5 pounds, and the patient had resumed her former manner of living, which was conducive to the accumulation of fat. The weight, when she decided to renew her treatment, had risen to 203 pounds. Treatment began at my private hospital upon the 28th of August, 1899, and ended upon the 5th of December, 1899. This time the treatment was not hindered by disturbing intermediate maladies such as the attack of influenza and the two attacks of gout during the first period of treatment. The function of the intestine had been greatly improved. Of course, it was decidedly retarded by a very pendulous abdomen. The gouty pains had by no means completely disappeared. The use of urotropin was continued, besides the diet which was regulated according to my princi- ples. The weight of the patient was as follows : Weight upon the 28th of August, 203.86 TREATMENT 173 pounds; upon the 2d of September as well as upon the Oth of September, 203 pounds; upon the 15th of September as, well as upon the 23d of September, 200 pounds ; upon the 30th of September, 198 pounds; upon the 7th of October, 100 pounds (health decidedly improved, can walk well) ; upon the 14th of October, 103 pounds; upon the 21st of October, 103 pounds; upon the 28th of October, 101 pounds; November 3d, 190 pounds; upon November 11th, ISO pounds; upon November 18th, 187 pounds; upon November 25th, 1S6 pounds; upon the 4th of December, 185.51 pounds. The total decrease in weight amounted to IS. 35 pounds. The patient lost weight slowly and steadily, about one pound a week. At the same time the general condition and bodily activity had greatly improved. The psychical depression had disappeared except for a few slight relapses. The gouty difficulties were present to only a slight extent, if at all. Later reports regarding the health of this patient have been very favorable. A more or less slow result which in the end may perhaps prove fairly sat- isfactory occurs in those cases in which the patients do not exactly follow the regulations, but make changes of their own accord. I shall mention only one case of this kind. A high government official (lawyer), forty-five years old, weighing 221 pounds ; circumference of the abdomen at the height of the navel 123 cm. He believed that he could not get along without beer and a larger amount of bread — and so increased this to 160 grams of rye bread — and took one liter of beer daily. In the main he followed directions, and to compensate for his deviation he walked every afternoon for an hour and a half. In the first six months he lost 31 pounds, in the second six months 6^ pounds, in the third six months 2.2 pounds, a total of 39| pounds. The cir- cumference of the abdomen diminished 34 cm. Entirely satisfied with these results, the patient continued to live according to the principles under which he had gotten rid of his numerous difficulties. Any one desirous of success with this method must have a certain knowl- edge of the modern physiology of nutrition, and must recognize the necessity of changes to meet the pathologic conditions peculiar to each individual and his general circumstances. These are essentially the rules according to which an obese person must arrange his diet if he desires to rid himself of superfluous fat and prevent its reaccumulation. To carry out this regime does not give rise to difficulties; the privations which are caused by it are as nothing in comparison with those which are caused by obesity and with the dangers which may in this way be avoided. It is presupposed that while carrying out these dietetic rules a suitable amount of exercise must be taken. One of the advantages of my method of treatment is that the patients may follow their usual occupations, and that thus the ordinary movements of the body may be made serviceable in the treatment. Especially exhausting muscular movements are inadvisable for persons who are both fat and anemic, since they give rise to certain diffi- culties, are almost always impossible to carry out, and are by no means so successful in reducing fat as they are often claimed to be. Banting in his letters upon corpulence relates very entertainingly how an excellent physician well known to him had advised, to prevent the increase of his corpulence, that before beginning his usual daily work he should take extra exercise. As the physician considered rowing very good for this purpose, Banting rowed a few hours early in the morning. He relates that by this means he gained muscular 13 174 OBESITY power — but simultaneously a voracious appetite, and adds ingenuously " As I yielded to this, I constantly increased in weight until my dear old friend (the previously mentioned physician) advised me to give up this kind of exercise." What I have previously advised in regard to exercise for the obese patient (Observation I) may in general be looked upon as sufficient. Quite a number of other diet rules have been proposed by various authors according to the methods advised by me in the nutrition of the obese. Of course, I cannot and will not enumerate all of these, for in the treatment of obesity the most varied diet schemes may be based upon the foundation given. But I shall mention the regime proposed by Hirschfeld, which is elucidated by two illustrations. As is evident from these, Hirschfeld requires a "uniform" limitation of all kinds of food, and maintains that the appetite can be satisfied without any excess of food. Example I. Breakfast: Coffee, without cream or sugar; 1 roll (50 grams). 2d Breakfast : 2 eggs. Dinner : Bouillon with about 30 grams of rice weighed raw ; 250 grams of lean meat, weighed raw, either boiled or broiled with a little fat. Afternoon : Coffee, without cream or sugar. Supper : 50 grams of cream cheese ; 100 grams of bread ; 10 grams of melted fat (goose fat). Example II. Breakfast : As in Example I. 2d Breakfast : Bouillon and 2 eggs. Dinner: Potato soup, 300 grams of meat, weighed raw. Supper : 200 grams of lean ham, 100 grams of bread. There is contained : In diet No. 1 . In diet No. 2. Albumin. Fat. 95 grams 134 " 43 grams 46 " Carbohydrates. 106 grams = 1,224 calories 122 " = 1,478 " In women it will be possible to get along with even less food. Incidentally, in speaking of "no-fat" cures, I mentioned that they (in contrast to my method of treatment) necessitate that the patient learn to endure his thirst. The withdrawal of water played a role in antifat cures even in antiquity. Pliny the Younger advised those who desired to become thin to refrain from fluids while eating, and even afterward to drink but little. This is not the place in which to follow in detail the history of these thirst cures. It may be only mentioned here that the father of the latest movement in this direction, which originated in Munich and for a time gave rise to much dis- cussion, was the founder of the Naturheilansstalt Brunnthal, near Munich, Dr. J. Steinbacher (died 1868). In his booklet, "Asthma, Fatty Heart, Corpulence, etc.," he has laid special stress on ridding the body of a part of its fluid in the cure of obesity. Oertel, following him, has developed this method in great detail, and it has been named after him the " Oertel Cure." The withdrawal of fluid, upon which the greatest stress is laid, in this method may be attained in various ways. First, by the limitation of the fluid intake. This is hard. Thirst is much more difficult to endure than hunger. Most persons very soon become nervous under it, and will not listen to reason. Sec- TREATMENT 175 ondly, much fluid may be withdrawn from the body by inducing sweating. In regard to this I need only mention the sun baths advised by Celsus for the obese. These depletion cures cause a loss of body albumin. Some of the reports of the so-called Oertel cure may be given here. Oertel permits the obese 156 to 170 grams of albumin, 75 to 120 grams of carbohydrates, 25 to 45 grams of fat. The upper limit Oertel allows only for those persons in whom the craving for food is great owing to hard muscular work, for example, mountain-climbing. On account of the importance which Oertel attaches to the ingestion of fluid, he has fixed the amount at 973 to 1,414 grams. A sample diet list given by Oertel is as follows: Breakfast: fine wheat bread 35 grams, coffee 120 grams, milk 30 grams, 2 soft-boiled eggs 90 grams (100 grams of broiled meat), sugar 5 grams (butter 12 grams). Second breakfast: mild Rhine wine, or bouillon, or water 100 grams, or Port wine 50 grams, solid food 50 grams of cold meat, and 20 grams of rye bread. Midday: light Rhine wine 250 grams, broiled beef 150 to 200 grams, salad or vegetables (cabbage) 50 grams, cereal 100 grams (bread 25 grams), fruit 100 grams. Afternoon: coffee, with milk and sugar as in the morning. Evening: mild Rhine wine or water 250 grams, caviar 12 grams (Kiel sprats 12 grams, smoked salmon 18 grams, 2 soft-boiled eggs = 90 grams), game 150 grams, cheese 15 grams, rye bread 20 grams (fruit 100 grams). The preceding diet list of Oertel's contains : Albumin. Fats. Carbohydrates. Water. 160 grams 42.5 grams 117.5 grams 1,440 grams The withdrawal of fluid in the treatment of obesity appears to have found no favor in this latest plan. It is of especial interest to note that this method, originating in Munich (where it was ostentatiously advertised) is now vigor- ously condemned, as is evident in the criticism of K. v. Hoesslin based upon a very rich experience. As the result of his observations v. Hoesslin arrives at the conclusion that in the so-called Oertel cure we are using in fact a true hunger cure. v. Hoess- lin even believes it questionable whether in antifat treatment the reduction in the amount of fluid plays any part. He does not regard Oertel's method as a commendable one, and holds the same view in regard to the Banting cure ; for though he looks upon its effect in depleting fat as good, its action upon the general condition he designates as bad. His method in the treatment of obesity consists of four parts, and depends upon nutrition by a pure fat-albu- min diet, modified according to the principles proposed by me. Without here going into detail in regard to the modifications in v. Hoesslin's diet lists, I will simply emphasize the fact that he does full justice to fat in the treatment of obesity, and that he pronormces the results obtained by him through diet alone to be very satisfactory. It is true he lays stress upon the fact that these results do not equal those attained by diet combined with the other three com- ponents of his obesity treatment. These consist in the simultaneous stimula- tion of metabolism by hydrotherapy, the augmentation of oxidation processes by increased muscular exercise, and finally, the administration of thyreoidin tablets. What of the treatment of obesity with thyreoidin tablets as mentioned by v. Hoesslin ? I have subjected this method to an accurate test, and have pub- 176 OBESITY lished the results in the Deutsche medicinische Wochenschrift, 1899, p. 1. When this treatment was introduced it became highly popular, but it proved by no means so harmless as many at first maintained. I shall content myself with the following statement in regard to it. I do not advise thyreoid treat- ment in obesity because, in the first place, the loss of weight produced by it is quite inconstant, and always ceases at once with the discontinuance of the thyreoid preparation. Further, this method of treatment is not rational be- cause the danger in the loss of body albumin is a considerable one. Finally, it is quite unnecessary because we are in possession of dietetic rules for the treatment of obesity which are as successful as they are devoid of danger. This view in regard to thyreoid gland treatment in obesity seems now likely to be generally accepted. In regard to the two other curative factors made use of by v. Hoesslin, namely, hydrotherapy and augmentation of the processes of oxidation by increased muscular exercise, there can be no objection to their use in conjunc- tion with an appropriate diet. It must be admitted that when these curative agents are wisely regulated by an able and experienced hand, and are indi- vidualized, the result is not only hastened, but in many respects heightened. E. v. Hoesslin, as physician-in-chief of the institution in New Wittelsbach near Munich, certainly has the advantage of splendid facilities and has acquired great experience. But with the remedial agents just discussed it is as true as it is of the dietetic measures that a permanent result may only be expected when the persons in question continue their muscular exercise. What is the character of the muscular movements which are of especial importance in the treatment of obesity? Those especially should be prac- tised which will influence most favorably, and to the greatest extent, the total metabolism, i. e., muscular movements in which most or all of the muscles are brought into action, as in the so-called free exercises of German turners and in exercises with gymnasium apparatus. The former, because they call for only a comparatively slight use of power, are particularly suitable for persons with feeble muscles. Muscular exercises of this kind practised in the open air, passing grad- ually and regularly from the light to the severe, are preferable as a rule to the exercise involved in games or sport. The latter may only be prescribed for the obese when they can be practised in moderation, and when they call for the most varied action of all the muscles. In permitting the practice of any sport we must make sure of course that there is a sound, competent heart and normal kidneys. This is especially true of bicycling, which is now in such vogue. But for obese persons of active habits, the best form of exercise is manual work performed in the field or the garden. This is, after all, the most natural. Besides this, walking, especially in a region of diversified scen- ery, mountain-climbing, and all sorts of mountain sports, provided always the heart is normal, are factors not to be underrated in the treatment of obesity. They are much preferable to spas and water cures, but need, nevertheless, to be carefully controlled. A weak heart which, even when the patient is at rest, does not function properly, cannot be expected to endure the strain of muscular exercise and exertions of this kind. When the heart is weak, passive TREATMENT 177 muscular exercise, and, best of all massage, are especially valuable. By light clothing, the consumption of heat, and with it the metabolism of the obese, may be decidedly increased. By clothing of this kind muscular exercise is facilitated. In winter it is advisable to wear woolen underclothing. Unfor- tunately when it is washed it generally loses its porosity, and with this its greatest advantage, and thus becomes merely expensive. In summer, on account of their great tendency to excessive sweat formation, the obese mostly prefer porous cotton underclothing. A sensible mode of life in which moderation in eating and drinking is maintained, and in which sufficient muscular exercise is secured, permits us to predict with some degree of certaint}^ that no superfluous body fat will accumulate, and that, where already present, it will disappear. If an indi- vidual predisposed to obesity will, after ridding himself of his superfluous fat in this manner, adhere to the prescribed mode of life, he may expect that no renewal of the accumulation of fat will take place in later life. I have endeavored in this article to suggest the methods known to us to-day of which we may avail ourselves in assisting the obese to regain their health without discomfort. Nevertheless, in the prognosis the physician is not to give way to illusions. In the course of years I have collected a con- siderable number of experiences which show that there are many obese per- sons who prove to be very satisfactory patients; who, regulating their mode of life in accordance with the condition of their bodies, improve, and may be entirely cured within a short space of time. It is not well, however, to be too sanguine. Often all hope is shattered by the epicurism and foolishness of these patients. Many of them, it is true, will submit for a certain time to the deprivations and obligations to which their condition subjects them, but will then return to the habits which have produced the obesity. If they belong to the minority who are in good circumstances, they go in the summer time to a " cure " which they expect in a few weeks to make them perfectly well. In- stead of pursuing the course of life which experience has shown to be sensible, and by which they may avoid the downward path to which their condition inevitably leads, they quietly pursue their sluggish way. For eleven months of the year they commit all sorts of dietetic sins, and then in the twelfth month submit to a mineral spring treatment and bath cure which is to cleanse the body and wash away all its burdens. I adhere to-day to the opinion which I have always expressed that every cure of this kind, as well as every drug treat- ment, particularly by means of purgatives of any kind, is to be rejected in obesity. This is particularly true of the treatment which Kisch has desig- nated as his method for the cure of the plethoric form of obesity (Kisch, " The Cure of Obesity," Berlin, 1891, p. 113, et seq.), and I am strengthened in my adverse opinion by the example which Kisch quotes to show the efficacy of his method, namely, a loss of 11 kilograms and 15 grams of weight within twenty- eight days in an uncomplicated case of obesity in a man aged forty-two years and weighing 146 kilograms and 75 grams. This procedure is by no means to be recommended. The cure, as practised by Kisch, consisted (apart from the dietetic treatment which in the main corresponded to the no-fat treat- ment) in the use of Marienbad mineral waters internally, for bathing, in 178 OBESITY steam baths, exercise amounting to 25,000 steps daily, and hydrotherapeutic measures. It is true that Kisch has proven it to be possible by this method to become lean. But, a priori, can one doubt that in such a treatment (the patient lost on the first day one kilogram and 25 grams) muscle as well as fat is lost ? The loss in weight by this treatment is not always so great as that which Kisch attained at Marienbad in four weeks. It varies between 3 and 13.2 per cent, of the patient's weight; on the average it amounts to 6.7 per cent., which, in my opinion, is more than is desirable in the rational treat- ment of obesity. It should therefore be avoided. In conclusion, I must mention the dangers which confront all who use acids, particularly vinegar, a practice which, unfortunately, we find very com- mon in young girls who, from vanity and a desire to remain slender, risk their health and even their lives. MYXEDEMA WITH SPECIAL REFERENCE TO ORGANOTHERAPY By C. A. EWALD, Berlin HISTORY At a meeting of the Congress of the British Medical Association at Lon- don in 1875, various medical curiosities were shown, among them a number of patients, mostly women, who, on account of their peculiar appearance and behavior, excited the greatest interest. At first glance one would have thought that a group of Eskimos or Samoans was present. Their swollen faces of strange yellow tint, almond-shaped eyes, and stupid expression, their clumsy figures, the leathery texture of their skins, the scant growth of hair, and their torpid mental state made them a truly remarkable spectacle. One could hardly realize that these were children of sea-encompassed Albion, so com- pletely in them had the characteristic features of the Anglo-Saxon race been eradicated. As explained by Dr. William Ord, these were cases of myxedema. We owe the recognition of these cases, and their classification as a special pathological group to be differentiated from cretinism and imbecility, to two English physicians, Sir William Gull and Dr. William Ord (in 1873 and 1878). The latter physician was also the first to designate the condition myxedema, on account of the peculiar muco-eclematous condition of the in- tegument, and Charcot later proposed the name " cachexie pacliydermique," which, in my opinion, is more suitable. As a matter of fact, the mucus con- tent of the skin, contrary to the assumption of the first observers, is but slight, although Shaw believed it to be fifty times greater than in the normal skin. The general thickening of the skin greatly overshadows this. However, an aptly chosen name soon takes root, even if it be not quite unobjectionable (I need only refer to the barbarous word "appendicitis"), and so it has been with the term " myxedema " ; every one knows nowadays what is meant by the term. Since then twenty-five years have passed, and numerous cases of myxedema have been described, particularly in England and America. The peculiarities of the disease have been thoroughly studied, and our understanding of its nature based upon this study has led to therapeutic success as far reaching and as remarkable as any in the entire realm of medicine, excepting only serumtherapy. In Germany, myxedema is comparatively rare. I am, however, in a posi- tion to relate the history of a very characteristic case : 179 180 MYXEDEMA The patient, a woman aged fifty-five, lias been known to me for six years ; the symptoms of the disease developed slowly and insidiously, and for a long time they were so little characteristic that it was hardly possible to differen- tiate the condition from the ordinary cachexia of old age. But the behavior and appearance of the patient were, even at that time, so peculiar that I had a photograph of her taken which is here reproduced (see Fig. 1). Later, however, the typical symptoms appeared (see Fig. 2). They improved and nearly disappeared under specific treatment (thyreoid extract), but returned after some time, the patient having discontinued her treatment. Fig. 3 shows the patient in this stage of her disease.1 ETIOLOGY Eegarding etiology, as little could be determined in my case as in other cases of myxedema. A tendency to nervous diseases and depressing influences of a psychical nature are said to be conducive to the development of the dis- ease. Whether alcohol, syphilis, and tuberculosis, those exterminators of the human race, play their part in this disease is very questionable, although sev- eral authorities (Pel, Greenfeld, and Byrom Bramwell) have called atten- tion to the occurrence of tuberculosis in the families of myxedematous patients, or in the patient himself. Several cases in the same family have also been observed. The sex of my patient confirms the general experience that women are attacked in the majority of instances, and Sir William Gull entitled his first communication, " On a Cretinoid State Supervening in Adult Life in Women." Full seven years after the first publication regarding myxedema, a male suffer- ing from this affection was observed by Savage (1880). In 1894, in a com- pilation of 127 cases of myxedema, Heinsheimer found only 10 men, i. e., 7.8 per cent. ; and this proportion would about correspond to the ratio if we tabulated all the cases that have been published up to the present time. Typical myxedema is a disease of adults, occurring most frequently be- tween the thirty-fifth and fiftieth years of life. It is, however, by no means limited to these ages, but may occur earlier, as the so-called infantile myx- edema, or even later (which is quite rare). SYMPTOMS The symptoms of myxedema consist of : 1. Changes in the external integuments (skin, hair, nails), and the absence, or, more strictly speaking, the degeneration of the thyreoid gland. 2. Disturbances of the cerebral and nervous functions. 3. Disturbances of nutrition (of metabolism) and of circulation. i The literature up to 1896 is almost complete in C. A. Eioald's " The Diseases of the Thyreoid Gland, Myxedema and Cretinism," in Nothnagel's " Special Pathology and Therapy," xxii, Part I; for later articles sec Ewald's article "Organotherapy," in Mendel's Jahresbericht fiir Neurotonic und PsycMatrie. Fig. 1. — W. M., Aged Forty-eight; Incipient Myxedema. Fig. 2. — W. M., Aged Fifty-two; Advanced Myxedema. Fig. 3. — W. M., Aged Fifty-three ; Myxedema in the Stage op Recovery after the Employment of 39.2 Grams of Thyreoidin. 184 MYXEDEMA These features are not equally developed nor even all present in every case, and my case was no exception to this rule. Of greatest importance in the diagnosis of the disease are the cutaneous symptoms. They make it possible for us to recognize the malady, prima vista, so to speak, and after a comparatively brief examination of the patient. They give the patient the characteristic stamp which I attempted briefly to portray at the beginning of this article. 1. Most frequently the disease begins unnoticed and insidiously, with a gradual swelling of the shin, at first in the face, then in the hands, arms, feet and legs ; finally and least noticeably upon the trunk. In the cheeks, around the eyelids, and upon the chin, puffiness is noticed; the lips and nose become swollen and thickened, the palpebral fissure is diminished by the swelling of the eyelids, and a hard, elastic edema of the whole face produces a stupid, dull expression. The tongue is thick, clumsy and too large for the mouth; the soft palate, the uvula, and the postpharyngeal wall, as well as the larynx, are swollen. Hence the voice becomes rough and hoarse with a peculiar deep sound. The gums also swell, bleed readily, and retract from the teeth, which have a tendency to caries and frequently drop out without any change of structure. The lobes of the ear are also coarse and misshapen. Upon both sides of the neck above the clavicle, swellings appear, which are soft to the touch, and from about the size of a plum to that of a hen's egg. These pads are not due to swollen glands, but consist of fat, connective tissue, and convo- lution of vessels (veins). The extremities appear swollen and shapeless, the hands like paws ; wider shoes and larger gloves become necessary. The skin is pale and looks anemic; occasionally it has a marbled appear- ance; to the touch it is cold, unelastic, hard and coarse. If pressure is made with the finger a slight impression is made, but the pitting does not remain. As a rule, this swelling is by no means uniformly distributed over the entire body. It attacks preferably either the face and the supraclavicular region or the extremities. Occasionally it disappears temporarily at the beginning of the disease (Ord), and then recurs, wandering here and there. The skin is dry, rough, desquamates decidedly, and not even by means of diaphoretics can sensible perspiration be induced, while insensible perspiration is lessened from 40 to 60 per cent, in comparison to the normal. The nails show longitudinal fissures and become brittle. The hair of the head and eyebrows falls out, and soon large areas are formed which are perfectly bald. Besides these striking changes there is a further defect which indeed can- not always be determined with certainty during life, but which in my patient, for example, was readily demonstrated; I mean the absence of the thyreoid. In place of the lobes of the gland normally situated upon both sides of the wind-pipe, the smooth wall of the trachea may be palpated from the cricoid cartilage to the jugulum. I shall revert later to this remarkable condition, and to its importance in pathogenesis. 2. The disturbances of the cerebral functions mostly set in with headache, sometimes with, a feeling of anxiety, and a heaviness in the limbs. The patients move about slowly and with uncertainty. The power of co-ordination is diminished, as is frequently shown in the attempts at walking. The patient SYMPTOMS 185 then conveys the impression of being under the influence of a high grade of nervous irritability with severe muscular tremor, so that it is impossible to maintain an erect altitude. The patient's appearance is peculiarly quiet and suggests mental limita- tion, an impression which is increased by the fact that the head is mostly bent forward so that the chin is held, or, more correctly, falls upon the chest, for the patient cannot keep the head erect. The power of thought lessens, and its exercise is apparently difficult. There is loss of memory, particularly in regard to the true duration of the illness ; now and then actual hallucinations appear. Speech itself is peculiar, being monotonous with a nasal or rough quality, and this, combined with a certain tendency of the patient after hav- ing once begun to speak to continue uninterruptedly like a wound-up clock- work, is looked upon by Ord as especially characteristic. I must admit that this latter condition has not yet been noticed by me in my very much more limited experience. Finally, actual convulsions and coma have been observed. The reports in regard to reflexes, cutaneous sensation, and electric irritability vary. In my case no disturbance of these functions was present. The tendon reflexes were prompt, and electric irritability both for the faradic and constant current was normal. The sensation of cold, and the lowered body tempera- ture which is the cause of this, may be considered as due in part to the nervous disturbances. The temperature in the axilla varies between 96.8° F. and 98.6° F. The patients feel " as if they were living in an eternal winter." Unquestionably, this sensation of cold depends upon the inability of the patients to regulate the body temperature so as to correspond with variations in the external temperature; they suffer particularly in cold and frosty weather. On the other hand, there is deficient energy of oxidation, a dimin- ished heat production, in the organism. This leads us to the discussion of the last point: 3. Disturbances of metabolism and of the circulation. The former is decidedly decreased. The urea or JST-excretion as well as the respiratory metab- olism (Magnus-Levy) is decreased. Albumin is occasionally found in the urine, sometimes only in traces, sometimes in larger amounts. According to the observations of Byrom Bramwell, as well as of Hun and Prudden, albumin is found in about 18 per cent, of the cases. In rare instances at the acme of the myxedematous stage, mucus is also found in the urine. In the blood there is a slight oligocythemia or a polycythemia. In women there is amenorrhea. The pulse is small, low and weak. Hemorrhages from the mucous membranes, particularly from the nose and mouth, are not rare. I have now sketched the most important symptoms. I omit the rarer ones as, for example, synovitis of the knee-joint, premature climacteric, tremor of the eyelids, contractures of the hands and feet, salivation. The characteristic symptoms of the affection under discussion are limited to tissue changes, par- ticularly of two organs, the skin and the thyreoid gland. The connective tis- sue of the corium is loosened, its individual fibers thickened and hyperplastic. The cell nuclei and the fibrillary elements of the gelatinous substances be- tween the individual fat lobes are increased. It seems as if the skin were saturated with a fluid or semi-fluid substance. Whether this actually con- 186 MYXEDEMA sists of mucus, i. e., of an edematous fluid containing considerable amounts of mucin, is not yet certain. This much, however, is assured, that the degree of this infiltration may vary decidedly in individual cases. In my patient there is now only slight swelling of the eyelids and of the cheeks, but at the height of the disease the entire face, shoulder-girdle, hands, forearms, and feet showed swelling which was everywhere unmistakable, and here and there extreme. In a case observed by Kast (Ponfick) the thickening of the skin was so extreme that numerous fissures formed, with intertrigo-like excoriations which were followed first by a phlegmon of the arm and later by a general fatal sepsis. In the internal organs usually no changes are found apart from the pre- viously mentioned atrophy of the thyreoid gland, but occasionally cirrhotic processes in the liver and kidneys, endarteritis obliterans, and enlargement of the pineal gland have been noted. The changes in the thyreoid gland are undoubtedly the most remarkable feature of this disease. In most cases, even during life, we observe that it is impossible to palpate the lobes of the thyreoid gland in the neck. It may be said that this condition is found in about 80 per cent, of the cases. In some instances, however, the atrophy of the gland cannot be determined with certainty, and in a few an enlargement has been noted. Yet in these cases, in so far as accurate observations have been obtained, there has always been found a strumous degeneration of the organ, which may also have resulted in a loss of function. I have been able to collect 36 reliable autopsy reports, in 33 of which, or 94.4 per cent, of the cases, there was atrophy of the thyreoid gland. The necropsy reports show that the gland substance had lost its char- acteristic structure, and had been changed into a more or less shrunken rem- nant, of hard, fibrous consistence and yellowish white color. Connective tissue proliferation leads to destruction of the parenchyma, so that only isolated re- mains of degenerated alveoli can be detected. Very recently Ponfick has reported an extremely careful histological investigation of the remains of the gland in a well-developed case of myxedema. He found " in wide areas almost total destruction of the follicles; here and there were the remains of rudi- mentary alveolar structures, all filled with colloid. Besides this atrophy there was an enormous increase and thickening of the connective tissue structure ; in a word, a picture which markedly resembled the terminal stage of degenera- tive inflammatory processes, such as are met with so frequently in the kidneys, liver, etc." PATHOLOGY I need hardly say that this degeneration of the thyreoid gland is the key to the entire pathological condition. Atrophy of the thyreoid gland is not only one of the symptoms of the disease; it is the causative factor. This fact is absolutely certain in spite of occasional objections. Its recognition forms a glorious page in the history of pathology. We owe this to the united labors of physiologists and clinicians, the fruit of which is a therapy which, as re- gards the certainty of success, may be placed side by side with the most reliable remedies of our therapeutic armamentarium. PATHOLOGY 187 I shall attempt to prove this in a few words, thereby taking an opportunity of referring to related conditions, namely, to sporadic and endemic cretinism, to infant ill' myxedema, and to the so-called cachexia strumipriva. Two observations stand out prominently like landmarks in the great num- ber of physiologic and clinical experiments and communications which resulted in the establishment of the importance of the thyreoid gland in the causation of myxedema. First, the experiment of M. Schiff, the results of which were for a long time discredited and even ridiculed, but at last completely proven. In this experiment an animal was subjected to thyreoidectomy, which under ordinary circumstances would have proved fatal, as Schiff had previously shown in 1859. But Schiff found that the animal did not succumb if the thyreoid gland were grafted into the abdominal cavity or under the skin, the specific constituents of the gland being thus preserved for the organism. Next came the important communications of Kocher and Eeverdin who observed after the extirpation of the thyreoid gland in man a condition of general cachexia with physical and mental phenomena which show a marked similar- ity to the symptoms of myxedema just described, and also correspond accu- rately to the phenomena developing in an animal after extirpation of the thyreoid. In other words cachexia strumipriva, produced experimentally or (in man) as the -result of an operation, is identical in nature with genuine myxedema. Now since in both cases the same defect is present, namely, absence of the thyreoid, it follows that the resulting insufficiency, that is, the complete loss of function of the thyreoid gland, is to be looked upon as the cause of these pathological phenomena. I cannot here discuss the different phases which the evolution of this view has undergone. But one stage at least I should like to bring into prominence, for it shows how difficult the proper interpretation of an experiment may sometimes be, and how obscured by complicating conditions. Some investigators did not succeed in producing the symptoms of cachexia strumipriva (or, more correctly, cachexia thyreopriva, as we are not speaking of the removal of a goiter) by thyreoidectomy, and consequently were justified in doubting the causal relation of the thyreoid gland. Then Gley showed that besides the great mass of the thyreoid there are in animals small, super- numerary glands, which had already been anatomically described by Sand- strom. These extra thyreoids, if not removed together with the gland, per- form vicariously the function of the latter. Only after this circumstance had been taken into consideration could constant results be obtained. In the same manner we may explain those observations (which, however, are in the minority) which show that in some cases cachexia strumipriva did not follow thyreoidectomy in man. This is because parts of the gland were not removed at the operation or because a rapid reproduction of the gland took place. But even a few isolated and trustworthy cases of this kind would not overbalance the enormous number of positive observations to the contrary. But let us proceed a step further. All over the world, as is well known, there are unfortunate individuals whose mental and bodily development is retarded, so that they present a stupid and misshapen appearance. They are called cretins, and their disease cretinism. From the fact that such ill-fated 188 MYXEDEMA persons are met with in isolated regions, and are particularly numerous in certain localities, and inasmuch as the development and distribution of the disease are apparently dependent upon the condition of the soil and the water- supply of the district in which the cretins accumulate, we call these cases " endemic cretinism." In other parts of the world they are only occasionally met with, and we then speak of them as cases of sporadic cretinism. In these cases as in myxedema there is an insufficient development, or an atrophy and disturbance of function of the thyreoid gland. Hence we speak of them as an atliyreosis chronica, in contrast to the results produced experimentally in ani- mals, or after loss of the thyreoid by operation in man in whom this state may be called cachexia thyreopriva. Accurate observation and study of the cases belonging to this group show that endemic cretinism is a condition of physical and intellectual degenera- tion, which occurs only where there are local predisposing causes, and a degen- eration of the thyreoid gland produced by these or going hand in hand with them. The disease begins its development even in fetal life. Sporadic cre- tinism, on account of its resemblance to myxedema of adults, is in early life also designated as infantile myxedema. In these cases we find mental weakness even to idiocy. Like actual typical myxedema, it is an occa- sional affection of the thyreoid gland with consequent loss of function, i. e., a disease not limited to a definite region. The course of genuine cretinism, as well as myxedema, is a very chronic one, lasting for decades, so that a cretin may attain relatively old age provided he does not die of some intercurrent disease. Cases of sporadic cretinism (infantile myxedema) have, as a rule, a briefer duration of life, and if not ameliorated by treatment scarcely survive the third, at most the fourth, decade. Cachexia thyreopriva runs a subacute course, and unless relieved by medical aid terminates in death after a com- paratively short time, at the longest four or five years ! THERAPY This is not the place in which to discuss the clinical symptoms of these diseases ; that degeneration of the thyreoid gland is unquestionably the causa- tive factor in all of them is the only circumstance important for us. This is clear not only from the general correspondence of the external pathologic phe- nomena, but, in particular, from the results of therapy founded especially upon the knowledge of the causal role of the thyreoid gland in these cases. The results of thyreoid therapy have proven, a fortiori, that the common cause of these diseases is an absence of function of the thyreoid, by which, it may be remarked in passing, they differ from goiter or struma. Properly speaking, in these cases we are dealing with a substitutiontherapy, replacing the lost or deficient glandular secretion by the administration of the glandular substance or its extracts. The surprising experiments of Schiff, previously mentioned, actually com- pelled the application of these principles in the human subject, and Bircher in 1890 by implantation of a human thyreoid in a woman with cachexia strumipriva first succeeded in obtaining a curative result. Shortly after THERAPY 189 Horsley proposed, in place of the human gland, to utilize the thyreoid of the sheep in myxedema and cretinism, and Bettencourt and Serrano noted a rapid improvement in a woman with myxedema, in whose abdomen they engrafted one-half of a sheep's thyreoid. When Murray, instead of employing the entire gland, subcutaneous] y injected its glycerin extract, and Mackenzie in 1892 administered the fresh gland or its extract internally with the same effect, and other observers showed that the dried glandular substance in tablet form acted in the same manner, the therapy of myxedema and of the related patho- logic conditions previously mentioned became as simple as it was reliable. In fact, reports came from all quarters regarding the almost remarkable action of this " organotherapy," which was particularly effective in myxedema, in infantile myxedema, and in cachexia strumipriva, while endemic cretinism, owing to its nature, could only be benefited to a slighter extent. The tablets which were administered were so prepared as to dosage that each tablet corre- sponded to 0.25 gram of the glandular substance; these were given in increas- ing doses of from 3 to 7 or 10 tablets per day, until (early or later) symptoms of intoxication, extreme or mild (the symptoms of so-called tliyreoidism) appear. It cannot be denied that the use of the entire gland has certain disadvan- tages, on account of the varying amount of active substance in the individual gland or tablet, the admixture of products of decomposition, etc. Obviously it would be desirable to isolate and to utilize the specific active substance. There have been numerous trials in this direction. At one time it was hoped that the desired body could be obtained in the form of a ferment, at another time it was supposed that it could be secured as a fixed chemical com- bination from the group of proteid substances or even as an alkaloid. I must mention that S. Fraenkel, in 1895, isolated a substance belonging to the guanidin group with the empiric formula, C6H11]Sr305, which he called " thyreo- antitoxin," and Drechsel and Kocher, Jr., isolated similar combinations from the gland. Then Baumann, in 1896, made the surprising discovery that the gland contained considerable amounts of iodin, and that this iodin was found in combination with organic substances, chiefly in his opinion with albumin, and to a smaller extent with globulin. This body Baumann called iodothyrin, later thyreoiodin, and showed that from the purest thyreoiodin 9.3 per cent, of iodin could be obtained in a crystalline form. Investigators are not yet quite unanimous as to the true nature of this thyreoiodin. Tambach assumes that the iodin is combined with various albumin bodies, and that iodothyrin forms only a part of the iodin-containing substances of the thyreoid gland. Accord- ing to Oswald, the iodin combined with albumin has the character of globulin, for which reason he called it thyreoglobulin. From this, by long-continued pepsin digestion, iodothyrin and iodin-containing albumoses and peptones can be split off. Besides these, a nucleoproteid is said to occur which, however, does not possess the specific action of the gland. Blum denies the presence of iodothyrin as a primary constituent; he thinks it is not preformed but is an artificial cleavage-product. However this may be, Baumann in associa- tion with Boos seemed to prove that thyreoiodin possesses the specific proper- ties of the natural gland, and acts as a substitute for its curative effects; it 14 190 MYXEDEMA also possesses the same toxic action, but has the advantages of a more exact dosage and absolute purity. These opinions were soon confirmed by others (Hofmeister, Ewald, Pfennig, Goldmann, and others), so that there can be no doubt that thyreoiodin may be employed in place of the natural gland. Whether it is actually an equivalent for the complete gland appears doubtful from the investigations of Gottlieb and Jaquet, who observed in a number of dogs after thyreoidectomy that thyreoiodin alone did not keep the animals alive, while Gottlieb by administering an extract from the complete gland (thyraden), and Jaquet by a substance called by him aiodin (a tannin precipi- tate of the extract of the gland with physiological salt solution) succeeded in sustaining them. I might also mention that Cunningham in England isolated a so-called colloid substance from the gland which is analogous to Baumann's thyreoiodin, i. e., the contents of the acini after previous peptic digestion of the gland tissue. He is consequently of the opinion that this colloid is the true active extractive product of the gland cell, while Oswald believes it to be a mixture of thyreoglobulin and nucleoproteid. In a similar manner, McLennan produced a preparation from iodoglobulin and thyreo- iodin which has received the name thyreoglandin. In view of all this it is obvious that the nature of the specifically active substance of the gland has by no means been definitely decided; on the contrary, each day brings new reports and new views. This is true also of another highly interesting discovery which science owes to Baumann, who was unfortunately too early removed from his sphere of activity. In a comparative estimation of the iodin contents of glands, some of which were procured from Freiburg and some from Hamburg and Berlin, it was shown that the iodin contents of the former were considerably less than in the glands brought from the two last mentioned cities. The glands obtained from Freiburg, in the same parts by weight, averaged 2.5 milligrams of iodin; those from Hamburg 3.83 milligrams, and those from Berlin 6.6 milligrams; in the investigations in North America made by Gideon Wells, the iodin contents of 20 glands, some from Chicago, some from Balti- more, Boston, New York, etc., averaged 10.79 milligrams. Now, in Frei- burg goiter is endemic and frequent, in Berlin and Hamburg comparatively rare, in America almost unknown. What can be more reasonable than to connect the slight amount of iodin in the glands from Freiburg (where, as may be remarked in passing, goiter is found conspicuously often even in the new-born and in young children) with the prevalence there of goiter? For many years strumous degeneration has been referred to a lack of iodin in the water, in the air, in the food, though no convincing proof of this has been established. Here, for the first time, we seem to have analytic evidence of the influence of iodin upon the development of goiter, or, more correctly, the relations of the iodin contents of the thyreoid gland to goiter. I expressly say " seem to have evidence/' for to make this assumption a certainty more com- prehensive investigations are necessary, and I am forced to admit that Oswald made numerous analyses of glands from Switzerland and from the regions where goiter occurs endemically and has demonstrated the exact opposite; namely, that the amount of iodin in glands from this district was greater than THERAPY 191 in those obtained elsewhere, while, on the other hand, Kositzki's researches in Styria confirmed Baumann's reports. No matter how diverse the manufactured preparations may be, their use evidently checks the previously described symptoms of myxedema, which give place to complete or almost complete health; therefore all must contain the active substance, though perhaps some more than others. The skin becomes soft, smooth and elastic; the edematous infiltration — the myxedema — disap- pears ; the hair which has fallen out is renewed. The general health returns to the norm, vigor and activity take the place of the preceding debility and indolence — briefly, so complete a transformation in the condition of the patient takes place that anything more extraordinary can hardly be imagined. The same is also true, mutatis mutandis, in the conditions previously described, viz. : infantile myxedema, cachexia thyreopriva, an abortive form of myx- edema which has been designated " myxoedeme fruste" and to some extent also in cretinism. To enter minutely into this subject would carry us too far, hence we will only remark that the influence of thyreoid preparations upon the length and caliber of the bones in infantile myxedema has been ob- served, and to a certain extent demonstrated, ad oculis, by means of radioscopy. We noted the curative effect of this remedy upon myxedema in my patient. As time has gone on the preparations of various English and German firms have been administered, as well as thyreoiodin pastilles, all with good results which, however, lasted only as long as the drug was given. After discontinuing the administration of the remedy for some time — in my case for a few months — we must always return to it, as signs of myx- edematous cachexia always recur. These usually consist of chilliness, malaise, and slight swellings in the face; occasionally, however, severe symptoms of. de- pression appear, particularly of a psychic nature. This is not to be wondered at, as our substitutiontherapy does not root up the evil, but only re-supplies some necessary products for metabolism, and for this reason the medication must be persistently carried on. At times the remedy becomes unneccesary, and it may be discontinued for a considerable interval, because a certain reserve accumulates, which, after the cessation of the specific therapy, is only gradually utilized and consumed by the organism. The same is also true, according to our present experiences, in cachexia strumipriva, while in infan- tile myxedema and cretinism this effect does not occur, and from the begin- ning we must carry on the thyreoid therapy almost continuously. One of my patients, a highly cultured woman, who has been taking thyreoid extract for five years, wrote me as follows: "I may say that (inconceivable as it may appear) under, organotherapy the system becomes decidedly accus- tomed to the taking of thyreoid gland, so that its therapeutic effect is weak- ened, and the doses must be constantly increased if improvement is to be expected. On the other hand, when we consider the toxic action, the debility and tiring of the heart, the damage to the stomach, etc., it appears that one does not become accustomed to it; the longer the drug is administered the greater the susceptibility." The latter remark points to the secondary effects of thyreoidtherapy, effects which, after prolonged use of the drug, appear to be more or less severe. 192 MYXEDEMA This secondary condition has been designated thyreoidism ; the disturb- ances may be separated into the nutritive and the nervous. The urine in- creases in amount, and its K-containing constituents, as well as the chlorids and phosphates, are increased. The body-weight decreases and, as was first shown by Wendelstadt, not over J of the loss in weight is of the body albumin ; the remainder is a decrease of fat and water, so that the increased combustion of fat may be referred to increased oxidation (Magnus-Levy) . In this process oxidation, during and for some time after the use of thyreoid, may rise 10 to 20 per cent, above the former values; there is therefore an increased metab- olism. As a nervous symptom we note primarily a decided increase in pulse frequency and cardiac palpitation, which may be looked upon as a definite indication that the dose is too large. After this headache, nausea, vomiting, and general debility may occur. Sometimes these symptoms increase to an alarming extent, and formerly, when this condition was not sufficiently under- stood, even fatal cases were observed. Therefore, when these symptoms appear (which may be soon or late, according to individual susceptibility) thyreoid preparations must be immediately stopped, and the treatment be interrupted. These toxic symptoms will then shortly disappear without causing permanent injury. This teaches the lesson that these preparations should not be used except on the advice and under the supervision of a physician, and their sale by an apothecary except upon prescription should be prohib- ited. How far thyreoidism is a phenomenon of specific intoxication, and how far toxic products of decomposition generated during the manufacture of the preparations are concerned in it, is doubtful. Fortunately, we have lately become able to combat these symptoms of thyreoidism, or better, to prevent their appearance ; as Mabille has proposed, we administer simultaneously with the thyreoid preparations small doses of arsenic, either as Fowler's solution or as arsenious acid. As a matter of fact, in my case I administered no less than 962 tablets without any deleterious effects, and during three months I gave 3 drops of Fowler's solution, i. e., upon the whole a minimal amount of 0.16 gram of arsenious acid. We may consider it as definitely settled that we are able by means of sub- stitutiontherapy and only in this way to influence the entire constitution to such a surprising extent, in the pathologic conditions which depend upon atrophic or degenerative changes in the thyreoid gland. "We should mention here also the value of thyreoid extract in the abortive forms of myxedema which Hertoghe has described under the designation "myxoedeme fruste." The use of thyreoid preparations should also be considered in local dis- ease of the thyreoid gland, namely, in the treatment of goiter. Although suc- cess in treatment is here limited to the so-called parenchymatous goiters of youth, i. e., to that form of goiter which is not so much the result of degenera- tive change as of a hypertrophic condition of the glandular tissue, their use is here of great value, v. Bruns was the first to employ thyreoid gland prepara- tions in simple goiter with the idea of diminishing the labor of the hyperactive gland. For it is self-evident that in such cases there is an increased demand in the organism for the product of the secretion of the gland, either because, from some unknown disturbance of metabolism, more thyreoiodin was required THERAPY 193 and so consumed by the organism, or because the supply of iodin was deficient while the activity of the gland was especially active, thus leading finally to hypertrophy of the organ, v. Brims, in fact, observed a decided diminution in the goiters after the administration of comparatively small doses, and Ewald, Stabel, and others in Germany obtained similar results. Wells in 1897 compiled 584 cases of simple goiter which were treated with different thyreoid extracts, of which cases 475, i. e., about 82 per cent., were improved. Nevertheless, in my experience, the cure is never complete; that is, the goiter does not completely disappear, although v. Brims reports this result in about 8 per cent, of his cases. As has been already stated, the best results are seen in youthful individuals in whom the goiter has not existed for too long a time. The older the patient and his goiter the slighter the changes which may be observed in the gland in favorable cases even after four to six days of treat- ment with thyreoid preparations. Usually, however, this becomes noticeable only during the second and third weeks of treatment. A diminution in the circumference of the neck of from 4 to 6 centimeters is frequent ; greater re- duction than this is exceptional. Even in these cases, after discontinuance of the remedy relapses occur, so that small doses must be repeated from time to time. I have the history of two girls, aged nineteen and twenty-one years re- spectively, the circumference of whose necks after the use of thyreoid prepara- tions was reduced in one from 37.6 to 35.1 centimeters, and in the other from 33.5 to 32.1 centimeters. Symptoms of thyreoidism did not appear. I must not fail to mention that equally favorable results have been obtained with thymus preparations by Mikulicz and Eeinbach. The conditions are very different in another disease which also implicates the thyreoid gland: Graves' disease. In this affection enlargement of the thyreoid, as is well known, is one of the three cardinal symptoms of the dis- ease— goiter, exophthalmos, tachycardia. But here we are no longer dealing with a vicarious or compensatory labor hypertrophy of the gland, but with an active increase of its secretion, which leads to the phenomena of thyreoidism occurring in the course of the disease. The use of thyreoid preparations in this malady is contraindicated, even if we omit entirely from consideration the fact that the cause of Graves' disease is not to be found in an affection of the thyreoid gland alone. We know that its cause is multiform and that other organs — as is shown by the cases without goiter — especially the sympathetic nervous system, are implicated. As a matter of fact all cautious and unbiased observers have been convinced of the complete failure of thyreoid therapy in Basedow's disease (exophthalmic goiter). Indeed it has been noticed that its use is not only useless, but often produces a decided aggravation of the symptoms. Although we have up to this point discussed the administration of thyreoid preparations only as true substitutiontherapy in diseases in which a disturb- ance of function of the thyreoid can be demonstrated, yet the list of the uses of the remedy has by no means been exhausted. We know of other dis- eases, or disease groups, in which, based upon the pharmacodynamic action of thyreoiodin, this remedy has been employed with more or less success. I 194 MYXEDEMA have stated before that the employment of thyreoid preparations increases metabolism, and causes a decrease in the fat of the organism; this has been experimentally proven. What was more natural than to attempt a cure of obesity by this means? Y. Davies in America, Leichtenstern and Ewald in Germany, were the first to publish favorable results of this kind. They ob- tained in obese persons reductions in weight of 5 kilograms and more in a few weeks without any special restriction of the food, and without producing marked debility, restlessness, fatigue, etc. This condition is due, as already remarked, to an increased combustion of carbohydrates and fat, while albumin decomposition is but little affected. Schrbdt has lately published a case in which a loss of 16 kilograms of weight occurred in an obese person, and, as was sbown by carefully conducted investigations of metabolism, this was almost wholly due to combustion of fat. The results are even better if the diet is regulated simultaneously, i. e., the fats and carbohydrates limited to a certain extent without, however, insisting on a dietetic cure for the reduction of fat in the strict sense of the word. Cabot has collected 145 cases of this kind, and reports favorable results in all but 6 cases, v. ISToorden, who is not well disposed to thyreoid treatment in obesity, nevertheless observed among 14 patients, who, in the course of four or five weeks, had taken upon the average 3 to 4 tablets per day, a reduction in weight of 5.4, 6.0, and 7.8 kilograms, and had only one complete failure. In thyreoiodin we should, therefore, pos- sess an almost ideal remedy for obesity if only it were always effective. Ee- ports of failure are, however, not wanting, and in several cases, instead of the desired loss of weight, symptoms of thyreoidism have appeared. This latter condition, with or without a simultaneous reduction of body fat, has been apt to supervene when the laity, without professional advice, have used the thyreoid preparations either too long or in too large doses. In another article, in re- ferring to a case of psoriasis treated by the thyreoid preparations, I have dis- cussed the question asked by Hertoghe, whether success or failure in these cases does not depend upon the condition of the thyreoid gland of the affected indi- vidual ; i. e., the treatment is only successful in cases in which the obesity (or the skin disease) is one of the manifestations of an affection produced by disturbance of the function of this organ, as the gland certainly has a decided influence upon metabolism. There can be no doubt, as has been determined from observations in myx- edema, of the effect of thyreoid in trophic processes of the shin. Hence thyreoid preparations are administered in various skin diseases, lichen planus, prurigo, adenoma sebaceum, ichthyosis, xeroderma, lupus, and, above all, in psoriasis; of course here also the success is varying and uncertain. In some quite chronic cases I have seen conspicuous improvement, and it is not too much to say a cure; in others there was no result in spite of treatment for several months. In the last case successfully treated, a spare man, aged fifty-three, whom I showed at the meeting of the Berlin Medical Society on July 18, 1900, the thyreoid gland could not be palpated. This man had a persistent, freely desquamating eruption, appearing in large blotches upon the trunk and ex- tremities, for the cure of which various remedies had been unsuccessfully employed for years. After the administration for three months of thyreoiodin THERAPY 195 tablets with arsenic — he received during this time 450 tablets which contained 0.25 gram of iodotlryrin and 0.16 gram of arsenious acid — the eruption almost disappeared, being replaced by small, isolated areas of about the size of a silver three-cent piece, and by natural, smooth, pink skin. Of 154 cases collected by Cabot, 63 were improved, 53 unimproved, and 22 aggravated. This is greatly in favor of my view previously expressed regarding the connec- tion between these diseases of the skin and disturbances in function of the thy- reoid gland; for "Wells, in a case of scleroderma in a woman aged fifty-one who had suffered for about one year from the affection, found the thyreoid gland, post mortem, to be greatly atrophied, so that in the fresh condition it weighed only 14 grams and when dried only 3.23 grams. The total amount of iodin was only 2.94 milligrams, i. e., only about one-fourth of the normal. Microscopically the connective tissue was greatly increased, the intima of the glandular vessels was proliferated, the lumen of the acini, for the most part without colloid, changed into small cysts which were filled with colloid mate- rial. The hypophysis' was hypertrophied, it weighed 0.7 gram, its acini were distended by colloid masses with uncommonly numerous eosinophile cells in the interacinous tissue. Wells remarks quite properly that if these changes could be determined constantly in scleroderma the fact would greatly favor a thyrogenous origin of this disease. Actuated by the same reasons as in the therapy of obesity and psoriasis, etc., physicians have used thyreoid preparations in mental disease, in tetanus, chorea and progressive myopathy. Favorable results in isolated cases have even been reported, particularly by Bruce from the Royal Edinburgh Asylum, by Mabon and Babcock from the St. Lawrence Hospital, and by Reinhold, Levy-Dorn, G-ottstein, and Bramwell in tetanus, etc. ; but invariable and con- vincing results have been obtained more rarely in these affections than in the diseases previously mentioned. Gauthier, Quenu, Reclus, Ferria and others have employed thyreoid treatment also in fractures with delayed union of bones, on account of the fact that the thyreoid gland has a predominant influ- ence upon the growth of bone; the results were apparently most gratifying, and the same reason led to the employment of this remedial agent in rachitis. But here the watchword for the present must be : temporize ! Confirma- tions are wanting ; and from this it may be concluded that the treatment has been tried by others, but without success. We cannot close this discussion without referring briefly to an organ apparently in close connection with the functions of the thyreoid gland, and by embryologic and anatomic analogies also histogenetically parallel with it. This is the hypophysis, the pituitary body, the anterior glandular part of which is developed, like the thyreoid, from the ectoderm, a diverticulum of the posterior pharyngeal wall, the structure of which also consists of acini which unite and form follicles containing more or less of a colloid substance. Unquestionably this gland has some relation to osseous growth, for it is almost invariably enlarged in acromegalia and giant growth. In isolated cases it has been known to attain the size of a hen's egg, and the sella turcica is abnormally developed. Nevertheless, this does not yet prove, as most authors too hastily assume, that the hypertrophy of the gland is the cause of these 196 MYXEDEMA anomalies of growth. It may be a mere coincidence, or vice versa, a resulting condition of disease of the bone, to a certain extent a reflex from the bone to the gland. After thyreoidectomy in animals the hypophysis is said to hyper- trophy vicariously (Hoffmeister), and in a few cases of myxedema hyper- trophy of the pituitary gland has been found. But Ponfick, to whom we owe two very accurately investigated cases of myxedema recently reported, found upon transverse section in one case the glandular portion of the hypoph- ysis enlarged, in the other case a decided destruction of the organ so that the tubules of the gland were replaced to a great extent by a " worthless fibrous mass." Here also there are evidently contradictions and enigmas which still await solution, especially as we can state nothing definite in regard to possible therapeutic results. Although we are completely in the dark in regard to these last-named affections, and for the present are compelled to await further investigations, this much is certain, that in thyreoid therapy we possess a remedy previously unknown with which to combat a number of chronic diseases, which even a short time ago were looked upon as incurable, and which it was thought impos- sible to influence therapeutically. This type of therapy has been designated organotherapy or opotherapy, 6ir6articularly described by P. Marie and Marinescu, I could find in only one of the cases investigated by me, but I do not doubt that it is frequently a natural consequence of the previously described alterations. The same may also be said of the muscles, in which also the hypertrophy of connective tissue is probably the primary factor and degeneration the occasional consequence. Besides these diffuse changes, fibro- mata mollusca, papillomata, and abnormal pigmentation are also observed. The sebaceous glands and the hair remain quite normal, nor was I able to find an}- decided abnormalities in the vessels. PATHOLOGICAL ANATOMY Of the pathological findings in internal organs I shall first briefly men- tion a number of the less constant ones. The internal organs may be impli- cated in the hvpertrophy so that splanchnomegalia has been spoken of. We cannot, however, determine in these findings in how far the observers were dealing with simple gigantism, and how far it was a progressive enlargement caused by acromegalia. This doubt applies to the large kidneys and livers 17 238 ACROMEGALIA of many acromegalics. In other organs, as in the heart and the spleen, pathologic enlargements occur, yet they mnst not be looked upon as conse- quences of the acromegalic process, but as independent diseases. Corresponding to the clinical symptoms, the frequently determined hyper- plasias or degenerations of the internal female genitalia and of the testicles are perhaps in intimate relation to the pathologic process, while the cutaneous parts of the external genitalia are frequently implicated in the acromegalic enlargements. In the pancreas, connective tissue hyperplasia has been described several times. On account of the frequent complication of acromegalia with dia- betes, we might easily interpret this as a result of the acromegalic process. But in the cases investigated by me, particularly in the one combined with diabetes, the pancreas was perfectly normal, while, in another case in which connective tissue increase was present, diabetes did not exist. The central nervous system, i. e., the base of the brain, may be involved directly and to a marked extent by the tumor of the hypophysis, particularly the infundibular region, the pons, and the optic chiasm. All other findings, such as column degeneration of the spinal cord, represent only accidental complications. In the cervical sympathetic, Marie and Marineseu found con- nective tissue increase and ganglion degeneration, and this was several times confirmed by other observers. In my cases I was unable to recognize decided changes in this region. The chief interest of pathological researches has been concentrated for a long time upon the so-called " blood-vessel glands." Of these the thymus gland first .attracted attention for a short time after Klebs had ascribed to it a predominant role in the disease. The enlargement of the thymus gland is, in fact, a very frequent finding. The gland may extend into the anterior mediastinum, so as to correspond with that of the new-born, though in com- parison it is actually larger. The adrenals are large but normal. The thy- reoid gland may develop into a massive goiter, or may be decidedly atrophic. The enlargement may be of any of the types usually found in goiters, without any predominant specific form being recognizable. The degenerative forms evi- dently have nothing in common with those characteristic of myxedema. In my case the glomus carotideum was examined, and found to be small and normal. In the pathology of acromegalia our greatest interest is in the hypophysis. Since the first undoubted autopsy findings of Verga in a case of acromegalia, the characteristic findings in the skeleton by v. Langer, and the observation of tumors of the mucous gland (pituitary body), the autopsies in acromegalia have been more numerous. In accordance with the size and character of the tumor, the description of the findings varies. There are extant descriptions of the pituitary gland which show that the authors did not consider this to be at all enlarged, and we can only base our assumption of an enlargement upon the fact that masses were mentioned as present. In other cases the enlarge- ments are distinct, but only of moderate degree. Thus, in two cases, I have found tumors about the size of a cherry, one of which eroded the groove of the pituitary body and the other the dorsum sella?. The enlargements are of every degree up to the size of a goose's egg or even an apple. These either PATHOLOGICAL ANATOMY 239 develop downward and penetrate the entire sphenoid hone to the pharynx, as in a case of Hansemann and in one of my cases, or develop upward and com- press and displace the organs at the base of the brain, as well as the nerves and venous sinuses situated upon both sides of the sella turcica. This has been variously described ; in one of my cases the development was upward and also, to a slight degree, downward. The tumor invariably develops from the anterior lobe of the gland, and in a few cases has boon described as simple hyperplasia of the gland. In other instances, adenoma or struma hyperplastica of the gland is directly mentioned. Besides these, in still other cases, prolif- eration, softening, cysts or connective tissue hyperplasia have been found. Finally, in a great number of cases the tumors have been regarded as malig- nant. Among these, isolated cases of gliomata have been mentioned. Claus and van der Stricht found a lymphadenoma. The majority of malignant tumors of the pituitary gland have been found to be sarcomata. Sternberg has laid particular stress upon the fact that in the six cases of malignant acromegalia which were known up to the time of the publication of his mono- graph, the tumors were all sarcomata. In the meantime Gubler, in a- case of malignant acromegalia histologically investigated by Hanau, and I myself in at least two cases, found tumors of the hypophysis which were similar to the malignant variety, and which upon superficial examination might also have been looked upon as sarcomatous. But we recognized the tumor cells as originating from the epithelium of the hypophysis, and designated these tumors as hyperplastic, and eventually as malignant adenomata. Hanau ex- pressed the suspicion that in the cases described as sarcomata the same ade- nomatous form of tumor was really present. I was able to demonstrate in my four cases that the character of the tumor was in the main the same, and that its origin could be found in the glandular epithelium of the anterior lobe of the pituitar}^ body. I wish to lay special stress upon a fact (also noted by Tamburini) that in at least three of my cases, a large part of the tumor consisted of a very peculiar form of epithelium, the " granular cells," which correspond to the so-called chromophilic cells of Flesch. These are the cells which are looked upon as the essential functionating cells of the normal gland. I presume that in every case of hypophysial tumor the hyperplastic prolifera- tion of the cells is the basis for a neoplasm, and that, in the further course, a malignant degeneration of the tumor starts in these cells ; or a malignant pro- liferation of other tissue elements may replace this primary new formation and so destroy it. When we consider the supposed importance of the hypophysial tumor in the clinical picture of acromegalia, we must admit that it is by no means free from objections. Several hypotheses in marked contrast to each other may be mentioned. The most extreme (in one direction) assumes that the tumor of the hypophysis is only a symptomatic enlargement of the organ which may be markedly developed, slightly developed, or entirely absent. In opposition to this is the conception that an abnormal function of the hypophy- sis is the sole cause of the disease. A more conservative view ascribes the disease to a primary anomaly of the " blood-vessel glands," among which the hypophysis is to some extent implicated. 240 ACROMEGALIA The question cannot now be determined with absolute certainty because we must admit that it is not yet fully recognized that the hypophysis is dis- eased in all cases of acromegalia. No less an authority than R. Virchow has maintained from the beginning that the changes in the hypophysis are a sec- ondary finding and were absent in some of his characteristic cases. A case from Virchow's Institute has lately been published by 0. Israel, which appar- ently proves this. These extraordinary differences in opinion can only be reconciled by the fact that the differential diagnosis of the disease is by no means so exact as might appear from the publications of P. Marie and Stern- berg. It must be borne in mind that any of the individual symptoms of the disease, the peculiar osseous growth, the changes in the soft parts, the macro- glossia, and even the tumor of the hypophysis may occur independently. Hence in many cases a difference of opinion may arise as to what symptom- complex justifies the diagnosis of acromegalia. Virchow lays great stress upon the changes in the bones of the extremities, and undoubtedly has fur- nished incontestable proof, which is confirmed by the case of 0. Israel, that they also occur without a tumor of the hypophysis. This was also recognized by Pierre Marie who diagnosticated a similar disease of the extremities as hypertrophic osteoarthropathy. I believe, however, that if we adhere to the name acromegalia for the classical, clinical and anatomical symptom-complex of P. Marie alone, we must admit that the changes in the soft parts and in the bones of the face have at least as much importance as those of the bones of the extremities. In the case of Israel clinical observation together with the autopsy findings in the bone reveal, as the celebrated author himself emphasized, that other impor- tant symptoms of acromegalia besides the tumor of the hypophysis were absent. It appears to me most important that there was no record of the acromegalic macroglossia and the corresponding deformity of the lower jaw. We may, therefore, safely deny that this case is acromegalia, and must agree with the author that it is inadvisable to deduce from it any far-reaching conclusions as to the nature of acromegalia. The fact is much more important that in literature quite a number of cases are mentioned in which true adenomata of the hypophysis were found with- out acromegalia. I still entertain the hope that by careful investigation with the most approved methods we may find these tumors to deviate from the type of those occurring in acromegalia. In a case recently examined by me, the question arises whether the age of the patient, sixty years, might not explain the absence of corresponding general symptoms. Opposed to the view that the tumor of the hypophysis is a symptom and not the cause of acromegalia is the fact that the common type of hypophysial tumors differs from the normal structure of the gland (as was especially apparent in all of my four cases which were minutely investigated) as well as from the other acromegalic hyper- plasias, which in the main are composed of connective tissue. The opinion that disease of the hypophysis produces the symptoms of acromegalia only by co-operation with the other blood-vessel glands is not in accordance with the fact that no other blood-vessel gland is so constantly involved in the disease as the pituitary body. Indeed tins is not even approxi- PATHOLOGICAL ANATOMY 241 mately the case. The symptoms which have heen recognized as consequences of diseases of the other blood-vessel glands are generally absent in the clinical picture of acromegalia; or, if they do occur, they represent distinct compli- cations, and the characteristic changes of acromegalia are not produced by disease of any of them. Finally, the especial, peculiar, histological structure of the hypophysial disease favors the opinion that this plays a role entirely different from that of the other blood-vessel glands. In so far as we can arrive at logical conclusions by exclusion and without experiment, we may maintain the view which was first expressed by Pierre Marie that disease of the hypophysis is the etiologic factor in acromegalia. We will now consider in what manner the hypophysis causes the disease. The original view of Pierre Marie that the changes are due to an absence of function of the degenerated hypophysis — as in myxedema by an absence of function of the thyreoid — is not substantiated by our more exact knowledge of the character of the glandular proliferation. Somewhat more reasonable and better founded are the hypotheses of Hansemann and Uthoff, who hold that the relation between the enlargement of the hypophysis and the affected parts is an altruistic hyperplasia. In whatever way the progressive development of the hypophysis is produced, in that way the progressive development of other parts (extremities, bones of the face and internal organs) is also brought about. According to Hansemann, altruistic hyperplasia may occur with organs that have an embryologic connection, as between the anterior lobe of the hypoph- ysis and the tongue, but we can hardly say that there is any such relation between the gland and the extremities. This view becomes even less tenable when it is clearly demonstrated that neither the changes of the hypophysis nor those of the extremity represent simple progessive hyperplasia, and that in both we are dealing with new tumor-like formations of entirely atypical nature. In my previously published articles, I have accepted the view of Tamburini, as do also Hanau and Woods Hutchinson, that the pathologic development of the hypophysis is due to a hyperactivity and over-production of the secre- tion which is to be utilized internally. Tamburini, at any rate, attributes the phenomena of growth to these causes, while the cachexia observed in the later stages of the disease is regarded as a consequence of the adenomatous and cystic degeneration of the gland. For several reasons this theory must now be somewhat modified. First, in its original form, the division of the disease into two phases is impossible. On the contrary, in the purest type of acromegalia, Sternberg's malignant form, the development of the tumor of the hypophysis is unquestionably combined with symptoms of peripheral hyperplasia and the injurious effects of this upon the entire organism. Tam- burini's theory is also difficult of acceptance because its adherents, as well as its opponents, have been forced to the conclusion that if his views are cor- rect, the secretion of the hypophysis must also influence the normal growth of the body ; Woods Hutchinson has gone so far as to declare that the hypophy- sis is the center for body growth. These difficulties lessen when the processes of peripheral growth are recog- nized as constant but less important consequences of acromegalia (which is 242 ACROMEGALIA clear to me), and the true nature of the disease is conceived as a tumor-like formation in the connective tissue which, as Erb and Ponfick have already pointed out, resembles that of elephantiasis and also myxedema. It might be more easy to ascribe the symptoms of the disease to the action of a specific toxic secretion which, under normal circumstances, possesses an unknown function, and which is present in the circulation in such slight amounts that no deleterious effect is produced. I refer to the zymogen-like granules secreted in the chromophilic cells which, in at least three of my cases, I found enor- mously increased, while in the normal gland their action appeared of less importance. I believe it may be strictly maintained that if there is a lessen- ing of the normal supply of the bodies to the circulation they may affect the activity of digestion as profoundly as the blood plasma as shown by recent investigations. Hence an over-production of them may cause severe damage to the tissues of the body. TREATMENT In conclusion I shall refer briefly to the therapy of the affection. I have only negative points to report, since, up to the present time, it has been abso- lutely without effect. Yet a knowledge of the pathology of the disease may prevent error in the choice of therapeutic measures. The uncritical way in which organotherapeutic " curative " results have been published led, as a matter of course, to the production of hypophysis tablets and their admin- istration to acromegalics as soon as it became known that in acromegalia the hypophysis appeared to be affected. Fortunately, it has been demonstrated both by the use of these and by animal experiment that the administration of the pituitary gland by mouth is quite harmless; we may assume that its active constituents are rendered inert by the digestive fluids. Otherwise, we would realize the unpleasant truth that this therapy must aggravate the dis- ease by increasing the materia peccans. Until a hypophysis antitoxin is pro- duced, the only rational treatment, based on the pathology of the disease, must be the extirpation of the hypophysial tumor. We cannot understand why the hand of the fearless surgeon who has dared to attack the neighboring Gasserian ganglion should halt at this operation. CHRONIC ARTICULAR RHEUMATISM By W. HIS, Basel In attempting to describe a disease so familiar and commonplace as chronic articular rheumatism (this appears to be the prevalent opinion in regard to it), it is almost necessary to begin with a captatio benevolentice. A few years ago, when I began to study this disease somewhat in detail, I learned that it had long attracted the attention of many scientists. The last of the greater compilations, that by Pribram, although by no means exhaustive, contains notes of over 500 investigations which refer to chronic articular rheumatism, and among the authors are found the most prominent names in medical sci- ence, of whom I shall mention Charcot, Bouchard, Lancereaux, Pierre Marie in France, the Garrods, father and son, in England, Kichard Volkmann, Senator, Baumler, and Albin Hoffmann in Germany. The disease is by no means a new one; it was familiar to the ancients who confounded it with gout and designated it by the collective term arthritis. It was not until the year 1800 that Landre-Beauvais expressly pointed out that the disease was a distinct entity. Alfred Garrod in his celebrated book on gout proved that the deposit of urate salts which is the materia peccans in the joints affected by gout never occurs in chronic articular rheumatism. Nevertheless, there are still some authors who, even in recent years, have endeavored to merge the two diseases, believing them to be one. This attempt is due to the fact that certain jmenomena in the joints, and many of the accompanying and subsequent symptoms in both diseases, may be the same; we shall refer later to this point more in detail. The manifestations of chronic articular rheumatism are very various, and if the descriptions of different authors are compared with one another, it is often difficult to believe that they are portraying the same disease. What one experienced observer describes as a frequent finding, another, no less experienced, has scarcely ever seen. Similar to this is the variety of opinions in regard to the etiology; greater diversity of views can scarcely be conceived. According to some authors, for instance, M. Schiiller and Bannatyne, chronic rheumatism is an infectious disease in which there can be invariably demon- strated certain microorganisms; to others (Bouchard, Lancereaux) the disease is the expression of a constitutional anomaly which is markedly hereditary, running in families, and showing itself by numerous other symptoms. Other writers believe that the affection is in the main a local process confined to the joints and periarticular tissues. Finally, there are some who consider it a disease of the central nervous system. 243 244 CHRONIC ARTICULAR RHEUMATISM Just as diverse is the nomenclature. Almost every author has attempted to arrange the varying pathological pictures in distinct groups (all mentioned by Pribram), and of the names that have been chosen some refer to the clinical course (for instance, Charcot's rheumatisme articulaire chronique progressif). some to the shapes assumed by the joint (arthritis deformans of Virchow and E. Volkmann, rheumatisme noueux of Trousseau), some to the anatomical findings (M. Schiiller's polyarthritis villosa) and some to their authors' etiolo- gic views, for example, rheumatisme goutteux, diathesique (Pierre Marie) and infectieux (Teissier and Eoque). This confusion is increased by the fact that the same title is applied to quite opposite pathological conditions. Thus, the rheumatisme deformant of the French, with effusion, proliferation of the capsule, and spindle-shaped swelling of the joint, is identical with what the German surgeons and clin- icians (following E. Volkmann) call chronic rheumatism in contrast with arthritis deformans, which is characterized by atrophy of the capsule and proliferation of the bone, in many joints or in one alone (for example, the malum senile coxae). This confusion can only be cleared up by describing briefly all the principal types of joint disease. 1. When a young person, after brief prodromal symptoms or a tonsilitis with fever, is attacked with painful swelling of the joints, the inflammation spreading from one joint to another, affecting large and small joints alike, and without predilection for any — when the endocardium, the myocardium, the pericardium, the pleurae, perhaps even the meninges are involved — we recognize in this picture an infectious disease, acute articular rheumatism, and we know that, as a rule, it runs its course without leaving permanent changes in the joints. Exceptionally, however, swelling of one or more joints and moderate pain and stiffness remain. After weeks or months the joint function is more or less completely restored or the diseased condition becomes permanent. This is chronic arthritis, resulting from an attack of typical acute articular rheumatism. Now as the primary forms of chronic arthritis may begin with acute febrile attacks, their differentiation is often difficult. Davaine closely studied the disease, and laid especial stress upon possible prodromes, splenic tumor, visceral complications, the ease with which the effusion in the joint may be displaced, the absence of trophic disturbances (atrophy of the muscles), and the absence of family predisposition to acute articular rheumatism. Unquestion- ably Davaine has arranged this in too schematic a manner, and, therefore, in any individual case we may waver for a time in our decision; the occur- rence of secondary chronic rheumatism is, however, recognized by all later authors. 2. The second form is prone to attack persons between thirty and forty years of age. The disease is ushered in with fever and pains in the joints, which are swollen but not to the same extent as in acute rheumatism. They have an elastic, tense feeling, but fluctuation is obtained with difficulty; the skin is slightly reddened, and is edematous above and below the joint so that the affected joint shows a spindle-shaped swelling. Gradually new joints are CHRONIC ARTICULAR RHEUMATISM 245 attacked or those affected improve, but a number of those first attacked always remain permanently diseased. The joints exhibit conspicuous regularity in the order of their involve- ment. First, the smaller joints of the body are attacked; the phalangeal and interphalangeal joints of the fingers with the exception of the thumb, the corresponding joints of the toes, then those of the hands, of the elbows and knees; the shoulder and hip are almost always exempt. The disease, how- ever, shows a preference for certain joints which are usually spared by acute polyarthritis, such as the jaw, the sternoclavicular joint and the sternocostal joints.1 Secondly the affection is conspicuously symmetrical: Almost always both hands, both feet, both knees are attacked; only the joints mentioned above are. as a rule, attacked unilaterally. The further course of the disease varies. Either the joints return more or less to the normal, to be similarly attacked after months or }rears (often acutely and with fever) or the affection is " chronic from the onset," and in time changes occur in the joints which prefigure the third form now about to be described. 3. The third form generally attacks elderly persons, particularly women during the menopause; the disease begins with indistinct nervous symptoms, drawing or tearing pains, furry sensations or formication, sensations of cold, etc., in the hands and feet. The patients notice that the motility of the fingers gradually decreases. Fine movements such as sewing, knitting, writ- ing, become difficult, particularly in the morning and during cold weather. Careful observers note that the ends of the joints and the basic and inter- phalangeal joints are slightly thickened; they feel hard and are not very tender on pressure. The fingers gradually deflect toward the ulnar side, and this is first noticeable in the proximal joint with the extended interphalangeal joints; finalty complete subluxation results in the basic joint, though in this, as well as the other changes, the thumb is rarely implicated. The inter- osseous spaces show deep grooves; the ball of the thumb and little finger are atrophied. The same changes take place in the toes. Muscular contractures appear early and cause abnormal positions of the extremities. Charcot, with his artistic mind, attempted to arrange these positions according to a system : A flexion and an extension type (more correctly a hyper-extension type) each type with several sub-varieties. If, with Vidal, we accept also an extension type (straight line) every imaginable form results, and if we reflect that the fingers of the same hand may present various types side by side, the value of this schematic division will not appear great. Besides the muscular con- tracture, changes in the joints add to the immobility; the capsule shrinks to fibrinous strands, the surfaces of the joints coalesce by connective tissue liga- ments, exostoses and ecchondroses appear: The final result in well marked cases is complete immobility of the joints in abnormal positions; the unfor- tunates are condemned to permanent invalidism, and fill a large part of our almshouses and homes for incurables. This form differs from the two first mentioned by its gradual and afebrile i These, however, although rarely, are sometimes attacked in acute polyarthritis ; indeed, the jaw may be the only joint attacked (Hamm, Manasse). 246 CHRONIC ARTICULAR RHEUMATISM onset its slow course, the absence of effusion into the joints, cutaneous edema and capsular swelling. It resembles them in a preference for the small joints and in the conspicuous symmetry; moreover, every possible transitional form occurs, so that they can only arbitrarily be differentiated. More correctly, perhaps, we may call them different developments of the same disease. There- fore I have not yet accepted the division which is often made (lately by Curschmann) into chronic articular rheumatism and arthritis deformans. I agree with Charcot, who designates the two as the exudative and the dry form of primary chronic progressive polyarthritis. 4. The fourth form is characterized by appearing in elderly persons and in the aged, by a markedly chronic course, by invariable limitation to one or more large joints, and frequently, although not always, by its connection with trauma. This is the arthritis deformans of R. Volkmann, the rheuma- tisme chronique partiel of Charcot, the best known type of which is the malum senile coxas. But this affection is not infrequently noted in the fourth and fifth decades of life, most often, perhaps, in the shoulder after a fall or contusion. Effusion is almost always absent. When the patient is at rest the pains are moderate or cease entirely; movement is limited to a great extent, muscle contractions or, at least, constrained positions, generally occur and atrophy is frequent (in the shoulder, mostly of the deltoid and triceps). Upon move- ment, friction and cracking are heard and felt in the ends of the joints. After the disease has lasted a long time deformities due to exostoses and ecchon- droses invariably appear. These will be described below. 5. The fifth form includes the chronic, deforming and ankylosing dis- eases of the vertebral column (Pribram). Julius Braun, in 1875, was the first to collect a large number of cases. Strumpell described the implication of the hip-joint in arthritis of the vertebral column. Pierre Marie in 1898 worked out the symptomatology of " spondylose rhizomelique " which appears in men immediately after the completion of their growth, and consists in com- plete adhesion of all vertebrae, scoliosis and kyphosis of the shoulder- and hip- joints, but with intact extremities. Another form was described by Bechterew in 1892 : Limited movement in the vertebral column with anterior curvature, particularly of the upper parts; associated with this pareses of the muscula- ture of the neck, trunk and extremities, and atrophy of the muscles of the back and scapula. Common to both of these forms are nervous disturbances — anesthesia and paresthesia, neuralgia, paralyses and muscular atrophies in varying form and extent. The Striimpell-Marie form distributes itself from below upward; Bechterew's variety from the shoulder to the hip. In the meantime, in a large number of observations, particularly those compiled by W. Anschutz, it was noted that a sharp differentiation of these forms is impracticable, that, on the contrary, numerous transitional stages are observed. Some of these begin at the upper or lower end of the vertebral column, with or without involvement of the joints of the trunk, or, finally, in combination with chronic arthritis of the extremities in one or another order. Joh. Muller described a case with extreme stiffness of the articulations of the ribs, respiration being maintained entirely by the diaphragm and the CHRONIC ARTICULAR RHEUMATISM 247 abdominal muscles; Clarke described a disease confined to the costovertebral joints of the twelfth pair of ribs. Anatomically the process produces changes in the ligaments of the intervertebral sheaths and of the vertebral joints in varying combinations (Schlesinger) ; the nervous disturbances are partly due to compression of the nerve roots, partly to chronic meningitis (Bechterew). Etiologically we must consider primary and secondary chronic arthritis, arthri- tis deformans, gonorrhea, syphilis and other infections. Whether the affections confined to the ligamentous apparatus and intervertebral sheaths are to be classed as chronic arthritis may be questionable. Baumler calls attention to the fact that stiffness of the hip-joints and lower vertebral articulations in consequence of the patient's increased weight may lead to disease of the upper vertebra?. E. Bennecke lays stress upon the action of frequent, though insig- nificant, trauma upon the vertebral sheaths and bony structures. In conclu- sion, similar clinical pictures are presented by contracture of the lumbar Fig. 4. — Rontgen Picture Showing Heberden's Nodes upon the Index and Little Finger, with Exostoses of the Second and Third Phalanges. 248 CHRONIC ARTICULAR RHEUMATISM muscles and those of the back. Beer, Zenner, and lately Cassirer and Senator have described such "myogenous" vertebral stiffness, some of which may be due to hysteria and some to acute fibrous myositis. These conditions indicate that chronic rigidity of the vertebra may be due to very different causes, but we may be certain that those forms which occur in connection with acute or chronic articular rheumatism or with disease of the joints of the extremities should be classed as chronic arthritis. 6. As the sixth and last type, I must mention those almost painless or only temporarily painful nodes which occur in the terminal joint of the three- jointed fingers, appearing upon their posterior surface, giving them an oval shape, hard to the touch, and gradually, from rigidity of the joint, fixing the fingers in a position of flexion or abduction. They are often looked upon as the signs of uric acid gout; E. Pfeiffer believes them to be a certain guide in diagnosis even in the absence of other gout}^ symptoms. Heberden, who discovered them, did not attribute them exclusively to gout, and I coincide in the opinion of the majority of later authors who find these Heberden's nodes occasionally in gout, occasionally in chronic arthritis, but most often as the only arthritic symptom in otherwise healthy individuals. The Rontgen picture shows them to be exostoses, and they form a connecting link between chronic rheumatism and arthritis deformans; with the former they have in common symmetry and multiplicity, with the latter, the bony, marginal proliferations, and the usually painful and chronic course. It is well to follow Charcot and to separate them as special forms of disease. This finishes the description of the most common types; but it must be added that in individual cases transitional stages occur which tend to merge the types into each other. For this reason clinical findings do not permit a fine differentiation, and an attempt has been made to found a classification upon the anatomical changes. PATHOLOGY The anatomical changes extend to all parts of the joint, cartilage, bone and capsule, and frequently also to the adjoining muscles, tendons and tendon sheaths. In the earlier stages these changes are relatively but little known; they are found as accidental lesions, and often run their course during the life of the patient without symptoms. Thus, the patient from whom illustra- tion 5 was taken was a chorus girl and dancer until a few weeks before her death. Moderate changes are noted by surgeons, who look upon chronic rheumatism as a border-land which should be gradually brought under their dominion. The later changes are well known anatomically, but they illumi- nate the problem of their origin as poorly as ulcerative phthisis explains the onset of pulmonary tuberculosis. Even to-day it is not quite clear whether the affection begins in the car- tilage of the joint or in the synovial membrane. Sometimes the one, some- times the other, appears to be the case; nevertheless both are early attacked. In the cartilage the basic substance appears completely detached, the cartilage cells proliferated, and sometimes discharged from their capsules into the joint fluid. PATHOLOGY 249 In some forms the amount of synovial fluid is increased, occasionally turbid but — and this is characteristic of chronic arthritis — never purulent. The villi of the synovial membrane are hyperemia (violet red), showing ■ppB»"— — ^^ ^^H H ^f ^1 1H [ 1 ^H 1 ^ JLl 1 ■ 1 IbbhW* Fig. 5. — Metatarsophalangeal Articulation of a Chorus Girl, Aged Forty-Five, with Beginning Chronic Arthritis without Symptoms; Death from Contracted Kidney. Fibrillation of the cartilaginous basic substance, proliferation of the cartilage cells, the capsules of which partially open into the joint cavity. The capsule of the joint is intact. marked proliferation; occasionally fatty degeneration is noted (lipoma arbo- rescens), and in well developed cases present the appearance of sheep's wool; the capsule and its surroundings show edematous infiltration. The bone appears unchanged in the early stages of the disease. In later stages the smooth surfaces are denuded of cartilage, the bone is bare, and, if joint movements have still been performed, shows grooves, re- sembling the crevasses of a glacier. Often the bared surface is dense and ivory-like, or it is covered by connective tissue which extends from the borders of the synovial membrane, from transformed cartilage cells, or even from the surfaces bare of cartilage. This connective tissue covers the joint surface (Kachel), and frequently adheres to the opposing joint ends (fibrous anky- losis). These connective tissue striae may calcify and finally ossify (bony ankylosis). Upon the border of the cartilage, wherever it is covered by synovial membrane, ecchondroses develop which are transformed into osteoids and finally into bony tissue. By these exostotic marginal proliferations, the joint end attains a mushroom form and resembles the crown of the antler of a deer. 250 CHRONIC ARTICULAR RHEUMATISM The bony substance becomes rarefied and fragile, the capsule, which was at first flaccid, proliferated, and infiltrated with serum, is transformed into fibrous tissue which cicatrizes around the ends of the joint and limits motion. In the proliferated villi, islands of cartilage or bony tissue form, and these may be thrown off as free joint bodies. The final stage is complete osseous or fibrous ankylosis of the joint which is fixed in more or less unnatural position and greatly deformed. All these processes are common to the various forms of chronic arthritis; at one time one, at another time another, becomes prominent. Thus, in the exudative form of progressive chronic polyarthritis, proliferation and edema- tous infiltration of the synovial membrane and its surroundings dominate the situation, hence the spindle-shaped form of the joints. The cartilage often appears to be secondarily implicated. In polyarthritis " sicca " which has a chronic beginning, the proliferation of the joint is not as marked as the fibrous transformation of the cartilage. The outlines of the joint ends as a consequence of this become prominent, and exostoses, if present, may be felt through the tense skin as hard, prom- inent nodules which may sometimes be seen. This form also shows a tendency to fibrous ankylosis. In senile deforming monoarthritis these osseous border proliferations with disappearance of cartilage play the main role in the limita- tion of movement; the capsule forms no essential part of the clinical picture. Finally, Heberden's nodes are exostoses which at first slightly limit motion. If the anatomical descriptions of later authors are compared (particularly Schuchardt and Weichselbaum) we are forced to agree with Charcot who declines sharply to separate the forms according to the anatomical findings. He regards them as in some sense branches of the same trunk. CLINICAL SYMPTOMS The clinical picture would be incomplete if only the joint lesions were considered. Very frequently there is early impairment of the general health. The cases occurring in young persons with fever are particularly apt to show from the onset emaciation and conspicuous cachexia. This can hardly be attributed to the fever. Occasionally the fever lasts for weeks and reaches 102° F. and higher, but there is no proportion between the height or duration of the fever and the emaciation. Indeed even after the temperature falls the patients remain weak. The inactivity of the patient, the want of fresh air, and the constant pain have been urged in explanation. But if we bear in mind that patients with disease of the spinal cord become abnormally fat despite the fact of constant pain and immobility, we cannot concur in this view, but must look upon these forms of arthritis as conspicuous instances of wasting disease. Amyloid degeneration (Eoese) which frequently appears confirms this. It is true other cases of arthritis belong to the fat plethoric type and here also transitional cases are recorded. Frequently, particularly in the young, there is moderate anemia and oligocythemia. Most of the muscles of the body take part in the emaciation; in some cases the entire musculature suffers but almost invariably the muscles in the neigh- CLINICAL SYMPTOMS 251 borhood of the joints are involved, and among these the extensors are most seriously affected. H' rheumatism attacks the hand the interossei atrophy very early, often before the patients notice any hindrance in movement. This occurs in the exudative as well as in the dry form. In the latter we find a very characteristic ulnar abduction of the basic joint of the fingers from the first to the fourth. An attempt has been made to explain this by contractures of the muscles or from the flaccid condition of the capsule; this, however, I believe to be incorrect. For in older persons this is frequently the first symp- tom noted, even before there is an}'- abnormal distention of the capsule or any muscular contractions. It is more reasonable to assume that the lumbricales atrophy simultaneously with the interossei, which normally have the property of adduction, besides that of extension of the basal phalanx. Later this devia- tion terminates in well marked subluxation. That the bones take part in the atrophy is well known ; in the senile monoarthritic deforming variety this begins in the end of the joint; but in the juvenile polyarthritic form the Eontgen picture often shows a conspicuous coalescence and disappearance of the spongiosa in the neighborhood of the affected joint. Perhaps this is the effect of immobilization. But since Sudeck has shown that in every form of arthritic inflammation, distortion or trauma may produce within a few weeks decided atrophy of the bones, transient or permanent, similar conditions should also be looked for in chronic arthritis. The sTcin and its structures take part in the process, and Herz has described a case in which, with every new attack, a glove-like desquamation of the skin of the hand and shedding of the nails occurred; such cases are rare. The changes resembling scleroderma are more frequent; the shining ivory-like skin adheres to the deformed joint, smooth and immovable. In the juvenile cases there is frequently an excessive func- tional liyperliidrosis. The contractures which occur particularly in the flexor muscles of the fingers and toes are important, but these may also be noted in the extensor groups which are to a high degree responsible for the terrible and incurable deformities in some of which the knees are drawn up to the chin. Frequently the tendons and tendon sheaths are involved in the process and along these structures tough subcutaneous nodules occasionally appear which may be temporary or permanent; these are also noted in acute rheumatism (see a dissertation by Eabinowitsch). Pribram asserts that he has only ob- served them in acute rheumatism; Fig. 6, however, is an example of such nodules in a case of undoubted chronic polyarticular arthritis. In conclusion, I must mention intermuscular or intramuscular, dense, cal- lous infiltrations which are rarely alluded to in literature, but are well known to orthopedists and masseurs, and are skilfully treated by them. The visceral complications are especially interesting on account of their importance in the conception of the disease. That the endocardium may be attacked has been admitted, and the frequency with which this happens varies in different reports from 4 per cent, to 80 per cent, of the cases. The second- ary and the senile deforming varieties do not attack the heart. In the statis- tics of primary chronic polyarthritis there are differences of opinion as to whether functional heart murmurs or only the genuine valvular affections have been included. Pribram, who was the first to call attention to this variation, 252 CHRONIC ARTICULAR RHEUMATISM gives the following statistics of his cases. In the forms beginning acutely, there were 53.4 per cent, of heart murmurs and 20 per Cent, of valvular disease; in cases chronic from the outset only 13.5 per cent, of heart murmurs and 4 per cent, of valvular disease. Chronic nephritis of benign character and showing but slight tendency to uremia is not infrequently observed. Among other complications those affecting the eye, such as iritis, iridocy- clitis and episcleritis, and the skin (various forms of erythema, eczema, urti- caria and psoriasis) are to be mentioned. The occurrence of multiple sym- metric lipomata has frequently been observed in connection with chronic arthritis, as well as bronchial asthma, dyspepsia, hemorrhoids and numerous nervous disturbances, and this gives rise to some confusion. These affections are spoken of particularly by authors who look upon chronic arthritis as an expression of a general constitutional anomaly. Lancereaux, in 1870, divided rheumatism into two classes, of which one, " qui ne laisse jamais des traces sur son passage " corresponds to acute articular rheumatism; the other he said was: "pas une maladie, mais un syndrome, Fig. 6. — Subcutaneous Nodules Situated upon the Dorsal Tendon Sheaths in a Case of Chronic Exudative Polyarthritis in a Young Girl. une manifestation d'un etat constitutionel," " le branche d'un grande f amille pathologique," " herpetisme" a vasomotor trophic neurosis, expressing itself in dynamic (migraine, epistaxis, neuralgias) and material disturbances in the skin and of the tissues deficient in blood-vessels. In this group is also included the triad of diabetes, obesity, and gout. Bouchard gives a similar definition of " arthritisme " ; both authors emphasize its conspicuous family and hered- CLINICAL SYMPTOMS 253 itary character, and even so careful an observer as Potain believes : " Ce n'est pas telle ou telle forme de rheumatisme qui se transmet, mais une predisposi- tion generale exposant a mi groupe commun d'affections dans laquelle il faut meme ranger la goutte." On this point it is difficult to arrive at a definite conclusion. When we read the clinical reports of German, French, English and American authors ■\ - \ ]|1 - ?,^^«^BBV IB 'J J ^^ifH :'.-'■'. , '. .. • Fig. 7. — Patellar Cartilage of a Young Man who, after Passing Through an Attack of Gout, Succumbed to Croupous Pneumonia. The cartilage shows a velvety fibrilla- tion of the matrix similar to the condition in chronic arthritis. The joints contained no deposits of urate salts. we receive the impression that certain forms of chronic polyarthritis frequently attack debilitated persons. One author has, however, gathered his clinical material in the hospital, among feeble, anemic, poorly nourished patients, cases of true arthritis pauperum, whereas the cases of others were among those living in affluence, the portion of the population debilitated by luxury and close intermarriage. Under such conditions we cannot regard the simultaneous appearance of two or more diseases as a proof of their identity, and since decisive statistics are not to be had, the critical skepticism of A. Hoffmann and other German authors is certainly justified. Yet the relation of arthritis to apparently dissimilar affections — and here I must mention psoriasis — becomes constantly more obvious. Adrian has re- cently reported 94 cases of this combination, which has been known in France for some time. Gerhardt was the first to observe the condition in Germany, 18 Fig. 8. — Radiograph of the Hand of a Gouty Patif.nt. At the point marked by the asterisk, gouty tophi are seen as translucent foci; at the dagger, exostoses similar to Heb- erden's nodes; at the double dagger, subluxation in the basal joint of the little finger. CLINICAL SYMPTOMS 255 and after a critical analysis he came to the conclusion that coincidence can be wholly excluded, since in liis and other cases the affections show simul- taneous exacerbations and improvement. Here, also, the relation existing between chronic; arthritis and gout must be considered. This much is certain: 1. That after gout has existed for a long time in a joint, proliferation of the cartilage, exostoses and disappear- ance of the capsules are found; 2. That atypical gout may give rise to poly- articular swelling, resembling the exudative form of arthritis ; 3. That in gouty families, individuals may present symptoms resembling chronic arthritis. But if we do not wish to lose ourselves in a realm of unfruitful speculation, we must adhere to the belief that gout is an affection characterized by a deposit of uric acid salts in the body and by the presence of uric acid in the blood. The latter point will decide the differential diagnosis of doubtful cases, in which we should place our dependence not upon the uncertain thread test of Garrod, but upon the more difficult chemical analysis. We may, therefore, look upon gout as one of the causes of chronic arthritic changes, while recognizing that the two diseases are by no means identical. The constitutional predisposition appears to be of especial importance in one form of chronic arthritis, namely, that marked by Heberden's nodes. Thejr are found isolated, especially in the aged, and then are frequently hered- itary; very often they are associated with asthma, migraine, neuralgia, sciatica and muscular rheumatism and particularly with gout. Bouchard was the first to describe nodosities of the middle joints of the fingers due to swelling of the second phalanx and occurring in cases of gastric dilatation; he gave them the name of " comptodactylie" and showed that this swelling disappeared with improvement in the gastric affection. Pribram also observed one case of this malady. I do not believe that it will be possible hereafter to deny the existence of a constitutional arthritis; but it is not necessary to adopt the scheme of the French, who look upon every non-infectious arthritis as an expression of an " herpetisme or arthritisme." In the future accurate weighing of all the circumstances will show whether definite anatomical lesions exist or an arthritis runs a particular course in persons with a predisposition of the type described by the French. The infectious theory of arthritis has many more supporters than has dyscrasia. The febrile form which comes in paroxysms with a relatively frequent endocarditis and severe general disturbances gives strong support to this view, and on several occasions microorganisms have been cultivated (by M. Schiiller, Bannatyne, Blaxall and Wohlmann) from the contents of the joint and their pathogenicity has been proven by animal experiment. Un- fortunately, the microorganisms described are not all the same, and so careful an investigator as Pribram found it impossible to detect any of them in the cases he examined. The pathogenic agent, therefore, as in the case of articular rheumatism, is not yet determined and the infectious nature of the disease is only a hypothesis, although a very probable one. As a third possibility, disease of the central nervous system has been con- sidered. This is suggested by the symmetry of the affection, the atrophy and 256 CHRONIC ARTICULAR RHEUMATISM contractures of the muscles, the trophic cutaneous disturbances, and the simi- larity of the chronic rheumatic joint changes to unmistakable nervous arthrop- athies occurring in tabes, syringomyelia, progressive muscular atrophy, hemi- plegia, progressive paralysis and also in peripheral neuritis. In the latter disease rarefaction of the bony substance with swelling of the distal ends of the extremities and the formation of club finger tips is observed (pulmonary osteoarthropathy of P. Marie, see the compilation of W. Berent). In diseases of the central nervous system disfiguring deformities appear with atrophy and proliferation of the bones and cartilage, and these show a great resemblance to senile monoarthritis, differing, however, by their more rapid course, absence of pain, fissures in the capsule, and extra-capsular, osseous and cartilaginous proliferations. To explain the muscular atrophy the assumption of a primary nervous affection is quite unnecessary, since Charrier has shown that this atrophy accompanies all joint inflammations, especially when they run their course with effusion (Kremer). Hoffa proved that they do not occur when the centrifugal nerves are severed; they are, therefore, trophoneuroses which are produced by reflex action initiated by the diseased joint surfaces. As anatomical investigation of the spinal cord has given positive results only in rare, exceptional cases (E. Wichmann) the neurotic explanation seems scarcely probable. Under certain circumstances, some forms of arthritis might be looked upon as infectious trophoneuroses, following Teissier and Eoque. It is, however, quite unlikely that the various forms of chronic articular rheumatism are due to any single cause. In the first place, we may exclude monoarthritis deformans, which is so closely allied to other senile changes (Weichselbaum) and which is so frequently produced by trauma. But it is also unlikely that there is any one cause for all cases of chronic polyarthritis, if we bear in mind the forms which are similar in all these symptoms, and yet are produced by various well known and quite distinct infectious diseases. Gerhardt in 1896 originated the term acute rheumatoid or pseudo-articular rheumatism, and defined it as follows : " Pseudo-articular rheumatism is that form of disease in which it may be proven, or where it is very likely, from its external appearance, that it is produced by the special pathogenic organ- isms of a definite infectious disease; the remaining cases are included under true articular rheumatism." These pseudo-rheumatisms have in common that they occur only in a minority of the individuals who are attacked by the infection in question and that the same organism which produces the infectious disease also produces joint pain, arthritic swelling or suppuration of the joint. In this sense we may speak of chronic rheumatoid ("pseudo-rheumatism" of Pribram) as an arthritis in which the exciting cause is one of the acute exanthemata, influenza, or pneumococcus infection, particularly gonorrhea, syphilis and tuberculosis. Gonorrhea is a clear example of the fact that the same microorganism, according to its virulence and the individual constitu- tion of the affected person, may cause any grade of the disease from a transi- tory arthritic pain and serous effusion to an incurable, chronic deforming arthritis and spondylitis. I should like to call particular attention to rheu- matic tuberculoid or tuberculous rheumatoid, a condition which lately has been TREATMENT 257 frequently described (Poncet, Maillard, II. Strauss, Barjon, Eoma, Total). The usual course of such cases is this: the disease begins as a subchronic or chronic articular rheumatism which finally becomes localized to one or more joints, and there develops typical tuberculous changes. This course resembles osteomyelitis, of which we observed a case in the clinic at Basel in an indi- vidual aged seventeen, in whom, after a fever lasting several months, accom- panied with wandering multiple joint swellings, muscular contractures, and exostoses, the epiphyses became loosened from the neck of the left femur, thus confirming the diagnosis. True chronic polyarthritis may owe its origin to various infections, or to constitutional causes of the type suggested by Lancereaux and Bouchard. Perhaps in some cases nervous disturbances may play a role. These cases cannot be diagnosed by rules, no matter how skilful the reasoning processes, but only by following the advice given by Archibald Garrod, to inquire into the family history of each individual case, its nervous disturbances, etc., and by carefully investigating the bacteria present. Perhaps in this manner a rational differentiation of the varying forms, which to-day is impossible, may in time be attained. TREATMENT As in all chronic diseases for which we have no specific, the number of remedies is legion. But, in giving a synopsis, I shall divide them into groups. First, internal remedies. I take for granted the knowledge that the anti- rheumatics, the salicylates, antipyrin and allied remedies often diminish pain, but never have the specific action which is the case in acute articular rheuma- tism. The salts of iodin are very useful, not only in gonorrheic and syphilitic rheumatoid, but also in the exudative polyarthritic form. Tonics are advised by the best authorities, and since experience has shown that in these affections the local difficulties are closely related to the general health of the patient, cod liver oil, iron, arsenic, quinin and strychnin preparations are of decided benefit in anemic, feeble, emaciated individuals, especially after febrile parox- ysms or after active treatment. The salts of lithia, and mineral waters containing lithia, have been advised on account of their action in gout, but there is no rational indication here for their use. In fact, in a disease in which excessively chronic and decided yet spontaneous changes occur, the value of any curative agent is always very uncertain. Menzer's successful trials of streptococcus serum, which were based upon the theory of an infectious etiology, are interesting but by no means con- clusive. The principal role in therapy is played by external physical remedies. Water must be mentioned first. That energetic applications of cold water are harmful in the first stages of inflammation is a common experience. Only after acute exacerbations have run their course, and after long continued sweating procedures, may cold douches, needle baths, and affusions be made use of by an experienced and careful hand, and then serve a useful purpose as a hardening process. 258 CHRONIC ARTICULAR RHEUMATISM Warm water in all forms is frequently employed, from the Priessnitz pack to a hot bath. The latter are used particularly in the form of natural springs, which are of ancient repute. Their effect is to be ascribed more to the tem- perature of the water and the duration of the bath than to the chemical constituents of the water (hydrogen sulphid, alkaline sulphates, calcium, gyp- sum, sodium chlorid, etc.). In rheumatism, the unaccountable experience is, that natural mineral waters may bring about improvement after the effect of hot water baths in the home has been exhausted. This effect is chiefly due to the cutaneous irritation of mineral waters rich in carbonic acid, such as those of Nauheim and Oeynhausen, or of mud baths combined with the thermic effect of the water. To these must be added the effect of applications of peat- soil, fango, natural sulphur, etc., and heat applied in various ways, sweat procedures, hot air and steam douches (the latter often producing a relaxa- tion of muscle contractures and stiffness), sand baths, local and general hot air baths and, finally, local inflammatory applications ; painting with tincture of iodin or ichthyol, compresses with iodin — potassium iodid salve (1 : 10 : 100), vesication, etc. All these applications have in common a tendency to produce hyperemia, and August Bier has contributed other original therapeutic methods. The irritating or anodyne effect of derivatives and counterirritants has always been explained on the hypothesis that the blood is drawn from the distant diseased parts to the surface. Bier has shown that this is incorrect; that, on the contrary, the deeper parts partake in the hyperemia, and that this produces the anodyne and absorbent effect. Bier stimulates this action still further by hot air and stasis. The former produces an intense, highly active, i. e., arterial, hyperemia, which is greater the higher the temperature of the agent. A simple apparatus, a wooden box with two openings to permit the en- trance and the exit of the hot air, and bandages on which to rest the affected member are sufficient for the purpose; the hot air is produced by a Quincke sweat tube, or a phenix a air cliaud, the tube being introduced into the open- ing of the box. Similar apparatus has been employed by Tallermann, and Lindemann has used electric heat; the effect of the electric light baths now in vogue, in which the electric bulbs radiate not only light but heat, is the same. For institutions these are very serviceable, as they are not dangerous and are easy to regulate. Bier's apparatus, however, has the enormous advan- tage that it may be constructed by a carpenter, at very slight cost, in the house of the patient, and be employed at the bedside. The effect of this remedy is excellent, as I am able to testify. The value of passive hyperemia attracted the attention of Bier on account of the rarity with which tuberculosis of the lungs is found associated with valvular disease of the heart. He attempted artificial blood stasis in tubercu- losis of the joints, and was so gratified with the success attained that he employed this method also in other joint diseases. Above the diseased area an elastic (rubber) bandage is applied so tightly that the extremity becomes edematous. However, the pressure must not be so great as to compress the arteries; the member must be warm, and the stasis must not produce the slightest pain. LITERATURE 259 The compression may be continued for a long time. I have carried on this treatment for several months at a time. Bier has lately, however, advised us to use the method for only one or two hours daily. The effect is at first to decrease the pain to such a degree that, for example, the tearing pains of gonorrheal arthritis soon cease, giving way to a feeling of well-being. The rule which Bier has expressly emphasized is this, that the stasis itself must never produce pain; as soon as this appears, the bandage must be loosened or removed. The further effect of stasis is to increase absorption. It is evident at once that joint effusion, edematous infiltrations of the capsule, and prolifera- tion of the joint villi are more amenable to some treatment than are ecchon- droses and osteophytes, that, therefore, the dry atrophic form of chronic arthritis is less susceptible to treatment than the hypertrophic proliferating forms with their spindle-shaped joints. Bier's hot air and stasis treatment, judged by the results, is by no means a panacea. The physician treating a case of chronic rheumatism must decide which symptoms most urgently call for relief. Fresh joint and capsule swellings require rest, the alleviation of pain, and the application of remedies which increase absorption, such as the salicylates, iodin, and heat. Older capsular contractures, in which immobility and fibrous ankylosis have occurred, require active and passive movements and the condition is often relieved by stasis. Muscular atrophy is benefited by faradic treatment and, above all, by massage. Contractures require applica- tions of heat, prolonged baths, hot air or steam douches, peat or fango poul- tices, and protection from cold. The earlier the treatment is begun, the better the result. Firm ankyloses and hyperostoses, particularly of the larger joints, require surgical and orthopedic treatment; practice with suitable apparatus may im- prove the gait, and prevent the bad consequences of too great weight upon the vertebral column. The operative treatment of mono- and polyarthritis, according to the few results reported by W. Muller and his pupil Elter, deserves further trial. LITERATURE A very complete compilation has recently been given by Pribram in Nothnagel's Handbuch, vii, 2. C. Adrian, "Ueber Arthropathia psoriatica." Grenzgebiete der Medicin, 1903, xi, p. 237. W. Anschutz, "Ueber die Versteifung der Wirbelgelenke." Grenzgebiete der Medicin, viii, p. 461. Bannatyne, Wohlmcnn and Blaxatt, Lancet, 25, April, 1896. Barjon, " Radiographic appliquee a l'etude des arthropathies deformantes," Paris, 1S97. Bechtereiv, "Steifigkeit der Wirbelsaule." Neurologisches Centralbl, 1893, und Zeitschr. f. Naturheilkunde, 1899, xv. Beer, "Rigiditat der Wirbelsaule." Wiener med. Blatter, 1897, Nr. 8 u. 9. 260 CHRONIC ARTICULAR RHEUMATISM W. Berent "Zur Aetiologie osteoarthropathischer Veranderungen." Berliner klin. Wochenschr., 1903, Nr. 4. A. Bier, "Hyperamie als Heilmittel," Leipzig, 1903; ferner 19. Congress fur innere Medicin in Berlin, 1901 ; Munchener med. Wochenschr., 1898 und 1901, Nr. 48. Bouchard, "Lecons sur les autointoxications," 1887. /. Braun, "Klinische und anatomische Beitrage zur Kenntnis der Spondylitis de- formans," Hannover, 1875. R. Cassirer, "Ueber myogene Wirbelsteifigkeit." Berliner klin. Wochenschr., 1902, Nr. 10 u. 11. Charrin, "Pr ogres Med." 1894. I. I. Clarke, "Note of a Painful Condition of the Twelfth Pair of Ribs." Clinical Soc. of London, October 11, 1902. H. Curschmann, "Berichte der med. Gesellschaft zu Leipzig." Schmidt's Jahrbucher, 1895. G. Davaine, " Etude comparee du rheum, art. aigu. et des poussees aigues du rheum. chronique." These, Paris, 1897. J. Elter, "Weitere Beitrage zur chirurgischen Behandlung der Arthritis deformans." Zeitschr. f. Chirurgie, 1903, 66, p. 387. Sir Alfred Garrod, "Natur und Behandlung der Gicht." German by Eisenmann. Wurzburg, 1861. Archibald Garrod, "Clinical and Pathological Relations of the Chronic Rheumatic Affections." Lancet, March 16, 1901. C. Gerhardt, "Ueber Rheumatoidkrankheiten." 14. Congress fiXr innere Medicin in Wiesbaden, 1896, p. 169. "Verhaltnis der Schuppenflechte zu Gelenkerkrankun- gen." Berliner klin. Wochenschr., 1894, Nr. 38. A. Hoffman, "Lehrbuch der Constitutionskrankheiten," Stuttgart, 1893. Herz, "Ueber das gleichzeitige Vorkommen von chronischen Haut- und Gelenker* krankungen." Wiener klin. Wochenschr., 1896, Nr. 26. Hoffa, " Zur Pathogenese der arthritischen Muskelatrophien." Volkmann's Sammlung klin. Vortrdge, 1892, N. F., Nr. 50. M. Kachel, " Untersuchungen liber Polyarthritis chronica adhsesiva." Ziegler's Beitrage, 1903, xxxiii, p. 327. O. Kremer, " Pathogenese der arthritischen Amyotrophien." Inaug.-Diss., Greifswaldj 1902. Lancereaux, "Atlas d'anatomie pathologique," Paris, 1871. "Traite de l'herpetisme, '' Paris, 1883; " Lecons de Clinique medicale," 1892, I. Landre-Beauvais, "Doit-on admettre une nouvelle espece de goutte sous le nom de goutte asthenique primitive?" These, Paris, an viii (1800). Lindemann, "Locale Behandlung von Gelenkrheumatismus, etc., mit elektrischen Heissluftapparaten." Therapeut. Monatshefte, Marz, 1900. L. Maillard, "Rheumatisme tuberculeux." Gazette hebdomad., 1900, No. 88. K. Manasse, "Zwei Falle von isolirter rheumat. Erkrankung der Kiefergelenke.'' Munchener med. Wochenschr., 1902, Nr. 20. Menzer, Deutsche med. Wochenschr., 1903, Nr. 67 und Zeitschr. f. klin. Medicin, 47, p. 109. J oh. Mutter, "Beobachtung liber reine Zwerchfell-Bauchathmung bei ankylosirender Wirbelgelenkentziindung." Verhandlungen der Wurzburger phys.-mcd. Gesell- schaft, 1901, p. 41. W. Mutter, " Zur Frage der operativen Behandlung der Arthritis deformans.," Archiv /. klin. Chirurgie, 47, 1894. LITERATURE 261 Pribram,, " Chronischer Gelenkrheumatismus und Osteoarthritis deformans." Noth- nagcl's Handbuch der spec. Pathologic und Therapie, vii, 2. E. Pfciffer, "Ueber Gichtfmger." Berliner klin. Wochenschr., 1891, Nr. 15. Potain, Semainc mcd., 20. Mai, 1891, p. 210. A. Poncet, " Rheumatisme tuberc. abarticulaire." Lyon mcd., 1902, No. 29; Gazette hebdomad., 1902, Nr. 58. Potal, "Rheum, artic. tub. chronique." Gazette hebdomad., 1902, No. 10. H. Rabinowitsch, "Beitrage zur Kenntnis des Gelenkrheumatismus mit Knotchen- bildung." Inaug.-Diss., Berlin, 1899. Roma, "Rheumat. tuberculeux." Gazette hebdomad., 1902, No. 93. Roese, "Ueber amyloidentartung bei chronischer Arthritis." Inaug.-Diss., Leipzig, 1S97. Schuchardt, "Krankheiten der Knochen mid Gelenke." Deutsche Chirurgie, 28. Lieferung. M. Schiiller, Berliner klin. Wochenschr., 1893, Nr. 36, 1900, Nr. 5 bis 7; 15. Congress fur innere Medicin, Berlin, 1S97. Schlesinger, "Chronische Steifigkeit der Wirbelsaule." Grenzgebiete der Medicin, 1900. Senator, "Krankheiten der Bewegungsorgane." Ziemssen's Handbuch der spec. Pathologic, xiii. Sudeck, "Acute (trophoneurotische) Knochenatrophie nach Entziindungen und Traumen der Extremitaten." Deutsche med. Wochenschr., 1902, Nr. 19. H. Strauss, "Acute Miliartuberculose unter dem Bild einer Polyarthritis." Charite- Annalen, xxiv. Tallermann und Mendelsohn, "Behandlung des chronischen Gelenkrheumatismus." Deutsche med. Wochenschr., 1898, Nr. 11. Teissier et Rogue, " Rheumatisme chronique." Traite de med. de Brouardel. Gilbert et Girode. Trousseau, "Clinique medicale." R. v. Volkmann, "Krankheiten der Gelenke.". "Pitha-Billroth'sche Chirurgie." Vidal, "Considerations sur le rheum, chron. primitiv." These, Paris, 1855. Weichselbaum, Virchow's Archiv, lv. Wohlmann, Brit. Med. Jour., November 11, 1900. PENTOSURIA . By F. BLUMENTHAL, Berlin Peior to the last few years all urine which gave a distinct and unquestion- able reduction test was considered to contain sugar, and permitted us to con- clude the presence of grape sugar; this view is no longer tenable. We know now that a variety of sugars are found in human urine all of which react to the recognized sugar tests (Trommer's, Nylander's, the phenylhydrazin test). Besides grape sugar we find milk sugar, which appears during the puerperal period in a woman who has an abundant secretion of milk yet does not nurse her child ; this, substance may persist in the urine for months post partum, in fact as long as the secretion of milk continues. Here the differential diag- nosis from grape sugar is accomplished very simply by the fermentation test ; milk sugar does not ferment with yeast, while grape sugar does. Eobinson and Lepine, and also Rosin and Laband, have lately described cases of levulo- suria which is characterized by its independence of the ingestion of carbo- hydrates, and this condition may be recognized by the decided levorotatory power developed during the fermentation test of the urine. Of less impor- tance is the occurrence of maltose, which occasionally appears in the urine in diseases of the pancreas, and the presence of which can scarcely be detected even by the most delicate chemical methods. Of more importance are the con- bined glycuronic acids and the pentoses. We refer here to the former substances because the combined glycuronic acids may be considered as pentose-carbonic acids, C5H10O5CO2. Combined glycuronic acids are found in the urine after the administration of numer- ous drugs, especially such as contain the aldehyd and ketone groups (Neu- bauer), and these may then be excreted in the urine in combination with gly- curonic acid. Among the best known of these drugs are: morphin, chloral, turpentine, menthol, antipyrin, etc. Glycuronic acid is also found in the urine combined with indoxyl and with phenol. As some of the combined glycuronic acids respond to the Trommer and Nylander tests, it may be of importance in such cases — particularly with doubtful tests — to search for the cause, and it is then not infrequently found that, at least in human urine, we are dealing with a very decided Lndieanuria. If Ibo patient who voids this reducing urine has taken any drug, the supposition is natural thai ii lias Keen excreted as glycuronic acid and lias thus caused the reduction. The urine coming from a case of pentosuria gives a distinct but somewhat delayed reaction with Trommer's test, and usually (as E. Salkowski first 262 PENTOSURIA 263 noted) the reduction with Trommer's test only takes place upon cooling, but then quite suddenly. The phenylhydrazin test is also positive with pentose; Nylander's test is not quite so distinct, and thus it happens that a person applying for life insurance is sometimes rejected on the ground that he is supposed to be a dia- 'betic. This happened in the case of a patient, aged thirty, who had been mar- ried for but a short time, and who, on account of his rejection for life insur- ance, was very unhappy. In great excitement he consulted a physician for a probable diabetes. Upon examination of the urine the physician at once be- came suspicious, for the urine was optically inactive in the polariscope and did not ferment with yeast. When the urine was examined more accurately (Prof. Salkowski) it was found that the sugar it contained was pentose. Here was a case in which the examination of a urine having reducing properties but optically inactive and non-fermentative led to the discovery of pentose ; the question may quite properly be asked, " How can such a diag- nosis be confirmed with certainty ? " A urine that contains pentose, and only such a one, gives the orci'n test. This is done in the following manner: 3 c.c. of urine are decomposed with about 6 c.c. of fuming hydrochloric acid; to this is added a few granules of orcin and the mixture is then heated to the boiling point. As soon as the mixture begins to boil, a bluish green color appears which is proof positive of pentose. Urine containing grape sugar or milk sugar does not give this reac- tion ; urine containing glycuronic acid gives the test only upon prolonged boil- ing, and then the precipitate is never greenish blue but more of a violet color. Before the orcin test was introduced into the chemistry of urine, the pli loroglucin test was used but it. was much less positive. According to E. Salkowski, this test may be carried out in the following manner: 3 c.c. of urine are decomposed with 3 c.c. of hydrochloric acid of a specific gravity of 1.019, to which a few granules of phloroglucin are added and the mixture is heated to the boiling point. Even after slight heating a cherry red color develops which gradually becomes more distinct, and finally (a point that is characteristic) turns greenish black. If amyl alcohol is then added, and the mixture shaken, the coloring matter is dissolved, and shows an absorption band between D and E, i. e., between yellow and green. Urines which contain large amounts of glycuronic acid show a brownish black color, but present the same absorption lines; urines which contain only traces of glycuronic acid show no absorption lines nor the characteristic colors indicative of pentose. I believe that the orcin test is more reliable than the phloroglucin test, as most of the glycuronic acids yield no reaction with the latter ; at least, not if the test is done in the manner I have indicated. In using the orcin test, one or two drops of liq. ferri sesquichlor. may be added, according to Bial ; this produces a beautiful blue color. Or BiaFs reagent may be used (acid, muriat. cone. 250.0; orcin 0.5; liq. ferri sesquichlor. 10 drops). Confusion with pentose, provided the urine is examined twenty-four hours after it has been voided, is only possible with two of the glycuronic acids at present known, 264 PENTOSURIA namely, with mentholglycuronic acid and turpentinglycuronic acid. Both of these glycuronic acids have the property of decomposing spontaneously, and as free glycuronic acid also reacts to the orcin test, they may be confounded. We are prevented from making this mistake, first, by the history, as mentholgly- curonic acid and turpentinglycuronic acid are only excreted after the inges- tion of menthol and turpentine ; secondly, by the odor of the urine ; menthol urine smells of peppermint, turpentine urine of violets. Therefore, in human urine, since the introduction of the orcin test, there can scarcely be any diffi- culty in the recognition of pentose. The circumstances are different in the urine of the herbivora. They frequently take up with their food a mass of pentosan, that is, the anhydrid of pentose. The pentosans have the same rela- tion to pentose that glycogen has to grape sugar. These pentosans are in part excreted as such and give the orcin test, as does pentose, for by heating with hydrochloric acid pentose is developed from pentosan. As the urine of the herbivora very frequently has reducing properties and therefore gives a more or less distinct orcin test, confusion with pentose is not impossible. In these cases the phenylhydrazin test must be employed ; if this is positive while the fermentation test is negative, pentose is present. If the fermentation test is positive, after fermentation has ceased the phenylhydrazin test must also be positive if pentose is present. After this slight digression, we return to the chemical analysis of the urine. If we have under consideration a urine that gives a positive reaction with Trommer's test, the phenylhydrazin test, the orcin and phloroglucin tests for pentose, if the urine is optically inactive and does not ferment, then the patient excreting such a urine has pentosuria. The question now arises, What does this condition indicate ? As it is certain that he is excreting sugar, i. e., pentose, there is unquestionably a disturbance in sugar metabolism. We are then confronted with another question, whether we are dealing with a variety of diabetes mellitus, a pentose diabetes, or something else. If we are dealing with a variety of diabetes mellitus, the combustion of carbohydrates must be diminished, as in the case of diabetes. Such a connection must be thought of, all the more so as Euff has produced pentose from derivatives of grape sugar by oxidation with potassium permanganate and hydrogen peroxid, and it is possible that the human organism may also carry on this process of oxidation. Further, as it is known that the pentose which occurs in nature and enters the body with the food, such as the 1-arabinose and 1-xylose, undergoes only partial combustion even in the healthy, it is not unnatural to explain pentosuria by conceiving that the patient, from the forms of sugar with six carbon atoms, forms pentose. This he incompletely oxidizes, and hence excretes a portion of it. If this view were correct, with the withdrawal of starch from the food pentosuria should disappear or at least lessen, and, on the other hand, with the profuse administration of starch or grape sugar the pentosuria should increase. But when we withdraw carbohydrates from patients who excrete pentose, it is always observed that the pentosuria continues, and apparently in the same degree as formerly, while the administration of even 100 grams of grape sugar after a strict diet free from sugar does not lead to a decided increase of the PENTOSURIA 265 pentosuria. From these results it is obvious that pentose in the animal organ- ism is not formed by the oxidation of hexose, i. e., the varieties of sugar with six atoms of carbon or their multiples. This to some extent also answers the question whether pentosuria is a variety of diabetes mellitus. The latter disease is characterized by the fact that the power to burn starches and hexoses is diminished. That this is not true of pentosuria, at least not of all cases of pentosuria, was shown by Bial and myself, for the administration at once of 100 grams of grape sugar caused no glycosuria. The combustion of d-galactose in our case of pentosuria was also entirely normal. It follows from this that the patient with pentosuria has no greater tendency to alimentary glycosuria than the healthy; hence if we look upon alimentary glycosuria as a proof of the existence of diabetes mellitus, the urine of the pentosuric is in this respect also entirely negative. There is good ground for the supposition that pentosuria is a pentose diabetes, in which metabolism for sugar with six atoms of carbon is normal, while the property of combustion for pentose is diminished or has entirely ceased. With food in the form of grain and fruit, and in beer and tea we ingest a. certain amount of pentosans; it is quite possible that pentosans are changed into pentose in the stomach by the action of hydrochloric acid; but the organism is incapable of oxidizing them and they are therefore excreted. This hypoth- esis is accepted by ISTaunyn and Liithje, and by others. Can this view be possible ? The pentose which we ingest with our food is the dextro-rotary 1-arabinose, while, as we know from the investigations of Carl jSTeuberg, inactive arabinose also occurs in the urine. Since inactive arabinose, as the researches of Emil Fischer have shown, can only occur by the combination of d-arabinose and 1-arabinose, the organism must, in addition to 1-arabinose, also furnish d-arabi- nose ; so that i-arabinose may be formed. The question whether the organism contains pentose groups has been dis- cussed for a long time. As is well known, Hammarsten found in the nucleo- proteid of the pancreas a reducing substance which he assumed to be pentose. E. Salkowski has produced phenylosazone, and, upon the basis of an analysis of the same, has determined with certainty that the reducing substance is pen- tose. On account of the abundant furfurol formation which is said to be char- acteristic of pentose, and which upon decomposition was shown to be present in the nucleo-proteids from various animal organs, and on account of the production of phenylosazones at the melting point of pentosazone, 157° to 160° C, I have maintained that all animal nucleins contain a pentose group, and that the pentose group is characteristic of nucleins just as is the group of xanthin bases, for I found no proteids which contain pentose except nucleins. I have also held that when an albumin body gives the phloroglucin test for pentose we are justified in declaring it to contain nuclein. This view at the time appeared to be decidedly opposed to the prevailing opinion. A. Kossel and Neumann had, two years previously, found no pentose group in nucleinic acid of the thymus gland. The former denied absolutely the presence of a carbohydrate group in the spermatic nucleinic acid. ISToll, the pupil of A. Kossel, forbore entering into this discussion. He believes that we must dis- 266 PENTOSURIA criminate sharply two reducing carbohydrates. One is loosely combined with the nucleins, and in the formation of nucleinic acid separates from nuclein; the second, a firmly combined atomic group with a molecule of nucleinic acid, causes the production of levulinic acid and formic acid, the latter of which does not form a reducing carbohydrate. In view of this, Kossel's adherents admitted the presence of a reducing carbohydrate in animal nuclein, but refrained from any expression regarding the nature of the reducing substance. Later, Friedrich Miiller questioned the opinion, then prevalent, that pentose was the sugar of the vegetable kingdom and did not occur in the animal king- dom. He believed there was often a confusion of pentose with glycuronic acid, a confusion which was by no means impossible on account of the test then in vogue. This diversity of views led Bergell and myself to make further researches in regard to pentosuria. From a urine supposed to contain pentose, he and I obtained a barium combination of the questionable sugar, the analysis of which showed we were, in fact, dealing with pentose. By this means, the presence of pentose in the urine of animals was further confirmed by Jastro- witz and Salkowski, and the production by Carl Neuberg of pure r-arabinose from so-called pentose urine furnished proof incontestable in every respect. Furthermore, Wohlgemuth, who at my suggestion examined the nucleo-proteid of the liver, produced from this a chemically pure phenylosazone which by analysis proved to be phenylpentosazone. The presence of pentose in animal organs was later confirmed by other competent observers. Thus Neumann, the former co-worker of Kossel, found that, with an improved technic, nucleinic acid obtained from the thymus gland gave a decided pentose reaction. The labors of Bang, Jacob, and Bergell, Friedenthal, Umber, Grund and others, proved the correctness of the theory first suggested by me that not only all vegetables but also all animal nucleo-proteids contained carbohydrates belong- ing to the pentose group. The question now arises, How was it possible that these groups were so long overlooked in the nucleins by prominent investigators, and that my earlier results were so long unconfirmed? This must be ascribed to the fact that in the nucleo-proteid of the thymus, as Umber and I determined in the pancreas proteid, the pentose group is very loosely combined. To obtain the nucleo- proteid of the thymus a solution of the same in an alkali and precipitation with acetic acid are sufficient to separate the greater portion of the pentose and to obtain a phosphorus-containing albumin body that no longer shows pentose but still contains some xanthin bases. And for the nucleo-proteid of the pan- creas Umber has shown that the pentose group is one of the first products of pepsin digestion which enters solution. This view might very readily coincide with that of Kossel's adherents who believe that the reducing carbohydrate is very loosely attached to the nucleo-proteid, for on the solution of thymus- nuclein in alkali a phosphorus-containing albumin body which still contains xanthin bases, i. e., a nuclein, is retained. I believe, therefore, that such a body free from pentose should, at most, be designated an atypical nuclein. That the pentose group is but loosely combined with the nucleins is cer- tainly not true of the pancreas nuclein, for Bang has obtained pentose from its nucleinic acid. PENTOSURIA 267 According to recent investigations of Neumann, pentose is present in the nucleinic acid of the thymus ; hence it follows that the pentose group is an integral constituent of at least some of the nucleinic acids, if not of all. Of the pentoses which occur in animal nucleins, that of the pancreas has been most minutely investigated. Bang supposed it to be dextro-rotary, and Neuberg has lately arrived at the surprising conclusion that the pancreatic pentose is 1-xylose. This latter theory is of great importance as bearing on the origin of pentose in chronic pentosuria. For, if on other grounds we were inclined to believe that the pentose of urine originates from the pancreatic nuclein such an opinion would by this result be proven to he erroneous. It is impossible to understand how xylose could be changed into arabinose. It is true that we have only proven for pancreatic nuclein that its pentose is 1-xylose ; the other nucleins have not been investigated in this respect. The researches in metabolism by Bial and myself have also made it appear unlikely that pentoses are formed in the pentosuric patient by an imperfect nuclein decomposition, since the metabolism of the ,pentosuric shows no such increased destruction of nucleins. Neither the excretion of uric acid nor the excretion of phosphoric acid is increased in pentosuria. It also appears to be impossible that the inactive arabinose in pentosuria originates from other nucleins, and not alone from the pancreas nucleins, and we must search else- where for an explanation of the origin of pentose. Carl Neuberg has given us important and interesting conclusions in this field. He demonstrated that the 1-xylose which is found in pancreatic nuclein originates from grape sugar; now we have assumed for a long time that glu- cose is partly oxidized from glycuronic acid. If we consider glycuronic acid as pentose carbonic acid, C5H10Or,C02, it need only give off its carbo-xylose group to produce dextro-rotary 1-xylose. This the organism requires for the construction of nucleins. On tlie other hand, in his opinion, the r-arabinose, the urinary sugar of pentosuria, originates in a very different manner. As is well known, milk sugar is split up in the intestine into dextrose and galactose; a portion of the galactose is certainly utilized for glycogen pro- duction. Another portion enters into cerebrin, for Thierfelcler was able to demonstrate the presence in cerebrin of galactose. The galactose contained in cerebrin, however, is dextro-rotary, like the galactose contained in food. But it is very easy to change this d-galactose to its inactive form, and then from the inactive galactose inactive arabinose may readily be produced by oxidation. Carl Neuberg is therefore of the opinion that inactive arabinose originates from derivatives of galactose. How far this view is correct is still uncertain, for the behavior of i-galactose must be tested in the organism of a pentosuric patient. The behavior of the ordinary d-galactose has been stud- ied by Bial and myself, but we were unable to determine an increase of pentose excretion. It is evident from these considerations regarding pentosuria that prior to its discovery by E. Salkowski we had but slight understanding of the sugar metabolism of the human organism, and that in pentosuria we are dealing with an anomaly of sugar metabolism which must be assumed to be an independent one. It has nothing in common with diabetes, and is also not to be regarded 268 PENTOSURIA as a pentose diabetes, for the property of combustion of the pentoses of the food is nowise altered. The same conditions are present here as in levulosuria, which Eosin and Laband have lately determined represents an anomaly in the production of levulose, not, however, dependent upon a disturbance of its combustion. I do not believe it can be doubted that in true diabetes we shall ultimately reach the point of separating a group of cases in which the forma- tion of grape sugar in the organism is disturbed; while there is no anomaly of combustion. I mean the eases with slight excretion of sugar ( 1 per cent, or less) and this almost entirely independent of the carbohydrate constituents of the food. Perhaps, also, in many severe cases such a disturbance in the syn- thesis of sugar may be found. Pentosuria is therefore an independent disturbance of metabolism, which is characterized by the fact that in this condition an inactive sugar has been found in nature for the first time. Thereby the law that the animal organism and plants can produce only active varieties of sugar has been proven erroneous. A second law, which for a long time was considered incontestable, namely, that the pentoses are the sugar of the vegetable king- dom only, and do not occur at all in the animal kingdom, has also been nullified. We must separate true chronic pentosuria from alimentary pentosuria. A large number of individuals do not possess the property of oxidizing large amounts of pentosan introduced with the food, but excrete a portion of these pentosans as pentose. This is alimentary pentosuria. The amount of pentose excreted is about 0.2 to 0.5 per cent. This pentose always arises from the pentosans which are taken up with the food, for the most part in the dextro- rotary 1-arabinose contained in fruits. This phenomenon we generally see in 'the summer when fruit is freely eaten (cherries, strawberries, whortleber- ries, plums). This alimentary pentosuria has nothing in common with chronic pento- suria, in which arabinose also occurs ; here not the dextro-rotary but the inac- tive appears in the urine. We now find, however, that besides chronic pen- tosuria the alimentary type may also exist, and I am in possession of records of cases in which both the inactive arabinose and the dextro-rotary appear in the urine. The proof of this has been deduced as follows : first, the urine without fermenting was dextro-rotary; secondly, only pentosazone could be produced from it ; and thirdly, according to Neuberg, a solution of the osazone in pyridin alcohol proved dextro-rotary. True chronic pentosuria, as we have seen, is characterized by the fact that, independently of food, inactive arabinose is excreted continuously. The amount of inactive arabinose varies in this condition between 0.3 and 1 per cent, by Knapp's method of titration. We find, however, cases also of chronic diabetes that are complicated by pentosuria, i. e., showing a slight excretion of pentose. To this group belong a number of diabetics in whose urine very small amounts of pentose have been demonstrated, as shown by Kiilz and Vogel. In these cases the pentose has not the sligbtest clinical importance so far as can be determined at this time. It occurs in such minute traces that its presence cannot be detected by our PENTOSURIA 269 common tests, and the utilization of several liters of urine is necessary to find the substance at all. We have no knowledge as to which pentose appears in the urine in diabetes (whether pentose of the food, or inactive arabinose, or pancreas pentose, i. e., 1-xylose), nor do we know whether it is particularly in the severe cases of diabetes that pentose is excreted. To quite a different group belong those cases of pentosuria in which, besides pentose, glycose appears transitorily in the urine. In this instance the gly- cosuria may have an accidental cause (morphin), as in the case of Jastrowitz and Salkowski which led to the discovery of pentosuria. We may, however, encounter the combination of true pentosuria with mild diabetes. I have seen such a case. The quantity of grape sugar amounted to 0.6 to 1 per cent., the amount of pentose was 0.3 to 0.5 per cent. As the urine was sent to me for investigation only a few times, I can say nothing further about the course of the case. Only this much could be determined, that the pentose found in the urine was inactive, therefore probably an inactive arabinose. The second group of chronic cases of pentosuria includes the pure cases, in which no other sugar than pentose is found. Up to this time the following cases are reported in literature : first, the case of Jastrowitz and E. Salkowski in which the glycosuria disappeared after morphin was stopped, while the pentosuria proved chronic ; secondly, the two cases described by Salkowski and myself. The first of these occurred in a merchant, thirty-six years of age, and always healthy, who was married and had four living children. The amount of pentose he excreted varied between 0.7 and 1 per cent., with an average amount of urine of a liter to a liter and a half per day. This case occurred in 1895 in the practice of Dr. L. Feilchenfeld who still has the patient under observation. Up to this time the pentosuria has never been associated with any serious symptoms. The patient repeatedly suffered from hydrocele, and the fluid obtained by puncture was examined by me and found to contain grape sugar but no pentose. The urine has also been utilized by C. Neuberg for the preparation of r-arabinose. The patient was decidedly thin. The third ease occurred in a banker, aged sixty-five. This patient (ac- cording to the report of Dr. Blumenthal, who treated him for over twenty years before the pentosuria was discovered) is said to have repeatedly had reducing substances in his urine, but grape sugar was never found until 1895, when the pentosuria was discovered. This case is especially interesting as, in the family of the patient, numerous chronic diseases occur, particularly diabetes and nervous diseases. Up to two years before death (which occurred in 1900) the urine in this case constantly showed about one per cent, of pentose. For some time before death he was treated by another physician; his death was due to arteriosclerosis. The autopsy showed calcification of the coronary arteries; the pathologist told me that nothing of special interest was found in the pancreas, but unfortunately he had not been informed of the existence of pentosuria. The fourth and fifth cases were published by Dr. Bial. The fourth was that of a merchant from Warsaw, aged thirty-seven, who suffered from mild 19 270 PENTOSURIA gastric and intestinal symptoms and supposed himself to be a diabetic. Small amounts of sugar had been frequently found in his urine, and a suitable diet had been advised. The report from a Warsaw chemical laboratory shows slight quantities of sugar found by Trommer's test and a positive reaction to phenylhydrazin. This patient was also conspicuously thin. Bial determined that pentose was present in the urine in July, 1898, as well as constantly for twenty days in July, 1899, but no grape sugar could be found. Case V (Bial). A druggist, twenty-eight years old, perfectly well. The amount of pentose in Case IV amounted to 0.3 per cent., in Case V, 0.35 per cent. Case VI. Eeported by Dr. Fritz Meyer. A merchant, aged thirty-nine, never previously ill, was rejected by a life insurance company six years ago, and before the discovery of pentosuria, on account of diabetes. He was treated in Carlsbad, was on a strict diet, and was declared to be cured as the examina- tion of his urine by the polariscope showed optical inactivity. Five years ago he married, and is now the father of a healthy child. His health, with the exception of a mild attack of perityphlitis, has always been good. In April, 1900, symptoms appeared which gave rise to the suspicion of a constitutional disease; his weight is said to have decreased decidedly; it amounted to 150 pounds. He complained of headache, lumbar pains, lassitude, vertigo, and severe neuralgia, particularly in the region of the sciatics. The urine amounted to 1,800 c.c. ; it was clear, contained no formed elements, and was without albumin. The urine reacted positively to Trommer's and Moore's tests ; being optically inactive it was examined for pentose, and pentosuria was determined. In the seventh case, the patient was an American lady, who had been several times under treatment in Carlsbad on account of supposed diabetes. Her case was always considered to be a severe one, for, in spite of the strictest diet, it was never possible to render the urine aglycosuric. In this case quite a decided amount of pentose was found, over 1 per cent., but not the slightest trace of grape sugar. The eighth case (Dr. Brat) occurred in a lady, aged sixty-two, who for several years was under professional treatment on account of a presumably mild diabetes. She had a slight degree of fatty heart, otherwise, however, she was quite well. This lady has been under my observation for more than a year, and in this entire time has never excreted grape sugar. In her case, however, the urine was somewhat dextro-rotary, 0.2 per cent., and I believe it therefore not unlikely that, besides inactive pentose, a dextro-rotary pentose was present in slight degree. Case IX. The brother of the patient just described (Case VIII), aged about fifty, perfectly well. His urine showed about 75 per cent, of pentose. According to analyses made by several chemists since 1892, 0.2 to 2 per cent, of sugar was determined. One found only a reducing property in the urine but no sugar. There is no question in my mind that the gentleman was not dia- betic, for a breakfast containing large amounts of sugar gave no results. The case is otherwise of no clinical interest ; the other brothers and sisters present neither diabetes nor pentosuria. PENTOSURIA 271 Additional cases of pentosuria have been described by Colombini in mor- phin habitues; by Caporelli in xanthoma, others by Reale and Romnie, and a case of alimentary pentosuria with glycosuria by Barszewsky. It is not remarkable that so many cases of pentosuria have been confounded with diabetes, for the qualitative tests are the same. The important ques- tion is, and remains : Has pentosuria anything in common with diabetes ? Have pentosurics on account of their pentosuria a special liability to become diabet- ics? On account of what has been above stated these questions must be answered negatively. Pentosuria is a disturbance of metabolism which is connected perhaps with cerebrin metabolism, perhaps with the formation of galactose. Negatively the principal point is that there is no evidence of insufficiency in the utilization of the carbohydrates consumed with the food. Another question now arises : What is the prognosis of pentosuria ? It is unwise to express a dogmatic opinion on this point since we have known the disease for only a decade. Notwithstanding this, it may be said that the prognosis is probably much more favorable than in mild diabetes, for the pen- tosuric utilizes fully the starches and other carbohydrates which are adminis- tered with the food, and the amount of pentose which he forms and excretes is small, at most from 15 to 20 grams per day. This, therefore, represents no more serious prognosis than the mildest cases of diabetes. Upon the other hand it must not be forgotten that sugar is circulating in the blood. That this is true is obvious from the. investigations conducted by Bial and myself, as we have proven the presence of arabinose in the blood. But the presence of a large quantity of sugar in the blood leads to arteriosclerosis, and may give rise to other changes. Whether the pentosuric is more susceptible to infections than a healthy person, as is the case with diabetics, is very difficult to say, for up to the pres- ent time the data are very scanty. Upon the whole, and in the majority of cases, the prognosis of pentosuria can certainly not be termed very serious. Eegarding therapy, such treatment as we employ in diabetes is out of place in pentosuria, as is obvious from all that has been stated. In general only this much is to be said: (1) A pure meat diet, according to the experience of Fritz Meyer and myself, is not well borne by pentosurics, for neuralgic symptoms, if present, are increased. (2) A milk diet is found to be particu- larly advantageous. In conclusion, a word regarding the frequency of the disease. Although it may be assumed from the, as yet, scant publications that pentosuria is a rare affection, I cannot admit that it is to be regarded as a curiosity like maltosuria. Such a comparison is incorrect, for pentosuria, in the first place, gives us a very interesting insight into disturbances of metabolism; and sec- ondly, it cannot be considered immaterial that a person, as in almost all of the cases that have been cited here, should be supposed for years to be a diabetic, and subjected to dietetic and mineral spring treatment which is absolutely out of place. In life insurance the decision is of the greatest importance. The pentosurics must at least be admitted to have as favorable a prognosis as the mild cases of diabetes. 272 PENTOSURIA If it be further remembered that nine cases have been detected in Sal- kowski's laboratory and in the First Medical Clinic of Berlin, the affection cannot be so rare as many believe. Hence a knowledge of this disturbance and of the means to its diagnosis is an absolute necessity for every physician. Briefly the most important diagnostic factors are as follows : Positive orcin test with negative fermentation test proves pure pentosuria; positive* orcin test and positive fermentation test denote pentosuria and glycosuria. A turning to the right of the polariscope does not prove the non-existence of pentosuria, for dextro-rotary pentose also occurs in the urine. DISEASES OF THE BLOOD BLOOD AND BLOOD EXAMINATION By A. LAZARUS, Charlottenburg (Berlin) The examination of the blood, in comparison with other clinical investi- gations, has very slowly forced its way into practice. While the conscientious physician rarely fails to make an examination of the urine or of the sputum in cases in which it seems necessary or at all useful, examinations of the blood, even the simplest, have up to the present been resorted to by a very small number of practitioners. The object of this article is to call attention to the necessity of clinical blood investigation, and to describe the simplest methods. It will then become a matter of routine to examine the blood no less frequently than the various other secretions, excretions, or inflammatory products. Of course, the importance of the results of blood investigation in different diseases of the blood is not always equally great. In the cases in which a dis- ease of the blood or of the blood-producing organs comes into question, an examination of the blood is more important than any other clinical research, and often this alone will guide us to a definite opinion. This is true of the various forms of anemia, of leukocytosis and leukemia, of many diseases of the bone-marrow, and in certain parasitic diseases of the blood. [There can hardly be said to be " many diseases of the bone-marrow " recognized to-day, and the blood has never yet helped much to advance our knowledge in this direction. Parasitic diseases of the intestine and other internal organs should be men- tioned here among those in which blood examination is of great diagnostic value. — Ed.] The number of cases is, however, disproportionately greater in which an examination of the blood, although actively complementing other methods, is alone not decisive. It may be of value in the differential diagnosis between various acute infectious diseases ; it may make clear the nature of many cases of poisoning; in the prognosis of many bacterial diseases we may under some circumstances find points of support in the condition of the blood ; the prophy- laxis and therapy of malaria, according to Eobert Koch's investigations, can only be made certain by regular examinations of the blood, and to these many other examples might be added [e. g., trichiniasis, filariasis, uncinariasis, trypanosomiasis. — Ed.] . That the history under some circumstances may become enriched by an examination of the blood is obvious if we remember that after recovery from 275 276 BLOOD AND BLOOD EXAMINATION certain infectious diseases protective bodies may be demonstrated in the blood serum. After these brief indications it will be seen that we have quite a large field of activity, even if we limit ourselves to such an investigation of the blood as is of immediate clinical importance. It is impossible, however, to omit a brief explanation of the normal physiology and anatomy of the blood, as this enables us to measure the degree of pathological change liable to occur. We must first decide upon the best method of obtaining the amount of blood necessary for investigation. Of course for clinical purposes only those methods of examination are valuable which need no more than one or two c.c, or — if there be a necessity for frequent repetition — a few drops of blood. Consequently, many clinical methods, compared with strict physiological processes, suffer more or less in reliability. This fact has lately given rise to an endeavor to modify certain physiological methods which hitherto have necessitated large quantities of blood. The results have, in the main, been rather unsatisfactory. This is true, for example, of the " clinical " estima- tion of the alkalinity of the blood, and of the iron and phosphorus in the blood. If large quantities of blood cannot be obtained, it is better to refrain entirely from such estimations than, by an appearance of exactness, to produce figures of questionable value. Fortunately, however, for many important clinical investigations, only a few drops of blood are necessary, and these are best obtained under aseptic precautions by a simple prick of the finger, of the toe, or of the lobe of the ear. [In America the finger is rarely used, as the pain of puncture is much greater than in the ear. An ordinary glover's needle (bayonet-pointed) is convenient, cheap and efficient. A sewing needle can be used but does not answer nearly as well. — Ed.] By friction or by active muscular movement these portions of the body may previously be made somewhat hyperemic. In general the choice of the place is immaterial; for smear preparations the finger is preferred. In very sensitive patients, provided the investigation is to be repeated fre- quently, the ear is chosen. The prick is made with half of a steel pen or with a Soennecken's lancet ; but we may also use the so-called " pistol knife " in which the needle-shaped knife may be adjusted, and, by pressure of the spring, inserted to an exact depth. If larger quantities of blood, i. e., a few cubic centimeters or more, are necessary it is advisable, provided there is no contra-indication, to obtain the material by wet cups; in which proceeding it must of course be remembered that blood thus obtained is more or less admixed with lymph. Finally punc- ture of a dilated vein of the arm by the aid of a Pravaz syringe, which is very readily performed, or an ordinary venesection may be resorted to. The withdrawal of blood, if performed aseptically, is entirely without dan- ger and, as a rule, does not disturb the patient in the least. We should never forget, before proceeding, to assure ourselves that we are not dealing with a hemophilic. In such persons, even with a simple puncture of the finger, there may be great difficulty in stopping the flow of blood. [In such cases a mere touch of the needle point to the skin will give us all the blood needed without producing any troublesome hemorrhage. — Ed.] HEMOGLOBIN 277 I. HEMOGLOBIN The exuding drop of blood shows even to the naked eye a number of prop- erties. The redder it is, the richer it is in oxyhemoglobin; the darker, the greater the amount of reduced hemoglobin. Accordingly, it is at once recog- nized from these properties whether the blood originates from the arterial and capillary vessels or from the venous system. In carbonic acid poisoning the color of the blood is particularly bright and, as a rule, is designated as cherry-red. In the red oxygen-containing blood differences in the intensity of the color- ing are readily determined, but these are frequently not easy of recognition in very dark venous blood. Such differences become more noticeable if the drop of blood is caught and spread out upon white linen or upon white blot- ting paper; the greater or lesser staining power of different drops of blood is very well demonstrated in this simple manner, and, with some practice, from the color of the stain a conclusion may be drawn as to the amount of' hemo- globin in the blood. Following this principle, Tallqvist has described a " hemoglobin scale " by the aid of which gross differences in the amount of hemoglobin may be quite accurately estimated. [The Tallqvist scale gives us not ideal accuracy but all the accuracy that we can use in diagnosis, prognosis and treatment. Its errors rarely exceed 10 per cent., and in the hands of the unskilled other and more " accurate " instruments often show more errors than this. The cheapness of the scale and the ease and quickness of using it are also important recommendations. — Ed.] Accuracy is greater with apparatus especially constructed for the estima- tion of the coloring power of the blood, the so-called hemoglobinometer. This apparatus is quite properly named ; for, in the main, it is the amount of hemo- globin contained which determines the coloring property of the blood; the importance of a few other coloring substances contained in the blood is in comparison quite insignificant. For clinical purposes a large number of blood colorimeters have been de- scribed; on account of their simplicity Gowers's hemoglobinometer and FleischPs hemometer are most used, and will now be described (Dare and Oliver). The principle of the Fleischl hemometer, as modified by Miescher, is the following : By the aid of a pipette which is furnished with the apparatus (Fig. 9 Mel.) an exactly determined amount of blood is dissolved in a measured quan- tity of distilled water; the color of this solution is compared with that of a colored glass wedge which, by its gradually increasing thickness, represents a scale of blood concentrations. The point in the wedge is now searched for which is just as intensely colored as the solution of blood that is to be exam- ined, and the number is read off which is found at this point of the glass wedge. If, for example, the color of the blood solution is equal to that desig- nated as 75 in the glass wedge, it means that the examined blood contains 15 per cent, of the normal amount of hemoglobin. Besides the estimation of the percentage of hemoglobin, this apparatus also makes it possible to 278 BLOOD AND BLOOD EXAMINATION reckon the absolute amount of hemoglobin in milligrams in 1 c.mm. of blood. [It is essential to remember that percentage readings are very misleading when applied to children, since their normal is about 75 per cent, of the normal of adult men. Women's blood contains 10-15 per cent, less coloring matter than men's. All hemoglobin instruments should be graduated in milligrams per c.mm. of blood instead of in percentages of a supposed " normal." — Ed.] The investigation is rather laborious because it can only be carried out with arti- ficial illumination. The apparatus is quite expensive on account of the diffi- culty in manufacturing the glass wedge. Its use, however, is valuable, for an investigator in constant practice is able to reduce the errors to 5 per cent, and less. The little apparatus of Growers works on the following principle: A tube contains a standard color solution which possesses the tint of a diluted watery Fig. 9. — Hemometeb. (After v. Fleischl-Miescher.) hemoglobin solution. In a graduated glass tube of the same size a small but accurately determined amount of blood is diluted with water until it is the same color as the color in the test-tube; naturally this occurs the sooner the thinner the blood is at the beginning. If, for example, an equalization of color is reached at 60, this indicates that the blood only contains 60 per cent, of hemoglobin in comparison to normal blood. This test is quite simple and it may be completed in a few minutes during the office hour; the apparatus is very cheap. With a well made instrument the errors may be reduced to from 10 to 5 per cent. I must call attention to the fact that the manufacture of this apparatus is carried on by some quite unreliable manufacturers, so that, for example, test solutions are* furnished in HEMOGLOBIN 279 color tints such as thin watery blood solutions never show. Probably because of these poor instruments, there has been a partial opposition to the use of the Gowers apparatus. A short time ago Sahli made a change in the Gowers hemoglobinometer, which appears to have added greatly to the value of the apparatus. For this purpose the measured quan- tity of blood is first placed in a slightly diluted hydro- chloric acid solution which produces a dark brown so- lution of hydrochlorate of Fig. 10. — Hemometee. (After Sahli.) Fig. 11. — Hemometer. (After Sahli.) hematin. This mixture is then diluted with water until it corresponds ex- actly in color to a test solution which is furnished with the apparatus, which also consists of hydrochlorate of hematin in a definite dilution. From the amount of water necessary to produce this correspondence in color, we may estimate the amount of hemoglobin in the drop of blood that has been tested. In its mechanism the apparatus is much superior to the original, as may be seen in the two illustrations which are placed side by side (Figs. 10 and 11). Among other instruments (of which there is a great number, each investi- gator having his favorite one) I should like to mention one of the latest, the practical importance of which upon a large scale must still be proven, and the use of which is somewhat more difficult than of those previously depicted ; the principle, however, is interesting, and differs greatly from that of the colorime- tric ones that have been described ; for this reason it is necessary to compare its results with those obtained by the aid of other instruments. I refer to the hemopliotograph of Gaertner (see Figs. 12 and 13). Gaertner started from the observation that the permeability of a diluted watery blood solution for the photographic rays of sunlight was in inverse proportion to its hemoglobin con- tent. For this reason he spreads the blood solution to be examined in a layer of definite and uniform thickness, lays photographic paper under it, and per- 280 BLOOD AND BLOOD EXAMINATION mits the sunlight to penetrate this for a definite time. The degree of black- ening which the paper shows under the blood layer is compared with a stand- ard scale, and then the hemoglobin is read from a table which has been obtained empirically. In quite a series of investigations I have compared the results obtained with the apparatus of Growers and Gtaertner and have found reasonable uniformity. patent arige Fig. 12. — Hemophotograph. (After Gaertner.) Fig. 13. — Hemophotograph. (After Gaertner.) When by the aid of some of these instruments a result has been obtained, it must always be borne in mind that no exact test has been made, that, on the contrary, all sorts of errors may be present. Those which are due to the imperfections of the instrument I have already pointed out; and we must always assume 5 to 10 per cent, of errors in the examination of a definite drop of blood, even although we are quite expert in the examination; with the novice this percentage may be much greater. Unfortunately, it is impos- sible by the use of more exact so-called physiologic methods to avoid these errors in the estimation of hemoglobin, partly because the methods are com- plicated, and partly because they require too large amounts of blood, and, therefore, cannot be utilized in practice. To these errors, which are, however, due to the methods or instruments, still others must be added which are due to a certain changeability in the blood itself. It is well known that the most varied influences may change the caliber of the blood-vessels, by stimulating the vaso-dilators or the vaso- constrictors; for example, light, heat, cold, muscular activity, etc. Accord- ing to the caliber of the vessels — of course within certain narrow limits — the number of corpuscles in the capillary blood will vary, and with this the amount of hemoglobin, the specific gravity, the total solids and the albumin contents of the blood. Moreover, if the blood to be examined is not obtained by puncture or incision of the blood-vessel directly, but, as in the great major- ity of cases, by a prick in the finger or by wet cups, the unavoidable admixture COUNTING THE BLOOD-CORPUSCLES 281 of tissue lymph to the blood means another source of error, although in itself not a great one. In spite of all these objections, which should be constantly borne in mind, the clinical estimation of hemoglobin is of great value; in practice it is un- questionably more important than all other methods of blood examination. The decision of the most important question, whether the patient be anemic or not, can only be made positively by a hemoglobin test. The physician should accustom himself to look upon an examination of a patient as com- plete only after the blood has been examined by the aid of a hemoglobinometer ; then a surprisingly large number of persons will be found whose blood will show quite a different condition from what might have been expected before the examination from their general appearance. My estimation is rather too low than too high when I say that fully one-half of those who are pale, who have pale mucous membranes and cool extremities, and for this reason usually designate themselves as " anemic," show a perfectly normal amount of hemo- globin. Such persons do not suffer from an abnormal composition of the blood, but from its abnormal distribution. That the greatest differences in regard to treatment will result from this in individual cases certainly requires no further demonstration. I shall only point to the futility of many a treat- ment by iron ; due to the fact that the treatment was begun without any indi- cation for it, i. e., without proof of a diminution in the amount of hemoglobin. A careful test of the amount of hemoglobin in the blood would in many cases cause us to relinquish the iron treatment and lead to the use of other cura- tive methods. In conclusion I must add that a diminution in hemoglobin may occasion- ally be discovered where the external appearances by no means indicate anemia ; of course a correct estimate of the degree of anemia in such cases must depend upon a test of the hemoglobin. The chief value of the clinical investigation of hemoglobin depends upon the fact that it soon informs us whether and to what degree the blood may be looked upon as anemic; from this we can determine whether to investigate the blood for other changes or not. II. COUNTING THE BLOOD-CORPUSCLES For this purpose we use exclusively the Thoma-Zeiss counting apparatus (Fig. 14). This consists of a pipette G with a mixing chamber E, in which the one or ten per cent, blood dilutions are made ; and of a counting chamber D and c in which under the microscope 400 divisions may be recognized, each containing 40V0 c.mm. In counting the red blood-corpuscles the following method is pursued : The blood is sucked up to a definite mark in the capillary tube, and then diluted with a preserving fluid. We use exclusively Hayem's solution, the composition of which is the following: Mercuric chlorid 0.5 Sodium sulphate 5.0 Sodium chlorid 1.0 Aq. dest 200.0 282 BLOOD AND BLOOD EXAMINATION A drop of the diluted solution is allowed to fall upon the counting cham- ber, the cover-glass is placed over it, and this is permitted to sediment for a short time. [Tiirck's emendation of this step in technic is of value. Before Fig. 14. — Hemocytometee. (After Thoma.) blowing out a drop of diluted blood upon the counting-disc, he puts on 2 corners of the shelf (W, Fig. 14), that is, to support the cover-glass, a minute drop of water. The diluted blood drop is then adjusted on the counting disc and as rapidly as possible the cover-glass is let down and pressed firmly into position by strong pressure with the thumbs. Newton's rings are then visible at once, and the cover-glass is sealed firmly in position. — Ed.] After which (using about 300 diameters magnifi- cation) as many as possible of the squares in view should be counted. If, for example, we have diluted the blood 1 : 100 and then count in 32 squares (Fig. 15) 300 red blood-corpuscles, the following calculation is made (we must multiply with 100 to compensate for the blood dilution) : 300X4000X100 „.750;000. I I ■ I '■ l ° I H Fig. 15. — The Microscopic Picture with Blood-Cor- puscles. (After Landois.) 32 = 3 This is the number of red blood-corpuscles con- tained in a c.mm. Any one in constant practice with this instrument possesses an exact meas- uring apparatus in which the danger of error is very slight; naturally, the aggregate of inaccuracies is less when more squares are counted. [Of course the amount of error depends on the number of squares counted. With men properly trained no constant practice is needed. My own practice is to count 100 squares. The error is then negligible. — Ed.] It must be noted that, particularly in extreme anemia, the number of blood-corpuscles may easily be reckoned as too low, since the microcytes which occur here are apt to be missed if we are using a low power. Obviously the observations we have made in regard to the variation in the composition of COUNTING THE LEUKOCYTES 283 the blood, in speaking of the hemoglobin test, are also true as regards the blood-count. In practice the value of the determination of the number of red blood- corpuscles is not very great, but it is important in any careful study of cases. This is obvious if we realize that the amount of hemoglobin and the number of blood-corpuscles are not always exactly proportional; that, for example, a diminution in the hemoglobin contents to 50 per cent, does not necessarily imply a diminution of erythrocytes from 5,000,000 to 2,500,000 ; they may be above or below this. We designate as the average " value " (V) of the indi- vidual corpuscle -^-, i. e., the division of the percental hemoglobin figure by the percental diminution or increase of the erythrocytes. [" Color-index " is the word generally used in America instead of " value." — Ed.] If, for exam- ple, the amount of hemoglobin has been reduced to 50 per cent., the erythro- cytes being 2,500,000 to the c.mm., the average " value " has remained 1 ; if, however, with 50 per cent, hemoglobin only 200,000 red blood-corpuscles are present, the V has even risen to 1.25 (f°)- On the other hand, the " value " is only 0.8 if we have only 40 per cent, hemoglobin and 2,500,000 red blood-corpuscles. This " value-estimation " is of importance for the rea- son that the various types of anemic conditions are distinguished by the " value " [or color-index] of the blood ; for example, in chlorosis or in post- hemorrhagic anemia [or, in fact, in any well-marked secondary or symp- tomatic anemia. — Ed.], V is often decidedly below 1, while in progressive pernicious anemia it is frequently decidedly above 1. The number of red blood-corpuscles to the c.mm. upon the average amounts in men to 5,000,000, in women to 4,500,000. [Hewes and other Americans have noted that in healthy American adults the number of red cells is usually near 6,000,000, often above that figure. — Ed.] In most anemic conditions this is reduced, and values below 1,000,000, even as low as 300,000, have been seen without absolutely precluding the recovery of the patient. On the other hand it must be emphasized that a normal number of erythrocytes is not proof against the presence of anemia, unless the amount of hemoglobin is also normal. Under certain circumstances, some of which have not yet been sufficiently explained, a decided increase of red blood-corpuscles occurs, a hyperglobulia. This is, for example, the case in the various forms of stasis of the circulation, but it is also the expression of an actual increase of blood formation. Under such circumstances, Turk, for instance, found 9,150,000 erythrocytes. [Cases of this type were first described by Cabot in 1899, later by Osier who noted particularly the enlargement of the spleen associated with the poly- cythemia.— Ed.] m. COUNTING THE LEUKOCYTES To count the white blood-corpuscles we use a dilution of only 1 to 10, which may be done in the large-bore mixing pipette in the Thoma apparatus. In order that counting may be facilitated the red blood-corpuscles are 284 BLOOD AND BLOOD EXAMINATION destroyed, and for this purpose the blood is diluted with 0.5 per cent, acetic acid solution. This process has only one disadvantage, viz., that the nuclei of erythroblasts which may be present cannot be differentiated from white blood-corpuscles. In general, however, this error is quite without im- portance. The normal number of white blood-corpuscles in a c.mm. of blood varies between 5,000 and 10,000. By an estimation of the absolute number of white and red blood-corpuscles we simultaneously learn their proportion to each other, the importance of which we shall describe somewhat more minutely at another place. IV. SPECIFIC GRAVITY The most exact method, one easily carried out with some practice, is that of Schmaltz. For this purpose we require one or more drops of blood, about 0.1 to 0.2 c.c. This is sucked up into small glass capillaries that have been previously weighed upon an accurate chemical scale, noting how much they weigh when empty, and how much after having been filled with distilled water at a temperature of 15° C. Then the weight of the tube filled with blood is determined, and the specific gavity of the blood is cal- culated by dividing its weight by the weight of the same amount of distilled water. Hammerschlag's method has been the most extensively used from the fact that it does not necessitate an expensive scale, but only a simple aerometer with divisions from 1.010 to 1.070. This process is based upon the physical law : " A body floats in a fluid of the same specific gravity." According to Hammerschlag a medium-sized drop of fresh blood is permitted to fall into a benzol chloroform mixture; if the blood after being dropped into the fluid sinks still lower, it is heavier than the mixture, and by the addition of a corresponding amount of chloro- form an attempt is made to compensate for this. If the drop of blood remains upon the surface it is lighter than its menstruum, which is now made lighter by the addition of more benzol. If, finally, the blood drop remains at the height at which it is first dropped, it possesses the specific gravity of the benzol chloroform mixture, which may easily be read off by the aid of the aerometer. As the blood drop under the influence of the fluid surrounding it readily changes its weight, splitting into many small particles, this process must be carried on very rapidly or fresh drops must be constantly made use of. The benzol chloroform mixture can always be utilized for new estimations, as it is readily freed from blood by filtration. In exactness, Schmaltz's pycnometer is decidedly superior to Hammer- schlag's method. In normal males the specific gravity of the total blood is 1.059, in normal women 1.056 upon the average. In general, the estimation of the specific gravity only complements or con- firms the results obtained by hemoglobin estimation. According to minute exact investigations the amount of hemoglobin and of the specific gravity SPECIFIC GRAVITY 285 are equal to one another, so that by this somewhat more complicated method of examination we learn no more than may be more simply determined. There are also tables from which we may read off directly the specific gravity of the blood with a definite amount of hemoglobin, and vice versa. This intimate dependence is clear without further explanation: The hemoglobin, as the principal constituent of the red blood-cell, determines the greatest fluctuation in the gravity of the total blood, especially since the fluid of the blood is of an extraordinary constancy in its composition. Only when the specific gravity of the blood serum becomes decidedly lighter than the normal will the parallelism between hemoglobin and specific gravity of the total blood be destroyed. Closely related to the estimation of the specific gravity- are the quantitative estimation of the total solids and the estimation of the amount of albumin or nitrogen of the blood. Neither method has as yet been adopted in practice, partly because they are much too difficult, and partly because they do not enable us to form any opinion which we cannot otherwise arrive at much more readily. It must be added that the result of the estimation of nitrogen in some cases cannot be utilized at all, for, besides the hemoglobin and the white blood-corpuscles, other nitrogen-containing substances, of other origin, may be present in the blood and in an indefinite amount. In reviewing what has been written in special works upon the subject regarding these methods of investigation, we must say that they have added nothing distinctly new to hematology. The investigations which have been made with the total blood have been extended for scientific purposes to the individual constituent parts, also par- ticularly to the estimation of the amount of albumin and of the specific gravity. The separation of the two integral parts, blood-corpuscles and sebum, may be made in a simple manner either by sedimentation or centrifu- gation. Material for investigation may be procured even from a few drops of blood; it is sucked up into small glass tubes in which the serum, at the latest in twenty-four hours, may be spontaneously expressed. As the most important result of these researches, it must be emphasized that the serum in some pathologic conditions does not take part in the changes of the total blood but retains its composition. Thus, according to Grawitz, the serum in chlorosis and in progressive pernicious anemia does not take part, or to a very slight extent, in the hydremia of the total blood, and invariably shows normal quantities of total solids. In chronic nephritis, the hydremia of the total blood is chiefly attributed to the decided increase of water in the serum. I shall mention still other methods of blood examination, although they have not as yet been considered of importance in practice; because it seems advisable briefly to describe some conditions of which mention is occasionally made. For, since the purpose of this article is the stimulation of more frequent hematologic investigation in practice, we must consider not only those methods which have been found of practical value, but those with which, in spite of great efforts, little or nothing has been demonstrated either theoret- ically or practically. 20 286 BLOOD AND BLOOD EXAMINATION V. ALKALINITY The estimation of the alkalinity of the blood must be first mentioned. That fresh blood has an alkaline reaction cannot be directly determined by the use of litmus paper on account of the color of the blood, but a particularly sensitive red litmus paper must be moistened with a dilute sodium chlorid solution, then the blood to be tested must be dropped upon it and the paper be rinsed again with a sodium chlorid solution. It is very difficult to deter- mine the degree of alkalinity with any accuracy. In the newer methods the blood to be used is made of a lacquer color, and this is titrated against a normal tartaric acid solution with lacmoid paper. For this purpose we usually require somewhat larger quantities of blood, 5 to 8 c.c. ; C. S. Engel has, however, constructed an " alkalimeter " which makes it possible to carry out the test with ^ c.c. of blood. How slight is the importance of these investigations, even to-day, is shown by the reports of various authors that even the normal values vary within wide limits; for instance, from 203 (Canard) to 508 (Loewy) mgm. NaOH in 100 c.c. of blood. With such differences in the normal value, it is not surprising that results obtained under pathologic conditions give rise to con- clusions still less definite. Thus, one author found increased alkalinity in certain diseases in which another found decided diminution. In the present status of the question, we must be cautious in introducing such an uncertain method of investigation into practice; for, since the result is finally expressed in figures which have a deceptive appearance of exact- ness, it is much more misleading than the most subjective method of exami- nation. We are by no means convinced of the biologic importance of the alkaline reaction of the blood. Many authors are inclined to look upon the bactericidal properties of the blood as bearing a certain parallel relation to the alkaline reaction of the blood, but are unable to prove the correctness of this view. Even with such a proof little appears to be gained. For it is self-evident that a definite degree of alkalinity means a relative optimum for bacteria, since the increase of alkalinity at once produces for them unfavorable conditions. I must call attention to the fact that Brandenburg may perhaps have opened a way out of these uncertainties by his recent investigations. Bran- denburg demonstrated that we must differentiate between the alkali combined with albumin and that combined with carbonic acid. These elements can be separated from one another since the latter is capable of diffusion, while the alkali combined with albumin is not. Thus it was shown that the diffusible part of alkali represents a very constant value corresponding to about 60 mgm. KaOH — while the non-diffusible part is exposed to the greatest variations. It is now conclusively shown that under pathological conditions even when there is great variation of the total alkalinity from the normal, the amount of diffusible alkali — " the alkali tension " — remains almost unchanged. SPECTROSCOPIC EXAMINATION 287 VI. VOLUME OF RED CELLS Some authors attach a certain value .to the determination of the volume of the red blood-cells in a definite amount of blood. For the correct estima- tion of this various instruments have been invented, and either those in which the blood-corpuscles are separated from the serum by centrifugation (" hema- tokrit ") or those in which this occurs by spontaneous sedimentation, can be employed. Every method should be rejected in which salt or a salt solution is used to prevent the coagulation of the blood. For the volume of red corpuscles remains uninfluenced only when it comes in contact with an isotonic salt solution; as, however, particularly in pathological conditions, a special concentration is isotonic for each kind of blood in each individual case, the estimation of the volume would first depend upon a previous determination of the isotonic salt solution; and such a difficult process can be of no use in practice. The method which we owe to Koppe is very valuable because coagulation is prevented in the centrifugal tubes of his hematokrit by the absolutely smooth walls of the tubes. As the blood, therefore, remains unmixed we may perhaps assume that, after complete centrifugation, the proper proportion of plasma and cells as it exists in the blood-vessels is shown. If, however, the pathology of the blood is investigated by estimations of volume, the figures obtained by these instruments show nothing that may be looked upon as enriching our knowledge or promoting our understanding of diseases of the blood; and I only refer to this method for the sake of completeness, with the express statement that at present it cannot be consid- ered a clinical method of investigation. VII. SPECTROSCOPIC EXAMINATION For certain methods of examination of the blood the use of the spectko- scope must be understood, for in the recognition of various hemoglobin com- binations which are characteristic of certain conditions, particularly of poison- ing, the spectroscopic investigation of the blood is absolutely necessary and enables us to reach conclusions not to be arrived at by the microscope or any other methods. The principle of this method must be considered as under- stood; but it may be mentioned that in qualitative investigations, as a rule, a so-called pocket spectroscope is sufficient, and that it is well to place the blood for examination in watery solutions of varying concentrations between two plane parallel glasses. The determination of CO-Hb and of methemoglobin, the former occurring in carbonic acid poisoning, the second in various forms of intoxication, par- ticularly with potassium chlorate, is of the greatest practical importance. The spectroscopic determination of methemoglobin, as may be noted from the adjoining table, is possible by characteristic absorption lines (Fig. 16). (The determination of CO-Hb is difficult on account of the similarity of the spec- trum with that of O-Hb. The differentiation is only certain when we observe 288 BLOOD AND BLOOD EXAMINATION that the line of CO-Hb does not disappear upon addition of reduction agents, for example, ammonium sulphate, because CO is firmly combined with hemo- globin; while the spectrum of O-Hb is changed by the same agent to that of reduced hemoglobin. A a B C 40 50 Hi j 1 1 hi 1 1 hi 111 ill i ill i.uiiuTiiii Liini i iuiiim 1 1 ii i in 1 1 mu mi 40 5o bo 70 80 Qo 100 A a B C 90 100 F uo yIG is. — The Various Absorption Spectra of Hemoglobin. In all of the spectra the various Fraunhofer lines and a scale in millimeters are drawn. (After Landois.) Finally, the slightest degree of hemoglobinemia may be demonstrated with certainty by the spectroscope in those cases in which ocular examination leaves a doubt as to whether or not the serum contains hemoglobin. VIII. AGGLUTINATIVE REACTIONS To the law of immunity which has made us acquainted with the vital importance of functional changes in the blood we owe a valuable diagnostic method. We know that in the natural infections of man, as well as in animal experiment, peculiar changes occur in the blood serum, under the AGGLUTINATIVE REACTIONS 289 influence of specific bacteria or bacterial toxins. Among these we may differ- entiate two classes : The antitoxic sera and the bactericidal sera ; the first variety is represented by the serum containing diphtheria antitoxin, the second by the energetic bacteriolytic action of the blood serum in convalescence from cholera. As a variety related to the last group the agglutinating serum may be included, which occurs during the course of, and after recovery from, many infections. We are most familiar with this condition in enteric fever, in which it first led to valuable and practical diagnostic results. The essential part of the phenomenon is that, in a mixture of such serum with typhoid bacilli in a culture medium, they are deprived of their motility and clump, i. e., " agglutinate." To determine this fact a few drops of serum, 1 to 2 c.c., are sufficient, and these may be most easily obtained by centrifuga- tion or sedimentation in thin glass tubes. The phenomenon may be demon- strated macroscopically as well as microscopically (Gruber-Widal reaction). In the former case, with nutritive bouillon after the addition of the serum, we see how a profuse uniform turbid accumulation of typhoid bacilli clears completely in from twelve to twenty-four hours, and a delicate flocculent precipitate forms which, even by powerful shaking of the test-tube, can no longer be disseminated. The microscopic test is carried out in the following manner: A drop of the typhoid culture which is to be utilized for the test is arranged as a hanging drop, so that we may convince ourselves of the active motility of the bacilli. If serum in an exact proportion is then carefully added to the collection of bacilli, and one drop is placed under the microscope in a positive reaction, we notice even after a few minutes, at latest after a quarter of an hour, a complete cessation of movement, a clumping of bacteria in large groups, as well as an indistinctness in their outlines. [Another method is the following: A 3-inch test-tube of small caliber is carried to the bedside of the patient together with a clean medicine dropper. Ten drops of water are allowed to fall from this dropper into the test-tube. The patient's ear is then punctured in the ordinary way and a full drop of blood is sucked into the dropper and then expelled into the water in the test-tube. The test-tube is then corked and carried to the laboratory where the culture is kept, and one drop of the blood and water mixture is mixed with one drop of the culture and examined between slide and cover. There is no need of separating serum and corpuscles in this test; the whole blood is equally serviceable. For public health work the blood may be dried on tin foil, folded in, and mailed to the State Laboratory where dilution is made by weight. This method is extensively and most successfully used by the State Board of Health in Michigan. — Ed.] The value of this reaction test can only be properly appreciated if it is carried out with certain precautions. First, we must assure ourselves of the proper composition of the typhoid culture to be used in testing, and must be sure that it is a fresh one. not older than a day. The serum requires, as already stated, a corresponding dilution, because even normal serum if undi- 290 BLOOD AND BLOOD EXAMINATION luted may cause agglutination; on the other hand, the dilution should not he too weak, as the agglutinating substances in some cases of enteric fever are not present in very large amounts, and if the serum be too greatly diluted they are inactive. It is best to begin with a dilution of one part of serum to thirty parts of bouillon, and, if a positive reaction be obtained, it should then be determined with how weak a dilution we can still secure a reaction. In some cases, a positive reaction has been obtained even after concentrations of 1-5,000. If the test gives a positive result with a high dilution, the diagnosis of enteric fever is thereby assured, with the one limitation that the serum may perhaps have received its agglutinating properties from a typhoid fever some time previously, even several years before. If, however, the result of the test is negative with a dilution of 1 : 30, it is well to repeat it in the course of the disease, daily if possible. Frequently it is noted that in the early course of the disease the serum, which at first showed no reaction while diluted, gradually in slighter concentration betrays the presence of agglutinating substance. But the diagnosis of enteric fever cannot be excluded with certainty even in case of a continued negative result of the reaction. The appearance of the reaction may be expected at the earliest upon the eighth day of the disease.1 [Since it is impossible to fix in any way — except arbitrarily — the first day of the disease, it is hard to make any accurate statement about the earliest appearance of Widal's reaction. At the time when patients first consult a physician, two-thirds of them show a positive agglutination reaction in the blood, but in a few it is delayed as late as the fifth or sixth week, or it may never appear. Over 95 per cent, of cases, however, show a reaction at some time in the course of the disease. Different epidemics vary greatly in these points, some showing a large pro- portion of early reactions, while in others physicians complain of the high percentage of negative reactions in the earlier weeks of the disease. — Ed.] In view of the very valuable diagnostic success of serum diagnosis in enteric fever, it may be readily understood that an attempt would be made to reach the same results in other diseases, but, unfortunately, there has been as yet no practical success. Endeavors specially directed to the recognition of tuberculosis by its specific agglutinating reaction may be looked upon as futile, since Robert Koch reached entirely negative results in this direction. IX. BACTERIOLOGICAL EXAMINATION The diagnosis and also the prognosis may, under some circumstances, be helped by the bacteriological investigation of the blood. There are quite a i Lately Prbscher (Centralbl. f. Bakteriologie, xxxi) has proposed a modification which indicates a decided practical improvement. According to this it is particularly valuable that a typhoid bouillon may be utilized in which the bacilli have been killed by the addition of one part of a forty per cent, formalin to 100 parts of bouillon. This bouillon may be used for weeks without losing its agglutinating property. For the action of the serum upon the bacilli Proseher allows from one to two hours at blood heat; for viewing the serum bouillon mixture which is kept in a bowl we employ a low power dry lens (about J6 enlargement). BACTERIOLOGICAL EXAMINATION 291 number of diseases in which, particularly in especially severe cases, the pathogenic agents enter the blood. Formerly we contented ourselves with a microscopic investigation of fresh or stained blood to determine the presence of bacteria. But this process should only be resorted to for the determination of the spirilli of relapsing fever, or, perhaps, of the bacilli of anthrax. In other cases it may lead to errors, first because of the small number of germs that may be present, and, secondly, because confusion with accidental bacterial contaminations may readily occur. It is therefore advisable to puncture a vein of the arm under strict antiseptic precautions, to withdraw 1 to 2 c.c. of blood, and to prepare cultures, best in bouillon, or to determine by animal experiments the probable presence of pathogenic bacteria. In this manner we are able to determine with certainty in the circulating blood the presence of streptococci, staphylococci, pneumococci, the bacilli of enteric fever, of the plague, of tuberculosis and others. [Typhoid bacilli have repeatedly been cultivated from the blood of doubtful febrile cases before the Widal reaction had appeared. Hence this procedure may be of great value in obscure cases. The same is true of the cultivation of pneumo- cocci from the blood in obscure pneumococcus infections and " central pneu- monias."— Ed.] The determination of the pathogenic agents just mentioned can only be designated as an auxiliary factor in diagnosis, but the recognition of spirilli in the blood is the only means for a positive diagno- sis of relapsing fever. As a rule this determina- tion is very easy, for the peculiar curved form of the spirilli (see Fig. 17) precludes confusion with other organisms. Their number is usually very large; our detection of them is greatly facilitated by their motility, and, finally, they stain readily with various anilin colors, for example, intensely with fuchsin, so that they may be easily found in a dry preparation even if present in the blood in very small numbers. -r, i ■, i ,, -,. • .I •_• i Fig. 17. — Relapsing Fever Probably m no other disease is the practical SpiRILLI. (After v. Jaksch.) importance of blood examination greater than in malaria. This is naturally not the place in which to describe the entire devel- opment of the malarial parasite, nor even to mention all of the varieties which occur in the blood, as a special article has been devoted to this important sub- ject.1 Here it need only be mentioned that, in many cases, we should look for the plasmodia in the blood, and should familiarize ourselves with the most important points in the technic of examination. In the investigation of the blood for malarial parasites for diagnostic purposes, the stained dry specimen is unquestionably the most suitable, and we shall explicitly describe its preparation in another place. For when very few parasites are in the blood, this method alone assures their detection, and 1 Compare the article by Loeffler in the volume on " Infectious Diseases." 292 BLOOD AND BLOOD EXAMINATION with very little practice it protects us more fully from error than an investi- gation of the fresh blood. The withdrawal of blood had best be made in the afebrile period; and even here it must be borne in mind that, for as long a time as possible prior to this, no quinin should be administered. Fixing the preparation is best accomplished by the use of absolute alcohol for five minutes. [It seems likely that all the fixing methods described in this article will soon be replaced by the fixation produced by methylic alcohol which is the menstruum in which the various " Eomanowsky " stains are dis- solved. Using Irishman's or Wright's modification of the Eomanowsky method we fix the specimen in the same fluid which later (when water has been added) stains the specimen. This saves much time, trouble, the apparatus and expense. The technic is given in detail below. — Ed.] Staining is best done either by a one per cent, methylene-blue solution, or by the Chenzinsky methylene-blue eosin mixture mentioned in another place, or after the method especially proposed for the study of malaria by Eomanowsky-Ziemann. With an enlargement of about 500 and the use of an oil immersion, it is not difficult even for the novice to recognize the fully developed plasmodium within the red blood-corpuscles. First, the blue tint which they acquire from the methylene-blue readily distinguishes them from the nucleus of the cell; this is an uncommonly delicate sky-blue in contrast with the darker blue of the nucleus, which more closely resembles the actual color of the material used in staining. [With the Eomanowsky stain which is now widely used in this country for all blood-specimens, the nucleus is colored crimson and its con- trast both with the blue of the parasite and the yellow of the surrounding corpuscle forms thus one of the most recognizable features of the organism. — Ed.] By the amount of pigment the recognition of the plasmodium is also decidedly facilitated. It is more difficult if only the very young forms of the plasmodia are present, those which are still very small, and have not as yet formed pigment. Occasionally the characteristic seal-ring shape facilitates their recognition; frequently, however, the apparently structureless forms may be confused with the nuclei or the fragments of a nucleus of the erythrocytes, or with the dots of " stippled " erythrocytes. Here the character of the staining in particular gives a point of support for their recognition. Observations made at a more favorable time, and eventually an examination of the fresh blood to determine the motility of these bodies, furnish convincing proof. How important it is to carry out an examination for plasmodia is shown by the fact that, according to Eobert Koch, the prophylaxis as well as the therapy of malaria is intimately connected with the results of the blood findings. The investigation itself, however, is so simple that it should never be omitted in any case in which long protracted, perplexing fever is present, or in which the history, or the condition of the spleen, or other clinical phenom- ena point to the possibility of a malarial infection. Especially in regions in which malaria is quite rare valuable time for the patient is frequently lost, because the physician has neglected the examination of the blood, supposing BACTERIOLOGICAL EXAMINATION 293 a septic disease or a tuberculosis, etc., to be present, and malaria has not been recognized as the true cause of the morbid phenomena. [In this country the opposite mistake is more common. Many cases of tuberculosis are miscalled malaria because they have chills, and no proper examination of the chest or of the blood is made. — Ed.] Among all the methods of blood examination used in the last decade un- questionably the most far-reaching results have been attained by the investi- gation of the normal and pathological histology of the blood ; this was particularly fostered by the technic of the dried preparation and the differ- ential stains introduced by Ehrlich. If a drop of fresh blood is placed under the microscope, enlarged about 500 times and examined with an oil immersion a number of important points may be observed. There will first be noted, provided the layer of blood is thin enough, the shape of the red blood-corpuscles, their depression, their hemoglobin staining; by this method also the rouleaux formation of the blood discs becomes plain. The structure of the white corpuscles may be recognized by this simple process, and various forms may be differentiated from one another. Thus the lymphocytes are perceived as cells about the size of a normal red blood-corpuscle, though some attain double or even three times this size; their nucleus is circular, takes up the greater part of the cell, and is sharply demarcated from the narrow protoplasmic border surrounding it. The majority of the leukocytes are conspicuous by their dense, decidedly refractive, fine granulations; one, two, or three faint nuclei deposited in them may be recognized. These cells are twice or three times as large as the erythrocytes. In a few of the leukocytes present (eosinophiles) the granula- tions are much more decidedly refractive, and the individual granules are much coarser. These two last named forms are alike in size, as well as in the conditions and the number and shape of their nuclei. The blood-plaques are most easily recognized by their agglutination in clumps and slight refractive power. Studies of the more minute structure of the leukocytes can only be made with difficulty by this simple method, as the forms not yet described are usually only present in very small numbers. Moreover, in a prolonged exam- ination, the blood soon suffers changes which produce disturbance. In con- sequence of this the investigation of the fresh blood is of very little service, and we are usually compelled to preserve the blood by a proper method and to stain it. For these purposes there is no better process than the dried staining process after Ehrlich [except the methylic alcohol fixation described below. — Ed.], and this is as simple in its operation as it is serviceable. It has the practical advantage that it allows the investigator to work quite inde- pendently of the presence of the patient, to choose the time and place of examination, and permits at any time a repetition of the investigation and a demonstration of the result obtained. The specimen is made as follows : Cover-glasses of about 18 mm., having a quadrangular shape and of special thinness (0.1 to 0.08 mm.) are used; 294 BLOOD AND BLOOD EXAMINATION Fig. 18 these are carefully cleansed in ether and alcohol so that fat, fiber and all parti- cles of dust are removed. [Water is sufficient for cleansing cover-glasses pro- vided they are properly polished with silk or tissue paper afterwards. — Ed.] On a cover-glass of this kind a small drop of blood which has exuded from a prick of the finger is collected; this glass is dropped, blood side downward, upon a second glass, with the result that the blood soon spreads out spon- taneously in a thin film between the two very flexible glasses to about three- quarters of their extent, as if in a capillary space. After a complete distribu- tion of the drop of blood, the glasses are removed from one another [by sliding off the upper of the two covers without any lifting or tilting, but strictly in the plane of their surfaces. — Ed.], and the blood is seen distributed upon each in a uniform layer. If the drop taken was small enough, the blood cells are found in an even layer side by side without over- lapping each other. In view of the fact that the red blood-corpuscles are dam- aged with extraordinary ease, especially by moisture, this maneuver should not be at- tempted with the unaided hand; for the moisture of the tip of the fingers is capable of changing the outlines of the red blood-corpuscles and of extracting their hemoglobin. For this reason, in the preparation of these specimens two forceps should be used in the manner depicted in Fig. 18. [For any one whose fingers are not habitually and obviously damp the use of forceps is unnecessary. —Ed.] When the blood films have dried, which usually happens within twenty to thirty seconds, it is necessary before subjecting them to the stain to fix the blood in a suitable manner. For practi- cal purposes it is sufficient usually if the specimens are placed for five minutes in a solution of 1.0 formol in 100 parts of absolute alcohol. After this method of fixation almost all the stains which need practically be considered may be em- ployed. If we intend, however, to pre- pare especially beautiful specimens, or to make investigations for scientific pur^ poses, then Ehrlieh's old method— fixation by heat alone— bad better be utilized. Most serviceable for this purpose is a small copper kettle (Fig. 19) inside of which a small quantity of toluol is brought to the boiling point. Fig. 19. BACTERIOLOGICAL EXAMINATION 295 The thin copper lid of the kettle will, a few minutes after the toluol has begun to boil, reach the temperature of the boiling point of toluol (111° C). Upon the plate heated in this manner the cover-glasses with the dried blood are placed for thirty to sixty seconds, and this fixation is quite sufficient for most of the staining methods. Among the methods of staining the blood those of Ehrlich have shown themselves to be the most successful. In particular his triacid solution, which in its application is quite simple, brings out a great many points, and fur- nishes reliable conclusions. The formula for its preparation is the following: The three stains, orange G-, acid fuchsin and methylene green, are prepared in saturated aqueous solutions, and are mixed in the following amounts and order (with thorough shaking during the process) : Orange Gr 13-14 c.c. Acid fuchsin 6-7 " Aq. dest. 15 " Alcohol 15 " Methyl green i5 . 5 " Alcohol 10 " Glycerin 10 " If the fixed blood preparation is allowed to float for about five minutes upon a few drops of this staining solution, the staining is finished. There is no danger of over-staining, even in a decidedly longer duration of staining. The cover-glass is then thoroughly rinsed in water, carefully dried between blotting papers and mounted in Canada balsam. For certain purposes, as we shall see later on, this triacid solution is not suitable, and we are compelled occasionally to use complementary stainings with methylene-blue, or with methylene-blue eosin mixtures. Formula? for such stains are the following: Very instructive pictures are obtained if we stain for half a minute with a solution of 0.5 eosin to 100 c.c. of a 60 per cent, alcohol, rinse in water, and subsequently stain for two minutes with a watery methylene-blue solution of 1-250. Specimens of great clearness and elegance are obtained by a careful appli- cation of the Chenzinsky's methylene-blue eosin mixture: Concentrated watery methylene-blue solution 40 c.c. 0.5 per cent, eosin solution in 70 per cent, of alcohol. . . 20 " Distilled water 40 " This solution must be filtered each time prior to use ; the staining requires from six to twenty-four hours and, to prevent evaporation and the precipita- tion of the staining material, must be carried out in air-tight closed cups. By the aid of these staining methods we are enabled to recognize a number of the peculiarities of the blood cells, which are indistinct or entirely unrecog- nizable in fresh blood. Some of the newer, particularly the so-called " uni- versal," stains have such glaring faults that, at least for the present, they 296 BLOOD AND BLOOD EXAMINATION appear to be unsuitable for practice. [After using and teaching Ehrlich's method as just described for eight years, I have recently discarded it in favor of one of the " universal " stains which our author here condemns. Leishman's " Komanowsky " stain made up by Wright's method (see Journal of Med. Research, 1902, vol. vii) is much quicker and easier to use, needs no fixing fluid or heating apparatus, and gives pictures which in 99 cases out of 100 are superior to those obtained by Ehrlich's method. The technic is as follows: Adjust the cover-glass film in Cornet's forceps. Flood it with the stain, using a medicine dropper and keeping the bottle tightly corked when not in use. After one minute add water drop by drop until a greenish iridescent scum appears on the surface. About 7 drops are needed with a £■ inch cover-glass. Allow the stain, so diluted, to act two minutes. Wash in water, and allow the preparation to stand one minute more in water. Dry in blotting paper and mount in Canada balsam. This stain brings out all that Ehrlich's method does and, besides this, stains the blood-plates, the granules of mast-cells, the chromatin of malarial parasites and the basophilic granules in abnormal red cells — all points of value. The only weak point of the Eomanowsky stains is the deceptive resemblance between certain megaloblasts, certain lymphocytes, and certain myelocytes. In perhaps 1 case in 100 this troubles a beginner; in perhaps 1 in 1,000 it troubles an expert; but in no case does this difficulty affect the essentials — the diagnosis, prognosis, or treatment of the case. — Ed.] In examining normal blood which has been stained according to these methods we note the following important peculiarities: The red blood- corpuscles have been wholly stained with orange, that is, with eosin, and this causes the unstained depression which is free from hemoglobin to stand out prominently. Among the white blood-corpuscles the lymphocytes must be first mentioned (see colored plate, Eow VII, a and b). Their nuclei show the above described configuration, and on staining with a triacid solution they are moderately well stained with methylene green, the protoplasm, however, being of a very pale yellowish color. [The nuclei are often so faintly stained as to be nearly invisible. The protoplasm frequently remains unstained or shows a faint gray color. — Ed.] In methylene-blue eosin preparations the nucleus is deeply stained with the blue stain, which is very frequently, however, found to be more marked in the blue color of the rim of the protoplasm. This is an expression of the fact that the protoplasm of the lymphocytes is more baso- philic than its nucleus. In the not infrequent cases in which it is difficult to determine the relation of a white blood-corpuscle to a definite cell group, this condition is always a positive sign that the cell must be looked upon as a lymphocyte; however, the absence of this reaction is not absolute proof that the cell is not related to the lymphocytes, for, as may be noted from the colored plate, the protoplasm occasionally shows a weaker stain with the basic staining material than the nucleus. The cells which, in fresh blood, we have recognized as finely granular and polynuclear, are shown, in staining with the triacid stain (IX, b) to have pale green colored nuclei and very fine, almost dust-like granulations of a BACTERIOLOGICAL EXAMINATION 297 reddish violet color, filling the entire protoplasm. The granulation owes this color to the chemical action of a combination of the acid fuchsin and the methylene-grcen produced by a " neutral " stain ; for this reason these granu- lations are designated as neutrophilic, and this variety of cells as polynuclear neutrophilic leukocytes. As this granulation only stains in "neutral" dyes, it remains unstained in the methylene-blue eosin mixtures that do not contain a " neutral " dye stuff, and we therefore find in the polynuclear leukocytes in this stain an entirely unstained protoplasm, while the nucleus shows an intense blue (IX, a). A small number of white blood-corpuscles by their staining and mor- phology show a close relationship to the group described above; they only differ in that the granulation is much more sparse, and that instead of a polymorphic and intensely stained nucleus a larger, less indented, quite faintly stained nucleus is present. These cells we designate as transitional forms (see colored plate VIII, c). They are the stages immediately prior to the polynuclear neutrophilic leukocytes which in part are formed from the fol- lowing groups: Large mononuclear leukocytes. This cell form is one which is most diffi- cult to differentiate from the lymphocytes; nevertheless this differentiation is absolutely necessary. In the triacid stain they are remarkable for their size, being three times as large as a normal red blood-corpuscle. Their nucleus is large, comprising about one-third of the cell, usually eccentrically placed, round, of a pale green stain ; their protoplasm is almost unstained and free of granulations (VIII, b). The cells stained in methylene-blue (VIII, a) are often decidedly more characteristic. We have one prominent sign which greatly facilitates the differentiation of this variety of cells from the larger forms of the lymph-cells; namely, that while (as has been mentioned above, and as may be noted from the colored plate) in the lymphocytes the boundary between the nucleus and the protoplasm is sharply marked, in the large mono- nuclear leukocytes the dividing line is indistinct, so that frequently we cannot determine where the nucleus begins and the protoplasm ends. The proto- plasm of this cell variety is apparently never more decidedly basophilic than its nucleus. The three last named cell forms constitute an intimately connected group, that is, links in a chain of development the beginning series of which are the large mononuclear leukocytes, and from these, by transformation and division of the nucleus as well as by the extension of granulations, the transitional forms and, later, the potynuclear neutrophilic leukocytes, arise. The cell forms which in fresh blood are conspicuous by their coarse granu- lations ma}r also be readily differentiated from the others in the stained preparation. Their nuclei stain with nuclear stains with medium intensity; the granulations which almost completely fill the protoplasm in the triacid solution are orange or copper color (X, b), and in eosin-containing solutions they are stained a brilliant red (X, a) ; unfortunately, in the reproduction they are not very well depicted. On account of this property of acid dyes (especially eosin) to attract these granulations, the entire cell is called oxyphilic, acidophilic or eosinophilic. 298 BLOOD AND BLOOD EXAMINATION Another variety of the white blood-corpuscles is the mast-cell (XI, a, h, c), the peculiarities of which cannot be recognized in fresh blood, but only upon the use of very definite methods of staining. [Mast-cells are beautifully stained by the Komanowsky method mentioned above.— Ed.] These cells are characterized by a quite coarse, often irregular, granulation which as a rule only partly fills up the protoplasm. Their distinctive feature, however, is the basophilic reaction of the granulations and their power to modify the color tone of most of the substances that stain them ("metachromasia"), so that, for example, with kresyl-violet E they stain almost pure brown. They also differ from other granulations by their ready solubility in water, so that they can only be stained in alcoholic, not in watery, stain solutions. There fore, the two staining mixtures mentioned above which are in most common use are not suitable for staining the granulations of the mast-cells, but we can best use for this purpose alcoholic solutions of methylene-blue, dahlia, or kresyl-violet R. [See last note. — Ed.] In the preparations stained with triacid the mast-cells are recognizable, since the insufficient staining of the granulation causes the cell to appear as if permeated by vacuoles (XI, c). They are frequently so sparse in normal blood that they can only be discov- ered by examining several preparations. These various cell forms may be determined in all normal blood by the aid of different stains, and in the adult they are found in about the propor- tion shown in the last division of Table A, where the large mononuclear leukocytes and the transitional forms, on account of their close relationship, are included in one group. In the arrangement of Table A the fact. is disclosed that the lymphocytes occupy a unique position among all the white blood-corpuscles. This is mainly due to their origin: They originate in the lymphatic tissue of the body, the principal mass of which consists of the lymph-glands ; lesser amounts of this variety of tissue are, however, also present in the bone-marrow, and it therefore, perhaps, contributes a small portion of the lymphocytes of the blood. The groups from the second to the fifth, however, originate exclusively in the bone-marrow; only under definite pathological conditions does the production of these varieties of cells also occur in other regions. The point of origin of the mast-cells, which is chiefly in the bone-marrow, must also be the con- nective tissue where they are formed in large quantities, particularly in certain pathological conditions. A second comprehensive difference between the lymphocytes and the five other varieties of cells consists in the fact that the latter have the property of active movement which the lymphocytes do not possess; we shall see later that this difference is of great importance for the conception of pathological processes. [It has been conclusively shown, I think, that lymphocytes do possess the power of ameboid movement. — Ed.] 3 f 6S s § ■> £ o 3 ° P-| be BACTERIOLOGICAL EXAMINATION 299 Table A THE WHITE BLOOD-CORPUSCLES OF THE NORMAL BLOOD Per cent. I. Lymphocytes (large and small) 22-25 II. Large mononuclear leukocytes ) co -! HI. Transitional forms j IV. Polynuclear neutrophilic leukocytes 70-72 i V. Eosinophilic leukocytes 2-4 VI. Mast-cells 0.01-0.5 The blood-plaques are recognizable in fresh blood by their lesser size (1-3 p.), their clump formation, and their slight refractive power; they stain a pale blue in methylene-blue solutions, and in the triacid stain from gray to grayish brown. [In most triacid preparations the blood-plates are invisible. With Eomanowsky stains they are dark plum color and are easily seen. — Ed.] Before entering upon the physiologic and pathologic importance of individ- ual cell forms we must first describe a few cell anomalies. In different patho- logical conditions decided changes in the shape and size of the red blood-corpus- cles are noted, and these we designate by the term poihilocytosis (Plate, Eow III). The average normal size of the red blood-corpuscle is from 8-9 p,; in some conditions of the blood, besides these " normocytes " there are also very small forms which may be only 2 to 3 yu, in size (" microcytes") ; on the other hand we may observe large forms which are frequently from 14-15 p., in rarer cases may even reach 18, 20 and 22 p, {macrocytes, megalocytes, gigantocytes) . Besides the changes in size, the manifold changes in the shape of the blood- corpuscles are important, and may be looked upon as an expression of seg- mentation and decomposition. Occasionally combined with these pure morphologic changes, but quite as f requently entirely independent of them, we note in the erythrocytes deviations from normal conditions which are shown by a diminution of their hemoglobin contents. For example, forms of various size are noted in which the central depression is very markedly extended so that only a comparatively small part of the disc, often only a quite narrow rim, appears to contain hemoglobin; i. e., to stain in the corresponding solution (see colored Plate, Bow III). A diminution in the amount of hemoglobin of the individual blood-corpus- cle is also occasionally shown by a generally weaker power of staining. Besides these slight deviations in tinctorial properties, the red blood discs frequently show marked qualitative anomalies; for instance, we note very frequently blood discs which do not take a pure stain with eosin or orange, but a mixed one, so that in staining with the triacid stain they are more or less grayish brown, in methylene-blue eosin solution from bluish red to lilac, and occasionally they may appear pure blue. This behavior, which now is generally designated as e( polycliromatophilic degeneration," may be explained by the fact that foreign substances which stain with the nuclear colors have [} 60-72 per cent, are normal limits, in my opinion. — Ed.] 300 BLOOD AND BLOOD EXAMINATION been deposited in the plasma of the red blood-corpuscle (see Plate, Bow II). [There are many, and on the whole convincing, reasons for regarding these granules as evidence of regeneration or of unripeness, but controversy is still active on the subject, and it seems best for the time to use some neutral term such as "basophilic stippling." — Ed.] Such a deposit of substances which, for example, stain in methylene-blue but not, however, in the triacid solution, is found in a granular or dust-like form in the protoplasm of the red blood-cells, whether this is normally stained or degenerated in the manner above described (polychromatophilia) (see Plate, Eow VI). We should be cautious in assuming the identity of these deposits with the granules of the white blood-corpuscles; therefore we should also avoid the designations granular, granulation, granulated erythrocytes, etc., and choose the non-implicating designation "stippled erythrocytes" Much less frequent than these staining anomalies of the red blood-corpus- cles is an additional one, the appearance in the circulating blood of nucleated red blood-corpuscles, " erythroblasts." It is well known that normally in the red bone-marrow nucleated red blood-corpuscles appear. These are about the size of the normal non-nucleated blood discs, but contain a nucleus of an extraordinarily intense stain and a protoplasm that usually appears in the color of the stains that color hemoglobin, more rarely in that of polychromato- philic degeneration. They are unquestionably the early stages of the normal erythrocytes, and for this reason are designated as normoblasts (see Plate, Eow IV). On the other hand, only under pathological conditions in the adult do we find another form of erythroblasts which are decidedly larger than the normal red blood discs, and have a diameter of 14, 16, even 20 /x and more. Their nucleus, as a rule, is but feebly stained by nuclear dyes, their protoplasm almost invariably shows the condition of polychromatophilic degen- eration. We designate this variety of cells as megaloblasts, or gigantoblasts (see Plate V, a, b), and recognize in them the embryonic stages of megalo- cytes and gigantocytes. In the white blood-corpuscles changes in form or in staining property are of slight importance. It should be mentioned that very frequently the proto- plasm of the lymphocytes at its border shows proliferation and segmentation, processes which indicate a degenerative condition without our being able to assign to them definite pathologic importance. Much more interesting is the appearance in the circulating blood of a cell form which, under normal conditions, is met with only in the bone-marrow. This is a mononuclear leukocyte of varying size (8 to 20 /a in diameter) (see Plate, Eow XII), the protoplasm of which is filled by a dense neutrophilic granulation ; Ehrlich has given this corpuscle the name " myelocyte." The white blood-corpuscles show variations of great importance in their number, both as regards their total number per cubic millimeter and in their proportion to the red blood-corpuscles (^r) and particularly, in the propor- tion of the individual forms of the white blood-corpuscles to one another. The estimation of the proportion of ^ is possible by the aid of Thoma's appa- ratus for counting the absolute numbers ; this may also be accomplished with BACTERIOLOGICAL EXAMINATION 301 the stained dry preparation. For this purpose we use the movable quadratic Ehrlich eye-piece (see Fig. 20). The principle of this diaphragm depends upon its making it possible to count the red and white blood-corpuscles in different large divisions of the field of view, so that, for example, the leuko- cytes are counted in a field six or nine times as large as the field in which the Fig. 20. — Ehrlich's Eye-piece with Iris Diaphragm. reds are counted. The total number determined after counting a larger series of fields of the red is then directly compared with the sum of the white by multiplying by six or nine. A prerequisite for a correct result by this method of estimation is an absolutely uniform layer of blood upon the cover-glass. The proportional relation of the individual varieties of blood-corpuscles to one another may be determined by a simple calculation of the cells when examining a dry preparation. We have described the fundamental characteristics of the blood cells in their normal and pathological condition, omitting everything that depends upon purely theoretic investigation and which has not yet been directly applied to practice, as well as that which is still being debated, and concerning which the views of competent observers are still at variance. How has it been possi- ble to utilize this material in general and special pathology? In the article upon Anemia (see this volume) due stress has been laid upon the pathological changes which the red blood-corpuscles undergo in the various anemias, and we may now limit ourselves to a description of the changes in the white blood cells in the same diseases. ■ In the first place, as regards the appearance of pathological cell forms, for the reasons indicated we have included only the myelocytes in our descrip- tion. But the circumstances under which these are found in the circulating blood agree in so many points with the circumstances under which the num- ber of white blood-corpuscles increases or decreases that they require no special elucidation. Consequently, the most important chapter in the pathology of the white blood-corpuscles is that which treats of the changes in their total number and the relative proportions of the individual leukocyte forms. Since, in general, we refer to the presence of leukocytes as leukocytosis, an increase of their 21 302 BLOOD AND BLOOD EXAMINATION total number we speak of as hyperleukocytosis, and a diminution, as hypoleu- Tcocytosis. [I prefer the term " leukocytosis " for an increase, and the term " leukopenia " for a decrease, in the circulating leukocytes. — Ed.] Even at the normal; the absolute number of white blood-corpuscles and the propor- tion of their different varieties show distinct variation ; in different pathologic conditions, however, and especially in infectious diseases, the deviation of these conditions from normal becomes more marked. We find the explanation for this in the principle of chemotaxis, according to which bacteria and their products of metabolism, as well as numerous other toxic substances, are capa- ble of attracting by chemical irritation the cells which have accumulated in the blood-forming organs, a condition which we designate as positive chemo- taxis; on the other hand under quite similar circumstances the leukocytes are repelled by the previously mentioned poisons, so that the number in the cir- culating blood is decreased, and this process we call negative chemotaxis. The self-evident presupposition for this attraction and repulsion of the leu- kocytes (since the condition is a notable example of action at a distance) is the property of the leukocytes to show active movement. For this reason we give to this state the name active leukocytosis. Active leukocytosis furnishes the most varied pictures, not only quantita- tively but qualitatively, because of the fact that the chemotaxic irritability of the different leukocyte varieties shows specific differences. Thus there are substances which only influence one variety of cell in a positive chemotaxic manner, being inert toward all others. This shows itself most frequently in a decided increase of the polynuclear neutrophilic leukocytes alone in numer- ous infectious conditions, as in septic diseases, diphtheria, and articular rheu- matism; other infections have a negative chemotaxic property for this cell form so that, for example, in enteric fever, we often find them decidedly diminished. On the other hand the eosinophilic leukocytes show marked power of attraction for the blood in bronchial asthma, in pemphigus, in trichi- nosis, and in several varieties of helminthiasis. More rare, but nevertheless cer- tain, is a chemotaxis of the mast-cells exhibited according to this principle. It is a peculiarity of the chemotaxic reaction that all leukocytes endowed with one type of granulations are attracted simultaneously even if the com- position of the nucleus varies; for example, the myelocytes react in the same way as the polynuclear neutrophilic leukocytes. For this reason, in accord- ance with the variety of the cell that is influenced, we speak of neutrophilic hyperleukocytosis or hypoleukocytosis of eosinophilic or mast-cell leukocytosis. Besides these specific leukocytoses, we diagnosticate another form of hyper- leukocytosis which we designate as a mixed form, because in this all cells that are capable of chemotaxic reaction are increased in the blood. This is myelogenous leukemia; we therefore arrive at the hypothesis, no matter how obscure to us the etiology and pathogenesis of myelogenous leukemia may still be, that in this disease a toxic substance is active which has the property of influencing all myelogenous cell varieties in a positive, chemotaxic manner. A form of white blood-corpuscles must still be mentioned which does not possess the active property of locomotion: these are the lymphocytes. [See notp at foot of p. 298.] It is therefore evident that this form is not subject to EXPLANATION OF THE COLORED PLATE IAU cells drawn with Leitz one-tioelfth oil immersion.) I. Erythrocytes, stained with triacid and with the Chenzinsky stains. II. Polychromatophilic "degeneration." III. Poikilocytosis; pessary forms. IV. (a) Normoblasts. (6) Free normoblast nucleus. V. (a) Megaloblast. (6) Gigantoblast. VI. " Stippled " erythrocytes. VII. Lymphocytes. VIII. Large mononuclear leukocytes: (a) with Chenzinsky. (b) with triacid. (c) transitional form. IX. Polynuclear neutrophilic leukocytes. X. Eosinophilic leukocytes : (a) with Chenzinsky. (6) with triacid. XI. Mast-cells: (a) with methylene-blue. (b) with dahlia. (c) with triacid. XII. Myelocytes. I I i rked. v. - . I I .euiate .Y.^anisnsdO $&} djjw bos bioei-tf.dJiw benifi-ta lS9^ooii^^a .1 ".£]oi}xneiT9§eb"oiIiifqo^xno-,doYJoniSn9d0d^ (») .biochtdtiw ( Acid, arsenicos. 0.06, piperis nigri pulv. 1.5, rad. liquir. pulv. 3.0, mucilag. gummi arab. q. s. ad pil. lx) of which one pill is taken once to three times daily To avoid irritating the stomach, these, like all other arsenic preparations, are not to be given upon an empty stomach, but only while eating or immediately after a meal. A very serviceable arsenic preparation is sodium cacodylate, also known under the name of arsycodile, which contains considerable arsenious acid (nearly two-thirds) and is well borne. The dose for adults is 0.025 to 0.1, and this is gradually increased in pills (sodium cacodylate 0.25 to 0.1, sacch. et gummi arab. q. s. ad pil. xx, daily one to five pills) or for children in solution (1:15, according to age three to ten drops). After prolonged use of this preparation, in some cases a disagreeable garlicky odor of the breath appears and causes us to desist from its use. Arsenic acts more readily by subcutaneous or parenchymatous injections (into the glandular substance) than by internal administration. Usually Fowler's solution is employed (beginning with 0.1 and cautiously increasing even up to one gram) or the solution of sodium arsenite advised by v. Ziems- sen, of which a somewhat larger dose is injected. But even here cacodylic acid is to be preferred on account of its greater solubility and larger contents of arsenic. A 10 per cent, solution of sodium cacodylate in sterilized water is used for about a week (one-half of a Pravaz syringeful being injected) ; it is then stopped for a few days, and then resumed, the same dose being injected, until gradually, with pauses of a few days, the dose is increased to an entire syringeful. Recently a preparation containing a large quantity of arsenic atoxyl (ani- lidmetarsenite) has been advised by Walter Schild, and this seems to deserve preference even above the cacod}date. Of a solution of two parts in ten of water, two to ten divisions of the hypodermic syringe are injected and the dose is gradually increased. The injections are almost painless, and are well borne. In the only case of Hodgkin's disease that I treated by this method the result appeared to be satisfactory, but the duration of observation was too brief to permit me to speak of a permanent success. A good auxiliary remedy in every arsenic treatment is formed by the min- eral waters containing arsenic and iron, those of Roncegno, Levico, Srebrenica (Guber spring), and of Cudowa (Eugene spring), which, on account of the arsenic they contain (and this is greatest in the Roncegno water and smallest in the Cudowa water), must be administered with all the caution with which we prescribe other arsenic preparations (therefore not upon an empty stom- ach), in from one to five tablespoonfuls for adults and as many teaspoonfuls for children; these waters are best administered in milk or Seltzer water. Besides, preparations of iodin have been administered internally and used as inunctions over the enlarged glands. They have, however, not proven par- ticularly serviceable. More effective are inunctions with potassium soap which, as is well known, 380 PSEUDO-LEUKEMIA is frequently beneficial in scrofulous glandular tumors. Ordinary green soap (sapo kalinus venalis) or the somewhat more agreeable fluid potassium soap (sapo kalinus) may be employed; of the former, according to the size and number of the enlarged glands, a piece the size of a cherry to that of a walnut, of the latter a teaspoonful to a tablespoonful and more, may be daily rubbed into the skin with a pellet of cotton until redness and burning are produced, when the rubbing is stopped and is not resumed until these irrita- tive symptoms have disappeared. Since it is often impossible to determine the nature of the glandular swell- ing, as I have previously stated, it is well to add to the soap substances which have a more or less specific action in particular diseases, for example, iodo- form in certain tuberculous processes (and also in many syphilitic ones). The potassium in the soap loosens the epidermis and the cement edges in the skin, and in this way the direct entrance of iodoform into the diseased tissue is facilitated. An inunction of this kind that I have used in other affections consists of : Iodoform 5.0, sapo kalinus and lanolin or unguentum adipis lanae or vaselin, aa 20.0. Extirpation of the glands, in so far as they are susceptible to operative interference, is unquestionably indicated in those cases in which a single gland or the pressure of several glands in this area causes disturbance or becomes dangerous. Opinions differ as to whether extirpation is advisable at an early period when only one or a few glands are slightly affected, since the results of such early excisions have varied. Some observers believe that extirpation of the glands, performed once or several times, induces a slower course or a long cessation of the disease, while others, on the contrary, have observed a more rapid growth of the glands to follow. The explanation of this variation may be that frequently, besides the external visible glands that may be reached, others lie more deeply hidden, or cannot be reached by the knife of the sur- geon, and the operative removal of the former, perhaps also of others which up to that time had not been implicated in the morbid processes, causes irritation. Early extirpation, therefore, can only be looked upon as an experiment which may meet with success, and this is the more likely the earlier it is attempted. Besides this treatment which is especially directed to the glandular swell- ing we must try by every means to reduce the anemia and improve the gen- eral condition. Above all, the patients should have the advantage of the most favorable hygienic conditions, nutritious food, fresh air either in the country or other suitable climate, as well as such measures as are possible in the indi- vidual circumstances for stimulating metabolism from the shin, such as fric- tion, baths, etc. All this may be most readily secured in properly chosen sanatoria. The most popular among these, probably on account of their well-known effect upon scrofulous glandular affections, are the sodium chlorid springs (particu- larly the stronger salt springs), and especially the iodin- and bromin-containing salt springs, such as those at Hall in Upper Austria, Krankenheil, Kdnigs- dorff-J astrzemb , Kreuznach and others. These springs are used for bathing, for poultices, and, with necessary caution, also for drinking. BANTI'S DISEASE 381 The most useful remedial measures for the latter purpose are tonics and roborants, and chiefly the preparations of iron and quinin. Arsenic when properly used has a tonic effect, and so improves the nutrition that if it is administered internally other remedial agents may be dispensed with, or sim- ply combined with arsenic. Lately a combination with ferrum cacodylicum in doses of 0.25-0.3 gram daily has been advised according to the following prescription: Ferr. cacodyl. 1.0, Aqu. cinnam. 25, of which 20 to 40 drops are taken three times daily. I need hardly say that in every dietetic and drug treatment attention to the digestive organs is of great importance, and if these show any disturbance of function, amelioration must here be first attempted. It is also self-evident that febrile conditions or possible complications are to be treated according to their special indications. [The X-ray treatment of Hodgkins disease seems at this time to promise more than any other. The number of cases is not large, but the results are often favorable. The technic is very simple; the affected glands are exposed to the X-ray for as long a period (every day or every second day) as the skin will stand without sustain- ing any " blush." Pressure symptoms due to substernal glands have thus been very notably relieved. — Ed.] BANTI'S DISEASE We turn now to the description of the second form of pseudo-leukemia, the lienal or splenic variety, in which enlargement of the spleen is predomi- nant or apparently occurs alone, i. e., without glandular enlargement. I say apparently, for, according to my investigations, the lymph-glands are almost always implicated. It is true that sometimes the enlargement affects only the deeper ones, particularly those glands situated in the abdominal cavity, and therefore recognizable only at autopsy. There are numerous cases, as I have mentioned previously, in which the spleen and lymph-glands are attacked simultaneously, and these cases are designated as pseudo-leukemia lymphatico- lienalis, and constitute a transitional stage between the two other forms. Aside from the glandular swelling and the course of the disease the clinical picture in the lienal form scarcely differs from that of the lymphatic form (Hodgkin's disease), and the description may consequently be brief. Besides the enlargement of the spleen, or even before this becomes notice- able, the earliest symptom is anemia, and Gretsel (Griesinger) has therefore designated the disease as " splenic anemia." But this name is not distinctive for, as later researches have shown, the blood finding does not, or at least not always, correspond morphologically to that of simple anemia. On the con- trary, manifold changes, particularly in regard to the number and proportional relations of the leukocytes, are met with, but never such a decided increase as in leukemia. At one time the blood may, in fact, resemble simple chronic anemia, i. e., the number of erythrocytes may be more or less decidedly de- creased, the hemoglobin to the same degree or even more decidedly diminished, and the proportion of leukocytes to erythrocytes, although varying not mark- edly, exceeds normal limits. [The very low color-index has been especially 26 382 PSEUDO-LEUKEMIA emphasized by Osier. — Ed.] At other times, with the same relation of the erythrocytes and of the hemoglobin, leukopenia is present; that is, there is a conspicuous diminution of the leukocytes below the lowest normal limits. In still other cases there is a relative decrease in the polynuclear neutrophilic leukocytes, which normally make up about three-quarters of the leukocytes. Sometimes the cells designated as lymphocytes are predominant, i. e., a lym- phocythemia is present. In conclusion, a blood change is found which in some respects resembles pernicious anemia; namely, nucleated erythrocytes of nor- mal or larger size (normoblasts and megaloblasts) are seen, and with this an increase in the leukocytes, sometimes of the polynuclears, sometimes of the lymphocytes. This latter blood composition is observed pre-eminently in infancy, and has been described by v. Jaksch as anemia infantum pseudoleukemia. This is a pseudo-leukemia which has special characteristics in the infantile organ- ism. Normally the infant's leukocytes are more numerous than those of the adult, and in the child the lymphocytes also are more profuse, and from the hyperemic red marrow of the growing bones nucleated young erythrocytes more readily enter the circulation. These nucleated erythrocytes, according to our present views, are to be regarded as immature corpuscles. Other blood lesions such as poikilocytosis, increase of the blood plaques, etc., are not characteristic. We must not expect that the same blood condition will be present in every case and at all times for, in the first place, these changes arise gradually in the blood with an increase of the anemia, and probably also with the growth in the spleen, corresponding to the growth in the glands, as in Hodgkin's disease. Thus, in this malady, as in the other form, periods of transitory improvement in the condition occur and the blood composition improves. Further febrile conditions may arise under the influence of which the number of leukocytes may change; for example, a leukopenia may give place to a leukocytosis; or, again, profuse hemorrhages in the disease may entirely alter the blood picture. In the splenic form of pseudo-leukemia, certainly in adults, hemorrhages are even more frequent than in the lymphatic form, especially hemorrhages from the nose and from the gastro- intestinal canal ; but there are also hemor- rhages from the gums, from the skin, and from the vitreous body of the eye, etc. [Osier has explained the gastric hemorrhages as due to the inability of the stomach veins (anastomosing with those of the spleen through the vasa brevia) to empty themselves on account of the cirrhotic process which forms part of the changes in the spleen. — Ed.] The urine is very similar to that of the lymphatic form. The implication of the liver in splenic pseudo-leukemia is very interest- ing. In the lymphatic form enlargement of the liver also occurs, due to the previously mentioned metastatic lymphomata or lymphomatoid formations. But these lymphomata are rarely of decided extent and rarely give rise to marked disturbance. In the splenic form, however, the liver is very fre- quently and conspicuously involved. Banti deserves credit for having first called attention to the combination of pscudo-leukcmic enlargement of the spleen with cirrhosis of the liver, and for having remarked the causal connec- BANTI'S DISEASE 383 tion between them; therefore quite properly this combination is designated as Banti's disease. The chief symptom by which cirrhosis of the liver may be recognized is ascites. Yet this may occur, as I have seen, in pseudo-leukemia in which the liver is not attacked, or to but an insignificant extent, so that besides cirrhosis of the liver, to which Banti refers the ascites in all cases, other causes may be operative. As such a cause I have mentioned displacement of the lymph channels in the abdominal cavity by enlarged lymph-glands, which, especially if combined with an anemic composition of the blood, and perhaps with stasis due to the marked enlargement of the spleen, may give rise to ascites. In some cases, disease of the portal vein may possibly be the cause. [A calcified thrombus of the portal vein has been found by Warthin in two cases of this disease (splenic anemia). — Ed.] Banti reports that in the disease named after him the intima of the portal vein from the anastomosis of the splenic veins to the liver has been found covered with coarse plaques similar to the sclerotic and atheromatous coats of the aorta. He assumes that toxic substances from the originally diseased spleen have reached the portal vein through the veins of the spleen, and later reached the liver, thus causing the pathological changes. In two cases belong- ing to this category upon which autopsies were held, and in which neither ascites nor liver cirrhosis was present (which, therefore, did not strictly rep- resent Banti's disease), these changes were not found either in the portal vein or in the splenic vein. They belong perhaps to a more advanced stage of the disease. But even if ascites is present the clinical picture deviates in many essential points from ordinary hepatic cirrhosis, that form known as " alcoholic liver." The enlargement of the spleen in pseudo-leukemia is much greater than in the latter, and the skin does not show the grayish yellow discoloration which is so usual in cirrhosis of the liver. On the contrary, it is pale, as in anemia, provided unusual circumstances do not bring about a darker pigmentation. For example, Osier has observed in some cases a melanotic discoloration due to an old malaria. Furthermore, the urine is usually of a different compo- sition, without bilirubin and urobilin, provided special complications, such as decided stasis due to ascites and the like, are not present. We must, however, agree with Banti that in the clinical condition named after him the enlargement of the spleen is the primary affection and not the result of enlargement of the liver. In the other cases of splenic pseudo-leu- kemia not associated with hepatic cirrhosis, it can no longer be doubted that the enlargement of the spleen is the primary affection to which the other disturbances, particularly the anemia and the abnormal composition of the blood, may be attributed. The anatomical condition of the splenic tumor is usually reported as dependent upon hyperplasia, but microscopic investigation shows variations which depend upon the extent to which the pulp and the Malpighian bodies as well as the trabeculae are implicated in the hyperplasia. It appears, or so I conclude from a case observed by me, that in early cases only the tissue of the pulp is hyperplastic owing to a decided increase of the lymph-cells in the 384 PSEUDO-LEUKEMIA reticulum. Afterward an enlargement of the Malpighian bodies with an in- crease in their cells is observed, so that they stand out as grayish white nodules of the size of a pea, having the characteristics of lymphomata. Finally, with the lapse of time the connective tissue proliferates, the capsule of the spleen becomes thickened, the spleen itself hardens and is permeated by more or less tense connective tissue strands by which the pulp is more and more obscured or absorbed. The follicles become thickened and enlarged and gradually lose their reticular structure and cellular stratification, being changed into tough fibro-cellular nodules. At last the normal structure of the spleen disappears to a greater or less degree, and only tough trabecular tissue remains. In this process, the larger vessels, the arteries, and particularly the veins, are often found thickened, sometimes also covered with chalk plates, such as Banti observed in the trunk of the splenic vein in cases complicated with hepatic cirrhosis. The cause of the enlargement of the spleen, i. e., the actual cause of the disease, is unknown. In the relation of the spleen to the blood, which, as I have already stated, may be compared to that of the lymph-glands to individual areas of tissue, it may certainly be considered that a deleterious element pres- ent in the blood exerts an irritation upon the spleen. What the nature of this irritation is we do not know. Specific bacteria or toxins, which nowadays so readily come into consideration, have not been found. Much favors the view that the damage originates in the gastro-intestinal canal, and thence reaches the blood. The circumstance that digestive disturbances, especially diarrhea, frequently precede enlargement of the spleen, and the fact that swelling of the lymph-glands in the abdominal cavity is rarely absent, favor this hypothesis. From this point of view the assumption is certainly justified that the dis- ease of the liver is not necessarily caused by enlargement of the spleen, but that it is the independent consequence of the same deleterious process. By this we do not intend to deny that the abnormally constituted blood which circulates from the spleen to the liver may cause pathological effects. It may be in con- sequence of the simultaneous action of both poisons — that of the gastro-intes- tinal canal and that of the spleen — that the hepatic cirrhosis sometimes devel- ops very early, at other times hardly at all. As a contribution to our knowledge of the etiology of pseudo-leukemia, it must be stated that in a fair proportion of cases the malady develops in the course of diseases in which enlargement of the spleen or a chronic splenic tumor already exists, or in the course of which it appears, e. g., in malaria, syphilis, particularly in that form which occurs in children, hereditary syph- ilis, and in rickets. The characteristic symptoms of the latter diseases grad- ually retrograde, while the splenic tumor persists or even increases; anemia and cachexia become more prominent, and gradually the boundary line between these maladies and pseudo-leukemia disappears, and it becomes impossible to say where the one begins and the other ceases. The character of the blood may in such instances decide the diagnosis, particularly if the change described by Ehrlich and Pinkus is present — or, at all events, a relative increase of the lymphocytes with a low count of leuko- BANTI'S DISEASE 385 cytes such as would exclude leukemia. But I have already mentioned that a hematological condition of this kind is not always present, even in cases that are to be strictly considered pseudo-leukemia. In these, another state of the blood combined with a characteristic enlargement of the spleen is of impor- tance in the diagnosis, namely, a simple high-graded anemia, i. e., oligocythe- mia and oligochromemia and this is especially so if leukopenia be also present. The recognition of splenic enlargement in cases of this kind can hardly be difficult, for the spleen early attains a size that is scarcely ever seen except in leukemia. Its lower border may reach anteriorly to the true pelvis, to the median line and even be}fond. The surface is smooth, and upon pressure the organ is but slightly or not at all painful. In the differential diagnosis all other hypertrophies of the spleen must be excluded, and this is usually not difficult, for acute enlargements do not come into consideration. The chronic enlargements, including tuberculosis and amyloid degeneration, which are somewhat rare, may be readily recognized, provided the etiologic factors and the condition of the other organs are. con- sidered. [" Idiopathic " splenic enlargement with anemia very slight or absent and no other symptoms at all is at times difficult to separate from some of the cases in this group. — Ed.] The diagnosis is made with less ease when ascites is present, not because there is any difficulty in determining the enlarge- ment of the spleen, but because the question then arises whether hepatic cir- rhosis is also present, and whether this or the enlarged spleen is the primary affection, i. e., whether Banti's disease has or has not developed. Here again an examination of the blood will aid in the decision provided the above-men- tioned changes are present. The enlargement of the spleen in primary hepatic cirrhosis is never so great as in Banti's disease, and, according to my experi- ence, the appearance of the skin and the condition of the urine in the latter affection are not the same as in hepatic cirrhosis. The course and termination, and therefore the prognosis of splenic pseudo- leukemia, do not differ greatly in adults from the lymphatic variety. The condition is different in children. Here not infrequently it is possible to bring about a decided improvement in the anemia and in the general condition, and even a diminution in the size of the spleen. I do not know whether or not this retrogression may be complete, but in cases not too far advanced I believe it possible. This difference in the nature of the disease in adults and in chil- dren may depend upon the action of the blood-forming organs, particularly the bone-marrow, which in children shows a more vigorous function. It is for this reason that children react more readily to deleterious agencies, and for this reason also an improvement is more easily brought about in children than in adults. In the treatment of this form of pseudo-leukemia the same factors must guide us as are decisive in the other variety, only that here not the enlarge- ment of the lymph-glands but that of the spleen is to be combated. Unfor- tunately drugs have even less power to influence this process than in the former instance. There are a certain number of so-called " splenic remedies," but they owe their reputation chiefly to their efficacy in malaria and in the en- largement of the spleen dependent upon this disease. Quinin is to be men- 386 PSEUDO-LEUKEMIA tioned first among these drugs, then piperin and eucalyptus. But, even in cases in which malaria has preceded, they have no effect upon the remaining splenic tumor ; and, besides, these patients have already taken quinin, arsenic or other remedies to a considerable extent. If not, arsenic in one of the forms previously mentioned may be employed, at least internally, on account of its stimulation to metabolism, and perhaps also because of its power in blood pro- duction. Subcutaneously atoxyl, which has already been mentioned, is espe- cially worthy of a trial. Parenchymatous injections of arsenic, of carbolic acid, etc., have been resorted to, but as these are not absolutely harmless, and are of questionable value, they are not advisable. Inunctions in the splenic region are useless, nor have I seen any benefit from massage or electricity. Somewhat more effective, it appears to me, is the application of cold to the splenic area, particularly in the form of the cold douche, the jet douche after Fleury, or the fan douche. These are best employed while the patient lies upon the right side of the body in a warm bath, with the left side of the abdo- men exposed. The most certain means of overcoming the splenic tumor and (in so far as this is considered to be actually the first of the main symptoms of the disease) to bring about recovery, is splenectomy. But this is neither so easy nor so harmless as the removal of the enlarged lymph-gland. Adhesions of the tumor to surrounding organs and marked hemorrhage present great difficulties in the operation, and endanger the life of the patient. Nevertheless lately, owing to improvements in technic, extirpation of the spleen has been success- fully accomplished in pseudo-leukemia, and in a number of cases has brought about the disappearance of the anemia and of the cachexia ; for what length of time is another question. Of course success is to be expected only when the disease has not existed for too long a time, and severe sequelae, such as cirrho- sis of the liver, multiple lymph-gland enlargement, etc., have not appeared. If ascites is present the attempt may be made to prevent its recurrence, and to bring about a decrease in the size of the spleen, producing a collateral circulation with the venous system of the body, by attaching the omentum and the spleen to the abdominal wall (after Talma or Schiassi). Extirpation of the spleen in children is less likely to be considered, for in them, as mentioned, the hygienic, dietetic and drug treatments are more effectual. Iodin and iron have proven serviceable, as well as arsenic; baths and a change of climate are to be recommended as in the lymphatic form. The same treatment is of course to be employed in adults. LITERATURE Askanazy, Ziegler's Beitr. zur path. Anatomie, Jena, 1888. Bonfils, Societe med. d' observation, Paris, 1856. G. Banti, "Lo Sperimentale," 1894, 1895; Ziegler's Beitr. zur allg. Path., etc., 1898, xxiv. Clarke, Brit. Med. Journ., 1901, ii, p. 701. /. Cohnheim, Virchow's Arch., xxiii. W. Ebstein, Bed. klin. Wochenschrift, 1887. LITERATURE 387 P. Ehrlich and F. Pinkus in Nothnagel's Spec. Path., 1901, vii, i. Fischer, Arch. f. klin. Chir., 1897, lv. Freudweiler, Dcutschcs Archiv f. klin. Med., 1897, Ixiv. Gretsel, Bed. klin. Wochenschrift, 1866, Nr. 20. E. Grawitz, Klin. Pathologie des Blutes, Berlin, 1902, 2 Aufl., p. 351 ff. R. v. Jaksch, Wiener klin. Wochenschr., 1889, Nr. 22, 23. A. Jolles, Zeitschr. f. klin. Med., 1898, xxxiv. Kundrat, Wiener klin. Wochenschr., 1893, Nr. 12, 13. J. H. Musser, Transactions of the Association of Amer. Physicians, 1901. Osier, Amer. Journ. of Med. Sc, 1900, January. Pel, Berliner klin. Wochenschr., 1885, 1 und 1887, 35. M. Reed, Johns Hopkins Hosp. Reports, x, 1902, Nos. 3-5. W. Schild, Berliner klin. Wochenschr., 1902, Nr. 13. H. Senator, Berliner klin. Wochenschr., 1901, Nr. 46. Sternberg, Centralbl. f. d. Grenzgeb. Med. u. Chir., 1899, ii. Wilks, Guy's Hosp. Reports, 1S56, ii. Talma, Berliner klin. Wochenschr., 1898, Nr. 38. B. Schiassi, "Un nuovo trattamento del Morbo del Banti," Bologna, 1902. THE HEMORRHAGIC DIATHESES By M. LITTEN, Berlin There is a group of diseases in which the essential symptom is a tendency to more or less extensive hemorrhage, which distributes itself over various organs and thus becomes dangerous to life. We designate this tendency to external and internal hemorrhages, which probably depend upon a change in the blood or in the blood-vessels, or in both, as the hemorrhagic diathesis. The diseases which belong to this group, which in some cases resemble one another so closely that it has sometimes been thought possible to combine them as one disease, were formerly designated " scurvy." But to-day there is much diversity of opinion as to how far this division is justified. In accordance with the present state of our knowledge, the following groups will be considered separately: 1. Scurvy; 2. Hemophilia; 3. Morbus maculosus Werlhofii. But even with these subdivisions it must be empha- sized that our knowledge does not often permit a sharp separation ; the boun- daries are partly artificial, being neither etiologically nor pathologico-anatom- ically defined with accuracy. SCURVY By scurvy we understand a general disturbance of nutrition which rarely occurs sporadically but usually epidemically, and almost always under the in- fluence of unfavorable, unhygienic circumstances, particularly that of improper food ; it is usually of insidious onset and slow course, and may terminate either in complete recovery or in death. The disease is characterized by a severe general cachexia and by a series of local disturbances chiefly due to a transitory hemorrhagic diathesis; this may present symptoms that completely coincide with those of hemophilia, of pur- pura hemorrhagica, or purpura rheumatica, but is sharply differentiated from the first by the fact that the changes are hereditary in the former affection and permanently present in the individual, while in the latter and in scurvy we are always dealing with an acquired disease which is generally transitory, and terminates in recovery or death, although frequently many relapses take place. HISTORY The history of scurvy is exceedingly interesting and important, as it dem- onstrates most forcibly the progress of hygiene and of scientific investigation. •388 SCURVY 389 When, after the discovery of America, shipping acquired new interest, when voyages which formerly were limited to the coasts of countries were extended over the open, wide sea, the brave seafaring men were confronted with new and quite peculiar conditions of life. Cut off for many months from land, exposed to the mercy of the winds and the waves, limited to the narrow confines of their ship, where they huddled together in large numbers, often exposed to great hardship, in the choice of food and drink they were entirely restricted to that brought from their homes, and particularly to such food as could be kept for a long time. Frequently they were compelled to subsist on food more or less tainted. It is obvious that such conditions would inevitably result in disease; and, great and brilliant as are the discoveries of that time, the great and hideous figure of scurvy, the disease which developed from these voyages of discovery, and which caused the failure of many expedi- tions, cannot be forgotten. In the year 1498, when Vasco de Gama undertook his celebrated voyage around the Cape of Good Hope, the crew was attacked by scurvy, and of 160 persons he lost in a short time more than one-third. We know well the deci- mating character of the disease which occurred in the expedition of Cartier in 1535, and in those of v. Monts, Pontgrave and Poutrincourt to Canada toward the end of the sixteenth century; in the French expedition of Dellon to India ; in the journey of the English fleet under Lord Anson around the world (1740-1744), in which voyage the disease recurred repeatedly in various latitudes, and 380 out of 500 men succumbed to the malady; in the North Polar expedition of Ellis (1746-1747) in search of the northwest passage to Hudson Bay; in the fleet of the English admiral, Gleary, who in 1780 re- turned with 2,400 scurvy patients, and in other expeditions. The reports of these expeditions are so definite that there can be no doubt of the identity of the disease. We have less information regarding the occur- rence of scurvy upon land, the first reliable report of which dated about a hundred years later, at which time the name scurvy or " scharbock " for the first time appeared. Our knowledge of the occurrence of the disease in an- tiquity is very limited, although it may be assumed that the peculiar condi- tions which favored the appearance of the pest, as later investigation has taught, must also have produced scurvy in earlier epochs. The best historical accounts of scurvy we owe to August Hirsch, whose description we have mainly followed. He succeeded, however, in finding in old medical writings only one form of the disease described which so far corresponds to the picture of scurvy that their identity may be assumed; namely, in the Hippocratic collec- tion, an affection described as etAcos aX\xla.riTr\%. Although the disease des- ignated as %r\rjvz