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11996'

L161— O-1096

Ketosis in
Domestic Animals

Clinical and
experimental
observations

By Jesse Sampson

Bulletin 524 : University of Illinois
Agricultural Experiment Station

ACKNOWLEDGMENT

IN THE PREPARATION of this bulletin the author is
indebted to many colleagues for their interest and assist-
ance. He is indebted to Dean Robert Graham of the Col-
lege of Veterinary Medicine for his encouragement and
support, and to other members of the faculty of the College of
Veterinary Medicine for generous aid and suggestions, par-
ticularly to those in the Department of Veterinary Physiology
and Pharmacology.

Special mention should be made of the help given by the
following members of the staff: Dr. C. C. Morrill, who sup-
plied the photographs shown in Figs. 1, 4, 5, and 8 (pages 430,
446, and 460) ; Dr. R. P. Link, who supplied the data shown in
Fig. 3 (page 443) and, with Dr. L. E. Boley, furnished the
data on ketosis in the horse, page 462 ; Dr. L. E. Boley and
Dr. Vera M. Hanawalt, who assisted in many ways during the
collection of data at the Illinois Agricultural Experiment Sta-
tion ; Dr. J. A. Henderson, who directed attention to several
references not readily available and made other suggestions.
Helpful criticisms were made by Dr. H. H. Mitchell and Dr.
T. S. Hamilton of the Laboratory of Animal Nutrition in the
Illinois Agricultural Experiment Station.

Former colleagues at Cornell University — Dr. C. E.
Hayden, Dr. M. G. Fincher, Dr. J. A. Dye, and Dr. Peter
Olaf son — gave valuable criticism. To Dr. H. H. Dukes of the
same institution the author is indebted for permission to cite
unpublished data obtained in experiments conducted by Dr.
Dukes and the author in the Department of Veterinary Physi-
ology at the New York State Veterinary College.

CONTENTS

Page

INTRODUCTION 407

I. KETOSIS IN RUMINANTS 410

KETOSIS (ACETONEMIA) IN CATTLE 41 1

Acetonemia Is an Old Disease 411

Economic Importance 415

Incidence 417

Progress in Study of Etiology 417

Ketonemia and hypoglycemia 417

Other changes in chemical constituents of blood 427

Changes in urine 427

Changes in milk 427

Relation of vitamins to ketosis of ruminants 428

Endocrine organs and ketosis of animals 429

Histopathology 431

Symptoms 431

Diagnosis 434

Treatment 435

Prevention 437

KETOSIS (PREGNANCY DISEASE) IN SHEEP 438

Numerous References to Ketosis in Ewes 439

Economic Importance 439

Incidence 440

Etiology Believed to Be Established 441

Gross and Microscopic Pathology 444

Symptoms 449

Cause of Death in Ketosis in Ruminants 450

Diagnosis 451

Treatment 452

Prevention 454

KETOSIS IN GOATS 455

II. KETOSIS IN OTHER DOMESTIC ANIMALS 456

KETOSIS IN THE SOW 456

KETOSIS IN RABBIT, CHICKEN, AND DUCK 461

KETOSIS IN DOG AND CAT 461

KETOSIS IN THE HORSE 462

SUMMARY 463

LITERATURE CITED 464

Urbana, Illinois December, 1947

Publications in the Bulletin series report the results of investigations made
or sponsored by the Experiment Station

KETOSIS IN DOMESTIC ANIMALS

By JESSE SAMPSON, Professor of Veterinary Research,
Agricultural Experiment Station"

INTRODUCTION

KETOSIS may be defined as an abnormal accumulation of the
so-called ketone or acetone bodies in the body. Ketonemia and
ketonuria refer to the presence of excess amounts of ketone
bodies in the blood and urine respectively. Acetonemia has the same
meaning as ketonemia and acetonuria is used synonymously with ke-
tonuria. The ketone bodies or ketone substances are organic chemical
compounds and include acetone, acetoacetic acid, and betahydroxy-
butyric acid.47

Origin of ketone bodies. The formation of ketone bodies is
called ketogenesis. A unanimity of opinion seems to prevail as regards
the source and origin of the ketone bodies. Specifically, authorities on
ketosis generally agree that the primary, if not the only, source of the
ketone bodies is the liver; furthermore, that the origin of these sub-
stances is mainly fat even tho it has been demonstrated that a small
number of amino acids, such as phenylalanine and tyrosine, may be
a potential source of these compounds. Betahydroxybutyric acid and
acetoacetic acid are believed to be partial oxidation products of butyric
acid. Acetone is thought to be a derivative of acetoacetic acid by the
loss of carbon dioxide.47

"Ketolysis" theory. — There are two divergent viewpoints regard-
ing the metabolic process that gives rise to ketone bodies in the body.
Apparently the first view, and until recently the more widely accepted,
is the theory of "ketolysis."117' 10 According to this theory fat catab-
olism, instead of going to completion to form carbon dioxide and water,
stops at the ketone stage whenever there is a deficiency of carbohydrate
in the metabolic mixture. An important function of carbohydrate
metabolism, adherents of the ketolysis theory claim, is that of con-
tinuing the catabolism and utilization of the ketone bodies formed
during fat catabolism. The ketolysis theory is illustrated by the oft
repeated statements that "Fats burn only in the presence of carbohy-
drates," or "Fats burn in the flame of carbohydrates."

" Also Professor of Veterinary Physiology and Pharmacology in the College
of Veterinary Medicine.

407

408 BULLETIN No. 524 {December,

"Antiketogenesis" theory. — The second, and at present the more
generally accepted point of view, is the theory of "antiketogenesis."18* 31
Optimum carbohydrate metabolism, according to this theory, inhibits
ketosis not "by increasing the utilization of acetone bodies, but by
keeping the production of these bodies down to a minimum (anti-
ketogenesis)."47 In other words, the first theory maintains that ketosis
is inhibited because catabolism (oxidation) of a minimum amount of
carbohydrate (glucose) aids catabolism and utilization of fat. The
second theory holds that ketosis is inhibited by the simple expedient
of increasing carbohydrate catabolism and decreasing fat catabolism.
This appears possible only if the liver has a liberal reserve of gly-
cogen.85' 82 Under certain conditions, discussed under experimental and
clinical studies of ketosis in cattle and sheep (pages 422 and 441),
the metabolic needs of the body, particularly for carbohydrate, are
greatly augmented. During such emergencies the body presumably
turns to fat in an effort to compensate for any carbohydrate deficit.
As Mirsky82 puts it, "A diminution in liver glycogen is the essential
prerequisite for an increase in fatty acid oxidation, resulting in an
accelerated rate of acetone body formation in the liver and a consequent
acetonemia."

Chemistry. That the chief source of ketone bodies is fat seems
to be well established.47 It is much less certain, however, just how
these substances are produced from fat in the liver. Oxidation of fat
in vivo apparently begins with hydrolysis of the fat molecule to
glycerol and fatty acid. Then further oxidation of these components
occurs. Glycerol, which represents about 10 percent of the fat mole-
cule, like glucose, probably gives rise to glycogen in the liver.47 Bio-
chemists have found great difficulty in following the changes that
occur during oxidation of the fatty acid fraction. A theory presented
by Knoop in 1904, however, provides a clue to a fundamental reaction
which may take place during intermediate fat metabolism. Knoop's
theory is that in each step in the breakdown of fatty acids that contain
an even number of carbon atoms (those present in natural fats)
oxidation occurs at the carbon atom in the Beta-position to the
carboxyl group. By this process two carbon atoms are split off in
each step until the 4-carbon atom stage is reached. At this stage,
acetoacetic acid is one of the products. This acid is then converted
to acetic acid, which undergoes further changes to carbon dioxide
and water.

A more recent explanation of fatty acid oxidation is known as
"beta oxidation-condensation" theory59 of MacKay and coworkers.

7947] KETOSIS IN DOMESTIC ANIMALS 409

This theory maintains that all fatty acid chains are oxidized at each
alternate carbon atom, the molecule splitting at each keto group to
form molecules of acetic acid except where a 3-carbon chain remains.
Such a chain forms proprionic acid, which can be changed to glucose.
Two molecules of acetic acid condense to form acetoacetic acid. For
further information on oxidation of fat and the formation of ketone
bodies, see discussion by Best and Taylor (1945).7

In vitro, oxidation of betahydroxybutyric acid gives rise to ace-
toacetic acid, and the spontaneous decomposition of acetoacetic acid
produces acetone and carbon dioxide. These reactions form the basis
of the Van Slyke quantitative method of analysis for ketone bodies in
blood and urine. These reactions are shown in the following diagrams
from Peters and Van Slyke (1932).93

CHs CHs CHa

CH(OH) CO CO

CH2 >CH2 — *CH3

oxidation by heat

COOH dichromate COOH CO2

B-hydroxybutyric acid Acetoacetic acid Acetone and carbon

dioxide

Analysis is first made for preformed acetone and acetoacetic acid.
A determination is then made for betahydroxybutyric acid. An alter-
nate procedure is a single determination in which heat and oxidation
of betahydroxybutyric acid by the dichromate are allowed to act
simultaneously, the result representing the sum of all three ketone
substances contained in the aliquot. In other words, by this technic
the total amount of ketone bodies is obtained by one distillation. The
technic for determining total ketone bodies is a popular procedure
because it is time saving. (The Barnes and Wick4 and the Weichsel-
baum and Somogyi141 technics are accurate procedures for the de-
termination of very small amounts of ketone bodies.) A common
practice is to express the results obtained by the analysis for either
betahydroxybutyric acid or total ketone bodies, as acetone.93

Physiologic and pathologic actions. Acetoacetic acid and beta-
hydroxybutyric acid behave like other acids in their effect on the acid-
base balance of the body; i.e., they tend to deplete the alkali or base
reserves and cause acidosis. In fact, the production of these acids in
diabetes mellitus of man may be so great as to lead to severe acidosis
(dangerous lowering of the alkali reserve) and coma94 (see discussions
on ketosis of the cow, ewe, and sow, pages 427, 442, 456).

Besides its acidic properties, acetoacetic acid is a toxic substance.7
Betahydroxybutyric acid, however, is relatively nontoxic. Acetone, on

410 BULLETIN No. 524 [December,

the other hand, is definitely poisonous to the body. According to
Sollmann,129 acetone given hypodermically to guinea pigs is more toxic
than methyl alcohol. Sollmann also states that inhalation of acetone
causes dyspnea, a progressive fall in body temperature, respiration,
and heart rate in proportion to the concentration of acetone inspired.
If guinea pigs inhale vapor containing 1 percent acetone for 48 hours,
or 5 percent for 5 to 8 hours, the spleen, lungs, and kidneys become
congested. At autopsy, pulmonary edema also is observed.

Altho the ketone bodies are produced by the liver, this organ is
apparently not capable of using them. Certain other tissues, partic-
ularly muscle, have the ability to utilize these substances.47 (Shaw
and coworkers122 have shown that B-hydroxybutyric acid is apparently
one source of energy for the active mammary gland in the cow.) If
the ketone bodies are produced in excess, the body tries to get rid of
the surplus by way of excretion thru the kidneys and the lungs.
Betahydroxybutyric acid and acetoacetic acid are neutralized and
eliminated in the urine largely in the form of sodium, potassium, and
ammonium salts. This accounts for the decrease in alkali reserve
which is often associated with ketosis. Acetone is eliminated mainly in
the urine but also to some extent in the expired air.94

It is therefore evident that when the processes of utilization and
elimination do not keep pace with the rate at which the ketone bodies
are produced, ketosis develops.59 The danger associated with ketosis
is a very real one. According to Sollmann,129 "It may be so severe that
animals die of coma before the fat depots are depleted. The coma is
due partly to acidosis, partly to the special toxicity of acetoacetic acid,
which causes air hunger or depression of the respiratory center."

I. KETOSIS IN RUMINANTS

Cattle, sheep, and goats are susceptible to ketosis. The economic
importance and world-wide distribution of clinical ketosis in the bovine
and ovine species is now universally recognized, but much less is
known about the importance and incidence of ketosis in the caprine
species (see page 455). Apparently nothing at all is known concerning
the susceptibility of such ruminants as the camel or members of the
deer family to ketosis. It will be no surprise, however, if future studies
reveal that some of these ruminants are susceptible to both experi-
mental and spontaneous ketosis, particularly under circumstances com-
parable to those which characterize the condition in cows and ewes.

1947] KETOSIS IN DOMESTIC ANIMALS 411

The reasons for this belief will be evident when the etiology of ketosis
in cattle and sheep is considered.

The ensuing discussion of ketosis of ruminants, especially of cattle
and sheep, probably explains why Groenewald, Graf, Bekker, Malan,
and Clark,45 in reporting results of a comprehensive investigation of
clinical and experimental pregnancy disease of ewes, concur with the
view expressed by Sampson, Gonzaga, and Hayden110 that ketosis in
these species has fundamental similarities, even tho spontaneous ke-
tosis is observed most often in late pregnancy in ewes in contrast to
early lactation in cows. Mclntosh,78 in discussing ketosis or acetonemia
of cows, also refers to these similarities and states that "In sheep there
is a striking counterpart of this disease which is referred to as a
Pregnancy Disease."

KETOSIS (ACETONEMIA) IN CATTLE

Acetonemia Is an Old Disease

According to Udall,137 the nervous form of the disease now known
as ketosis or acetonemia of cows was probably recognized as early as
1849 by Landel, who described it under the name of "mania puer-
peralis." Fleming's37 classic textbook, Veterinary Obstetrics, refers to
the reports of Storrar, Harms, Rolls, Robellet, Gunther, and Landel
on mania puerperalis of cows. Mr. Robellet's account appeared first
in Recueil de Med. Veterinaire and was later translated and incorpo-
rated in a report published by Rolls103 in The Veterinary Journal. Since
the nervous form of acetonemia of cows has been mistaken for rabies
even in recent times, the report by Robellet is of unusual interest.
Furthermore, Robellet employed chloral hydrate therapy, a practice
which some veterinarians still follow in treating acetonemia.116' 98
Robellet described his case as follows:

An affection in a cow, simulating Rabies, cured by chloral. On the 28th
of June, 1874, at eleven o'clock p.m., M. Dubost, of Chassaguy, came to
ask me to go as soon as possible to attend one of his cows, which was very
ill. This cow had calved on the 24th of the same month ; parturition had
taken place normally, and nothing had been noticed afterwards to indicate
either suffering or disease. On the morning of the day I was called, she
refused to eat at pasture ; the attendant noticed that she left the other
animals, and constantly licked her fore legs. In the cowshed she would
take no food, and licked herself until about eight o'clock p.m. She then
appeared restless, and bit all the things surrounding her. On my arrival,
the owner showed me a medium-sized cow, four years old. I approached
her cautiously, and found that she really bit her manger, her rack, and
food, which she allowed to fall again on the litter without masticating it;

412 BULLETIN No. 524 [December,

she also seized her breast and fore legs, but without breaking the skin.
I tried to ascertain the state of the pulse, and did so without difficulty,
the cow apparently not noticing me ; the artery was full, pulsations
sixty per minute ; the eyes, unnaturally open, were red, fixed, haggard,
and the pupils dilated ; the buccal mucous membrane was slightly inflamed,
a frothy saliva surrounding the borders of the lips; respiration was not
troubled, the respiratory movements being regular and about twenty per
minute. At times the cow stretched out her fore parts, bellowed, pawed
the ground with her fore feet, and seemed to defy an invisible enemy.
Taking advantage of her placing herself in one of these attitudes, I held
a prong-handle to her; she seized it frantically and bit it, shaking her
head violently.

These symptoms caused me to suspect Rabies. This, in fact, was the
diagnosis I gave, and I asked the owner if a mad dog had not been seen
in the neighborhood. His distinct denial, and the assurance with which
he declared his cow had not been bitten, slightly embarrassed me. Never-
theless, I doubled the chain she was fixed by, separated her from the others,
and then thought of treatment. I had read, some days before, the researches
of M. M. Horand and Peuch on chloral ; I remembered M. Peuch's ex-
periments with it in Canine Rabies ; and notwithstanding his failures,
relying on the well-known efficacy of this drug against any form of
nervous excitement, I administered an ounce and a half (50 grammes) in
two drenches of tea. I gave them myself, one a quarter of an hour after
the other, taking care to administer them gently, in order that the liquid
might go directly into the abomasum, and the effect be prompt. Several
minutes after the administration of the second drench, the cow, which
had continued showing the same symptoms, hung her head, and without
staggering, fell like an inert mass on the ground, then rose at once of her
own accord. Ten minutes after, the same occurrence took place ; the cow
again fell suddenly, but she at once jumped up again. The animal remained
in the same excited condition. I left her about two o'clock a.m. The next
day, at ten o'clock a.m., I returned, but what was my astonishment to
find that all the alarming symptoms of the night before had disappeared ;
the cow was lying on her near side, and was peacefully ruminating. On my
entry she rose and began to eat her litter ; there was no fever ; the ex-
pression of the eye was mild, and apart from slight weakness and prostra-
tion, the cow might have been considered cured. The owner told me that
half-an-hour after my departure she appeared to suffer less, and not so
frequently ; then having fallen a third time, she became drowsy, and
remained lying about three hours, after which she rose apparently well.

This observation is interesting in several ways: first, what disease
had I to deal with? Rabies alone presents the symptoms described above.
The cow, however, recovered, and this diagnosis must therefore be false.
Was this nervous excitement dependent on epileptic vertigo, or simply
nervous lactation? We doubt it. Can we ascribe it to acute Enteritis, or
to any poisoning, or to both these? No. There was neither Tympanitis,
Diarrhoea, nor Colic. One fact is certain, that it was a disease greatly
resembling Rabies, yet not really it. ... This observation also shows the
efficacy of chloral. The dose of an ounce and a half was not sufficient to
produce sleep; but the prostration of strength and the drowsiness were

7947] KETOSIS IN DOMESTIC ANIMALS 413

favorable to recovery. My father, veterinary surgeon at Briguais, now an
old practitioner, tells me that during his long experience he has only met
with two cases of this singular affectation ; the subjects were also cows
newly calved ; both recovered, but more slowly, doubtless owing to his not
having at his disposal so powerful an anaesthetic as chloral.

Rolls, commenting that he recalls no similar case reported in Eng-
lish veterinary publications, gives the following account of his ex-
perience with the disease which Fleming called mania puerperalis:
In the evening of January 12th, 1874, I was sent for in great haste to visit

a cow at W . . B On my arrival, I elicited the following

details from the cowman. The animal was five years old, had calved about
a fortnight before, during the night, and had eaten her "cleansing." She
had gone on favourably until the last day or two, when, as she seemed
rather poorly, he had given her a "red drench," which had not, however,
purged her. She had also recently been turned out into a fresh piece of
grass, while it was covered with white frost. Her calf had been removed
the night before.
>(V\ " .

According to Rolls, the cow showed the following symptoms:

Very wild excited expression ; eyes staring ; ears warm ; pulse full, rather
strong and quick; jaws continually moving, as if in the act of biting;
frothing at the mouth ; the under part of the tongue purple and livid-
looking. The movement of the jaws cannot be stopped by attempting to
hold them together. When left quietly to herself, she continually gnaws
her fore legs, without, however, making a wound ; when interrupted, she
will gnaw the manger, the woodwork of the place, or anything presented
to her. Thus, if hay was offered her she would seize it, masticate it with
the continuous and violent movement of the jaws, and swallow it. When
offered to her, she also swallowed some sloppy bran-mash and chilled
water. Although she has eaten nothing the greater part of the day, she
looks full ; and there is the peculiar sour smell often met with in cows
suffering from gastric derangement, but specially when it occurs shortly
after parturition. The bowels are in fair condition.

The impression left on my mind at this period was that the cow was
suffering from gastric derangement, and that the nervous phenomena de-
pended on, and originated in, that disorder. Treatment: — Venesection
from the subcutaneous abdominal vein, to the extent of a gallon. Ad-
minister extract belladonna 3 ij., to be repeated if necessary, ol. lini, Oj.
About three hours after my departure the convulsive movements ceased,
and the animal seemed much better. 14th. — Cow much better ; no con-
vulsive movements, but there is still an excited expression about her. Gave
a dose of ext. belladonna. 15th, etc. — Cow goes on favourably, feeds and
ruminates, but copious purgation has commenced ; this continuing for two
days, I thought it advisable to check it, and for that purpose gave tinct.
opii. cum pulv. gentian rad. in rice gruel. This speedily had the desired
effect, and after two or three days the animal was turned out to grass.

March 9th, 1875. I was stopped on my morning round to see the same
cow. The cowman reports: she calved a fortnight since, has not eaten her
"cleansing," as she was closely watched. Yesterday her calf was taken

414 BULLETIN No. 524 [December,

from her and this morning she was found suffering from a similar attack;
the jaws moving in the same way, and gnawing her fore legs, but not so
violently. He had bled her from the jugular vein, and before he left home
she seemed easier. On my arrival I found the cow looking very wild and
excited; pupils of eyes normal; ears warm; pulse eighty per minute, full
and strong; frothy about the mouth; under part of the tongue livid; grind-
ing her teeth occasionally ; the fore legs were wet and covered with saliva
from her gnawing them — this she has now ceased. The bowels were in
normal condition. Gave her an opiate I happened to have with me ;
ordered bran-mashes to keep her bowels regular. The cow was no further
trouble, and was turned out to grass on the llth inst.

In some remarks pertinent to his own observations as well as to
those reported by Robellet, Rolls says:

The two preceding cases will, I think, be at once admitted to be identical
in their nature. In my patient's first attack, gastro-intestinal derangement
was no doubt present for some few days before the nervous affection
appeared. That such was the case is shown by the symptoms, sour smell,
slight tympany, the excessive purgation on the third day, which was totally
out of proportion to the amount of aperient medicine given, also the cow-
man's statement that she had not seemed very well for a day or two. On
the second occasion, not the slightest gastro-intestinal derangement could
be detected, and the transition from health to disease appears to have
been sudden.

In M. Robellet's case, no symptoms of derangement of the digestive
organs were noticed, and in his speculative queries as to the true nature of
this affection, he appends to that special question a strong negative. We
may, therefore, I think, conclude that the view I first took of the affection
being connected with derangement of the digestive apparatus is erroneous,
and that its true nature consists in extreme nervous excitement caused by
the removal of the calf. The breeder informs me that she showed no symp-
toms of any disease, nor any special excitement, after her previous calvings,
and was sold by him, with calf at foot, to present owner early in 1873.

Fleming's37 comments on these cases are enlightening. Referring to
the cause of the disease, he states:

Rolls thought that in the case he describes, depriving the animal of its
calf was the cause of the attack; Harms ascribes the symptoms to chills,
which cause brain congestion ; while Storrar looks upon the malady as epi-
leptic, dyspeptic, and uterine. The animal affected has calved some few days
previously — say from four to fourteen, or even more days ; she has been
heartily eating her food; giving milk . . . [rich in cream] ; and the usual
uterine lochial discharge has been suppressed. Or the case might be thus
stated: An excessive drain upon the system by the mammary glands, caus-
ing, perhaps the suppression of the uterine cleansing, with the peculiar
smell about the animal, and more marked in her milk, which is referred to
by Mr. Rolls, followed by a more or less severely developed attack of indi-
gestion. These causes act upon the nervous centres, so as to produce the
extraordinary excitement which has been described. The dyspeptic signs
are the more prominently shown — such as a desire to eat any thing un-

7947] KETOSIS IN DOMESTIC ANIMALS 415

clean in preference to good food, or coarse straw in preference to roots or
hay. The bowels become torpid, and the supply of milk nearly ceases.

We can scarcely bring ourselves to believe that this condition is due to
psychial influences, and are rather inclined to attribute it to cerebral irri-
tation from some physical cause — either indigestion, constipation, or
deranged circulation in the brain, and connected with the parturient state.

In regard to treatment, Fleming offers this advice:

If indigestion or constipation are present, purgatives should be adminis-
tered, with stimulant or tonic medicines, according to the indications. When
there is much fury or excitement, narcotics in large doses may be given —
the best, perhaps, being chloral hydrate. Great attention must be paid to
the diet. Giinther abstracted blood in large quantity, and gave extract of
stramonium. He, also, on the supposition that the brain was congested,
applied strong stimulants to the back of the head and to the spine.

Under the subject "Depraved Appetite," Law65 presumably dis-
cusses ketosis when he refers to "digestive disorder" as a contributing
cause, altho he seems to imply that traumatic pericarditis may be
a more serious sequel of pica than is the presence of ketone bodies in
blood and urine. Among the other causes of pica or depraved appetite,
Law mentions heredity, soil, and hence crop deficiencies, heavy de-
mands on cows for secretion of milk and reproduction, and permanent
stabling of cows during winter and spring months. For opinions of
others as to the cause or causes of the disease now specifically referred
to as either acetonemia or ketosis of cows, see etiology, page 417.

Economic Importance

Accurate appraisal of the economic loss caused by ketosis of cows
is difficult because the disease is not associated with high mortality as
is true of clinical ketosis of ewes. Observations reported from widely
separated areas, however, suggest that clinical ketosis is responsible
for a heavy loss to the dairy industry^ especially in lower milk produc-
tion. It is also of considerable importance to the beef-cattle industry as
it occurs frequently in the heavier-milking cows of the beef breeds^8
Severely affected cows, if not given prompt and specific treatment, may
die, or if they eventually recover, are often unprofitable producers and
have a low market value if sold for slaughter. Sjollema and Van Der
Zande,128 in describing symptoms and calling attention to the economic
importance of acetonemia of cows in Holland, state:

Other symptoms are a small and capricious appetite, an impression of seek-
ing some particular substance, pica, dry faeces, forced and deep breathing,
irregular rumination, and a decreased milk yield. The animals lose much
weight, become thin and listless, and the gait is often more or less paretic.
... In exceptional cases, if diarrhoea appears, the disturbance may cause
death.

416 BULLETIN No. 524 [December,

In America, Truax136 of Iowa has said:

Acetonemia of dairy cows, though comparatively rare, is a doubly serious
condition. Constitutional damage to affected cows is grave and sometimes
fatal while milk yields from herds wherein this queer disease exists are,
more often than not, unfit for use. Because of these factors, owners of such
cattle become greatly discouraged, often to a point approaching com-
plete disgust.

Truax described ketosis in a herd of 18 head of dairy cattle, 12 of
which were mature cows. Three of the 12 cows were affected with
ketosis but manifested "no unusual symptoms other than the character-
istic odor of acetone in the milk and breath. However, the owner
emphasized that, at the onset, they had suffered a bad loss in weight.
In his own words, 'they had all gone to pieces.' '

Magill,72 of South Carolina, writing on field observations of bovine
acetonemia said:

I feel that not very many of these cases will die even though no treatment
is given. However, they do not milk more than one-half to three-fourths of
their normal flow and many will continue to yield the repellent acetone
odor in the milk for a long time, rendering it unfit for table use.

Fincher,35 reporting on acetonemia as he has observed it in the
dairy herds in the state of New York, said:

This disturbance of metabolism is thought by some to be unimportant be-
cause relatively few cattle die from uncomplicated acetonemia. The owners
of good dairy herds soon learn to appreciate the importance of this disease
when one takes the trouble to diagnose it regularly and accurately. Our
clients recall cases which showed symptoms of acetonemia and finally died
under treatment that we applied before acetonemia was recognized. . . .
The loss in production of milk because of acetonemia is not to be ignored.
Cows with acetonemia have to be discarded because of emaciation and low
milk production, and in many of these instances an early diagnosis and
the use of a specific treatment for acetonemia would have kept the cow in
production.

Duncan, Huffman, and Tobin,29 in reporting on ketosis of cows in
the state of Michigan state: "Since this disease became recognized, its
economic importance from the standpoint of loss in flesh, milk produc-
tion, and production of off-flavored milk has become more apparent,"
According to Knodt, Shaw, and White61 of Connecticut, "The prob-
lem of ketosis is becoming of as great concern to dairymen as it has
been to professional workers. ..." And in the opinion of Forbes,38
"The economic features of the problem stem from the facts that in
dairy cows the milk production and the general condition of the animal
are severely affected, while in the pregnant ewe death is likely to occur
or the young, when born, are unthrifty."

1947] KETOSIS IN DOMESTIC ANIMALS 417

Incidence

From what has been said concerning the economic importance of
acetonemia to the dairy industry, it seems evident that ketosis of cows
occurs wherever dairying is practiced. There is also other evidence of
its wide distribution. Hayes,49 who was among the first to describe
acetonemia in America, reported it from Texas ; while Alston,2 about
the same time, reported it from Mississippi. In his first report on ace-
tonemia, Alston named the disease "palsy after calving." Ketosis or
acetonemia of cows has been reported at various times in recent years
from many other states. Among these, not in chronological order, have
been reports from Alabama, Louisiana, Tennessee, Oklahoma, Georgia,
Florida, Kentucky, Indiana, Ohio, Kansas, Idaho, Missouri, Pennsyl-
vania, New Jersey, Massachusetts, Wisconsin, Minnesota, Nebraska,
and California. Presumably clinical ketosis or acetonemia of cows
occurs more frequently in the dairy herds of the South90 and East
than elsewhere; yet Sampson and Boley107 have reported that aceto-
nemia is not uncommon in the dairy herds of Illinois, a state located
in the corn belt of the United States.

As mentioned earlier, Sjollema and Van Der Zande128 reported
acetonemia in the dairy herds of Holland, and Hupka56 stated that
acetonemia undoubtedly was a common disease of dairy cattle in
Germany. It has also been reported from such other countries as Den-
mark,137 Norway,13 Sweden,137 England,137 and Canada.78 Messervy,7"
of the Royal Veterinary College of London, has made the significant
statement that "Though acetonemia has been known to exist in [the
Island of] Jersey for over 40 years it was described as dyspepsia."

Progress in Study of Etiology

Ketonemia and hypoglycemia. Practically all investigators who
have studied spontaneous, or clinical, ketosis of cows and ewes have
concluded that ketonemia and hypoglycemia are the most constant
changes found in the blood of affected animals. In severe ketosis of
cows (acetonemia) and of ewes (pregnancy disease) hypoglycemia is
usually pronounced. Ordinarily, therefore, an inverse relationship
exists between the levels of total ketone bodies and sugar of the blood
in ketosis of ruminants.113' 45' 102

Quantitative data on ketone bodies in blood and urine of cows
affected with clinical ketosis were, so far as the author is aware, first
published by Sjollema and Van Der Zande128 in Holland, and by
Sampson and Errington,109 and Sampson, Gonzaga, and Hayden110 in

418 BULLETIN No. 524 {December,

America. The data of Sampson and coworkers were obtained by chemi-
cal analysis of the blood of a Jersey heifer which, so far as could be
determined, was affected with uncomplicated acetonemia. The heifer
showed symptoms commonly associated with the so-called "digestive"
type of acetonemia: lack of appetite, sharp reduction of milk flow,
rapid loss of body weight, listlessness, and elimination of dry, hard,
mucus-covered feces. Normal parturition had occurred several weeks
before symptoms became noticeable. A concentration of 64 milligrams
of total ketone bodies for each 100 cubic milliliters of blood was found
before treatment was given.

Altho in the majority of cases of acetonemia of cows the level of
total ketone bodies of the blood is less than 64 milligrams for each 100
cubic milliliters, values greater than this are not uncommon, as shown
in Table 1. Such values are in sharp contrast to those found for nor-
mal bovine blood, which ordinarily contains less than 5 milligrams

TABLE 1. — TOTAL KETONE BODIES AND SUGAR IN BLOOD OF HEALTHY

Cows AND Cows AFFECTED WITH KETOSIS (ACETONEMIA)

(Ketone bodies expressed as acetone")

Healthy cows

Cows affected with ketosis

Cow

Ketone
bodies

Sugar

Cow

Ketone
bodies

Sugar

10

mg/100 ml
. 7 07

mg/100 ml
40.68
53.11
50.85
55.37
54.24
40.68
36.16
59.89
42.94

48.21

1 .

mg/100 ml
176.10

mg/100 ml
No detn.
36.16
42.94
44.07
36.16
18.08
42.94
36.16
31.64

28.51

435 ...

.74

2

70 . 93

556

62

3

. . . . 21.95

689

2 23

4

22.06

691

.99

5.

56.79

725

2.11

6

. ... 45.01

438

2 98

7.

32.12

540

0

8

27.90

721

99

9

49 . 35

2.21

55.80

• Van Slyke's method93 was employed for all determinations of ketone bodies given in this and
other tables reporting Illinois data.

percent and a maximum of approximately 6 to 7 milligrams per-
Cent2o, no, 12, 29, 62, 108 ( see a]so faDie \ ) jn fa\s connection, contrary

to the opinions expressed by Eden and Green,32 and Duncan et a/.,29
Sampson and Hayden113 believe that cows affected with even mild
ketonemia, i.e., when the content of total ketone bodies of the blood
may be only 10 milligrams percent, usually manifest one or more
symptoms observed in typical acetonemia, such as capricious appetite,
reduced milk yield, and excessive loss of body weight.

If it is accepted that ketonemia and hypoglycemia .are the primary
changes in the blood of cows affected with spontaneous ketosis, the

1947] KETOSIS IN DOMESTIC ANIMALS 419

question arises as to their significance. Some believe that ketonemia is
of minor importance and that the symptoms can be attributed largely
to low blood sugar. For example, Hupka56 states that the syndrome of
acetonemia of cows seems to be due to hypoglycemia. That hypo-
glycemia is the cause of symptoms observed in acetonemia, he says, is
supported by the low sugar content of the blood and knowledge of the
effects of large doses of insulin in producing intense hypoglycemia in
humans and animals. Hupka cites observations of Kruse who found
that large doses of insulin given to apparently healthy cows caused
such symptoms as depression, reeling, pressing forward, muscle twitch-
ing, salivation, licking, and deranged vision. (Pica, or depraved appe-
tite, so often observed in cows affected with ketosis is probably
associated with hypoglycemia. Best and Taylor7 say: "It will be re-
membered that one of the early symptoms observed in experimental
animals and also in human subjects after the administration of insulin
is an increase in hunger. In animals an attempt to consume material of
little nutritive value which under ordinary conditions they would not
attempt to eat is often observed.")

According to Hupka, the belief that acetonemia of cows is primarily
a hypoglycemic condition is also supported by the knowledge that
symptoms soon disappear after sugar is given. Roepke102 also is in-
clined to look upon hypoglycemia as much more significant than
ketonemia in acetonemia of cows. He says:

A low blood sugar level is another important finding in the more severe
cases. The seventy of the clinical symptoms, especially the nervous reac-
tions, muscular incoordination and depression, follow rather closely the
degree of hypoglycemia. Nervous reactions and muscular incoordination
usually do not appear until blood sugar levels are" reduced to about one-
half that of normal. Nerve cells use only carbohydrate as a source of
energy, and, therefore, suffer quickly when a low blood sugar level devel-
ops. The prompt improvement frequently observed after the intravenous
administration of dextrose also serves to illustrate the close relationship
between hypoglycemia and some of the clinical symptoms. The severity of
the clinical symptoms does not parallel closely the blood ketone concentra-
tion. Cows with high blood ketone values do not necessarily show muscular
incoordination and nervous reactions, unless the blood sugar values are
low, as mentioned above.

The importance of low blood sugar could hardly be stated more
clearly. Altho the author agrees with Hupka and Roepke that hypo-
glycemia is highly significant in acetonemia of cows, he is persuaded
that ketonemia also is highly significant because clinical ketosis has
been observed in cows with blood-sugar values in the normal
range110-12'107 (see also Table 1). Furthermore such evidence of re-

420 BULLETIN No. 524 [December,

covery as normal appetite and milk flow often does not appear until
ketonemia is dissipated.107

Reference to statements made on page 409 of the pathologic physi-
ology of ketosis furnishes evidence as to the deleterious effects of the
ketone bodies. It is well to bear in mind that even tho the ketone sub-
stances are looked upon as normal products of fat metabolism, it does
not follow that an excess of these compounds, especially acetone and
acetoacetic acid, in the blood and tissues can be tolerated with im-
punity.129' 19 For example, Mirsky,82 in discussing the question of
toxicity of the ketone bodies in diabetes mellitus of humans says, "For
some time minor controversies occurred with reference to the relative
importance of the acidosis or the toxic effects of the acetone bodies
themselves in the production of the coma. Today the physician is aware
that both are important."

Sampson and Hayden113 have called attention to the fact that
ketonemia in severe acetonemia of cows and in pregnancy disease of
ewes is often as intense as the ketonemia found in severe diabetes
mellitus of man. Limited data show that approximately 50 percent of
the total concentration of ketone bodies in spontaneous ketosis of cows
and ewes is in the form of preformed acetone and acetoacetic acid.45- 123
The toxic effects of acetone and acetoacetic acid can be demonstrated
by injecting relatively small amounts of these compounds into experi-
mental animals.105

The writer disagrees with the opinion frequently expressed that
ketonemia occurs in a large number of diseases of animals. So far as
he is aware, evidence has not been presented to show that significant
ketonemia occurs in steers, bulls, wethers, and rams no matter what
the disease with which they are affected. A mild ketonemia apparently
may develop in white-snakeroot poisoning.24

A significant spontaneous ketosis of the ovine and bovine species
in this country is limited almost exclusively to females during preg-
nancy and lactation (see also pages 431 and 449). This opinion is based
on published and unpublished data collected by the writer and his
associates since 1930, first at Cornell University and later at the Uni-
versity of Illinois. Hendershot50 has reported that severe ketosis occurs
in cattle of different ages and different sex in certain areas of the
Hawaiian Islands when the animals must subsist on forage known as
the Kiawe bean.

The brilliant studies of Mann and his associates73' 74 proved that
the liver is the primary source of blood sugar, exclusive of that which
enters the blood from the intestine.

1947] KETOSIS IN DOMESTIC ANIMALS 421

Furthermore, as McCleod77 has indicated, it is not likely that the
lactic acid which escapes into the blood during muscular contraction
and is later changed to glycogen in the liver, as shown by Cori,23 is a
significant source of sugar except in violent exercise. This apparently
leaves but one other important source, the conversion of protein to
glucose in the liver. That this process presumably can and probably
does occur is evidenced by the refractoriness of mature animals to the
development of dangerous hypoglycemia during prolonged fasting.84* 28
In emergencies, however, such as may exist in late pregnancy and the
first few weeks of lactation, when there is an increased demand for
energy,102' 38> 45 the available reserve of sugar stored in the liver as
glycogen may be rapidly depleted and, unless a liberal supply of glucose
is maintained by the ingestion of large amounts of sugars and starches,
a transitory lowering of blood sugar develops. While this is in progress,
the liver, as Mirsky82 points out, presumably turns to fat in an attempt
to make up for the carbohydrate deficit, and increased catabolism of
fat causes excess production of ketone bodies. This state of affairs, if
not arrested by ingestion and absorption of either carbohydrate or a
potential carbohydrate former (e.g., protein) continues until more and
more energy is derived from tissue protein and less from depot fat.
Concurrent with the increase in protein catabolism, there is apparently
an increase in available sugar and any lowering of the sugar content
of the blood is again restored to normal level.84 Since protein is more
antiketogenic than ketogenic,77 an increase in protein catabolism might
well account for the observed tendency of cows with mild ketosis to
recover without treatment.120 Similarly, the tendency of ewes affected
with mild pregnancy disease to recover after the lambs are born may
possibly be attributed in part to the antiketogenic effect of the break-
down of tissue protein as well as, presumably, to the sudden tho transi-
tory reduction in the demand for energy immediately following
parturition.

Is there experimental evidence to support the view that carbohy-
drate deficiency is the cause of hypoglycemia and ketonemia in rumi-
nants? The answer is that experimental evidence supports this view as
regards ewes but only limited experimental data are available to answer
the question with respect to cows. From a carefully planned experiment
to study the influence of diet on ketonemia in pregnant ewes, FYaser,
Godden, Snook, and Thomson40 draw these conclusions:

An inverse correlation exists between ketonaemia on the one hand, and
body weight and blood sugar on the other. Thus, with a fall in body weight
there is observed a corresponding fall in the blood sugar level, while at the
same time the ketones in the blood increase. . . It is evident from these

422 BULLETIN No. 524 [December,

figures that ketonaemia tends to increase with underfeeding, still more
with fasting, and to decrease when food intake is increased.

Reference is again made to the observations of Fraser et al. in the
discussion on ketosis, or pregnancy disease, of ewes (page 442). Simi-
larly, Groenewald, Graf, Bekker, Malan, and Clark,45 in a critical study
of experimentally induced ketosis or pregnancy disease of ewes, found
that intense hypoglycemia and severe ketonemia occurred in ewes that
were underfed ; whereas in ewes that received an adequate ration,
sugar and ketones of the blood remained at normal levels. For further
comment on the observations of Groenewald and coworkers, see
page 441.

Forbes38 demonstrated that under certain conditions fasting caused
a definite lowering of sugar and a significant rise in ketones of the
blood. For the production of experimental ketosis in cows and goats
Forbes states that it is necessary that —

. . . the animals be in good condition and that they be nearing parturition
or in early lactation. The first requirement should be met so that the fasting
animal may catabolize a sufficient amount of fat that ketone bodies in
excess of the amount utilizable will be formed. This is borne out by con-
sideration of the clinical experiences in ketosis and pregnancy disease in
which the most severe cases have occurred in the animals that were in
better condition at the start of the attack.

Furthermore, according to Forbes, the reason that —

. . . the dairy cow is more susceptible to ketosis during early lactation than
during late pregnancy, when goats and sheep are more susceptible, might
be explained by the fact that years of selective breeding have developed
an animal that produces several times more milk than she was originally
destined to do, and this strain on her system is even greater tha*n that of
pregnancy. That this strain is great, and that the cow is not completely
adapted to it, is shown by the consistently negative mineral, nitrogen, and
energy balances associated with the onset of a heavy lactation. Also, it has
been shown that during lactation the blood lipids are significantly higher
than during pregnancy in the dairy cow — the values tending to rise
quickly parallel to the milk flow and then to drop gradually as the milk
flow decreases. This is evidence of the intense fat metabolism associated
with a heavy lactation and explains in part why a ketosis can be most
readily produced at this time in the dairy cow.

From the clinical standpoint the bulk of available evidence supports
the belief that carbohydrate deficiency is the primary cause of hypo-
glycemia and ketosis in ruminants. Evidence on this point with refer-
ence to ewes appears in the discussion of pregnancy disease.

Evidence for and against the carbohydrate or caloric deficit point
of view for ketosis of cows is presented here. In support of this con-
ception may be cited the opinions of Forbes,38 whose observations have

1947] KETOSIS IN DOMESTIC ANIMALS 423

already been referred to, and those of Sampson and Hayden,112 Hen-
derson,51 Roepke,102 Duncan, Huffman, and Tobin,29 and Mclntosh.78
Sampson and Hayden have stated:

It is highly probable that the essential cause of the severe ketosis associated
with acetonemia of milk cows and pregnancy disease of ewes is a dis-
turbance in carbohydrate metabolism, due either to a lack of sufficient
carbohydrate or carbohydrate forming material in the ration or to an
insufficient supply of available carbohydrate stored in the body [liver].

It is evident, of course, that enough carbohydrate or carbohydrate-
forming material may be supplied by the ration and yet carbohydrate
deficiency may develop if the demands of the body for glucose are high
and the animal stops eating or if for some reason the carbohydrate
ingested is not assimilated and made available.

Henderson, in reporting a case of severe ketosis in a high-producing
Holstein-Friesian cow, says that apparently she secreted the dry matter
represented by approximately 25 pounds of milk daily at the expense of
her body tissues.

The fat, protein, and minerals which go to form this quantity of milk might
well be sacrificed without great inconvenience, but any considerable nega-
tive carbohydrate balance cannot long be tolerated without serious deple-
tion, of the [glycogen] reserves [in the liver], and presumably ketosis.

-Duncan, Huffman, and Tobin made a detailed study of acetonemia
in a purebred herd of dairy cattle in which a large number of the cows
in lactation were affected. Duncan et al. concluded:

The results would seem to indicate that high-producing cows on ordinary
roughage rations may be constantly demanding quickly soluble sugars to
satisfy the demand for endogenous carbohydrate metabolism, which cannot
be supplied indefinitely thru the catabolism of proteins and fats and dimin-
ishing deposits of glycogen, since the hay ordinarily used for stall feeding
is usually low in sugar in comparison to pasture plants. This may account
for the tendency for ketosis to occur more frequently in cattle during the
winter months.

Roepke said:

The more severe cases of acetonemia, which continue for three or four
weeks and require a number of intravenous dextrose injections to keep
them going along reasonably well, occur usually from 10 days to six weeks
after calving. Such cows are usually high-producing cows and the disease
occurs at a time when the stimulus for milk production is at its maximum.
At this time there is a tendency for a cow to utilize more energy for milk
production than can be replenished by the amount of food she is able to
consume and digest. High-producing cows during the early lactation period
usually draw on their carbohydrate and fat reserves and show a weight
loss.

Mclntosh has this to say:
When high producing cows commence to secrete large quantities of milk

424 BULLETIN No. 524 [December,

following parturition, sugar is removed very rapidly from the blood as it
traverses the mammary gland. For this reason an increased amount of
sugar must be available and be constantly added to the blood. This sugar is
obtained in part from the food the animal consumes and from the liver
glycogen. If the cow can eat enough sugar-producing food and her liver
can maintain the necessary glycogen level to meet with the lactation de-
mand nothing will happen. On the other hand, if the blood sugar level is
not maintained energy requirements will have to be provided from some
other source and it is then that the oxidation of fat in extraordinary
amount commences. The mobilization of these fat substances (ketones) may
exceed their removal from the blood and in turn lead to an excessive ac-
cumulation of them resulting in ketosis. It is, therefore, believed that the
failure of the liver to maintain an adequate level of glycogen is a major
factor in the onset of ketosis. This may be the result of an inadequate diet
or an error in the formulation of the diet or that the character of the diet
is such that it interferes with normal functioning of the liver and may even
cause retrogressive changes in it.

The belief that carbohydrate or caloric deficit is the major contrib-
uting cause of the development of ketosis of cows has been questioned
by Shaw118 because in one herd of high-producing Holstein cattle, the
incidence of ketosis was apparently not reduced by feeding molasses
(one or two pints daily in addition to the regular ration for several
weeks in late pregnancy) prior to parturition. On the basis of these
observations Shaw concluded that "since the liberal feeding of molasses
prior to parturition failed to prevent ketosis, a soluble carbohydrate
deficiency is not indicated." Shaw recognizes, however, that apparently
there is a close relation between the amount of liver glycogen and the
development of ketosis in cows because he also says:

It is apparent that the hypoglycemia observed following parturition is
closely associated with the initiation of milk secretion and the demands of
the mammary gland for blood glucose. Under normal conditions these de-
mands are apparently not excessive. With depleted glycogen reserves, the
sudden increase in the utilization of glucose by the gland would be expected
to lower the liver glycogen content still further. ... A sudden increase in
the mobilization of glucose undoubtedly takes place with the initiation of
milk secretion and probably is a major factor in the development of ketosis.
This could account for the development of ketosis if the liver glycogen was
low at the time of parturition. Some degree of more or less permanent
damage to the liver might account for the failure of many cases to respond
readily to glucose therapy. The annual recurrence of severe ketosis in some
cows following parturition could also be explained on this basis.

It will be noted that altho Shaw's interpretations are not in accord
with the belief that a carbohydrate or caloric deficit is probably the
most significant influence, they closely parallel other opinions concern-
ing the relation of liver glycogen to spontaneous ketosis of ruminants.

7947] KETOSIS IN DOMESTIC ANIMALS 425

With reference to the amount of oxidizable carbohydrate available
to the fasting ruminant, Ritzman and Benedict97 made the interesting
observation that the sheep, altho carrying a large amount of material
in the rumen,

... is similar to other animals in its reaction to fasting, in that its supply
of oxidizable carbohydrate (glycogen) is small and a respiratory quotient
indicating predominantly fat combustion is reached not far from forty-
eight hours after ingestion of food.

Despite the fact that the reserve glycogen stored in the liver is im-
portant in maintaining an adequate concentration of glucose in the
blood when sugar is not absorbed from the intestine for any consider-
able length of time, it is well to recognize the transitory nature of this
source of sugar. In discussing the significance of hepatic glycogen,
Soskin130 says:

The liver glycogen thus represents a reserve of carbohydrate upon which
the liver may draw quickly while the gluconeogenetic processes are acceler-
ating to an adequate rate. While this reserve is important for temporary
emergencies, it is not always sufficiently appreciated that it represents a
rather small amount of carbohydrate as compared to the body's daily re-
quirements. If we assume, for example, that a man weighing 70 kgm. with
a liver weight of 1800 gm. has an average good glycogen store of about
6 percent, this would mean a total liver glycogen of 108 gm. If gluconeo-
genesis were to cease, this amount of carbohydrate could supply the re-
quirements of his extra hepatic tissues (roughly 14 gm. kgm. per hour) for
about 6 hours only. The relative importance of the gluconeogenetic proc-
esses as compared to the liver glycogen reserve is obvious.

On the basis of the foregoing statement by Soskin that if gluco-
neogenesis were to come to a standstill, the reserve glycogen stored in
the liver of man would supply the extra-hepatic need for sugar for
only six hours, it seems equally obvious that the stored glycogen in the
liver of either the cow or the ewe is also inadequate to supply the
extra-hepatic requirements for sugar for more than a short time.
Apparently, as Ritzman and Benedict have shown, decreasing amounts
of swgar are absorbed from the intestinal tract of the ruminant (sheep)
48 to 72 hours after the last ingestion of feed (when fed an ordinary
ration) and then the animal must depend upon the reserve glycogen in
the liver for glucose until the process of gluconeogenesis is sufficiently
accelerated to supply the demand.

As to the amount of available glycogen present in the bovine liver,
the data of Knodt and Petersen60 indicate that the dairy cow probably
has a low reserve. These investigators analyzed the livers of 20 cows
and found the glycogen content ranged from .15 to .38 percent, with
an average of only .25 percent. Knodt and Petersen state that these

426 BULLETIN No. 524 [December,

low values may have been accounted for in part by the effect of fasting
"since these cows had probably not been fed for at least 24 hours
previous to slaughter." Roderick, Harshfield, and Merchant101 found
that livers of six apparently normal pregnant ewes contained from
3.36 to 4.29 percent glycogen with an average of 3.77 percent. These
data are on a fresh basis.

According to Sisson and Grossman,126 the average weight of the
bovine liver is approximately 5 kilograms and that of the ovine liver
about 600 grams. Using the average value of .25 percent of Knodt and
Petersen for liver glycogen content, a simple calculation reveals that
the liver of the cow contains only about 12.5 grams of reserve glycogen.
This is probably too low, as Knodt and Petersen have indicated, but
even if we use the value for sheep, i.e., 3.77 percent, and the calculation
made on the basis of a 5-kilogram liver, less than 200 grams of glycogen
would be available for emergency needs. The 600-gram liver of the
ewe would contain only 22.6 grams of available glycogen, assuming
that the average glycogen content is 3.77 percent.

It seems clear, therefore, that in advanced pregnancy or during
heavy lactation, when there is an increasing demand for glucose, the
store of reserve glycogen in the liver would soon be depleted if it were
not replenished from the glucose entering the blood from the intestinal
tract. Even if a maximum storage of liver glycogen, certainly a desir-
able state, were effected by feeding liberal amounts of concentrated,
easily assimilated carbonaceous feeds, such as molasses or corn sugar,
with ordinary rations composed of cereal grains and roughage or silage,
depletion of reserve liver glycogen would presumably occur whenever
the pregnant or heavily lactating cow or ewe went "off feed" or was
fed an inadequate ration, especially a ration low in energy or caloric
value.

A number of investigators who have studied ketosis, or pregnancy
disease, of sheep believe that it is often beneficial to supplement the
ration fed to ewes during the latter part of gestation with small amounts
of molasses or other easily assimilated carbohydrate.75' 45 Presumably
there is just as much justification for feeding several pounds of easily
assimilated molasses or corn sugar with the average ration of concen-
trates and roughage fed to the high-producing dairy cow during the
early part of lactation (or even before the onset of lactation, i.e., before
parturition) when she is most susceptible to the development of ketosis,
as there is to feed concentrated, readily available molasses or sugar to
the pregnant ewe. Molasses may be beneficial primarily because of its
effect as an appetizer to increase the palatability of the ration. It also
has a laxative effect.

1947] KETOSIS IN DOMESTIC ANIMALS 427

The practice of feeding molasses or sugar should not, however, be
considered an infallible measure for preventing ketosis in either cows
or ewes. This is suggested by the report of Ritzman and Benedict and
by the knowledge that only a relatively small reserve of glycogen can
be stored in the liver under the most favorable circumstances. Further-
more, Hamilton46* has reported that when glucose, to the extent of ap-
proximately 20 percent of the energy intake of steers and sheep, is
added to the ration, the microorganisms in the rumen apparently fer-
ment this sugar entirely to the exclusion of cellulose, which otherwise
would be fermented in comparable amounts.

Other changes in chemical constituents of blood. In severe ke-
tosis of the bovine there is often a lowering of the carbon dioxide
combining power or alkali reserve of the blood, but in the majority of
cases values are within the normal range.128' 112> 29> 32 Acidosis is there-
fore not believed to be an important factor, but the true significance of
changes in the acid-base equilibrium of the blood and tissues is still
unknown. There is often a marked increase in blood cholesterol,128 but
in uncomplicated ketosis of cows normal values are usually found for
calcium, inorganic phosphorus, magnesium, chlorides, and nonprotein
nitrogen.128' 110- 112' 29

Changes in urine. Sjollema and Van Der Zande128 reported as
much as 10 to 13 grams of total ketone bodies per kilogram of urine
in acetonemia in contrast to .1 to .7 gram per kilogram of normal urine
of cows. High concentrations of ketone bodies in urine of cows affected
with ketosis also have been reported by Sampson and associates,
Duncan et a/.,29 and others.38' 123 Sjollema's maximum value of .7 gram
is probably too high because the urine of healthy cows rarely contains
as much as .3 gram per liter.112' 61 Urine of cows affected with ketosis is
often acid because of the high content of ketone substances. For the
same reason, there is usually a great increase in the content of ammonia
in the urine of these cows110 (see page 410). Sjollema and Van Der
Zande reported 10 to 20 times more calcium per liter of urine of cows
affected with acetonemia than in normal bovine urine. a In some cases
of ketosis of cows the urine is colorless while in others the normal
straw color seems to be intensified.

Changes in milk. That milk produced by cows affected with
ketosis may contain an appreciable amount of ketone substances has
been observed by both practicing veterinarians and research workers.
For example, Sjollema and Van Der Zande128 reported 3 to 4.5 grams

a The author has observed, however, that many cows affected with ace-
tonemia excrete relatively small amounts of calcium in the urine.

428 BULLETIN No. 524 [December,

of total ketone bodies per kilogram in the milk of some cows affected
with acetonemia. In contrast, milk of normal cows contains only traces
of ketone bodies.29' 107' 62

Total ketone bodies in milk of cows before recovery from aceto-
nemia are shown below (Illinois data, ketone bodies expressed as
acetone) :

mg/100 ml mg/100 ml

Cowl 31.25 Cow 4 5.46

Cow 2 7 .44 Cow 5 8 . 68

Cow 3 30.38 Cow 6 17.86

No ketone bodies were found after these cows recovered.

Relation of vitamins to ketosis of ruminants. No critical evi-
dence has as yet been presented to indicate the existence of any re-
lationship between vitamins and ketosis of animals. The possibility
of vitamin BI deficiency in acetonemia of cows has been suggested by
Carlstrom,16 but it is difficult to explain a deficiency of this vitamin
because the concentrates of rations fed to dairy cows are ordinarily
well fortified with BI and also because the mature ruminant has the
ability to synthesize this vitamin in the rumen.28' 76 Patton90' 91» 92 be-
lieves that acetonemia is a vitamin A deficiency, but this belief is
based upon meager and conflicting evidence. For a review of this
evidence, the reader is referred to the original articles published by
Patton.

Attention is called to the difficulty which may be encountered when
an attempt is made to produce experimentally vitamin A deficiency in
the dairy cow. For example, Schmidt115 found that it required ap-
proximately 24 months to produce symptoms of vitamin A deficiency
in five Jersey cows fed a ration which was extremely deficient in
vitamin A or its precursor, carotene. According to Schmidt, night
blindness is the first noticeable symptom to develop in the syndrome
of vitamin A deficiency, and it seems significant that so far as the
author is aware night blindness has never been described as a symptom
of uncomplicated acetonemia of cows. (Freer and Hayden42 mention
temporary blindness in one case of acetonemia.) Schmidt also em-
phasizes swellings, particularly of the front legs, in vitamin A de-
ficiency. This symptom is rarely, if ever, observed in acetonemia of
cows. Furthermore, ketosis has occurred in cows that were fed liberal
amounts of green alfalfa and clover hay and even in cows with ac-
cess to green pasture,107' 12> 123> 98 altho it seems evident that it is less
likely to develop during the pasture season than during the months
when cows are kept indoors and stall-fed.29 In this connection the
observations reported by Sutton and Soldner134 on the seasonal con-

1947] KETOSIS IN DOMESTIC ANIMALS 429

centration of vitamin A in the blood of dairy cattle are of interest.
These investigators found that vitamin A content of the blood of dairy
cows was highest during the months of October to March and lowest
during May and June.

It is now recognized that determinations for vitamin A in blood
may not provide sufficient evidence for diagnosing a vitamin A dis-
turbance.87' 88 Apparently the liver may contain appreciable amounts of
vitamin A even tho an animal is in a state bordering on cachexia.
Moore, cited by Linton and Brownlee,67 found that extreme emacia-
tion in rats did not necessarily reduce the vitamin A reserves of the
liver; and Linton67 has shown that livers of hens and geese which had
been starved to death contained large reserves of vitamin A in spite of
the rigors of starvation. Further comment on vitamin A and ketosis
is given on pages 436, 437, 453.

Endocrine organs and ketosis of animals.a With the possible
exception of the dog, evidence so far accumulated does not indicate
that natural, or spontaneous, ketosis of animals is associated with a
specific dysfunction of any endocrine organ. Diabetes mellitus has
been reported occasionally in dogs, but we are aware of only one
report of spontaneous diabetes occurring in ruminants, one in swine,
and none in other species of domestic animals. The sole case of diabetes
in ruminants was described by Sjollema and Van Der Zande128 in a
cow. Spontaneous, or natural, ketosis has been studied in the cow, ewe,
goat, and sow, and in none of these has it been shown that a lack of
insulin and impairment of the animal's ability to utilize carbohydrate
were involved.

A possible relationship has been suggested between dysfunction of
the pituitary gland and ketosis of cows,36 but more evidence is needed
before a conclusion is warranted.

There is little doubt, on the other hand, but that the liver is in-
volved, tho there is some question whether this organ belongs to the
endocrine system. In the light of our present knowledge of carbohy-
drate and fat metabolism, however, the processes that lead to ketosis
appear to be more physiologic than pathologic in nature.47 If true
hepatic dysfunction occurs in ketosis of ruminants, it probably does
not develop until late in the syndrome, when treatment with glucose or
similar carbohydrate often fails to prevent death of affected animals.107

* The discussion on endocrine organs was prepared before Shaw120* pub-
lished results of a study on the relation of the adrenal cortex to ketosis in the
cow. Shaw concluded that the adrenals are probably not involved in ketosis of
the bovine, but that cortical extract might nevertheless prove beneficial in
treatment.

430

BULLETIN No. 524

[December,

1947] KETOSIS IN DOMESTIC ANIMALS 431

Histopathology

The histopathology of ketosis in ruminants has been studied more
thoroly in ewes than in cows. In fact, relatively few reports have been
made of such studies in the bovine. A much lower mortality in ketosis
of cows than in ketosis of ewes probably explains the scarcity of
such observations. Furthermore, histopathologic studies of ketosis in
cows have been limited largely to those organs which usually show
gross changes, namely, the liver and kidneys.

Sjollema and Van Der Zande128 examined the liver of a cow that
had died of acetonemia 10 days after parturition. The liver was yellow
and somewhat enlarged. Microscopic examination showed some fatty
degeneration. Similar fatty degeneration was seen in the heart, and
kidneys._Fatty changes in the liver of a cow that died of ketosis were
also observed by Roderick and Harshfield." Such changes have also
been reported by Mclntosh,78 who states, "Post-mortem examination
of cows which die from the disease ketosis or acetonemia reveals a
fatty liver. ..." Morrill114 made a careful histopathologic study of
the liver of a pregnant beef heifer affected with severe ketosis and
found a high content of lipoidal material (Fig. 1).

Additional comment on fatty changes in the liver and kidneys of
ruminants affected with ketosis appears in the discussion of pregnancy
disease of ewes, pages 445-447.

Symptoms

Ketosis in cows has been described many times during recent years.
Sampson, Morrill, and Alberts114 published a detailed report on spon-
taneous ketosis in a Hereford heifer during advanced pregnancy, and
Kingman et a/.58 and Rainey95 also call attention to the fact that cows
in late pregnancy may develop clinical ketosis. Ketosis in the bovine
is, however, primarily post parturient. Data collected by Henderson51
on age, breed, and time of year in relation to incidence of ketosis in
cattle are shown in Table 2. According to Messervy,79 the incidence of
ketosis of cows in the Island of Jersey is about the same thruout
summer, autumn, and winter. And Schwab116 states that acetonemia
occurs at all seasons of the year in Wisconsin.

Certain striking manifestations have been mentioned in nearly all
descriptions of bovine ketosis or acetonemia, but it cannot be said that
all cows affected with ketosis show the same symptoms. Usually,
however, if the affected cow is lactating there is (1) a marked de-
crease in milk production,8 (2) increasing somnolence, and (3) rapid

* Occasionally a cow affected with ketosis continues to produce .well, but in
such cows the loss of condition is usually greater than normal in spite of high
caloric intake.

432 BULLETIN No. 524 [December,

TABLE 2. — RELATION OF AGE, BREED, AND MONTH OF YEAR
TO PRESENCE OF KETOSIS (ACETONEMIA) IN Cows*

Relation of age

Calves born

Cows in
each
class

Cases of
acetonemia

Approxi-
mate
ratio

Calves born

Cows in
each
class

Cases of
acetonemia

Approxi-
mate
ratio

1.

165

8

1:21

5. . .

. 45

4

1:11

2

132

12

1:11

6

26

2

1-13

3

98

14

1: 7

27

2

1:13

4.

72

8

1: 9

Relation of breed

Holstein

Jersey

Guernsey

Ayrshire

Brown
Swiss

Shorthorn

260

131

89

93

36

20

24

13

11

7

0

0

Approximate ratio (1 :)

11

10

8

13

Relation of season

Jan. Feb. Mar. Apr. May June July Aug. Sept. Oct. Nov. Dec.

Number of parturi-

85

61

58

27

25

19

33

41

50

71

66

75

Cases of acetonemia
Approximate ratio
(1:)

8
10

7
8

14
4

5
5

1

25

2
9

2
16

2
20

2

25

3
23

3

22

6
12

» Data of Henderson slightly modified. Cornell Veterinarian 28, 173-195 (1938).

emaciation.128- 107 A few cows are in an excited state, and such cases
have frequently been erroneously diagnosed as rabies (see pages 411
and 412). Cows affected with the nervous type of ketosis may
push against a fence, wall, stanchion or other immovable objects.
Often they walk on their "knees" and manifest other unusual move-
ments. With some exceptions, affected cows have an irregular and
often complete lack of appetite. Body temperature, respiratory and
pulse rates are usually normal (except in cases of the nervous type).
JThe feces are often hard, dry and covered with mucus, altho diarrhea
is observed in a few cases. Atony of the rumen may or may not be
present. Th£ abdomen is often "tucked up" and the cow stands with
the hind feet pushed forward under the body. In some cases scoliosis
is a prominent symptom. The head is often carried in a lowered posi-
tion and, if the cow is lying down, the head often rests in the flank
as in milk fever. The eye is usually dull and lusterless (Fig. 2).

The dejected and listless attitude assumed by most cows affected
with ketosis, together with the elimination of hard dry feces, probably
accounts for Hupka's56 classification of bovine ketosis into "digestive"
and "nervous" types. Actually this classification is misleading. As

1947]

KETOSIS IN DOMESTIC ANIMALS

433

Severe uncomplicated ketosis (acetonemia) of nonnervous type in a high-
producing dairy cow. This cow was in excellent condition at the time of
calving. A marked loss of body weight occurred during the attack. The cow
was very weak when these pictures were taken and died after treatment
with chloral hydrate. See page 436 for further comment. (Fig. 2)

Sjollema and Van Der Zande128 point out, even tho the symptoms
"resemble those of indigestion . . . acetonemia causes changes in the
composition of the urine which are different from those due to acute
indigestion. In some cases a veterinarian made the diagnosis of
acetonemia, but found he was mistaken when we declared the urine
to indicate an acute indigestion." Also it is significant that the usual
treatments for indigestion in cows are ordinarily not effective for
ketosis. It would seem advisable, therefore, to discontinue the use of
the term digestive and describe ketosis of cows as nervous and non-
nervous types.

In addition to the symptoms that have been mentioned, many cows
affected with ketosis show evidence of pica and an exaggerated desire
for licking their bodies or nearby objects. (For further comment on
symptoms see clinical discussions by Udall137 and by Hutyra, Marek,
and Manninger.57)

Finally, the cow affected with severe ketosis may be unable to rise,
somnolence is increased and is frequently followed by coma and
death. An interpretation of the symptoms and an explanation of the
histopathology and death in ketosis of cows are purposely omitted here.
These topics are considered from a comparative viewpoint in the
discussion of ketosis in ewes, page 450.

434 BULLETIN No. 524 [December,

Diagnosis

In discussing the diagnosis of ketosis in cows, Sampson105 has
stated :

The writer does not believe an accurate differential diagnosis can be made
without recourse to a test of the urine for the presence of ketone bodies.
In many instances it is difficult to determine whether a cow is affected
with atony of the rumen, metritis, ketosis, or a combination of all three
without checking the urine for ketones. [Indigestion, metritis, and ketosis
may occur simultaneously or independently.] Even a light purple color,
if the test is made with undiluted urine, should* not be dismissed without
some possible significance because the cow may be in the very early stage
of an attack. Some veterinarians responsible for the health of individual
dairy herds have adopted the practice of testing the urine of all milk cows
at frequent intervals during lactation. TJie urine test, tho a useful tool
in diagnosis, is not infallible because it does not detect such complicating
diseases as metritis, indigestion, traumatic gastritis, or milk fever,,^he
careful clinician will not overlook these possibilities in arriving at a
diagnosis.

A number of writers29' 32> 14 have been disturbed because (1) the
urine of apparently healthy cows may give a positive reaction to
Rotheras' test (or a modification of this test) for acetoacetic acid
and acetone, and (2) a positive test fails to reveal the exact in-
tensity of ketonuria and ketonemia. Experience in using the Ross
modification of Rotheras' method on a large number of samples of
urine is helpful in interpreting results. For example, if an appreciable
amount of ketone bodies is present and continues to be eliminated in
the urine, there is an excellent chance that definite symptoms will
develop and furthermore that even when mild ketonuria and ketonemia
are present, careful observation may reveal either a decrease in milk
flow, an irregular appetite, or excessive loss of body weight. // metritis,
indigestion, and other conditions which may affect the appetite are ab-
sent, it seems highly probable that a positive test for ketone bodies in
urine of lactating cows should be looked upon as a danger signal — a
warning that the animal is metabolising fat at a faster rate than is
desirable and that an increase in consumption of readily available
carbohydrate is indicated. Because of this view the author does not
recommend, as Sjollema127 and Roepke102 have suggested, that urine
be diluted 1 to 10 before a test is made for ketone bodies. A test made
of diluted urine, however, takes little additional time and may be
helpful in differential diagnosis.

A detection of the odor of acetone in the expired air of affected
cows is helpful in establishing a diagnosis of ketosis, but is not as
reliable as the urine test. If facilities are available, it is advisable to

1947] KETOSIS IN DOMESTIC ANIMALS 435

make quantitative determinations of blood sugar and calcium and
blood and urine ketone bodies as these determinations are helpful in
clinching a diagnosis. A qualitative testa of the milk for ketone sub-
stances may also be advisable.26

Treatment

The classic studies of Mann and his associates73' 74 on the physi-
ology of the liver have shown that intravenous administration of
glucose is the most effective method of alleviating hypoglycemia. The
effectiveness of carbohydrate therapy for hypoglycemia and ketonemia
in ketosis of ruminants has been so thoroly demonstrated clinically as
well as experimentally that there can hardly be any doubt as to its
specificity. 132* 107> 102> 123> 119 In fact, carbohydrate therapy is so specific
for acetonemia of cows that unless the condition is complicated by milk
fever or some other disease, there is little to be gained from any other
treatment. If milk fever is a complication, calcium gluconate as well as
glucose is indicated.35 As it is often difficult to determine whether milk
fever is involved unless a chemical analysis is made for blood calcium,
the administration of both glucose and calcium gluconate may be
justified, particularly when ketosis develops shortly before or soon
after parturition. Calcium gluconate, however, especially when given
intravenously, must be administered with much greater caution than
glucose. If ketosis is associated with metritis, indigestion, or other
disorders, appropriate treatment for these conditions should supple-
ment carbohydrate therapy.

Sterile glucose solution seems to be admirably suited for intra-
venous administration to ruminants. Ordinary 50 percent dextrose
solution or solutions containing both dextrose and calcium gluconate
are widely used by veterinarians. It is often advantageous to supple-
ment intravenous administration of dextrose by drenching or feeding
the cow corn sugar or a feeding grade of molasses. Three to six
pounds may be given for several days, depending on the severity of
the ketosis and the response to treatment. Udall's137 textbook contains
additional information on carbohydrate therapy for ketosis of cows.

The first report on the use of chloral hydrate in treating acetonemia
appears to be that of Robellet (see page 411). Still a popular treatment
with some veterinarians, it has its greatest usefulness in treating the
nervous type of acetonemia.98 According to Udall,137 it is often used in

a Roepke, in a conversation with the author in December, 1947, recom-
mended the following test: To 5 cc. of milk add approximately 2.5 grams of
2-percent nitroprusside mixture (2 grams of sodium nitroprusside plus 98
grams of ammonium sulfate). Shake well and add 1 cc. of concentrated
ammonium hydroxide.

436 BULLETIN No. 524 [December,

30-gram doses given once or twice daily. It is a dangerous form of
therapy when ketosis is complicated by milk fever,35 and even in un-
complicated acetonemia if the cow is weak or emaciated.107* 105 The
cow shown in Fig. 2 was affected with severe ketosis. Chemical analysis
of the blood revealed the following data: calcium 10.3 mg. percent,
sugar 27.12 mg. percent, total ketone bodies as acetone 132.31 mg.
percent. The veterinarian who treated this case preferred chloral hy-
drate to glucose and, despite the fact that the dose given (approxi-
mately 30 grams) was not excessive, the cow failed to revive from the
stupor produced by the drug. It should be mentioned that this cow
was very weak and was affected with the nonnervous type of ketosis.

Sodium bicarbonate and insulin have been recommended,127 but it
is doubtful if either is beneficial. Haldane46 has shown that admin-
istration of sodium bicarbonate may cause ketonemia presumably by
interfering with normal oxidation of sugar in the body. On the other
hand, MacKay, Wick, Carne, and Barnum71a believe the ketogenic
effect of alkalosis is caused by a decrease in protein catabolism with
a consequent reduction in glucose formation. Insulin is not indicated
because, as previously mentioned on pages 417, 429, ketosis in rumi-
nants is not associated with diabetes mellitus. In fact, it is probably
contraindicated, for, as Soskin130 points out, an excess of insulin in the
body may increase glycogen in the muscle at the expense of glycogen in
the liver. By causing sugar in the blood to be deposited in muscle but
not in liver tissue, excess insulin apparently removes glycogen from the
liver to maintain the normal concentration of glucose in the blood.
This is the reverse of that which is desired ; namely, that the glycogen
content of the liver be increased.

Vitamin B^6- 22 and vitamin A71> 90> 133 also have been recommended
in treating ketosis of ruminants but, as stated in the discussion of
etiology on page 428, it is difficult to explain the rationale of such
treatments. Vitamins Ba and A, however, should be used, if it can be
proved that these compounds are distinctly beneficial. Miller81 has
suggested that if vitamin A is beneficial in the treatment of acetonemia,
the action may be the result of increased hepatic glycogen. According
to Miller, a large excess of vitamin A may be responsible for in-
creasing the glycogen content of the liver.

Much more critical evidence than is now available is needed before
a final decision can be reached as to the true value of either vitamin
B! or A therapy for ketosis. At the present time, observations reported
by Forbes,38 Shaw, Matterson, Surgenor, and Hourigan,121 and Shaw119
cast serious doubt on the beneficial effects claimed for vitamin BX (as
well as other members of the B-complex) and A in treating acetonemia

7947] KETOSIS IN DOMESTIC ANIMALS 437

of cows. Forbes states that the favorable results obtained by Carlstrom
with thiamin hydrochloride could not be repeated by him ; and Shaw
et al., and Hayden, Fincher, Roberts, Gibbons, and Danks48 failed to
confirm the results reported by Patton90- 91> 92 with vitamin A. Shaw
and associates reported:

Nine cows with severe ketosis as shown by ketonemia, hypoglycemia and
lack of appetite had an average blood-plasma carotene level of 321.8
micrograms per 100 ml. of plasma (range 131 to 768). Vitamin A was
determined on seven of these animals and was found to average 24 micro-
grams per 100 ml. of plasma (range 14.4 to 33.6). The oral administration
of from one to four million units of vitamin A per day for as long as
three weeks was completely ineffective in improving the appetite, or al-
leviating the hypoglycemia and ketonemia.

Hayden and associates48 concluded:

It is not unreasonable to assume that vitamin A deficiency would be over-
come by proper vitamin A therapy. We conclude that none of the cases
of ketosis we have so treated have been due to vitamin A deficiency. The
vitamin may have been of some help in some of these cases but it has in
no sense been a specific or needed therapy.

On the other hand, Krill (personal communication} states that
vitamin A therapy has been beneficial in some cases of ketosis in cows
that did not respond to "the usual line of treatment for acetonemia."
As it has been shown that large doses of some vitamin A concentrates
produce toxic effects in rats, the possibility of exceedingly large, re-
peated doses of certain forms of vitamin A products having a del-
eterious effect in cows cannot be ignored.104

Prevention

It seems evident that at least two conditions are essential for
the prevention of ketosis in high-producing cows: (1) a liberal
ration made up of palatable nutritious feeds must be provided* and
(2) the cow must have a good appetite. These two conditions also
have been shown to be of paramount importance for the prevention of
ketosis or pregnancy disease of ewes33' 107> 45> 6> 125> 140> 54- 66 (see pages
440,441 and 454).

Sampson105 and Forbes38 have called attention to the importance of
several influences which may affect the appetite of cows. Among these
may be mentioned such abnormal conditions as metritis, indigestion, or
any other illness and, according to Nevens86 and Blaxter,9 even such
physiological factors as breed and individual animal likes and dislikes

" Rations for dairy cattle are given in Illinois Circular 502, "Feeding the
Dairy Herd."

438 BULLETIN No. 524 [December,

/"

for certain feeds. Jgmpson and Forbes also believe that the common
practice of sharply reducing the feed intake for one week or longer
after parturition, may contribute to an attack of acetonemia in some
high-producing cows. Good judgment on the part of the herdsman is
needed to determine whether the caloric intake should be reduced and
how rapidly it should be restored or increased during this period. As
mentioned elsewhere (page 423), the incidence of ketosis presumably
is significantly lower when cows have access to luxuriant pasture than
when they are stall-fed.29

KETOSIS (PREGNANCY DISEASE) IN SHEEP

As stated on page 420, a significant ketosis in cattle and sheep is
apparently restricted largely to females during pregnancy and lactation.
Furthermore, in ewes ketosis is primarily pre parturient, whereas in
cows it is primarily post parturient.

At least 19 names have been given to ketosis of sheep, but the fact
that it occurs mainly during gestation probably explains why the name
pregnancy disease has been adopted by most writers. Groenewald and
associates45 mention the following list of names to illustrate the nu-
merous terms ketosis of sheep has acquired:

acute parenchymatous hepatitis, acetonemia, acute partum eclampsia,
acidosis, domsiekte, ewe-paralysis, eclampsia, fatty infiltration of the liver,
ketonaemia, ketosis, lambing paralysis, lambing sickness, ophaalzieckte,
pregnancy disease, preparturient paralysis, parturient paresis, pregnancy
toxaemia, parturient fever, sleepy sickness, stercoraemia, tremblings, twin
tremblings, uterine acetonaemia, and white liver.

In 1933 Sampson, Gonzaga, and Hayden110 reported:

Data we have thus far accumulated indicate that there is a definite ketosis
(acetonemia) in cases of so-called pregnancy disease in ewes. The blood
and urine picture resembles very closely that found in the blood and urine
from cows with typical cases of acetonemia. ... In all probability the
etiological factors, whatever they may be, are the same in both the
acetonemia seen in cows and the acetonemia met with in pregnancy disease
of ewes.

Since 1933 more and more evidence has accumulated to support
the above point of view. For example, Groenewald and associates,45 in
a report published in 1941 of results obtained in a critical study of
pregnancy disease or domsiekte of ewes in South Africa, make the
following statements:

As it is extremely likely that there are at least common factors in the
"pregnancy disease" of different species, short reference will be made to
the literature on this category of conditions. The parallel between preg-

1947] KETOSIS IN DOMESTIC ANIMALS 439

nancy disease in sheep and acetonaemia in the cow would appear to be
especially close. This is pointed out by Sampson et al. (1933) and by
Webster (1935). The latter author states that no similar condition has
been seen in goats, pigs or horses. Hudson (1931) describes an acetonaemia,
hypoglycaemia, and nervous symptoms in cows shortly after calving, all
of which closely correspond to the changes seen in domsiekte. It is quite
conceivable that the drainage of lactation in the cow would take the place
of that of gestation in the sheep in the chain of aetiological factors.
Furthermore it must be remembered that cases of domsiekte have been
reported after lambing.

The parallel with Milk Fever in the cow does not appear to be so
close, especially in that the classical calcium treatment for Milk Fever
does not appear to assist in domsiekte . . . and also that the blood calcium
during domsiekte is reported to be normal.

Numerous References to Ketosis in Ewes

The imposing list of names (page 438) given to ketosis, or preg-
nancy disease, of sheep suggests that it has been described many times.
Groenewald and coworkers45 state that apparently one of the first
definite references to pregnancy disease of the ewe was that of Steele,
who in 1890 described a disease which he called "parturient fever in
sheep." Henning, cited by Groenewald and associates, stated in 1932
that domsiekte of ewes "has been known in the Cape Colony for more
than 50 years." Roderick and Harshfield," in the excellent report
published by them in 1932 on studies of pregnancy disease in North
Dakota, state that observations reported by Gilruth of New Zealand in
1909 probably were among the earliest discussions on the problem.

Thus despite the fact that until comparatively recent years very
little information was available with reference to etiology, pathologic
physiology, and prevention of ketosis of ewes, the syndrome was prob-
ably recognized as a specific disease of sheep as early as 1890 or even
perhaps at a much earlier date in the 1800's.

Economic Importance

General agreement among investigators who have studied ketosis
of sheep indicates that a mortality of 1 to 25 percent may be expected
when pregnancy disease makes its appearance in a flock of breeding
ewes. Occasionally the losses are much higher than 25 percent. For
example: Dimock, Healy, and Hull27 of Kentucky reported a 60 per-
cent loss in one flock of 100 ewes. Similar heavy losses from pregnancy
disease have been reported in such widely separated regions as South
Africa45 and Australia.52 In 1940 Elder and Uren33 stated:
One of the chief losses suffered by the sheep industry in Missouri is that

440 BULLETIN No. 524 [December,

due to pregnancy disease, which causes its greatest trouble during the
months of January and February. This disease occurs in all parts of
Missouri, and in some cases the losses have been very heavy.

The economic loss from pregnancy disease is especially severe
because about 90 percent of ewes affected carry more than one fetus ;"
hence the loss of lambs is in itself no small item. The total loss con-
tinues to be heavy altho a steady decrease may be expected as more
and more flock owners adopt feeding and management practices which
have proved effective in preventing the disease (see page 454).

Incidence

Roderick and Harshfield99 and Groenewald et a/.45 state that the
occurrence of pregnancy disease seems to be world-wide; but according
to the latter investigators the main countries where it occurs are the
United States, Australia, Great Britain, New Zealand, South Africa,
Canada, Holland, France, Germany, and Austria.

In the United States it is apparently observed in all states and in
all breeds of sheep. Marsh75 states that it is observed in small flocks
but is apparently not common in range flocks. Roderick and Harshfield
report that it has been observed in "western" ewes shipped to North
Dakota. The author has observed several severe outbreaks of preg-
nancy disease in large flocks composed of "western" ewes in Illinois.
Cross (personal communication} writes from Colorado:

We see this condition in milk cows occasionally, but it is most commonly
observed by us in ewes. This condition is especially prevalent on the west-
ern slope of Colorado where large numbers of range ewes are run. These
ewes are wintered on the desert and, as spring approaches, feed becomes
progressively short and the ewes are losing weight at the time when they
are approaching termination of pregnancy. This condition is further aggra-
vated by snow storms which from time to time cover the available forage.

In the spring, just before the ewes are to lamb, they are moved from
the desert to the high mountain areas. This journey is usually made by
train, but in some instances they are driven overland. Upon arriving at
their destination in the high mountain areas, large numbers of these ewes
suffer from ketosis, and the loss is often alarming.

We have been able to solve this problem very satisfactorily by feeding
the ewes a sufficient amount of concentrate of either corn or cotton cake
while on the desert so that they are actually gaining weight to some degree
as the end of pregnancy approaches. We have also found that it is neces-
sary to provide abundant feed for the ewes just prior to and during their
journey to the mountains.

Published reports from such widely separated states as New York
and California indicate that ketosis, or pregnancy disease, of ewes
probably occurs in all sections of the Americas where sheep are raised.

1947] KETOSIS IN DOMESTIC ANIMALS 441

Etiology Believed to Be Established

Enough critical evidence is available to warrant the definite state-
ment that the etiology of ketosis, or pregnancy disease, in ewes is now
reasonably well established. No useful purpose will be served, there-
fore, by reviewing the theories which have been put forth from time to
time as to the cause of the disease. An excellent recapitulation of these
theories is given by Groenewald and associates45 who concluded:

Many of the suggested causes such as mineral deficiency, toxic absorption
from the uterus and lack of exercise, can be discarded. Age, overfatness
and changes in the climatic or feeding conditions can be looked upon as
predisposing or indirect causes. The disease is essentially a disturbance of
metabolism, especially with regard to the carbohydrates, and this is usually
manifested by a loss of body weight. Pregnancy is a powerful predisposing
cause and acts through the increased drainage on the maternal system.

Results of well-planned experimental studies by Fraser, Godden,
Snook, and Thomson,40- 41 and Groenewald, Graf, Bekker, Malan, and
Clark45 confirmed the earlier observations of Roderick and Harsh-
field," Hopkirk,52 and Roderick, Harshfield, and Hawn100 that typical
ketosis, or pregnancy disease, occurs in ewes fed adequate as well as
inadequate rations. Groenewald et al. also helped clarify the problem
by showing that it was not a lack of exercise per se which is respon-
sible for the development of pregnancy disease in well-nourished ewes
but rather the sudden reduction in the amount of nutrients consumed
by these ewes. Sudden changes in weather, e.g., a heavy snow fall and
extremely cold weather, and sudden changes in feed are believed to
have an adverse effect on the appetite of pregnant ewes. At any rate,
Roderick et al., Hopkirk, Fraser et al., and Groenewald et al. have defi-
nitely demonstrated that a sharp reduction in an adequate ration fed to
ewes in advanced pregnancy causes ketosis and symptoms indistinguish-
able from those found in natural pregnancy disease. In all countries
where pregnancy disease has been described, however, the great major-
ity of cases occur in ewes that are underfed during pregnancy, espe-
cially during the last one-third of the gestation period. Inasmuch as
there is little evidence that fat can be changed to carbohydrate in the
body (except the glycerol fraction of the fat molecule)47 the funda-
mental cause would seem to be an inadequate consumption of readily
available carbohydrate or potential carbohydrate, such as protein. (See
also page 423.)

Ketonemia and hypoglycemia are often as intense in ketosis of
ewes as of cows. Comparative data published by Sampson and
Hayden113 reveal that ketonemia and hypoglycemia often are as severe
in ketosis, or pregnancy disease, of the ewe as in ketosis, or acetonemia,

442

BULLETIN No. 524

[December,

TABLE 3. — TOTAL KETONE BODIES AND SUGAR IN BLOOD OF HEALTHY EWES

IN ADVANCED PREGNANCY, AND OF EWES AFFECTED WITH EXPERIMENTAL

AND CLINICAL KETOSIS (PREGNANCY DISEASE)

(Ketone bodies expressed as acetone; sugar determined by
Shaffer, Hartmann, and Somogyi93 method)

Healthy ewes in advanced
pregnancy

Experimental ketosis

Spontaneous ketosis

Ewe

Ketone
bodies

Sugar

Ewe

Ketone
bodies

Sugar

Ewe

Ketone
bodies

Sugar

1923

mg

mg

1737

mn

mg

1

mg

mg

100 ml

4 78

100 ml
42.94
38.42
45.20
42.94
42.94
43.00
51.98
42.94
39.55

100 ml
23.81
27.77
40.92
32.74
16.99
18.85
20.58
21.82

100 ml
14.69
53.11
22.60
24.86
31.64
24.86
21.47
15.82

100 ml
67 21

100 ml
No detn.
21.47
31.64
23.73
16.95
40.68
50.85
18.08
18.08

1707

75

1933

2

96.22

1895

. . 1.12

37

3

. 19.47

1852

1 86

1801

4

35 96

1841

5 15

1868

5

47.24

1983 .

. . 1.98

1901

6

. 25.42

1757

1 24

1954

7

15 25

1918

99

1834

8

29.76

1849 ....

.50

9

. 36.45

Average .

.. 2.04

43.32

Average. .

25.43

26.13

. Average. .

. 41.44

27.68

of the cow (see also Tables 1 and 3). The author and his coworkers at
the Illinois Agricultural Experiment Station have confirmed the obser-
vations of Hopkirk, of Roderick, Harshfield, and Hawn, of Fraser
et al., and Groenewald and associates that severe ketonemia and hypo-
glycemia can be readily produced in ewes during late pregnancy either
by fasting or by rations low in caloric value. Data obtained in fasting
experiments at the Illinois Station are shown in Table 3. See also Fig.
3. Symptoms of experimental ketosis are ordinarily indistinguishable
from symptoms observed in natural ketosis in the ewe. Normal values
for total ketone bodies and sugar of blood of healthy ewes and ewes
affected with spontaneous ketosis, also shown in Table 3, compare
favorably with other published data.99' 110) 106> 15

As is true in acetonemia of cows, the alkali reserve or carbon
dioxide combining power of the blood may be definitely lower than
normal in ewes affected with pregnancy disease.110 Acidosis, as judged
by the alkali reserve, however, is apparently of less significance in
ketosis of cows and ewes than in ketosis of humans.107' 29> 82

Also, as in acetonemia in the cow, such constituents as calcium,"
inorganic phosphorus, magnesium, chlorides, iron and hemoglobin of
the blood usually show no abnormal changes in ketosis of the

"According to Dr. A. K. Sutherland (personal communication), a disease
characterized by hypocalcemia occurs in sheep in Australia. It usually develops
in ewes during the early part of lactation, but may also occur in late pregnancy.

1947]

KETOSIS IN DOMESTIC ANIMALS

443

ewe.112> 45> 138> 139 But contrary to what has been reported in ketosis of
the cow, there does not appear to be a cholesteremia in ketosis of the
ewe.45

In the early stages of pregnancy disease, values for nonprotein
nitrogen of the blood are ordinarily found to be in the normal range.
In the late stages of the disease, however, high nonprotein nitrogen
values are the rule. Sampson et a/.110 have stated that high concentra-
tions of nonprotein nitrogen are probably associated with oliguria and

234
DAYS OF FAST

Relation between concentration of blood sugar and blood ketones. Graph
shows average values in blood of four fasting ewes in advanced pregnancy.
Total ketone bodies are expressed as acetone. (Fig. 3)

in some cases anuria and are probably indicative of uremia. Groene-
wald and associates45 have also reported high values for nonprotein
nitrogen in blood of ewes affected with ketosis during the advanced
stages but, as suggested by Fraser et a/.,40 are inclined to attribute this
marked rise to increased catabolism of protein. Nevertheless Groene-
wald and associates call attention to two ewes in which a daily elimina-

444 BULLETIN No. 524 [December,

tion of urine was only 86 ml. and 20 ml. respectively. It may be that
both increased protein catabolism and, in some cases at least, oliguria
and anuria contribute to the rise in the nonprotein nitrogen of blood.
The author's opinion is that blood pressure is often so low in advanced
pregnancy disease that the rate of urine formation is decidedly sub-
normal. Further study is therefore needed to determine the cause or
causes and the significance of the increase in nonprotein nitrogen of
blood in severe ketosis of sheep.

Changes in urine. The changes in urine in ketosis of ewes are
similar to changes found in urine of cows affected with acetonemia.
For example, there is a pronounced ketonuria. The concentration of
ketone bodies in urine of the ewe suffering from pregnancy disease
often is as great as it is in urine of the cow suffering from acetonemia.
Sampson, Gonzaga, and Hayden110 found 735.5 mg. of total ketone
bodies as acetone per 100 ml., or roughly 7 grams per liter of urine
in one case of mild pregnancy disease. The author has unpublished
data showing that urine of ewes affected with severe ketosis may con-
tain as much as 14 grams of total ketone bodies per liter. These values
are unusually high for urine of ewes affected with pregnancy disease,
but they compare favorably with maximum values of 10 to 13 grams
of ketone bodies per kilogram of urine reported by Sjollema and Van
Der Zande128 in acetonemia of the cow.

The content of ammonia also is ordinarily greatly increased in
urine of ewes affected with pregnancy disease. The explanation for
such a high content of ammonia is probably the same as that for the
marked increase of ammonia usually found in urine of cows affected
with acetonemia (see page 427). Apparently no extensive data are
available with reference to the content of calcium and other constitu-
ents in urine in ketosis of the ewe. Urine of cows and ewes affected
with ketosis is often acid to litmus, whereas normal urine of ruminants
is alkaline.28 In uncomplicated ketosis of the cow and ewe there may
be an albuminuria which ordinarily disappears when the animal re-
covers. Tests for sugar in the urine of either cows or ewes affected
with ketosis are invariably negative unless concentrated solutions of
sugar have been administered prior to such tests. Lactose may be found
in urine of cows, however, near the onset of lactation.28

Gross and Microscopic Pathology

As mentioned on page 431, the histopathology of ketosis in rumi-
nants has been studied more thoroly in the ewe than in the cow. Inves-
tigators agree apparently that pathologic changes are limited primarily

I

1947} KETOSIS IN DOMESTIC ANIMALS 445

to the liver and kidneys. Roderick and Harshfield," Dimock, Healy, and
Hull,27 and Clark,45 for example, have given excellent descriptions of
these changes. Roderick and Harshfield, in describing the changes in
the liver, state:

The liver often presents a striking appearance on necropsy. There is a
marked alteration in the color from the reddish brown of a normal animal,
so that it assumes a tawny yellow, clay, or putty color. It is very friable
and the cooked appearance is evidence of the extreme degree of paren-
chymatous injury. . . . The livers of a large number of our cases, about
50 of them, have been examined histologically and a remarkable uniform-
ity in the character of the microscopic changes is seen. The differences are
largely a matter of degree and extent of the injury. The cytoplasm of the
cells, rather than the nuclei, is involved. There seems to be little actual ne-
crosis, for the nuclei are ordinarily intact although pressed to one side of
the cell by the fat globules. Vacuolation of the cytoplasm is common while
the cells in many areas have a granular appearance. The use of a fat stain
(Oil-Red-O) clearly shows the extensive degree of injury and the enormous
extent of the retrograde fatty changes. This condition of the liver in ewes
in winter and spring is really pathognomonic for pregnancy disease. It is
doubtful if any other disease of livestock involves such an extensive degree
of fatty change in the liver. A study of the references given under human
toxemias of pregnancy reveals that the pathology of that disease shows a
remarkable similarity to the changes in the livers in these sheep.

The intense fatty infiltration of the liver which is characteristically
found in ketosis, or pregnancy disease, of the ewe is shown in Figs.
4 and 5.

With respect to the pathology of the kidneys in ketosis of the ewe,
Roderick and Harshfield state:

The kidneys in pregnancy disease likewise show a remarkable uniformity
in the character of the lesions which are present. Previous comment was
made on the lack of gross changes in the kidneys. There seems to be little
recognizable change in the glomeruli, but there is apparently some swelling
of the epithelium lining the convoluted tubules. Casts have not been en-
countered in our kidney sections. The most significant finding is the
presence of fat droplets in the epithelial cells of the ascending and de-
scending limbs of Henle's loops at the edge of the cortex. More advanced
cases show a greater degree of involvement. . . . This characteristic lesion
of the disease has not been observed in normal sheep. No trace of any
cellular infiltration has been observed, so it is no doubt a toxic injury
rather than one of inflammation.

Clark agrees with Roderick and Harshfield that marked fatty
changes are present in the liver and kidneys of ewes affected with
ketosis, or pregnancy disease, but he does not seem to attach the same
significance to these changes. In illustration, Clark states:

Although this fatty infiltration of the liver is the most apparent change
seen in Domsiekte (pregnancy disease) and is probably constantly present,

446

BULLETIN No. 524

[December,

Liver from sheep with advanced ketosis (pregnancy disease). Yellow dis-
coloration was widespread. Note fine mottling, which denotes variation in
distribution of fatty changes within the lobules. (Fig. 4)

Section from liver shown in Fig. 4. Note tendency toward more marked
concentration of fat in peripheral parts of the lobules. C = central vein.
Hematoxylin-eosin. X 170. (Fig. 5)

1947] KETOSIS IN DOMESTIC ANIMALS 447

it cannot, of course, be considered specific. The degree of fatty infiltration
does not show any relation to the severity of the symptoms. In fact sheep
that showed no symptoms presented fatty infiltration of the liver to the
same extent as those that died in coma. Further, the normal pregnant sheep
from group 1 which was slaughtered for the collection of comparative

material showed a fatty infiltration equal to many of the Domsiekte cases.

»

With respect to the kidneys in pregnancy disease, Clark sum-
marizes his observations in these words:

It will be seen that the kidney changes constitute a nephrosis in the gen-
erally accepted meaning of that term, and these findings confirm those of
Roderick and Harshfield (1932) in all respects except that more advanced
lesions were found, consisting of the formation of casts and the presence
of glomerular degeneration.

The observations reported by Clark of the presence of casts and
the evidence of glomerular degeneration in the kidneys seem to be in
accord with the findings of Dimock, Healy, and Hull. These authors
reported the results of observations made in autopsies of 106 ewes
that were "dead from acidosis or that were killed in an advanced stage
of the disease."

Dimock et al. state:

Microscopical examination of kidneys from different ewes revealed a
variety of changes varying from a simple granular degeneration, most
pronounced in the convoluted tubes, to complete disintegration of the
cytoplasm of the cells lining the tubules. . . . The glomeruli were not, as
a rule, appreciably abnormal except that occasionally an individual
glomerulus showed congestion and hemorrhage, and in a few glomeruli
a granular exudate was observed within the capsule but separated from
the cellular structure of the glomerulus.

It seems evident that complete agreement has not been reached
among pathologists as to the extent and significance of changes in
the liver and kidneys, particularly in the liver, of ewes that succumb
to ketosis and that further study is needed.

Clark mentions the interesting observation that "in all cases the
adrenals were enlarged and exhibited marked degenerative changes.
The organ was extremely friable, it often being almost impossible to
extract it whole from the surrounding fat. On section the cortex was
flabby and yellow." Apparently these abnormal changes in the adrenals
have not been observed by others. Clark sums up his observations as
follows:

The post-mortem findings in these eight cases of undoubted Domsiekte
were: General cyanosis, fat necrosis especially of the perirenal and
omental fat. Fatty changes of the liver, renal cortex and adrenal cortex
and atrophy of the lymph glands.

448

BULLETIN No. 524

[December,

5 bo

bo <u

o g

CO

1947] KETOSIS IN DOMESTIC ANIMALS 449

According to Clark, changes that occur in the lymph glands are
probably responsible for a decrease in the number of lymphocytes
found in the blood.

The investigators who have been mentioned in the discussion on
gross and microscopic pathology of ketosis of the ewe appear to hold
the opinion that no significant changes are found in other organs and
tissues of the body exclusive of those described in the preceding
paragraphs.

Symptoms

In general, most of the symptoms of uncomplicated ketosis in the
ewe closely resemble the symptoms associated with .the nonnervous
type of ketosis in the cow. Trembling, twitching or shaking movements
of the head are often observed in ketosis of the ewe but extreme
excitability which sometimes characterizes the nervous type of ketosis
in cattle apparently does not occur in sheep. In the following discus-
sion on symptoms any reference to ketosis in the cow refers to the
nonnervous type of acetonemia.

As in the cow, one of the characteristic symptoms of ketosis in
the ewe is lack of appetite. Also, as in the cow, the feces are often
covered with mucus and flecked with blood. The rate of respiration
may be rapid in the early stage. The rapid breathing has sometimes led
to the error of diagnosing pregnancy disease as hemorrhagic sep-
ticemia. The heart beat and pulse are often weak and almost im-
perceptible. Usually no significant change occurs in body temperature.
Other symptoms often observed are grinding of the teeth and blindness.
These symptoms are apparently less common in ketosis of the cow than
in ketosis of the ewe.

The early stages of ketosis in the ewe are characterized by in-
creasing somnolence or listlessness. The affected ewe is reluctant to
rise and often moves with an unsteady gait. Ewes affected with
ketosis are usually in advanced pregnancy and any evidence of "slug-
gishness" at this time may be erroneously attributed to pregnancy.
Actually a healthy ewe, even in late pregnancy, has no difficulty in
getting up and can walk and run with surprising ease. When the ewe
is standing, the head is frequently held in a lowered position, as is
often observed in ketosis of the cow (Fig. 6). Sometimes the head and
neck are bent far backward. This position is often accompanied by
twitching or shaking movements of the head. The syndrome rapidly
becomes more acute, the ewe is unable to rise and passes into a deep
stupor. Death usually occurs quietly with no evidence of struggling.

450 BULLETIN No. 524 [December,

Cause of Death in Ketosis in Ruminants

Sampson, Morrill, and Alberts114 have stated that if ketosis oc-
curred in pregnant cows as often as it does in pregnant ewes, the rate
of mortality might be expected to be as high among cows as among
ewes. The burden of pregnancy is undoubtedly an added hazard and
can be looked upon not only as a predisposing cause of ketosis but
also as an indirect cause of high mortality of affected ewes.

It is evident also from what has been said concerning the signifi-
cance of the rise in nonprotein nitrogen of the blood in advanced
pregnancy disease that the immediate cause of death in ketosis of the
ruminant, particularly in ketosis of the ewe, is still doubtful. That
uremia may be an important contributing factor can hardly be ques-
tioned because, as Roderick and Harshfield," Dimock et al.,21 and
Clark45 have shown, definite changes occur in the kidneys. The true
significance of these changes remains to be determined.

The author believes the views expressed by Hupka and Roepke
(page 419) with reference to the significance of hypoglycemia in ke-
tosis of the cow are of even greater importance in ketosis of the ewe.
Roderick and Harshfield, and Sampson and Hayden, and others have
clearly demonstrated that as the syndrome of pregnancy disease grows
more acute, hypoglycemia also is likely to become more pronounced.
Hyperglycemia may, however, be found in the terminal stage,45 but
it should be recalled that fluctuations in the concentration of blood
sugar are not uncommon during a state of hypoglycemia. In illustration
Bodansky and Bodansky11 state:

What is so generally overlooked is that the blood sugar value determined
at any given point in an hypoglycemic seizure may have no relation what-
ever to the symptoms at the moment. Under conditions of instability or of
disturbed homeostasis, the blood sugar may change almost from minute to
minute. Thus, the concentration of blood sugar obtained during an attack
is probably quite different from the concentration at the onset of the
seizure, reflecting in all probability the resultant effect of the primary
factor and of the compensatory mechanisms brought into play by the
falling blood sugar.

It seems logical to believe that a rise in blood sugar in the late
stage of pregnancy disease could be explained on this basis. As Riggs
and Griffith,96 Baker,3 and Sherrill and MacKay124 have shown, pro-
longed hypoglycemia causes permanent functional damage to the brain.
Pathologic changes in the brain caused by hypoglycemia are not readily
detectable, and this fact might account for the failure of Roderick and
Harshfield and of Clark to find evidence of injury to this organ.
Clark45 states:

1947] KETOSIS IN DOMESTIC ANIMALS 451

No visible lesions were discovered in the brain either macroscopically or
microscopically. The microscopical study was, however, only carried out
on Helle's and Formalin fixed material under the routine stains. It is
admitted that more detailed cytological studies are necessary before any
definite statement can be made.

Altho Roderick and Harshfield were apparently successful in dem-
onstrating some degree of dysfunction of the liver in pregnancy disease,
additional study is needed, especially with respect to the glycogen-
storing function of the organ. There is also a need for careful study
of the ability of the ewe to utilize carbohydrate in the advanced stage
of ketosis. As is evident from the discussion on histopathology, the
significance of the enormous amount of fat usually present in the liver
in ketosis of the ewe is not well understood. The presence of this
large amount of fat in the liver of cows and ewes affected with ketosis
is in all probability the result of carbohydrate deficiency and the sub-
sequent transfer of depot fat to the hepatic tissue. More work is
needed on the probable deleterious effects of the ketone bodies, par-
ticularly of the acetoacetic acid fraction.

It must be admitted that at the present time the immediate cause of
death in ketosis of ewes and cows is not definitely known. Further
investigation may reveal that no single cause is responsible but rather
that a combination of causes, including such influences as a disturbed
carbohydrate- fat metabolism in the liver, possibly a decreased ability to
utilize carbohydrate, functional damage to the central nervous system,
and impaired function of the kidneys, is involved. To this must be
added toxemia whenever the fetus dies in utero. These cases are not
common because the lambs (and apparently calves also) are usually
found alive even in the advanced stage of ketosis or pregnancy disease
in ruminants.

Diagnosis

The author agrees with Roderick and Harshfield" that: "The
occurrence alone of several losses in a flock of ewes in advanced
pregnancy is a sufficient basis for suspecting the disease" (ketosis, or
pregnancy disease). If the ewe shows the symptoms which have been
enumerated and a positive test is obtained for ketone bodies in the
urine, a diagnosis of ketosis is usually warranted.

If, in addition to the symptoms that have been mentioned, circling
movements are observed, there is a good chance that the ewe is
affected with listerellosis as well as ketosis. If the urine is free from
ketone bodies and circling movements are a prominent symptom, the
chances are that the ewe is affected only with listerellosis. It is also
helpful in making a differential diagnosis if the history indicates that

452 BULLETIN No. 524 [December,

losses have occurred in" nonpregnant ewes, or in lambs, wethers, or
rams. For more detailed discussions on the symptoms and pathology
of listerellosis in sheep, see Ola f son89 and Graham et a/.44

The author has mentioned elsewhere (page 420) that on the basis
of his observations he does not believe a significant spontaneous ketosis
occurs in lambs, wethers, rams, and nonpregnant ewes. Groenewald
et a/.45 showed that moderate ketonemia and ketonuria could be pro-
duced in nonpregnant ewes after a prolonged fast. That this is a
natural occurrence, however, seems a remote possibility. Lambs,
wethers, and rams appear to be as susceptible to listerellosis as ewes ;
hence if losses have occurred in these classes of sheep, ketosis, or preg-
nancy disease, can ordinarily be eliminated from further consideration
unless losses have also occurred among pregnant ewes.

So-called feedlot hyperglycemia, or "overeating disease," also oc-
curs in all classes of sheep, but lambs are especially susceptible. As
sudden death characterizes this disease, it should not be confused with
ketosis. Also, the urine is free from ketone bodies and sometimes
contains a large amount of sugar.

The autopsy findings are also helpful in diagnosing ketosis in a
flock of breeding ewes. As in the cow, a positive test for ketone bodies
in urine of a pregnant ewe should not be regarded as without some
significance even tho definite symptoms are not detectable. The syn-
drome may be in the very early stage.

Treatment

In a discussion of the physiologic basis of therapy for ketosis in
the ruminant, Sampson and Boley107 say:

It was recognized early in the study of ketosis in ruminants that all forms
of treatment were ineffective for the advanced stage of pregnancy disease
in sheep. The results of dextrose therapy, however, were sufficiently en-
couraging to warrant further trials with this agent. These trials have
clearly demonstrated that a liberal administration of dextrose or similar
carbohydrate is often highly effective for ketosis in pregnant ewes pro-
vided ( 1 ) the treatment is begun during the early stage of the disease, and
(2) oliguria, anuria and other complications have not developed.

Poor results with carbohydrate therapy, which seems to be as
specific for ketosis in the ewe as in the cow, can usually be explained
on the basis that treatment was either started too late or that it was not
continued long enough. Flock owners often fail to call a veterinarian
to make a diagnosis until several ewes have died and others are in the
advanced stage of the disease. It cannot be emphasized too strongly
that early diagnosis and prompt treatment are imperative for favorable

7947] KETOSIS IN DOMESTIC ANIMALS 453

results with any form of therapy in ketosis of pregnant ewes. The cost
of treatment may become prohibitive if daily injections of dextrose are
administered by a veterinarian, but such a procedure is neither neces-
sary nor desirable. After one injection perhaps, subsequent treatment
can be carried out by careful drenching. For this purpose several
ounces of either molasses, sorghum, corn sugar, or other concentrated
carbohydrate can be diluted with a pint of water and given by the
owner with an ordinary 2-ounce syringe. Two or more treatments daily
are recommended until the appetite is restored. If the attack is not
too severe and if it develops a short time before parturition, recovery
with or without treatment often occurs after the lambs are born.

Groenewald et al.45 also recommend the use of carbohydrate therapy
in ketosis of the ewe, but caution that this may not be entirely effective.
These investigators state: "It can be understood, therefore, that the
administration of glucose alone will not be expected to cure all the
symptoms of domsiekte, but its use is rational and strongly indicated."

Clark, Groenewald and Malan,21 in a report published in 1943, call
attention to the need for increasing peristalsis as well as to the need
for sugar. They state:

It is considered that the main object to be attained in any treatment is
to get purgation. It has been noted that ruminal atony and constipation
of the large intestine is an almost constant finding in cases of domsiekte
and no permanent improvement can be expected till this is relieved. Lentin
acts well but 120 cc. of raw linseed oil has also been found effective.
Rapidly absorbable carbohydrate such as glucose or sugar is ... indicated.

At the present time if treatment is attempted, the administration of
glucose or similar carbohydrate has largely replaced other forms of
therapy. Groenewald et a/.45 mention insulin, calcium carbonate, calcium
gluconate, formaldehyde, adrenalin, sodium bicarbonate, and bone meal
as other agents besides glucose which have been employed by various
investigators in treating ketosis of sheep. Roderick and Harshfield,"
in addition to some of the substances mentioned, administered solutions
containing either calcium chloride or magnesium sulfate without any
apparent benefit.

Recently it has been suggested that vitamin A therapy may be in-
dicated for ketosis in ewes.39 On the basis of the negative results
obtained by Shaw et al.,121 Hayden et al.** and Hendershot50 with vita-
min A therapy in ketosis of the bovine, it does not seem likely that it
will prove any more effective for ketosis in sheep. Furthermore,
Barren5 and Underwood, Curnow, and Shier138 have shown that the
vitamin A content of livers of ewes affected with pregnancy disease
is about the same as that in livers of healthy ewes. Underwood and his

454 BULLETIN No. 524 [December,

associates conclude that it appears "extremely unlikely that vitamin A
deficiency can have anything to do with the incidence of pregnancy
toxemia."

Prevention

For many years after pregnancy disease was first recognized, lack
of agreement continued as to the measures that might be taken to
prevent the disease;45 but now that the etiology is established beyond
reasonable doubt, the problem has become fairly simple.

The lack of agreement on prevention is explained by the fact that
even tho pregnancy disease was found not to be caused by infection
and was believed to be the result of improper feeding, knowledge of
its occurrence in both adequately and inadequately fed ewes resulted in
a confusion of ideas concerning methods of feeding to prevent it. For
example, flock owners were often advised to reduce the ration in
advanced pregnancy, a practice which we now know is usually contra-
indicated because, as mentioned on page 441, the sudden decrease in
feed consumed, irrespective of cause, leads to an attack of ketosis and
symptoms of pregnancy disease in well-nourished ewes. If pregnancy
disease develops in a flock that is fed a liberal ration, it is frequently
advantageous to feed a small amount of molasses (see page 426).
Hull54 recommends that under such circumstances a ration of yellow
corn and alfalfa hay "may be supplemented by three quarts of molasses
per hundred ewes per day for three or four days." Some flock owners
feed a small amount of molasses thruout the greater part of pregnancy.

In general, pregnancy disease rarely becomes a problem in flocks
that are well fed, especially if ewes are fed liberally during the last
third of pregnancy. The experience of many farmers who have kept
a breeding flock of sheep for a number of years clearly demonstrates
that if each ewe is fed a daily ration of about 1 to li/2 pounds of
concentrates, such as equal parts by weight of shelled corn and whole
oats, and at least an equal amount of good-quality legume hay during
the last 6 to 8 weeks before lambing, the incidence of ketosis may be
expected to be very low.

As mentioned on page 441, most cases of pregnancy disease in sheep
occur in flocks that are underfed. In most outbreaks of the disease it
is found that the breeding flock is in poor condition and losing weight
despite a sincere belief on the part of many owners that the ewes are
in good flesh. Increasing the ration usually is all that is needed to stop
further losses from ketosis in these flocks.

Attention has been called (page 438) to the observation that clinical
ketosis is not diagnosed as often in cows that have access to good

1947] KETOSIS IN DOMESTIC ANIMALS 455

pasture as in stabled animals. This observation also applies to sheep
because pregnancy disease is not a problem in ewes that lamb during
the months when the flock has access to an abundance of succulent
grass or legume pasture."

All pregnant animals should have a moderate amount of exercise
thruout pregnancy. Ewes are no exception.

KETOSIS IN GOATS

Forbes38 has reported some interesting results on experimental
ketosis in goats. (Lukens70 has shown that pancreatectomy causes a
mild diabetes in this species.) Forbes investigated the effects of in-
adequate caloric intake on blood sugar and blood ketones in two goats
during pregnancy and lactation. Forbes found that:

The blood sugar values under the low-calory treatment reached minimum
figures of 28 mg. per 100 cc. during late pregnancy, 32 mg. during early
lactation, 46 mg. after 11 weeks lactation, and 24 mg. during early preg-
nancy. These figures may be contrasted with the normal values of 45-60 mg.
. . . The ketone levels for the blood of the goats under the low-calory treat-
ment reached maximum values of 25 mg. per 100 cc. during late pregnancy,
18 mg. during early lactation, 4.0 mg. after 11 weeks lactation, and 3.7 mg.
during early pregnancy. These figures may be contrasted with normal
values of 2-4 mg.

Forbes' results with pregnant goats are somewhat comparable to the
results obtained by Fraser et a/.40 with pregnant ewes (see page 421).
Gilyard and Gilyard43 have described typical clinical ketosis in the
goat. Their report refers to observations made in a herd of goats, in
which twelve fatal cases occurred among pregnant does. The herd
had been fed mixed hay but no grain. Paresis and coma, with normal
body temperature, were characteristic symptoms. The urine of one
sick doe was found to contain 450 mg. of ketones per 100 ml. Treat-
ment with 10-percent glucose, 1 liter given subcutaneously and 300 ml.
given intraperitoneally, lowered the ketonuria but was not effective in
saving the doe. No more cases developed after the tenth day following
the addition of grain and molasses to the ration. The data would have
been more complete had analyses been made for blood sugar and blood
ketones; yet the symptoms, severe ketonuria, and the apparent bene-
ficial effect of adding grain and molasses to the ration are almost
certain proof that these goats were affected with spontaneous ketosis
and hypoglycemia.

" Rations for pregnant ewes are given in Illinois Circular 532, "The
Sheep Enterprise."

456 BULLETIN No. 524 [December,

II. KETOSIS IN OTHER
DOMESTIC ANIMALS

KETOSIS IN THE SOW

Our knowledge of ketosis in swine is limited because it has been
known for only a relatively short time that spontaneous ketonemia oc-
curs in this species. Credit for this important observation belongs to
Hull and Nolan55 who, in 1940, described three cases which had been
diagnosed in the Department of Animal Pathology at the Kentucky
Agricultural Experiment Station.

In 1943 Sampson and Hanawalt111 published data which apparently
confirmed the earlier findings of Hull and Nolan. The data of Sampson
and Hanawalt were obtained in the course of observations of a pe-
culiar disorder in a sow which had been correctly diagnosed by a prac-
ticing veterinarian as uncomplicated ketosis, or acetonemia. So far as
is known, this was the first report of ketosis in swine to be made from
Illinois. Furthermore, so far as the author is aware, spontaneous ke-
tosis in swine has been reported from only one other state (New
York)22 besides Kentucky and Illinois.

Biester,8 of Iowa, in 1925 described a condition in a pig weighing
approximately 25 pounds which he believed to be diabetes mellitus,
The diagnosis was based on evidence of severe glycosuria, 6.6 percent,
and a marked lowering of the pig's tolerance for sugar. On autopsy
of the pig, histopathologic examination of the tissues revealed that the
cells of the islands of Langerhans in the pancreas were atrophic and
degenerated. The report fails to mention whether tests were made for
evidence of ketosis.

Only limited study has been made of experimental ketosis in swine.
There are probably a number of reasons for this, but the belief ex-
pressed by Woods142 that the pig "has a low liability to ketosis" is
possibly the most important one. Woods so concluded when he failed
to find evidence of ketosis in a 20-pound pig at the end of a fast of
11 days. That young pigs have indeed a low liability to ketosis ap-
parently has been confirmed by Hanawalt and Sampson, 46b who found
that no significant ketonemia or ketonuria developed in pigs weighing
approximately 30 pounds even after they were deprived of all food
(but not water) for as long as 28 days. Nevertheless, since it has been
found that spontaneous ketosis occurs in the porcine species, further
study of the effect of fasting and of certain other influences on the
concentration of ketone bodies and of certain other constituents in

1947] KETOSIS IN DOMESTIC ANIMALS 457

blood of swine of different ages and under various experimental
conditions is highly desirable.

Evidence so far available seems to indicate that spontaneous, or
natural, ketosis in swine is not often associated with diabetes mellitus
and it is significant, perhaps, that experimental pancreatectomy ap-
parently causes only a mild form of diabetes in this species.69

Reference to the report by Hull and Nolan55 of clinical ketosis in
swine will be restricted to their observations on two cases inasmuch
as the values for blood and urine ketone bodies in Case 3 seem hardly
large enough to warrant a diagnosis of either ketonemia or ketonuria.
In Case 1 symptoms of ketosis developed in a Poland China sow,
weighing about 160 pounds, at approximately the seventh week after
farrowing. The ration fed before farrowing was composed of corn
and tankage, while after farrowing the sow received about 1/2 pint of
tankage and 3 to 6 ears of yellow corn each day. The amounts of
tankage and corn fed before farrowing are not given. The sow had
had access to "scant pasturage." An extraordinarily rapid loss of body
weight and lameness were prominent symptoms, according to the
owner, within three weeks after farrowing. Hull and Nolan state that
the history and symptoms were suggestive of posterior paralysis. They
mention also that a post-mortem examination of the sow revealed
pathologic changes in the liver and kidneys, presumably of the nature
of fat phanerosis.

In Case 2 ketosis was demonstrated in a three-year-old sow at ap-
proximately one month post-partum. A decrease in body weight from
400 pounds to 275 pounds had occurred in this period. The ration fed
during pregnancy is not mentioned, but after farrowing the sow was
given 3 to 4 ears of corn and some tankage each day. This sow also had
had access to "scant pasturage." The sow was not far from death
when submitted for diagnosis and was therefore killed. At autopsy,
changes in the liver and kidneys were found similar to those observed
in Case 1 .

Hull and Nolan do not include data on the concentration of the
ketone compounds in the blood and urine of normal swine, but
Hanawalt and Sampson (unpublished data) have found that blood and
urine of healthy pregnant and lactating sows contain only traces of
ketone bodies.

The description of the symptoms and results of chemical deter-
minations on blood and urine given in the report by Sampson and
Hanawalt of ketosis in the sow are quite similar to those already
known to characterize uncomplicated ketosis in the cow and ewe.
Hypoglycemia does not seem to be as severe in the sow as in the CQW

458 BULLETIN No. 524 [December,

and ewe, but further study is needed before a definite statement can
be made with respect to this point.

Observations on ketosis of swine at the Illinois Agricultural Ex-
periment Station have thus far been limited to four cases diagnosed
in sows during the early part of lactation. This group of four animals
includes the sow referred to in the report by Sampson and Hanawalt.
Two of the sows were from the same farm in Illinois, while another,
found to be affected with what appeared to be uncomplicated ketosis,
originated in a herd of swine in a neighboring state. One veterinarian
reported that several sows had died before he submitted a typically
affected animal to the laboratory for diagnosis.

Several or all of the following symptoms were observed in the four
sows: lack of appetite, rapid loss of body weight, wobbly gait, and
varying degrees of somnolence. In uncomplicated ketosis the body
temperature was normal. Respiration did not seem to be noticeably
affected. Sows that developed ketosis seemed to be "good milkers" (Fig.
7), but no critical evidence was obtained to verify this observation.

With reference to the cause of ketosis in swine, Sampson and
Hanawalt111 made the following statements:

It seems probable that the fundamental cause is the same whether ketosis
occurs in cows, ewes, or sows ; namely, an insufficient intake of readily
available carbohydrate or potential carbohydrate material. Under certain
circumstances, such as late pregnancy and the early stage of lactation, an
inadequate intake of concentrated carbohydrate in the form of starches
and sugars might be due to various causes. For example, either inappetence
(associated with constipation or a digestive disturbance of any form), or
a marked decrease in the daily feed allowance would reduce the carbo-
hydrate intake. Any appreciable decrease in daily feed consumption would

Ketosis (acetonemia) in a sow several days after farrowing, (a) During the
attack; (b) six weeks later, when the sow had recovered and was still nurs-
ing a litter of ten pigs. (Fig. 7)

1947~\ KETOSIS IN DOMESTIC ANIMALS 459

TABLE 4. — TOTAL KETONE BODIES AND SUGAR IN BLOOD OF HEALTHY
Sows AND Sows AFFECTED WITH CLINICAL KETOSIS

(Ketone bodies expressed as acetone)

Healthy sows*

Sows affected with ketosisb

Sow

Ketone
bodies

Sugar

c~_ Ketone
Sow bodies

Sugar

1

mg/100 ml
Trace

mg/100 ml
56.50
40.68
80.23
71.19

5

mg/100 ml
68 20

mg/100 ml
61.02=
58.76
79.10
54.24

2

Trace

6

36 08

3

Trace

7

95 23

4

Trace

8

41 17

* Sows 1 and 2 were in late pregnancy, and Sows 3 and 4 in early lactation.
b Sows 5, 6, 7, and 8 were in early lactation.

c This value was obtained in analysis of blood collected 24 hours after subcutaneous injection
of 125 grams of dextrose.

soon be reflected in a decreased glycogen supply stored in the liver. Such
a condition, as Mirsky81 points out, could result in an increase in the
oxidation of fatty acids in the liver and excess production of ketone bodies.

The etiology of ketosis in swine is a challenging problem for further
research.

Illinois data on the concentrations of ketone bodies and sugar in
blood of healthy sows and sows affected with ketosis are shown in
Table 4. The data reveal that values for blood ketone bodies in spon-
taneous ketosis of the sow may be as high as or higher than values
often obtained in determinations for ketone bodies in blood of cows and
ewes affected with severe ketonemia.

On the basis of the data given in Table 4 for blood sugar, it might
be inferred that hypoglycemia is not associated with ketosis in swine.
That such an inference probably is not correct is indicated by the
observations of Hull and Nolan, who found that hypoglycemia (20 mg.
percent) is sometimes as severe in ketosis of the sow as it is in some
cases of ketosis in the cow and ewe. Further study of spontaneous
ketosis in sows is needed, however, to determine the frequency and
the intensity of hypoglycemia in this species. Apparently normal con-
centrations are found for calcium, magnesium, inorganic phosphorus,
hemoglobin, nonprotein nitrogen, and chlorides of the blood of sows
affected with ketosis, but more observations are needed before a definite
statement can be made.111

Knowledge of the histopathology of ketosis in swine is also limited.
Reference has been made to the observations reported by Hull and
Nolan. Morrill has made a careful study of gross and microscopic
changes in tissues of several sows affected with ketosis and has sum-
marized his findings (unpublished) as follows:

460

BULLETIN No. 524

[December,

The pathological changes found in the livers and kidneys of the few cases
of porcine ketosis coming to autopsy at the Illinois Station have resembled
rather closely those described for sheep and cattle.

The liver in general is not visibly enlarged, but is pale yellow to ochre
in color and friable, and the cut surface imparts a greasy film to the knife.
The discoloration may be completely diffuse or may vary within the lobule,
the periphery being yellow and the central portion reddish brown. Micro-
scopic examination of sections of livers in which lipoidal substances have
been retained and stained with a fat-soluble dye reveal the presence of
fatty changes, either diffuse or more marked near the periphery of the
lobules [Fig. 8].

The kidneys also show diffuse yellowish discoloration of variable de-
gree. Application of histological procedures to demonstrate the presence
of lipoidal material reveals widespread fatty changes in the epithelium,
particularly in convoluted tubules and to a considerable extent in collecting
tubules.

Treatment and prevention. There is some evidence that thera-
peutic and prophylactic measures recommended for ketosis of the cow
and ewe are just as applicable for ketosis of the sow, but more in-
formation is needed.111

Section from liver of sow with ketosis. Greater concentration of fat occurred
in peripheral parts of the lobules. C = central vein. Sudan IV-hematoxylin.
X 40. (Fig. 8)

1947~\ KETOSIS IN DOMESTIC ANIMALS 461

KETOSIS IN RABBIT, CHICKEN, AND DUCK

Only limited information is available on the susceptibility of other
domestic animals to spontaneous and experimental ketosis, particularly
ketosis caused by fasting or by inadequate consumption of antiketogenic
food. Hunger causes ketonuria in the rabbit,17 and Sampson and Dukes
(unpublished data) found that fasting may produce an appreciable
ketonemia in well-nourished hens. Similarly, Mirsky, Nelson, Grayman,
and Korenberg83 found that fasting causes a rapid accumulation of
ketone bodies (up to as much as 45 mg. percent) in the blood of
normal ducks.

On the other hand, whereas pancreatectomy produces typical dia-
betes accompanied by ketosis in the rabbit,135 this operation produces
at most only a mild form of diabetes in the chicken64 and duck.131' 83
(Batt, cited by Dukes,28 found that the fasting chicken has an average
blood sugar concentration of approximately 185 mg. percent and con-
firmed the observations of others that pancreatectomy does not cause
severe diabetes in this species.)

KETOSIS IN DOG AND CAT

The adult dog has been found to be comparatively resistant to the
development of ketosis during fasting.1' 25 It is not clear from the
literature, however, to what extent the pregnant bitch has been used in
studies of the relation of fasting to ketosis in dogs. Apparently fasting
may cause hypoglycemia in the well-nourished lactating bitch.77 Pup-
pies, in contrast to older dogs, develop a marked ketosis with fasting.1

Phlorhizin administration and pancreatectomy have been the two
common procedures employed in producing experimental diabetes
mellitus in the dog.1 The administration of anterior pituitary ex-
tract34' 143 and alloxan30 are newer technics of producing experimental
diabetes and its attendant symptoms.

On the basis of evidence now available it would appear that spon-
taneous or clinical ketosis is of rare occurrence in dogs.57 Furthermore,
when it is observed it is apparently associated with diabetes mellitus.
The literature contains a number of references to diabetes mellitus in
dogs, but evidence on which the diagnosis of the disease was made is
often lacking. Milks and Stephenson80 published a report on several
cases of diabetes in dogs and included in their description of each
case results of chemical determinations on blood and urine and ob-
servations made at autopsy of affected animals.

462 BULLETIN No. 524 [December,

The data of Milks and Stephenson revealed that hyperglycemia,
ketonemia, ketonuria, and glycosuria characterized these cases. An
apparent complete lack of pancreatic tissue in three of the dogs pro-
vided additional evidence in support of the diagnoses. A summary of
the data reported by Milks and Stephenson is given in Table 5.

TABLE 5. — TOTAL KETONE BODIES AND SUGAR OF BLOOD AND URINE
IN DIABETES MELLITUS OF DOGS*

(Ketone bodies expressed as acetone)

Dog

Blood

Urine

Comment on condition of
pancreas at autopsy

Ketone
bodies

Sugar

Ketone ~a.
bodies

1

mg/100 ml
22.63

mg/100 ml
435
513

328

466

260

gm/100 ml gm/100 ml
.29 6.11
High

4.00

1.37
40.00

'. 32 1 '. 36
6.25

3.33

No pancreas could be found.
Pancreatic tissue less than 1 cm. in
diameter.
Pancreas largely replaced by scar tis-
sue and fat.
No pancreatic tissue could be found.
(Pancreas not mentioned.)
Pancreas has practically disappeared.
Pancreas appeared normal.
Pancreas replaced by connective
tissue.
No pancreatic tissue could be found.

2

3

4. . .

5

6. .

7

4.09

8

9

26 32

» From data of Milks and Stephenson. Cornell Veterinarian 27, 169-177 (1937).

Pancreatectomy causes severe diabetes in the cat,68 but presumably
little is known concerning the incidence of spontaneous ketosis in this
species.

KETOSIS IN THE HORSE

So little information is available on ketosis in the horse that further
reference to the condition in this species is hardly justified. The con-
centration of ketone bodies in the blood of normal horses is presum-
ably the same as for other domestic animals.

Illinois studies showed only a trace of ketone bodies in the blood
of nine healthy draft horses. These horses consisted of 2 mares not
pregnant, a mare to foal in 10 days, one foaled 10 days before, one
bred two weeks before, a filly not pregnant, and 3 geldings. Another
mare, not pregnant, showed 5.08 milligrams of ketone bodies per 100
milliliters (expressed as acetone).

Future studies may reveal that pregnant and lactating mares are
as susceptible to ketosis as the cow, the ewe, and the sow.

1947] KETOSIS IN DOMESTIC ANIMALS 463

SUMMARY

The foregoing discussion reviews and appraises the rapidly grow-
ing knowledge on clinical (spontaneous) and experimental ketosis in
domestic animals, with special emphasis on ketosis of the cow, the ewe,
and the sow. Evidence so far accumulated seems to indicate that the
theory of "antiketogenesis" is as applicable to domestic animals as it is
to humans.

The economic importance of clinical ketosis in cattle and sheep is
now recognized in most, if not all, parts of the world. Cows affected
with severe ketosis (acetonemia) often show a 50-percent or greater
reduction in milk production. Furthermore, if proper treatment is not
given, they may become worthless or die. Death losses from clinical
ketosis (pregnancy disease) in sheep are high, since 90 percent of
affected ewes ordinarily succumb unless treatment is begun during the
early stage. Lambs, if born, are usually unthrifty and often do not
survive.

Experimental ketosis, apparently indistinguishable from clinical ke-
tosis, may be induced in cows and ewes by subjecting the animals to
partial or complete inanition. Animals that are (1) fat, (2) nearing
parturition, or (3) in early lactation are most susceptible.

The chief pathological changes in tissues and organs of cows and
ewes succumbing to ketosis are usually limited to the liver and kidneys.
The liver has a yellow color and contains an enormous amount of fat;
while the kidneys, besides having a high fat content, often show de-
generative changes.

The cause of death of cows and ewes that die of what is believed
to be uncomplicated ketosis has not been determined, but disturbed
carbohydrate- fat metabolism in the liver, functional damage to the
central nervous system, and impaired kidney function may be impor-
tant contributing influences.

Many products have been used in treating ketosis of the cow and
ewe. The most effective seems to be some form of concentrated carbo-
hydrate such as glucose.

Evidence now available seems to indicate that two conditions are
essential in preventing clinical ketosis in the pregnant or lactating cow
and ewe (and in all probability in the goat and sow as well): (1) an
adequate daily ration of nutritious feeds and (2) a good appetite on
the part of the animal.

Clinical and experimental ketosis in the goat and sow presumably
are fundamentally similar to clinical and experimental ketosis in the

464 BULLETIN No. 524 [December,

cow and ewe, but further study is needed before definite conclusions
are warranted. The extent of spontaneous ketosis, if it occurs, in other
domestic animals, specifically in the pregnant or lactating female, such
as the mare and bitch, has not been established.

Information of great value has resulted from clinical and experi-
mental observations made during recent years, but additional study
is necessary for a clarification and more complete understanding of
many aspects of ketosis in animals.

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