ASCITES

Pathogenesis
The development of ascites (defined as the accumulation of a transudate or
modified transudate in the peritoneal cavity) is another consequence of portal
hypertension but the pathogenesis is complex and has really been studied
only in humans; it is assumed that the mechanisms of ascites are similar in
dogs. One way in which dogs differ from humans is that dogs do not develop
the "spontaneous" infection of ascites of liver origin by extension of gut
bacteria into the fluid that results in peritonitis, which is commonly reported
in people. The presence of ascites is a poor prognostic indicator in humans with
chronic hepatitis, and the same appears to be true in dogs. Hypoalbuminemia
contributes to the development of ascites but by itself is rarely sufficient to
cause fluid accumulation; portal hypertension is a critical contributing factor.
The development of ascites in patients with liver disease also seems to lead
to sodium retention by the kidneys. In many cases there is systemic
hypotension and increased renal sodium retention, partly as a result of reduced
glomerular filtration rate and decreased sodium delivery to the tubules and
partly as a result of increased release of renin-angiotensin-aldosterone (RAAS)
that results in increased sodium retention in the distal tubules. This leads to
an increase in circulating fluid volume, precipitating the formation of ascites,
which in turn reduces venous return because of increased pressure on the
caudal vena cava and initiates a vicious cycle of renal sodium retention and
ascites. Therefore aldosterone antagonists are usually most effective in
dogs with ascites secondary to portal hypertension, whereas loop diuretics,
such as furosemide used alone, can be ineffective or even, in some cases,
actually increase the volume of effusion by causing a further decrease in
systemic blood pressure as a result of hemoconcentration and secondary
increases in R A A S activation.
Treatment
Treatment of ascites associated with liver failure revolves around the use of
diuretics: first aldosterone antagonists - (spironolactone, 1 to 2 mg/kg
administered P O ql2h)
Spironolactone usually takes 2 or 3 days to reach full effect, and the
resolution of ascites can be monitored by weighing the patient daily (any
acute changes in weight will be due to fluid shifts).

furosemide (2-4 mg/kg administered P O ql2h.

Dietary sodium restriction has also been recommended

Hypokalemia & Hyponatremia should be avoided because it can precipitate H E

(see preceding section
Therapeutic paracentesis is indicated only in patients with ascites that is
severe enough to compromise breathing.- accompanied by concurrent
intravenous administration of a colloid plasma expander, plasma, or albumin; to
prevent to pulmonary edema.
Small volume paracentesis: follow up with intravenous plasma expansion
with 2 to 5 ml/kg of gelofuscin or hemaccel
Large volume paracentesis: volume expand preferably with albumin using
8 g albumin/I of ascites removed (i.e., 100 ml of 2 0 % albumin per 3 liters of
ascites). Failing that, use fresh frozen plasma (10 ml/kg slowly)

Treatment for Canine Herpes virus

There is no effective treatment for CHV.
Prevention
In breeding kennels, promote proper husbandry practices and maintain warm
ambient temperatures for neonates.
Kennels- Isolation & Disinfection
administer hyperimmune antiserum((harvested from seropositive bitches that
recently have produced CHV-infected litters), 1 to 2ml, intraperitoneally, for
prophylaxis in newborn puppies.
Immunization
Ascites
Ascites is a common feature of severe chronic liver disease. Mechanisms of
ascites and edema formation in liver disease include hypoalbuminemia, portal
hypertension, and sodium and water retention.
Rupture of the biliary tract causing bile peritonitis also is associated with
abdominal fluid accumulation.
Signalment and History
The signalment often provides important clinical information, because breed
predilections for specific liver diseases have been recognized, and young
animals are more likely to be presented for congenital hepatic disorders such as
portosystemic shunt.

 The history may provide important information

regarding the potential for exposure to known causes
of hepatic injury such as drug therapy, surgical and
anesthetic procedures, and toxins or infectious
agents.
Determine if the animal has a history of intolerance
to drugs normally metabolized by the liver, such as
sedatives, tranquilizers, anticonvulsants, and anesthetics.
Determine the current vaccination status and exposure potential for infectious agents known to affect
the liver, such as leptospirosis, infectious canine
hepatitis, and feline infectious peritonitis (FIP).
Physical Examination
Skin and Mucous Membranes
Evaluate the sclera, oral mucous membranes, and
skin for jaundice. Jaundice is not clinically detectable
until serum bilirubin concentrations are >2.5 to
3.0 g/dl. In cats, subtle jaundice often is best detected
on the palatine mucosa.
Evaluate the skin and mucous membranes for evidence of bleeding. Pallor may be detected with blood
loss anemia.
Abdominal Palpation
Palpate the abdomen carefully. The normal liver can be
difficult to palpate in dogs and cats, and the edges are

normally sharp, not rounded.

Hepatomegaly is caused by passive venous congestion, diffuse inflammation, nodular hyperplasia,
cysts, bile engorgement, marked biliary hyperplasia
(cats), and infiltration by fat, glycogen, and neoplastic cells.
Pain on palpation of the liver (hepatodynia) usually
indicates acute liver disease. The pain is caused by
stretching of the liver capsule and must be differentiated from pain arising in the pancreas, stomach, or
spleen.
Moderate to severe abdominal effusion may be
detected.
Neurologic Exam
Perform a neurologic examination in animals with a
history of neurologic signs. With HE, the neurologic
examination may be normal or suggestive of diffuse
cerebral disease (e.g., depression and dementia, disorientation, pacing, circling, head pressing, hypersalivation, seizures, or coma).
Rectal Exam
Perform a rectal examination and obtain a fecal sample
to evaluate for melena (indicative of GI bleeding) and
acholic feces.
Routine Laboratory Evaluations
Because clinical findings in hepatobiliary disease often

are vague, hepatic disease may not be suspected untilChapter 71 / Diseases of

the Liver and Biliary Tract 749
biochemical tests identify elevated liver enzyme activity
or other evidence of hepatic dysfunction (e.g., hyperbilirubinemia or hypoalbuminemia). Liver function
studies such as serum bile acid (SBA) concentrations
are used to achieve the following:
Identify occult liver disease
Assess liver function when there is increased
liver enzyme activity but normal serum bilirubin
concentrations
Determine whether significant hepatic dysfunction is
present to warrant performing a liver biopsy
Monitor response to therapy
Findings consistent with liver disease on routine laboratory tests are described below.
Complete Blood Count
Mild to moderate anemia may occur secondary to liver
disease because of blood loss (e.g., gastroduodenal
ulceration or coagulopathy) or may be associated
with normocytic-normochromic anemia of chronic
disease.
Erythrocytic microcytosis is a common finding in dogs
and cats with portosystemic shunts. Decreased serum
iron concentration, normal to increased serum ferritin concentration, and accumulation of stainable
iron in the liver suggests that microcytosis is associ-

ated with abnormal iron metabolism (impaired iron

transport or sequestration of iron) rather than
absolute iron deficiency. Decreased availability of
iron for hemoglobin synthesis appears to occur
despite adequate tissue iron stores.
Target cells and poikilocytosis (acanthocytes and elliptocytes) may occur in dogs and cats with various types
of hepatic disease, due to altered red blood cell
(RBC) membranes.
Urinalysis
Urine specific gravity may be isosthenuric or hyposthenuric if liver disease is associated with PU/PD.
Bilirubinuria is a sensitive indicator of abnormal
bilirubin metabolism, and this finding precedes
hyperbilirubinemia

and

jaundice.

Bilirubinuria

imparts a yellow-orange color to the urine. Bilirubin

crystals may form in the presence of bilirubinuria.
Trace amounts of bilirubin may be found in concentrated urine of normal dogs (especially males).
Bilirubinuria is always abnormal in cats and suggests

underlying

hemolytic

or

hepatobiliary

disease.
Urine urobilinogen is a colorless product of enteric bacterial degradation of bilirubin that is absorbed from
the gut. A small portion of urobilinogen escapes the
enterohepatic circulation and is excreted in the

urine. The finding of urobilinogenuria indicates an

intact enterohepatic circulation of bilirubin pigments. The absence of urobilinogenuria in a jaundiced animal suggests common bile duct obstruction.
However, this test is not reliable in a clinical setting
because many non-hepatic factors affect urine urobilinogen concentration, including altered intestinal
flora, GI bleeding, intestinal absorption, renal excretion, urine pH, urine volume, and urine storage.
Ammonium biurate crystals are commonly detected in
animals with portosystemic shunts.
Key Point Suspect liver disease in any cat or dog
with ammonium biurate crystalluria (except in dalmatians and bulldogs).
Liver Enzymes
Evaluation of serum liver enzyme activity is used as a
screening test to detect liver disease. Increases in liver
enzyme activity are not specific for the underlying
hepatic disorder. However, liver enzymes can be used to
categorize the underlying pathophysiologic mechanism. Increases in liver enzyme activity may occur secondary to hepatocellular injury and leakage (Fig. 71-1),
or due to increased production stimulated by bile retention (cholestasis) or drug induction (Fig. 71-2).
Many systemic diseases can secondarily affect the
liver (reactive hepatopathy), causing increased liver

enzyme activity, but these are not necessarily associated

with clinical liver disease. For example, feline hyperthyroidism is commonly associated with increased liver
enzyme activity without significant hepatic dysfunction.
ALT
AST
Figure 71-1.

With hepatocyte injury, leakage of alanine amino-

transferase (ALT) from the cytoplasm results in increased serum activity. Aspartate aminotransferase (AST) is primarily associated with
mitochondria but is also present in the cytoplasm. Release of AST
from the mitochondria requires a severe insult. Thus, with hepatocyte
injury, ALT is more readily released and its activity level will usually
be higher than that of serum AST.750

Section 6 / Digestive System

Key Point Liver enzymes do not evaluate liver function. Thus, severe hepatic dysfunction may coexist
with normal liver enzyme activity; conversely,
increased liver enzyme activity may be detected in
animals without significant hepatic dysfunction.
Alanine Aminotransferase
Increased alanine aminotransferase (ALT) activity indicates hepatocyte injury with leakage of enzyme from the
cytoplasm of the hepatocyte (see Fig. 71-1). The magnitude of ALT increase generally correlates with the
number of injured hepatocytes.
The largest increases in ALT activity occur with hepatocellular necrosis and inflammation (up to 100

times normal). Increases also occur with increased

hepatocyte membrane permeability, such as that
caused by hypoxia. Severe cholestasis can also cause
secondary hepatocyte injury, with increases in ALT up
to 20 to 40 times normal. Increased production of
ALT by regenerating hepatocytes may account for
persisting increases in enzyme activity after resolution
of the initial injury.
Anticonvulsant drug therapy (primidone, phenytoin,
and phenobarbital) in dogs can be associated with
mild increases in ALT activity (2 times normal) in the
absence of obvious hepatocellular injury.
Corticosteroid therapy or hyperadrenocorticism is
associated with mild to moderate (210 times normal)
increases in ALT activity.
Small amounts of ALT are present in canine skeletal
muscle; it has been shown that severe skeletal muscle
degeneration or necrosis (canine muscular dystrophy, necrotizing myopathy, polymyositis) may be associated with increases in ALT activity of 5 to 25 times
normal. When increased ALT activity is caused by
muscle injury, creatine kinase (CK) and AST activity
are also markedly increased. Whether ALT is liver
specific in cats remains to be determined.
Aspartate Aminotransferase
Hepatocyte injury is associated with increased AST activ-

ity secondary to leakage from mitochondria and cytoplasm of hepatocytes (see Fig. 71-1).
AST is not liver specific in dogs and cats; it is present
in significant quantities in hepatocytes and skeletal
muscle tissue.
Comparison of activities of ALT, AST, and CK, a
muscle enzyme, can indicate whether AST activity is
increased due to hepatic or muscle injury.
Key Point Increased AST activity associated with
hepatic injury generally parallels but is less than
the increase in ALT activity, and CK is normal.
Increased AST activity due to skeletal muscle injury
is associated with increased CK activity and normal
or mildly increased ALT activity.
In some cats with liver disease, AST may be more
sensitive than ALT in detecting hepatic disease.
Alkaline Phosphatase
Increases in serum alkaline phosphatase (ALP) activity
are due to accelerated production of this enzyme, stimulated by cholestasis or drug induction (see Fig. 71-2).
ALP is a membrane-associated enzyme present in many
tissues; however, only liver, bone, and corticosteroidinduced isoenzymes contribute to serum ALP activity.
Serum ALP activity in normal dogs and cats is usually
due to the liver isoenzyme. An increase in this type of
ALP activity indicates intrahepatic or extrahepatic

cholestasis.
Cholestasis
ALP
Bile canaliculi
Bile ducts
Impaired flow
Bile canaliculi
Hepatocytes
Bile ducts
GGT
Normal
Figure 71-2.

Impaired bile flow (cholesta-

sis) causes increased synthesis of alkaline phosphatase (ALP) and gamma-glutamyltransferase

(GGT). ALP is a sensitive indicator of cholestasis in dogs but is less sensitive in cats (see text).
With cholestatic disorders, increased ALP activity precedes hyperbilirubinemia. ALP and GGT
lack specificity in differentiating between intrahepatic and extrahepatic cholestasis.Chapter 71 / Diseases of the Liver and Biliary
Tract 751
Young growing animals or animals with severe bone
disease may have mild increases in ALP activity due
to the bone isoenzyme.
Cats generally have smaller increases in serum ALP
activity with hepatobiliary disease than do dogs owing
to a limited capacity for ALP production and a

shorter serum half-life (6 hours in cats versus 72

hours in dogs). Therefore, even small increases in
serum ALP activity (23 times normal) in cats suggest
significant cholestasis.
Exogenous or endogenous glucocorticoids are associated with hepatic production of a novel isoenzyme
of ALP, corticosteroid-induced ALP (CIALP), in dogs
but not in cats. The CIALP isoenzyme can be distinguished from the liver isoenzyme (LALP) by levamisole inhibition using an automated analyzer.
Increased CIALP activity is a consistent finding in
dogs with spontaneous hyperadrenocorticism and
absence of this isoenzyme is uncommon in this
disorder.
Key Point Hypercortisolism caused by glucocorticoid therapy or hyperadrenocorticism (Cushings
disease) is the most common pathologic cause of
increased serum ALP activity in dogs; it is usually
attributed to an increase in CIALP.
Increase in ALP activity associated with corticosteroid
therapy varies considerably with the individual dog
and the drug, dose, and duration of therapy. In the
first 7 to 10 days of oral or parenteral glucocorticoid
therapy, increases in ALP are primarily due to LALP
activity. By 7 days, CIALP activity begins to increase,
and it predominates in the serum after a month of

therapy. Chronic treatment with otic, ophthalmic,

and topical preparations is also capable of inducing
ALP activity. Increases in CIALP activity do not necessarily imply the presence of iatrogenic hyperadrenocorticism, a suppressed pituitary-adrenal axis,
or corticosteroid-induced hepatopathy, nor does it
indicate

that

corticosteroid

therapy

must

be

discontinued.
Increased CIALP activity is a sensitive but not a specific test for exposure to excess glucocorticoids (iatrogenic or endogenous). Increases in CIALP activity
may be detected with diabetes mellitus, anticonvulsant drug therapy, primary hepatic disorders including neoplasia, hypothyroidism, and chronic illnesses
(associated with disease-related stress and increased
endogenous cortisol secretion). In this setting, a
mixed pattern of increased CIALP and LALP activity
is seen.
Increased CIALP activity associated with exogenous
or endogenous glucocorticoids may be accompanied
by mild to moderate (210 times normal) increases
in ALT activity that typically are of lesser magnitude
than increases in ALP activity.
Anticonvulsant drug therapy is associated with
enzyme induction of the liver isoenzyme of ALP
in dogs (but not in cats) in the absence of obvious

hepatocellular injury. CIALP activity also may be

increased in some dogs. Reported maximal increases
for induced serum ALP activity include those caused
by phenobarbital (30 times normal), primidone (5
times normal), and diphenylhydantoin (3 times
normal).
Gamma-Glutamyltransferase
This membrane-associated enzyme is present in many
tissues. Increased serum gamma-glutamyltransferase
(GGT) activity usually reflects cholestasis and increased
production by hepatocytes (see Fig. 71-2).
Increased GGT activity parallels increased ALP activity in dogs, including increases associated with excess
corticosteroids.
Anticonvulsant therapy causes mild (23 times
normal) increases in serum GGT activity in dogs.
In cats, serum GGT is more sensitive for detecting
hepatobiliary disease than ALP. Serum GGT activity
exceeds serum ALP activity in most hepatobiliary diseases; an exception is hepatic lipidosis, in which GGT
activity may be normal or mildly increased despite a
moderate to severe elevation of serum ALP.
Other Biochemical Tests
Numerous biochemical tests can be altered by liver
disease, including serum bilirubin, albumin, globulin,
urea nitrogen, glucose, and cholesterol. Many of these

parameters reflect some aspect of liver function;

however, they lack sensitivity or specificity for liver
disease.
Bilirubin
Increased serum bilirubin concentration occurs secondary to hemolysis or cholestasis. Evaluate for underlying hemolytic disorders by performing a complete
blood count (CBC) to detect anemia.
Fractionation of the total serum bilirubin into conjugated and unconjugated components (van den
Bergh test) to distinguish the mechanism of hyperbilirubinemia is of little diagnostic value because
there is considerable overlap in hemolytic, hepatocellular, and extrahepatic biliary disorders.
Lipemia falsely elevates serum bilirubin concentration; the absence of concurrent bilirubinuria suggests
pseudohyperbilirubinemia.
Albumin
Albumin is synthesized exclusively by the liver. Because
of a large reserve capacity for albumin production,
hypoalbuminemia does not occur until the functional
hepatic mass is reduced 70% to 80%.752
Key Point Hypoalbuminemia

associated

Section 6 / Digestive System

with

hepatic disease implies chronicity because of the

long half-life of albumin.
With chronic liver disease, fluid retention and dilu-

tion of existing serum albumin may also contribute

to hypoalbuminemia.
When the serum albumin is <1.5 g/dl, hypoalbuminemia contributes to the development of ascites
and edema.
Hypoalbuminemia is not specific for liver disease,
and other causes of hypoalbuminemia such as urinary
and gastrointestinal (GI) loss must be excluded.
Inappropriate dietary protein restriction should be
avoided since it can worsen hypoalbuminemia.
Globulin
Hyperglobulinemia due to increased gamma globulins occurs in some dogs and cats with chronic liver
disease. The most likely mechanism is a systemic
response to antigens that escape from the GI tract
because of impaired hepatic mononuclear phagocyte
system function or portosystemic shunting.
Significant hypoglobulinemia does not usually occur
with liver disease despite the livers role in the synthesis of alpha and beta globulins.
Blood Urea Nitrogen
Blood urea nitrogen (BUN) concentration may be
decreased secondary to liver disease because the liver is
responsible for converting ammonia to urea. However,
many non-hepatic factors (e.g., PU/PD, fluid diuresis,
and low-protein diet) can also decrease BUN levels.

Glucose
Hypoglycemia may occur secondary to hepatic dysfunction because of impaired hepatic gluconeogenesis,
decreased hepatic glycogen stores, and decreased
hepatic insulin degradation. However, because <30% of
liver function is sufficient to maintain euglycemia, hypoglycemia is an insensitive indicator of hepatic function.
Because it indicates severe liver dysfunction, liverassociated hypoglycemia is a poor prognostic factor,
except in dogs and cats with congenital portosystemic
shunts.
Some hepatic neoplasms such as hepatocellular carcinoma and adenoma, leiomyosarcoma, and hemangiosarcoma have been associated with profound
hypoglycemia.
Also consider non-hepatic causes of hypoglycemia
such as sepsis, hypoadrenocorticism, and insulinoma
(see Chapters 33 and 35).
Cholesterol
Hypercholesterolemia occurs with acute cholestatic
disorders because of increased synthesis of cholesterol and decreased incorporation of cholesterol into
bile acids; however, there are many non-hepatic
causes of hypercholesterolemia.
Although cholesterol is synthesized in the liver,
hypocholesterolemia secondary to liver disease is

uncommon; it has been noted with congenital portosystemic shunts and phenobarbital-induced hepatic
disease.
Electrolytes
Serum electrolyte changes secondary to liver disease are
variable.
In acute liver failure, serum electrolyte concentrations are usually normal.
With chronic liver disease, total body potassium
depletion and sodium and water retention are
common, and the serum sodium concentration is
usually normal or decreased.
Liver Function Tests
Liver function tests can document clinically significant
hepatic dysfunction when liver disease is suspected,
based on historical, clinical, laboratory, and radiographic findings. SBA determinations have largely
replaced the use of organic anion dyes such as sulfobromophthalein (Bromsulphalein) and indocyanine
green (ICG). Blood ammonia concentration and
ammonia tolerance tests can specifically evaluate the
portal circulation (for portosystemic shunts) and detect
HE.
Key Point The test of choice for clinical evaluation
of liver function is the combined fasting and 2-hour
postprandial SBA test.

Serum and Urine Bile Acids

The normal physiology of bile acid metabolism is shown
in Figure 71-3A. In health, bile acids are confined to the
enterohepatic circulation, and systemic concentrations
are low. SBA concentrations increase in the systemic circulation with all types of liver disease (Fig. 71-3B).
Because the liver has a large reserve capacity for synthesis of bile acids, even severe hepatic dysfunction does
not cause decreased SBA concentrations.
Fasting Serum Bile Acid Concentration
A fasting serum bile acid (FSBA) concentration obtained
after a 12-hour fast is a sensitive, specific measure of
hepatobiliary function in dogs and cats. Normal FSBA
values in dogs and cats are <20 mmol/L. When concentrations exceed 30 mmol/L, a liver biopsy may be warranted to evaluate the underlying liver disease.
Increased concentrations occur with hepatocellular
and cholestatic disorders that interfere with hepatic
uptake or secretion of bile acids and with portosys-Chapter 71 / Diseases of the
Liver and Biliary Tract 753
temic shunting, in which bile acids are diverted
directly into the systemic circulation (see Fig. 71-3B).
Serial evaluation of SBA concentration to monitor
liver function may not have merit unless the SBA concentration returns to normal. This is because there
are wide fluctuations in SBA concentration in a given
patient with liver disease within a 24-hour period

(although all values are abnormal).

Dogs and cats receiving the oral synthetic bile acid,
ursodiol, may have an increase in SBA concentration
because of the absorption of the drug and reflection
of its presence in the serum.
Interference in bile acid measurement can occur
with hemolysis or lipemia.
In dogs with unexplained increases in SBA, consider
the possibility of small intestinal bacterial overgrowth
causing increases in unconjugated bile acids.
Healthy Maltese dogs were reported to have significantly higher SBA (mean 70 mmol/L 50; range 1
362 mmol/L) as measured by the enzymatic spectrophotometric method than as measured by highperformance liquid chromatography, suggesting the
presence of additional reacting substances or unusual
bile acids in their serum. However, a methodological
problem related to lipemia or hemolysis cannot be
excluded. It is also possible that these dogs had
underlying hepatic microvascular dysplasia.
When hepatic disease causes hyperbilirubinemia,
measurement of SBA concentrations does not
provide any additional diagnostic information. SBA
concentrations are most helpful diagnostically in
dogs and cats with anicteric liver disease.
Postprandial Serum Bile Acid Concentration

Postprandial serum bile acid (PPSBA) concentration is

an endogenous challenge test of liver function. Whether
PPSBA concentration is a more useful diagnostic test
than FSBA concentration remains unclear. In dogs,
similar information is provided by either test in most
hepatobiliary disorders. Notable exceptions include
dogs with portosystemic shunts or cirrhosis, because with
these disorders, FSBA can be in the normal range. In
cats, the diagnostic efficacy of PPSBA exceeds that of
FSBA for all hepatic disorders, including portosystemic
shunts. For best diagnostic utility, paired FSBA and 2hour PPSBA is recommended. To perform the PPSBA
concentration test, take the following steps:
Obtain a serum sample for FSBA concentration, and
then feed at least 2 teaspoons of food to small dogs
and cats (<5 kg) and at least 2 tablespoons to larger
patients.
To ensure gallbladder contraction, feed a diet high
in fat (e.g., Hills Pet Prescription Diet p/d and Hills
Pet Prescription Diet c/d for cats). For encephalopathic animals in which a high-protein diet is contraindicated, substitute a protein-restricted diet and
add a few milliliters of corn oil per feeding.
Obtain a second serum sample 2 hours after feeding.
Results: In normal dogs and cats, PPSBA concentrations are <25 mmol/L and peak 2 hours after a meal.

A liver biopsy may be indicated when concentrations

are >30 mmol/L.
On occasion, FSBA is higher than PPSBA. This probably occurs because of sporadic gallbladder contraction during fasting, which releases bile into the
intestinal tract, resulting in increased SBAs.
Urine Bile Acids
Recently, urine bile acids (UBAs) have been investigated as a diagnostic tool in dogs and cats. Normally
only small amounts of bile acids are present in the
Liver
synthesis
Enterohepatic
circulation
Intestinal
clearance A
Systemic
circulation
Renal
clearance
Liver
synthesis
Enterohepatic
circulation
Systemic
circulation

Portosystemic
shunt
Hepatobiliary disease
Intestinal
clearance
Renal
clearance B
Figure 71-3.

A, Bile acids are synthesized in the liver, secreted into

the biliary system, and stored in the gallbladder during fasting. With
ingestion of a meal, cholecystokinin release stimulates gallbladder
contraction and entry of bile acids into the intestinal tract. Bile acids
are efficiently reabsorbed in the distal ileum and carried in the portal
blood back to the liver, thus completing the enterohepatic circulation.
In the healthy animal, the liver removes 90% to 95% of bile acids from
the portal circulation during the first pass of the enterohepatic circulation. This allows only small amounts of bile acids to escape to the
systemic circulation. Normal serum concentrations are therefore low
(fasting < 15 mmol/L, postprandial < 25 mmol/L). B, Hepatocellular
dysfunction or cholestasis interferes with hepatic uptake, storage, and
secretion of bile acids. Thus, impaired extraction of bile acids from
the portal blood results in increased serum bile acid concentrations.
With portosystemic shunting, bile acids in the portal blood are
diverted directly into the systemic circulation.754

Section 6 / Digestive System

urine. Liver disease and increased SBA result in

increased excretion of bile acids in the urine. Potential
advantages of UBA over a random FSBA are that UBA

may reflect an average value over time, ease of sample

collection, and lack of interference from oral ursodiol
administration.
UBAs are normalized with urine creatinine (Cr), and
values are expressed as UBA/Cr (mmol/mg) 100.
Values greater than 7.3 are abnormal in dogs. Values
greater than 4.4 are abnormal in cats.
Timing of urine collection to the 4- to 8-hour postprandial period may improve diagnostic performance,

particularly

in

dogs

with

congenital

portosystemic shunting where sensitivity of UBA

(taken 4 to 8 hours after eating) was 100% compared
with 84% for FSBA and 98% for PPSBA.
The role of UBA in the evaluation of hepatobiliary
function awaits further clinical evaluation.
Blood Ammonia Concentration
Ammonia is metabolized by the liver, and normal
plasma concentrations are low. Measurement of
ammonia is technically difficult, and appropriate
sample handling requires heparinized blood samples to
be stored immediately on ice, cold-centrifuged, and
assayed as soon as possible.
Measurement of blood ammonia concentration primarily is indicated to document HE. However,
normal values do not exclude this diagnosis, because
other toxins can contribute to the encephalopathy.

 Portosystemic shunting (congenital or acquired) is

the most common mechanism of hyperammonemia,
but severe, diffuse hepatic disease (especially acute
hepatic necrosis) also increases blood ammonia concentrations.
Blood ammonia values have poor sensitivity in detecting other types of hepatobiliary disease without portosystemic shunting.
Blood ammonia concentration is not a suitable
screening test for congenital portosystemic shunt in
young Irish wolfhounds since a transient metabolic
hyperammonemia unassociated with liver disease
occurs in this breed.
Congenital urea cycle enzyme deficiency is a rare
cause of hyperammonemia.
Ammonia Tolerance Test
This is a more sensitive test than blood ammonia concentration for documenting portosystemic shunting.
However, the ammonia tolerance test (ATT) is contraindicated if resting ammonia levels are already
increased, because no further diagnostic information
will be obtained and performing an ATT can cause signs
of HE. Note: The ATT is not recommended for use in cats.
The test is performed in a fasted dog by giving
100 mg/kg of ammonium chloride (do not exceed a
total dose of 3 g), either as a dilute solution by

stomach tube or as a powder in a gelatin capsule.

Take a heparinized blood sample before and 30
minutes (stomach tube method) or 45 minutes
(capsule method) after administering the ammonium chloride. Vomiting may occur but does not
invalidate the test.
In normal dogs, there is no increase in blood
ammonia concentration or a mild increase (<2 times
greater than baseline). In dogs with portosystemic
shunting, results are consistently abnormal (up to 10
times baseline values).
The ATT and paired FSBA and PPSBA tests have equal
sensitivity in detecting portosystemic shunting. Consequently, the SBA testing has largely replaced blood
ammonia and ATT. Paired FSBA and PPSBA provide
a better screening test because it detects a broader
range of hepatobiliary disorders, and bile acids are
stable, permitting routine laboratory analysis.
Protein C
Protein C, an anticoagulant protein synthesized in the
liver, has been investigated as a clinical marker of liver
disease. Preliminary results show decreased protein C
concentrations in 100% of dogs with liver failure, 98%
of dogs with portosystemic shunt, and 30% of dogs with
hepatic microvascular dysplasia. The role of protein C
in the detection of liver disease awaits further clinical

studies.
Parameters of Hemostasis
The liver plays a central role in the coagulation and fibrinolytic systems. The liver is responsible for synthesis
of all coagulation factors except factor 8, von Willebrand factor. Fibrinogen, antithrombin, and protein C
are all synthesized in the liver and can be decreased with
hepatic dysfunction. Activated coagulation factors and
fibrinolytic enzymes are also cleared by the liver.
Mechanisms of excessive bleeding associated with
hepatobiliary disease include primary failure of hepatocytes to synthesize clotting factors, DIC, and
vitamin K deficiency. Vitamin K deficiency in hepatobiliary disease is usually caused by malabsorption of
vitamin K secondary to complete bile duct obstruction. However, a vitamin Kresponsive coagulopathy
may sometimes be detected in dogs and cats with
severe hepatic insufficiency, possibly due to marked
intrahepatic cholestasis causing vitamin K malabsorption or the inability of the liver to reactivate
vitamin K from its inactive (epoxide) form.
Clinical evidence of bleeding secondary to hepatobiliary disease is uncommon; however, the frequency
of abnormal coagulation tests is much higher.
Coagulation Tests
Measure prothrombin time (PT) to evaluate the

extrinsic coagulation system and activated partialChapter 71 / Diseases of the

Liver and Biliary Tract 755
thromboplastin time (APTT) to evaluate the intrinsic
coagulation system. These tests can be abnormal in
the presence of liver disease. Activated coagulation
time also can be used as a rapid screening test for
abnormalities of the intrinsic coagulation system. For
further discussion of these tests, see Chapter 23.
The PIVKA (proteins induced by vitamin K absence)
clotting time is a more sensitive test than PT or APTT
to detect bleeding tendencies in dogs and cats with
liver disease. Normalization of PIVKA clotting time
may occur after treatment with vitamin K 1 .
The combination of prolonged PT and APTT, low
plasma fibrinogen, increased fibrin degradation
products, fragmented RBCs, and thrombocytopenia
suggests DIC (see Chapter 23).
Thrombocytopenia and Platelet Dysfunction
Thrombocytopenia may occur secondary to splenic
sequestration of platelets associated with portal
hypertension or consumption of platelets from DIC.
Platelet function defects also have been documented
in dogs with liver disease, which may account for
clinical bleeding tendencies in the presence of
normal coagulation tests and platelet numbers. Use
mucosal bleeding time to detect platelet function
abnormalities.

Blood Gas Analysis

Various acid-base imbalances may occur secondary to
liver disease, including respiratory alkalosis, metabolic
alkalosis, metabolic acidosis, and mixed acid-base
disturbances.
Abdominal Fluid Analysis
Ascitic fluid that accumulates secondary to liver disease and hypoalbuminemia is usually a transudate. With
hepatic venous congestion from vena caval obstruction or cardiac causes, the fluid typically is a modified
transudate with protein concentration > 2.5 g/dl.
Rupture of the biliary tract is associated with bile peritonitis. Grossly, the abdominal fluid appears yellow or
green. Chemical tests for bilirubin are positive, and
concentrations of bilirubin are higher in abdominal
fluid than in serum. Cytologic examination reveals
a mixed inflammatory infiltrate and bile-laden
macrophages. Bacteria may be seen if bile peritonitis
is complicated by sepsis.
Diagnostic Imaging
Survey Radiography
Abdominal radiographs are useful to evaluate for the
following:
Changes in liver size (hepatomegaly, microhepatica)
Altered tissue characteristics such as mineralized
hepatic densities (choleliths) and radiolucencies

(abscesses)
Presence of abdominal effusion
If hepatic neoplasia is suspected, take thoracic films
to evaluate for pulmonary metastases.
Ultrasonography
Ultrasonography can be used to image the liver noninvasively, especially when abdominal effusion precludes survey radiographic evaluation. A normal
ultrasonographic appearance of the liver does not eliminate the possibility of significant hepatic pathology;
however, ultrasonography is diagnostically useful to
achieve the following:
Detect focal parenchymal abnormalities such as
masses, abscesses, cysts, and regenerative nodules.
The ultrasonographic appearance of these focal
lesions often is similar, and biopsy is required for
differentiation.
Document that a palpable mass is associated with the
liver.
Investigate disorders of the biliary tract and gallbladder, such as biliary obstruction, cholelithiasis, or gallbladder mucocele.
Detect vascular lesions such as portosystemic shunts,
hepatic arteriovenous fistulas, and hepatic venous
congestion.
Obtain percutaneous liver biopsies (see below).

 Identify abnormalities in other abdominal organs

that may be a cause or effect of liver disease (e.g., pancreas, spleen, kidneys, bladder, GI tract, adrenal
glands, and lymph nodes). For example, urate or uric
acid urolithiasis may be detected in animals with portosystemic shunts, the primary tumor may be identified in animals with hepatic metastases, and
identification of adrenal gland enlargement may aid
the diagnosis of steroid hepatopathy.
Angiography
Angiography is useful to diagnose vascular disorders
involving the liver, such as congenital and acquired portosystemic shunts, hepatic arteriovenous fistulas, and
vena caval obstruction causing hepatic venous obstruction (see under Congenital Portosystemic Shunt).
Liver Cytology
Fine-needle aspiration (FNA) of the liver for cytology is
commonly performed because it is easy and safe, does
not require sedation or anesthesia, and provides rapid
preliminary information. However, the diagnostic accuracy of cytology versus histopathology of the liver is controversial. Studies suggest a lack of correlation exists as
much as 50% of the time. Cytology of impression smears
of liver biopsy tissue correlates better than samples
obtained by fine-needle aspirate.
Cytology of the liver is most useful if the pathologic

process is diffuse and architectural relationships

(which can be obtained only by histopathology) are
not essential to the diagnosis. Examples include vacuolar hepatopathies such as feline hepatic lipidosis,756
System
diffuse hepatic neoplasia, and liver disease associated
with infectious agents such as histoplasmosis.
In cats, primary liver diseases such as lymphoma and
cholangitis may be accompanied by hepatic vacuolar
changes. These cats may be misdiagnosed as idiopathic hepatic lipidosis if cytology only reflects the
vacuolated hepatocytes.
For focal lesions, accuracy is improved when the fineneedle aspirate is guided by ultrasound.
Poor correlation of cytology with histopathology
occurs in primary inflammatory liver diseases,
although it may be better for detection of suppurative inflammation than for lymphocytic-plasmacytic
inflammation.
Liver Biopsy
Liver biopsy often is required to definitively characterize the nature and severity of hepatic disease, to differentiate acute from chronic disorders, and to assess
response to therapy. Selection of the best procedure for
obtaining a liver biopsy depends on numerous factors,
including liver size, presence of coagulopathy, diffuse
versus focal hepatic lesions, presence of biliary tract

Section 6 / Digestive

obstruction, presence of other intra-abdominal abnormalities, likelihood of surgical resection of a mass, tolerance of general anesthesia, available equipment, and
expertise of the clinician.
Key Point Perform a hemostasis screen prior to
liver biopsy to detect coagulopathy. After the
biopsy is performed, monitor for bleeding from the
biopsy site.
Biopsy Methods
Ultrasound-Guided Needle Biopsy
This technique is the most common percutaneous
method used for liver biopsy. However, it is dependent
on the availability of equipment and clinician expertise.
With ultrasound-guided biopsy, it is possible to obtain
tissue from focal lesions (whether superficial or deep
within the hepatic parenchyma), avoid structures
adjacent to the liver, and monitor post-biopsy
bleeding.
Ultrasound-guided biopsy may be difficult if the liver
is small or the ultrasonographer lacks experience.
Because needle biopsy specimens are smaller than
wedge biopsies, they may not be representative of
underlying liver pathology. In one study, the morphologic diagnosis made by needle biopsy correlated
with the definitive diagnosis obtained by wedge
biopsy in only 48% of dogs and cats.

Laparoscopy
Laparoscopy provides direct visualization of the liver
and adjacent structures such as the pancreas and extrahepatic biliary tract. Biopsies also are obtained under
direct visualization.
Laparoscopy is a useful alternative to ultrasoundguided needle biopsy when the liver is small.
It is preferable to ultrasound-guided biopsy when
excess bleeding is anticipated and to laparotomy
when delayed wound healing (hypoalbuminemia) is
anticipated.
Laparoscopy requires heavy sedation or anesthesia
and is subject to equipment availability and clinician
expertise.
Laparotomy
Laparotomy is indicated for liver biopsy when a surgically correctable disease is suspected, such as extrahepatic biliary tract obstruction or a single, large hepatic
mass (see Chapter 72 for a description of the procedure
for surgical biopsy).
Laparotomy makes it possible to obtain large samples
of liver tissue and monitor for post-biopsy bleeding.
Disadvantages include the need for general anesthesia, the relatively high risk of complications, and the
risk of delayed wound healing in hypoalbuminemic
patients.

Biopsy Analysis
To prepare biopsy tissue for histopathology, place
samples in 10% buffered formalin and allow them to
fix for 24 hours. The volume of fixative should be 20
times the volume of biopsy tissue.
To prepare needle biopsy samples, gently remove
liver tissue from the biopsy needle and place it on
tissue paper; fold the paper and place it in a formalin jar.
Perform routine light microscopy on liver tissue
stained with hematoxylin and eosin (H&E).
Additional stains may be requested, including
trichrome for fibrous connective tissue, periodic acidSchiff (PAS) for glycogen, rhodanine or rubeanic
acid for copper, Prussian blue for iron, Congo red for
amyloid, oil red O for fat, and silver or acid-fast stains
for infectious organisms.
Submit fresh liver tissue for bacterial and fungal
culture as indicated.
Perform quantitative copper analysis on fresh hepatic
tissue.
Place samples for electron microscopy in chilled,
buffered 2.5% glutaraldehyde.

Table 71-1. GENERAL THERAPY OF HEPATOBILIARY DISEASEcontd

Therapeutic Goals Therapeutic Regimen

Correct metabolic imbalances See fluid therapy above.

(e.g., dehydration, azotemia,
hypokalemia, alkalosis, and
hypoglycemia)
Avoid drugs or therapies that When possible, avoid sedatives, tranquilizers,
anticonvulsants, analgesics, anesthetics,
exacerbate HE methionine-containing products, diuretics, or stored blood
transfusion.
Control seizures For refractory seizures in dogs, use loading dosages of sodium
bromide IV (3% NaBr 600800 mg/kg
over 24 hours) or potassium bromide orally (KBr 100200 mg/kg q6h for 24 hours),
followed by KBr at a dosage of 1530 mg/kg q12h PO f or IV phenobarbital g at
reduced doses in
dogs and cats (monitor serum concentrations to adjust the dose). Avoid
benzodiazepines. For
status epilepticus, consider general anesthesia with propofol to control seizures.
Intubate and use
mechanical respirator to maintain pO 2 and pCO 2 . Give mannitol (0.51 g/kg by IV
bolus over 20
minutes) for suspected cerebral edema.
For chronic, stable seizure management or long-term therapy in dogs, give
potassium bromide
(1530 mg/kg q12h PO in food). For maintenance therapy in cats, consider
topiramate (3.125 mg
q12h PO initially, then 6.25 mg q12h PO).
For short-term perioperative anticonvulsant therapy for congenital PSS, consider
felbamate
(1520 mg/kg q8h PO), levetiracetam (2030 mg/kg q12h), or topiramate h (510
mg/kg q12h
PO) in dogs or topiramate (3.125 mg q12h PO initially, then 6.25 mg q12h PO) in
cats.

Control infection Give systemic antibiotics (see below).

Control ascites and edema Give a low-sodium diet; combine furosemide (12 mg/kg
q12h PO) i and spironolactone (12 mg/kg
q12h PO) g , or spironolactone and hydrochlorothiazide (Aldactazide, j 2 mg/kg q12h
PO).
Use paracentesis for relief of dyspnea or extreme abdominal distention, synthetic
colloids such as
hetastarch (1020 ml/kg/day IV in dogs and 1015 ml/kg/day IV in cats) or human
albumin 25%
(2 ml/kg in dogs), or plasma transfusion for albumin replacement (2545 ml/kg).
Control coagulopathy and anemia Give vitamin K 1 (0.51.5 mg/kg q12h, IM or SC
for three treatments, then weekly as needed for
dogs and cats); fresh plasma or fresh-frozen plasma (10 ml/kg); or a fresh blood
transfusion
(1015 ml/kg). For DIC, give heparin (75100 IU/kg q812h SC). For dogs with vWD
and liver
failure, give DDAVP once (1 mg/kg diluted in 1020 ml of saline and given IV slowly
over 10
minutes or undiluted SC) (effective for 46 hours).
Control gastrointestinal ulceration Give famotidine (0.51.0 mg/kg q1224h PO or
IV), nizatidine (2.55.0 mg/kg q24h PO), or
omeprazole d (0.51.0 mg/kg q24h PO) and sucralfate e (1-g tablet/25 kg q8h PO).
Control infection and endotoxemia Give systemic antibiotics (e.g., amoxicillin,
ampicillin, cephalosporins, aminoglycosides, and
metronidazole k ).
a May be given SC if animal is mildly dehydrated and is not vomiting.
b Neomycin has been associated with rare ototoxicity and nephrotoxicity; its use
should be restricted to acute management of HE.
c Crystalline lactulose (powder) is also available commercially (Kristalose, Bertek
Pharmaceuticals) as 10- or 20-g packets (syrup concentration is 10 g/15 ml).

d Partially metabolized by the liver; use a reduced dose in animals with liver failure.
Inhibits hepatic P-450 enzymes.
e Beware of drug-associated constipation, which may worsen HE.
f Avoid bromide in cats due to cough and asthma-like side effects.
g Can be used in dogs and cats with congenital PSS, but avoid in animals with
acquired liver disease.
h Start at the low end of the dose range due to impaired hepatic metabolism.
i Dose may be doubled if there is no effect in 47 days.
j GD Searle & Co., Chicago, IL.
k Partially metabolized by liver. Use a reduced dosage (7.5 mg/kg q12h PO) in
animals with liver failure.
DDAVP, desmopressin acetate; DIC, disseminated intravascular coagulation; GI,
gastrointestinal; HE, hepatic encephalopathy; NPO, nothing per os; NSAIDs,
nonsteroidal anti-inflammatory drugs; vWD, von Willebrand disease.
Adapted from Johnson SE: Liver and biliary tract. In Anderson NV (ed): Veterinary
Gastroenterology, 2nd ed. Philadelphia: Lea & Febiger, 1992, p 504.
is present or impending, because alkalosis augments
the entry of ammonia into the CNS and can exacerbate signs of HE.
Give Nutritional Support
Nutritional support is important for promoting hepatic
regeneration and maintenance of body weight.
Modify the diet as needed to control complications
of hepatic disease, such as HE, hypoproteinemia, and
ascites (see Table 71-1).
Supply the bulk of the calories by carbohydrates,
which provide an easily assimilated source of nonprotein calories.

 Avoid high-protein diets that may exacerbate signs of

HE. Indiscriminate protein restriction is discouraged,
however, because adequate protein intake is important for normal hepatic regeneration and to counteract hypoproteinemia.
When voluntary food intake is lacking, provide other
methods of nutritional support, such as feeding
through a gastrostomy tube (see Chapter 3).Chapter 71 / Diseases of the Liver and
Biliary Tract 759
Control Complications
Hepatic Encephalopathy
Goals for treatment of HE are summarized in Table 711. Restrict dietary protein intake. Increase dietary
soluble fiber (see Table 71-1). Prevent formation and
absorption of enteric toxins.
Give antibiotics (e.g., neomycin, amoxicillin, or
metronidazole) to alter the urease-producing bacterial population in the colon, thus decreasing conversion of urea to ammonia (see Table 71-1).
Lactulose, a synthetic disaccharide, often is effective
in controlling signs of HE and decreasing arterial
blood ammonia concentrations through its actions as
a cathartic and colonic acidifier (see Table 71-1). It
usually is given in combination with antibiotics.
Key Point Detect and control GI hemorrhage, which
could provide enteric bacteria with a source of
protein for toxin production. Give fresh rather than

stored blood if a transfusion is required, because

stored blood contains substantial amounts of
ammonia.
Ascites and Edema
Ascites in liver disease usually is associated with hypoalbuminemia, portal hypertension, and renal retention of
sodium and water.
For treatment of ascites, restrict dietary sodium and
use diuretics to promote urinary sodium and water
excretion (see Table 71-1).
For temporary support of plasma colloid osmotic
pressure in hypoproteinemic animals, consider
plasma transfusion to supply albumin or colloid
administration such as hetastarch (see Table 71-1 and
Chapter 5).
Avoid using abdominocentesis to treat ascites except
when required for relieving respiratory distress.
Coagulopathy and Anemia
Hemostatic defects associated with hepatobiliary disease
can be attributed to primary failure of hepatocytes to
synthesize clotting factors, vitamin K deficiency, or DIC.
Parenteral administration of vitamin K 1 corrects coagulopathy caused by vitamin K deficiency within 24 to
72 hours, but no response is seen when bleeding is
caused by hepatocyte failure or DIC (see Table 71-1).
For treatment of DIC and other coagulopathies, see

Chapter 23.
Gastrointestinal Ulceration
Dogs and cats with hepatobiliary disease are at
increased risk for GI ulceration. Possible mechanisms
include gastric acid hypersecretion, impaired gastric
mucosal blood flow secondary to portal hypertension,
and decreased gastric epithelial cell turnover.
GI bleeding is deleterious in patients with HE
because blood is a substrate for ammonia production.
Manage GI ulceration with an H 2 blocker for control
of acid secretion and with sucralfate for mucosal cytoprotection, as described in Chapter 67. Famotidine
and nizatidine are preferable to cimetidine and ranitidine as H 2 blockers in animals with liver disease,
because they do not inhibit hepatic microsomal
enzymes.
Key Point The proton pump inhibitor, omeprazole,
inhibits hepatic microsomal enzymes and undergoes hepatic metabolism, making it less predictable for use in animals with liver disease.
Infection and Endotoxemia
An increased incidence of infection may be seen in
animals with hepatic disease as enteric bacteria and
endotoxins gain access to the systemic circulation as a
result of impaired hepatic mononuclear phagocyte
system function or portosystemic shunting. Septicemia

and endotoxemia may, in turn, perpetuate liver injury.

Give systemic antibiotics to control extrahepatic
infections or sepsis. Penicillins, cephalosporins, or
aminoglycosides are good choices because they are
eliminated primarily by renal mechanisms.
Renal Failure
Renal dysfunction and azotemia may complicate liver
disease, especially chronic liver dysfunction, and can be
pre-renal, primary renal, or both.
Pre-renal mechanisms that decrease effective circulating volume and renal perfusion include dehydration (including that induced by diuretics),
hypoalbuminemia, ascites, and overzealous abdominal paracentesis. Appropriate fluid therapy is essential to avoid pre-renal azotemia.
Primary renal failure may occur with pre-existing
renal disease or may result from infectious or toxic
agents (e.g., leptospirosis) that affect the liver and
kidneys concurrently or secondary to advanced liver
disease.
Hepatoprotectants
Consider ancillary treatment with the hepatoprotectants listed in Table 71-2. These do not appear to be
toxic when used as described.
Hepatoprotectants include a varied group of compounds (prescription drugs, nutraceuticals, vitamins)

that may protect the liver from injury caused by free

radicals, bile salts, drugs, environmental toxins, or
other insults.
Nutraceuticals are products that have characteristics
of both a nutrient and a pharmaceutical. They are
readily available through health food stores or Inter-760
System

Section 6 / Digestive

Table 71-2. HEPATOPROTECTANTS

Product Preparation Dosage Mechanism of Action Comments
S-adenosylmethionine
Denosyl SD4 20 mg/kg PO q24h (D&C) Intermediary
metabolite: indirect Dont break enteric-coated tablets. Use
(SAMe) (Nutramax Labs): glutathione precursor (antioxidant), only foil-wrapped
products. Food
90 and 225 mg tab choleretic (cats), detoxification. decreases absorption. No side
effects are
Supports membrane function. noted. Can be used in acetaminophen
toxicity. Expensive.
Acetylcysteine 10% or 20% Dilute at least 1 : 4 with Glutathione precursor. Antidote
for acetaminophen toxicity.
solution saline. Give 140 mg/kg May have protective effects for other
IV through 0.25-mm filter drug-induced (carprofen, potentiated
over 2030 min, then sulfas, methimazole, diazepam) or toxin70 mg/kg PO or IV q6h induced liver injury. Safe. May cause
for seven treatments (D&C) nausea and vomiting when given orally.
Milk thistle (Silybin) Marin (Nutramax 6100 mg total dose PO q24h
Antioxidant, anti-inflammatory, Silybin has low bioavailability;
Labs: silybin, per package insert (D); antifibrotic. Protects against Amanita
improved when complexed with

vitamin E, zinc)* 918 mg total dose PO q24h mushroom toxicity (experimental) in

phosphatidylcholine (Marin, Sil-phos).
9-, 24-, or 70-mg (C) dogs. Other products have variable potency
tab; Sil-phos and absorption.
(Indea Labs)
Vitamin E (alpha- Many available 50400 IU PO q24h (D&C) Membrane-associated
antioxidant. Natural Vitamin E (d-a tocopherol) has
tocopherol) Protects liver against oxidative injury. greater bioavailability than
synthetic
(d,l) form. In severe cholestasis, use
water-soluble form.
Ursodiol Actigall (Ciba): 15 mg/kg PO q24h (D&C) Hydrophilic bile acid. Shifts bile
acid Used in cholestatic disorders;
300-mg caps pool to less toxic hydrophilic bile acids. contraindicated in biliary
obstruction.
Choleretic in dogs (cats unknown). Side effects are rare (vomiting).
Protects hepatocyte membranes. Expensive.
Modulates immune response.
L-carnitine Many available 250 mg PO q24h (C) Essential cofactor for transport of
fatty May improve fatty acid oxidation in
acids into mitochondria for oxidation. obese cats undergoing weight loss but
will not prevent hepatic lipidosis. Used
in ancillary treatment of hepatic
lipidosis.
Zinc Zinc acetate: To decrease Cu Induces intestinal metallothionein, Many zinc
products are available
Galzin (Gate absorption: 100-mg which preferentially binds Cu and (acetate, sulfate,
gluconate). Avoid zinc
Pharmaceuticals); elemental zinc PO decreases absorption. Zinc has methionine if
impending HE. Calculate

many others q12h for 23 months, antioxidant and antifibrotic effects; dose on
elemental zinc content. Monitor
available then 50 mg PO q12h supports cell membrane function and blood zinc
levels: Ideal = 200400 mg/dl;
(D). For zinc immune response. avoid >800 mg/dl (hemolysis). Do not give
supplementation in concurrently with Cu chelator (will be
chronic liver disease: chelated). Nausea, vomiting, decreased
12 mg/kg PO q12h (D) appetite (less with zinc acetate).
Vitamin C (ascorbic Many available 100500 mg PO q24h (D&C)
scavenger; functions in Avoid in Cu-associated hepatopathy.

Free radical

acid) converting vitamin E back to active

form. Acts as pro-oxidant in the
presence of high iron, Cu levels.
C, cats; Cu, copper; D, dogs; HE, hepatic encephalopathy.
*No zinc in the 9 mg tab for cats.Chapter 71 / Diseases of the Liver and Biliary Tract
761
net mail-order sites, yet for many of these products
there is a lack of safety and efficacy data.
Lack of a regulatory mechanism for nutraceuticals is
not justification for ignoring the potential therapeutic benefits of some of these products. However, most
of these drugs have not been studied adequately in
spontaneous hepatobiliary diseases of dogs and cats
to prove efficacy.
ACUTE HEPATIC FAILURE
Acute hepatic failure occurs when a sudden severe
insult to the liver compromises at least 70% to 80% of
functional hepatic tissue. The clinical manifestations

and laboratory findings associated with acute hepatic

failure reflect general liver failure and are not specific
for the underlying cause of injury.
Etiology
Causes of acute hepatic injury in dogs and cats include
hepatotoxins, infectious or parasitic agents, systemic or
metabolic disorders, or miscellaneous causes of liver
injury (Table 71-3). In many cases, a specific cause
cannot be identified.
Toxin-Induced Injury
Hepatic injury may occur after exposure to a wide
variety of industrial chemicals, organic solvents, pesticides, heavy metals, and biologic toxins (see Table
71-3). Exposure can be unobserved in a free-roaming
animal that drinks from a contaminated water source.
When hepatic necrosis is severe and widespread,
rapid deterioration and death in 3 to 4 days often
occur. With less extensive damage, complete recovery
is possible.
Drug-Induced Injury
Drug-induced injury is a recognized cause of acute
hepatic failure in dogs and cats. The incidence of druginduced hepatic disease is unknown but is probably
underestimated. Hepatic drug reactions are categorized
as dose dependent or idiosyncratic.
Dose-Dependent Hepatotoxins

These hepatotoxins predictably damage the liver in an

exposed population. The effect is dose-related and
reproducible experimentally. All members of a species
are affected at high doses. Toxicity is due to the parent
drug or a consistently generated toxic metabolite.
If a hepatotoxic reaction occurs, lowering the dose,
rather than stopping the drug, can be tried.
Examples of dose-related hepatotoxins include acetaminophen, tetracycline, stanozolol (cats only), and
possibly phenobarbital (dogs only).
Idiosyncratic Hepatotoxins
These hepatotoxins cause hepatic injury at therapeutic
doses in only a few individuals in the exposed population. These reactions are unpredictable and infrequent;
most individuals treated with the drug do not have a
reaction, even at high doses. Affected individuals
appear to be unusually susceptible, possibly because
they generate a unique toxic intermediate metabolite.
An immunologic response may or may not be involved.
Within susceptible individuals, toxicity may be more
pronounced at higher doses. Because of the unpredictable nature of the reaction, they can be difficult to
recognize clinically.
If an idiosyncratic reaction occurs, the drug must be
discontinued or it could result in the death of the
patient.

 Examples include halothane and methoxyflurane,

carprofen and other NSAIDs, lomustine, mebendazole, oxibendazole, potentiated sulfonamides, and
methimazole.
Drugs that have been incriminated as potential hepatotoxins include analgesics, anticonvulsants, and
antimicrobials (see Table 71-3). Specific clinical
details regarding known drug reactions in dogs and
cats are summarized in Table 71-4.
Key Point Dose-dependent hepatotoxic drugs cause
predictable liver injury in all animals of a species,
especially at high or excessive doses, whereas
idiosyncratic hepatotoxic drugs affect only certain
uniquely susceptible animals, even at low or therapeutic doses.
Infectious Agents
Infectious causes of acute hepatic injury (see Table 713) include leptospirosis (see Chapter 19), toxoplasmosis (see Chapter 21), histoplasmosis (see Chapter 20),
FIP virus (see Chapter 10), and infectious canine
hepatitis virus (see Chapter 16).
Miscellaneous Systemic Diseases
Hepatic injury can occur secondary to various systemic
conditions, including those discussed below.
Hemolytic Anemia
Hemolysis,

especially

immune-mediated

hemolytic

anemia in dogs, can be complicated by centrilobular

necrosis attributed to acute hepatocellular hypoxia
or DIC-induced sinusoidal thrombosis. The hepatic
injury generally resolves with resolution of the anemic
crisis.
Anesthesia, Surgical Hypotension,
Hypoxia, and Shock
Conditions that decrease liver blood flow can lead to
hypoxia and hepatic damage. In the postoperative762
System

Section 6 / Digestive

Table 71-3. CAUSES OF ACUTE HEPATIC INJURY IN DOGS

AND CATS
Hepatotoxins Infectious or Parasitic Agents
Drugs and Anesthetics Viral
Acetaminophen (D&C)

Infectious canine hepatitis (adenovirus I)

Amiodarone (D) Canine herpesvirus

Aspirin (D&C)

Feline infectious peritonitis (coronavirus)

Anticonvulsants Feline calicivirus (virulent strains)

Phenobarbital* (D)
Phenytoin* (D) Bacterial
Primidone* (D) Cholangiohepatitis
Valproic acid* (D) Leptospirosis
Diazepam (C) Liver abscess
Aprindine (D) Bacillus piliformis (Tyzzers Disease)
Azathiaprine (D) Salmonella spp.
Carprofen (D) Francisella tularensis (Tularemia)
Danazol (D)

Glipizide (C) Fungal

Griseofulvin (C) Histoplasma
Halothane (D) Coccidioides
Itraconazole (D&C)

Blastomyces

Ketoconazole (D&C)

Others

Lomustine (CCNU)* (D)

Macrodantin (D) Protozoal and Parasitic
Mebendazole (D) Toxoplasma
Megestrol acetate (C) Babesia
Methimazole (C) Cytauxzoon felis
Methotrexate (D) Dirofilaria (Postcaval syndrome)
Methoxyflurane (D)
Mibolerone (D) Rickettsial
Mithramycin (D) Ehrlichia canis
Mitotane (D) Rickettsia rickettsii
Oxibendazole (D)
Phenazopyridine (C) Systemic or Metabolic Disorders
Potentiated sulfonamides (D) Acute pancreatitis
Stanozolol (C) Acute hemolytic anemia
Tetracycline (D&C)

Extraheptic infection, septicemia and

Thiacetarsamide (D) endotoxemia

Tolbutamide (D) Idopathic feline hepatic lipidosis
Inflammatory bowel disease
Biologic Substances
Aflatoxin (contaminated dog food) Traumatic, Thermal, or Hypoxic Injury
Amanita mushrooms

Blue-green algae Abdominal trauma

Sago palms Diaphragmatic hernia with liver entrapment
Hymenoptera toxins (hornet sting) Heat stroke
Indigofera sp. (toxic plant) Liver lobe torsion
Pennyroyal oil Shock
Surgical hypotension and hypoxia
Chemicals
Carbon tetrachloride
Dimethylnitrosamine
Galactosamine
Metals (copper, iron, zinc,
phosphorus)
Organochloride pesticides
Salt poisoning
Many others
*Usually causes chronic rather than acute hepatic disease.
D, dog; C, cat.Chapter 71 / Diseases of the Liver and Biliary Tract

763

Table 71-4. SELECTED HEPATOTOXIC DRUG REACTIONS IN DOGS AND CATS

Onset of Signs Hepatic Suggested
Drug Species

and Key Features Lesions Mechanism Comments

Analgesics
Acetaminophen Canine Initial toxicity is Centrilobular Dose-related Dose-related
injury (doses exceeding 200 mg/kg
(Tylenol, and feline
Treatment: N-

cyanosis and necrosis and in dogs and 120 mg/kg in cats).

McNeil) methemoglobinemia. congestion, acetylcysteine (140 mg/kg IV or PO

initially, then

Acute hepatic vacuolar 70 mg/kg IV or PO q6h for 36 hours) and ascorbic

failure a occurs in hepatopathy acid (30 mg/kg q6h for 36 hours). SAMe (20 mg/kg
dogs but is less likely and bile stasis PO q24h) can also serve as a glutathione
source.
in cats. Cimetidine (510 mg/kg IV q812h for at least 3 days)
inhibits hepatic P-450 enzymes and prevents further
conversion of acetaminophen to toxic product.
Carprofen (Rimadyl,
Canine Acute hepatic Hepatocellular Idiosyncratic Evaluate
liver and kidney function prior to starting
Pfizer) failure a within 530 necrosis, treatment. Concurrent renal tubular necrosis
and
days after starting ballooning glucosuria may occur. Rapid recovery in Labradors
drug. Labrador degeneration, after stopping drug and giving supportive care. A 50%
retrievers may be cholestasis mortality rate in non-Labrador breeds. Whether dogs
at increased risk. with carprofen hepatotoxicity can be safely switched
to another NSAID without experiencing a hepatic
reaction is unknown.
Anticonvulsants
Phenobarbital Canine Chronic liver disease Hepatocellular Dose- related?
Phenobarbital causes chronic hepatic disease and
and cirrhosis. hypertrophy cirrhosis when given at high doses (serum
Anorexia, lethargy, and vacuolar concentrations >40 mg/ml) or for long periods
weight loss, sedation, hepatopathy (months to years). Dogs with phenobarbital
PU/PD, icterus, (early); bridging hepatotoxicity may improve when dosage is
decreased
ascites, portal fibrosis, to therapeutic range as determined by serum
encephalopathy. nodular phenobarbital levels or when potassium bromide
ALP, ALT, regeneration, therapy is substituted for phenobarbital. Incidence of

GGT, total biliary hyperplasia, chronic hepatic disease from long-term

anticonvulsant
bilirubin, SBA, mild inflammatory therapy is approximately 614%.
Hepatocutaneous
hypoalbuminemia, infiltrates syndrome has also been described in dogs on
hypocholesterolemia, long-term phenobarbital therapy.
coagulopathy.
Diazepam Feline Acute hepatic Diffuse hepatic necrosis
with hepatotoxicity die within 15 days of initial

Idiosyncratic Most cats

failure a within 413 administration of drug. In cats treated with oral

days of starting oral diazepam, monitor baseline liver enzymes before and
drug administration. within 5 days after starting therapy; if enzymes are
increased, discontinue drug and give supportive therapy.
Antimicrobials
Ketoconazole Canine Asymptomatic with Not characterized Idiosyncratic b May be
dose-related phenomenon: >40 mg/kg/day in
(Nizoral, Janssen and feline
serum enzyme

ALT, ALP, or dogs. In humans, asymptomatic

Pharmaceuticals) rarely acute hepatic elevations are considered harmless and

enzymes usually
failure. a return to normal despite continued therapy. Therapy
should be discontinued if ALT >3 times normal or if
clinical signs or jaundice occur. Recovery is usually
uneventful.
Itraconazole Canine Asymptomatic with Not characterized Dose- related?
Hepatotoxicity most likely at higher doses. Therapy
(Sporanox, and feline
normal or if

ALT or anorexia. should be stopped if ALT >3 times

Janssen anorexia occurs. When appetite returns, can reinstitute

Pharmaceuticals) itraconazole at half the original dose.

Table continued on following page764

Section 6 / Digestive System

Table 71-4. SELECTED HEPATOTOXIC DRUG REACTIONS IN DOGS AND CATScontd

Onset of Signs Hepatic Suggested
Drug Species

and Key Features Lesions Mechanism Comments

Tetracycline Canine Not characterized. Vacuolar hepatopathy

Experimental hepatic injury induced by high doses

Dose-related

and feline given IV. Avoid in animals with PSS. Unlikely to be

clinically important as a hepatotoxin. Not clear whether
doxycycline has same effect on liver.
Potentiated Canine Acute hepatic failure a Diffuse necrosis or Idiosyncratic Multiple
exposures may predispose to reaction, but
sulfonamides c 536 days after periportal hepatitis previous exposure to
sulfonamides is not required.
starting therapy. and intrahepatic Dogs with intrahepatic cholestasis recover rapidly
cholestasis after drug withdrawal. High mortality with diffuse
hepatic necrosis. Consider treatment with
N-acetylcysteine and vitamin C or SAMe to promote
detoxification of toxic intermediate, nitroso-SMX.
Steroids
Glucocorticoids Canine Chronic hepatopathy, Centrilobular Dose-related Lesions
reversible after treatment is discontinued. Does
(various types) but hepatic failure vacuolization but considerable
cats.
rare. Signs indicative due to glycogen individual
of hypercortisolism accumulation variation
(e.g., PU/PD,
polyphagia,

not occur in

hepatomegaly, and
lethargy). ALP,
usually with induction
of steroid isoenzyme
of ALP. Mild ALT;
normal total bilirubin.
SBA within normal
limits or mildly
(<60 mmol/L).
Stanozolol Feline Increased ALT and Hepatic lipidosis Dose-related Most cats recover
after discontinuing stanozolol and
(Winstrol-V, hyperbilirubinemia; after supportive care.
Pharmacia and anorexia.
Upjohn)
Miscellaneous
Methimazole Feline Acute hepatic Necrosis and Idiosyncratic Clinical signs resolve
within 7 days of stopping therapy.
(Tapazole, Lilly) failure a within 2 cholestasis Biochemical resolution by 45 days.
months of starting
therapy.
Lomustine Canine Chronic liver disease Hepatocellular Idiosyncratic Median time to
detection of hepatic disease from
(CCNU) with decreased vacuolization, last dose of CCNU was 11 weeks (range of 2
49
(CeeNu, Bristol- appetite, weight loss, mild to moderate weeks). Cumulative drug
doses and number of
Meyers Squibb) PU/PD, vomiting, periportal doses tends to be higher in dogs that
develop
ascites and ALT, inflammation, hepatotoxicity than in those that do not. Majority

 ALP, fibrosis, of affected dogs die of progressive chronic liver

hypoalbuminemia. hemosiderin- disease.
laden Kupffer
cells
a Typical manifestations of acute hepatic failure include anorexia, depression,
vomiting, and jaundice accompanied by ALT, ALP, and serum bilirubin.
b For drug reaction accompanied by clinical signs and hyperbilirubinemia.
c Includes trimethoprim-sulfadiazine, trimethoprim-sulfamethoxazole, and
ormetoprim-sulfadimethoxine.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; GGT, gammaglutamyltransferase; NSAID, nonsteroidal anti-inflammatory drug; PSS,
portosystemic shunt; PU/PD, polyuria/polydipsia; SAMe,
S-adenosylmethionine; SBA, serum bile acid.Chapter 71 / Diseases of the Liver and
Biliary Tract 765
period it is difficult to differentiate hepatic damage or
jaundice caused by the hypoxic effects of anesthesia and
surgery from other potential causes, such as toxic injury
induced by anesthetic agents (e.g., halothane or
methoxyflurane) and other drugs, postoperative infections, endotoxemia, or a combination of these factors.
Acute Pancreatitis
Pancreatitis in dogs and cats often is characterized by
increased serum concentrations of liver enzymes resulting from secondary hepatic injury from released
enzymes and inflammatory cytokines (see Chapter 73).
Hepatic lesions usually resolve with resolution of the
pancreatitis and require no special treatment. Less
commonly, jaundice results from partial to complete

obstruction of the common bile duct associated with

peripancreatic inflammation, pancreatic abscess, or pancreatic healing by fibrosis. Surgical intervention to
relieve biliary obstruction is indicated in animals with
pancreatic abscess or if jaundice persists after resolution
of acute pancreatitis, which usually indicates pancreatic
fibrosis as a cause of biliary obstruction (see Chapter 73).
Extrahepatic Bacterial Infections
Septicemia and endotoxemia associated with infections
such as pneumonia, pyometra, peritonitis, and abscesses
can cause jaundice, mild to moderate increases in liver
enzyme activity (especially ALP), and increased SBA
concentration.

Liver

biopsy

reveals

intrahepatic

cholestasis without significant necrosis or inflammation.

The hepatic injury resolves when the infection is controlled.
Clinical Signs
Clinical signs of acute hepatic failure often are nonspecific and overlap signs of disorders of other body
systems. Clinical signs reflect general hepatic dysfunction rather than the specific underlying cause. Signs of
extrahepatic or multisystemic disease often provide
important diagnostic clues when hepatic injury occurs
secondary to acute pancreatitis, hemolytic disease, septicemia or endotoxemia, and many infectious diseases.
Acute onset of anorexia, lethargy, vomiting, and diar-

rhea are the most common presenting signs of acute

hepatic failure.
Other potential findings include PU/PD, jaundice,
excessive bleeding, and HE.
Diagnosis
When acute hepatic failure is diagnosed, attempt to
identify the underlying cause with a complete history,
ancillary diagnostic testing, and if indicated, a liver
biopsy. In many cases, a specific cause cannot be
identified.
When acute hepatic failure is accompanied by jaundice, consider diseases of the extrahepatic biliary
tract, such as biliary obstruction and rupture. Surgical intervention may provide both diagnostic and
therapeutic benefit.
History
Attempt to document recent or potential exposure to
any drug, toxin, or infectious disease, especially those
listed in Table 71-3.
Suspect a drug- or toxin-induced cause of acute
hepatic failure when clinical and biochemical evidence of acute hepatic dysfunction is associated with
recent exposure to a potential hepatotoxin.
Consider toxin-induced injury even in the absence of
known exposure to toxins, because potential hepatotoxins can be present in contaminated dog food (afla-

toxins), pond water (cyanobacteria, or blue-green

algae), and many other unobserved sources.
Although numerous drugs have been incriminated
(see Tables 71-3 and 71-4), remember that an idiosyncratic reaction can occur with any drug. With most
drug- and toxin-induced disorders, the diagnosis is
presumptive and cannot be proved.
To confirm the diagnosis, discontinue the drug and
observe for clinical improvement, which usually occurs
within several weeks, even after chronic drug administration. Recurrence of hepatic damage after a challenge dose of the same drug (or inadvertent reexposure) supports the diagnosis of drug-induced
hepatotoxicity. Note: This is not recommended as a diagnostic procedure because it is potentially dangerous,
especially with a drug that causes hepatic necrosis.
Determine if there is a history of recent surgical or
anesthetic procedures that may be associated with
drug- or hypoxia-related hepatic damage.
Evaluate the animals vaccination status for infectious
diseases that can involve the liver, such as leptospirosis and infectious canine hepatitis.
Determine if there are any subtle chronic signs of
illness that suggest that the underlying liver disease
may be chronic rather than acute and that the
current illness may be exacerbation or decompensa-

tion of chronic liver disease.

Physical Examination
Physical findings often reflect general hepatic dysfunction rather than the specific etiology (see previous
discussion of physical examination findings under
Diagnostic Strategy for Liver Disease).
Hepatodynia may occur with any cause of acute
hepatic injury that results in swelling and stretching
of the liver capsule.
Findings of weight loss and ascites are indicative of a
chronic rather than an acute process.
Signs of extrahepatic or multisystemic disease may be
important clues when liver injury occurs secondary to
systemic disorders.
For example, fever may be present with infectious
causes of hepatic injury such as leptospirosis, infec-766
System
tious canine hepatitis, bacterial cholangitis, liver
abscess, systemic mycoses, and extrahepatic infections that secondarily involve the liver.
Fever and acute abdominal pain are presenting
signs of acute pancreatitis but can also occur with
cholangitis and hepatic abscess.
When jaundice is accompanied by pallor, consider
immune hemolytic anemia.
Laboratory Evaluation
Acute hepatotoxicity frequently is associated with

Section 6 / Digestive

abnormal serum biochemical analyses, liver function

tests, and urinalysis.
Because diffuse hepatic necrosis is the most common
lesion associated with acute hepatic failure, increased
ALT activity is the most consistent finding, and values
are often markedly increased. Increased ALP activity
may also occur.
Other potential findings include hyperbilirubinemia,
increased SBA concentrations, hypoglycemia, hyperammonemia, and coagulopathy. Hypoalbuminemia
usually suggests chronic rather than acute liver
disease.
Some hepatotoxins (e.g., carprofen) and infectious
agents (e.g., leptospirosis) may concurrently damage
the kidneys; thus, biochemical evidence of concomitant renal failure may be present.
An inflammatory CBC suggests possible acute pancreatitis or underlying infectious disease. Evaluate
serum amylase and lipase (dogs) and pancreatic
lipase immunoreactivity (PLI) (dogs and cats) to
diagnose acute pancreatitis.
Abdominal Imaging
Liver size on abdominal radiographs usually is
normal to increased unless massive hepatic necrosis
causes parenchymal collapse and microhepatica.
Key Point A small liver generally suggests chronic

rather than acute hepatic disease.

Additional radiographic and ultrasonographic findings may be noted, depending on the underlying
disorder (Table 71-5).
Liver Biopsy
Perform a liver biopsy when the cause of acute hepatic
failure is not suggested by preliminary laboratory
evaluation.
Histopathologic examination of hepatic tissue can
help establish the cause and distinguish between
acute and chronic liver disease. Diffuse hepatic
necrosis is the histologic lesion most consistently associated with acute hepatic failure.
If overt bleeding is present, liver biopsy may be
contraindicated.
Ancillary Diagnostic Procedures
Perform ancillary diagnostic procedures (see Table
71-5) to diagnose underlying causes of acute hepatic
failure.
Treatment
Management of the patient with acute hepatic failure
is first directed toward supportive therapy (see Table
71-1). In many cases, even though the cause remains
unidentified or specific therapy is unavailable, supportive care alone may allow adequate time for
hepatic regeneration to occur.

 Maintenance of fluid, electrolyte, and acid-base

balance is the cornerstone of supportive therapy (see
Chapter 5).
Prevent or control complications such as hypoglycemia, HE, coagulopathy, and endotoxemia (see
Principles of Treatment for Liver Disease).
Whenever possible, institute specific treatment for
the underlying cause; for example, administer
injectable penicillin or amoxicillin for treatment of
possible leptospirosis. Discontinue use of a suspect
drug to prevent further hepatic injury and observe
for clinical improvement.
With the exception of acetylcysteine for acetaminophen toxicity and milk thistle (silybin) for
Amanita mushroom poisoning, no specific antidotes
are available for drug- or toxin-induced hepatic
injury. However, hepatoprotectants (Table 71-2) may
be helpful in treating hepatotoxicity but have not
been adequately evaluated.
INFECTIOUS AND PARASITIC
HEPATIC DISEASE
The liver can be involved in many systemic infections
(Table 71-6). In some disorders, such as leptospirosis
and infectious canine hepatitis, the liver is a target
organ, and evidence of liver failure dominates the clinical presentation. In other infections, such as many of

the systemic protozoal infections, the liver is involved as

a result of widespread invasion of organs with a large
mononuclear phagocyte population, such as the spleen,
lymph nodes, and bone marrow (see Table 71-6). Signs
of hepatic dysfunction may or may not be present and
may be overshadowed by more obvious extrahepatic
involvement. Liver cytology and biopsy can be diagnostically useful for identification of these organisms.
Systemic infections are covered in detail elsewhere in
this book. Infections localized to the hepatobiliary tract
are covered in greater detail here.
Infectious Causes of Liver Disease
Several specific infectious diseases that involve the liver
are listed in Table 71-6 and are discussed elsewhere inChapter 71 / Diseases of the
Liver and Biliary Tract 767
this book, including leptospirosis (see Chapter 19),
ehrlichiosis and rickettsial diseases (Chapter 17), toxoplasmosis (see Chapter 21), systemic mycoses (see
Chapter 20), FIP virus (see Chapter 10), and infectious
canine hepatitis virus (see Chapter 16).
Hepatic Abscess
Hepatic abscesses from bacterial infection of the liver
occur uncommonly in dogs and cats. Abscesses may
form as a solitary large mass, multiple small masses scattered throughout the liver, or microabscesses that are
only detected histologically.
Etiology

 Potential sources of bacteria include hematogenous

spread, translocation of intestinal bacteria into the
portal blood, ascension via bile ducts, penetrating
abdominal and caudal thoracic wounds, and direct
extension from local suppurative diseases. Umbilical
infections are the most common cause of hepatic
Table 71-5. ANCILLARY DIAGNOSTIC EVALUATIONS FOR HEPATOBILIARY DISEASE
Diagnostic Evaluation Intended Diagnosis (Rule Out)
Bacterial cultures
Liver, gallbladder, bile Bacterial cholangiohepatitis, cholecystitis, hepatic abscess
Blood, urine, infected tissues Extrahepatic infections and sepsis
Serologic tests (antibody titers) Leptospirosis
Mycoses (histoplasmosis, coccidioidomycosis, blastomycosis)
Toxoplasmosis
Feline infectious peritonitis
Bartonellosis
Other infectious diseases
Microfilaria exam Heartworm disease
Heartworm antigen or antibody tests Heartworm disease
Fecal sedimentation (formalin-ether technique) Liver fluke infection
Serum amylase and lipase Acute pancreatitis in dogs
Serum pancreatic lipase immunoreactivity Pancreatitis in cats and dogs
Serum T 4 Feline hyperthyroidism
Coombs test Immune hemolytic anemia
Lymph node aspiration cytology Mycoses
Lymphoma

Hepatic fine-needle aspiration cytology Infectious agents (e.g., mycoses)

Neoplasia (e.g., lymphoma)
Feline hepatic lipidosis
Hepatic abscess (ultrasound guided)
Abdominocentesis Ruptured biliary tract
Feline infectious peritonitis
Neoplasia
Thoracic radiography Mycoses
Toxoplasmosis
Heartworm disease
Metastatic neoplasia
Diaphragmatic hernia
Abdominal radiography Hepatic abscesses
Emphysematous cholecystitis
Cholelithiasis
Pancreatitis
Abdominal ultrasonography Focal and diffuse hepatic parenchymal abnormalities
Biliary or gallbladder disease
Portosystemic shunt(s)
Hepatic arteriovenous fistulas
Pancreatic disease
Diaphragmatic hernia
Angiography
Portogram Portosystemic shunt(s)
Portal vein obstruction
Hepatic venography Obstruction of caudal vena cava and hepatic veins

Celiac arteriography Hepatic arteriovenous fistulas

Nuclear imaging
Portal scintigraphy Portosystemic shunting
Modified from Johnson SE: Diseases of the liver. In Ettinger SJ, Feldman EC (eds):
Textbook of Veterinary Internal Medicine, vol. 2, 4th ed. Philadelphia: WB
Saunders, 1995, p 1316.768

Section 6 / Digestive System

abscesses in puppies (Staphylococcus) and kittens

(Streptococcus).
Escherichia coli and anaerobic bacteria are most commonly identified; mixed bacterial infections are
common.
Hypoxia of hepatic tissue caused by hepatic neoplasia, liver lobe torsion, or trauma may predispose the
patient to abscess formation, because small numbers
of anaerobes (e.g., Clostridium spp.) normally are
present in the liver and can proliferate under these
conditions.
Systemic diseases that are associated with immunosuppression (e.g., feline leukemia virus and feline
immunodeficiency virus) or that predispose the
Table 71-6. INFECTIOUS DISEASES WITH POTENTIAL HEPATOBILIARY INVOLVEMENT
*
Disease Agent Refer To
Viral
Infectious canine hepatitis Canine adenovirus I Chapter 16
Systemic neonatal herpesvirus Canine herpesvirus Chapter 16
Canine acidophil cell hepatitis Unknown Chapter 16

Feline infectious peritonitis Feline coronavirus Chapter 10

Feline systemic hemorrhagic-like febrile disease Feline calicivirus (virulent strains)
Chapter 11
Bacterial
Leptospirosis Leptospira interrogans sensu strictu Chapter 19
Acute hepatic failure Serovars icterohaemorrhagiae, canicola, autumnalis, pomona,
bratislava, bataviae, hardjo, and Leptospira kirshneri serovar
grippotyphosa
Chronic hepatitis Serovars grippotyphosa and australis
Tyzzers disease Bacillus piliformis Chapter 69
Nocardiosis Nocardia species Chapter 19
Actinomycosis Actinomyces species Chapter 19
Tuberculosis Mycobacterium tuberculosis, M. bovis, M. avium Chapter 19
Salmonellosis Salmonella typhimurium Chapter 69
Brucellosis Brucella canis Chapter 19
Bartonellosis (dogs) Bartonella henselae, B. clarridgeiae Chapter 19
Hepatic abscess Gram-negative bacteria (especially Escherichia coli), anaerobes,
mixed infections common, Staphylococcus species (puppies)
Cholangitis/cholangiohepatitis Gram-negative bacteria (especially Escherichia coli),
anaerobes
Cholecystitis Gram-negative bacteria (especially Escherichia coli), Campylobacter
jejuni, Clostridium species
Yersiniosis Yersinia pestis Chapter 19
Tularemia Francisella tularensis Chapter 19
Fungal
Histoplasmosis Histoplasma capsulatum Chapter 20
Blastomycosis Blastomyces dermatitidis Chapter 20

Coccidioidomycosis Coccidioides immitis Chapter 20

Aspergillosis Aspergillus terreus Chapter 20
Others
Protozoal
Toxoplasmosis Toxoplasma gondii Chapter 21
Babesiosis Babesia canis, B. gibsoni Chapters 21 & 22
Cytauxzoonosis Cytauxzoon felis Chapters 21 & 22
Hepatozoonosis Hepatozoon canis Chapter 21
Leishmaniasis Leishmania species Chapter 21
Encephalitozoonosis Encephalitozoon cuniculi Chapter 21
Rickettsial
Ehrlichiosis Ehrlichia species Chapter 17
Rocky Mountain spotted fever Rickettsia rickettsii Chapter 17
Algal
Protothecosis Prototheca species Chapter 69
Parasitic
Canine schistosomiasis Heterobilharzia americana
Visceral larval migrans Toxocara canis
Liver flukes Platynosomum concinnum (feline)
Amphimerus pseudofelineus (feline)
Canine hepatic capillariasis Capillaria hepatica
Canine hepatic alveolar echinococcosis Echinococcus multilocularis
*Not necessarily associated with clinical hepatobiliary disease.Chapter 71 / Diseases
of the Liver and Biliary Tract 769
patient to infection (e.g., diabetes mellitus) may predispose the patient to hepatic abscesses.
Systemic infections (urinary tract infection, pneumo-

nia), pancreatitis, gallbladder rupture, and previous

surgical liver biopsy have also been associated with
hepatic abscesses.
Clinical Signs
Signs are attributed to sepsis, inflammation, and
hepatic dysfunction and include anorexia, lethargy,
fever, vomiting, and diarrhea.
Rupture of a hepatic abscess leads rapidly to peritonitis, septic shock, and death.
Diagnosis
Physical examination findings are often vague but
may include depression, fever, hepatomegaly, abdominal tenderness, and abdominal effusion.
Potential laboratory findings include neutrophilia
with a left shift (or neutropenia and degenerative left
shift if rupture occurs), thrombocytopenia, markedly
increased ALT and ALP activity (although they may
be in the normal range), hyperglobulinemia, hyperbilirubinemia, hypoglycemia, and septic suppurative
abdominal effusion. Increased ALT and ALP activity
occur in less than 50% of cats with hepatic abscesses.
Radiolucent areas may be seen on abdominal radiographs when gas-producing organisms are involved.
Ultrasonography may reveal one or more parenchymal abscess cavities. They appear as poorly echogenic
lesions that may be round, oval, or irregular in shape.

Ultrasound-guided FNA for cytology and culture may

be diagnostic.
Diagnosis often is established at exploratory laparotomy to determine the cause of septic peritonitis.
Perform aerobic and anaerobic cultures of abdominal effusion, blood, and hepatic tissue.
Treatment
Treatment of large, unifocal hepatic abscesses
requires surgical excision of the affected liver lobe
(see Chapter 72).
Ultrasound-guided percutaneous abscess drainage
has been advocated for medical management of
single lesions. No complications were observed in
one series of cases.
Initiate broad-spectrum antibiotics such as intravenous penicillin combined with an aminoglycoside
(e.g., gentamicin or amikacin) while awaiting culture
results. Monitor renal function during aminoglycoside therapy, and base further therapy on results of
sensitivity testing. Give long-term antibiotic therapy
(but not aminoglycosides) for at least 6 to 8 weeks.
The mortality rate was high (79%) in a recent series
of cats with hepatic abscesses as compared with dogs
(50%).
Liver Fluke Infection
Liver fluke infection is uncommon in cats and rare in

dogs. Infection usually is asymptomatic but may cause

clinical biliary tract disease when associated with
marked biliary fibrosis, cholangitis, cholangiohepatitis,
or extrahepatic bile duct obstruction. Cholangiocarcinoma has been reported in cats chronically infected
with Platynosomum concinnum.
Etiology
P. concinnum (Platynosomum fastosum) is the most
important liver fluke in cats and is found in tropical
and subtropical geographic areas, including Hawaii,
Florida, and the Caribbean. In endemic areas, the
prevalence of infection is high.
Other liver flukes that have been identified in cats
include Amphimerus pseudofelineus (Opisthorchis pseudofelineus), Opisthorchis tenuicollis, Opisthorchis sinensis,
and Metorchis conjunctus (Metorchis complexus).
Liver flukes require two intermediate hosts for their
life cycle. Adult flukes reside in the gallbladder and
bile ducts. Embryonated eggs are shed in the feces
and ingested by a snail, the first intermediate host for
all liver flukes. The house gecko, skink, lizard, and
Bufo toad are second intermediate hosts for P. concinnum; fish are second intermediate hosts for the other
species of flukes.
Clinical Signs
Most infected cats are asymptomatic for liver fluke

infection.
Liver fluke infection occasionally is associated with
anorexia, weight loss, diarrhea, vomiting, jaundice,
hepatomegaly, abdominal distention, and death.
Diagnosis
Operculated fluke eggs can be identified in feces by
a formalin-ether technique (a sedimentation procedure). Routine methods for flotation do not consistently identify eggs. With complete bile duct
obstruction, no eggs will be passed in the feces. Eggs
may be identified on cytologic examination of the
bile.
Other laboratory findings are inconsistent and often
unremarkable. Eosinophilia, hyperbilirubinemia, and
increased serum ALP and ALT activity are sometimes
detected.
A possible relationship between positive feline
immunodeficiency virus status and infection with A.
pseudofelineus has been suggested.
At laparotomy or necropsy, the bile ducts and gallbladder may be distended and thick walled and may
contain inspissated bile and small (<12 mm long)
adult flukes. The liver frequently is enlarged. In many
cases, no visible abnormalities are present.770

Section 6 / Digestive System

Treatment
Minimal information is available about treatment of

liver flukes.
Praziquantel (Droncit), 40 mg/kg, given orally or parenterally once a day for 3 consecutive days, or fenbendazole (Panacur) 50 mg/kg PO q24 for 10 to 14
days, has been suggested.
Drugs used unsuccessfully include mebendazole, levamisole, thiabendazole, diamphenethide, and rafoxanide. At least one follow-up fecal examination by
formalin-ether sedimentation should be performed
30 days following treatment.
Manage complications such as biliary obstruction and
secondary bacterial cholangitis or cholangiohepatitis
as described elsewhere in this chapter.
FELINE HEPATIC LIPIDOSIS
Hepatic lipidosis is an excessive accumulation of triglyceride in the liver that occurs when there is an imbalance
between the rate of deposition and the rate of mobilization of fat from the liver. It is the most common liver
disease in cats and is associated with severe intrahepatic
cholestasis and hepatic failure. Mortality is high if the
disorder is untreated.
Etiology
General mechanisms of hepatic lipidosis include nutritional, metabolic, hormonal, toxic, and hypoxic liver
injury. Diabetes mellitus is a well-recognized and easily
diagnosed cause of hepatic lipidosis. Drug- (tetracy-

cline, stanozolol) or toxin-induced injury can also cause

histologic lesions of lipidosis. Hepatic lipidosis often
occurs secondary to other systemic disorders associated
with anorexia and a catabolic state, especially cholangitis, pancreatitis, inflammatory bowel disease (IBD), and
systemic neoplasia. The term idiopathic hepatic lipidosis is
used when no other underlying causative disease is
identified.
The following mechanisms may be important in the
development of idiopathic hepatic lipidosis:
Cats have higher nutritional requirements for
protein, essential amino acids, and essential fatty
acids than dogs.
Systemically ill cats have a propensity for accumulating fat in their hepatocytes.
Profound anorexia and stress may be associated with
hormonal (catecholamines, other) alterations that
influence fat metabolism and predispose the patient
to peripheral fat mobilization and hepatic fat uptake.
Obese cats do not seem to be able to adapt to metabolism of fat for energy during periods of starvation.
Key Point Persistent anorexia and rapid weight
loss are hallmarks of severe hepatic lipidosis. It
most commonly develops in overweight cats that
experience prolonged (usually >2 weeks) inappetence, sometimes triggered by a stressful event.

 The exact mechanism or biochemical aberration in

cats with hepatic lipidosis is unknown. However, there
appears to be an imbalance in the mobilization of
peripheral fat, the hepatic use of fatty acids for
energy, and the hepatic dispersal of triglycerides.
Clinical Signs
Hepatic lipidosis is a disease of middle-aged or older
cats without breed or gender predilection. Many
affected cats are obese prior to the onset of disease.
Prolonged anorexia, often several weeks in duration,
is the most consistent clinical sign.
Other findings include lethargy, vomiting, constipation or diarrhea, and weight loss. Weight loss can be
dramatic and may exceed 25% of the previous weight.
Overt signs of HE (hypersalivation, severe depression, stupor) are uncommon.
Overt bleeding occurs in 20% of cases.
Diagnosis
Clinical findings and laboratory evaluation in cats with
hepatic lipidosis suggest hepatic disease, but liver biopsy
is required to distinguish hepatic lipidosis from other
causes of hepatic disease such as cholangitis, FIP, and
neoplasia. When hepatic lipidosis occurs secondary to
another disorder, additional testing is required to identify the primary disease (e.g., pancreatic lipase
immunoreactivity for pancreatitis or GI endoscopy and

biopsy for IBD).

History
The history may reveal precipitating causes of anorexia
such as stressful events (e.g., boarding, surgery, or
change in living arrangements), a diet change for
weight reduction, or non-hepatic diseases associated
with anorexia.
Physical Examination
Findings include hepatomegaly, jaundice, muscle
wasting, seborrhea, and pallor.
Ventroflexion of the head and neck occurs in some
cats and may represent muscle weakness associated
with electrolyte imbalances (hypokalemia, hypophosphatemia) or thiamine deficiency.
Laboratory Evaluation
Hematologic findings are nonspecific and include
a

nonregenerative,

normocytic,

normochromic

anemia with poikilocytosis and mature neutrophilia

and lymphopenia (stress response). Hemolysis may
occur secondary to hypophosphatemia or Heinz
bodies.Chapter 71 / Diseases of the Liver and Biliary Tract
Serum ALP, ALT, and AST activities; FSBA and PPSBA
concentrations; and total serum bilirubin concentration usually are increased. Increases in liver enzymes
precede increases in total bilirubin and bile acids.
Key Point Serum ALP activity is generally higher in

771

cats with lipidosis than with other hepatic diseases.

Serum GGT activity, which usually parallels or
exceeds serum ALP activity in most feline hepatic
diseases, is normal or only mildly increased in
hepatic lipidosis.
Other potential findings include hypokalemia, hyperammonemia,

hypoalbuminemia,

and

decreased

BUN. Many affected cats have abnormal coagulation

tests, especially PIVKA values and hypofibrinogenemia. In one study, PIVKA values improved in 50% of
the cats treated with vitamin K 1 , suggesting acquired
vitamin K deficiency.
Consider serum pancreatic lipase immunoreactivity
to evaluate for concurrent pancreatitis.
Consider serum cobalamin (B 12 ) levels if an underlying intestinal disorder suspected.
Radiography and Ultrasonography
Radiographically, the liver is normal to increased in
size.
Ultrasonographic findings include hepatomegaly
and diffuse hyperechogenicity of the liver. Ascites is
rare. Evaluate for concurrent pancreatitis or other
disorders causing secondary hepatic lipidosis.
Fine-Needle Aspiration Cytology
FNA cytology is a less invasive alternative to liver
biopsy that can provide similar information. Results

of FNA cytology occasionally can be misleading

because the small sample size may not be representative of the pathologic process in the liver.
Correct coagulopathy with vitamin K 1 prior to performing liver aspirate or liver biopsy.
On cytologic evaluation, hepatocytes are foamy and
vacuolated, and inflammatory cells are absent.
Liver Biopsy
Liver biopsy is required for definitive diagnosis but is
not routinely performed unless there is failure to
respond to appropriate therapy or a high level of suspicion of another primary hepatic disorder.
Grossly, the liver is enlarged, yellow, greasy, and
friable with rounded edges. Biopsy specimens usually
float in formalin.
On routine H&E staining, there is severe vacuolization of hepatocytes (>50% of acinar unit involved).
Oil red O stain performed on formalin-fixed
(nonparaffin-embedded) frozen tissue can confirm
excess fat in the vacuoles.
Inflammation or necrosis usually is absent.
Treatment
Because of lack of information regarding the underlying cause, treatment is primarily supportive. The greatest success has been with aggressive nutritional support.
During initial stabilization, correct dehydration, elec-

trolyte imbalances, coagulopathies and any complications of liver failure. A nasogastric tube can be placed
for short-term nutritional support. CliniCare (Abbott
Veterinary Diets) can be used initially through the nasogastric tube while stabilizing the patient prior to anesthesia for a longer-term feeding tube (gastrostomy or
esophagostomy tube).
Initial Fluid Therapy
Use intravenous fluid therapy with a balanced electrolyte solution supplemented with potassium chloride in the initial stages of treatment (see Table 71-1).
Hepatic lactate metabolism may be impaired in cats
with hepatic lipidosis; thus, avoid lactated Ringers
solution.
If hypokalemia persists despite supplementation,
evaluate serum magnesium concentration to see
if hypomagnesemia is the cause of refractory
hypokalemia.
Key Point Avoid dextrose supplementation unless
hypoglycemia is documented, because glucose
may promote hepatic lipid accumulation if caloric
needs are not being adequately met.
Monitor serum phosphorus concentration and treat
with IV potassium phosphate if levels decline to
<2 mg/dl (see Chapter 5). Hemolysis may occur secondary to severe hypophosphatemia.

 Abnormal blood coagulation test results and excess

bleeding occasionally respond to vitamin K 1 therapy,
suggesting severe cholestasis and vitamin K malabsorption (see Table 71-1). Consider fresh blood transfusion as needed for management of anemia.
Treat HE as described in Table 71-1, using a lowprotein diet, lactulose, and amoxicillin, neomycin, or
metronidazole.
Consider antibiotic therapy with amoxicillin to
prevent infection secondary to compromised hepatic
clearance of enteric organisms. Avoid tetracycline
because it can predispose the patient to hepatic lipid
accumulation.
Nutritional Therapy
Provide the daily caloric requirement (4060 kcal/kg
of body weight per day) via nasogastric, esophagostomy, or gastrostomy tube. An endoscopically placed
gastrostomy tube is preferable because long-term
nutritional therapy (at least 36 weeks) is necessary
in most cases. Nasogastric tubes are adequate for772
System
short-term management and are preferable to forcefeeding. Techniques for placement of indwelling
feeding tubes are described in Chapter 3.
Feed Maximum Calorie (Iams), Prescription Diet a/d
(Hills Pet Nutrition), or other complete and balanced feline diet that can be delivered through a tube

Section 6 / Digestive

in small feedings.
Initially, give one-fourth to one-half of the daily
dietary caloric requirement through the tube,
divided into 4 to 6 feedings per day. Gradually
increase the total amount fed over 3 to 4 days until
maintenance requirements are achieved.
Use a restricted-protein diet only if hyperammonemia or overt signs of HE occur.
Key Point Do not rely on appetite stimulant medications, because they rarely achieve the consistent
caloric intake required for effective reversal of lipidosis. Avoid diazepam, in particular, because it has
been associated with idiosyncratic hepatic necrosis in cats.
If vomiting or delayed gastric emptying is a problem,
give metoclopramide (0.4 mg/kg SC q8h, 30 minutes
before feeding), or feed a liquid enteral diet by constant rate infusion into the feeding tube. Dilution of
the diet with water may also improve tolerance.
Dietary Supplements
Numerous vitamins and supplements have been empirically recommended in the treatment of idiopathic
hepatic lipidosis, but further controlled studies are
needed to determine clinical usefulness. Consider each
of the following:
B complex vitamins added to the fluids (12 ml).

 Cobalamin (B 12 ), 250 mg SC initially while awaiting

serum cobalamin levels. If decreased serum cobalamin is documented (usually indicating primary
intestinal disease), continue it long term (see
Chapter 69).
Thiamine (if severe ventroflexion of neck), at a
dosage of 50 to 100 mg PO q24h, for 1 week (or
added to IV fluids).
L-Carnitine, 250 to 500 mg PO q24h, as an essential
cofactor for fatty acid oxidation (for relative carnitine
deficiency).
Taurine, at a dosage of 250 to 500 mg PO q24h, for
the initial 7 to 10 days. Plasma taurine is decreased in
many cats with hepatic lipidosis, and taurine is
required for bile acid conjugation.
Vitamin E (water-soluble form), 50 to 100 units total
dose per cat PO q24h, as an antioxidant.
S-adenosylmethionine (SAMe) (Denosyl SD, Nutramax
Labs), 20 to 40 mg PO q24h, as a glutathione source,
because decreased hepatic glutathione levels occur in
hepatic lipidosis.
Response to Treatment and Prognosis
With aggressive nutritional and supportive care,
approximately 60% to 85% of cats with lipidosis
respond within 3 to 6 weeks. Biochemical improvement (decreases in bilirubin, ALP, and ALT) is

usually seen within 1 to 2 weeks of initiating tube

feeding. Normalization may take several weeks. Do
not remove the tube until the cat is eating on its own
for at least a week.
Recurrence is rare and there is no evidence of residual hepatic damage.
The earlier treatment is initiated, the better the
prognosis.
Key Point Monitor serum liver enzymes and institute nutritional support early in obese cats that
become inappetent or undergo rapid weight loss
secondary to other disease processes.
Consider the potential for lipidosis in any obese cat
placed on a reducing diet. Monitor liver enzymes to
evaluate for onset of lipidosis. Consider l-carnitine
supplementation (250 mg/cat/day) in obese cats
undergoing dietary weight reduction.

Progressive Right-Sided CHF

Chronic right-sided CHF with refractory ascites generally stems from one of the following problems: mitral
valve regurgitation that is complicated by pulmonary
hypertension and tricuspid regurgitation; superimposition of atrial fibrillation on any heart disease; dilated
cardiomyopathy; or pulmonary hypertension (including dirofilariasis and idiopathic PH).

 In addition to standard therapy of furosemide,

spironolactone, dietary sodium restriction, and
digoxin or pimobendan, there should be increased
emphasis on dietary sodium restriction. Exercise
restriction also may be beneficial (controlled walks
only).
Thoracocentesis should be done for any dog with a
large pleural effusion.
Tense ascites should be partially drained (about 1 / 3 to
1 / 2 of the volume) to relieve discomfort, but be
careful about distinguishing hepatomegaly from
ascites. Recurring body cavity effusions indicate that
adjustment in medical therapy will be needed.
Spironolactone dosage can be increased to 1 to 2
mg/kg, PO, q12h.
For pulmonary hypertension that has been documented by Doppler echocardiography, a trial course
of sildenafil (Viagra) at 1 to 2 mg/kg, PO, q12h may
be of some benefit, but clinical trials are lacking and
the drug is expensive.
Pimobendan clearly can benefit some dogs with
chronic cardiac ascites and should be obtained whenever possible
If these measures fail, consider prescribing hydrochlorothiazide, but remember that sequential nephron
blockage can induce acute volume depletion and

renal failure, so start with low every other day dosing

(12 mg/kg, PO, daily) and recheck renal function
and electrolytes after 3 or 4 doses have been given.
An alternative (and safer) approach to more advanced
diuretic therapy is to administer oral furosemide and
spironolactone and enhance the furosemide effect by
intermittent dosing of furosemide subcutaneously.
While this can be done through repeated hospital
visits, in most cases, we preload syringes for clients
and instruct them in proper techniques for subcutaneous injection.
Initially substitute one of the oral doses of
furosemide with the same injectable dosage. Start
with an every other day regimen.
PATIENT FOLLOW-UP
When assessing the effectiveness and tolerability of cardiovascular drug therapy, consider the following key
points:
The client interviewreview the medications; consider the owners overall assessment of quality of life;
discuss the dogs appetite, activity, and ability to sleep
comfortably; respiratory symptoms; and exercise
capacity.
Identify any signs of possible drug intoxication.
Concentrate on the physical examination signs of
CHF: elevated jugular venous pressure, hepatomegaly,

ascites, thoracic auscultation, and overall body condition (cachexia).

Measure the arterial blood pressure.
Test renal function and measure electrolytes if
indicated.
Assess the cardiac rhythm by auscultation; record an
ECG if indicated by auscultation.
Determine if thoracic radiography is indicated;
review the chest films for control of edema and
effusions.
Determine serum concentrations of drugs if indicated (e.g., serum digoxin).
CHF PROGRESSION
Congestive heart failure may become complicated or
progressive for a number of reasons related to cardiac
or extracardiac issues. Some of the factors to consider
include
Progression of valvular disease or myocardial dysfunction
Heightened neurohormonal compensation
In dogs with MR, cardiac complications of ruptured
chorda tendinea, left atrial tear, atrial fibrillation
Medication problems: insufficient or excessive therapy for stage of disease; poor client compliance or
inadequate follow up; negative inotropic drugs (betablockers, calcium-channel blockers, anti-arrhythmics)

 Excessive exercise
Poor or unpalatable diet, excessive sodium intake Chapter 147 / Heart Failure in
Dogs 1507
Medical conditions that increase cardiac demands
and workload: hypertension, hyperthyroidism (iatrogenic in dogs), anemia, infections (especially with
fever)
Other medical conditions: neoplasia, renal failure,
chronic respiratory disease
Environmental stress (heat, high humidity)
Iatrogenic causes: excessive or inappropriate drug
therapy causing hypotension, dehydration, renal
failure
PROGNOSIS
The prognosis of canine CHF depends on the cause,
severity, and care received.
Many dogs survive >1 year following the first signs of
CHF provided they receive optimal veterinary and
home care, including extra-label drugs such as
carvedilol and pimobendan combined with standard therapy of furosemide-spironolactone, an
ACEI, and dietary modifications.
The prognosis for DCM is always more guarded, especially in Doberman pinschers. Once CHF has progressed to severe (functional class IV) failure, the
outlook is generally guarded-to-poor and a 3- to 9month prognosis is typical.

 There are no critical studies that prospectively examine

prognostic criteria across all groups. The multicenter
enalapril (North America) and benazepril (European) studies clearly indicate improved survival and
reduction of clinical signs in canine CHF caused by
DCM or chronic valvular disease when an ACEI is
added to background therapy of furosemide +/digoxin.
Where pimobendan is available to treat canine DCM
or advanced valvular heart disease, the long-term
outcome also appears more favorable when compared to conventional therapy with furosemide and
digoxin or even furosemide and an ACEI. (Though
it is illogical not to combine pimobendan with
furosemide and an ACEI.)
Beta-blockers slow the progression of cardiac dilatation and HF in experimental canine myocardial
diseases, and a drug like carvedilol should be part of
the long-term treatment regimen, especially in DCM,
provided it is tolerated.
Causes of Death
The causes of death in chronic CHF vary but are most
often related to one of the following:
Sudden electrical event (such as asystole or ventricular fibrillation)
Hypoxemia (pulmonary edema, pleural effusion)

 Pulmonary embolism leading to fatal hypotension

Multi-systemic organ failure
Client desire for euthanasia. This is a particularly
common ending and pertains to many factors that
include effectiveness of therapy, severity of signs,
client (and veterinarian) perceptions about quality of
life, and issues of care (medication frequency, visits
to the veterinary hospital, costs) among other factors.

CANINE CARDIOMYOPATHY
Myocardial diseases are a common cause of heart
failure, arrhythmia, and cardiovascular mortality in the
dog, following chronic valvular heart disease in preva-1542
Cardiopulmonary System
lence and clinical importance. Recognized forms of cardiomyopathy in dogs include the following conditions.
Dilated Cardiomyopathy (DCM)The most common
canine myocardial disease is idiopathic (genetic)
dilated cardiomyopathy. DCM is characterized by
decreased left ventricular ejection fraction, cardiac
remodeling with LV dilatation, and congestive heart
failure. Arrhythmiasboth atrial and ventricular
are common during all phases of the disease.
Sudden cardiac death is relatively common in
affected breeds.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Section 11 /

Aside from DCM, the most often recognized form

of cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy (ARVC), best characterized in
the boxer dog, and associated with ventricular ectopy,
syncope, heart failure, and sudden cardiac death. A
less common variant of this disease is right ventricular dysplasia, characterized by severe replacement of
myocardium with connective tissue and progressive
right-sided CHF.
Persistent Atrial StandstillThis disorder is caused by
replacement of atrial myocardium with fibrous connective tissue. Consequences are chronic bradycardia
and right-sided CHF, mainly affecting Springer
spaniels.
Idiopathic Hypertrophic Cardiomyopathy (HCM)The
condition of true HCM is rare in dogs but included
in the differential diagnosis of left-sided CHF and
sudden death. Hypertrophic cardiomyopathy must
be distinguished from congenital subaortic stenosis,
mitral malformation causing dynamic subvalvular
aortic stenosis, hypertensive heart disease with secondary hypertrophy, and disease caused by iatrogenic
thyrotoxicosis.
Secondary CardiomyopathiesCauses of canine myocardial disease include profound hypothyroidism, iatrogenic hyperthyroidism, doxorubicin (Adriamycin)

administration, catecholamine injury (including

pheochromocytoma), head trauma (brain-heart syndrome), systemic carnitine deficiency, severe taurine
deficiency, protracted myocardial ischemia, and
Duchennes myopathy.
Cardiomyopathy of OverloadChronic volume or pressure overload (caused by congenital shunts, valvular
diseases, and hypertension) can progress to the cardiomyopathy of overload, wherein the ventricle is
hypertrophied and systolic myocardial function
impaired.
Tachycardia-induced CardiomyopathyRelentless supraventricular or ventricular tachycardias are causes of
reversible myocardial failure.
Inherited Arrhythmogenic Cardiomyopathy in German ShepherdsThis is a malignant ventricular tachycardia of
young German shepherds that has been described in
detail by Moise and colleagues.
MyocarditisCardiac inflammation in dogs can be
due to Chagas disease (in endemic areas), septicemia, Lyme disease, and in newborn puppies by
parvovirus.
Overview and Pathophysiology of Canine DCM
Dilated cardiomyopathy is an idiopathic, genetic, or
familial myocardial disease characterized by left ventricular or biventricular dilation, reduced myocardial

contractility, and histologic abnormalities within the

ventricle.
Necropsy studies and 2D echocardiography often
demonstrate four-chamber dilatation with profound enlargement of the left ventricle and left
atrium.
CHF is often identified in canine patients and at
post-mortem examination.
Microscopic lesions include absence of inflammation, attenuated wavy fibers, or fibro-fatty replacement of myocytes; interstitial fibrosis; and other
alterations in the cytoskeletal matrix.
Extramural coronary arteries are normal and the
valves unremarkable, except in older dogs with
concurrent mitral or tricuspid valve endocardiosis.
The disease in most dogs is believed to be familial,
and in Doberman pinschers is probably a dominant
trait. The time-course of progression of DCM is
reportedly great; however, some patients clearly
develop LV dysfunction within a very short time interval.
A deficiency of a myocardial metabolic substrate
(such as L-carnitine or taurine) is identified in a very
small percentage of affected dogs, often related to
familial disease or gross dietary deficiencies. While
supplementation with these micronutrients or other

nutriceuticals (such as coenzyme Q 10 ) may be beneficial to the energetics of a failing cardiac muscle,
such treatment does not reverse canine DCM except
in rare cases of systemic substrate depletion.
As systolic dysfunction progresses, there is a limited
cardiac output which is compensated for by activation
of neurohormones and cytokines released to support
arterial blood pressure.
Neurohormonal assault causes further myocardial
damage.
As the left ventricular ejection fraction continues
to decrease, the heart dilates, and ventricular diastolic dysfunction can be recognized by detailed
echocardiographic studies.
Secondary atrioventricular valvular regurgitation
often develops leading to murmurs of mitral or
tricuspid regurgitation.
Exercise capacity is reduced as an early sign of
heart failure.
Arterial under-filling promotes renal sodium retention, which expands the plasma volume. CombinedChapter 150 / Cardiomyopathy
1543
with reduced left ventricular performance, venous
pressures increase and CHF ensues.
Arrhythmias can occur at any time during the course
of DCM. Syncope, sudden cardiac death, or the onset
of CHF are potential consequences of rhythm dis-

turbances. Sudden death is especially common in

Doberman pinschers with DCM. Frequently, biventricular CHF is precipitated by development of AF in
a dog with previously compensated DCM (See
Figure 150-3).
Dilated cardiomyopathy occurs most often in middleaged and older large and giant breed dogs, such
as the Doberman pinscher, Great Dane, Irish
wolfhound, Newfoundland, and boxer, but DCM can
affect dogs of any age and many other breeds.
Often male dogs are predisposed or more likely to
be affected at a young age. In breeds at risk, older
dogs often tend to be females.
In addition to a high prevalence in the larger
breeds, DCM is recognized regularly in a variety of
spaniel and retriever breeds, in Dalmatians, and
Portuguese water dogs. DCM occurs sporadically in
small canine breeds.
The genetic and familial basis for DCM is obvious
in many breeds, but the specific mutations
or alleles responsible have not yet been demonstrated.
The four most common clinical presentations of
DCM are: (1) occult DCM; (2) CHF; (3) cardiac
arrhythmia; and (4) sudden cardiac death. The first
three of these conditions will be reviewed. The reader

is also directed to the Chapter Heart Failure in the

Dog for detailed descriptions of treatment plans for
canine heart failure; Cardiovascular Drugs for discussions of the clinical pharmacology and use of
drugs for heart failure and arrhythmias; and Cardiac
Rhythm Disturbances for a review of electrocardiographic features of arrhythmias.
Occult Dilated Cardiomyopathy
Occult DCM refers to the overtly healthy dog with
evidence of systolic dysfunction by echocardiography.
Some also consider the diagnosis of occult DCM
viable when a breed-at-risk for DCM, such as a Doberman pinscher or Irish wolfhound, develops persistent
or recurrent atrial or ventricular arrhythmias that can
not be attributed to another recognized cause.
In this regard, there is some cross-over and reasonable debate between the designation of occult
DCM with arrhythmia and a normal echocardiogram and that of arrhythmogenic cardiomyopathy,
in which the principle disturbance is electrical
and the echocardiogram is normal (see below).
Myocardial dysfunction certainly develops in many,
but not all dogs with persistent cardiac arrhythmias.
But there is little doubt that many dogs with DCM
spend time as arrhythmogenic cardiomyopathy
before progressing to a more typical dilated form.

 For the purpose of this discussion, we classify dogs

with persistent arrhythmias and a normal echocardiogram as arrhythmogenic cardiomyopathy and
those with LV dysfunctionwith or without
arrhythmiasas occult DCM. While this distinction may seem academic, there is a clear trend to
use cardioprotective drugs such as beta-blockers
and ACEIs in dogs with occult DCM. Thus, ones
perspective on the requirement to demonstrate systolic dysfunction before labeling a patient occult
DCM may influence whether or not early intervention is prescribed.
Most diagnoses of occult DCM are made after a
breeder requests that a cardiologist screen an
important dog or following a veterinary examination that uncovers a murmur or arrhythmia.
EchocardiographyThe diagnosis of occult DCM is
traditionally based on echocardiographic examinaLAP
RAP
RV
LV
PA
LA
A
EDV

LAE

EDP
TR
PA
AP
2

AF VT
RV function
Stroke volume
Venous P

pulmonary PH/RV

edema
MR
1

2 Gallop

Chamber compliance
Dilation
Contractility
( Ejection fraction)
AO
velocity
and acceleration
CVP

Ascites

Figure 150-3.

Diagrammatic representation of

dilated cardiomyopathy. Explanation of the abbreviations can be found in the text.1544

Section 11 / Cardiopulmonary System

tion, with the minor axis estimate of LV systolic function (the shortening fraction) as the diagnostic
criterion.

 LV shortening fraction = LV diastolic dimension

minus the LV systolic dimension, divided by the LV
diastolic dimension).
Values below 25% are considered suspicious for
occult DCM, but there is no unanimity about one
specific figure that indicates myocardial failure.
Some healthy dogs live for many years with shortening fractions <20%. A single linear approach to
diagnosis also can be questioned because larger
dogs shorten relatively more in the apical to basilar
direction, and this motion is not assessed by shortening fraction.
However, some data in Doberman pinschers indicate that specific ventricular measurements, such
as an end-diastolic dimensions of >49 mm or endsystolic dimensions >42 mm, are highly predictive
of DCM.
Before accepting a diagnosis of occult DCM, the
clinician should request more detailed echocardiographic measures of systolic function including
LV short-axis shortening area (normally >48%),
apical-to-basilar mitral annular motion, and volumetric estimates of LV ejection fraction (normally
>4550% in single plane models). Advanced
Doppler methods of assessment are also available
but require further definition.

 Serial echocardiographic examinations are very

helpful in establishing a downward trend in LV
function. One should accept however that a 5% to
8% day-to-day variation is not uncommon in measured or calculated echocardiographic variables, so
that large differences and trends are more meaningful than tiny up or down movements.
Holter ECGThe 24-hour ambulatory ECG is a useful
adjunct in the diagnosis of occult DCM or arrhythmogenic cardiomyopathy. The Holter recording may
help establish the diagnosis in breeds highly prone to
DCM with cardiac arrhythmias, such as Doberman
pinschers. Most cardiologists consider >50 VPCs per
day clearly abnormal. Some consider even lower
numbers of VPCs abnormal. In dogs in which ventricular ectopy is evident from auscultation and
routine ECG, a Holter recording provides more
objective information about the severity of the
rhythm disturbance.
Other diagnosticsFuture directions are likely to lead
to more dependence on biomarkers (troponins, natriuretic peptides) for identification of myocardial
disease in breeds at risk or when screening echocardiograms return ambiguous results.
Breeders are always hoping for tests that will
provide the earliest recognition of disease, but it is

unrealistic to expect phenotype testing, no matter

how sophisticated, to identify all genetically
affected animals within a breeding line.
Many dogs that develop DCM do not demonstrate
any signs until their later years, long after breeding
has ceased.
In this regard, genetic testing will be a better
answer for this particular group of clients and
dogs.
Management of occult DCM involves protection of
the myocardium and management of serious arrhythmias.
An ACEI is prescribed for dogs with documented
occult DCM based on echocardiography. Enalapril
or benazepril at 0.5 mg/kg PO once or twice daily
is appropriate. If LV function is very poor, b.i.d.
dosing should be attained over a 2-week time. In
the report of OGrady and colleagues, in Doberman pinschers, treatment with enalapril roughly
doubled the time duration between diagnosis of
occult DCM and onset of overt signs of heart
failure.
Beta-blockade with carvedilol or metoprolol also is
cardioprotective and should be considered in dogs
with occult DCM.
In large breed dogs, long-acting metoprolol is usu-

ally well tolerated ( 1 / 2 of a 25-mg tablet, q12h).

Carvedilol (Coreg) is relatively expensive, but dogs
with occult DCM are more likely to tolerate
it than dogs with overt CHF. Optimal target
dosages are unknown, but initial dosing of
0.1 mg/kg PO q12h can be increased every 2 to
4 weeks to a target of 0.4 to 0.5 mg/kg q12h. If
lethargy or exercise intolerance develops, insure
that CHF has not been precipitated.
Blood pressure and renal function tests should be
followed with these medications.
If cardiac arrhythmias are also present, a 24-hour
Holter ECG should be done to assess arrhythmia
severity (unless a routine ECG already shows that it
is severe) and antiarrhythmic therapy considered.
This is discussed more fully below under arrhythmogenic cardiomyopathy.
PrognosisPrediction of survival in occult DCM is
difficult
One of the problems relates to that of precisely
establishing a diagnosis of occult DCM.
Once unambiguous evidence of LV systolic dysfunction is identified (LVSF typically 15% or less in
a dog with sinus rhythm and normal ventricular
conduction), the development of CHF is likely
within 6 to 12 months, even in the setting of

cardioprotective drugs.
When less stringent criteria are set for diagnosis of
occult DCM, many dogs will still be alive 2 to 4 years
later.
DCM with Congestive Heart Failure
Advanced cases of DCM usually present with a history
of exercise intolerance and clinical signs of CHF.Chapter 150 / Cardiomyopathy
1545
Syncope related to ventricular arrhythmia or neural
mediated syncope (inappropriate bradycardia and
vasodilation) may be reported by the owner.
Physical examination reveals signs typical of CHF:
There can be marked weight loss and cachexia.
The arterial blood pressure usually is normal owing
to vasoconstriction and neurohormonal activation,
but it will be decreased in profound DCM with
cardiogenic shock.
Auscultation may reveal atrial and ventricular
gallops, systolic murmurs, or arrhythmias.
The intensity of the first heart sound and strength
of the arterial pulse is often diminished, indicating
reduced LV contractility and stroke volume.
Crackles of pulmonary edema or a pleural fluid
line may be evident.
Clinical signs of left-sided CHF include tachypnea,
respiratory distress, abnormal breath sounds, and
coughing related to pulmonary edema.

 Right-sided CHF is characterized by jugular pulses

and jugular venous distension, hepatomegaly, and
ascites.
Pleural effusion is common in biventricular failure.
Diagnostic studies in advanced cases of DCM.
The standard 6-lead ECG may demonstrate a
number of abnormalities:
Cardiomegaly (wide or tall P-waves; wide or
increased amplitude QRS complexes).
Myocardial disease (wide QRS, slurred R-wave
descent with ST-segment coving, small complexes in boxers and English bulldogs; left
bundle branch block).
Atrial or ventricular premature complexes; atrial
fibrillation; or ventricular tachycardia.
The signal averaged ECG may demonstrate late
potentials indicating increased risk for ventricular
fibrillation.
Thoracic radiography reveals cardiomegaly and
typical vascular and pulmonary parenchymal
features of heart failure. Pleural effusion is
common.
The echocardiogram shows left ventricular dilation with reduced LV shortening fraction. Other
common findings include:
Increased mitral E-point to septal separation.

Decreased LV or septal wall excursions.

LA dilation.
Variable right-sided cardiomegaly.
Doppler evidence of mitral regurgitation and
tricuspid regurgitation.
Possible evidence for pulmonary hypertension.
Diastolic ventricular dysfunction with a restrictive
filling pattern.
Routine chemistry laboratory tests are usually normal
or reflect intercurrent disease, consequences of CHF,
or complications of CHF therapy.
Specialized blood tests for taurine may be performed in selected cases (mainly in American
cocker spaniels, golden retrievers, Newfoundlands,
breeds atypical for DCM, and in dogs receiving all
lamb and rice diets).
Cardiac troponin-I is usually elevated along with
increased plasma ANP and BNP.
Therapy of CHF associated with DCM is discussed in
detail in Chapter 147.
Principles of Hospital Management of CHF include
Administer furosemide (25 mg/kg IV); follow this
with repeated IV or IM injections. Alternatively
begin a constant rate infusion of furosemide.
Provide supplemental oxygen by nasal prongs or
other method appropriate for the size of the dog.

If oxygen is unavailable, direct a fan to the facial

region to minimize dyspnea.
Administer nitroglycerin ointment topically (11.5
inches for a large breed dog q12h).
Treat life-threatening pulmonary edema with afterload reduction using an infusion of sodium nitroprusside (0.52.5 mcg/kg/min is the typical dosage
range) with careful attention paid to arterial blood
pressure. Titrate the infusion to a systolic value of
90 to 100 mm Hg. A less effective alternative for
load reduction is enalapril at 0.25 to 0.5 mg/kg PO
q12h.
Perform thoracocentesis if there is a moderate to
large pleural effusion.
For CHF with systemic hypotension begin an infusion of dobutamine (2.510 mcg/kg/min) for 24 to
48 hours. Dobutamine can have benefits beyond
the period of infusion.
In the setting of hypotension, arterial vasodilators
such as nitroprusside or an ACEI should be avoided
until the pressure is stabilized by dobutamine.
In dogs with AF, digoxin (0.01mg/kg PO q12h for the
first two doses; 0.005 mg/kg PO q12h thereafter) is
prescribed to control the ventricular rate response.
Principles of long-term home management of CHF
include

 Furosemide (24 mg/kg PO q8-12h)

Spironolactone (12 mg/kg PO once or twice daily)
Enalapril or benazepril (0.25 mg/kg PO q12h;
increase to 0.5 mg/kg PO q12h after the first
reevaluation)
Digoxin (0.0030.005 mg/kg PO q12h) unless
there are contraindications for therapy such as ventricular ectopy or renal failure.
Pimobendan (Vetmedin, 0.20.3 mg/kg PO q12h)
if available, generally supplants digoxin except in
AF when both drugs are administered.
A sodium-restricted diet.
A b-blocker may be considered to blunt the
cardiotoxic effects of the sympathetic nervous
system; however, heart failure must be well controlled first. Consider carvedilol (Coreg), starting
at 0.05 to 0.1 mg/kg PO q12h; up-titrate the dose
every 2 to 4 weeks to a target of 0.2 to 0.4 mg/kg
PO q12h.1546
Having

Section 11 / Cardiopulmonary System

pimobendan

on-board

facilitates

up-

titration of the beta-blocker.

Unfortunately, the prescription drug (Coreg) is
expensive.
Dosing can be difficult in that dogs may not tolerate the negative inotropy of any b-blocker.
When AF complicates CHF, diltiazem (up-titrate

from 0.52.0 mg/kg PO q8h) is prescribed to

control ventricular rate (see details in next section).
Once heart rate is controlled, a long-acting form of
diltiazem can be substituted (using the same total
daily dose, but administered once or twice daily).
Fish oil supplements containing omega-3 fatty acids
may improve appetite and reduce cardiac cachexia
(EPA3040 mg/kg PO daily; DHA2025 mg/
kg PO daily).
In dogs with a diagnosis of hypothyroidism, ensure
that the plasma level is checked to prevent iatrogenic hyperthyroidism, a condition that increases
the demand for cardiac output and is arrhythmogenic. In general, even a giant breed dog with
hypothyroidism should not receive more than 0.6
to 0.8 mg of L-thyroxin daily.
For serious ventricular arrhythmias in the setting of
CHF: mexiletine (58 mg/kg tid) plus a low dose
beta-blocker. Amiodarone or procainamide are
alternatives, but results have not always been favorable. Optimally, a Holter ECG should be used to
assess therapy.

Fatty Liver Syndrome

Fatty liver syndrome (FLS), or hepatic lipidosis, commonly is seen in budgerigars, cockatiels, Amazon

parrots, or any bird on a high-fat (especially all-seed)

diet. Accumulation of fat in the liver is usually gradual,
and with severity it will cause the destruction of normal
liver cells and may progress to fibrosis.
Etiology
The etiology of FLS is unknown; however, malnutrition appears to play a major role.
Most birds with FLS are obese and on a high-fat diet
consisting primarily of seeds.
Unlike FLS in cats, anorexia does not appear to play
a role in the development of this disorder.
Clinical Signs
Most affect birds are obese, although with chronicity
significant weight loss may occur.
The most common clinical signs are lethargy,
anorexia, depression, biliverdinuria, and poor feathering. Diarrhea and/or vomiting may also be seen.
Budgerigars frequently have overgrown, soft, friable
beaks, with focal areas of hemorrhage.
Sudden death has been reported in budgerigars,
cockatiels, and Amazon parrots, with hepatic lipidosis as the only identifiable lesion on necropsy.
Diagnosis
Obtain radiographs of the abdomen to detect
hepatomegaly.
Increased AST, bile acid, and cholesterol concentra-

tions are usually present on the serum biochemistry

profile.
Liver biopsy is necessary to confirm the diagnosis.
Grossly, the liver is enlarged, yellowish, and friable.
Treatment
Administer intravenous or interosseous fluids to critically ill birds. If anorexic, forced alimentation with
low-fat gruel is indicated (see Chapter 168).
Place the bird on a strict low-fat diet containing at
least 12% protein. Eliminate seeds from the diet.
Ideally, a commercial avian pellet formula should
make up at least 40% of the diet, with the remainder
consisting of vegetables, fruits, and grains or legumes.
Hepatic Fibrosis
Etiology
Hepatic fibrosis is a common sequela to chronic liver
disease.
The primary insult can be infectious (e.g., bacterial,
viral, or chlamydial) or non-infectious (e.g., FLS).
Fibrosis can persist after elimination of the primary
insult.
Diagnosis
Radiographs usually reveal a normal-sized or small
liver shadow.
Increase in serum AST concentration is variable.
With severe disease, AST may be normal. Bile acid

concentrations are increased.

Liver biopsy is required for definitive diagnosis of
hepatic fibrosis.
Ascites is seen in severe (end stage) disease. Clinical
signs of ascites include abdominal distention and
dyspnea due to compression of air sacs.
Treatment
Supportive care in the form of fluid therapy, nursing
care, and appropriate diet are essential in the treatment of hepatic disease.
If significant ascites is present, perform abdominocentesis.
Colchicine has been reported to be beneficial in the
treatment of chronic liver disease by interfering with
collagen precursor synthesis. Doses have been extrapolated from those used in cats.
Ursodeoxycholic acid has been used anecdotally for
its immune-modulating effects, induction of choleresis, and effect on the circulating bile pool. Doses have
been extrapolated from those used in cats.
Antibiotic therapy may be indicated if bacterial
hepatitis is suspected to limit inflammation and subsequent fibrosis. Common choices include doxycycline (Vibramycin, Pfizer), 25 to 50 mg/kg PO q24h,
or a combination of enrofloxacin (Baytril, Bayer), 10
to 20 mg/kg PO q24h, and metronidazole (Flagyl,

Searle), 50 mg/kg PO q12h.

If hepatic encephalopathy is suspected, administer
lactulose at a dosage of 0.3 to 1.0 ml/kg PO q12h;
decrease the dose if diarrhea develops. Metronidazole may be added to alter colonic flora.

Congestive Heart Failure

Clinical Signs
Ferrets appear to compensate well for early cardiac
insufficiency, perhaps because a slight decrease in
activity is not readily apparent to owners.
Ferrets with congestive heart failure (CHF) may
present with clinical signs that resemble symptoms
associated with other disease entities, such as
anorexia, ascites, coughing, dehydration, dyspnea,
exercise intolerance, generalized weakness, hindlimb
weakness, hypothermia, lethargy, tachypnea, and
weight loss.
Pale or cyanotic mucus membranes and a prolonged
capillary refill time (CRT) may be noted on physical
examination.
Jugular pulses may be present when right-sided CHF
is present.
Femoral pulses may be weak, irregular, or normal.
Ascites, hepatomegaly, or splenomegaly may be noted
on abdominal palpation.

 Murmurs may be noted on auscultation, and are

typically associated with valvular insufficiency.
Diagnosis
History and physical examination findings are important in the diagnosis of heart disease.
Perform a complete physical examination, including
auscultation of the heart, and evaluation of the capillary refill time. Observe for tachypnea or dyspnea
and auscult the lungs. Palpate the abdomen and
examine for ascites.
Key Point Proceed with further testing only if the
ferret is stable. Otherwise, administer furosemide
and oxygen therapy.
Diagnosis requires information obtained by radiography, ECG, and echocardiography.
Obtain whole-body radiographs. The cardiac silhouette typically appears enlarged and globoid in shape
with rounded right and left ventricles. Ascites,
hepatomegaly, pleural effusion, and pulmonary
edema may be present as well.
Evaluate a CBC, serum biochemical profile, and urinalysis to determine if azotemia, electrolyte abnormalities, or other systemic diseases are present.
Perform a heartworm test if the history is supportive
for potential exposure.
If thoracic or abdominal effusion is present, perform

thoraco- or abdominocentesis and submit fluid for1842

of Avian and Exotic Pets
cytologic examination. Perform centesis as described
for cats; take into consideration the relatively caudal
position of the heart in ferrets. Sedation is usually
necessary. A modified transudate is typically associated with CHF.
Perform

standard

six-lead

electrocardiography

(ECG) if possible (Table 175-6 lists normal ferret

ECG parameters). Sedation may be necessary. Electrocardiography may reveal atrial premature contractions,

atrial

tachycardia,

atrial

fibrillation,

ventricular premature contractions, and ventricular

tachycardia.
Key Point Sedation with isoflurane is recommended when necessary. Sedation with ketamine
or a ketamine-diazepam combination raises the
heart rate. The heart rate tends to decrease with
ketamine-xylazine sedation; therefore, avoid using
xylazine in ferrets with suspected cardiac disease.
Echocardiography is the most useful diagnostic tool
in the ferret. The same echocardiographic changes
observed in the dog and cat are seen in the ferret.
(Table 175-7).
Treatment
Key Point Treatment of acute CHF should focus on
improving oxygenation and reducing cardiac

Section 12 / Diseases

preload and afterload.

Place the ferret in an oxygen-rich environment.
Administer supportive care such as subcutaneous
fluids (e.g. 0.45% saline and 2.5% dextrose), and
provide nutritional support for ferrets that are
anorexic.
Administer diuretics such as furosemide (14 mg/kg)
IM or IV bidtid.
Nitroglycerin 2% ointment may be applied to the
skin in the axilla, inguinal area, or on a hairless body
surface.
Angiotensin-converting enzyme (ACE) inhibitors
may be given to reduce afterload and preload.
Give enalapril (Enacard, Merck Agvet Division)
(0.5 mg/kg) PO q48h, then titrate up to q24h if
possible. ACE inhibitors may cause hypotension in
ferrets, titrate to effect.
Table 175-6. ELECTROCARDIOGRAPHIC DATA FOR 52
CLINICALLY NORMAL FERRETS*
Parameter Mean SD (Range) Value
(n = 25) (n = 27)
Age (mo) 1020 Average, 5.2
Male:female ratio All male 1.25
Body weight (kg) 1.4 0.2 NA
Heart rate (beats/min) 196 26.5 (140240) 233 22
Rhythm

Normal sinus NA 67%

Sinus arrhythmia NA 33%
Frontal plane MEA (degrees) 86.13 2.5 (79.690) 77.22 12
Lead II
P amplitude (mV) NA 0.122 0.007
P duration(s) NA 0.024 0.004
PR interval(s) 0.056 0.0086 (0.040.08) 0.047 0.003
QRS duration(s) 0.044 0.0079 (0.0350.06) 0.043 0.003
R amplitude (mV) 2.21 0.42 (1.43) 1.46 0.84
QT interval(s) 0.109 0.018 (0.080.14) 0.12 0.04
NA, not available; MEA, mean electrical axis.
*All ferrets were sedated with ketamine-xylazine.
Data from Bone L, Battles AH, Goldfarb RD, et al: Electrocardiographic values from
clinically normal,
anesthetized ferrets (Mustela putorius furo). Am J Vet Res 49:18841887, 1988.
Data adapted from Fox JG: Biology and diseases of the ferret. Philadelphia, Lea &
Febiger, 1988, p 170;
and Edwards J: Unpublished data, 1987.
Table 175-7. MEAN ECHOCARDIOGRAPHIC
VALUES FOR 34 NORMAL ADULT FERRETS
Parameter Mean Value
Left ventricle, end-diastolic 11.0 mm
Left ventricle, end-systolic 6.4 mm
Left ventricular posterior or free wall 3.3 mm
Fractional shortening 42%
End-point septal separation None

From Sitinas N, Beeber N, Skeels M: Unpublished data, 1992. When diuretics and
ACE inhibitors are used together
it is important to monitor for azotemia.
Perform thoracocentesis or abdominocentesis when
indicated.
Monitor body weight, CRT, heart rate and rhythm,
hydration status, mucous membrane color, respiratory rate, respiratory effort, BUN, creatinine, and
serum electrolytes.
Key Point Chronic therapy typically includes the
use of ACE inhibitors, and diuretics with the addition of digoxin in ferrets with dilated cardiomyopathy. Whenever possible, try to titrate the
diuretic dose to the lowest possible dose without
recurrence of pleural effusion or pulmonary
edema.
Administer digoxin elixir (0.01 mg/kg) PO sidbid to
ferrets with dilated cardiomyopathy.
Side effects associated with digoxin include anorexia,
arrhythmias, diarrhea, lethargy, and vomiting.
Serum digoxin levels should be monitored every 4 to
8 weeks. Normal values have not been published for
the ferret; reference values for dogs and cats are used
for interpretation.
Use of antiarrhythmic drugs such as atenolol or diltiazem is not well documented in the ferrets, but may
be useful in the treatment of ferrets with hyper-

trophic cardiomyopathy.
Salt-free diets may be beneficial; however, they are
often unpalatable to ferrets. Instruct the owner to
avoid feeding snacks, treats, or food items with a highsalt content.
Management includes periodic reevaluation of heart
rate and rhythm, serum electrolytes, and renal values.
Radiographs should be used to monitor for the
development of pulmonary edema or changes in the
cardiac silhouette. ECG and echocardiography
should be repeated periodically as well.

Dilated Cardiomyopathy
Etiology
The cause of dilated cardiomyopathy (DCM) in the
ferret is unknown.
Clinical Signs
Abdominal

enlargement

secondary

to

ascites,

anorexia, dyspnea, lethargy, and weight loss are often

noted.
Ascites, heart murmur, pale mucous membranes,
tachycardia, and weakness may be noted on physical
examination.
Moist rales and increased respiratory sounds may be
noted when pulmonary edema is present.
Pleural effusion may be present, and may cause an

increased inspiratory effort. The heart may sound

muffled on auscultation.
Coughing generally is not noted.
Diagnosis
See the CHF section in this chapter.
Treatment
Treatment is the same as that described for CHF.
Taurine supplementation does not appear to have
any effect on DCM in the ferret.
Follow-Up Care
See the CHF section in this chapter.
Hypertrophic Cardiomyopathy
Etiology
The cause of hypertrophic cardiomyopathy (HCM) is
unknown.
Clinical Signs
Clinical signs may be compatible with those described
for CHF or DCM (see above).
Other clinical signs are similar to those described for
the cat, and include acute onset of congestive heart
failure and/or sudden death.
Diagnosis
Follow the same guidelines described for DCM.
Include HCM on the rule-out list when evidence of
cardiac disease is noted on the physical examination
or diagnostic evaluation.

 Radiographs may not be beneficial in the diagnosis

of HCM.
Echocardiography should be used for definitive
diagnosis.
Treatment
Treatment should be aimed toward alleviating signs
of CHF and improving the diastolic efficiency of the
left ventricle.
Administer beta-adrenergic blocking drugs such as
atenolol (3.1256.25 mg) PO sid. Titrate to effect.
Administer calcium channel blockers such as diltiazem (3.757.5 mg) PO bid. Titrate to effect.
Diuretics are indicated if symptoms of CHF are
present (see above).

Heartworm Disease
Natural and experimental heartworm infections have
been reported in ferrets (see Chapter 152). The clinical presentation of heartworm disease typically resembles that of cats; however, the life cycle of Dirofilaria
immitis in ferrets is similar to the life cycle present in the
dog. Reported adult worm burdens range from 1 to 10.
The presence of only one adult worm in the heart can
be lethal.
Etiology
Heartworm disease is caused by the canine heart-

worm Dirofilaria immitis, a filarial nematode that is

transmitted via mosquitoes.
Ferrets that are housed outdoors in endemic areas
are at greatest risk of infection; however, ferrets kept
indoors also can become infected.
Clinical Signs
Clinical signs include coughing, dyspnea, hepatomegaly, inappetence, lethargy, melena, weakness, and
symptoms associated with right-sided CHF (pulmonary edema, pleural effusion, ascites). Sudden
death due to pulmonary artery obstruction may also
occur.
Microfilaria may be present in the blood of approximately 50% of infected ferrets.
Diagnosis
Diagnosis is based on the history, clinical signs, heartworm test results, radiographs, and echocardiography.
If the history is compatible with cardiac failure,
inquire about possible mosquito exposure.
Physical examination findings resemble those of
heart failure (see above).
Key Point Minimize stress in ferrets suspected of
heartworm disease. If symptoms of congestive
heart failure are present, delay further diagnostic
evaluation until the patient is stabilized (see Treat-

ment of Congestive Heart Failure).

Obtain whole body radiographs. Thoracic changes
may include cardiomegaly with enlargement of the
right atrium, caudal vena cava, and right ventricle.
Pleural edema and pleural effusion may be present
as well. Radiographic changes in the peripheral pulmonary arteries are not typically noted because the
worms tend to reside in the right side of the heart
and in the main pulmonary artery. Abdominal
changes often include hepatomegaly, splenomegaly,
and ascites.
If possible, draw blood for the modified Knotts test
for microfilaria. Microfilaria are identified in approximately 50% of infected ferrets.
Submit blood for an enzyme-linked immunosorbent
assay (ELISA) for Dirofilaria antigen. Antigen is produced by adult female heartworms; there is a potential for false negative test results in ferrets with low
worm burdens. A commercial assay (Snap Heartworm
Antigen Test Kit; IDEXX Laboratories Inc., Portland,
ME) has been used to detect heartworm infection in
the ferret.
Perform a CBC, serum biochemical profile, and urinalysis to rule out the presence of other systemic
diseases.
If pleural or abdominal effusion is present, submit

fluid for cytology. A modified transudate is typically

noted when CHF is present.
Echocardiography may be used to visualize heartworm(s) in the pulmonary artery, right ventricle, and
right atrium; dilation of the right ventricle and right
atrium may be assessed as well. Doppler echocardiography may be used to evaluate the patient for the
presence of pulmonary hypertension.
Treatment
Treatment of heartworm disease in ferrets is difficult.
Success is dependent on early diagnosis, diligent supportive care, and long-term antithrombotic therapy
in conjunction with adulticide therapy.
If signs of CHF are present, treat this first, and stabilize the patient (see the CHF section).
If the patient is symptomatic and microfilaremia
positive:
Administer microfilaricidal therapy: Ivermectin
(50 g/kg) SC every 30 days until clinical signs
and microfilaremia resolve.
Follow with adulticide therapy: melarsomine
(Immiticide, Rhone Merieux, Athens, GA) using a
two-stage protocol:
Stage 1: Administer a single dose of melarsomine
(2.5 mg/kg) IM.
Stage 2: 1 month later, administer two injections of

melarsomine (2.5 mg/kg) IM given 24 hours

apart.
Transient swelling at the site of injection is common.
Administer prednisone (0.5 mg/kg) PO sidtid during
adulticide treatment and for as long as clinical signs
persist.
If pleural effusion is present administer diuretics (see
the CHF section).
Cage confinement is important for 4 to 6 weeks after
treatment.
Perform a post-treatment ELISA for heartworm
antigen 3 months after adulticide therapy. Repeat
every 30 days if results are positive. Most ferrets
become seronegative 4 months after treatment.
Begin heartworm prevention 1 month after adulticide treatment.
If ferrets are microfilaria negative, administer adulticide therapy as described above.Prevention
Key Point Because of the high mortality associated
with heartworm disease, recommend preventive
therapy for all ferrets in heartworm-endemic areas.
Ivermectin may be given as preventive therapy beginning 1 month before and continuing 2 months after
mosquito season. Liquid ivermectin 1% may be
diluted in propylene glycol (0.3 ml ivermectin in
30 ml propylene glycol) and administered at a dose

of (0.2 ml/kg) PO every month. This solution must

be stored in an amber glass bottle out of sunlight.
Feline Heartguard (Merck Agvet) may be administered using the dose appropriate for a 1- to 5-lb cat.
If possible, house all ferrets in endemic areas within
structures with mosquito-proof screening.
Follow the same recommended guidelines for heartworm prevention in dogs and cats.

upportive treatment of patients with hepatic disease

addresses general pathophysiologic mechanisms
common to many hepatic diseases. Although some
treatments (e.g., antioxidants) apply to both acute and
chronic disorders, supportive treatments are commonly
discussed in the context of chronic inflammatory and
neoplastic hepatic diseases. Some supportive treatments
(e.g., antifibrotics) are by their very nature more applicable to chronic disease. Since most of these treatments are
administered orally, their use in both acute and chronic
cases may be limited by a patients ability to take oral
medication.
Ideally treatment of hepatic disease should be aimed
at a specific underlying etiology. Given the enormous
regenerative capacity of the liver, timely identification
and elimination of any underlying cause offer the best

hope for disease resolution in both acute and chronic

cases. Evidence from human medicine suggests that fibrosis and even cirrhosis may be reversible in some cases
when a specific etiology can be addressed (Rocky, 2005).
In cases in which an underlying cause can be identified
and eliminated, supportive care of hepatic disease may
be finite. In chronic inflammatory disease, especially
when the etiology is not known, or in advanced neoplastic disease when the etiology cannot be eliminated,
supportive treatments are recommended indefinitely.
Our understanding of the causes of chronic inflammatory hepatobiliary disease is extremely limited, a fact
that hampers research by limiting our ability to stratify
patients and interpret results according to etiology. Lack
of standardized supplement preparations with which to
undertake clinical trials can also be a limiting factor in
research. Recommendations for standardized clinical and
histologic approaches to canine and feline hepatobiliary disease were recently published by the World Small
Animal Veterinary Association Liver Standardization
Group and, if widely adopted, should facilitate future
research (Rothuizen J et al, 2006). Most recommendations for supportive care of small animal hepatic diseases,
regardless of the etiology, are extrapolated from human
medicine or are based on anecdotal experience and individual case reports rather than on evidence from pro-

spective, randomized, placebo-controlled clinical trials

involving large numbers of patients. The treatment recommendations in this chapter should be accepted with
these limitations in mind.
Treatment of hepatic disease incorporates the following general principles:
Address the underlying cause, if known (e.g.,
withdrawal of an hepatotoxic drug).
Reduce and prevent inflammation.
Reduce and prevent copper accumulation, if
applicable.
Reduce and prevent oxidative damage.
Reduce and prevent fibrosis.
Provide adequate nutrition.
Treat complications as needed (e.g., hepatic
encephalopathy, coagulopathy, gastric ulceration,
fluid/electrolyte disturbances, ascites, and
infection/endotoxemia)
This chapter reviews antioxidant and antifibrotic treatments commonly used for supportive care of hepatic disease and discusses treatment of hepatic diseaseassociated
coagulopathy and ascites. For information concerning
treatment of specific hepatic diseases, antiinflammatory
treatments, treatment of copper accumulation, treatment
of gastric ulceration, and management of hepatic encephalopathy, the reader is referred to the other chapters in

this section.
antioxidants
It is well established that oxidative stress plays a role in
the pathogenesis of liver disease in both humans and animals. Cats with hepatic lipidosis and both dogs and cats
with obstructive biliary and inflammatory hepatic disorders exhibit reduced glutathione concentrations. This
likely predisposes them to oxidative hepatic injury, given
the ability of glutathione to detoxify reactive oxygen species. Accordingly, use of antioxidants and compounds that
replenish hepatic glutathione stores seems warranted in
the supportive treatment of canine and feline hepatobiliary disease (Center, Warner, and Erb, 2002). In addition
to the substances discussed in the following paragraphs,
zinc and ursodeoxycholate are proposed to benefit liver
disease patients through antioxidant effects, although
these are more often used for their copper-reducing and
choleretic properties, respectively. Vitamin C ( l -ascorbic
acid) has also been recommended for its antioxidant
and free-radical scavenging properties, but its use is less
common than other antioxidants and therefore is not
discussed.
vitamin E
Vitamin E refers collectively to the antioxidant compounds
known as tocopherols and tocotrienols. -Tocopherol is the
most biologically active form of vitamin E. The D stereoiso-

mer is abundant in nature, where it is synthesized by plants.

Synthetic vitamin E contains both D and L stereoisomers
of -tocopherol (Matthai, 1996). Food sources of vitamin
E include vegetable oils, nuts, seeds, and grains. Because
C H A P T E R 128
Hepatic Support Therapy
BEnTE FLATLAnD, Knoxville, Tennesseethe various vitamin E isomers have differing
biologic activities, preparations of vitamin E are standardized to international units (IU). One IU is equivalent to the activity of
1 mg of synthetically prepared dl--tocopherol. Vitamin E
is fat soluble and requires bile and pancreatic juice for
maximal intestinal absorption. High dosages of vitamin E
may interfere with absorption of other fat-soluble vitamins and may predispose to development of vitamin
Kdependent coagulopathy. Vitamin E supplementation
traditionally has been thought harmless; however, a recent
metaanalysis of vitamin E use in humans with various diseases revealed that supplementation at dosages above 150
units/day was associated with increased all-cause mortality. This finding led to recommendations against vitamin E supplementation, particularly at dosages above 400
units/day (Miller et al., 2005).
In veterinary hepatology vitamin E is a commonly
used antioxidant. Dosage recommendations for dogs have
been reported in conference proceedings and vary from
10 units/kg every 24 hours orally to 250 or 400 units/dog

every 24 hours orally. I have used the 10-unit/kg every24-hour oral dose most commonly. Dosing small patients
can be problematic since commonly available vitamin E
preparations contain 400 or 1000 units. Controlled clinical trials evaluating efficacy and safety of vitamin E supplementation in canine and feline liver disease patients
are unavailable. I do not recommend vitamin E supplementation in liver disease patients with evidence of vitamin K deficiency. In such cases Sadenosylmethionine
(SAMe) or milk thistle is a preferred antioxidant.
milk thistle (silymarin)
The term silymarin refers collectively to the four flavonolignan isomers (silybin, isosilybin, silydianin, silychristine) that comprise the active ingredients of the herb milk
thistle (Silybum marianum). Silybin is the most biologically active isomer and comprises 50% to 70% of silymarin. These flavonolignans are found throughout the milk
thistle plant but are concentrated in its fruit and seeds.
Commercially available preparations of silymarin vary in
content and bioavailability, a fact that makes dosage recommendations difficult and hampers use of silymarin in
carefully designed, prospective clinical trials. Accordingly
in 2005 the national Center for Complementary and
Alternative Medicine (nCCAM) issued a request for industry collaboration to develop a well-characterized, standardized formulation of silymarin that could be used in

human liver disease clinical trials. If such a standardized

formulation is developed, it has the potential to benefit
veterinary medicine also.
The primary effect of silymarin is thought to be as an
antioxidant and free-radical scavenger, but it is also proposed to have antifibrotic, antiinflammatory, and immunomodulatory actions. In humans silymarin is used
primarily to treat alcoholic liver disease, viral hepatitis,
and toxin-induced liver disease. Randomized controlled
clinical trials using silymarin in specific human liver diseases have yet to be published.
In experimental animal models silymarin has been
shown to ameliorate hepatic injury secondary to acetaminophen, carbon tetrachloride, radiation, iron overload, alcohol, cold ischemia, and the death cap mushroom
(Amanita phalloides). Indeed, silymarin is so effective at
reducing A. phalloides toxicosis by preventing hepatocyte
uptake of mushroom toxins in both humans and dogs
that an intravenous formulation has been developed
specifically for the purpose of treating mushroom poisoning in humans (Seeff, 2001). In veterinary medicine,
clinical trials evaluating efficacy of silymarin in dogs and
cats with naturally occurring hepatic disease have not
been published. Dosage recommendations reported in
conference proceedings vary, but 20 to 50 mg/kg every
24 hours orally (dogs and cats) is commonly recom-

mended. A veterinary product is now available containing

silybin bound to phosphatidylcholine for improved gastrointestinal absorption (Marin, nutramax Laboratories,
Inc., 5 to 10 mg/kg every 24 hours orally).
S-adenosylmethionine
SAMe is present in almost all bodily tissues and fluids
and is a nucleotide-like molecule synthesized from the
amino acid methionine and adenosine triphosphate.
Of particular importance in the liver, SAMe plays a crucial role in transmethylation, transsulfuration, and aminopropylation pathways. These metabolic pathways are
responsible for metabolism of various endogenous and
xenobiotic compounds, generation of endogenous sulfur
compounds, and production of molecules important in
cell signaling and gene transcription, respectively (Center
et al., 2005). Among sulfur compounds generated by the
transsulfuration pathways is glutathione, an important
component of the endogenous antioxidant system of the
liver (Center, Warner, and Erb, 2002).
A commercial veterinary form of SAMe is available
(Denosyl , nutramax Laboratories, Inc.) and has been investigated. Oral administration of SAMe has been shown to
significantly increase plasma SAMe concentrations in dogs
and cats, with a peak effect occurring 1 to 4 hours after
the dose in fasted animals. SAMe administration in dogs
and cats increases hepatic glutathione concentrations and

improves markers of red blood cell and hepatocyte redox

status, justifying its use as a supportive treatment in canine
and feline hepatobiliary disease (Center et al., 2005).
A recommended dosage of SAMe in dogs and cats is
20 mg/kg every 24 hours orally. Administering SAMe to
fasted animals is recommended to maximize its absorption. Although numerous preparations of SAMe are available through health food stores and other sources, these
may have varying bioavailability. Use of the commercially
available veterinary preparations in dogs and cats is recommended for consistency.
SAMe has been shown to ameliorate oxidative stress
induced by corticosteroid administration in dogs,
although it does not prohibit corticosteroid-induced
hepatic vacuolar change (Center et al., 2005). Clinical trials evaluating the role and efficacy of SAMe in specific
canine and feline liver disorders are lacking and represent
the next step in our understanding of the role of SAMe in
the management of canine and feline hepatobiliary disease. The availability of a veterinary formulation of SAMe
with proven bioavailability in dogs and cats will continue
to facilitate research involving this compound.
cHAPter 128 Hepatic support therapy 555556 section VI Gastrointestinal
Diseases
antiFiBrotics
Hepatic fibrogenesis is an active area of research in human
medicine, and potential therapeutic targets continue to

be revealed as mechanisms of fibrogenesis are elucidated.

Current understanding of hepatic fibrogenesis emphasizes
the importance of hepatic stellate cells (also known as Ito
cells, lipocytes, or perisinusoidal cells) in the development
and maintenance of fibrosis. Future antifibrotic treatments
may include compounds that interfere with hepatic stellate cell activation and/or function (Rocky, 2005).
colchicine
Colchicine is a plant alkaloid derived from Colchicum
autumnale (autumn crocus, meadow saffron) and has been
a mainstay of antifibrotic treatment in both human and
veterinary medicine. Colchicine is purported to inhibit
fibrosis by binding selectively and reversibly to microtubules, inhibiting their polymerization and thus collagen
secretion. Aggregate data from numerous studies of various human liver diseases reveal that colchicine generally
is safe and may improve biochemical markers of, and even
mortality from, hepatic disease. However, the drug does
not appear to decrease fibrosis in humans, making its recommendation as an antifibrotic drug problematic. Use of
colchicine has been recommended for treatment of canine
hepatic diseases with fibrosis based on a few individual case
reports, but critical evaluation of its efficacy in a large number of dogs has not been published. The recommended dosage for colchicine in dogs is 0.014 to 0.03 mg/kg every 24
hours orally (Honeckman, 2003). Overdosage can be fatal,

as demonstrated by a case report of accidental colchicine

poisoning in a dog ingesting an unknown quantity of colchicine but calculated to be between 0.5 and 3.6 mg/kg
(Wagenaar, 2004). To my knowledge colchicine has not
been used for treatment of feline hepatic disease, and no
cat dosage is present in the veterinary literature.
other antifibrotics
Other substances with proposed antifibrotic effects include
interferon-, milk thistle, penicillamine, prednisone, ursodeoxycholic acid, and zinc. none of these compounds
have been critically evaluated for their ability to inhibit
fibrosis in dogs and cats with liver disease, and there is no
evidence to support their use specifically for that purpose
at this time. nevertheless milk thistle, penicillamine, prednisone, ursodeoxycholic acid, and zinc are already used in
veterinary hepatology for other reasons (e.g., copper reduction in the case of penicillamine); thus any potential antifibrotic effect would be a coincidental benefit. For further
information concerning the use of penicillamine, ursodeoxycholate, and zinc, the reader is referred to Chapters 129
and 130 in this section.