Inflammatory Liver Diseases in the Dog & Cat Jana Gordon, DVM ...

Background
Inflammatory Liver Diseases in the Dog & Cat
Jana Gordon, DVM
The liver plays an important role in carbohydrate, lipid and protein metabolism as well as vitamin and mineral
storage. The liver is also vital in detoxification of metabolic products (ammonia, uric acid), hormones and drugs.
There are several diseases of the liver in the dog & cat that can result in inflammation. The two most common
disorders in the dog are acute and chronic hepatitis. In the cat two forms of cholangitis, lymphocytic and
neutrophilic, are most common.
Signalment
There is no age, sex or breed predisposition to acute hepatitis. Breeds with an increased incidence of chronic
hepatitis include the beagle, Bedlington terrier, Cairn terrier, cocker spaniels (English and American), Dalmatian,
Doberman pinscher, English Springer Spaniel, German shepherd dog, Labrador retriever, Samoyed, Scottish
terrier, Skye terrier, standard poodle and West Highland white terrier. Middle aged dogs are more commonly
affected with chronic hepatitis and in certain breeds there is a sex predilection (e.g. female Doberman pinschers).
There does not appear to be any breed or sex predisposition in the development of inflammatory liver disease in
cats although some of the original reports suggested that the disease was more common in Persians.
Neutrophilic cholangitis is more common in older cats and lymphocytic cholangitis is more common in younger
cats.
Etiology
Acute and chronic hepatitis is often idiopathic but can also occur because of exposure to chemicals, drugs,
hepatotoxins and infectious agents. Immune dysregulation has also been proposed in chronic hepatitis. The liver
is particularly susceptible to toxic injury because of its rich blood supply that will bring large quantities of
potentially toxic substances to the liver from the intestinal tract. Infectious diseases such as infectious canine
hepatitis and leptospirosis have also been associated with acute hepatitis and proposed as an etiologic agent for
more chronic forms of hepatitis. Metals such as copper and iron are sometimes increased with more chronic
forms of hepatitis. Copper accumulation as a primary defect is inherited as an autosomal recessive trait in the
Bedlington terrier where there is a defect in copper metabolism in hepatocytes so it is not excreted normally into
the bile. As a result, copper gradually accumulates in the hepatocytes resulting in inflammation. In other breeds
reported to have high quantities of copper in their livers (Corgi, Dalmatian, Doberman pinscher, West Highland
white terrier, Skye terrier, cocker spaniels, Labrador retriever) it is not known whether it is the primary cause of
hepatitis (i.e. some sort of defect leading to accumulation) or the result of secondary damage due to inflammation
or cholestasis (impaired excretion secondary to underlying liver disease). Some dogs fail to develop chronic
hepatitis despite increased amounts of copper in their livers. Iron accumulation is believed to be secondary in
hepatitis, but may contribute to hepatic injury and inflammation. In chronic hepatitis immune dysregulation is
suspected to play a role but whether it is the cause of disease or a response to the inciting event is unknown.
The presence of lymphocytes and plasma cells is fairly common with chronic hepatitis and CD3 + T lymphocytes
were the most common lymphoid cell in the liver of a group of dogs with chronic hepatitis. Antinuclear antibodies
and antibodies to hepatocytes have also been found in some dogs supporting the role of an immune response.
There are other systemic inflammatory or infectious diseases that can cause chronic hepatitis but, as mentioned
previously, in most cases the cause is unknown and the term idiopathic is used.
Neutrophilic cholangitis is believed to be due to bacterial infections originating from the gastrointestinal tract.
Staphylococcus spp, E. coli and anaerobes are most commonly isolated. Most cases of lymphocytic cholangitis
are believed to be idiopathic. Recently bacterial DNA were identified in the bile of cats with lymphocytic
cholangitis. The bacteria are believed to have ascended from the intestinal tract as a result of biliary dilatation.
Inflammatory bowel disease and pancreatitis have been associated with neutrophilic and lymphocytic cholangitis
in cats. Helicobacter spp. have also been found in the bile and biliary ducts of a small number of cats with
cholangitis. Liver flukes (Metorchis conjunctus, Parametorchis complexum, Platynosomum concinnum) have
been associated with the development of cholangitis in the cat.
Clinical Signs

In acute hepatitis the signs tend to be more acute and severe. Lethargy, anorexia, vomiting and icterus are
common. These animals may present with signs of hepatic encephalopathy and may be depressed, moribund or
comatose and occasionally seizure. Fever may occur. Dogs may be dehydrated so mucous membranes may be
tacky. Disseminated intravascular collapse (DIC) with petecchia and other signs of bleeding (hematemesis,
melena) may be seen in severely affected cases. There might be pain and hepatomegaly on abdominal
palpation. In chronic hepatitis, dogs may be normal or present with weight loss, polydipsia, polyuria, intermittent
vomiting, diarrhea, decreased appetite and abdominal distention. Hepatic encephalopathy, icterus and bleeding
tendencies are occasionally seen in more advanced stages but seizures are rare. The liver may be normal,
enlarged or decreased in size in these dogs.
Clinical signs in cats with neutrophilic cholangitis are more acute and severe. Signs include lethargy, anorexia,
vomiting, abdominal pain, icterus, and fever. Lymphocytic cholangitis tends to be more chronic with mild nonspecific
signs noted initially that become more severe and apparent as the disease progresses. Initially there may
be mild weight loss that goes unnoticed followed by intermittent decreases in appetite, vomiting, diarrhea, and
icterus. Some cats with lymphocytic cholangitis develop polyphagia, generalized lymphadenopathy and
hepatomegaly. Ascites is uncommon but may occur due to portal hypertension in more chronic forms of
lymphocytic cholangitis with extensive fibrosis, cirrhosis or sclerosing cholangitis. Acholic feces are also
uncommon in cats but suggest complete obstruction of the common bile duct or severe sclerosing cholangitis.
Laboratory Findings
In acute hepatitis neutrophilia is common. A regenerative anemia and thrombocytopenia secondary to DIC are
less common. With chronic hepatitis, the anemia may be non-regenerative due to chronic disease, decreased red
cell survival or intestinal hemorrhage. Rarely, dogs with copper-associated hepatitis develop an acute hemolytic
anemia.
In cats with cholangitis, the hemogram may be unremarkable or a neutrophilia and lymphopenia may be seen with
lymphocytic cholangitis. A neutrophilia with a left shift may be present with neutrophilic cholangitis. Occasionally
there may be changes in RBC morphology that are most likely due to the effects of abnormalities in phospholipid
and cholesterol metabolism on cell membranes. Anemia may occur due to reasons discussed previously.
Liver enzymes are usually elevated with acute and chronic hepatitis but may also be elevated with the
administration of many drugs and in non-hepatic diseases (e.g. pancreatitis, peritonitis, sepsis,
hyperadrenocorticism, diabetes mellitus). Elevations in ALT and ALP are common and the degree of elevation
variable. In some cases of advanced chronic hepatitis (e.g. extensive cirrhosis) the liver enzymes may be normal
due to significant loss of functional hepatocytes. In acute and chronic hepatitis, bilirubin may be increased due to
hepatocellular damage and cholestasis. Increases in bilirubin are often more marked in acute than chronic
hepatitis. Bilirubinemia results in bilirubinuria.
Serum ALP and GGT are membrane-associated enzymes that increase with biliary disorders in the cat. These
enzymes are increased in most cats with cholangitis. Cats do not have a drug or glucocorticoid inducible form of
ALP so increases in ALP are highly suggestive of hepatobiliary disease. Serum GGT is often increased to a
greater extent that ALP. Serum ALT increases to some extent in most cats with cholangitis. Because of
inflammation and biliary stasis, bilirubin is increased in most cats with cholangitis. Cats with neutrophilic
cholangitis or an obstruction of the extrahepatic biliary ducts often have higher total bilirubin than cats with
lymphocytic cholangitis.
Indicators of hepatic synthetic function such as BUN, glucose and albumin are usually normal in cats with
cholangitis. Glucose may be decreased with fulminant hepatic failure in dogs. This is more common in severe
forms of acute hepatitis. Blood urea nitrogen is commonly decreased in dogs with liver disease. This may be due
to medullary washout (secondary to polydipsia), decreased protein intake (inappetence, dietary restriction) or
decreased synthesis. Albumin may be decreased due to inflammation (acute hepatitis) or severe diffuse
parenchymal dysfunction (acute and chronic hepatitis). Decreased protein intake and sequestration in ascetic
fluid may contribute to decreases in albumin. Globulins are increased in some cats with lymphocytic cholangitis
secondary to increased immunoglobulin production. Cholesterol may be increased with hepatobiliary disease
secondary to cholestasis (hepatitis, cholangitis) but may be decreased as a result of decreased functional mass
(hepatitis).

Bile acids and ammonia are most often performed in dogs with hepatitis when there is question as to liver function
or, in the case of ammonia, monitoring for evidence of hepatic encephalopathy. Bile acids will be increased with
loss of functional hepatocytes (impaired extraction) or cholestasis (impaired excretion). This test does not
differentiate between types of hepatobiliary disease. Ammonia may be increased with hepatobiliary disease as
well. A decrease in functional hepatocytes decreases urea synthesis and more ammonia is left in circulation. .
The liver synthesizes many coagulation proteins including the procoagulants factor II, VII, IX and X and the
anticoagulants antithrombin III, protein S and protein C. In dogs and cats with liver disease, prothrombin time
(PT), activated partial thromboplastin time (APTT) and proteins inactivated by vitamin K (PIVKA) may be
increased. This may be due to decreased synthesis of coagulant or anticoagulant proteins (hepatitis) or from
failure of vitamin K to activate these proteins (cholangitis). For this reason, abnormalities in coagulation can occur
with severe parenchymal or cholestatic diseases.
Diagnostic Imaging
Radiographically, the liver may be variably sized with decreased abdominal detail if ascites is present. Ultrasound
is important in evaluating the hepatic parenchyma, the biliary tract, the gall bladder and additional abdominal
organs (intestinal tract, pancreas, lymph nodes, etc) to identify predisposing or concurrent diseases. Ultrasound
may reveal fluid and normal, nodular or heterogenous hepatic echotexture. If cirrhosis is present (chronic
hepatitis) the surface of the liver may be irregular. Extrahepatic bile ducts may be mildly to moderately dilated
with cholangitis in cats. In cases of concurrent extrahepatic biliary duct obstruction (EHBDO) extra- and, in more
chronic cases, intrahepatic ducts may be dilated. The cause of the obstruction may or may not be visualized.
The gall bladder wall may be normal or thickened with cholangitis. Choleliths are uncommon in cats but may
cause EHBDO. Acquired portosystemic shunts, typical seen as aberrant vessels in proximity to the kidneys, are
seen in some cases of chronic hepatitis when extensive fibrosis has led to portal hypertension. Ultrasound can
also be utilized to obtain diagnostic samples for cytology, culture and histopathology.
Liver Sampling
Aspirates of the liver parenchyma for cytology are not recommended for the diagnosis of inflammatory liver
diseases of the dog and cat. Histology is also required to provide information about disease severity and to
provide prognostic information such as degree of necrosis, the presence of nodular regeneration and amount and
location of fibrosis. Liver biopsies can also be used to monitor treatment and progression of disease. Clotting
factor deficiencies may occur so a platelet count, PT and APTT or, alternatively, a PIVKA test should be
performed within 24 hours of the biopsy procedure. Biopsies require heavy sedation or general anesthesia and
can be taken via the tru-cut method, a surgical wedge technique or utilizing laparoscopy. Tru-cut biopsies can be
taken under ultrasound guidance or during surgical laparotomy. There are three types of tru-cut instrumentation:
manual, semi-automatic and those used with a biopsy gun. Livers surrounded by effusion or that contain more
fibrous tissue are easier to biopsy with automated guns. There is concern about a report of vagally mediated
shock in cats utilizing the biopsy guns. Semi-automatic tru-cuts are recommended in cats because they are less
likely to be associated with vagally mediated shock and are easier to handle than manual needles. A minimum of
3 good quality samples (1 to 2 cm each) from a 16 g needle should be taken. Wedge biopsies are taken at
surgery or laparoscopically and are considered superior for more superficial lesions. Large pinch biopsies can be
taken during laparoscopy but also limits sampling to superficial sites. Laparoscopy is also less invasive than a
laparotomy but requires specialized equipment. Quantification of copper and iron is routinely performed in cases
of chronic hepatitis in dogs and wedge biopsies are preferred over tru-cut samples. Fresh or deparaffinized
samples can be used for copper and iron quantification.
In cats, neutrophilic cholangitis is likely due to bacterial infection of the biliary tree so cytology and culture of bile is
recommended. Bile can be obtained via cholecentesis with ultrasound guidance or during surgery. A
contraindication to cholecentesis is EHBDO due to possible rupture and subsequent bile peritonitis. Bile can also
be manually expressed from the gall bladder into the duodenum and collected at surgery. Cytology may reveal
an increased number of neutrophils and bacteria with neutrophilic cholangitis. Infection is rarely occurs with
lymphocytic cholangitis but, if present, is likely secondary. Bacterial culture should be performed for aerobic and
anaerobic bacteria and include a sensitivity to guide antibiotic therapy.
With hepatitis, there is an initial insult that damages hepatocytes leading to apoptosis and necrosis. In most
instances inflammatory cells are then recruited and, depending on the amount of damage to the structural
framework of the liver, complete regeneration may occur. If extensive damage and cell death has occurred, focal

hepatocellular and ductular proliferation may result in nodular regeneration. As a result of chronic inflammation,
fibrosis may occur. Cirrhosis also occurs as a result of this distortion of normal architecture and is defined by the
presence of non-functional regenerative nodules within the parenchyma. In both forms of hepatitis inflammatory
cells include neutrophils, lymphocytes and plasma cells. In acute hepatitis, neutrophils are more common
whereas in chronic hepatitis lymphocytes and plasma cells are the predominant inflammatory cells. In copperassociated
hepatitis, accumulated copper causes hepatocellular necrosis leading to inflammation, chronic
hepatitis and, if untreated, cirrhosis. Normal hepatic copper levels are < 500 ppm. Damage occurs at levels >
1,000 ppm. Bedlington terriers homozygous recessive for the defect in the COMMD1 gene may accumulate
copper up to 6 years of age then it decreases but levels may increase up to 12,000 ppm. The diagnosis is made
by repeated liver biopsies at 6 and 15 months. Unaffected dogs will be normal at 6 months. Heterozygotes will
have increased copper levels at 6 months that have decreased at 15 months. Affected homozygotes will be
increased at 6 months and even higher at 15 months. There is also a DNA test (VetGen®) available that
identifies the COMMD1 deletion. In other breeds, copper levels are variable and a primary defect has not been
identified.
Histologic changes in neutrophilic cholangitis may be focal, multifocal or diffuse. Cholestasis is a common but
non-specific finding in all forms of cholangitis. Neutrophils are found in the lumen of the bile ducts early in
disease and may extend into the ductular epithelial cells. In acute cases edema and neutrophils are often found in
the portal regions. Neutrophils occasionally extend into parenchyma and form microabscesses. In more chronic
cases a mixed inflammatory cell infiltrate consisting of neutrophils, lymphocytes, plasma cells and pigment-laden
macrophages in the bile ducts, portal and periportal regions is found with variable amounts of fibrosis and bile
duct proliferation. Fibrosis may be periportal or portal-to-portal (bridging). Involvement of the gall bladder can
occur (neutrophilic cholecystitis) with intraluminal and intramural neutrophils early on followed by a mixed
inflammatory cell infiltrate in more chronic cases.
In lymphocytic cholangitis small lymphocytes are found in the biliary epithelium and around the bile ducts in the
portal areas. Plasma cells and eosinophils may also be found in varying amounts. Bile duct proliferation occurs
in more chronic cases. Fibrosis is variable and may be periportal or portal-to-portal. Sclerosing cholangitis is a
term used when fibrosis surrounds bile ducts. Lymphocytic cholangitis may be difficult to differentiate from small
cell lymphosarcoma in the liver. Involvement of the gall bladder can also occur with lymphocytic cholangitis
(lymphoplasmacellular cholecystitis) in which mural lymphocytes and plasma cells are found that may form
aggregates in the gall bladder wall.
Treatment
A detailed discussion of the treatment of hepatic encephalopathy will not be provided here but some of the
therapeutics for inflammatory liver disease also addresses hepatic encephalopathy
Dietary modifications are typically made for treatment of hepatic encephalopathy (dog, cat), elevated hepatic
copper (dog) and portal hypertension (dog, cat). Recommendations depend upon clinical presentation but diets
with lower quantities of higher quality protein, increased digestible carbohydrates and lower sodium are utilized.
Low protein will decrease the amount of ammonia produced in the intestinal tract and increasing the quality allows
for continued cell repair. Soluble carbohydrates are metabolized by colonic bacteria allowing for increases in
branched chain amino acids that trap ammonia within the colon so it cannot be absorbed. Soluble fiber also
increases fecal mass and stimulates evacuation. Sodium restriction may be helpful with ascites due to portal
hypertension. These diets may also have increased zinc and lower copper levels to decrease copper
accumulation. There may be increased amounts of the antioxidants vitamins C and E. Anorectic cats with
cholangitis should be supplemented with arginine and taurine as well.
Hepatitis is rarely due to a bacterial infection so antibiotics are not recommended. An exception to this would be
infection with Leptospira spp.. Antibiotics are occasionally used in cases of fulminant acute hepatitis when there
is concern about the liver’s ability to combat infection but this is unlikely because of the reserve capacity of the
liver. Because neutrophilic cholangitis is usually bacterial in origin, antibiotics are a cornerstone to treatment of
this disease and should be based on culture and sensitivity. This underscores the importance of obtaining bile for
culture. Infections should be treated for 4 to 6 weeks. Initial therapy with an antibiotic that covers enteric gram
negatives and anaerobes may be administered while awaiting results of the culture and sensitivity.

Some bile acids are more hydrophilic than others. Less hydrophilic (more hydrophobic or lipophilic) bile acids are
more toxic and induce cellular apoptosis and alter mitochondrial membrane permeability increasing free radical
production and oxidative damage. Ursodeoxycholic acid (UDA) also increases glutathione and metallothionein in
hepatocytes that help reduce oxidative damage. Ursodeoxycholic acid is a natural hydrophilic bile acid that
increases the bile acid pool which dilutes out more harmful bile acids and induces choloresis. This improves bile
flow so there is less contact of potentially toxic bile acids with cell membranes thus reducing oxidative damage to
cells. Ursodeoxycholic acid is commonly administered to dogs with acute and chronic hepatitis as well as cats
with cholangitis. In acute hepatitis and suppurative cholangitis, UDA may be given for 2 weeks past resolution of
disease. In chronic hepatitis and cholangitis UDA may be given life-long.
Glucocorticoids are not administered in cases of acute hepatitis because most dogs respond well to supportive
care and in rare cases in which infection is involved they would be contraindicated. The use of glucocorticoids is
common with chronic hepatitis but is reserved for dogs with inflammatory lesions. Reasons for this were
previously discussed under etiology. There is also evidence that glucocorticoids increase quality of life and
survival times in dogs with chronic hepatitis. Glucocorticoids are not typically administered in cases of
neutrophilic cholangitis due to the likelihood of an underlying bacterial infection. An exception would be the use of
short course (1 to 3 days) anti-inflammatory doses given to decrease inflammation of the biliary tree and increase
bile flow. In lymphocytic cholangitis there appears to be preponderance of CD3+ T cells and increased MHC II
expression in the portal regions. MHC II expression is also found on bile duct epithelial and Kupffer cells. This
suggests an immune-mediated mechanism for disease and is the primary reason for use of glucocorticoids in cats
with this disease. The use of glucocorticoids is controversial. In cats with signs of active inflammation within their
livers (lymphocytes, plasma cells), glucocorticoids may control inflammation and prevent progression of the
disease.
The primary sources of free radicals in the liver are the mitochondria in the hepatocytes, cytochrome P450
enzyme systems and Kupffer cells that have been activated by endotoxins. Free radicals take up electrons from
neighboring molecules causing oxidative damage to lipids, proteins and DNA. Glutathione (GSH) peroxidase and
superoxide dismutase (SOD) are normal cellular defenses. S-adenylmethionone (SAMe) is natural metabolite
found in hepatocytes. It is a precursor for cysteine which is one of the amino acids that makes up GSH. SAMe is
also a methyl donor for methylation reactions that are important in normal liver function. SAMe is most commonly
given to dogs and cats with liver disease that are at a risk of oxidative damage. Silymarin (silibinin) is the active
ingredient from the milk thistle fruit and increases SOD. Silymarin and SAMe have been shown to be effective in
reducing oxidative damage in dogs and humans with mushroom (Amanita phalloides) and acetaminophen toxicity.
Vitamin E is a fat soluble vitamin that decreases membrane peroxidation and free radical production. There are
no studies supporting or refuting its use in dogs and cats with liver disease. Because it is fat soluble, large doses
may interfere with the absorption of other fat soluble vitamins such as vitamin K. For this reason it is not
recommended in liver diseases in which vitamin K deficiency (severe cholestasis) is a concern.
Inflammation and damage to hepatocytes results in fibrosis. Colchicine is believed to stimulate collagenase which
should break down collagen. There is no proven benefit in man or animals regarding efficacy.
Chelation therapy is most often used in dogs with primarily centrilobular or heavy copper staining or in dogs with
quantitative copper levels > 1500 ppm. Penicillamine and trientene are chelators used to mobilize copper from
hepatocytes into circulation where it is excreted in the urine. Intestinal side effects can occur and they are
teratogenic. There has been more experience with penicillamine as a chelator in dogs but trientene has been
used and is effective. Follow-up biopsies at 6 month intervals are recommended to obtain hepatic copper levels <
500 ppm. Affected Bedlingtons should be on low dose chelation therapy life-long. Some dogs with copper
accumulation can be managed without chelators utilizing zinc and low copper diets long term. Zinc increases the
production of metallothionein in intestinal epithelial cells. Metallothionein binds dietary copper and it is lost as the
intestinal epithelial cells are sloughed. Side effects are intestinal upset and hemolysis (at higher serum
concentrations).
Extensive fibrosis and cirrhosis leads to portal hypertension and ascites. The ascites leads to a decrease in
intravascular volume and activation of the renin-angiotensin-aldosterone system (RAAS) causing sodium
retention (with water) and potassium loss. This exacerbates portal hypertension. Aldosterone antagonists, such
as spirinolactone, are preferred because they antagonize the effects of aldosterone. Loop and thiazide diuretics
cause intravascular volume depletion and further potassium loss which activate the RAAS. Unfortunately
spirinolactone has weak diuretic effects and it is often necessary to add another more potent diuretic to control
ascites.

Cholecystectomy is performed in instances of severe gall bladder disease in cats with cholangitis.
Cholecystoduodenostomy is performed in cases of common bile duct obstruction to maintain bile flow from the
liver to the intestinal tract. There is a high perioperative mortality rate for cats that undergo biliary diversion
surgery, particularly when the obstruction is due to neoplasia. Biliary stents have been placed in a small number
of cats with extrahepatic biliary tract obstruction due to pancreatitis but is also associated with a high
perioperative mortality rate and poor long term survival.
Prognosis
The prognosis is dependent upon the underlying cause of hepatitis. In general acute hepatitis carries a better
prognosis than chronic hepatitis. If, however, there is extensive damage to the liver complications such as DIC,
multi-organ failure and death may occur. With persistent inflammation acute hepatitis may develop into chronic
hepatitis. Follow-up biopsies 4 to 6 weeks after resolution of disease (clinical signs, laboratory data) can identify
this. The prognosis for chronic hepatitis is more guarded. Dogs with chronic hepatitis can live for days to years
with complete resolution in some dogs. Chronic hepatitis requires treatment until histologic recovery is noted
which is lifelong in most cases. Fibrosis and cirrhosis are irreversible so dogs with extensive fibrosis or cirrhosis
will not have resolution of their disease. Cirrhosis is a poor prognostic indicator.
Cats with neutrophilic cholangitis have a good prognosis with treatment. In cases of lymphocytic cholangitis the
prognosis depends on the extent of fibrosis present. Cats with more extensive fibrosis, portal hypertension and
ascites carry a more guarded prognosis.
References
Brain PH, Barrs VR, Martin P, et al. Feline cholecystitis and acute neutrophilic cholangitis: clinical findings,
bacterial isolates and response to treatment in six cases. J Feline Med Surg 2006 Apr;8(2):91-103.
Buote NJ, Mitchell SL, Penninck D, et al. Cholecystoenterostomy for treatment of extrahepatic biliary tract
obstruction in cats: 22 cases (1994-2003). J Am Vet Med Assoc 2006 May 1;228(9):1376-82.
Center SA. Current considerations for evaluating liver function in Consultations in Feline Internal Medicine.
August JR ed. pp 89-107.
Center SA, Erb HN, Joseph SA. Measurement of serum bile acids concentrations for diagnosis of hepatobiliary
disease in cats. J Am Vet Med Assoc 1995 Oct 15;207(8):1048-54.
Center SA, Warner K, Corbett J, et al. Proteins invoked by vitamin K absence and clotting times in clinically ill
cats. J Vet Int Med 2000 May-June; 14(3):292-7.
Day MJ. Immunohistochemical characterization of the lesions of feline progressive lymphocytic
cholangitis/cholangiohepatitis. J Comp Path 1998 Aug;119(2):135-47.
Gagne JM, Armstrong PJ, Weiss DJ, et al. Clinical features of inflammatory liver disease in cats: 41 cases (1983-
1993). J Am Vet Med Assoc 1999 Feb 15;214(4):513-6.
Greiter-Wilke A, Scanziani E, Soldati S, et al. Association of Helicobacter with cholangiohepatitis in cats. J Vet Int
Med 2006 Jul-Aug;20(4):822-7.
Haney DR, Christiansen JS, Toll J. Severe cholestatic liver disease secondary to liver fluke (Platynosomum
concinuum) infection in three cats. J Am Anim Hosp Assoc 2006 May-Jun;42(3):234-7.
Hoffman G, Rothuizen J. Copper-associated hepatitis in Current Veterinary Therapy XIV Bonagura JD, Twedt DC
ed. pp. 557-62.
Mayhew PD, Weisse CW. Treatment of pancreatitis-associated extrahepatic biliary tract obstruction by
choledochal stenting in seven cats. J Small Anim Hosp 2008 Mar;49(3):133-8.

Otte CM, Gutierrez OP, et al. Detection of bacterial DNA in the bile of cats with lymphocytic cholangitis. Vet
Microbiol 2011
Rothuizen J. General principles in the treatment of liver disease in Textbook of Veterinary Internal Medicine 6 th
ed. Ettinger SJ, Feldman EC eds pp. 1435-42.
Rothuizen J, Desmet VJ, van den Ingh TSGAM, et al. Sampling and handling of liver tissue in WSAVA Standards
for Clinical and Histological Diagnosis of canine and Feline Liver Diseases Rothuizen J, Bunch SE, et al ed. pp. 5
– 14.
Trainor SA, Center JF, Randolph CE, et al. Urine sulfated and nonsulfated bile acids as a diagnostic test for liver
disease in cats. J Vet Int Med 2003;17(2)145-53.
Van den Ingh T, Van Winkle T, et al. Morphological classification of parenchymal disorders of the canine and
feline liver: 2 Hepatocellular death, hepatitis and cirrhosis in WSAVA Standards for Clinical and Histological
Diagnosis of canine and Feline Liver Diseases Rothuizen J, Bunch SE, et al ed. pp. 85-102.
Van den Ingh T, Cullen JM, Twedt DC, et al Morphological classification of biliary disorders of the canine and
feline liver in. WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Disease:
WSAVA Liver Standardization Group. Rothuizen J, Bunch SE, Charles JA, et al eds. pp 68-71.
Vogel G, Tuchweber B, Trost W, et al. Protection by silibinin against Amanita phalloides intoxication in beagles.
Toxicol Appl Pharmacol 1984 May;73(3):355-62.
Wallace KP, Center SA, Hickford FH, et al. S-adenosyl-L-methionine (SAMe) for the treatment of acetaminophen
toxicity in a dog. J Am Anim Hosp 2003 May-Jun;38(3):246-54.
Webster CRL History, clinical signs, and physical findings in hepatobiliary disease in Textbook of Veterinary
Internal Medicine 6 th ed. Ettinger SJ, Feldman EC eds pp. 1422-34.
Weiss DJ, Gagne JM, Armstrong PJ Relationship between inflammatory hepatic disease and inflammatory bowel
disease, pancreatitis, and nephritis in cats. J Am Vet Med Assoc 1996 Sep 15;209(6):1114-6.
Willard MD. Inflammatory canine hepatic disease in Textbook of Veterinary Internal Medicine 6 th ed. Ettinger SJ,
Feldman EC eds pp. 1442-7.
Willard MD, Twedt DC. Gastrointestinal, pancreatic, and hepatic disorders in Small Animal Clinical Diagnosis by
Laboratory Methods 4 th ed Willard MD, Tvedten H ed. pp. 229-42.