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

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

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


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Background<br />

<strong>Inflammatory</strong> <strong>Liver</strong> <strong>Diseases</strong> <strong>in</strong> <strong>the</strong> <strong>Dog</strong> & <strong>Cat</strong><br />

<strong>Jana</strong> <strong>Gordon</strong>, <strong>DVM</strong><br />

The liver plays an important role <strong>in</strong> carbohydrate, lipid and prote<strong>in</strong> metabolism as well as vitam<strong>in</strong> and m<strong>in</strong>eral<br />

storage. The liver is also vital <strong>in</strong> detoxification of metabolic products (ammonia, uric acid), hormones and drugs.<br />

There are several diseases of <strong>the</strong> liver <strong>in</strong> <strong>the</strong> dog & cat that can result <strong>in</strong> <strong>in</strong>flammation. The two most common<br />

disorders <strong>in</strong> <strong>the</strong> dog are acute and chronic hepatitis. In <strong>the</strong> cat two forms of cholangitis, lymphocytic and<br />

neutrophilic, are most common.<br />

Signalment<br />

There is no age, sex or breed predisposition to acute hepatitis. Breeds with an <strong>in</strong>creased <strong>in</strong>cidence of chronic<br />

hepatitis <strong>in</strong>clude <strong>the</strong> beagle, Bedl<strong>in</strong>gton terrier, Cairn terrier, cocker spaniels (English and American), Dalmatian,<br />

Doberman p<strong>in</strong>scher, English Spr<strong>in</strong>ger Spaniel, German shepherd dog, Labrador retriever, Samoyed, Scottish<br />

terrier, Skye terrier, standard poodle and West Highland white terrier. Middle aged dogs are more commonly<br />

affected with chronic hepatitis and <strong>in</strong> certa<strong>in</strong> breeds <strong>the</strong>re is a sex predilection (e.g. female Doberman p<strong>in</strong>schers).<br />

There does not appear to be any breed or sex predisposition <strong>in</strong> <strong>the</strong> development of <strong>in</strong>flammatory liver disease <strong>in</strong><br />

cats although some of <strong>the</strong> orig<strong>in</strong>al reports suggested that <strong>the</strong> disease was more common <strong>in</strong> Persians.<br />

Neutrophilic cholangitis is more common <strong>in</strong> older cats and lymphocytic cholangitis is more common <strong>in</strong> younger<br />

cats.<br />

Etiology<br />

Acute and chronic hepatitis is often idiopathic but can also occur because of exposure to chemicals, drugs,<br />

hepatotox<strong>in</strong>s and <strong>in</strong>fectious agents. Immune dysregulation has also been proposed <strong>in</strong> chronic hepatitis. The liver<br />

is particularly susceptible to toxic <strong>in</strong>jury because of its rich blood supply that will br<strong>in</strong>g large quantities of<br />

potentially toxic substances to <strong>the</strong> liver from <strong>the</strong> <strong>in</strong>test<strong>in</strong>al tract. Infectious diseases such as <strong>in</strong>fectious can<strong>in</strong>e<br />

hepatitis and leptospirosis have also been associated with acute hepatitis and proposed as an etiologic agent for<br />

more chronic forms of hepatitis. Metals such as copper and iron are sometimes <strong>in</strong>creased with more chronic<br />

forms of hepatitis. Copper accumulation as a primary defect is <strong>in</strong>herited as an autosomal recessive trait <strong>in</strong> <strong>the</strong><br />

Bedl<strong>in</strong>gton terrier where <strong>the</strong>re is a defect <strong>in</strong> copper metabolism <strong>in</strong> hepatocytes so it is not excreted normally <strong>in</strong>to<br />

<strong>the</strong> bile. As a result, copper gradually accumulates <strong>in</strong> <strong>the</strong> hepatocytes result<strong>in</strong>g <strong>in</strong> <strong>in</strong>flammation. In o<strong>the</strong>r breeds<br />

reported to have high quantities of copper <strong>in</strong> <strong>the</strong>ir livers (Corgi, Dalmatian, Doberman p<strong>in</strong>scher, West Highland<br />

white terrier, Skye terrier, cocker spaniels, Labrador retriever) it is not known whe<strong>the</strong>r it is <strong>the</strong> primary cause of<br />

hepatitis (i.e. some sort of defect lead<strong>in</strong>g to accumulation) or <strong>the</strong> result of secondary damage due to <strong>in</strong>flammation<br />

or cholestasis (impaired excretion secondary to underly<strong>in</strong>g liver disease). Some dogs fail to develop chronic<br />

hepatitis despite <strong>in</strong>creased amounts of copper <strong>in</strong> <strong>the</strong>ir livers. Iron accumulation is believed to be secondary <strong>in</strong><br />

hepatitis, but may contribute to hepatic <strong>in</strong>jury and <strong>in</strong>flammation. In chronic hepatitis immune dysregulation is<br />

suspected to play a role but whe<strong>the</strong>r it is <strong>the</strong> cause of disease or a response to <strong>the</strong> <strong>in</strong>cit<strong>in</strong>g event is unknown.<br />

The presence of lymphocytes and plasma cells is fairly common with chronic hepatitis and CD3 + T lymphocytes<br />

were <strong>the</strong> most common lymphoid cell <strong>in</strong> <strong>the</strong> liver of a group of dogs with chronic hepatitis. Ant<strong>in</strong>uclear antibodies<br />

and antibodies to hepatocytes have also been found <strong>in</strong> some dogs support<strong>in</strong>g <strong>the</strong> role of an immune response.<br />

There are o<strong>the</strong>r systemic <strong>in</strong>flammatory or <strong>in</strong>fectious diseases that can cause chronic hepatitis but, as mentioned<br />

previously, <strong>in</strong> most cases <strong>the</strong> cause is unknown and <strong>the</strong> term idiopathic is used.<br />

Neutrophilic cholangitis is believed to be due to bacterial <strong>in</strong>fections orig<strong>in</strong>at<strong>in</strong>g from <strong>the</strong> gastro<strong>in</strong>test<strong>in</strong>al tract.<br />

Staphylococcus spp, E. coli and anaerobes are most commonly isolated. Most cases of lymphocytic cholangitis<br />

are believed to be idiopathic. Recently bacterial DNA were identified <strong>in</strong> <strong>the</strong> bile of cats with lymphocytic<br />

cholangitis. The bacteria are believed to have ascended from <strong>the</strong> <strong>in</strong>test<strong>in</strong>al tract as a result of biliary dilatation.<br />

<strong>Inflammatory</strong> bowel disease and pancreatitis have been associated with neutrophilic and lymphocytic cholangitis<br />

<strong>in</strong> cats. Helicobacter spp. have also been found <strong>in</strong> <strong>the</strong> bile and biliary ducts of a small number of cats with<br />

cholangitis. <strong>Liver</strong> flukes (Metorchis conjunctus, Parametorchis complexum, Platynosomum conc<strong>in</strong>num) have<br />

been associated with <strong>the</strong> development of cholangitis <strong>in</strong> <strong>the</strong> cat.<br />

Cl<strong>in</strong>ical Signs

In acute hepatitis <strong>the</strong> signs tend to be more acute and severe. Lethargy, anorexia, vomit<strong>in</strong>g and icterus are<br />

common. These animals may present with signs of hepatic encephalopathy and may be depressed, moribund or<br />

comatose and occasionally seizure. Fever may occur. <strong>Dog</strong>s may be dehydrated so mucous membranes may be<br />

tacky. Dissem<strong>in</strong>ated <strong>in</strong>travascular collapse (DIC) with petecchia and o<strong>the</strong>r signs of bleed<strong>in</strong>g (hematemesis,<br />

melena) may be seen <strong>in</strong> severely affected cases. There might be pa<strong>in</strong> and hepatomegaly on abdom<strong>in</strong>al<br />

palpation. In chronic hepatitis, dogs may be normal or present with weight loss, polydipsia, polyuria, <strong>in</strong>termittent<br />

vomit<strong>in</strong>g, diarrhea, decreased appetite and abdom<strong>in</strong>al distention. Hepatic encephalopathy, icterus and bleed<strong>in</strong>g<br />

tendencies are occasionally seen <strong>in</strong> more advanced stages but seizures are rare. The liver may be normal,<br />

enlarged or decreased <strong>in</strong> size <strong>in</strong> <strong>the</strong>se dogs.<br />

Cl<strong>in</strong>ical signs <strong>in</strong> cats with neutrophilic cholangitis are more acute and severe. Signs <strong>in</strong>clude lethargy, anorexia,<br />

vomit<strong>in</strong>g, abdom<strong>in</strong>al pa<strong>in</strong>, icterus, and fever. Lymphocytic cholangitis tends to be more chronic with mild nonspecific<br />

signs noted <strong>in</strong>itially that become more severe and apparent as <strong>the</strong> disease progresses. Initially <strong>the</strong>re may<br />

be mild weight loss that goes unnoticed followed by <strong>in</strong>termittent decreases <strong>in</strong> appetite, vomit<strong>in</strong>g, diarrhea, and<br />

icterus. Some cats with lymphocytic cholangitis develop polyphagia, generalized lymphadenopathy and<br />

hepatomegaly. Ascites is uncommon but may occur due to portal hypertension <strong>in</strong> more chronic forms of<br />

lymphocytic cholangitis with extensive fibrosis, cirrhosis or scleros<strong>in</strong>g cholangitis. Acholic feces are also<br />

uncommon <strong>in</strong> cats but suggest complete obstruction of <strong>the</strong> common bile duct or severe scleros<strong>in</strong>g cholangitis.<br />

Laboratory F<strong>in</strong>d<strong>in</strong>gs<br />

In acute hepatitis neutrophilia is common. A regenerative anemia and thrombocytopenia secondary to DIC are<br />

less common. With chronic hepatitis, <strong>the</strong> anemia may be non-regenerative due to chronic disease, decreased red<br />

cell survival or <strong>in</strong>test<strong>in</strong>al hemorrhage. Rarely, dogs with copper-associated hepatitis develop an acute hemolytic<br />

anemia.<br />

In cats with cholangitis, <strong>the</strong> hemogram may be unremarkable or a neutrophilia and lymphopenia may be seen with<br />

lymphocytic cholangitis. A neutrophilia with a left shift may be present with neutrophilic cholangitis. Occasionally<br />

<strong>the</strong>re may be changes <strong>in</strong> RBC morphology that are most likely due to <strong>the</strong> effects of abnormalities <strong>in</strong> phospholipid<br />

and cholesterol metabolism on cell membranes. Anemia may occur due to reasons discussed previously.<br />

<strong>Liver</strong> enzymes are usually elevated with acute and chronic hepatitis but may also be elevated with <strong>the</strong><br />

adm<strong>in</strong>istration of many drugs and <strong>in</strong> non-hepatic diseases (e.g. pancreatitis, peritonitis, sepsis,<br />

hyperadrenocorticism, diabetes mellitus). Elevations <strong>in</strong> ALT and ALP are common and <strong>the</strong> degree of elevation<br />

variable. In some cases of advanced chronic hepatitis (e.g. extensive cirrhosis) <strong>the</strong> liver enzymes may be normal<br />

due to significant loss of functional hepatocytes. In acute and chronic hepatitis, bilirub<strong>in</strong> may be <strong>in</strong>creased due to<br />

hepatocellular damage and cholestasis. Increases <strong>in</strong> bilirub<strong>in</strong> are often more marked <strong>in</strong> acute than chronic<br />

hepatitis. Bilirub<strong>in</strong>emia results <strong>in</strong> bilirub<strong>in</strong>uria.<br />

Serum ALP and GGT are membrane-associated enzymes that <strong>in</strong>crease with biliary disorders <strong>in</strong> <strong>the</strong> cat. These<br />

enzymes are <strong>in</strong>creased <strong>in</strong> most cats with cholangitis. <strong>Cat</strong>s do not have a drug or glucocorticoid <strong>in</strong>ducible form of<br />

ALP so <strong>in</strong>creases <strong>in</strong> ALP are highly suggestive of hepatobiliary disease. Serum GGT is often <strong>in</strong>creased to a<br />

greater extent that ALP. Serum ALT <strong>in</strong>creases to some extent <strong>in</strong> most cats with cholangitis. Because of<br />

<strong>in</strong>flammation and biliary stasis, bilirub<strong>in</strong> is <strong>in</strong>creased <strong>in</strong> most cats with cholangitis. <strong>Cat</strong>s with neutrophilic<br />

cholangitis or an obstruction of <strong>the</strong> extrahepatic biliary ducts often have higher total bilirub<strong>in</strong> than cats with<br />

lymphocytic cholangitis.<br />

Indicators of hepatic syn<strong>the</strong>tic function such as BUN, glucose and album<strong>in</strong> are usually normal <strong>in</strong> cats with<br />

cholangitis. Glucose may be decreased with fulm<strong>in</strong>ant hepatic failure <strong>in</strong> dogs. This is more common <strong>in</strong> severe<br />

forms of acute hepatitis. Blood urea nitrogen is commonly decreased <strong>in</strong> dogs with liver disease. This may be due<br />

to medullary washout (secondary to polydipsia), decreased prote<strong>in</strong> <strong>in</strong>take (<strong>in</strong>appetence, dietary restriction) or<br />

decreased syn<strong>the</strong>sis. Album<strong>in</strong> may be decreased due to <strong>in</strong>flammation (acute hepatitis) or severe diffuse<br />

parenchymal dysfunction (acute and chronic hepatitis). Decreased prote<strong>in</strong> <strong>in</strong>take and sequestration <strong>in</strong> ascetic<br />

fluid may contribute to decreases <strong>in</strong> album<strong>in</strong>. Globul<strong>in</strong>s are <strong>in</strong>creased <strong>in</strong> some cats with lymphocytic cholangitis<br />

secondary to <strong>in</strong>creased immunoglobul<strong>in</strong> production. Cholesterol may be <strong>in</strong>creased with hepatobiliary disease<br />

secondary to cholestasis (hepatitis, cholangitis) but may be decreased as a result of decreased functional mass<br />


Bile acids and ammonia are most often performed <strong>in</strong> dogs with hepatitis when <strong>the</strong>re is question as to liver function<br />

or, <strong>in</strong> <strong>the</strong> case of ammonia, monitor<strong>in</strong>g for evidence of hepatic encephalopathy. Bile acids will be <strong>in</strong>creased with<br />

loss of functional hepatocytes (impaired extraction) or cholestasis (impaired excretion). This test does not<br />

differentiate between types of hepatobiliary disease. Ammonia may be <strong>in</strong>creased with hepatobiliary disease as<br />

well. A decrease <strong>in</strong> functional hepatocytes decreases urea syn<strong>the</strong>sis and more ammonia is left <strong>in</strong> circulation. .<br />

The liver syn<strong>the</strong>sizes many coagulation prote<strong>in</strong>s <strong>in</strong>clud<strong>in</strong>g <strong>the</strong> procoagulants factor II, VII, IX and X and <strong>the</strong><br />

anticoagulants antithromb<strong>in</strong> III, prote<strong>in</strong> S and prote<strong>in</strong> C. In dogs and cats with liver disease, prothromb<strong>in</strong> time<br />

(PT), activated partial thromboplast<strong>in</strong> time (APTT) and prote<strong>in</strong>s <strong>in</strong>activated by vitam<strong>in</strong> K (PIVKA) may be<br />

<strong>in</strong>creased. This may be due to decreased syn<strong>the</strong>sis of coagulant or anticoagulant prote<strong>in</strong>s (hepatitis) or from<br />

failure of vitam<strong>in</strong> K to activate <strong>the</strong>se prote<strong>in</strong>s (cholangitis). For this reason, abnormalities <strong>in</strong> coagulation can occur<br />

with severe parenchymal or cholestatic diseases.<br />

Diagnostic Imag<strong>in</strong>g<br />

Radiographically, <strong>the</strong> liver may be variably sized with decreased abdom<strong>in</strong>al detail if ascites is present. Ultrasound<br />

is important <strong>in</strong> evaluat<strong>in</strong>g <strong>the</strong> hepatic parenchyma, <strong>the</strong> biliary tract, <strong>the</strong> gall bladder and additional abdom<strong>in</strong>al<br />

organs (<strong>in</strong>test<strong>in</strong>al tract, pancreas, lymph nodes, etc) to identify predispos<strong>in</strong>g or concurrent diseases. Ultrasound<br />

may reveal fluid and normal, nodular or heterogenous hepatic echotexture. If cirrhosis is present (chronic<br />

hepatitis) <strong>the</strong> surface of <strong>the</strong> liver may be irregular. Extrahepatic bile ducts may be mildly to moderately dilated<br />

with cholangitis <strong>in</strong> cats. In cases of concurrent extrahepatic biliary duct obstruction (EHBDO) extra- and, <strong>in</strong> more<br />

chronic cases, <strong>in</strong>trahepatic ducts may be dilated. The cause of <strong>the</strong> obstruction may or may not be visualized.<br />

The gall bladder wall may be normal or thickened with cholangitis. Choleliths are uncommon <strong>in</strong> cats but may<br />

cause EHBDO. Acquired portosystemic shunts, typical seen as aberrant vessels <strong>in</strong> proximity to <strong>the</strong> kidneys, are<br />

seen <strong>in</strong> some cases of chronic hepatitis when extensive fibrosis has led to portal hypertension. Ultrasound can<br />

also be utilized to obta<strong>in</strong> diagnostic samples for cytology, culture and histopathology.<br />

<strong>Liver</strong> Sampl<strong>in</strong>g<br />

Aspirates of <strong>the</strong> liver parenchyma for cytology are not recommended for <strong>the</strong> diagnosis of <strong>in</strong>flammatory liver<br />

diseases of <strong>the</strong> dog and cat. Histology is also required to provide <strong>in</strong>formation about disease severity and to<br />

provide prognostic <strong>in</strong>formation such as degree of necrosis, <strong>the</strong> presence of nodular regeneration and amount and<br />

location of fibrosis. <strong>Liver</strong> biopsies can also be used to monitor treatment and progression of disease. Clott<strong>in</strong>g<br />

factor deficiencies may occur so a platelet count, PT and APTT or, alternatively, a PIVKA test should be<br />

performed with<strong>in</strong> 24 hours of <strong>the</strong> biopsy procedure. Biopsies require heavy sedation or general anes<strong>the</strong>sia and<br />

can be taken via <strong>the</strong> tru-cut method, a surgical wedge technique or utiliz<strong>in</strong>g laparoscopy. Tru-cut biopsies can be<br />

taken under ultrasound guidance or dur<strong>in</strong>g surgical laparotomy. There are three types of tru-cut <strong>in</strong>strumentation:<br />

manual, semi-automatic and those used with a biopsy gun. <strong>Liver</strong>s surrounded by effusion or that conta<strong>in</strong> more<br />

fibrous tissue are easier to biopsy with automated guns. There is concern about a report of vagally mediated<br />

shock <strong>in</strong> cats utiliz<strong>in</strong>g <strong>the</strong> biopsy guns. Semi-automatic tru-cuts are recommended <strong>in</strong> cats because <strong>the</strong>y are less<br />

likely to be associated with vagally mediated shock and are easier to handle than manual needles. A m<strong>in</strong>imum of<br />

3 good quality samples (1 to 2 cm each) from a 16 g needle should be taken. Wedge biopsies are taken at<br />

surgery or laparoscopically and are considered superior for more superficial lesions. Large p<strong>in</strong>ch biopsies can be<br />

taken dur<strong>in</strong>g laparoscopy but also limits sampl<strong>in</strong>g to superficial sites. Laparoscopy is also less <strong>in</strong>vasive than a<br />

laparotomy but requires specialized equipment. Quantification of copper and iron is rout<strong>in</strong>ely performed <strong>in</strong> cases<br />

of chronic hepatitis <strong>in</strong> dogs and wedge biopsies are preferred over tru-cut samples. Fresh or deparaff<strong>in</strong>ized<br />

samples can be used for copper and iron quantification.<br />

In cats, neutrophilic cholangitis is likely due to bacterial <strong>in</strong>fection of <strong>the</strong> biliary tree so cytology and culture of bile is<br />

recommended. Bile can be obta<strong>in</strong>ed via cholecentesis with ultrasound guidance or dur<strong>in</strong>g surgery. A<br />

contra<strong>in</strong>dication to cholecentesis is EHBDO due to possible rupture and subsequent bile peritonitis. Bile can also<br />

be manually expressed from <strong>the</strong> gall bladder <strong>in</strong>to <strong>the</strong> duodenum and collected at surgery. Cytology may reveal<br />

an <strong>in</strong>creased number of neutrophils and bacteria with neutrophilic cholangitis. Infection is rarely occurs with<br />

lymphocytic cholangitis but, if present, is likely secondary. Bacterial culture should be performed for aerobic and<br />

anaerobic bacteria and <strong>in</strong>clude a sensitivity to guide antibiotic <strong>the</strong>rapy.<br />

With hepatitis, <strong>the</strong>re is an <strong>in</strong>itial <strong>in</strong>sult that damages hepatocytes lead<strong>in</strong>g to apoptosis and necrosis. In most<br />

<strong>in</strong>stances <strong>in</strong>flammatory cells are <strong>the</strong>n recruited and, depend<strong>in</strong>g on <strong>the</strong> amount of damage to <strong>the</strong> structural<br />

framework of <strong>the</strong> liver, complete regeneration may occur. If extensive damage and cell death has occurred, focal

hepatocellular and ductular proliferation may result <strong>in</strong> nodular regeneration. As a result of chronic <strong>in</strong>flammation,<br />

fibrosis may occur. Cirrhosis also occurs as a result of this distortion of normal architecture and is def<strong>in</strong>ed by <strong>the</strong><br />

presence of non-functional regenerative nodules with<strong>in</strong> <strong>the</strong> parenchyma. In both forms of hepatitis <strong>in</strong>flammatory<br />

cells <strong>in</strong>clude neutrophils, lymphocytes and plasma cells. In acute hepatitis, neutrophils are more common<br />

whereas <strong>in</strong> chronic hepatitis lymphocytes and plasma cells are <strong>the</strong> predom<strong>in</strong>ant <strong>in</strong>flammatory cells. In copperassociated<br />

hepatitis, accumulated copper causes hepatocellular necrosis lead<strong>in</strong>g to <strong>in</strong>flammation, chronic<br />

hepatitis and, if untreated, cirrhosis. Normal hepatic copper levels are < 500 ppm. Damage occurs at levels ><br />

1,000 ppm. Bedl<strong>in</strong>gton terriers homozygous recessive for <strong>the</strong> defect <strong>in</strong> <strong>the</strong> COMMD1 gene may accumulate<br />

copper up to 6 years of age <strong>the</strong>n it decreases but levels may <strong>in</strong>crease up to 12,000 ppm. The diagnosis is made<br />

by repeated liver biopsies at 6 and 15 months. Unaffected dogs will be normal at 6 months. Heterozygotes will<br />

have <strong>in</strong>creased copper levels at 6 months that have decreased at 15 months. Affected homozygotes will be<br />

<strong>in</strong>creased at 6 months and even higher at 15 months. There is also a DNA test (VetGen®) available that<br />

identifies <strong>the</strong> COMMD1 deletion. In o<strong>the</strong>r breeds, copper levels are variable and a primary defect has not been<br />

identified.<br />

Histologic changes <strong>in</strong> neutrophilic cholangitis may be focal, multifocal or diffuse. Cholestasis is a common but<br />

non-specific f<strong>in</strong>d<strong>in</strong>g <strong>in</strong> all forms of cholangitis. Neutrophils are found <strong>in</strong> <strong>the</strong> lumen of <strong>the</strong> bile ducts early <strong>in</strong><br />

disease and may extend <strong>in</strong>to <strong>the</strong> ductular epi<strong>the</strong>lial cells. In acute cases edema and neutrophils are often found <strong>in</strong><br />

<strong>the</strong> portal regions. Neutrophils occasionally extend <strong>in</strong>to parenchyma and form microabscesses. In more chronic<br />

cases a mixed <strong>in</strong>flammatory cell <strong>in</strong>filtrate consist<strong>in</strong>g of neutrophils, lymphocytes, plasma cells and pigment-laden<br />

macrophages <strong>in</strong> <strong>the</strong> bile ducts, portal and periportal regions is found with variable amounts of fibrosis and bile<br />

duct proliferation. Fibrosis may be periportal or portal-to-portal (bridg<strong>in</strong>g). Involvement of <strong>the</strong> gall bladder can<br />

occur (neutrophilic cholecystitis) with <strong>in</strong>tralum<strong>in</strong>al and <strong>in</strong>tramural neutrophils early on followed by a mixed<br />

<strong>in</strong>flammatory cell <strong>in</strong>filtrate <strong>in</strong> more chronic cases.<br />

In lymphocytic cholangitis small lymphocytes are found <strong>in</strong> <strong>the</strong> biliary epi<strong>the</strong>lium and around <strong>the</strong> bile ducts <strong>in</strong> <strong>the</strong><br />

portal areas. Plasma cells and eos<strong>in</strong>ophils may also be found <strong>in</strong> vary<strong>in</strong>g amounts. Bile duct proliferation occurs<br />

<strong>in</strong> more chronic cases. Fibrosis is variable and may be periportal or portal-to-portal. Scleros<strong>in</strong>g cholangitis is a<br />

term used when fibrosis surrounds bile ducts. Lymphocytic cholangitis may be difficult to differentiate from small<br />

cell lymphosarcoma <strong>in</strong> <strong>the</strong> liver. Involvement of <strong>the</strong> gall bladder can also occur with lymphocytic cholangitis<br />

(lymphoplasmacellular cholecystitis) <strong>in</strong> which mural lymphocytes and plasma cells are found that may form<br />

aggregates <strong>in</strong> <strong>the</strong> gall bladder wall.<br />

Treatment<br />

A detailed discussion of <strong>the</strong> treatment of hepatic encephalopathy will not be provided here but some of <strong>the</strong><br />

<strong>the</strong>rapeutics for <strong>in</strong>flammatory liver disease also addresses hepatic encephalopathy<br />

Dietary modifications are typically made for treatment of hepatic encephalopathy (dog, cat), elevated hepatic<br />

copper (dog) and portal hypertension (dog, cat). Recommendations depend upon cl<strong>in</strong>ical presentation but diets<br />

with lower quantities of higher quality prote<strong>in</strong>, <strong>in</strong>creased digestible carbohydrates and lower sodium are utilized.<br />

Low prote<strong>in</strong> will decrease <strong>the</strong> amount of ammonia produced <strong>in</strong> <strong>the</strong> <strong>in</strong>test<strong>in</strong>al tract and <strong>in</strong>creas<strong>in</strong>g <strong>the</strong> quality allows<br />

for cont<strong>in</strong>ued cell repair. Soluble carbohydrates are metabolized by colonic bacteria allow<strong>in</strong>g for <strong>in</strong>creases <strong>in</strong><br />

branched cha<strong>in</strong> am<strong>in</strong>o acids that trap ammonia with<strong>in</strong> <strong>the</strong> colon so it cannot be absorbed. Soluble fiber also<br />

<strong>in</strong>creases fecal mass and stimulates evacuation. Sodium restriction may be helpful with ascites due to portal<br />

hypertension. These diets may also have <strong>in</strong>creased z<strong>in</strong>c and lower copper levels to decrease copper<br />

accumulation. There may be <strong>in</strong>creased amounts of <strong>the</strong> antioxidants vitam<strong>in</strong>s C and E. Anorectic cats with<br />

cholangitis should be supplemented with arg<strong>in</strong><strong>in</strong>e and taur<strong>in</strong>e as well.<br />

Hepatitis is rarely due to a bacterial <strong>in</strong>fection so antibiotics are not recommended. An exception to this would be<br />

<strong>in</strong>fection with Leptospira spp.. Antibiotics are occasionally used <strong>in</strong> cases of fulm<strong>in</strong>ant acute hepatitis when <strong>the</strong>re<br />

is concern about <strong>the</strong> liver’s ability to combat <strong>in</strong>fection but this is unlikely because of <strong>the</strong> reserve capacity of <strong>the</strong><br />

liver. Because neutrophilic cholangitis is usually bacterial <strong>in</strong> orig<strong>in</strong>, antibiotics are a cornerstone to treatment of<br />

this disease and should be based on culture and sensitivity. This underscores <strong>the</strong> importance of obta<strong>in</strong><strong>in</strong>g bile for<br />

culture. Infections should be treated for 4 to 6 weeks. Initial <strong>the</strong>rapy with an antibiotic that covers enteric gram<br />

negatives and anaerobes may be adm<strong>in</strong>istered while await<strong>in</strong>g results of <strong>the</strong> culture and sensitivity.

Some bile acids are more hydrophilic than o<strong>the</strong>rs. Less hydrophilic (more hydrophobic or lipophilic) bile acids are<br />

more toxic and <strong>in</strong>duce cellular apoptosis and alter mitochondrial membrane permeability <strong>in</strong>creas<strong>in</strong>g free radical<br />

production and oxidative damage. Ursodeoxycholic acid (UDA) also <strong>in</strong>creases glutathione and metallothione<strong>in</strong> <strong>in</strong><br />

hepatocytes that help reduce oxidative damage. Ursodeoxycholic acid is a natural hydrophilic bile acid that<br />

<strong>in</strong>creases <strong>the</strong> bile acid pool which dilutes out more harmful bile acids and <strong>in</strong>duces choloresis. This improves bile<br />

flow so <strong>the</strong>re is less contact of potentially toxic bile acids with cell membranes thus reduc<strong>in</strong>g oxidative damage to<br />

cells. Ursodeoxycholic acid is commonly adm<strong>in</strong>istered to dogs with acute and chronic hepatitis as well as cats<br />

with cholangitis. In acute hepatitis and suppurative cholangitis, UDA may be given for 2 weeks past resolution of<br />

disease. In chronic hepatitis and cholangitis UDA may be given life-long.<br />

Glucocorticoids are not adm<strong>in</strong>istered <strong>in</strong> cases of acute hepatitis because most dogs respond well to supportive<br />

care and <strong>in</strong> rare cases <strong>in</strong> which <strong>in</strong>fection is <strong>in</strong>volved <strong>the</strong>y would be contra<strong>in</strong>dicated. The use of glucocorticoids is<br />

common with chronic hepatitis but is reserved for dogs with <strong>in</strong>flammatory lesions. Reasons for this were<br />

previously discussed under etiology. There is also evidence that glucocorticoids <strong>in</strong>crease quality of life and<br />

survival times <strong>in</strong> dogs with chronic hepatitis. Glucocorticoids are not typically adm<strong>in</strong>istered <strong>in</strong> cases of<br />

neutrophilic cholangitis due to <strong>the</strong> likelihood of an underly<strong>in</strong>g bacterial <strong>in</strong>fection. An exception would be <strong>the</strong> use of<br />

short course (1 to 3 days) anti-<strong>in</strong>flammatory doses given to decrease <strong>in</strong>flammation of <strong>the</strong> biliary tree and <strong>in</strong>crease<br />

bile flow. In lymphocytic cholangitis <strong>the</strong>re appears to be preponderance of CD3+ T cells and <strong>in</strong>creased MHC II<br />

expression <strong>in</strong> <strong>the</strong> portal regions. MHC II expression is also found on bile duct epi<strong>the</strong>lial and Kupffer cells. This<br />

suggests an immune-mediated mechanism for disease and is <strong>the</strong> primary reason for use of glucocorticoids <strong>in</strong> cats<br />

with this disease. The use of glucocorticoids is controversial. In cats with signs of active <strong>in</strong>flammation with<strong>in</strong> <strong>the</strong>ir<br />

livers (lymphocytes, plasma cells), glucocorticoids may control <strong>in</strong>flammation and prevent progression of <strong>the</strong><br />

disease.<br />

The primary sources of free radicals <strong>in</strong> <strong>the</strong> liver are <strong>the</strong> mitochondria <strong>in</strong> <strong>the</strong> hepatocytes, cytochrome P450<br />

enzyme systems and Kupffer cells that have been activated by endotox<strong>in</strong>s. Free radicals take up electrons from<br />

neighbor<strong>in</strong>g molecules caus<strong>in</strong>g oxidative damage to lipids, prote<strong>in</strong>s and DNA. Glutathione (GSH) peroxidase and<br />

superoxide dismutase (SOD) are normal cellular defenses. S-adenylmethionone (SAMe) is natural metabolite<br />

found <strong>in</strong> hepatocytes. It is a precursor for cyste<strong>in</strong>e which is one of <strong>the</strong> am<strong>in</strong>o acids that makes up GSH. SAMe is<br />

also a methyl donor for methylation reactions that are important <strong>in</strong> normal liver function. SAMe is most commonly<br />

given to dogs and cats with liver disease that are at a risk of oxidative damage. Silymar<strong>in</strong> (silib<strong>in</strong><strong>in</strong>) is <strong>the</strong> active<br />

<strong>in</strong>gredient from <strong>the</strong> milk thistle fruit and <strong>in</strong>creases SOD. Silymar<strong>in</strong> and SAMe have been shown to be effective <strong>in</strong><br />

reduc<strong>in</strong>g oxidative damage <strong>in</strong> dogs and humans with mushroom (Amanita phalloides) and acetam<strong>in</strong>ophen toxicity.<br />

Vitam<strong>in</strong> E is a fat soluble vitam<strong>in</strong> that decreases membrane peroxidation and free radical production. There are<br />

no studies support<strong>in</strong>g or refut<strong>in</strong>g its use <strong>in</strong> dogs and cats with liver disease. Because it is fat soluble, large doses<br />

may <strong>in</strong>terfere with <strong>the</strong> absorption of o<strong>the</strong>r fat soluble vitam<strong>in</strong>s such as vitam<strong>in</strong> K. For this reason it is not<br />

recommended <strong>in</strong> liver diseases <strong>in</strong> which vitam<strong>in</strong> K deficiency (severe cholestasis) is a concern.<br />

Inflammation and damage to hepatocytes results <strong>in</strong> fibrosis. Colchic<strong>in</strong>e is believed to stimulate collagenase which<br />

should break down collagen. There is no proven benefit <strong>in</strong> man or animals regard<strong>in</strong>g efficacy.<br />

Chelation <strong>the</strong>rapy is most often used <strong>in</strong> dogs with primarily centrilobular or heavy copper sta<strong>in</strong><strong>in</strong>g or <strong>in</strong> dogs with<br />

quantitative copper levels > 1500 ppm. Penicillam<strong>in</strong>e and trientene are chelators used to mobilize copper from<br />

hepatocytes <strong>in</strong>to circulation where it is excreted <strong>in</strong> <strong>the</strong> ur<strong>in</strong>e. Intest<strong>in</strong>al side effects can occur and <strong>the</strong>y are<br />

teratogenic. There has been more experience with penicillam<strong>in</strong>e as a chelator <strong>in</strong> dogs but trientene has been<br />

used and is effective. Follow-up biopsies at 6 month <strong>in</strong>tervals are recommended to obta<strong>in</strong> hepatic copper levels <<br />

500 ppm. Affected Bedl<strong>in</strong>gtons should be on low dose chelation <strong>the</strong>rapy life-long. Some dogs with copper<br />

accumulation can be managed without chelators utiliz<strong>in</strong>g z<strong>in</strong>c and low copper diets long term. Z<strong>in</strong>c <strong>in</strong>creases <strong>the</strong><br />

production of metallothione<strong>in</strong> <strong>in</strong> <strong>in</strong>test<strong>in</strong>al epi<strong>the</strong>lial cells. Metallothione<strong>in</strong> b<strong>in</strong>ds dietary copper and it is lost as <strong>the</strong><br />

<strong>in</strong>test<strong>in</strong>al epi<strong>the</strong>lial cells are sloughed. Side effects are <strong>in</strong>test<strong>in</strong>al upset and hemolysis (at higher serum<br />

concentrations).<br />

Extensive fibrosis and cirrhosis leads to portal hypertension and ascites. The ascites leads to a decrease <strong>in</strong><br />

<strong>in</strong>travascular volume and activation of <strong>the</strong> ren<strong>in</strong>-angiotens<strong>in</strong>-aldosterone system (RAAS) caus<strong>in</strong>g sodium<br />

retention (with water) and potassium loss. This exacerbates portal hypertension. Aldosterone antagonists, such<br />

as spir<strong>in</strong>olactone, are preferred because <strong>the</strong>y antagonize <strong>the</strong> effects of aldosterone. Loop and thiazide diuretics<br />

cause <strong>in</strong>travascular volume depletion and fur<strong>the</strong>r potassium loss which activate <strong>the</strong> RAAS. Unfortunately<br />

spir<strong>in</strong>olactone has weak diuretic effects and it is often necessary to add ano<strong>the</strong>r more potent diuretic to control<br />


Cholecystectomy is performed <strong>in</strong> <strong>in</strong>stances of severe gall bladder disease <strong>in</strong> cats with cholangitis.<br />

Cholecystoduodenostomy is performed <strong>in</strong> cases of common bile duct obstruction to ma<strong>in</strong>ta<strong>in</strong> bile flow from <strong>the</strong><br />

liver to <strong>the</strong> <strong>in</strong>test<strong>in</strong>al tract. There is a high perioperative mortality rate for cats that undergo biliary diversion<br />

surgery, particularly when <strong>the</strong> obstruction is due to neoplasia. Biliary stents have been placed <strong>in</strong> a small number<br />

of cats with extrahepatic biliary tract obstruction due to pancreatitis but is also associated with a high<br />

perioperative mortality rate and poor long term survival.<br />

Prognosis<br />

The prognosis is dependent upon <strong>the</strong> underly<strong>in</strong>g cause of hepatitis. In general acute hepatitis carries a better<br />

prognosis than chronic hepatitis. If, however, <strong>the</strong>re is extensive damage to <strong>the</strong> liver complications such as DIC,<br />

multi-organ failure and death may occur. With persistent <strong>in</strong>flammation acute hepatitis may develop <strong>in</strong>to chronic<br />

hepatitis. Follow-up biopsies 4 to 6 weeks after resolution of disease (cl<strong>in</strong>ical signs, laboratory data) can identify<br />

this. The prognosis for chronic hepatitis is more guarded. <strong>Dog</strong>s with chronic hepatitis can live for days to years<br />

with complete resolution <strong>in</strong> some dogs. Chronic hepatitis requires treatment until histologic recovery is noted<br />

which is lifelong <strong>in</strong> most cases. Fibrosis and cirrhosis are irreversible so dogs with extensive fibrosis or cirrhosis<br />

will not have resolution of <strong>the</strong>ir disease. Cirrhosis is a poor prognostic <strong>in</strong>dicator.<br />

<strong>Cat</strong>s with neutrophilic cholangitis have a good prognosis with treatment. In cases of lymphocytic cholangitis <strong>the</strong><br />

prognosis depends on <strong>the</strong> extent of fibrosis present. <strong>Cat</strong>s with more extensive fibrosis, portal hypertension and<br />

ascites carry a more guarded prognosis.<br />

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