Inflammatory liver disease in the cat (Proceedings)

Inflammatory liver disease is second only to hepatic lipidosis as a cause of hepatobiliary disease in cats in the United States. Inflammatory liver diseases have been traditionally classified by their cellular infiltrate and pattern of distribution. The inflammatory cells involved are primarily neutrophils, lymphocytes and plasma cells which led to the descriptors neutrophilic, lymphocytic or lymphoplasmacytic. The cells may be found within the bile ducts, the epithelial cells lining the bile ducts, the hepatic parenchyma, and the gall bladder. These patterns of distribution have led to the use of the terms cholangitis, cholangiohepatitis and cholecystitis. Current classification schemes developed by the WSAVA Liver Standardization Group have led to the use of neutrophilic cholangitis and lymphocytic cholangitis to define the two major forms of inflammatory liver disease seen in the cat. Cholangitis less commonly consists of a mixed cellular infiltrate including neutrophils, lymphocytes, plasma cells, and occasional eosinophils. This mixed cholangitis is believed to be a more chronic form of neutrophilic cholangitis.

Signalment

There does not appear to be any breed or sex predisposition in the development of inflammatory liver disease 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

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 idiopathic. 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

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 non-specific 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

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 decreased red blood cell survival, chronic disease or chronic intestinal bleeding. Liver enzyme elevations are common.

Serum alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (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. Alanine aminotransferase (ALT) is a hepatocellular enzyme that increases in the face of hepatocellular damage which occurs to some extent in most cats with cholangitis. Bilirubin is a normal product of hemoglobin and myoglobin catabolism that is eliminated in the bile. 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. Bile acids are synthesized in the liver to aid in the digestion and absorption of fats in the intestinal tract. They are excreted in the bile and a large fraction is reabsorbed in the ileum then removed from circulation by the liver. When evaluating bile acids a sample is obtained after a 12 hour fast followed by a test meal and a second post-prandial sample obtained at 2 hours. Post-prandial bile acids are the most sensitive test of liver function in cats with cholestatic disease. This means that bile acids may be abnormal before ALP, GGT and ALT in some cats with cholangitis. When evaluating for hepatobiliary disease, testing bile acids is not necessary in the presence of increased bilirubin because both test hepatic uptake and biliary excretion so if the bilirubin is increased the bile acids will be increased as well. Other indicators of hepatic synthetic function such as BUN, glucose and albumin are usually normal. Cholesterol may be elevated with biliary obstruction. Globulins are increased in some cats with lymphocytic cholangitis secondary to increased immunoglobulin production. Cholestasis leads to impaired absorption of fat soluble vitamins including vitamin K. Prolonged anorexia, antibiotic use, small intestinal disease or severe hepatic disease may also contribute to low vitamin K. Vitamin K is important for the activation of many pro- and anti-coagulant factors such as factors II, VII, IX, X, protein C and protein S. Spontaneous bleeding is very rare but hemorrhage secondary to trauma during procedures such as liver biopsy and feeding tube placement can occur.

Bilirubinuria occurs in the presence of hyperbilirubinemia because cats, unlike dogs, are not able to conjugate bilirubin in their kidneys. More recently a urine bile acids test has become available. The advantages are no venipuncture is required, no fasting is necessary and hemolysis and lipemia will not affect this test. Urine is collected 4 to 8 hours after a meal. The bile acids are measured in relation to creatinine. Normal in the cats is < 4.4 µmol/mg. Urine bile acids have been shown to correlate well with serum bile acids and are helpful in identifying cats with hepatobiliary disease.

Diagnostic Imaging

Abdominal radiographs may reveal hepatomegaly or decreased abdominal detail secondary to ascites. 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. The hepatic parenchyma may be normal or have an increased or mixed echogenicity largely dependent on the amount of fibrosis present. Extrahepatic bile ducts may be mildly to moderately dilated with cholangitis. In cases of 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. Choleliths are uncommon in cats but may cause EHBDO. Ultrasound can also be utilized to obtain diagnostic samples for cytology, culture and histopathology.

Liver Sampling

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.

Aspirates of the liver parenchyma for cytology are not recommended for the diagnosis of cholangitis because in addition to identifying the inflammatory cell type, evaluating the location of these cells and presence and extent of fibrosis is necessary to adequately diagnose, treat and provide prognostic information regarding the disease. Histology of the liver is required to differentiate neutrophilic, lymphocytic and mixed inflammatory cell cholangitis. Clotting factor deficiencies are common so a prothrombin time (PT) and activated partial thromboplastin time (APTT) or, alternatively, a PIVKA test (proteins induced by vitamin K absence) in addition to a platelet count should be performed within 24 hours of the biopsy procedure. The PIVKA has been shown to be more sensitive in detecting clinical bleeding than the PT or APTT in clinically ill cats. If the PT or APTT are greater than twice normal or the PIVKA's are increased then 0.5 to 1.5 mg/kg vitamin K1 (phytonadione) should be given SQ or IM q 12 hours for 36 hours prior to biopsy. It is important to remember that normal clotting times do not preclude hemorrhage. Biopsies require 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. Tru-cut needles have an inner sharp needle with an indentation proximal to the needle point that is inserted into the liver. The liver then fills the indentation and an outer needle with a cutting edge moves over the inner needle effectively slicing off a piece of liver. There are three types: 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 reports of a high percentage 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 and are only 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.

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

Antibiotics - 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.

Ursodeoxycholic acid – some bile acids are more hydrophilic than others. Less hydrophilic bile acids are more toxic and induce cellular apoptosis and alter mitochondrial membrane permeability increasing free radical production and oxidative damage. Ursodeoxycholic acid also increases glutathione and metallothionein in hepatocytes that help reduce oxidative damage. Ursodeoxycholic acid is a synthetic 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 cats with all forms of inflammatory cholangitis/cholangiohepatitis. The dose is 10 to 15 mg/kg once daily or divided twice daily. In neutrophilic cholangitis it may be given for 4 to 6 weeks. In some cats with lymphocytic cholangitis it is given life long.

Glucocorticoids – 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. Doses of 2 – 4 mg/kg/day are given for 2 to 4 weeks then tapered. Affected cats may require intermittent or lifelong treatment.

Antioxidants – the primary sources of free radicals in the liver are the mitochondria and cytochrome P450 enzyme systems within the hepatocytes as well as 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. The antioxidants used most commonly in cats with biliary disease are S-adenylmethionine (SAMe), sylimarin and vitamin E. S-adenylmethionone is natural metabolite found in hepatocytes and 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. SAMe caplets are enteric coated so should not be split and food interferes with absorption so give on an empty stomach. The dose is approximately 20 mg/kg/day. Silymarin is the active ingredient from the milk thistle fruit. The active ingredient is sylibin which decreases inflammation, decreases lipid peroxidation, scavenges free radicals and decreases free radical production. If using milk thistle make sure it is 70 – 80% silymarin. The dose is unknown but 50 – 100 mg/day/cat divided has been recommended. Nutramaxx® has a product Denamarin® which contains a much more potent form of silybin, siliphos, so it is given at a much lower dose. Silymarin and SAMe have been shown to be effective in reducing oxidative damage in dogs with mushroom (Amanita phalloides) and acetaminophen toxicity. Vitamin E (a-tocopherol) has anti-inflammatory properties and protects cell membrane phospholipids from lipid peroxidation. Doses of 10 to 15 IU/kg/day are recommended.

Surgery - cholecystectomy is performed in instances of severe gall bladder disease. 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 peri-operative mortality rate and poor long term survival.

Prognosis

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.

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