The icteric cat: diagnosis and treatment of common feline hepatopathies

Feline cholangiohepatitis syndrome (CCHS) and hepatic lipidosis are 2 of the most common feline hepatopathies.1,2 Signs of both conditions are mostly varied and nonspecific.1 In these conditions, icterus results from decreased clearance of bilirubin, diarrhea results from portal hypertension or cholestasis, and vomiting results from decreased toxin clearance or direct vagal stimulation.3

Hepatic encephalopathy (HE) occurs either from portosystemic shunting3 or is caused by hepatic lipidosis from amino acid imbalance. HE manifests as ptyalism, dullness, ataxia, and/or seizures.4 Polyuria/polydipsia may result from medullary washout (low urea), dehydration, or HE. Dysuria may be noted from ammonium biurate urolithiasis.5 Anesthesia intolerance may result from decreased hepatic metabolism of GABAergic drugs (benzodiazepines). Gastrointestinal bleeding can be seen with portal hypertension or coagulopathy.

The minimum data base should include a complete blood count (CBC), chemistry profile, urinalysis, coagulation testing, and diagnostic imaging. Liver function testing (serum bile acids; ammonia level) is redundant with icterus. CBC may reveal target cells and/or acanthocytes caused by altered lipoprotein or cholesterol synthesis and transport. Leukocytosis and/or inflammatory leukogram may be present relative to primary pathology. Heinz bodies are common, with hepatic lipidosis as a result of oxidative stress and glutathione deficiency. Elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are seen with hepatic damage, and elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) are seen with cholestasis. Decreased synthetic function can result in hypoalbuminemia, hypocholesterolemia, hypoglycemia, decreased blood urea nitrogen, and hyperbilirubinemia. Hyperbilirubinuria precedes hyperbilirubinemia and can be an earlier indicator of decreased hepatic function in the cat. Urinalysis may also reveal ammonium biurate and/or bilirubin crystalluria, and lipid droplets are common with hepatic lipidosis.6

Subclinical coagulopathies are common, especially with cholestatic hepatopathies like hepatic lipidosis that result in decreased enterohepatic circulation and relative vitamin K deficiency.7 Abdominal radiographs may be useful to assess liver size or look for choleliths, but abdominal ultrasound is more sensitive to assess hepatic parenchyma, biliary tree, gall bladder, and adnexal structures.

Feline cholangiohepatitis syndrome

CCHS has been classified by the World Small Animal Veterinary Association Liver Standardization Project into 4 categories: neutrophilic cholangitis, lymphocytic (non-neutrophilic) cholangitis, destructive cholangitis, and chronic cholangitis associated with liver fluke infestation. CCHS can occur in cats of any age, often with vague signs, acute to chronic, including weight loss, anorexia or polyphagia, lethargy, vomiting, fever, jaundice, hepatomegaly, polydipsia, ptyalism, pallor, nonregenerative anemia, poikilocytosis, and elevated liver enzymes, with or without neutrophilic leukocytosis. It is often seen in conjunction with pancreatitis and enteritis, in which case the term triaditis is used.4

Neutrophilic CCHS commonly occurs in younger cats with more acute signs. Biliary/pancreatic inflammation is common, ie, triaditis. CBC reveals neutrophilia with or without left shift. Chemistry profile can reveal a moderate increase in ALT, AST, and GGT; variable increases in ALP and bilirubin; and normal cholesterol unless there is concurrent extrahepatic bile duct obstruction (EHBDO) or diabetes mellitus. Diagnostic imaging may reveal mineral densities, choleliths, regional ileus, sternal lymphadenopathy, biliary tree thickening, biliary sludge, and/or pancreatitis. Primary bacterial infection is common. E coli is the most common isolate, but many bacteria have been implicated.5 Bacteria can be seen on cytology more commonly than histopathology, so cytology of liver tissue imprint and bile may be helpful in addition to histopathology and cultures. Neutrophilic CCHS may transform into lymphocytic CCHS.

Lymphocytic CCHS most commonly occurs in middle-aged to older cats who have been ill more than several weeks and who usually have a predisposing condition such as inflammatory bowel disease, primary cholangitis, pancreatitis, EHBDO, cholelithiasis, cholecystitis, neoplasia, chronic extrahepatic or systemic bacterial infection, or chronic trematode infection. CBC reveals inconsistent anemia, poikilocytosis, and/or lymphocytosis. Chemistry profile and diagnostic imaging findings are similar to those with neutrophilic CCHS. Lymphocytic CCHS requires liver biopsy with histopathology for diagnosis. Samples reveal lymphocytic or lymphoplasmacytic inflammation around the portal triads with fibrous tissue deposition over time. Chronic disease can result in lymphoproliferation, which can evolve into lymphoma, or immune-mediated destruction of the bile ducts, which can cause complete biliary tree occlusion.6

Treatment of CCHS should center on management of the underlying concurrent disease if present. Broad-spectrum antimicrobial therapy should be given for 3 to 6 months for neutrophilic CCHS and until biopsies return and based on clinical signs for lymphocytic CCHS. Empiric antimicrobial therapy should include coverage for gram-negative and anaerobic bacteria. Biochemical abnormalities should normalize if disease and bacteria are eradicated. If there is failure to improve, the clinician should consider whether the underlying condition was adequately treated, whether there is chronic infection somewhere, whether there is transformation to lymphocytic CCHS, or whether there is concurrent hepatic lipidosis.7

Lymphocytic CCHS is often treated with prednisolone for immunosuppressive and anti-inflammatory effects, but full remission is rare with monotherapy. Concurrent metronidazole can be helpful to modulate cell-mediated immunity and decrease endotoxin. Chlorambucil may be effective in some cases. Methotrexate is used for biopsy-confirmed sclerosing cholangitis. It is important to maintain adequate nutrition to prevent secondary hepatic lipidosis. Fluid therapy should ensure supplementation of B vitamins and maintenance of normal serum potassium. Ursodeoxycholic acid should be given after extrahepatic biliary duct obstruction has been ruled out. Antioxidant therapy with vitamin E and/or SAMe (S-adenosylmethionine) should be implemented.8

CCHS can have a very long remission or cure with chronic medical management. The disorder commonly spontaneously cycles, and clinical flare-ups can occur. There are no long-term prospective studies on treatment efficacy. Death is most commonly due to biliary cirrhosis or progression to lymphoma or related to progression of underlying primary pathology (ie, enteropathy).

Hepatic lipidosis (fatty liver syndrome)

Hepatic lipidosis is an acquired cholestatic disorder resulting from excessive accumulation of triglycerides in hepatocytes (> 80%). It typically occurs secondary to another disease such as other hepatopathies (ie, cholangiohepatitis), pancreatitis, gastrointestinal disease (ie, irritable bowel disease), diabetes mellitus, respiratory disease (ie, asthma), septicemia, neoplasia (ie, lymphoma), renal/lower urinary disease, cardiomyopathy, hyperthyroidism, anemia, neurologic disease, and/or trauma.

Clinical signs are varied and can include vomiting, anorexia, weakness and/or cervical ventroflexion, history of weight loss, icterus, hepatic encephalopathy, bleeding, diarrhea, hepatomegaly, dehydration, and/or pallor. CBC may reveal poikilocytosis (63%), nonregenerative anemia (22%), Heinz bodies, acute hemolysis, hyperbilirubinemia (95%), elevated ALP (80%), ALT (72%), AST (89%) with normal GGT (if idiopathic/no primary pathology), hypokalemia (30%), hypophosphatemia (17%), hypomagnesemia, prolonged clotting times (25% to 60%), elevated bile acids, hyperammonemia, or elevated serum β-hydroxybutyric acid.9 More than 80% of hepatocytes are vacuolated and lipid filled on cytology. Cytology is important to rule out lymphoma and decrease the odds of significant neutrophilic inflammation, but histopathology may be needed for definitive diagnosis and an optimal long-term treatment plan.

Cats have a unique metabolism, which informs us of certain nutritional supplements in the treatment of hepatic lipidosis. Cats continue to use protein for the production of energy even with low protein availability. They depend on dietary intake of arginine, taurine, methionine, and cysteine; are adapted for a low-carbohydrate diet; have an increased requirement for dietary B vitamins compared with other mammals; and require vitamins A and D from animal tissues. Taurine stabilizes membranes and can reduce hepatic lipid content. Carnitine is an essential cofactor of fatty acid metabolism, urea cycle, and GSH synthesis. Vitamin E protects against oxidative damage. SAMe, a carnitine and glutathione precursor, protects the liver against oxidant injury and is an important cofactor in many reactions. Vitamin B deficiencies may be one of the causes and consequences of hepatic lipidosis, as they are necessary for the synthesis of carnitine and SAMe.10

The cornerstone of treatment for hepatic lipidosis is nutrition. Once the patient is stable, feeding tube placement should be considered. It is important to monitor for refeeding syndrome, which occurs from insulin release and intracellular shifting of electrolytes like potassium and phosphorus. Fluid therapy should be supplemented with potassium, magnesium, and phosphorus as indicated, and lactated or acetated solutions avoided. Other therapies should include vitamin K, vitamin E, vitamin B complex, vitamin B12, L-carnitine, SAMe (or N-acetyl cysteine for acute crisis), taurine, and omega fatty acids.

Negative prognostic findings include older age, dullness, weakness, ptyalism, hypoproteinemia, hypoalbuminemia, elevated creatine kinase, hypocholesterolemia, hepatic failure at presentation, anemia, hypokalemia, and lack of aggressive nutritional and supportive care. Survival ranges from 50% to 85%. Decrease in serum β-hydroxybutyrate during hospitalization is associated with survival.9 Hepatic lipidosis is considered frequently fatal without intervention and treatment.

Diagnosis

Hepatic sampling is important for diagnosis. Ultrasound-guided liver aspirate and cytology can reveal lipidosis, vacuolar change, or diffuse hepatic neoplasia like lymphoma. Bleeding can be seen from coagulopathy, especially with cholestasis secondary to hepatic lipidosis. Stabilization of the patient and treatment with 2 to 3 doses of vitamin K1 is recommended prior to liver aspiration.7

Cholangiohepatitis cannot be diagnosed with liver cytology and requires liver biopsy and histopathology. Ultrasound-guided biopsy has approximately 50% discordance compared with surgical and laparoscopic biopsies, according to the results of one study, and may not give enough tissue to reveal accurate diagnosis or quantitate copper. Surgical biopsies or laparoscopy allow for obtaining large biopsies and assessment of other organs. Liver samples should be submitted for histopathology, cultures (aerobic/anaerobic) with or without quantitative copper analysis, special stains, immunohistochemistry, and/or molecular testing as indicated.10

Kelly Cairns, DVM, MS, DACVIM (SAIM), is vice president of medical excellence and education at Thrive Pet Healthcare, with over 20 years of veterinary experience. A graduate of Colorado State University’s veterinary program in Fort Collins, she completed a small animal rotating internship at Cornell University in Ithaca, New York, and an internal medicine residency at The Ohio State University in Columbus, earning board certification as a small animal internal medicine specialist. Cairns is an adjunct faculty member at Lincoln Memorial University College of Veterinary Medicine in Harrogate, Tennessee, and serves on several boards, including the Chicago Veterinary Medical Association. A dedicated member of the Feline Veterinary Medical Association for 20 years, she has specialized in feline internal medicine, building a subpractice that drew patients from across the US. Cairns is passionate about advancing veterinary education and supporting the profession’s well-being.

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