The work-up of cats with liver disease includes a comprehensive history and physical examination, followed by a complete blood count, serum chemistry panel, urinalysis, abdominal imaging via radiography and/or ultrasound, and nuclear scintigraphy when indicated. Additional liver function tests such as a coagulogram and bile acids test can be done to evaluate hepatocellular function further, although bile acid testing is not warranted in hyperbilirubinaemic animals. Culture of bile is warranted in cats with cholangitis. Finally, hepatic aspiration cytology or biopsy should be performed to attain a definitive diagnosis and prognosis for the animal.

Feline Idiopathic Hepatic Lipidosis

In North America, hepatic lipidosis (50%), inflammatory liver disease (25%), malignant lymphoma (5%) and carcinoma (4%) are the major causes of feline liver disease. Less common feline hepatic disorders include portal vascular anomalies, necrosis, bile duct obstruction and cysts. Feline idiopathic hepatic lipidosis (IHL) is a well recognised syndrome characterised by accumulation of excess triglycerides in hepatocytes with resulting cholestasis and hepatic dysfunction. Many cats with IHL are obese and often present with a history of prolonged anorexia after a stressful event. The aetiopathogenesis of this syndrome is poorly understood, but is created by an imbalance between mobilisation of peripheral fat stores to the liver and hepatic utilisation of fatty acids for energy and dispersal of triglycerides as lipoproteins. The prognosis for this life-threatening disorder has improved dramatically during the past several years, and >85% of afflicted cats can recover following early diagnosis and aggressive supportive care.

Diagnosis

The majority of cats with IHL have an underlying disorder (renal disease, neoplasia, pancreatitis, cardiac disease, small intestinal disease) precipitating the IHL. A history of overconditioning, inappetence for 5-7 days, weight loss and demonstration of variable gastrointestinal signs prevail. On presentation, most cats are jaundiced and have non-painful, smoothly contoured hepatomegaly. Less common findings include severe weakness with ventroflexion of the head and neck and ptyalism. Common haematological findings include poikilocytosis and a predisposition to Heinz body formation. Increased liver enzyme activities, including alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and high total bilirubin (there is no diagnostic value to the ratio of unconjugated to conjugated fractions) are commonly found. Importantly, the serum gamma-glutamyl transferase (GGT) activity is normal or minimally increased in contrast to cats with underlying necroinflammatory liver disease (e.g., cholangitis). Hypokalaemia and hypophosphataemia are important causes of morbidity and mortality, and can contribute to haemolysis, muscle weakness and ventroflexion of the head and neck. Approximately 50% of cats develop a coagulopathy, with fewer demonstrating spontaneous bleeding. Determination of serum bile acid concentrations offers no diagnostic value in IHL cats as these animals are universally jaundiced. Concentrations of serum vitamin B12 (cobalamin) should be evaluated in cats with IHL, as deficiencies have been well documented.

Abdominal radiography commonly reveals hepatomegaly although this imaging modality is of less diagnostic value compared to abdominal ultrasonography (US). Abdominal US usually reveals an enlarged liver with a hyperechoic hepatic parenchyma. There are usually no changes associated with the gall bladder, and abdominal effusions are uncommon. Careful evaluation of the pancreas and intestinal tract is warranted in all cats because of the high association with pancreatitis and inflammatory bowel disease. Hepatic needle aspiration under ultrasound guidance can be used to confirm the diagnosis of severe diffuse hepatic triglyceride accumulation. A liver biopsy is performed when the cat fails to respond to medical and nutritional support, or when the clinicopathological features and US features are not consistent with IHL.

Treatment

Initial management should be directed toward correcting complications such as dehydration, electrolyte abnormalities, hepatic encephalopathy and infection. Any underlying causes for the lipidosis (diabetes mellitus, pancreatitis, neoplasia, cardiac disease, etc.) should be identified and treated whenever possible. Provision of adequate daily energy intake is the cornerstone of successful medical management of cats with IHL. An adequate supply of energy is needed to:

 Prevent catabolism of amino acids for energy

 Inhibit peripheral lipolysis

 Avoid excessive energy consumption, which will promote hepatic triglyceride accumulation.

Enteral feeding devices (oesophagostomy or gastrostomy tubes) are indicated in cats with IHL to ensure provision of adequate calories. Most cats with IHL can be fed commercially available therapeutic or maintenance diets containing 25-40% fat (dry matter (DM)). Dietary protein should not be restricted unless the cat is showing signs of hepatic encephalopathy. The daily energy requirement for cats with IHL should initially be based on the cat's current bodyweight (if mildly to moderately obese). The amount fed is gradually increased in 25% increments; until the cat is being fed at its resting energy requirement (RER) (usually takes 5-7 days). A simple logarithmic formula that can be used to determine the cat's RER is 70 x BW (kg)^0.75. A linear formula can also be applied to cats that are heavier than 2kg [(BW (kg) x 30] + 70. Hypokalaemia is commonly found and was present in 19 of 66 cats (29%) with severe IHL. Hypokalaemia may develop due to inadequate potassium intake, vomiting, magnesium depletion and concurrent renal failure. Hypokalaemia was significantly related to non-survival in this group of cats, and it may prolong anorexia and exacerbate hepatic encephalopathy. Diets for cats with IHL should be potassium-replete (0.8-1.0% potassium on a DM basis), or potassium supplementation (2-6 mmol potassium gluconate per day) should be considered. Carnitine transports long chain fatty acids across the inner mitochondrial membrane into the mitochondrial matrix for β-oxidation. Carnitine also removes potentially toxic acyl groups from cells and equilibrates ratios of free CoA/acetyl-CoA between the mitochondria and cytoplasm. Centre and colleagues showed that diets supplemented with l-carnitine can safely facilitate rapid weight loss in privately owned obese cats. Current recommendations include supplementing cats with a dose of 250-500 mg L-carnitine/day. Additional dietary supplements that should be considered include vitamin B12 and S-adenosylmethionine.

Food aversion appears to be an important component of the anorexia of cats with hepatic lipidosis. Cats that refuse to eat a diet that they associate with nausea may continue to avoid that diet even after full recovery due to their association with the unpleasant sensation. One should therefore tube-feed these cats as soon as the diagnosis of IHL has been made, rather than offer several commercial diets that the cat can develop an aversion to. Cats should not be offered any food by mouth for approximately 10 days following placement of a feeding tube. Cats showing an interest to eat can then be presented with food. The prognosis for IHL is influenced to a large degree by the ability of the clinician or owner to meet the cat's caloric requirements aggressively via enteral feeding. The use of appetite stimulants can be attempted, but usually results in failure to meet the cat's caloric requirement and frustration for the owner and cat. Caution should be exercised with the use of anabolic steroids and diazepam, particularly in patients with liver disease, due to the potential for hepatotoxicity.

Feline Cholangitis

Inflammation centered on the biliary tree is a common form of hepatic disease, and appears to be the second most common form of liver disease after IHL. Histological classification of the term 'feline cholangitis/cholangiohepatitis' is controversial, with poor consensus amongst pathologists in the nomenclature used. Two major types of inflammatory liver disease were described in 1996 based on histological features; cholangiohepatitis (acute or suppurative and chronic or nonsuppurative) and lymphocytic portal hepatitis. A new simplified classification scheme was proposed by the WSAVA Liver Diseases and Pathology Standardization Research Group in 2002. Three distinct forms of cholangitis have been recognised in cats:

 Neutrophilic (referable to ascending bacterial infection but also rarely reported in protozoal infections)

 Lymphocytic (thought to be immune-mediated)

 Chronic cholangitis associated with infection by liver flukes (Amphimerus pseudofelineus, Platynosomum concinnum, etc.)

Neutrophilic (bacterial) cholangitis (historically referred to as acute cholangiohepatitis) is characterised by infiltration of large numbers of neutrophils into portal areas of the liver and into bile ducts. Disruption of the periportal limiting plate of the bile duct results in necrosis of hepatocytes adjacent to portal areas and infiltration of neutrophils into hepatic lobules. Neutrophilic cholangitis may begin as an ascending bacterial infection within the biliary tract; however, bacteria are only isolated in a few cases. Organisms include Bacteroides, Actinomyces, Escherichia coli, Clostridium and alpha-haemolytic Streptococcus. Neutrophilic cholangitis can be divided into two categories: acute and chronic. Their distinction histologically is based on the presence of increased plasma cells, lymphocytes with or without macrophages with the chronic phase.

Lymphocytic cholangitis is felt to represent a later stage of neutrophilic cholangitis, or may represent a separate disease entity. It is characterised by a moderate to marked infiltration of the portal areas by small lymphocytes with or without biliary hyperplasia, portal or periductal fibrosis, or bridging fibrosis. Diseases frequently associated with lymphocytic cholangitis include inflammatory bowel disease and pancreatitis; 83% of cats with cholangitis had concurrent inflammatory infiltrates in the duodenum and/or jejunum and 50% had pancreatic lesions. This association has lead to the use of the term 'triaditis' to describe affected cats. Inflammatory bowel disease may give rise to retrograde bacterial invasion of the common bile duct with resultant pancreatitis and cholangitis.

The new proposed histological classification scheme does not recognise portal lymphoplasmacytic inflammation in which infiltrates are confined to portal areas and not centered on or involving bile ducts as a specific subtype of cholangitis. Sparse lymphocytes and plasma cells may be found in the portal areas of healthy young cats, often in close association with bile ducts. Increased numbers of portal lymphocytes and plasma cells are commonly identified in portal areas of cats over 10 years of age, often in conjunction with extrahepatobiliary disorders. The new classification scheme also does not recognise the previous classification of 'lymphocytic portal hepatitis'.

Chronic cholangitis secondary to fluke infestation is characterised by severe ectasia of the bile ducts, mild to severe hyperplasia of the biliary epithelium, severe concentric periductal fibrosis and the occasional presence of adult flukes and/or operculate eggs within bile duct lumina.

Clinical Signs

Clinical signs associated with inflammatory liver diseases are variable and nonspecific and are frequently similar to those associated with IHL. Partial or complete anorexia is the most common, and sometimes the only, clinical sign. Other less frequently observed clinical signs include weight loss, lethargy, vomiting, diarrhoea and fever. Cats with neutrophilic cholangitis tend to be younger (mean age 5.7 years) than cats with lymphocytic cholangitis (mean age 9.0 years) or IHL (mean age 6.2 years). Male cats are more frequently affected with neutrophilic cholangitis. Cats with neutrophilic cholangitis are more acutely and severely ill than cats with most other types of liver disease. Prominent clinical signs in neutrophilic cholangitis include fever, lethargy and dehydration.

Laboratory Evaluation

Haematological and biochemical testing are essential to establish a diagnosis of liver disease. Although there are trends that differentiate inflammatory liver diseases from IHL and hepatic neoplasia, liver cytology or histopathology is essential to establish a definitive diagnosis. Laboratory changes typically seen with neutrophilic cholangitis include mild to moderate neutrophilia and left shift, normal to slight increase in serum bilirubin and serum ALP and a substantial increase in ALT. This profile tends to differentiate neutrophilic cholangitis from lymphocytic cholangitis, hepatic lipidosis and hepatic neoplasia. Laboratory changes typical of lymphocytic cholangitis include substantial increases in serum bilirubin, ALP and ALT. Other associated changes may include mild nonregenerative anaemia, hyperglobulinaemia, lymphocytosis and hyperglycaemia. When cats with inflammatory liver diseases are compared to IHL, IHL cases tend to have higher total bilirubin concentrations, and higher ALT and serum ALP without a corresponding increase in serum GGT activity. Hyperthyroid cats frequently have changes in ALT and serum ALP that may be indistinguishable from those associated with inflammatory liver diseases. The increased enzyme concentrations normalise with treatment of hyperthyroidism.

Liver Imaging

Abdominal ultrasonography is often helpful in evaluation of extrahepatic disorders associated with cholangitis. Most cats with neutrophilic or lymphocytic cholangitis or with lymphocytic portal hepatitis have variable or no detectable alterations in the echogenicity of the hepatic parenchyma. Bile duct abnormalities in cats with cholangitis include gall bladder and/or common bile duct distension, cholelithiasis, cholecystitis and bile sludging. The normal gall bladder is anechoic and appears round in the transverse scan and pear-shaped in the longitudinal scan. It is important to remember that gall bladder filling occurs normally with fasting, therefore, caution must be exercised in interpreting gall bladder enlargement in an anorectic or fasting cat. The common bile duct can usually be seen as an anechoic, tortuous, tubular structure 2-4 mm in diameter with an echogenic wall. The thickened gall bladder wall has a layered or 'double-walled' appearance. Bile sludge within the gall bladder or common bile duct appears echogenic.

Liver Cytology/Histopathology

Liver cytology or tissue biopsy is essential in differentiating inflammatory liver diseases from IHL and neoplasia. The use of fine needle aspirates eliminates the need for anaesthesia and markedly reduces the chance of haemorrhage. The diagnostic utility of liver cytology is lower in cats with inflammatory liver disease. Ultrasound-guided aspiration and biopsy techniques more consistently produce diagnostic specimens than do blind techniques. Ultrasound-guided fine needle aspiration can be used to sample bile as well as hepatic parenchyma for cytology and bacterial culture.

Treatment

The major specific therapy for neutrophilic cholangitis is antibiotics. Surgical intervention has been recommended if discrete choleliths or complete biliary obstruction is identified. When complete extrahepatic bile duct obstruction is identified, surgical decompression and biliary-to-intestinal diversion (i.e., cholecystoduodenostomy or cholecystojejunostomy) are recommended. Bacterial culture and sensitivity testing of bile, liver aspirate or biopsy specimens, choleliths, or gall bladder specimens, should be used to select appropriate antimicrobial agents whenever possible. Antibiotics chosen for treatment of cholangiohepatitis should be excreted in the bile in active form, and should be active against aerobic and anaerobic intestinal coliforms. Tetracycline, ampicillin, amoxicillin, erythromycin, chloramphenicol and metronidazole are excreted in the bile in active form; however, several of these have significant adverse effects. Erythromycin is not effective against gram-negative bacteria, tetracycline is hepatotoxic and chloramphenicol may cause anorexia. As a result, ampicillin or amoxicillin combined with clavulanic acid are frequently used. All are broad-spectrum antibiotics, effective against both gram-negative and gram-positive organisms, and are well tolerated by cats. These drugs may be combined with fluoroquinolones to extend the spectrum to anaerobes and more coliforms. Treatment with antibiotics for 2 months or longer is recommended. Cats with lymphocytic cholangitis typically require antibiotic therapy combined with immunomodulatory therapy with prednisolone at 5 mg orally q12h with a gradual taper over 6-8 weeks. Chlorambucil can also be used as an immunomodulator (combined with prednisolone at a dose of 2 mg orally every 4 days for cats with more severe disease. Chlorambucil should be given for at least 8 weeks, prior to tapering based on clinical response and laboratory evaluations. Low-dose methotrexate can also be used in cats with lymphocytic cholangitis failing to respond to prednisone and chlorambucil.

Ursodeoxycholic acid (Actigall) is recommended for cats with all types of inflammatory liver disease. It has antiinflammatory, immunomodulatory and antifibrotic properties as well as increasing fluidity of biliary secretions. Ursodeoxycholic acid has safely been administered to cats at a dose of 10-15 mg/kg q24h orally. Adverse effects in cats are uncommon and are usually limited to mild diarrhoea. Antioxidants such as S-adenosylmethionine or vitamin E (alphatocopherol) should also be considered to prevent or decrease lipid peroxidation in the hepatocytes. S-Adenosylmethionine is dosed at 20 mg/kg q24h on an empty stomach, and is available in 90 mg tablets from Nutromax. Vitamin E is typically dosed at 10-100 IU/kg administered once daily with meals.

Cats with neutrophilic cholangitis require aggressive supportive care. These cats are frequently acutely ill and have fluid and electrolyte derangements, which should be corrected. Treatment with injectable vitamin K1 (5 mg/cat q12h s.c. for three treatments) can be given if bleeding diatheses develop. Hepatic encephalopathy appears to be relatively uncommon in cats with acquired liver diseases and is manifest most frequently by excessive salivation. Hepatic encephalopathy can be managed by giving lactulose orally (0.5-1.0 ml/ kg q8h orally) with or without addition of enteric antibiotics (neomycin 20 mg/kg q8-12h orally). Response of cholangitis cats to therapy should be monitored through use of serial complete blood counts and chemistry profiles. Persistent increases in ALT activity and serum total bilirubin concentration and/or increasing ALP activity suggest that treatment has been inadequate.

Prognosis

Limited studies of the response of cholangitis cases to antibiotic treatment suggest that survival of cats with neutrophilic and lymphocytic cholangitis is similar. Approximately half of the cats die or are euthanased within 90 days of diagnosis. The other half has prolonged survival. Hopefully, initiation of standard treatment protocols combined with surgical correction of bile duct obstruction (when needed) will increase the number of cats with long-term survival.

References

1.  Center SA, Crawford MA, et al. A retrospective study of 77 cats with severe hepatic lipidosis; 1975-1990. Journal of Veterinary Internal Medicine 1993; 7: 349-359.

2.  Center SA, Warner KL, Erb HN. Liver glutationine concentrations in dogs and cats with naturally occurring liver disease. American Journal of Veterinary Research 2002; 63: 1187-1197.

3.  Rothuizen R, Bunch SE. Morphological classification of biliary disorders of the canine and feline liver. In: WSAVA standards for clinical and histological diagnosis of canine and feline liver diseases. Saunders Ltd, 2006; 1-144.