Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN
Professor of Small Animal Medicine, University of California, Davis, School of Veterinary Medicine, Davis, CA, USA
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-recognized syndrome characterized 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 etiopathogenesis of this syndrome is poorly understood, but may relate to protein deficiency, excessive peripheral lipolysis, excessive lipogenesis, inhibition of lipid oxidation or inhibition of the synthesis and secretion of very low-density lipoproteins. The prognosis for this life-threatening disorder has improved dramatically during the past several years as a result of long-term enteral feeding (i.e., three to eight weeks or longer).
Treatment of Hepatic Lipidosis
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: 1) prevent catabolism of amino acids for energy, 2) inhibit peripheral lipolysis, and 3) avoid excessive energy consumption which will promote hepatic triglyceride accumulation. Enteral feeding devices (esophagostomy or gastrostomy tubes) are indicated in cats with hepatic lipidosis to ensure provision of adequate calories. Most cats with IHL can be fed commercially-available therapeutic or maintenance diets containing 25-40% fat (DM). Dietary protein should not be restricted unless the cat is showing signs of hepatic encephalopathy. Commercial veterinary diets containing 30 to 45% protein on a DM basis are well tolerated by affected cats. The daily energy requirement for cats with IHL should initially be based on the cat's current body weight (if mildly to moderately obese), or based on the cats optimal body weight plus 25% of extra body weight if markedly obese. The amount fed is gradually increased in 25% increments; until the cat is being fed at its RER (usually takes 5-7 days). A simple logarithmic formula that can be used to determine the cat's resting energy requirement (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. Hypokalemia was present in 19 of 66 cats (29%) with severe hepatic lipidosis. Hypokalemia may develop due to inadequate potassium intake, vomiting, magnesium depletion, and concurrent renal failure. Hypokalemia was significantly related to nonsurvival in this group of cats. Hypokalemia is deleterious because 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 mEq 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. Center and colleagues showed that diets supplemented with L-carnitine can safely facilitate rapid weight loss in privately owned obese cats. Based on these findings, Dr. Center recommends supplementing cats with a dose of 250-500 mg L-carnitine/day to cats with IHL. Additional dietary supplements that should be considered include vitamin B12 and S-adenosylmethionine. Vitamin B12 (cyanocobalamin) should be administered subcutaneously at a dosage of 250 μg per cat administered once weekly for 6 weeks. It is recommended that serum B12 concentrations be rechecked approximately 1-2 weeks following cessation of B12 administration, as some cats may need repeated administration of this vitamin.
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 hepatic lipidosis 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 expressing 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 aggressively meet the cat's caloric requirements 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.
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 hepatic lipidosis. 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 recognized in cats:
1. Neutrophilic (usually referable to ascending bacterial infection but also rarely reported in protozoal infections).
2. Lymphocytic (thought to be immune mediated).
3. Chronic cholangitis associated with infection by liver flukes (Amphimerus pseudofelineus, Platynosomum concinnum, etc).
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) is recommended. Bacterial culture and sensitivity testing of bile (optimal), 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 side 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 is 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. The anti-inflammatory and immunosuppressive properties of prednisolone may be beneficial in limiting hepatocellular injury. Additionally, prednisolone may enhance appetite. An immunosuppressive dose of prednisolone (2.2-4 mg/kg q24h) should be used initially. The dosage is slowly tapered to an alternate day dose (1-2 mg/kg q48h) for long term maintenance. Biochemical values should be monitored prior to each reduction in dosage. If the clinical and biochemical response is satisfactory, doses as low as 0.5 mg/kg q 48 hours may be sufficient for long term maintenance. Long term corticosteroid treatment is well tolerated by most cats and side effects are usually minimal. Chlorambucil can also be used as an immunomodulator (combined with prednisone) at a dose of 2 mg q 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 anti-inflammatory, 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 to 15 mg/kg q24h PO. Efficacy has not been established for any type of feline liver disease, but clinical trials in human patients with hepatitis support improved quality of life. Adverse effects in cats are uncommon and usually limited to mild diarrhea. Antioxidants such as S-Adenosylmethionine or vitamin E should also be considered to prevent or decrease lipid peroxidation in the hepatocytes. S-Adenosylmethionine is dosed at 20 mg/kg SID for cats, and is available in 90 mg tablets from Nutromax. Vitamin E is typically dosed at 10 to 100 IU/kg administered once daily.
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 q 1-2 days IM) 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 PO) with or without addition of enteric antibiotics (neomycin 20 mg/kg q8-12h PO).
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 SAP activity suggest that treatment has been inadequate. Low dose weekly methotrexate therapy has been used in a few affected cats.
Limited studies of the response of cholangitis cases to antibiotic treatment suggest that survival of cats with neutrophilic and lymphocytic cholangitis are similar. Approximately half of the cats die or are euthanized within 90 days after 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 are available upon request.