Treatment of liver disease: Medical and nutritional aspects (Sponsored by Nestle Purina)

Few controlled studies have investigated treatments for liver disease in dogs and cats. My basic treatment goals for patients with this disease are

• Remove or correct the inciting etiology

• Provide adequate nutrition and prevent malnutrition

• Provide specific treatment of the hepatic disease and related complications

• Provide an environment for optimal hepatic function and regeneration.

Nutritional management

The liver is paramount in an animal's metabolism, playing a key role in regulating protein, carbohydrates, fat, vitamins, and minerals. Metabolic derangements that occur with liver disease can lead to malnutrition, impaired hepatic regeneration, and the clinical consequences of hepatic insufficiency.

Basic nutritional concepts

Anorexia and weight loss occur commonly in patients with liver disease. Therefore, one of the most important aspects in liver disease therapy is ensuring that the patient has appropriate energy intake to minimize catabolism.1 When treating liver disease, there is a common misconception regarding the fat content in the diet. This is especially true of nutritional management of feline hepatic lipidosis, as some believe that affected patients should be fed lower-fat diets. Fat not only improves palatability but also provides important energy density to the diet. In general, lipid restriction is unnecessary in patients with liver disease.

Carbohydrates should make up no more than 35% and 45% of the diet's total calories in cats and dogs, respectively.1,2 Adequate carbohydrate intake is important to maintain glucose concentrations. Additionally, feeding small yet frequent meals throughout the day may help maintain glucose concentrations.

A misconception also exists regarding the optimal dietary protein content in animals with liver disease. It was previously thought that patients with liver disease should be placed on a protein-restricted diet to reduce the liver's workload and the production of detrimental nitrogenous waste products. This assumption, however, is not well substantiated. Many veterinary nutritionists and gastroenterologists now believe restricting protein could be detrimental, especially in patients with a negative nitrogen balance.1,3 The goal of dietary protein intake is to adjust the quantities and types of nutrients to meet the patient's nutrient requirements and to avoid the production of excess nitrogen byproducts, which cause hepatic encephalopathy.

It is always important to provide the patient with a high-quality, highly digestible protein source.1 Poor-quality proteins may aggravate hepatic encephalopathy and fail to promote hepatic regeneration. In some instances, the protein requirements for patients with liver disease may actually be greater than those for healthy animals. Most high-quality commercial or prescription diets are suitable for this purpose. As a general recommendation, dietary protein should represent 15% to 20% of the digestible kilocalories (kcal) of the diet.1 In general, most highly digestible diets, such as gastrointestinal diets, would be adequate for most liver conditions. Clinically, protein restriction should be instituted only in patients with evidence of protein intolerance; most often these are patients with portosystemic shunts or signs of hepatic encephalopathy.4 Because cats have such a high protein requirement, I rarely—if ever—limit protein intake in cases of feline liver disease, such as lipidosis, and I find hepatic encephalopathy is an uncommon consequence in cats.

Specific therapy

Anti-inflammatory therapy

Decreasing inflammation is a specific therapy for chronic hepatitis in dogs and possibly for some types of cholangitis in cats. The general impression is that anti-inflammatory therapy is beneficial in some if not all cases of chronic hepatitis, but this approach remains controversial because there are no good controlled studies in dogs. A study by Strombeck found that some dogs with chronic hepatitis had prolonged survival times when treated with corticosteroids.5 A suggested dose of 1 to 2 mg/kg/day using either prednisone or prednisolone should be instituted. After several weeks or when there is evidence of clinical improvement the dose is gradually tapered to 0.5 mg/kg/day or every other day. The only accurate way to evaluate a dog's response to therapy is to rebiopsy the liver six to eight months after treatment was initiated. It is impossible to determine improvement in dogs treated with corticosteroids based on liver enzyme activities because of the concurrent steroid hepatopathy. Because of the side effects of corticosteroids and the inability to successfully monitor liver enzymes while a patient is receiving corticosteroids, other immune suppressive therapy may be a more rational approach.

Azathioprine, an effective immunosuppressant, has been shown to increase survival in humans with chronic hepatitis, when used in conjunction with corticosteroids.6 I have also recently been using cyclosporine in some chronic hepatitis cases, with a good clinical response. In dogs thought to have immune-mediated chronic hepatitis, my experience using cyclosporine at a dose of 5 mg/kg b.i.d. or every 24 hrs (without corticosteroids) has been very encouraging. The veterinary formulation, Atopica, is a microemulsified drug with properties identical to those of Neoral and the modified generic counterpart. When there is evidence of clinical response at 5 mg/kg b.i.d., I will often decrease the dosage to once-a-day therapy and eventually to alternate-day therapy.

Copper reduction

Hepatic copper concentrations can increase in dogs, either because of a primary genetic defect in hepatic copper metabolism—noted in some breeds—or because of diminished copper excretion secondary to cholestatic liver disease.7 When this occurs, it is important to feed diets with a lower copper content and to avoid nutritional supplements with additional copper. A restricted copper intake of about 1.25 mg/1,000 kcal of metabolizable energy has been suggested.3 Most diets list their copper content on the label; if not, the manufacturer should be able to provide this information. In cases of breed-associated copper hepatotoxicity, copper-specific chelators (e.g. penicillamine, trientine) are the standard therapies used to remove excess hepatic copper. Chelators bind with copper either in the blood or tissues and promote copper removal through the kidneys. Penicillamine (Cuprimine; 250-mg capsules) is the copper chelator most frequently recommended for use in dogs.8 The dose is 15 mg/kg b.i.d. given on an empty stomach. Side effects include anorexia and vomiting.

Because of its antifibrotic and hepatoprotective properties, zinc therapy has a number of potential benefits in dogs with chronic hepatitis. In humans with Wilson's disease who have been decoppered with chelators, zinc given as the acetate, sulfate, gluconate, or other salt has proven effective in preventing hepatic copper reaccumulation.9 Oral zinc therapy works by causing an induction of the intestinal copper-binding protein metallothionein, a protein with a high affinity for copper that prevents the transfer of copper from the intestine into the blood.8 An initial induction dose of 15 mg/kg body weight (or 50 to 100 mg b.i.d.) of elemental zinc given twice a day is suggested.10 After one to three months of induction, the dose can be reduced in half. The goal is to reach serum zinc concentrations > 200 μg/dl but < 500 μg/dl. The zinc, which must be administered on an empty stomach, frequently causes vomiting.

Choleretic drugs

When bile acid concentrations cause damage by increasing cell membrane permeability in patients with chronic hepatitis, ursodeoxycholic acid (ursodiol—Actigall; 300-mg capsules) is a choleretic agent found to have positive effects. A synthetic hydrophilic bile acid, this drug essentially changes the composition of the bile acid pool from more toxic hydrophobic bile acids to less toxic hydrophilic bile acids. Ursodeoxycholic acid has been shown to increase bile acid dependent flow and to reduce hepatocellular inflammatory changes and fibrosis, and also to have immunomodulating effects. The dose for ursodeoxycholic acid is 15 mg/kg daily. No toxicity has been observed even with obstructive disease.11

Antifibrotic drugs

Corticosteroids, zinc, and penicillamine all have some antifibrotic effects but are used predominantly for their other effects. Colchicine has been used to treat humans with chronic hepatitis and other types of liver fibrosis. But we lack convincing data showing that colchicine is beneficial in treating humans or dogs with liver disease.12 Two case reports involving the use of colchicine to treat dogs show questionable results. Regardless, a dose of 0.03 mg/kg/day has been suggested.

Antibiotics

Antibiotics are indicated for primary hepatic infections, such as bacterial hepatitis, cholangitis, or leptospirosis. The selection of appropriate antibiotics is based on culture and sensitivity results. However, there is evidence that bacterial colonization can take place secondarily in any diseased liver. For this reason, it may be prudent to prescribe antibiotic therapy for a trial of several weeks in patients with significant hepatic disease (e.g. chronic hepatitis). Amoxicillin, amoxicillin-clavulanic acid, cephalosporin, or metronidazole is suggested. In addition to its anaerobic antibacterial mechanisms, metronidazole may have some immunosuppressive properties. Because of the drug's hepatic metabolism, I would give metronidazole in patients with liver disease at a dose of 7.5 to 10 mg/kg b.i.d., a much lower dose than that used for other bacterial infections.

Liver support

There is recent interest in managing certain types of liver disease by using vitamins and various nutraceuticals. There are, however, few published reports that show benefits of this approach in treating clinical disease, and much of the information gathered to date has been generated from in vitro studies.

Vitamins

The liver is the major organ for vitamin metabolism. Both vitamin storage and the conversion of provitamins to their metabolically active state take place in the hepatocytes of the liver.13

• Vitamin E (alpha-tocopherol) functions as a cellular membrane-bound antioxidant. Evidence now shows that during liver disease, oxidative damage occurs from free radical generation.14 Dietary supplementation with vitamin E reduces oxidant injury to hepatic tissue.14 Bedlington terriers with copper-associated hepatopathy have oxidant damage in their mitochondria and reduced mitochondrial vitamin E concentrations. Vitamin E has also shown a protective effect in the liver from copper-related oxidant damage and bile acids.14 Vitamin E is inexpensive and safe when supplemented at a dose of 10 IU/kg/day. d-Alpha-tocopherol, the natural form of vitamin E, is recommended because of its greater uptake, dispersion, and bioactivity compared with the more common synthetic dl-alpha-tocopherol formulation.

• Ascorbic acid (vitamin C) is an important soluble intracellular antioxidant that helps convert oxidized tocopherol radicals back to active alpha-tocopherol. Vitamin C is also necessary for the synthesis of carnitine, which is important for the transport of fat into mitochondria. While vitamin C supplementation may be a beneficial adjunct in treating liver disease, excessive amounts of vitamin C may be deleterious in patients with increased hepatic copper or iron concentrations.14

• Vitamin K stores in the liver can become depleted with advanced liver disease and can lead to serious coagulopathies. Deficiency of this vitamin can stem from reduced intestinal absorption due to cholestatic liver disease or advanced liver dysfunction, which are associated with a failure of hepatic conversion to the vitamin K-dependent coagulation factors (i.e. factors II, VII, IX, and X). This failure can result in prolongation of coagulation as measured by prothrombin time or activated partial thromboplastin time. Vitamin K1 (phytonadione), given at 0.5 to 2 mg/kg every 12 hours subcutaneously for two to three doses (or until normalization of prothrombin time), is recommended for dogs and cats with hepatic disease.5

• B12 vitamin deficiency is common in cats with gastrointestinal, pancreatic, or liver disease, and in particular, in cats with idiopathic hepatic lipidosis.15 The recommended dosage of cobalamin in cats is 250 μg given subcutaneously weekly until normal cobalamin concentrations are maintained.

Nutraceuticals

A nutraceutical is a nondrug substance produced in a purified or extracted form and administered orally to provide agents required for normal body structure and function. Nutraceuticals are administered with the intent of improving the health and well-being of animals. Because nutraceuticals are not classified as drugs, they are not subject to Food and Drug Administration approval showing purity, safety, and efficacy. Consequently, it is best to remember the admonition "let the buyer beware" when purchasing nutraceuticals, as some may not be what they are labeled to be.

• S-adenosyl-methionine (SAMe), a naturally occurring molecule that has both hepatoprotective and antioxidant properties, is produced from the amino acid methionine. SAMe initiates one of three major biochemical pathways involved in cell membrane integrity: glutathione production and cell regeneration. Hepatic glutathione is important because it prevents oxidative stress,16 and SAMe replenishes glutathione stores.16

• N-acetylcysteine, the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl groups. It promotes glutathione synthesis and is used to treat drug-induced hepatotoxicity.17 N-acetylcysteine can be given intravenously; a loading dose of 140 mg/kg is given, followed by 70 mg/kg t.i.d.

• L-carnitine is a vitamin-like substance found in most cells. Its primary function is to transport long-chain fatty acids across the inner mitochondrial membrane into the mitochondria for ß-oxidation, forming acetyl CoA fragments. Carnitine deficiency may result in hepatocyte triglyceride accumulation, leading to accumulation of toxic acetyl CoA metabolites that can, in turn, impair mitochondrial respiration and function.18 Carnitine is used to treat obesity in cats and may play a role in the pathogenesis of idiopathic feline hepatic lipidosis.18 Supplementation of 250 mg of carnitine a day in cats with lipidosis may increase survival rates, but this is not yet documented.

• Silymarin, a product of milk thistle, grows wild throughout Europe and has been used there for more than 2,000 years as a medical remedy for liver disease. Research has shown that silymarin has antioxidant and hepatoprotective properties both in vitro and in vivo.19 Silymarin is an extract of milk thistle; its most biologically active component is the isomer silybin (silibinin). When silybin is complexed with phosphatidylcholine, oral uptake and bioavailability are greater.20 Silymarin is considered a nutritional supplement, and therefore is not subject to FDA regulatory standards. Silybin is available in several veterinary-labeled products, many of which have combined it with phosphatidylcholine and vitamin E or SAMe.

Summary

Patients with liver disease have complex medical and nutritional needs. Practitioners should formulate individualized therapeutic and dietary plans for these patients. Because there are few good controlled studies evaluating different therapies for liver disease, it is important to carefully monitor each patient and adjust that patient's treatment as indicated, based on clinical response, laboratory changes, and histology findings.

David C. Twedt, DVM, DACVIM

Department of Clinical Sciences

College of Veterinary Medicine & Biomedical Sciences

Colorado State University

Fort Collins, Colo.

References

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20. Filburn CR, Kettenacker R, Griffin DW. Bioavailability of a silybin-phosphatidylcholine complex in dogs. J Vet Pharmacol Ther 2007;30:132-138.