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Update on hepatoprotective therapies (Proceedings)

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Nov 01, 2010

Hepatoprotective agents are receiving attention for their role in the ancillary treatment of liver disease in dogs and cats. These products include both prescription drugs and dietary supplements (vitamins, minerals, herbs, nutraceuticals). A drug is defined as "any substance, food, or nonfood that is used to treat, cure, mitigate, or prevent a disease and any nonfood substance that is intended to affect the structure or function of man or animals". In order for a compound to become a drug, it must be shown to be safe and effective for its intended use, undergoing an extensive FDA drug approval process that is lengthy and costly. Dietary supplements are often dispensed without medical supervision and FDA oversight is minimal. Goals for treatment of hepatic disease are to identify and treat the underlying cause if possible and to modulate general pathophysiologic mechanisms common to many hepatic diseases, such as inflammation, copper accumulation, oxidative damage, and fibrosis. This is a review of the most common hepatoprotective agents used in the treatment of canine and feline liver disease.

S-adenosylmethionine (SAMe) is an endogenous molecule produced in the body from the amino acid methionine and ATP by the enzyme methionine adenosyltransferase synthetase. SAMe is metabolized via three major biochemical pathways: transmethylation, trans-sulfuration, and aminopropylation. These pathways are responsible for metabolism of various endogenous and exogenous compounds, production of molecules important in cell signaling and gene transcription, and generation of endogenous sulfur compounds. SAMe is essential to all cells but is especially important in the liver because of the liver's central role in metabolism. The trans-sulfuration pathway generates most endogenous sulfur compounds including cysteine, which is used to form glutathione, an oxidant and free radical scavenger. Glutathione is a major physiologic defense mechanism against oxidative stress in the liver. Conversion of methionine to SAMe can be impaired in many types of liver disease in humans and experimental animals, resulting in decreased hepatocyte glutathione concentrations and increased risk for oxidative injury. Evaluation of hepatic glutathione levels in dogs and cats with severe spontaneous liver disease revealed that decreased levels of glutathione are common in necroinflammatory liver disease, extrahepatic bile duct obstruction, and feline hepatic lipidosis. Oral administration of SAMe to healthy dogs and cats has been shown to increase plasma SAMe concentrations and hepatic glutathione concentrations. SAMe also prevents glutathione depletion in dogs with steroid-induced hepatopathy. SAMe has been shown to have a protective effect on the erythrocytes in cats and dogs with acetaminophen toxicity and to protect against hepatic injury. Although the therapeutic indications for use of SAMe in dogs and cats with spontaneous hepatobiliary disease are largely unknown, SAMe would likely be beneficial in necroinflammatory diseases (chronic hepatitis, copper- associated hepatitis, feline cholangitis), cholestatic disorders (cholecystitis, gallbladder mucocele), and metabolic (canine vaculolar hepatopathy, feline hepatic lipidosis), toxic (acetaminophen) and ischemic hepatopathies.

There are two commercially available veterinary products (Denosyl-SD4®; Nutramax Laboratories and Zentonil®; Vetoquinol). Both are formulated as patented stabilized salts, in foil-wrapped packets (because the salts are hydroscopic). The enteric coating is necessary to prevent inactivation in gastric acid. Consequently, the enteric-coated tablets should not be broken or crushed. Giving the drug on an empty stomach will also improve absorption. It should be noted that there is considerable variation in product purity, and lack of bioavailability may be an issue in some over-the-counter human SAMe products. SAMe is administered orally at a recommended dose of 20 mg/kg/day in both dogs and cats. There is a low incidence of side effects. Nausea, refusal of food, or anxiety may occur in the post-pill interval (hours); this problem may resolve with time. Some cats may develop post-pill vomiting which may necessitate discontinuing treatment.