Web Chapter 53 Ideally treatment of hepatic disease should be aimed at a specific underlying cause. Given the enormous regenerative capacity of the liver, timely identification and elimination of any underlying cause offer the best hope for disease resolution in acute and chronic cases. Evidence from human medicine suggests that fibrosis and even cirrhosis may be reversible in some cases when a specific cause can be addressed (Rocky, 2005). In cases in which an underlying cause can be identified and eliminated, supportive care of hepatic disease may be finite. In chronic inflammatory disease, especially when the cause is not known, or in advanced neoplastic disease when the cause cannot be eliminated, supportive treatments are recommended indefinitely. Current understanding of the causes of chronic inflammatory hepatobiliary disease is extremely limited, a fact that hampers research by limiting the ability to stratify patients and interpret results according to cause. Lack of standardized supplement preparations with which to undertake clinical trials also can be a limiting factor in research. Recommendations for standardized clinical and histologic approaches to canine and feline hepatobiliary disease were published by the World Small Animal Veterinary Association Liver Standardization Group and, if widely adopted, should facilitate future research (Rothuizen et al, 2006). Most recommendations for supportive care of small animal hepatic diseases, regardless of the etiology, are extrapolated from human medicine or are based on anecdotal experience and individual case reports rather than on evidence from prospective, randomized, placebo-controlled clinical trials involving large numbers of patients. The treatment recommendations in this chapter should be accepted with these limitations in mind. Treatment of hepatic disease incorporates the following general principles: • Address the underlying cause, if known (e.g., withdrawal of a hepatotoxic drug) • Reduce and prevent inflammation • Reduce and prevent copper accumulation, if applicable • Reduce and prevent oxidative damage • Treat complications as needed (e.g., hepatic encephalopathy, coagulopathy, gastric ulceration, fluid/electrolyte disturbances, ascites, and infection/endotoxemia) Oxidative stress plays a role in the pathogenesis of liver disease in humans and animals. Cats with hepatic lipidosis and dogs and cats with obstructive biliary and inflammatory hepatic disorders exhibit reduced glutathione concentrations. This likely predisposes them to oxidative hepatic injury, given the ability of glutathione to detoxify reactive oxygen species. Accordingly, use of antioxidants and compounds that replenish hepatic glutathione stores seems warranted in the supportive treatment of canine and feline hepatobiliary disease (Center, Warner, and Erb, 2002). In addition to the substances discussed in the following paragraphs, zinc and ursodeoxycholate are proposed to benefit liver disease patients through antioxidant effects, although these are used more often for their copper-reducing and choleretic properties, respectively. Vitamin C (l-ascorbic acid) also has been recommended for its antioxidant and free-radical scavenging properties, but its use is less common than other antioxidants and therefore is not discussed. Vitamin E refers collectively to the antioxidant compounds known as tocopherols and tocotrienols. α-Tocopherol is the most biologically active form of vitamin E. The D stereoisomer is abundant in nature, where it is synthesized by plants. Synthetic vitamin E contains D and L stereoisomers of α-tocopherol (Matthai, 1996). Food sources of vitamin E include vegetable oils, nuts, seeds, and grains. Because the various vitamin E isomers have differing biologic activities, preparations of vitamin E are standardized to international units (IU). One IU is equivalent to the activity of 1 mg of synthetically prepared dl-α-tocopherol. Vitamin E is fat soluble and requires bile and pancreatic juice for maximal intestinal absorption. High dosages of vitamin E may interfere with absorption of other fat-soluble vitamins and may predispose to development of vitamin K–dependent coagulopathy. Vitamin E supplementation traditionally has been thought harmless; however, a recent metaanalysis of vitamin E use in humans with various diseases revealed that supplementation at dosages greater than 150 units/day was associated with increased all-cause mortality. This finding led to recommendations against vitamin E supplementation, particularly at dosages above 400 units/day (Miller et al, 2005). In experimental animal models silymarin has been shown to ameliorate hepatic injury secondary to acetaminophen, carbon tetrachloride, radiation, iron overload, alcohol, cold ischemia, and the death cap mushroom (Amanita phalloides). Indeed, silymarin is so effective at reducing A. phalloides toxicosis by preventing hepatocyte uptake of mushroom toxins in humans and dogs that an intravenous formulation has been developed specifically for the purpose of treating mushroom poisoning in humans (Seeff et al, 2001). In veterinary medicine, clinical trials evaluating efficacy of silymarin in dogs and cats with naturally occurring hepatic disease have not been published. A silybin-phosphatidylcholine complex given to normal cats was found to be safe and demonstrate antioxidant activity (Webb et al, 2012). Dosage recommendations reported in conference proceedings vary, but 20 to 50 mg/kg every 24 hours orally (dogs and cats) commonly is recommended. A veterinary product is now available containing silybin bound to phosphatidylcholine for improved gastrointestinal absorption (Marin, 5 to 10 mg/kg every 24 hours orally).
Hepatic Support Therapy
Antioxidants
Vitamin E
Milk Thistle (Silymarin)
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