Chapter 53: Hepatic Support Therapy

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Hepatic Support Therapy

Supportive treatment of patients with hepatic disease addresses general pathophysiologic mechanisms common to many hepatic diseases. Although some treatments (e.g., antioxidants) apply to acute and chronic disorders, supportive treatments commonly are discussed in the context of chronic inflammatory and neoplastic hepatic diseases. Some supportive treatments (e.g., antifibrotics) are inherently more applicable to chronic disease. Because most of these treatments are administered orally, their use in acute and chronic cases may be limited by a patient’s ability to take oral medication.

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:

This chapter reviews antioxidant and antifibrotic treatments commonly used for supportive care of hepatic disease and discusses treatment of hepatic disease–associated coagulopathy and ascites. For information concerning treatment of specific hepatic diseases, antiinflammatory treatments, treatment of copper accumulation, treatment of gastric ulceration, and management of hepatic encephalopathy, the reader is referred to other chapters in the text.


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

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 veterinary hepatology vitamin E is a commonly used antioxidant. Dosage recommendations for dogs have been reported in conference proceedings and vary from 10 units/kg every 24 hours orally to 250 or 400 units/dog every 24 hours orally. The author has used the 10-unit/kg every-24-hour oral dosage most commonly. Dosing small patients can be problematic because commonly available vitamin E preparations contain 400 or 1000 units. Controlled clinical trials evaluating efficacy and safety of vitamin E supplementation in canine and feline liver disease patients are unavailable. The author does not recommend vitamin E supplementation in liver disease patients with evidence of vitamin K deficiency. In such cases S-adenosylmethionine (SAMe) or milk thistle is a preferred antioxidant.

Milk Thistle (Silymarin)

The term silymarin refers collectively to the four flavonolignan isomers (silybin, isosilybin, silydianin, silychristin) that make up the active ingredients of the herb milk thistle (Silybum marianum). Silybin is the most biologically active isomer and makes up 50% to 70% of silymarin. These flavonolignans are found throughout the milk thistle plant but are concentrated in its fruit and seeds. Commercially available preparations of silymarin vary in content and bioavailability, a fact that makes dosage recommendations difficult and hampers use of silymarin in carefully designed, prospective clinical trials. Accordingly in 2005 the National Center for Complementary and Alternative Medicine (NCCAM) issued a request for industry collaboration to develop a well-characterized, standardized formulation of silymarin that could be used in human liver disease clinical trials. If such a standardized formulation is developed, it has the potential to benefit veterinary medicine also.

The primary effect of silymarin is thought to be as an antioxidant and free-radical scavenger, but it also is proposed to have antifibrotic, antiinflammatory, and immunomodulatory actions. In humans silymarin is used primarily to treat alcoholic liver disease, viral hepatitis, and toxin-induced liver disease. Large randomized controlled clinical trials using silymarin in specific human liver diseases are lacking; however, small clinical studies suggest some benefit in specific conditions.

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).

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Chapter 53: Hepatic Support Therapy

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