Update on hepatoprotective therapies (Proceedings)

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.

N-acetylcysteine (NAC), the acetylated form of the amino acid L-cysteine, is rapidly hydrolyzed to cysteine, which is subsequently available for glutathione synthesis. NAC is the treatment of choice for acetaminophen-induced red blood cell and hepatic injury in dogs and cats. It provides a ready source of intracellular glutathione to detoxify reactive intermediates generated by P-450 metabolism of acetaminophen. NAC has additional hepatoprotective effects including enhanced mitochondrial energy metabolism, improved oxygen delivery in acute liver failure (due to effects on vascular tone), and anti-inflammatory activity. NAC should be considered for the treatment of acetaminophen toxicity, Heinz body anemia, suspected toxin-related hepatic injury (including carprofen, potentiated sulfonamide, azathioprine toxicity in dogs and diazepam and methimazole toxicity in cats), acute liver failure of any cause, and severe hepatic lipidosis in cats. For treatment of acetaminophen toxicity, NAC (10% solution) is diluted 1:2 or more with saline and given IV through a nonpyrogenic 0.25um filter at an initial dose of 140 mg/kg over a 20-30 minute period. A maintenance dose of 70 mg/kg is given IV or orally every 6 hours for 7 treatments. For acute liver failure in humans, a constant rate infusion of 100 mg/kg/24 hours has been used. NAC appears to be well tolerated in dogs and cats. NAC is rapidly absorbed from the gastrointestinal tract but may cause nausea and vomiting. If oral medications can be tolerated, oral SAMe should be used instead for glutathione replacement.

Ursodeoxycholic acid (UDCA) (Actigal; Ciba Geneva) is a synthetic, hydrophilic bile acid that is used in the treatment of cholestatic hepatobiliary disorders and chronic hepatitis in humans. UDCA is the major bile acid in black bear's bile and has long been used in Chinese traditional medicine. The hepatoprotective effects of UDCA are not fully understood. UDCA is believed to be beneficial by expanding the bile acid pool and displacing potentially hepatotoxic hydrophobic bile acids, which may accumulate in cholestasis, but this explanation is probably simplistic. Additional mechanisms for hepatoprotection include stimulation of choleresis, anti-apoptotic effects, stabilization of mitochondrial function, and immunomodulatory actions. Although no controlled clinical studies have been performed, UDCA is believed to be useful in dogs and cats as adjunctive therapy in any cholestatic (including early gallbladder mucocele in dogs) or necroinflammatory hepatic disorder (cholangitis in cats; chronic hepatitis and copper-associated liver disease in dogs). It is contraindicated in mechanical biliary obstruction because of its choleretic action. UCDA appears to be safe when used at a dose of 15 mg/kg PO q24 in both dogs and cats. Absorption is enhanced in the presence of food. Bioavailability decreases with advanced cholestasis and twice daily administration may be necessary. Actigall® comes as a 300 mg. capsule which can be compounded into 30 mg. capsules to aid in dosing cats and small dogs. UDCA appears to be well tolerated in dogs and cats, although vomiting and diarrhea may rarely occur. UDCA may increase the bioavailability of cyclosporine and vitamin E. The therapeutic effects of UCDA may be enhanced in the presence of SAMe.

Milk thistle (Silymarin) comes from the milk thistle plant (Silybum marianum), which grows worldwide. The active derivative, silymarin, is highest in concentration in the fruit and seeds, but is present throughout the plant. A standard milk thistle extract typically contains 60-70% silymarin, which actually consists of a complex of flavonolignans including silybin, isosilibin, silidianin, and silicristin. The most biologically active isomer is silybin. Milk thistle has been used in Europe for over 2000 years as a home remedy for liver disease. In the last 30 years, it has become the most researched plant extract used for treatment of liver disease in humans. Silymarin has antioxidant, anti-inflammatory, and antifibrotic effects. Silymarin also inhibits hepatic uptake of phalloidin, the toxic principle of the Amanita mushroom, which causes acute liver failure. Silymarin was protective in beagles with experimental mushroom toxicity (50-150 mg/kg IV when given 5-24 hours after ingesting Aminita phalloides), showing less hepatic damage and improved survival compared to the control group. It was also effective in preventing hepatotoxicity in experimental dogs given carbon tetrachloride. Treatment with Silymarin may be warranted in dogs and cats with hepatotoxicity, hepatobiliary disorders associated with cholestasis, and necroinflammatory liver diseases.

Clinical studies documenting the effectiveness of silymarin treatment in dogs and cats with spontaneous hepatobiliary disease have not been published. Silymarin is poorly absorbed from the gastrointestinal tract. Commercially available preparations vary in content and bioavailability and there is no assurance of extract purity. The therapeutic dose for dogs and cats is unknown. A dose of 20-50 mg/kg/day divided into 3-4 doses has been suggested. More recently, studies suggest intestinal absorption and bioavailability are improved by combining silybin, with phosphatidylcholine (Siliphos). This product is commercially available as a combined product with vitamin E and zinc (Marin; Nutramax) or with SAMe (Denamarin; Nutramax). Silymarin appears to have very low toxicity and there are no known contraindications. Silymarin can suppress certain P450 enzymes, which may be an important consideration for drug interactions in patients taking multiple drugs.

Vitamin E (α-tocopherol) is a nutritional antioxidant found in all cell membranes. It is an essential nutrient derived from food and nutritional supplements. Mammalian cells cannot synthesize it. Vitamin E is an important defense mechanism against peroxidation membrane damage but also has other nonantioxidant functions that may be beneficial in the liver disease. Increased production of free radicals has been implicated in a variety of experimentally-induced hepatic diseases, including hepatic copper and iron accumulation, alcohol consumption, cholestasis, ischemia-reperfusion injury, and drug-induced hepatic injury (such as phenobarbital and CCl4). Free radicals may contribute to oxidative hepatocellular injury, if not counteracted by cytoprotective mechanisms. Antioxidants, such as vitamin E, are important to scavenge free radicals and prevent oxidative injury. In experimental studies (in vitro and in vivo), vitamin E can protect against this type of injury. Little information is available on Vitamin E supplementation in dogs and cats with liver disease. However, Bedlington terriers with copper-associated hepatitis have reduced mitochondrial vitamin E, which correlates with markers of oxidative damage. Dogs with chronic hepatitis treated for 3 months with a vitamin E supplemented diet had increased serum and liver vitamin E concentrations and evidence of protection against oxidative injury based on an increase in hepatic glutathione (GSH):GSSH ratio compared to untreated dogs. However, there was no significant difference in clinical, laboratory, or histologic features in this time period. Vitamin E is recommended for dogs and cats with hepatic disorders likely to be accompanied by oxidative membrane injury such as necroinflammatory disorders (chronic hepatitis, copper-associated chronic hepatitis), cholestatic hepatobiliary disorders (including feline hepatic lipidosis), hepatotoxicity, and ischemia-reperfusion injury. A dose of 10-15 IU/kg per day (50 – 400 IU/day) is recommended. Vitamin E appears to be safe and inexpensive. The natural form, d-α tocopherol, is recommended over the synthetic dl-α-tocopherol because it has greater uptake, dispersion, and bioactivity. If severe cholestasis is present, absorption may be compromised, and higher doses may be required. An emulsified formulation is available (Vedco, AgriLabs; Dyrvet, Schering-Plough) for parenteral administration and should be considered in animals with severe cholestasis such hepatic lipidosis in cats.

Suggested Reading: Webster CRL et al. Vet Clin North Am 39:631-652, 2009; Flatland B. Kirk's Current Vet Therapy XIV, 554-557, 2009.