Drug Therapy Conventional and Alternative Therapies

Although ALD remains a major cause of morbidity and mortality in the United States, there is no FDA-approved therapy for either alcoholic cirrhosis or alcoholic hepatitis. However, there are several drugs that have been widely used. We will discuss only therapies available in the United States for which there generally are large randomized human studies. Our first line of therapy in ALD includes corticosteroids and pentoxifylline.

Corticosteroids

Corticosteroids have been the most extensively studied form of therapy for alcoholic hepatitis, but their role remains

limited. The rationale for steroid use is to decrease the immune response and proinflammatory cytokine response. Most meta-analyses support the use of steroids for severe acute alcoholic hepatitis, including the most recent study by Mathurin and colleagues. This study reported significantly improved survival at 28 days (85% versus 65%) in severely ill alcoholic hepatitis patients having a discriminant function (DF) of > 32. Independent prognostic factors associated with survival at 28 days in this meta-analysis were steroid treatment, age, and creatinine. It is important to note that patients studied were highly selected, and infections (eg, spontaneous bacterial peritonitis [SBP]), gastrointestinal bleeding, and many other common complications were exclusions for entry into these studies. Most investigators agree that if corticosteroids are to be used, they should be reserved for those with relatively severe liver disease (DF > 32), and possibly those with hepatic encephalopathy. Steroids have well-documented side effects, including enhancing the risk of infection, which is already substantial in patients with AH (AH). Thus, a major disadvantage to corticosteroids is their lack of applicability in many patients with AH.

Pentoxifylline

Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor which increases intracellular concentrations of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate, and decreases production of proinflammatory chemokines/cytokines, including TNF. Akriviadis and colleagues performed a prospective, randomized, double blind clinical trial of PTX in severe alcoholic hepatitis (DF > 32). Forty-nine patients received 400 mg of PTX orally 3 times daily and 52 received placebo (vitamin B12) for 4 weeks. PTX treatment improved survival. Twelve patients on PTX died (24.5%) compared with 24 (46%) patients on placebo. PTX also decreased hepatorenal syndrome as a cause of death. Six of the 12 (50%) PTX-treated patients who died did so of renal failure compared with 22 of the 24 (92%) control patients who died of renal failure. Multivariate analysis revealed age, serum creatinine at randomization, and treatment with PTX as independent factors associated with survival. our group currently uses PTX (400 mg orally 3 times daily) in patients with AH and with alcoholic cirrhosis because of its anti-inflammatory properties, its protective effects against hepa-torenal syndrome, and its excellent safety profile.

Propylthiouracil

Chronic alcohol feeding in animals models produces a hyper-metabolic state with increased oxygen consumption similar to the hypermetabolic state associated with hyperthyroidism. This may lead to relative hypoxia, especially in the central lobular area, or zone 3 of the liver. Propylthiouracil (PTU) has been postulated to attenuate this hypermetabolic state, to function as an antioxidant, and to improve portal blood flow. However, a recent Cochran review evaluated PTU therapy for ALD, including alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or cirrhosis, and no beneficial effect was noted. We do not recommend use of PTU in ALD.

Colchicine

Colchicine has been suggested as a treatment for ALD because of its antifibrotic effects. It has many potential therapeutic mechanisms of action including inhibition of collagen production, enhancement of collagenase activity, and anti-inflammatory functions. Initial positive studies led to a large VA cooperative study evaluating colchicine therapy in alcoholic cirrhosis and no significant benefit was observed.

TNF-a Inhibitors

Cytokine induced acute inflammatory response is one underlying basic mechanism responsible for cellular injury in alcoholic hepatitis. Serum TNF- a has been shown to be elevated in patients with acute alcoholic hepatitis, particularly in the more severe cases. TNF-a antibodies (infliximab) and receptor antagonists (Entanercept) have shown promising results in some chronic inflammatory diseases like Crohn's disease and rheumatoid arthritis. Small studies using infliximab or Entanercept in acute alcoholic hepatitis showed improvement in the Maddrey's DF, as well a reduction in TNF-inducible cytokines such as IL-6 and IL-8, and larger randomized studies are underway.

Silymarin (Milk Thistle)

Silymarin is probably the most widely used form of complementary and alternative medicine (CAM) in the treatment of liver disease in the United States. It has antioxidant activities, it protects against lipid peroxidation, and it has anti-inflammatory and antifibrotic effects. Large controlled trials of silymarin have been performed in Europe, with varying results using doses between 140 to 150 mg orally 3 times daily. In all studies performed thus far, the drug appears quite safe.

S-ADENOSYLMETHIONINE

S-Adenosylmethionine (SAMe), or AdoMet, is an obligatory intermediate in the conversion of methionine to cysteine in the hepatic transsulfuration pathway. SAMe is a precursor for the synthesis of polyamines, choline, and reduced glutathione (GSH), and it is the major methylat-ing agent for a vast number of molecules via specific methyltransferases. Patients with ALD have elevated plasma methionine levels, markedly delayed clearance of an oral methionine load, and decreased hepatic methionine adeno-syltransferase (MAT) activity (the enzyme responsible for conversion of methionine to SAMe). Hepatic-specific MAT

is highly sensitive to oxidative stress, and it is likely that subnormal hepatic MAT activity reported in ALD is due to oxidation of the active site. Studies from our laboratories have shown that SAMe downregulates production of the proinflammatory cytokine, TNF, in animal models of liver injury and in peripheral blood monocytes or macrophage cell lines in vitro. Mato and colleagues recently reported that patients with alcoholic liver cirrhosis who were randomized to receive SAMe (400 mg 3 times daily) for 2 years had decreased liver mortality/liver transplantation (16% versus 30%) compared to the placebo treated group.

Other Antioxidants

Vitamin E Vitamin E deficiency has been well documented in ALD. Vitamin E has been used extensively with hepato-protective effects in experimental models of liver injury, such as that induced by carbon tetrachloride or ischemia. Vitamin E has multiple potential beneficial effects including membrane stabilization, reduced NFkB activation and TNF production, and inhibition of hepatic stellate cell activation and collagen production. Unfortunately, the major randomized study of vitamin E in ALD did not show significant benefit and likely used an inadequate dose (500 mg).

GSH Prodrugs GSH is a tripeptide, which is synthesized from glutamate, cysteine, and glycine. GSH prodrugs have been used extensively in virtually every known experimental model of hepatotoxicity with beneficial results. The glutathione prodrug, N-acetylcysteine (given as Mucomyst) is the standard therapy for acetaminophen toxicity in humans. Maintaining adequate hepatocyte GSH levels has been documented to prevent acetaminophen liver injury. GSH pro-drugs can directly affect the hepatocyte, and they can also positively modulate proinflammatory cytokine production with inhibition of cytokines such as TNF and IL-8. However, large, randomized studies of GSH prodrugs using mortality as an outcome indicator are lacking in ALD.

Dilinoleoylphosphatidylcholine Dilinoleoylphosphatidyl-choline (a form of lecithin/soybean extract) has antioxidant, antifibrotic, and anticytokine activity in experimental rat models of ALD. However, a recently completed VA cooperative study failed to show significant benefit in human ALD.

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