Which is useful to decrease moality and renal failure in acute liver disease due to alcoholism
Pentoxyfylline Therapies for Acute Alcoholic Hepatitis and/or Alcoholic Cirrhosis Coicosteroids The rationale underlying the use of coicosteroids in acute alcoholic hepatitis is to ameliorate the characteristic inflammatory response which accompanies this disorder. These agents have well-known effects on the immune response, and reduce cytokine production, suppress the formation of acetaldehyde adducts and inhibit the production of collagen. Coico.ste raids have been studied in several randomized double-blind trials, and have been subject to a number of meta-analyses. Despite this intense interest, neither the source studies nor the meta-analyses have reached a consensus conclusion regarding the efficacy of coicosteroids in the treatment of acute alcoholic hepatitis. The most recent study of Mathurin et al. re-analysed the original data from three randomized trials that included patients with severe illness (102 patients were treated with placebo and 113 were treated with steroids). The 28-day survival was higher in the coicosteroid group, so that, for every five patients treated, one death was avoided. This benefit was consistent during the first year of treatment, but disappeared at 2 years of follow-up. Despite the apparent benefit of coicosteroids in severe illness, many clinicians remain sceptical about their use. One explanation for this phenomenon is that many potential candidates for coicosteroid therapy have one or more contraindications to treatment, such as coincidental bacterial infections, gastrointestinal bleeding or renal failure. An additional reason may be the conflicting data .from trials, including meta-analyses, which have failed to demonstrate a benefit of coicosteroids. Oxpentifylline (Pentoxifylline) Oxpentifylline (pentoxifylline) is a phosphodiesterase inhibitor used in the treatment of intermittent claudication. - In addition to improving the responses of red blood cells to defonning stress, oxpentifylline (pentoxifylline) inhibits the output of TNF-a by modulating the transcription of the TNF-a gene. Recently, Akridis et al. repoed a randomized, placebo-controlled clinical trial of oxpentifylline (pentoxifylline) involving 101 patients with severe alcoholic hepatitis. - Hepatorenal syndrome was the cause of death in six of 12 cases (50%) in the treated group and 22 of 24 cases (91.7%) in tire placebo group. Thus, the benefit of oxpentifylline (pentoxifylline) in treating acute alcoholic hepatitis appears to be related to a significant decrease in the risk of developing hepatorenal syndrome. - Although these data provide evidence of a dramatic benefit, they await the validation of independent randomized controlled clinical trials. Anti-TNF Therapy Acute alcoholic hepatitis is a potentially impoant indication for the use of direct anti-TNF-a agents, although the liming of their administration in relation to the last use of alcohol and the provision of appropriate prophylaxis against infection may be critical practical issues. - Up to now, only two human studies utilizing direct anti-TNF therapy in acute alcoholic hepatitis have been repoed. In one, the monoclonal antibody anti-TNF-a (infliximab) was compared with placebo in patients with alcoholic hepatitis receiving coicosteroids. - Although the histology did not improve, the 28-day Maddrey score Unproved significantly in the group receiving anti-TNF. Unfounately, moality data were not repoed and, in their absence, the interpretation of the Maddrey score as a surrogate end-point is questionable. In another recent study, open-label uncontrolled use of infliximab was described in 12 patients with acute alcoholic hepatitis. The authors repoed that more than 80% of patients survived for 15 months from the initiation of therapy. Although TNFa messenger RNA expression in the liver did not change, the expression of IL-8, a cytokine regulated mainly by TNF-a, was almost absent on day 28.1 Both studies provide suppo for randomized controlled trials of -04 appropriate power to determine whether anti-TNF-a treatment is efficacious in acute alcoholic hepatitis. Despite the evidence that alcoholic liver disease is associated with enhanced oxidative stress, this research has not been translated into clinical therapy. Studies published in abstract form have failed to show that different kinds of antioxidants (when compared with coicosteroids or placebo) confer any benefit in the treatment of acute alcoholic hepatitis. Turning to the use of antioxidants in the setting of cirrhosis, there have been several trials using silymarin (milk thistle) as antioxidant. In a double-blind, prospective, randomized clinical trial involving 170 patients with cirrhosis (91 patients with alcoholic cirrhosis), 87 patients were treated with 140 mg silymarin three times daily and 83 patients received placebo. The mean observation period was 41 months. Fifty of 87 (58%) silymarin-treated patients, as opposed to 32 of 83 (39%) placebo-treated patients, survived for 4 years or longer. This difference, which was significant at the P Another goal of antioxidant therapy involves the enhancement of the cell's own antioxidant capacity, which is the rationale for external supplementation of S-adenosyl methionine. A randomized, double-blind trial of S-adenosyl methionine or placebo was perfonned in 123 alcoholic cirrhotic patients. The overall moality/liver transplantation at the end of the trial decreased, from 30% in the placebo group to 16% in the treated group, although this difference was not statistically significant. In summary, there remains a lack of compelling evidence that antioxidants, such as silymarin, or membrane stabilizers, such as S-adenosyl methionine, exe a substantial salutary effect in patients with cirrhosis due to alcohol-mediated liver injury. Propylthiouracil The rationale underlying the use of propylthiouracil in the treatment of alcoholic liver disease rests on the observation that the most severe alcohol-induced damage is often in the perivenular area (zone 3), thereby resembling ischaemic injury. The putative mechanism of propylthiouracil to produce a benefit in this setting is by reducing hepatic oxygen consumption by hepatocytes. An initial trial by Halle et al. found no benefit of propylthiouracil in the treatment of alcoholic hepatitis. Some years later, Orrego et al. observed, in a larger coho, that the administration of propylthiouracil reduced the moality due to alcoholic liver disease. This randomized placebo-controlled clinical trial was remarkable Pr the care taken to monitor alcohol consumption by the study paicipants and thereby control for the greatest confounding factor complicating the interpretation of investigations of treatment for alcoholic liver disease. Despite such admirable study design and the demonstration of a statistically impressive benefit in propylthiouracil recipients compared with controls, propylthiouracil has not gained currency as a treatment for alcoholic liver disease. Moreover, a recent meta-analysis, including data from 710 patients with several forms of alcoholic liver disease, could not demonstrate any benefit of propylthiouracil on moality, liver-related moality, liver complications or liver histology. Colchicine Colchicine is an inhibitor of collagen synthesis. Unfounately, results regarding the use of colchicine in the treatment of liver cirrhosis are conflicting. The most potent data in suppo of its use come from the study by Kershenobich et al. In their study of colchicine for the treatment of all forms of cirrhosis, the 5-year survival rate was 74% in the colchicine-treated group compared with 34% in the placebo group. The 10-year survival rate was twice as great for the colchicinetreated group. This study was confounded by the high dropout rate. Fuhermore, a recent meta-analysis conducted by Rambaldi and Gluud, combining the results of 14 randomized clinical trials involving 1150 patients, demonstrated no significant beneficial effects of colchicine on moality, liver-related moality. complications of liver failure, liver biochemistry, liver histology or alcohol consumption. Conversely, colchicine was associated with a significantly increased risk of adverse events. Phosphatidylcholine Encouraging results have been obtained with some 'super' nutrients in the treatment of alcoholic liver disease. Phosphatidylcholine, purified from polyunsaturated lecithin, was discovered to oppose ethanol-induced fibrosis by decreasing the activation of stellate cells to transitional cells, and possibly also by stimulating collagenase activity. Recent evidence has suggested that phosphatidylcholine may have an effect on alcohol-induced liver damage by decreasing the activities of cytochrome P450 2E1, an oxidative enzyme implicated in alcohol metabolism, and by modulating TNF-a. Recently, a randomized, prospective, double-blind, clinical trial comparing phosphatidylcholine with placebo was conducted in 789 male alcoholics at 20 Veterans Affairs Medical Centers. All subjects demonstrated hepatic fibrosis that did not meet the criteria for cirrhosis on liver biopsy prior to the initiation of the study. Treatment was maintained for 2 years. No histological benefit was observed in the treated group compared with the placebo group
>Pentoxyfylline
>Orlistat
>S-Adenosyl methionine
>Syrlamysin