Randomized, Controlled Trial of S-adenosylmethionine in Alcoholic Liver Disease
Randomized, Controlled Trial of S-adenosylmethionine in Alcoholic Liver Disease
Background: Alcoholic liver disease is one of the most important causes of chronic liver
 disease in this country. There is currently no treatment for chronic alcoholic liver disease
 other than abstinence. Hepatic methionine metabolism is abnormal in these patients and one of
 the consequences is depletion of S-adenosylmethionine (SAMe) levels, which can affect
 numerous important cellular processes. SAMe has been increasingly utilized for the treatment
 of liver diseases although the protective mechanisms remain unclear. A recent randomized
 double-blind trial using SAMe in patients with alcoholic liver disease and found improvement
 in 2-year survival in those with less advanced liver disease. However, important changes in
 methionine metabolism and histological changes were not included in the study. Aim: The goal
 of this study is to determine the effect of SAMe administration on key metabolic
 abnormalities of the methionine cycle and on the recovery from alcoholic liver disease.
Methods: This is a randomized, double blind, placebo-controlled trial. Thirty patients with
 stable alcoholic hepatitis (Maddrey Score < 32) without cirrhosis who meet entry criteria
 will receive either 400 mg of SAMe (n=15) or placebo (n=15) three times a day for the
 duration of one year. History, physical assessment, various blood tests and a liver biopsy
 will be performed prior to treatment. Patients will have repeat blood tests on subsequent
 follow-up visits every month for the first two months, then every two months thereafter. They
 will also be encouraged to abstain from alcohol during these visits. A post-treatment liver
 biopsy will be obtained at the end of the trial. The primary outcome parameters include serum
 homocysteine, SAMe and TNFalpha levels, and the expression of key hepatic enzymes of the
 methionine cycle and of hepatic SAMe and glutathione levels. Histological progression of
 alcoholic liver disease, clinical and biochemical indices of liver disease, and quality of
 life assessment will also be examined.
Inclusion Criteria:

 -  Patients must be chronic alcohol users, defined by a history of ethanol consumption on
 average > 40g/day for women and 60g/day for men for at least 1 year before inclusion.

 -  The presumptive diagnosis for alcoholic hepatitis will be: recent binge drinking;
 compatible physical findings (one or more: jaundice, enlarged liver, hepatic bruit,
 abdominal pain, loss of appetite, nausea); and a compatible biochemical profile
 (moderate elevation of AST over ALT, elevated total serum bilirubin); or a
 liver-spleen colloid scan suggestive of reticulo-endothelial redistribution and
 hepatic arterialization.

 -  The diagnosis of alcoholic hepatitis must be confirmed on liver biopsy, showing
 typical features of acute sclerosing hyaline necrosis 70.

 -  The degree of portal fibrosis as determined on liver biopsy, graded according to the
 Knodell score-modified by Ishak 71 must be less than or equal to 5 out of a possible
 score of 6, 6 indicating cirrhosis.

 -  The alcoholic hepatitis must be "stable", i.e. not requiring treatment by either
 pentoxifylline 72 or prednisone, with a Maddrey Score 73 {(PTpatient - PTcontrol) x
 4.6 + TBmg/dL} < 32.

 -  Patients must be willing to participate in the trial, remain abstinent to alcohol, and
 compliant to the treatment regimen, and undergo a post-treatment liver biopsy.

 Exclusion Criteria:

 -  Patients who have either compensated cirrhosis (biopsy proven) or a clinical picture
 of severe cirrhosis defined as Child's class C and/or with a recent history (within
 one month) of decompensated liver disease (history of ascites, encephalopathy or
 variceal bleeding within one month of trial entry). These patients have reduced life
 expectancy below one year and are most often severely coagulopathic and cannot be
 biopsied.

 -  Patients who have severe acute alcoholic hepatitis of poor prognosis defined as a
 Maddrey Score > 32. These patients have a mortality rate of 50% during their
 hospitalization period when untreated by either prednisone or pentoxifylline.

 -  Patients who are receiving hepatotropic treatments such as colchicine, penicillamine,
 corticosteroids, ursodeoxycholic acid, and pentoxifylline.

 -  Patients who are receiving known hepatotoxic long-term treatments such as NSAIDs,
 statins, neuroleptics, certain anti-convulsive medications, or high-dose
 acetaminophen.

 -  Patients suspected of having hepatocellular carcinoma.

 -  Patients who have contra-indications to liver biopsy.

 -  Patients who have a liver biopsy that does not yield sufficient specimen for analyses.

 -  Patients who have untreated deficiencies of folic acid, vitamin B6 or B12.

 -  Patients who have chronic active Hepatitis B or C, hemochromatosis, autoimmune
 hepatitis, or a cholangiopathy.

 -  Patients with psychotic disorders, and in particular manic depression (contra
 indication to SAMe treatment).