Lynda Rennie-Tankersley

A randomized placebo controlled trial of vitamin E for alcoholic hepatitis

BACKGROUND/AIMS The effect of vitamin E administration on clinical and laboratory parameters of liver function and on markers of fibrogenesis was assessed in patients with mild to moderate alcoholic hepatitis in a double blind placebo controlled randomized trial. METHODS Twenty-five patients received 1000 I.U. of vitamin E per day, while 26 patients received placebo for 3 months. The patients were followed for 1 year after entry into the trial. RESULTS Vitamin E did not result in significant greater decreases in serum aminotransferases and serum bilirubin or in greater increases in serum albumin as compared with placebo. Prothrombin time did not change, while serum creatinine remained in the normal range. Monocyte nuclear nuclear factor-kappa B binding activity decreased in patients who remained abstinent, regardless of whether they received vitamin E. As regards markers of hepatic fibrogenesis, vitamin E treatment decreased serum hyaluronic acid (P<0.05) while serum aminoterminal peptide of type III procollagen did not change in either group. Four patients in the treatment group and five in the placebo group died during the 1-year study. CONCLUSIONS Vitamin E treatment improves serum hyaluronic acid but has no beneficial effects on tests of liver function in patients with mild to moderate alcoholic hepatitis.

Endotoxin Enhances Liver Alcohol Dehydrogenase by Action through Upstream Stimulatory Factor but Not by Nuclear Factor-κB

Liver alcohol dehydrogenase (ADH) is increased by physiological stress and by chronic administration of growth hormone (GH). Endotoxin plays a role in the pathogenesis of alcoholic liver disease. The effect of lipopolysaccharide (LPS), the endotoxin component of Gram-negative bacteria, was determined on liver ADH. LPS given daily to rats for 3 days increased ADH mRNA, ADH protein, and ADH activity. Nuclear factor-κB (NF-κB) in the liver nuclear extracts bound to an oligonucleotide specifying region −226 to −194 of the ADH promoter, whereas upstream stimulatory factor (USF) was shown previously to bind to a more proximal site. LPS increased NF-κB and USF binding to the ADH promoter. The NF-κB (p65) and NF-κB (p50) expression vectors inhibited the transfected ADH promoter activity, which contrasts with the previously demonstrated stimulation by an USF expression vector. The binding activities of STAT5b and of C/EBPβ, which mediate the effect of GH on ADH, were not changed or decreased, respectively, by LPS, indicating that GH plays no intermediary role in the effect of LPS. This study shows that LPS increases ADH and that this effect is mediated by increased binding of USF to the ADH promoter and not by NF-κB, which has an inhibitory action.