Gastroenterology

Gastroenterology

Volume 119, Issue 6, December 2000, Pages 1637-1648
Gastroenterology

Liver, Pancreas, and Biliary Tract
Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial,☆☆

https://doi.org/10.1053/gast.2000.20189Get rights and content

Abstract

Background & Aims: An earlier pilot study from our liver unit suggested benefit from treatment with pentoxifylline (PTX), an inhibitor of tumor necrosis factor (TNF), in severe acute alcoholic hepatitis. The aim of the present study was to evaluate this treatment in a larger cohort of patients. Methods: One hundred one patients with severe alcoholic hepatitis (Maddrey discriminant factor ≥ 32) entered a 4-week double-blind randomized trial of PTX (400 mg orally 3 times daily) vs. placebo. Primary endpoints of the study were the effect of PTX on (1) short-term survival and (2) progression to hepatorenal syndrome. On randomization, there were no differences in demographic and clinical characteristics or laboratory values (including TNF) between the 2 groups. Results: Twelve (24.5%) of the 49 patients who received PTX and 24 (46.1%) of the 52 patients who received placebo died during the index hospitalization (P = 0.037; relative risk, 0.59; 95% confidence interval, 0.35–0.97). Hepatorenal syndrome was the cause of death in 6 (50%) and 22 (91.7%) patients (P = 0.009; relative risk, 0.29; 95% confidence interval, 0.13–0.65). Three variables (age, creatinine level on randomization, and treatment with PTX) were independently associated with survival. TNF values on randomization were not predictive of survival; however, during the study period they increased markedly in nonsurvivors compared with survivors in both groups. Conclusions: Treatment with PTX improves short-term survival in patients with severe alcoholic hepatitis. The benefit appears to be related to a significant decrease in the risk of developing hepatorenal syndrome. Increasing TNF levels during the hospital course are associated with an increase in mortality rate.

GASTROENTEROLOGY 2000;119:1637-1648

Section snippets

Patient selection

The study was performed on patients hospitalized between August 1992 and May 1997 in the Liver Unit of the University of Southern California at Rancho Los Amigos Medical Center, in Downey, California. The study was approved by the Institutional Review Board before its initiation and periodically thereafter during the 5-year period of its conductance. Informed consent was obtained from all participating patients. Each patient had a history of heavy ethanol abuse and an admission diagnosis of

Patient characteristics

One hundred two patients were enrolled. There was 1 dropout: a patient from the PTX group left the hospital against medical advice 1 day after randomization. He received only 3 capsules of PTX and therefore was excluded from analysis. Of the remaining 101 patients, 49 (35 men and 14 women) received PTX and 52 (40 men and 12 women) received placebo. Mean age was 42.4 ± 8.2 years for the PTX group and 40.8 ± 8.7 years for the control group (P = 0.36; Table 1).

Demographic and clinical

Discussion

Increased production of TNF by monocytes12 and Kupffer cells20 has been reported in patients with acute alcoholic hepatitis, and levels of TNF correlated with mortality in some studies.7 Predisposition for alcoholinduced steatohepatitis appears to be genetically determined through increased TNF gene expression.21 TNF can cause hepatocyte injury either directly by binding to cytokine receptors or indirectly by attracting and activating neutrophils.22, 23, 24 Administration of human recombinant

References (41)

  • W DePew et al.

    Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy

    Gastroenterology

    (1980)
  • E Rodriguez-Rodriguez et al.

    Cytokine levels in acute alcoholic hepatitis: a sequential study

    Drug Alcohol Depend

    (1995)
  • JA Bianco et al.

    Phase I–II trial of pentoxifylline for the prevention of transplant-related toxicities following bone marrow transplantation

    Blood

    (1991)
  • MJ Ramond et al.

    A randomized trial of prednisolone in patients with severe alcoholic hepatitis

    N Engl J Med

    (1992)
  • TF Imperiale et al.

    Do corticosteroids reduce mortality from alcoholic hepatitis?

    Ann Intern Med

    (1990)
  • TB Reynolds et al.

    Treatment of acute alcoholic hepatitis

    Gastroenterol Int

    (1989)
  • M Black et al.

    Corticosteroids in severe alcoholic hepatitis

    Ann Intern Med

    (1989)
  • GLA Bird et al.

    Increased plasma tumor necrosis factor in severe alcoholic hepatitis

    Ann Intern Med

    (1990)
  • A Khoruts et al.

    Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients

    Hepatology

    (1991)
  • DB Hill et al.

    Increased plasma interleukin-8 concentrations in alcoholic hepatitis

    Hepatology

    (1993)
  • Cited by (688)

    • Alcoholic Hepatitis: The Rising Epidemic

      2023, Medical Clinics of North America
    • Identification and management of acute alcohol intoxication

      2023, European Journal of Internal Medicine
    • Alcoholic hepatitis

      2023, Comprehensive Guide to Hepatitis Advances
    View all citing articles on Scopus

    No reprints available.

    ☆☆

    Financial support for TNF measurements was kindly provided by Hoeschst-Roussel Pharmaceuticals Inc.

    View full text