Glucocorticosteroids in acute alcoholic hepatitis: The evidence of a beneficial effect is getting even weaker (2010)

The effect of glucocorticosteroid therapy in acute alcoholic hepatitis has been debated for more than 40 years [1Conn H.O. Steroid treatment of alcoholic hepatitis. The yeas and the nays.Gastroenterology. 1978; 74: 319-322PubMed Scopus (24) Google Scholar, 2Christensen E. Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables.Gut. 1995; 37: 113-118Crossref PubMed Scopus (146) Google Scholar, 3Christensen E. Alcoholic hepatitis – glucocorticosteroids or not?.J Hepatol. 2002; 36: 547-548Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 4Rambaldi A. Saconato H.H. Christensen E. Thorlund K. Wetterslev J. Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008; 27: 1167-1178Crossref PubMed Scopus (177) Google Scholar]. Although a large number of controlled clinical trials have been performed, there is still insufficient evidence to support glucocorticosteroids for patients with alcoholic hepatitis [[4]Rambaldi A. Saconato H.H. Christensen E. Thorlund K. Wetterslev J. Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008; 27: 1167-1178Crossref PubMed Scopus (177) Google Scholar]. Since autoimmunity is not a significant feature of this disease, the rationale behind the use of glucocorticosteroids, is to block cytotoxic and inflammatory pathways [[5]Tan H.H. Virmani S. Martin P. Controversies in the management of alcoholic liver disease.Mt Sinai J Med. 2009; 76: 484-498Crossref PubMed Scopus (27) Google Scholar]. However, the potential side-effects of glucocorticosteroids are numerous including anti-anabolism, muscle breakdown (proteolysis), immunosuppression, increased susceptibility to infection, and increased risk of GI bleeding. Originally, glucocorticosteroids were claimed to benefit any patient with alcoholic hepatitis. Later the beneficial effect was restricted to those with hepatic encephalopathy, later again, to those with a Maddrey discriminant function ⩾32. Most recently, the group with a claimed beneficial effect of glucocorticosteroids has been reduced even further. In a study from Glasgow the beneficial effect was confined to the subgroup of patients with a Maddrey discriminant function ⩾32 and a Glasgow alcoholic hepatitis score ⩾9 [[6]Forrest E.H. Morris A.J. Stewart S. Phillips M. Oo Y.H. Fisher N.C. et al.The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.Gut. 2007; 56: 1743-1746Crossref PubMed Scopus (102) Google Scholar]. However, this study was not performed as a controlled study. In the minority of the patients, who were included in randomised controlled trials, there was no significant beneficial effect of glucocorticosteroid therapy in the subgroup in question [[6]Forrest E.H. Morris A.J. Stewart S. Phillips M. Oo Y.H. Fisher N.C. et al.The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.Gut. 2007; 56: 1743-1746Crossref PubMed Scopus (102) Google Scholar]. Recently the so-called Lille prognostic model has been used to identify ‘responders’ and ‘non-responders’ to glucocorticosteroid therapy in alcoholic hepatitis [[7]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (503) Google Scholar]. This model has been developed and validated exclusively for glucocorticosteroid treated patients [[7]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (503) Google Scholar]. The predominant variable in the Lille model is the one week change in bilirubin. A decrease in this variable from day 0 to day 7 is considered a major indicator of being a ‘responder’ to glucocorticosteroid therapy. The ‘non-responders’, according to the Lille model, have a six month survival of only 25% on glucocorticosteroid therapy [[7]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (503) Google Scholar]. In a recent meta-analysis based on individual data from the five latest randomised controlled trials, the beneficial effect of glucocorticosteroids was confined to the subgroup of ‘responders’ according to the Lille model [[8]Mathurin P. O’Grady J. Carithers R.L. Martin P. Ramond M.-R. Louvet A. et al.Corticosteroids improve 28-day survival in patients with severe alcoholic hepatitis: individual data analysis of the last 5 randomized controlled trials.Hepatology. 2008; 48: S635ACrossref Scopus (26) Google Scholar]. The ‘non-responders’ according to the model had no significant effect from glucocorticosteroid therapy. The problem with this analysis is that the Lille model has only been shown to apply to glucocorticosteroid treated patients. The control groups in this meta-analysis were not treated with glucocorticosteroids and the Lille model may not apply to those patients. Most likely the coefficients in the model would be different in the control patients. There could even be an interaction between the therapy (glucocorticosteroid/control) and the variables included in the model calling for a comprehensive analysis based on data from both treatment and control patients [[9]Christensen E. Schlichting P. Andersen P.K. Fauerholdt L. Juhl E. Poulsen H. et al.A therapeutic index that predicts the individual effects of prednisone in patients with cirrhosis.Gastroenterology. 1985; 88: 156-165Abstract Full Text PDF PubMed Scopus (28) Google Scholar]. Considering all these reasons, the results of this meta-analysis seem questionable. Furthermore, the study was based on a selected part of the available trials [[4]Rambaldi A. Saconato H.H. Christensen E. Thorlund K. Wetterslev J. Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.Aliment Pharmacol Ther. 2008; 27: 1167-1178Crossref PubMed Scopus (177) Google Scholar], possibly suggesting a selection bias. The Lille group has recognized that infections may be a serious problem of glucocorticosteroid therapy in alcoholic hepatitis [[10]Louvet A. Wartel F. Castel H. Dharancy S. Hollebecque A. Canva-Delcambre V. et al.Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor.Gastroenterology. 2009; 137: 541-548Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar]. Nevertheless, it has been suggested that all patients with the disease should have at least one week of glucocorticosteroids to see if they would be ‘responders’ (decrease in bilirubin from day 0 to day 7) according to the Lille model. This strategy implies that potential ‘non-responders’ would need to receive one week of therapy, which may be deleterious, and possibly lead to a six month survival probability of only 25% [[7]Louvet A. Naveau S. Abdelnour M. Ramond M.J. Diaz E. Fartoux L. et al.The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.Hepatology. 2007; 45: 1348-1354Crossref PubMed Scopus (503) Google Scholar]. Such a strategy seems very problematic. Over the years the evidence in favour of glucocorticosteroid therapy in alcoholic hepatitis has steadily decreased, and now it seems to be the time to move on other to therapies with more potential, e.g., pentoxifylline. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.