Correspondence

Glucocorticoids plus N-Acetylcysteine in Alcoholic Hepatitis

N Engl J Med 2012; 366:476-477February 2, 2012

Article

To the Editor:

The study by Nguyen-Khac et al. (Nov. 10 issue)1 sidesteps old contentious issues regarding the use of glucocorticoid therapy in alcoholic hepatitis. Among the 8 references cited in support of glucocorticoid treatment, 2 in fact concluded that the therapy was of no benefit.2,3 In addition, 8 of 13 clinical trials published since 1971 showed that glucocorticoid therapy had no benefit as compared with placebo, although 5 of these did suggest an association with decreased short-term mortality.

The rationale for treating alcoholic hepatitis with antiinflammatory agents is soft. It is illogical to inhibit cytokines instead of targeting the putative pathogens that induce them. Exposing immunocompromised patients with severe alcoholic hepatitis to high-dose steroids exacerbates their already increased risk of infection, and the benefits are far from proven. In a multicenter trial of prednisolone and infliximab in the treatment of severe alcoholic hepatitis, increased mortality in the infliximab group caused premature termination of the study.4

In the study by Nguyen-Khac et al., N-acetylcysteine was associated with fewer infectious complications, but the primary outcome was not improved. The idea of adding one unproven treatment to another has little merit.

Gerond Lake-Bakaar, M.D.
Harvard Medical School, Boston, MA
glakebak@bidmc.harvard.edu

No potential conflict of interest relevant to this letter was reported.

4 References

1. 1

   Nguyen-Khac E, Thevenot T, Piquet M-A, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011;365:1781-1789
   Full Text | Web of Science | Medline

2. 2

   Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis: natural history and evaluation of prednisolone therapy. Ann Intern Med 1971;74:311-321
   Web of Science | Medline

3. 3

   Mendenhall CL, Anderson S, Garcia-Pont P, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984;311:1464-1470
   Full Text | Web of Science | Medline

4. 4

   Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004;39:1390-1397
   CrossRef | Web of Science | Medline

Author/Editor Response

Since 1978, when patients with severe alcoholic hepatitis were first identified with the use of Maddrey's discriminant function (with a value greater than 32 indicating severe disease), the evidence has been growing that survival is improved by treatment with glucocorticoids. Even a negative meta-analysis,1 in addition to a reanalysis of a negative trial,2 reported better survival when the discriminant function was used to identify patients with severe disease. The American Association for the Study of Liver Disease has issued clear guidelines for the use of glucocorticoids.3 In a prospective study,4 246 patients with severe alcoholic hepatitis were treated with glucocorticoids. The overall incidence of infections after treatment was 23.7%. However, in the patients with a treatment response (defined according to the Lille model, in which a score of <0.45 after 7 days of medical treatment indicates response), only 11.1% had infections as compared with 42.5% of the patients who did not respond to treatment glucocorticoid treatment (P<0.001).

Infections caused by glucocorticoids are feared. However, 25.6% of patients with severe alcoholic hepatitis are infected before glucocorticoid treatment, suggesting a need for routine screening for infection before treatment begins.4 In one study, the risk of infection in the group of patients with severe alcoholic hepatitis who were treated with glucocorticoids was no higher than it was in a control group of patients with cirrhosis who were not treated with glucocorticoids.5

It is time to move on to other questions, as we have done by showing an improvement in early survival by combining glucocorticoids with N-acetylcysteine. In our study, there were fewer deaths from the hepatorenal syndrome and fewer infections in the group treated with glucocorticoids plus N-acetylcysteine as compared with the group treated with glucocorticoids alone.

Eric Nguyen-Khac, M.D., Ph.D.
Amiens University Hospital, Amiens, France

Thierry Thevenot, M.D., Ph.D.
Besançon University Hospital, Besançon, France

Marie-Astrid Piquet, M.D., Ph.D.
Caen University Hospital, Caen, France

Since publication of their article, the authors report no further potential conflict of interest.

5 References

1. 1

   Rambaldi A, Saconato HH, 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;27:1167-1178
   CrossRef | Web of Science | Medline

2. 2

   Mathurin P, Mendenhall CL, Carithers RL Jr, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002;36:480-487
   CrossRef | Web of Science | Medline

3. 3

   O'Shea RS, Dasarathy S, McCullough AJ, et al. Alcoholic liver disease. Hepatology 2010;51:307-328
   CrossRef | Web of Science | Medline

4. 4

   Louvet A, Wartel F, Castel H, et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 2009;137:541-548
   CrossRef | Web of Science | Medline

5. 5

   Richardet J, Valtier S, Campillo B. Evaluation du risqué infectieux au cours de la corticotherapie pour hépatite alcoolique grave. Journées Francophones de pathologie digestive 2008, Palais des Congrés de Paris. Abstract.