|Home | About | Journals | Submit | Contact Us | Français|
Correspondence to: Ashwani K Singal, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905-0001, United States. firstname.lastname@example.org
Telephone: +1-507-2664056 Fax: +1-507-2664056
The treatment of choice for patients with severe alcoholic hepatitis (AH) is use of corticosteroids. Many randomized well designed studies have been reported from all over the world on the use of corticosteroids in the treatment of AH. However, the data on the efficacy of corticosteroids in these patients have been conflicting. Initial meta-analyses also failed to show beneficial effects of corticosteroids. Based on individual data meta-analysis showing clear benefit of corticosteroids amongst patients with severe AH (modified discriminant function of 32 or more), led American College of Gastroenterology to recommend use of corticosteroids as the first line treatment option amongst patients with severe AH. However, corticosteroids are relatively contraindicated amongst patients with severe AH and coexistent sepsis, gastrointestinal bleeding, and acute pancreatitis. These patients may be candidates for second line treatment with pentoxifylline. Further, specific treatment of AH with corticosteroids far from satisfactory with as many as 40%-50% of patients failing to respond to steroids, thus classified as non-responsive to steroids. The management of these patients is a continuing challenge for physicians. Better treatment modalities need to be developed for this group of patients in order to improve the outcome of patients with severe AH. This article describes at length the available trials on use of corticosteroids and pentoxifylline with their current status. Route of administration, dosage, adverse effects, and mechanisms of action of these two drugs are also discussed. Finally, an algorithm with clinical approach to management of patients who present with clinical syndrome of AH is described.
Patients with severe alcoholic hepatitis (AH) have a short-term mortality of about 40%-50%. Therefore, these patients should be identified early and treated appropriately. Two established specific agents for treating severe AH are corticosteroids and pentoxifylline.
The choice for treating patients with established and diagnosed cases of severe AH is corticosteroids. There have been 12 randomized placebo controlled trials (RCT) to assess the benefit of corticosteroids in AH patients (Table (Table1).1). Results from these RCTs, conducted during the last 40 years, have varied with the sample size, inclusion/exclusion criteria, disease severity, end-points, type of corticosteroid used and treatment duration. These studies have shown conflicting data on the benefit of steroids with only five studies showing a survival benefit (Table (Table11).
Meta-analyses of RCTs provide the best evidence for efficacy. To date, four meta-analyses have been published on the efficacy of steroids in AH[2-5]. The latest Cochrane analysis concluded that there is no clear evidence that steroids are effective in the management of AH. The potential for bias is due to heterogeneous data. However, the same meta-analyses concluded that steroids do have survival benefit for patients with severe AH (discriminant function index, DFI ≥ 32).
One of the means to tackle the issue of heterogeneity is to perform meta-analysis on the individual patient data from each study. This had been performed earlier by Mathurin and colleagues from France where they analyzed individual patient data from 3 RCTs. The results of this meta-analysis showed that steroids have survival advantage for severe AH with 28 d survival of 85% among treated patients and 65% for patients receiving placebo (P = 0.001). This was also associated with improvement of liver function starting within the first week of starting the steroids.
Corticosteroids act by reducing inflammatory cytokines such as tumor necrosis factor-α (TNF-α), intercellular adhesion molecule 1, interlukin (IL)-6 and IL-8[7,8]. Inflammation is a major component of AH pathogenesis. In fact, in one study, peripheral white blood cell count > 5500/cm and the amount of polymorphonuclear leucocytic infiltration on the liver biopsy specimen were independent predictors for response and survival on steroid treatment.
Although, many agents have been used across different studies, prednisolone is preferred (but not demonstrated to be better) over prednisone as the latter requires conversion within the liver to its active form, prednisolone. The drug is given orally in a dose of 40-60 mg/d for a total duration of 4 wk. The treatment is then tapered over next 2-3 wk. If the patient is unable to take it orally due to nausea, vomiting or altered sensorium, an intravenous preparation such as methylprednisolone may be used until the patient is capable to take medication by mouth.
It is prudent to screen patients for any contraindication prior to starting steroids. One of the most important contraindications is the presence of infection which is fairly common among patients with severe AH. This used to be considered an absolute contraindication for steroids. However, the latest data from France have shown that if a patient is adequately treated for an established infection, steroids can be safely started and even improve the outcome in these patients. In this study, all 246 patients studied prospectively were treated with steroids. Patients with infection (25% of the group) were treated adequately with antibiotics prior to starting steroids. Survival with steroids at 2 mo was similar, irrespective of the presence of infection prior to starting steroids (71% vs 72%, P = 0.99).
Other contra-indications are an active gastrointestinal bleeding, renal failure, acute pancreatitis, active tuberculosis, uncontrolled diabetes and psychosis. Patients should be assessed for response to steroids. It has been shown that a decrease in bilirubin at 1 wk (early change in bilirubin, ECBL) is a reliable and specific marker for response. Patients who achieved ECBL had a better survival at 6 mo compared to patients who did not achieve ECBL (98.3% vs 23%, P < 0.0001). Based on ECBL and other variables, French workers have derived a score (Lille score) based on the patient’s age, serum albumin, ECBL, renal insufficiency and prothrombin time. Patients with a Lille score of ≥ 0.45 are defined as non-responders to steroids (NRS). This score, with a cut off at 0.45, has an accuracy of 75% in predicting death at 3-6 mo. Patients should also be screened for infective complications while on steroids. Occurrence of sepsis and infective complications while the patient is on steroids is a poor prognostic sign. A total of 57 patients developed infection after starting steroids which occurred more frequently among NRS than responders to steroids (42% vs 11%, P < 0.000001). Lille score was an independent predictor for the occurrence of infection after starting steroids.
For patients who have contraindications to steroids, the second option for treatment is oral pentoxifylline (PTX), a phosphodiesterase and a possible TNF-α inhibitor (Figure (Figure1).1). The drug was first shown to have beneficial effect in AH in a double blind placebo controlled RCT. The study showed survival benefit at 1 mo with the use of PTX compared to placebo (76% vs 54%). This benefit was attributed mainly to the prevention of the hepatorenal syndrome (HRS) among patients treated with PTX as compared to placebo (50% vs 92%, P < 0.05). Later, many studies (reported as abstracts) confirmed this observation of beneficial effect of PTX in the prevention of HRS (Table (Table2).2). A study published recently comparing steroids to PTX showed superiority of PTX in the treatment of AH patients with better survival rate at 3 mo (85% vs 65%, P = 0.04). This was again mainly due to prevention of HRS by PTX (6 of 34 patients receiving steroids developed HRS compared to none of 34 receiving PTX). However, the latest Cochrane systematic review of 5 RCTs (4 reported as abstracts) concluded that there is not enough evidence for survival benefit of PTX in the treatment of AH. However, the problem with these studies is a small sample size. Further, four of these five studies are reported as abstracts.
The question of whether PTX is a salvage option for patients with NRS was answered by a study in which patients were identified as NRS at 1 wk (Lille score ≥ 0.45) and randomized to PTX or placebo. Steroids were continued in both the groups for 28 d. The use of additional PTX failed to demonstrate survival advantage at 2 mo (36% vs 31%, P > 0.05). Further, there was no benefit shown on the biochemical parameters. Clearly, PTX was not shown to be an option for patients with NRS. However, the drug has not been studied in patients with NRS without additional steroids. Since patients with NRS are prone to develop infectious complications, this might have abrogated the benefit of PTX. Occurrence of infective complications and/or sepsis as cause of death was not reported in this study. Although the evidence for efficacy of PTX for severe AH is weak, this drug may be a second line option and is worth considering until newer and more effective agents are developed.
PTX is given orally at a dose of 400 mg three times a day for a total duration of 28 d. Although an anti-TNF agent, the TNF levels were not shown to be different among patients receiving PTX and those receiving placebo. The exact mechanism of action of PTX is not entirely clear. Neutralization of TNF-α by PTX may explain the protective effect of this drug on HRS although the exact mechanism is not clear.
Peer reviewers: Shivendra D Shukla, PhD, Professor, Department of Medical Pharmacology & Physiology, University of Missouri, School of Medicine M517B Medical Sciences Building One Hospital Drive Columbia, Missouri 65212, United States; Henning Grønbæk, MD, PhD, Associate Professor, Medical Department V, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark
S- Editor Zhang SJ L- Editor Roemmele A E- Editor Zheng XM