EASL Clinical Practice Guidelines

Alcoholic hepatitis (alcoholic steatohepatitis)

Definition, incidence, and diagnosis

Alcoholic hepatitis is a clinical syndrome, i.e. recent onset of jaundice and/or ascites in a patient with ongoing alcohol misuse. Historically, it was referred to as “acute alcoholic hepatitis”. Although the clinical presentation may present abruptly, the term “acute” is not recommended, since it is an exacerbation of an underlying chronic liver disease and usually follows an extended course. ASH, a disease defined histologically, is the predominant cause of this syndrome, which can also result from infection, massive micro-vesicular steatosis, stone migration, drug-induced liver injury, etc. ASH is defined by the coexistence of steatosis, hepatocyte ballooning, and an inflammatory infiltrate with PMNs. The lesions defining alcoholic steatohepatitis do not differ in essence from those described in non-alcoholic steatohepatitis. ASH, however, is usually associated with more severe clinical course and histological lesions than NASH.

The annual incidence of ASH remains largely unknown. A retrospective Danish study based on diagnosis codes estimated the incidence to range from 24 to 46 per million in women and men, respectively [165]. Concerning its prevalence, a large study using systematic biopsies in 1604 alcoholic patients, symptomatic or not, showed the prevalence of ASH to be 20% of cases [107]. In symptomatic patients including those with decompensated liver disease, the prevalence of ASH is not well known, partly because most centers rely on clinical criteria and do not consider transjugular liver biopsy as a routine practice in the management of patients with decompensated ALD. Relying only on clinical criteria carries a 10–50% risk of wrongly classifying patients with or without ASH [[166], [167], [168]]. In a recent prospective cohort study of 250 patients, histological proven severe ASH was observed in 6% of the patients with a chronic hepatic decompensation and in 25% of the patients who developed an acute-on-chronic liver failure during admission [169].

Progressive jaundice is the main presenting feature of symptomatic ASH. It may be associated with fever with or without infection, weight loss and malnutrition, and a large tender liver. In severe cases, ASH may induce liver decompensation with ascites, encephalopathy, and gastrointestinal bleeding. With respect to biological tests, AST levels are typically elevated to 2–6 times the upper limit of the normal range with AST/ALT ratio greater than 2 and increased bilirubinemia and neutrophilia are also frequently observed. Depending upon the severity, serum albumin may be decreased, prothombin time prolonged and the international normalized ratio (INR) may be elevated. Patients with severe forms of ASH are prone to develop bacterial infection and acute renal failure due to Type 1 hepatorenal syndrome [170].

Prognostic models in alcoholic steatohepatitis

Prognostic models have been designed to identify patients with ASH at high risk of early death 1–2 months after hospitalization. The Maddrey discriminant function (DF) was the first score to be developed and remains the most widely used. Severe forms of ASH are defined as DF ⩾32 [[171], [172]]. In the absence of treatment, the 1-month spontaneous survival of patients with a DF ⩾32 has fluctuated between 50% and 65% [[172], [173]].

Other prognostic scores such the MELD (Model for End-Stage Liver Disease), the GAHS (Glasgow ASHScore) and the ABIC score (age, serum Bilirubin, INR, and serum Creatinine score) have been proposed in the setting of ASH. The initial studies testing those scores suggest higher diagnostic accuracy in predicting 28-day and 90-day outcome than DF, but external validation is still required and the proposed cut-off of those scores need to be tested outside the initial population of their development [[174], [175], [176], [177]].

It is important to stress that actual definition of severe forms is only based on two categories (severe versus non-severe) and early mortality risk. However, a proportion patients classified as having “non-severe ASH” die at later time points (i.e. up to 6 months). The ABIC score classified patients according to low, intermediate and high risk of death [174]. Such classification will permit the evaluation of drugs and help to calculate the sample size for such purpose.

Early improvement in liver function has a major impact on short-term mortality [254]. Several studies have demonstrated the utility of repeated testing and calculation of prognostic scores [[175], [176], [177]]. For example, a ⩾2 points change in the MELD score in the first week has been shown to predict in-hospital mortality [177]. A similar observation was obtained with the Lille score which includes the reduction in serum bilirubin at day 7 [178]. Based on a recent meta-analysis of individual patient data using 2 new cut-offs of the Lille score, three prognostic groups predicting the 6-month survival could be defined [179].

Management of ASH

General measures

Regardless of the severity, abstinence is the cornerstone of therapy and early management of alcohol abuse or dependence is warranted in all patients with ASH. Malnutrition is frequent and nutrition status should be evaluated. Considering the potential risk of Wernicke's encephalopathy, supplementation with B-complex vitamins is recommended. Independent from hepatic encephalopathy, a daily protein intake of 1.5 g/kg of body weight should be ensured. Liposoluble vitamins deficiency should be compensated.

Patients with symptomatic forms of ASH often develop acute renal failure which negatively impacts survival [170]. The most frequent causes of acute renal failure are Type 1 hepatorenal syndrome and tubular necrosis whereas glomerulonephritis or interstitial nephritis are uncommon [180]. Severe forms of ASH should be considered as a risk factor of radiocontrast-induced nephropathy. Measures aimed at preventing the development of renal failure are recommended. They include volume expansion if needed and early treatment of hepatorenal syndrome.

Infections are frequent and difficult to diagnose in these patients since SIRS criteria is common at admission and could reflect either the inflammatory state associated with the ASH episode or an ongoing bacterial infection. Systematic body fluid sampling and close clinical monitoring are advised for early detection of infection. In the absence of scientific evidence, criteria for initiating empirical antibiotic administration, although it is widely used, remain debated. In patients with severe ASH, infection screening at admission is particularly warranted because a quarter of them are infected at admission [181]. Patients with severe ASH and clinical or biological deterioration during their hospital stay disclose a even higher risk of infection and should be screened repeatedly.

Specific therapy in severe forms of alcoholic steatohepatitis

The following recommendations apply only to severe forms of ASH, as defined using the above prognostic scores predicting a high risk of early death (Table 3, Fig. 2).

Table 3
Comparison of the elements that constitute 5 prognostic instruments in alcoholic hepatitis (adapted from [254]).


Maddrey score, Maddrey discriminant function; GAHS, Glasgow Alcoholic Hepatitis Score; ABIC score, age, serum Bilirubin, INR, and serum Creatinine (ABIC) score; MELD score, Model-for-End-Stage-Liver-Disease score.


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Fig. 2
Therapeutic algorithm for the treatment of patients with alcoholic steatohepatitis (ASH). ∗A Lille score ⩾0.45 indicating non-response and increased risks of infection and death. In non responders, the interruption of corticosteroids is recommended particularly in those classified as null responders (Lille score >0.56). View Large Image | View Hi-Res Image | Download PowerPoint Slide

Corticosteroids

Meta-analyses of the literature yielded inconsistent results than can be mainly attributed to the wide variations in disease severity [182]. Three meta-analyses concluded that the survival effect of corticosteroids was restricted to severe disease [[183], [184], [185]], whereas Cochrane meta-analyses questioned the efficacy of corticosteroids in AH [[186], [187]]. The most recent Cochrane meta-analysis reported that corticosteroids significantly reduced mortality in the subgroup of trials that enrolled patients with a DF of at least 32 or hepatic encephalopathy [187]. Analysis of individual data from the five most recent randomized controlled trials [[168], [172], [173], [188], [189]] showed that patients allocated to corticosteroid treatment had higher 28-day survival than patients allocated to non-corticosteroid treatment [179].

Most studies indicate that only a limited proportion of patients with severe forms of ASH benefit from corticosteroids. Thus, early identification of non-responders to corticosteroids is important to define stopping rules [190] and limit unnecessary exposure [178]. For example, after 7 days on corticosteroids, a Lille score above 0.45 predicts poor response [178]. In poor responders, the interruption of corticosteroids is recommended particularly in those classified as null responders (Lille score >0.56) [179]. In poor responders, an early switch to pentoxifylline [191] or the use of a molecular adsorbent recirculating system (MARS) appears not to modify the outcome. Novel therapies are urgently needed for poor responders. In these patients, early liver transplantation may be considered after a careful selection process [192].

The applicability of corticosteroid therapy is limited by concerns about heightened risks of sepsis and gastrointestinal hemorrhage. Patients with gastrointestinal bleeding [184] or hepatorenal syndrome may be less responsive to steroid treatment than patients without these complications. In such circumstances, the outcome of patients may be related to these complications rather than to ASH itself. Up to now, in severe AH, infection has classically been viewed as a contraindication for corticosteroid treatment, although specific data are lacking. In patients with sepsis, pentoxifylline can be considered as a first line therapy. However, a recent study suggests that corticosteroid treatment may not be precluded in patients with infection after appropriate antibiotic therapy [181].

Pentoxifylline

Pentoxifylline has been evaluated in patients with ASH for its antioxidant and anti-TNF properties. When compared to placebo, patients with severe AH (DF ⩾32) treated with pentoxifylline exhibited a higher 6-month survival. This survival benefit was not accompanied by significant changes in liver function but related to a marked reduction in the incidence of hepatorenal syndrome [193]. One subsequent randomized controlled trial in patients with cirrhosis related or not with ALD also supported the preventive effect of pentoxifylline on hepatorenal syndrome [194]. However, a sensitivity analysis restricted to the subgroup of patients with severe AH (DF ⩾32), failed to show a significant difference in survival between the pentoxifylline and placebo treated patients.

One study comparing pentoxifylline to corticosteroids observed better outcome in pentoxifylline-treated patients, which was related to prevention of hepatorenal syndrome [195]. A recent, large randomized controlled trial of 270 patients with severe AH testing the combination of prednisolone and pentoxifylline (PTX) failed to show any benefit over corticosteroids alone [196].

Anti-TNF agents

A pilot randomized study in patients with severe ASH showed that single dose infliximab in combination with corticosteroids was well tolerated and associated with a significant improvement in Maddrey's score at day 28 [197]. However, the size of this study did not allow comparison with a control group [198]. However, the effectiveness of anti-TNFα was not confirmed in two randomized controlled trials testing multiple doses of infliximab [199] or etanercept [200]. In fact, anti-TNFα treatment was associated with a higher probability of severe infections and deaths. It may be speculated that repeated or excessive TNF blockade negatively affects liver regeneration.

N-acetylcysteine

N-acetylcysteine is an antioxidant substance and replenishes glutathione stores in hepatocytes. In a randomized controlled trial of N-acetylcysteine alone versus placebo there was no evidence of a significant effect [201]. In another randomized trial, N-acetylcysteine alone was inferior to corticosteroids in terms of short-term survival [173]. More recently, a randomized controlled trial observed that patients treated with combination therapy (corticosteroids and N-acetylcysteine) had better 1-month survival than patients treated with corticosteroids alone [202]. The rates of hepatorenal syndrome and of infection were lower in patients treated with corticosteroids and N-acetylcysteine. However, there was no significant difference in survival between the two groups at 6-months, the primary planned end point. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects. This strategy and the question of optimal duration of N-acetylcysteine administration should be evaluated in additional studies.

Enteral nutrition

Malnutrition due to impaired caloric intake and increased catabolism is frequent in patients with ASH. The recommended protein-caloric intake is often difficult to achieve orally in a significant proportion of patients with ASH.

A randomized controlled trial comparing enteral nutrition versus corticosteroids did not show any difference in 28-day mortality rate [203]. However, deaths occurred earlier with enteral nutrition whereas steroid therapy was associated with a higher mortality rate in the weeks following the treatment period. Enteral nutrition probably deserves to be tested in combination with corticosteroids.

Other therapies

There are no randomized studies evaluating extracorporeal liver supports, although pilot studies reported improvement in circulatory disturbances, liver, and renal parameters. None of these studies have a sufficient sample size to draw any conclusions regarding the use of these systems as a therapeutic option in patients with severe forms of ASH [204].

Three randomized controlled trials did not observe significant effects of propylthiouracil on short-term survival in patients with ASH [[205], [206], [207]]. Two studies did not observe any effect of colchicine on short-term survival [[208], [209]]. Thus, evaluation of propylthiouracil or colchicine is no longer recommended in future studies evaluating short-term survival.

Need for future studies

The treatment of ASH remains controversial and is one of the main challenges in ALD [170]. Short-term survival has been the primary outcome of studies evaluating therapy in severe forms of ASH. However, assuming a one or two-sided type I error ⩽0.05 and a power ⩾80%, this approach requires huge, unrealistic sample sizes. To overcome this limitation, it may be relevant to consider alternative end points, including early markers of poor outcome and/or combinations of criteria.

Little therapeutic information has been collected in patients with intermediate risk of death who are currently exempt from most clinical trials. Therefore, studies with appropriate designs and end points should focus on this patient population.

Recommendations

Suggestions for future studies

  1. Development of non-invasive tools for the diagnosis of ASH is of major interest.
  2. Use of primary end points other than short-term mortality should be encouraged to facilitate testing of new therapies in patients with ASH.
  3. Future studies should also focus on patients with ASH of intermediate severity since they have substantial mortality at 6-months.
  4. Translational studies should identify the molecular patterns, including liver inflammation and regeneration signaling, associated with differences in outcomes.