J R Coll Physicians Edinb 2007; 37:3–8 PAPER © 2007 Royal College of Physicians of Edinburgh A clinical approach to alcoholic hepatitis EH Forrest Consultant Hepatologist, Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, Scotland ABSTRACTThere has been a dramatic increase in alcoholic liver disease in Scotland Published online March 2007 over recent years. Alcoholic hepatitis is perhaps the most florid manifestation of this, however considerable controversy exists regarding its diagnosis and Correspondence to E Forrest, management. This review indicates that it is possible to confidently make a Department of Gastroenterology, diagnosis of alcoholic hepatitis on clinical grounds using a minimum threshold of Wards 8/9, Glasgow Royal Infirmary, serum bilirubin as a diagnostic criterion. All patients with alcoholic hepatitis need Castle Street, Glasgow G4 0SF GENERAL MEDICINE nutritional assessment and support. The severity of alcoholic hepatitis can be tel. +44 (0)141 211 0734 ascertained using the Discriminant Function, however the Glasgow Alcoholic Hepatitis Score appears to be more specific and accurate predictor of outcome. fax. +44 (0)141 552 6126 Patients with severe disease should be considered for specific treatment. The evidence is in favour of corticosteroids which have the added benefit of allowing e-mail Ewan.Forrest@northglasgow. responsiveness to the treatment to be assessed after one week. Pentoxifylline scot.nhs.uk may be a useful alternative to corticosteroids. The patients with alcoholic hepatitis and concomitant sepsis have a very poor prognosis. Previously regarded as a contraindication to specific treatment, it might be beneficial to broaden the indications for corticosteroids or pentoxifylline in these patients. KEYWORDS Alcoholic hepatitis, corticosteroids, Pentoxifylline LIST OF ABBREVIATIONS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), Discriminant Function (DF), non-alcoholic steatohepatitis (NASH), modified Discriminant Function (mDF), Glasgow Alcoholic Hepatitis Score (GAHS), International Normalised Ratio (INR), Model of End-stage Liver Disease (MELD), prothrombin time (PT) DECLARATION OF INTERESTS No conflict of interests declared. Alcohol related mortality in Scotland has increased by Vomiting 45% 236% between 1980 and 2002.1 Alcohol related liver Hepatomegaly 86% disease accounts for many of these deaths. Whilst many patients presenting with alcoholic liver disease will have Splenomegaly 7% cirrhosis, more than 60% will have evidence of an alcohol ↑ AST 85% related hepatitis.2 Alcoholic hepatitis is the most florid manifestation of alcohol related liver disease, but is ↑ Bilirubin 65% potentially reversible. It is widely appreciated as being a ↑ Alk Phos 64% common reason for acute medical admission and ↑γ recognised to have a 28 day mortality of up to 60%.3 GT 91% However there exists considerable debate regarding the ↑ WCC 29% diagnosis of this condition and little consensus upon its ↓ management. The following article is not a systematic Albumin 48% review, but rather a description of a clinical approach to Ascites 28% this condition. Encephalopathy 5% WHAT IS ALCOHOLIC HEPATITIS? TABLE 1 Clinical and laboratory associations of biopsy-proven alcoholic hepatitis.2 In view of the importance of this diagnosis, this may seem an odd question. However the answer to the question features are seen in NASH. However with a compatible depends upon who you are. To a pathologist the answer history and biochemical picture, histology is the ‘gold is quite simple. The pathognomic features of alcoholic standard’ for diagnosis of alcoholic hepatitis. hepatitis are a steatohepatitis often with Mallory bodies. There is an associated neutrophil infiltrate and the However there are problems with obtaining histology in damage is most apparent around the central veins (zone the clinical setting. The presence of ascites and/ or a 3). These appearances are not entirely specific as identical coagulopathy will often contraindicate percutaneous liver 3 EH Forrest Study Criteria Number % with Alcoholic Score Given 1 2 3 Hepatitis Age <50 50 - ‘Alcoholism and Liver 666 86·6% 9 WCC (10 /l) <15 15 - Dysfunction’6 Urea (mmol/l) <5 5 - mDF > or 324, 7–9 272 84·2% PT ratio or INR <1·5 1·5–2·0 >2·0 μ 10–14 Bilirubin 80–85 mol/l 129 99·2% Bilirubin (μmol/l) <125 125–250 >250 TABLE 2 Accuracy of a clinical diagnosis of alcoholic hepatitis relative to different criteria. TABLE 4 The Glasgow Alcoholic Hepatitis Score. Scoring System Formula Day 28 Outcome Day 84 Outcome (Sen/Spec; (Sen/Spec; Discriminant (4·6 x PT) + PPV/NPV; Accuracy) PPV/NPV; Accuracy) Function Serum Bilirubin (mg/dl) GENERAL MEDICINE Day 1 GAHS</ 9 54/89; 61/86; 43/90; 67/77; Modified 4·6 (PTPATIENT – PTCONTROL) + Data 81% 75% Discriminant Serum Bilirubin (γmol/l) / 17·1 Function mDF</ 32 82/39; 29/88; 79/40; 38/80; MELD score 3·8 x loge(bilirubin, mg/dl) + 49% 53% 11·2 x loge(INR) + 9·6 x loge(creatinine, mg/dl) Day 6–9 GAHS</ 9 66/85; 54/91; 56/88; 67/83; Data 81% 78% TABLE 3 Scoring systems used in the assessment of alcoholic hepatitis. mDF</ 32 92/41; 30/95; 88/44; 41/89; 52% 57% TABLE 5 Accuracy of GAHS. biopsy. These risks can be minimised by performing a are: a history of recent excessive alcohol ingestion; serum transjugular liver biopsy, but the appropriate expertise bilirubin >80 µmol/l; AST <500 iu (or ALT <300 iu); and may not be immediately available. Thus, histology may not exclusion of autoimmune, chronic viral or malignant liver be obtainable, or reliance upon it for diagnosis may result disease. Characteristic features of alcoholic hepatitis (but in delay before appropriate management can be instituted. not necessary for diagnosis) include pyrexia, hepatomegaly, a hepatic bruit, ascites, encephalopathy, an Alcoholic hepatitis to the clinician is different to that of AST:ALT ratio greater than 1.5, and a peripheral the pathologist. Most clinicians would suspect alcoholic leucocytosis. hepatitis at the onset of jaundice, possibly other manifestations of decompensated liver disease such as Whilst nearly all patients who fulfil these criteria will have ascites and encephalopathy, in the context of excessive features of alcoholic hepatitis on biopsy, approximately alcohol ingestion. However in an excellent study by 50–60% will also have established cirrhosis. There is no Hislop et al, patients throughout Scotland and North East evidence that co-existing cirrhosis worsens the short- England were biopsied in the assessment of alcoholic liver term outcome of patients with alcoholic hepatitis, disease.2 It is clear from this that there is a discrepancy indicating that it is the acute inflammatory process which between the histological picture of alcoholic hepatitis and is primarily responsible for the poor prognosis of these the commonly recognised presentation of the condition patients. The presence of cirrhosis (confirmed or (see Table 1). Only 65% of patients with histological suspected) should therefore not prevent consideration of evidence of alcoholic hepatitis in this study were specific treatment for alcoholic hepatitis. jaundiced and only 5% had signs of encephalopathy. ASSESSMENT OF SEVERITY (TABLES 3 AND 4) So the practical clinical question is how definite can we be about a diagnosis of alcoholic hepatitis without a biopsy? A clinical diagnosis of alcoholic hepatitis still encompasses An accuracy of about 80% has been quoted for the clinical a wide spectrum of disease. Assessment of the severity of diagnosis of alcoholic hepatitis when compared with alcoholic hepatitis is vital not only to identify those histology. This is certainly true in many studies which rely patients with a poor prognosis, but also to target upon the modified discriminant function (mDF; see treatment effectively. In 1978 the DF was first described below) as a diagnostic criterion.4–9 However if only those in a placebo-controlled study of the benefit of studies with a minimum level of bilirubin as a criterion for corticosteroid therapy in 55 patients with alcoholic diagnosis are looked at, the accuracy rises to nearly 100% hepatitis.15 The DF was calculated between 7 and 12 days (see Table 2).10–14 Therefore it seems possible to after admission. Patients with a DF greater than 93 and determine criteria for the diagnosis of clinically relevant treated with placebo had a 25% 28-day survival while alcoholic hepatitis without reliance upon histology. These those with a score less than or equal to 93 had a survival 4 J R Coll Physicians Edinb 2007; 37:3–8 © 2007 RCPE A clinical approach to alcoholic hepatitis Figure 1A Figure 1B FIGURE 1 Effect of Corticosteroids and Pentoxifylline upon Survival relative to GAHS. A) Survival at Day 28 and Day 84 in GENERAL MEDICINE Patients with an mDF 32 and a GAHS <9: Relative to the GAHS and Corticosteroid/ Pentoxifylline Treatment. B) Survival at Day 28 and Day 84 in Patients with an mDF 32 and a GAHS 9: Relative to the GAHS and Corticosteroid/ Pentoxifylline Treatment. (* = p<0·05 cf no treatment. # = p<0·005 cf no treatment.) of 100%. In 1989 the DF was modified in the context of study identified the optimal cut point to be 11.19 In a further placebo controlled corticosteroid trial involving contrast, the GAHS has a constant cut-point of nine for 66 patients.2 A modified Discriminant Function of greater scores calculated on admission or on day seven for both than 32 and/or the presence of encephalopathy in placebo 28 and 84 day mortality. In addition, the GAHS appears treated patients was associated with a 65% 28-day to be accurate, irrespective of whether the INR or the survival.16 A recent re-analysis of a previously published prothrombin time ratio is used, and does not rely upon placebo controlled corticosteroid trial confirmed this creatinine measurement. The measurement of serum observation with a 68% 28-day survival in placebo treated creatinine is based on the Jaffe reaction by many analysers.