Review article: the diagnosis and management of alcoholic hepatitis
Dr S. M. Cohen, Section of Hepatology, Rush University Medical Center, 1725 West Harrison Street, no. 158, Chicago, IL 60612, USA.
Background Alcoholic hepatitis is a severe, cholestatic liver disease occurring in patients with alcohol abuse. Mortality is substantial; however, therapies may improve clinical outcomes.
Aim To provide an updated review of the epidemiology, diagnosis, staging and treatment of alcoholic hepatitis.
Methods A MEDLINE literature search was performed to identify pertinent articles. Relevant clinical abstracts were also reviewed.
Results Severe alcoholic hepatitis occurs in a small fraction of patients who abuse alcohol. The 28-day mortality ranges from 30% to 50% in most series. Diagnosis is generally based on clinical features, with a limited role for liver biopsy. Beneficial treatment options include alcohol abstinence and nutritional therapy. Despite variable results in clinical trials, corticosteroids and pentoxifylline appear to provide moderate survival benefit. Anti-tumour necrosis factor agents and antioxidants have not proven beneficial, and should be limited to clinical trials. Liver transplant is not a frequent option given the active or recent alcohol use.
Conclusions Severe alcoholic hepatitis is a clinically-diagnosed condition associated with significant mortality. Alcohol abstinence and nutritional therapy have been associated with improved clinical parameters and should be considered in all patients. Corticosteroid therapy and pentoxifylline therapy appear to show moderate survival benefit and should be considered as first-line therapeutic agents.
Introduction and epidemiology of alcoholic hepatitis
Alcoholic liver disease is a general term describing a spectrum of conditions ranging from reversible fatty liver to alcoholic hepatitis to cirrhosis, all of which can be present simultaneously. The acute syndrome of alcoholic hepatitis is a severe, cholestatic liver disease that occurs in the setting of chronic alcohol abuse and carries a particularly poor prognosis with 28-day mortalities ranging from 30% to 50%.1, 2 This article provides a review of the diagnosis and management of alcoholic hepatitis. A MEDLINE literature search was performed to identify pertinent references using the keywords ‘alcoholic liver disease’, ‘acute alcoholic hepatitis’, ‘alcoholic hepatitis’ and ‘alcoholic steatohepatitis’. In addition, abstracts accepted over the last 5 years into the annual meetings of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver and Digestive Disease Week were reviewed using the same keywords.
The typical age at presentation of alcoholic hepatitis is between 40 and 50 years,3–5 with the majority occurring before age 60. The reasons why only a minority of alcoholics develop alcoholic hepatitis are incompletely understood. Environmental and host factors which increase the risk of alcoholic cirrhosis (and therefore may be important to development of alcoholic hepatitis) include female gender, Hispanic ethnicity, drinking multiple types of alcohol (e.g. beer, wine and spirits), drinking alcohol between mealtimes, poor nutrition, obesity and polymorphisms in several genes.6–10 Although women are at increased risk of developing liver disease when they drink alcohol,6 the majority of patients with alcoholic hepatitis are males because men are twice as likely as women to abuse alcohol.7
The lower limit of alcohol use for the development of cirrhosis is in the range of 30–50 g of ethanol per day [12 ounces (355 mL) of beer, 5 ounces (125 mL) of wine or 1.5 ounces (45 mL) of spirits contain approximately 12–14 g of ethanol].6, 11 The amount of alcohol consumption which places an individual at risk of developing alcoholic hepatitis is not known. However, in practice, most patients with alcoholic hepatitis drink more than 100 g/day,10 with 150–200 g/day being common.3 The typical patient has drunk heavily for two or more decades,3 although an occasional patient has abused alcohol for <10 years. Abstinence for several weeks prior to admission is not uncommon. However, clinical presentation after abstinence for more than 3 months should raise concern for underlying advanced alcoholic cirrhosis or other causes of chronic liver disease. Occasional patients deny alcohol abuse and discreet discussions with family members are required to obtain the true history of the patient’s alcohol use.12
The diagnosis of alcoholic hepatitis can be determined with sufficient certainty to institute specific drug treatment based on the appropriate alcohol history, physical examination and laboratory data alone.
Physical examination usually reveals a malnourished patient with fever, low blood pressure and tachycardia. Jaundice and ascites are universal and a significant number of patients have hepatic encephalopathy.3 If palpable, the liver is usually enlarged and tender. A minority have an audible bruit in the right upper quadrant, believed to be due to increased blood flow in the hepatic artery.13
Laboratory tests are important in making a diagnosis.14, 15 The AST is greater than the ALT, with the AST usually less than 400 IU/mL (often <200 IU/mL). Total and direct bilirubin levels are elevated, with bilirubin exceeding 15 mg/dL in severe cases. Serum sodium and albumin are low, while INR is elevated. White blood cell (WBC) count is elevated, occasionally to >15 000/mm3, with a predominance of neutrophils (PMN). Rarely, a leukaemoid reaction with extremely elevated WBCs can be seen. Serum creatinine is usually normal; an elevated creatinine is ominous for the development of type-1 hepatorenal syndrome.
The differential diagnosis includes diseases which cause jaundice, including acute viral hepatitis, most causes of cirrhosis and drug induced liver injury. Up to 25% of patients are infected with hepatitis C,16 but this does not appear to change the short-term prognosis17 and is not a contraindication to treatment with corticosteroids. Serum tests for ceruloplasmin, ferritin and iron are often unreliable because of the hepatic inflammation and the hepatocyte death. However, genetic testing for haemochromatosis remains reliable. Cholangitis can also cause jaundice, fever and abdominal pain; however, a long coexistent history of alcohol use and ascites are uncommon. Diffuse hepatocellular carcinoma is a rare cause of ascites and jaundice. Non-alcoholic steatohepatitis rarely causes jaundice or ascites (except in end-stage disease) and is usually associated with an elevated ALT/AST ratio.
Bacterial infection is frequent,3, 18 and all patients should have cultures of blood, ascites and urine, with additional evaluation for infection based on symptoms (e.g. sputum). However, routine prophylactic antibiotic use is not recommended. Ultrasound examination of the abdomen is reliable to exclude biliary tract obstruction. Findings of parallel tubular structures in the liver, presumed due to a dilated hepatic artery adjacent to a portal vein radical, have been reported in patients with alcoholic hepatitis.19
Whether liver biopsy needs to be performed in all patients with a clinical diagnosis of alcoholic liver disease is debatable. Liver biopsy may be helpful to confirm the diagnosis, evaluate the impact of co-existing diseases (such as viral hepatitis), rule out other diagnoses and to evaluate the degree of fibrosis. In a study from 1979, as many as 20% of patients with alcohol abuse presenting with abnormal liver tests were found to have a non-alcohol related cause of their liver disease.20 This study and others have looked at the specificity and sensitivity of clinical diagnosis compared to histological diagnosis for alcoholic liver disease in general, but little data have looked at the use of clinical versus histological factors in specifically diagnosing the syndrome of alcoholic hepatitis. Only one abstract that evaluated clinical parameters versus histological parameters in diagnosing alcoholic hepatitis exists.21 In that study, only 70% of patients with a clinical diagnosis of severe alcoholic hepatitis (based on clinical parameters and a Maddrey discriminant function (DF) of >32 (see below)] had biopsy confirmation of the disease.
If liver biopsy is deemed necessary, it should probably be performed by the transvenous route to reduce the risk of hemorrhage.22–24 Typical findings of alcoholic hepatitis include steatosis, hepatocyte injury (ballooning, presence of Mallory’s hyaline, ‘megamitochondria’, necrosis, apoptosis), portal and lobular inflammation (not only predominantly neutrophils, but also lymphocytes25) and fibrosis [pericellular (intrasinusoidal) fibrosis, often with co-existent bridging fibrosis or cirrhosis].26, 27 Histological changes of alcoholic hepatitis can improve quickly in some patients with alcohol abstinence.28 In others, histological changes can persist for months and therefore cannot be used to establish return to alcohol use.29
The severity of alcoholic hepatitis can be assessed by calculating Maddrey’s discriminant function, the MELD score or the Glasgow score. In clinical practice, any of these scoring systems can be used to select patients suitable for drug treatment.
Maddrey’s discriminant function, calculated as total bilirubin (in mg/dL) + 4.6 × prothrombin time (in seconds prolonged), was published in 1978 based on laboratory and clinical data collected in the 1960s and 1970s.1 The DF was slightly modified in 19892 such that a DF score of >32 signified significant or severe alcoholic hepatitis and a recommendation to institute specific drug treatment (see below). The advantages of DF are that it can be calculated from routine blood tests and that it has been used in multiple clinical trials to select patients for treatment. A disadvantage of DF is the use of the prothrombin time as this test is not standardized and ‘seconds prolonged’ can vary depending on the type of thromboplastin used by the clinical laboratory.30
The Model for End-stage Liver Disease (MELD) score predicts short-term survival in patients with cirrhosis31 and is used to select patients for liver transplantation.32 MELD has been compared with DF as a measure of alcoholic hepatitis severity; a score above 2133 or 2434 identifies patients with increased short-term mortality. MELD can be readily calculated (e.g. http://www.unos.org/resources/meldPeldCalculator.asp?index=98). MELD uses INR, a test which is standardized throughout the world,35 although it remains a ‘less than ideal’ test of coagulation in patients with liver disease.30, 36, 37
Investigators from Glasgow have presented a five-item scale, akin to the Child–Turcotte–Pugh scale, containing four laboratory variables (bilirubin, blood urea nitrogen, prothrombin time and WBC count) along with patient age to score the severity of alcoholic hepatitis.38 Analysis of their retrospectively collected data from more than 200 patients with alcoholic hepatitis identified a score of 9 or greater on the Glasgow alcoholic hepatitis scale as having an increased mortality. This subset of patients had improved survival when corticosteroid therapy was instituted.39
Treatment of alcoholic hepatitis can be divided into three components: treatment of alcoholism, nutritional support and specific drug treatments. Liver transplantation will be discussed in a separate section.
Abstinence improves survival in alcoholic hepatitis.40, 41 The treatment of alcoholism is probably best handled by addiction experts. Short-term abstinence is improved by the use of naltrexone (100 mg/day) or participation in intensive behavioural counselling.42 Acamprosate did not reduce alcohol use in alcoholic subjects participating in trials conducted in the USA,42, 43 although it was reported to improve abstinence and reduce alcohol consumption in European studies.44, 45 Baclofen, a gamma aminobutyric acid B-receptor agonist, reduces craving among alcohol-dependent subjects without liver disease46, 47 and is safe and effective at maintaining abstinence among alcohol dependent subjects with alcoholic cirrhosis.48
Gastroenterologists and hepatologists should provide emotional and medical support for the patient and family, especially early in recovery. In addition to encouraging patients to participate in substance abuse programmes, patients should be clearly advised that a return to alcohol use at any time in the future may result in decompensated alcoholic liver disease, with the possibility of death. Patients should be notified that ascites, jaundice and even significant fibrosis may improve or resolve in patients who maintain sobriety.40, 41, 49, 50
Essentially, all of patients with a DF >32 are malnourished and the degree of malnutrition correlates with survival.3, 51, 52 The pathophysiology of malnutrition in alcoholic hepatitis patients includes poor intake of nutrients, malabsorption (especially of fat and fat-soluble vitamins) and increased rate of catabolism.53, 54 Assessment of the degree of malnutrition can be performed using urinary creatinine excretion and mid-arm muscle area for subjects without ascites or oedema, while creatinine-height index is preferable for patients with ascites.55 Other methods of assessment have included assessment of muscle mass, grip strength, response to skin tests (frequently anergic) and serum levels of prealbumin, vitamins (e.g. vitamin A, folic acid, B12) and minerals (e.g. phosphorus, zinc).3, 51, 52 In clinical practice, it is usually not necessary to perform a detailed assessment of degree of malnutrition as all patients require nutritional support.
There are no published guidelines from nutrition or liver disease societies regarding the appropriate dosing of vitamin or mineral supplements in patients with alcoholic hepatitis. It has been recommended to provide B-vitamins (especially thiamine), folic acid and vitamin K at several times the minimum daily allowance.53 It is common to provide these intravenously for the first few days. Daily oral multimineral supplementation (without iron) should also be provided. Most patients are deficient in zinc, probably due to decreased oral intake and increased urinary loss.56, 57 In animal models of alcoholic liver disease, zinc replacement prevents apoptosis and translocation of bacteria across the small intestines.58 Thus, zinc replacement at a dose of approximately 200 mg/day should also be considered. The optimal duration of vitamin and mineral support is not established, but it is reasonable to continue these for at least 6 months, with oral zinc continuing for 12 months or longer.
Because of the prevalence and severity of malnutrition in alcoholic hepatitis, parenteral and enteral nutritional support have been evaluated in multiple clinical trials.59, 60 The general consensus is that nutritional support results in a more rapid improvement in liver disease, but does not improve survival. One clinical trial comparing nutritional support with prednisolone treatment is noteworthy. Cabre et al.61 randomized patients with alcoholic hepatitis to 28 days of treatment with a special diet containing 2000 calories or to treatment with prednisolone and a standard hospital diet (i.e. standard treatment). The 2000 calorie treatment enteral diet consisted of 72 g of protein, 345 g of carbohydrates and 36 g of fat. Patients were followed up for 12 months. Survival during the first 28 days was similar in the two groups. However, several patients who received corticosteroids developed infections after day 28, resulting in a survival advantage for nutritional support, which began at 6 months and continued through 12 months. Because of the relatively small size of the study, the improvement in survival with nutritional support was not statistically significant. Nevertheless, the improvement in survival, especially when compared with corticosteroid treatment, was impressive, providing a basis for the consideration of nutritional therapy in addition to specific drug therapy.
Nutritional support consists of 1.2–1.5 g of protein and an energy intake of 35–40 kcal/kg of ideal body weight per day.62 Many patients are anorexic; early placement of a fine-bore feeding tube should be considered in patients who do not voluntarily consume sufficient calories. It is uncommon for the higher protein intake to precipitate or worsen hepatic encephalopathy.63, 64 Due to the underlying malnutrition, patients with hepatic encephalopathy should be treated initially with lactulose, not protein restriction.
Prednisolone, 40 mg/day for 28 days (with or without a 2-week taper), is the most widely recommended drug to treat alcoholic hepatitis.65 The mechanism of action is believed to be decreased transcription of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha). Indications for starting prednisolone include a DF >32, MELD >20, Glasgow score >8 or the presence of hepatic encephalopathy. Standard contraindications include recent upper gastrointestinal bleeding, renal insufficiency and uncontrolled infection.
Prednisolone treatment of alcoholic hepatitis has been evaluated in 13 randomized controlled trials, which have been evaluated in at least three meta-analyses.66–69
Table 1 outlines the mortality rates from 16 of the studies which have been subjected to further analysis by the various meta-analyses.1, 2, 70–83 Caution must be used in interpreting the data from this table as the inclusion criteria, exclusion criteria, dose of corticosteroids and duration of corticosteroids differed among the studies. In addition, the quoted mortality rates ranged from 1 month to several months.
Table 1. Corticosteroid trials for the treatment of alcoholic hepatitis
|Helman et al.70||5% (1/20)||35% (6/17)||<0.01|
|Porter et al.71||55% (6/11)||77% (7/9)||N.S.|
|Campra et al.72||35% (7/20)||36% (9/25)||N.S.|
|Blitzer et al.73||35% (6/17)||31% (5/16)||N.S.|
|Mendenhall and Goldberg74||33% (4/12)||12% (2/17)||N.S.|
|Lesesne et al.75||29% (2/7)||100% (7/7)||<0.01|
|Galambos76||75% (6/8)||67% (6/9)||N.S.|
|Shumaker et al.77||50% (6/12)||47% (7/15)||N.S.|
|Maddrey et al.1||4% (1/24)||19% (6/32)||<0.05|
|Depew et al.78||53% (8/15)||54% (7/13)||N.S.|
|Theodossi et al.79||63% (17/27)||57% (16/28)||N.S.|
|Mendenhall et al.80||23% (22/94)||27% (25/93)||N.S.|
|Bories et al.81||17% (4/24)||24% (5/21)||N.S.|
|Carithers et al.2||6% (2/35)||35% (11/31)||0.006|
|Ramond et al.82||13% (4/32)||55% (16/29)||0.001|
|Richardet et al.83||0% (0/12)||0% (0/11)||N.S.|
The results of the clinical trials and of the meta-analyses are conflicting with some reports suggesting a survival benefit, while other reports fail to confirm any benefit. Furthermore, a Cochrane review of 15 trials did not find improved overall survival with corticosteroid treatment.84 However, this analysis did show an improved survival with corticosteroid use when only studies with ‘low bias risk’ were evaluated and only patients with a DF > 32 and/or the presence of hepatic encephalopathy were examined.
An analysis that combined and reanalysed the primary data from three of the larger clinical trials of prednisolone vs. placebo did show a survival benefit for corticosteroids.85 Only patients with a DF >32 were included in the analysis, which required excluding several patients from one of the three studies. Survival at day 28 was 85% for patients receiving prednisolone as compared with 65% in patients receiving placebo (P < 0.001). Based on this study, five patients would need to be treated to prevent one death. Also, survival at 6 months was greater in patients receiving prednisolone as compared with patients receiving placebo (65% vs. 50%, P < 0.01). More recently, Mathurin et al.86 combined the primary data from two additional clinical trials of corticosteroids versus placebo (in total, data from five clinical trials) and reconfirmed the survival benefit with prednisolone treatment.
Given conflicting results in various studies with the use of corticosteroids for alcoholic hepatitis, it is difficult to recommend these agents firmly. However, if the clinical decision is made to initiate corticosteroid therapy, a short therapeutic trial is reasonable with the ability to terminate the treatment if a clinical benefit is unlikely to occur. Measuring the change in total bilirubin during the first week of treatment can predict outcomes. One approach is to stop treatment in patients in whom the bilirubin is higher at day 7 than it was prior to starting corticosteroids.87 A more complicated, but improved, approach is to calculate the Lille score (http://www.lillemodel.com) after 7 days of therapy.88 This score utilizes baseline bilirubin, bilirubin at day 7, creatinine, albumin, INR (or prothrombin time) and age. A Lille score >0.45, seen in approximately 40% of patients with severe alcoholic hepatitis, signifies failure of prednisolone and warrants its discontinuation. Survival at 28 days in this group of patients is approximately 25%. Switching these patients to pentoxifylline (PTX) treatment did not appear to improve survival.89
Pentoxifylline, 400 mg three times per day for 28 days, is an alternative treatment for alcoholic hepatitis. Indications for PTX treatment are similar to those for corticosteroids. A potential benefit of PTX treatment is that it can be used in patients with infection and in patients with renal insufficiency.
Pentoxifylline is a nonselective phosphodiesterase inhibitor that increases the intracellular concentration of adenosine 3′, 5′-cyclic monophosphate (cAMP). Increases in cAMP decrease expression of cytokines such as TNF-alpha, IL-8 and macrophage inflammatory protein-1α.90 However, in one study, serum TNF-alpha failed to decrease in subjects receiving PTX,91 suggesting that other mechanisms of action may be important.
One randomized controlled trial of PTX has been published.91 This trial randomized 101 subjects with severe alcoholic hepatitis (defined as a DF ≥32) to treatment with either placebo or to PTX 400 mg orally TID for 28 days. Mortality during the initial hospitalization was significantly higher for subjects receiving placebo than for those receiving PTX (46.1% vs. 24.5%, P < 0.04). Improvement in survival with PTX was due to a reduction in the number of deaths from hepatorenal syndrome (six deaths in the PTX group vs. 22 deaths in the placebo group, P < 0.001). There were no reported serious adverse events related to PTX use.
Several additional clinical trials, reported in abstract form, both support92, 93 and refute94, 95 the effectiveness of PTX in the treatment of alcoholic hepatitis and cirrhosis. A well-designed trial comparing prednisolone with PTX in subjects with a DF ≥32 would be a welcome addition to the field of alcoholic hepatitis treatment.
The pro-inflammatory cytokine TNF-alpha is believed to contribute to the fever, anorexia, malnutrition and liver injury (inflammation, apoptosis, etc.) that occur in alcoholic hepatitis.96 Because of the effectiveness of anti-TNF treatment in inflammatory diseases such as rheumatoid arthritis and Crohn’s disease, anti-TNF treatments were tested in patients with advanced alcoholic hepatitis. Small and/or uncontrolled trials suggested that infliximab with97 or without prednisolone98, 99 improved patient outcomes. However, a prospective, randomized, blinded trial comparing prednisolone monotherapy against combination treatment with prednisolone plus infliximab was stopped early because of increased mortality in patients receiving prednisolone plus infliximab (mortality at 2 months was 18% with prednisolone and 39% with prednisolone + infliximab).100 Death because of infection (4 vs. 1) and the number of subjects with infection (13 vs. 3) were significantly higher among subjects receiving prednisolone + infliximab. Although this study has been criticized for the use of high doses of infliximab (10 mg/kg at days 0, 14 and 28), other studies, using smaller doses of infliximab, have also reported relatively high infection rates.99 Boetticher et al.101 conducted a randomized, placebo-controlled, double-blind trial of 1 month of etanercept treatment compared with placebo in 48 subjects with alcoholic hepatitis and MELD score>15. Mortality at 6 months was significantly higher in subjects that received etanercept (57.7% vs. 22.7%. P < 0.05). As with infliximab, more patients receiving etanercept developed infections (9 vs. 2) and died of infections (3 vs. 0). At present, anti-TNF-alpha treatments should not be used in alcoholic hepatitis, except in carefully designed clinical trials.
The basis for evaluating antioxidants is the presence of oxidative stress and the reduction in antioxidant capabilities in alcoholic liver disease, and the effectiveness of N-acetylcysteine as a treatment for acetaminophen-induced acute liver failure.102, 103 Unfortunately, clinical trials have failed to demonstrate that antioxidant treatment, either alone or with prednisolone, is beneficial in alcoholic hepatitis. Phillips4 compared prednisolone treatment with combination antioxidant treatment in 101 patients with DF >32. The study was stopped early because survival at 30 days was significantly better among subjects receiving prednisolone (30% mortality) compared with antioxidant treatment (46% mortality, P = 0.05). Stewart et al.5 tested whether the addition of antioxidant treatment, consisting of N-acetylcysteine for 1 week along with Coenzyme Q and several vitamins and minerals daily for 6 months, to standard treatment (i.e., prednisolone in subjects without sepsis or renal failure) improved survival in severe alcoholic hepatitis. Survival at 180 days was similar for subjects who received antioxidants and those who receive placebo (52.8% vs. 55.8%, P = 0.699). Thus, although antioxidant treatment remains theoretically attractive, it cannot be currently recommended in the absence of positive data from randomized controlled studies.
The scientific basis for using propylthiouracil (PTU) is the hypermetabolic state and associated hypoxia of acinar zone 3 that is present in alcoholic liver disease.104, 105 One well-conducted, large trial reported that PTU improved 2-year survival in compliant patients with alcoholic liver disease, especially in severely ill patients (mortality 55% in patients receiving placebo as compared with 25% in patients receiving PTX, P < 0.03).106 Unfortunately, meta-analysis of the various PTU clinical trials have failed to demonstrate consistently a survival benefit.107 Thus, PTU is not currently recommended as a treatment for alcoholic hepatitis.108
Anabolic steroids such as oxandralone and testosterone increase muscle mass in healthy men and have been used in an attempt to increase the incorporation of nutrients into muscle mass in alcoholic hepatitis. Despite the theoretical benefit of these agents, they have not demonstrated a short-term survival benefit in alcoholic hepatitis.3 Only one study demonstrated improved survival at 6 months in patients receiving oxandralone.80 Given a lack of convincing data, oxandralone is not routinely used to treat alcoholic hepatitis.109
Other treatments, including colchicine (antifibrotic, anti-inflammatory), insulin-glucagon (pro-growth) and milk thistle (antioxidant),110 have also been used to treat alcoholic hepatitis, but without success.
Although liver transplantation prolongs survival in patients with decompensated liver disease, its use in alcoholic hepatitis requires careful consideration.111 Because of the high cost and the limited availability of cadaveric livers, there is general consensus that liver transplantation should be reserved for patients who are most likely to derive long-term survival benefit. Furthermore, because of the importance of societal support for the donation of livers, and the general belief that alcohol abuse is a ‘self-inflicted’ disease, care must be taken in selecting alcoholic patients for liver transplantation. In addition, other general eligibility factors must be considered prior to listing these patients for transplant as they are often severely malnourished, may have alcoholic cardiomyopathy and may have a component of organic alcoholic brain injury.
Recidivism remains the major concern for alcoholics who receive a liver transplant. Recidivism in patients with alcoholic cirrhosis (most of whom were abstinent for more than 6 months prior to transplant) depends on the definition of alcohol use. Some degree of alcohol use occurs in approximately 20–40% of alcoholics following liver transplantation, with up to 25% of liver recipients returning to abusive drinking habits.112–115 Predicting which patients with alcoholic hepatitis will maintain sobriety is difficult, particularly because patients may have spent a significant amount of time in the hospital (without access to alcohol) and because they are ill (disincentive to drink alcohol). Even among addiction specialists, there is limited ability to select patients who are less likely to return to heavy alcohol use.112, 114 Although UNOS has not published guidelines for abstinence in patients with alcoholic hepatitis, most transplant centres continue to require 6 months of abstinence prior to transplantation.116 The Berlin group has demonstrated significantly less recidivism in those patients who were abstinent for >6 months prior to transplantation.112 A prospective study of relatively early liver transplantation in highly selected patients with alcoholic hepatitis is in progress in France.
In the Berlin study, overall graft and patient survival following liver transplant for alcoholic cirrhosis was shown to be similar to that for viral hepatitis.112 However, patients returning to ‘abusive’ alcohol use after transplantation had a significant decrease in survival compared to those recipients who remained abstinent.
Alcoholic hepatitis occurs in a minority of subjects who drink large quantities of ethanol on a daily basis for many years. The clinical diagnosis of alcoholic hepatitis can be made based on the appropriate alcohol intake history, fever, jaundice, ascites, elevated WBC, AST<400 IU/mL and elevated AST:ALT ratio. Liver biopsy may help confirm the diagnosis, but is not required. The biopsy may demonstrate hepatocyte ballooning, Mallory’s hyaline, neutrophilic infiltration and perisinuosidal fibrosis. Mortality for severe alcoholic hepatitis is quite high, in the range of 40% over a 28-day period. Assessment of disease severity can be made using the Maddrey’s discriminant function, MELD score or Glasgow score. Alcoholism should be treated in consultation with an addiction specialist. Patients need to understand that if they return to heavy drinking, they are very likely to re-develop alcoholic hepatitis. Essentially, all patients are malnourished. Nutritional supplementation, consisting of vitamins and minerals (including zinc), protein (at least 1.2 g/day) and calories, is essential and should be administered by enteral feeding tube if patients are too ill to eat voluntarily. Prednisolone 40 mg/day for 28 days is the most widely recommended treatment, although it should not be used in patients with recent upper gastrointestinal bleeding, elevated creatinine or uncontrolled infection. PTX 400 mg TID for 28 days is an alternate treatment option. Other treatments, such as antioxidants or anti-TNF-alpha treatment, are not recommended. Liver transplantation is infrequently recommended during the early phases of alcoholic hepatitis. Potential problems with liver transplantation include recidivism, malnutrition and disease in other organs (e.g. heart, brain).
Declaration of personal interests: The authors wish to thank Dr Timothy Morgan for his invaluable assistance in the preparation of this manuscript. Declaration of funding interests: None.