Alcoholic liver disease
Authors: Robert S. O'Shea, Srinivasan Dasarathy, Arthur J. McCullough
Journal: Hepatology (2009)

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology and represents the position of both associations. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the development and use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guideline Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines).3, 4 AASLD, American Association for the Study of Liver Diseases; AH, alcoholic hepatitis; ALD, alcoholic liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUDIT, Alcohol Use Disorders Identification Test; GAHS, Glasgow Alcoholic Hepatitis Score; GGT, gamma glutamyl transpeptidase; MDF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; PTU, propylthiouracil; SAMe, S-adenosyl L-methionine; TNF, tumor necrosis factor. Alcoholic liver disease (ALD) encompasses a spectrum of injury, ranging from simple steatosis to frank cirrhosis. It may well represent the oldest form of liver injury known to humankind. Evidence suggests that fermented beverages existed at least as early as the Neolithic period (circa 10,000 B.C.),5 and liver disease related to it almost as long. Alcohol remains a major cause of liver disease worldwide. It is common for patients with ALD to share risk factors for simultaneous injury from other liver insults (e.g., coexisting nonalcoholic fatty liver disease, or chronic viral hepatitis). Many of the natural history studies of ALD, and even treatment trials, were performed before these other liver diseases were recognized, or specific testing was possible. Thus, the individual effect of alcohol in some of these studies may have been confounded by the presence of these additional injuries. Despite this limitation, the data regarding ALD are robust enough to draw conclusions about the pathophysiology of this disease. Possible factors that affect the development of liver injury include the dose, duration, and type of alcohol consumption; drinking patterns; sex; ethnicity; and associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis, and genetic factors. Geographic variability exists in the patterns of alcohol intake throughout the world.6 Approximately two-thirds of adult Americans drink some alcohol.7 The majority drink small or moderate amounts and do so without evidence of clinical disease.8-10 A subgroup of drinkers, however, drink excessively, develop physical tolerance and withdrawal, and are diagnosed with alcohol dependence.11 A second subset, alcohol abusers and problem drinkers, are those who engage in harmful use of alcohol, defined by the development of negative social and health consequences of drinking (e.g., unemployment, loss of family, organ damage, accidental injury, or death).12 Failure to recognize alcoholism remains a significant problem and impairs efforts at both the prevention and management of patients with ALD.13, 14 Although the exact prevalence is unknown, approximately 7.4% of adult Americans were estimated to meet DSM-IV criteria for the diagnosis of alcohol abuse and/or alcohol dependence in 199415; more recent data suggest 4.65% meet criteria for alcohol abuse and 3.81% for alcohol dependence.16 In 2003, 44% of all deaths from liver disease were attributed to alcohol.17 Population level mortality from alcoholic liver disease is related to per capita alcohol consumption obtained from national alcoholic beverage sales data. There are conflicting data regarding a possible lower risk of liver injury in wine drinkers.18, 19 One epidemiologic study has estimated that for every 1-liter increase in per capita alcohol consumption (independent of type of beverage), there was a 14% increase in cirrhosis in men and 8% increase in women.20 These data must be considered in the context of the limitations of measuring alcohol use and defining alcoholic liver disease. The scientific literature has also used a variety of definitions of what constitutes a standard drink (Table 2). Most studies depend on interviews with patients or their families to quantify drinking patterns, a method that is subject to a number of biases, which may lead to invalid estimates of alcohol consumption.21 Although there are limitations of the available data, the World Health Organization's Global Alcohol database, which has been in existence since 1996, has been used to estimate worldwide patterns of alcohol consumption and allow comparisons of alcohol related morbidity and mortality.22 The burden of alcohol-related disease is highest in the developed world, where it may account for as much as 9.2% of all disability-adjusted life years. Even in developing regions of the world, however, alcohol accounts for a major portion of global disease burden, and is projected to take on increasing importance in those regions over time.22, 23 The spectrum of alcohol-related liver injury varies from simple steatosis to cirrhosis. These are not necessarily distinct stages of evolution of disease, but rather, multiple stages that may be present simultaneously in a given individual.24, 25 These are often grouped into three histological stages of ALD: fatty liver or simple steatosis, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis or cirrhosis.26 These latter stages may also be associated with a number of histologic changes (which have varying degrees of specificity for ALD), including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis.24 Fatty liver develops in about 90% of individuals who drink more than 60 g/day of alcohol,27 but may also occur in individuals who drink less.28 Simple, uncomplicated fatty liver is usually asymptomatic and self limited, and may be completely reversible with abstinence after about 4-6 weeks.29 However, several studies have suggested that progression to fibrosis and cirrhosis occurs in 5%-15% of patients despite abstinence.30, 31 In one study, continued alcohol use (>40 g/day) increased the risk of progression to cirrhosis to 30%, and fibrosis or cirrhosis to 37%.32 Fibrosis is believed to start in the perivenular area and is influenced by the amount of alcohol ingested.33, 34 Perivenular fibrosis and deposition of fibronectin occurs in 40%-60% of patients who ingest more than 40-80 g/daily for an average of 25 years. Perivenular sclerosis has been identified as a significant and independent risk factor for the progression of alcoholic liver injury to fibrosis or cirrhosis.33, 35 Progression of ALD culminates in the development of cirrhosis, which is usually micronodular, but may occasionally be mixed micronodular and macronodular.36 A subset of patients with ALD will develop severe alcoholic hepatitis (AH), which has a substantially worse short-term prognosis.37 AH also represents a spectrum of disease, ranging from mild injury to severe, life-threatening injury, and often presents acutely against a background of chronic liver disease.38, 39 The true prevalence is unknown, but histologic studies of patients with ALD suggest that AH may be present in as many as 10%-35% of hospitalized alcoholic patients.40-42 Typically, symptomatic patients present with advanced liver disease, with concomitant cirrhosis in more than 50%, and superimposed acute decompensation. Even patients with a relatively mild presentation, however, are at high risk of progressive liver injury, with cirrhosis developing in up to 50%.43, 44 The likelihood that AH will progress to permanent damage is increased among those who continue to abuse alcohol. Abstinence from alcohol in one small series did not guarantee complete recovery. Only 27% of abstaining patients had histologic normalization, whereas 18% progressed to cirrhosis, and the remaining patients had persistent AH when followed for up to 18 months.45 Unlike many other hepatotoxins, the likelihood of developing progressive alcohol-induced liver disease or cirrhosis is not completely dose-dependent, because it occurs in only a subset of patients. A number of risk factors have been identified that influence the risk of development and progression of liver disease. The amount of alcohol ingested (independent of the form in which it is ingested) is the most important risk factor for the development of ALD.46 The relationship between the quantity of alcohol ingested and the development of liver disease is not clearly linear.47, 48 However, a significant correlation exists between per capita consumption and the prevalence of cirrhosis.49 The risk of developing cirrhosis increases with the ingestion of >60-80 g/day of alcohol for 10 years or longer in men, and >20 g/day in women.6, 50 Yet, even drinking at these levels, only 6%-41% develop cirrhosis.6, 51 In a population-based cohort study of almost 7000 subjects in two northern Italian communities, even among patients with very high daily alcohol intake (>120 g/day), only 13.5% developed ALD.50 The risk of cirrhosis or noncirrhotic chronic liver disease increased with a total lifetime alcohol intake of more than 100 kg, or a daily intake >30 g/day.50 The odds of developing cirrhosis or lesser degrees of liver disease with a daily alcohol intake of >30 g/day were 13.7 and 23.6, respectively, when compared with nondrinkers.50 The type of alcohol consumed may influence the risk of developing liver disease. In a survey of more than 30,000 persons in Denmark, drinking beer or spirits was more likely to be associated with liver disease than drinking wine.18 Another factor that has been identified is the pattern of drinking. Drinking outside of meal times has been reported to increase the risk of ALD by 2.7-fold compared to those who consumed alcohol only at mealtimes.52 Binge drinking, defined by some researchers as five drinks for men and four drinks for women in one sitting, has also been shown to increase the risk of ALD and all-cause mortality.53, 54 Women have been found to be twice as sensitive to alcohol-mediated hepatotoxicity and may develop more severe ALD at lower doses and with shorter duration of alcohol consumption than men.55 Several studies have shown differing blood alcohol levels in women versus men after consumption of equal amounts of alcohol.56 This might be explained by differences in the relative amount of gastric alcohol dehydrogenase, a higher proportion of body fat in women, or changes in alcohol absorption with the menstrual cycle.57 Based on epidemiological evidence of a threshold effect of alcohol, a suggested “safe” limit of alcohol intake had been 21 units per week in men and 14 units per week in women who have no other chronic liver disease58, 59 (where a unit is defined as the equivalent of 8 g of ethanol). However, other data suggest that a lower quantity may be toxic in women, implying a lower threshold of perhaps no more than 7 units per week.47 A higher risk of liver injury may be associated with an individual's racial and ethnic heritage.60 The rates of alcoholic cirrhosis are higher in African-American and Hispanic males compared to Caucasian males and the mortality rates are highest in Hispanic males.61 These differences do not appear to be related to differences in amounts of alcohol consumed.62 The presence and extent of protein calorie malnutrition play an important role in determining the outcome of patients with ALD. Mortality increases in direct proportion to the extent of malnutrition, approaching 80% in patients with severe malnutrition (i.e., less than 50% of normal).63 Micronutrient abnormalities, such as hepatic vitamin A depletion or depressed vitamin E levels, may also potentially aggravate liver disease.64 Diets rich in polyunsaturated fats promote alcohol-induced liver disease in animals,65 whereas diets high in saturated fats may be protective. Obesity and excess body weight have been associated with an increased risk of ALD.66, 67 In addition to environmental factors, genetic factors predispose to both alcoholism and ALD.68-70 Children of alcoholics raised in adopted families had a significantly higher rate of alcohol dependence than did adopted children of nonalcoholics, who served as controls (18% versus 5%).71 In population-based studies, monozygotic twins were approximately twice as likely to drink as dizygotic twins; among those who drank, monozygotic twins were more likely to have a similar frequency and quantity of alcohol consumption.72 Moreover, monozyotic twins have a significantly higher prevalence of alcoholic cirrhosis than do dizygotic twins.73 Finally, polymorphisms of genes involved in the metabolism of alcohol (including alcohol dehydrogenase, acetaldehyde dehydrogenase and the cytochrome P450 system), and in those which regulate endotoxin-mediated release of cytokines have been associated with ALD.74, 75 However, to date, specific genetic abnormalities for susceptibility to alcohol abuse and the development of ALD have not yet been firmly established. There is a clear synergistic relationship between chronic viral hepatitis and alcohol, resulting in more advanced liver disease jointly than separately. The combination of hepatitis C virus and alcohol predisposes to more advanced liver injury than alcohol alone,76, 77 with disease at a younger age, more severe histological features, and a decreased survival.78 In a large cohort study of the effect of heavy alcohol abuse in patients with posttransfusion hepatitis C, the risk of cirrhosis was elevated 30-fold.79 Although the precise toxic threshold for alcohol is not known, and may be lower and nonuniform among patients at risk, it seems prudent in light of these data to advise patients with hepatitis C to abstain from even moderate quantities of alcohol. The diagnosis of ALD is based on a combination of features, including a history of significant alcohol intake, clinical evidence of liver disease, and supporting laboratory abnormalities.80 Unfortunately, the ability to detect these is constrained by patient and physician factors, as well as diagnostic laboratory shortcomings. Denial of alcohol abuse and underreporting of alcohol intake are common in these patients.81, 82 Physicians underestimate alcohol-related problems and make specific recommendations even less frequently.83, 84 Both the physical findings and laboratory evidence for ALD may be nondiagnostic, especially in patients with mild ALD or early cirrhosis.85 Therefore, the clinician must have a low threshold to raise the issue of possible ALD, and has to rely on indirect evidence of alcohol abuse, such as questionnaires, information from family members, or laboratory tests to strengthen or confirm a clinical suspicion.86 Clinicians commonly fail to screen patients, and thus fail to recognize or treat alcoholism appropriately.87 The clinical history which may suggest alcohol abuse or alcohol dependence includes the pattern, type, and amount of alcohol ingested, as well as evidence of social or psychological consequences of alcohol abuse. These may be suggested by other injuries or past trauma, such as frequent falls, lacerations, burns, fractures, or emergency department visits.88 Biochemical tests have been considered to be less sensitive than questionnaires in screening for alcohol abuse,89, 90 but may be useful in identifying relapse.91, 92 Various questionnaires have been used to detect alcohol dependence or abuse, and include the CAGE, the MAST (Michigan Alcoholism Screening Test), and the Alcohol Use Disorders Identification Test (AUDIT).89, 93 The use of a structured interview, using instruments such as the Lifetime Drinking History, is often used as a gold standard for quantifying lifetime alcohol consumption.94 The CAGE questionnaire was originally developed to identify hospitalized inpatients with alcohol problems, and remains among the most widely used screening instruments. It has been faulted, however, on several measures: it focuses on the consequences of alcohol consumption rather than on the amount of actual drinking, and it refers to lifetime patterns of behavior, rather than short-term or recent changes. Its virtues, however, include its ease of implementation: it is short (four questions), simple (yes/no answers), and can be incorporated into the clinical history or is self-administered as a written document. As a result of its longevity, it has been tested in a wide range of populations. One meta-analysis of its characteristics, using a cutoff of more than two positive responses, found an overall pooled sensitivity and specificity of 0.71 and 0.90, respectively.95 The CAGE questionnaire is familiar to most physicians, and has been suggested for use in general screening96 (Table 3). The AUDIT is a 10-item questionnaire developed by the World Health Organization to avoid ethnic and cultural bias97 and focuses on the identification of heavy drinkers. It has a higher sensitivity and specificity than shorter screening instruments (with sensitivity ranging from 51%-97%, and specificity of 78%-96% in primary care).98 It has been suggested that it has three advantages over other screening tests: it may identify drinkers at risk who are not yet alcohol-dependent; it includes a measure of consumption; and lastly, it includes both current and lifetime drinking time spans. It is more likely to detect problem drinking before overt alcohol dependence or abuse might be diagnosed, and thus may be more robust and effective across a variety of populations.99-101 One possible algorithm for clinicians suggests asking about quantity of alcohol consumed, and number of heavy drinking days in the preceding year (i.e., ≥ 5 drinks/day for men or ≥ 4 drinks/day for women), as well as a version of the AUDIT questionnaire102 (Table 4). An AUDIT score of ≥8, or having had one or more heavy drinking days constitutes a positive screening test, and should prompt further evaluation to rule out an alcohol use disorder.102 Regardless of which screening instrument is selected, however, it is important for clinicians to incorporate screening into their general practice.98, 103 This may be especially important, because some data suggest that these screening instruments may improve the ability of physicians to predict long-term clinical outcomes, including hospitalization for alcohol-related diagnoses.104 A biomarker in longstanding use, gamma glutamyl transpeptidase (GGT), has been evaluated in a number of settings, including large population surveys.105, 106 Unfortunately, low sensitivity and specificity limit the usefulness of elevated GGT to diagnose alcohol abuse,107-109 the levels of which may fluctuate with extensive liver injury.110 Lower levels of GGT (<100) or a total bilirubin/GGT ratio > 1 have been described as a predictor of 1-year mortality in patients with alcoholic cirrhosis,110 although this has not consistently added prognostic ability to other laboratory tests.111 In combination with other biomarkers, however, GGT may add independent information in diagnosing alcohol abuse or problem drinking.112 Macrocytosis is seen in individuals abusing alcohol but this condition lacks sensitivity. A combination of raised GGT and mean corpuscular volume or changes in these values over time in hospitalized patients may improve the sensitivity for diagnosing alcohol abuse. Multiple other candidate biomarkers that may detect alcohol use or abuse objectively have been studied.113, 114 Carbohydrate-deficient transferrin has been the best studied, but has limited sensitivity and specificity.115 Its test characteristics are also influenced by a number of other factors, including age, sex, body mass index, and other chronic liver diseases.116-118 Despite enthusiasm about a possible quantitative, reliable assay of alcohol consumption or abuse, the lack of sensitivity and specificity prevent reliance on any single biomarker.119 The diagnosis of ALD is made by documentation of alcohol excess and evidence of liver disease.120 No single laboratory marker definitively establishes alcohol to be the etiology of liver disease. Furthermore, alcohol may be one of a number of factors causing liver injury, and the specific contributory role of alcohol alone may be difficult to assess in a patient with multifactorial liver disease. A number of laboratory abnormalities, including elevated serum aminotransferases, have been reported in patients with alcoholic liver injury, and used to diagnose ALD.121 Serum aspartate aminotransferase (AST) is typically elevated to a level of 2-6 times the upper limits of normal in severe alcoholic hepatitis. Levels of AST more than 500 IU/L or an alanine aminotransferase (ALT) > 200 IU/L are uncommonly seen with alcoholic hepatitis (other than alcoholic foamy degeneration, or concomitant acetaminophen overdose),122 and should suggest another etiology. In about 70% of patients, the AST/ALT ratio is higher than 2, but this may be of greater value in patients without cirrhosis.123-125 Ratios greater than 3 are highly suggestive of ALD.126 Physical exam findings in patients with ALD may range from normal to those suggestive of advanced cirrhosis. As in other forms of chronic liver disease, physical exam features generally have low sensitivity, even for the detection of advanced disease or cirrhosis, although they may have higher specificity.127 It has been suggested, therefore, that the presence of these features may have some benefit in “ruling in” the presence of advanced disease.127 Features specific for ALD are perhaps even more difficult to identify. Palpation of the liver may be normal in the presence of ALD, and does not provide accurate information regarding liver volume.128 Certain physical exam findings have been associated with a higher likelihood of cirrhosis among alcoholics.129 Although some of the physical findings are more commonly observed in ALD (parotid enlargement, Dupuytren's contracture, and especially those signs associated with feminization) than in non-ALD, no single physical finding or constellation of findings is 100% specific or sensitive for ALD.130 Some of the physical exam features may also carry some independent prognostic information, with the presence of specific features associated with an increased risk of mortality over 1 year. These include (with their associated relative risks): hepatic encephalopathy (4.0), presence of visible veins across the anterior abdominal wall (2.2), edema (2.9), ascites (4.0), spider nevi (3.3), and weakness (2.1).131 Although this is somewhat helpful clinically, findings from the physical exam must be interpreted with caution, because there is considerable heterogeneity in the assessment of each of these features when different examiners are involved.132 Several authors have reported the detection of an hepatic bruit in the setting of AH.133 This has been used in some centers as a diagnostic criterion for AH.134 However, the sensitivity, as well as the specificity of this finding is uncertain.135 In one series of 280 consecutive hospitalized patients, only 4 of 240 (or 1.7%) with AH and cirrhosis had an audible bruit.136 Caution about adopting this as a diagnostic criterion has therefore been advised.137 It is important for physicians caring for these patients to recognize that ALD does not exist in isolation, and that other organ dysfunction related to alcohol abuse may coexist with ALD, including cardiomyopathy,138, 139 skeletal muscle wasting,140 pancreatic dysfunction, and alcoholic neurotoxicity.141 Evidence of these must be sought during the clinical examination, so that appropriate treatment may be provided.142 Imaging studies have been used to diagnose the presence of liver disease but do not have a role in establishing alcohol as the specific etiology of liver disease. However, the diagnosis of fatty change, established cirrhosis and hepatocellular carcinoma may be suggested by ultrasound, computed tomography scan, or magnetic resonance imaging (MRI) and confirmed by other laboratory investigations.143, 144 The major value of imaging studies is to exclude other causes of abnormal liver tests in a patient who abuses alcohol, such as obstructive biliary pathology, or infiltrative and neoplastic diseases of the liver.145 MRI has been used as an adjunct to diagnose cirrhosis, and to distinguish end-stage liver disease related to viral hepatitis infection from ALD. Specific features that may be suggestive of alcoholic cirrhosis include a higher volume index of the caudate lobe, more frequent visualization of the right posterior hepatic notch, and smaller size of regenerative nodules of the liver in patients with cirrhosis on the basis of ALD versus chronic viral hepatitis.146 Although changes were identified on ultrasound and MRI, it is unclear whether these results are generalizable.146, 147 Although not essential in the management of ALD, a liver biopsy is useful in establishing the diagnosis.144 As many as 20% of patients with a history of alcohol abuse have a secondary or coexisting etiology for liver disease.148 In the absence of decompensated disease, clinical and biochemical indicators are poor markers of the severity of liver disease, and a biopsy is useful in establishing the stage and severity of liver disease.144, 149 The histological features of alcohol-induced hepatic injury vary, depending on the extent and stage of injury. These may include steatosis (fatty change), lobular inflammation, periportal fibrosis, Mallory bodies, nuclear vacuolation, bile ductal proliferation, and fibrosis or cirrhosis.24 These may coexist in the same biopsy, however, and are not individually pathognomonic of ALD. The clinical diagnosis of AH is made based on a typical presentation, with severe liver dysfunction in the context of excessive alcohol consumption, and the exclusion of other causes of acute and chronic liver disease. In the subset of patients with AH, a liver biopsy may demonstrate specific histologic features, including confluent parenchymal necrosis, steatosis, deposition of intrasinusoidal and pericentral collagen, ballooning degeneration, and lobular inflammation affecting the perivenular regions in the earliest stages.34 The liver may be infiltrated with polymorphonuclear cells, typically clustered around cytoplasmic structures known as Mallory bodies,150 which represent aggregated cytokeratin intermediate filaments and other proteins. In addition to confirming the diagnosis and staging the extent of disease, specific features on liver biopsy also convey prognostic importance. The severity of inflammation (i.e., degree of polymorphonuclear cell infiltration) and cholestatic changes correlate with increasingly poor prognosis, and may also predict response to corticosteroid treatment in severe AH.151, 152 Megamitochondria in alcoholic hepatitis may be associated with a milder form of AH, a lower incidence of cirrhosis and fewer complications with a good long-term survival.153 AH is associated with perivenular and pericellular fibrosis which may be a harbinger of future cirrhosis, especially in patients who continue to abuse alcohol or those who are coinfected with hepatitis C virus.33, 154 Mallory bodies, giant mitochondria, neutrophilic infiltration, and fibrosis may be seen in conditions other than ALD.155 Although a liver biopsy may not be practical in the management of all patients, it has been shown that physicians' clinical impression may correlate only moderately well with the histologic findings on liver biopsy. Studies that have included a liver biopsy in all patients with presumed AH have shown histologic confirmation in only 70%-80% of patients.156 The incentive to make a definitive histologic diagnosis, however, is partly dependent on the possible risks of a biopsy, as well as the risks involved with particular treatments. If no treatment for ALD or AH is contemplated, based on noninvasive estimates of an individual patient's prognosis, it usually is not necessary to make a histologic diagnosis. Alternatively, if an investigational treatment or a therapy with associated risk is contemplated, the risk-benefit ratio involved in pursuing a liver biopsy may change. Clinicians should discuss alcohol use with patients, and any suspicion of possible abuse or excess should prompt use of a structured questionnaire and further evaluation (Class I, level C). For patients with a history of alcohol abuse or excess and evidence of liver disease, further laboratory tests should be done to exclude other etiologies and to confirm the diagnosis (Class I, level C). Patients with ALD and suggestive symptoms should be screened for evidence of other end-organ damage, as appropriate (Class I, level C). For patients with a clinical diagnosis of severe AH for whom medical treatment is contemplated, or for those in whom reasonable uncertainty exists regardi