Alcoholic Liver Disease

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 (Table AUDIT of or had one or more heavy drinking days constitutes a positive screening and to an alcohol use of which screening is however, it is important for clinicians to screening into their general This may be especially because some data suggest that these screening instruments may the ability of to clinical including for alcohol-related A in gamma glutamyl has been in a number of including large Unfortunately, low sensitivity and specificity limit the of elevated to alcohol the levels of which may with liver levels of or a total have been as a of mortality in patients with alcoholic this has not ability to other laboratory In combination with other however, may independent information in alcohol abuse or problem is in individuals alcohol but this A combination of raised and or changes in these over time in hospitalized patients may the sensitivity for alcohol abuse. other that may detect alcohol use or abuse have been has been the but has sensitivity and Its are also influenced by a number of other factors, including age, body and other chronic liver Despite about a possible of alcohol consumption or abuse, the of sensitivity and specificity on The diagnosis of ALD is by of alcohol excess and evidence of liver laboratory alcohol to be the of liver disease. alcohol may be one of a number of factors liver injury, and the specific role of alcohol may be to in a patient with liver disease. A number of laboratory abnormalities, including elevated have been reported in patients with alcoholic liver injury, and used to aspartate is elevated to a level of times the of in severe alcoholic of more than or an alanine are with alcoholic hepatitis than alcoholic or concomitant and suggest In about of patients, the is higher than but this may be of in patients without than are of findings in patients with ALD may range from to those of advanced cirrhosis. As in other of chronic liver disease, physical have low even for the of advanced disease or cirrhosis, may have higher It has been that the presence of these may have some benefit in the presence of advanced specific for ALD are perhaps even more to of the liver may be in the presence of ALD, and not provide information regarding liver physical findings have been associated with a higher likelihood of cirrhosis among Although some of the physical findings are more commonly in ALD and especially those associated with than in no physical or of findings is specific or sensitive for of the physical may also some independent with the presence of specific associated with an increased risk of mortality over These include (with their associated relative hepatic presence of across the and Although this is findings from the physical must be with because there is in the of each of these when are Several authors have reported the of an hepatic in the of This has been used in some as a diagnostic for However, the as well as the specificity of this is In one series of hospitalized patients, only 4 of with AH and cirrhosis had an about this as a diagnostic has been It is important for for these patients to recognize that ALD not in and that other organ related to alcohol abuse may with ALD, including and alcoholic Evidence of these must be the clinical so that treatment may be studies have been used to the presence of liver disease but do not have a role in alcohol as the specific of liver disease. However, the diagnosis of fatty cirrhosis and may be suggested by or magnetic resonance and by other laboratory The major of studies is to other of liver tests in a patient who alcohol, such as or and diseases of the has been used as an to cirrhosis, and to liver disease related to viral hepatitis infection from ALD. Specific that may be of alcoholic cirrhosis include a higher of the more frequent of the hepatic and of of the liver in patients with cirrhosis on the of ALD versus chronic viral Although changes were identified on and MRI, it is these are Although not in the management of ALD, a liver is useful in the As many as of patients with a history of alcohol abuse have a or coexisting for liver In the of disease, clinical and are of the of liver disease, and a is useful in the and of liver The histological of alcohol-induced hepatic injury on the extent and of These may include steatosis and fibrosis or These may in the however, and are not of ALD. The clinical diagnosis of AH is based on a presentation, with severe liver in the context of alcohol and the of other of acute and chronic liver disease. In the subset of patients with AH, a liver may specific histologic features, including steatosis, deposition of and and the perivenular regions in the The liver may be with known as which represent and other In addition to the diagnosis and the extent of disease, specific on liver also The of (i.e., of and changes with and may also to treatment in severe in alcoholic hepatitis may be associated with a form of AH, a lower of cirrhosis and with a AH is associated with perivenular and fibrosis which may be a of cirrhosis, especially in patients who continue to abuse alcohol or those who are with hepatitis C and fibrosis may be in other than Although a liver may not be in the management of all patients, it has been shown that clinical may only well with the histologic findings on liver that have a liver in all patients with AH have shown histologic in only of The to make a histologic however, is on the possible of a as well as the involved with no treatment for ALD or AH is based on estimates of an individual it usually is not to make a histologic an treatment or a with associated risk is the involved in a liver may Clinicians alcohol use with patients, and of possible abuse or excess use of a structured questionnaire and level patients with a history of alcohol abuse or excess and evidence of liver disease, laboratory tests be to other and to confirm the diagnosis level with ALD and be for evidence of other damage, as level patients with a clinical diagnosis of severe AH for treatment is or for those in exists