308 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010 Table 1. Grading System for Recommendations estimate worldwide patterns of alcohol consumption andClassiﬁcation Description allow comparisons of alcohol related morbidity and mor- Class I Conditions for which there is evidence and/or general tality.22 The burden of alcohol-related disease is highest in agreement that a given diagnostic evaluation, the developed world, where it may account for as much as procedure or treatment is beneﬁcial, useful, and 9.2% of all disability-adjusted life years. Even in develop- effective. Class II Conditions for which there is conﬂicting evidence ing regions of the world, however, alcohol accounts for a and/or a divergence of opinion about the major portion of global disease burden, and is projected to usefulness/efﬁcacy of a diagnostic evaluation, take on increasing importance in those regions over procedure or treatment. time.22,23 Class IIa Weight of evidence/opinion is in favor of usefulness/ efﬁcacy. Class IIb Usefulness/efﬁcacy is less well established by II. Disease Spectrum evidence/opinion. Class III Conditions for which there is evidence and/or general The spectrum of alcohol-related liver injury varies agreement that a diagnostic evaluation/procedure/ from simple steatosis to cirrhosis. These are not necessar- treatment is not useful/effective and in some cases may be harmful. ily distinct stages of evolution of disease, but rather, mul- tiple stages that may be present simultaneously in a givenLevel of Evidence Description individual.24,25 These are often grouped into three histo- Level A Data derived from multiple randomized clinical trials logical stages of ALD: fatty liver or simple steatosis, alco- or meta-analyses. Level B Data derived from a single randomized trial, or holic hepatitis, and chronic hepatitis with hepatic ﬁbrosis nonrandomized studies. or cirrhosis.26 These latter stages may also be associated Level C Only consensus opinion of experts, case studies, or with a number of histologic changes (which have varying standard-of-care. degrees of speciﬁcity for ALD), including the presence of Mallory’s hyaline, megamitochondria, or perivenular and perisinusoidal ﬁbrosis.24ure to recognize alcoholism remains a signiﬁcant problem Fatty liver develops in about 90% of individuals whoand impairs efforts at both the prevention and manage- drink more than 60 g/day of alcohol,27 but may also occurment of patients with ALD.13,14 Although the exact prev- in individuals who drink less.28 Simple, uncomplicatedalence is unknown, approximately 7.4% of adult fatty liver is usually asymptomatic and self limited, andAmericans were estimated to meet DSM-IV criteria for may be completely reversible with abstinence after aboutthe diagnosis of alcohol abuse and/or alcohol dependence 4-6 weeks.29 However, several studies have suggested thatin 199415; more recent data suggest 4.65% meet criteria progression to ﬁbrosis and cirrhosis occurs in 5%-15% offor alcohol abuse and 3.81% for alcohol dependence.16 In patients despite abstinence.30,31 In one study, continued2003, 44% of all deaths from liver disease were attributed alcohol use (Ͼ40 g/day) increased the risk of progressionto alcohol.17 to cirrhosis to 30%, and ﬁbrosis or cirrhosis to 37%.32 Population level mortality from alcoholic liver disease Fibrosis is believed to start in the perivenular area andis related to per capita alcohol consumption obtained is inﬂuenced by the amount of alcohol ingested.33,34from national alcoholic beverage sales data. There are Perivenular ﬁbrosis and deposition of ﬁbronectin occursconﬂicting data regarding a possible lower risk of liver in 40%-60% of patients who ingest more than 40-80injury in wine drinkers.18,19 One epidemiologic study has g/daily for an average of 25 years. Perivenular sclerosis hasestimated that for every 1-liter increase in per capita alco-hol consumption (independent of type of beverage), therewas a 14% increase in cirrhosis in men and 8% increase in Table 2. Quantity of Alcohol in a Standard Drinkwomen.20 These data must be considered in the context of Region Amount Rangethe limitations of measuring alcohol use and deﬁning al-coholic liver disease. The scientiﬁc literature has also used USA 12 g 9.3–13.2 g Canada 13.6 g 13.6 ga variety of deﬁnitions of what constitutes a standard UK 9.5 g 8–10 gdrink (Table 2). Most studies depend on interviews with Europe 9.8 g 8.7–10.0 gpatients or their families to quantify drinking patterns, a Australia and New Zealand 9.2 g 6.0–11.0 g Japan 23.5 g 21.2–28.0 gmethod that is subject to a number of biases, which maylead to invalid estimates of alcohol consumption.21 Adapted from Turner.263 To standardize, many authorities recommend conver- Although there are limitations of the available data, the sion to grams of alcohol consumed. To convert concentrations of alcohol, usually listed in volume percent (equivalent to the volume of solute/volume of solution ϫWorld Health Organization’s Global Alcohol database, 100), the percentage of alcohol by volume (% vol/vol) is multiplied by the speciﬁcwhich has been in existence since 1996, has been used to gravity of alcohol, 0.79 g/mL.264
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 309been identiﬁed as a signiﬁcant and independent risk factor odds of developing cirrhosis or lesser degrees of liver dis-for the progression of alcoholic liver injury to ﬁbrosis or ease with a daily alcohol intake of Ͼ30 g/day were 13.7cirrhosis.33,35 Progression of ALD culminates in the de- and 23.6, respectively, when compared with nondrink-velopment of cirrhosis, which is usually micronodular, ers.50but may occasionally be mixed micronodular and ma- The type of alcohol consumed may inﬂuence the riskcronodular.36 of developing liver disease. In a survey of more than A subset of patients with ALD will develop severe al- 30,000 persons in Denmark, drinking beer or spirits wascoholic hepatitis (AH), which has a substantially worse more likely to be associated with liver disease than drink-short-term prognosis.37 AH also represents a spectrum of ing wine.18disease, ranging from mild injury to severe, life-threaten- Another factor that has been identiﬁed is the pattern ofing injury, and often presents acutely against a back- drinking. Drinking outside of meal times has been re-ground of chronic liver disease.38,39 The true prevalence is ported to increase the risk of ALD by 2.7-fold comparedunknown, but histologic studies of patients with ALD to those who consumed alcohol only at mealtimes.52suggest that AH may be present in as many as 10%-35% Binge drinking, deﬁned by some researchers as ﬁve drinksof hospitalized alcoholic patients.40-42 Typically, symp- for men and four drinks for women in one sitting, has alsotomatic patients present with advanced liver disease, with been shown to increase the risk of ALD and all-causeconcomitant cirrhosis in more than 50%, and superim- mortality.53,54posed acute decompensation. Even patients with a rela- Women have been found to be twice as sensitive totively mild presentation, however, are at high risk of alcohol-mediated hepatotoxicity and may develop moreprogressive liver injury, with cirrhosis developing in up to severe ALD at lower doses and with shorter duration of50%.43,44 The likelihood that AH will progress to perma- alcohol consumption than men.55 Several studies havenent damage is increased among those who continue to shown differing blood alcohol levels in women versusabuse alcohol. Abstinence from alcohol in one small series men after consumption of equal amounts of alcohol.56did not guarantee complete recovery. Only 27% of ab- This might be explained by differences in the relativestaining patients had histologic normalization, whereas18% progressed to cirrhosis, and the remaining patients amount of gastric alcohol dehydrogenase, a higher pro-had persistent AH when followed for up to 18 months.45 portion of body fat in women, or changes in alcohol ab- sorption with the menstrual cycle.57 Based onIII. Risk Factors epidemiological evidence of a threshold effect of alcohol, a suggested “safe” limit of alcohol intake had been 21 Unlike many other hepatotoxins, the likelihood of de- units per week in men and 14 units per week in womenveloping progressive alcohol-induced liver disease or cir- who have no other chronic liver disease58,59 (where a unitrhosis is not completely dose-dependent, because it occurs is deﬁned as the equivalent of 8 g of ethanol). However,in only a subset of patients. A number of risk factors have other data suggest that a lower quantity may be toxic inbeen identiﬁed that inﬂuence the risk of development andprogression of liver disease. women, implying a lower threshold of perhaps no more The amount of alcohol ingested (independent of the than 7 units per week.47 A higher risk of liver injury mayform in which it is ingested) is the most important risk be associated with an individual’s racial and ethnic heri-factor for the development of ALD.46 The relationship tage.60 The rates of alcoholic cirrhosis are higher in Afri-between the quantity of alcohol ingested and the develop- can-American and Hispanic males compared toment of liver disease is not clearly linear.47,48 However, a Caucasian males and the mortality rates are highest insigniﬁcant correlation exists between per capita consump- Hispanic males.61 These differences do not appear to betion and the prevalence of cirrhosis.49 The risk of devel- related to differences in amounts of alcohol consumed.62oping cirrhosis increases with the ingestion of Ͼ60-80 The presence and extent of protein calorie malnutri-g/day of alcohol for 10 years or longer in men, and Ͼ20 tion play an important role in determining the outcomeg/day in women.6,50 Yet, even drinking at these levels, of patients with ALD. Mortality increases in direct pro-only 6%-41% develop cirrhosis.6,51 In a population-based portion to the extent of malnutrition, approaching 80%cohort study of almost 7000 subjects in two northern in patients with severe malnutrition (i.e., less than 50% ofItalian communities, even among patients with very high normal).63 Micronutrient abnormalities, such as hepaticdaily alcohol intake (Ͼ120 g/day), only 13.5% developed vitamin A depletion or depressed vitamin E levels, mayALD.50 The risk of cirrhosis or noncirrhotic chronic liver also potentially aggravate liver disease.64 Diets rich indisease increased with a total lifetime alcohol intake of polyunsaturated fats promote alcohol-induced liver dis-more than 100 kg, or a daily intake Ͼ30 g/day.50 The ease in animals,65 whereas diets high in saturated fats may
310 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010be protective. Obesity and excess body weight have been evidence of alcohol abuse, such as questionnaires, infor-associated with an increased risk of ALD.66,67 mation from family members, or laboratory tests to In addition to environmental factors, genetic factors strengthen or conﬁrm a clinical suspicion.86predispose to both alcoholism and ALD.68-70 Children ofalcoholics raised in adopted families had a signiﬁcantly A. Screening for Alcohol Abusehigher rate of alcohol dependence than did adopted chil- Clinicians commonly fail to screen patients, and thusdren of nonalcoholics, who served as controls (18% versus fail to recognize or treat alcoholism appropriately.87 The5%).71 In population-based studies, monozygotic twins clinical history which may suggest alcohol abuse or alco-were approximately twice as likely to drink as dizygotic hol dependence includes the pattern, type, and amount oftwins; among those who drank, monozygotic twins were alcohol ingested, as well as evidence of social or psycho-more likely to have a similar frequency and quantity of logical consequences of alcohol abuse. These may be sug-alcohol consumption.72 Moreover, monozyotic twins gested by other injuries or past trauma, such as frequenthave a signiﬁcantly higher prevalence of alcoholic cirrho- falls, lacerations, burns, fractures, or emergency depart-sis than do dizygotic twins.73 ment visits.88 Biochemical tests have been considered to Finally, polymorphisms of genes involved in the me- be less sensitive than questionnaires in screening for alco-tabolism of alcohol (including alcohol dehydrogenase, ac- hol abuse,89,90 but may be useful in identifying re-etaldehyde dehydrogenase and the cytochrome P450 lapse.91,92 Various questionnaires have been used to detectsystem), and in those which regulate endotoxin-mediated alcohol dependence or abuse, and include the CAGE, therelease of cytokines have been associated with ALD.74,75 MAST (Michigan Alcoholism Screening Test), and theHowever, to date, speciﬁc genetic abnormalities for sus- Alcohol Use Disorders Identiﬁcation Test (AUDIT).89,93ceptibility to alcohol abuse and the development of ALD The use of a structured interview, using instruments suchhave not yet been ﬁrmly established. as the Lifetime Drinking History, is often used as a gold There is a clear synergistic relationship between standard for quantifying lifetime alcohol consumption.94chronic viral hepatitis and alcohol, resulting in more ad- The CAGE questionnaire was originally developed tovanced liver disease jointly than separately. The combina- identify hospitalized inpatients with alcohol problems,tion of hepatitis C virus and alcohol predisposes to more and remains among the most widely used screening in-advanced liver injury than alcohol alone,76,77 with disease struments. It has been faulted, however, on several mea-at a younger age, more severe histological features, and a sures: it focuses on the consequences of alcoholdecreased survival.78 In a large cohort study of the effect of consumption rather than on the amount of actual drink-heavy alcohol abuse in patients with posttransfusion hep- ing, and it refers to lifetime patterns of behavior, ratheratitis C, the risk of cirrhosis was elevated 30-fold.79 Al- than short-term or recent changes. Its virtues, however,though the precise toxic threshold for alcohol is not include its ease of implementation: it is short (four ques-known, and may be lower and nonuniform among pa- tions), simple (yes/no answers), and can be incorporatedtients at risk, it seems prudent in light of these data to into the clinical history or is self-administered as a writtenadvise patients with hepatitis C to abstain from even mod- document. As a result of its longevity, it has been tested inerate quantities of alcohol. a wide range of populations. One meta-analysis of its characteristics, using a cutoffIV. Diagnosis of more than two positive responses, found an overall The diagnosis of ALD is based on a combination of pooled sensitivity and speciﬁcity of 0.71 and 0.90, respec-features, including a history of signiﬁcant alcohol intake, tively.95 The CAGE questionnaire is familiar to most phy-clinical evidence of liver disease, and supporting labora- sicians, and has been suggested for use in generaltory abnormalities.80 Unfortunately, the ability to detect screening96 (Table 3). The AUDIT is a 10-item question-these is constrained by patient and physician factors, as naire developed by the World Health Organization towell as diagnostic laboratory shortcomings. Denial of al-cohol abuse and underreporting of alcohol intake arecommon in these patients.81,82 Physicians underestimate Table 3. The CAGE Questionnaire265alcohol-related problems and make speciﬁc recommenda- 1. Have you ever felt you should cut down on your drinking? 2. Have people annoyed you by criticizing your drinking?tions even less frequently.83,84 Both the physical ﬁndings 3. Have you ever felt bad or guilty about your drinking?and laboratory evidence for ALD may be nondiagnostic, 4. Have you ever had a drink ﬁrst thing in the morning to steady your nervesespecially in patients with mild ALD or early cirrhosis.85 or to get rid of a hangover (eye-opener)?Therefore, the clinician must have a low threshold to raise Scoring: Each response is scored as 0 or 1, with a higher score indicative ofthe issue of possible ALD, and has to rely on indirect alcohol-related problems, and a total of 2 or more clinically signiﬁcant.
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 311 Table 4. AUDIT Questionnaire102 Questions 0 1 2 3 4 1. How often do you have a drink Never Monthly or less 2 to 4 times 2 to 3 times 4 or more times containing alcohol? a month a week a week 2. How many drinks containing 1 or 2 3 or 4 5 or 6 7 to 9 10 or more alcohol do you have on a typical day when you are drinking? 3. How often doyou have 5 or more Never Less than monthly Monthly Weekly Daily or almost drinks on one occasion? daily 4. How often during the last year have Never Less than monthly Monthly Weekly Daily or almost you found that you were not able daily to stop drinking once you had started? 5. How often during the last year have Never Less than monthly Monthly Weekly Daily or almost you failed to do what was normally daily expected of you because of drinking? 6. How often during the last year have Never Less than monthly Monthly Weekly Daily or almost you needed a ﬁrst drink in the daily morning to get yourself going after a heavy drinking session? 7. how often during the last year have Never Less than monthly Monthly Weekly Daily or almost you had a feeling of guilt or daily remorse after drinking? 8. How often during the last year have Never Less than monthly Monthly Weekly Daily or almost you been unable to remember what daily happened the night before because of your drinking? 9. Have you or someone else been No Yes, but not in Yes, during the injured because of your drinking? the last year last year10. Has a relative, friend, doctor or No Yes, but not in Yes, during the other health care worker been the last year last year concerned about your drinking or suggested you cut down? To score the AUDIT questionnaire, sum the scores for each of the 10 questions. A total Ն 8 for men up to age 60, or Ն4 for women, adolescents, or men overage 60 is considered a positive screening test.avoid ethnic and cultural bias97 and focuses on the iden- Regardless of which screening instrument is selected,tiﬁcation of heavy drinkers. It has a higher sensitivity and however, it is important for clinicians to incorporatespeciﬁcity than shorter screening instruments (with sen- screening into their general practice.98,103 This may besitivity ranging from 51%-97%, and speciﬁcity of 78%- especially important, because some data suggest that these96% in primary care).98 It has been suggested that it has screening instruments may improve the ability of physi-three advantages over other screening tests: it may identify cians to predict long-term clinical outcomes, includingdrinkers at risk who are not yet alcohol-dependent; it hospitalization for alcohol-related diagnoses.104includes a measure of consumption; and lastly, it includes A biomarker in longstanding use, gamma glutamylboth current and lifetime drinking time spans. It is more transpeptidase (GGT), has been evaluated in a number oflikely to detect problem drinking before overt alcohol settings, including large population surveys.105,106 Unfor-dependence or abuse might be diagnosed, and thus may tunately, low sensitivity and speciﬁcity limit the useful-be more robust and effective across a variety of popula- ness of elevated GGT to diagnose alcohol abuse,107-109 thetions.99-101 One possible algorithm for clinicians suggests levels of which may ﬂuctuate with extensive liver inju-asking about quantity of alcohol consumed, and number ry.110 Lower levels of GGT (Ͻ100) or a total bilirubin/of heavy drinking days in the preceding year (i.e., Ն 5 GGT ratio Ͼ 1 have been described as a predictor ofdrinks/day for men or Ն 4 drinks/day for women), as well 1-year mortality in patients with alcoholic cirrhosis,110as a version of the AUDIT questionnaire102 (Table 4). An although this has not consistently added prognostic abil-AUDIT score of Ն8, or having had one or more heavy ity to other laboratory tests.111 In combination with otherdrinking days constitutes a positive screening test, and biomarkers, however, GGT may add independent infor-should prompt further evaluation to rule out an alcohol mation in diagnosing alcohol abuse or problem drink-use disorder.102 ing.112 Macrocytosis is seen in individuals abusing alcohol
312 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010but this condition lacks sensitivity. A combination of the physical ﬁndings are more commonly observed inraised GGT and mean corpuscular volume or changes in ALD (parotid enlargement, Dupuytren’s contracture,these values over time in hospitalized patients may im- and especially those signs associated with feminization)prove the sensitivity for diagnosing alcohol abuse. Multi- than in non-ALD, no single physical ﬁnding or constel-ple other candidate biomarkers that may detect alcohol lation of ﬁndings is 100% speciﬁc or sensitive for ALD.130use or abuse objectively have been studied.113,114 Carbo- Some of the physical exam features may also carry somehydrate-deﬁcient transferrin has been the best studied, independent prognostic information, with the presencebut has limited sensitivity and speciﬁcity.115 Its test char- of speciﬁc features associated with an increased risk ofacteristics are also inﬂuenced by a number of other factors, mortality over 1 year. These include (with their associatedincluding age, sex, body mass index, and other chronic relative risks): hepatic encephalopathy (4.0), presence ofliver diseases.116-118 Despite enthusiasm about a possible visible veins across the anterior abdominal wall (2.2),quantitative, reliable assay of alcohol consumption or edema (2.9), ascites (4.0), spider nevi (3.3), and weaknessabuse, the lack of sensitivity and speciﬁcity prevent reli- (2.1).131 Although this is somewhat helpful clinically,ance on any single biomarker.119 ﬁndings from the physical exam must be interpreted with caution, because there is considerable heterogeneity in theB. Diagnosis of ALD assessment of each of these features when different exam- The diagnosis of ALD is made by documentation of iners are involved.132 Several authors have reported thealcohol excess and evidence of liver disease.120 No single detection of an hepatic bruit in the setting of AH.133 Thislaboratory marker deﬁnitively establishes alcohol to be the has been used in some centers as a diagnostic criterion foretiology of liver disease. Furthermore, alcohol may be one AH.134 However, the sensitivity, as well as the speciﬁcityof a number of factors causing liver injury, and the speciﬁc of this ﬁnding is uncertain.135 In one series of 280 con-contributory role of alcohol alone may be difﬁcult to as- secutive hospitalized patients, only 4 of 240 (or 1.7%)sess in a patient with multifactorial liver disease. A num- with AH and cirrhosis had an audible bruit.136 Cautionber of laboratory abnormalities, including elevated serum about adopting this as a diagnostic criterion has thereforeaminotransferases, have been reported in patients with been advised.137alcoholic liver injury, and used to diagnose ALD.121 Se- It is important for physicians caring for these patientsrum aspartate aminotransferase (AST) is typically elevated to recognize that ALD does not exist in isolation, and thatto a level of 2-6 times the upper limits of normal in severe other organ dysfunction related to alcohol abuse may co-alcoholic hepatitis. Levels of AST more than 500 IU/L or an exist with ALD, including cardiomyopathy,138,139 skeletalalanine aminotransferase (ALT) Ͼ 200 IU/L are uncom- muscle wasting,140 pancreatic dysfunction, and alcoholicmonly seen with alcoholic hepatitis (other than alcoholic neurotoxicity.141 Evidence of these must be sought duringfoamy degeneration, or concomitant acetaminophen over- the clinical examination, so that appropriate treatmentdose),122 and should suggest another etiology. In about 70% may be provided.142of patients, the AST/ALT ratio is higher than 2, but this maybe of greater value in patients without cirrhosis.123-125 Ratios D. Hepatic Imaginggreater than 3 are highly suggestive of ALD.126 Imaging studies have been used to diagnose the pres- ence of liver disease but do not have a role in establishingC. Physical Examination alcohol as the speciﬁc etiology of liver disease. However, Physical exam ﬁndings in patients with ALD may the diagnosis of fatty change, established cirrhosis andrange from normal to those suggestive of advanced cirrho- hepatocellular carcinoma may be suggested by ultra-sis. As in other forms of chronic liver disease, physical sound, computed tomography scan, or magnetic reso-exam features generally have low sensitivity, even for the nance imaging (MRI) and conﬁrmed by other laboratorydetection of advanced disease or cirrhosis, although they investigations.143,144 The major value of imaging studies ismay have higher speciﬁcity.127 It has been suggested, to exclude other causes of abnormal liver tests in a patienttherefore, that the presence of these features may have who abuses alcohol, such as obstructive biliary pathology,some beneﬁt in “ruling in” the presence of advanced dis- or inﬁltrative and neoplastic diseases of the liver.145 MRIease.127 Features speciﬁc for ALD are perhaps even more has been used as an adjunct to diagnose cirrhosis, and todifﬁcult to identify. Palpation of the liver may be normal distinguish end-stage liver disease related to viral hepatitisin the presence of ALD, and does not provide accurate infection from ALD. Speciﬁc features that may be sugges-information regarding liver volume.128 Certain physical tive of alcoholic cirrhosis include a higher volume index ofexam ﬁndings have been associated with a higher likeli- the caudate lobe, more frequent visualization of the righthood of cirrhosis among alcoholics.129 Although some of posterior hepatic notch, and smaller size of regenerative
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 313nodules of the liver in patients with cirrhosis on the basis sicians’ clinical impression may correlate only moderatelyof ALD versus chronic viral hepatitis.146 Although well with the histologic ﬁndings on liver biopsy. Studieschanges were identiﬁed on ultrasound and MRI, it is un- that have included a liver biopsy in all patients with pre-clear whether these results are generalizable.146,147 sumed AH have shown histologic conﬁrmation in only 70%-80% of patients.156 The incentive to make a deﬁn-E. Liver Biopsy in ALD itive histologic diagnosis, however, is partly dependent on Although not essential in the management of ALD, a the possible risks of a biopsy, as well as the risks involvedliver biopsy is useful in establishing the diagnosis.144 As with particular treatments. If no treatment for ALD ormany as 20% of patients with a history of alcohol abuse AH is contemplated, based on noninvasive estimates of anhave a secondary or coexisting etiology for liver disease.148 individual patient’s prognosis, it usually is not necessaryIn the absence of decompensated disease, clinical and bio- to make a histologic diagnosis. Alternatively, if an inves-chemical indicators are poor markers of the severity of tigational treatment or a therapy with associated risk isliver disease, and a biopsy is useful in establishing the stage contemplated, the risk-beneﬁt ratio involved in pursuingand severity of liver disease.144,149 a liver biopsy may change. The histological features of alcohol-induced hepatic Recommendation:injury vary, depending on the extent and stage of injury. 1. Clinicians should discuss alcohol use with pa-These may include steatosis (fatty change), lobular in- tients, and any suspicion of possible abuse or excessﬂammation, periportal ﬁbrosis, Mallory bodies, nuclear should prompt use of a structured questionnaire andvacuolation, bile ductal proliferation, and ﬁbrosis or cir- further evaluation (Class I, level C).rhosis.24 These may coexist in the same biopsy, however, 2. For patients with a history of alcohol abuse orand are not individually pathognomonic of ALD. The excess and evidence of liver disease, further laboratoryclinical diagnosis of AH is made based on a typical pre- tests should be done to exclude other etiologies and tosentation, with severe liver dysfunction in the context of conﬁrm the diagnosis (Class I, level C).excessive alcohol consumption, and the exclusion of other 3. Patients with ALD and suggestive symptomscauses of acute and chronic liver disease. In the subset of should be screened for evidence of other end-organpatients with AH, a liver biopsy may demonstrate speciﬁc damage, as appropriate (Class I, level C).histologic features, including conﬂuent parenchymal ne- 4. For patients with a clinical diagnosis of severecrosis, steatosis, deposition of intrasinusoidal and pericen- AH for whom medical treatment is contemplated, ortral collagen, ballooning degeneration, and lobular for those in whom reasonable uncertainty exists re-inﬂammation affecting the perivenular regions in the ear- garding the underlying diagnosis, a liver biopsy shouldliest stages.34 The liver may be inﬁltrated with polymor- be considered. This decision will depend on localphonuclear cells, typically clustered around cytoplasmic expertise and ability in performing a liver biopsy instructures known as Mallory bodies,150 which represent patients with coagulopathy, the patient’s severity ofaggregated cytokeratin intermediate ﬁlaments and other illness, and the type of therapy under considerationproteins. In addition to conﬁrming the diagnosis and (Class I, level C).staging the extent of disease, speciﬁc features on liver bi-opsy also convey prognostic importance. The severity of V. Prognostic Factorsinﬂammation (i.e., degree of polymorphonuclear cell in- A. Prognosis in Alcoholic Hepatitisﬁltration) and cholestatic changes correlate with increas- Decisions regarding treatment are critically dependentingly poor prognosis, and may also predict response to on the ability to estimate a given patient’s prognosis.corticosteroid treatment in severe AH.151,152 Megamito- Many individual clinical and laboratory features, alongchondria in alcoholic hepatitis may be associated with a with speciﬁc histologic features have also been tested asmilder form of AH, a lower incidence of cirrhosis and measures of disease prognosis. In AH, the Maddrey dis-fewer complications with a good long-term survival.153 criminant function (MDF), a disease-speciﬁc prognosticAH is associated with perivenular and pericellular ﬁbrosis score, has been used to stratify a patient’s severity of ill-which may be a harbinger of future cirrhosis, especially in ness.157 The initial formula was derived in the context ofpatients who continue to abuse alcohol or those who are clinical trials of alcoholic hepatitis, and later modiﬁed to:coinfected with hepatitis C virus.33,154 Mallory bodies, MDF ϭ 4.6 (Patient’s prothrombin time Ϫ control pro-giant mitochondria, neutrophilic inﬁltration, and ﬁbrosis thrombin time) ϩ total bilirubin (mg/dL).158 Patientsmay be seen in conditions other than ALD.155 with a score of greater than or equal to 32 were at the Although a liver biopsy may not be practical in the highest risk of dying, with a one month mortality as highmanagement of all patients, it has been shown that phy- as 30%-50%.151 In particular, those with evidence of both
314 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010 Table 5. Prognostic Scoring Systems Used for Patients with Alcoholic Hepatitis Derivation Name Set Elements Test Characteristics1. Maddrey (modiﬁed) n ϭ 66 MDF ϭ 4.6 (Patient’s PT Ϫ control PT) ϩ total bilirubin (mg/dL). Poor prognosis if score Ն 32 Discriminant Function (1989)1582. MELD score (2001)†160 n ϭ 1179 MELD Score ϭ 3.8 * loge(bilirubin in mg/dL) ϩ 11.2 * loge(INR) Poor prognosis if Ͼ18 ϩ 9.6 * loge(creatinine mg/dL) ϩ 6.43. Glasgow Alcoholic Hepatitis n ϭ 241 Score*: Poor prognosis if score Ͼ 8 (for score (2005)161 1 2 3 score calculated on hospital Age Ͻ50 Ն50 – day 1 or day 7) WCC Ͻ15 Ն15 – Urea (mmol/L) Ͻ5 Ն5 – PT ratio Ͻ1.5 1.5–2.0 Ն2 Bilirubin (mg/dL) Ͻ7.3 7.3–14.6 Ͼ14.6 *The GAH score is calculated by summing the points assigned for each of the 5 variables: age, white blood cell count, blood urea nitrogen, PT as a ratio of the patientto the control, and the bilirubin. This is done on hospital day 1 or on day 7. †The MELD score has also been used to estimate 90-day mortality166; an online calculator is available: www.mayoclinic.org/meld/mayomodel7.html.hepatic encephalopathy and an elevated MDF were at Several studies have also demonstrated the utility ofhighest risk. Although relatively easy to use, and based on repeat testing and calculation of these indices during thestandard laboratory tests, several drawbacks to the use of course of hospitalization, including MELD or MDF scorethe MDF have been noted. Although it is a continuous at one week, and degree of change. A change of Ն2 pointsmeasure, its interpretation (using a threshold of 32) has in the MELD score in the ﬁrst week has been shown toconverted it into an essentially categorical method of clas- independently predict in-hospital mortality.164 Thesiﬁcation. Once patients have exceeded that threshold, GAHS was recently derived, and its test characteristicstheir risk for dying is higher, but not speciﬁed. Dynamic compared to the MDF and the MELD scores. Although itmodels, which incorporate the changes in laboratory had an overall higher accuracy, it was substantially lessstudies over time, have also been used to estimate the sensitive for predicting one month and three month mor-outcome in patients, including the change in bilirubin in tality compared to either the MDF or the MELD.161 Thethe ﬁrst week of hospitalization, which is signiﬁcantly degree of portal hypertension may be a sensitive markerassociated with outcome of patients with alcoholic hepa- for the severity of liver injury.167 A recently proposedtitis treated with prednisolone.159 scoring system combines measurements of a marker of Table 5 outlines some of the prognostic scoring sys- portal hypertension, asymmetric dimethylarginine and itstems used for patients with alcoholic hepatitis. stereoisomer, to predict outcomes.168 This combined Other scoring systems have also been proposed to strat- score has been compared to the CTP score, MELD, andify patients, including the combined clinical and labora- MDF, and shown to have an overall sensitivity of 73%tory index of the University of Toronto,131 the Beclere and speciﬁcity of 83%, which was at least as good as othermodel,151 the MELD (Model for End-Stage Liver Dis-ease) score,160 and the Glasgow Alcoholic Hepatitis Score scoring systems.168 These results, however, require further(GAHS).161 The diagnostic abilities of the latter two validation.models have been tested against the MDF and other scor- As the goal of early detection of patients at highest risking systems for cirrhosis (such as the Child-Turcotte- of poor outcome requires maximization of the sensitivityPugh score, or CTP) in terms of speciﬁc test of the test score, it would seem reasonable to use the MDFcharacteristics, including sensitivity and speciﬁcity, at (with a cutoff of 32, and/or the presence of encephalopa-least in some populations.162,163 Because of the inherent thy) to select patients for therapy.trade-offs involved in setting test thresholds, optimal cut Recommendation:points are not clearly established for each of these indices. 5. Patients presenting with a high clinical suspicionSome investigators have suggested speciﬁc cutoffs for of alcoholic hepatitis should have their risk for poorthese indices, including an MDF Ն32 or a MELD outcome stratiﬁed using the Maddrey Discriminantscore Ͼ 11, that appear to be roughly equivalent in ability Function, as well as other available clinical data.to detect patients with a poor prognosis, with similar sen- Evaluating a patient’s condition over time with serialsitivity and speciﬁcity.162 Others have suggested higher calculation of the MELD score is also justiﬁed (ClassMELD cutoffs of 18,164 19,165 or 21166 (Table 6). I, level B).
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 315 Table 6. Comparisons of Diagnostic Indices Author Patient Population Outcome AUROCSheth 162 N ϭ 34 patients with alcoholic hepatitis MELD Ͼ 11: MELD: 0.82 hospitalized 1997-2000. 21% 30 day mortality Sensitivity 86% MDF: 0.86 Speciﬁcity: 81% MDF Ն 32: Sensitivity 86% Speciﬁcity 48%Srikureja164 N ϭ 202 AH patients admitted 1997-2002. 29 Admission MELD Ն 18: Admission MELD: 0.89 inpatient deaths Sensitivity 85% Admission CTP: 0.87 Speciﬁcity 84% Admission DF: 0.81 Admission MDF Ն 32: Sensitivity 83% Speciﬁcity 60% Admission CTP Ն 12: Sensitivity 76% Speciﬁcity 80%Dunn166 N ϭ 73 AH patients admitted 1995-2001. 16 Admission MELD Ͼ 21: Admission MELD: 0.83 deaths in 90 days. Outcome: 30 day mortality Sensitivity 75% Admission MDF: 0.74 Speciﬁcity 75% MDF Ͼ 41: Sensitivity 75% Speciﬁcity 69Soultati165 N ϭ 34 patients admitted 2000-2005; 2 MELD Ն 30.5: MELD: 0.969 deaths/30 days, 5 deaths/90 days. Outcome: Sensitivity 1 MDF: 0.984 30 day mortality Speciﬁcity 0.937 MDF Ն 108.68: Sensitivity 1 Speciﬁcity 0.969 AUROC: area under the ROC curve, with optimal test results closest to 1VI. Therapy the time course of follow-up and the deﬁnition of recidi- vism (e.g., any alcohol consumption versus moderate to Therapy of ALD is based on the stage of the disease and harmful drinking), but over the course of 1 year, relapsethe speciﬁc goals of treatment.169,170 Complications of rates range from 67%-81%.181 Therefore, several medica-cirrhosis, including evidence of hepatic failure (encepha- tions have been tried to help sustain abstinence. One oflopathy) as well as portal hypertension (ascites, variceal the ﬁrst agents to be used, disulﬁram, was approved by thebleeding), are treated as in patients with non-ALD, with U.S. Food and Drug Administration in 1983. However, aadditional attention given to other organ dysfunction as- review of the published literature concluded that theresociated speciﬁcally with alcohol.170 was little evidence that disulﬁram enhances abstinence,182A. Abstinence and based on its poor tolerability, its use has been largely Abstinence is the most important therapeutic interven- supplanted by newer agents. Naltrexone, which was ap-tion for patients with ALD.171 Abstinence has been shown proved in 1995 for the treatment of alcoholism, is a pureto improve the outcome and histological features of he- opioid antagonist and controls the craving for alcohol.patic injury, to reduce portal pressure and decrease pro- However, it also has been shown to cause hepatocellulargression to cirrhosis, and to improve survival at all stages injury. A Cochrane systematic review of the use of nal-in patients with ALD.171-174 However, this may be less trexone and nalmefene (another opioid antagonist) in 29likely to occur in female patients.172,175,176 This improve- randomized clinical trials concluded that short-termment can be relatively rapid, and in 66% of patients ab- treatment with naltrexone lowers the risk of relapse.183staining from alcohol, signiﬁcant improvement was Acamprosate (acetylhomotaurine) is a novel drug withobserved in 3 months.177 Continued alcohol ingestion structural similarities to the inhibitory neurotransmitterresults in an increased risk of portal hypertensive bleeding, gamma amino butyric acid (GABA), and is associatedespecially in patients who have previously bled, and wors- with a reduction in withdrawal symptoms.184 In 15 con-ens both short-term and long-term survival.178 trolled trials, acamprosate has been shown to reduce with- Recidivism is a major risk in all patients at any time drawal symptoms, including alcohol craving, but itsfollowing abstinence.179,180 Estimates vary, depending on effects on survival are not yet known.185 Its effect is more
316 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010pronounced in maintaining rather than inducing remis- alone. For those with more severe disease and therefore asion when used in combination with counseling and sup- more dismal prognosis, however, medical treatmentport. In detoxiﬁed alcoholics, it has been shown to should be considered.decrease the rate of relapse, maintain abstinence, and de- 1. Nutrition Therapy. The presence of signiﬁcantcrease severity of relapse when it occurs. It has not been protein calorie malnutrition is a common ﬁnding in alco-shown to have a signiﬁcant impact on alcoholics who have holics, as are deﬁciencies in a number of vitamins andnot been detoxiﬁed or become abstinent. Whether it has trace minerals, including vitamin A, vitamin D, thiamine,any additional effect in combination with naltrexone is folate, pyridoxine, and zinc.193 In a Veterans Administra-controversial. A recent large randomized controlled clin- tion Cooperative study of 363 patients with alcoholicical trial did not suggest substantial beneﬁt of acamprosate hepatitis, 100% of patients were found to have proteincompared to naltrexone or to intensive counseling in and/or combined protein calorie malnutrition, based onmaintaining abstinence.186 There is a paucity of data anthropometric and laboratory testing.194 Moreover, theabout the use of these interventions in patients with ad- severity of malnutrition correlated with disease severityvanced liver disease. One randomized clinical trial in pa- and outcomes.194tients with cirrhosis suggested beneﬁt in achieving and This early ﬁnding was the motivation for a number ofmaintaining abstinence with the use of baclofen, a ␥-ami- clinical trials of anabolic steroids, nutritional supplemen-nobutyric acid B receptor agonist.187 tation, or aggressive enteral feeding. Several of these stud- Recommendations: ies showed improvement in biochemical markers of liver 6. In patients with evidence of alcohol-induced function or nutritional parameters, but were unable toliver disease, strict abstinence must be recommended, demonstrate an improvement in short-term survival.195because continued alcohol use is associated with dis- At least in some trials, however, subgroups of patientsease progression (Class I, level B). who achieved nutritional goals and positive nitrogen bal- 7. Naltrexone or acamprosate may be considered in ance had improved survival compared to those who didcombination with counseling to decrease the likelihood of not.196 As an example, in one study the mortality rate wasrelapse in patients with alcohol abuse/dependence in 3.3% in the 30 patients in whom positive nitrogen bal-those who achieve abstinence (Class I, level A). ance was achieved, but 58% in patients who remained in negative nitrogen balance.196B. Therapy for Alcoholic Hepatitis A recent study of nutritional therapy compared the The cornerstone of therapy of alcoholic hepatitis is outcomes of 35 patients randomized to 1 month of en-abstinence, although even patients who become abstinent teral tube feeding of 2000 kcal/day versus 40 mg of pred-remain at increased risk of developing cirrhosis. However, nisone/day.197 No difference in mortality was noted, butthe risk of cirrhosis is clearly higher in those who continue the time course of deaths was different, with the patientsto drink,188,189 particularly among women.175,190 Al- randomized to enteral feeding dying at a median of 7 days,though there are no clear dose– effect data, a threshold versus 23 days in the steroid treated group. Patientsexists for the development of alcoholic hepatitis, with risk treated with nutritional support who survived past theincreasing with consumption beyond 40 g of alcohol per ﬁrst month seemed to have a decreased mortality com-day.46,191 Furthermore, after an episode of AH, there is no pared to the steroid-treated patients (8% versus 37%).197safe amount of alcohol consumption which can be recom- Although technically a negative study, the similar overallmended, as alcoholic hepatitis can persist or redevelop. mortality rate in the treatment groups suggests a role forThere is a signiﬁcant risk of recidivism in patients who nutritional intervention,198 particularly in light of the rel-attempt to cut back but not stop drinking altogether.192 atively benign risk:beneﬁt ratio. Based on these data,Complete abstinence is therefore a reasonable lifetime other societies have recommended oral or parenteral sup-recommendation. plements for patients with AH at risk of undernutri- The need to consider therapy is less urgent in patients tion.199with alcoholic hepatitis who have a low risk of complica- 2. Steroids. The most extensively studied interven-tions as deﬁned by an MDF score of Ͻ 32, without he- tion in alcoholic hepatitis is the use of steroids, based onpatic encephalopathy, or a low MELD score (e.g., MELD 13 clinical trials that date back almost 40 years (Table 7).Ͻ18), or GAHS score of Ͻ8. This is particularly true in Most of these trials were small, and therefore had onlythose whose liver score improves during hospitalization, limited statistical power to detect even moderate treat-with a decrease in total bilirubin, as they will likely im- ment effects; ﬁve suggested an improvement in outcome,prove spontaneously with abstinence and supportive care with decreased short term mortality in steroid-treated pa-
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 317 Table 7. Clinical Trials of Steroids in Patients with Alcoholic Hepatitis. No. of Deaths: Deaths: Author Date Patients Intervention placebo steroidPorter266 1971 20 Prednisolone: 40 mg IV ϫ 10 days, then tapered: 4 7/9 6/11 mg/day ϫ 1 week, 2 mg/day ϫ 11 days, then 2 mg every 3rd day ϫ 15 daysHelman267 1971 37 Prednisolone: 40 mg/day ϫ 4 weeks, then tapered 6/17 1/20 over 2 weeksCampra268 1973 45 Prednisone: 0.5 mg.kg ϫ 3 weeks, then 0.25 mg/kg 9/25 7/29 ϫ 3 weeksBlitzer269 1977 33 Prednisolone:40 mg/day ϫ 14 days, then 20 mg/day 5/16 6/12 ϫ 4 days; 10 mg/day ϫ 4 day; 5 mg/day ϫ 4 daysLesesne270 1978 14 Prednisolone: 40 mg/day ϫ 30 days, then tapered 7/7 2/7 over 2 weeksShumaker271 1978 27 Prednisolone: 80 mg/day ϫ 4-7 days, then tapered 7/15 6/12 off over 4 weeksMaddrey157 1978 55 Prednisolone: 40 mg/day ϫ 30 days 6/31 1/24Depew272 1980 28 Prednisolone: 40 mg/day ϫ 28 days, then tapered 7/13 8/15 over 14 daysTheodossi273 1982 55 Prednisolone: 1 g ϫ 3 days 16/28 17/27Mendenhall274 1984 178 Prednisolone: 60 mg ϫ 4 days; 40 mg/day ϫ 4 days; 50/88 55/90 30 mg/day ϫ 4 days; 20 mg/day ϫ 4 days; 10 mg/day ϫ 7 days; 5 mg/day ϫ 7 daysBories275 1987 45 Prednisolone: 40 mg/day ϫ 30 days 2/21 1/24Carithers158 1989 66 Prednisolone: 32 mg/day ϫ 28 days, then 16 mg/day 11/31 2/35 ϫ 7 days, then 8 mg/day ϫ 7 daysRamond276 1992 61 Prednisolone: 40 mg/day ϫ 28 days 16/29 4/32tients compared to placebo-treated patients, whereas trials in patients with comparable measures of disease se-eight showed no effect. It is important to note, however, verity (i.e., an MDF Ն32). The result showed a signiﬁ-that these trials used varying inclusion and exclusion cri- cant increase in short-term survival among treatedteria, dosing, and were done in a variety of patient popu- patients compared to control patients: 84.6% versuslations. Three meta-analyses have analyzed data from 65%.207 This represents a modest absolute reduction inthese trials and showed an improvement in survival in risk, but a 30% relative risk reduction, and translates intotreated patients200-202; one meta-regression, however, us- a number needed to treat of 5, i.e., ﬁve patients need to being different statistical weighting of the varying trials, was treated to avert one death. This last meta-analysis alsounable to show any difference.203 The most recent meta- excluded a recent trial comparing steroids to a combina-analysis of these data did not show a statistically signiﬁ- tion of antioxidants, which showed a similar protectivecant effect of steroids on mortality among all patients effect of corticosteroids among treated patients.208 Al-treated, although it did demonstrate an effect of steroids though it is possible that antioxidants themselves may bein the subgroup of patients with hepatic encephalopathy detrimental,209 the doses used seem unlikely to accountand/or a MDF score Ն 32.204 The presence of substantial for the differences in survival, and the consistency of thestatistical heterogeneity in this subgroup of studies pre- data suggest a protective effect of steroids.vented the authors from reporting an overall beneﬁcial Although the doses and durations of steroid treatmenteffect. The implication of this ﬁnding is unclear, as statis- used in the clinical trials were variable, the best availabletical heterogeneity among subgroups is a function of both evidence suggests a dose of prednisolone (40 mg/day for 4clinical differences and/or methodologic differences weeks then tapered over 2-4 weeks, or stopped, dependingamong studies, and these analyses may be reﬂect bias or on the clinical situation) should be used in favor of pred-confounding.205 One potential approach to resolve this is nisone.210 It is important to recognize that the efﬁcacy ofthe use of individual patient data across clinical trials, steroids has not been evaluated in patients with severewhich represents the “gold standard” approach to meta- alcoholic hepatitis and concomitant pancreatitis, gastro-analysis.206 Although it is impractical to retrieve and com- intestinal bleeding, renal failure, or active infection,bine primary data from all the clinical trials in this ﬁeld, which were exclusion criteria in many of the early studieswhere large variation in studies over time exists, this ap- of alcoholic hepatitis.proach was pursued with the use of a combined dataset, An important issue in all studies of medical therapy,using pooled primary data from three placebo controlled and one that has been recognized for some time in this
318 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010literature, is the possibility that these therapies may not be substantial decreases in other prognostic markers, includ-effective at an advanced stage of disease. Just as there is a ing cytokine levels and MDF scores were seen in patientsthreshold for the use of steroids (i.e., identifying patients treated with combination therapy. Another trial, per-at high risk of mortality deﬁned by a MDF score Ն32 ), formed at 19 centers in France, randomized 36 patientsthere may also be a ceiling beyond which medical thera- with biopsy proven alcoholic hepatitis and an MDF Ն 32pies aimed at decreasing the inﬂammatory cascade may to prednisolone (40 mg/day for 4 weeks), versus pred-cause more harm than beneﬁt. One study examined this nisolone along with inﬂiximab (10 mg/kg, given at studyissue, and suggested that patients with a MDF Ͼ 54 were entry, and again at 2 weeks and 4 weeks after entry).216at a higher mortality risk from use of steroids than from The trial was stopped prematurely after seven deaths hadnot being treated.211 This cutoff, however, needs to be occurred in the inﬂiximab group, compared with three inconﬁrmed. the prednisolone arm. Four of the seven deaths in the One recently derived model used six variables to pre- inﬂiximab arm were related to infectious etiologies, com-dict 6-month mortality in patients who were universally pared to one in the prednisolone group. The design, andtreated with steroids (including age, renal insufﬁciency in particular, the dose of inﬂiximab chosen in the study,(serum creatinine Ͼ 1.3 or creatinine clearance Ͻ 40), has been criticized as predisposing to these infections.217albumin, prothrombin time, bilirubin, and change in bil- The utility of etanercept (given six times over 3 weeks)irubin over 1 week), and showed an improved prognostic was tested in 48 patients with moderate to severe alcoholicability compared to MDF or GAHS scores.212 This hepatitis (MELD score Ͼ 15); unfortunately, no signiﬁ-model, available on the internet (www.lillemodel.com) cant difference in 1-month mortality was seen in themay allow identiﬁcation of patients who remain at high treated patients compared to patients given placebo, andrisk to be treated with other interventions. an increased mortality was seen at 6 months.218 3. Anticytokine Therapy. A wealth of evidence sug- Although a strong rationale remains for the use of anti-gests that dysregulated cytokines, including tumor necro- TNF therapy in alcoholic hepatitis, there is also a theoret-sis factor alpha (TNF␣) and a host of downstream ical basis for minimizing TNF inhibition, because it playscytokines play a pivotal role in the pathophysiology of a role in liver regeneration as well as apoptosis.219 Thus, inAH. Thus, several agents have been studied that impact light of the poor clinical outcomes observed in the largestthe immunologic milieu, targeting speciﬁc cytokines, and of the inﬂiximab trials and the etanercept study, the use ofTNF␣ in particular. these parenteral TNF inhibitors should be conﬁned to Among the ﬁrst agents to be studied was pentoxifyl- clinical trials, and recommendations regarding speciﬁcline, an oral phosphodiesterase inhibitor which also in- therapy will need to await the results of these trials. Therehibits the production of TNF␣, among other cytokines. A are no substantive clinical data comparing the use of ste-randomized placebo controlled clinical trial tested pen- roids or nutrition to speciﬁc anti-TNF therapies.toxifylline in 101 patients with clinical evidence of severe 4. Combination Therapy. Although it is assumedAH.213 The in-hospital mortality in the treated patients that each of these different treatments may operate viawas 40% lower than in the placebo arm, with the bulk of independent mechanisms, there are only minimal datathe reduction related to a substantially lower likelihood of regarding the comparative beneﬁt of sequential therapiesdeveloping hepatorenal syndrome (HRS). HRS was re- or combined approaches. One study tested the use ofsponsible for 50% of the 12 deaths in the treatment arm, pentoxifylline in 29 patients with severe AH (MDF Ͼ 32)compared to 91.7% of the 24 deaths in the placebo group. who did not respond to steroids based on a drop in bili- Other speciﬁc inhibitors of TNF that have been stud- rubin level after 1 week of prednisolone treatment. Com-ied include inﬂiximab, a monoclonal chimeric anti-TNF pared to previously treated patients (who were continuedantibody, and etanercept, a fusion protein containing the on steroids despite lack of bilirubin response), there wasligand-binding portion of the human TNF receptor fused no improvement in 2-month survival, thus arguingto the Fc portion of human immunoglobulin G1.214 In against a two-step strategy with an early switch to pentoxi-the ﬁrst clinical trial of inﬂiximab, 20 patients with biopsy fylline.220 Several older studies had examined the role ofproven alcoholic hepatitis and an MDF score between 32 anabolic steroids with nutritional interventions (based onand 55 (based on the original Maddrey score, which dem- the presumption that both interventions acted via a sim-onstrated an increased mortality at a score Ͼ 93) were ilar mechanism, i.e., correction of protein calorie malnu-randomized to either 5 mg/kg of inﬂiximab plus 40 mg/ trition).221 One pilot study evaluated the role of steroidsday of prednisone (n ϭ 11) or to prednisone alone.215 No in combination with enteral nutrition in 13 patients withsubstantial difference in overall mortality was found, but severe AH, and found an overall mortality of 15%—pos-
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 319 Fig. 1. Proposed algorithm for alcoholic hepatitis.sibly an improvement from expected.222 With the advent A proposed treatment algorithm for alcoholic hepatitisof new therapies, it is necessary to reconsider the risk- is shown in Fig. 1.beneﬁt ratio of medical treatment. It has been suggested Recommendations:that it may be possible to use less toxic therapies at a lower 8. All patients with alcoholic hepatitis should bethreshold of disease severity.223 However, the exact role of counseled to completely abstain from alcohol (Class I,these new therapies, and the threshold for their use, is still level B).undeﬁned. 9. All patients with alcoholic hepatitis or advanced 5. Other Treatments. Many other therapeutic inter- ALD should be assessed for nutritional deﬁcienciesventions have been studied in alcoholic hepatitis, but have (protein-calorie malnutrition), as well as vitamin andnot been able to show convincing beneﬁt, including trials mineral deﬁciencies. Those with severe disease shouldof antioxidants (vitamin E, silymarin, combination anti- be treated aggressively with enteral nutritional ther-oxidants), antiﬁbrotics (colchicine), antithyroid drugs apy (Class I, level B).(propylthiouracil [PTU]), promoters of hepatic regener- 10. Patients with mild-moderate alcoholic hepati-ation (insulin and glucagons), anabolic steroids (oxan- tis— deﬁned as a Maddrey score of <32, withoutdrolone and testosterone), as well as calcium channel hepatic encephalopathy, and with improvement inblockers (amlodipine), polyunsaturated lecithin, and a serum bilirubin or decline in the MDF during the ﬁrstnumber of complementary and alternative medicines (re- week of hospitalization—should be monitored closely,viewed in O’Shea and McCullough224). In addition tomedical treatment directed at the underlying pathophys- but will likely not require nor beneﬁt from speciﬁciologic abnormalities, several studies have tested other ag- medical interventions other than nutritional supportgressive interventions in patients with AH, such as a and abstinence (Class III, level A).molecular adsorbent recirculating system.225 Although 11. Patients with severe disease (MDF score ofthe results of early studies were optimistic, with better >32, with or without hepatic encephalopathy) andthan predicted outcomes in treated patients, a further case lacking contraindications to steroid use should beseries was less promising.226 Case reports have also de- considered for a four week course of prednisolone (40scribed the outcome of patients with severe AH treated mg/day for 28 days, typically followed by discontinu-with leukocytapharesis after failing to improve substan- ation or a 2-week taper) (Class I, level A).tially on steroids.227,228 These reports are promising, but 12. Patients with severe disease (i.e., a MDF > 32)recommendations regarding their appropriate use must could be considered for pentoxifylline therapy (400 mgawait results of comparative studies of outcomes in these orally 3 times daily for 4 weeks), especially if there arepatients. contraindications to steroid therapy (Class I, level B).
320 O’SHEA, DARASATHY, AND MCCULLOUGH HEPATOLOGY, January 2010 Fig. 2. Proposed therapeutic algorithm for the long-term management of alcoholic liver disease.VII. Long-Term Management of ALD reduce hospitalizations for infections over a 1-year peri- od.231 A proposed algorithm for the management of ALD is Long-term aggressive nutritional therapy by the enteralshown in Fig. 2. or oral route in patients with alcoholic cirrhosis is sup- ported by studies that have shown improved nutritional1. Nutritional Therapy status.232,233 Although controversial, this may possibly Protein calorie malnutrition is common in ALD, is prevent complications of cirrhosis.195,234 Multiple feed-associated with an increased rate of major complications ings, emphasizing breakfast and a nighttime snack, with aof cirrhosis (infection, encephalopathy, and ascites), and regular oral diet at higher-than-usual dietary intakes (1.2-indicates a poor prognosis.194 1.5 g/kg for protein and 35-40 kcal/kg for energy) seem A total of 13 studies (seven randomized and six open- beneﬁcial.235,236 Finally, during intermittent acute illnesslabel studies) have examined the effect of oral or enteral or exacerbations of the underlying chronic liver disease,nutritional supplementation in patients with alcoholic above normal protein intake (1.5 g/kg body weight), andcirrhosis, with interventions that ranged from 3 days to 12 kilocalorie intake (40 kcal/kg) improves protein caloriemonths (reviewed in Stickel et al.229). Most of these stud- malnutrition,234 and should be considered in the treat-ies are limited by small sample sizes and short durations of ment of these patients.therapy. In one study, enteral feeding for 3-4 weeks in 35 Recommendation:hospitalized, severely malnourished or decompensated 13. Patients with alcoholic cirrhosis should receivepatients with alcoholic cirrhosis seemed to improve sur- frequent interval feedings, emphasizing a night timevival (P Ͻ 0.065), hepatic encephalopathy, liver tests and snack and morning feeding, to improve nitrogen bal-Child-Pugh score, as compared with controls receiving a ance (Class I, level A).standard oral diet.197 In longer-term studies, equinitrog-enous amounts of dietary branched chain amino acids 2. Medical Therapies(BCAA) were compared with casein supplements for 3-6 A number of other agents have been tested in patientsmonths in patients with chronic hepatic encephalopa- with ALD. These include PTU, which was thought tothy,230 and shown to improve encephalopathy, nitrogen decrease the hypermetabolic state induced by alco-balance and serum bilirubin compared with casein. Sup- hol.237,238 A Cochrane review of 6 randomized controlledplemental protein and 1000 kcal in decompensated pa- trials of PTU in alcoholic liver disease, with a total of 710tients with alcoholic cirrhosis have also been shown to patients administered either PTU or placebo did not
HEPATOLOGY, Vol. 51, No. 1, 2010 O’SHEA, DARASATHY, AND MCCULLOUGH 321show any beneﬁt of PTU over placebo on the total or liver cantly inﬂuence the course of patients with alcoholic liverrelated mortality, complications of liver disease or liver disease.254histology in patients with alcoholic liver disease.239 A pos- Recommendations:sible beneﬁt of supplementation with S-adenosyl L-methi- 14. PTU and colchicine should not be used in theonine (SAMe), a precursor to glutathione, has also been treatment of patients with ALD; SAMe should be usedstudied extensively.240 One trial demonstrated a statisti- only in clinical trials (Class III, level A).cally signiﬁcant improvement in survival in patients with 15. The use of complementary or alternative med-Childs A and B cirrhosis randomized to SAMe compared icines in the treatment of either acute or chronicto placebo.241 Despite a strong theoretical rationale, and a alcohol-related liver disease has shown no convincingnumber of supportive clinical trials,240,242 a Cochrane re- beneﬁt and should not be used out of the context ofview of published data, based on nine randomized con- clinical trial (Class III, level A).trolled trials with 434 patients in different stages of ALD,did not demonstrate any signiﬁcant beneﬁt of SAMe on VIII. Liver Transplantation for ALDtotal mortality, liver related mortality, complications or ALD is the second most common indication for liverliver transplantation in patients with ALD.243 transplantation (LT) for chronic liver disease in the West- Colchicine, which has both anti-inﬂammatory and an- ern world.255 Despite this, it is estimated that as many astiﬁbrotic properties, has also been tested in alcoholic cir- 95% of patients with end-stage liver disease related torhosis after several small clinical trials, had suggested alcohol are never formally evaluated for candidacy forimprovement in ﬁbrosis on serial liver biopsies in treated liver transplantation.256 This is attributed to perceptionspatients.244,245 However, a systematic meta analysis by the that ALD is self-induced, the possibility of recidivism orCochrane group of 15 randomized trials with 1714 pa- noncompliance, and the shortage of organs.179tients (including patients with alcoholic ﬁbrosis, alcoholic A 6-month period of abstinence has been recom-hepatitis, and/or alcoholic cirrhosis as well as patients mended as a minimal listing criterion.257 This time periodwith viral induced or cryptogenic ﬁbrosis and/or cirrho- allows chemical dependency issues to be addressed; insis)246 showed no beneﬁt of treatment on overall mortal- patients with recent alcohol consumption, it may alsoity, liver related mortality, liver tests or histology. In allow sufﬁcient clinical improvement to make LT unnec-addition, there was an increased risk of adverse effects essary. This requirement for a ﬁxed abstinence period hasrelated to colchicine therapy. not been shown to accurately predict future drinking by Emerging data suggest a role for TNF-␣ mediated ap- alcoholic candidates for LT.258 Despite some data sug-optosis in alcoholic hepatitis and, therapy targeting this gesting that patients with ALD were more ill at the time ofcytokine to inhibit apoptosis may be effective.247 Thalid- LT, and likely to have prolonged intensive care unit staysomide, misoprostol, adiponectin and probiotics have and increased blood product requirements,259 overall sur-been shown in preliminary reports to have anticytokine vival rates are generally similar between alcohol-relatedproperties.248-251 Although promising, these treatments and non–alcohol-related LT recipients.260can not be considered as standard treatment for ALD and Patients who underwent LT for alcoholic liver diseaseAH until further evidence of efﬁcacy has been obtained. are highly likely to drink after transplantation.260 It has been suggested that the consequences of alcohol use are3. Complementary and Alternative Medicine minimal for many recipients, because the amounts con-Treatment Options sumed are small and infrequent, but there are little reliable Various alternative treatment options have been tested data to support this contention. Rates of recidivism be-in the therapy of ALD. Silymarin, the presumed active tween 11%-49% (deﬁned as any alcohol consumptioningredient in milk thistle, is postulated to protect patients after transplantation) at 3-5 years after LT have been re-from ALD on the basis of its antioxidant properties. Six ported.179,261 In general, however, only a small fraction ofpublished trials of the use of silymarin in patients with those who undergo liver transplantation for ALD revert toALD252 have tested its effects on normalizing liver tests heavy alcohol use or abuse.256 Poor follow-up and non-and improving liver histology. One study suggested a pos- compliance with therapy are observed in only a minoritysible survival beneﬁt compared to placebo.253 However, a of patients, and graft rejection rates are similar for patientsCochrane systematic review and meta analysis of the 13 with ALD compared to those without ALD.255,260published studies of silymarin in ALD and other liver An important issue that is still unresolved is the role ofdiseases determined that the overall methodological qual- LT in patients with alcoholic hepatitis, who are generallyity of the studies was low. Based on the few high quality excluded from transplant.257 In one study using retro-trials, it was concluded that milk thistle does not signiﬁ- spective histological analysis of the explanted liver, super-