Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases
Authors: David W. Crabb, Gene Y. Im, Gyongyi Szabo, Jessica L. Mellinger, Michael R. Lucey
Journal: Hepatology (2019)

Supported by the American Association for the Study of Liver Diseases. Potential conflict of interest: Dr. Lucey received grants from Gilead, AbbVie and Pharmasolutions. Dr. Szabo consults and received grants from Allergan. She consults for Terra Firma, Glympse, Quest, Arrow, GLG, Salix and Tobira. She received grants from Gilead, Genfit, Intercept, Verlyx, Novartis, SignaBlok and Shire. She holds intellectual property rights with Up to Date. Purpose and Scope of the Guidance Alcohol‐associated liver disease (ALD) represents a spectrum of liver injury resulting from alcohol use, ranging from hepatic steatosis to more advanced forms including alcoholic hepatitis (AH), alcohol‐associated cirrhosis (AC), and acute AH presenting as acute‐on‐chronic liver failure. ALD is a major cause of liver disease worldwide, both on its own and as a co‐factor in the progression of chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), iron overload, and other liver diseases. ALD develops through several stages, beginning with hepatic steatosis, and, in some individuals, gradually progressing through AH (the histological correlate of which is alcoholic steatohepatitis), culminating in cirrhosis (Fig. 1).1 Progression through these various stages is dependent on continued heavy alcohol use and other risk factors, including female sex, genetic susceptibility, diet, and comorbid liver disease. ALD carries a significant stigma in society. It is increasingly recognized by providers that patients and their families seek to reduce the stigma of ALD, and a change from the term "alcoholic" to "alcohol‐associated" will help; thus, alcohol‐associated liver disease, alcohol‐associated steatohepatitis, and alcohol‐associated cirrhosis are suggested, retaining the familiar abbreviations (ALD, ASH, and AC, respectively). Due to longstanding usage, the term "alcoholic hepatitis" will likely persist.Figure 1: Natural history of alcohol‐associated liver disease. Images courtesy of Dr. M. Isabel Fiel.This 2019 ALD Guidance provides a data‐supported approach to the prevalence, clinical spectrum, diagnosis, and clinical management of ALD and alcohol use disorders (AUDs). The Guidance was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of published literature on the topics. The quality (level) of the evidence and the strength of each guidance statement are not formally rated. Updates to the 2010 Guideline include an emphasis on AUD definition, screening, and treatment; new alcohol biomarkers; additional genetic and environmental susceptibility factors; a consensus definition of AH, and review of recent studies of corticosteroids and guidance on the role of transplantation in the management of AH. Prevalence and Burden of Alcohol‐Associated Liver Disease Alcohol‐associated liver disease includes a variety of clinical disorders: steatosis, ASH, AH of varying degrees of severity, AC, and AC complicated by hepatocellular carcinoma (HCC). ALD comprises a substantial portion of the overall cirrhosis burden, both in the United States and worldwide, and is responsible for rising rates of liver‐related mortality in the United States, especially among younger patients.3 In the United States, mortality due to all ALD was estimated at 5.5 per 100,000 in 2012; the relative contribution of ALD to all cirrhosis mortality is predicted to increase as the proportion of deaths due to hepatitis C virus (HCV) cirrhosis declines.3 More recently, AC mortality was shown to have increased from 2008 to 2016, particularly among patients ages 25‐34 years old.4 Cirrhotic and noncirrhotic ALD prevalence has been estimated at approximately 2% in the general US population, whereas AC in the US Veterans' population was estimated at 327 per 100,000 enrollees.7 In privately insured US patients, AC has been estimated at approximately 100 per 100,000 enrollees, and, overall, rates are projected to rise over time.3 Worldwide, AC deaths account for about 10% of all alcohol‐attributable deaths, and nearly half of those deaths are due to liver disease, resulting in the loss of 22.2 million disability‐adjusted life years annually.10 In the United States, ALD competes with chronic HCV as the leading indication for liver transplantation (LT).12 Medical costs are high for AC, driven in part by the higher number of admissions for these patients.9 In addition, deaths related to alcohol use are frequently underestimated due to the stigma of alcohol use and lack of candor in reporting.10 In women, AC prevalence may be increasing at a faster rate than in men, mirroring the rise in alcohol use in women in the United States.9 The incidence of AH has been difficult to estimate, as diagnostic accuracy of administrative coding is less reliable for AH.15 The incidence of AH varies worldwide. In the United States, admissions for AH were found to have increased to 0.83% of all admissions for 2010.13 In Denmark, the incidence of AH for the period 1999‐2008 rose from 37 to 46 per million persons per year in men and 24 to 34 per million persons per year for women.17 A similar study in Finland reported increased incidence rates for AH from 37 to 65 cases per million persons per year for men and from 13 to 27 cases per million persons per year for women.18 In both of these cases, estimates were based on diagnostic coding, which may be less accurate and highlights the difficulty in estimating the burden of AH. Accurate assessment of the full spectrum of ALD prevalence is challenging, particularly given the difficulty with identifying earlier, asymptomatic stages of ALD, such as ASH or moderate AH, challenges that may be overcome with broader use of noninvasive steatosis and fibrosis assessment tools and increased awareness for the need to diagnose early‐stage disease. Many studies underestimate the true prevalence and burden by counting as ALD only those patients without additional liver diseases such as HCV, in spite of the fact that concomitant ALD rates are as high as 61% in some patients with other liver diseases, in particular nonalcoholic steatohepatitis (NASH), HCV, and hemochromatosis.14 These factors may result in as much as a 2‐fold underestimate for ALD‐related mortality.11 Diagnosis of Alcohol Use Disorders Since publication of the Diagnostic and Statistical Manual (Fifth Edition), the former categories of alcohol abuse and dependence have been replaced by the term "alcohol use disorder," characterized as mild, moderate, or severe based on the accumulation of negative consequences and symptoms (Table 1).20 Alcohol use is common in the United States, with many people drinking moderate amounts without significant consequences.21 However, more severe forms of AUD, defined by escalating alcohol consumption despite attempts to cut back, negative personal consequences, and the appearance of alcohol craving, are also on the rise.21 Rates of AUD and high‐risk drinking have risen dramatically, with the prevalence of AUD in two nationally representative surveys of US adults increasing by 50% between 2001 and 2013, with even greater increases reported among women, minorities, and those of lower socioeconomic status.22 The type of alcohol consumed and the prevalence of binge drinking (five or more drinks occurring monthly or more often) changed over the same time period (2000‐2013) with substantial increases observed for consumption of distilled spirits (+11.5%), wine (+7.7%), and binge drinking.22 Worldwide, alcohol consumption varies geographically, with the highest rates of reported per capita alcohol consumption occurring in northern and eastern European countries and Russia.14 Table 1 - Diagnostic Criteria for Alcohol Use Disorder Your Experience in the Past Year 1. Alcohol is often taken in larger amounts or over a longer period than intended. The presence of at least 2 of these symptoms indicates an AUD: Mild: 2‐3 symptoms Moderate: 4‐5 symptoms Severe: 6 or more symptoms 2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. 3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects. 4. Craving, or a strong desire or urge to use alcohol. 5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol. 7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use. 8. Recurrent alcohol use in situations in which it is physically hazardous. 9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. 10. Tolerance, defined as either of the following: Need for markedly increased amounts of alcohol to achieve intoxication or desired effect; or Markedly diminished effect with continued use of the same amount of alcohol. 11. Withdrawal, as manifested by either of the following: The characteristic alcohol withdrawal syndrome; or Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms. Screening, Brief Intervention, and Referral to Treatment The public health approach to the problem of alcohol use is termed "screening, brief intervention, and referral to treatment." This process begins with screening for and assessing the level of alcohol use. Discussion of alcohol use can be off‐putting for patients, who may feel stigmatized or judged.23 As such, a nonjudgmental, open, and accepting interview style can help maintain therapeutic alliance, and limit underreporting and denial of AUDs.24 The symptoms of AUD and ALD may not be readily apparent, particularly in early stages of ALD. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has published a brief guide for clinicians to help assess alcohol use (including more severe AUDs), provide brief intervention, pharmacotherapy, and refer more severe cases to treatment.25 Of note, NIAAA guidelines for limits on drinking apply to general populations rather than patients with ALD (i.e., there is no known safe level of alcohol consumption for patients with ALD). Similarly, the US Preventive Services Task Force (USPSTF) has recently published its recommendations regarding "Unhealthy Alcohol Use in Adolescents and Adults: Screening and Behavioral Counseling Interventions." The summary statement recommended screening for unhealthy alcohol use in primary care settings in adults 18 years or older, including pregnant women, and providing persons engaged in risky or hazardous drinking with brief behavioral counseling interventions to reduce unhealthy alcohol use.26 Efforts to uncover harmful alcohol use are aided by the use of structured, validated screening tools. The NIAAA recommends a one‐question initial screen: "How many times in the past year have you had 5 or more drinks in a day (for men) or 4 or more drinks in a day (for women)?" This is the NIAAA definition of binge drinking (five drinks in men; four in women over 2 hours). If the patient reports even a single episode, performing the Alcohol Use Disorders Inventory Test (AUDIT) is recommended.27 The AUDIT is used widely and is recommended by the USPSTF. Its original form included 10 questions on consumption (Q1‐Q3), dependence symptoms (Q4‐Q6), and any alcohol‐associated problems (Q7‐Q10), with a score greater than 8 being predictive of harmful or hazardous alcohol use, and scores greater than 20 suggestive of alcohol dependence (now termed moderate/severe AUD).27 Questions 1‐3 are often used alone (the "AUDIT‐C") as a more efficient means of screening for problem alcohol use, but this shorter form does not provide information on more severe alcohol use problems.29 The AUDIT‐C is brief, convenient, and performs better than the CAGE and other questionnaires in identifying alcohol misuse.30 AUDIT‐C scores of at least 4‐5 may indicate harmful alcohol use. These screening tests do not provide a diagnosis of AUD, but rather point to the need for a formal assessment. The NIAAA Clinicians' Guide outlines brief intervention and referral to treatment for the general public; space limitations prevent a more thorough discussion of brief interventions.31 Screening in general medicine and specialty clinics has been shown to help identify patients with ALD early, and by coupling this with a discussion of the implications for liver disease, may be motivational for alcohol reduction.32 Mandatory alcohol use screening of inpatients and in the emergency department effectively identifies heavy users, assists ALD diagnosis, and improves connection to treatment of AUD.33 Importantly, use of screening tools such as AUDIT has been shown to improve detection as well as the ability to predict long‐term clinical outcomes, including hospitalization for alcohol‐associated diagnoses.34 Biomarkers of Alcohol Use Biomarkers of alcohol use refer to moieties in urine, blood, or hair, which identify metabolites or surrogates of alcohol use and provide an estimated timeframe of recent drinking. The American Society of Addiction Medicine and American Psychiatric Association suggest the use of alcohol biomarkers as an aid to diagnosis, to support recovery, and as catalysts for discussion with the patient, rather than as tools to "catch" or punish patients.36 Principles of use include discussing biomarker use with patients before testing, to maintain therapeutic alliance and improve alcohol use disclosure. Each of the alcohol biomarkers described subsequently has limitations. They should not be used on their own to confirm or refute alcohol use, but should be combined with other lab testing (including other alcohol biomarkers), physical exam, and the clinical interview. Liver‐related enzymes, bilirubin, or gamma‐glutamyl transferase (GGT) or evidence of macrocytic anemia may suggest alcohol use, but on their own are inadequate to establish alcohol use in ALD.38 GGT is an enzyme found in the cell membranes of several body tissues, including liver and spleen. Although it is frequently elevated in heavy drinking and has greater sensitivity than AST, it is not specific for alcohol use.40 Carbohydrate‐deficient transferrin (CDT) is generated as a result of alcohol inhibition of transferrin glycosylation. Typically reported as the percentage of CDT (%CDT) per total transferrin, to account for differences in total transferrin levels, CDT has a half‐life of 2‐3 weeks.41 The utility of CDT is limited by its low sensitivity of 25%‐50% in several studies and by false‐positive results arising in patients with severe liver disease in the absence of alcohol use.42 However, posttransplant use of %CDT appears to be more accurate, likely due to improved liver function.45 A small (about 0.1%) amount of alcohol is metabolized by uridine diphosphoglucuronate–glucuronosyltransferase and uridine diphosphoglucuronate–sulfotransferase, producing ethyl glucuronide (EtG) and ethyl sulfate (EtS).47 Both are excreted in the urine, but are also found in blood and hair. Although false positives and false negatives have been reported, sensitivity and specificity of urinary EtG for detection of alcohol use were 89% and 99%, respectively, among patients with ALD before and after LT.48 Other studies in patients with mixed etiology of liver disease, including cirrhosis, found sensitivities of 76% and 82% for drinking within 3 days of the test for EtG and EtS, respectively, with higher specificities of 93% and 86%, respectively.49 Urinary EtG and EtS detection times can also be prolonged in renal failure, resulting in a longer window of positive results after alcohol ingestion in patients with kidney disease. Phosphatidylethanol (PEth) is a phospholipid formed by the reaction of phosphatidylcholine with ethanol catalyzed by phospholipase D in the erythrocyte cell membrane.50 PEth has a half‐life of approximately 10‐14 days, although this can be longer with more chronic, repeated heavy alcohol consumption and does not appear to be influenced by age, body mass index (BMI), sex, kidney disease, or liver disease.51 Women may have higher PEth levels for a given amount of alcohol consumption compared with men.58 Although there are interindividual variations in PEth metabolism, PEth has been validated in a study of chronic liver disease patients who had not undergone LT at a cutoff of 80 ng/mL for four drinks per day or more with a sensitivity of 91% (95% confidence interval [CI], 82%‐100%) and specificity of 77% (95% CI, 70%‐83%).59 Another study of PEth use in patients with ALD before and after LT revealed a sensitivity of 100% (CI, 79%‐100%) and specificity of 96% (CI, 91%‐99%) for a cutoff of over 20 ng/mL.50 The performance of the current best biomarkers for alcohol use are given in Tables 2 and 3. Table 2 - Performance of Biomarkers of Alcohol Use in Alcoholic Liver Disease. Detection Time, Cutoff Values, and Performance of Individual Tests Test Source Detection Time Cutoff Values Sensitivity Specificity PPV NPV Clinical Use CDT/%CDT* Blood 2‐3 weeks 1.7%‐2.6% 21%‐50% 50%‐100% 64%‐100% 86%‐93% Lower sensitivity and specificity EtG Urine 3 days 500 ng/mL 76%‐89% 93%‐99% 81%‐90% 91%‐99% False positives and greater patient awareness of testing EtG Hair Months 30 pg/mg 81%‐100% 83%‐98% 68%‐95% 86%‐100% Costly, requires significant hair sample, limited availability EtS Urine 3 days 75 ng/mL 82% 86% 70% 93% Often used to confirm + EtG PEth Blood 2‐3 weeks 20 ng/mL 97%‐100% 66%‐96% 85% 100% More costly than urine EtG *Not all studies used the preferred disialotransferrin glycoform that best correlates with alcohol intake. Some studies conducted on posttransplant patients show better performance than pretransplant patients.Abbreviations: NPV, negative predictive value; and PPV, positive predictive value. Table 3 - Performance of Biomarkers of Alcohol Use in Alcoholic Liver Disease. Direct Comparison of Test Performance Characteristics in Patients with Alcoholic Liver Disease Before and After Liver Transplantation Sensitivity Specificity PPV NPV Andresen‐Streichert42 %CDT 21% (6‐45) 100% (96‐100) 100% (39‐100) — Urine EtG 71% (41‐91) 98% (94‐100) 90% (58‐99) 95% (89‐98) Hair EtG 84% (54‐98) 92% (82‐97) 68% (41‐89) 96% (88‐99) PEth 100% (79‐100) 96% (91‐99) 85% (62‐96) 100% (96‐100) Staufer43 %CDT 25% 98% 64% 93% Urine EtG 89% 99% 89% 99% Abbreviations: NPV, negative predictive value; and PPV, positive predictive value. Guidance Statements All patients receiving care in primary care and gastroenterology/hepatology outpatient clinics, emergency departments, and inpatient admissions should be screened routinely for alcohol use using validated questionnaires. Brief intervention, pharmacotherapy, and referral to treatment should be offered to patients engaged in hazardous drinking (AUDIT‐C ≥4, AUDIT >8, binge drinkers). Alcohol biomarkers can be used to aid in diagnosis and support recovery. Urine and hair ethyl glucuronide, urine ethyl sulfate, and PEth are not affected by liver disease, and therefore are preferable. Treatment of Alcohol Use Disorders Because abstinence is the single most important factor in improving survival from ALD, multidisciplinary management with addiction specialists and referral to treatment for AUD, particularly in patients with moderate to severe AUDs or clinically evident ALD, is mandatory. We present a review of different types of treatment, with a focus on treatments that have been studied in patients with ALD. Many patients, however, will be reluctant to see a professional mental health provider. For patients who are ambivalent about alcohol cessation, motivational interviewing has been shown to help patients change behaviors, including alcohol use.60 A new online resource developed by NIAAA is now available to help people and their families recognize AUD and find high‐quality care through an easily accessible and user‐friendly web‐based system, the NIAAA Alcohol Treatment Navigator.61 Psychosocial and Behavioral Approaches to Alcohol Use Disorder Treatment in Patients with ALD There are a wide variety of alcohol use disorder treatments available to patients, although relatively few have been studied in patients with ALD. Major categories of treatment include inpatient alcohol rehabilitation, group therapies, individual therapy, family/couples counseling, and mutual aid societies (such as Alcoholics Anonymous). Within counseling sessions, various modalities of treatment are available that target different mechanisms of behavior change. These include cognitive‐behavior therapy (CBT), motivational interviewing, motivational enhancement therapy (MET), contingency management, 12‐step facilitation, network therapy, and couples/family counseling.24 Psychosocial treatment has been studied in a limited fashion in ALD. A recent systematic review of treatment trials in ALD found that integrating AUD treatment providers alongside medical providers in clinic produced better abstinence rates than usual care, which typically means a referral to a treatment provider outside the liver center.62 Types of AUD treatment evaluated in both randomized and observational trials include CBT, MET, psycho‐education, and motivational interviewing, with modalities combined in varying ways in each trial. Five randomized controlled trials (RCTs) were reported, three of which enrolled patients with AC exclusively and only one of which showed statistically significant benefit with an integrated intervention combining alcohol use disorder treatment with medical care.63 Other observational studies evaluated psychosocial interventions for patients with HCV and AUD and showed modest improvement in abstinence with integrated care, again producing improved outcomes.66 However, there are few data to show that one treatment modality is consistently superior to another across all categories of populations.70 Based on these findings, integrated, multidisciplinary care remains the best option for management of advanced ALD and AUD, although it may not be practical in all resource settings.71 Relapse Prevention Medications Pharmacotherapy for AUDs includes both Food and Drug Administration (FDA) and non‐FDA approved medications provided in Table 4. There are three FDA‐approved medications: disulfiram, naltrexone, and acamprosate. The number needed to treat to prevent return to any drinking is estimated to be approximately 12 for acamprosate and 20 for naltrexone. Disulfiram and naltrexone undergo hepatic metabolism and can cause liver damage, whereas acamprosate has no hepatic metabolism. Of note, none of these medications have been studied in patients with AH and AC. In addition, there are several medications with some benefit in relapse prevention that have not been FDA‐approved for AUD treatment. These agents include gabapentin, baclofen, topiramate, ondansetron, and varenicline.72 Baclofen, a gamma‐aminobutyric acid–B (GABA‐B) receptor agonist, is the only AUD pharmacotherapy that has been tested in an RCT in patients with AC with AUD as well as in two small, uncontrolled observational studies.71 In a randomized trial consisting of patients with both compensated and decompensated AC, a 12‐week course of baclofen (10 mg three times daily) resulted in improved rates of total alcohol abstinence and decreased relapse compared with the control during 1 year of observation while exhibiting an acceptable safety profile.71 Notably, patients with hepatic encephalopathy were excluded from this trial, as baclofen may impair mentation, a side effect that may be exacerbated in more advanced liver disease. Based on limited data, and in the absence of an RCT demonstrating efficacy, acamprosate does not appear to be toxic to the liver and is probably safe. Table 4 - Relapse Prevention Medications in Alcoholic Liver Disease Medication Dosing Metabolism (M) and Excretion (E) Mechanism of Action ALD Considerations Naltrexone* 50 mg/d orally or 380 mg monthly sq M: Hepatic Opioid receptor antagonist Not studied in patients with ALD Hepatotoxicity concerns E: Mostly renal, fecal 2%‐3% Acamprosate* 666 mg tid M: None NMDA receptor antagonist Not studied in patients with ALD No reported instances of hepatotoxicity E: Renal Gabapentin 600‐1,800 mg/d M: None Modulates GABA activity through action at presynaptic calcium channels Not studied in patients with ALD Monitor closely for renal dysfunction and worsening mental status/sedation E: Renal 75%, fecal 25% Baclofen 30‐60 mg/d M: Hepatic, limited GABA‐B receptor agonist Single RCT in patients with ALD showed benefit E: Renal Topiramate 75‐400 mg/d M: Not extensively metabolized GABA action augmentation, glutamate antagonism Not studied in patients with ALD E: Renal Adapted from Winder et al.237*FDA‐approved for AUD treatment. Disulfiram is not included on this list because it is not recommended for use in patients with ALD.Abbreviations: GABA, gamma‐aminobutyric acid; NMDA, N‐methyl‐D‐aspartate; sq, subcutaneous; and tid, 3 times per day. Guidance Statements Referral to AUD treatment professionals is recommended for patients with advanced ALD and/or AUD, to ensure access to the full range of AUD treatment options. Multidisciplinary, integrated management of ALD and AUD is recommended and improves rates of alcohol abstinence among patients with ALD. Based on limited data, the use of acamprosate or baclofen can be considered for the treatment of AUD in patients with ALD. Pathophysiology and Risk Factors for Alcohol‐Associated Liver Disease Given the widespread levels of heavy alcohol use worldwide, it is clear that a minority of heavy drinkers develop significant liver disease. The injurious effect of alcohol on the liver is not linearly dose‐dependent, but there is a threshold beyond which the risk for serious liver disease increases with increasing levels of consumption.79 According to the "Dietary Guidelines for Americans 2015‐2020," US Department of Health and Human Services and US Department of Agriculture, the upper limit of safe drinking appears to be one standard drink per day for women and two standard drinks for men.80 Furthermore, the NIAAA defines binge drinking as a pattern of drinking that brings blood alcohol concentration levels to 0.08 g/dL, and that typically occurs after four drinks for women and five drinks for men, in about 2 hours.81 The Substance Abuse and Mental Health Services Administration, which conducts the annual National Survey on Drug Use and Health, uses an almost identical definition while adding "on at least 1 day in the past month."82 By NIAAA definition, a standard drink contains 14 g alcohol (equivalent to 12 oz. beer [5% alcohol], 8‐9 oz. malt liquor, 5 oz. table wine, or 1.5 oz. distilled spirits). A simplification would be to adopt the European standard that one standard measure of any form of alcohol is constituted by 10 g. The upper threshold of safe consumption continues to be reviewed, with a recent analysis suggesting that alcohol use should be limited to one drink per day for men and women, or even that any drinking may have adverse health consequences.83 The pathophysiology of ALD is complex. Heavy alcohol use results in accumulation of fat through effects on the redox state of the liver and on a number of transcription factors that regulate pathways involved in fatty acid synthesis (increased) and oxidation (decreased). In some individuals, changes in gut permeability lead to increased portal vein endotoxin, activation of the innate immune response, and liver cell inflammation, injury, apoptosis and necrosis, and fibrosis through cytokine and oxidative stress cascades. These cascades involve interactions among the resident macrophages (Kupffer cells), myofibroblasts, endothelial cells, and hepatocytes.85 Interruption of these pathways has resulted in improvement in liver injury, and these results help explain current therapy with anti‐inflammatory and anti‐oxidant agents. There are ongoing trials examining anti‐cytokine and gut‐directed therapies. Table 5 lists the factors that influence the risk of alcohol‐associated liver injury.86 Women have a greater risk of liver injury compared with men for any level of drinking.88 Wine consumption was less likely to be associated with cirrhosis than other beverages.89 Daily drinking conferred greater risk of ALD, and smoking independently increases the risk for cirrhosis.90 A meta‐analysis of studies of alcohol consumption and cirrhosis risk confirmed increased risk for women.83 There is evidence that binge drinking increases the risk of ALD.92 Coffee consumption protects against cirrhosis of many causes, including ALD as well as AH.93 Table 5 - Factors Affecting the Risk of Alcoholic Liver Disease Implicated in increasing the risk of alcohol‐associated liver injury Alcohol dose above threshold of 1 drink/day (women), 2 drinks/day (men) Pattern of consumption: daily drinking; drinking while fasting, binge drinking Smoking cigarettes Women compared with men Genetics*: PNPLA3, TM6SF2, MBOAT7, HSD17B13 Increased BMI Presence of comorbid conditions: chronic viral hepatitis, hemochromatosis, NAFLD, NASH Implicated in ameliorating the risk of alcohol‐associated liver injury Coffee consumption Equivocal data regarding effect on the risk of alcohol‐associated liver injury Type of alcohol consumed Moderate alcohol use in patients with high BMI *Typically in studies of genetic predisposition, one allele