Diagnosis and Treatment of Alcohol-Associated Liver Diseases 2019 Practice Guidance PDF

PRACTICE GUIDANCE | Hepatology, VOL. 71, NO. 1, 2020  Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Dis...

PRACTICE GUIDANCE | Hepatology, VOL. 71, NO. 1, 2020  Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases David W. Crabb,1 Gene Y. Im ,2 Gyongyi Szabo,3 Jessica L. Mellinger,4 and Michael R. Lucey5 carries a significant stigma in society. It is increasingly Purpose and Scope of the recognized by providers that patients and their families Guidance seek to reduce the stigma of ALD, and a change from the term “alcoholic” to “alcohol-associated” will help; Alcohol-associated liver disease (ALD) represents thus, alcohol-associated liver disease, alcohol-associated a spectrum of liver injury resulting from alcohol use, steatohepatitis, and alcohol-associated cirrhosis are sug- ranging from hepatic steatosis to more advanced forms gested, retaining the familiar abbreviations (ALD, ASH, including alcoholic hepatitis (AH), alcohol-associated and AC, respectively). Due to longstanding usage, the cirrhosis (AC), and acute AH presenting as acute-on- term “alcoholic hepatitis” will likely persist. chronic liver failure. ALD is a major cause of liver dis- This 2019 ALD Guidance provides a data-supported ease worldwide, both on its own and as a co-factor in approach to the prevalence, clinical spectrum, diagno- the progression of chronic viral hepatitis, nonalcoholic sis, and clinical management of ALD and alcohol use fatty liver disease (NAFLD), iron overload, and other disorders (AUDs). The Guidance was developed by liver diseases. ALD develops through several stages, consensus of an expert panel and provides guidance beginning with hepatic steatosis, and, in some individ- statements based on formal review and analysis of pub- uals, gradually progressing through AH (the histological lished literature on the topics. The quality (level) of the correlate of which is alcoholic steatohepatitis), culminat- evidence and the strength of each guidance statement ing in cirrhosis (Fig. 1).(1,2) Progression through these are not formally rated. Updates to the 2010 Guideline various stages is dependent on continued heavy alcohol include an emphasis on AUD definition, screening, and use and other risk factors, including female sex, genetic treatment; new alcohol biomarkers; additional genetic susceptibility, diet, and comorbid liver disease. ALD and environmental susceptibility factors; a consensus Abbreviations: ABIC, age, serum bilirubin, international normalized ratio, and serum creatinine; AC, alcoholic cirrhosis; AH, alcoholic hepatitis; AKI, acute kidney injury; ALD, alcoholic liver disease; AUD, alcohol use disorder; AUDIT, Alcohol Use Disorders Inventory Test; AUROC, area under the receiver operating characteristics curve; BMI, body mass index; CDT, carbohydrate-def icient transferrin; CI, conf idence interval; CPT, Child-Pugh-Turcotte; EtG, ethyl glucuronide; EtS, ethyl sulfate; FDA, Food and Drug Administration; GAHS, Glasgow Alcoholic Hepatitis Score; G-CSF, granulocyte-colony stimulating factor; GGT, gamma-glutamyl transferase; GIB, gastrointestinal bleeding; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; MDF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; NAC, N-acetylcysteine; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIAAA, National Institute on Alcohol Abuse and Alcoholism; PEth, phosphatidylethanol; RCT, randomized controlled trial; SIRS, systemic inflammatory response syndrome; STOPAH, Steroids or Pentoxifylline for Alcoholic Hepatitis; UNOS, United Network for Organ Sharing. Received May 30, 2019; accepted May 31, 2019. Supported by the American Association for the Study of Liver Diseases. © 2019 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.30866 306  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. definition of AH, and review of recent studies of corti- 22.2 million disability-adjusted life years annually.(10,11) costeroids and guidance on the role of transplantation in In the United States, ALD competes with chronic the management of AH. 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.(9,13) Prevalence and Burden of In addition, deaths related to alcohol use are frequently underestimated due to the stigma of alcohol use and lack Alcohol-Associated Liver of candor in reporting.(10,14) In women, AC prevalence Disease may be increasing at a faster rate than in men, mirroring the rise in alcohol use in women in the United States.(9) Alcohol-associated liver disease includes a variety of The incidence of AH has been difficult to estimate, clinical disorders: steatosis, ASH, AH of varying degrees as diagnostic accuracy of administrative coding is less of severity, AC, and AC complicated by hepatocellular reliable for AH.(15,16) The incidence of AH varies carcinoma (HCC). ALD comprises a substantial por- worldwide. In the United States, admissions for AH tion of the overall cirrhosis burden, both in the United were found to have increased to 0.83% of all admis- States and worldwide, and is responsible for rising rates sions for 2010.(13) In Denmark, the incidence of AH for of liver-related mortality in the United States, especially the period 1999-2008 rose from 37 to 46 per million among younger patients.(3-5) In the United States, mor- persons per year in men and 24 to 34 per million per- tality due to all ALD was estimated at 5.5 per 100,000 sons per year for women.(17) A similar study in Finland in 2012; the relative contribution of ALD to all cirrho- reported increased incidence rates for AH from 37 to 65 sis mortality is predicted to increase as the proportion cases per million persons per year for men and from 13 of deaths due to hepatitis C virus (HCV) cirrhosis to 27 cases per million persons per year for women.(18) declines.(3,6) More recently, AC mortality was shown to In both of these cases, estimates were based on diagnos- have increased from 2008 to 2016, particularly among tic coding, which may be less accurate and highlights patients ages 25-34 years old.(4) Cirrhotic and noncir- the difficulty in estimating the burden of AH. rhotic ALD prevalence has been estimated at approx- Accurate assessment of the full spectrum of ALD imately 2% in the general US population, whereas AC prevalence is challenging, particularly given the diffi- in the US Veterans’ population was estimated at 327 per culty with identifying earlier, asymptomatic stages of 100,000 enrollees.(7,8) In privately insured US patients, ALD, such as ASH or moderate AH, challenges that AC has been estimated at approximately 100 per 100,000 may be overcome with broader use of noninvasive ste- enrollees, and, overall, rates are projected to rise over atosis and fibrosis assessment tools and increased aware- time.(3,9) Worldwide, AC deaths account for about 10% ness for the need to diagnose early-stage disease. Many of all alcohol-attributable deaths, and nearly half of those studies underestimate the true prevalence and bur- deaths are due to liver disease, resulting in the loss of den by counting as ALD only those patients without 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. ARTICLE INFORMATION: From the 1 Indiana University School of Medicine, Indianapolis, IN; 2 Icahn School of Medicine at Mount Sinai, New York, NY; 3 University of Massachusetts Medical School, Worcester, MA; 4 University of Michigan Hospitals & Health Centers, Ann Arbor, MI; 5 University of Wisconsin School of Medicine, Madison, WI. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: David W. Crabb, M.D. Fifth Third Bank Building, Fifth Floor Indiana University School of Medicine Indianapolis, IN 46202-5112 720 Eskenazi Avenue E-mail: [email protected] 307  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 FIG. 1. Natural history of alcohol-associated liver disease. Images courtesy of Dr. M. Isabel Fiel. additional liver diseases such as HCV, in spite of the fact that concomitant ALD rates are as high as 61% Diagnosis of Alcohol Use in some patients with other liver diseases, in particular nonalcoholic steatohepatitis (NASH), HCV, and hemo- Disorders chromatosis.(14,19) These factors may result in as much Since publication of the Diagnostic and Statistical as a 2-fold underestimate for ALD-related mortality.(11) Manual (Fifth Edition), the former categories of 308  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. alcohol abuse and dependence have been replaced by SCREENING, BRIEF the term “alcohol use disorder,” characterized as mild, INTERVENTION, AND REFERRAL moderate, or severe based on the accumulation of TO TREATMENT negative consequences and symptoms (Table 1).(20) Alcohol use is common in the United States, with The public health approach to the problem of many people drinking moderate amounts with- alcohol use is termed “screening, brief intervention, out significant consequences.(21) However, more and referral to treatment.” This process begins with severe forms of AUD, defined by escalating alco- screening for and assessing the level of alcohol use. hol consumption despite attempts to cut back, Discussion of alcohol use can be off-putting for negative personal consequences, and the appearance patients, who may feel stigmatized or judged.(23) As of alcohol craving, are also on the rise.(21) Rates of such, a nonjudgmental, open, and accepting interview AUD and high-risk drinking have risen dramati- style can help maintain therapeutic alliance, and limit cally, with the prevalence of AUD in two nation- underreporting and denial of AUDs.(24) The symp- ally representative surveys of US adults increasing toms of AUD and ALD may not be readily appar- by 50% between 2001 and 2013, with even greater ent, particularly in early stages of ALD. The National increases reported among women, minorities, and Institute on Alcohol Abuse and Alcoholism (NIAAA) those of lower socioeconomic status.(22) The type has published a brief guide for clinicians to help assess of alcohol consumed and the prevalence of binge alcohol use (including more severe AUDs), provide drinking (five or more drinks occurring monthly brief intervention, pharmacotherapy, and refer more or more often) changed over the same time period severe cases to treatment.(25) Of note, NIAAA guide- (2000-2013) with substantial increases observed lines for limits on drinking apply to general popula- for consumption of distilled spirits (+11.5%), wine tions rather than patients with ALD (i.e., there is no (+7.7%), and binge drinking.(22) Worldwide, alcohol known safe level of alcohol consumption for patients consumption varies geographically, with the high- with ALD). Similarly, the US Preventive Services est rates of reported per capita alcohol consumption Task Force (USPSTF) has recently published its rec- occurring in northern and eastern European coun- ommendations regarding “Unhealthy Alcohol Use in tries and Russia.(14) Adolescents and Adults: Screening and Behavioral 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. 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 exacer- bated by the effects of alcohol. The presence of at least 2 of these 7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use. symptoms indicates an AUD: 8. Recurrent alcohol use in situations in which it is physically hazardous. Mild: 2-3 symptoms 9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological prob- Moderate: 4-5 symptoms lem that is likely to have been caused or exacerbated by alcohol. Severe: 6 or more symptoms 10. Tolerance, defined as either of the following: A Need for markedly increased amounts of alcohol to achieve intoxication or desired effect; or B Markedly diminished effect with continued use of the same amount of alcohol. 11. Withdrawal, as manifested by either of the following: A The characteristic alcohol withdrawal syndrome; or B Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms. 309  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 Counseling Interventions.” The summary statement including hospitalization for alcohol-associated recommended screening for unhealthy alcohol use in diagnoses.(34,35) primary care settings in adults 18 years or older, includ- ing pregnant women, and providing persons engaged in risky or hazardous drinking with brief behavioral BIOMARKERS OF ALCOHOL USE counseling interventions to reduce unhealthy alcohol Biomarkers of alcohol use refer to moieties in urine, use.(26) blood, or hair, which identify metabolites or surrogates Efforts to uncover harmful alcohol use are aided by of alcohol use and provide an estimated timeframe of the use of structured, validated screening tools. The recent drinking. The American Society of Addiction NIAAA recommends a one-question initial screen: Medicine and American Psychiatric Association sug- “How many times in the past year have you had 5 or gest the use of alcohol biomarkers as an aid to diagno- more drinks in a day (for men) or 4 or more drinks sis, to support recovery, and as catalysts for discussion in a day (for women)?” This is the NIAAA definition with the patient, rather than as tools to “catch” or of binge drinking (five drinks in men; four in women punish patients.(36,37) Principles of use include dis- over 2 hours). If the patient reports even a single epi- cussing biomarker use with patients before testing, to sode, performing the Alcohol Use Disorders Inventory maintain therapeutic alliance and improve alcohol use Test (AUDIT) is recommended.(27) The AUDIT is disclosure. Each of the alcohol biomarkers described used widely and is recommended by the USPSTF. Its subsequently has limitations. They should not be used original form included 10 questions on consumption on their own to confirm or refute alcohol use, but (Q1-Q3), dependence symptoms (Q4-Q6), and any should be combined with other lab testing (includ- alcohol-associated problems (Q7-Q10), with a score ing other alcohol biomarkers), physical exam, and the greater than 8 being predictive of harmful or hazard- clinical interview. ous alcohol use, and scores greater than 20 suggestive Liver-related enzymes, bilirubin, or gamma- of alcohol dependence (now termed moderate/severe glutamyl transferase (GGT) or evidence of macrocytic AUD).(27,28) Questions 1-3 are often used alone (the anemia may suggest alcohol use, but on their own are “AUDIT-C”) as a more efficient means of screening inadequate to establish alcohol use in ALD.(38,39) for problem alcohol use, but this shorter form does GGT is an enzyme found in the cell membranes not provide information on more severe alcohol use of several body tissues, including liver and spleen. problems.(29) The AUDIT-C is brief, convenient, and Although it is frequently elevated in heavy drinking performs better than the CAGE and other question- and has greater sensitivity than AST, it is not specific naires in identifying alcohol misuse.(30) AUDIT-C for alcohol use.(40) Carbohydrate-deficient transferrin scores of at least 4-5 may indicate harmful alcohol (CDT) is generated as a result of alcohol inhibition use. These screening tests do not provide a diagnosis of transferrin glycosylation. Typically reported as the of AUD, but rather point to the need for a formal percentage of CDT (%CDT) per total transferrin, to assessment. The NIAAA Clinicians’ Guide outlines account for differences in total transferrin levels, CDT brief intervention and referral to treatment for the has a half-life of 2-3 weeks.(41) The utility of CDT is general public; space limitations prevent a more thor- limited by its low sensitivity of 25%-50% in several ough discussion of brief interventions.(31) studies and by false-positive results arising in patients Screening in general medicine and specialty clinics with severe liver disease in the absence of alcohol has been shown to help identify patients with ALD use.(42-44) However, posttransplant use of %CDT early, and by coupling this with a discussion of the appears to be more accurate, likely due to improved implications for liver disease, may be motivational liver function.(45,46) for alcohol reduction.(32) Mandatory alcohol use A small (about 0.1%) amount of alcohol is screening of inpatients and in the emergency depart- metabolized by uridine diphosphoglucuronate– ment effectively identifies heavy users, assists ALD glucuronosyltransferase and uridine diphosphoglucu- diagnosis, and improves connection to treatment of ronate–sulfotransferase, producing ethyl glucuronide AUD.(33) Importantly, use of screening tools such as (EtG) and ethyl sulfate (EtS).(47) Both are excreted AUDIT has been shown to improve detection as well in the urine, but are also found in blood and hair. as the ability to predict long-term clinical outcomes, Although false positives and false negatives have been 310  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. reported, sensitivity and specificity of urinary EtG for The performance of the current best biomarkers for detection of alcohol use were 89% and 99%, respec- alcohol use are given in Tables 2 and 3. tively, among patients with ALD before and after LT.(48) Other studies in patients with mixed etiology Guidance Statements of liver disease, including cirrhosis, found sensitivities All patients receiving care in primary care and of 76% and 82% for drinking within 3 days of the test gastroenterology/hepatology outpatient clinics, for EtG and EtS, respectively, with higher specifici- emergency departments, and inpatient admissions ties of 93% and 86%, respectively.(49) Urinary EtG and should be screened routinely for alcohol use using EtS detection times can also be prolonged in renal validated questionnaires. failure, resulting in a longer window of positive results Brief intervention, pharmacotherapy, and referral after alcohol ingestion in patients with kidney disease. to treatment should be offered to patients engaged Phosphatidylethanol (PEth) is a phospholipid in hazardous drinking (AUDIT-C ≥4, AUDIT >8, formed by the reaction of phosphatidylcholine binge drinkers). with ethanol catalyzed by phospholipase D in the Alcohol biomarkers can be used to aid in diag- erythrocyte cell membrane.(50) PEth has a half-life nosis and support recovery. Urine and hair ethyl of approximately 10-14 days, although this can be glucuronide, urine ethyl sulfate, and PEth are longer with more chronic, repeated heavy alcohol not affected by liver disease, and therefore are consumption and does not appear to be influenced preferable. by age, body mass index (BMI), sex, kidney disease, or liver disease.(51-57) Women may have higher PEth levels for a given amount of alcohol consumption compared with men.(58) Although there are inter- Treatment of Alcohol Use individual variations in PEth metabolism, PEth has been validated in a study of chronic liver disease Disorders patients who had not undergone LT at a cutoff of Because abstinence is the single most important 80 ng/mL for four drinks per day or more with a factor in improving survival from ALD, multidisci- sensitivity of 91% (95% confidence interval [CI], plinary management with addiction specialists and 82%-100%) and specificity of 77% (95% CI, 70%- referral to treatment for AUD, particularly in patients 83%).(59) Another study of PEth use in patients with moderate to severe AUDs or clinically evident with ALD before and after LT revealed a sensitiv- ALD, is mandatory. We present a review of differ- ity of 100% (CI, 79%-100%) and specificity of 96% ent types of treatment, with a focus on treatments (CI, 91%-99%) for a cutoff of over 20 ng/mL.(50) that have been studied in patients with ALD. Many 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 post- transplant patients show better performance than pretransplant patients. Abbreviations: NPV, negative predictive value; and PPV, positive predictive value. 311  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 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-Streichert(42) %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) Staufer(43) %CDT 25% 98% 64% 93% Urine EtG 89% 99% 89% 99% Abbreviations: NPV, negative predictive value; and PPV, positive predictive value. patients, however, will be reluctant to see a profes- treatment providers alongside medical providers in sional mental health provider. For patients who are clinic produced better abstinence rates than usual care, ambivalent about alcohol cessation, motivational which typically means a referral to a treatment pro- interviewing has been shown to help patients change vider outside the liver center.(62) behaviors, including alcohol use.(60) A new online Types of AUD treatment evaluated in both ran- resource developed by NIAAA is now available to domized and observational trials include CBT, MET, help people and their families recognize AUD and psycho-education, and motivational interviewing, find high-quality care through an easily accessible and with modalities combined in varying ways in each user-friendly web-based system, the NIAAA Alcohol trial. Five randomized controlled trials (RCTs) were Treatment Navigator.(61) reported, three of which enrolled patients with AC exclusively and only one of which showed statistically PSYCHOSOCIAL AND significant benefit with an integrated intervention BEHAVIORAL APPROACHES TO combining alcohol use disorder treatment with med- ALCOHOL USE DISORDER ical care.(63-65) Other observational studies evaluated psychosocial interventions for patients with HCV TREATMENT IN PATIENTS WITH and AUD and showed modest improvement in absti- ALD nence with integrated care, again producing improved There are a wide variety of alcohol use disorder outcomes.(66-69) However, there are few data to show treatments available to patients, although relatively that one treatment modality is consistently superior to few have been studied in patients with ALD. Major another across all categories of populations.(70) Based categories of treatment include inpatient alcohol reha- on these findings, integrated, multidisciplinary care bilitation, group therapies, individual therapy, family/ remains the best option for management of advanced couples counseling, and mutual aid societies (such ALD and AUD, although it may not be practical in as Alcoholics Anonymous). Within counseling ses- all resource settings.(71) sions, various modalities of treatment are available that target different mechanisms of behavior change. RELAPSE PREVENTION These include cognitive-behavior therapy (CBT), motivational interviewing, motivational enhancement MEDICATIONS therapy (MET), contingency management, 12-step Pharmacotherapy for AUDs includes both Food facilitation, network therapy, and couples/family and Drug Administration (FDA) and non-FDA counseling.(24) approved medications provided in Table 4. There Psychosocial treatment has been studied in a lim- are three FDA-approved medications: disulfiram, ited fashion in ALD. A recent systematic review of naltrexone, and acamprosate. The number needed to treatment trials in ALD found that integrating AUD treat to prevent return to any drinking is estimated 312  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. TABLE 4. Relapse Prevention Medications in Alcoholic Liver Disease Metabolism (M) and Medication Dosing Excretion (E) Mechanism of Action ALD Considerations Naltrexone* 50 mg/d orally or M: Hepatic Opioid receptor antagonist Not studied in patients with ALD 380 mg monthly sq E: Mostly renal, fecal 2%-3% Hepatotoxicity concerns Acamprosate* 666 mg tid M: None NMDA receptor antagonist Not studied in patients with ALD E: Renal No reported instances of hepatotoxicity Gabapentin 600-1,800 mg/d M: None Modulates GABA activity Not studied in patients with ALD E: Renal 75%, fecal 25% through action at Monitor closely for renal dysfunction and presynaptic calcium worsening mental status/sedation channels Baclofen 30-60 mg/d M: Hepatic, limited GABA-B receptor agonist Single RCT in patients with ALD showed E: Renal benefit Topiramate 75-400 mg/d M: Not extensively metabolized GABA action augmen- Not studied in patients with ALD E: Renal tation, glutamate antagonism Note: 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. to be approximately 12 for acamprosate and 20 Guidance Statements for naltrexone. Disulfiram and naltrexone undergo Referral to AUD treatment professionals is rec- hepatic metabolism and can cause liver damage, ommended for patients with advanced ALD and/ whereas acamprosate has no hepatic metabolism. Of or AUD, to ensure access to the full range of AUD note, none of these medications have been studied treatment options. in patients with AH and AC. In addition, there are Multidisciplinary, integrated management of several medications with some benefit in relapse ALD and AUD is recommended and improves prevention that have not been FDA-approved for rates of alcohol abstinence among patients with AUD treatment. These agents include gabapen- ALD. tin, baclofen, topiramate, ondansetron, and vareni- Based on limited data, the use of acamprosate or cline.(72-75) Baclofen, a gamma-aminobutyric acid–B baclofen can be considered for the treatment of (GABA-B) receptor agonist, is the only AUD AUD in patients with ALD. pharmacotherapy that has been tested in an RCT in patients with AC with AUD as well as in two small, uncontrolled observational studies.(71,76,77) In a randomized trial consisting of patients with both Pathophysiology and compensated and decompensated AC, a 12-week course of baclofen (10 mg three times daily) resulted Risk Factors for Alcohol- in improved rates of total alcohol abstinence and decreased relapse compared with the control during Associated Liver Disease 1 year of observation while exhibiting an acceptable Given the widespread levels of heavy alcohol safety profile.(71,78) Notably, patients with hepatic use worldwide, it is clear that a minority of heavy encephalopathy were excluded from this trial, as drinkers develop significant liver disease. The inju- baclofen may impair mentation, a side effect that rious effect of alcohol on the liver is not linearly may be exacerbated in more advanced liver disease. dose-dependent, but there is a threshold beyond Based on limited data, and in the absence of an which the risk for serious liver disease increases with RCT demonstrating efficacy, acamprosate does not increasing levels of consumption.(79) According to appear to be toxic to the liver and is probably safe. the “Dieta​r y Guide​lines​ for Ameri​cans 2015-2020,” 313  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 US Depar​tment​of Healt​h and Human​Servi​ces and TABLE 5. Factors Affecting the Risk of Alcoholic Liver Disease US Depar​tment​of Agric​ulture, the upper limit of Implicated in increasing the risk of alcohol-associated liver injury safe drinking appears to be one standard drink per Alcohol dose above threshold of 1 drink/day (women), 2 drinks/day (men) day for women and two standard drinks for men.(80) Pattern of consumption: daily drinking; drinking while fasting, binge Furthermore, the NIAAA defines binge drinking drinking as a pattern of drinking that brings blood alcohol Smoking cigarettes Women compared with men concentration levels to 0.08 g/dL, and that typically Genetics*: PNPLA3, TM6SF2, MBOAT7, HSD17B13 occurs after four drinks for women and five drinks Increased BMI for men, in about 2 hours.(81) The Substance Abuse Presence of comorbid conditions: chronic viral hepatitis, hemochromato- sis, NAFLD, NASH and Mental Health Services Administration, which Implicated in ameliorating the risk of alcohol-associated liver injury conducts the annual National Survey on Drug Use Coffee consumption and Health, uses an almost identical definition while Equivocal data regarding effect on the risk of alcohol-associated liver injury adding “on at least 1 day in the past month.”(82) By Type of alcohol consumed Moderate alcohol use in patients with high BMI NIAAA definition, a standard drink contains 14 g alcohol (equivalent to 12 oz. beer [5% alcohol], *Typically in studies of genetic predisposition, one allele of a risk 8-9 oz. malt liquor, 5 oz. table wine, or 1.5 oz. dis- gene will be associated with increased risk compared with the alter- tilled spirits). A simplification would be to adopt nate allele; thus, each of these genes are listed as being implicated in increasing risk. 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 and smoking independently increases the risk for cir- be reviewed, with a recent analysis suggesting that rhosis.(90,91) A meta-analysis of studies of alcohol con- alcohol use should be limited to one drink per day sumption and cirrhosis risk confirmed increased risk for men and women, or even that any drinking may for women.(83) There is evidence that binge drinking have adverse health consequences.(83,84) increases the risk of ALD.(92) Coffee consumption The pathophysiology of ALD is complex. Heavy protects against cirrhosis of many causes, including alcohol use results in accumulation of fat through ALD as well as AH.(93-97) effects on the redox state of the liver and on a num- Studies of monozygotic versus dizygotic twins sug- ber of transcription factors that regulate pathways gest a heritability of about 50% for AUD, and subse- involved in fatty acid synthesis (increased) and oxida- quent genome-wide studies show this to be a complex tion (decreased). In some individuals, changes in gut polygenic disorder.(98,99) Polymorphisms in the alco- permeability lead to increased portal vein endotoxin, hol-metabolizing genes alcohol dehydrogenase 2 activation of the innate immune response, and liver (ADH2) and aldehyde dehydrogenase 2 (ALDH2) have cell inflammation, injury, apoptosis and necrosis, and been strongly linked to risk of AUDs, but not with fibrosis through cytokine and oxidative stress cas- risk of liver disease.(100) Polymorphisms in the gene cades. These cascades involve interactions among the for the alcohol oxidizing enzyme, cytochrome P450 resident macrophages (Kupffer cells), myofibroblasts, Family 2 Subfamily E Member 1 (CYP2E1), confer a endothelial cells, and hepatocytes.(85) Interruption of minor risk for ALD.(101) Studies of racial and ethnic these pathways has resulted in improvement in liver predisposition have shown that Hispanics are at sub- injury, and these results help explain current ther- stantially increased risk of developing ASH, NASH apy with anti-inflammatory and anti-oxidant agents. and cirrhosis, and of developing AH compared with There are ongoing trials examining anti-cytokine and non-Hispanic whites and African Americans.(102,103) gut-directed therapies. Genetic variants have been associated with dif- Table 5 lists the factors that influence the risk of ferential risk of ALD. Patatin-like phospholipase alcohol-associated liver injury.(86-91) Women have a domain-containing protein 3 (PNPLA3) polymor- greater risk of liver injury compared with men for phism has been associated with risk of AC and AH, any level of drinking.(88) Wine consumption was less as have polymorphisms in the transmembrane likely to be associated with cirrhosis than other bever- 6 superfamily member 2 (TM6SF2), and mem- ages.(89) Daily drinking conferred greater risk of ALD, brane bound O-acyltransferase domain-containing 314  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. 7 (MBOAT7) genes.(104-107) PNPLA3 and TM6SF2 patients with ALD meet the criteria for AUD, failure polymorphisms are also associated with increased risk to recognize AUD remains a significant clinical prob- of HCC in ALD.(108,109) Most recently, Abul-Husn lem.(115) Providers need to have a high index of suspi- et al. described a polymorphism related to a hepatic cion for AUD in patients presenting with nonspecific lipid droplet protein hydroxysteroid 17-beta dehy- symptoms and signs given in Table 6.(116) drogenase 13 (HSD17B13), the presence of which confers protection against the progression from ste- ALCOHOL-ASSOCIATED atosis to steatohepatitis in alcohol-associated and STEATOSIS non-alcohol-associated chronic liver disease.(110) Co-existent heavy alcohol use by patients with cer- Patients with alcohol-associated steatosis are usually tain other liver diseases promotes the development of asymptomatic. A palpably enlarged liver may be found advanced fibrosis and cirrhosis. The most common are in the absence of jaundice or stigmata of advanced liver NAFLD, HCV, and hemochromatosis. Even moderate disease. Among the common liver enzymes, elevations of alcohol use in NAFLD may worsen fibrosis and risk of aspartate aminotransferase and GGT are the best indi- HCC.(111) Conversely, the different elements of the met- cators of recent excessive alcohol consumption.(117,118) abolic syndrome were found to be important risk factors Hepatic steatosis is readily identified on sonography, for alcohol-associated liver injury.(112) The interaction computed tomography, and magnetic resonance imaging between alcohol use and progression of HCV disease is (MRI) of the liver.(119) MRI is more accurate for quan- well-established: A recent French study showed that the tifying fat than other radiologic techniques, with the patients with concomitant AUDs had greatly increased added advantage that MRI can assess fat over the entire risk of liver complications, need for transplantation, and volume of the liver.(120) Liver biopsy is rarely needed for liver-related death.(113) Alcohol use (above 60 g/day) the diagnosis of alcohol-associated steatosis. Treatment was also associated with a markedly increased risk of consists of avoidance of alcohol, with attention to the cirrhosis in patients with hemochromatosis.(114) TABLE 6. Symptoms and Signs Associated With Alcoholic Liver Disease Guidance Statements Symptoms Patients without liver disease should be edu- Odor of alcohol on breath* cated about safe levels of alcohol use for men (no Nonspecific more than two standard drinks per 24 hours) and Tiredness Abdominal pain women (no more than one standard drink per Day/night reversal (sleepy by day, wakeful at night) 24 hours). Peripheral neuropathy Patients with ALD or other liver diseases, in par- Weight gain (due to ascites) Weight loss (due to loss of proximal muscle mass) ticular NAFLD, NASH, viral hepatitis, and he- Confusion (as part of hepatic encephalopathy) mochromatosis, should be counseled that there Loss of sexual drive is no safe level of drinking, and that they should Amenorrhea abstain. Signs Skin: Spider angiomata, palmar erythema, leukonychia, ecchymoses Eyes: Icteric conjunctivae Musculoskeletal: Loss of proximal muscle mass, especially temporal Diagnosis and Treatment of wasting Cardiovascular: Systemic hypotension; tachycardia suggests alcohol withdrawal syndrome* Alcohol-Associated Liver Abdominal: Ascites, hepatomegaly, splenomegaly, bruits, caput medusa Reproductive: Gynecomastia, gonadal atrophy in men Diseases Neurological: ◦ Alcohol withdrawal syndrome*: Fine tremor, psychomotor agitation, transient hallucinations or illusions There is no unique presentation of ALD that can be ◦ Hepatic encephalopathy: Coarse flapping tremor (asterixis), altered distinguished with confidence from other forms of liver consciousness ◦ Wernicke-Korsakoff syndrome disease. Alcohol use is often not disclosed by the affected Hands: Dupuytren’s contracture patient, whereas liver injury, whether due to alcohol or other causes, often proceeds silently. Although not all *Specific for alcohol; otherwise nonspecific. 315  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 common association with NAFLD; thus, lifestyle mea- slow the progression of fibrosis and its consequences, sures that address obesity, physical activity, and alcohol and in anticipation of evaluation for LT. It is import- use are often needed. Alcohol-associated steatosis is ant to realize that decompensation of a patient with reversible with cessation of alcohol use. cirrhosis may reflect the onset of AH, as most patients with AH have already developed AC; thus, an oppor- ALCOHOL-ASSOCIATED tunity for treatment may be lost. CIRRHOSIS ALCOHOLIC HEPATITIS Cirrhosis is often diagnosed at the time of decom- pensation or may be uncovered in the course of eval- There is a broad spectrum of clinical presentation uating abnormal physical findings or laboratory tests. of patients with AH who may exhibit few signs or Signs and symptoms are listed in Table 6. Abdominal symptoms, or present with liver failure. AH per se is a imaging may reveal hepatic nodularity or signs of por- clinical syndrome (criteria are described subsequently tal hypertension, and transient elastography may pro- and in Fig. 2) with a distinct histopathological cor- vide evidence of increased liver stiffness. AC cannot relate, called ASH. The histological features of AH be differentiated from other causes of cirrhosis except may be present in patients with no symptoms and through careful evaluation of drinking history and mild laboratory abnormalities. Its histological features exclusion of other causes of liver disease. The progno- consist of neutrophilic lobular inflammation, degener- sis of AC is assessed just as other forms of cirrhosis, ative changes in hepatocytes (ballooning and Mallory- namely, using the Child-Pugh-Turcotte (CPT) and Denk bodies), steatosis, and pericellular fibrosis.(121) the Model for End-Stage Liver Disease (MELD or However, these features are variable in individual MELD-Na) score. The outcome of AC is crucially cases, and are often co-existent with frank cirrhosis. influenced by the patient’s ability to abstain, both to In addition, liver biopsy cannot distinguish between FIG. 2. Consensus definitions for alcoholic hepatitis.(123) Abbreviations: AH, alcoholic hepatitis; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; and SMA, smooth muscle antibody. 316  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. ASH and NASH. The role of liver biopsy is therefore Guidance Statements to resolve diagnostic dilemmas and to establish con- The diagnosis of AH (definite, probable, possible) sistency regarding AH in patients recruited to clinical should be made using the published consensus trials.(122) However, because uncertainty persists in a criteria (Fig. 2). fair number of patients, a consensus statement regard- ing the clinical diagnosis of AH, and when biopsy con- firmation of ASH was most valuable, was published ASSESSING PROGNOSIS IN AH in 2016.(123) The statement was intended to improve consistency in diagnosis of AH across research stud- Lab-Based Prognostic Scores ies and clinical trials, and to guide clinical decision Several validated, lab-based scoring systems can making about the use of potentially toxic medications be used to assess the severity and short-term prog- such as corticosteroids (Fig. 2). It categorizes patients nosis of AH (Tables 7 and 8). Common elements are with putative AH into three groups: those with defi- shared between the scores, particularly those of the nite biopsy-proven AH, those with probable AH, and MELD score, and are easily obtained.(129) Providers those with possible AH who would require biopsy can use smartphone applications or online calculators confirmation of histological features of ASH. like www.lille​model.com to calculate these scores with Noninvasive tests for AH are sorely needed. A careful awareness of the units of measurement being study of a panel of serum biomarkers of liver injury used. These scoring systems perform similarly well in and inflammation in patients with AH demonstrated predicting short-term outcome (up to 6 months) in that circulating fragments of cytokeratin-18 (CK-18) AH. The Maddrey discriminant function (MDF) was and the main constituent of Mallory-Denk bodies, derived from the results of an early clinical trial com- termed M65 and M30, both had an area under the paring corticosteroids to placebo and later modified receiver operating characteristic curve (AUROC) of to identify patients with AH with high risk of short- 0.84 to estimate the presence of AH.(124) These data term mortality (30%-50% at 28 days) when the MDF suggest that we may have biomarkers that have diag- was at least 32.(130) (Fig. 3). In contrast, a MDF of less nostic significance for AH soon. In addition, there may than 32 accurately identifies those with mild/moder- be characteristic “breathprints” in AH.(125) Transient ate AH, conferring low, but not zero, risk of mortality elastography and serum liver fibrosis markers like the with supportive care. The additional ability to dis- enhanced liver fibrosis test and the FibroTest may criminate between patients achieving a survival ben- have a role in assessing fibrosis in compensated ALD, efit from corticosteroids and those who do not, has and in following improvement of inflammation with given the MDF time-tested value in patient care and recovery.(126-128) At present, none of these have been a universal inclusion criterion in clinical trials of AH. adequately validated for routine clinical use in the Although not validated outside the United Kingdom, diagnosis of AH. the Glasgow Alcoholic Hepatitis Score (GAHS) has TABLE 7. Characteristics of Lab-Based Prognostic Scores in Alcoholic Hepatitis Bili PT/INR Cr/BUN Age Alb WBC Stratification Clinical Use MDF + + - - - - Severe: ≥32 Initiate corticosteroids MELD + + + - - - Severe: ≥21, but a continu- Prognosis only ous scale ABIC + + + + - - Low: 19,000 recipients), a figure unanticipated by pre- NASH (impaired fatty acid metabolism, apoptosis, vious expert consensus.(198,199) Furthermore, in the inflammation driven by enteric endotoxin) provides United States between 2004 and 2013, the number of the opportunity for future repurposing of pharma- new LT wait-list registrants with ALD increased by cologic treatments being developed for NASH. In 45%, from 1400 to 2024.(200) addition, a major initiative from the NIAAA has sup- The true denominator of patients with ALD who ported large multi-institutional consortia with the task could potentially benefit from LT is unknown, so of identifying new therapeutic targets and performing whether patients with ALD are underreferred for LT early-phase clinical studies to develop and test new compared to those with other liver diseases cannot be treatments for AH.(194,195) These treatments attempt determined.(201,202) Negative perceptions among the to influence different pathophysiologic mechanisms general public and general practitioners that AUD in AH, including disrupted gut-barrier function lead- and ALD are due to failures of personal responsibility, ing to bacterial and endotoxin translocation; innate concern about the risk of relapse before and after LT, 323  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. 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Hepatology, January 2020 and the perception of rationing of limited organs also a slip (brief alcohol use with regained abstinence likely reduce appropriate referral.(203) Furthermore, after self-recognition of harm) and relapse (a sus- the plasticity of ALD, particularly improvement with tained alcohol use of at least four drinks in a day, or at abstinence, can render LT less beneficial and con- least one drink for at least 4 days in succession).(198) found decisions regarding referral.(204) In contrast, Furthermore, strict adherence to the 6-month rule the clinical events surrounding decompensated AC, penalizes some patients with recent drinking who such as gastrointestinal bleeding or SIRS, mimic or are at low risk of relapse, because they are unlikely to overlap acute-on-chronic liver failure due to recent survive that duration.(212) The emergence of early LT alcohol use or comorbid infection. The complexity for severe AH (discussed subsequently) has changed of management, lack of access to specialty care, and the dynamic regarding the value of a fixed interval of high mortality can limit the emergence of suitable LT pre-LT abstinence. Thus, the consensus regarding the candidates.(205) appropriateness and application of the 6-month rule appears to be diminishing in the United States, just as TIMING OF REFERRAL AND it has done in Europe.(213) The AASLD Practice Guideline recommends that SELECTION OF CANDIDATES FOR potential LT candidates with ALD undergo evalu- LT FOR ALD ation by a mental health provider for full psychiat- The clinical indicators that inform the managing ric diagnosis and adequate treatment planning.(214) provider that LT evaluation should be considered A number of groups have attempted to codify the are new onset decompensation (ascites, encephalop- pre-LT psychosocial assessment into a prognostic athy, jaundice, or variceal hemorrhage), an episode of score: the Michigan alcoholism prognostic scale, the spontaneous bacterial peritonitis, diagnosis of HCC, high-risk alcoholism relapse, the “Alcohol Relapse or MELD-Na greater than 21.(167,206) Patients with Risk Assessment,” and the Stanford Integrated ALD who fail to improve after 3 months of absti- Psychosocial Assessment for Transplantation.(215-219) nence, particularly with CPT class C cirrhosis, These scores have some common features such as should be referred and considered for LT.(205) The the favorable value of social integration indica- selection of appropriate patients with ALD for LT tors (e.g., a spouse or partner [sometimes called a is unique among LT indications, as the patient’s his- “rehabilitation relationship”], stable home and work, tory of addiction to alcohol is of primary importance. insight into AUD) and the negative significance of Determining the time of last alcohol use and predict- a history of failed rehabilitation attempts or pre- ing the likelihood of achieving abstinence before and existing psychiatric disorders.(220) Regardless of the after LT are best evaluated by an expert in addiction evaluation measures, a formal psychological evalua- medicine working within the transplant team.(207-209) tion is only able to separate an AUD LT candidate Up until recently, LT centers in the United States into high-risk or lesser-risk strata. Taken together required patients with ALD to be abstinent from alco- with the complexity of AUD, it follows that there hol for a minimum of 6 months before listing for LT, is no single measure that reliably predicts alcohol often called the “6-month rule.”(208) In a 1997 consen- relapse after LT. sus conference of the AASLD and American Society of Transplantation, the 6-month rule was justified on OUTCOMES OF LT FOR ALD the grounds that it allowed time to assess liver recov- ery that in turn might obviate the need for LT.(210) It Liver allograft and recipient survival for ALD also has additional value in more stable patients by are among the highest of all indications for LT.(221) ascertaining commitment to abstinence through par- Studies that permit the patient to reveal alcohol use ticipation in alcohol rehabilitation. Since then, studies without penalty while on the transplant list sug- have demonstrated that, while duration of abstinence gest that up to 25% will drink during evaluation or before LT is linked to future abstinence, the 6-month waiting for LT.(64) After LT, studies using different rule alone is an inadequate predictor of drinking after methodologies, including retrospective review of the LT.(211) These studies are confounded by method- medical record, prospective protocol interviews or cross- ological flaws, such as failing to distinguish between sectional use of biomarkers like hair, serum, or urine 324  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. EtG and PEth, show that approximately 20%-25% rates as high as 70% at 6 months.(135) Until recently, of ALD recipients return to drinking in the first adherence to the 6-month abstinence requirement by 5 years.(43,222-225) Because this is a highly selected most LT centers essentially excluded these patients group of patients, this may reflect the risk of relapse from consideration for LT.(211) Results from retro- in the lowest-risk-stratified population. DiMartini spective analyses of explant histology and United et al. described several patterns of drinking after LT Network for Organ Sharing (UNOS) data demon- for ALD, including early relapse with restoration of strate similar outcomes of survival and relapse in sobriety, early relapse that persists, and relapse after those with histologic or listing diagnosis of AH com- many months of sobriety following LT.(223) Early rec- pared to patients with ALD adhering to the 6-month ognition of the pattern of relapse may inform tailored rule.(227,228) A seminal prospective, multicenter study interventions to restore sobriety. Relapse to harmful in France and Belgium demonstrated that LT per- drinking, in contrast to minor slips, has damaging formed “early” (i.e., before 6 months of abstinence) consequences for the liver allograft. New onset AH was life-saving in patients with life-threatening liver and recurrent fibrosis in the allograft progressing failure due to AH.(170) Mathurin et al. applied a rig- to cirrhosis are well-documented adverse outcomes orous selection process to patients with severe AH following LT. In the post-transplant setting, severe having nonresponse to corticosteroids and requiring AUD relapse leads to liver fibrosis and cirrhosis in the complete consensus of multiple medical teams as little as 5 years.(222) In a French multicenter study before wait-listing. Comprehensive psychosocial of 712 patients transplanted for ALD between 1990 assessments by an addiction specialist were per- and 2007, severe relapse (defined as mean alcohol formed to identify those with lower risk of alcohol consumption of >20 g/day in women and >30 g/day relapse. Severe AH as the first liver-decompensating in men for a period of at least 6 months) occurred event was a key inclusion criterion meant to pri- in 18% (n = 128), with a median delay between LT oritize those previously unaware of their liver dis- and severe relapse of 25 months.(222) In this group, ease from alcohol. After about 90% of patients with 32% (n = 41) of patients developed cirrhosis after a severe AH who had not responded to steroids were little over 5 years following LT (range 1.8-13.9 years). excluded for poor psychosocial profiles, 26 underwent Nearly two-thirds of these individuals died, with early LT with improved 6-month survival compared a median time from diagnosis of cirrhosis to death with historical controls (77% ± 8% versus 23% ± 8%; being 1.1 years (range 0.1-7.6 years). Furthermore, as P < 0.001), low impact on available organs, and low mentioned previously, excessive alcohol use is harmful rates of relapse. The findings of this trial further even when ALD had not been the primary indica- challenged the notion of the 6-month waiting period tion cited for LT.(226) This highlights the clandestine as the only AUD-related criterion for LT eligibility. nature of AUD and how the role of alcohol may be Efforts to confirm these findings have largely come underappreciated in the LT evaluation. from the United States.(229,230) A multicenter retro- spective American study has extended these observa- Guidance Statements tions to 147 patients with AH, median MELD score of 39, who underwent LT before 6 months of absti- Patients with decompensated alcohol-associated nence (median abstinence of 55 days) from 2006 cirrhosis, CPT class C or MELD-Na of at least through 2017 at 12 US centers.(231) These patients 21 should be referred and considered for liver had no prior diagnosis of liver disease or episodes of transplantation. AH. Cumulative patient survival after LT was 94% Candidate selection for liver transplantation in at 1 year and 84% at 3 years, with cumulative inci- alcohol-associated cirrhosis should not be based dence of sustained alcohol use of 10% at 1 year (95% solely on a fixed interval of abstinence. CI, 6%-18%) and 17% at 3 years (95% CI, 10%- 27%) after LT. There are several issues that require further study EARLY LT FOR SEVERE AH in early LT for AH. The most critical is how best to Patients with severe AH not responding to med- consistently and uniformly select appropriate patients ical therapy have a grim prognosis, with mortality who have excellent post-LT survival and low risk of 325  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License CRABB ET AL. Hepatology, January 2020 relapse following LT. Because existing studies are lim- moderate AH, are needed, and may become feasi- ited to patients with severe AH not responding to or ble with broader use of noninvasive steatosis and ineligible for medical therapy presenting with their fibrosis assessment tools. first liver decompensating event (i.e., no prior diagno- 2. Well-constructed studies of the incidence of AH sis of liver disease or episodes of AH), these should be in the United States are needed. Particular atten- important considerations in selecting candidates for tion should be paid to diversity of sex, racial back- early LT. Furthermore, among patients who fulfilled ground, and age. these criteria, the previously mentioned multicenter 3. Patients with ALD have been omitted from stud- American study group recently derived a predictive ies of efficacy of treatments for AUD. Studies model of four pre-LT variables that may identify are needed to assess the efficacy of psychosocial patients at low risk for sustained alcohol use follow- and pharmacological treatments in initiating and ing LT, but that require validation.(232) These variables maintaining abstinence by patients with ALD. were greater than 10 drinks/day at initial presenta- 4. The potential for serial measurements of biomark- tion (4 points), multiple prior rehabilitation attempts ers in patients with ALD are needed, with the (4 points), prior alcohol-associated legal issues (2 points), dual endpoints of abstinence and stabilization or and prior illicit substance use (1 point), with a com- improvement in liver disease. posite “SALT” score of less than 5, having a 95% nega- 5. Studies of medical agents that abrogate the patho- tive predictive value (95% CI: 89%-98%) for sustained physiological mechanisms that lead to chronic alcohol use following LT. Also, the optimal use and alcohol-associated liver injury are needed. These timing of AUD treatment following LT remains to processes include chronic inflammation, the role of be defined.(233) In addition, there are concerns about the gut microbiota, progressive fat accumulation, potentially negative public perception and its effects and progressive fibrotic injury. on organ donation, which together with the other 6. New clinical trials are needed both in moderate issues outlined previously, have limited wider adop- (MELD ≤ 20) and severe AH (MELD >20) to tion of this emerging indication for LT.(234) However, improve the management of AH. survey and UNOS studies suggest a growing interest 7. Prospective clinical studies of the utility of LT in in early LT for AH in the United States, with at least selected patients with severe AH are needed. In one-quarter of all centers having performed at least particular, areas for investigation include processes one (but most less than five) with representation from of patient selection, monitoring alcohol use before every UNOS region, so consultation with those cen- and after LT and treatment of AUD before and ters could be considered for a minority of appropriate after LT. patients with life-threatening AH.(235,236) Guidance Statements Liver transplantation may be considered in care- AASLD APPROVAL fully selected patients with favorable psychosocial This practice guidance was approved by the profiles in severe AH not responding to medical American Association for the Study of Liver Diseases therapy. on February 21, 2019. Acknowledgments: This updated guidance was pro- SUGGESTIONS FOR FUTURE duced in collaboration with the AASLD Practice RESEARCH Guidelines Committee, which approved the scope of The following are important areas in the diagnosis the guidance and provided the peer review that was and treatment of patients with ALD for which addi- led by Patricia D. Jones, M.D., MSCR. Members of the AASLD Practice Guidelines Committee include tional research/data are needed: George Ioannou, M.D., FAASLD (Chair); Alfred 1. Studies providing the accurate assessment of the Sidney Barritt IV, M.D., MSCR; James R. Burton, Jr., prevalence of ALD, particularly identifying ear- M.D.; Udeme Ekong, M.D.; Ruben Hernaez, M.D., lier, asymptomatic stages of ALD such as ASH or MPH, Ph.D.; Whitney E. Jackson, M.D.; Binu John, 326  15273350, 2020, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30866 by INASP - NEPAL, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hepatology, Vol. 71, No. 1, 2020 CRABB ET AL. M.D., MPH; Patricia D. Jones, M.D., MSCR; Patrick 17) Sandahl TD, Jepsen P, Thomsen KL, Vilstrup H. Incidence and S. Kamath, M.D.; David G. Koch, M.D.; Lopa Mishra, mortality of alcoholic hepatitis in Denmark 1999–2008: a nation- M.D., FAASLD (Board Liaison); David J. Reich, wide population based cohort study. J Hepatol 2011;54:760-764. M.D., FACS; Barry Schlansky, M.D., MPH; Amit 18) Sahlman P, Nissinen M, Pukkala E, Färkkilä M. Incidence, survival and cause-specific mortality in alcoholic liver dis- G. Singal, M.D., M.S. (Vice-Chair); James R. Spivey, ease: a population-based cohort study. Scand J Gastroenterol M.D.; and Elizabeth C. Verna, M.D., M.S. 2016;51:961-966. 19) Alavi M, Janjua NZ, Chong M, Grebely J, Aspinall EJ, Innes H, et al. 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