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In order to understand and curb the harms related to alcohol, it will be necessary to think beyond patterns of use that meet criteria for a diagnosis of alcohol use disorder or addiction. Current research suggests that regular daily alcohol use does not confer a health benefit, and, for many persons, even relatively low consumption is associated with a health risk. Determining a safe limit for alcohol consumption is challenging both for the individual person and for society. We conclude that excessive drinking is always risky. We provide a list of circumstances, such as chronic illness, driving a vehicle, or pregnancy where persons should be advised to abstain from alcohol. We recognise the need to encourage less consumption of alcohol, particularly in young adults and older adults with co-morbid conditions (especially if taking multiple medications). Finally, we offer the modest proposal that, for persons without the contributing negative influences described above, consumption which adheres to one drink per session, with interspersed abstinent days, does not constitute a meaningful risk to health., Competing Interests: Conflict of interest Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions., (© 2024. Springer Nature Limited.)

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH., Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method., Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247)., Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39., Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51)., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Early liver transplant (LT) for alcohol-associated disease (i.e., without a specific sobriety period) is controversial but increasingly used. Using the multicenter American Consortium of Early Liver Transplantation for Alcoholic Hepatitis (ACCELERATE-AH) cohort, we aimed to develop a predictive tool to identify patients pretransplant with low risk for sustained alcohol use posttransplant to inform selection of candidates for early LT. We included consecutive ACCELERATE-AH LT recipients between 2012 and 2017. All had clinically diagnosed severe alcoholic hepatitis (AH), no prior diagnosis of liver disease or AH, and underwent LT without a specific sobriety period. Logistic and Cox regression, classification and regression trees (CARTs), and least absolute shrinkage and selection operator (LASSO) regression were used to identify variables associated with sustained alcohol use post-LT. Among 134 LT recipients for AH with median period of alcohol abstinence pre-LT of 54 days, 74% were abstinent, 16% had slips only, and 10% had sustained alcohol use after a median 1.6 (interquartile range [IQR]: 0.7-2.8) years follow-up post-LT. Four variables were associated with sustained use of alcohol post-LT, forming the Sustained Alcohol Use Post-LT (SALT) score (range: 0-11): >10 drinks per day at initial hospitalization (+4 points), multiple prior rehabilitation attempts (+4 points), prior alcohol-related legal issues (+2 points), and prior illicit substance abuse (+1 point). The C statistic was 0.76 (95% confidence interval [CI]: 0.68-0.83). A SALT score ≥5 had a 25% positive predictive value (95% CI: 10%-47%) and a SALT score of <5 had a 95% negative predictive value (95% CI: 89%-98%) for sustained alcohol use post-LT. In internal cross-validation, the average C statistic was 0.74. Conclusion: A prognostic score, the SALT score, using four objective pretransplant variables identifies candidates with AH for early LT who are at low risk for sustained alcohol use posttransplant. This tool may assist in the selection of patients with AH for early LT or in guiding risk-based interventions post-LT., (© 2018 by the American Association for the Study of Liver Diseases.)

Background & Aims: The American Consortium of Early Liver Transplantation for Alcoholic Hepatitis comprises 12 centers from 8 United Network for Organ Sharing regions studying early liver transplantation (LT) (without mandated period of sobriety) for patients with severe alcoholic hepatitis (AH). We analyzed the outcomes of these patients., Methods: We performed a retrospective study of consecutive patients with a diagnosis of severe AH and no prior diagnosis of liver disease or episodes of AH, who underwent LT before 6 months of abstinence from 2006 through 2017 at 12 centers. We collected data on baseline characteristics, psychosocial profiles, level of alcohol consumption before LT, disease course and treatment, and outcomes of LT. The interval of alcohol abstinence was defined as the time between last drink and the date of LT. The primary outcomes were survival and alcohol use after LT, defined as slip or sustained., Results: Among 147 patients with AH who received liver transplants, the median duration of abstinence before LT was 55 days; 54% received corticosteroids for AH and the patients had a median Lille score of 0.82 and a median Sodium Model for End-Stage Liver Disease score of 39. Cumulative patient survival percentages after LT were 94% at 1 year (95% confidence interval [CI], 89%-97%) and 84% at 3 years (95% CI, 75%-90%). Following hospital discharge after LT, 72% were abstinent, 18% had slips, and 11% had sustained alcohol use. The cumulative incidence of any alcohol use was 25% at 1 year (95% CI, 18%-34%) and 34% at 3 years (95% CI, 25%-44%) after LT. The cumulative incidence of sustained alcohol use was 10% at 1 year (95% CI, 6%-18%) and 17% at 3 years (95% CI, 10%-27%) after LT. In multivariable analysis, only younger age was associated with alcohol following LT (P = .01). Sustained alcohol use after LT was associated with increased risk of death (hazard ratio, 4.59; P = .01)., Conclusions: In a retrospective analysis of 147 patients who underwent early LT (before 6 months of abstinence) for severe AH, we found that most patients survive for 1 year (94%) and 3 years (84%), similar to patients receiving liver transplants for other indications. Sustained alcohol use after LT was infrequent but associated with increased mortality. Our findings support the selective use of LT as a treatment for severe AH. Prospective studies are needed to optimize selection criteria, management of patients after LT, and long-term outcomes., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol-dependent liver transplantation (LT) patients who resume alcohol consumption are at risk for a number of alcohol-related problems including liver injury and liver failure. Post-LT patients are strongly advised to remain abstinent. However, we do not know how well this population complies due to a lack of valid methods (self-report and/or biomarkers) to identify alcohol use. Studies suggest as many as 50% resume alcohol use within 5 years. Phosphatidylethanol (PEth) is a new cell-membrane phospholipid biomarker to identify alcohol use in the past 28 days. This prospective study followed 213 LT recipients at 2 U.S. liver transplant centers., Methods: Sample included 213 LT subjects; 70.9% (n = 151/213) had a history of alcohol dependence prior to transplantation and 29.1% (n = 62/213) served as non-alcohol-dependent controls. Subjects participated in face-to-face interviews to assess alcohol use using a 30-day calendar. The protocol called for collecting blood samples at baseline, 6-, and 12-month follow-up., Results: Seventy percent (149/213) who reported no alcohol use had consistently negative PEth levels (<8 ng/ml). A total of 26.4% (57/213), 44 alcohol-dependent patients and 13 controls, had a positive PEth test of >8 ng/ml either at baseline and/or during the follow-up period. Alcohol-dependent subjects (23.8%; n = 36/151) and 16.1% (n = 10/62) controls reported no alcohol use but had at least 1 positive PEth test. Of the 11.2% (24/213) post-LT subjects who reported recent alcohol use, over half (11/24) had a positive PEth. The 13 self-reported alcohol users with a negative PEth level reported insufficient drinking to trigger PEth formation., Conclusions: Adoption of PEth as part of routine posttransplant care of LT recipients will enable early identification of patients at risk of alcohol use and facilitate abstinence in patients with a history of alcohol dependence and alcohol-related liver damage., (Copyright © 2017 by the Research Society on Alcoholism.)

Objective: We investigated patterns of use of alcohol and its clinical effects among cirrhotic subjects who participated in a randomized clinical trial comparing the efficacy of transjugular intravenous portosystemic shunt and distal splenorenal shunt., Methods: There were 132 cirrhotic subjects, 78 with alcoholic liver disease (ALD), who were followed for a median of 49 months (range 2-93 months). Alcohol use was assessed by patient questionnaire, with corroboration by family members., Results: Twenty-eight subjects (21%) were drinking at study entry and 60 subjects (45%) drank during follow-up. Heavy drinking (>4 drinks/day) was recorded in 25 ALD subjects, but in no non-ALD subjects (P < 0.0001). Drinking by ALD subjects was associated with a 153% increase in gamma-glutamyl transpeptidase (GGT) (P < 0.0001). The frequencies of death (46%vs 30%), ascites (33%vs 20%), encephalopathy (56%vs 42%), and variceal bleeding (11%vs 3%) were greater in the ALD group. In a Cox proportional hazards model only "ever heavy drinking" was associated with death (P= 0.0099), while recent heavy drinking increased the hazard of variceal hemorrhage dramatically (odds ratio 10.85)., Conclusions: Whereas most cirrhotic subjects, alcoholic or not, did not drink during 5 yr of observation, heavy alcohol use occurred exclusively in ALD patients. Alcohol use by ALD subjects was associated with elevations in GGT and was linked to death and with rebleeding from shunt dysfunction.

Background: Hepatoxicity has been reported with oral naltrexone. Hepatic safety data were examined from a 6-month study evaluating the efficacy and safety of a now available extended-release formulation of naltrexone (XR-NTX) in patients with alcohol dependence., Methods: In all, 624 patients (68% male; median age of 44 years) were randomly assigned to XR-NTX 380 mg (n = 205), XR-NTX 190 mg (n = 210), or placebo (n = 209)., Results: There were no significant differences in alanine aminotransferase, aspartate aminotransferase, or bilirubin levels between the study groups at study initiation or at subsequent assessments. Gamma-glutamyltransferase in the XR-NTX 380 mg group was lower compared with placebo at weeks 4, 8, 12, and 20. Both high (>3 times the upper limit of normal) liver chemistry tests (LCTs) and hepatic-related adverse events were infrequent in all study groups. In patients who were drinking heavily throughout the study, obese subjects, or those taking nonsteroidal anti-inflammatory drugs, there was no increase in frequency of high LCTs or hepatic-related adverse events in patients receiving XR-NTX (either dose) compared with placebo., Conclusion: Extended-release formulation of naltrexone does not appear to be hepatotoxic when taken at the recommended clinical doses in actively drinking alcohol-dependent patients.

Patients with clinical acute alcoholic hepatitis (AAH) are not considered suitable candidates for orthotopic liver transplantation (OLT). The histological correlates of AAH are often seen in the explanted liver at the time of transplantation. The importance of these findings remains inconclusive regarding their role as a prognostic marker for patient or allograft health. Our aim was to examine the explanted liver of patients with purely alcoholic liver disease (ALD) for findings of histologic AAH and to correlate these to patient and graft outcomes. We compared patients with and without histological AAH with patients transplanted for non-ALD. Of 1,097 liver transplant recipients, 148 had ALD and 125 were non-ALD control patients with similar demographics. Thirty-two of 148 ALD patients had histologic AAH, and 116 had bland alcoholic cirrhosis (BAC). Twenty-eight percent of the ALD patients reported <6 months abstinence, and 54% reported <12 months abstinence. There was a statistically significant relationship between the presence of histologic AAH and abstinence durations<12 months (P=0.009), but not <6 months. Overall, posttransplantation patient and graft survival between the ALD and non-ALD groups was not significantly different (P=0.53). Furthermore, patient and graft survival between ALD patients with histologic AAH and BAC were similar (P=0.13 and P=0.11, respectively). The rate of posttransplantation relapse among ALD patients was 16%; however, there was no increase in graft loss, nor was there decreased survival compared with controls. The patients with histologic AAH and those with BAC had no differences in posttransplantation relapse (P=0.13). In multivariate analysis, patient and graft survival was not influenced by pretransplantation abstinence or posttransplantation relapse. In conclusion, histological alcoholic hepatitis in the explant did not predict worse outcome regarding relapse, and allograft or patient survival for liver transplant recipients. Caution should be exercised when liver histology is used to discriminate among suitable candidates for OLT concerning alcoholic patients., (Copyright (c) 2007 AASLD.)

Few studies have examined the value of treating alcohol addiction either before or after liver transplantation. Nevertheless, most liver transplant programs and many insurance companies require 6 months to 1 year of abstinence from alcohol as a condition of eligibility for liver transplantation (the 6-month rule). We believe there are potentially harsh clinical consequences to the implementation of this rule. For example, the natural history of alcohol use disorders often involves brief fallbacks to drinking ("slips"), but when alcoholic liver transplant candidates slip, most are removed from consideration for transplantation or are required to accrue another 6 months of sobriety. Because there is no alternative treatment to liver transplantation for most patients with end-stage liver disease, the 6-month rule could be lethal in some circumstances. In this review, we survey the literature concerning the ability of the 6-month rule to predict drinking by alcoholic patients who undergo liver transplantation and examine its impact on the health consequences of drinking before and after liver transplantation. We believe that fostering candor between the alcoholic patient and the transplant team is the key to recovery from alcoholism. We conclude that it is unethical to force alcoholic liver patients who have resumed alcohol use while waiting for or after transplantation to choose between hiding their drinking to remain suitable candidates for transplantation or risk death by asking for treatment of alcoholism. Consequently, we advocate a flexible approach to clinical decision making for the transplant professional caring for an alcoholic patient who has resumed drinking and provide specific guidelines for patient management.

Objective: Previous cross-section studies suggested that blood ethanol concentrations (BAC) increase with age. To establish this, and to account for putative gender differences, we studied four cohorts of nonalcoholic subjects., Method: Fifty-seven subjects were studied: 14 men and 14 women in the young (21-40 years) and 14 men and 15 women in the old (> or = 60 years) groups. All subjects received ethanol (0.3 g/kg) on three occasions: orally (PO) after an overnight fast; PO after a standard meal; and by intravenous (IV) infusion after a standard meal., Results: In all four cohorts, PO ethanol in the fasted state produced the greatest average areas under the curve (AUC) for ethanol, followed by IV ethanol and PO ethanol, both in the fed state. Pooled by age, blood ethanol AUCs were significantly greater in old subjects given PO ethanol when fasted (p = .001) and IV ethanol when fed (p < .004) but not after PO ethanol in the fed state. Pooled by gender, blood ethanol AUCs did not separate men and women in any of the experiments. Corrected for relative volumes of distribution (Vdist) among the four cohorts, only elderly women evidenced AUC values that could not be explained by Vdist alone and only in the fasted state. Both elderly men and women in the fasted state showed higher average peak ethanol levels than gender-matched younger cohorts; this effect was most pronounced in elderly women (47% vs 12%)., Conclusions: The data confirm the influence of age, but fail to confirm that of gender, on blood ethanol response after a moderate dose of ethanol. They also show that feeding state can negate differences due to Vdist alone. In the fasted state, Vdist alone explains AUC and peak increases in elderly men but not in elderly women. Neither gastric metabolism nor motility account for age/BAC differences since these were independent of route. These data suggest caution for elderly drinkers or for those prescribing alcoholic beverages to elderly persons as well as for studies of ethanol ingestion that do not account for age and for feeding state.

The purposes of this study were to determine among a cohort of long-term alcoholic survivors after liver transplantation (1) the incidence of alcohol use, (2) its effect on allograft integrity and extrahepatic health, and (3) the validity of the pretransplant alcohol prognosis screening process. Retrospective clinical cohort study of all alcoholic patients undergoing orthotopic liver transplantation at a single center from February 1987 until January 1991 with follow-up through December 1994, giving a median duration of follow-up of 63 months (range, 6-89 months). Multidisciplinary liver transplantation program at a tertiary-care academic medical center. Fifty alcoholic, long-term liver transplant recipients. The frequency of alcohol relapse, defined as any alcohol use in the period after transplantation, was determined by two questionnaire studies and by clinical follow-up. Allograft integrity was assessed by coded review of serial percutaneous allograft biopsies. Potential systemic effects of alcohol relapse were assessed by chart review. The alcohol prognosis screening process was evaluated by retrospectively comparing pretransplant estimates of putative indicators of alcoholism prognosis in posttransplant alcohol users and abstainers. Thirty-three recipients (66%) consistently denied any alcohol use throughout the duration of posttransplant follow-up, whereas 17 (34%) were identified as having consumed alcohol at least once since the transplant. There were no significant differences at the time of evaluation between abstainers and alcohol users in age, sex distribution, severity of liver dysfunction, median duration of abstinence, or University of Michigan alcoholism prognosis score. The median interval from transplantation to alcohol relapse was 17 months, with a range of 3 to 45 months. Recurrent alcohol use was associated with significant medical complications sufficient to require admission to the hospital in 6 patients. One patient died of graft dysfunction, noncompliance with immunosuppressant medications, and presumed graft rejection while drinking. Mild or progressive hepatitis, which was the most common abnormality in posttransplant liver biopsy findings, was equally distributed between both alcohol users and abstainers and sometimes occurred in the absence of antibody to hepatitis C virus antibodies. There was a similar frequency of biopsy-proven acute cellular rejection in alcohol users and abstainers. Typical histological features of alcoholic liver injury were present in posttransplant biopsies from 1 alcohol user only. Alcohol use by alcoholics is uncommon in the first 5 years after liver transplantation, and alcohol-associated liver injury is unusual. Mild nonspecific hepatitis is common in both alcohol users and nonusers alike. Among a small subset of alcoholic transplant recipients, drinking behavior after liver transplantation is associated with considerable morbidity, requiring hospital admissions and occasionally leading to graft loss and death.

The effect of alcohol intoxication on regional cerebral blood flow (rCBF) is unclear. The few published studies provide a mixed picture of alcohol effects, suggesting that blood flow increases at low doses and decreases at higher doses of alcohol. Using the cerebral blood flow agent 99mtechnetium hexamethyl-propylene-amine-oxime (HMPAO) and image reconstruction with single photon emission computed tomography (SPECT), we evaluated the effect of an oral dose of ethanol (0.6 g/kg) on rCBF in two age-stratified groups of healthy, nonalcoholic men (12 age 22-37 and 12 age 63-77). Intoxication was associated with a significant 4% increase in global cortical CBF (t = 2.54, p = 0.02). Changes in HMPAO uptake were negatively correlated to ethanol levels in the entire group (r = -0.47, p = 0.04). This relationship was seen in the older subgroup (r = -0.70, p = 0.05), but not in the younger group (r = -0.34, p = 0.26). In contrast, the younger group showed a significant positive correlation between rCBF and increases in acetate levels (r = 0.71, p < 0.01), which was not seen in the older group (r = -0.02, p = 0.96). These findings suggest that both acetate and alcohol contribute to the changes in CBF seen in the intoxication syndrome and that their relative influence is age-dependent.