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Background and Aims: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model., Approach and Results: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts., Conclusions: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ ., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Liver transplantation (LT) for alcohol-associated hepatitis (AH) remains controversial due to concerns about candidate selection subjectivity, post-LT alcohol relapse, and the potential exacerbation of LT disparities. Our aim was to design, perform, and examine the results of a simulated selection of candidates for LT for AH. Medical histories, psychosocial profiles and scores, and outcomes of 4 simulation candidates were presented and discussed at 2 multidisciplinary societal conferences with real-time polling of participant responses. Candidate psychosocial profiles represented a wide spectrum of alcohol relapse risk. The predictive accuracy of four psychosocial scores, Dallas consensus criteria, sustained alcohol use post-LT, Stanford Integrated Psychosocial Assessment for Transplant, and QuickTrans, were assessed. Overall, 68 providers, mostly academic transplant hepatologists, participated in the simulation. Using a democratic process of selection, a significant majority from both simulations voted to accept the lowest psychosocial risk candidate for LT (72% and 85%) and decline the highest risk candidate (78% and 90%). For the 2 borderline-risk candidates, a narrower majority voted to decline (56% and 65%; 64% and 82%). Two out of 4 patients had post-LT relapse. Predictive accuracies of Dallas, Stanford Integrated Psychosocial Assessment for Transplant, and Quicktrans scores were 50%, while sustained alcohol use post-LT was 25%. The majority of voting outcomes were concordant with post-LT relapse in 3 out of 4 patients. When defining "success" in LT for AH, providers prioritized allograft health and quality of life rather than strict abstinence. In this simulation of LT for AH using a democratic process of selection, we demonstrate its potential as a learning model to evaluate the accuracy of psychosocial scores in predicting post-LT relapse and the concordance of majority voting with post-LT outcomes. Provider definitions of "success" in LT for AH have shifted toward patient-centered outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Alcohol-associated liver disease due to harmful alcohol use and NAFLD associated with metabolic syndrome are the 2 most common liver diseases worldwide. Control of respective risk factors is the cornerstone in the long-term management of these diseases. Furthermore, there are no effective therapies. Both diseases are characterized by metabolic derangements; thus, the focus of this review was to broaden our understanding of metabolic targets investigated in NAFLD, and how these can be applied to alcohol-associated liver disease. Conserved pathogenic pathways such as dysregulated lipid metabolism, cell death pathways including apoptosis and activation of innate immune cells, and stellate cells mediate both alcohol and NAFLDs, resulting in histological abnormalities of steatosis, inflammation, fibrosis, and cirrhosis. However, pathways such as gut microbiome changes, glucose metabolism and insulin resistance, inflammatory signaling, and microRNA abnormalities are distinct in these 2 diseases. In this review article, we describe conserved and distinct pathogenic pathways highlighting therapeutic targets that may be of potential in both diseases and those that are unique to each disease., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Data on the liver transplant (LT) outcomes of women with acute liver failure (ALF) due to liver diseases unique to pregnancy (P-ALF) are limited. Using United Network of Organ Sharing (UNOS) data (1987-2021), we analyzed waitlist and post-LT outcomes of ALF in women of childbearing age comparing P-ALF versus ALF due to liver diseases not unique to pregnancy. Baseline characteristics were compared between groups at the time of listing for LT. Of 3542 females aged 16-43 years and listed for LT for ALF, 84 (2%) listed for P-ALF were less likely to be Black (11 vs. 21%, p =0.033), have lower international normalized ratio (2.74 vs. 4.53 p <0.002), but more likely to have respiratory failure (56% vs. 41%, p <0.005), be on pressors (58% vs. 43%, p <0.005), and require dialysis (23% vs. 10%, p <0.001). The cumulative 90-day waitlist mortality (WLM) was lower in P-ALF vs. ALF due to liver diseases not unique to pregnancy (7.4 vs. 16.6%, p <0.001). Posttransplant survival rates at 5 years were similar (82% vs. 79%, p =0.89). In a Fine and Gray regression model controlled for listing year and Model for End-Stage Liver Disease score, 90-day WLM was lower in P-ALF with a sub-HR of 0.42 (95% CI: 0.19-0.94, p =0.035). Of 84 women with P-ALF and listed for LT, 45 listed for hemolysis-elevated liver enzymes-low platelets (HELLP) versus 39 for acute fatty liver of pregnancy had higher 90-day WLM (19.3% vs. 5.7% p <0.005). The 90-day WLM was about 10-fold higher in HELLP versus acute fatty liver of pregnancy with a sub-HR of 9.97 (95% CI: 1.64-60.55, p =0.013). In this UNOS database analysis of ALF among women of childbearing age, the waitlist outcome is better in women with P-ALF compared to women with ALF due to liver diseases not unique to pregnancy. Among women with P-ALF, the 90-day WLM is worse for HELLP versus acute fatty liver of pregnancy. Further studies are needed to improve the management of HELLP and prevent the development of ALF in this subgroup population., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: The precision of clinical criteria and the utility of liver biopsy for diagnosis or prognosis remain unclear in patients with alcohol-associated hepatitis (AH). We systematically reviewed the literature to answer these questions., Methods: Four databases were searched for studies describing the precision of clinical criteria (National Institute on Alcohol Abuse and Alcoholism, European Association for Study of Liver, or classical) and the role of histology in AH. The precision(positive predictive value) of criteria was pooled through random-effects meta-analysis, and its variation was investigated through subgroups and meta-regression of study-level factors with their percent contribution to variation (R2). The risk of bias among studies was evaluated through the QUADAS2 tool (PROSPERO-ID-CRD4203457250)., Results: Of 4320 studies, 18 in the systematic review and 15 (10/5: low/high risk of bias, N=1639) were included in the meta-analysis. The pooled precision of clinical criteria was 80.2% (95% CI: 69.7-89.7, I2:93%, p < 0.01), higher in studies with severe AH (mean-Model for End-Stage Liver Disease > 20) versus moderate AH (mean-Model for End-Stage Liver Disease < 20): 92% versus 67.1%, p < 0.01, and in studies with serum bilirubin cutoff 5 versus 3 mg/dL (88.5% vs.78.8%, p = 0.01). The factors contributing to variation in precision were Model for End-Stage Liver Disease (R2:72.7%), upper gastrointestinal bleed (R2:56.3%), aspartate aminotransferase:aspartate aminotransferase ratio (R2:100%), clinical criteria (R2:40.9%), bilirubin (R2:22.5%), and Mallory body on histology (R2:19.1%).The net inter-pathologist agreement for histologic findings of AH was variable (0.33-0.97), best among 2 studies describing AH through simple and uniform criteria, including steatosis, ballooning, and neutrophilic inflammation. Few studies reported the utility of histology in estimating steroid responsiveness (N = 1) and patient prognosis (N = 4); however, very broad septa, pericellular fibrosis, and cholestasis were associated with mortality. Bilirubinostasis was associated with infection in 1 study., Conclusions: Clinical criteria are reasonably precise for diagnosing severe AH, while there is an unmet need for better criteria for diagnosing moderate AH. Histologic diagnosis of AH should be simple and uniform., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Alcohol-associated liver disease (ALD) has emerged as the leading indication for liver transplantation (LT) worldwide, with 40% of LTs in the United States performed for ALD in 2019. The ALD-related health care burden accelerated during the COVID-19 pandemic, especially in young individuals. Alcohol use disorder (AUD), which focuses on the negative effects of alcohol on psychosocial, physical, and mental health, is present in the majority of patients with ALD, with moderate to severe AUD in 75%-80%. During the last decade, early liver transplantation (eLT) has emerged as a lifesaving treatment for selected patients with alcohol-associated hepatitis; these patients may have a higher risk of using alcohol after LT. The risk of alcohol use recurrence may be reduced during the pretransplant or post-transplant period with AUD treatment using behavioral and/or pharmacological therapies and with regular monitoring for alcohol use (self-reported and complemented with biomarkers like phosphatidylethanol). However, AUD treatment in patients with ALD is challenging due to patient, clinician, and system barriers. An integrated model to provide AUD and ALD care by hepatologists and addiction experts in a colocated clinic starting from LT evaluation and selection to monitoring listed candidates and then to following up on recipients of LT should be promoted. However, the integration of addiction and hepatology teams in an LT program in the real world is often present only during evaluation and candidate selection for LT. Data are emerging to show that a multidisciplinary integrated AUD treatment within an LT program reduces recurrent alcohol use after LT. If we want to continue using early liver transplantation for patients with severe alcohol-associated hepatitis, LT programs should focus on building integrated multidisciplinary care teams for the integrated treatment of both AUD and ALD., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Competing Interests: Ashwani K. Singal consults and is on the speakers’ bureau for CLD Foundation. He consults for Pleiogenix. He advises DURECT and MTP; is on the speakers’ bureau of Medscape and received royalties from Up-to-Date. The remaining author has no conflicts to report.

Objectives: Management of alcohol use disorder (AUD) is rarely used in patients with liver disease. We performed a systematic review to examine the impact of AUD management among patients with liver disease., Methods: Twenty studies fulfilling the inclusion and exclusion criteria on 38,329 patients (7072 receiving AUD intervention) with liver disease (15 with liver disease and 6 liver transplant [LT] recipients) were analyzed. One study was common to both groups. Variable follow-up period across studies was weighted for sample size and converting to person-years. Primary outcome was alcohol use, and secondary outcomes were liver decompensation and patient mortality., Results: Abstinence and alcohol relapse rates/person-year with AUD intervention among liver disease patients were 0.41 (0.27-0.55) and 0.42 (0.30-0.755), similar for integrated (colocated liver and addiction clinics) versus concomitant (separate hepatology and addiction clinics) intervention. Compared with standard of care, odds for decompensation with AUD intervention (n = 1), 30-day readmission (n = 1), and patient mortality (n = 2) were lower by 44%, 59%, and 58% respectively. Similar figures were 1.24 (0.86-1.80) for abstinence and 0.52 (0.24-0.14) for relapse. Among LT recipients, odds for alcohol relapse and mortality with follow-up integrated with addiction team versus hepatology alone were 0.48 (0.25-0.72) and 0.29 (0.08-0.99), respectively., Conclusions: Follow-up of LT recipients in an integrated clinic with addiction team is associated with improved outcomes. Simultaneous management of AUD in patients with liver disease improves liver-related outcomes. Large prospective studies are needed to examine benefits of AUD intervention in patients with liver disease., Competing Interests: LL reports honoraria from the UK Medical Council on Alcoholism (editor-in-chief for Alcohol and Alcoholism) and book royalties from Routledge outside the submitted work. AKS reports outside the submitted work personal fees from Gilead, Medscape Gastroenterology, Chronic Liver Disease Foundation, UpToDate, and ACG; nonfinancial support from American Association for the Study of Liver Diseases and American Porphyria Foundation; and grants from National Institute on Alcohol Abuse and Alcoholism and National Institute of Diabetes and Digestive and Kidney Diseases outside the submitted work. MAE and MA report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Patients with preexisting chronic liver disease (CLD) may experience a substantial burden from both coronavirus 2019 (COVID-19) infection and pandemic-related life disruption. We assessed the impact of the COVID-19 pandemic on patients with CLD. Patients enrolled in our Global Liver Registry were invited to complete a COVID-19 survey. As of June 2021, 2500 patients (mean age ± SD, 49 ± 13 years; 53% men) from seven countries completed the survey. Of all survey completers, 9.3% had COVID-19. Of these patients, 19% were hospitalized, 13% needed oxygen support, but none required mechanical ventilation. Of all patients including those not infected with COVID-19, 11.3% reported that the pandemic had an impact on their liver disease, with 73% of those reporting delays in follow-up care. The Life Disruption Event Perception questionnaire confirmed worsening in at least one area (food/nutrition, exercise, social life, vocation/education, financial situation, housing, or health care) in 81% and 69% of patients with and without a history of COVID-19, respectively (p = 0.0001). On a self-assessed Likert health score scale (range, 1-10; 10 indicates perfect health), patients with a COVID-19 history scored lower (mean ± SD, 6.7 ± 2.2 vs. 7.4 ± 2.2, respectively; p < 0.0001) despite reporting similar health scores if there was no pandemic (mean ± SD, 8.5 ± 1.4 vs. 8.4 ± 1.6, respectively; p = 0.59). After adjustment for country of enrollment, liver disease etiology and severity, age, sex, body mass index, diabetes, and history of psychiatric comorbidities, COVID-19 was found to be independently associated with lower self-assessed health scores (beta = -0.71 ± 0.14; p < 0.0001). The COVID-19 pandemic resulted in a substantial burden on the daily life of patients with CLD., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD., (© 2021 American Association for the Study of Liver Diseases.)

Background and Aims: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality in Latin America, yet the impact of public health policies (PHP) on liver disease is unknown. We aimed to assess the association between alcohol PHP and deaths due to ALD in Latin American countries., Approach and Results: We performed an ecological multinational study including 20 countries in Latin America (628,466,088 inhabitants). We obtained country-level sociodemographic information from the World Bank Open Data source. Alcohol-related PHP data for countries were obtained from the World Health Organization Global Information System of Alcohol and Health. We constructed generalized linear models to assess the association between the number of PHP (in 2010) and health outcomes (in 2016). In Latin America, the prevalence of obesity was 27% and 26.1% among male and female populations, respectively. The estimated alcohol per capita consumption among the population at 15 years old or older was 6.8 L of pure alcohol (5.6 recorded and 1.2 unrecorded). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of male and 40.0% of female populations. A total of 19 (95%) countries have at least one alcohol-related PHP on alcohol. The most frequent PHP were limiting drinking age (95%), tax regulations (90%), drunk-driving policies and countermeasures (90%), and government monitoring systems and community support (90%). A higher number of PHP was associated with a lower ALD mortality (PR, 0.76; 95% CI, 0.61-0.93; P = 0.009), lower AUD prevalence (PR, 0.80; 95% CI, 0.65-0.99; P = 0.045), and lower alcohol-attributable road traffic deaths (PR, 0.81; 95% CI, 0.65-1.00; P = 0.051)., Conclusions: Our study indicates that in Latin America, countries with higher number of PHP have lower mortality due to ALD, lower prevalence of AUD, and lower alcohol-attributable road traffic mortality., (© 2021 by the American Association for the Study of Liver Diseases.)

The Coronavirus Disease 2019 (COVID-19) pandemic has exacted a heavy toll on patients with alcohol-associated liver disease (ALD) and alcohol use disorder (AUD). The collective burden of ALD and AUD was large and growing, even before the COVID-19 pandemic. There is accumulating evidence that this pandemic has had a large direct effect on these patients and is likely to produce indirect effects through delays in care, psychological strain, and increased alcohol use. Now a year into the pandemic, it is important that clinicians fully understand the effects of the COVID-19 pandemic on patients with ALD and AUD. To fill existing gaps in knowledge, the scientific community must set research priorities for patients with ALD regarding their risk of COVID-19, prevention/treatment of COVID-19, changes in alcohol use during the pandemic, best use of AUD treatments in the COVID-19 era, and downstream effects of this pandemic on ALD. Conclusion: The COVID-19 pandemic has already inflicted disproportionate harms on patients with ALD, and ongoing, focused research efforts will be critical to better understand the direct and collateral effects of this pandemic on ALD., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States., Approach and Results: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months., Conclusion: In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population., Approach and Results: We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P < 0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P < 0.001), whereas HCV-ACLF declined by 45.2% (P < 0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (β = 0.90; P = 0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR] = 1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR = 1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3., Conclusions: NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality., (© 2020 by the American Association for the Study of Liver Diseases.)

Goals: The goals of this study were to evaluate trends in hospitalizations and in-hospital mortality among US adults with alcohol-associated cirrhosis and alcoholic hepatitis., Background: Alcohol-associated liver disease contributes to significant liver-related morbidity in the United States, among which inpatient care is a major driver of clinical and economic burden., Methods: Using the 2007-2014 National Inpatient Sample, alcohol-associated cirrhosis and alcoholic hepatitis hospitalizations were identified. Survey-weighted annual hospitalization trends were stratified by sex, race/ethnicity, and age and compared using χ2 and Student's t-test methods. Adjusted multivariate logistic regression models evaluated predictors of in-hospital mortality., Results: Among 159,973 alcohol-associated liver disease hospitalizations, 83.7% had a primary diagnosis of alcohol-associated cirrhosis and 18.4% had a primary diagnosis of alcoholic hepatitis. Sex-specific differences in hospitalizations emerged, with significantly higher hospitalization rates seen in males versus females among both alcoholic hepatitis [incidence rate ratio=3.71, 95% confidence interval (CI): 3.47-4.01, P<0.01] and alcohol-associated cirrhosis (incidence rate ratio=2.68, 95% CI: 2.21-3.71, P<0.01). Differences in hospitalization and mortality by ethnicity were observed for both alcohol-associated cirrhosis and alcoholic hepatitis. African Americans with alcohol-associated cirrhosis had significantly higher in-hospital mortality compared with non-Hispanic whites [odds ratio (OR)=1.13, 95% CI: 1.04-1.24, P<0.01], whereas Native Americans (OR=1.88, 95% CI: 1.06-3.34, P=0.030) and Asian/Pacific Islanders (OR=2.02, 95% CI: 1.00-4.06, P=0.048) with alcoholic hepatitis had significantly higher in-hospital mortality compared with non-Hispanic whites., Conclusions: This study demonstrated increasing alcohol-associated cirrhosis and alcoholic hepatitis hospitalizations in the United States. The highest rates were observed in men and among Native American and Hispanic ethnic minorities. Significant ethnicity-specific disparities in mortality were observed., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Data on prevalence and profile of nonalcoholic fatty liver disease (NAFLD) among individuals who are lean (normal body mass index) is unclear. Published data from studies comparing lean with obese NAFLD or with healthy subjects on prevalence, comorbidities, liver chemistry and histology, and metabolic/inflammatory markers were analyzed. Data were reported as odds ratio and 95% confidence interval for categorical variables and difference of means for continuous variables. Analysis of 53 studies on 65,029 subjects with NAFLD (38,084 lean) and 249,544 healthy subjects showed a prevalence of lean NAFLD at 11.2% in the general population. Among individuals with NAFLD, the prevalence of lean NAFLD was 25.3%. Lean NAFLD versus healthy subjects had higher odds for abnormalities on metabolic profile, including metabolic syndrome and its components, renal and liver function, and patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) G allele; and inflammatory profile, including uric acid and C-reactive protein. The abnormalities were less severe among lean versus obese NAFLD on metabolic syndrome with its components, renal and liver chemistry, liver stiffness measurement, PNPLA3 and transmembrane 6 superfamily member 2 polymorphisms, and uric acid levels as markers of inflammation. Lean NAFLD had less severe histologic findings, including hepatocyte ballooning, lobular inflammation, NAFLD activity score, and fibrosis stage. Limited data also showed worse outcomes between obese versus lean NAFLD. Conclusion: Lean NAFLD is a distinct entity with metabolic, biochemical, and inflammatory abnormalities compared to healthy subjects and a more favorable profile, including liver histology of steatohepatitis and fibrosis stage, compared to obese NAFLD. We suggest that prospective multicenter studies examine long-term hepatic and extrahepatic outcomes in individuals with lean NAFLD., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals Inc., on behalf of American Association forthe Study of Liver Diseases.)

Morbid obesity is considered a relative contraindication for liver transplantation (LT). We investigated if body mass index (BMI; lean versus obese) is a risk factor for post-LT graft and overall survival in nonalcoholic steatohepatitis (NASH) and non-NASH patients. Using the United Network for Organ Sharing (UNOS) database, LT recipients from January 2002 to June 2013 (age ≥18 years) with follow-up until 2017 were included. The association of BMI categories calculated at LT with graft and overall survival after LT were examined. After adjusting for confounders, all obesity cohorts (overweight and class 1, class 2, and class 3 obesity) among LT recipients for NASH had significantly reduced risk of graft and patient loss at 10 years of follow-up compared with the lean BMI cohort. In contrast, the non-NASH group of LT recipients had no increased risk for graft and patient loss for overweight, class 1, and class 2 obesity groups but had significantly increased risk for graft (P < 0.001) and patient loss (P = 0.005) in the class 3 obesity group. In this retrospective analysis of the UNOS database, adult recipients selected for first LT and NASH patients with the lowest BMI have the worse longterm graft and patient survival as opposed to non-NASH patients where the survival was worse with higher BMI., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Acute-on-chronic liver failure (ACLF) is characterized by multiple organ failure (OF) with high short-term mortality. There is lack of population-based data on trends on etiology specific ACLF related burden. National Inpatient Sample (2006-2014) was queried using ICD-09 codes for admissions with cirrhosis and ACLF (≥2 extrahepatic OF). Of 1,928,764 admissions for cirrhosis between 2006 and 2014, 112,174 (5.9%) had ACLF (4.5%, 1.2%, and 0.2% with ACLF 1, 2, and 3, respectively). The brain was the most common OF in 11.9%, followed by respiratory failure in 7.7%, cardiac failure in 6.3%, and renal failure in 5.6%. ACLF increased by 24% between 2006 and 2014 with a 63% increase in 179,104 patients with nonalcoholic steatohepatitis (NASH) cirrhosis (3.5% to 5.7%); a 28% increase in patients with 429,306 alcoholic cirrhosis (5.6% to 7.2%); a 25% increase in patients with 1,091,053 with other etiologies (5.2% to 6.5%); and no significant change in 229,301 patients with viral hepatitis (VH) (4.0% to 4.1%). In-hospital mortality was higher among ACLF patients compared with patients without ACLF (44% versus 4.7%; P < 0.0001). Each NASH-related ACLF patient compared with other etiologies had a longer mean length of stay (14 versus 12 days), was associated with higher median total charges (US $151,196 versus US $134,597), and had more frequent use of dialysis (45% versus 36%) and longterm care (32% versus 26%; P < 0.0001 for all). Results remained similar in a subgroup analysis after including half of admissions with cryptogenic cirrhosis as NASH. In conclusion, NASH cirrhosis is the most rapidly growing indication for ACLF-related hospitalization and use of hospital resources. In the setting of improved treatment options for chronic hepatitis, the health care burden of chronic viral-related liver disease remains stable. Population-based strategies are needed to reduce the health care burden of cirrhosis, particularly related to NASH., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on post-LT outcomes in recipients with NASH. From the United Network for Organ Sharing-Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m 2 at the time of LT and/or received dialysis within 2 weeks preceding LT (n = 937); group 2 with recipients who had eGFR ≥30 mL/minute/1.73 m 2 and who did not receive renal replacement therapy prior to LT (n = 2812); and group 3 with recipients who underwent simultaneous liver-kidney transplantation (n = 339). We examined the association of pretransplant renal dysfunction with death with a functioning graft, all-cause mortality, and graft loss using competing risk regression and Cox proportional hazards models. The mean ± standard deviation age of the cohort at baseline was 58 ± 8 years, 55% were male, 80% were Caucasian, and average exception Model for End-Stage Liver Disease score was 24 ± 9. The median follow-up period was 5 years (median, 1816 days; interquartile range, 1090-2723 days). Compared with group 1 recipients, group 2 recipients had 19% reduced trend for risk for death with a functioning graft (subhazard ratio [SHR], 0.81; 95% confidence interval [CI], 0.64-1.02) and similar risk for graft loss (SHR, 1.25; 95% CI, 0.59-2.62), whereas group 3 recipients had similar risk for death with a functioning graft (SHR, 1.23; 95% CI, 0.96-1.57) and graft loss (SHR, 0.18; 95% CI, 0.02-1.37) using an adjusted competing risk regression model. In conclusion, recipients with preserved renal function before LT showed a trend toward lower risk of death with a functioning graft compared with SLKT recipients and those with pretransplant severe renal dysfunction in patients with NASH., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease is an increasingly prevalent condition, and its more severe progressive state, nonalcoholic steatohepatitis (NASH), is currently the second most common indication for wait-listed adults in the United States. The association of portal vein thrombosis (PVT) prior to or at transplant and poor graft and patient outcomes is not well established, particularly among NASH patients who inherently have an increased hypercoagulable profile. Using the United Network for Organ Sharing data set, we analyzed graft and patient outcomes of patients transplanted for the indication of NASH with and without PVT. Of 3689 NASH transplant recipients, the prevalence of PVT was 12% (450 with PVT and 3239 without PVT). NASH transplant recipients with PVT had inferior graft and patient survival compared with NASH transplant recipients without PVT, even after adjusting for recipient and donor demographic characteristics, body mass index, synthetic dysfunction, and presence of diabetes. In a multivariate Cox regression model, NASH transplant recipients with PVT had a 37% increased risk of graft failure (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.15-1.63; P < 0.001) and 31% increased risk of overall death (HR, 1.31; 95% CI, 1.09-1.58; P < 0.001) compared with NASH transplant recipients without PVT at transplant. This difference in graft and patient survival was most pronounced in the early posttransplant period. These results demonstrate that NASH patients with PVT have decreased graft and patient survival independent of recipient and donor factors., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a multicentric prospective cohort study using data from 4 different cohorts on well-characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End-Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score <3), moderate (3-4), and high (>4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90-day survival (53% versus 77%; P < 0.001). Those with AKI risk score of >4 had significantly lower 90-day survival as compared with those with risk scores between 3 and 4 and <3 (47% versus 68% versus 88%; P < 0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short-term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Background: Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Different pharmacological therapies have variable efficacy. We performed a systematic review and meta-analysis to compare the efficacy of various drugs in the treatment of HRS., Study: Randomized controlled trials comparing active drug with placebo or comparing 2 different drugs were included in this analysis. Primary study outcome was reversal of HRS. Secondary outcomes were HRS relapse and patient survival. Subgroup analysis was performed on patients with type 1 HRS., Results: Thirteen randomized controlled trial were eligible for analysis. Terlipressin plus albumin was more efficacious than placebo plus albumin (odds ratio=4.72; 95% confidence interval, 1.72-12.93; P=0.003) or midodrine plus albumin and octreotide (odds ratio=5.94; 95% confidence interval, 1.69-20.85; P=0.005), for HRS reversal. However, no significant difference was noted comparing terlipressin plus albumin versus noradrenaline plus albumin, octreotide plus albumin versus placebo plus albumin or noradrenaline plus albumin versus midodrine plus albumin and octreotide. None of the comparisons showed difference on HRS relapse or patient survival. Subgroup analysis revealed that terlipressin was more effective than placebo for type 1 HRS reversal, but no significant differences were noted between any other comparisons, and none of the comparisons showed difference on HRS relapse or patient survival., Conclusions: Intravenous infusion of terlipressin is the most effective medical therapy for reversing HRS. Intravenous infusion of noradrenaline is an acceptable alternative. Studies are needed as basis for developing pharmacological strategies to reduce relapse of HRS and improve patient survival.

Background and Aim: Data are scanty on allocating simultaneous liver kidney (SLK) based on model for end-stage disease (MELD) score. Diabetes mellitus (DM) and hypertension (HTN) are frequent in cirrhosis patients. We analyzed transplant recipients with DM and/or HTN to compare MELD-based outcomes of SLK to liver transplantation alone (LTA)., Materials and Methods: Of 13,584 first deceased donor liver transplantation among patients with DM and/or HTN (1530 or 11.2% SLK), MELD score predicted SLK [1.02 (1.01-1.03)]. SLK was beneficial for 5-year patient survival at MELD score ≥43 (78.6% vs. 62.6%, P=0.017), but not at MELD score <29 (74.8% vs. 76.2%, P=0.63). Among 11,405 recipients (976 SLK) at MELD score <29, SLK (n=816) was beneficial compared with 706 LTA [75% vs. 64%, P<0.001; 0.71 (0.55-0.91)] at serum creatinine (SC) ≥2 but not at SC<2 [73% vs. 76%, P=0.32; 0.85 (0.60-1.2)]. Among patients with MELD score 29 to 42, SLK (n=484) and LTA (n=1403) had similar survival [69% vs. 69%, P=0.58; 0.9 (0.7-1.5)]. Among patients with MELD score ≥43, SLK (n=70) was associated with 35% improved patient survival at 5 years compared with 222 LTA [0.65 (0.46-0.93)]., Conclusions: Among patients with DM and/or HTN, SLK is useful at: (a) MELD score <29 and SC≥2 and (b) MELD score ≥43. Prospective studies are needed to confirm these findings as basis to optimize use of SLK.

Unlabelled: Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoporphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure., Conclusion: This article provides an overview of porphyria with diagnostic approaches and management strategies for specific porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management., (© 2014 by the American Association for the Study of Liver Diseases.)

Background and Aim: Data on outcome of patients after liver transplantation (LT) for cirrhosis due to hepatitis C virus (HCV+) alcohol are limited., Methods and Results: Analysis from United Network for Organ sharing data set (1991 to 2010) for cirrhotics with first LT for HCV (group I, N=17,722), alcohol or alcoholic cirrhosis (AC; group II, N=9617), and alcohol+HCV (group III, N=6822). Five-year graft and patient survival for group III were similar to group I (73% vs. 69%; P=0.33 and 76% vs. 76%; P=0.87) and worse than group II (70% vs. 74%; P<0.0001 and 76% vs. 79%; P<0.0001). Cox regression analysis adjusted for recipient and donor characteristics showed (a) graft survival for group III similar to group I [hazard ratio (HR) 1.03 (95% confidence interval (CI), 0.97-1.09)] and worse than group II [HR 1.27 (95% CI, 1.19-1.35)] and (b) patient survival for group III worse than both groups I [HR 1.09 (95% CI, 1.02-1.15)] and II [HR 1.27 (95% CI, 1.19-1.36)]. In group III, graft failure was common for graft and patient loss and de novo malignancy more common compared with group I., Conclusions: Patients undergoing LT for cirrhosis due to combined alcohol and HCV have (a) graft survival similar to patients with HCV cirrhosis and worse than AC and (b) worse patient survival compared with AC and HCV cirrhosis. Better strategies for anti-HCV treatment and screening for tumors are needed for patients undergoing LT for combined alcohol and HCV.

Objectives: Hepatocellular carcinoma (HCC) is a common complication among patients with cirrhosis. Data are limited on the impact of HCC on in-hospital mortality from acute variceal hemorrhage (AVH) in patients with cirrhosis., Methods: National in-hospital sample (1998 to 2007) was used to analyze admissions with AVH in cirrhotics to study impact of concomitant HCC on the in-hospital mortality., Results: Of 27,442 admissions with cirrhosis and AVH, 540 had HCC. Admissions with HCC differed from those without HCC for age, sex, race, hospital characteristics, and complications of cirrhosis. A total of 2633 (9.6%) patients died during average hospital stay of 6 days with higher in-hospital mortality among admissions with HCC compared with without HCC (19% vs. 9%; P<0.0001). On logistic regression analysis, in-hospital mortality decreased by about 9%/y during 1998 to 2007 [odds ratio, 0.91 (95% confidence interval, 0.89-0.92)]. Receipt of endoscopic treatment was associated with reduced in-hospital mortality. After adjusting for all variables including calendar year and endoscopic treatment, HCC independently predicted in-hospital mortality from AVH: odds ratio, 2.15 (95% confidence interval, 1.67-2.77). Logistic regression model using clinically important variables predicted in-hospital mortality with area under the receiver operating characteristics of 0.80 with strong predictors being presence of HCC, hepatorenal syndrome, hypovolemic shock, sepsis, portosystemic encephalopathy, and use of Sengstaken Blakemore tube., Conclusions: HCC predicts in-hospital mortality from AVH in patients with cirrhosis. Studies are needed to examine and understand mechanisms of these findings to further develop better modalities of management of AVH in patients with cirrhosis and HCC.

Unlabelled: Data on liver transplantation for patients with alcoholic hepatitis are limited. Using the United Network for Organ Sharing database (2004-2010), adults undergoing liver transplantation for a listing diagnosis of alcoholic hepatitis were matched for age, gender, ethnicity, and model for endstage disease (MELD) score, donor risk index, and year of transplantation with three patients transplanted for a listing diagnosis of alcoholic cirrhosis. Study outcomes of graft and patient survival on follow-up were also analyzed for cohorts based on the diagnosis of the explant (46 alcoholic hepatitis and 138 alcoholic cirrhosis) and diagnosis at both listing as well as of the explant (11 alcoholic hepatitis and 33 alcoholic cirrhosis). Five-year graft and patient survival of alcoholic hepatitis and alcoholic cirrhosis patients were 75% and 73% (P = 0.97) and 80% and 78% (P = 0.90), respectively. Five-year graft and patient survival rates were also similar for cohorts based on diagnosis of the explant and diagnosis at listing as well as explant. Cox proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease (alcoholic hepatitis versus alcoholic cirrhosis) on the graft and patient survival. The causes of graft loss and patient mortality were similar in the two groups, and were not alcohol-related in any patient., Conclusion: Compared with alcoholic cirrhosis, patients with alcoholic hepatitis have similar posttransplantation graft and patient survival. Based on these preliminary findings, liver transplantation may be considered in a select group of patients with alcoholic hepatitis who fail to improve with medical therapy. Prospective studies are needed to assess the long-term outcome after liver transplantation in patients with alcoholic hepatitis., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background and Aims: Current treatment for genotype (GT) 2 or 3 hepatitis C virus infection is pegylated interferon and ribavirin (RBV) 800 mg/d for 24 weeks. This meta-analysis was carried out to assess whether the treatment duration can be reduced in patients with rapid virologic response (RVR) METHODS: Literature was searched for studies comparing short-term (12 to 16 wk) and 24 weeks treatment in GT 2 or 3 with RVR., Results: Six studies (n=2434) were included and data on end-of-treatment response (ETR), sustained virologic response (SVR), and relapse rates (RR) were obtained. Pooled odds ratio (95% CI) for SVR and RR were 0.54 (0.35-0.85; P=0.008) and 3.12 (1.99-4.91; P<0.00001) favoring 24 weeks of treatment. Reducing treatment duration to 12 to 16 weeks and retreating relapses for 24 weeks was cost-effective., Conclusions: Reducing treatment duration to 12 to 16 weeks for GT 2 or 3 HCV patients with RVR is associated with a lower SVR and a higher RR. Advantages of short-term treatment include better patient compliance, lower rate of adverse effects, and cost. Short-term treatment may be an option for patients unable to tolerate treatment. Further studies are needed to identify factors predicting relapse with short-term treatment in GT 2 or 3 patients with RVR.

Recurrent venous thrombosis following liver transplantation for Budd-Chiari syndrome is common, particularly in the setting of an underlying myeloproliferative disorder. We describe a patient who developed refractory ascites due to portal vein thrombosis following liver transplantation for Budd-Chiari syndrome in the setting of paroxysmal nocturnal hemoglobinuria. Extensive portal vein thrombosis, dense abdominal adhesions, and portosystemic collaterals precluded the use of a transjugular intrahepatic portosystemic shunt or surgical portosystemic shunt to manage the patient's ascites. Splenic artery embolization to decrease portal hypertension was performed, and this resulted in complete resolution of ascites. This case demonstrates the successful use of splenic artery embolization to manage ascites due to portal vein thrombosis following liver transplantation. Splenic artery embolization may be considered as an alternative option for the management of refractory ascites due to portal hypertension in patients who are unable to undergo safe transjugular intrahepatic portosystemic shunt or surgical shunt placement., ((c) 2007 AASLD.)

Background: Since the discovery of the hepatitis C virus (HCV), extensive literature has emerged on alcohol and HCV interaction., Goal: To understand the impact of alcohol and HCV infection on the severity of liver disease and the mechanisms of interaction between the two., Study: Of 1269 articles (1991 to 2006) searched through MEDLINE and cited cross references, 133 were thoroughly reviewed to assess: (a) prevalence of combined alcohol use and HCV, (b) severity of liver disease (c) treatment response, and (d) mechanisms of interaction between HCV and alcohol. Data on study design, patient demographics, diagnostic tests used, and study outcomes were extracted for critical analysis., Results: Prevalence of HCV is 3-fold to 30-fold higher in alcoholics compared with the general population. Patients with HCV infection and alcohol abuse develop more severe fibrosis with higher rate of cirrhosis and hepatocellular cancer compared with nondrinkers. Increased oxidative stress seems to be the dominant mechanism for this synergism between alcohol and the HCV. Abstinence is the key to the management of liver disease due to HCV and alcohol. Data have shown that lower response rates to interferon in alcoholics with HCV infection are likely due to noncompliance., Conclusions: Alcoholics with HCV infection have more severe liver disease compared with nondrinkers. Patients should be encouraged to enroll in rehabilitation programs so as to improve treatment adherence and response.