An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study.

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/ .

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Changing landscape of alcohol-associated liver disease in younger individuals, women, and ethnic minorities.

Alcohol use is the most important determinant of the development of alcohol-associated liver disease (ALD) and of predicting long-term outcomes in those with established liver disease. Worldwide, the amount, type, and pattern of use of alcohol vary. Alcohol use and consequent liver disease have been increasing in certain ethnic groups especially Hispanics and Native Americans, likely due to variations in genetics, cultural background, socio-economic status, and access to health care. Furthermore, the magnitude and burden of ALD have been increasing especially in the last few years among females and young adults who are at the prime of their productivity. It is critical to recognize the problem and care for these patients integrating cultural aspects in liver clinics. At the federal level, a societal approach is needed with the implementation of public health policies aiming to reduce alcohol consumption in the community. By addressing these challenges and promoting awareness, we can strive to reduce the burden of ALD, especially in high-risk demographic groups to improve their long-term health outcomes. Finally, we need studies and quality research examining these changing landscapes of demographics in ALD as a basis for developing therapeutic targets and interventions to reduce harmful drinking behaviours in these high-risk demographic groups.

Prevalence of Elevated ALT in Adolescents in the US 2011-2018.

OBJECTIVE: The objective of this study is to characterize suspected nonalcoholic fatty liver disease (NAFLD) using elevated alanine aminotransferase (ALT) in a diverse and nationally representative cohort of adolescents and to characterize higher ALT elevation in adolescents with obesity. METHODS: Data from the National Health and Nutrition Examination Survey 2011-2018 were analyzed for adolescents 12-19 years. Participants with causes for elevated ALT other than NAFLD were excluded. Race and ethnicity, sex, body mass index (BMI), and ALT were examined. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males) using the biologic upper normal limit (ULN). Elevated ALT thresholds up to 2X-ULN were examined among adolescents with obesity. Multivariable logistic regression was used to determine the association of race/ethnicity and elevated ALT, adjusting for age, sex, and BMI. RESULTS: Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity. For White, Hispanic, and Asian adolescents, prevalence was 15.8%, 21.8%, and 16.5% overall, 12.8%, 17.7%, and 27.0% in those with overweight, and 43.0%, 43.5%, and 43.1% in those with obesity, respectively. Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity). Prevalence of ALT at 2X-ULN was 6.6% in adolescents with obesity. Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT. CONCLUSIONS: Prevalence of elevated ALT in U.S. adolescents is high, affecting 1 in 6 adolescents during 2011-2018. The risk is highest in Hispanic adolescents. Asian adolescents with elevated BMI may comprise an emerging risk group for elevated ALT.

Association of Previous Gastric Bypass Surgery and Patient Outcomes in Alcohol-Associated Cirrhosis Hospitalizations.

BACKGROUND AND AIM: Roux-En-Y gastric bypass (RYGB) is associated with risk of alcohol use disorder. The impact of RYGB among patients with alcohol-associated liver disease (ALD) remains unknown. METHODS: A retrospective cohort from National Inpatient Sample (01/2006-09/2015) database on 421,156 admissions with alcohol-associated cirrhosis (AC) was stratified for non-primary discharge diagnosis of previous RYGB. Admissions with RYGB (cases) were matched 1:3 to without RYGB (controls) based on propensity score on demographics, calendar year, socioeconomic status (insurance and zip code income quartile), obesity, diabetes, anxiety, and alcohol use disorder. Primary outcome was concomitant discharge diagnosis of alcoholic hepatitis (AH) or development of acute on chronic liver failure (ACLF). RESULTS: Of 10,168 admissions (mean age 49 yrs., 75% females, 79% whites), cases (N = 2542) vs. controls had higher prevalence of concomitant AH (18.8 vs. 17%, P = 0.032), hepatic encephalopathy (31 vs. 25%), infection (28 vs. 24%), and grade 3 ACLF (13 vs. 5%), P < 0.001. Conditional logistic regression models showed higher odds for AH, hepatic encephalopathy, and infection among cases. In-hospital mortality of 6.3% (43% in ACLF) was lower in cases, but similar in the sub-cohorts of AH (N = 1768) or ACLF (N = 768). Results were similar in a sensitivity analysis of matched cohort of 2016 hospitalizations (504 cases) with primary discharge diagnosis of AC. CONCLUSION: Among patients with AC, previous RYGB is associated with increased likelihood of concomitant AH, hepatic encephalopathy, and infection, but similar in-hospital mortality. Prospective studies are needed to validate, determine causality, and understand mechanisms of these findings among patients with alcohol-associated cirrhosis.

Patients with type 2 diabetes and elevated fibrosis-4 are under-referred to hepatology and have unrecognized hepatic decompensation.

BACKGROUND AND AIM: The American Association for the Study of Liver Diseases recommends a high index of suspicion for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes (T2D) and an elevated fibrosis-4 index (FIB-4). We investigated the referral pattern of patients with T2D and FIB4 > 3.25 to the hepatology clinic and evaluated the clinical benefits to the patient. METHODS: We included patients aged 18-80 years with T2D and a FIB4 score >3.25 who had visited the internal medicine, family medicine, endocrinology clinic from 01/01/2014-5/31/2019. The first time point of high-risk FIB-4 was identified as the baseline for time-to-event analysis. The patients were classified based on whether they had visited the hepatology clinic (referred vs not referred). RESULTS: Of the 2174 patients, 290 (13.3%) were referred to the hepatology clinic, and 1884 (86.7%) were not referred. In multivariate analyses, the referred patients had a lower overall mortality risk (Hazard Ratio: 0.57; 95% CI: 0.38-87). Notably, the referred patients had the same rate of biochemical decompensation, as measured by progression to MELD ≥ 14, but a substantially higher rate of diagnosis in cirrhosis (27, 19-38) and cirrhosis complications, including ascites (2.9, 2.0-4.1), hepatic encephalopathy (99, 13-742), and liver cancer (14, 5-38). CONCLUSIONS: We found that patients with T2D and high-risk FIB4 are associated with better overall survival after referral to a hepatology clinic. We speculate that the survival difference is due to the increased recognition of cirrhosis and cirrhosis complications in the referred populations.

Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study.

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).

Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group.

BACKGROUND & AIMS: While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease. METHODS: We conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center. RESULTS: While alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers. CONCLUSIONS: While our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.

Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID-19 are open for study. APPROACH AND RESULTS: We conducted a multicenter study in the United States of 112 adult LT recipients with COVID-19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age- and sex-matched nontransplant patients with chronic liver disease and COVID-19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51-23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38-24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39-38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04-46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID-19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68-28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75-35.69) in LT recipients. CONCLUSIONS: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

Multicultural Awareness and a Comprehensive Team Approach to Liver Transplantation: A Case Report.

Patients being considered for a liver transplant undergo a rigorous evaluation process to identify the medical and psychosocial factors that may impact transplant success. The American Association for the Study of Liver Disease outlines recommendations for medical factors, but guidelines for psychosocial factors, such as multiculturalism, are less clear. The aim of this unique case study was to highlight the importance of multicultural awareness in the context of liver transplantation. More specifically, the report follows an American Indian man from initial diagnosis through psychological assessment and transplantation in order to illustrate the benefits of a comprehensive, multicultural team approach. Various components of multiculturalism are discussed, including the patient's ethnicity, intellectual functioning, socioeconomic status, and mental health history. Consideration of these factors by the patient's treatment team ultimately led to the patient's candidacy for transplant, as well as effective psychosocial support throughout the transplant process and recovery. Incorporation more specific psychosocial recommendations into national liver transplantation guidelines would likely improve the evaluation process and outcomes.

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18.

Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in the plasma of consented healthy controls and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of nonsurviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patients. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated that serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients, and M65 values and the M30/M65 ratio are capable of predicting early stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations, as they do not strongly correlate with traditional cell death markers.

Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C.

UNLABELLED: The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53). CONCLUSIONS: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.

Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice.

Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.

Determining Prognosis of ALD and Alcohol-associated Hepatitis.

Alcohol-associated hepatitis has a poor prognosis in terms of short-term mortality and often presents with symptoms, such as jaundice, acute renal failure, and ascites. There are many prognostic models that have been developed to predict short-term and long-term mortality in these patients. Current prognostic models can be divided into static scores, which are measured at admission, and dynamic models, which measure baseline and after a certain amount of time. The efficacy of these models in predicting short-term mortality is disputed. Numerous studies across the world have compared prognostic models, such as the Maddrey's discriminant function, the model for end-stage liver disease score, model for end-stage liver disease score-Na, Glasgow alcohol-associated hepatitis score, and the age-bilirubin-international normalized ratio-creatinine (ABIC) score, to each other to determine which score is more useful for a particular context. There are also prognostic markers such as liver biopsy, breath biomarkers, and acute kidney injury that are able to predict mortality. The accuracy of these scores is a key to determining when treatment with corticosteroids is futile since there is an increased risk of infection in those treated with it. Furthermore, although these scores are helpful in predicting short-term mortality, the only factor that is able to predict long-term mortality in patients with alcohol-related liver disease is abstinence. Numerous studies have proven that even though corticosteroids provide a treatment for alcohol-associated hepatitis, it is a temporary one, at best. The purpose of this paper is to compare the historical models to current ones in their ability to predict mortality in patients with alcohol-related liver disease by analyzing multiple studies that have examined these prognostic markers. This paper also isolates the knowledge gaps in the ability to delineate which patients would benefit from corticosteroids and patients who would not and provides potential models for the future that could narrow this gap.

Roles of Radiological Tests in Clinical Trials and the Clinical Management of Nonalcoholic Fatty Liver Disease.

Radiological testing is now routinely used for clinical trial prescreening, diagnosis, and treatment and referral. The CAP performs well in detecting fatty liver but is unable to grade and track longitudinal changes. MRI-PDFF is a better technique for evaluating longitudinal changes and is used as a primary endpoint in trials of antisteatotic agents. The probability of detecting liver fibrosis using radiological testing techniques is high when performed at referral centers, and reasonable imaging strategies include the combination of FIB-4 and VCTE, the FAST Score, MAST, and MEFIB. The strategy currently recommended is the sequential application of FIB-4 and VCTE.

MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis.

Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20-33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732-0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713-0.775; p = 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691-0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723-0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727-0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724-0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708-0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687-0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805-0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD).

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD. METHODS: In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression. RESULTS: The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39-0.84, p=0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66 95% CI 0.48-0.92) than lifetime non-drinkers. CONCLUSIONS: In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD.

The interaction of rs738409, obesity, and alcohol: a population-based autopsy study.

OBJECTIVES: The objective of this study was to access the prevalence of alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) histology in the general population, which had been otherwise difficult to access because of inherent misclassification bias in surrogate marker studies and referral bias in patient case series. The interaction among rs738409, obesity, and alcohol remains controversial. This population-based autopsy study investigated the histological prevalence of ALD and NAFLD, and interactions among rs738409, obesity, and alcoholism. METHODS: A total of 170 alcoholic and 235 nonalcoholic cases were selected from 1,034 adult car accident autopsies in 17 Kansas and Missouri counties from 2000 to 2010. The nonalcoholic group had undetectable blood alcohol concentration, while the alcoholic group had a blood alcohol concentration ≥0.08%. RESULTS: The age-standardized prevalences of hepatic steatosis, steatohepatitis, and advanced fibrosis were 56, 6, and 18% among alcoholics and 36, 4, and 6% in nonalcoholics, respectively. The interaction terms among alcohol, body mass index (BMI), and genotype were not significant. rs738409 GC or GG genotype was associated with 1.9-fold odds (95% confidence interval (CI), 1.2-2.9) of a higher NAFLD Activity Score (NAS). Alcohol had 3.5-fold odds (95% CI, 2.0-5.9), while every 5-unit increase in BMI had 1.9-fold odds (95% CI, 1.7-2.5). A negative interaction between alcohol and BMI towards fibrosis had been observed (P=0.045). Every 5-unit increase in BMI had 2.2-fold odds (95% CI, 1.5-2.5) of fibrosis among nonalcoholics, but not in alcoholics. CONCLUSIONS: This study assessed the prevalence of fatty liver histology in the general population from an autopsy study perspective. The finding of an additive interaction among rs738409, obesity, and alcohol towards NAS may be useful in targeting preventative care to patients at highest risk for ALD. The negative interaction between alcohol and obesity towards fibrosis supported previous findings and suggests the need for future research to explore potential mechanisms that may improve treatment of nonalcoholic steatohepatitis-related fibrosis.