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BackgroundHigh alcohol intake is associated with increased mortality. We aimed to identify factors affecting mortality in people drinking extreme amounts of alcohol.MethodsWe obtained information from the UK Biobank on approximately 500,000 participants aged 40-70 years at baseline assessment in 2006-2010. Habitual alcohol intake, lifestyle and physiological data, laboratory test results, and hospital diagnoses and death certificate data (to June 2020) for 5136 men (2.20% of male participants) and 1504 women (0.60%) who reported consuming ≥80 or ≥50 g/day, respectively, were used in survival analysis.ResultsMortality hazard ratios for these excessive drinkers, compared to all other participants, were 2.02 (95% CI 1.89-2.17) for all causes, 1.89 (1.69-2.12) for any cancer, 1.87 (1.61-2.17) for any circulatory disease, and 9.40 (7.00-12.64) for any liver disease. Liver disease diagnosis or abnormal liver function tests predicted not only deaths attributed to liver disease but also those from cancers or circulatory diseases. Mortality among excessive drinkers was also associated with quantitative alcohol intake; diagnosed alcohol dependence, harmful use, or withdrawal syndrome; and current smoking at assessment.ConclusionsPeople with chronic excessive alcohol intake experience decreased average survival, but there is substantial variation in their mortality, with liver abnormality and alcohol dependence or other alcohol use disorders associated with a worse prognosis. Clinically, patients with these risk factors and high alcohol intake should be considered for early or intensive management. Research can usefully focus on the factors predisposing to dependence or liver abnormality.

Background & aimsOnly a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk.MethodsThree cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC).ResultsA combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption.ConclusionsA risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions.Lay summaryExcessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

Objective To determine the projected burden of hepatitis B virus (HBV) in China, the intervention strategies that can eliminate motherto-child transmission (MTCT) by 2030 or earlier and the measurable parameters that can be used to monitor progress towards this target. Methods We developed a dynamic, sex- and age-stratified model of the HBV epidemic in China, calibrated using hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) prevalence data from sequential national serosurveys (1979-2014) and the numbers of HBV- related cancer deaths (2012). We determined whether China can achieve elimination of MTCT of HBV by 2030 under current prevention interventions. We modelled various intervention scenarios to represent different coverage levels of birth-dose HBV vaccination, hepatitis B immunoglobulin to newborns of HBsAg-positive mothers and antiviral therapy (tenofovir) to HBeAg-positive pregnant women. Findings We project that, if current levels of prevention interventions are maintained, China will achieve the elimination target by 2029. By modelling various intervention scenarios, we found that this can be brought forward to 2025 by increasing coverage of birth-dose vaccination, or to 2024 by the administration of tenofovir to HBeAg-positive pregnant women. We found that achievement of the target by 2025 would be predicted by a measurement of less than 2% MTCT in 2020. Conclusion Our results highlight how high-quality national data can be combined with modelling in monitoring the elimination of MTCT of HBV. By demonstrating the impact of increased interventions on target achievement dates, we anticipate that other high- burden countries will be motivated to strengthen HBV prevention policies. Objectif Determiner la charge exercee par le virus de l'hepatite B (VHB) en Chine, les strategies d'intervention qui pourraient eliminer la transmission de la mere a l'enfant (TME) d'ici 2030 au plus tard, et les parametres mesurables pouvant etre utilises pour suivre les progres realises dans ce domaine. Methodes Nous avons developpe, pour l'epidemie de VHB en Chine, un modele dynamique stratifie selon l'age et le sexe. Nous l'avons calibre a l'aide des donnees de prevalence de l'antigene de surface (HBsAg) et de l'antigene e (HBeAg) de l'hepatite B, issues des enquetes serologiques nationales de type sequentiel (1979-2014) et du nombre de deces par cancer associes au VHB (2012). Nous avons etabli si les interventions de prevention actuelles permettraient a la Chine d'eliminer la TME du VHB d'ici 2030. Nous avons modelise plusieurs scenarios d'intervention pour representer differents niveaux de couverture de vaccination contre le VHB a la naissance, d'injection d'immunoglobuline aux enfants nes de meres HBsAg-positives, et de traitement antiviral (tenofovir) administre aux femmes enceintes HBeAg-positives. Resultats Nous estimons que si les interventions de prevention actuelles sont maintenues, la Chine atteindra l'objectif d'elimination prevu d'ici 2029. En modelisant divers scenarios d'intervention, nous avons decouvert que cet objectif pourrait meme etre concretise pour 2025 en augmentant la couverture de vaccination a la naissance, voire 2024 en administrant du tenofovir aux femmes enceintes HBeAg-positives. Nous avons egalement constate qu'un taux de TME inferieur a 2% en 2020 prefigurait la realisation de l'objectif pour 2025. Conclusion Nos resultats mettent en lumiere la facon dont des donnees nationales de qualite peuvent etre combinees a des modeles pour surveiller l'elimination de la TME du VHB. En demontrant l'impact de l'accroissement des interventions sur les echeances des objectifs, nous esperons motiver d'autres pays durement touches a renforcer leurs politiques de prevention du VHB. Objetivo Determinar la carga prevista del virus de la hepatitis B (VHB) en China, las estrategias de intervencion que pueden eliminar la transmision maternofilial (TMT) para 2030 o antes y los parametros mensurables que se pueden aplicar para vigilar los avances logrados en la consecucion de este objetivo. Metodos Se elaboro un modelo dinamico, estratificado por sexo y edad, de la epidemia del VHB en China, que se calibro mediante el uso de datos de prevalencia del antigeno HBs y del antigeno HBe obtenidos a partir de encuestas serologicas nacionales secuenciales (1979-2014) y de la cantidad de muertes por cancer causadas por el VHB (2012). Se determino si China puede lograr la eliminacion de la TMT del VHB para 2030 con las actuales intervenciones de prevencion. Se elaboraron varios escenarios de intervencion para representar diferentes niveles de cobertura de la vacunacion contra el VHB en dosis al nacer, de la inmunoglobulina de la hepatitis B a los recien nacidos de madres con pruebas positivas para el antigeno HBs y de la terapia antivirica (tenofovir) a las mujeres embarazadas con pruebas positivas para el antigeno HBe. Resultados Se preve que, si se mantienen los niveles actuales de intervenciones de prevencion, China lograra el objetivo de eliminacion para 2029. Mediante la elaboracion de modelos de varios escenarios de intervencion, se descubrio que este objetivo se puede adelantar para 2025 al aumentar la cobertura de la vacunacion de dosis al nacer o para 2024 al administrar tenofovir a las mujeres embarazadas que den positivo en la prueba del antigeno HBe. Ademas, se observo que el logro del objetivo para 2025 se podria predecir mediante la medicion de menos del 2 % de la TMT en 2020. Conclusion Los resultados de este analisis destacan como se pueden combinar los datos nacionales de alta calidad con la elaboracion de modelos para vigilar la eliminacion de la TMT del VHB. Al demostrar el impacto del aumento de las intervenciones en las fechas de cumplimiento de los objetivos, se preve que otros paises con una gran carga del VHB estaran motivados para reforzar las politicas de prevencion de este virus. [phrase omitted], Introduction The global momentum towards the elimination of viral hepatitis is growing. The World Health Assembly adopted the first global viral hepatitis elimination target in 2016 in calling for a [...]

Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.

Background and Aims: As screening for the liver disease and risk‐stratification pathways are not established in patients with type‐2 diabetes mellitus (T2DM), we evaluated the diagnostic performance and the cost‐utility of different screening strategies for MASLD in the community. Methods: Consecutive patients with T2DM from primary care underwent screening for liver diseases, ultrasound, ELF score and transient elastography (TE). Five strategies were compared to the standard of care: ultrasound plus abnormal liver function tests (LFTs), Fibrosis score‐4 (FIB‐4), NAFLD fibrosis score, Enhanced liver fibrosis test (ELF) and TE. Standard of care was defined as abnormal LFTs prompting referral to hospital. A Markov model was built based on the fibrosis stage, defined by TE. We generated the cost per quality‐adjusted life year (QALY) gained and calculated the incremental cost‐effectiveness ratio (ICER) over a lifetime horizon. Results: Of 300 patients, 287 were included: 64% (186) had MASLD and 10% (28) had other causes of liver disease. Patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287) and 3% (8/287), respectively. Among those with significant fibrosis classified by LSM≥8.1 kPa, false negatives were 54% from ELF and 38% from FIB‐4. On multivariate analysis, waist circumference, BMI, AST levels and education rank were independent predictors of significant and advanced fibrosis. All the screening strategies were associated with QALY gains, with TE (148.73 years) having the most substantial gains, followed by FIB‐4 (134.07 years), ELF (131.68 years) and NAFLD fibrosis score (121.25 years). In the cost‐utility analysis, ICER was £2480/QALY for TE, £2541.24/QALY for ELF and £2059.98/QALY for FIB‐4. Conclusion: Screening for MASLD in the diabetic population in primary care is cost‐effective and should become part of a holistic assessment. However, traditional screening strategies, including FIB‐4 and ELF, underestimate the presence of significant liver disease in this setting. [ABSTRACT FROM AUTHOR]