26 May 2021 In Liver Disease
BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 x 10(-17) ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 x 10(-10) ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 x 10(-8) ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
26 May 2021 In Liver Disease
BACKGROUND & AIMS: Increasingly populations are both overweight/obese and consume alcohol. The risk of liver disease from the combination of these factors is unclear. We performed a systematic review and meta-analysis to address this important gap in evidence. Protocol registered with PROSPERO(CRD42016046508). METHODS: We performed electronic searches of Ovid Medline, Embase Classic + Embase, until 17th June 2020 for cohort studies of adults without pre-existing liver disease. Primary outcome was morbidity/mortality from chronic liver disease. Exposures were alcohol consumption categorised as within or above UK recommended limits (14 units/112 g per week) and BMI categorised as normal, overweight or obese. Non-drinkers were excluded. A Poisson regression log-linear model was used to test for statistical interaction between alcohol and BMI and to conduct a one-stage meta-analysis. RESULTS: Searches identified 3129 studies-16 were eligible. Of these, nine cohorts (1,121,514 participants) had data available and were included in the analysis. The Poisson model showed no significant statistical interaction between alcohol consumption and BMI on the risk of chronic liver disease. Compared to normal weight participants drinking alcohol within UK recommended limits, relative risk of chronic liver disease in overweight participants drinking above limits was 3.32 (95% CI 2.88 to 3.83) and relative risk in obese participants drinking above limits was 5.39 (95% CI 4.62 to 6.29). CONCLUSIONS: This meta-analysis demonstrated a significantly increased risk of chronic liver disease in participants who were both overweight/obese and consumed alcohol above UK recommended limits. This evidence should inform advice given to patients and risk stratification by healthcare professionals.
23 February 2021 In Liver Disease

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Whether moderate alcohol consumption plays a role for progression of NAFLD is disputed. Moreover, it is not known which tool is ideal for assessment of alcohol consumption in NAFLD. This study aimed to evaluate if moderate alcohol consumption assessed with different methods, including the biological marker phosphatidylethanol (PEth), is associated with advanced fibrosis in NAFLD.

METHODS: We conducted a cross-sectional study of patients with biopsy-proven NAFLD. All participants were clinically evaluated with medical history, blood tests, and anthropometric measurements. Alcohol consumption was assessed using PEth in blood, the questionnaire AUDIT-C, and clinical interview.

FINDINGS: 86 patients were included of which 17% had advanced fibrosis. All participants reported alcohol consumption < 140g/week. Average weekly alcohol consumption was higher in the group with advanced fibrosis. Moderate alcohol consumption, independently of the method of assessment, was associated with increased probability of advanced fibrosis (adjusted OR 5.5-9.7, 95% CI 1.05-69.6). Patients with type 2 diabetes mellitus (T2DM) consuming moderate amounts of alcohol had a significantly higher rate of advanced fibrosis compared with those consuming low amounts (50.0-60.0% vs. 3.3-21.6%, p<0.05).

CONCLUSIONS: Moderate alcohol consumption, irrespective of assessment method (clinical interview, AUDIT-C, and PEth), was associated with advanced fibrosis. PEth in blood >/= 50ng/mL may be a biological marker indicating increased risk for advanced fibrosis in NAFLD. Patients with T2DM consuming moderate amounts of alcohol had the highest risk of advanced fibrosis, indicating a synergistic effect of insulin resistance and alcohol on the histopathological progression of NAFLD.

23 February 2021 In Liver Disease

OBJECTIVE: To study the interaction of alcohol consumption with body mass index (BMI) in the development of hepatic steatosis and mortality.

PARTICIPANTS AND METHODS: We conducted a retrospective cohort study of 18,506 participants without fatty liver disease or cirrhosis at enrollment in the Mayo Clinic Biobank from April 9, 2009, through March 31, 2016. Participants were classified by self-reported alcohol consumption status (nondrinkers, moderate drinkers [0 to 2 drinks per day], and heavy drinkers [>2 drinks per day]). The primary outcome of interest was the incidence of hepatic steatosis, identified by International Classification of Diseases, Ninth Revision code and confirmed with imaging. The secondary outcome of interest was all-cause mortality. Multivariate Cox regression analysis determined the impact of alcohol consumption stratified by BMI on outcomes compared with nondrinkers.

RESULTS: The cohort (mean +/- SD age, 55.8+/-16.9 years; 63.8% female; mean +/- SD BMI, 28.8+/-6.1 kg/m(2)) of 18,506 participants included 3657 (19.8%) nondrinkers, 14,236 (76.9%) moderate drinkers, and 613 (3.3%) heavy drinkers at enrollment. After a median follow-up of 5.8 years (interquartile range, 3.8 to 7.2 years), 684 participants had development of hepatic steatosis and 968 died. In moderate drinkers, the risk of hepatic steatosis development was high in the obese group (adjusted hazard ratio [AHR], 1.31; 95% CI, 1.03 to 1.67), insignificant in the overweight group (AHR, 0.86; 95% CI, 0.58 to 1.26), and decreased in the normal-BMI group (AHR, 0.48; 95% CI, 0.26 to 0.90). Heavy drinkers had an increased risk of hepatic steatosis irrespective of BMI. Moderate alcohol use was associated with decreased mortality in the normal-weight (AHR, 0.44; 95% CI, 0.34 to 0.58) and overweight (AHR, 0.70; 95% CI, 0.56 to 0.88) groups but not in the obese group (AHR, 0.80; 95% CI, 0.64 to 1.00).

CONCLUSION: In obese individuals, even moderate alcohol use is associated with the development of hepatic steatosis. Moderate alcohol consumption is associated with lower mortality in normal-BMI and overweight individuals but not in those who are obese.

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