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Corrigendum to: 'A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers' [J Hepatol 2022 (76) 275-282].
Whitfield, JB, Schwantes-An, TH, Darlay, R, Aithal, GP, Atkinson, SR, Bataller, R, Botwin, G, Chalasani, NP, Cordell, HJ, Daly, AK, et al
Journal of hepatology. 2022;(5):1244-1245
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A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
Whitfield, JB, Schwantes-An, TH, Darlay, R, Aithal, GP, Atkinson, SR, Bataller, R, Botwin, G, Chalasani, NP, Cordell, HJ, Daly, AK, et al
Journal of hepatology. 2022;(2):275-282
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Abstract
BACKGROUND & AIMS Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS Three 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). RESULTS A 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. CONCLUSIONS A 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 SUMMARY Excessive 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.
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Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting.
Avila, MA, Dufour, JF, Gerbes, AL, Zoulim, F, Bataller, R, Burra, P, Cortez-Pinto, H, Gao, B, Gilmore, I, Mathurin, P, et al
Gut. 2020;(4):764-780
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Abstract
Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
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The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease.
Chambers, ES, Byrne, CS, Rugyendo, A, Morrison, DJ, Preston, T, Tedford, C, Bell, JD, Thomas, L, Akbar, AN, Riddell, NE, et al
Diabetes, obesity & metabolism. 2019;21(2):372-376
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Plain language summary
Non-alcoholic fatty liver disease (NAFLD) is characterised by an accumulation of fat within the liver, and is strongly associated with obesity. Recent investigations suggest that diet, the gut microbiota and liver fat storage could be linked through a mechanism involving short chain fatty acids (SCFA), in particular the SCFA propionate, which are produced by the gut bacteria. The aim of this randomised controlled study was to evaluate whether an inulin-propionate ester (IPE) has benefits in patients with NAFLD. Subjects with NAFLD received either 20 g/d of inulin (control) or IPE for 42 days. 18 subjects completed the trial. Intrahepatocellular lipids IHCL (a marker of fat accumulation in the liver) increased post supplementation in both groups with no significant difference between control and IPE group. There was a change in insulin resistance (HOMA-IR) which was significantly different between groups, with a non-significant increase in the inulin-control group and decrease in the IPE group. There were no within- or between-group differences in body composition. The authors discuss these unexpected results and suggest that the SCFA acetate, from inulin fermentation by gut bacteria, may have led to an increase in IHCL which was attenuated by the propionate.
Abstract
The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non-alcoholic fatty liver disease (NAFLD). Eighteen adults were randomized to receive 20 g/d of an inulin-propionate ester (IPE), designed to deliver propionate to the colon, or an inulin control for 42 days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between the groups (P = 0.082), however, IHCL significantly increased within the inulin-control group (20.9% ± 2.9% to 26.8% ± 3.9%; P = 0.012; n = 9), which was not observed within the IPE group (22.6% ± 6.9% to 23.5% ± 6.8%; P = 0.635; n = 9). The predominant SCFA from colonic fermentation of inulin is acetate, which, in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate-mediated increase in IHCL.
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Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study.
Lemoine, M, Shimakawa, Y, Njie, R, Taal, M, Ndow, G, Chemin, I, Ghosh, S, Njai, HF, Jeng, A, Sow, A, et al
The Lancet. Global health. 2016;(8):e559-67
Abstract
BACKGROUND Despite the introduction of immunisation for hepatitis B virus (HBV) in the 1990s, HBV-related morbidity and mortality remain high in sub-Saharan Africa. Identification and treatment of asymptomatic people with chronic HBV infection should reduce the disease burden. We therefore assessed the feasibility of a screen-and-treat programme for HBV infection in The Gambia, west Africa, and estimated the proportion of HBV-infected people who had significant liver disease in need of treatment. METHODS Between Dec 7, 2011, and Jan 24, 2014, individuals living in randomly selected communities in western Gambia were offered hepatitis B surface antigen (HBsAg) screening via a point-of-care test. The test was also offered to potential blood donors attending the central hospital in the capital, Banjul. HBsAg-positive individuals were invited for a comprehensive liver assessment and were offered treatment according to international guidelines. We defined linkage to care as visiting the liver clinic at least once. Eligibility for treatment was judged in accordance with the 2012 European Association for the Study of the Liver guidelines. FINDINGS HBsAg screening was accepted by 5980 (weighted estimate 68·9%, 95% CI 65·0-72·4) of 8170 adults from 27 rural and 27 urban communities and 5559 (81·4%, 80·4-82·3) of 6832 blood donors. HBsAg was detected in 495 (8·8%, 7·9-9·7) individuals in communities and 721 (13·0%, 12·1-13·9) blood donors. Prevalence was higher in men (239 [10·5%, 8·9-12·1] of 2328 men vs 256 [7·6%, 6·5-8·7] of 3652 women; p=0·004) and middle-aged participants. Linkage to care was high in the communities, with 402 (81·3%) of 495 HBsAg-positive individuals attending the clinic. However, only 300 (41·6%) of 721 HBsAg-positive people screened at the blood bank linked into care. Of those who attended the clinic, 18 (4·4%, 2·5-7·7) patients from the communities and 29 (9·7%, 6·8-13·6) from the blood bank were eligible for treatment. Male sex was strongly associated with treatment eligibility (odds ratio 4·35, 1·50-12·58; p=0·007). INTERPRETATION HBV infection remains highly prevalent in The Gambia. The high coverage of community-based screening, good linkage into care, and the small proportion of HBsAg carriers who need treatment suggest that large-scale screening and treatment programmes are feasible in sub-Saharan Africa. FUNDING European Commission (FP7).
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Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis.
Singh, S, Murad, MH, Chandar, AK, Bongiorno, CM, Singal, AK, Atkinson, SR, Thursz, MR, Loomba, R, Shah, VH
Gastroenterology. 2015;(4):958-70.e12
Abstract
BACKGROUND & AIMS Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons. METHODS We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. RESULTS We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons. CONCLUSIONS In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.