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Aims Wernicke–Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. Methods Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. Results Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case–control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10−11). Conclusion This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.

Introduction Genome-wide association studies (GWAS) of alcohol dependence syndrome (ADS) offer a platform to detect genetic risk loci. However, the majority of the ADS GWAS undertaken, to date, have utilized a case-control design and have failed to identify consistently replicable loci with the exception of protective variants within the alcohol metabolizing genes, notably ADH1B. have failed to identify consistently replicable loci. The ADS phenotype shows considerable variability and of the ADS phenotype means that the use of quantitative variables as a proxy for the severity of ADS has the potential to facilitate identification of risk loci by increasing statistical power. The current study aims to examine the influences of using binary and adjusted quantitative measures of ADS on GWAS outcomes and on calculated polygenic risk scores (PRS). Methods A GWAS was performed in 1251 healthy controls with no history of excess alcohol use and 739 patients with ADS classified using binary DMS-IV criteria. Additional two GWASs were undertaken using a quantitative score based on DSM-IV criteria, which were applied assuming both normal and non-normal distributions of the phenotypic variable. PRS analyses were performed utilizing the data from the binary and the quantitative trait analyses. Results No associations were identified at genome-wide significance in any of the individual GWAS; results were comparable in all three. The top associated single nucleotide polymorphism was located on the alcohol dehydrogenase gene cluster on chromosome 4, consistent with previous ADS GWAS. The quantitative trait analysis adjusted for the distribution of the criterion score and the associated PRS had the smallest standard errors and thus the greatest precision CONCLUSION: Further exploitation of the use of qualitative trait analysis in GWAS in ADS is warranted.

International audience; BACKGROUND and 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=1690, GenomALC-2: n=3037, UK Biobank: relevant n=6898) 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 eight genetic loci identified previously as associated with alcohol-related cirrhosis and three 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 three single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated for cirrhosis risk. The odds ratio (OR) and 95% confidence intervals (CI) for the extreme score quintiles (Q1-Q5) 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 score, compared to those without diabetes and a low-risk score, had ORs increased to 14.7 (7.69;28.1) (GenomALC-1) and 17.1 (11.3;25.7) (UK Biobank). Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76±0.06 versus 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 three genetic risk variants and diabetes status can provide meaningful risk stratification for cirrhosis in excess drinkers, allowing earlier prevention planning including intensive intervention. LAY SUMMARY: Excessive chronic drinking leads to liver cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. Our study has developed a genetic risk score (GRS) test that can identify patients at high risk and shows that the risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and high GRS. Risk assessment using this test has potential for early and personalised management of this disease in high-risk patients.

BACKGROUND: The gene-signature-MELD (gs-MELD) score has been shown to be a strong predictor of 6-month survival in severe alcoholic hepatitis (AH). Currently, only a few studies have evaluated the long-term prognosis of patients with severe AH. AIM: To assess the prognostic value of the gs-MELD score at 5 years in patients with severe AH. METHODS: Forty-eight consecutive patients with AH (25 males, median age 52 years [95% IC: 48–56]) were included. RESULTS: The median gs-MELD score was 2.6 (95% CI: 2.2–3.0). According to the gs-MELD score, 22 patients (46%) were considered to have a poor prognosis. During a median follow-up of 29 months (95% CI: 4–43), 19 patients (40%) were abstinent and 24 patients (50%) died. At 5 years, rates of survival were 61% (95% CI: 41–81) and 26% (95% CI: 11–55) in patients with low and high gs-MELD scores (p=0.001), and 81% (95% CI: 58–96) and 22% (95% CI: 10–47) in abstainers and in consumers (p

Objective: Hepatic encephalopathy is a common complication of cirrhosis; it is characterised by neuropsychometric/neurophysiological abnormalities. Its pathophysiology is complex but glial neuronal communication is likely to be disrupted and to impact on oscillatory networks and cortical connectivity. The aim of this study was to use multichannel electroencephalography (EEG) to investigate functional connectivity, as a surrogate for cortical networks, in patients with cirrhosis. Methods: Resting EEGs were recorded in 98 healthy controls and in 264 patients with cirrhosis characterised psychometrically using the Psychometric Hepatic Encephalopathy Score (PHES). Functional connectivity was calculated using the phase-lag index with stratification into standard EEG frequency bands. The findings were validated in a further cohort of 39 healthy controls and 106 patients with cirrhosis. Results: Widespread disruption in functional connectivity was observed in the patients compared with the controls; connectivity was increased in the theta (4–8 Hz) band and decreased in the delta (1–3.5 Hz), alpha (8.5–13 Hz) and beta (13.5–26.5 Hz) bands. Changes were apparent even in patients who were psychometrically unimpaired compared with healthy controls viz mean ± SEM theta 0.107 ± 0.001 vs. 0.103 ± 0.002 (p < 0.05) and alpha 0.139 ± 0.003 vs. 0.154 ± 0.003 (p < 0.01); more pronounced changes were observed with increasing neuropsychometric impairment. The findings were replicated in the second cohort. Conclusions: Cortical networks are disturbed in patients with cirrhosis even in the absence of psychometric impairment. Significance: These findings will facilitate further exploration of the pathophysiology of this condition and provide a robust means for assessing treatment effects in research settings.

Constitutional, environmental, and genetic risk factors influence the development of alcohol-related cirrhosis. The amount of alcohol consumed and whether excessive drinking continues after the identification of pre-cirrhotic liver damage are key risk factors. Female sex, ethnicity, obesity, coffee consumption, cigarette smoking, and exposure to other causes of liver injury also influence the risk of disease development. More recently several genetic loci have been robustly associated with the risk for developing significant alcohol-related liver disease. It remains unclear whether additional risk factors are involved in the development of the clinical syndrome of alcoholic hepatitis, but the genetic evidence is suggestive.

Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease., info:eu-repo/semantics/published

Introduction Hepatic encephalopathy (HE) is a frequent complication of cirrhosis but its development is not inevitable. There is evidence, from candidate gene studies, that the propensity to develop HE may be genetically determined but the findings are inconsistent. The aim of this study was to undertake a GWAS of HE in chronic liver disease. Methods Genomic DNA was available in 857 participants in the UK STOPAH alcoholic hepatitis trial and 120 participants in the Royal Free Hospital (RFH) HE surveillance study. All had chronic liver disease and the majority were of British/Irish ancestry. Information on HE status was available in 777 participants in STOPAH and 109 in the RFH cohort. Cases were defined in the STOPAH cohort as those presenting with/developing overt HE (OHE) within 28 days of admission based on West Haven criteria, and in the RFH cohort on a combination of West Haven criteria, the PHES test and EEG theta frequency. Controls were defined as STOPAH participants who did not present/develop OHE within 28 days and in the RFH cohort as participant classified as neuropsychiatrically unimpaired or as having minimal HE. Samples were genotyped using three different SNP arrays (Illumina core exome chip, Psych Chip and OmniExpress array). Separate GWAS analyses were undertaken of each array using Plink (v1.9) followed by meta-analysis in METAL (v1.5.0). The primary analysis was adjusted first for population stratification and second for age, sex, and model for end-stage liver disease (MELD) score. Linear regression association analysis was also conducted in the RFH cohort (n=111) using the additional HE defining variables. Results A total of 206 (26.5%) of the STOPAH participants and 33 (30.3%) of the RFH cohort had OHE. Single variants in TMEM135 (Transmembrane Protein 135), CACNB2 (Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2), and WBP2 (WW Domain Binding Protein 2) showed suggestive association (P Conclusions TMEM135 influences key metabolic pathways involved in the pathophysiology of HE, namely oxidative stress and glutamine and glutamate homeostasis. MUC7 influences factors which result in a reduction in systemic inflammation and influences the gut microbiota. These interesting associations need further exploration in extended cohorts.

Introduction Alcoholic liver disease (ALD) is a complex disorder, resulting from the interplay of environmental and genetic factors. Severe alcoholic hepatitis (AH) is an acute clinical manifestation of ALD, which has a high associated mortality but develops in only a minority of patients, estimated to be Methods Cases with severe AH were recruited from the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial (n = 812). Controls with a history of alcohol dependence but without evidence of significant liver injury were recruited from the Centre of Hepatology, Royal Free Hospital, London (n = 936). All participants were of white British/Irish descent. DNA was genotyped using two platforms Illumina HumanCoreExome BeadChip (Illumina, San Diego, USA) and Illumina PsychArray Beadchip (Illumina, San Diego, USA). Separate GWAS analyses were undertaken on each array using Plink v1.9 followed by meta-analysis in METAL. MAGMA gene and gene-set analyses were carried out using FUMA. Results The variant rs738409 in PNPLA3 was associated with severe AH at genome-wide significance (PTHRESHOLD Conclusions The pivotal role of PNPLA3:rs738409 in determining the risk for developing severe AH was confirmed in this study. In addition, potential risk loci were identified in ATP2C2, which encodes a Mn+/Ca2+ transporter and is highly expressed in the gastrointestinal tract; PHYH which is implicated in phytanic acid metabolism; phytanic acid binds to and/or activates the transcription factors PPAR-alpha and retinoid X receptor; and ANGPT1 which encodes the angiogenic promoter angiopoietin 1. Additionally, a number of potential pathways were identified, through gene set analysis, which appear to be involved in severe AH, influencing lipid metabolism and inflammation. These novel findings open new avenues for investigation and therapeutic endeavour.

Cirrhosis develops in10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population.To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes.Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology.Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; IThe risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.

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.

The chewing of the leaves of Catha edulis (khat) has been implicated in the development of liver disease, but no controlled observations have been undertaken. The objective of the present study was to determine whether khat chewing is associated with development of chronic liver disease (CLD). A case-control study was conducted at two public hospitals in Harar, Ethiopia, between April 2015 and April 2016. A consecutive sample of 150 adult hospital attendees with CLD were included as cases, and 300 adult hospital attendees without clinical or laboratory evidence of CLD were included as controls. Khat consumption was quantified in "khat years"; 1 khat year was defined as daily use of 200 g of fresh khat for 1 year. A logistic regression model was used to control for confounders. There was a significant association between chewing khat and the risk for developing CLD (crude odds ratio, 2.64; 95% confidence interval [CI], 1.56-4.58). In men, this risk, following adjustment for age, alcohol use, and chronic hepatitis B/C infection, increased with increasing khat exposure; thus, compared to never users the adjusted odds ratios were for low khat exposure 3.58 (95% CI 1.05-12.21), moderate khat exposure 5.90 (95% CI 1.79-19.44), and high khat exposure 13.03 (95% CI 3.61-47.02). The findings were robust in a post hoc sensitivity analysis in which individuals with identifiable risk factors for CLD were excluded. Conclusion A significant association was observed between chewing khat and the risk for developing CLD, and in men the association was strong and dose-dependent, suggesting a causal relationship; as the prevalence of khat chewing is increasing worldwide, these findings have major public health implications. (Hepatology 2018;68:248-257).

Associations between the γ-aminobutyric acid type-A receptors (GABAA) and alcohol dependence risk have been reported, although the receptor subunit driving the association is unclear. Recent work in mice has highlighted a possible role for variants in the Gabr β1 subunit (Gabrβ1) in alcohol dependence risk, although this gene does not contain any common nonsynonymous variants in humans. However, the GABAA receptor is a heteropentamer so multiple potential variants within the gene complex could generate the alcohol dependence phenotype. The association between GABRβ1 variants and alcohol dependence risk was explored in a British and Irish population of alcohol-dependent cases (n=450) and ancestrally-matched controls screened to exclude current or historical alcohol misuse (n=555). Twelve common single nucleotide polymorphisms (SNPs) and a rare nonsynonymous variant, rs41311286, were directly genotyped; imputation was then performed across the whole gene. No allelic association was observed between alcohol dependence risk and any of the directly genotyped or imputed SNPs. However, post-hoc testing for genotypic association identified five common intronic SNPs that showed modest evidence for association after correction for multiple testing; two, rs76112682 and rs141719901, were in complete linkage disequilibrium [Pcorrected=0.02, odds ratio (95% confidence interval)=5.9 (1.7-2.06)]. These findings provide limited support for an association between GABRβ1 and the risk for developing alcohol dependence; further testing in expanded cohorts may be warranted.

Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.

Background and aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Approach and results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). Conclusions Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) 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 genomic conserved and regulatory 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 outcomes.

BACKGROUND: The presence of oesophageal varices is associated with the risk of upper gastrointestinal bleeding. Endoscopic variceal ligation is used to prevent this occurrence but the ligation procedure may be associated with complications. OBJECTIVES: To assess the beneficial and harmful effects of band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 9 February 2019. SELECTION CRITERIA: We included randomised clinical trials comparing band ligation verus no intervention regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. Included participants had cirrhosis and oesophageal varices with no previous history of variceal bleeding. DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. The primary outcome measures were all‐cause mortality, upper gastrointestinal bleeding, and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RRs) with 95% confidence intervals (CIs) and I(2) values as a marker of heterogeneity. In addition, we calculated the number needed to treat to benefit (NNTTB) for the primary outcomes . We assessed bias control using the Cochrane Hepato‐Biliary domains; determined the certainty of the evidence using GRADE; and conducted sensitivity analyses including Trial Sequential Analysis. MAIN RESULTS: Six randomised clinical trials involving 637 participants fulfilled our inclusion criteria. One of the trials included an additional small number of participants (< 10% of the total) with non‐cirrhotic portal hypertension/portal vein block. We classified one trial as at low risk of bias for the outcome, mortality and high risk of bias for the remaining outcomes; the five remaining trials were at high risk of bias for all outcomes. We downgraded the evidence to moderate certainty due to the bias risk. We gathered data on all primary outcomes from all trials. Seventy‐one of 320 participants allocated to band ligation compared to 129 of 317 participants allocated to no intervention died (RR 0.55, 95% CI 0.43 to 0.70; I(2) = 0%; NNTTB = 6 persons). In addition, band ligation was associated with reduced risks of upper gastrointestinal bleeding (RR 0.44, 95% CI 0.28 to 0.72; 6 trials, 637 participants; I(2) = 61%; NNTTB = 5 persons), serious adverse events (RR 0.55, 95% CI 0.43 to 0.70; 6 trials, 637 participants; I(2) = 44%; NNTTB = 4 persons), and variceal bleeding (RR 0.43, 95% CI 0.27 to 0.69; 6 trials, 637 participants; I² = 56%; NNTTB = 5 persons). The non‐serious adverse events reported in association with band ligation included oesophageal ulceration, dysphagia, odynophagia, retrosternal and throat pain, heartburn, and fever, and in the one trial involving participants with either small or large varices, the incidence of non‐serious side effects in the banding group was much higher in those with small varices, namely ulcers: small versus large varices 30.5% versus 8.7%; heartburn 39.2% versus 17.4%. No trials reported on health‐related quality of life. Two trials did not receive support from pharmaceutical companies; the remaining four trials did not provide information on this issue. AUTHORS' CONCLUSIONS: This review found moderate‐certainty evidence that, in patients with cirrhosis, band ligation of oesophageal varices reduces mortality, upper gastrointestinal bleeding, variceal bleeding, and serious adverse events compared to no intervention. It is unlikely that further trials of band ligation versus no intervention would be considered ethical.

BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as 'overt' hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, 'minimal' hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST‐120 (spherical carbon adsorbent), and polyethylene glycol. OBJECTIVES: To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. SEARCH METHODS: We searched the Cochrane Hepato‐Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators. SELECTION CRITERIA: We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST‐120, and polyethylene glycol versus placebo or non‐absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I(2) statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato‐Biliary domains and the certainty of the evidence using GRADE. MAIN RESULTS: Eleven randomised clinical trials fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST‐120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non‐absorbable disaccharide. We classified eight of the 11 trials as at 'high risk of bias' and downgraded the certainty of the evidence to very low for all outcomes. Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non‐absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I(2) = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I(2) = 0%), AST‐120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I(2) = 0%). Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non‐absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST‐120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial). Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non‐absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I(2) = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I(2) = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non‐serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol. Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo‐controlled trials evaluating sodium benzoate (MD −32.00 µg/dL, 95% CI −46.85 to −17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD −12.00 µmol/L*week, 95% CI −23.37 to −0.63; 178 participants; 1 trial), ornithine phenylacetate (MD −27.10 µmol/L, 95% CI −48.55 to −5.65; 231 participants; 1 trial), and AST‐120 (MD −22.00 µg/dL, 95% CI −26.75 to −17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI −1.10 to 19.11; 85 participants; 2 trials; I(2) = 0% ), AST‐120 (MD 5.20 units not specified, 95% CI −2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD −29.28 µmol/L, 95% CI −95.96 to 37.39; 90 participants; 2 trials; I(2) = 88%). Five trials received support from pharmaceutical companies while four did not; two did not provide this information. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.

Introduction Percutaneous gastrostomy tubes are widely considered a safe and effective means for providing long-term enteral nutrition. However, placement is associated with high risk of death in the weeks following insertion. The Royal Free Hospital Gastrostomy Risk Score (RFH-GRS), was designed to facilitate risk-benefit assessment of patients referred for gastrostomy (Russell-Dalton et al. Clin Nutr 2019; 29:252.). It allocates a categorical score to eight factors viz. age, prognosis, nutritional status, severity of dysphagia, anatomical suitability, anti-coagulation status, comorbidities (Charlson Comorbidity Index) and recent infection; the maximum total is 40. Scores are stratified to facilitate risk-benefit assessment viz. 0–5: low risk, likely benefit; 6–10: moderate risk, likely benefit; 11–14: medium-high risk, benefits may still outweigh the risk; and ≥15: high risk, unlikely to benefit. The aim of this one-year prospective study was to further evaluate the predictive validity of the RFH-GRS. Methods All gastrostomy referrals from 1 January to 31 December 2018 were allocated a RFH-GRS score as part of their eligibility assessment. Patients were followed until death, or the end of the study period. Risk-benefit was assessed by comparing RFH-GRS and survival outcomes in patients who did and did not undergo the procedure. Results Eighty-four patients were referred (58% men; median [range] age, 72 [1–6] yr); dysphagia was the main indication in 71.4%. Of the 84 referrals, 50 underwent placement, while 34 did not: too well (n=11), too unwell (n=14), declined (n=3), unsuitable anatomy (n=6). The median RFH-GRS was 10 (range –0). Patients with scores of –0 who underwent the procedure had a 93% 90-day survival, compared with 89% in those who did not. However, 1-year survival rates were 93% and 68% indicating clear long-term benefit (Figure 1). Patients with scores of 1–4 who underwent the procedure benefited in the short term with an 18% difference in 90-day survival (70% vs 52%) but 1-year survival rates were similar at 55% and 50%. Patients with scores ≥15 who underwent the procedure had a significantly lower 90-day survival compared to those who did not (15% vs 33%). Conclusion This prospective study provides further evidence to support the use of the RFH-GRS as a risk-benefit assessment tool in patients referred for gastrostomy placement.

Introduction Acute upper gastrointestinal bleeding (AUGIB) is a common complication of peptic ulcer disease (PUD) defined as not only peptic ulceration but also erosive gastritis and duodenitis, Helicobacter pylori (H. pylori) infection is the major cause of PUD. NICE guidelines recommend that patients identified with PUD should be tested and treated for H pylori if infected. Post-eradication testing is mandated to confirm successful eradication. The aim of this study was to determine compliance with national guidelines for the management of H. pylori in those with PUD-associated AUGIB. Methods Retrospective data were collected on all patients presenting to the Royal Free Hospital, London, with non-variceal AUGIB between 1 January and 31 December 2017. Prospective data were collected between 1 February and 1 April 2018. Compliance with guidelines was judged using predetermined criteria and classified as: poor ( 75%); or excellent (>90%). Results A total of 203 patients presented with non-variceal AUGIB during 2017, of whom 148 underwent endoscopy. Sixty-seven of those endoscoped met criteria for H. pylori testing but only 35 (52.2%) were investigated despite an absence of active bleeding or high-risk stigmata (compliance poor) (table 1). Of the 32 cases not tested, 22 exhibited overt ulceration at endoscopy, with the remaining cases demonstrating erosive changes. Four of the 55 non-endoscoped patients were tested for H pylori by other means. Overall, 15 (38.5%) of the 39 patients investigated tested positive for H pylori; 14 (93.3%) were prescribed eradication therapy (compliance excellent) while a further five patients were treated empirically. Of the 19 treated patients, only nine (47.4%) underwent post-eradication testing (compliance poor); all however tested negative. Prospective compliance rates in 36 patients exhibited similar poor compliance although samples were small (table 1). Conclusion Approximately 50% of patients presenting with AUGIB with endoscopic features of PUD were not tested for H. pylori. Almost 40% of those who were tested were infected. Post-eradication investigation rates were particularly low. No clear explanation for this level of non-compliance with guidelines is apparent but enforcement is clearly warranted.

Introduction Helicobacter pylori (H. pylori) infection is the primary cause of peptic ulcer disease and is globally prevalent. Although eradication therapy is effective, emerging antibiotic resistance rates are of considerable concern. H. pylori infection is more prominent in deprived populations but the effects of ethnicity and social determinants of health on H. pylori resistance is unclear. The aim of this study was to establish the significance of socioeconomic and ethnic influences on H. pylori resistance. Methods The study population comprised of patients with recurrent/previous H. pylori infection plus current dyspeptic symptoms referred to the Royal Free Hospital, London, from 1 January 2017 to 1 September 2018, for endoscopic investigations. Gastro/duodenal biopsy samples were sent for culture and sensitivity testing. Demographic and clinical data were collected. Self-reported ethnic origin was recorded. Deprivation was analysed on a postcode basis, using the 2015 English Indices of Deprivation, by means of average decile ranking (1–10). Ethnic and socioeconomic differences between patients exhibiting resistance and those fully sensitive/culture negative were explored. Results A total of 107 patients, including 26 children, (61.7% female; median (range) age 37.5 (4–81) years; 43.9% Caucasian, 39.2% Asian), were sampled. Five were excluded (3 contaminated, 2 inappropriate samples). Forty of the remaining 102 samples yielded positive cultures; of these 6/40 were fully sensitive but 34 (33% of total sample) displayed antibiotic resistance, most commonly to metronidazole (91.2%), and/or clarithromycin (77.4%). Dual resistance was present in 52.9%. Resistance to amoxicillin (n=2) and levofloxacin (n=3) was also identified. The remaining 62 samples were culture negative. There were no differences in the age or sex distributions between the two cohorts. Likewise, there was no significant difference in the ethnic distribution between patients displaying antibiotic resistance and those sensitive/culture negative (Asian 47% vs. 35% Chi2P=0.25) (figure 1A). Deprivation analysis showed very similar average decile rankings in both patient groups although distribution was skewed to the deprived end of each domain in both (figure 1B). Conclusion One-third of biopsy samples referred for sensitivity testing, during the study period, exhibited antibiotic resistance, most commonly to first and second line eradication therapies. No significant differences were observed in ethnicity or in deprivation between patients exhibiting resistance and those sensitive/culture negative. However, trends identified in this study need to be further explored. Abstract PTU-067 Figure 1 Comparative analysis of resistant vs. sensitive/no culture cohorts. (A) Ethnicity (B) Deprivation

Introduction Percutaneous gastrostomy feeding tubes are used to provide long term artificial nutrition in patients with adequate intestinal absorptive capacity. Placement is associated with low immediate morbidity; however, the early mortality rate is high. Current selection for gastrostomy placement has a significant subjective element. In consequence there is a need for a validated, objective assessment tool, based on easily accessible information, to identify the risk–benefit of gastrostomy placement on an individual basis. The aim of this study was to derive and validate a Royal Free Hospital-Gastrostomy Risk Score (RFH-GRS). Methods Extensive demographic and clinical data were collected on the 234 patients referred for gastrostomy placement, at the Royal Free Hospital, London, between 1 January 2016 and 31 December 2017; the entire cohort was followed until death or 31 December 2017. Multivariate analysis identified age, multimorbidity (assessed using the Charlson Comorbidity Index), prognosis, and recent infection as independent predictors of survival. Four further factors were identified by experienced nutritional practitioners for inclusion in the RFH-GRS viz. nutritional status using the MUST score, severity of dysphagia, anti-coagulation status and anatomical suitability. Each variable was allocated an appropriate categorical score. The maximum total score was 31 for the multivariate model and 40 for the RFH-GRS. Scores were then retrospectively allocated to the 234 gastrostomy referrals and the predictive validity for survival of the two scores compared. Results The median (range) multivariate model score was 5 (1–11); the median RFH-GRS was 10 (2–18). The quartiles within these ranges were used to allocate patients to one of four score groups. Comparison of cumulative survival, based on these groups, showed that the RFH-GRS had superior predictive validity (Figure 1). Patients with a RFH-GRS of – have a low risk of an adverse outcome following gastrostomy placement; 6–10 a moderate risk, so they are likely to benefit; 11–14 a medium to high risk so benefits may still outweigh the risk, and ≥15 a high risk, making it unlikely that they would benefit from the procedure. Conclusion The RFH-GRS is a simple, validated tool for the assessment of patients referred for gastrostomy placement. It utilises routinely collected data and hence can be easily applied.

The presence of overt hepatic encephalopathy (HE) is associated with structural, metabolic and functional changes in the brain discernible by use of a variety of magnetic resonance (MR) techniques. The changes in patients with minimal HE are less well documented. Twenty-two patients with well-compensated cirrhosis, seven of whom had minimal HE, were examined with cerebral 3 Tesla MR techniques, including T1- and T2-weighted, magnetization transfer and diffusion-weighted imaging and proton magnetic resonance spectroscopy sequences. Studies were repeated after a 4-week course of oral L-ornithine L-aspartate (LOLA). Results were compared with data obtained from 22 aged-matched healthy controls. There was no difference in mean total brain volume between patients and controls at baseline. Mean cerebral magnetization transfer ratios were significantly reduced in the globus pallidus and thalamus in the patients with cirrhosis irrespective of neuropsychiatric status; the mean ratio was significantly reduced in the frontal white matter in patients with minimal HE compared with healthy controls but not when compared with their unimpaired counterparts. There were no significant differences in either the median apparent diffusion coefficients or the mean fractional anisotropy, calculated from the diffusion-weighted imaging, or in the mean basal ganglia metabolite ratios between patients and controls. Psychometric performance improved in 50 % of patients with minimal HE following LOLA, but no significant changes were observed in brain volumes, cerebral magnetization transfer ratios, the diffusion weighted imaging variables or the cerebral metabolite ratios. MR variables, as applied in this study, do not identify patients with minimal HE, nor do they reflect changes in psychometric performance following LOLA. Electronic supplementary material The online version of this article (doi:10.1007/s11011-016-9881-3) contains supplementary material, which is available to authorized users.

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH., Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the beneficial and harmful effects of medical interventions for prevention and treatment of hepatic encephalopathy in adults with cirrhosis.

BACKGROUND: Non‐selective beta‐blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non‐selective beta‐blocker with additional intrinsic alpha(1)‐blocking effects, which may be superior to traditional, non‐selective beta‐blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non‐selective beta‐blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato‐Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non‐selective beta‐blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I(2) values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato‐Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I(2) = 0%, low‐quality evidence). There appeared to be no differences between carvedilol versus traditional, non‐selective beta‐blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I(2) = 45%, very low‐quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I(2) = 14%, low‐quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long‐term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non‐selective beta‐blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non‐serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I(2) = 88%; very low‐quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non‐selective beta‐blockers both in absolute (MD ‐1.75 mmHg, 95% CI ‐2.60 to ‐0.89; 368 participants; 6 trials; I(2) = 0%; low‐quality evidence) and percentage terms (MD ‐8.02%, 95% CI ‐11.49% to ‐4.55%; 368 participants; 6 trials; I(2) = 0%; low‐quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I(2) = 42%; very low‐quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non‐selective beta‐blockers on mortality, upper gastrointestinal bleeding, serious or non‐serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long‐term, double‐blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Introduction Disease severity, disease aetiology and nutritional status are important determinants of outcome in patients with cirrhosis. Functional decline, reflected by health-related quality of life (HRQOL), mental health, and degrees of disability and frailty may also play an important role. However, it is unclear whether these factors influence outcome after liver transplantation. This study aimed to assess the predictive validity of indices of functional decline in determining transplantation outcome in patients with cirrhosis. Methods Twenty-eight consecutive patients (mean [range] age 52 [29–66] yr; 75% men; four (14.3%) alcohol–related; mean MELD 13.2 [7–30]) transplanted for end stage liver disease/HCC were included. All were assessed pre-transplantation, as follows: disease severity: MELD and Child Pugh (CP); nutritional status: The Royal Free Hospital-Nutritional Prioritising Tool; HRQOL: Chronic Liver Disease Questionnaire and Euro Quol-5 Dimension Tool; mental health: Beck Anxiety and Depression Indices; disability: Activities (ADL) and Independent Activities of Daily Living (IADL); and frailty: Clinical Frailty Scale, Short Physical Performance Battery and Fried Frailty Criteria plus two composite instruments, the Bristol Prognostic Index and Karnofsky Age MELD Model. Variables associated with the primary outcome (death/retransplantation) were identified using Cox regression analysis. Variables associated with secondary outcomes, including the total units of blood transfused and the length of hospital stay, were identified using linear regression analysis. Results Patients were followed for a mean of 143 [3–326] days; two (7.1%) died and four (14.3%) were retransplanted. IADL was the only tool significantly associated with mortality in this cohort. Each unit increase in the IADL (decreasing frailty) was associated with a 45% decrease in mortality after adjustment for MELD (Hazard Ratio (HR) 0.55, 95% CI, 0.33–0.92). The total mean LOHS was 28 [7–112] days. The CP score was significantly associated with LOHS (F(1, 25)=6.01, p=0.02, R2=0.19); each unit increase in CP was associated with an increase in LOHS of 6.5 days. The mean units of blood transfused was 46 [3–178]; The amount transfused increased by 11.33 (p=0.03) and 4.2 (p=0.01) units for each unit increase in CP and MELD scores respectively. Conclusions Disease severity and functional decline, characterised by the IADL score are significantly associated with short to medium term transplant outcomes in this cohort. Longer-term follow is required to validate these Results.

Introduction Disease severity and nutritional status are important determinants of outcome in patients with cirrhosis. Health-related quality of life, mental health, disability and frailty all affect outcome. However it is unclear if these measures of functional decline provide information additional to that provided by conventional outcome measures. This study aimed to determine whether indices of functional decline correlate with nutritional status and disease severity. Methods Eighty-six consecutive patients (mean [range] age 54.6 [24–81] yr: 59 men; mean MELD 12.7 [6–37]) attending the hepatology service at the Royal Free Hospital, London were included. All underwent the following assessment in a single sitting: disease severity: MELD; nutritional status: The Royal Free Hospital-Nutritional Prioritising Tool (RFH-NPT); quality of life: Chronic Liver Disease Questionnaire (CLDQ) and Euro Quol-5 Dimension Tool (EQ-5D); mental health: Beck Anxiety/Depression Indices (BAI; BDI); disability: Activities (ADL) and Independent Activities of Daily Living (IADL); frailty: Clinical Frailty Scale (CFS), Short Physical Performance Battery (SPPB) and Fried Frailty Criteria (FFC) plus two composite measures, the Bristol Prognostic Index and Karnofsky Age MELD Model (KAM). Results There was a significant degree of cross correlation between the tools used to assess functional decline (|R| between 0.05–0.58). There were significant correlations between indices of functional decline and nutritional status with the exception of the disability indices (table 1). However, only the Bristol and KAM tools, which contain a measure of disease severity, correlated with MELD. Conclusion In patients with cirrhosis indices of functional decline correlate with nutritional status but not with disease severity. These indices likely provide information of value in determining outcome not captured using conventional outcome measures. Information on their predicative validity would help determine their clinical utility.

Introduction Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926) and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC) within this population. The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 and the development of HCC. Methods Risk variants in PNPLA3, TM6SF2 and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analysed using multivariate logistic regression. Results The development of HCC was independently associated with PNPLA3 rs738409 (OR 1.84 [95% CI 1.55–2.18], p=1.85×10–12) and TM6SF2 rs58542926 (OR 1.66 [1.30–2.13], p=5.13×10–05) using an additive model and after controlling for sex, age, body mass index and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (OR 1.04 [0.88–1.24], p=0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for carriage of both variants combined. Conclusions Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol–related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimise patient care.