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BackgroundPatients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn’s disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition.MethodsPaired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model.ResultsIn human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf.ConclusionsExpression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.

Background Single nucleotide polymorphisms (SNPs) in genes including PNPLA3, TM6SF2, HSD17B13 and SERPINA1 have been identified as risk modifiers of progression in chronic liver disease (CLD). However, it is unclear whether genotyping for these risk variants is useful in clinical routine. Methods Liver disease severity was assessed by liver stiffness measurement (LSM) and by presence of clinical manifestations of advanced-chronic liver disease (ACLD) in 779 consecutive CLD patients at the time of referral to a tertiary center. The associations of risk variants with CLD severity were calculated individually and in a combined model using a polygenic risk-score. Results Non-alcoholic fatty liver disease (NAFLD) was the most common etiology (n = 511, 65.6%), and ACLD was present in 217 (27.9%) patients. The PNPLA3-G-allele remained independently associated with higher LSM (adjusted-B: 2.508 [95%CI: 0.887–4.130], P = 0.002) or the presence of ACLD (aOR: 1.562 [95%CI: 1.097–2.226], P = 0.013). SERPINA1-Z-allele was also independently associated with LSM (adjusted-B: 4.558 [95%CI: 1.182–7.934], P = 0.008), while the other risk alleles did not attain statistical significance. Combining these risk alleles into a polygenic risk-score was significantly associated with LSM (adjusted-B: 0.948 [95%CI: 0.153–1.743], P = 0.020). Conclusion PNPLA3 risk-variants are linked to liver disease severity at the time of first referral to an outpatient hepatology clinic.

Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.Die alkoholbedingte Lebererkrankung (ALD) betrifft jedes Jahr weltweit Millionen von Patienten, und ihre Zahl nimmt zu. Die Krankheitsstadien reichen von Steatose über Steatohepatitis und Fibrose bis hin zu Zirrhose, schwerer alkoholbedingter Hepatitis und Leberkrebs. ALD wird in der Regel erst in einem fortgeschrittenen Stadium diagnostiziert, in dem es keine wirksamen Therapien gibt. Ein wichtiges Forschungsziel ist die Verbesserung der Diagnose, der Prognose und auch der Behandlung von ALD im Frühstadium. Dies erfordert jedoch eine Priorisierung dieser Krankheit für finanzielle Investitionen in die Grundlagen- und klinische Forschung, um die Mechanismen genauer zu untersuchen und Biomarker und therapeutische Ziele für die Früherkennung und -behandlung zu ermitteln. Themen von Interesse sind die Kommunikation der Leber mit anderen Organen des Körpers, insbesondere das Darmmikrobiom, die individuelle genetische Konstitution, systemische und angeborene Entzündungen in der Leber einschließlich bakterieller Infektionen, sowie das Schicksal und die Anzahl der hepatischen Sternzellen und die Zusammensetzung der extrazellulären Matrix in der Leber. Darüber hinaus wirken mechanische Kräfte und schädigende Belastungen auf das hochentwickelte Gefäßsystem der Leber, einschließlich des besonders ausgestatteten sinusoidalen Endothels und der Gallenwege, zusammen, um den hepatozytären Import und Export von Nähr- und Giftstoffen zu vermitteln und sich durch morphologische und funktionelle Veränderungen an die chronische Lebererkrankung anzupassen. Alle vorgenannten Parameter tragen zu den Folgen des Alkoholkonsums und dem Risiko der Entwicklung fortgeschrittener Krankheitsstadien einschließlich Zirrhose, schwerer alkoholischer Hepatitis und Leberkrebs bei. In der vorliegenden Sammlung fassen wir den aktuellen Wissensstand zu diesen alkoholbedingten Parametern der Lebererkrankung zusammen, wobei wir den Aspekt der Entzündung ausklammern, der in dem begleitenden Übersichtsartikel von Lotersztajn und Kollegen dargestellt wird.

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M.

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of

Models predicting an individual's 10-year risk of cirrhosis complications have not been developed for a community setting. Our objectives were to assess the performance of existing risk scores - both with and without genetic data - for predicting cirrhosis complications in the community.We used a 2-stage study design. In stage 1, a systematic review was conducted to identify risk scores derived from routine liver blood tests that have demonstrated prior ability to predict cirrhosis-related complication events. Risk scores identified from stage 1 were tested in a UK Biobank subgroup, comprising participants with a risk factor for chronic liver disease (stage 2). Cirrhosis complications were defined as hospitalisation for liver cirrhosis or presentation with hepatocellular carcinoma. Discrimination of risk scores with and without genetic data was assessed using the Wolbers C-index, Harrell's adequacy index, and cumulative incidence curves.Twenty risk scores were identified from the stage-1 systematic review. For stage-2, 197,509 UK biobank participants were selected. The cumulative incidence of cirrhosis complications at 10 years was 0.58%; 95% CI 0.54-0.61 (1,110 events). The top performing risk scores were aspartate aminotransferase-to-platelet ratio index (APRI: C-index 0.804; 95% CI 0.788-0.820) and fibrosis-4 index (FIB-4: C-index 0.780; 95% CI 0.764-0.795). The 10-year cumulative incidences of cirrhosis complications for participants with an APRI score exceeding the 90Accessible risk scores derived from routine blood tests (particularly APRI and FIB-4) can be repurposed to estimate 10-year risk of cirrhosis morbidity in the community. Genetic data improves performance only minimally.New approaches are needed in community settings to reduce the late diagnosis of chronic liver disease. Thus, in a community cohort, we assessed the ability of 20 routine risk scores to predict 10-year risk of cirrhosis-related complications. We show that 2 routine risk scores in particular - "APRI" and "FIB-4" - could be repurposed to estimate an individual's 10-year risk of cirrhosis-related morbidity. Adding genetic risk factor information to these scores only modestly improved performance.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling. ispartof: GASTROENTEROLOGY vol:159 issue:2 pages:534-+ ispartof: location:United States status: published

Context Recently, the novel metabolic dysfunction-associated fatty liver disease (MAFLD) definition has been introduced. Objective To assess the relevance of MAFLD for mortality. Methods Single-center cohort-study using colorectal cancer screening program involving 4718 subjects aged 45 to 80 who were grouped according to their body mass index (BMI) and the presence or absence of MAFLD. Mortality was compared among these groups by performing a systematic read-out of the national health insurance system, fatty liver (FL) was diagnosed using ultrasound. Results Overall prevalence of FL was 47.9%: 1200 (25.4%) patients were lean (BMI Conclusion Presence of MAFLD does not increase mortality in a cohort of individuals aged 45 to 80 years.

International audience; Introduction - Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. Methods - We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. Results - The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10) and higher premorbid body mass index (26.37 ± 0.16 kg/m) than controls (24.44 ± 0.18 kg/m, P = 5.77 × 10). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. Discussion - If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina).Associations with variants rs738409 inThis study identifies rs2242652 in

Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD., Employing a candidate gene approach, Mancina et al. identify a genetic variant of the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene that reduces susceptibility to fatty liver disease. Functional studies in vitro and in vivo demonstrate that targeting PSD3 protects against fatty liver disease.

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.

The prevalence of colorectal adenoma and advanced adenoma (AA) differs between sexes. Also, the optimal age for the first screening colonoscopy is under debate. We, therefore, performed a sex-specific and age-adjusted comparison of adenoma, AA and advanced neoplasia (AN) rates in a real-world screening cohort. In total, 2824 asymptomatic participants between 45- and 60-years undergoing screening colonoscopy at a single-centre in Austria were evaluated. 46% were females and mean age was 53 ± 4 years. A propensity score for being female was calculated, and adenoma, AA and AN detection rates evaluated using uni- and multivariable logistic regression. Sensitivity analyses for three age groups (group 1: 45 to 49 years, n = 521, 41% females, mean age 47 ± 1 years; group 2: 50 to 54 years, n = 1164, 47% females, mean age 52 ± 1 years; group 3: 55 to 60 years, n = 1139, 46% females, mean age 57 ± 2 years) were performed. The prevalence of any adenoma was lower in females (17% vs. 30%; OR 0.46, 95% CI 0.38–0.55; p

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

The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte®) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1.

International audience; 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 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 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 × 10 ) 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.

BACKGROUND & AIMS Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC). METHODS Healthy controls (n = 212), patients with alcohol abuse without liver disease (n = 382), and patients from a discovery cohort of alcohol-associated cirrhosis (n = 372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n = 355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n = 145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes. RESULTS Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p

Objectives: The European Society of Cardiology endorsed SCORE2 to assess cardiovascular risk. The aim of this observational, retrospective study was to assess whether SCORE2 is associated with colorectal neoplasia in an asymptomatic screening population. Further, we evaluated if SCORE2 predicts tumor-related mortality. Methods: We included 3408 asymptomatic patients who underwent a screening colonoscopy. We calculated SCORE2 for each participant and stratified patients according to their predicted 10-year risk of cardiovascular disease: SCORE2 0–4.9%, SCORE2 5–9.9%, and SCORE2 ≥ 10%. We assessed the association between SCORE2 as a continuous variable, the presence of colorectal neoplasia using multilevel logistic regression, and SCORE2 and mortality using Cox regression. Results: In total, 1537 patients had a SCORE2 of 0–4.9%, 1235 a SCORE2 of 5–9.9%, and 636 a SCORE2 ≥ 10%. The respective rates of colorectal neoplasia were 20%, 37%, and 44%. SCORE2 was associated with the presence of any (OR 1.11 95%CI 1.09–1.12; p < 0.001) and advanced colorectal neoplasia (OR 1.06 95%CI 1.08–1.13; p < 0.001) in univariate analysis. After multivariable adjustment (age, sex, family history, and metabolic syndrome) a higher SCORE2 remained associated with higher odds for any (aOR 1.04 95%CI 1.02–1.06; p = 0.001) and advanced (aOR 1.06 95%CI 1.03–1.10; p < 0.001) colorectal neoplasia. SCORE2 was associated with both all-cause (HR 1.11 95%CI 1.09–1.14; p < 0.001) and tumor-related mortality (HR 1.10 95%CI 1.05–1.14; p < 0.001). Conclusions: We found that SCORE2 is associated with the presence of colorectal neoplasia. Clinicians could kill two birds with one stone calculating SCORE2. In patients with a high SCORE2, screening colonoscopy aside from cardiovascular risk mitigation could improve outcomes.

INTRODUCTION: Although a milder metabolic phenotype of nonalcoholic fatty liver disease (NAFLD) in lean patients (body mass index [BMI] 30 kg/m2). Diagnosis of NAFLD was established using ultrasound (cohort I) and controlled attenuation parameter (cohort II). RESULTS: The prevalence of lean patients with NAFLD was 6.7%/16.1% in the overall cohort I/II and 19.7%/40.0% in lean subjects of cohort I/II. Compared with lean subjects without NAFLD, lean patients with NAFLD had a higher prevalence of dyslipidemia, dysglycemia, and the metabolic syndrome, together with a higher median Framingham risk score in both cohorts (all P < 0.001). On multivariable analyses, NAFLD in lean subjects was associated with higher odds of metabolic syndrome (adjusted odds ratio cohort I: 4.27 [95% confidence interval (CI): 2.80–6.51], P < 0.001; cohort II: 2.97 [95% CI: 1.40–6.33], P < 0.001), and higher Framingham risk score (regression coefficient B cohort I: 1.93 [95% CI: 0.95–2.92], P < 0.003; cohort II: 1.09 [95% CI: 0.81–2.10], P = 0.034), among others. Only 69.8% of lean patients with NALFD in cohort I and 52.1% in cohort II fulfilled the novel criteria for metabolic associated fatty liver disease. DISCUSSION: NAFLD in lean patients is associated with the metabolic syndrome and increased cardiovascular risk. Novel metabolic associated fatty liver disease criteria leave a considerable proportion of patients unclassified.

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

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.

Background & Aims Approximately one‐third of patients with non‐alcoholic fatty liver disease (NAFLD) show signs of mild‐to‐moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established. Methods & Results For this retrospective study, 299 consecutive patients with biopsy‐proven NAFLD and a mean follow‐up of 8.4 (±4.1; range: 0.3‐18.0) years were allocated to one of four groups according to presence of hepatic iron in the reticuloendothelial system (RES) and/or hepatocytes (HC): 156 subjects (52%) showed no stainable iron (NONE), 58 (19%) exclusively reticuloendothelial (xRES), 19 (6%) exclusively hepatocellular (xHC) and 66 (22%) showed a mixed (HC/RES) pattern of iron deposition. A long‐term analysis for overall survival, hepatic, cardiovascular or extrahepatic‐malignant events was conducted. Based on multivariate Cox proportional hazards models any reticuloendothelial iron was associated with fatal and non‐fatal hepatic events. Specifically, xRES showed a cause‐specific hazard ratio (csHR) of 2.4 (95%‐CI, 1.0‐5.8; P = .048) for hepatic as well as cardiovascular fatal and non‐fatal events combined (csHR 3.2; 95%‐CI, 1.2‐8.2; P = .015). Furthermore, the mixed HC/RES iron pattern showed a higher rate of combined hepatic fatal and non‐fatal events (csHR 3.6; 95%‐CI, 1.4‐9.5; P = .010), while xHC iron deposition was not associated with any defined events. Conclusions The presence of reticuloendothelial‐accentuated hepatic iron distribution patterns is associated with detrimental long‐term outcomes reflected in a higher rate of both liver‐related and cardiovascular fatal and non‐fatal events.