PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma.

BACKGROUND AND AIMS: NAFLD is the most common form of liver disease worldwide, but only a subset of individuals with NAFLD may progress to NASH. While NASH is an important etiology of HCC, the underlying mechanisms responsible for the conversion of NAFLD to NASH and then to HCC are poorly understood. We aimed to identify genetic risk genes that drive NASH and NASH-related HCC. APPROACH AND RESULTS: We searched genetic alleles among the 24 most significant alleles associated with body fat distribution from a genome-wide association study of 344,369 individuals and validated the top allele in 3 independent cohorts of American and European patients (N=1380) with NAFLD/NASH/HCC. We identified an rs3747579-TT variant significantly associated with NASH-related HCC and demonstrated that rs3747579 is expression quantitative trait loci of a mitochondrial DnaJ Heat Shock Protein Family (Hsp40) Member A3 ( DNAJA3 ). We also found that rs3747579-TT and a previously identified PNPLA3 as a functional variant of NAFLD to have significant additional interactions with NASH/HCC risk. Patients with HCC with rs3747579-TT had a reduced expression of DNAJA3 and had an unfavorable prognosis. Furthermore, mice with hepatocyte-specific Dnaja3 depletion developed NASH-dependent HCC either spontaneously under a normal diet or enhanced by diethylnitrosamine. Dnaja3 -deficient mice developed NASH/HCC characterized by significant mitochondrial dysfunction, which was accompanied by excessive lipid accumulation and inflammatory responses. The molecular features of NASH/HCC in the Dnaja3 -deficient mice were closely associated with human NASH/HCC. CONCLUSIONS: We uncovered a genetic basis of DNAJA3 as a key player of NASH-related HCC.

A model for individualized prediction of liver-related death in outpatients with alcohol-associated cirrhosis.

INTRODUCTION: In alcohol-associated cirrhosis, an accurate estimate of the risk of death is essential for patient care. We developed individualized prediction charts for 5-year liver-related mortality among outpatients with alcohol-associated cirrhosis that take into account the impact of abstinence. METHODS: We collected data on outpatients with alcohol-associated cirrhosis in a prospective registry. The model was derived, internally and externally validated, and compared with the Child-Pugh and the Model For End-Stage Liver Disease (MELD) scores. RESULTS: A total of 527 and 127 patients were included in the derivation and validation data sets, respectively. A model was developed based on the 3 variables independently associated with liver-related mortality in multivariate analyses (age, Child-Pugh score, and abstinence). In the derivation data set, the model combining age, Child-Pugh score, and abstinence outperformed the Child-Pugh and the MELD scores. In the validation data set, the Brier score was lower for the model (0.166) compared with the Child-Pugh score (0.196, p = 0.008) and numerically lower compared with the MELD score (0.190) (p = 0.06). The model had the greatest AUC (0.77; 95% CI 0.68-0.85) compared with the Child-Pugh score (AUC = 0.66; 95% CI 0.56-0.76, p = 0.01) and was numerically higher than that of the MELD score (AUC = 0.66; 95% CI 0.56-0.78, p = 0.06). Also, the Akaike and Bayesian information criterion scores were lower for the model (2163; 2172) compared with the Child-Pugh (2213; 2216) or the MELD score (2205; 2208). CONCLUSION: A model combining age, Child-Pugh score, and abstinence accurately predicts liver-related death at 5 years among outpatients with alcohol-associated cirrhosis. In this study, the model outperformed the Child-Pugh and the MELD scores, although the AUC and the Brier score of the model were not statically different from the MELD score in the validation data set.

A machine learning-based classification of adult-onset diabetes identifies patients at risk of liver-related complications.

Background & aims: Diabetes mellitus is a major risk factor for fatty liver disease development and progression. A novel machine learning method identified five clusters of patients with diabetes, with different characteristics and risk of diabetic complications using six clinical and biological variables. We evaluated whether this new classification could identify individuals with an increased risk of liver-related complications. Methods: We used a prospective cohort of patients with a diagnosis of type 1 or type 2 diabetes without evidence of advanced fibrosis at baseline recruited between 2000 and 2020. We assessed the risk of each diabetic cluster of developing liver-related complications (i.e. ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma), using competing risk analyses. Results: We included 1,068 patients, of whom 162 (15.2%) were determined to be in the severe autoimmune diabetes subgroup, 266 (24.9%) had severe insulin-deficient diabetes, 95 (8.9%) had severe insulin-resistant diabetes (SIRD), 359 (33.6%) had mild obesity-related diabetes, and 186 (17.4%) were in the mild age-related diabetes subgroup. In multivariable analysis, patients in the SIRD cluster and those with excessive alcohol consumption at baseline had the highest risk for liver-related events. The SIRD cluster, excessive alcohol consumption, and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or transient elastography. Using a simplified classification, patients assigned to the severe and mild insulin-resistant groups had a three- and twofold greater risk, respectively, of developing significant fibrosis compared with those in the insulin-deficient group. Conclusions: A novel clustering classification adequately stratifies the risk of liver-related events in a population with diabetes. Our results also underline the impact of the severity of insulin resistance and alcohol consumption as key prognostic risk factors for liver-related complications. Impact and implications: Diabetes represents a major risk factor for NAFLD development and progression. This study examined the ability of a novel machine-learning approach to identify at-risk diabetes subtypes for liver-related complications. Our results suggest that patients that had severe insulin resistance had the highest risk of liver-related outcomes and fibrosis progression. Moreover, excessive alcohol consumption at the diagnosis of diabetes was the strongest risk factor for developing liver-related events.

Dietary strategies in non-alcoholic fatty liver disease patients: From evidence to daily clinical practice, a systematic review.

Lifestyle modification comprising calorie restriction (CR) and increased physical activity enabling weight loss is the first-line of treatment for non-alcoholic fatty liver disease (NAFLD). However, CR alone is not optimal and evidence suggests that dietary pattern and composition are also critical in NAFLD management. Accordingly, high consumption of red and processed meat, saturated fat, added sugar, and sweetened beverages are associated with an increased risk of developing NAFLD and hepatocellular carcinoma, while other foods and compounds such as fish, olive oil, and polyphenols are, in contrast, beneficial for metabolic disorders. Therefore, several dietary interventions have been studied in order to determine which strategy would be the most beneficial for NAFLD. The evidence regarding the effectiveness of different dietary interventions such as low carbohydrate/low-fat diet, time-restricted eating diet, CR, and the well-studied Mediterranean diet is summarized.

Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis.

BACKGROUND & AIMS: Identifying individuals at higher risk of developing hepatocellular carcinoma (HCC) is pivotal to improve the performance of surveillance strategies. Herein, we aimed to evaluate the ability of single nucleotide polymorphisms (SNPs) to refine HCC risk stratification. METHODS: Six SNPs in PNPLA3, TM6SF2, HSD17B13, APOE, and MBOAT7 affecting lipid turnover and one variant involved in the Wnt-ß-catenin pathway (WNT3A-WNT9A rs708113) were assessed in patients with alcohol-related and/or HCV-cured cirrhosis included in HCC surveillance programmes (prospective CirVir and CIRRAL cohorts). Their prognostic value for HCC occurrence was assessed using Fine-Gray models combined into a 7-SNP genetic risk score (GRS). The predictive ability of two clinical scores (a routine non-genetic model determined by multivariate analysis and the external aMAP score) with/without the GRS was evaluated by C-indices. The standardised net benefit was derived from decision curves. RESULTS: Among 1,145 patients, 86 (7.5%) developed HCC after 43.7 months. PNPLA3 and WNT3A-WNT9A variants were independently associated with HCC occurrence. The GRS stratified the population into three groups with progressively increased 5-year HCC incidence (Group 1 [n = 627, 5.4%], Group 2 [n = 276, 10.7%], and Group 3 [n = 242, 15.3%]; p <0.001). The multivariate model identified age, male sex, diabetes, platelet count, gamma-glutamyltransferase levels, albuminemia and the GRS as independent risk factors. The clinical model performance for 5-year HCC prediction was similar to that of the aMAP score (C-Index 0.769). The addition of the GRS to both scores modestly improved their performance (C-Indices of 0.786 and 0.783, respectively). This finding was confirmed by decision curve analyses showing only fair clinical net benefit. CONCLUSIONS: Patients with cirrhosis can be stratified into HCC risk classes by variants affecting lipid turnover and the Wnt-ß-catenin pathway. The incorporation of this genetic information modestly improves the performance of clinical scores. IMPACT AND IMPLICATIONS: The identification of patients at higher risk of developing liver cancer is pivotal to improve the performance of surveillance. Risk assessment can be achieved by combining several clinical and biological parameters used in routine practice. The addition of patients' genetic characteristics can modestly improve this prediction and will ultimately pave the way for precision medicine in patients eligible for HCC surveillance, allowing physicians to trigger personalised screening strategies.

Salvage transjugular intrahepatic portosystemic shunt in patients with cirrhosis and refractory variceal bleeding: A systematic review with meta-analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) may be used as a salvage treatment in patients with cirrhosis and refractory variceal bleeding. AIM: To synthesize the available evidence on the efficacy of TIPS in patients with cirrhosis and refractory variceal bleeding. METHODS: Meta-analysis of trials evaluating TIPS in patients with cirrhosis and refractory variceal bleeding, including subgroup analysis to assess the impact of recent changes in the management of variceal bleeding (i.e., the use of Polytetrafluoroethylene-covered TIPS and the availability of pre-emptive TIPS as a first-line treatment for acute variceal bleeding). RESULTS: Twenty-three studies with 1430 patients were included. The pooled estimate rates were 0.33 (95% CI = 0.29-0.37) for death at 1 month-6 weeks, 0.46 (95% CI = 0.40-0.52) for death at 1 year, and 0.09 (95% CI = 0.06-0.11) for death due to rebleeding in the follow-up. The pooled estimate rates for death at 1 month or 6 weeks were similar in subgroup analyses including studies that did not use covered TIPS or that did not include patients after the pre-emptive TIPS area compared to the ones that did (pooled estimate rate 0.33 [95% CI = 0.28-0.38] and 0.32 [95% CI = 0.25-0.39], respectively). The pooled estimate rates were 0.16 (95% CI = 0.13-0.18) for rebleeding, 0.25 (95% CI = 0.17-0.36) for occurrence of hepatic encephalopathy, and 0.08 (95% CI = 0.05-0.13) for access to liver transplantation after TIPS insertion. CONCLUSIONS: One third of patients with cirrhosis and refractory variceal bleeding treated with salvage TIPS died within the first 6 weeks. Recent improvements in the management of variceal bleeding did not improve the survival of patients presenting with refractory variceal bleeding.

Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma.

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37-1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43-1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23-3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31-9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08-4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27-3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44-3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling. RESULTS: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies. CONCLUSION: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. LAY SUMMARY: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

New concepts in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and occurs mainly in the context of chronic liver disease at cirrhosis stage. The Barcelona Clinic Liver Cancer classification, first established in 1999, is the most commonly used staging system for HCC in Western countries that link tumor burden, liver function and performance status with prognosis and therapeutic management. Since the first publication of this classification, it has been implemented in several clinical guidelines and recent major therapeutic advances in the management of HCC have modified the therapeutic landscape of HCC. Accordingly, an updated version was recently published in 2022, incorporating an expert clinical decision-making component and the concept of treatment stage migration. This update also introduces the positive results of recent randomized clinical trials, and introduces atezolizumab/bevacizumab (A/B) as a first-line combination regimen for patients with advanced HCC. Finally, the complexity of the management of patients with HCC highlights the need for a multidisciplinary approach including input from hepatology, surgery, radiology, medical oncology, and radiation oncology.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.

BACKGROUND & AIMS: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. METHODS: Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors. RESULTS: We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/ß-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors. CONCLUSIONS: These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. LAY SUMMARY: Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.

Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.

BACKGROUND: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-ß-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING: Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

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

Plasma-Signature-Model for End-Stage Liver Disease Score to Predict Survival in Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability. METHODS: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients. RESULTS: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices. CONCLUSIONS: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

Endoscopic duodenal mucosal resurfacing for nonalcoholic steatohepatitis (NASH): a pilot study.

Background and study aims Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide with limited treatment options. Duodenal mucosal resurfacing (DMR) has been associated with improvement in glycaemic parameters and liver function tests (LFTs) in type 2 diabetes. This study aimed to assess the effect of DMR in patients with NASH. Patients and methods This was a single-center, open-label pilot study. Patients with definite, biopsy-proven NASH (nonalcoholic fatty liver disease activity score [NAS] ≥ 4) underwent a single DMR procedure followed by a 2-week postprocedural diet, without lifestyle intervention. The primary outcome was either resolution of NASH with no worsening of fibrosis or improvement in fibrosis (≥ 1 stage) with no worsening of NASH at 12 months. Secondary outcomes were changes in key histological parameters of NASH, surrogate markers of fibrosis, LFTs, and metabolic factors at 12 months. Results From 2017 to 2019, 14 patients underwent successful DMR, of whom 11 were included in the analysis. After 12 months, no resolution of NASH was observed, while three patients (27 %) had marginal improvement in fibrosis with no worsening of NASH. Serious adverse events related to the procedure were reported in two patients out of 14 (14 %). Neither weight loss nor improvement in NAS score, or in the other secondary outcomes, were observed at 12 months. Conclusions In this small and heterogenous study population, we found that DMR, in the absence of lifestyle intervention, did not induce NASH resolution and marginally improved liver fibrosis at 12 months.