Abstinence is associated with better outcomes in patients with alcohol-related hepatocellular carcinoma: Results of an observational study.

BACKGROUND: Patients with alcohol-related cirrhosis and hepatocellular carcinoma (HCC) may have reduced survival compared to those with HCC related to other causes. The impact of abstinence in alcohol-related HCC is unknown. We compared access to curative treatment and the prognosis of patients with HCC according to the cause of cirrhosis and evaluated the impact of abstinence on the prognosis of patients with alcohol-related HCC. PATIENTS AND METHODS: Data for patients with cirrhosis and HCC were prospectively collected in a single center. A logistic regression model was used to identify factors associated with access to curative treatment. Multivariate Fine and Gray proportional hazards models were used to identify factors associated with 5-year survival after adjustment for lead-time bias. RESULTS: Two hundred patients were included, 114 (57 %) with non-alcohol-related HCC and 86 (43 %) with alcohol-related HCC (35 abstainers, 51 consumers). During follow-up, 21 patients were transplanted and 156 died. The proportion of patients who had access to curative treatment was 65 % in abstainers, 44 % in consumers, and 57 % in patients with non-alcohol-related cirrhosis (p = 0.06). In multivariate analyses, abstinence was not associated with better access to curative treatment. After adjustment for lead-time bias, the 5-year cumulative incidence of overall death was significantly lower in abstainers than in consumers and in patients with non-alcohol-related cirrhosis (52 % vs. 78 % vs. 81 %, respectively, p = 0.04). In multivariate analyses, abstainers had lower risk of death than consumers (SHR: 0.47, 95 % CI: 0.28-0.80, p = 0.005). CONCLUSION: Abstinence improves the outcome of patients with alcohol-related cirrhosis once HCC has occurred.

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.

Viral clade is associated with severity of symptomatic genotype 3 hepatitis E virus infections in Belgium, 2010-2018.

BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: 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. DESIGN: 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). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

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.

Portal vein recanalisation alone to treat severe portal hypertension in non-cirrhotic patients with chronic extrahepatic portal vein obstruction.

Background & Aims: We aimed to evaluate long-term outcome of patients with chronic non-cirrhotic extrahepatic portal vein obstruction (CNC-EHPVO) who underwent portal vein recanalisation (PVR) without transjugular intrahepatic portosystemic shunt (TIPS) insertion and to determine factors predicting PVR failure and stent occlusion. Methods: This retrospective monocentric study included all patients who underwent PVR without TIPS insertion in the context of CNC-EHPVO between the years 2000 and 2019. Primary patency was defined by the absence of a complete stent occlusion on follow-up imaging. Results: A total of 31 patients underwent PVR with a median follow-up of 52 months (24-82 months). Indications were gastrointestinal bleeding (n = 13), abdominal pain attributed to CNC-EHPVO (n = 7), prior to abdominal surgery (n = 4), and others (n = 7). Technical success was obtained in 27 patients. PVR failure was associated with extension within the intrahepatic portal veins (p = 0.005) and recanalisation for abdominal pain (p = 0.02). Adverse events occurred in 6 patients with no mortality. Anticoagulation was administered in 21 patients after technical success of PVR. In patients with technical success, 5-year primary patency was 73% and was associated with improved muscle mass (p = 0.007) and decreased spleen volume (p = 0.01) at 1 year. Furthermore, 21 (78%) patients with PVR technical success were free of portal hypertension complication at 5 years. Conclusions: PVR without TIPS insertion was feasible and safe in selected patients with CNC-EHPVO and portal hypertension with past or expected complications. Primary patency at 5 years was obtained in 3 of 4 patients with technical success of PVR and was associated with a control of complications of CNC-EHPVO. PVR was associated with improvement of sarcopenia and decreased spleen volume at 1 year. Lay summary: Patients with chronic obstruction of the portal vein and without cirrhosis or malignancy can develop complications related to the high pressure in the venous system. The present study reports long-term favourable outcome of patients in whom the obstruction was treated with stents.

The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis.

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P = 2.9 × 10-5 ). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P = 3.1 × 10-6 ). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P = 0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P = 0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.

Granulocyte colony-stimulating factor for alcoholic hepatitis: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND & AIMS: Granulocyte colony-stimulating factor (G-CSF) treatment has been proposed as a therapeutic option for patients with severe alcoholic hepatitis (AH). The aim of this study was to synthesise available evidence on the efficacy of G-CSF in AH. METHODS: This is a meta-analysis of randomised controlled trials evaluating the risk of death at 90 days and the risk of infection. RESULTS: Seven studies were included. Of a total of 396 patients, 336 had AH, 197 patients were treated with G-CSF, and 199 received placebo or pentoxifylline. In overall meta-analysis, G-CSF therapy was associated with a reduced risk of death at 90 days (odds ratio [OR] 0.28; 95% CI 0.09-0.88; p = 0.03). There was high heterogeneity between studies (p <0.001; I 2 = 80%). Five studies were performed in Asia and 2 in Europe. In the subgroup analysis of studies performed in Asia, G-CSF was associated with a reduced risk of death (OR 0.15; 95% CI 0.08-0.28; p <0.001; heterogeneity: p = 0.5, I 2 = 0%). In European studies, G-CSF tended to increase mortality compared with controls, although the difference was not significant (OR 1.89; 95% CI 0.90-3.98; p = 0.09; heterogeneity: p = 0.8, I 2 = 0%). In Asian studies, occurrence of infection was less frequent in G-CSF patients than in controls (OR 0.12; 95% CI 0.06-0.23; p <0.001; heterogeneity: p = 0.7, I 2 = 0%), whilst in European studies, this occurrence was not statistically different (OR 0.92; 95% CI 0.50-1.68; p = 0.78; heterogeneity: p = 0.5, I 2 = 0%). In sensitivity analyses, excluding studies that included patients with acute-on-chronic liver failure (ACLF) other than AH, patients with less severe AH, or patients with non-response to corticosteroids, results were similar to those of overall analyses, both for mortality and occurrence of infection. CONCLUSIONS: Granulocyte colony-stimulating factor therapy may improve the prognosis of patients with severe AH. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear. LAY SUMMARY: The main finding of this meta-analysis is that the use of granulocyte colony-stimulating factor (G-CSF) is associated with a mortality reduction of more than 70% at 3 months amongst patients with alcoholic hepatitis (AH) compared with controls who did not receive this therapy. However, owing to the high heterogeneity observed in the overall analysis caused by conflicting results between the Asian and European studies, G-CSF cannot currently be recommended for patients with AH, particularly in Europe. Whether these differences can be explained by ethnic differences or disparities in patient selection and disease severity remains unclear.

Histologic parameter score does not predict short-term survival in severe alcoholic hepatitis.

BACKGROUND AND AIM: The alcoholic hepatitis histologic score has been proposed as a new prognostic tool to assess the risk of death in alcoholic hepatitis. We aimed to evaluate its prognostic value in patients with severe alcoholic hepatitis. METHODS: Liver biopsies were analysed independently by two pathologists according to the alcoholic hepatitis histologic score. The Laennec staging system was also used to evaluate fibrosis. RESULTS: One hundred and seven patients were included, and 89% of the patients received corticosteroids. The alcoholic hepatitis histologic score was available in 105 patients. Histologic scoring showed mild, moderate and severe scores in 10, 29 and 66 patients, respectively. Laennec staging was available for 53 patients, among whom 49 had cirrhosis, including 7 with Laennec 4A, 15 with 4B and 27 with 4C. Survival rates in mild, moderate and severe alcoholic hepatitis histologic score groups were 90%, 72% and 69% at 28 days (p = 0.6), 80%, 52% and 63% at 3 months (p = 0.3), and 70%, 41% and 58% at 6 months (p = 0.3), respectively. Within the alcoholic hepatitis histologic score, fibrosis demonstrated the best interobserver reproducibility (agreement = 100%, Κ = 1.00). Compared to patients with Laennec 4B or 4C cirrhosis, survival rates for patients without cirrhosis or with Laennec 4A cirrhosis were 100% vs 83% at 28 days (p = 0.16), 91% vs 68% at 3 months (p = 0.13), and 82% vs 64% at 6 months (p = 0.2), respectively. In multivariate analysis adjusted for age and for model for end-stage liver disease score, the alcoholic hepatitis histologic score and Laennec stage were not associated with 6-month mortality. CONCLUSIONS: The alcoholic hepatitis histologic score is not predictive of short-term survival in this cohort of patients with severe alcoholic hepatitis.

Liver transplant for alcoholic hepatitis: a current clinical overview.

INTRODUCTION: Current management of severe alcoholic hepatitis is based on corticosteroid therapy and abstinence from alcohol. As liver transplantation is lifesaving in alcoholic hepatitis patients at high risk of early death, refractory alcoholic hepatitis has become a new indication for liver transplantation in highly selected non-responders to corticosteroids. AREAS COVERED: This review summarizes the conditions under which liver transplantation may be considered, the available data on liver transplantation for refractory alcoholic hepatitis and explores the ethical considerations surrounding the use of liver transplantation in these patients. EXPERT OPINION: Selection of candidates should be made according to available scientific results on post-liver transplantation outcomes and the risk of alcohol relapse. Currently, a strict selection process based on a good psychosocial profile, including social stability, no previous treatments for alcohol dependence, no current drug use, and no co-existing severe mental disorder, seems to be the best way to manage these issues. Well-defined selection criteria for candidate selection and accurate tools to predict alcohol relapse after liver transplantation are still needed.

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.

BACKGROUND AND AIMS: 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. METHODS: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

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.

Gene signature-MELD score and alcohol relapse determine long-term prognosis of patients with severe alcoholic hepatitis.

BACKGROUND: The gene-signature-model for end stage liver disease (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 = .001), and 81% (95% CI: 58-96) and 22% (95% CI: 10-47) in abstainers and in consumers (P < .001) respectively. In multivariable competing risk regression modelling, gs-MELD score (subdistribution hazard ratio: 5.78, 95% CI: 2.17-15.38, P < .001) and recurrent alcohol consumption (subdistribution hazard ratio: 12.18, 95% CI: 3.16-46.95, P < .001) were independently associated with 5-year mortality. CONCLUSIONS: Both gs-MELD score and alcohol consumption drive AH long-term prognosis. The gs-MELD score may guide the development of molecularly targeted therapies in AH.

Systematic review with meta-analysis: automated low-flow ascites pump therapy for refractory ascites.

BACKGROUND: Few effective treatments are available for patients with cirrhosis and refractory ascites. New treatment modalities are needed for these patients. AIM: To synthesise the available evidence on the efficacy and safety of automated low-flow ascites pump therapy in patients with cirrhosis and refractory ascites. METHODS: Electronic databases were searched for trials evaluating automated low-flow ascites pump therapy in patients with refractory ascites. RESULTS: Nine studies were included. Eight were case series, one was a randomised controlled trial. Pooled estimate rates were 0.62 (95% CI = 0.49-0.74) for the absence of requirement of large volume paracentesis (LVP) after pump insertion, 0.30 (95% CI = 0.17-0.47) for acute kidney injury, 0.27 (95% CI = 0.13-0.49) for bacterial peritonitis and 0.20 (95% CI = 0.09-0.37) for urinary tract infection. There was high heterogeneity between studies which was often reduced or eliminated in sensitivity analyses by excluding studies of patients with a mean or median model for end-stage liver disease (MELD) score > 15. Results of sensitivity analyses were similar to those of overall analyses. Mean increase in serum creatinine level after pump insertion was 23 µmol/L (95% CI = 10-35) with no heterogeneity between studies. The pooled estimate rate for pump-related side effects was 0.77 (95% CI = 0.64-0.87) with low heterogeneity between studies. CONCLUSION: This meta-analysis demonstrates that most patients treated with automated low-flow ascites pump therapy do not require LVP after pump insertion. Acute kidney injury occurs in 30% of patients and creatinine levels increase by a mean of 23 µmol/L after pump insertion. Bacterial peritonitis and urinary tract infection occur in 27% and 20% of patients respectively.

Correction: Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related Cirrhosis.

Author Pierre Deltenre, MD should appear in the author list in position 25, between Felix Braun and Thomas Berg. He should also have a PhD degree added to his name.