Dataset Information

Impact of a Loss-of-Function Variant in HSD17B13 on Hepatic Decompensation and Mortality in Cirrhotic Patients.

ABSTRACT: A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinical, demographic, and biochemical data, and we performed a genotyping analysis for common variants previously associated with liver disease risk (HSD17B13 rs72613567:TA and PNPLA3 rs738409). Patients homozygous for the TA allele showed a higher MELD score (p = 0.047), Child-Turcotte-Pugh score (p = 0.014), and INR levels (p = 0.046), as well as decreased albumin (p = 0.004) at baseline. After multivariate analysis, patients with the "protective" variant indeed had an increased risk of hepatic decompensation [aHR 2.37 (1.09-5.06); p = 0.029] and liver-related mortality [aHR 2.32 (1.20-4.46); p = 0.012]. Specifically, these patients had an increased risk of developing ascites (Log-R 11.6; p < 0.001), hepatic encephalopathy (Log-R 10.2; p < 0.01), and higher mortality (Log-R 14.1; p < 0.001) at 5 years of follow-up. Interactions with the etiology of the cirrhosis and with the variant rs738409 in PNPLA3 are also described. These findings suggest that the variant rs72613567:TA in HSD17B13 has no protective effect, but indeed increases the risk of decompensation and death in patients with advanced chronic liver disease.

SUBMITTER: Gil-Gomez A

PROVIDER: S-EPMC9569581 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Impact of a Loss-of-Function Variant in <i>HSD17B13</i> on Hepatic Decompensation and Mortality in Cirrhotic Patients.

Gil-Gómez Antonio A Rojas Ángela Á García-Lozano María R MR Muñoz-Hernández Rocío R Gallego-Durán Rocío R Maya-Miles Douglas D Montero-Vallejo Rocío R Gato Sheila S Gallego Javier J Francés Rubén R Soriano Germán G Ampuero Javier J Romero-Gómez Manuel M

International journal of molecular sciences 20221006 19

A common splice variant in HSD17B13 (rs72613567:TA) was recently found to be associated with a reduced risk of developing chronic liver disease in NAFLD patients and a reduced risk of progression to advanced fibrosis and cirrhosis. In this study, we aimed to evaluate the prognosis of cirrhotic patients harboring this variant. We performed a retrospective analysis on 483 prospectively recruited patients from four different hospitals in Spain, followed-up for at least 5 years. We collected clinica ...[more]

PMID: 36233142

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Project description:Background & aimsThe loss-of-function rs72613567 T > TA-variant in the 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) gene might protect from alcoholic and non-alcoholic fatty liver disease (ALD/NAFLD) and associated fibrosis/cirrhosis. We investigated the impact of the T > TA-variant on hepatic decompensation and mortality and investigated its implications on retinol and sex steroid metabolism in patients who had already developed advanced chronic liver disease (ACLD).MethodsRetrospective analysis in prospectively characterized patients with viral hepatitis- and ALD/NAFLD-induced portal hypertension (hepatic venous pressure gradient (HVPG) ≥ 6 mmHg) diagnosed at the Medical University of Vienna.ResultsAmong 487 patients who were followed longitudinally, 166 (34%) were heterozygous and 24 (5%) were homozygous for the 'protective' TA-allele. Patients harbouring at least one TA-allele had a lower MELD (9 (8-12) vs 10 (8-13) points; P = .003) and showed a trend towards lower HVPG (16 ± 6 vs 17 ± 7 mmHg; P = .067). Interestingly, in competing risk analyses adjusted for age, HVPG and MELD, harbouring the TA-allele was associated with numerically increased risks for mortality (adjusted subdistribution hazard ratio (aSHR): 1.3 (95% confidence interval (95% CI): 0.888-1.91); P = .18), liver-related death (aSHR: 1.34 (95% CI: 0.9-1.98); P = .15) and hepatic decompensation (aSHR: 1.29 (95% CI: 0.945-1.77); P = .11). This might be explained by trends towards worse outcomes (eg liver-related death: aSHR: 1.64 (95% CI: 0.95-2.84); P = .076) in patients with viral hepatitis-induced ACLD. In a cross-sectional analysis of 211 additional patients, serum retinol levels were comparable between HSD17B13 genotypes, but in males, serum testosterone levels numerically decreased with an increasing number of TA-alleles.ConclusionIn patients with viral hepatitis- and ALD-induced portal hypertension, the T > TA-variant was not protective of hepatic decompensation and mortality. Further studies should investigate the pathophysiological mechanisms underlying the effects of HSD17B13 genotype at different stages of liver disease.

Project description:Background and aimThe nuclear farnesoid X receptor (FXR) regulates critical pathways of hepatic metabolism, inflammation, and gut mucosal barrier. Thus, we investigated the association of FXR-single nucleotide polymorphism (SNPs) with hepatic decompensation and liver-related mortality in patients with advanced chronic liver disease.MethodsTwo FXR-SNPs (rs56163822 G > T and rs35724 G > C) were genotyped in a cohort of 402 prospectively characterized patients with hepatic venous pressure gradient (HVPG) ≥ 6 mmHg.ResultsOnly 19 patients (4.7%) harbored a rs56163822 T-allele and had less pronounced liver disease as indicated by lower Child-Pugh score (CPS, 6 ± 1 vs 7 ± 2 points, P = 0.034) and higher albumin levels (38.9 ± 4.9 vs 35.9 ± 5.9 g/L, P = 0.026). In contrast, n = 267 (66.4%) patients harbored minor rs35724 allele (G/C or C/C) and had more advanced liver disease, as indicated by a higher model of end-stage liver disease (11 ± 4 vs 10 ± 3, P = 0.016), while other baseline characteristics were similar across FXR-SNP genotypes. In compensated CPS-A patients, the rs35724 minor allele was independently protective for the development of ascites (adjusted hazard ratio [aHR] = 0.411, 95% confidence interval (95% CI): 0.191-0.885; P = 0.023) and tended to reduce the risk of hepatic decompensation (aHR = 0.625, 95% CI: 0.374-1.044, P = 0.072) in multivariate analyses. Of note, transplant-free survival was longer in patients with rs35724 minor allele and HVPG ≥ 10 mmHg (at 5 years: 68.2% vs 55.8%, P = 0.047) and those with HVPG ≥ 16 mmHg (63.3% vs 44.0%, P = 0.021). After adjusting for established risk factors, the rs35724 minor allele was independently associated with reduced liver-related mortality in the overall cohort (aHR = 0.658, 95% CI: 0.434-0.998, P = 0.049), in compensated CPS-A patients (aHR = 0.488, 95% CI: 0.252-0.946, P = 0.034), in patients with HVPG ≥ 10 mmHg (aHR = 0.547, 95% CI: 0.346-0.864, P = 0.010), and in patients with HVPG ≥ 16 mmHg (aHR = 0.519, 95% CI: 0.307-0.878, P = 0.014).ConclusionThe FXR-SNP rs35724 was associated with a reduced risk for development of ascites and liver-related mortality in patients with advanced chronic liver disease.

Project description:To validate prognostic scores for acute decompensation of cirrhosis and acute-on-chronic liver failure in Brazilian patients.This is a prospective cohort study designed to assess the prognostic performance of the chronic liver failure-consortium (CLIF-C) acute decompensation score (CLIF-C AD) and CLIF-C acute-on-chronic liver failure score (CLIF-C ACLF), regarding 28-d and 90-d mortality, as well as to compare them to other prognostic models, such as Model for End-Stage Liver Disease (MELD), MELD Sodium (MELD-Na), Child-Pugh (CP) score, and the CLIF-C Organ Failure score (CLIF-C OF). All participants were adults with acute decompensation of cirrhosis admitted to the Emergency Department of a tertiary hospital in southern Brazil. Prognostic performances were evaluated by means of the receiver operating characteristic (ROC) curves, area under the curves (AUC) and 95%CI.One hundred and thirteen cirrhotic patients were included. At admission, 18 patients had acute-on-chronic liver failure (ACLF) and 95 individuals had acute decompensation (AD) without ACLF, of which 24 eventually developed ACLF during the course of hospitalization (AD evolving to ACLF group). The AD group had significantly lower 28-d (9.0%) and 90-d (18.3%) mortality as compared to the AD evolving to ACLF group and to the ACLF group (both P < 0.001). On the other hand, 28-d and 90-d mortalities were not significantly different between AD evolving to ACLF group and ACLF group (P = 0.542 and P = 0.708, respectively). Among patients with ACLF, at 28 d from the diagnosis, CLIF-C ACLF was the only score able to predict mortality significantly better than the reference line, with an AUC (95%CI) of 0.71 (95%CI: 0.54-0.88, P = 0.021). Among patients with AD, all prognostic scores performed significantly better than the reference line regarding 28-d mortality, presenting with similar AUCs: CLIF-C AD score 0.75 (95%CI: 0.63-0.88), CP score 0.72 (95%CI: 0.59-0.85), MELD score 0.75 (95%CI: 0.61-0.90), MELD-Na score 0.76 (95%CI: 0.61-0.90), and CLIF-C OF score 0.74 (95%CI: 0.60-0.88). The same occurred concerning AUCs for 90-d mortality: CLIF-C AD score 0.70 (95%CI: 0.57-0.82), CP score 0.73 (95%CI: 0.62-0.84), MELD score 0.71 (95%CI: 0.59-0.83), MELD-Na score 0.73 (95%CI: 0.62-0.84), and CLIF-C OF score 0.65 (95%CI: 0.52-0.78).This study demonstrated that CLIF-C ACLF is the best available score for the prediction of 28-d mortality among patients with ACLF. CLIF-C AD score is also useful for the prediction of mortality among cirrhotic patients with AD not fulfilling diagnostic criteria for ACLF, but it was not superior to other well-established prognostic scores.

Project description:HSD17B13 encodes hydroxysteroid 17-β dehydrogenase 13, a novel liver lipid-droplet associated protein that is involved in the regulation of lipid biosynthetic processes. A protein-truncating HSD17B13 variant (rs72613567) was shown to protect individuals from alcoholic and non-alcoholic liver disease. Since steatosis is a common feature in Wilson's disease (WD), we aimed to assess whether the HSD17B13 variant modulates the phenotypic presentation and progression of WD.MethodsThe HSD17B13:TA (rs72613567) variant was determined by allelic discrimination real-time PCR in 586 patients. The HSD17B13 genotype was correlated with the phenotypic presentation. The age of onset and the type of symptoms at presentation were used as markers of the WD phenotype.ResultsThe overall HSD17B13:TA allele frequency in patients with WD was 23.3% (273/1,172), not significantly different from the reported minor allele frequency. There was a significantly lower HSD17B13:TA allele frequency in patients with fulminant WD compared to all other phenotypic WD groups (11.0% vs. 24.0%, p < 0.01). Among the patients with fulminant WD there was a trend for a gender effect; none of the male patients carried the HSD17B13:TA allele. HSD17B13:TA allele frequency was more common in patients with minimal or no fibrosis (49 [31.1%] had simple steatosis and 20 minimal changes at biopsy) than in patients with cirrhosis or advanced fibrosis (22.3%, p = 0.025).ConclusionsThe HSD17B13:TA allele modulates the phenotype and outcome of WD. This allele likely ameliorates hepatic fibrosis and reduces the transition from copper induced hemolysis to fulminant disease in patients with WD.Lay summaryWilson's disease is a hereditary disease caused by accumulation of copper in the liver and other tissues. It presents with a variety of clinical symptoms. In this study we explored the role of a recently described gene mutation (HSD17B13:TA) which apparently protects the liver against toxins like alcohol. The results indicate that this mutation plays a role in the evolution of liver disease. Patients with Wilson's disease who carry this mutation are more likely to have mild disease, while the absence of the mutation is associated with the most severe form - fulminant Wilson's disease.

Project description:The rs738409 C>G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis.To investigate its impact on hepatic decompensation and (liver-related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter.We performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease-induced portal hypertension (hepatic venous pressure gradient [HVPG] ? 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014-2017; n = 153; cross-sectional study).While survival was similar between PNPLA3-C/C and -C/G patients, we observed substantially increased mortality in PNPLA3-G/G patients. PNPLA3-G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3-G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1-4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22-3.98; P = 0.009; liver-related: aSHR: 2.2, 95% CI: 1.08-4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ? 10 mm Hg), PNPLA3-G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27-4.29; P = 0.006). PNPLA3-genotype had no influence on controlled attenuation parameter or the prevalence of values ?248 dB/m.PNPLA3-G/G-genotype seems to double the risks of hepatic decompensation and (liver-related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis.

Dataset Information

Impact of a Loss-of-Function Variant in HSD17B13 on Hepatic Decompensation and Mortality in Cirrhotic Patients.

Publications

Impact of a Loss-of-Function Variant in <i>HSD17B13</i> on Hepatic Decompensation and Mortality in Cirrhotic Patients.

Similar Datasets

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