Influence of Genetic Variants on Disease Regression and Outcomes in HCV-Related Advanced Chronic Liver Disease after SVR

Abstract

Genetic variants including PNPLA3-rs738409 C>G, TM6SF2-rs58542926 C>T, MBOAT7-rs641738 C>T, and HSD17B13-rs72613567 T>TA have been shown to influence progression to advanced chronic liver disease (ACLD) in patients with chronic hepatitis C (CHC). We aimed to investigate their impact on disease regression (i.e., changes in hepatic venous pressure gradient [HVPG] and non-invasive surrogates [liver stiffness measurement (LSM), von Willebrand factor (VWF), and VWF/platelet count ratio (VITRO)]) and clinical outcomes after CHC cure in 346 patients with pre-treatment ACLD. Patients carrying the PNPLA3 minor allele had more advanced liver disease prior to antiviral therapy, confirming its impact on liver disease progression. In a subgroup of 88 patients who underwent paired HVPG-measurements and were genotyped for all SNP/indels, PNPLA3/TM6SF2/MBOAT7/HSD17B13 genotypes were not associated with changes in HVPG. In line, changes in non-invasive surrogates of portal hypertension (LSM/VWF/VITRO) were comparable between carriers and non-carriers of the PNPLA3 G-allele in the overall cohort. Finally, carriage of PNPLA3 G-allele was not associated with the development of hepatic decompensation, de-novo hepatocellular carcinoma, or transplant-free mortality during a median follow-up of 42 months after the end of antiviral treatment. Therefore, genetic variants in PNPLA3/TM6SF2/MBOAT7/HSD17B13 do not impact the regression of portal hypertension and clinical outcomes in patients with pre-treatment ACLD after CHC cure.

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease

“…After excluding all patients with Child-Turcotte-Pugh (CTP) stage C who were not candidates for liver transplantation (i.e., patients in whom surveillance is not recommended [19]), a history or a current diagnosis of HCC, porto-sinusoidal vascular disease, previous orthotopic liver transplantation (OLT), or an HCC diagnosis/OLT during treatment from the dataset, 527 patients were included. Notably, subgroups of these patients have been previously investigated with regard to changes in HVPG and their prognostic value [4,5], the diagnostic/predictive ability of non-invasive markers for portal hypertension and hepatic decompensation [11], the predictive value of VITRO for hepatic decompensation [20], the influence of genetic variants on liver disease regression [21], as well as changes in coagulation after HCV-cure [22].…”

The genetics of portal hypertension: Recent developments and the road ahead

“…Besides promoting intracellular fat accumulation in hepatocytes, PNPLA3 plays a key role in the trans‐activation of HSC, 42 by regulating the dismissal of retinol‐esters during HSC activation, and the PNPLA3 variant has been linked to a more inflammatory and fibrogenic phenotype in HSC 43,44 . Even though in small initial studies genetic variants in PNPLA3 do not seem to impact the risk of disease progression and severity in patients with HIV/HCV coinfection, nor the regression of PH in patients with chronic hepatitis C viral eradication, 45,46 carriage of the PNPLA3 p.I148M variant has been associated with the risk of disease progression and decompensation in patients with portal hypertension due to SLD 47,48 . These data suggest that a large fraction of patients with severe SLD may be predisposed to develop PH due to shared genetic mechanisms with SLD.…”