Gene Predicts Recovery from Decompensated HCV Cirrhosis

Winston Dunn, MD

A gene linked to risk for steatosis predicted likelihood of patients with sustained virologic response (SVR) after direct-acting antiviral (DAA) treatment recovering from decompensated hepatitis C cirrhosis.

"Patients with decompensated cirrhosis experience a variety of outcomes," observed Winston Dunn, MD, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO, and colleagues, "and the prognostic factors for clinical recovery from decompensated cirrhosis after SVR remain unknown."

Dunn and colleagues hypothesized that genetic variability in genes related to steatosis contribute to the heterogeneous clinical recovery of patients with HCV cirrhosis after DAA treatment.

"Our working hypothesis is that patients with a genetic disposition to NASH (non-alcoholic steatohepatitis)…continue to undergo steatohepatitis-like injury and therefore fail to recover," Dunn told MD Magazine^®.

The investigators identified a study population of 56 HCV patients who had attained SVR with DAA treatment but remained with Child-Pugh-Turcott (CPT) class B or C cirrhosis. A cheek swab was collected from each to determine genotype, and 3 single nucleotide polymorphisms (SNP) linked to steatosis: rs738409 of the Palatin-Like Phospholipase Domain-Containing 3 (PNPLA3) gene; rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2); and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7).

The primary patient outcomes analyzed against genotypes were changes in CPT and Model for End-Stage Liver Disease (MELD) scores at 12, 24, and 48 weeks after confirmed SVR 12 weeks after treatment (SVR12). The analysis adjusted for potential confounders such as baseline CPT and MELD scores, age, gender, body mass index (BMI), history of diabetes, previous heavy alcohol use, HCV genotype 3, treatment with a protease inhibitor regimen and/or ribavirin, and treatment duration.

Dunn and colleagues reported that the PNPLA3 genotype CC had more overall CPT improvement on average than either the CG or GG genotypes. PNPLA3 CG/GG were associated with slower biochemical recovery (with higher MELD scores) and slower clinical recovery (higher CPT scores). In addition, hepatic encephalopathy and elevated bilirubin were more prominent in patients with the PNPLA3 CG/GG compared with the PNPLA3 CC genotype. The rs738409 SNP of PNPLA3 was identified in a subgroup of patients with suboptimal clinical recovery, but the results with rs5854296 and rs641738 were not significant.

Although the study linked PNPLA3 CG/GG with a subgroup of patients with decompensated HCV cirrhosis having suboptimal clinical recovery despite SVR, Dunn indicated that clinical screening for these apparently unfavorable PNPLA3 genotypes, to help target liver transplantation candidates for example, is not yet warranted.

"The effect of PNPLA3 is relatively modest compared to the measurable degree of liver decompensation," Dunn explained. "Currently, patients with a MELD score of about 14 undergo a liver transplant evaluation. Having an unfavorable PNPLA3 genotype is roughly equivalent to having 2 points higher MELD score."

"This kind of study will be very useful clinically when we can put together a panel of genetic scores to predict survival collectively," Dunn said.

The study, “PNPLA3 Gene Predicts Clinical Recovery After Sustained Virologic Response in Decompensated Hepatitis C Cirrhosis,” was published in BMJ Open Gastroenterology.