Division for Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
BACKGROUND & AIMS:
Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C.
Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m=126, f=76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed.
Insulin resistance (HOMA-IR ⩾3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08±1.61 (mean±SD) and 2.94±2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92±3.15; F0-2: 2.38±2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3±21.5 vs. 9.1±14.2; p<0.001), HOMA-IR ⩾3.0 (17.7±17.8 vs. 8.8±15.4%; p<0.001), and BMI>25.0kg/m(2) (14.7±17.0 vs. 9.1±16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p=0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p=0.007) as independent risk factors for insulin resistance.
Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.