Elevated serum CK18 levels in chronic hepatitis C patients are associated with advanced fibrosis but not steatosis

Abstract

Cytokeratin-18 (CK-18) is a major intermediate filament protein in liver cells. The M30 fragment of CK-18 has been identified as a useful marker of apoptosis associated with fibrosis and steatosis in nonalcoholic steatohepatitis (NASH). We sought to assess the relationship of this marker and steatosis in a cohort of adult patients with chronic hepatitis C. The study cohort included sera from 267 treatment-naïve chronic hepatitis C (CHC) patients and 100 healthy controls with normal alanine aminotransferase (ALT). Biopsies from CHC patients were assessed for METAVIR fibrosis stage, Histology Activity Index (HAI) inflammation score and steatosis grade by expert histopathologists. The M30 fragment of CK-18 was quantified by ELISA. Wilcoxon Rank Sum, Spearman Correlation and Linear Regression tests were performed for statistical analysis. Median CK-18 levels were higher in CHC patients compared to controls (411 vs 196 U/L, P < 0.0001). Fibrosis stage was associated with increasing serum CK-18 levels (P = 0.015) and CK-18 levels were higher for F2-F4 vs F0-F1 (500 vs 344 U/L; P = 0.001). There was no association between CK-18 and increasing steatosis grade 1, 2 or 3 (460.7 vs 416.8 vs 508.3 U/L; P = 0.35) and presence or absence of steatosis (445.3 vs 365.8 U/L; P = 0.075). Fibrosis stage was independently associated with serum M30 in a multivariable linear regression model (P = 0.03). CK-18 levels were higher in CHC compared to healthy controls and associated with hepatic fibrosis. There was no difference in CK-18 M30 levels between CHC patients with and without steatosis. Although apoptosis may still contribute to hepatitis C virus (HCV)-mediated steatosis, our results suggest that serum CK-18 will not be a clinically useful test for identifying significant steatosis in CHC.