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

Abstract

SUMMARY 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.

The Clinical Significance of Serum Apoptotic Cytokeratin 18 Neoepitope M30 (CK-18 M30) and Matrix Metalloproteinase 2 (MMP-2) Levels in Chronic Hepatitis B Patients with Cirrhosis

“…In our study, statistically significant differences in CK-18 M30 and MMP-2 levels between CHB patients and the control group (P = 0.001) indicated that both markers can be used to show liver damage (Figure 1 and 2). Similar to our findings, Jazwinski et al ( 26 ) reported that CK-18 levels were significantly higher in CHC patients than in controls. Kronenberger et al ( 27 ) found that CK-18 levels in patients with CHC and persistently normal ALT levels were significantly higher than in controls.…”

Serum Osteopontin and Cytokeratin-18 in Chronic Hepatitis C Patients

“…They also reported that fibrosis stage was associated with increasing serum CK-18 M30 levels (P=0.015) [16]. Bantel et al, studied the apoptotic marker CK-18 M30 in the serum, low levels of CK-18 M30 were detectable in the control group, and in contrast patients with different grades of disease activity revealed considerably elevated levels of casepase generated fragement CK-18 which agreed with this study.…”

“…OPN is dramatically unregulated both at mRNA and protein levels during the pathogenesis of hepatic fibrosis and in other inflammatory processes [15]. Activated hepatic stellate cells are mainly responsible for the increased expression and synthesis of OPN during fibrogenesis and the increased OPN induces collagen type I production [16].…”

Cytokeratin-18 and uric acid predicts disease severity in Taiwanese nonalcoholic steatohepatitis patients

“…The concordant results were also proved in patients of morbid obesity, pediatric patients and even chronic hepatitis C patients [12,22,23]. Liver fibrosis is the final result of a wide variety of types of liver injury.…”