Serum Cytokeratin-18 Fragment Levels Are Useful Biomarkers for Nonalcoholic Steatohepatitis in Children

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). Noninvasive methods to identify children with NASH are urgently needed. The aim of this study was to evaluate the use of plasma cytokeratin-18 (CK18) fragment levels, a marker of increased hepatocyte apoptosis, as a non-invasive biomarker for pediatric NASH. METHODS: Consecutive children with biopsy-proven NAFLD were included and blood samples were collected at the time of the biopsy. The diagnosis of NASH was based on Brunt's criteria. Histological features were scored: steatosis (0-3), lobular inflammation (0-3), ballooning (0-2), and portal inflammation (0-2). NAFLD activity score was calculated (0-8) and fibrosis stage was scored (0-4). We measured plasma CK18 levels using the M30-Apoptosense enzyme-linked immunosorbent assay kit. RESULTS: A total of 201 subjects were included in the study. The mean age was 10.7 +/- 2.5 years and 37% were male. NASH was diagnosed in 140 patients with a mean NAFLD activity scoring of 4.4 +/- 1.3. CK18 levels were significantly higher in subjects with NASH compared with not NASH (322.1 U/l +/- 104.8 vs. 164.2 U/l +/- 62, respectively; P < 0.001). The risk of having NASH on liver biopsy increased with increased CK18 levels (P < 0.001). For every 10 U/l increase in CK18 levels, the likelihood of having NASH increased by 70% after adjusting for multiple confounders. The performance of CK18 level for the diagnosis of NASH was excellent with an area under the receiver operating characteristics curve of 0.933. CONCLUSIONS: CK18 is a promising non-invasive biomarker for NASH in children with fatty liver disease.