Serum fragmented CK18 levels measured by highly sensitive detection system is correlated with liver fibrosis and is novel non-invasive biomarker for NASH diagnosis

Caspase-cleaved cytokeratin 18 (CK18) fragments is recognized as a useful biomarker for diagnosis of nonalcoholic steatohepatitis (NASH). However, CK18 fragment measurement is not applied in clinical practice due to a wide variety of cutoff values. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay (CLEIA) with new monoclonal antibodies and measured serum fragmented CK18 (fCK18) levels in 54 NASH patients and 100 healthy individuals. Serum fCK18 levels were correlated with ALT and AST (p<0.0001), and were increased in the stage of steatosis (0 vs. 2 or 3: p<0.05), hepatocyte ballooning (0 vs. 1: p<0.01, 0 vs. 2: p<0.001) and lobular inflammation resulted in an association with NAS (NAFL or NAFL+NASH vs. NASH: p<0.01). Serum fCK18 levels were associated with Matteoni (2 vs. 3: p<0.01, 2 vs. 4: p<0.001), brunt grade (0 vs. 1, 2 or 3: p<0.01, 1 vs. 3: p<0.05) and fibrosis stage (1 vs. 2 or 3-4: p<0.05). Serum fCK18 levels were elevated in NAFLD, NAFL＋NASH or NASH patients compared to healthy individuals (p<0.001). ROC analyses yielded AUC values of 0.9181, 0.9278 and 0.957 for serum fCK18 in NAFLD, NAFL+NASH and NASH patients, respectively (p<0.0001). In conclusion, serum fCK18 levels using highly sensitive CLEIA are correlated with liver function and NASH pathology resulted in novel non-invasive biomarker for NASH diagnosis.