The diagnosis of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and fibrosis relies on liver biopsy. Non-invasive assessments are urgently needed.


To evaluate cell apoptotic marker cytokeratin-18 M30 and total cell death markers cytokeratin-18 M65/M65ED for the assessment and monitoring of NAFLD.


A cohort of 147 patients with biopsy-proven NAFLD and 73 controls were enroled, including 51 patients who received paired liver biopsies 36 months apart. Biomarkers were determined by enzyme-linked immunosorbent assay.


M30, M65 and M65ED increased in a stepwise fashion in control subjects, patients with non-NASH, NAFLD and NASH (all < 0.001). All biomarkers had similarly high accuracy over 0.9 in predicting NAFLD and moderate accuracy around 0.7 in predicting NASH. Among patients with paired liver biopsies, changes in M30, M65 and M65ED positively correlated with disease progression (rho = 0.42, 0.32 and 0.39; = 0.002, 0.023 and 0.005 respectively), and only changes in M65 and M65ED correlated with fibrosis progression (rho = 0.29, 0.34; = 0.038, 0.015 respectively). Both M30 and M65 had area under receiver-operating characteristics curve above 0.8 in predicting disease progression. At cut-off of 236 U/L, changes of M65ED had 88% NPV and 59% PPV to exclude and predict fibrosis progression.


Cytokeratin-18 M30 and M65/M65ED have moderate accuracy in detecting non-alcoholic steatohepatitis. Changes in the biomarkers also correlate with histological progression. However, development of new biomarkers is still required to improve the diagnostic accuracy.