Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease

J Hepatol. 2014 Jan;60(1):167-74. doi: 10.1016/j.jhep.2013.07.042. Epub 2013 Aug 20.


Background & aims: Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/histological parameters.

Methods: 424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n=275) and histology (n=318).

Results: Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137-329] vs. 122 [IQR: 98-155]U/L) or with vs. without NASH (232 [IQR: 151-387] vs. 170 [IQR: 135-234]U/L, both p<0.001). Plasma CK-18 raised significantly with any increase in steatosis, inflammation and fibrosis, but there was a significant overlap across disease severity. The CK-18 AUROC to predict NAFLD, NASH or fibrosis were 0.77 (95% CI=0.71-0.84), 0.65 (95% CI=0.59-0.71) and 0.68 (95% CI=0.61-0.75), respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63% (57-70%)/83% (69-92%), 58% (51-65%)/68% (59-76%) and 54% (44-63%)/85% (75-92%), respectively. CK-18 correlated most strongly with ALT (r=0.57, p<0.0001) and adipose tissue IR (insulin-suppression of FFA: r=-0.43; p<0.001), less with steatosis, lobular inflammation and fibrosis (r=0.28-0.34, all p<0.001), but not with ballooning, BMI, metabolic syndrome or T2DM.

Conclusions: Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study.

Keywords: Cytokeratin-18; Diabetes; Fatty liver; Insulin resistance; NAFLD; NASH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biomarkers / blood
  • Fatty Liver / blood*
  • Fatty Liver / diagnosis
  • Fatty Liver / pathology
  • Female
  • Humans
  • Insulin Resistance
  • Keratin-18 / blood*
  • Liver / pathology
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / diagnosis
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Predictive Value of Tests


  • Biomarkers
  • Keratin-18