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

Kenneth Cusi, Zhi Chang, Steve Harrison, Romina Lomonaco, Fernando Bril, Beverly Orsak, Carolina Ortiz-Lopez, Joan Hecht, Ariel E. Feldstein, Amy Webb, Christopher Louden, Martin Goros, Fermin Tio

Research output: Contribution to journalArticlepeer-review

195 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)167-174
Number of pages8
JournalJournal of Hepatology
Issue number1
StatePublished - Jan 2014


  • Cytokeratin-18
  • Diabetes
  • Fatty liver
  • Insulin resistance
  • NASH

ASJC Scopus subject areas

  • Hepatology


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