To the Editor:

The multicenter study by Feldstein and colleagues1 on the usefulness of caspase-generated cytokeratin-18 (CK-18) fragments in the noninvasive diagnosis of nonalcoholic steatohepatitis (NASH) is definitely interesting. The authors convincingly demonstrated that elevated levels of CK-18 fragments, which serve as markers of hepatocyte apoptosis, are a strong and independent biochemical correlate of NASH, as well as of the presence of liver fibrosis. These results confirm and expand our original observation that CK-18 fragments might serve to noninvasively distinguish steatohepatitis in the setting of nonalcoholic fatty liver disease.2 Altogether, these findings hold great promise to downgrade the role of invasive liver biopsy as the only reliable way of diagnosing NASH and monitoring disease progression.

Of note, the authors have also provided evidence that the addition of routinely available laboratory tests did not significantly improve the sensitivity and specificity of CK-18 fragments to diagnose NASH.1 It is possible, however, that the addition of biomarkers that cover different pathophysiological facets of steatohepatitis (beside hepatocyte apoptosis) may further improve the diagnostic ability of CK-18 fragments. In this regard, it would be interesting to analyze the predictive value of CK-18 fragments in relation to biomarkers associated with the metabolic facets of NASH, i.e., novel biochemical markers of the metabolic syndrome that have been proven to be valuable tools to identify patients with NASH, such as soluble RAGE (receptor for advanced glycation end-products)3 and pentraxin 3.4 The promise for the future is not only to further validate the clinical usefulness of existing biomarker panels for NASH incorporating measurements of CK-18 fragments,5 but also to develop novel combinations of different enzyme-linked immunosorbent assay–based assays with improved sensitivity and specificity that may definitely reduce the need for liver biopsies.


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  • 1
    Feldstein AE, Wieckowska A, Rocio Lopez A, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarker for nonalcoholic steatohepatitis: A multicenter validation study. HEPATOLOGY 2009; doi:10.1002/hep.23050.
  • 2
    Yilmaz Y, Dolar E, Ulukaya E, Akgoz S, Keskin M, Kiyici M, et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 2007; 13: 837844.
  • 3
    Yilmaz Y, Ulukaya E, Gul OO, Arabul M, Gul CB, Atug O, et al. Decreased plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) in patients with nonalcoholic fatty liver disease. Clin Biochem 2009; doi:10.1016/j.clinbiochem.2009.02.003.
  • 4
    Yoneda M, Uchiyama T, Kato S, Endo H, Fujita K, Yoneda K, et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol 2008; 8: 53.
  • 5
    Younossi ZM, Jarrar M, Nugent C, Randhawa M, Afendy M, Stepanova M, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg 2008; 18: 14301437.

Yusuf Yilmaz M.D.*, * Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey.