Serum markers of hepatocyte apoptosis: Current terminology and predictability in clinical practice
Authors: Dina G. Tiniakos, George V. Papatheodoridis
Journal: Hepatology (2009)

We read with interest the article by Feldstein et al.,1 in which they validated the use of cytokeratin-18 (CK-18) fragment serum levels as a noninvasive biomarker for the diagnosis of nonalcoholic steatohepatitis (NASH) in a large cohort of adults with biopsy-proven nonalcoholic fatty liver disease (NAFLD). According to their conclusions, this test can be reliably used to diagnose NASH among patients with suspected NAFLD in clinical practice. This is an important study, because it confirms the significant associations between high CK-18 fragment levels and NASH reported in previous smaller studies in other cohorts of adults2, 3 or even children with NAFLD.4 However, we would like to draw your attention to two issues: terminology and predictability. The "Keratin Nomenclature Committee" recently established the new consensus nomenclature for mammalian keratin genes and proteins,5 which is based on and extends the first comprehensive keratin nomenclature developed back in 1982.6 According to this new nomenclature, which is in agreement with the nomenclature of the Human Genome Organisation (HUGO) for both gene and protein names,5 it is suggested the term "keratin" be used instead of "cytokeratin", because it covers all intermediate filament-forming proteins with specific physicochemical properties produced in any vertebrate epithelia.5 Thus, the term "keratin-18 (K-18)" is now more appropriate than "cytokeratin-18 (CK-18)" for all manuscripts. K-18 and keratin-8 (K-8) are the only cytoplasmic intermediate filaments of hepatocytes but are not hepatocyte-specific, because they are also expressed in most simple epithelial cells including bile duct cells.7 K-18 fragment serum levels, which are increasingly used as a biomarker of hepatocyte apoptosis, are also not liver-specific, because these levels may be elevated in patients with epithelial tumors.8 Moreover, this marker is not specific for NASH, because it is increased in several liver diseases with ongoing necroinflammation and fibrosis, such as chronic hepatitis C or B.9, 10 The specificity issues are substantially limited if the test is used in patients with probable NAFLD. However, even in such patients followed in specialized centers, its diagnostic accuracy does not seem to be excellent. In the study by Feldstein et al.,1 the area under the receiver operating characteristic (AUROC) curve for NASH diagnosis was 0.83 (not excellent) with sensitivity and specificity values of 75% and 81% or 65% and 92% for cutoff values of 246 or 292 U/L, respectively. In 58 adult patients with NAFLD studied in our center, K-18 fragment levels offered an AUROC curve of 0.87 and sensitivity and specificity values of 60% and 93%, respectively, for a cutoff of 250 U/L (G. V. Papatheodoridis, unpublished data). Similar findings for variable cutoff values were previously reported by others with the best results reported in the first relevant study.2, 3 Thus, measurement of K-18 fragment levels will probably be helpful in the noninvasive diagnosis of NAFLD, particularly in cases with rather high levels. The specificity issues should be restricted by ensuring the NAFLD diagnosis, but a decision may not be easy in a large proportion of NAFLD cases with K-18 values of <300 U/L, and particularly <200 U/L. Dina G. Tiniakos*, George V. Papatheodoridis , * Laboratory of Histology and Embryology, University of Athens, Greece, 2nd Department of Internal Medicine, Medical School, University of Athens, Greece.