Potential conflict of interest: Nothing to report.
Serum markers of hepatocyte apoptosis: Current terminology and predictability in clinical practice†
Article first published online: 25 AUG 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 51, Issue 2, pages 717–718, February 2010
How to Cite
Tiniakos, D. G. and Papatheodoridis, G. V. (2010), Serum markers of hepatocyte apoptosis: Current terminology and predictability in clinical practice. Hepatology, 51: 717–718. doi: 10.1002/hep.23251
- Issue published online: 25 JAN 2010
- Article first published online: 25 AUG 2009
- Accepted manuscript online: 25 AUG 2009 12:00AM EST
To the Editor:
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.
- 1Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multi center validation study. HEPATOLOGY 2009; doi:10.1002/hep.23050., , , , , .
- 2In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. HEPATOLOGY 2006; 44: 27–33., , , , , .
- 3Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 2007; 13: 837–844., , , , , , et al.
- 4Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2008; 47: 481–485., , , , , .
- 5New consensus nomenclature for mammalian keratins. J Cell Biol 2006; 174: 169–174., , , , , , et al.
- 6The catalog of human cytokeratins: patterns of expression in normal epithelial tumors and cultured cells. Cell 1982; 31: 11–24., , , , .
- 7Intermediate filament cytoskeleton of the liver in health and disease. Histochem Cell Biol 2008; 129: 735–749., , , .
- 8Cytokeratin markers come of age. Tumor Biol 2007; 28: 189–195..
- 9Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. HEPATOLOGY 2004; 40: 1078–1087., , , , , , et al.
- 10Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection. Gut 2008; 57: 500–506., , , , , , et al.
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.