An apoptosis biomarker for prediction of nonalcoholic steatohepatitis

Abstract

We read with interest the article by Feldstein et al. that evaluated the use of cytokeratin-18 (CK-18) fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis (NASH).1 The authors reported that plasma levels of an apoptosis-associated CK-18 fragment were significantly elevated in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) as compared to healthy individuals. Moreover, they observed significantly higher CK-18 fragment levels in NASH compared to “borderline diagnosis” or simple steatosis. The authors conclude that such noninvasive determination of CK-18 fragments allows the prediction of NASH and severity of disease in patients with NAFLD. Liver biopsy is still considered the gold standard for assessment of liver disease activity, although it remains associated with several disadvantages including high costs and risks of clinical complications. Noninvasive techniques that can monitor disease activity and distinguish NASH from simple steatosis are therefore urgently needed.2 The multicenter study by Feldstein and coworkers is therefore of great clinical importance. Caspase-generated CK-18 fragments are released during hepatocyte apoptosis, a fundamental process in virtually all acute and chronic liver diseases that are characterized by inflammation, steatosis, or fibrosis.3-6 Previous studies in patients with chronic HCV infection have shown that activation of hepatic caspases closely correlates with inflammation.7 In addition, detection of caspase-generated CK-18 fragments in sera from patients with chronic hepatitis C virus (HCV) infection has recently been associated with fibrotic liver injury.8 Another study showed a correlation of CK-18 fragment levels with the proportion of HCV-associated liver steatosis.9 In this latter study, only patients with minimal inflammatory disease activity and low stages of fibrosis were included, suggesting that even under conditions of mild inflammation, CK-18 fragment levels correlate with the extent of steatosis. Hepatocyte apoptosis and elevated CK-18 fragment levels are also prominent features of cholestatic liver diseases.10 Furthermore, presumably due to increased cell turnover, elevated serum levels of CK-18 fragments have been reported even in noncirrhotic hepatocellular carcinoma.10 In conclusion, CK-18 fragments represent a strong predictor and useful noninvasive biomarker for the diagnosis of NASH in well-defined patients. However, it should be taken into account that a variety of hepatic pathologies may result in elevated CK-18 fragment levels. Thus, this marker is not specific for NASH but rather a general indicator of severe liver disease. Heike Bantel*, Matthias J. Bahr*, Klaus Schulze-Osthoff , * Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.