In vivoassessment of liver cell apoptosis as a novel... : Hepatology (original) (raw)

Rapid Communication

In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease

Wieckowska, Anna1; Zein, Nizar N.1; Yerian, Lisa M.2; Lopez, Rocio A.3; McCullough, Arthur J.1; Feldstein, Ariel E.4,*

1_Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH_

2_Department of Anatomical Pathology, Cleveland Clinic Foundation, Cleveland, OH_

3_Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, OH_

4_Department of Pediatric Gastroenterology and Cell Biology, Cleveland Clinic Foundation, Cleveland, OH_

*Departments of Pediatric Gastroenterology and Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195

Email:[email protected]

Received 2 March 2006; Accepted 8 April 2006

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Institutes of Health; Grant sponsor: National Center for Research Resources; Grant sponsor: General Clinical Research Center; Grant Number: M01 RR-018390; Grant sponsor: AGA Research Scholar Award.

Potential conflict of interest: Nothing to report.

fax: 216-444-2974

Abstract

In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3–generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median [interquartile range]: 765.7 U/L [479.6–991.1], 202.4 U/L [160.4–258.2], 215.5 U/L [150.2–296.2], respectively; P < .001). Cytokeratin-18 fragment levels independently predicted NASH (OR 1.95; 95% CI 1.18–3.22; P = .009 for every 50 U/L increase). A cutoff value of 395 U/L calculated using the receiver operating characteristic curve approach showed a specificity of 99.9%, a sensitivity of 85.7%, and positive and negative predictive values of 99.9% and 85.7%, respectively, for the diagnosis of NASH. In conclusion , these findings strongly suggest that determination of hepatocyte caspase activation in the blood is a strong and independent predictor of NASH in human subjects. These data highlight the potential usefulness of this test as a noninvasive diagnostic means of determining histological disease severity in patients with NAFLD.