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Noninvasive Biomarker Test for Fatty Liver
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"Detection of caspase activity in the blood of patients with nonalcoholic fatty liver disease as a novel biomarker of disease severity"
A. Wieckowska2; N. Zein2; L. Yerian3; A. R. Lopez4; A. E. Feldstein1
1. Pediatric Gastroenterology and Cell Biology, Cleveland Clinic, Cleveland , OH, USA.
2. Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, USA.
3. Pathology, Cleveland Clinic , Cleveland, OH, USA.
4. Biostatistics, Cleveland Clinic , Cleveland, OH, USA.
In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH) and determine the stage and grade of the disease. Noninvasive tools are urgently needed. We have previously demonstrated that caspase 3 activation and hepatocyte apoptosis are prominent pathologic features of human NAFLD and correlate with disease severity (1). Increasing evidence from both human and experimental studies supports these initial observations. Thus, the aims of our study were to quantify hepatocyte apoptosis in serum from patients with NAFLD using a novel noninvasive serum test; and correlate it with histopathological markers of disease severity.
METHODS: Our cohort consisted of 41 consecutive patients undergoing a liver biopsy for clinically suspected NAFLD. Serum was obtained from each patient at the time of liver biopsy and caspase 3 generated cytokeratin-18 fragments were measured in triplicate using the M30-apoptosense ELISA kit. Histology was assessed blindly by an experienced hepatopathologist according to the NIDDK NASH CRN scoring system. Patients were subsequently divided in 4 groups according to their histology: controls (n = 10, normal biopsy), simple fatty liver (n = 8), borderline NASH (n = 2) and definitive NASH (n = 21).
RESULTS: Caspase 3 activity was markedly increased in patients with definitive NASH as compared to simple steatosis and controls [Median (Q25, Q75): 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 < 0.001]. Moreover, a significant positive correlation was observed between caspase 3 activity levels and stage of fibrosis (r = 0.55, p<0.001). A cutoff value of 479.6 U/L calculated using the receiver operating characteristic curve approach predicted fibrotic NASH with a specificity of 91%, a sensitivity of 83%, with positive and negative predictive values of 94% and 77%, respectively.
CONCLUSIONS: The results demonstrate that determination of apoptotic caspase cleavage products in serum accurately differentiates NASH from simple steatosis and predicts stage of fibrosis in patients with NAFLD and identify a potential novel biomarker of disease severity in this condition. Supported by the National Institutes of Health, National Center for Research Resources, General Clinical Research Center Grant M01 RR-018390.
(1) Feldstein et al. Gastroenterology 2003;125:437
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