Caspase Activity a Novel Biomarker for NAFLD Severity

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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. A study in this journal several years ago (Feldstein et al, Gastroenterology 2003;125:437), demonstrated that caspase 3 activation and hepatocyte apoptosis are prominent pathologic features of human NAFLD and correlate with disease severity.

Results of a new study presented May 21st at Digestive Disease Week 2006 in Los Angeles, California, finds that detection of caspase activity in the blood of patients with NAFLD may be used as a novel and noninvasive biomarker of disease severity. “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,” say researchers led by Dr. Anna Wieckowska of the Department of Gastroenterology and Hepatology at the Cleveland Clinic, in Cleveland, Ohio.

The study 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).

The study found 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 < .001). Moreover, a significant positive correlation was observed between caspase 3 activity levels and stage of fibrosis (r = 0.55, P < .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.

According to the study team, these 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.”