Evaluation of Biomarkers of NAFLD in a Cohort of Morbidly Obese Patients

Abstract

Hepatocyte apoptosis is a key event in nonalcoholic fatty liver disease (NAFLD), and serum apoptotic markers are emerging as surrogate markers for NAFLD. We studied the role of caspase-cleaved cytokeratin18 in the diagnosis of fibrosis in a cohort of 127 morbidly obese patients and also performed a review of the literature biomarkers of NAFLD and fibrosis. Here, we found that cleaved caspase 18 correlated with liver steatosis and liver injury as assessed by serum transaminase levels. Furthermore, hepatocyte apoptosis as assessed by cleaved CK18 and TUNEL staining correlated with the extent of fibrosis as assessed by Sirius Red staining and serum hyaluronic acid. These results underscore the important role of hepatocyte apoptosis in the pathogenesis of fibrosis in NAFLD, which led to the utilization of surrogate markers for apoptosis in the noninvasive diagnosis of NAFLD. We furthermore reviewed current literature of biomarkers of NAFLD and fibrosis.

Figure 1

NAS versus M30 assay. As expected, the NAS score correlates with its individual parameters steatosis, ballooning, and lobular inflammation. M30 is higher in patients with histologically established NASH (NAS ≧ 5;) (a). Serum transaminase levels are higher in patients with NASH (b). M30 correlates with histological steatosis, but not lobular inflammation (c). ALT and AST are significantly higher in patients with M30 ≧ 275 U/L (d). (*= P < .05; ^#= P < .01).

Figure 2

Histological assessment in NAFLD. NASH is histologically defined by increased steatosis, fibrosis, and lobular inflammation (a/b). Apoptosis is a key feature of NASH, which is accompanied by an increase in TUNEL positive cells (c/d). Hepatocyte apoptosis triggers HSC activation and thus fibrogenesis. Representative slides with quantification of collagen by Sirius red staining (e/f).

Figure 3

Association between apoptosis and fibrosis. Although fibrosis, as quantified by a pathologist in H&E sections is not increased in NASH, collagen staining and serum hyaluronic acid indicate more fibrosis in NASH (a). Hepatocyte apoptosis and serum hyaluronic acid are increased in advanced fibrosis (b, c). Cell death rate is associated with fibrotic areal in histological slides from NASH patients (d). Hyaluronic acid is correlated with serum cleaved CK18 (e). Linear increase in publications/year on serum markers of NAFLD (f).