Apoptotic Markers Indicate Nonalcoholic Steatohepatitis in Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement. Methods: In 192 PCOS patients [age, 29.0 ± 6.7 yr; body mass index (BMI), 31.5 ± 8.2 kg/m2] and 73 age-matched controls (age, 28.6 ± 8.0 yr; BMI, 24.1 ± 4.6 kg/m2), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only. Results: M30 levels were significantly elevated in PCOS patients after correction for BMI (304.7 ± 223.1 vs. 86.3 ± 165.6 U/liter; P < 0.001). M30 correlated significantly with BMI, AUCI, glucose secretion, low-density lipoprotein, low high-density lipoprotein, and free androgen index. AUCI turned out to be the only independent M30-determining factor in the multiple regression analysis with an effect size of 7.9%. Fifty-one of 186 (27.4%) PCOS patients showed M30 levels of at least 395 U/liter, indicating NASH. Conclusion: These data demonstrate elevation of apoptotic cell death, its correlation with IR, and a high prevalence of NASH in PCOS patients. Given this high prevalence, PCOS may be a risk factor for progressive hepatic sequelae. Incidence data are of strong interest. Hepatic apoptotic markers correlate with insulin resistance and indicate a high prevalence of nonalcoholic steatohepatitis in patients with PCOS.