Abstract and Introduction
Objective: Nonalcoholic fatty liver disease (NAFLD) is common in obese adolescents with polycystic ovary syndrome (PCOS), but there are no inexpensive ways to accurately identify NAFLD in PCOS. The objective was to develop a simple clinical score to screen for NAFLD risk in obese adolescents with PCOS.
Design: This is a secondary analysis of 3 cross-sectional studies on metabolic characterization of obese adolescents with PCOS. 108 overweight and obese adolescents with PCOS (BMI > 90th percentile, age 12-19 years) were enrolled from 2012 to 2018.
Methods: Magnetic resonance imaging was used to quantify hepatic fat fraction (HFF). A development cohort of 87 girls were divided by presence of NAFLD (HFF > 5.5%). A logistic regression model with the outcome of NAFLD and candidate predictor variables was fit. A simplified model (PCOS-HS index) was created using backwards stepdown elimination. Validation was performed using 200 bootstrapped sample and in a second cohort of 21 PCOS participants.
Results: 52% of the development cohort had NAFLD. The PCOS-HS index that included BMI percentile, waist circumference, ALT and SHBG had an AUCROC of 0.81, sensitivity 82%, specificity 69%, negative predictive value (NPV) 78% and positive predictive value 74%, using a threshold of 0.44 to predict HS. A threshold of 0.15 ruled out NAFLD with a NPV 90%. In the validation cohort, the model showed an accuracy of 81%, sensitivity of 91% and specificity of 70%.
Conclusions: We developed a clinical index to identify NAFLD in girls with PCOS who would need further evaluation and treatment.
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of disease stages ranging from simple hepatic steatosis (HS) without inflammation or fibrosis (NAFL) to steatohepatitis (NASH) or cirrhosis. About 20% of patients will progress to NASH. Given the current rise of obesity and type 2 diabetes (T2D), the prevalence of NASH is predicted to increase by 63% by 2030, leading to a 178% increase in liver-related deaths. Moreover, the clinical burden of NAFLD is not restricted to hepatic disease but includes the development of cardiovascular diseases and metabolic complications.
Polycystic ovary syndrome (PCOS) is a common disorder in women, affecting 15%-20% of women with obesity. PCOS is associated with increased peripheral insulin resistance (IR) in obese and nonobese adolescents, and adipose and hepatic IR in obese adolescents.[3,4] Several studies have shown an increased prevalence of NAFLD in women with PCOS, in comparison with women without PCOS of similar BMI. A recent meta-analysis calculated an OR of NAFLD of 3.0 in obese women and 2.0 in nonobese women with PCOS relative to women without PCOS. We demonstrated that excess NAFLD is also present in obese adolescent girls with PCOS with a prevalence of 50% when measured by the gold standard MRI-proton density fat fraction (MRI-PDFF), compared to only 13% in equally obese adolescents without PCOS.
Endocrine Society Guidelines recommend screening for NAFLD in women with PCOS and metabolic risk factors by using serum transaminases, followed by noninvasive quantification of fibrosis if elevated. Furthermore, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines recommend universal screening in obese and overweight children with metabolic risk factors after the age of 9 years old. The recommended screening test is ALT, using a threshold 2 times higher than sex-specific upper limit normal (ULN) from NHANES data (ULN = 22.1 IU/L for girls). The sensitivity of ALT in detecting hepatic steatosis is lower in girls than boys, even at a low threshold (>20 UI/L) although data could not be calculated for female specific cut-offs due to sample size limitations. European Association for the Study of Liver (EASL) also favour universal screening for NAFLD in patients with metabolic risk factors, which includes obese adolescent with PCOS, using steatosis biomarkers or ultrasound. Several noninvasive NAFLD risk indices have been assessed,[8,10–16] but most of those are not readily applicable in a clinical setting and none were developed specifically for a population with PCOS, who appear to have a unique predisposition for NAFLD.
Obese adolescents with PCOS are likely at risk of progressive NAFLD because of the high risk of T2D and IR and development of NAFLD at an early age, all risk factors for progressive disease. Several new treatments for NAFLD are currently under investigation and may be clinically available in the near future. Consequently, the development of a noninvasive, simple and inexpensive screening tool to identify patients at high risk for NAFLD who would benefit from additional more invasive or costly methods of testing is critical.
The aim of this study was to develop and validate a simple, predictive model using clinically available data, including hormonal markers specific to PCOS such as testosterone or sex-hormone binding globulin (SHBG), to accurately predict NAFLD in obese adolescents with PCOS. This predictive model is an easy screening tool for clinicians allowing identification of probability of NAFLD in adolescents with obesity and PCOS requiring further investigation.
Clin Endocrinol. 2019;91(4):544-552. © 2019 Blackwell Publishing