Adolescent females with NAFLD and PCOS have an adverse metabolic phenotype compared with other females and males Short Title : Adverse metabolic impact of NAFLD combined with PCOS

Background and aims: Nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) share risk associations of adiposity and insulin resistance. We examined the impact of a PCOS diagnosis on the metabolic phenotype of adolescent girls with NAFLD and compared this to girls without PCOS or NAFLD and to age-matched boys. Methods: Community-based adolescents from the Raine Cohort participated in assessments for NAFLD (572 girls and 592 boys) and PCOS (244 girls). 199 girls attended both assessments. Results: Amongst the 199 girls, PCOS was diagnosed in 16.1% and NAFLD in 18.6%. NAFLD was diagnosed in 10.1% of the boys. NAFLD was more prevalent in girls with PCOS than girls without PCOS (37.5% vs. 15.1%, p=0.003). Girls with NAFLD plus PCOS had greater adiposity (waist circumference, body mass index, suprailiac skinfold thickness [SST], serum androgens, high-sensitivity C-reactive protein (hsCRP), ferritin, homeostasis model assessment for insulin resistance (HOMA-IR), and lower serum sex hormone binding globulin levels than girls with NAFLD without a PCOS diagnosis (all p<0.05). Girls with NAFLD plus PCOS had similar adiposity, HOMA-IR and adiponectin levels to boys with NAFLD, but more adiposity, serum leptin and HOMA-IR than both girls and boys without NAFLD. PCOS (OR 2.99, 95% CI 1.01-8.82, P=0.048) and SST (OR 1.14, 95% CI 1.081.20, p<0.001) independently predicted NAFLD in adolescent girls, however serum androgens and HOMA-IR levels did not. Conclusions: Adolescent girls with NAFLD plus PCOS have a similar metabolic phenotype to boys with NAFLD. Increasing SST and pre-existing PCOS independently predict NAFLD in adolescent girls.