Sex differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy-related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy-related characteristics and NAFLD in 1,170 adolescent offspring aged 17 years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (P 5 0.02), higher maternal prepregnancy BMI (P < 0.001), higher maternal weight gain by 18 weeks' gestation (P < 0.001), and maternal smoking during pregnancy (P 5 0.04). Paternal age or body mass index (BMI) were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (P < 0.001), maternal prepregnancy BMI (P < 0.001), and lower family socioeconomic status (SES) at time of birth (P 5 0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.49-8.05; P 5 0.004) and maternal weight gain 6.0 kg by the 18th week of gestation (OR, 1.10; 95% CI, 1.04-1.15; P < 0.001). In adolescent males, family SES at the time of birth (OR, 9.07; 95% CI, 1.54-53.29; P 5 0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. Conclusion: Early-life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early-mid gestational weight gain were associated with NAFLD in female offspring, whereas lower family SES at birth was associated with NAFLD in male offspring independent of adolescent obesity. (HEPATOLOGY 2018;67:108-122). SEE EDITORIAL ON PAGE 7N onalcoholic fatty liver disease (NAFLD) is a common, potentially progressive, complex chronic liver disorder. NAFLD associates with insulin resistance (IR) and features of metabolic syndrome (MetS).(1,2) Obesity is a dominant risk factor for NAFLD, with both subcutaneous and visceral adiposity being associated with NAFLD.(3) Recent data describe considerable risk of liver-related morbidity and mortality with progressive adiposity gains during the life course, from childhood through adulthood. (4)(5)(6)(7)(8)(9)

Liver Diseases in the Perinatal Period: Interactions Between Mother and Infant

“…Steatosis in these infants correlates with their gestational age . Furthermore, longitudinal studies have shown an increased risk of NAFLD in adolescents born to obese mothers . Multiple pathways are involved in the development of neonatal NAFLD, including mitochondrial dysfunction, nutritional reprograming of the epigenome, dysbiosis, and immune dysregulation.…”

“…(33) Furthermore, longitudinal studies have shown an increased risk of NAFLD in adolescents born to obese mothers. (34,35) Multiple pathways are involved in the development of neonatal NAFLD, including mitochondrial dysfunction, nutritional reprograming of the epigenome, dysbiosis, and immune dysregulation. Mechanistic studies performed in nonhuman primates and mice models indicate that exposure to excess maternal macronutrients, independent of diabetes and/or obesity, reduces mitochondrial biogenesis and nutrient sensing, and promotes oxidative stress and triglyceride storage, priming the fetal liver for NAFLD.…”

Perinatal programming of adolescent nonalcoholic fatty liver disease: A case for gender inequality?

“…Moreover, maternal obesity was associated with higher serum leptin, glucose, and insulin levels and higher homeostatic model assessment for insulin resistance (HOMA‐IR) scores in adolescent girls, but higher serum leptin only in boys. Paternal prepregnancy obesity predicted NAFLD and increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels only in adolescent boys, indicating an assortative (i.e., father‐to‐son) effect . In an earlier analysis of the Framingham Heart Study, paternal but not maternal early onset obesity was linked to higher serum ALT levels in the offspring, although in that study no association with serum AST levels and no gender differences were reported, and the average age of the offspring cohort was 42 years (4), suggesting that findings in these two studies may reflect differences between adolescent and adult NAFLD.…”

“…Moreover, it remains unclear whether these changes persist later in life. In this issue of Hepatology, Ayonrinde et al expand upon earlier findings regarding developmental programming for NAFLD . The authors analyzed the Western Australian Pregnancy (Raine) Cohort Study for the perinatal history of 1170 adolescent offspring diagnosed with NAFLD by liver ultrasound at age 17.…”

“…Multiple regression analysis by Ayonrinde et al established a striking sexual dimorphism with regard to perinatal predictors of adolescent NAFLD . Thus, after adjusting for adolescent obesity, maternal prepregnancy obesity and gestational weight gain >6 kg by week 18 independently predicted NAFLD in adolescent girls, whereas lower socioeconomic status at birth was the only independent predictor of NAFLD in adolescent boys.…”