Sex Hormone Relations to Histologic Severity of Pediatric Nonalcoholic Fatty Liver Disease

Abstract

Context: Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD.

Objective: To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD.

Design: Baseline assessment of longitudinal cohorts and randomized clinical trials.

Setting: Nonalcoholic Steatohepatitis Clinical Research Network.

Patients: Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States.

Main outcome measures: We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression.

Results: Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction <0.001). Higher testosterone was related to improved features of steatosis and fibrosis (P for sex interaction = 0.003 and 0.01, respectively) in boys, but detrimental in girls. In boys and girls, higher estrone, estradiol, and testosterone were associated with lower portal inflammation grade; higher estradiol was positively associated with hepatic ballooning severity; DHEAS was inversely associated with hepatic ballooning and NASH severity (all P < 0.05). Androstenedione was not associated with NAFLD features.

Conclusions: Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.

Keywords: estrogen; histology; progesterone; puberty; sex hormone binding globulin; testosterone.

Figure 1.

Multivariable adjusted geometric means and 95% confidence intervals of SHBG and sex hormones by features of NAFLD, overall and separately in boys and girls from the NASH-CRN. *Statistically significant P value across levels of the NAFLD. feature (P < 0.05) in boys and girls combined. DHEAS, dehydroepiandrosterone; NAFLD: nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.