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 impact severity of pediatric NAFLD Objective To examine associations of circulating sex hormone binding globulin (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 U.S 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

Dietary quercetin and vitamin E supplementation modulates the reproductive performance and antioxidant capacity of aged male breeder chickens

“…The liver senses the body's metabolic status and adjusts energy homeostasis in a sex-dependent manner ( Grossmannn et al, 2019 ). Many studies have reported that a reduction in reproductive function is associated with liver injury or dysfunction ( Polyzos et al, 2013 ; Bubnov et al, 2017 ; Mueller et al, 2020 ). Therefore, the liver also improves male reproductive performance.…”

Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease

“…Paediatric NAFLD is histologically characterized by portal inflammation that can progress to fibrosis in the absence of detectable hepatocyte degeneration or ballooning, in contrast to NAFLD in adults, which is characterized by mostly lobular inflammation and considerable ballooning 78 . Interestingly, levels of SHBG are inversely correlated with NAFL severity and although oestradiol levels do not correlate with NAFLD stage, testosterone levels are inversely correlated with fibrosis severity in boys 79 . Therefore, sex hormones are likely to also exert major effects in the paediatric population, but will not be further discussed in this Review owing to the scarcity of epidemiological and mechanistic studies 80 .…”

Role of the Gut Microbiota in Regulating Non-alcoholic Fatty Liver Disease in Children and Adolescents

“…For example, estradiol treatment in rats decreases CCL4-induced liver fibrosis (129). In addition, an increased serum estradiol concentration was associated with lower-grade portal inflammation in girls with NAFLD (124). In another study, 17β-estradiol attenuated weight gain in ovariectomized ob/ob mice fed a high-fat diet (131).…”

“…In Australia, a small-scale study showed that whereas the prevalence of NAFLD was significantly higher in females than in males, the NAFLD in males was associated with more adverse metabolic features and greater visceral adiposity (123). These gender-associated differences implicate the involvement of sex hormones (e.g., estrogen) in the development of NAFLD in adolescents (124). In particular, estrogen (e.g., estradiol, esterone) is required for the normal development and functioning of the female reproductive system as well as various non-reproductive organ pathologies, including brain damage and liver diseases; estrogen also influences gut microbiota diversity (124)(125)(126)(127)(128)(129)(130).…”