Testosterone is Associated With Nonalcoholic Steatohepatitis (NASH) and Fibrosis in Pre-Menopausal Women With NAFLD.

BACKGROUND Higher testosterone contributes to imaging-confirmed nonalcoholic fatty liver disease (NAFLD) in women, but whether testosterone influences their disease severity is unknown. METHODS The association of free testosterone (free T) with nonalcoholic steatohepatitis (NASH) was determined in pre-menopausal women with biopsy-confirmed NAFLD (n=207). Interaction testing was performed for age and free T given decline in testosterone with age, and association of aging with NASH. Regression models adjusted for abdominal adiposity, diabetes, and dyslipidemia. RESULTS Median age was 35 yrs (IQR 29-41); 73% were white, 25% Hispanic; 32% had diabetes, 93% abdominal adiposity, and 95% dyslipidemia. 69% had NASH, 67% any fibrosis, and 15% advanced fibrosis. Higher free T levels were associated with NAFLD severity in younger women (interaction p values <0.02). In the youngest age quartile, free T was independently associated with NASH (OR 2.3, 95% CI 1.2-4.4), NASH fibrosis (2.1, 95% CI 1.1-3.8), and higher fibrosis stage (OR 1.9, 95% CI 1.1-3.4), p values ≤ 0.02. In these women, the proportion with NASH (from 27% to 88%) and NASH fibrosis (from 27% to 81%) steadily rose with higher free T quartiles (p<0.01). Free T was additionally associated with abdominal adiposity among all pre-menopausal women (OR 2.2, 95% CI 1.2-4.1, p=0.015). CONCLUSIONS In young women with NAFLD, higher testosterone levels conferred a two-fold higher risk of NASH and NASH fibrosis, and increased risk of abdominal adiposity, supporting a potential mechanistic link of abdominal fat on testosterone-associated liver injury. Testosterone may represent an early risk factor for NASH progression in young women, prior to their onset of more dominant, age-related metabolic risk factors.