Causal mediation analysis of Subclinical Hypothyroidism in children with obesity and Non-Alcoholic Fatty Liver Disease

Context Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity and a leading cause of liver disease in children. Subclinical hypothyroidism (SH) occurs with obesity and may contribute to dysmetabolic state that predisposes to NAFLD. Objective To assess the relationship between SH and NAFLD in children with biopsy-proven NAFLD compared to controls. Design and Methods In this retrospective study of cases from a registry of children with biopsy-proven NAFLD and age-matched controls, the association of SH with NAFLD and other cardiometabolic parameters was assessed followed by causal mediation analyses under the counter-factual framework. Results Sixty-six cases and 4067 age-matched controls were included in the study. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (2.3 ±1.6 vs 1±1.6, p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, LDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4 th quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 44% of the effect of modified BMI-z score on NAFLD. This comprises of 16.2% (OR = 1.1, p < 0.001) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 26.5% (OR = 1.1, p = 0.01) as an autonomous effect of TSH on NAFLD regardless of the obesity. Conclusions The association of SH and biopsy-proven NAFLD is demonstrated in a predominately Latino population. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.