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

Background Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Subclinical hypothyroidism (SH), also associated with obesity, may contribute to the 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 children with biopsy-proven NAFLD and age-matched controls, the association of SH with NAFLD 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 4th 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 children from predominantly Latino population. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial This is a retrospective study and not a clinical trial. ### Funding Statement This work is supported in part by NIH-NIDDK K23 DK 110539 to VVT and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Not Applicable The data used in the study is not freely available due to ethical restrictions and can be shared under appropriate IRB-approved data use agreements.