Effect of TSH on Non-Alcoholic Fatty Liver Disease (NAFLD) independent of obesity in children of predominantly Hispanic/Latino ancestry by causal mediation analysis.

Presley H. Nichols,Vidhu V. Thaker,Yue Pan,Ali A. Mencin,Martina Pavlicova,Benjamin May,John C. Rausch,Robert Siegel

doi:10.1371/journal.pone.0234985

Abstract

BackgroundNonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD.ObjectiveTo assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls.Design and methodsIn this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed.ResultsSixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children’s Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-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 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001).ConclusionsThe association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.

Highlights

Non-alcoholic fatty liver disease (NAFLD), defined as hepatic steatosis by imaging or histology without a secondary cause of hepatic fat accumulation [1], has become the most common chronic liver disease in children in parallel with the rising prevalence of obesity [2]
Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4th quartile of TSH and Nonalcoholic Fatty Liver Disease (NAFLD)
Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified Body mass index (BMI)-z score on NAFLD

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD), defined as hepatic steatosis by imaging or histology without a secondary cause of hepatic fat accumulation [1], has become the most common chronic liver disease in children in parallel with the rising prevalence of obesity [2]. The spectrum of NAFLD includes simple steatosis through steatohepatitis. It is not surprising that a close relationship has been observed between elevated TSH levels (eTSH) and cardiometabolic risk factors and NAFLD in adults [6,7,8]. A small number of studies in Caucasian children, primarily from Europe, have shown the association between eTSH and NAFLD defined by hepatic ultrasound in children and adolescents with obesity [9,10,11,12]. Elevated TSH levels (eTSH), associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD

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Results

Conclusion