Association Between Primary Hypothyroidism and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Background: It is currently uncertain whether primary hypothyroidism is associated with nonalcoholic fatty liver disease (NAFLD). We performed a meta-analysis of relevant studies to quantify the magnitude of association between primary hypothyroidism and risk of NAFLD. Methods: We searched PubMed, Web of Science and Scopus databases from January 2000 to March 2018 using predefined keywords to identify observational cross-sectional, case-control, and longitudinal studies in which NAFLD was diagnosed by imaging or biopsy. Data from selected studies were extracted and meta-analysis was performed using random-effects modeling. Results: A total of 12 cross-sectional and 3 longitudinal studies enrolling 44,140 individuals were included in the final analysis. Hypothyroidism (defined either by self-reported history of hypothyroidism with use of levothyroxine replacement therapy or by presence of abnormal thyroid function tests) was associated with an increased risk of prevalent NAFLD (n = 12 studies; random-effects odds ratio 1.42 [95% confidence interval (CI) 1.15-1.77]; I-2 = 51.2%), independently of age, sex, body mass index and other common metabolic risk factors. The magnitude of risk paralleled the underlying severity of NAFLD histology (n = 3 studies; randomeffects odds ratio 2.73 [CI 1.90-3.93]; I-2 = 0%), and tended to increase across the different definitions used for diagnosing hypothyroidism. Meta-analysis of data from the three longitudinal studies showed that subclinical hypothyroidism was not independently associated with risk of incident ultrasound-defined NAFLD over a median of 5 years (random-effects hazard ratio 1.29 [CI 0.89-1.86]; I-2 = 83.9%). Sensitivity analyses did not alter these findings. Funnel plot did not reveal significant publication bias. Conclusions: This large and updated meta-analysis shows that the presence of variably defined hypothyroidism is significantly associated with the presence and severity of NAFLD. However, the observational design of the eligible studies does not allow for proving causality.