Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.