Thyroid-Liver Axis: Mechanistic Insights and Clinical Implications.

The thyroid gland and liver share a complex bidirectional relationship that is fundamental to metabolic regulation and hormonal homeostasis. Thyroid hormones (THs) regulate hepatic lipid handling, glucose metabolism, mitochondrial function, and energy balance, while the liver governs TH transport, activation, metabolism, and clearance. Increasing evidence links thyroid dysfunction with metabolic dysfunction-associated steatotic liver disease (MASLD), fibrosis progression, and adverse metabolic outcomes. This narrative review provides an updated synthesis of the mechanistic, clinical, and therapeutic aspects of thyroid-liver interactions and their implications for clinical practice. A comprehensive review of mechanistic, clinical, translational, and therapeutic studies examining thyroid dysfunction, liver disease, thyroid hormone sensitivity, and emerging thyroid hormone-based therapies was conducted. Thyroid dysfunction contributes to MASLD, dyslipidemia, insulin resistance, and hepatic injury, whereas liver disease alters TH metabolism and complicates the interpretation of thyroid function tests, including the occurrence of nonthyroidal illness syndrome. Emerging evidence suggests that reduced intrahepatic TH signaling and altered tissue-level hormone sensitivity play central roles in steatosis and fibrosis progression. Clinically, recognition of these interactions may improve the interpretation of thyroid abnormalities in liver disease and support risk stratification in metabolic liver disorders. The development of liver-targeted thyroid hormone receptor-β agonists, including resmetirom, represents a major therapeutic advance with potential to reshape management strategies for metabolic dysfunction-associated steatohepatitis (MASH). However, important controversies remain regarding the diagnostic utility of thyroid hormone sensitivity indices, long-term safety of thyromimetics, and the role of thyroid hormone replacement in liver-directed therapy, highlighting the need for robust prospective studies.