Re-evaluating the Concept of Peripheral Hypothyroidism

Abstract

Context: Isolated peripheral hypothyroidism comprises a group of disorders in which cellular thyroid hormone action is impaired because of defects in membrane transport or intracellular metabolism, despite normal or increased thyroid hormone secretion. Because serum T4, T3, and TSH concentrations often remain within the normal range and sensitive markers of tissue thyroid status are lacking, diagnosis remains challenging. This review examines the causes of isolated peripheral hypothyroidism and recent advances in its management. Evidence Acquisition: A MEDLINE search covering 2010 - 2025 was conducted using the terms peripheral hypothyroidism, tissue-specific hypothyroidism, and cellular hypothyroidism, supplemented by manual screening of reference lists. After abstract screening, full-text articles were assessed for eligibility, duplicates were removed, and only studies with appropriate designs were included. Results: The causes can be categorized into four groups: 1) decreased peripheral T3 availability, as observed in patients receiving levothyroxine (LT4) monotherapy who have persistent symptoms associated with low serum T3:T4 ratios despite normal serum T4, T3, and TSH concentrations; 2) peripheral cellular dysfunction, reported in metabolic dysfunction-associated steatotic liver disease (MASLD), skeletal muscle changes during weight regain, and organ-specific conditions involving the heart, lungs, and kidneys, suggesting widespread tissue involvement; 3) altered deiodinase activity, including shifts toward reverse T3 production during cellular dysfunction and consumptive hypothyroidism caused by marked DIO3 overexpression in tumors such as hemangiomas; and 4) thyroid hormone receptor alterations, such as thyroid hormone receptor mutations causing resistance. Conclusions: Isolated peripheral hypothyroidism comprises a diverse and often underrecognized group of disorders because standard biochemical tests may appear normal. Promising therapies include thyroid hormone combinations, such as levothyroxine plus slow-release T3, and thyromimetics, such as resmetirom for MASLD. This review synthesizes recent findings on cellular hypothyroidism, diagnostic challenges, and emerging multidisciplinary management strategies. Improved biomarkers and multidisciplinary evaluation are still needed to advance its diagnosis and management.