Are We Restoring Thyroid Hormone Signaling in Levothyroxine-Treated Patients With Residual Symptoms of Hypothyroidism?

Introduction: Levothyroxine (LT4) at doses that maintain the serum thyroid-stimulating hormone levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates the signs and symptoms of overt hypothyroidism in the majority of patients, owing to the endogenous activation of thyroxine to triiodothyronine, the biologically active thyroid hormone. Still, a small percentage of the patients (10%-20%) exhibit residual symptoms, despite having normal serum thyroid-stimulating hormone levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life. Objective: To provide a summary of progress in the approach of patients with hypothyroidism that exhibit residual symptoms despite treatment. Methods: We reviewed the current literature and here we focused on the mechanisms leading to a deficiency of T3 in some LT4-treated patients, the role of residual thyroid tissue and the rationale for combination therapy with LT4 thorn liothyronine (LT3). Results: A score of clinical trials comparing therapy with LT4 versus LT4 thorn LT3 concluded that both are safe and equally effective (neither is superior); however, these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4 thorn LT3; desiccated thyroid extract has also been used with similar results. A practical approach to patients with residual symptoms and on initiation of combination therapy with LT4 thorn LT3 is provided. Conclusion: A recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4. & COPY; 2023 AACE. Published by Elsevier Inc. All rights reserved.