Combination therapy with levothyroxine and liothyronine in hypothyroid patients with persistent symptoms: A case series

Levothyroxine (LT4) monotherapy remains the standard treatment for hypothyroidism in current clinical practice. However, a subset of patients on LT4 continue to experience fatigue and other hypothyroid symptoms despite normal thyroid-stimulating hormone (TSH) and free T4 (FT4) levels. Three patients with symptomatic hypothyroidism on LT4 monotherapy were transitioned to combination therapy with liothyronine (LT3) by reducing LT4 dosage and adding LT3 5 μg daily. All had a normal TSH and low total triiodothyronine T3 levels. LT3 was administered in the morning alongside LT4, with one patient requiring an additional afternoon dose ( 3:00 and 5:00 p.m) for symptom control. Laboratory values and clinical symptoms were reassessed after initiating combination thyroid hormone therapy. A 67-year-old woman with idiopathic bradycardia and fatigue experienced marked improvement in energy and bradycardia, accompanied by normalization of T3 levels and improved heart rate at clinic visits. A 58-year-old woman with post-ablative hypothyroidism reported improved fatigue and modest weight loss. A 40-year-old man post-thyroidectomy for papillary thyroid carcinoma noted improvement of fatigue, daytime sleepiness and serum T3 concentrations. Across all three cases, total T3 levels increased, and symptom burden decreased following LT4 + LT3 therapy. In select hypothyroid patients with persistent symptoms and low total T3 despite normal TSH, addition of liothyronine to levothyroxine may improve both biochemical and clinical outcomes. These findings highlight the potential benefit of individualized thyroid hormone replacement strategies in optimizing thyroid hormone status. Teaching Points • Combination therapy with levothyroxine (LT4) and liothyronine (LT3) is not standard practice for hypothyroidism management in most community settings. • A subset of patients on LT4 monotherapy continue to experience persistent hypothyroid symptoms despite having normal TSH and free T4 levels. • In patients with low total T3 levels and ongoing symptoms such as fatigue or symptomatic bradycardia, the addition of LT3 may lead to clinical improvement. • A comprehensive thyroid panel—including TSH, free T4, and total T3—should be obtained in patients who remain symptomatic to guide individualized therapy. Clinical Relevance Levothyroxine is the standard hypothyroidism treatment, but some patients remain symptomatic despite normal labs. This case series describes three patients who improved after switching to combination therapy with levothyroxine and liothyronine. These findings highlight the potential role of dual thyroid hormone therapy for patients with persistent symptoms despite biochemical euthyroidism.