Combination Thyroid Hormone Replacement; Knowns and Unknowns

Abstract

Hypothyroidism is common throughout the world and readily diagnosed with thyroid function tests. Management should be straightforward but appears not to be the case. Thyroid hormone replacement with levothyroxine monotherapy is the standard treatment which is effective in the majority of cases. However, 10–15% of patients established on levothyroxine do not feel their health is entirely restored and some patients prefer the addition of liothyronine. Proponents of liothyronine argue that the ratio of T3 and T4 hormones is substantially altered on T4 monotherapy and therefore both hormones may be needed for optimal health. This remains controversial as clinical trials have not demonstrated superiority of combination therapy (levothyroxine and liothyronine) over levothyroxine monotherapy. There is now a pressing need for further studies and in particular randomized controlled trials in this area. To help design and facilitate dedicated trials and better understand thyroid hormone replacement, this review summarizes the evidence where there is established knowledge and agreement (knowns) and areas where research is lacking (unknowns). Agreements include the extent of dissatisfaction with levothyroxine monotherapy, biases in testing for hypothyroidism and prescribing levothyroxine, as well as variable thresholds for prescribing levothyroxine and challenges in liothyronine dosing. The review will also highlight and summarize the unknowns including the long-term safety profile of liothyronine, and potential biomarkers to identify individuals who might benefit most from combination therapy.

Patient satisfaction and quality of life in hypothyroidism: An online survey by the british thyroid foundation

“…Dissatisfaction with treatment is a phenomenon that has been documented repeatedly among a minority of patients who are treated for hypothyroidism and is associated with persistent symptoms despite apparently adequate treatment with L‐T4, as assessed by biochemical measures 1 . Much attention has been focused in the last 20 years on attempts to improve patient outcomes by using L‐T4 + L‐T3 24 or DTE 32 . However, several randomized controlled studies have failed to demonstrate better patient outcomes with L‐T4 + LT3 combination therapy compared to L‐T4 alone 33,34 and a single randomized controlled trial found no difference between DTE and L‐T4 treatment 35 .…”

“…Several randomized controlled trials have shown that L‐T4 + L‐T3 combination treatment fails to achieve better symptom control compared to L‐T4 alone (reviewed by Taylor et al 24 ). Nonetheless, despite the evidence for lack of efficacy, some professional thyroid organizations including the British and European Thyroid Associations recommend that a trial of L‐T4 + L‐T3 may be appropriate in selected patients who complain of residual unexplained symptoms 25‐27 …”

Diagnosis and Management of Hypothyroidism in Gulf Cooperation Council (GCC) Countries

“…Although the majority of patients with hypothyroidism respond to levothyroxine treatment, some individuals experience persistent symptoms despite adequate serum thyroxine correction. The combined use of levothyroxine and liothyronine, a synthetic form of T 3 , has been investigated in patients who have persistent symptoms of hypothyroidism with levothyroxine monotherapy; however, there is inconsistent evidence of the superiority of combination therapy over monotherapy with levothyroxine [31,33]. Patients with elevated TSH levels are classified into two groups according to their symptoms and free T 4 level, subclinical and overt hypothyroidism; for patients diagnosed with overt hypothyroidism, thyroid replacement therapy with levothyroxine is indicated.…”

“…Although the majority of patients with hypothyroidism respond to levothyroxine treatment, some individuals experience persistent symptoms despite adequate serum thyroxine correction. The combined use of levothyroxine and liothyronine, a synthetic form of T 3 , has been investigated in patients who have persistent symptoms of hypothyroidism with levothyroxine monotherapy; however, there is inconsistent evidence of the superiority of combination therapy over monotherapy with levothyroxine [ 31 , 33 ].…”

T3 therapy in hypothyroidism. Still more questions than answers

“…Studies have shown that individuals with genetic variations in deiodinase type 2 and the thyroid hormone transporter protein MCT10 experience additional benefits with combined LT3 + LT4 therapy, though the sample size was small (3). On the other hand, single nucleotide polymorphisms may have little discriminatory power to determine which patients could benefit from combination therapy (3).…”