In a study that compared the effectiveness of levothyroxine (LT4), desiccated thyroid extract (DTE) and levothyroxine + liothyronine (LT4+LT3) for the treatment of primary hypothyroidism, some patients who remained symptomatic despite normal TSH levels post-treatment, improved with LT4 + LT3 or DTE therapy.¹

This study, with a prospective, randomized, double-blind, crossover design, examined the effect of three different forms of thyroid hormone replacement therapy viz. LT4 alone,  LT4 + LT3 or DTE alone in 75 patients with hypothyroidism on LT4 for a minimum of 6 months. Patients were randomized to one of the three treatment groups for 22 weeks. The 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI) scores after treatment were selected as the primary endpoints. The etiology, biochemical and metabolic parameters, preference of treatment were the secondary outcomes.

Results published in the Journal of Clinical Endocrinology and Metabolism show that the serum TSH levels were generally within the normal reference range, between 0.27 and 4.20, in all the three groups, though levels were slightly higher in patients on DTE. However, in patients on DTE or LT4 + LT3, the fasting total T3 level was 30-50% higher, while the serum T4 levels were 30% lower. The total T4/T3 ratio declined by 38% after crossover to LT4 + LT3 and by 56% after crossing over to DTE. No differences relating to body weight, serum lipid levels (i.e., total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol), SHBG and leptin serum levels were observed between the three treatment groups. Blood pressure readings were comparable between all three groups, a slight elevation in heart rate was noted in patients receiving DTE.

In subgroup analysis, one-third of patients on LT4 monotherapy, who were most symptomatic at baseline, as assessed by the BDI, VMS-IV and TSQ-36 and GHQ-12 scores, showed significant improvement after crossing over to LT4 + LT3 or DTE treatment groups. They also preferred DTE or LT3+LT4 instead of LT4.

In 46 patients, the hypothyroidism had an autoimmune cause; it occurred post-thyroidectomy in 16 patients, post-radioactive iodine in 4 patients and was idiopathic in 9 patients. But the etiology of hypothyroidism had no impact on the outcomes. Similarly, no impact of the presence of Thr92AlaD2 polymorphism was noted.

The American Association of Clinical Endocrinologist (AACE) recommends against the use of DTE and LT3 and also does not support the use of LT3+LT4 in the treatment of hypothyroidism. Likewise, the British Thyroid Association (BTA), the European Thyroid Association (ETA), the American Thyroid Association (ATA) and the National Institute for Health and Care Excellence (NICE) guidelines do not recommend the routine use of DTE, LT3 or LT3+LT4 although they state that a patient who has not responded from LT4 monotherapy can be put on a trial of LT3+LT4.²

According to the authors, monotherapy with LT4 is the preferred form of thyroid replacement therapy; but some patients may continue to have symptoms regardless of TSH in the normal reference range. They also note that their trial is the first to compare the three different types of thyroid hormone replacement therapy in patients with hypothyroidism. Overall, there were no major differences in the outcomes between the three treatment groups in this trial. But some patients on LT4 monotherapy with high symptom scores improved significantly after shifting to LT4 + LT3 or DTE treatment. These were also the patients who preferred the combination therapy or thyroid extract over T4. They suggest that “thyroid hormone signaling in a minority of the patients on LT4 remain subnormal and can be improved (perhaps restored) with therapy containing T3”. Hence, some patients may benefit from the use of combination therapy.

These include those who remain symptomatic or dissatisfied in spite of achieving biochemical euthyroidism on T4, as well as those who are unable to achieve euthyroid levels while on relatively high doses of T4.

Reference

1. Shakir MKM, et al. Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in hypothyroidism. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4400-e4413. doi: 10.1210/clinem/dgab478.
2. Idrees T, et al. Liothyronine and desiccated thyroid extract in the treatment of hypothyroidism. Thyroid. 2020 Oct;30(10):1399-1413. doi: 10.1089/thy.2020.0153.