BACKGROUND
Hypothyroidism is common, affecting 2-3% of the US population. When you include mild forms (subclinical hypothyroidism), up to 25% of certain populations may be affected. Thyroxine (T₄) is the main thyroid hormone secreted by the thyroid gland. It is converted to triiodothyronine (T₃) in other areas of the body where thyroid hormone acts. The thyroid also secretes T₃ at a low level. Most of the actions of thyroid hormone are attributed to T₃.

Levothyroxine (L-T₄), the pill form of T₄, is the most commonly recommended treatment for hypothyroidism. Long-term experience with this therapy suggests that it is safe and effective and is accepted by most patients with hypothyroidism, resolving most, if not all, of their hypothyroid symptoms. However, despite returning the thyroid hormone levels to normal, a certain percentage of hypothyroid patients continue to have symptoms attributed to hypothyroidism. This has led to a desire by patients to find alternative treatments to L-T₄ alone. One such treatment is the use of combination therapy, adding L-T₃ (liothyronine) with L-T₄ to increase blood T₃ levels. As a consequence, combination therapy with L-T₄/L-T₃ began to be used, despite the lack of evidence suggesting a real benefit. Interesting new data have emerged to suggest a genetic basis why some patients may do better on combination therapy. Rarely, changes in the enzyme that converts T₄ to T₃ (type 2 deiodinase) causes it to not work well. In these patients, more of their blood T₃ levels may come from the thyroid rather than from the conversion of T₄. Thus, in those patients, L-T₄/L-T₃ combination therapy may be preferred.

To help address this, the American Thyroid Association (ATA), the British Thyroid Association (BTA), and the European Thyroid Association (ETA) developed a consensus statement in which they reviewed the latest evidence of hypothyroidism treatment with L-T₄/L-T₃ and developed recommendations for future clinical trials.

THE FULL ARTICLE TITLE
Jonklaas J et al 2020 Evidence based use of LT4/LT3 combinations in treating hypothyroidism: A consensus document. Thyroid. Epub 2020 Dec 4. PMID: 33276704.

SUMMARY OF THE STUDY
To draft this consensus statement, a task force consisting of 12 experts in all aspects of LT₄/LT₃ combination therapy was formed. Comments from members of all three societies, as well as input from two patients involved in the conference, were also taken into account. A total of 34 consensus items were available for voting, of which 28 received at least a 75% approval and 13 full approval. The following are selected highlights from the published statement:

The statement assessed new experimental data in the laboratory that suggests T₄ may lead to a “normal” TSH while reducing T₃ generation in other areas of the body due to effect of the type 2 deiodinase in the brain. The task force also evaluated results from available clinical trials of combination therapy (including desiccated thyroid extracts). The analysis of these trials did not show any consistent benefits of combination treatment in hypothyroid patients; however, the numerous limitations did not allow it to draw a definite conclusion on the issue.

After analyzing the numerous points of criticism of the above-mentioned trials, the task force provided some useful suggestions for a protocol for future adequately powered and high-quality randomized, controlled trials in hypothyroid patients who appear not to have full replacement by L-T₄ monotherapy despite hormone levels in the normal range. The main suggestions were to consider the severity of hypothyroidism and evaluate the presence of other medical issues (heart diseases, cancer, or psychiatric disorders). In addition, the trial studies should be at least one year in duration and include: (i) adults with normal serum TSH at baseline obtained after a stable L-T₄ replacement dose; (ii) hypothyroid patients treated with at least 1.2 μg/kg/day of L-T₄ (thus including only patients without residual thyroid function); and (iii) patients with persistent hypothyroid symptoms or dissatisfaction and concurrently decreased baseline serum T₃ concentrations during L-T₄ monotherapy.

The task force concluded that the goal of future L-T₄/L-T₃ combination studies should give L-T₃ at least twice a day while waiting for the development of a sustained release L-T₃ preparation which is not yet available for clinical use.

Future studies need to be able to evaluate thyroid-related quality of life in a standard way, such as measured by thyroid-specific surveys like ThyrPRO. Patient preferences for thyroid hormone replacement therapy should be considered as secondary endpoint in clinical trials.

The task force also analyzed the effects of the genetic changes in the type 2 deiodinase enzyme found in some patients. Since the impact of these genetic changes is still unclear, the task force suggested that future studies be performed of the subgroup of patients with these genetic changes to clarify the potential benefit of combination therapy.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Future clinical trials of L-T₄/L-T₃ combination therapy should be guided by the recommendations developed in this consensus statement. The results of such redesigned trials could lead to improved understanding of the treatment of hypothyroid patients with thyroid hormone replacement therapy.

— Alan Farwell, MD

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