T4 + T3 combination therapy: any progress?

Abstract

Guidelines on T4 + T3 combination therapy were published in 2012. This review investigates whether the issue is better understood 7 years later. Dissatisfaction with the outcome of T4 monotherapy remains high. Persistent symptoms consist mostly of fatigue, weight gain, problems with memory and thinking and mood disturbances. T4 monotherapy is associated with low serum T3 levels, which often require TSH-suppressive doses of L-T4 for normalization. Peripheral tissue thyroid function tests during T4 treatment indicate mild hyperthyroidism at TSH < 0.03 mU/L and mild hypothyroidism at TSH 0.3–5.0 mU/L; tissues are closest to euthyroidism at TSH 0.03–0.3 mU/L. This is explained by the finding that whereas T4 is usually ubiquinated and targeted for proteasomal degradation, hypothalamic T4 is rather stable and less sensitive to ubiquination. A normal serum TSH consequently does not necessarily indicate a euthyroid state. Persistent symptoms in L-T4 treated patients despite a normal serum TSH remain incompletely understood. One hypothesis is that a SNP (Thr92Ala) in DIO2 (required for local production of T3 out of T4) interferes with its kinetics and/or action, resulting in a local hypothyroid state in the brain. Effective treatment of persistent symptoms has not yet realized. One may try T4 + T3 combination treatment in selected patients as an experimental n = 1 study. The 2012 ETA guidelines are still valid for this purpose. More well-designed randomized clinical trials in selected patients are key in order to make progress. In the meantime the whole issue has become rather complicated by commercial and political overtones, as evident from skyrocketing prices of T3 tablets, aggressive pressure groups and motions in the House of Lords.

Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

“…Second, it is not clear whether “pulsatile” T3 levels during LT3 dosing have different effects on T3 action, in both pituitary and elsewhere. There are little data to inform this, but if “pulsatile” T3 has a greater effect on TSH suppression than a similar amount of T3 distributed evenly throughout the 24-h period, this could explain why the trials that showed a preference for LT3 in combination with LT4 were generally associated with lower, sometimes “subnormal” TSH levels [89]. In support of this, it is noted that in the Thyroid Epidemiology, Audit, and Research (TEARS) retrospective review of patients in Scotland, of 400 individuals using LT3, compared with 33,995 patients taking LT4, no excess of cardiovascular disease including atrial fibrillation was noted despite TSH levels being substantially lower in LT3 users (1.07 vs. 2.08 mIU/L, p < 0.001), suggesting that a lower TSH on LT3 therapy does not necessarily reflect over-replacement [38].…”

What Is the Quality of Life in Patients Treated with Levothyroxine for Hypothyroidism and How Are We Measuring It? A Critical, Narrative Review

“…), most of the investigators felt that the potential benefits for QoL did not provide a clear clinical rationale in favor of LT4 + LT3. However, the frequent patient preference for LT4 + LT3 (for as-yet unknown reasons) [ 51 ] reinforces Wiersinga’s suggestion that robust clinical trials in selected patient subpopulations are essential for making progress in this field [ 99 ].…”

“…From the early 2000s onwards, it has often been suggested that patients who experience persistent symptoms of hypothyroidism and/or poor QoL during treatment with LT4 alone may benefit from LT4 + LT3 combination treatment. However, almost 20 years later, the merits and limitations of this strategy are still subject to debate [ 97 , 98 , 99 ].…”

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

“…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 . Although L‐T4 + L‐T3 treatment in trials may not have been optimized, 36 it seems that other factors may be of importance in determining satisfaction and QOL associated with treatment of hypothyroidism. It is therefore worth exploring these as they might provide new avenues for improving patient satisfaction and QOL.…”