Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study

This impressive study provides answers, but also raises further questions about what we are aiming for with thyroid hormone replacement. The authors interpret their data as supporting current guidelines, which are based on TSH measurement, and quote an ideal reference range of 2.0 – 2.5 mU/L. However, their data could be interpreted differently: TSH values across a wide range made very little difference to outcomes unless they were frankly hypothyroid (TSH > 10 mU/L) or frankly hyperthyroid (TSH < 0.1 mU/L). In reality, up to 60% of hypothyroid patients do not meet guideline targets for TSH. 1

It is well established, and acknowledged by the authors, that to keep TSH on target and to alleviate symptoms of hypothyroidism, usually requires a higher level of free T4 than prevails in normal, euthyroid subjects. 2 Symptom relief relies on achieving a suitable level of triiodothyronine (T3) at the tissue level. In patients treated with L-thyroxine, achieving tissue euthyroidism usually requires higher levels of free T4 and lower levels of TSH than are considered normal, or ideal. This study reassures us that lower, but not completely suppressed, levels of TSH are perfectly safe. Indeed, patients with lower TSH were at decreased risk of heart failure. This is almost certainly due to the protective effect of T3 on the heart. 3

The high free T4 required in many patients to both alleviate symptoms and to “normalise” TSH is undesirable. Recent studies show that higher free T4 (even within the quoted normal range) is associated with adverse outcomes, including atrial fibrillation and cognitive decline, and may additionally be an independent risk factor for atherosclerosis. 4 Treatment of hypothyroidism with T3 or combined T3 and T4 has not been recommended generally, but the evidence pendulum is now swinging in its favour, 5 and the reality is that many physicians do prescribe combined T3 and T4 when faced with a patient who is not satisfied with L-thyroxine treatment on its own. 6

Treating hypothyroidism with L-thyroxine to achieve a “target” TSH value does not hit the mark for many hypothyroid patients. This timely study by Thayakaran and colleagues again highlights the tenuous relationship between plasma TSH concentration and successful outcomes in the treatment of hypothyroidism.

References
1. Eligar V, Taylor PN, Okosieme OE, et al. Thyroxine replacement: a clinical endocrinologist's viewpoint. Ann Clin Biochem 2016;53(Pt 4):421-33.
2. Carr D, McLeod DT, Parry G, et al. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 1988;28(3):325-33.
3. Kannan L, Shaw PA, Morley MP, et al. Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circulation 2018;11(12):e005266.
4. Anderson JL. Circulating Thyroxine: A Major New Risk Marker for Atherosclerosis? Circ Res 2017;121(12):1304-06.
5. McAninch EA, Bianco AC. The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy. Front Endocrinol (Lausanne) 2019;10:446.
6. Jonklaas J, Tefera E, Shara N. Physician Choice of Hypothyroidism Therapy: Influence of Patient Characteristics. Thyroid 2018;28(11):1416-24.