Addressing Residual Hypothyroid Symptoms During Levothyroxine Treatment

An association between thyroid function and mood disorders has been appreciated for many decades. Thyroid imbalance affects mental health, and the biological basis of this connection is well characterized. Even in euthyroid individuals, iiodothyronine (T3) has been noted to improve mood. T3 enhances neurogenesis (the birth of new neurons) in the hippocampus – a brain region linked to mood and memory. Enhanced neurogenesis may restore hippocampal atrophy observed in depressed patients.

Thyroid hormones directly regulate the metabolism of every cell in the body. Specifically, thyroxine (T4) is converted to the more biologically active form, triiodothyronine (T3), which binds to nuclear receptors inside the cell, upregulating the transcription of genes related to metabolism.

Hypothyroidism (too little thyroid hormone) suppresses cellular metabolism. The brain is the most energetically demanding organ in the body. Hence, the brain is very sensitive to the impairments of metabolism that results from a hypothyroid state. Profound hypothyroidism can even result in coma. Conversely, hyperthyroidism can cause anxiety and even a sympathomimetic toxidrome with psychosis.

Implications For Patients

Levothyroxine has been the most prescribed drug in the US for many years in a row. Levothyroxine is synthetic thyroxine (T4) used for thyroid replacement in deficient patients with hypothyroidism.

However, a subset of patients suffering from thyroidal illness have complained that levothyroxine (T4) therapy alone is insufficient to resolve symptoms. Endocrinologists could not reconcile these complaints with the fact that test results often showed normalized TSH results after levothyroxine therapy. (TSH or thyroid-stimulating hormone is a sensitive indicator of thyroid levels). These patients responded better to combination T4/T3 therapy, as is found in products like Armour Thyroid.

Websites like Stop The Thyroid Madness were started to give a voice to patients whose hypothyroid symptoms failed to resolve in spite of thyroid replacement therapy with levothyroxine (T4).

The recent paper Scope and Limitations of Iodothyronine Deiodinases in Hypothyroidism explicitly addresses the limitations of treatment with levothyroxine alone. The paper discusses a genetic variation (Thr92AlaD2) or polymorphism that affects the gene encoding deiodinase iiodothyronine 2. This enzyme converts thyroxine (T4), to the more biologically active form, iiodothyronine (T3). Patients with this genetic variation are much more likely to respond to combination T3/T4 therapy, raising the question about whether genetic testing for this variation should be part of the standard thyroid workup.

The paper also emphasizes that type 2 iodothyronine deiodinase in the hypothalamus is less sensitive to degradation. In contrast, type 2 iodothyronine deiodinase in the periphery is very sensitive to local T4 concentrations. (In the periphery, T4 inactivates and marks the enzyme for destruction so that it has a very brief half-life). This finding challenges the assumption that tissue levels of T3 and TSH can be fully restored by administration of levothyroxine by itself. This is because the levothyroxine dose that normalizes serum levels of TSH is lower than the dose that normalizes serum T3, which explains the increased T4:T3 ratio observed in patients treated with levothyroxine.

These studies underscore the importance of remaining receptive to patient feedback. For many years endocrinologists dismissed patient experience about levothyroxine vs combined T4/T3 therapy because laboratory TSH values were almost dogmatically used to assess thyroid function at the exclusion of other information. Many patients have insisted that they felt better on combination T4/T3 or Armour thyroid therapy, and recent studies now provide a biological basis for this phenomenon.