5th April 2024

Regulation of thyroid hormones

Physiology

Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the production of thyroid stimulating hormone (TSH) from the anterior pituitary. TSH, in turn, stimulates the production of T4 (a pro-hormone which is converted to T3 in the liver and kidney) and T3 (an active form which acts on nuclear receptors). Thyroid hormones are mainly protein bound in circulation. The free T4 and T3 exert negative feedback on TRH and TSH, suppressing their release. Where there is thyroid hormone derangement, a good understanding of this negative feedback mechanism will help to determine the likely aetiology (see Table 1).

To summarise the pattern of derangement:

• Raised T3/T4 with low TSH suggests overproduction of thyroid hormones. Causes include: Graves, toxic multinodular goitre, postpartum thyroiditis, subacute thyroiditis, amiodarone induced thyrotoxicosis
• Raised TSH with low T3/T4 suggests a problem with the production of thyroid hormones. Examples listed in table 2
• Low TSH with low T3/T4 implies pathology in the hypothalamic- pituitary axis, that is, lack of production of TRH/TSH leading to low levels of T3/T4. Examples listed in table 2

In addition to the above, physiological and pharmacological factors can affect thyroid hormones. This includes pregnancy, where there is an increase in production and reduced excretion of thyroxine binding globulin (TBG) by oestrogen. In addition, the human chorionic gonadotropin hormone stimulates production of thyroid hormones. This reduces production of TSH through negative feedback. The biochemical picture is raised total T3/T4, normal free T3/T4 and low TSH. These physiological changes rarely cause clinical problems.

Amiodarone can cause both hyper and hypothyroidism. Amiodarone induced thyrotoxicosis (AIT) can either be due to excess iodine load increasing thyroid hormone production (type I AIT) or inflammation (type II AIT). Type I AIT usually presents with a goitre and is associated with an underlying thyroid disorder. Cessation of amiodarone and switch to another anti-arrhythmic should be considered. Generally, type I AIT is treated with antithyroid medication as the underlying process is increased production and type II is treated with steroids as the underlying process is thyroiditis.

Amiodarone induced hypothyroidism is caused by excess iodine inhibiting iodide organification and T4 and T3 synthesis.  In such cases, it is not essential to stop amiodarone but levothyroxine can be commenced to achieve an euthyroid state.

Sick euthyroid syndrome

This results from a reduction in binding proteins, reduced peripheral conversion of T4 to T3 and reduced production of TSH. This should be suspected in patients with critical systemic illnesses, deprivation of calories and following major surgery. The biochemical picture is of low T3, low/normal T4 and low/normal TSH. Thyroid function tests should be repeated once the patient has recovered from their illness.

References

• National Institute for Health and Care Excellence (UK). Thyroid disease assessment and management. Published 9ᵗʰ November 2019. Available at: https://www.nice.org.uk/guidance/ng145/chapter/recommendations
• UpToDate. Laboratory assessment of thyroid function. Last updated 5ᵗʰ October 2021. Accessed Available at: https://www.uptodate.com/contents/laboratory-assessment-of-thyroid-function?search=thyroid%20function%20tests&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
• 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-associated Thyroid Dysfunction. European thyroid journal. Eur Thyroid J 2018;7:55–66. Available at: https://www.karger.com/Article/Fulltext/486957
• Euthyroid sick syndrome. Stat Pearls. Last updated 30ᵗʰ October 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482219/