The terminology in this subject is a bit confused and has changed over time, so older studies will have the older terminology. The phrase ‘Impaired Sensitivity to Thyroid Hormone’ tends to be used to describe any form of disruption to thyroid hormone action. It used to be called ‘Reduced Sensitivity to Thyroid Hormone’ but ‘reduced’ was changed to ‘impaired’ because there is the possibility of increased sensitivity. There are three major forms of impaired sensitivity that are recognised. They feature abnormal blood tests results and have profound effects from birth (or conception).
Thyroid Hormone Cell Membrane Transport Defects
This is where there is a defect in proteins that carry thyroid hormone across the cell membrane into the cells. There are a number of cell membrane transporters, the best known being the Monocarboxylate transporter 8 (MCT8). Mutations of the MCT8 transporter results in severe psychomotor defects. This is also known as ‘Allan-Herndon-Dudley syndrome’. MCT8 deficiency is a recessive X-linked defect that affects males, while females are carriers.
The MCT8 – AHDS Foundation gives a good introduction to the MCT8 cell membrane transport defect along with this video.
Thyroid Hormone Metabolism Defects
I have little knowledge of this. It’s caused by mutations in a gene affecting selenoprotein synthesis. The deiodinases, the enzymes that strip an iodine atom of thyroid hormones (e.g. convert T4 to T3) are selenoproteins. Patients with this defect have impaired deiodinase with multiple effects. This is a very rare condition. Alexandra Dumitrescu and Sam Refetoff have written an excellent review if you want to know more.
Genetic Resistance to Thyroid Hormone (RTH).
This was first described by Sam Refetoff in 1967. In 1989 it was discovered that RTH is caused by a mutation in the thyroid hormone receptor beta gene (TRβ). There are four thyroid hormone receptors TRα1, TRα2, TRβ1 and TRβ2 formed by alternate splicing by the TRα and TRβ genes. TRα2 is not active. TRα1 and TRβ1 are expressed in varying proportions throughout tissues in the body. TRβ2 is expressed almost exclusively in the pituitary and hypothalamus.
RTH is broken down into three forms: –
- Generalised resistance to thyroid hormone (GRTH). The pituitary and most peripheral tissues are affected.
- Pituitary resistance to thyroid hormone (PRTH). The pituitary is resistant to a greater degree than peripheral tissues.
- Peripheral resistance to thyroid hormone (PerRTH). Peripheral tissues are affected but not the pituitary. There has been only one reported case.
These groupings are used less often now because GRTH and PRTH tend to occur in all patients to varying degrees. Since the pituitary is affected these patients tend to have high fT3 or fT4 with a normal or elevated TSH. These patients are sometimes misdiagnosed with hyperthyroidism.
Mutations of the TRβ are found in about 85% of patients, it is not known why mutations are not found in the other 15%. The degree of RTH in tissues varies according to the extent TRβ genes are present. For example, the liver expresses many TRβ1 receptors and few TRα1, the liver suffers more resistance and patients have higher cholesterol levels. On the other hand, the heart predominantly expresses TRα1 receptors which are unaffected. This, combined with elevated hormone levels results in a rapid heartbeat.
The team at Addenbrooke’s Hospital have discovered mutations of the TRα gene. These patients usually present with growth retardation and cases are thankfully very rare. We will focus on TRβ1 receptors for reasons that will be explained later.
Let’s take a look at Resistance to Thyroid Hormone (RTH) in more detail.