Resistance to thyroid hormone

Resistance to thyroid hormone (RTH) is the clinical syndrome of reduced sensitivity to thyroid hormones due to variants in the thyroid receptor (TR) subunits. There are two autosomal dominant forms and pathogenic variants can arise de novo. The more common form is resistance to thyroid hormone due to variants in the β chain of TR (RTHβ). Resistance to thyroid hormone α (RTHα) due to variants in the α subunit of TR is rarer. The overall population frequency of RTH is around 1 in 40,000.

RTHβ results in elevated circulating thyroid hormone levels with a non-suppressed thyroid stimulating hormone (TSH). Individuals may be asymptomatic, and in this scenario, cases are most commonly detected when routine thyroid function blood tests are found to be discordant or “funny”. Individuals with RTHβ may also present with clinical features due to a combination of both insensitivity to thyroid hormone (e.g. dyslipidaemia) and overexposure to thyroid hormone (e.g. palpitations) due to the different level of expression of TRβ in the various tissues.

RTHα is challenging to diagnose as it results in features of hypothyroidism in specific tissues in the context of normal or near‐normal thyroid function tests. For example, developmental delay and constipation can reflect hypothyroidism at the tissue level in the brain and GI tract, respectively. In the cases of RTHα described to date, biochemical assessment of thyroid function shows a free thyroxine hormone (fT4) level in the lower half of the reference range, free triiodothyronine hormone (fT3) level in the upper half of the reference range or just above the reference range and a normal TSH. THRA variants are, therefore, most often identified by massively parallel sequencing (commonly called next generation sequencing) when investigating childhood conditions including developmental delay and short stature.

RTHβ results from to loss-of-function pathogenic variants in THRB. Genetic testing for RTHβ should be considered for individuals with biochemical features of RTH (thyroid hormone excess with a non-suppressed TSH) where other causes have been excluded, including assay interference and TSHoma. RTHβ is included in the R145 (congenital hypothyroidism) and R182 (hyperthyroidism) panels in the National Genomic Test Directory.

RTHα results from loss-of-function pathogenic variants in THRA. It should be considered in individuals with clinical features of hypothyroidism who have near-normal thyroid function tests. RTHα is also included in the R145 (congenital hypothyroidism) panel and in the R182 (hyperthyroidism) panel. In addition, RTHα is also included in DDG2P Paediatric disorders’ super panel, and R21 (Fetal anomalies with a likely genetic cause), R412 (Fetal anomalies with a likely genetic cause; non-urgent) and R29 (intellectual disability – microarray and sequencing) panels.

Most cases of RTH are detected in the course of investigations by endocrinologists into discordant thyroid function tests and the diagnosis is secured with genetic testing.

For information about testing, see Presentation: Patient with resistance to thyroid hormone.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to endocrinology. Please refer to the local pathway for your region for this condition.

RTH is inherited in an autosomal dominant manner. In both forms, a family history can be helpful in alerting the clinician to the possibility of RTH.

Some individuals with RTHβ are asymptomatic and therefore specific treatment is not required. Symptomatic patients with RTHβ should be managed in centres with relevant expertise. For those with palpitations or other symptoms of thyroid hormone excess, beta blockers can be used for symptom relief. Goitre is often seen in people with RTH, but is rarely clinically significant. Ablative treatments (surgery and radioactive iodine) are best avoided as post-ablative thyroid hormone replacement and monitoring is challenging in the context of RTHβ. There are reports of people with RTHβ with problematic goitres responding to alternate day oral T3 therapy or Triac (3,5,3′-Triiodothyroacetic Acid). In pregnant women with RTHβ carrying an unaffected child, antithyroid drugs are sometimes used to maintain a maternal fT4 at less than 50% over the upper limit of the reference range. These cases should be managed jointly by obstetricians and endocrinologists with expertise in RTH management.

There is only very limited data about the treatment of RTHα, with little long-term follow-up data. Thyroid hormone replacement with levothyroxine is used, often in high doses to overcome resistance. The therapeutic aim is to achieve fT4 and fT3 levels in the reference range (this often results in TSH suppression due to negative feedback on the hypothalamic-pituitary-thyroid axis).

This condition may be identified before any symptoms appear, for example through the Generation Study. Therefore, management of these individuals may differ from those presenting symptomatically.

For clinicians

• NHS England: National Genomic Test Directory and eligibility criteria
• NHS England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource

References:

• Erbaş İM, Demir K. ‘The Clinical Spectrum of Resistance to Thyroid Hormone Alpha in Children and Adults‘. Journal of Clinical Research in Pediatric Endocrinology 2021: volume 13, issue 1, pages 1–14. DOI: 10.4274/jcrpe.galenos.2020.2019.0190
• Moran C, Schoenmakers N, Visser WE and others. ‘Genetic disorders of thyroid development, hormone biosynthesis and signalling‘. Clinical Endocrinology 2022: volume 97, issue 4, pages 502–514. DOI: 10.1111/cen.14817
• Pappa T and Refetoff S. ‘Resistance to Thyroid Hormone Beta: A Focused Review‘. Frontiers in Endocrinology 2021: volume 12, article number 656551. DOI: 10.3389/fendo.2021.656551

For patients

• British Thyroid Foundation: Rare thyroid disorders
• You and Your Hormones: Resistance to thyroid hormone (from the Society for Endocrinology)