Thyroid Hormone Resistance

Thyroid hormone resistance is reduced tissue response to thyroid hormone, with raised free thyroxine and free triiodothyronine and a non-suppressed thyroid stimulating hormone.

Most cases are resistance to thyroid hormone beta from variants in THRB, with autosomal dominant inheritance, an incidence of about 1 in 40,000 births and no sex difference. Resistance alpha from THRA variants is much rarer.

Variants impair receptor binding or co-factor interaction and act in a dominant negative way. Penetrance varies between tissues, so features differ between patients.

Pathophysiology.

The pituitary resets its feedback set point, so thyroid stimulating hormone stays normal or raised at high thyroid hormone levels and the gland enlarges. Tissues vary in resistance: the heart (which expresses the alpha receptor) is relatively sensitive, giving tachycardia.

Resistance alpha affects tissues rich in the alpha receptor (bone, gut, brain, heart) and causes low normal thyroxine and high normal triiodothyronine.

• Goitre, tachycardia, anxiety, attention deficit and learning difficulty, short stature in children, hearing loss and recurrent ear infection.
• Some patients are asymptomatic, and others show mixed features of hypothyroidism and thyrotoxicosis.
• Resistance alpha: constipation, macrocephaly, delayed development, skeletal dysplasia and anaemia.

Red flags.

• Previous treatment with thyroid ablation or antithyroid drugs for presumed Graves disease, with rising thyroid stimulating hormone.
• Headache or visual change (consider a thyrotroph adenoma).

• Raised free thyroxine and free triiodothyronine with thyroid stimulating hormone normal or raised, on repeat testing.
• Exclude assay interference and familial dysalbuminaemic hyperthyroxinaemia, and review drugs (amiodarone, heparin).
• THRB sequencing and family testing confirm the diagnosis. Sex hormone binding globulin is normal and the alpha subunit to thyroid stimulating hormone molar ratio is under 1.
• Pituitary MRI only if a thyrotroph adenoma is possible (no family history, raised sex hormone binding globulin, or high alpha subunit ratio).
• Resistance alpha: low or low normal free thyroxine, raised free triiodothyronine to thyroxine ratio and normal thyroid stimulating hormone. THRA sequencing.

Differential diagnosis.

• Thyroid stimulating hormone secreting adenoma.
• Familial dysalbuminaemic hyperthyroxinaemia and assay interference.
• Drug effects and non-thyroidal illness recovery.
• Graves disease (thyroid stimulating hormone suppressed).

• Most patients need no treatment. Do not ablate the thyroid or use antithyroid drugs, which increase thyroid stimulating hormone and goitre.
• Symptomatic tachycardia: propranolol 10 to 40 mg three to four times daily or atenolol 25 to 50 mg daily.
• Triiodothyroacetic acid can lower thyroid stimulating hormone and goitre size in selected patients at specialist centres, with its own dosing and monitoring.
• Treat attention deficit and hearing loss as needed. Resistance alpha: a therapeutic test of levothyroxine at an individual dose with monitoring.

Special groups. Pregnancy: avoid antithyroid drugs in an affected mother, because an affected foetus needs high thyroid hormone for normal development, while an unaffected foetus of an affected mother is exposed to high maternal hormone, which can lower birth weight. Specialist review of both is advised. Genetic counselling is advised.

Monitoring. Thyroid function yearly, growth and development in children, and heart rate.

Referral and escalation. Endocrinology and clinical genetics; paediatric endocrinology for children.