Hyperthyroidism: Special Circumstances
Hyperthyroidism and pregnancy
Pregnancy affects thyroid status in numerous ways (Figure 12.1a). TSH has a similar molecular structure to β human chorionic gonadotrophin (β-HCG), therefore the hyperemesis of pregnancy (which is characterised by raised β-HCG) can be associated with mild biochemical hyperthyroidism. This usually resolves spontaneously in the second trimester of pregnancy.
Graves’ disease in pregnancy
Patients with Graves’ disease require observation during pregnancy every 4–6 weeks, because of the increased risk of maternal complications as well as reduced fetal growth (Figure 12.1b). Pregnancy usually has a beneficial effect on autoimmune disease, including Graves’ disease, such that the dose of anti-thyroid medication can usually be reduced or even stopped. Propylthiouracil (PTU) is preferred to carbimazole in the first trimester because congenital malformations (notably choanal atresia and aplasia cutis) have not been described with PTU. Carbimazole is preferred during the second and third trimesters, because of the increased risk of PTU-associated hepatitis later in pregnancy. Placental transfer of TSH receptor stimulating antibodies can affect the fetus so additional scans are performed during pregnancy to ensure there is no evidence of tachycardia, goitre or growth restriction, which are signs of fetal hyperthyroidism.
Patients with Graves’ disease who have had previous surgery or RAI require fetal monitoring during pregnancy. In this situation, although the mother has had her thyroid removed or ablated, there is still a risk of placental antibody transfer to the fetus and neonatal thyrotoxicosis. Signs of this include irritability and failure to thrive during the first 3 weeks of life.
Breastfeeding is safe on anti-thyroid medication, as long as doses are not excessive. Hyperthyroidism often becomes worse after delivery, because the immunosuppressive effect of pregnancy is removed, demanding an appropriate dosage increase in thionamide therapy.
Subclinical hyperthyroidism refers to a suppressed TSH with normal fT4 and fT3, often in the upper part of the normal range. Subclinical hyperthyroidism suggests a degree of autonomous thyroid hormone production. This is often due to the presence of nodular thyroid disease. Patients may not be symptomatic, but are at risk of the same long-term complications as frank hyperthyroidism (notably AF and osteoporosis), especially if the TSH is completely unmeasurable. Treatment is indicated to control symptoms, and can also be considered on a case-by-case basis in asymptomatic patients, dependent on comorbidities (e.g. AF) and extent of TSH suppression. Surveillance alone, until the development of frank hyperthyroidism, is an alternative.
Elevated fT4 with unsuppressed TSH
Thyroid results are usually easy to interpret. A high fT4 with a suppressed TSH is the norm in hyperthyroidism. It is unusual in clinical practice to see a high fT4 with non-suppressed TSH. In this situation it is important to consider assay interference, TSHoma and thyroid hormone resistance (Figure 12.1c).
If the thyroid results do not fit with the clinical presentation, blood should be sent to another laboratory for confirmation by another method. Equilibrium dialysis is the most accurate way to measure fT4, and eliminates the possibility of interfering antibodies affecting the result. Antibodies to TSH (heterophile antibodies) can make the TSH look falsely high or low, and these can be detected. Familial dysalbuminaemic hyperthyroxinaemia (FDH) should also be considered in the context of high fT4 and normal TSH. FDH leads to falsely elevated T4 due to an abnormal albumin, which has a higher affinity for thyroxine than TBG.
TSHoma and thyroid hormone resistance
If the high fT4 and non-suppressed TSH is not due to assay interference, the differential diagnosis lies between TSHoma and thyroid hormone resistance.
TSHoma is a rare TSH-secreting pituitary tumour, which drives fT3 and fT4 production from the thyroid. Patients present with symptoms of hyperthyroidism, or mass effect from the pituitary tumour if it is a macroadenoma. If MRI confirms a pituitary tumour, trans-sphenoidal surgery is indicated, although somatostatin analogues are also effective in achieving biochemical control.
Thyroid hormone resistance
Thyroid hormone resistance causes high fT3/fT4 and non-suppressed TSH due to reduced end-organ unresponsiveness to thyroxine. This is caused by an inactivating mutation in the thyroid hormone receptor β (TR-β) gene. This condition is autosomal dominant and there is usually a family history of unusual thyroid function results. There may be variable sensitivity to thyroid hormones in different tissues. A diagnosis of thyroid hormone resistance can be confirmed by genetic testing.
Distinuishing TSHoma from thyroid hormone resistance
SHBG is produced by the liver, and is elevated in hyperthyroid states. In TSHoma, patients are truly hyperthyroid and therefore typically have high SHBG levels, while thyroid hormone resistance is associated with low or normal SHBG. TRH injection (the TRH test) typically leads to a flat TSH response in TSHoma, with an exaggerated rise seen in thyroid hormone resistance. Patients with TSHoma will usually also display a raised α-subunit, have evidence of a pituitary tumour on MRI 11 onine PET) and normalise thyroid function in esponse to somatostatin analogues.