Thyroid hormone resistance

At a Glance

Resistance to thyroid hormone (RTH) is characterized by a reduced responsiveness of target tissues to endogenous thyroid hormones. It is an autosomal dominant disorder with an incidence of about 1 in 40,000 live births. Patients are usually identified by a combination of elevated FT4 and FT3, normal or slightly increased TSH, and goiter. Despite elevated FT4, symptoms of hyperthyroidism are usually absent. In children, hyperactivity/learning disability, developmental delays, and sinus tachycardia are possible.

Caveats include the absence of ongoing nonthyroidal illness, medications affecting thyroid function, defect in hormone transport (e.g., monocarboxylate transporter 8 (MCT8) deficiency), defect in metabolism (e.g., deiodinase deficiency), or other circulating thyroid antibodies.

Prior to the recognition of the gene defect for RTH, RTH was grouped into the clinical categories of generalized resistance (GRTH), pituitary resistance (PRTH), or both. In GRTH, all thyroid responsive tissues (pituitary, as well as peripheral) are resistant to thyroid hormone action. As a result, patients have high levels of FT4 with near normal TSH, yet they do not have symptoms of hyperthyroidism as very high concentrations of thyroid hormones are needed to overcome tissue hyposensitivity. Thus, these patients can be euthyroid or even hypothyroid.

In PRTH, there is predominantly pituitary resistance to circulating thyroid hormones. In this condition, the peripheral tissues are responsive to elevated thyroid hormones, and the patient may suffer from agitation or tachycardia, although very high levels of thyroid hormones are needed to evoke a response at the pituitary level. Thus, as a rule of thumb, absence of overt thyrotoxic symptoms are associated with GRTH, whereas the presence of thyrotoxic symptoms is more typical of PRTH. A rare case of an isolated peripheral tissue resistance (PTRTH) has been described. At present, the general consensus is that GRTH and PRTH represent a single genetic entity.

What tests should I request to confirm my clinical Dx? In addition, what follow-up tests might be useful?

Serum FT4 and FT3 are elevated, and, paradoxically, serum TSH is normal or elevated. These comprise the sine qua non for the biochemical diagnosis of RTH. Other tests provide only supportive evidence, thus, serum thyroxine binding globulin (TBG) levels are normal, whereas total T3 and T4 may be elevated. Thyroglobulin (TG) levels may also be elevated as a consequence of goiter.

Since RTH is hereditary, as follow-up testing, FT4, FT3, and TSH should be performed on first degree relatives (i.e., parents, siblings, and children). If follow-up testing of family members is negative, a pituitary adenoma should be excluded by measurement of the alpha subunit of TSH. In pituitary adenomas, there is a disproportionate increase in the alpha subunit of TSH relative to whole TSH. Finally, genetic testing for RTH mutation (thyroid hormone receptor beta, TRb gene) analysis is indicated.(Table 1)

Table 1.
FT4 and FT3 TSH
High Normal to high

Are There Any Factors That Might Affect the Lab Results?

Inherited deficiency of TBG, although rare, can theoretically affect FT4 levels as TBG is an important binding protein for T4. Normal levels of TBG can be useful in excluding TBG deficiency. It is important to measure both T4 and T3, since reduced conversion of T4 to T3 would lead to elevated T4, FT4, but no increase in T3/FT3 levels. Reduced conversion (deiodinase deficiency) of T4 to T3 can be inherited or acquired as in acute nonthyroidal illness.

What Lab Results are Absolutely Confirmatory?

RTH mutation (thyroid hormone receptor beta) analysis is confirmatory in 85% of cases of RTH, and more than 100 mutations have been described.

Additional Issues of Clinical Importance

The main differential diagnosis is with a TSH producing pituitary adenoma. As discussed, the alpha subunit of TSH is increased disproportionately in TSH producing adenomas. Additionally, TSH levels are very high in TSH producing pituitary adenomas (>10 mU/L), there is absence of TSH circadian rhythm, supraphysiologic doses of thyroid hormone do not suppress TSH, and there is no response to the TRH test.

Errors in Interpretation

It is important to appreciate that 15% of cases with RTH have no detectable mutations in the TRb gene. RTH in the absence of a detectable mutation in the TRb gene is clinically and biochemically indistinguishable from RTH with a TRb mutation. In such instances, reduced tissue sensitivity to thyroid hormones can be demonstrated using the L-T3 suppression test.