Approach to a low TSH level: Patience is a virtue

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Elevated human chorionic gonadotropin

The alpha subunit of human chorionic gonadotropin (hCG) is homologous to the alpha subunit of TSH. Thus, hCG in high concentrations has mild thyroid-stimulating activity.

The serum hCG concentration is highest in the first trimester of pregnancy and hCG’s thyroid-stimulating activity can suppress the serum TSH level, but in most cases the TSH level remains within the “normal range” of pregnancy.21,22 The hCG levels observed during the first trimester of pregnancy are usually associated with a low TSH and normal free thyroid hormone levels. In pregnant women who are not on T4 therapy for hypothyroidism, a persistently suppressed TSH (< 0.1 μIU/mL) after the first trimester or elevations of the free thyroid hormones at any point during pregnancy suggest that the suppressed TSH is secondary to autonomous thyroid function, as seen in Graves disease and toxic nodular goiters, warranting further investigation. Iodine radioisotope imaging studies are forbidden during pregnancy.

If the hCG concentration is markedly elevated and for a prolonged time, as in hyperemesis gravidarum and gestational trophoblastic disease (hydatidiform mole, a benign condition, and choriocarcinoma, a malignant condition), overt hyperthyroidism can develop, with elevated free T4 and free T3.21,23


Euthyroid sick syndrome and/or medication effect. When the TSH level is low secondary to euthyroid sick syndrome or a drug, or both, the free T3 level is usually found to be also low, which may be solely related to a component of euthyroid sick syndrome or secondary to the drugs themselves, as drugs such as corticosteroids and amiodarone inhibit the conversion of T4 to T3.


Toxic nodular goiter vs early Graves disease

If the free T3 is elevated and the TSH is low (suppressed), even in the absence of symptoms, a diagnosis of subclinical hyperthyroidism would be inappropriate, because by definition the free T4 and free T3 levels must be normal for a diagnosis of subclinical hyperthyroidism. The diagnostic possibilities are toxic nodular goiter and early Graves disease.

The combination of high T3, suppressed TSH, and normal T4 is usually associated with toxic nodular goiter, whereas T3 and T4 are typically both elevated in Graves disease (although T3 is usually more elevated than T4).24

Figure 3. Left, an iodine 123 scan from a patient with Graves disease. Note the diffuse homogenous uptake of the thyroid gland. Right, an iodine 123 scan from a patient with a toxic multinodular goiter. Note the nodular areas of increased intensity with suppression (low uptake) of the surrounding thyroid tissue.

The patient should undergo iodine 123 nuclear imaging (“iodine uptake and scan”). Diffuse uptake of iodine 123 supports the diagnosis of Graves disease; patchy and nodular areas of increased iodine 123 uptake support the diagnosis of a toxic nodular goiter (Figure 3).

The patient should also be tested for TSH receptor antibodies (TRAB), both stimulating and blocking, which are very specific for Graves disease.

Natural thyroid preparations

Natural thyroid preparations, which can contain large amounts of T3, can also yield the combination of normal free T4 and high free T3. Since these preparations contain both T4 and T3, they usually result in low TSH, normal free T4, and elevated free T3 levels when given in supratherapeutic doses. However, if these preparations are consumed in large enough quantities, both the free T4 and free T3 can be elevated. This is in contrast to supratherapeutic monotherapy with T3 (liothyronine), which usually results in low TSH, low free T4, and high free T3.

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