A 34-year-old woman presents to the outpatient endocrinology clinic 4 months postpartum. She says that 2 months ago she developed palpitations, heat intolerance, and difficulty sleeping. Her primary care physician diagnosed postpartum thyroiditis after laboratory evaluation revealed that her thyrotropin (thyroid-stimulating hormone, TSH) level was low at 0.005 μIU/mL (reference range 0.4–5.5), and that her free thyroxine (T4) level was elevated at 2.4 ng/dL (reference range 0.7–1.8). She was prescribed atenolol (Tenormin) to treat the symptoms.
On follow-up testing 6 weeks later, her TSH level had risen, but it was still low at 0.085 μIU/mL, and her free T4 level was now low at 0.6 ng/dL. She was referred to an endocrinologist for further management.
How should this patient be further evaluated and managed?
LOW TSH HAS MANY CAUSES
Follow up the finding of a low TSH by measuring free T4 and free T3
The finding of a low TSH level should always be followed up by measuring the thyroid hormones, ie, T4 and triiodothyronine (T3).
The levels of free T4 and free T3 should be used, not total levels, when interpreting an abnormal TSH value. This especially applies in the acute and inpatient settings, in which many patients are malnourished and consequently have low serum levels of thyroid-binding globulin and albumin. In this situation, total T4 and T3 levels may be low and not accurately represent a patient’s true thyroid status. Likewise, in women who are pregnant or taking an estrogen-containing contraceptive, the total T4 and T3 levels may be high, secondary to an increase in thyroid-binding globulin synthesis, but the free T4 and free T3 are normal (in the absence of a pathologic process).
However, depending on the analytical method, even measurements of the free hormones may be affected by the protein changes that occur during severe illness or pregnancy. Also, some drugs can affect free hormone levels by displacing the hormones from their binding proteins.
Most commercial laboratories estimate the levels of free thyroid hormones by indirect methods. Short of measuring the free thyroid hormones directly using equilibrium dialysis and ultrafiltration (the gold standard), no test or assay is 100% accurate. Even the determination of free hormone levels can be flawed if the assay is unreliable. Some clinicians still prefer the free thyroid index (FTI) and T3 or T4 resin uptake to assess free T4, and the total T3 to assess T3 status.
The degree of TSH suppression should also be taken into account. A frankly suppressed TSH level (< 0.1 μIU/mL) would favor overt thyrotoxicosis in the correct clinical context (ie, if the levels of free T4, free T3, or both were normal or high).
Figure 1 outlines how to interpret a low TSH level and formulate the appropriate diagnosis and plan. In this process, it is crucial to consider the patient’s history, to note signs or symptoms of thyroid disease (hyperthyroidism or hypothyroidism), and to ask about medication exposure. Furthermore, repeating the thyroid function tests (and reviewing previous values) to observe the trend is consistently invaluable when deriving a diagnosis.
LOW TSH, LOW FREE T4, LOW FREE T3
The history of present illness (especially if the illness is prolonged and critical), a review of previous thyroid function tests, and, sometimes, a complete evaluation of the remaining hypothalamic-pituitary axes are crucial in correctly interpreting this combination of thyroid function tests. Clinical judgment is required, and referral to an endocrinologist is warranted. The diagnostic possibilities are:
Central hypothyroidism. A low TSH level is not always due to suppression caused by high thyroid hormone levels, other conditions, or medications. If thyroid hormone levels are low, a low TSH value can be the result of a central process (hypothalamic or pituitary or both).
Severe euthyroid sick syndrome (also called “nonthyroidal illness” or “low T3 syndrome”). In this condition, the free T3 level is usually low, and in severe cases the free T4 level can also be low.1,2
LOW TSH, LOW FREE T4, HIGH FREE T3
T3 toxicosis from an exogenous source
The combination of low TSH, low free T4, and elevated free T3 concentrations is consistent with ingestion of supratherapeutic doses of exogenous T3, ie, liothyronine (Cytomel).
Rarely is T3 therapy used alone to treat hypothyroidism. An exception is in patients who undergo thyroid hormone withdrawal in anticipation of radioactive iodine treatment after having undergone total thyroidectomy for differentiated thyroid cancer.
T3 therapy, when used, is often given in combination with T4 therapy, either levothyroxine (Synthroid and others) or as part of a T4-T3 natural thyroid preparation derived from porcine thyroid tissue (Armour Thyroid, Nature-Throid). Natural thyroid preparations may contain large amounts of T3, and when they are given in supratherapeutic doses, they can cause a similar profile (low TSH, low free T4, and elevated free T3). However, the free T4 level is usually in the normal range because the preparations also contain T4.
T3 toxicosis from an endogenous source
Sometimes the thyroid gland produces disproportionately large amounts of T3, usually from an autonomous nodule. Although the free T4 level may be low in this situation, it is usually in the normal range.
Serum thyroglobulin can be assayed to help determine whether the source of excess T3 is exogenous (in which case the thyroglobulin level is low) or endogenous (in which case the thyroglobulin is elevated). If it is endogenous, the patient should be referred to an endocrinologist for further evaluation.