A 66-year-old man with abnormal thyroid function tests

CASE CONTINUED: LOW TSH, LOW-NORMAL FREE T₄, LOW TOTAL T₃

The attending physician ordered serum TSH, free T₄, and total T₃ measurements, which yielded the following:

• TSH 0.1 mU/L (0.5–5.0)
• Total T₃ 55 ng/dL (80–180)
• Free T₄ 0.9 ng/dL (0.9–2.4).

2. Which best explains this patient’s abnormal thyroid test results?

• His acute illness
• Central hypothyroidism due to pituitary infarction
• His albuterol therapy
• Subclinical thyrotoxicosis
• Hashimoto thyroiditis

Since euthyroid patients with an acute illness may have abnormal thyroid test results (Table 2),^5–7 thyroid function testing is not recommended unless there is a strong indication for it, such as new-onset atrial fibrillation, atrial flutter, or focal atrial tachycardia.¹ In such patients, it is important to know whether the test abnormalities represent true thyroid disorder or are the result of a nonthyroidal illness.

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In healthy people, T₄ is converted to T₃ (the principal active hormone) by type 1 deiodinase (D1) mainly in the liver and kidneys, whereas this reaction is catalyzed by type 2 deiodinase (D2) in the hypothalamus and pituitary. Type 3 deiodinase (D3) converts T₄ to reverse T₃, a biologically inactive molecule.¹² D1 also mediates conversion of reverse T₃ to diiodothyronine (T₂) (Figure 1).

Several conditions and drugs can decrease D1 activity, resulting in low serum T₃ concentrations (Table 3). In patients with nonthyroidal illness, decreased D1 activity can be observed as early as the first 24 hours after the onset of the illness and is attributed to increased inflammatory cytokines, free fatty acids, increased endogenous cortisol secretion, and use of certain drugs.^13,14 In addition, the reduced D1 activity can decrease the conversion of reverse T₃ to T₂, resulting in elevated serum reverse T₃. Increased D3 activity during an acute illness is another mechanism for elevated serum reverse T₃ concentration.¹⁵

Thyroid function testing in patients with nonthyroidal illness usually shows low serum total T₃, normal or low serum TSH, and normal, low, or high serum free T₄. However, transient mild serum TSH elevation can be seen in some patients during the recovery period.¹⁶ These abnormalities with their mechanisms are shown in Table 2.^5–7 In several commercial kits, serum direct free T₄ can be falsely decreased or increased.⁸

THE DIFFERENTIAL DIAGNOSIS

Our patient had low serum TSH, low-normal serum direct free T₄, and low serum total T₃. This profile could be caused by a nonthyroidal illness, “true” central hypothyroidism, or his glucocorticoid treatment. The reason we use the term “true” in this setting is that some experts suggest that the thyroid function test abnormalities in patients with acute nonthyroidal illness represent a transient central hypothyroidism.¹⁷ The clinical presentation is key in differentiating true central hypothyroidism from nonthyroidal illness.

In addition, measuring serum cortisol may help to differentiate between the 2 states, as it would be elevated in patients with nonthyroidal illness as part of a stress response but low in patients with true central hypothyroidism, since it is usually part of combined pituitary hormone deficiency.¹⁸ Of note, some critically ill patients have low serum cortisol because of transient central adrenal insufficiency.^19,20

The serum concentration of reverse T₃ has been suggested as a way to differentiate between hypothyroidism (low) and nonthyroidal illness (high); however, further studies showed that it does not reliably differentiate between the conditions.²¹

GLUCOCORTICOIDS AND THYROID FUNCTION TESTS

By inhibiting D1, glucocorticoids can decrease peripheral conversion of T₄ to T₃ and thus decrease serum total T₃. This effect depends on the type and dose of the glucocorticoid and the duration of therapy.

In one study,²² there was a significant reduction in serum total T₃ concentration 24 hours after a single oral dose of dexamethasone 12 mg in normal participants. This effect lasted 48 hours, after which serum total T₃ returned to its pretreatment level.

In another study,²³ a daily oral dose of betamethasone 1.5 mg for 5 days did not significantly reduce the serum total T₃ in healthy volunteers, but a daily dose of 3 mg did. This effect was more pronounced at a daily dose of 4.5 mg, whereas a dose of 6.0 mg had no further effect.

Long-term glucocorticoid therapy also decreases serum total T₄ and total T₃ by lowering serum thyroid-binding globulin.²⁴

Finally, glucocorticoids can decrease TSH secretion by directly inhibiting thyrotropin-releasing hormone.^25,26 However, chronic hypercortisolism, whether endogenous or exogenous, does not cause clinically central hypothyroidism, possibly because of the negative feedback mechanism of low thyroid hormones on the pituitary and the hypothalamus.²⁷

Other drugs including dopamine, dopamine agonists, dobutamine, and somatostatin analogues can suppress serum TSH. As with glucocorticoids, these drugs do not cause clinically evident central hypothyroidism.²⁸ Bexarotene, a retinoid X receptor ligand used in the treatment of cutaneous T-cell lymphoma, has been reported to cause clinically evident central hypothyroidism by suppressing TSH and increasing T₄ clearance.²⁹