Pitfalls to Avoid While Interpreting Thyroid Function Tests: Five Illustrative Cases

Michael J. Fowler, MD, Aaron F. Pannone, BA, Lewis S. Blevins, Jr., MD

Disclosures

South Med J. 2002;95(5) 

In This Article

Case 2

A 21-year-old woman was referred for evaluation of "hyperthyroidism." She had felt well at the time of a gynecologic examination to renew her oral contraceptive pill prescription. Physical examination was normal. Routine thyroid function tests revealed a serum TSH level of 2.5 µU/mL, a total T4 level of 17 µg/dL, and a T3 uptake of 20%. A diagnosis of hyperthyroidism was made. She was treated with methimazole. Ten weeks later, she complained of weakness and fatigue, a lump in her neck, and hoarseness. Physical examination revealed diastolic hypertension, a nontender thyroid that was twice normal size, delayed relaxation of the deep tendon reflexes, and periorbital puffiness. Thyroid function tests revealed a serum TSH level of 88 µU/mL, a total T4 level of 8.5 µg/dL, and a T3 uptake of 15%. Magnetic resonance imaging of the sella, done because of a suspected TSH-secreting pituitary adenoma, was normal. These findings prompted endocrine consultation.

Discussion

This case presentation illustrates the consequences of misinterpretation of thyroid function tests in women taking oral contraceptives. Only a small fraction of T4 circulates in the "free" or unbound state. Approximately 99.9% of T4 in the circulation is bound to serum proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin, albumin, and lipoproteins.[9,10] About 99.7% of T3 is bound to its carrier protein, transthyretin. Alterations in serum levels of these binding proteins will alter the total levels of the thyroid hormones in serum. As an example, oral estrogen administration affects the glycosylation of TBG and delays its clearance, leading to an increased serum concentration of TBG and, intuitively, an increased number of available sites to bind T4.[11] Since the bound and free fractions of T4 are in equilibrium, an increase in the number of T4 binding sites will be accompanied by a fall in the free T4 level. The normal hypothalamic-pituitary-thyroid axis will respond to the fall in T4 levels, and thyroid hormone synthesis will increase. Once TBG levels are stable and the new sites are occupied such that the basal equilibrium between free and bound T4 is restored and the free T4 remains normal, thyroid hormone synthesis will return to baseline to maintain normal free T4 levels. Total T4 levels are, however, increased as a consequence of the increased concentration of TBG and the increased number of T4 molecules in the serum as a result of the increased number of available binding sites. Factors that result in decreased TBG levels lead to opposite, adaptive responses and lower total T4 levels, while free T4 levels are maintained in the normal range.

The T3 uptake test, or T3 resin uptake test, as it is also known, was developed to permit one to identify and account for alterations in TBG. The details of the test are beyond the scope of this manuscript. Suffice it to say that, when the total T4 level is determined, the free T4 economy can be estimated by calculation of the free T4 index. This figure is derived by multiplying the free T4 by the T3 uptake result, and expressed as a decimal. In the case presented, the basal free T4 index is calculated as follows:

17 x 0.2 = 3.4

Normal results vary depending on the laboratory but, in general, results between 1.5 and 4.5 are normal. Thus, this result confirms that the patient presented was euthyroid, as evidenced by her clinical history, examination, and measurement of her serum TSH level. After the initiation of antithyroid drugs, she had clinical manifestations of hypothyroidism, her free thyroxine index fell to 1.28 (a low result reflective of a low T4 state), her TSH level rose appropriately in response to T4 and T3 deficiency, and she had a goiter as a result of excessive TSH stimulation.

While calculation of the free T4 index is a useful exercise, measurement of the free T4 level by radioimmunoassay or equilibrium dialysis can eliminate judgment errors in the interpretation of total T4 and T3 levels. The only drawback of relying on the measurement of free T4 is that clinically important causes of alterations of TBG will not be recognized by the assessment of thyroid function ( Table 2 ). Another useful way to interpret total T4 and T3 uptake results is to evaluate the pattern of results deviations from their respective normal ranges. As a general rule, alterations in TBG levels lead to discordant changes in total T4 levels and the T3 uptake, while alterations in thyroid function lead to concordant changes in total T4 levels and the T3 uptake ( Table 3 ).

Familial dysalbuminemic hyperthyroxinemia is a clinically important yet underrecognized autosomal dominant disorder that is characterized by an elevated total T4 level, a normal T3 uptake, and, thus, an elevated free T4 index, in a euthyroid patient with a normal serum TSH concentration.[12] In affected patients, serum concentrations of TBG are normal. They do, however, have circulating albumin that has a high affinity for T4, and increases binding in much the same was as an excess TBG level would. The T3 uptake result is usually normal, since total T3 levels are normal, and the abnormal albumin does not bind T3. A T4 uptake test can be performed by a reference laboratory when this disorder is suspected. As expected, the T4 uptake is typically low, and the free T4 index, calculated as the product of the total T4 and the T4 uptake, is usually normal.

Euthyroid hyperthyroxinemia, the situation when the total T4 level is elevated in the setting of euthyroidism, is relatively common and due to a number of different disorders ( Table 4 ).[13] Treating physicians should be aware of these clinical scenarios to avoid errors in the interpretation of seemingly abnormal thyroid function tests.

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