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

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


South Med J. 2002;95(5) 

In This Article

Case 1

A 72-year-old woman presented with chronic fatigue, malaise, and weight loss. Physical examination was said to have been unrevealing. The serum thyroid-stimulating hormone (TSH) concentration was 2.4 µU/mL (normal, 0.32 to 5.0 µU/mL) and the free thyroxine (T4) level was 0.7 ng/dL (normal, 0.9 to 1.9 ng/dL).[2] Her symptoms persisted, and she had nausea and vomiting. A repeat evaluation 2 years later revealed a woman appearing chronically ill, with pallor, absence of secondary sexual hair, and delayed relaxation of the deep tendon reflexes. Laboratory studies revealed the following values: serum TSH, 4.5 µU/mL; total T4, 4.7 µg/dL (normal, 5 to 11 µg/dL); triiodothyronine (T3) uptake, 29% (normal, 25% to 35%); and calculated free T4 index, 1.4 (normal, 1.5 to 4.0). She was found to have hyponatremia, which prompted the discovery of adrenal dysfunction and led to an ultimate diagnosis of panhypopituitarism due to a 3 cm pituitary adenoma.


This case illustrates the typical thyroid function test abnormalities seen in patients with central hypothyroidism, which accounts for approximately 5% of all cases of hypothyroidism.[3] As in this patient, central hypothyroidism may herald significant pituitary disease, and it is often overlooked for several years. Most patients have clinical or biochemical evidence of additional pituitary dysfunction. Some, however, have isolated deficiencies of TSH due to limited pituitary disease, abnormalities of the thyrotropin-releasing hormone (TRH) receptor, or deficiencies in the TSH ß-subunit gene.[3]

Thyroid stimulating hormone is a peptide hormone, composed of a distinct ß-subunit and a common a-subunit that is secreted by the thyrotroph cells of the anterior pituitary gland. It is secreted in a pulsatile fashion and in a diurnal variation, with most of the mass of TSH secreted during sleep. The regulation of TSH secretion by the pituitary is via several mechanisms, including negative feedback by T4 and T3; stimulation by TRH; and inhibition by somatostatin, glucocorticoids, and dopamine.[4] Thyroid stimulating hormone binds to its receptor on the follicular cells of the thyroid gland to stimulate numerous processes essential for the production and release of T4 and T3. These cellular processes include follicular cell differentiation and proliferation, iodine uptake and organification, and thyroid peroxidase activity.

Central hypothyroidism may result from any hypothalamic or pituitary disorder that impairs the synthesis and/or secretion of TSH and leads to impaired thyroid hormone synthesis. Hypothalamic diseases lead to impaired secretion of TRH and consequent impaired TSH gene transcription, translation, and impaired posttranslational processing and release of pituitary TSH. Pituitary disorders may reduce the actual number of thyrotroph cells and lead to a decrease mass or quantity of TSH secreted. Evidence suggests that some cases of central hypothyroidism may be attributed to impaired biologic activity of TSH due to defects in glycosylation and alterations in the diurnal variation of TSH secretion.[5,6,7] In the latter circumstance, TSH levels may be in the normal range, but the lack of a nocturnal rise in TSH results in impaired thyroid hormonogenesis, possibly due to a decrease in the daily mass of TSH secreted by the pituitary gland.

The cardinal laboratory finding in central hypothyroidism is a low or low-normal free T4 level or free thyroxine index. Serum TSH levels are inappropriately low, normal, or even slightly elevated. Triiodothyronine levels are often normal or low-normal as 5'-deiodinase activity is increased and T4 is more readily converted to T3. Thyroid stimulating hormone responses to TRH injections are usually absent or blunted. Some patients have responses characterized by a delay in the time to a peak TSH level and a prolongation of TSH secretion in response to TRH.[3] We do not advocate routine use of the TRH stimulation test by primary physicians, due to its expense, relatively low yield, and the numerous caveats that must be kept in mind when evaluating the TSH response. Assessment of the nocturnal TSH surge may be a sensitive and reliable test for central hypothyroidism in children and adults.[8]

Several clinical scenarios may mimic the biochemical findings of central hypothyroidism. Hospitalized patients with severe illness may have low T4 and T3 states and low or suppressed TSH levels. There is considerable controversy over whether to administer T4 or T3 to these patients. Phenytoin has complex effects on the clearance of T4 and T3 and on TSH secretion.[9] It is not unusual to find low T4 levels and normal TSH levels in treated patients. Patients taking supraphysiologic doses of T3, either inappropriately as a supplement or as therapy for chronic fatigue, or as thyroid hormone replacement therapy, often have suppressed TSH levels. The fall in TSH secretion leads to a corresponding fall in endogenous thyroid hormone production and T4 levels; T3 levels are often elevated. Resolution of long-standing hyperthyroidism after I-131 therapy, antithyroid drug therapy, or the natural history of the underlying disease, is often marked by low T4 and T3 levels, and a low TSH level until the pituitary thyrotrophs recover from chronic suppression.