Serum thyroxine. Thyroxine is frequently used as the major screening test for hypothyroidism, since the T4 level is low in most cases. There is some overlap between hypothyroid patients and normal persons in the lower part of the T4 reference range, since persons with mild, early, or subclinical disease may be inadvertently included in groups of clinically normal persons used to establish the reference range. There is some evidence that nearly all hypothyroid patients within euthyroid population reference limits have T4 values in the lower 50% of the reference range, so that T4 values in the upper half of the reference range are generally reliable in excluding hypothyroidism. Laboratory error, of course, must be considered if the laboratory result does not conform to the clinical picture. If the patient specimens are kept at room temperature for more than 48-72 hours, as might happen when they are sent by mail, increase in fatty acids during transit may falsely increase T4values when competitive binding (displacement) T4 methods rather than radioimmunoassay methods are used. Conditions that alter T4 results, such as TBG changes, non thyroidal illness, and certain medications must be remembered. Some endocrinologists are using TSH assay as a screening test instead of T4.

Triiodothyronine-radioimmunoassay. T3-RIA has not proved very useful in the diagnosis of hypothyroidism. The majority of reports indicate that one fourth to one third of hypothyroid patients have T3-RIA values within normal range. In some cases, typically in Hashimoto’s thyroiditis or after treatment of hyperthyroidism with radioactive iodine, it is thought that normal-range T3-RIA values are due to preferential secretion of T3 in what has been called the “failing gland syndrome.” Test alterations due to non thyroidal illness, age-related decrease, and TBG alterations further complicate interpretation.

Thyroid hormone-binding ratio. The THBR (T3U) test is another test that has not been very helpful in screening for myxedema because of substantial overlap with the euthyroid reference range. The major benefit from its use in possible hypothyroidism is for detection of TBG abnormality.

Serum thyrotropin (TSH) assay. Serum TSH levels are increased in the great majority of patients with primary hypothyroidism, and serum TSH assay is currently the most useful first-line confirmatory test. Since secondary hypothyroidism (pituitary failure) is uncommon and dysfunction due to hypothalamic etiology is rare, TSH assay has also been advocated as a screening test. Until recently TSH assay had not found wider use in screening for thyroid disease in general because of considerable overlap in the low range between hyperthyroid and euthyroid persons. This occurred because in most TSH assay kits the lower limit of the euthyroid reference range is relatively close to zero. In addition, these kits had relatively poor sensitivity in the low range, so that it was difficult to separate hyperthyroid values, which typically are subnormal, from zero on one hand and lower limit of normal on the other. Some euthyroid lowerormal specimens demonstrated the same problem. Therefore, TSH assay was restricted mostly to diagnosis of hypothyroidism. As mentioned earlier, several ultra sensitive TSH kits have recently become available that have adequate sensitivity in the low range to reliably separate decreased TSH values from low normal values. The ultra sensitive TSH is now being advocated by some investigators as the best single screening test for thyroid disease in general. But as I mentioned earlier, in my experience, at present all ultra sensitive TSH kits are not equally reliable. The TSH levels may be increased, usually (but not always) to mild degree, in some clinically euthyroid patients with a variety of conditions (see the box). When the TSH level is elevated in conditions other than primary hypothyroidism, TSH values are usually less than twice the upper reference range limit. However, sometimes they may be as high as 3 times the upper limit and occasionally even higher.

Primary hypothyroidism constitutes 95% or more of hypothyroid cases. The TSH assay in conjunction with the serum T4 assay is sufficient for diagnosis in the great majority of these patients (decreased T4 level with TSH level elevated more than twice and preferably more than 3 times the upper reference limit). In equivocal cases, a TRH test may be useful either to confirm primary hypothyroidism or to differentiate primary from secondary or tertiary etiology. As noted in the section on the TRH test, usefulness of the TRH test may be limited in severe non thyroidal illness. In those circumstances, a TSH stimulation test might be useful.

It has been reported that there are several subgroups of patients with primary hypothyroidism, ranging from those with classic symptoms and markedly elevated TSH values to those with milder symptoms and only mildly elevated TSH values to those with equivocal or single symptoms and T4 and TSH values remaining within population reference range and only the TRH test result abnormal.

About 5%-10% of patients referred to psychiatrists with symptoms of mood depression (“melancholia”) have been reported to have laboratory evidence of hypothyroidism. This evidence ranges from decreased T4and elevated TSH levels to an exaggerated TRH test response as the only abnormality.

In secondary hypothyroidism, the thyroid is normal but malfunction occurs in either the hypothalamus or the pituitary. Typically, both T4 (or FT4) and TSH values are decreased. In a few cases, the TSH value is within normal range; the TSH however is structurally defective and cannot stimulate the thyroid normally.

Thyrotropin-releasing hormone (TRH) test. A more complete discussion of the TRH test is located in the early part of this chapter. The TRH test has been mentioned as a confirmatory test for hypothyroidism. The TRH test has also been used to differentiate secondary from tertiary hypothyroidism. A significant increase in TSH after administration of TRH should theoretically suggest a hypothalamic rather than pituitary etiology for nonprimary hypothyroidism. Unfortunately, 40% of TSH hyposecretors of pituitary origin demonstrate adequate response to TRH stimulation. Therefore, only proof of pituitary hyposecretion by a poor response is considered sufficiently reliable for definite diagnosis. Even a poor response may not be reliable in the presence of severe non thyroidal illness.