If the history and findings on physical examination suggest that the patient may have thyrotoxicosis, the diagnosis can be readily confirmed by the combined finding of an abnormally high concentration of serum thyroid hormones and, because of negative feedback inhibition on the pituitary, a subnormal serum TSH level, not previously measurable as such. Serum free T4 concentration is increased in approximately 95% of ambulatory hyperthyroid patients; an occasional hyperthyroid patient may have increased serum T3 alone (T3-thyrotoxicosis). Because the serum concentrations of thyroid hormones are influenced by the concentration of serum binding proteins, clinicians should first order the determination of the level of free T4 in conjunction with serum TSH level to establish the diagnosis. Major improvements in sensitivity of the serum TSH determination have occurred during the past several years. The original TSH radioimmunoassay method has been replaced with "sensitive" or "ultrasensitive" TSH assays. When the less sensitive TSH radioimmunoassay determinations were used, many euthyroid individuals had undetectable serum TSH levels and could not be distinguished from hyperthyroid patients with suppressed TSH. Testing with thyrotropin-releasing hormone was frequently employed to separate these groups. The newer sensitive TSH assays clearly define a lower limit of the normal range for TSH, generally between 0.3 and 0.5 mU/L, varying according to the individual assay. The serum TSH level in hyperthyroid patients should be clearly subnormal; that is, less than 0.1 mU/L.[18] The combination of an increase in serum free T4 level and a decrease in serum sensitive TSH level to less than 0.1 mU/L, therefore, suggests the diagnosis of hyperthyroidism. At the present time, we do not recommend sensitive TSH assays alone for evaluation of thyroid function. This is because of the relatively short-term clinical experience with these assays and the frequency of decreased values caused by drugs and possibly other factors in sick patients who do not have thyroid disease. An occasional hyperthyroid patient may have a decrease in the concentration of serum sensitive TSH but serum free T4 concentration in the normal range. In these patients, a raised level of serum free T3 will confirm the diagnosis of hyperthyroidism that results predominantly from increased T3 secretion as well as provide a quantitative assessment of the severity of the thyrotoxic state.
Several other combinations of laboratory values may be confusing to the clinician and may warrant consultation with an endocrinologist. Thus, the concentration of serum sensitive TSH may be decreased in some individuals with serum free T4 and serum free T3 concentrations within the normal range. Similar to T4, serum T3 is also bound to serum proteins, and the free T3 concentration may be a useful test to diagnose hyperthyroidism. In the absence of medications that suppress TSH secretion, these patients probably have mild thyrotoxicosis with minimal hypersecretion of thyroid hormone. Their abnormal thyroid state may be further established by a T3-suppression test or by demonstration of a lack of response of serum TSH to thyrotropin-releasing hormone. Hyperthyroid patients with raised levels of serum free T4 and free T3 but with normal or increased levels of serum TSH may rarely be encountered. Their hyperthyroidism is caused by increased and autonomous TSH secretion, generally from a pituitary tumor.
Last, other euthyroid patients may have raised levels of serum T4 and/or a raised serum free T4 index but normal levels of serum sensitive TSH. Some of these individuals may have familial dysalbuminemic hyperthyroxinemia[19] or may have circulating anti-T4 and/or anti-T3 antibodies. Since these patients are clinically euthyroid, they should be encountered infrequently unless large populations are screened for thyroid dysfunction, which is not currently recommended as cost-effective strategy. The diagnosis of hyperthyroidism is more complex in sick patients because of the broad array of influences of nonthyroidal illnesses on the serum thyroid hormone-binding proteins and thyroid hormone metabolism as well as the presence of circulating inhibitors of T4 and T3 binding to proteins. In hyperthyroid patients with mild illness, serum T4 and T3 levels will remain increased above the normal range; in moderate illness, the serum T3 level may fall into the normal range, but the serum T4 level generally remains elevated. However, in severe illness, serum T4 and T3 levels both may either decrease into the normal range or even become subnormal.[20] [21] [22] In all of these clinical settings, serum TSH concentration should be less than O.1 mU/L in hyperthyroid patients who also have a nonthyroidal disease. However, the nonthyroidal illness itself or treatment with dopamine or with large doses of corticosteroids may also result in similar subnormal concentrations of serum TSH.[23] In such instances, serial monitoring of serum TSH levels and/or thyrotropin-releasing hormone testing may be required. Further testing may be required to establish the etiology of the thyrotoxic state after the diagnosis of thyrotoxicosis has been established by the approach discussed above. If the patient has a diffusely enlarged thyroid gland and exophthalmos, the etiology is almost certainly Graves' disease. The presence of one or more thyroid nodules in a patient with hyperthyroidism suggests a toxic adenoma or toxic multinodular goiter which can be confirmed simply by a thyroid scan with radioactive iodine. The concentration of radioactive iodine by the nodules and the absence of uptake in the remainder of the thyroid gland establish the diagnosis. Radioactive iodine should not be administered to pregnant women or nursing mothers. If one of these common etiologies of hyperthyroidism is not established, a radioactive iodine uptake determination should be performed. The thyroidal radioiodine uptake is generally elevated in Graves' disease but is clearly subnormal in hyperthyroidism caused by subacute thyroiditis, "silent" (lymphocytic) thyroiditis, postpartum thyroid dysfunction, or thyrotoxicosis factitia. Finally, these forms of thyroiditis and thyrotoxicosis factitia can be distinguished from one another by determination of serum thyroglobulin. Since thyroglobulin is a protein that is produced uniquely by the thyroid gland, its serum concentration will be elevated in any form of thyrotoxicosis emanating from the thyroid gland, but will be decreased in thyrotoxicosis factitia.[24]