A new immunochemiluminometric TSH assay (ICMA) was shown to offer improved analytical (+2 SD of zero) and functional (20% interassay coefficient of variation) sensitivity [0.003 vs 0.045 +/- 0.005 (+/- SE; range, 0.01-0.07); 0.018 vs. 0.23 +/- 0.02 (range, 0.10-0.35, mU/L); analytical vs. functional sensitivity limit for the ICMA vs. 10 other TSH immunometric assays, respectively]. The ICMA was used to study the physiological relationship between serum TSH and free T4 [as reflected by free T4 index (FT4I)] values at both steady state and 14 days after acute pharmacological T4 administration (3 mg oral T4 load plus 0.3 mg daily). At steady state, an inverse log/linear relationship was found between serum TSH and FT4I values (log TSH = 2.56 - 0.022 FT4I; r = 0.84; P less than 0.001). Ten to 14 days after acute T4 suppression in 5 euthyroid subjects, serum TSH/FT4I levels had plateaued after decreasing in parallel to the slope of the steady state relationship, suggesting that the degree of T4 suppression of TSH can be predicted from an individual's pituitary TSH/free T4 set-point and the magnitude of the serum T4 elevation achieved. Ambulatory and hospitalized patient sera, previously identified as having low (less than 0.1 mU/L) TSH levels by a less sensitive assay, were restudied by the TSH ICMA. Normal TSH values ranged from 0.39-4.6 mU/L, whereas the majority of hyperthyroid patients [52 of 54 (96% ambulatory) and 22 of 23 (96%, hospitalized)] had undetectable (less than 0.005 mU/L), basal TSH levels and absent TRH stimulated TSH responses. In contrast, most (32 of 37; 86%) of hospitalized nonhyperthyroid patients with low (less than 0.1 mU/L) TSH values due to nonthyroidal illness or glucocorticoid treatment had detectable (greater than 0.01 mU/L) basal and TRH stimulated TSH levels. The positive relationship between basal and TRH-stimulated TSH levels was shown to extend down to the detectability limit of the assay (0.005 mU/L), which further supported the authenticity of the subnormal TSH ICMA measurements. The new TSH ICMA is considered to represent the first of a third generation of clinical TSH assays, since it has a functional (interassay) sensitivity that is 2 orders of magnitude greater than that of typical first generation TSH RIAs and 1 order of magnitude greater than current second generation TSH immunometric methods. Such third generation TSH assays will facilitate both the optimization of T4 therapy as well as the diagnosis of hyperthyroidism in hospitalized patients with nonthyroidal illness.

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Thyroglobulin (Tg) measurement is primarily used to monitor patients with differentiated thyroid carcinoma (DTC) for tumor recurrence. Serum Tg levels principally integrate 3 variables: the mass of thyroid tissue present (benign or neoplastic); the degree of thyrotropin (TSH) receptor stimulation and tumor's intrinsic ability to synthesize and secrete Tg--a factor that needs to be assessed by a preoperative serum Tg determination. Serum Tg measurements should be interpreted relative to the TSH status of the patient. When TSH is low (on levothyroxine [LT4] therapy) basal serum Tg may be undetectable and recombinant human thyrotropin (rhTSH) administration may be needed to increase serum Tg into the measureable range. The Tg fold response to rhTSH (rhTSH-stimulated Tg/basal Tg) is an index of the tumor's sensitivity to TSH. Normal thyroid remnant and well-differentiated thyroid tumors display a greater (>10-fold) serum Tg response to TSH stimulation compared with less well-differentiated tumors (<3-fold). The factors influencing the response include the magnitude and chronicity of the serum TSH elevation, the mass of thyroid tissue and the TSH receptor status of the tumor. Technical problems still compromise the clinical utility of serum Tg measurement. Thyroglobulin autoantibodies are present in approximately 20% of all DTC patients and cause either underestimation or overestimation of serum Tg measurements made by immunometric assay (IMA) and radioimmunoassay (RIA) methods, respectively. Other technical problems include poor interassay precision, "hook" effects (IMA methods), intermethod standardization differences, and suboptimal sensitivity for detecting small amounts of tumor during TSH suppression. When TSH is suppressed, the basal serum Tg provides an integrated index of thyroid tissue mass and its capability to secrete Tg. Serial measurements of basal Tg concentrations can be used to monitor tumor progression or regression. The development of a low (<1 ng/mL) serum Tg (on LT4 therapy) by the second postoperative year signifies a low 5-year recurrence risk whereas a rising serum Tg in the face of TSH suppression is an abnormal response consistent with recurrence. The optimal degree of TSH suppression for a patient should be based on clinical judgment, relative to tumor staging and the risks from iatrogenic hyperthyroidism. Despite current technical limitations, serum Tg measurement is the cornerstone of long-term monitoring for most DTC patients. For optimal use of serum Tg, it is necessary to understand the pathophysiology of Tg secretion, the limitations of Tg methods and the use of rhTSH to overcome the insensitivity of current Tg methods.

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