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The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid peroxidase) was increased nearly 3-fold in patients with differentiated thyroid cancers (DTC) compared with the general population (40% vs. 14%, respectively). Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC patients and 10% of the general population. Serial postsurgical serum TgAb and serum Tg patterns correlated with the presence or absence of disease. Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two immunometric assay (IMA) methods to study TgAb interference. TgAb interference, defined as a significant intermethod discordance (>41.7% coefficient of variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera, was found in 69% of the TgAb-positive sera. TgAb interference was characterized by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in sera containing high TgAb concentrations. However, some sera displayed marked interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL) causing interference. Exogenous Tg recovery tests were an unreliable means for detecting TgAb interference. Specifically, the exogenous Tg recovered varied with the type and amount of Tg added and the duration of incubation employed. Further, recoveries of more than 80% were found for some sera displaying gross serum RIA/IMA discordances. The measurement of serum Tg in DTC patients with circulating TgAb is currently problematic. It is important to use a Tg method that provides measurements that are concordant with tumor status. IMA methods are prone to underestimate serum when TgAb is present, increasing the risk that persistent or metastatic DTC will be missed. The RIA method used in this study provided more clinically appropriate serum Tg values in the group of TgAb-positive patients with metastatic DTC. Furthermore, as serial serum TgAb measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may be an additional clinically useful tumor marker parameter for following TgAb-positive patients. Disparities between serial serum Tg and TgAb measurements might alert the physician to the possibility of TgAb interference with the serum Tg measurement and prompt a more cautious use of such data for clinical decision-making.

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TRH stimulation tests (n = 1109) were performed on 1061 ambulatory and 43 hospitalized patients with varying thyroid status, using a TSH immunochemiluminometric assay with third and fourth generation sensitivity characteristics (functional sensitivity, 0.01 and 0.001 mU/L, respectively). TRH test results were analyzed as both absolute (stimulated minus basal TSH) and fold (stimulated/basal TSH) responses. The absolute TRH response varied 8-fold across the physiological TSH range, whereas the mean fold response remained almost constant (mean +/- SEM, 8.5 +/- 0.2). The fold response became progressively attenuated as basal TSH values declined below physiological levels, becoming essentially absent in clinically thyrotoxic patients with markedly depressed basal serum TSH levels (0.007 +/- 0.002 mU/L). Progressive attenuation also occurred at hypothyroid TSH levels; a markedly impaired fold response (2.5 +/- 0.4) was characteristic of primary hypothyroid patients with basal TSH values greater than 50 mU/L. In untreated central hypothyroid patients with near-normal basal TSH levels, the TRH fold response was impaired (1.7 +/- 0.2), whereas in T4-replaced central hypothyroid patients, fold responses were near normal (5.6 +/- 1.2). Neither nonthyroidal illness, age, or sex appeared to influence the pattern of fold TRH response in the populations evaluated. When using third and fourth generation TSH methodology, the TRH-stimulated TSH fold response is more diagnostically useful than the absolute TRH response. However, if patients have an intact hypothalamic-pituitary axis, there appears to be no diagnostic advantage gained by TRH testing over an accurately measured basal TSH value.

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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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A new TSH immunoenzymometric assay was found to be capable of discriminating between the serum TSH values of normal subjects [2.28 +/- 1.02 (+/-SD); range, 0.6-6.5 microU/ml] and those of clinically euthyroid, antithyroid drug-treated (n = 22) or clinically thyrotoxic (n = 34) patients. While a wide spectrum of basal TSH values was found in the antithyroid drug group [ranging from undetectable (less than 0.05 microU/ml: 57%) to 17.9 microU/ml], all clinically thyrotoxic patients had undetectable values. In 33 patients receiving chronic oral T4 therapy for treatment of goiter (n = 15) or thyroid cancer (n = 18), 48% (6 of 33) had undetectable basal TSH levels and no TSH response to TRH stimulation. Detectable TSH levels were found in 42% (14 of 33), and TRH responsiveness was found in 52% (17 of 33). The TSH response to TRH stimulation was less than 2.0 microU/ml in 7 patients. Serum free T4 index, free T3 index, and free T4 levels and oral T4 dosage were inferior predictors of TRH responsiveness compared to the basal TSH value. No patient receiving more than 0.2 mg T4 daily or having a free T4 index above 18, a free T3 index above 205 or a free T4 level above 3.0 ng/dl had a TSH response to TRH. Seventy-six percent (16 of 21) of the patients, when reevaluated 1-6 weeks after increased oral T4 dosage, had a significant reduction in their serum thyroglobulin level. This was true of both patients with initially detectable (11 of 14) as well as undetectable (5 of 7) basal serum TSH levels. These findings support the concept that subnormal and, for that matter, as yet undetectable levels of circulating TSH may exert stimulatory effects on thyroid tissue.

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This study was undertaken to evaluate the heterogeneity and stability of 125I-labeled human thyroglobulin (Tg) tracers. Tg, labeled with 125I by either a Chloramine T (CT) or a Glucose Oxidase/Lactoperoxidase (GO) method, showed considerable heterogeneity of labeled components, the relative proportions of which were a function of the Tg preparation and the iodination method used. The four largest components had apparent molecular weights as follows: A = 1 200 000 Da; B = 670 000 Da; C = 530 000 Da and D = 290 000 Da. Both B and C were immunoactive. B was considered to be 19S Tg. A non-specific binding difference, (NSB delta) between nonhuman matrices used for diluting standards and human sera was found for the partly immunoactive aggregate component A, (5-20%) and the nonimmunoactive component D, (20-50%), but was minimally present for components B and C (less than 5%). The [125I]19S Tg(B), stored at -70 degrees C, showed rapid spontaneous decomposition with time (50% lost by 8 days), with generation of C, D and iodide. The loss of B was related to specific activity and was least in GO labels. 125I labeling of Tg by GO produced tracers with better immunoactivity, stability and lower NSB delta than comparative CT tracers. Definitive purification and repurification of [125I]Tg tracers before use is necessary in order to remove degradation products with the potential to compromise the accuracy and specificity of serum Tg radioimmunoassay (RIA) measurement.

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Although ratios of urinary cyclic AMP (cAMP) to creatinine were found in this study to be elevated in hyperthyroidism, as previously reported, this elevation appears to result primarily from a decrease in the rate of urinary creatinine excretion associated with the hyperthyroid state and not to be due to an increase in the urinary cAMP production rate. Indeed, there was no significant alteration observed in the urinary cAMP excretion found in 15 hyper-, 12 eu-, and 5 hypothyroid subjects. However, a slight, but significant increase in the 24-hour urinary cAMP excretion was noted in ambulating hyperthyroid subjects (8.5 +/- 2.4 muMol/day; normal 5.2 +/- 1.6 muMol/day; P less than .05). In contrast, the effect of the infusion of 0.05 mug/kg/min of epinephrine over a 2-hour period, resulted in a significantly greater rise in urinary cAMP excretion in hyperthyroid patients (0.83 +/- 0.07 muMol/h) compared to euthyroid subjects (0.53 +/- 0.4 muMol/h; P less than .005). Furthermore, hypothyroid subjects had no significant rise in urinary cAMP excretion after epinephrine infusion (P less than .001). Cardiovascular end-organ response to the epinephrine infusion was also greater in the hyperthyroid subjects and virtually absent in the hypothyroid group. These results suggest that there may be a significant alteration in the cAMP generating systems in states of thyroid hormone excess or insufficiency, and that provocative stimuli, such as epinephrine, may have its end-organ response modified by thyroid hormone effects on adenylate cyclase-cyclic AMP generating systems.

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An outbreak of meningococcal disease occurred among basic combat trainees at Fort Lewis, Wash., in the first 3 months of 1971. After five recruits developed meningitis within a 2-week period, 8,721 recruits were given 100 mg of minocycline every 12 hr for 5 days. No new cases of meningococcal disease occurred for almost 5 weeks. Then six additional cases occurred among recruits who had entered training after the initial course of minocycline and who had not received the drug. Minocycline was given to all 6,130 of these men, and again occurrence of new cases was halted abruptly. One week later, group C polysaccharide vaccine was administered to all recruits in the first 6 weeks of training and subsequently to all new entering trainees. No new cases of meningitis occurred in the next 3 months. Surveys showed that minocycline significantly lowered the meningococcal carrier rate for 4 to 5 weeks. No strains of Neisseria meningitidis, among 341 isolated after minocycline treatment, were resistant to the drug. Prophylaxis with minocycline clearly interrupted the course of this outbreak due to sulfa-resistant meningococci. Although immunization is the preferred method of prophylaxis, minocycline may be useful until a suitable polyvalent vaccine is available.

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