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Context: Thyroid storm (TS) is a rare but life-threatening manifestation of thyrotoxicosis. Predictive features and outcomes remain incompletely understood, in part because studies comparing TS with hospitalized thyrotoxic patients have rarely been performed., Objectives: Our objectives were to compare the diagnosis and outcomes in TS versus hospitalized compensated thyrotoxic (CT) patients and to assess differences in diagnostic classification using the Burch-Wartofsky scores (BWSs) or Akamizu (Ak) criteria for identifying TS., Design, Setting, and Patients: This was a retrospective cohort study of hospitalized patients during a 6-year period at an academic tertiary hospital, with age ≥ 18 years, TSH <0.01 mIU/L, and clinically diagnosed TS or CT., Outcome Measures: In-patient mortality, hospital and intensive care unit length of stay, intubation, and ventilator duration were assessed., Results: Twenty-five TS and 125 CT patients were identified and analyzed. All but 1 TS patient received thionamides, β-blockade, glucocorticoids, and iodides within 24 hours of diagnosis. CT patients received thionamides and β-blockade alone. In the acute hospital setting, rates of fever (>100.4 °F), heart rate (>100 beats/min), altered mentation, and a precipitating event were all higher for TS than for CT patients. Altered mentation was the only clinical feature significantly different between TS and the subset of CT patients defined as TS by BWS or Ak criteria (P < .001). TS patients had greater in-patient mortality, hospital and intensive care unit length of stay, and ventilation requirements than CT patients., Conclusions: In acutely hospitalized thyrotoxic patients, the presence of central nervous system dysfunction distinguished clinically diagnosed TS from patients with BWS- or Ak-defined TS. Because TS patients had significantly worse outcomes in this study, thyrotoxic patients with possible TS and central nervous system dysfunction may derive the greatest benefit from aggressive supportive and TS-specific treatments.

Background: The clinical use of serum thyroglobulin (Tg) as a tumor marker in papillary thyroid cancer (PTC) patients following total thyroidectomy continues to evolve, due in part to the introduction of more sensitive (second generation) Tg immunometric assays (Tg(2G)IMA, functional sensitivity ≤ 0.10 ng/mL), and the implementation of new recommendations against radioactive iodine ablation (RAIA) for patients at the lowest risk of recurrence. As a result, there is a need to establish the optimal timing and interpretation of serum Tg values while on levothyroxine-induced suppression of thyrotropin (TSH) in thyroidectomized PTC patients with a thyroid remnant. This study examines the pattern of decline and eventual baseline value of unstimulated Tg (uTg) concentrations following total thyroidectomy in patients with low-risk PTC who did not receive RAIA., Methods: The medical records of consecutive patients with thyroid cancer seen at the Los Angeles County + USC Medical Center were retrospectively reviewed. Serial uTg and TSH values from Tg-antibody negative low-risk PTC patients treated with total thyroidectomy and no RAIA were analyzed. Patients were stratified by degree of TSH suppression to assess the effect on uTg. Serial postoperative uTg values were evaluated for the temporal pattern of decline and ultimate baseline. Patients with medullary thyroid cancer (MTC) were studied as a surgical reference group., Results: Records from 577 consecutive thyroid cancer patients were reviewed, of which 36 met all criteria for inclusion. By 6 months, uTg fell to <0.5 ng/mL in 61% of patients and all patients demonstrated uTg < 0.5 ng/mL 2 years after surgery. During a median follow up of 5.7 years, uTg values remained below this level. The median uTg values in patients with papillary microcarcinoma, PTC, and MTC were similar at 0.11, 0.12, and 0.09 ng/mL, respectively. Further decline in uTg was not observed once the TSH was <0.5 mIU/L., Conclusions: The uTg values during TSH suppression in Tg antibody-negative, low-risk PTC patients who did not receive RAIA were below 0.5 ng/mL by 6 months postoperatively in most cases and remained stable over the duration of patient follow-up.

To determine the heritable component of Graves' disease (GD) more precisely, a disease survey questionnaire completed by 13,726 California-born twin pairs over the age of 37 years was used as the foundation of this study. On the basis of this survey, each member of pairs reporting a past diagnosis of GD was then sought for an extensive telephone interview to seek diagnostic confirmation. Successful diagnostic evaluation occurred in 108 cases, of which 99 affected twin pairs form the basis of this report. The results indicate that the estimated pairwise concordance for is 17% in monozygotic (MZ) twins, and 1.9% in dizygotic (DZ) twins, which are in close agreement with a recent report from a Danish twin population. Moreover, the reported 3.9% occurrence of GD found in the first-degree relatives of affected twin pairs supports these findings. In contrast, only 0.45% of all twins, 0.27% of the spouses of twins, and approximately 0.16% of the first-degree relatives of unaffected twins were reported to have GD. Additionally, among the unaffected MZ twins of patients with GD, 17% reported having chronic thyroiditis and 10% other nonthyroid autoimmune conditions such as lupus erythematosus, pernicious anemia, or idiopathic thrombocytopenic purpura. Thus, a genetic predisposition appears to be shared for both thyroid and some nonthyroid autoimmune diseases. While it seems that GD is a strongly and nonspecifically heritable condition, the relatively low level of twin concordance indicates that this disease likely requires a nonheritable etiologic determinant(s) as well.

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.

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.

Background: In a relatively short period of time, therapeutic laparoscopy has become an everyday part of the general surgeon's life. Although laparoscopy provides distinct clinical advantages, it is not yet clear that it lessens the stress response typical of elective surgical procedures, and as such, the morbidity of surgery. The hypothesis that laparoscopic cholecystectomy produces less of a metabolic and stress hormonal response than open cholecystectomy was tested in a prospective randomized trial., Study Design: Twenty otherwise healthy women between 18 and 45 years of age with a history of uncomplicated symptomatic cholelithiasis undergoing either laparoscopic (n = 10) or open cholecystectomy (n = 10) were studied. The hormonal response of the adrenocortical (serum adrenocorticotropic hormone, cortisol, and urinary free cortisol), adrenomedullary (plasma and urinary epinephrine and norepinephrine), thyroid (thyroid-stimulating hormone, thyroxine, and triiodothyronine), pituitary (antidiuretic hormone and growth hormone), and glucose (serum glucose, glucagon, and insulin) homeostatic axes were measured serially over a 24-hour period., Results: No difference was seen between the laparoscopic and open groups in operative time (mean plus or minus standard error of the mean, 70 +/- 6 minutes compared with 77 +/- 6.3 minutes) or hospital stay 1.3 +/- 0.2 compared with 1.1 +/- 0.1 days). Assessment of postoperative pain using an analog pain score was less in the laparoscopic group (4.9 +/- 1.3 compared with 12.3 +/- 2.5, p = 0.01). The response of the adrenocortical, adrenomedullary, thyroid, and glucose axes were similar or identical in both groups. Antidiuretic hormone levels were greater in the laparoscopic group at one hour intraoperatively (281 +/- 79 pg/mL compared with 54 +/- 18 pg/mL, p < 0.01), and at extubation (122 +/- 18 pg/mL compared with 36 +/- 7 pg/mL, p < 0.01). Serum glucose levels were greater immediately following laparoscopic cholecystectomy. Glucose and insulin levels were greater at four, 12, and 24 hours after open cholecystectomy., Conclusions: Elective laparoscopic and open cholecystectomy for uncomplicated cholelithiasis result in similar degrees of perioperative hormonal stimulation. The different hormonal responses in the immediate and later postoperative periods after laparoscopic and open cholecystectomy suggest differential stressful stimuli between the two procedures.

The magnitude and temporal pattern of serum TSH suppression after single or multiple doses of thyroid hormone (T3, T4, or triiodothyroacetic acid) were studied using third and fourth generation TSH assays (sensitivities, 0.01 and 0.001 mU/L, respectively). A constant T3 dose (263 micrograms i.v.) administered at a uniform clock time (1200 h) produced identical serum TSH suppression patterns, (percent of control TSH vs. hours) in euthyroid and hypothyroid subjects. The percent log TSH vs. log time plot revealed three temporally distinct linear suppression phases: phase 1, a rapid TSH suppression, onset 1 h and lasting for 10-20 h; phase 2, slower suppression, onset between 10 and 20 h and lasting for 6-8 weeks; and phase 3, an invariable low TSH level (< 0.01 mU/L) with chronic T3 suppression (100 micrograms four times a day). TSH escaped maximal suppression at a similar serum T3 level in both euthyroid and hypothyroid subjects (2.9 +/- 0.2 vs. 3.5 +/- 0.5 nmol/L, respectively; P > 0.9), despite different basal serum T3 values (2.0 +/- 0.1 vs. 0.6 +/- 0.1 nmol/L, respectively; P < 0.01). Two milligrams of triiodothyroacetic acid or 2 mg T4 given iv at 1200 h produced TSH suppression patterns similar to T3. The phase 1 suppression varied with the clock time of T3 administration, (steeper responses were seen at 2400 vs. 1200 h), whereas phase 2 responses were unaltered. This study shows that thyroid hormone suppression of TSH is a complex, biphasic, nonlinear process, which is reproducible and independent of thyroid status or the thyroid hormone analog used. It is hypothesized that phase 1 reflects inhibition of release of preformed hormone, whereas phase 2 likely reflects inhibition of de novo synthesis and/or thyrotroph storage of TSH. In contrast, phase 3 secretion seems to represent basal constitutive TSH release, which may have relevance to the role of thyroid hormone-suppressive therapy in the treatment of patients with benign or neoplastic thyroid disease.

Previous studies have suggested that T3 metabolism relies more on nondeiodinative conjugation than on direct deiodinative degradation for its disposal in man. To better define this process, tracer T3 kinetic studies were performed in five euthyroid subjects before and after iopanoic acid (IA) administration to selectively impair T3 deiodinative disposal. Both a low IA (0.5-g load, followed by 0.5 g/day for 7 days) and a high IA (3.0-g load, followed by 3.0 g/day for 7 days) dosing schedule were employed to achieve varying levels of deiodinase inhibition. Additionally, the high IA dose was repeated with simultaneous oral T3 administration (100 micrograms daily) to normalize serum T3 levels that were reduced by IA-induced inhibition of T4 to T3 conversion. The results demonstrated that baseline serum T3 (2.3 +/- 0.1 nmol/L) and T3/T4 (1.9 +/- 0.1 x 10(-2)) values were significantly reduced by both the low IA (1.5 +/- 0.1 nmol/L and 1.2 +/- 0.1 x 10(-2), respectively) and the high IA (1.5 +/- 0.1 nmol/L and 0.9 +/- 0.2 x 10(-2), respectively) dosing schedule and that the addition of oral T3 to the high IA regimen restored both the T3 and T3/T4 levels to near-normal values (2.9 +/- 0.3 nmol/L and 1.7 +/- 0.2 x 10(-2), respectively). Low IA also significantly decreased T3 clearance (30 +/- 4 to 18 +/- 2 L/day; P < 0.005) and fractional urinary tracer recovery (70 +/- 3% to 37 +/- 4%; P < 0.005), whereas high IA produced only a minimal further reduction in clearance (16 +/- 2 L/day; P < 0.01) and urinary tracer recovery (32 +/- 3%; P < 0.05). Surprisingly, oral administration of T3 to the high IA regimen significantly increased T3 clearance (23 +/- 4 L/day; P < 0.01) without changing urinary tracer recovery (34 +/- 5%) compared to the effects of high IA alone. Evaluation of the urinary T3 metabolite pattern demonstrated that the major products of T3 metabolism were T3 sulfate and 3,3-diiodothyronine sulfate. These observations confirm previous results suggesting that the majority of nondeiodinative T3 disposal occurs via T3 sulfate formation. The additional finding that such nondeiodinative disposal may also be influenced by the circulating T3 level leads us to propose that sulfotransferase enzyme systems may play an important role in regulating the prereceptor availability of this ligand.

This article describes the major pathophysiologic alterations that occur in patients with long-standing hypothyroidism and how these alterations may predispose them to the development of a decompensated state, commonly referred to as myxedema coma. Early recognition and the employment of appropriate interventions serve as the cornerstone for successful management of this condition. The use and limitations of thyroid hormone therapy for treatment of this condition are emphasized.

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.

A study employing a newly developed fourth generation immunometric serum TSH assay (assay limit 0.001 mu/l was performed to determine the temporal pattern of inhibition of serum TSH in response to a maximal suppressive dose of thyroid hormone (T3, T4 and TRIAC) as compared to the pattern produced by dopamine (DA) and dexamethasone (DEX). Mean onset of inhibition was 24, 48 and 68 minutes for thyroid hormone, DA and DEX, respectively. The inhibitory pattern was uniform and reproducible for the same or different individuals if data were normalized respective to basal TSH values. Inhibitory pattern with thyroid hormone formed two distinct log linear functions: A rapid phase (phase 1) spanning 48 minutes to 24 hours and a slower phase (phase 2) bridging 24 to 1,000 hours. A diurnal variation in phase 1, but not in phase 2 suppression, was observed. A phase 1 response was also produced by DA and DEX but not phase 2. Low dose TRH infusion studies indicated that thyroid hormone and DEX inhibited thyrotroph response at or beyond the TRH receptor, while DEX appeared to inhibit endogenous TRH secretion. No additive effects of DA or DEX on T3 inhibition were seen in phase 1. These studies provide new insight into the mechanism by which these endocrine factors complementarily regulate TSH secretion in man.

The sulfated conjugate of T3 (T3S) has long been recognized as a normal product of peripheral thyroid hormone metabolism. In order to better understand the role that T3S may play in this process, the metabolic handling of T3S was studied in euthyroid man. After the iv administration of [125I]T3S in man, T3S was found to be rapidly metabolized with estimated mean MCR of 135 +/- 15 liters/day (L/D) after a bolus injection and 127 +/- 8 L/D employing a constant infusion. The primary route of T3S disposal was by deiodination with an efficiency of 92%. The administration of propylthiouracil (PTU, 300 mg every 6 h x 5 days) and iopanoic acid (IA, 500 mg every day x 5 days), both inhibitors of deiodination, decreased clearance compared to control (87 +/- 9 L/D, P less than 0.01 and 46 +/- 10 L/D, P less than 0.002, respectively). A 3-day fast also reduced the clearance of T3S (56 +/- 10 L/D, P less than 0.002). All three maneuvers decreased the total urinary deiodination fraction of tracer T3S (control 91 +/- 2%, PTU 70 +/- 9%, P less than 0.04, IA 26 +/- 3%, P less than 0.0001, and fasting 58 +/- 6%, P less than 0.01). A strong correlation between T3S clearance and deiodination was noted for fasting and IA only (r = 0.78, P less than 0.003). However, no relationship between clearance and deiodination was noted with PTU administration presumably as a result of a compensatory increase in biliary losses of T3S. The urinary thyronine excretion pattern demonstrated the presence of small amounts of labeled T3,3,3'-T2, and 3,3'-T2S with the major metabolite being T3S itself. TSH levels were not influenced by the infusion of stable T3S designed to achieve a serum value greater than 50 ng/dL. No absorption of intact T3S was detected after its oral ingestion. In conclusion, T3S is rapidly cleared from the serum, primarily by deiodination, may undergo nondeiodinative disposal when hepatic deiodination is inhibited by PTU but not with IA or fasting, and has no intrinsic biological activity. Thus, T3S may serve as a metabolite of T3 for its rapid deiodinative disposal. Although the precise role T3S plays in human thyroid hormone metabolism has not been defined, the metabolic characteristics of T3S appear similar to that of an unidentified alternate T4 metabolite formed in low T3 states of fasting and nonthyroidal illness.

To determine the influence of prolonged fasting and refeeding on rT3 metabolism in man, five euthyroid obese subjects underwent a 13-day fast, followed by a refeeding period. Each patient received an iv dose of 25 muCi [125I]rT3 during the fed control period, on days 7 and 13 of the fast, and on the fourth day after refeeding with a regular diet. Serial blood and urine samples were obtained to determine serum rT3 clearance and production rates and the urinary tracer rT3 deiodination fraction. Significant increases in serum rT3 values were noted by day 7 and remained elevated for the duration of the fast (P less than 0.01). Normalization of rT3 levels occurred after 4 days of refeeding. Both 7 and 13 days of fasting decreased rT3 clearance [132.6 +/- 8.3 L/day (P less than 0.001) and 132.2 +/- 9.5 L/day (P less than 0.001), respectively] without changing rT3 production (36.8 +/- 5.3 and 33.0 +/- 3.7 nmol/D, respectively) compared to control values (207.0 +/- 10.9 L/day and 31.8 +/- 3.8 nmol/day, respectively). Refeeding did not restore rT3 clearance (151.2 +/- 6.9 L/day; P less than 0.002), but significantly reduced blood rT3 production (18.4 +/- 3.8 nmol/day; P less than 0.003). The fractional deiodination of rT3 was significantly reduced on day 7 (42.5 +/- 4.6%; P less than 0.01) and day 13 (41.9 +/- 3.7%; P less than 0.01) of fasting compared to the control value (69.2 +/- 2.8%), while refeeding only partially restored deiodination to baseline (48.4 +/- 5.1%; P less than 0.04). The clearance of rT3 was highly dependent on the fractional deiodination rate (r = 0.83; P less than 0.001). Although rT3 production remained constant during fasting, reduced rT3 production was seen on the fourth day of refeeding. This unique observation explained the fall in serum rT3 to prefasting levels after 4 days of refeeding when rT3 clearance was still inhibited. This study, in context with previous investigations, indicates that T4 conversion to circulating T3 and rT3 in fasting is a highly complex and multifaceted process requiring further investigation to elucidate the mechanism responsible for these alterations.

A hidden pool of rT3 production represents a source of rT3 that is minimally reflected in circulating rT3 levels. To test for the existence of such a source of rT3 production in man, varying doses of the generalized deiodinase inhibitor iopanoic acid (IA) were administered to four hyperthyroxinemic subjects. The doses employed included low-IA (0.5-g load, then 0.5 g/day for 5 days), mid-IA (1.0-g load, then 1.0 g/day for 5 days), and high-IA (3.0-g load, then 3.0 g/day for 5 days). Each patient received 25 microCi [125I]rT3, iv, in the high T4 state and on day 3 of each IA dosing regimen. Serial blood and urine samples were obtained to determine serum rT3 clearance rates and the urinary thyronine metabolite patterns. Although total serum rT3 values were increased by all IA dosages (P less than 0.001), rT3 was lower with high-IA administration (P less than 0.02) than with low- or mid-IA regimens. Low-IA decreased rT3 clearance to 33 +/- 2 L/day (P less than 0.005), while increasing the daily rT3 production to 76 +/- 8 nmol/day (P less than 0.04) compared to the control values (150 +/- 10 L/day and 53 +/- 8 nmol/day, respectively). Mid-IA also reduced rT3 clearance (23 +/- 4 L/day; P less than 0.005) without changing rT3 production (50 +/- 10 nmol/day), while high-IA reduced both rT3 clearance (21 +/- 2 L/day; P less than 0.005) and production (39 +/- 9 nmol/day; P less than 0.04). Intravenously administered tracer rT3 could not be detected in the urine in the high T4 state, but rT3 could not be detected in the urine in the high T4 state, but was prominent after IA administration. It is concluded that a hidden pool of rT3 production exists in vivo in man. Further, low dose IA serves as a selective inhibitor of liver and kidney deiodinase systems, allowing reflection of this hidden rT3 pool in the blood and urine. It would appear that hypertrophy of this hidden pool of rT3 production occurs in high T4 states and may account for the majority of the unrecognized deiodinative metabolites of T4 generated in hyperthyroxinemia.

Selection of appropriate laboratory determinations will enable the clinician to diagnose thyroid dysfunction readily in the majority of patients. At the present time, estimation of free thyroxine and a "sensitive" thyrotropin assay are recommended as the principal laboratory tests for thyroid disease. A decrease in serum free thyroxine estimate and a raised level of serum thyrotropin confirm the diagnosis of hypothyroidism caused by thyroid gland failure. An increase in free thyroxine estimate combined with a serum sensitive thyrotropin level suppressed to less than 0.1 mU/L establishes the diagnosis of thyrotoxicosis. In sick patients, a normal or raised serum free thyroxine estimate together with a normal level of serum thyrotropin suggests that the patient has neither hypothyroidism nor thyrotoxicosis. Patients with severe illnesses, generally in the intensive care unit, and those treated with certain drugs, as well as individuals with unusual thyroid disorders, may present with confusing laboratory findings. An understanding of the regulation of the thyroid hormone system and/or judicious consultation with an endocrinologist should enable the clinician to diagnose thyroid disease, if present, in such patients.

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.

A feasibility study was undertaken prospectively to identify early clinical and laboratory factors predictive of acute hospital mortality in patients with the acquired immunodeficiency syndrome and concurrent Pneumocystis carinii pneumonia. Twenty-six patients hospitalized with bronchoscopy-proved P carinii pneumonia were studied. Nineteen patients survived their episode of P carinii pneumonia, while 7 subjects did not. The only clinical factor associated with mortality was a history of a shorter duration of pulmonary symptoms. Univariate analysis showed decreased total CD8 cell count, total lymphocyte count, serum hemoglobin, serum albumin, total thyroxine, and total triiodothyronine values consistent with a poor outcome. Multivariate logistic regression analysis showed that the single best prognostic indicator of acute mortality appeared to be a total serum triiodothyronine value less than 0.70 nmol/L obtained early in the hospital course, and that the combination of serum triiodothyronine and hemoglobin values provided a better indication for survival. These preliminary observations would appear to justify the further exploration of serial serum triiodothyronine measurements as a potentially valuable prognostic indicator for the treatment of patients with acquired immunodeficiency syndrome infected with P carinii and possibly other intercurrent infectious illnesses.

Thyroid function was evaluated in the Marshallese who were accidentally exposed to fallout-containing radioiodine isotopes in 1954. Measurements of thyrotrophin (TSH, thyroid-stimulating hormone) levels and free thyroxine (T4) index (FT4I) have revealed that, among 86 persons exposed on Rongelap and Ailingnae atolls, 14 have shown evidence of thyroid hypofunction. This was first noted in some individuals about ten years after exposure. Only two of these showed clinical evidence of hypothyroidism. The most marked TSH elevations were noted in nine persons exposed when younger than 6 years, with estimated doses to the thyroid from 390 to 2,100 rad. Most of this group subsequently had surgery for removal of thyroid nodules. The remaining five cases have been noted more recently among 36 surviving adults exposed at an older age who showed no other detectable thyroid abnormalities. This group had received estimated thyroid doses ranging from 135 to 335 rad and showed modest elevation of serum TSH levels (6 to 9 microU/mL) and a slightly subnormal FT4I. No abnormalities were found in persons on Utirik who received substantially less radiation, and hypothyroidism was present in less than 1% of the control, unexposed Marshallese. The high prevalence of a thyroid hypofunction in these persons indicates that this condition, as well as thyroid nodularity, can be a delayed complication of exposure to early fallout from a nuclear explosion. The fact that a significant fraction of the radiation to the thyroid was from short-lived radioiodine isotopes (132I, 133I, 135I), as opposed to 131I, may account for the severity of the thyroid damage.

The effect of cyproheptadine hydrochloride on release of prolactin (PRL), growth hormone (GH) and cortisol following insulin-induced hypoglycaemia was investigated in a group of eight adult female and male subjects. The results of this study demonstrated that cyproheptadine does not influence the release of these three hormones under the conditions employed in this study. The conflicting observation concerning the action of cyproheptadine on pituitary function as reported in the literature, may be a reflection of the diversity of pharmacological actions of this drug. Thus, any purported influence this drug might have on pituitary hormonal release should be interpreted with caution.

The effects of diabetes mellitus on serum thyroid hormone parameters were studied in 54 patients divided into 4 groups. Treated asymptomatic patients (group I) had normal thyroid values which did not correlate with serum or urinary glucose. Untreated nonketoacidotic patients (group II) showed a mild persistent depression in T3 and an elevation in rT3. Patients with ketoacidosis with a brief history of symptoms (group III) had a moderate T3 decrease and a mild rT3 elevation which quickly resolved with treatment. Ketoacidotic patients with a long history of symptoms (group IV) had marked depression of T3 and elevation of rT3 which was only partially rectified by treatment. Serum T4 was generally normal, except for a minimal decrease on the day after admission, probably resulting from rehydration and a subsequent increase associated with an increase in TSH. We concluded that thyroid hormone parameters were not influenced by variations in serum glucose, but seemed to reflect the effects of a preexisting catabolic state, ketoacidosis, or both.

The relationship between the changes in serum thyroid hormone levels and nitrogen economy during caloric deprivation were investigated in ten obese men during a 40 d, 400 kcal protein-supplemented weight-reducing diet. This regimen induced increases in the serum levels of total T4, free T4 and total rT3, and decreases of total T3, while serum TSH remained unchanged. There were progressive decreases in total body weight and urinary losses of total nitrogen and 3-methylhistidine, with the early negative nitrogen balance gradually returning towards basal values during the 40 days. Subjects with the largest weight loss had the most increase in the serum levels of total T4 and free T4 index and the greatest decrease in T3. The magnitude of the increase of the nitrogen balance from its nadir was correlated with the extent of the reduction of T3 and increase of T3 uptake ratio and free T4 levels. The decrease in the urinary excretion of 3-methylhistidine correlated with the increase in free T4 and rT3 levels. Nadir serum transferrin values were directly related to peak rT3 values, and the lowest albumin concentrations occurred in subjects with the highest total T4 and free T4 index values. Further, the maximum changes in the serum thyroid hormone levels preceded those of the nutritional parameters. These relationships suggest that: (1) increases in serum rT3 and free T4 and reductions in T3 concentrations during protein supplemented weight reduction may facilitate conservation of visceral protein and reduce muscle protein turnover; and (2) the variation in the magnitude of these changes may account for the heterogeneity of nitrogen economy.

Serum total reverse triiodothyronine (rT3) levels are normal in patients with renal diseases with and without renal insufficiency but elevated in nonrenal nonthyroidal illnesses. To evaluate the role of secondary hyperparathyroidism of renal diseases in this difference, serum thyroid hormone levels were studied in 27 patients with primary hyperparathyroidism (PHP) and normal renal function. In PHP, total T3 levels were reduced (118 +/- 6 ng/dL, normal: 147 +/- 3 ng/dL) and correlated with PTH levels. Serum rT3 levels were also decreased (27 +/- 3 ng/dL, normal: 34 +/- 2 ng/dL). Values for serum total thyroxine (T4), T3 uptake ratio, free T4 index, and thyrotrophin were not altered. Serum rT3 levels were increased (63 +/- 13 ng/dL) in patients with hypercalcemia due to malignant neoplasms who had low T3 levels, undetectable PTH and normal renal function. Thus, PTH excess may be the factor responsible for the failure of rT3 levels to increase in PHP and secondary hyperparathyroidism.

Eight methods for estimating free serum T4 were compared for 26 patients with nonthyroidal illness (NTI) and 16 hypothyroid patients with comparable total T4 (TT4) concentrations. Free T4 values were determined by equilibrium dialysis, enzyme immunoassay (Abbott), antibody-coated tube (Clinical Assays), antibody-coated microfine silica (Corning Immunophase), microencapsulated antibody (Damon), and free T4 index using the T3 uptake ratio or thyroxine-binding globulin method. Equilibrium dialysis, Clinical Assays and Abbott methods usually provided free T4 estimates in the normal range in NTI patients with low TT4 values and differentiated them from hypothyroid patients with comparable TT4 levels. In contrast, the other methods gave decreased free T4 estimates in the low TT4-NTI groups and often did not distinguish them from hypothyroid patients. The normal free T4 estimates by equilibrium dialysis, Clinical Assays, and Abbott methods in the low TT4-NTI patients are consistent with the previous findings of normal T4 disposal rates in these patients. These three methods may assist the clinician in differentiating the low T4 state of NTI from overt thyroxine deficiency of hypothyroidism.

A 48-h dopamine (DA) infusion (5-7.5 microgram/kg . min) given to six healthy euthyroid males resulted in a suppression of thyroidal iodine release and serum TSH by 44 +/- 3% (P less than 0.01), serum T3 by 9 +/- 2% (P less than 0.01), and serum T4 by 5 +/- 1% (P less than 0.05) below baseline levels, without a significant change in serum rT3 levels. In critically ill patients receiving DA (2-21 microgram/kg . min) for treatment of shock, serum TSH values and T4 production rates were decreased 60% and 56%, respectively, below the respective levels observed in non-DA-treated patients (P less than 0.01). Serial serum samples collected before and during DA therapy revealed a decrease of 52% in TSH (P less than 0.005) and 30% in T4 (P less than 0.05). The finding of a normal serum TSH value during DA theray in a critically ill patient with primary hypothyroidism emphasized the inhibitory potential of DA on TSH secretion. These findings indicate that the prolonged administration of pharmcological doses of DA significantly reduced serum TSH levels and thyroid hormone secretion in normal and critically ill patients, most likely by a direct inhibition of pituitary TSH with a secondary effect on thyroid gland secretion. Therefore, DA therapy probably prolongs and aggravates the low T4 state in critical illness.

Intestinal 47Ca absorption was measured at 2 and 24 h after isotope ingestion in six patients with hyperthyroidism and seven normal subjects. Although 47Ca absorption was not different at 2 h, it was significantly lower (P < 0.01) after 24 h in the patients with hyperthyroidism. Factors related to the effects of thyroid hormone on intestinal function, in addition to abnormalities of vitamin D metabolism, are probably responsible for the defect.

ātients with end-stage chronic renal failure (CRF) and those receiving dialysis therapy have normal or decreased serum total T4 (TT4), reduced serum total T3 (TT3), and normal total reverse T3 (TrT3) levels. Those with nonrenal nonthyroidal illnesses or malnutrition have low TT4 and TT3 but elevated TrT3 values. To evaluate the mechanism(s) for the normal TrT3 levels in CRF, we performed intravenous bolus kinetic studies of rT3 and T4 in patients with CRF, in those treated with chronic hemodialysis, in patients with nonrenal nonthyroidal illnesses, and in normal subjects. The CRF patients were selected to have good nutritional status as indicated by normal serum transferrin, relative body weight, and body mass index values. The CRF patients had normal TrT3, TT4, and free T4 values, increased free fraction of rT3, free rT3, and thyroxine-binding globulin levels, and decreased TT3 concentrations. Noncompartmental analysis of the rT3 kinetics indicated normal production rate, reduced cellular clearance rate, and increased pool size and residence time values in both the CRF and nonrenal patients. In CRF, the serum clearance rate was normal, but the fractional rate of exit, permeability, extravascular binding, and the apparent volume of distribution were increased. In contrast, the nonrenal patients had reduced serum clearance rate, permeability, and extravascular binding, whereas the fractional rate of exit and apparent volume of distribution were not significantly altered. The T4 kinetics in CRF paralleled those of the nonrenal patients, with a reduced fractional rate of exit and permeability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Skin fibroblasts from the shoulder and lower extremities of normal individuals, as well as from patients with pretibial myxedema (PTM) were grown in culture. When cells reached the monolayer stage, they were labeled with 3H-glucosamine and tested for hyaluronic acid synthesis in the presence of either serum from PTM patients or normal human serum. All the fibroblasts from the pretibial area synthesized 2 to 3 times more hyaluronic acid when incubated with PTM sera than when incubated in normal human serum. Fibroblasts cultured from skin of the back or prepuce did not respond to PTM sera. This heat-stable, protease-sensitive, and dialyzable, fibroblast-stimulating factor is not a 7S gamma-globulin. The enhanced sensitivity to PTM sera exhibited by fibroblasts from the lower extremities may explain why the lesions in this disease are restricted primarily to that area.

A new method for the measurement of the conversion ratio (CR) of T4 to T3 in euthyroid man is described. In contrast to previously described studies, this investigation relied on sampling of urine rather than plasma after isotopic labeling of the study subject. The CR value determined in six euthyroid men was 0.482 +/- 0.014. Thus, approximately half of the daily T4 production is converted to T3 as determined by this method. A major advantage of this technique is its reproducibility, as demonstrated by the low coefficient of variation of 6.8% in the study group, which is not significantly different from the 6.7% coefficient of variation for replicate determinations on the same sample. Thus, this method may be useful tool in comparing the CR of T4 to T3 in man under varying conditions even if only small differences in conversion efficiencies exist between groups. One apparent discrepancy observed in the present study is that the calculated T3 produced from the conversion of T4 exceeded the simultaneously calculated daily T3 production rate measured in blood. The cause of this discrepancy is presently unknown, but may represent T3 produced from T4 by renal or extrarenal sources which is excreted without contributing to the T3 blood production rate. However, the reproducibility of the method and the smaller amounts of labeled isotope required show promise that this technique may be useful in assessing T4 to T3 conversion in a variety of altered metabolic states.

The low thyroxine (T(4)) state of acute critical nonthyroidal illnesses is characterized by marked decreases in serum total T(4) and triiodothyronine (T(3)) with elevated reverse T(3) (rT(3)) values. To better define the mechanisms responsible for these alterations, serum kinetic disappearance studies of labeled T(4), T(3), or rT(3) were determined in 16 patients with the low T(4) state and compared with 27 euthyroid controls and a single subject with near absence of thyroxine-binding globulin. Marked increases in the serum free fractions of T(4) (0.070+/-0.007%, normal [nl] 0.0315+/-0.0014, P < 0.001), T(3) (0.696+/-0.065%, nl 0.310+/-0.034, P < 0.001), and rT(3) (0.404+/-0.051%, nl 0.133+/-0.007, P < 0.001) by equilibrium dialysis were observed indicating impaired serum binding. Noncompartmental analysis of the kinetic data revealed an increased metabolic clearance rate (MCR) of T(4) (1.69+/-0.22 liter/d per m(2), nl 0.73+/-0.05, P < 0.001) and fractional catabolic rate (FCR) (32.8+/-2.6%, nl 12.0+/-0.8, P < 0.001), analogous to the euthyroid subject with low thyroxine-binding globulin. However, the reduced rate of T(4) exit from the serum (Kii) (15.2+/-4.6 d(-1), nl 28.4+/-3.9, P < 0.001) indicated an impairment of extravascular T(4) binding that exceeded the serum binding defect. This defect did not apparently reduce the availability of T(4) to sites of disposal as reflected by the increased fractional disposal rate of T(4) (0.101+/-0.018 d(-1), nl 0.021+/-0.003, P < 0.001). The decreased serum T(3) binding was associated with the expected increases in MCR (18.80+/-2.22 liter/d per m(2), nl 13.74+/-1.30, P < 0.05) and total volume of distribution (26.55+/-4.80 liter/m(2), nl 13.10+/-2.54, P < 0.01). However, the unaltered Kii suggested an extravascular binding impairment comparable to that found in serum. The decreased T(3) production rate (6.34+/-0.53 mug/d per m(2), nl 23.47+/-2.12, P < 0.005) appeared to result from reduced peripheral T(4) to T(3) conversion because of decreased 5'-deiodination rather than from a decreased T(4) availability. This view was supported by the normality of the rT(3) production rate. The normal Kii values for rT(3) indicated a comparable defect in serum and extravascular rT(3) binding. The reduced MCR (25.05+/-6.03 liter/d per m(2), nl 59.96+/-8.56, P < 0.005) and FCR (191.0+/-41.19%, nl 628.0+/-199.0, P < 0.02) for rT(3) are compatible with an impairment of the rT(3) deiodination rate. These alterations in thyroid hormones indices and kinetic parameters for T(4), T(3), and rT(3) in the low T(4) state of acute nonthyroidal illnesses can be accounted for by: (a) decreased binding of T(4), T(3), and rT(3) to vascular and extravascular sites with a proportionately greater impairment of extravascular T(4) binding, and (b) impaired 5'-deiodination activity affecting both T(4) and rT(3) metabolism.

A patient who had been treated with large doses of thyroid hormone for several years developed features of secondary hypothyroidism after thyroid hormone withdrawal. These findings were low serum T4 (3.8 micrograms/dl), T3 (23 ng/dl), and a failure of serum TSH to rise after TRH injection. Serum PRL values rose normally after TRH administration, and evaluation of other pituitary hormones was normal. When retested 3 months later, at which time the serum T4 was 5.5 micrograms/dl, the patient was somewhat less hypothyroid and there was an exaggerated TSH response to exogenous TRH, indicating recovery of pituitary TSH reserve. Indirect assessment of endogenous TRH reserve capacity was consistent with impairment of endogenous TRH activity. Repeat studies performed 7 months later indicated some improvements in this indirect assessment of endogenous TRH reserve capacity but a continued exaggerated TSH response to exogenous TRH administration. Further testing at 28 months revealed a serum T4 value of 7.8 micrograms/dl and a serum T3 value of 141 ng/dl. At this time, the TSH response to TRH was normal and the patient was considered fully recovered. A causal relationship between high doses of thyroid hormone and the presumptive impairment of endogenous TRH reserve is suggested.

A new method is described for the estimation of T4 to T3 conversion in man and is applied to the study of hyperthyroid and hypothyroid clinical states. The method employs simultaneous iv injection of [125I]T4 and [131I]T3 with isolation of the labeled T3 tracers in 4- to 8-day pooled urine samples by a combination of solvent extraction, desalting, and immunoprecipitation procedures. Using [131I]T3 as a recovery standard, the T4 to T3 conversion ratio was found to be 0.470 +/- 0.011 in euthyroid subjects. This confirmed our earlier findings of 0.482 +/- 0.014 using a paper chromatographic method and nonsimultaneous isotope administration. The conversion ratio was increased in hypothyroidism to 0.535 +/- 0.011 (P less than 0.02) and decreased in hyperthyroidism to 0.415 +/- 0.009 (P less than 0.01). These changes parallel the fraction of the radioiodine collected in the urine for both T4 and T3; normal values are 77 +/- 4% for T4 and 76 +/- 4% for T3, values in hypothyroidism are 79 +/- 1% for T4 and 79 +/- 3% for T3, and values in hyperthyroidism are 58 +/- 3% for T4 and 58 +/- 5% for T3 (P less than 0.01). These findings indicate that 1) urinary T4 to T3 conversion values are highly reproducible in euthyroid as well as hyperthyroid and hypothyroid states; 2) the reduction in T4 to T3 conversion in hyperthyroidism probably reflects increased T4 disposal by nondeiodinative pathways and possibly the reverse in hypothyroid states; and 3) since urinary T4 to T3 conversion values in euthyroid subjects exceeded all reported conversion values in blood, there may be an alternate pathway of T3 production and disposal which is not reflected in the blood T3 production rate.

It has been shown that both serum triiodothyronine (T3) and plasma fibronectin values decline with fasting and increase with treatment of diabetic ketoacidosis in a paralles manner. To evaluate the mechanism responsible for these changes, we examined the effects of both oral T3 administration and fasting in six healthy, adult subjects. Initial plasma fibronectin values were normal in four subjects (group 1) and decreased in two subjects (group 2). Initial serum T3 and thyroxine (T4) values were normal in both groups. Despite a substantial rise in serum T3 values with oral T3 administration, plasma fibronectin fell in group 1 subjects. Fasting caused a significant decline in serum T3 levels, but only a small further decline of plasma fibronectin concentrations. Serum T3 levels rose after 1 week of refeeding, whereas plasma fibronectin levels in group 1 did not return toward normal. Plasma fibronectin values did not change in group 2 subjects with oral T3, fasting, or refeeding. In conclusion, there is no simple cause-and-effect relationship between previously observed changes in plasma fibronectin and serum T3 concentrations. High doses of oral T3 will lower plasma fibronectin levels in subjects with initially normal plasma fibronectin values and a normal caloric intake.

This study reports in vitro and in vivo parameters of T4 metabolism in patients with critical nonthyroidal illnesses who were selected because of serum total T4 values less than 3 micrograms/dl and normal TSH levels. Despite the depressed total T4 concentrations, the normal serum free T4 values (7 of 9 patients), T4 production rates (8 of 9), and TSH responses to TRH (8 of 8) provided evidence for normal free T4 availability to peripheral tissues. Elevated rT3 values in 10 of 14 patients were consistent with this view. However, serum free T4 index determinations markedly underestimated free T4 (20 of 20). This resulted from failure of the T3 uptake measurement to reflect the defective state of serum T4 binding. Defective serum T4 binding to carrier proteins was evidenced by the 2- to 3-fold increase in both the free fraction and the MCR values for T4. The normal early distribution phase, despite defective serum T4 binding, suggested an additional abnormality of deficient extravascular T4 binding. The blunted TSH response to TRH and the low normal values for both T4 production rates and free T4 levels measured by equilibrium dialysis indicated mild pituitary suppression, possibly related to elevated serum cortisol levels. Since an overt deficiency of free T4 availability does not appear to exist in the low T4 state of critical nonthyroidal illness, T4 therapy cannot currently be recommended.

This study concerns the optimization of the human TSH (h-TSH) radioimmunoassay with special emphasis on reducing the heterogeneity of the 125I h-TSH tracer. Enzymatic iodination of h-TSH with glucose oxidase/lactoperoxidase was shown to be superior to either low or high dose chloramine-T procedures, producing a high specific activity reagent (70--150 microCi/microgram) with minimal evidence of damage. Tracer purification procedures not only affected initial immunoactivity but also storage stability and heterogeneity of the resulting 125I h-TSH. Tracers purified by combining concanavalin A-Sepharose adsorption and high resolution gel filtration (Sephadex G100), produced significantly lower (p less than 0.001) serum h-TSH measurements than were observed in less purified tracer materials. Concanavalin A-Sepharose adsorption yield of the 125I h-TSH iodination products closely correlated with the yield (r = 0.85, p less than 0.001) and immunoactivity (r = 0.90, p less than 0.001) of the tracer produced, thus making this an ideal method for initial tracer purification. Storage of tracer adsorbed to a solid support (concanavalin A-Sepharose) reduced technical manipulations without compromising tracer performance. Loss of specific activity was minimized by storage at -70 degrees C. The assay developed using these technical approaches showed a sensitivity limit of 0.005 +/- 0.001 (S.E.M.) microU/tube; 50% displacement at 0.18 +/- 0.08 (S.E.M.) microU/tube and complete delineation between euthyroid (n = 49, 2.44 +/- 0.18 (S.E.M.) mU/l, range 1.00--6.08) and hyperthyroid (n = 62, 0.34 +/- 0.02 (S.E.M.) mU/l, range 0.10--0.85), serum h-TSH levels.

Comparative serum Tg RIA studies were used to evaluate the contamination of 125I-19S Tg (B) (670 000 Da) with a smaller partially immunoactive degradation product (C) (530 000 Da). B and C tracers prepared either by enzymic (GO), chloramine T (CT) or Bolton Hunter (BH) iodination methods were tested. B tracers, (either GO or CT), gave consistently higher Tg values vs C tracers at serum Tg levels greater than 30 ng/ml. No difference in values was seen with C tracers of either GO, CT or BH origin. The immunological nonidentity between B and C tracers was shown by nonparallelism between diluted high Tg sera and the Tg RIA standards. Nonparallelism existed above 30 ng/ml with all C tracers irrespective of iodination method and was, in addition, present with CT-B tracers from 3/4 Tg preparations. Only B tracers, prepared by GO or BH, consistently showed adequate parallelism. The ubiquitous nature of C contamination of B tracers prompted a comparative study of serum Tg RIA values between four different laboratories. Good interlaboratory agreement was shown for Tg values less than 30 ng/ml, whereas there was a 10- to 20-fold difference in values for sera with high Tg levels (greater than 100 ng/ml). The observed/expected ratio of values, in serial dilutions of a high Tg sera, measured in two of the laboratories, suggested that nonparallelism accounted for some interlaboratory differences. Contamination of 125I-19S Tg (B) by its breakdown product C, has potential to lower absolute serum Tg values and produce non-parallelism in diluted high Tg sera which results in aberrantly low Tg RIA values. This problem potentially limits the clinical application and relevance of serum Tg measurements in thyroid cancer patients, especially those with metastases associated with high serum Tg levels.

The purpose of the present study was to evaluate in man the relative thyrotroph and lactotroph response to a 48-h low dose constant TRH infusion. Before, during, and after the 75 ng/min TRH constant infusion, serum samples were obtained every 4 h in six euthyroid ambulating male subjects for measurements of TSH, PRL, T4, and T3. The TSH response, employing a specific and sensitive human TSH RIA, demonstrated a significant rise from the mean basal pre-TRH value of 2.35 +/- 0.64 microU/ml (+/- SEM) to 3.68 +/- 0.80 (P < 0.005) during the TRH infusion; this value fell below the basal level to 1.79 +/- 0.47 (P < 0.05) post infusion. Serum T4 values were increased above basal both during (P < 0.025) and after (P < 0.025) TRH infusion, whereas serum T3 values were not significantly changed throughout the entire study period. The daily TSH nocturnal surge was augmented in both absolute and relative terms during the first 24 h or the TRH infusion, unchanged during the second 24 h of infusion, and inhibited during the first postinfusion day. Other than a minimal increase in serum PRL during the first few hours of the infusion, no significant alteration in the mean basal concentration or circadian pattern of PRL secretion was evident during or after the low dose TRH infusion. These findings would indicate that 1) near-physiological stimulation of the pituitary with TRH produces a greater stimulation of TSH release than of PRL release and 2) the factor or factors producing the circadian TSH surge may not be mediated through fluctuations in endogenous TRH.

A serial blood-lipid-lowering study at the University of Southern California yielded unexpected findings on routine thyroid function monitoring. After 1 year of combined colestipol and niacin therapy, patients had reduced total serum thyroxine (T4) levels and increased triiodothyronine uptake ratios, an indicator of apparent decreases in thyroxine-binding globulin levels. Calculation of the free T4 index partially but not completely corrected for the apparent decrease in thyroxine-binding globulin, as determined by a relatively small decrease in the free T4 index compared with a large decrease in T4. Sequential sampling, using three separate methods, showed reduced thyroxine-binding globulin levels. The mechanism for these changes is unknown, but the fact that these patients were essentially euthyroid needs emphasis because the use of combined colestipol and niacin therapy is becoming more widespread.