Thyroid-stimulating Hormone Assay Research Articles

Incomplete thyrotroph suppression determined by third generation thyrotropin assay in subacute thyroiditis compared to silent thyroiditis or hyperthyroid Graves' disease.

Serum TSH concentrations were determined by both second and third generation assays in three types of thyrotoxicosis associated with subacute thyroiditis, silent thyroiditis, and hyperthyroid Graves' disease at the time of each patient's initial visit to the clinic. Serum TSH concentrations as measured by the second generation assay with an analytical sensitivity of 0.04 mU/L were below the detection limit in every patient. In contrast, serum TSH concentrations as measured by the third generation assay with an analytical sensitivity of 0.009 mU/L were below the detection limit in 18 of 21 (86%) patients with Graves' disease, 18 of 20 (90%) with silent thyroiditis, but only 4 of 18 (22%) with subacute thyroiditis. Changes in serum TSH concentrations were studied in healthy volunteers given daily 75 micrograms of T3; their serum TSH concentrations on the second generation assay fell below the detection limit within 3 days in every subject. However, the TSH concentration measured by the third generation assay remained above the detection limit in 6 of 8 normal subjects even on the 14th day of therapy. The reason for incomplete TSH suppression in most subacute thyroiditis patients may be that these patients had notable neck pain, and their initial visit to the clinic may have occurred earlier after the onset of disease than with patients who have had silent thyroiditis or Graves' disease. Thus, the serum TSH concentration had not decreased sufficiently below the detection limit at the time blood was drawn. The data suggest also that the highly sensitive TSH assay, if the level is above the detection limit, can be used to suppose that the short duration of the initiation of thyrotoxicosis indicates a case of subacute thyroiditis.

Incomplete Thyrotroph Suppression Determined by Third Generation Thyrotropin Assay in Subacute Thyroiditis Compared to Silent Thyroiditis or Hyperthyroid Graves' Disease

Incomplete Thyrotroph Suppression Determined by Third Generation Thyrotropin Assay in Subacute Thyroiditis Compared to Silent Thyroiditis or Hyperthyroid Graves' Disease

Primary open angle glaucoma and hypothyroidism: Chance or true association?

The prevalence of hypothyroidism in British patients with primary open angle glaucoma (POAG) was examined. A recently reported study from Montreal had shown a significant increase (p < 0.004) in biochemical hypothyroidism (23.4%) in a population of 64 POAG patients compared with controls (4.7%). Mechanisms for a possible causal association between the two diseases are discussed, including mucopolysaccharide deposition in the trabecular meshwork and vasculopathy altering ocular bloodflow. Reports of improved glaucoma control following treatment of hypothyroidism are discussed. This study examined 100 consecutive patients with POAG in a specialist glaucoma clinic. All patients were questioned regarding symptoms of thyroid dysfunction and previous thyroid disease. All patients not already taking thyroxine underwent an assay of thyroid stimulating hormone. The 4% (95% CI 1.1-9.4%) prevalence of overt hypothyroidism in our study shows no clinically significant increase either over controls in the Montreal study or over our local population. We conclude that in our local population there is no evidence for a clinically important association of hypothyroidism with glaucoma.

Thyroid Function in Children With Different Lipoprotein Profiles: Observations in a Biracial (Black/White) Population- The Bogalusa Heart Study

AbstractAbnormalities of thyroid function are associated with hyperlipidemia, a risk factor for coronary artery disease that starts in childhood. We investigated the age-, race-, and sex-related differences in thyroid function and its relation to serum lipoprotein levels in children (n = 363) aged 6 to 18 years from the biracial (black/white) community of Bogalusa, Louisiana, using an ultrasensitive thyroid-stimulating hormone (TSH) assay. Serum levels of lipoprotein cholesterol fractions, triglycerides, triiodothyronine (T3), thyroxine (T4), and the Tanner stage of sexual development were determined. Serum T3 (P < 0.0001), T4 (P < 0.0001), and TSH (P < 0.0020) levels decreased significantly with Tanner stage. Serum T4 levels were significantly higher (P < 0.0001) in both black and white females than their male counterparts. An unexpected finding was a significantly increased mean serum TSH in whites (2.09 + 0.91; mean + standard error of mean) when compared to blacks (1.74 + 0.10; P = 0.0185). Overall, no significant correlation was noted between serum lipoprotein variables and TSH. However, those with the highest low-density lipoprotein to very low-density lipoprotein cholesterol fractions had a higher T4 and a T4frSH i'atio than those with the lowest low-density lipoprotein to very lowdensity lipoprotein cholesterol fractions. In summary, it is concluded that there is no simple relationship between lipoproteins and TSH or thyroid hormone levels in children.

EVALUATING THYROID DISEASE: WHICH TEST IS BEST?

The development of newer sensitive thyrotropin assays (sTSH) and of non-protein-bound free thyroxine assays (FT4) has led to conflicting

Validation of an immunoassay for canine thyroid-stimulating hormone and changes in serum concentration following induction of hypothyroidism in dogs

Objective— To validate a new immunoradiometric assay for canine thyroid-stimulating hormone (cTSH) and to document changes in serum cTSH concentration during induction of hypothyroidism in dogs. Animals— Six healthy adult male Beagles. Procedure— Sensitivity, specificity, precision, and accuracy of the cTSH assay were evaluated in vitro. Hypothyroidism was induced in dogs by IV administration of sodium iodide I 131 solution. Subsequently, l-thyroxine was administered orally to normalize serum thyroxine concentrations. Results— The cTSH assay appeared to be specific and was sufficiently sensitive to detect cTSH in the serum of these dogs prior to induction of hypothyroidism. There was a 35-fold increase in mean serum cTSH concentration following induction of hypothyroidism, and 35 days after initiation of thyroid replacement therapy, mean serum cTSH concentration was not significantly greater than mean baseline value. Clinical Implications— Assay of serum cTSH is likely to prove helpful in the differential diagnosis of primary, secondary, and tertiary hypothyroidism in dogs, and in monitoring response to thyroid hormone replacement treatment. (J Am Vet Med Assoc 1996;209:1730–1732)

Screening for Mild Thyroid Failure at the Periodic Health Examination

To estimate the cost-effectiveness of periodic screening for mild thyroid failure by measurement of serum thyroid stimulating hormone (TSH) concentration. Cost-utility analysis using a state-transition computer decision model that accounted for case finding, medical consequences of mild thyroid failure, and costs of care during 40 years of simulated follow-up. Periodic health examinations in offices of primary care physicians. Hypothetical cohorts of women and men screened every 5 years during the recommended periodic examination, beginning at age 35 years. Adding the serum TSH assay to total serum cholesterol screening was compared to cholesterol screening alone. Discounted quality-adjusted life years (QALYs) and direct medical costs from a societal perspective. The cost-effectiveness of screening 35-year-old patients with a serum TSH assay every 5 years was $9223 per QALY for women and $22595 per QALY for men. The cost-effectiveness became more favorable when age at first screening was increased for both sexes and was always more favorable for women than men. Reduced progression to overt hypothyroidism and relief of symptoms increased QALYs, but did not substantially reduce direct medical costs. Finding hypercholesterolemia induced by mild thyroid failure reduced direct medical costs, but did not substantially increase QALYs. The cost of a TSH assay and the importance to patients of symptoms associated with thyroid failure were the most influential factors in sensitivity analyses. The cost-effectiveness of screening for mild thyroid failure compares favorably with other generally accepted preventive medical practices. Physicians should consider measuring serum TSH concentration in patients aged 35 years and older undergoing routine periodic health examinations. The cost-effectiveness of screening is most favorable in elderly women.

Results of a Community Thyroid Screening Program: Who Will Benefit?

To describe the results of a community-based thyroid screening program. We review the recruitment process, the screening questionnaire, the laboratory procedure, and the data analysis. News media advertisements and facility-sponsored communications were used to recruit 1,176 participants, each of whom completed a health questionnaire and had blood withdrawn for a thyroid-stimulating hormone (TSH) assay. Most participants were female (78%), Caucasian (92%), and age 50 years or older (61%). Data from 1,139 participants were analyzed. Abnormal TSH values were found in 107 participants: TSH was low in 21 (2%) and elevated in 86 (8%). Elevated TSH values occurred in 8% of females, 7% of males, 8% of Caucasians, and 7% of Hispanics. Although the percentage of elevated TSH values tended to increase with advancing age, primarily in females, 5% of participants younger than 50 years of age had an elevated TSH. No associations were apparent between abnormal TSH values and health maintenance organization membership, self-rating of overall health, or presence of thyroid-related symptoms. Participants who rated their overall health as "excellent" or "very good" accounted for 48% of the TSH values >12 microIU/mL. Experience gained from the conduct of this screening program may help shape the expectations of future screening programs that use disease awareness and self-motivation and provide insights into program design that may maximize participation by the desired target audiences.

Low TSH Levels in Nursing Home Residents Not Taking Thyroid Hormone

Many practitioners perform a thyroid stimulating hormone (TSH) assay as a screening test in older patients. The introduction of sensitive TSH assays with lower normal limits has created a laboratory abnormality that is often of uncertain significance. Mechanisms include autonomous overproduction of thyroid hormone, nonthyroidal illness including medication effects, and hypothalamic/pituitary dysfunction. To characterize the clinical status and course of nursing home residents with low TSH and normal total T4 levels in the absence of treatment with thyroid hormone. Retrospective chart review was performed to determine participants status at the time of low TSH level, with additional recording of follow-up thyroid hormone levels, cardiac rhythm, and mortality. Mortality was compared with that of a control group matched for age and sex. A nursing home for veterans and their spouses. Forty subjects with low TSH and initially normal total T4 were identified. Only three subjects were subsequently diagnosed as hyperthyroid. TSH levels of 18 subjects subsequently normalized, and four additional subjects had low total T3 levels suggesting a nonthyroidal mechanism. Seven subjects died during the first 4 months of follow-up compared with three in a control group (P < .001). Nine of the 40 subjects had a history of or current atrial fibrillation. No new atrial fibrillation was documented during 388 months of EKG follow-up. Low total T3 levels, TSH normalization, and excess mortality suggest that nonthyroidal illness plays a role in the pathogenesis of low TSH determinants in the nursing home. Autonomous production of thyroid hormone also plays a role. We believe that the term "subclinical hyperthyroidism" should be used only if the clinician believes that autonomous overproduction of thyroid hormone is the cause of a low TSH level. If subsequent research shows correctable adverse consequences associated with subclinical hyperthyroidism from autonomous overproduction of thyroid hormone, a more aggressive diagnostic approach will be needed to define the mechanism of a low TSH level at the time of its discovery.

Influence of specimen carryover on sensitive thyrotropin (TSH) assays: is there a problem?

A relatively slow transition has occurred from so-called 1st-generation thyrotropin (TSH) assays (e.g., RIAs) through 2nd-generation assays (e.g., IRMAs) to 3rd-generation assays (e.g., immunochemiluminometric assays). Analysis of data from a modified internal quality-control design, followed up by a computer simulation, showed that specimen carryover has minimal effect on 2nd-generation TSH assays. However, extension of the simulation to a 3rd-generation assay showed the possibility of substantial effects in the subnormal region. Carryover of 1:1250 (0.08%), for example, may reduce the theoretical 10-fold precision improvement claimed for 3rd-generation assays to nearer fourfold. Simulation results suggest maximum allowable specimen carryover of approximately 1:10,000 (approximately 0.01%) for 3rd-generation TSH assays. We suggest that when automated specimen handling is used in a TSH assay, a well-designed carryover experiment should become a routine part of reports that claim 3rd-generation (or better) performance characteristics.

Evaluation of an immunoradiometric assay for thyrotropin in serum and plasma samples of dogs with primary hypothyroidism

A commercially available immunoradiometric assay was used to measure the thyrotropin (TSH; thyroid-stimulating hormone) concentration in the serum and plasma of 23 dogs. The basal concentration in five dogs with histologically confirmed primary hypothyroidism (median 0.18 microg/l, range 0.16-0.72 microg/l) was slightly, but not significantly, higher than that in 13 clinically healthy dogs (median 0.09 microg/l, range 0.06-0.34 microg/l). The TSH values in 11 euthyroid dogs with various dermatological diseases (median 0.09 microg/l, range 0.05-0.53 microg/l) were significantly lower than in the hypothyroid dogs, but there was considerable overlap. The assay alone was therefore not capable of giving a firm diagnosis.

Thyroid function testing based on assay of thyroid-stimulating hormone: assessing an algorithm's reliability.

To assess the ability of an algorithm for thyroid-function testing (based on assay of thyroid-stimulating hormone [TSH]) to discern euthyroidism in patients with and without conditions affecting thyroid function. The Australian Health Insurance Commission (HIC) specifies clinical categories for which Medicare rebate is given for assay of both TSH and free thyroxine (FT4), but otherwise rebates for thyroid function testing are given for TSH assay only. A prospective study was made of paired TSH and FT4 results of 1000 consecutive assays categorised by indication for testing. An FT4 value within the reference range was accepted as indicating euthyroidism; the reliability of an initial TSH measurement as the sole indicator of thyroid disease was assessed against this criterion standard. A large suburban teaching hospital. Success or failure of the algorithm, with failure defined as an abnormal FT4 level missed because the TSH level was normal. The algorithm failure rate both overall and in the patients not in the HIC clinical categories was 2.7%, and there was no significant difference in algorithm failure rate in the patients in the various HIC clinical categories. The categories and failure rates were: patients being monitored for thyroid disease, 3.4%; patients with the "sick euthyroid" syndrome, nil; patients with psychosis or dementia, 1.1%; patients taking drugs affecting thyroid function, 2.1%; and patients with pituitary dysfunction, one of six cases. The range of FT4 values in patients in whom the algorithm failed was 6.4-29.5 pmol/L in those without thyroid disease and 3.4-27.4 pmol/L in those with thyroid disease. In patients being monitored for thyroid disease, the proportion of abnormal values of TSH alone was significant (P<0.001). We have shown that the HIC's imposition of a TSH-based algorithm by financial fiat is also scientifically acceptable. Use of this algorithm in hospitals (including psychiatric hospitals) will result in substantial savings.

Clinical use of sensitive assays for thyroid-stimulating hormone.

To review the optimal use of sensitive assays for thyroid-stimulating hormone (TSH) by clinicians. The available literature pertinent to the clinical application of sensitive TSH testing was identified through a systematic MEDLINE search and reviewed. Selection of materials for inclusion was based on clinical validity of the data and relevance to the study question. Sensitive TSH assays have contributed greatly to our basic knowledge of thyroid physiology and are a powerful clinical tool in the diagnosis and treatment of thyroid disease. The clinical applicability of these assays, as is our understanding of their appropriate use, is rapidly expanding. Based upon the best evidence and current understanding of thyroid physiology, strategies are presented for appropriate use of sensitive TSH assays in healthy outpatients, in patients who are likely to have a disturbed hypothalmic-pituitary-thyroid axis, and in patients on levothyroxane therapy. Although many clinical questions regarding the use of sensitive TSH assays remain to be studied, it has emerged as a powerful tool for the diagnosis and management of thyroid disease. Optimal use of sensitive TSH assays requires an understanding of TSH physiology and measurement, coupled with appropriate application and interpretation in specific clinical settings.

Current status and performance goals for serum thyrotropin (TSH) assays

Current medical needs dictate that laboratories offer thyrotropin (TSH) assays that can reliably measure low TSH concentrations--a prerequisite for using the more cost-effective TSH-centered strategy currently recommended by the American Thyroid Association. This study reviews the functional performance of the TSH immunometric assay methods currently used in clinical practice. Methodological differences between methods, the rationale for using the 20% interassay CV as the functional sensitivity limit for patient reports, and both TSH-related and non-TSH-related specificity problems are reviewed. We recommend that manufacturers and clinical laboratories use a clinically relevant standard protocol for functional sensitivity assessments. In this protocol, human serum pools are analyzed in random order 10 or more times across a clinically realistic time span (which approximates to 6-8 weeks for TSH measurements used in an outpatient setting). Laboratories should independently establish and periodically check their functional sensitivity by the standard protocol and enlist the manufacturer's help to accomplish this if necessary. Manufacturers should (a) develop promotional material that realistically projects the assay's functional sensitivity expected in a clinical laboratory setting, (b) ensure that new clinical laboratory users achieve the projected functional sensitivity target when using the standard protocol, and (c) focus on the typical functional sensitivity obtained by clinical laboratory users rather than the assay's "generation" achieved under ideal conditions. If manufacturers and laboratories collaborate to solve the sensitivity and specificity problems discussed here, clinical laboratories should be better able to consistently deliver reliable serum TSH measurements across the full range of TSH concentrations encountered in clinical practice.

Immunoradiometric and luminescence immunoenzymometric assay of human thyrotropin from dried blood spots for screening of neonatal hypothyroidism.

Two monoclonal antibodies to thyrotropin prepared in our laboratory were employed for the development of two-site immunometric assays in two modifications for the estimation of human thyrotropin in dried blood spots designed for the screening of neonatal hypothyroidism. The immunoradiometric assay using the second antibody labelled with 125I is simple and fast (one incubation step lasting 2 h). The detection limit of 1 mU/l and the absence of the hook effect up to a concentration of more than 1000 mU/l are optimal for neonatal screening; the presence of other glycoprotein hormones does not interfere with the assay. In the luminescence immunoenzymometric assay the second antibody is labelled with peroxidase. In spite of the two-step configuration the method is fast (4.5 h) and enables specific determination of thyrotropin levels in the range of 2.4-1100 mU/l. The conditions and properties of both immunometric assays described are comparable with the time-resolved immunofluorometric assay widely used in Europe.

Controversies in the management of cold, hot, and occult thyroid nodules

Some aspects of thyroid nodule evaluation and management remain controversial. Radionuclide scanning provides functional information about nodules and differentiates cold from hot nodules. Although thyroid cancers are cold on scan, most cold nodules are benign. Ultrasonography visualizes the thyroid gland and nodules with remarkable clarity and provides structural information about location, number, size, and consistency of nodules. Widespread application of ultrasonography has resulted in the frequent discovery of incidental (occult) nodules in the general population. The clinical significance of these nodules remains unknown, and their management has created a dilemma for physicians. Current cost-effective evaluation of nodules does not include scanning or ultrasonography as routine frontline tests. In most centers, fine-needle aspiration biopsy has supplanted imaging studies as the routine initial procedure for differentiating benign from malignant nodules. Cytologic diagnosis is reliable and inexpensive, and it results in a better selection of patients for surgery. Limitations include falsenegative diagnoses, nondiagnostic results, and indeterminate “suspicious” results. Laboratory test results are usually normal, but determination of serum thyrotropin may identify a hot nodule, and plasma calcitonin may help diagnose medullary thyroid carcinoma. Treatment of thyroid nodules is controversial. In some practices, benign colloid nodules are treated with suppressive doses of levothyroxine. Recent reports cast doubt on the efficacy of this approach, and it is no longer acceptable to select patients for surgical treatment on the basis of suppressive therapy. Furthermore, suppressive levothyroxine therapy may be associated with significant bone and cardiac side effects, especially in elderly patients and postmenopausal women. Our approach is observation for most patients, and we suggest a careful risk-benefit analysis when suppression is considered. Hot (autonomous) nodules can be treated with radioiodine, surgery, or ethanol injection. The use of sensitive thyrotropin assays has revealed that the “euthyroid” hot nodule is often associated with subclinical hyperthyroidism, warranting treatment if risks of osteoporosis are significant. Small (≤1.5 cm) occult nodules can be observed. Larger (>1.5 cm) nodules can be selectively evaluated by ultrasonographically guided fine-needle aspiration. It is prudent to consider cost of care, risk-benefit analysis, and the low incidence of malignancy in thyroid nodules when diagnostic tests are selected and the treatment plan is outlined.

AquaLite bioluminescence assay of thyrotropin in serum evaluated

We studied a new commercially available thyrotropin (TSH) assay, the AquaLite Bioluminescence TSH-Immunoassay (SeaLite Inc.). This assay has a detection limit of 0.005 mIU/L and a functional sensitivity of 0.017 mIU/L and meets the requirements of a third-generation TSH assay. Using this assay, we measured serum TSH in 153 euthyroid individuals and in the following patients: 32 primary hypothyroids; 38 primary hyperthyroids; 35 with thyroid cancer receiving suppressive therapy with levothyroxine (L-T4); 33 receiving replacement L-T4 aimed at reaching and maintaining a euthyroid status; 23 with subclinical hyperthyroidism; and 52 hospitalized for nonthyroidal illnesses (NTI). The AquaLite TSH assay perfectly discriminated hypothyroid and untreated hyperthyroid patients from euthyroid subjects and clearly discriminated between overtly and mildly hyperthyroid patients. Intermethod comparisons showed that the AquaLite and the Nichols assays were more effective than the ACS-180 and the TOSOH assays in discriminating among hyperthyroid patients, including patients over-treated with L-T4.

Thyroid screening.

Preview The ultrasensitive third-generation assay for thyrotropin (TSH) is now the "gold standard" for measuring thyroid activity. Who should be screened with it, and what further studies should be done if results are abnormal? Which patients with subclinical disease should receive treatment? Drs Brody and Reichard discuss these and other issues and provide an algorithm for thyroid screening.

Advances in the management of patients with thyroid disease

Discoveries related to thyroid immunology, especially concerning the thyroid-stimulating hormone (TSH) receptor, may facilitate new immunologic approaches to the therapy of Graves' disease and the thyroiditis syndromes. Advances in genetics are being applied to the thyroid hormone resistance syndromes and papillary and medullary carcinomas. The development of ever more sensitive TSH assays has led to the detection of subclinical thyroid disease, which has special implications for the sick and elderly patients. Sensitive TSH assays also allow more precise titration of levothyroxine (T4) dosages, especially for patients with a past history of thyroid cancer. Evidence continues to accumulate suggesting that postmenopausal women on T4 doses that suppress the TSH level below 0.1 ulU/mL have lower bone mineral density than matched patients with healthy TSH levels. Also, pregnant hypothyroid women need higher T4 doses to normalize the TSH levels. In the evaluation of thyroid nodules, fine-needle aspiration biopsy is the single most definitive modality in selecting the patients for surgery. Scintigraphy provides a complimentary role, especially in defining autonomously functioning thyroid adenomas (AFTA), because these should not be treated with T4 suppression. Ultrasound-guided needle biopsy is occasionally helpful with nodules that are difficult to palpate. Concern for possible tracheal compression after treatment of toxic multinodular goiter with large doses of radioactive iodine (I-131) in the range of 50 to 150 mCi (1.85 to 5.5 GBq) does not seem warranted. Work, primarily out of Italy, suggests AFTA can be ablated with repeat ethanol injections. Residual tissues after thyroidectomy for differentiated carcinoma can be "stunned" by tracer doses of 131I greater than 3.0 mCi (111 MBq), which diminishes the uptake and effectiveness of a subsequent therapy dose. Positron emission tomograph, imaging with thallium-201, and Technetium 99m Sestamibi can identify a small number of patients shown to have metastases from differentiated thyroid carcinoma by increasing thyroglobulin levels in the absence of 131I uptake. Several groups have recently advocated treating such patients empirically with 131I.

Sensitive assay of thyroid stimulating hormone in depressed patients

A decreased thyroid stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) has been noted in major depression. Some authors found a positive correlation between baseline TSH levels and TSH response to TRH, especially with sensitive assays of TSH. Serum TSH was assayed by a sensitive method in 55 depressed patients and 38 healthy volunteers. Patients were subclassified according to DSM-III as suffering from major depression ( n = 40) and non-major depression ( n = 15). The patients' mean score on the Hamilton Rating Scale for Depression (HRSD) was 50 (SD = 10). The TSH value was significantly lower in depressed patients compared with healthy control subjects, and in major compared with non-major depression. No differences in TSH levels distinguished the various subtypes of major depression. There was a significant negative correlation between global HRSD scores and TSH concentrations. The most anxious patients tended to have significantly lower TSH values compared with the least anxious subjects. Total HRSD insomnia scores correlated negatively with TSH concentrations after log transformation. The sensitive determination of TSH may also provide an index of thyroid function in depression that is simpler to implement than measurements of the TSH response to TRH.