Discrepancy between the basal level of TSH and the thyrotropic response to TRH during thyroid hormone treatment of differentiated thyroid cancers

Serum TSH (Thyroid Stimulating Hormone) was measured before and 30 minutes after a 200 microgram intravenous TRH (Protiréline*) injection in 270 patients. These patients have been treated for one year at least, by a suppressive thyroid therapy after thyroidectomy for a differentiated thyroid carcinoma. 314 tests were performed. We used an ultrasensitive TSH method (Ciba-Corning-Diagnostics). The normal range (mean :1.68 mUI/l; range: 0.45 to 3.80 mUI/l) was determined in 116 euthyroid patients. Minimal response to TRH was studied in 35 untreated patients with hyperthyroidism (TSH TO: less than 0.30 mUI/l and delta TSH: less than 0.09 mUI/l). There was a relationship (r = 0.916) between TSH response 30 minutes after TRH stimulation (T30) and basal TSH value: in a logarithmic scale (fitting of the data by a bi-gaussian model). TRH tests were classified too, by basal TSH values (TO) and delta TSH (TSH at T30-TSH at TO). In 201 tests in which TO TSH was less than 0.30 mUI/l (maximal value in hyperthyroidism), 50 showed a delta TSH higher than 0.15 mUI/l (25% of the cases) and in 6 cases (3%), delta TSH was even higher than 2.0 mul/l; in 67 of the 75 tests (89.3%) where TSH TO is less than 0.15 mUI/l, delta TSH is no (less than 0.15 mUI/l). In 93 tests where TO TSH was upper than 0.45 mUI/l (minimal value in euthyroidism), delta TSH was higher than 2.0 mUI/l in 87 cases (93.6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Analytical evaluation of third generation TSH assay. Application to the exploration of thyrotropin suppression in differentiated thyroid cancer]

Intravenous TRH (200 micrograms Protiréline) injection was performed in 137 patients who had undergone thyroidectomy for differentiated thyroid carcinoma and treated by a suppressive thyroid therapy. Serum thyroid stimulating hormone (TSH) was measured before and 30 minutes after the injection. 143 tests were performed. The TSH method used was a chemiluminometric assay (Chiron Diagnostics). We study the analytical characteristics of the method. The limit of detection was 0.003 mUI/l. Interassay precision showed a functional sensitivity of 0.015 m UI/l with 20% interassay CV in agreement with the third generation criterion. There was a good correlation between TSH values at T0 and T30 minutes. In 143 tests, 40 (28%) showed a basal TSH value less than 0.003 mUI/l; delta TSH (TSH at T30-TSH at T0) was less than 0.015 mUI/l in about 68% of the cases and less than 0.031 mUI/l for the others. In 20% of the tests (29) TSH T0 were between 0.003 and 0.015 mUI/l and delta TSH less than 0.204 mUI/l. Finally the 74 remaining tests with a basal TSH value higher than the functional sensitivity of the method showed delta TSH less than 0.4 mUI/l if the TSH T0 was less than 0.05 mUI/l. The delta TSH remained less than 0.6 mUI/l if the TSH T0 was less than 0.1 mUI/l. Inversely, if TSH T0 was higher than 0.1 mUI/l delta TSH could be higher than 1.0 mUI/l. Third generation TSH assay allows us to abandon TRH test for the follow-up of thyroidectomized patients with suppressive thyroid hormonotherapy in so far as TSH assay is well established. We conclude that a basal TSH less than the functional sensitivity (0.015 mUI/l) can predict a TSH response to TRH stimulation test less than 0.2 mUI/l.     

Diagnostic relevance of suppressed basal concentrations of TSH compared with the negative TRH test in detection and exclusion of hyperthyroidism

To evaluate the sensitivity of basal TSH concentrations as determined by an "ultrasensitive" IRMA-assay (RIA-gnost h-TSH-monoclonal, Behring) versus a "negative" TRH test (defined as an increment of TSH less than or equal to 0.2 mU/l 20 min after administration of 400 micrograms TRH iv) in the diagnosis of hyperthyroidism we examined 193 consecutive patients from our thyroid outpatient clinic: 34 patients displayed hyperthyroidism (total T4: 184.4 +/- 26.0 mumol/l, effective thyroxine index: 1.25 +/- 0.08), whereas 12 had isolated T3-hyperthyroidism (total T3: 3.47 +/- 0.48 nmol/l). Employing the producer's definition of subnormal ("suppressed") bTSH concentrations (less than or equal to 0.1 mU/l), only 19 (41.3%) hyperthyroid patients would have been detected; on the other hand, one euthyroid patient would have been recognized false positively as hyperthyroid. Using the TRH test as criterion led to the correct diagnosis in 42 (sensitivity: 91.3%) hyperthyroid patients, whereas two had low bTSH concentrations (less than or equal to 0.5 mU/l), but a normal TSH response to TRH (greater than 2.0 mU/l). Raising the threshold concentration to 0.2 and, subsequently, to 0.4 mU TSH/l increased the number of correct results to 38 (sensitivity: 82.6%) and 43 (93.5%), respectively. This was associated with a concomitant decrease in specificity in the diagnosis of hyperthyroidism from 93.7 (0.1 mU/l) to 27.9% (0.4 mU/l). In conclusion, despite ultrasensitive methods for estimation of low TSH concentrations, the TRH test remains an irreplaceable tool for the correct diagnosis of hyperthyroidism.     

The immunofluorometric TSH assay as first-line test for suspected thyroid dysfunction

In this study of 103 patients with suspected thyroid dysfunction, the diagnostic value of a single basal immunofluorometric (IFMA) TSH measurement was evaluated and compared with the classical TRH test with RIA-TSH measurements, plasma TT4 concentrations and FT4I. A single basal TSH determination accurately predicted the TRH-stimulated TSH response, making the TRH test redundant in most patients. Because undetectable basal TSH did not always exclude a small rise in TSH, the TRH test could still be indicated in patients receiving thyroxine suppression therapy for thyroid cancer. Basal TSH differentiated accurately between euthyroidism and thyroid dysfunction, especially at the decision values of 0.20 and 4.0 mU/l, as proposed in this study. For diagnosis of clinical and subclinical hypo- and hyperthyroidism, additional measurement of TT4 and/or FT4I is necessary. A 2-yr follow-up of patients with subclinical thyroid dysfunction did not show progression to clinical disease. In some of the patients with subclinical hypothyroidism, substitution therapy with thyroxine had been started after initial testing. Indications for treatment of subclinical thyroid dysfunction are discussed.     

HUMAN SERUM THYROTROPHIN MEASUREMENT BY ULTRASENSITIVE IMMUNORADIOMETRIC ASSAY AS A FIRST-LINE TEST IN THE EVALUATION OF THYROID FUNCTION

An ultrasensitive immunoradiometric assay (IRMA) using two monoclonal anti-TSH antibodies has been used for TSH measurements in basal conditions and after TRH stimulation. The results have been compared with those obtained by conventional radioimmunoassay (RIA). The IRMA method had very high sensitivity (0.07 microU/ml). Detectable serum TSH concentrations were found in all normal subjects by IRMA, but in only 76% by RIA. No overlap was observed with the results obtained by IRMA in untreated overtly hyperthyroid patients, in whom serum TSH was below the limit of detection. The relationship between basal and TRH-stimulated serum TSH concentrations by IRMA and RIA was evaluated in 176 subjects including normals and patients with untreated and treated hyperthyroidism, functioning thyroid adenoma, nontoxic goitre and patients on L-thyroxine therapy. A normal TSH response to TRH was observed in virtually all patients with detectable basal serum TSH by both methods. When patients with undetectable basal serum TSH levels were considered, all but one (98%) had no TSH response to TRH by IRMA. On the contrary using RIA, an absent response was found only in 47% of subjects, a blunted responses in 10% and a normal response in 42%. These data indicate that basal serum TSH measurements by IRMA allows a complete discrimination of normal from hyperthyroid patients and can avoid the need for TRH stimulation tests.     

Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay

A new commercially available chemiluminescent TSH assay demonstrates an 8- to 10-fold increase in sensitivity over a sensitive immunoradiometric assay, allowing increased ability to distinguish partial from more complete thyrotroph suppression. Sera were analyzed from 145 patients who had TSH concentrations below 0.08 mU/L in the immunoradiometric assay. Most patients with overt hyperthyroidism had undetectable TSH concentrations in the chemiluminescent assay. Three groups of patients were identified, in which a large subgroup had undetectable values in the immunoradiometric assay and detectable values in the chemiluminescent assay (12 of 17 patients under treatment for hyperthyroidism who had recently normalized their serum thyroid hormone levels, 33 of 68 patients taking L-T4, and 4 of 8 patients with endogenous subclinical hyperthyroidism). In addition, several patients with undetectable basal and detectable TRH-stimulated TSH values in the immunoradiometric assay had detectable basal TSH values in the chemiluminescent assay. The utility of first generation TSH immunometric assays was their ability to distinguish hyperthyroidism from euthyroidism. The clinical utility of increasingly sensitive TSH assays will be to distinguish degrees of thyrotroph suppression in subclinical hyperthyroidism.     

THE SCREENING OF PATIENTS WITH SUSPECTED THYROTOXICOSIS USING A SENSITIVE TSH RADIOIMMUNOASSAY

A radioimmunoassay was optimized to measure serum TSH with maximum sensitivity (sTSH). With this assay sTSH was less than 0.5 mIU/l in 100% of 64 patients with proven thyrotoxicosis and greater than 0.5 mIU/l in 92% of 76 normal subjects. sTSH correctly predicted the TSH response to TRH (delta TSH) in 93% of 125 patients with suspected thyrotoxicosis. In this group thyrotoxicosis was excluded by an sTSH greater than 0.5 mIU/l in 52% of patients thus avoiding the need for further testing.     

Hyperthyroidism caused by a pituitary thyrotrophin-secreting tumour with excessive secretion of thyrotrophin-releasing hormone and subsequently followed by Graves' disease in a middle-aged woman

A 46-year-old woman had signs of thyrotoxicosis and galactorrhoea. Serum immunoreactive TSH and its alpha-subunit increased in the presence of high serum triiodothyronine (T3), thyroxine (T4), and free T4 concentrations, whereas beta-subunit TSH was undetectable. Exogenous TRH failed to increase serum TSH. Serum TSH was markedly suppressed by glucocorticoid, but was increased by antithyroid drug. L-Dopa or bromocriptine partially suppressed, but nomifensine had no influence on serum TSH. Serum prolactin (Prl) was above normal and markedly increased by TRH, but depressed by bromocriptine and not suppressed by nomifensine. Plasma TRH was normal in the hyperthyroid state, but was increased by glucocorticoid and antithyroid drug. Excess thyroid hormone depressed plasma TRH concentrations. Basal serum GH levels were constantly low. Transsphenoidal removal of the tumour normalized serum hormones (T3, T4 free T4, TSH, alpha-subunit and Prl), and eradicated the clinical signs of hyperthyroidism and galactorrhoea. Histological study of the tumour tissue demonstrated both thyrotrophes and somatotrophes. A reciprocal relationship between serum TSH and T4 concentrations shifted to a higher level before but was normalized after removal of the tumour. Ten months later, the clinical signs of thyrotoxicosis and the increase in serum thyroid hormone recurred without a concomitant increase in serum TSH and its alpha-subunit. Thyroidal auto-antibodies were slightly positive, but thyrotrophin-binding inhibitor immunoglobulin (TBII) was negative. Administration of antithyroid drug produced a euthyroid state, but 3 years later, discontinuation of the treatment resulted in recurrent hyperthyroidism without suppressed plasma TRH and with no evidence of regrowth of the pituitary tumour. It is suggested that the patient initially had hyperthyroidism owing to excessive TSH secretion from the tumour caused by abnormal TRH secretion, and subsequently had hyperthyroidism owing to Graves' disease.     

Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre

OBJECTIVE Basal plasma T4, T3 and TSH concentrations are usually normal in patients presenting with non-toxic nodular goitre. Using the evaluation of TSH response to TRH in a large series of such patients living In an area with normal iodine intake, we evaluated the prevalence of subclinical hyperthyroidism and the relationship between thyroid hormonal status and ultrasonographic parameters. PATIENTS A prospective study of 242 consecutive patients (group I), referred with non-autoimmune nodular goitre, normal plasma free T4, total T3 and TSH levels, without (subgroup IA, 222 patients) or with (subgroup IB, 20 patients) clear-cut autonomous area(s) on scintigraphy. These patients were compared to 135 controls (group II). MEASUREMENTS Plasma free T4 (FT4), total T3 (T3T) and TSH measurements. Evaluation of TSH response to TRH (A level of increased TSH = peak TSH level during TRH test-basal TSH level), thyroid scintigraphy and morphological characteristics (number and total volume of nodule(s) and volume of extranodular tissue) determined by ultrasonography. RESULTS In subgroup IA, (1) the mean (± SEM) basal TSH level (0.94± 0.04 μ/l) and the mean value of increased TSH after TRH (4.92 ± 0.34 μ/l) were lower (P<0.001) than in group II (1.28 ± 0.05 μ/l and 7.24 ± 0.25 μ/l, respectively). The prevalence of SH (Δ level of increased TSH below the mean – 3 SD in controls) was 17.2%; (2) the mean FT4 level and the mean T3T value were not different (P>0 05) from those of group II. In subgroup IB, (1) the mean basal TSH level (0.57 ± 0.11 μ/l) and the mean Increment of TSH after TRH (2.81 ± 0.62 μ/l) were lower (P < 0001) than in subgroup IA. The prevalence of subclinical hyperthyroidism was 750%; (2) the mean FT4 level (17.2± 0.9 pmol/l) was not different from that in group II. However, the mean T3T value (1.99 ± 0.01 nmol/l) was higher (P< 0.001) than in group II (1.65 ± 0.05). In group I, subgroup IA and IB, there were significant (P< 0.05, at least) correlations between the numbers of nodules and both basal TSH levels and Δ values of increased TSH or FT4 levels or T3T values. No correlations were found between other ultrasonographic data and plasma thyroid parameters. CONCLUSIONS This study demonstrates a high prevalence of subclinical hyperthyroidism in patients presenting with non-toxic nodular goitres and suggests that the number of nodules, but not their total volume, is an important factor in the development of this condition.     

THE ROLE OF A HIGHLY SENSITIVE AMPLIFIED ENZYME IMMUNOASSAY FOR THYROTROPHIN IN THE EVALUATION OF THYROTROPH FUNCTION IN HYPOPITUITARY PATIENTS

Using a highly sensitive amplified enzyme-linked immunoassay (AEIA) for thyrotrophin (TSH), we have assessed the ability of a single basal measurement of TSH to predict the subsequent response of TSH to TRH in a group of 11 patients with known pituitary pathology and some evidence of hypopituitarism. All patients were clinically euthyroid. Basal levels of AEIA-TSH ranged from less than 0.2 mU/l ('undetectable') to 0.9 mU/l; within this range there was no correlation with the subsequent TSH levels at 30 min in the TRH test. The TSH response in the TRH test did not correlate with the direct measurements of prevailing thyroid hormone levels (Total T4 or Free T4). We suggest that in patients with pituitary disease, the formal TRH test yields additional information regarding residual thyrotroph function that cannot reliably be predicted by a single basal TSH value, even when measured by a sensitive method. The current and potential thyroid status in patients with hypopituitarism must continue to rest on the overall picture provided by clinical assessment, direct measurement of thyroid hormones and the TRH test response. A basal TSH alone gives little useful information regarding thyroid status in such patients.     

CLINICAL USEFULNESS OF A HIGHLY SENSITIVE ENZYME-IMMUNOASSAY OF TSH

Using a recently developed sensitive enzyme immunoassay (EIA) for TSH, serum TSH levels in normal subjects and patients with various thyroid disorders were measured. The minimum detectable concentration was less than 0.005 mU/l. An excellent correlation was observed between TSH values measured by EIA and by sensitive radioimmunoassay (r = 0.932). In 26 normal subjects, serum TSH ranged from 0.30 to 2.65 mU/l (geometric mean 0.97 mU/l). In 27 untreated hyperthyroid Graves' patients, serum TSH was detected in all but one, ranging from 0.005 to 0.19 mU/l (geometric mean 0.040). These values were proved to be specific for human TSH by absorption, recovery, cross-reactivity and dilution studies; non-specific serum effects were also ruled out. In 10 patients with destructive thyroiditis, similar TSH values (0.005-0.20 mU/l, mean 0.032) were observed. However, no significant correlations between TSH and circulating thyroid hormone levels were observed in these thyrotoxic conditions. Furthermore, 9 untreated Graves' patients did not respond to a single i.v. injection of TRH. In 13 hypothyroid patients with hypothalamo-pituitary disorders, 10 had basal TSH levels of less than 0.4 mU/l, and TRH tests in five gave peak TSH values of more than 0.8 mU/l, which were associated with significant increases in serum T3. In three patients with Sheehan's syndrome, elevated basal TSH levels were observed. Two of them responded to TRH, but these TSH elevations were not associated with T3 increases. In conclusion, this sensitive EIA could measure TSH levels in most patients with thyrotoxicosis and central hypothyroidism. However, the true significance of these measured values needs to be elucidated by future studies.     

Contribution of chemiluminescence for determination of low value TSH in patients with dysthyroidism during negative TRH test]

TSH values performed by immunoradiometric method were compared with chemiluminescent method in 28 hyperthyroid patients with negative TRH-test. This last method gives a better sensitivity (0.020 mUI/L vs. 0.050 mUI/L) and reproducibility (5% V.C. vs. 40%). The measure of undetectable TSH by immunoradiometric assay becomes possible with chemiluminescence. Due to this increase of sensitivity, the TRH-test needs to be reconsidered and allows to discriminate various degrees of TSH suppression.     

Use of the 2nd generation TRAK human assay did not improve prediction of relapse after antithyroid medical therapy of Graves' disease

OBJECTIVE: Antithyroid drug treatment (ATD) is used world-wide in the treatment of thyrotoxicosis in patients with Graves' disease (GD). The main problem is a relapse rate of 30 to 50% within 2 years after the treatment has stopped. The measurement of thyrotropin receptor antibodies (TRAb) in serum has been used to confirm the diagnosis of GD in selected patients with a diagnostic specificity of 70 to 90%. However, in predicting the recurrence of thyrotoxicosis after discontinuing ATD it has been of little value. The aim of this study was to evaluate the ability of TRAb measured by the more sensitive recombinant human TSH receptor method to predict risk of recurrence of GD after discontinuing ATD. MATERIALS, PATIENTS AND METHODS: One hundred and twenty nine patients with newly diagnosed GD were included. Of these, 58 had relapse of hyperthyroidism in a follow-up of at least 11 months (median 18 months, range 11-49) after discontinuing ATD. In 122 Graves' patients TRAb were measured at the time of diagnosis and in all patients when discontinuing ATD by a competitive radioreceptor assay using recombinant human TSH receptors (TRAK human assay). RESULTS: We found an increased diagnostic specificity (99%) compared with the old TRAK porcine assay. The predictive values of a positive and negative test in relation to the prediction of a relapse of GD were found to be only 55% and 62% respectively when using a cut-off level of 1.5 IU/l, and the predictive value of a positive test decreased to 49% and of a negative test to 60% at a lower cut-off limit (1 IU/l). CONCLUSION: Our study confirms that the new TRAK human assay had a superior diagnostic sensitivity in comparison with the old TRAK porcine assay. Despite the higher diagnostic sensitivity of the TRAK human method, we could not find any improvement of predictive values for relapse of hyperthyroidism in the measurement of TRAb at the end of ATD.     

ASSESSMENT OF THYROXINE SUPPRESSION IN THYROID CARCINOMA PATIENTS WITH A SENSITIVE IMMUNORADIOMETRIC TSH ASSAY

Serum TSH was determined with a sensitive radioimmunometric method (TSH IRMA) in 57 patients on suppression therapy with T4 after operation for differentiated thyroid carcinoma. When using a conventional RIA technique basal TSH was not detectable and remained so even after stimulation with TRH. With the TSH IRMA method 46 patients had a basal TSH below the detection limit (0.02 mU/l) (81%) and in seven patients the values were between 0.02 and 0.05 mU/l (12%). In 23 of these patients there was a small increment of 0.01-0.15 mU/l. In two patients the basal TSH was 0.08 and 0.09 mU/l, and the increment after TRH was less than 0.7 mU/l. In two other patients with basal values close to 0.2 mU/l the increment after TRH was more than 1.0 mU/l. An undetectable basal TSH value did not thus predict an absent response to TRH. The responses were, however, in all but two cases, so small that they could be regarded as clinically insignificant. Therefore, the authors conclude that a basal TSH of 0.1 mU/l, as measured with a TSH IRMA method with a detection limit of 0.05, is a sufficient indication of TSH suppression in carcinoma patients on T4 therapy and that further testing with the TRH-stimulation test is unnecessary.     

EFFECTS OF THYROID HORMONES (T4, T3), BROMOCRIPTINE AND TRIAC ON INAPPROPRIATE TSH HYPERSECRETION

Inappropriate TSH hypersecretion was diagnosed in a 38-year-old woman (case 1) and in a 38-year-old man (case 2). Both of them had earlier been treated by ablative therapy for hyperthyroidism. The present diagnosis was based on elevated basal serum TSH levels despite elevated serum free thyroid hormone levels. Both of them had exaggerated TSH responses to TRH (peak value 240 mU/l in case 1 and 408 mU/l in case 2). Their albumin and prealbumin levels were normal. The serum TBG level was normal in case 1 but was elevated in case 2. Serum levels of alpha-subunits of TSH, and pituitary CT scans were normal. Despite mild clinical hyperthyroidism, peripheral indices of thyroid hormone action were normal. They had also relatives with apparent resistance to thyroid hormones. In view of the possibility that prolonged pituitary thyrotrophic stimulation is detrimental, various therapeutic approaches to suppress TSH levels were tried. Both T3 and T4 treatments lowered serum TSH levels, but were poorly tolerated. Acute administration of L-dopa or bromocriptine reduced serum TSH levels, but this was not seen during long-term therapy. TRIAC treatment lowered serum TSH levels, and the drug was well tolerated. Serum TSH responses to TRH were not blunted during T3, T4 or TRIAC treatments. Somatostatin also reduced serum TSH levels, but did not potentiate the effect of low dose T3 therapy. Our results suggest that the patients had unbalanced pituitary and peripheral thyroid hormone resistance, predominantly at the pituitary level. Of the drugs studied, TRIAC seemed to be the most suitable therapy.     

Surveillance of TSH-suppressive levothyroxine treatment in thyroid cancer patients: TRH testing versus basal TSH determination by a third generation assay.

OBJECTIVE, DESIGN AND METHODS: Although TRH testing has been eliminated in the diagnosis of most benign thyroid diseases, it is still controversial whether or not it can be replaced by ultrasensitive determination of basal TSH for monitoring optimal TSH suppression in thyroid cancer patients. We compared basal and TRH-stimulated TSH values measured by a 2 nd generation assay (lower detection limit 0.1 mU/l) and by a 3 rd generation assay (lower detection limit 0.005 mU/l) in 209 thyroidectomized thyroid cancer patients under suppressive levothyroxine treatment. RESULTS: In the 2 nd generation assay all patients had basal TSH values < 0.1 mU/l (criterion of admission in the study), and the TRH-stimulated TSH values were above the lower detection limit in 47% of the patients (range < 0.1-1.0 mU/l). In the 3 rd generation assay TSH was above the lower detection limit in 67% under basal conditions (range < 0.005-0.098 mU/l), and in 83% after TRH stimulation (range < 0.005-1.000 mU/l). We observed close correlations (p < 0.001) between basal and TRH-stimulated TSH in the 3 rd generation assay (r = 0.86), between TRH-stimulated TSH in the 2 nd and 3 rd generation assay (r = 0.95), and between TRH-stimulated TSH in the 2 nd generation assay and basal TSH in the 3 rd generation assay (r = 0.73). The ratio between TRH-stimulated and basal TSH values was in the average range 7-9 : 1. Subdividing the patients in three subgroups based on the TRH-stimulated TSH values from the 2 nd generation assay, the corresponding basal TSH values (median and [25.-75. percentile]) from the 3 rd generation assay were < 0.005 [< 0.005-0.010] mU/l in subgroup A (2 nd generation stim. TSH: < 0.15 mU/l), 0.032 [0.021-0.040] mU/l in subgroup B (2 nd generation stim. TSH: 0.15-0.4 mU/l), and 0.066 [0.046-0.085] mU/l in subgroup C (2 nd generation stim. TSH: > or = 0.5 mU/l). CONCLUSIONS: Even in those thyroid cancer patients where a high degree of TSH suppression is the therapeutic goal, 3 rd generation TSH assays enable a reliable adjustment of the levothyroxine dose by basal TSH determinations. In laboratories still using 2 nd generation assays, the monitoring of maximal TSH suppression in patients with high-risk thyroid cancer should be performed by TRH testing.     

TSH determination in central hypothyroidism

Central hypothyroidism is one of the limitations of the use of sensitive TSH assays as first line screen in evaluating thyroid function. Studies on this subject are however scarce. The aim of the present study is to evaluate the usefulness of TSH assay before and after TRH on a large series of patients with central hypothyroidism. Fifty two patients presenting with post-partum hypopituitarism (Sheehan's Syndrome), 32 hypothyroids and 20 euthyroids were studied, as well as 21 normal females. There was no difference in TSH basal levels (TSH0) between the hypothyroid (1.43 +/- 0.98 mU/l), the euthyroid patients (1.45 +/- 0.83 mU/l) and the controls (1.32 +/- 0.58 mU/l). Delta TSH (TSH 30 mn after TRH-TSH0) was higher (p < 0.001) in the control group (8.48 +/- 3.76 mU/l) than in the euthyroid group (2.63 +/- 2.22 mU/l) that had a better (p < 0.001) response than the hypothyroid group (0.93 +/- 1.11 mU/l). Ten euthyroid patients had impaired response to TRH, while 6 hypothyroids had a normal test. This test has no advantage over basal TSH in central hypothyroidism diagnosis. TRH test gives many misleading results and have an elevated cost/benefit ratio as compared with the characteristic combination of low thyroxinemia and non elevated TSH0.     

The variations in thyroid function tests compatible with clinical euthyroidism after medical and surgical treatment for Graves' disease

Eight widely used tests of thyroid function (clinical and biochemical) were performed simultaneously on 46 thyrotoxicosis patients who were clinically well at a standardised interval after medical or surgical treatment. The aim was to establish the range of thyroid function compatible with clinical normality. While clinical scoring systems gave broadly similar results between surgically and medically-treated patients, thyroid biochemistry showed major differences. Thus while 87% of medically-treated and 74% of surgically-treated patients were classified clinically euthyroid by the clinical indices devised by Crooks and Billewicz, the TRH test was exaggerated in 77% of the latter group but in only 13% of the former. On the other hand, half of the 26% of surgical patients with a clinical index suggesting hyperthyroidism had normal thyroid hormone levels and exaggerated TRH tests. No patient was categorised as clinically hypothyroid despite basal TSH levels as high as 21 mU/L (N : less than 5 mU/L) and T4 levels as low as 42 nmol/L (N: 70.150 nmol/L). Substitution of FT4 index for total T4 did not significantly alter the classification or ranking of patients in either treatment group. The early (20-minute) 132I uptake was normal in all but one case. We conclude that abnormal laboratory tests of thyroid function are found frequently after treatment in thyrotoxicosis patients with few or no clinical features of thyroid disturbance.     

Improved sensitivity of serum thyrotropin measurements. Studies on serum sex hormone-binding globulin in patients with reduced serum thyrotropin

Most serum TSH assays have a working sensitivity (i.e. the lowest TSH value with an inter-assay coefficient of variation below 10%) around 0.15-0.4 mU/l, which also is the critical area for cut off for further thyroid profile testing when serum TSH is used as a "first line test". A new assay (BeriLux hTSH) based on chemiluminescence was evaluated, and demonstrated a theoretical sensitivity (mean + 2 SD of the zero standard) of 0.005 mU/l and a working sensitivity as low as 0.04 mU/l. Reference range was 0.18-2.60 mU/l (N = 33). Sixty-eight percent (13/19) of hyperthyroid patients had serum TSH less than 0.005 mU/l, all had serum TSH less than 0.037 mU/l. We studied two groups of patients with normal free T4 and T3 indices but serum TSH less than 0.15 mU/l as measured by an immunoradiometric assay. Thirty-five percent (7/20) of patients with nontoxic goitre and 5% (1/20) of L-T4 treated patients had serum TSH less than 0.005 mU/l; and in 60% (11/20) and 30% (6/20), respectively, the levels overlapped the total range for hyperthyroidism. Serum levels of sex hormone-binding globulin expressed as percent of the reference median for the relevant sex (SHBG%) were elevated in both groups of patients (p less than 0.01). Approximately 50% of those with serum TSH overlapping the hyperthyroid range had serum SHBG% levels above reference range. In conclusion, this assay seems superior to most previously reported assays concerning working sensitivity, but it still leaves us with a group of clinically euthyroid patients who has unmeasurably low serum TSH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low basal thyrotropin with normal thyroid function in primary hyperparathyroidism

TSH serum levels and thyroid function in 32 patients with primary hyperparathyroidism and hypercalcemia were compared to those of 30 age and sex-matched normal subjects. Serum T3 and T4 concentrations in hyperparathyroidism were not different from normal. However, basal serum TSH concentrations measured with an ultrasensitive immunoradiometric assay were significantly lower than normal (1.09 +/- 0.49 vs 2.06 +/- 0.85 mU/l, p less than 0.001). In hyperparathyroidism, TSH, but not T4 or T3, was negatively correlated with serum calcium, not with iPTH. The increase in TSH (delta TSH) 30 min after the iv injection of TRH was also significantly blunted in patients with primary hyperparathyroidism; delta TSH was highly correlated with basal TSH in hypercalcemic patients. The basal TSH concentration was higher and no longer different from normal (1.70 +/- 1.2 mU/l) 2 to 12 months after removal of the parathyroid adenoma, when serum calcium was normalized, whereas T3 and T4 did not change. A low basal TSH with normal T4 and low T3 was found in 13 patients with hypercalcemia of malignancy. In these patients, TSH increased after treatment of hypercalcemia with 3-amino-l,hydroxypropylidene-1, 1-bisphosphonate, whereas T4 did not change. The results suggest that the set point of pituitary thyroid feedback control could be decreased in chronic hypercalcemia and that hypercalcemia could render the thyroid more sensitive to TSH.