Effective laboratory evaluation of thyroid status.

This article focuses on recent developments in thyroid-related laboratory tests, including analytical methods, clinical utility, and limitations of TSH, FT4, T4, FT3/T3, thyroglobulin, and thyroid autoantibodies and the effective use of these tests in the diagnosis of various forms of hypothyroidism or hyperthyroidism, and the management of patients undergoing T4 replacement, T4 suppression, or antithyroid drug therapy.

Diagnostic performance of sensitive measurements of serum thyrotropin during severe nonthyroidal illness: their role in the diagnosis of hyperthyroidism.

Serum thyrotropin (TSH) concentrations were measured serially in 14 heart-transplant recipients (group 1) and 21 patients undergoing coronary artery bypass surgery (group 2), all without thyroid disease, and randomly in 158 patients hospitalized for various other nonthyroidal illnesses, including 144 judged euthyroid (group 3), six with increased FT4 and (or) T3 (group 4), and eight classified hypothyroid by conventional tests. The serial measurements indicated profound fluctuations. In group 1, TSH was subnormal in 21% of studies and increased in 10%. In group 2, corresponding abnormalities were found in 7% and 13%, respectively. Transiently low or high TSH tended to be associated with normal free thyroxin (FT4), prolonged subnormal TSH (greater than 1 week) with subnormal FT4. By contrast, subnormal TSH plus elevated FT4, or high TSH plus low FT4, were not encountered, making it unlikely that they occur by chance in severely ill patients who are not also hyper- or hypothyroid. In group 3, a suppressed TSH (plus borderline high FT4, T3/FT3) identified four cases of subclinical hyperthyroidism; however, another 11% of patients had subnormal and 10% had above-normal TSH, paired with normal FT4 and no evidence of thyroid disease. In group 4, suppressed TSH confirmed hyperthyroidism in five of six patients, and all in group 5 had increased TSH. We conclude that, in the hospital setting, sensitive TSH measurement can help to detect or confirm mild hyperthyroidism, but the positive predictive value of TSH alone may be as low as 35%.

Significance of thyroid dysfunction in human cardiac allograft procurement.

Twenty-two potential cardiac allograft donors had evaluation of thyroid function performed just prior to cardiectomy. Despite statistically significant abnormal thyroid function, no correlation to graft function or failure was observable. Multiple myocardial microinfarcts, undetected at the time of donor selection were detected in two hearts that were abandoned prior to transplantation and possibly another heart that failed as an allograft in a heart-lung transplant recipient.

Should a woman taking propylthiouracil breast-feed?

Thyroid function was tested in mother and her son. The mother was taking propylthiouracil for treatment of hyperthyroidism, and she was breast-feeding. Thyroid function was normal in both.

Clinical experience with sensitive thyrotropin measurements: diagnostic and therapeutic implications.

A two-site immunoradiometric assay for serum thyrotropin (TSH) was modified to improve the analytical sensitivity. The sensitivity achieved (detection limit, approximately 0.1 microU/ml; lower limit of quantitative measurement, approximately 0.4 microU/ml) was comparable to that of the best competitive binding research assays, yet this assay can be performed routinely. Serum TSH was 1.82 +/- 0.69 (mean +/- s.d.) (range 0.4-3.4 microU/ml) in healthy individuals and 1.83 +/- 0.90 microU/ml (range 0.7-3.7 microU/ml) in patients with nonthyroidal disorders. By contrast, 97% of clinically hyperthyroid patients (Graves' disease, toxic nodular goiter) with high serum free T4 (FT4) and T3 had suppressed serum TSH values, i.e., less than 0.3 microU/ml. Among patients with euthyroid Graves' ophthalmopathy or nontoxic goiter those clinically suspected of mild hyperthyroidism had TSH values less than 0.3 microU/ml, while those judged euthyroid had normal values. A large proportion of thyroid patients on antithyroid drugs (poorly to well-controlled) had suppressed TSH. Of Graves' patients in remission (normal FT4 and T3), 75% had normal TSH, but individual levels changed significantly over time, suggesting that a progressive decline in TSH may be useful in predicting recurrences. In hypothyroid patients taking L-T4, serum TSH was subnormal in patients with elevated FT4, but TSH was also low in six patients clinically suspected to be thyrotoxic despite normal FT4 and T3 and in 32% of asymptomatic patients with normal thyroid hormone levels. Conversely, 23% of thyroid cancer patients who had undergone thyroidectomy were taking insufficient L-T4 to completely suppress TSH secretion. In 25 individuals who underwent thyrotropin releasing hormone (TRH) stimulation tests, the baseline serum TSH value correlated well with the peak serum TSH value post-TRH (r = 0.85). We conclude that sensitive TSH measurements could establish or confirm the diagnosis of hyperthyroidism in equivocal cases, replace most TRH-stimulation tests and be of value in optimizing L-T4 suppression therapy for thyroid cancer patients post-thyroidectomy.

Differences in radioimmunoassay results for thyroglobulin that affect management of patients with thyroid cancer.

We compared two commercial assays for measurement of serum thyroglobulin [Nuclear Medical Systems (NMS) and "CIS" (Damon Diagnostics)] with each other and with one developed at Stanford (J Clin Endocrinol Metab 49:557-564, 1979). The NMS assay is a competitive-binding RIA, the CIS and Stanford assays are two-site immunoradiometric assays. The kit standards varied in thyroglobulin concentration. The NMS standards differed in immunoreactivity from thyroglobulin in clinical specimens and from the other standards. Also, nonparallelism between standards and patients' sera in the NMS assay suggested a less-specific antiserum. Results by the CIS and Stanford assays correlated well (n = 120, r = 0.964), those by the NMS assay less strongly (n = 101, r = 0.855 vs CIS, r = 0.888 vs Stanford). Clinical evaluation in 50 patients treated for differentiated thyroid carcinoma (10 with metastases and 40 currently disease-free) indicated good agreement for positive results by the three assays. The CIS and the Stanford assay both gave high results (greater than or equal to 25 micrograms/L) in all 10 cases with metastases; the NMS RIA identified eight of these patients (thyroglobulin greater than or equal to 30 micrograms/L), but excluded two with anti-thyroglobulin autoantibodies. In subjects without disease, however, the percentage of undetectable thyroglobulin (negative result), as opposed to low measurable thyroglobulin (inconclusive result) varied considerably: 85% by CIS, 30% by NMS, and 75% by the Stanford assay.

Effect of heparin on serum free thyroxine linked to post-heparin lipolytic activity.

A possible association between free T4 (fT4) changes, occurring after heparin administration, and the post-heparin lipolytic activity, i.e., the release of lipases and the lipolysis of triglycerides to non-esterified fatty acids (NEFAs) was studied. In 19 patients heparin increased mean fT4 values obtained by equilibrium dialysis from 23.4 to 38.6 pmol/l (P less than 0.01) and mean fT4 values measured by GammaCoat two-step RIA from 17.0 to 24.1 pmol/l (P less than 0.01), the results of the two methods agreeing well (rs = 0.88). Concurrently, NEFAs increased from a mean of 0.55 to 2.20 mmol/l (P less than 0.01) and fT4 increases were significantly correlated with post-heparin NEFAs (rs = 0.69, P less than 0.001). In vitro addition of palmitic acid to sera increased fT4 concentrations to values similar to those observed in vivo. Post-heparin fT4 increases were also strongly correlated to the concentrations of triglycerides (rs = 0.63, P less than 0.01). Hypertriglyceridaemia was associated with pronounced fT4 increases after heparin administration, and normolipidaemia with moderate or no changes. These results suggest that the effect of heparin on fT4 is linked to the activation of lipases by heparin and is mediated by NEFAs, which, at high concentrations, compete with thyroxine for binding proteins.

Serum free thyroxine values in term, premature, and sick infants.

Free thyroxine concentrations were determined by radioimmunoassay in 96 infants within an intensive care nursery and in 32 healthy term infants. Sera for free T4 levels were drawn simultaneously with the filter paper specimens for T4 obtained to screen these infants for congenital hypothyroidism. The mean free T4 level in 20 adults was 1.38 +/- 0.03 ng/dl (mean +/- SEM). The mean in the ICN infants was 3.48 +/- 0.18 ng/dl and in healthy term infants, 4.24 +/- 0.23 ng/dl. Like T4, free T4 correlated positively with increasing gestational age and birth weight, and was lower in infants with RDS. Although 66% of the ICN infants had T4 levels below the statistically selected screening level (fifth percentile), all of these infants had free T4 levels greater than 0.8 ng/dl. Two additional infants with untreated congenital hypothyroidism has free T4 levels of 0.3 and 0.4 ng/dl. The measurement of free T4 appears to be an accurate indicator of thyroid function in these infants.

Hyperthyroxinemia in patients with acute psychiatric disorders.

Thyroid function tests were measured in 645 patients admitted to an acute psychiatric disorders unit. Thirty-three percent had elevated serum thyroxine (T4), and 18 percent had an elevated free T4 index (FTI). Serum triiodothyronine (T3) was low, normal, or minimally elevated in 77 patients, with a high initial free T4 index. Twenty-two patients with an initial elevation of their free T4 index were serially followed (study group). Serum T4, free T4 index, and free T4 fell in every patient: serum T4 from 13.95 +/- 1.93 micrograms/dl (mean +/- standard deviation: SD) to 9.33 +/- 2.4 micrograms/dl (p less than 0.001); free T4 index, from 6.15 +/- 0.83 to 3.79 +/- 1.1 (p less than 0.001); free T4, from 2.43 +/- 0.65 mg/dl to 1.38 +/- 0.35 ng/dl (p less than 0.001). Serum T3 was initially normal or low, and then fell in 17 patients, and rose in five. Serial testing of thyrotropin-releasing hormone (TRH) demonstrated both flat and normal responses in patients with a variety of psychiatric diagnoses and at varying stages of thyroid disease activity.

Disparate effects of heparin on free thyroxine as measured by two radioimmunoassays: concise communication.

Free thyroxine (FT4) has been measured in two groups of patients, before and after heparin, using equilibrium dialysis (ED) and two radioimmunoassays, RIA-I and RIA-II. In Group A, nine patients were tested before and after 12-24 hr of intravenous heparin, FT4 (ED) rose from 1.9 +/- 0.5 to 2.8 +/- 3.0 ng/dl, and RIA-I from 1.37 +/- 0.37 to 1.89 +/- 1.21 ng/dl, whereas RIA-II results fell from 0.97 +/- 0.38 to 0.66 +/- 0.32 ng/dl. In Group B, ten patients were tested before and after 15 min of intravenous heparin. FT4 (ED) rose from 1.7 +/- 0.7 to 3.2 +/- 1.6 ng/dl (p less than 0.02), and RIA-I rose from 1.3 +/- 0.46 to 2.02 +/- 0.01 ng/dl (P less than 0.05), whereas RIA-II results fell from 1.07 +/- 0.38 to 0.63 +/- 0.31 ng/dl (P less than 0.02). The correlation coefficient between FT4 (ED) and RIA-I in 38 paired results was 0.96, but there was no correlation between FT4 (ED) and RIA-II results.

Free thyroxine by solid phase radioimmunoassay: improvement in the laboratory diagnosis of thyroid status in severely ill patients.

During severe systemic illness total thyroid hormone levels are often low, and measurement of total hormones often does not differentiate between euthyroid and hypothyroid patients. Therefore, we examined serum free thyroxine levels by radioimmunoassay (antibody-coated tubes, Clinical Assays) as an alternative diagnostic test in three groups of severely ill patients with subnormal triiodothyronine. Free thyroxine estimates agreed with the clinical impression and TSH in 91% of cases in group 1 (47 patients with no history or clinical evidence of thyroid disorder), in 96% of cases in group 2 (24 euthyroid patients with a previous history of thyroid disease, including some on thyroid replacement) and 90% of cases in group 3 (10 hypothyroid patients). By contrast, the free thyroxine index did so in only 53% (group 1), 46% (group 2) or 100% (group 3). Sequential studies showed little change in free thyroxine and TSH levels in euthyroid patients during illness and recovery, and a good negative correlation between free thyroxine and TSH in hypothyroid patients. Free thyroxine measurements (and TSH) discriminate between euthyroid and hypothyroid sick patients better than other thyroid function tests including the free thyroxine index, and can be employed routinely: a distinct advantage over free thyroxine measured by equilibrium dialysis.

Follow-up of patients with differentiated thyroid cancer using serum thyroglobulin measured by an immunoradiometric assay. Comparison with I-131 total body scans.

An immunoradiometric assay for thyroglobulin (Tg), which allows quantification of Tg in the presence of anti- Tg, has been evaluated in patients with differentiated thyroid cancer. All patients had undergone thyroidectomy plus I- 131 ablation. Three separate studies have been conducted. 1. Tg levels were compared with I- 131 whole-body scans made at 48 hr in 22 patient studies. Both tests gave similar results in 19 of the studies, but in three patients the results of the tests were discordant. 2. Tg levels were compared with clinical status in 18 patients who were free of disease; 15 had Tg values < 5 ng/ml, and three had measurable but normal Tg values. Three patients with metastatic disease had measurable Tg, and in two the values were above normal. 3. Sequential Tg measurements were made at intervals of 3 mo in 19 patients on thyroxine. Fifteen of these patients had identical results on two or more occasions.

Radioimmunoassay of free thyroxine in serum: comparison with clinical findings and results of conventional thyroid-function tests.

We have evaluated a radioimmunoassay for free thyroxine (FT4) involving antibody-coated tubes (GammaCoat 125I Free T4RIA; Clinical Assays, Div. of Travenol Labs, Inc.). The coefficient of correlation between FT4 and the FT4 index was 0.98 for all patients with various thyroid disorders, 0.77 for hospitalized patients with miscellaneous diseases, and 0.74 for healthy individuals. FT4 values also agreed well with triiodothyronine or thyrotropin concentrations in these patients and were consistent with each patient's clinical status. Patients with severe nonthyroidal illnesses and abnormal thyroid-function tests, despite clinical euthyroidism, had normal FT4 values. In this group, the mean FT4 was almost identical to that in the controls, although mean thyroxine, triiodothyronine, and FT4 index differed significantly and the correlation between FT4 and FT4 index was poorer (r = 0.66). For most patients, the diagnostic value of FT4 measurements is comparable to that of the FT4 index, and it may be superior in patients with severe nonthyroidal illnesses. The test costs less and saves time as compared to the FT4 index computation, and it can be used routinely with thyrotropin assay for the diagnosis of hypothyroidism or with triiodothyronine assay for the diagnosis of hyperthyroidism.

A solid phase, sandwich-type radioimmunoassay for antithyroglobulin: elimination of false positive results and semiquantitative measurement of antithyroglobulin in the presence of elevated thyroglobulin.

Thyroid disorders can be associated with elevated concentrations of serum antithyroglobulin antibodies (anti-Tg) and/or thyroglobulin (Tg), but none of the available anti-Tg assays deals with anti-Tg measurements in the presence of abnormally high Tg levels. The competitive binding radioassay produces falsely elevated values for anti-Tg if serum Tg is elevated and either falsely elevated or depressed values if both Tg and anti-Tg are abnormally high. The falsely elevated anti-Tg values can be identified by measuring the formation of Tg[125I]anti-Tg complexes in the supernatant of the anti-Tg assay (supernatant assay). For screening purposes, we modified the original anti-Tg RIA into a solid phase, sandwich-type RIA. Anti-Tg in serum or standard is first bound to plastic cups coated with Tg and then quantitated by binding of [125I]Tg. This assay has a detection limit of 2 U/ml serum, intra- and interassay coefficients of variation of 9--15%, and a normal range of less than 2 U/ml. When sera with normal Tg concentrations were analyzed, the results for anti-Tg obtained by the competitive binding RIA and the new sandwich RIA were comparable as far as positives and negatives were concerned, and the numerical values for positive sera correlated moderately well (r = 0.79); the sandwich assay, in general, gave lower values for anti-Tg. The major advantages of the sandwich anti-Tg RIA are the elimination of false positive results and its applicability to sera containing high levels of both Tg and anti-Tg. In the latter case, the results indicate the level of free anti-Tg present, as opposed to antibody present in the form of Tg-anti-Tg complexes.