Serum Thyroid Hormone Binding Research Articles

Clinical recognition and evaluation of patients with inherited serum thyroid hormone-binding protein mutations.

There are three important thyroid hormone-binding proteins in human serum, thyroxine-binding globulin, transthyretin, and albumin. Genetic variation in these proteins can lead to altered thyroid hormone binding and abnormalities in serum tests of thyroid hormone. Importantly, patients harboring these mutations are euthyroid; thus, the recognition of these conditions is crucial to prevent unnecessary repeated testing and treatment. This article provides an updated overview of serum thyroid hormone transport biology and reviews the underlying genetic alterations, clinical presentation, and appropriate evaluation of patients with suspected mutations in serum thyroid hormone-binding proteins.

Transport of thyroid hormone in brain.

Thyroid hormone (TH) transport into the brain is not only pivotal for development and differentiation, but also for maintenance and regulation of adult central nervous system (CNS) function. In this review, we highlight some key factors and structures regulating TH uptake and distribution. Serum TH binding proteins play a major role for the availability of TH since only free hormone concentrations may dictate cellular uptake. One of these proteins, transthyretin is also present in the cerebrospinal fluid (CSF) after being secreted by the choroid plexus. Entry routes into the brain like the blood–brain-barrier (BBB) and the blood–CSF-barrier will be explicated regarding fetal and adult status. Recently identified TH transmembrane transporters (THTT) like monocarboxylate transporter 8 (Mct8) play a major role in uptake of TH across the BBB but as well in transport between cells like astrocytes and neurons within the brain. Species differences in transporter expression will be presented and interference of TH transport by endogenous and exogenous compounds including endocrine disruptors and drugs will be discussed.

Species-dependent effects of the phenolic herbicide ioxynil with potential thyroid hormone disrupting activity: modulation of its cellular uptake and activity by interaction with serum thyroid hormone-binding proteins

Ioxynil, a phenolic herbicide, is known to exert thyroid hormone (TH) disrupting activity by interfering with TH-binding to plasma proteins and a step of the cellular TH-signaling pathway in restricted animal species. However, comparative studies are still lacking on the TH disruption. We investigated the interaction of [125I]ioxynil with serum proteins from rainbow trout, bullfrog, chicken, pig, rat, and mouse, using native polyacrylamide gel electrophoresis. Candidate ioxynil-binding proteins, which included lipoproteins, albumin and transthyretin (TTR), differed among the vertebrates tested. Rainbow trout and bullfrog tadpole serum had the lowest binding activity for ioxynil, whereas the eutherian serum had the highest binding activity. The cellular uptake of, and response to, ioxynil were suppressed by rat serum greater than by tadpole serum. The cellular uptake of [125I]ioxynil competed strongly with phenols with a single ring, but not with THs. Our results suggested that ioxynil interferes with TH homeostasis in plasma and with a step of cellular TH-signaling pathway other than TH-uptake system, in a species-specific manner.

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

Endocrine sequelae of cancer and cancer treatments

Exposure to cancer and its treatments, including chemotherapy and radiotherapy, may result in late adverse effects including endocrine dysfunction. Endocrine disorders are the most commonly reported long-term complications of cancer treatment, especially by adult survivors of childhood cancers. This review will explore the endocrinologic adverse effects from non-endocrine cancer therapies. Searches including various Internet-based medical search engines such as PubMed, Medline Plus, and Google Scholar were conducted for published articles. One hundred sixty-nine journal articles met the inclusion criteria. They included case reports, systematic analyses, and cohort reports. Endocrine disorders including hypothalamus dysfunction, hypopituitarism, syndrome of inappropriate anti-diuretic hormone secretion, diabetes insipidus, growth hormone disorders, hyperprolactinemia, gonadotropin deficiency, serum thyroid hormone-binding protein abnormalities, hypothyroidism, hyperthyroidism, hypomagnesium, hypocalcemia, hyperparathyroidism, hyperparathyroidism, adrenal dysfunction, gonadal dysfunction, hypertriglyceridemia, hypercholesterolemia, diabetes mellitus, and glycosuria were identified and their association with cancer therapies were outlined. The journal articles have highlighted the association of cancer therapies, including chemotherapy and radiotherapy, with endocrine dysfunction. Some of the dysfunctions were more often experienced than others. Especially in patients treated with radiotherapy, some endocrinologic disorders were progressive in nature. Recognition and awareness of endocrine sequelae of cancer treatments may permit for early detection and appropriate follow-up care for cancer survivors, thus improving their overall health and quality of life.

Synthesis of Thyroid Hormone Binding Proteins Transthyretin and Albumin by Human Trophoblast

Mechanisms regulating materno-fetal transfer of thyroid hormone are not well understood. Modulation of trophoblast type 3 iodothyronine deiodinase (D3) may play an important role. The objective of this study was to investigate trophoblast thyroid hormone binding proteins that may modulate interactions between D3 and T4. Placentas were obtained by informed consent from women delivering normal infants by repeat cesarean section at 38-40 wk gestation. T4 and T3 binding was examined in human placenta. Serum thyroid hormone binding proteins were identified by Western blotting, and their mRNA was examined by RT-PCR. Presence of these proteins in trophoblast was determined by immunocytochemistry and immunofluorescence. Cytosol was progressively purified to reveal additional thyroid hormone binding proteins that were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Effects of mefenamic acid on placental deiodination were examined by HPLC. We detected high-affinity T4 and T3 binding in human placental cytosol. All three major serum-binding proteins, T4 binding globulin (TBG), transthyretin (TTR), and albumin, were present in cytosol. TTR mRNA and albumin mRNA were detected in human placenta, and TTR and albumin were identified histochemically in syncytiotrophoblasts. Neither TBG mRNA nor TBG was detected, suggesting that plasma TBG had contaminated the cytosol preparation. Low-affinity thyroid hormone binding proteins alpha-1-antitrypsin and alpha-1-acid glycoprotein were also identified. Addition of mefenamic acid, a potent inhibitor of thyroid hormone binding, to placental cytosol significantly enhanced deiodination of T4 by D3. Placenta produces a series of thyroid hormone binding proteins that may modify thyroid hormone deiodination and materno-fetal thyroid hormone transport.

The non-thyroidal illness syndrome after coronary artery bypass grafting: a 6-month follow-up study

The non-thyroidal illness syndrome (NTIS) is considered a transient and completely reversible phenomenon, but it has been shown that it may last for several days postoperatively after coronary artery bypass grafting (CABG) surgery. This study was undertaken to assess thyroid function 6 months after uncomplicated CABG. The thyroid profile was evaluated in 40 consecutive patients undergoing CABG preoperatively, at 0, 12, 48, and 120 h postoperatively, and at 6-month follow-up. Triiodothyronine (T3), free T3 (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were assayed using a microparticle enzyme immunoassay. T4 and total serum thyroid hormone-binding capacity (T-uptake) were measured on the same samples using a fluorescence polarization immunoassay. Patients with severe systemic illness and patients treated with amiodarone were excluded. All patients were euthyroid at admission. Mean age was 67.4+/-9.0 years. There were 31 (77.5%) men. Typical NTIS was observed in all patients, and the FT3 concentration was still reduced by postoperative day 5 (p<0.0001). At 6-month follow-up, all patients were free from cardiac symptoms, and no new cardiac events were recorded. The thyroid profile was normal in 35 patients (87.5%). One patient (4.5%) had developed overt hypothyroidism. Two patients had isolated low T3 and FT3 levels with normal TSH. Two patients had moderately increased FT3 levels with suppressed TSH. In most uncomplicated patients, thyroid function returns to normal 6 months after CABG. However, we observed significant alterations of the thyroid profile in 5 out of 40 patients. Further studies are needed to define the long-term consequences of postoperative NTIS.

Selective consumption of thyroxine-binding blobulin during cardiac bypass surgery

A study of serum thyroid hormone binding proteins and thyroid hormone concentrations during and after coronary artery bypass graft (CABG) surgery shows a marked difference in the response of thyroxine binding globulin (TBG) and transthyretin (TTR). The effects of CABG on TBG and TTR were compared in 32 patients during the day of surgery. In a few of these patients, additional determinations were performed to 5 days. When corrected for dilution, TTR concentrations decline gradually after surgery, with no significant decrease over the first 24 hours. In contrast, a rapid decrease of TBG to a mean level of 60% of the preoperative control at 12 hours after the start of surgery appears to account for the concomitant decrease of serum T4. The rate at which the TBG concentration decreased far exceeds the reported fractional clearance of TBG and therefore implies accelerated consumption rather than inhibition of production. TBG is a member of the serine protease inhibitor (SERPIN) superfamily. We propose that its rapid consumption is due to protease cleavage at inflammatory sites. This may explain the previously observed accumulation of thyroxine iodine at such sites.

Thyrotropin-releasing hormone in critical illness

The aim of this study was to examine the effect of dopamine infusion on the thyrotropin (TSH), thyroid hormone, prolactin, and growth hormone responses to thyrotropin-releasing hormone (TRH) in critically ill patients. Prospective, randomized, controlled, open-labeled clinical study. The intensive care unit, University Hospital Gasthuisberg, Leuven, over a 1-month period. In 15 critically ill patients receiving dopamine treatment (5 micrograms/kg/min) for a mean of 43.3 +/- 1.2 (SEM) hrs after trauma or cardiac surgery, we studied the TSH, thyroid hormone, prolactin, and growth hormone responses to the administration of two consecutive intravenous TRH boluses of 200 micrograms, with a 6-hr interval. The dopamine infusion was continued in the control group and discontinued in the study group. Serum concentrations of TSH, prolactin, and growth hormone were measured before and 20, 40, 60, and 120 mins after TRH administration. Serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, and thyroid hormone binding globulin were determined before and 120 mins after each TRH injection. There was a > 100-fold interindividual variation in the baseline TSH concentration and in the TSH peak value after TRH administration. Two consecutive doses of TRH evoked a mean 16% increase in serum T4 concentration (p = .003) and a mean 47% increase in T3 (p = .001), whereas serum reverse T3 and thyroid hormone binding globulin values remain unaltered. Each of the TRH boluses increased serum growth hormone concentrations in the continued dopamine and discontinued dopamine groups, by a median of 60% (p = .001) and 68% (p = .001), respectively. Three hours after dopamine withdrawal, there was a three-fold increase of the peak TSH response (p = .001), a higher T3 response (p = .01), and a ten-fold increase of the peak prolactin value (p = .001) in response to TRH administration. The TSH response to TRH administration in critical illness presents a striking interindividual variation and dopamine dependent. Repeated TRH administration results in a repetitive increase of TSH, prolactin, growth hormone, T4, and T3, without increasing reverse T3. These observations point toward a potential for TRH as a strategy for reversing the euthyroid sick syndrome, growth hormone deficiency, and immune dysfunction associated with critical illness.

Vulnerability of the developing brain to thyroid abnormalities: environmental insults to the thyroid system.

Neurologic development follows orderly patterns that can be severely disturbed when thyroid hormones are deficient or excessive. Should this occur at appropriate development periods, irreversible neurologic damage can result. The nature of the deficits depends upon the specific development period and the severity of the thyroid disturbance. PCBs and dioxins are structurally similar to the thyroid hormones. Their binding characteristics are similar to those of thyroid hormones and all three groups bind to the cytosolic Ah receptor, the thyroid hormone receptor and the serum thyroid hormone binding protein transthyretin. Depending upon the dose of toxin and the congener used, the toxins either decrease or mimic the biological action of the thyroid hormones. Either effect, if occurring during brain development, can have disastrous consequences. Children and animals exposed to PCBs or dioxins in utero and/or as infants can exhibit varying degrees of behavioral disorders. These disorders resemble those seen in children exposed to thyroid hormone deficiencies in utero and/or in infancy. The mechanism of developmental neurotoxicity of PCBs and dioxins is not known but data suggest it could be partially or entirely mediated by alterations in availability and action of thyroid hormones during neurological development. It is possible that transient exposure of the mother to doses of toxins presently considered nontoxic to the mother could have an impact upon fetal or perinatal neurological development. If the toxins act via their effect on thyroid hormone action, it is possible that doses of toxins that would normally not alter fetal development, could become deleterious if superimposed on a pre-existing maternal/or fetal thyroid disorder.

Familial dysalbuminaemic hyperthyroxinaemia and inherited partial TBG deficiency: first report

Abnormalities of the serum thyroid hormone binding proteins are not uncommon but, when properly assessed, they do not present diagnostic difficulties. In contrast, the presence of two inherited defects of thyroid hormone transport, of the type presented in the family described here, may cause a major problem in diagnosis and has not been described previously. All conventional thyroid function tests were carried out. In addition, thyroid hormone binding to serum proteins was assessed by agarose gel electrophoresis, and thyroxine binding globulin by immunoassays and by immunodiffusion. The affinity of TBG for thyroxine and its maximal binding capacity were assessed by Scatchard analysis. Tests carried out on 22 members of the family revealed familial dysalbuminaemic hyperthyroxinaemia in 10 family subjects. All five living siblings of the propositus had familial dysalbuminaemic hyperthyroxinaemia and two tested transmitted this trait to their children and grandchildren. This was not the case with the propositus. Partial thyroxine binding globulin deficiency only, inherited presumably from the propositus' mother, was found in two family members. Both thyroxine binding globulin deficiency and familial dysalbuminaemic hyperthyroxinaemia were detected in the propositus and in his male nephew, masking the typical laboratory abnormalities associated with each of these defects. Coexistence of two inherited defects of thyroid hormone transport proteins produce atypical thyroid function test abnormalities, which can be misinterpreted as thyroid hormone dysfunction.

Decreased peripheral 3,5,3'-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues.

T4, rT3, and T3 kinetic studies have been performed in a T4-substituted female who showed an increased serum T4/T3 ratio and substantially increased rT3 serum levels in the presence of normal serum thyroid hormone binding properties. The kinetic studies were performed to discriminate between T4 transport inhibition into plasma T3-producing tissues and inhibition of extrathyroidal T4 to T3 conversion. The principal findings were that both T4 and rT3 transport were inhibited into the rapid equilibrating pool (REP), which mainly consists of the liver. The plasma T3 production rate was decreased. Despite an elevated serum free T4 level, serum TSH was elevated, pointing to T4 transport inhibition at the level of the thyrotroph as well. Transport of T4 and rT3 was normal to the slowly equilibrating pool, whereas no transport inhibition of T3 was found to either pool. Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.

Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat.

Naturally occurring and synthetic flavonoids are potent inhibitors of thyroid hormone 5'-deiodination and binding to human serum transthyretin (TTR) in vitro. We now describe the inhibitory effect of the most potent flavonoid, 3-methyl-4',6-dihydroxy-3',5'-dibromo-flavone (EMD 21388), on the serum protein binding of T4 and T3 and subsequent alterations of pituitary-thyroid function in the rat. Eight to 10 mumol/liter EMD 21388 added to pooled rat serum completely displaced [125I]T4 or [125I]T3 binding from TTR, the major thyroid hormone-binding protein in the rat, and markedly increased the percentages of free T4 and T3, measured by equilibrium dialysis. One to 4 h after the ip administration of 2 mumol EMD 21388/100 g BW to euthyroid rats, [125I]T4 and [125I]T3 binding to TTR decreased, serum T4 and T3 concentrations decreased, and the percentages of free T4 and free T3 increased. No changes were observed in the free T4 and free T3 concentrations. Serum TSH concentrations decreased at 1 h and were very low thereafter. EMD 21388 administration did not affect the elevated serum TSH concentrations in hypothyroid rats, strongly suggesting that the flavonoid does not directly affect TSH secretion. No changes were observed in hepatic type I 5'-deiodinase in euthyroid rats and pituitary type I and type II 5'-deiodinase in euthyroid and hypothyroid rats after EMD 21388 administration. We conclude that the ip administration of EMD 21388 to euthyroid rats inhibits T4 and T3 binding to TTR, with subsequent increases in the percentages of free T4 and free T3 and decreased serum T4 and T3 concentrations. The decrease in the serum TSH concentration was possibly due to transcient increases in the serum free T4 and/or free T3 concentrations, resulting in increased pituitary thyroid hormone content.

The microheterogeneity of rat TBG

Isoelectric focusing (IEF) of native sera from immature or adult rats and of purified or partially purified rat serum thyroid hormone-binding proteins, demonstrates that rat TBG is a microheterogeneous protein. Autoradiography and radioactivity scans of the IEF plates show that it consists of at least four main isoforms, with bands at pH 4.35, 4.45, 4.5 and 4.55. This pattern is remarkably similar to that reported for human TBG. This is the first demonstration of the polymorphism of this recently discovered major binding protein of the rat.

Drug and fatty acid effects on serum thyroid hormone binding.

We directly compared the competitor potency for serum T4 binding of 11 nonsteroidal antiinflammatory drugs; the diuretics furosemide, ethacrynic acid, and bumetanide; diphenylhydantoin; the cholecystographic contrast agents iopanoate and ipodate; and six long-chain nonesterified fatty acids (NEFA) using equilibrium dialysis. To avoid artefacts that occur in competitor studies with diluted serum or isolated binding proteins, we used undiluted normal serum, with drugs added at concentrations that achieved high therapeutic total and free serum levels at equilibrium. Drug addition was based on the measured free fraction of each drug in serum. The free T4 fraction in normal serum (Tris buffer, pH 7.4; 37 C) was between 1.40 X 10(-4) and 1.53 X 10(-4). Drug-induced increases in T4 free fraction were: fenclofenac, 90%; aspirin, 62%; meclofenamic acid, 39%; diflunisal, 37%; mefenamic acid, 31%; and furosemide, 31%. Significant increases of 7-15% occurred with diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin. Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive at the concentrations studied. Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive. The effect of 5 mmol/L oleic acid in serum could be reproduced by addition of 0.5 mmol/L to serum diluted 1:10, indicating that protein binding of NEFA is the major determinant that limits their competitor potency. These findings provide a basis for anticipating which potential inhibitors may cause important changes in serum thyroid hormone binding. The time course of such effects will be influenced by the pharmacokinetics of the inhibitor itself as well as the equilibrium findings described here.

Thyroid functions before and after maintenance hemodialysis in patients with chronic renal failure.

To study the factors involved in the low thyroid hormone levels in patients with chronic renal failure (CRF), we investigated thyroid functions just before and after hemodialyses (HD) in 32 such patients who were on maintenance HD. In addition, we measured serum thyroid hormone binding inhibitor activities (THBI) in another set of 37 patients. None of the patients had been suspected of having thyroid diseases. HD duration and aging did not have a significant effect on the results of the thyroid function tests. Before each HD, the serum concentrations of T3, T4, FT3, FT4, rT3, PBI, FT3I, FT4I, FT3/T3, FT4/T4, T4/TBG, T4/TSH and FT4/TSH were lower, and those of TSH, TBG, and thyroglobulin (Tg) were higher in the patients than in normal controls. The thyroid hormone concentrations were negatively correlated with the BUN and creatinine levels. The Tg levels were positively correlated with the BUN levels. After each HD, almost all the thyroid function tests including T4/TBG ratio showed improvements, which indicated that hemodilution and a decrease in the T4-binding affinity of TBG with thyroid hormones were the major factors in the low thyroid hormone levels in CRF patients. However, even after HD, T3, FT3, rT3, T4/TSH and FT4/TSH were still lower and TSH and Tg were still higher in the patients. These data suggested that the CRF patients were in a subclinical hypothyroid state. THBI was high in patients with CRF and did not change following HD. NEFA did not seem to contribute to the high THBI before HD, because they were in the normal range. However, as NEFA became very high after HD and possessed THBI, we calculated the corrected THBI (C-THBI) by subtracting the effect of NEFA from total THBI. C-THBI was high before HD and decreased after HD. Therefore, it was suggested that this C-THBI contributed to the abnormalities in the affinity of TBG with thyroid hormones. From these studies, it is concluded that (1) the patients with CRF may be in a subclinical hypothyroid state, although hemodilution was seen to have a strong effect on the thyroid hormone concentrations, and (2) C-THBI may have an effect on the affinity of TBG with thyroid hormones and play an additional role in low thyroid hormone levels in these patients. The mechanisms of hypothyroidism and the nature of C-THBI remain to be clarified.

Thyroid hormone metabolism in nonthyroidal illnesses. II. A new method for measuring serum thyroid hormone binding inhibitor and its clinical application

It is well known that serum T3 and T4 concentrations are often decreased in patients with nonthyroidal illnesses (NTI). The purpose of this study was to elucidate the possible role of serum thyroid hormone binding inhibitor (THBI) in lowering serum T4 in patients with NTI using the originally developed method for measuring THBI. 125I.T4 and 0.05 micromilligram of pooled normal serum was applied to the Sephadex G.25 column equilibrated in advance by 0.1N NaOH, and 4 micromilligram of 0.075M veronal buffer, pH 8.6 (Buffer) was added. 125I.T4 thus adsorbed on the column was then eluted by adding the charcoal treated thyroxine-free serum (used as thyroxine binding protein (TBP) solution) with THBI which had been extracted from the serum by diethyl ether or standard sodium oleate solution (0.125 approximately 1.0 mumol/column). When the radioactivity of the eluate was counted, the gradual decrease in radioactivity was observed with increase in sodium oleate due to the inhibition of 125I.T4 and TBP binding. Thus, THBI in serum could be expressed as mumol sodium oleate equivalent from the dose response curve for binding inhibition. Coefficients of intrassay and interassay variations in this assay were 6 and 17%, respectively when sera from patients with acute myocardial infarction (AMI) were measured. THBI from 15 normal controls ranged from 0 to 0.27 (mean +/- SD: 0.11 +/- 0.08) mumol sodium oleate equivalent, the normal range being less than 0.27 mumoles. In 12 patients with AMI and 12 with end-stage malignancy (cancer), serum T4 levels were below the normal range in 9 and 8 cases, respectively. In these patients, serum THBI was positive in as many as 10 (83%) and 11 (92%) cases, respectively. Serum T4 and THBI were serially measured after admission in patients with AMI. Serum T4 concentrations showed their lowest values on the first, second or third hospital day and they gradually increased to the normal range by the seventh day. On the other hand, serum THBI showed their highest value on the first hospital day in 8 cases of AMI, and they gradually decreased thereafter. A statistically significant negative correlation was observed between serum T4 and THBI in these patients (r = -0.63, p less than 0.01). Moreover, statistically significant positive correlations were observed between serum THBI and FFA in both AMI and cancer patients (r = 0.89, p less than 0.01; r = 0.88, p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Do residue levels of polychlorinated biphenyls (PCBs) in human blood produce mild hypothyroidism?

PCBs are nearly ubiquitous environmental contaminants, occurring in most human adipose tissue and blood samples. It has recently been recognized that PCBs and related compounds share important structural properties with thyroid hormones and can bind thyroid hormone binding proteins. It is reasonable that such specific binding interactions can modulate the distribution of these compounds in the body and alter hormone-protein interactions that are responsible for the maintenance of normal thyroid status. Most of the available evidence indicates that the levels of free thyroid hormones in plasma are a reflection of the maintenance of normal thyroid status in any individual. A theoretical model for the transport of thyroid hormones in blood has been extended to estimate the modulating effects of PCBs on free thyroid hormones. Using conservative assumptions based on experimental data, our calculations indicate that PCB concentrations normally found in humans can effect significant increases in free thyroxine levels in serum by competing with serum thyroid hormone binding proteins. Experimental data are discussed which support the proposal that antagonist binding of PCBs to thyroid hormone binding proteins in serum could produce varying degrees of hypothyroidism. The biological result is compatible with the "equilibrium hypothesis" in which thyroid hormone redistributes between specific and nonspecific binding proteins rather than emphasizing the importance of free hormone as the active moiety.

Elevation of Free Thyroxine Measurements in Patients without Thyrotoxicosis

The recent development of single step analogue assay techniques to measure free thyroxine in serum has meant that this estimation has become widely used as a first line test of thyroid function. However these assays are subject to in-vitro interference in two ways: where there is a variant serum albumin in familial dysalbuminaemic hyperthyroxinaemia, or where there are circulating thyroid hormone binding antibodies. In both these situations a spuriously high result for free thyroxine is obtained. This may have serious implications for patient management and we describe 10 patients in whom the finding of a misleadingly high free thyroxine concentration led to confusion in diagnosis and, in eight of the 10, to inappropriate antithyroid treatment. Clinicians should be aware of these technical problems and where a result for the free thyroxine concentration seems inappropriate to the patient's clinical state then measurement of thyrotrophin (TSH) by a sensitive immunometric method should be performed. If the results remain confusing the presence of a variant serum albumin or thyroid hormone binding antibodies should be sought.

Seasonal changes in serum thyroid hormone binding proteins in the woodchuck (Marmota monax).

To evaluate the role of serum T4- and T3-binding proteins in the elevation of serum T4 and T3 concentrations in the woodchuck in the fall and winter, blood was collected from woodchucks during the four seasons of the year (seasonal study) and from 2-week fasted woodchucks in the summer (fasting study) and the serum concentrations of total T4 and T3 were measured. The distribution of [125I]4 and [125I]T3 tracers among the serum binding proteins and the serum T4-binding globulin (TBG) binding capacity for T4 was determined by polyacrylamide gel electrophoresis. Plasma concentrations of both T4 and T3 were highest in the winter. The major T4-binding protein in the woodchuck is TBG. There was an increase in both [125I]T4 and [125I]T3 tracer binding to serum TBG in fall and winter, and TBG binding capacity for T4 was 2-fold higher in winter than in summer. There were increases in TBG binding and in the TBG T4 binding capacity in the 2-week starved animals. The increased binding of T4 and T3 by TBG in the fall and winter may be partially responsible for the increased serum concentrations of T4 and T3 in the fall and winter in the woodchuck, a time when secretion of T4 and T3 by the thyroid gland is very low. This may be facilitated by the low or absent food consumption at these times of the year.