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A case of euthyroid hypothyroxinaemia caused by the interference of the patient's serum with the Abbott thyroxine TDx assay is reported. This cause of falsely low serum thyroxine levels is probably rare but possibly underrecognized. Clinical implications are discussed.
Results are described on the association of decreased serum total thyroxine (T4) and free thyroxine index (FTI) with antiepileptic drug therapy in a group of randomly selected chronically medicated outpatients (n = 291). For monotherapy subgroups (n = 164), the highest incidence (T4, 23.9%; FTI, 25.4%) of below normal values occurred in patients medicated with carbamazepine (CBZ), followed by phenytoin [(PHT) T4, 13.2%; FTI, 7.9%], and phenobarbital [(PB) (T4, 3.4%; FTI, 0%]. No T4 and FTI values below normal were detected in any patients (n = 30) on chronic valproic acid (VPA) monotherapy. For CBZ monotherapy (n = 67), women (n = 37) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 30). Therefore, the order of decreasing T4 and FTI effect was as follows: CBZ (women) greater than CBZ (men) greater than PHT greater than PB greater than VPA. For polytherapy subgroups (n = 127), the highest incidence (T4, 51.9%; FTI, 48.1%) was found in patients medicated with PHT and CBZ, followed by PHT and VPA (T4, 37.0%; FTI, 23.9%), and PHT and PB (T4, 17.2%; FTI, 10.3%). For PHT and CBZ poly-therapy (n = 52), women (n = 21) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 31). The magnitude of the decreasing T4 and FTI effect was greater for polytherapy subgroups (versus monotherapy subgroups) and in order as follows: PHT + CBZ (women) greater than PHT + CB (men) greater than PHT + VPA greater than PHT + PB.(ABSTRACT TRUNCATED AT 250 WORDS)
We evaluated the performance of an automated 48 detector KinetiCount gamma counter using solid phase reagents for total thyroxin (TT4) and free thyroxin (FT4). Interassay coefficients of variations (CV) for both total T4 and free T4 ranged from 5.4% to 13%. Between-method correlation coefficients were 0.9798 for TT4 and 0.8844 for FT4. Detection limits for TT4 and FT4 were 3 micrograms/l and 3 ng/l, respectively. TT4 was linear up to 200 micrograms/l. The recovery of TT4 was between 99 to 101%. A computer-stored standard curve for total T4 was stable over a 6-day period. The 48 counting chambers demonstrated stability over a 45-day period with no significant changes in counting efficiency (p greater than 0.5). Precision between the 48 chambers gave a CV of 1.6%. Crosstalk between chambers was less than 0.3% with count rates up to 80,000 cpm. We conclude that the KinetiCount immunoassay system using solid phase separation technology performs well and is suitable for routine clinical use.
Free thyroxine (FT4) values determined by direct radio-immunoassay and the free thyroxine index (FTI) determined by indirect calculation were compared in 431 consecutive sera from patients with suspected thyroid dysfunction . Sensitivity and specificity were similar for both tests in the thyrotoxic, hypothyroid and euthyroid ranges with appropriate thyroid-binding globulin (TBG) concentrations. However, FT4 was superior to FTI in the euthyroid group with high concentrations of TBG, FT4 is therefore a useful alternative to FTI as a screening test for thyroid dysfunction, and is likely to be a better discriminator of thyroid status in patients with high TBG levels.
OBJECTIVE: To determine whether measurement of baseline serum concentrations of total thyroxine (T4), and triiodothyronine (T3), free T4, and thyrotropin (thyroid-stimulating hormone; TSH) would aid in the diagnosis of hypothyroidism in dogs. DESIGN: Prospective case series. ANIMALS: 54 dogs with hypothyroidism, 54 euthyroid dogs with nonthyroidal disease initially suspected to have hypothyroidism, and 150 clinically normal dogs. PROCEDURE: In the 54 dogs with hypothyroidism, diagnosis was established on the basis of clinical signs, results of routine laboratory and TSH stimulation tests, exclusion of concurrent nonthyroidal disease, and a good clinical response to treatment with L-thyroxine. Blood samples were collected from all dogs and were tested for thyroid hormone and TSH concentrations. Reference ranges for hormone concentrations were established on the basis of results for the 150 clinically normal dogs. RESULTS: Of the 54 hypothyroid dogs, 48 (89%) had low total T4 concentrations, 3 had low-normal concentrations, and 3 had high concentrations because of T4 autoantibodies. In contrast, only 10 (18%) euthyroid dogs had low total T4 concentrations. Only 3 of 31 (10%) hypothyroid dogs had low T3 concentrations; 23 had concentrations within the reference range, and 5 had high concentrations because of T3 autoantibodies. Only 3 of 38 euthyroid dogs had low T3 concentrations. Of the hypothyroid dogs, 53 (98%) had low free T4 concentrations and 1 had a low-normal concentration. Only 4 (7%) euthyroid dogs had low free T4 concentrations. Of the hypothyroid dogs, 41 (76%) had high TSH concentrations, and 13 had TSH concentrations within the reference range. Of the euthyroid dogs, only 4 (8%) had high TSH concentrations. Of all single hormone measurements evaluated, measurement of free T4 concentration had the highest sensitivity (0.98), specificity (0.93), and accuracy (0.95) as a test for hypothyroidism; measurement of total T4 concentration had a lower sensitivity (0.89), specificity (0.82), and accuracy (0.85). Compared with measurement of total or free T4 concentration, measurement of TSH concentration had a lower sensitivity (0.76) and accuracy (0.84) but specificity (0.93) equal to that for measurement of free T4 concentration. When T4 (total or free) and TSH concentrations were evaluated together, specificity was higher than when T4 or TSH concentration was evaluated alone. Only 1 euthyroid dog had low T4 (total and free) and high TSH concentrations. CLINICAL IMPLICATIONS: Results indicate that measurement of serum free T4 and TSH concentrations is useful for diagnosis of hypothyroidism in dogs. About a quarter of the dogs with confirmed hypothyroidism, however, will have serum TSH concentrations within reference limits.
The purpose of this study was to evaluate seasonal influences on thyroid hormone levels of healthy outdoor dogs in Hokkaido. We surveyed serum basal total thyroxine (tT4), free thyroxine (fT4), and canine thyroid-stimulating hormone (cTSH) levels, and tT4 levels after administration of TSH for a year. Basal tT4 levels decreased in January, and increased in August and September. fT4 levels increased in January and November. No significant seasonal variation was found in cTSH. tT4 levels after administration of TSH in August and November increased. These results suggested that the thyroid gland may have been activated in November. We should take seasonal variation into consideration when thyroid function is tested.
Concentrations and activities of the following agents were estimated: triiodothyronine (T3), thyroxine (T4), effective thyroxine (ETR), thyreotrophin (TSH), and growth hormone (HGH). Blood samples were collected in pregnancy, labour and from the umbilical cord of the newborns. It was demonstrated that in normal pregnancy the concentrations of T3, ETR, and TSH did not differ significantly from the values considered as normal in non-pregnant women. The concentration of T4 was distinctly higher in the course of pregnancy (139 to 157 nmol/l versus 110 nmol/l in non-pregnant subjects). The HGH concentration increased during pregnancy from 5.6 to 14.3 micrograms/l. The cord blood demonstrated comparable values of ETR and HGH and in half of the cases of TSH also with those observed in the mothers. In the other one half of the cases, TSH activity was fourtimes higher than the material value. The T3 and T4 were lower than values in the mothers. The results presented are the normal values for further planned investigations of endocrinology of pregnancy, especially for studies into course of pregnancy in women who work in noxious conditions.
BACKGROUND: This study was designed to assess both central and peripheral aspects of thyroid function in combat-related posttraumatic stress disorder (PTSD), with the particular purpose of finding a mechanistic explanation for an imbalance between serum levels of free thyroxine (T4) and total T4 previously observed in pilot work. METHODS: A total of 96 male combat veterans with PTSD diagnosed by DSM-III-R (72 from the West Haven, Conn, Veterans Affairs Medical Center and 24 from the Menlo Park, Calif, Veterans Affairs Medical Center) were compared with 24 male control subjects. One or more serum samples were analyzed by radioimmunoassays for levels of total T4, free T4, total triiodothyronine (T3), free T3, T4-binding globulin, and thyrotropin. RESULTS: The pilot observation of moderately elevated total T4 levels with no elevation in free T4 levels in patients with PTSD was confirmed, suggesting the hypotheses that (1) there may be an increased peripheral conversion of free T4 by deiodination to T3 or (2) there may be an increased binding of T4 secondary to elevated T4-binding globulin levels. Our findings support both hypotheses. The PTSD groups all showed a marked and sustained elevation in levels of both total T3 and free T3, as well as elevated T3/T4 ratios, supporting the increased T3 conversion hypothesis. The PTSD groups also showed a marked and sustained increase in T4-binding globulin levels, supporting the increased binding hypothesis. Thyrotropin levels did not differ between PTSD and control groups. CONCLUSIONS: These findings demonstrate an unusual pattern of thyroid alterations, featuring substantial elevations in total T3, free T3, and T4-binding globulin levels, in combat-related PTSD that differs from established endocrinopathies, such as classic hyperthyroidism, T3 thyrotoxicosis, or chronic T4-binding globulin elevation.
The ability of plasma to bind thyroxine (T4) was examined in the turtle, Pseudemys scripta, in relation to variations in thyroidal state associated with age, sex, environment, and surgical and chemical manipulations. Relative plasma binding activity was assessed by use of binding to [125I]T4 on minicolumns of Sephadex G-25 (fine). Hypothyroidism induced by surgical thyroidectomy (Tx) or goitrogen (Methimazole) treatment resulted in a marked depression of plasma binding (50- to 100-fold) in juveniles, and T4 treatment restored binding after 4-6 weeks in long-term Tx animals and increased levels in intact animals. Among intact turtles or those made slightly hypothyroid by partial thyroidectomy, binding was consistently correlated with plasma T4. For example, juvenile turtles kept under continuous light and constant temperature (28 degrees) for 4.5 months showed a pronounced depression of plasma T4 (2.6 +/- 1.1 ng/ml) and binding capacity compared to animals raised under variable conditions (T4 = 69.6 +/- 22 ng/ml) for the last 2 months. Plasma T3 was less than 1 ng/ml in all cases. Binding levels in adult turtles were similar to juveniles, but females had significantly higher binding levels than males which paralleled differences in their plasma T4 (137 +/- 17.4 vs 83.9 +/- 13.8 ng/ml). These variations in binding were independent of total plasma protein and albumin. Plasma T4 binding measured on Sephadex G-25 was reversible and reduced by addition of exogenous T4. The affinity for T3 was 10- to 100-fold less than for T4. When plasma preincubated with [125I]T4 was electrophoresed on polyacrylamide slab gels (7% nonreducing) only a small percentage of radiolabel was associated with albumin and the majority with a slower migrating protein(s). Addition of unlabeled T4 displaced binding from the slower migrating region to the albumin and dye front (unbound). In contrast, plasma from Tx turtles showed only minimal binding and radiolabel was associated primarily with the albumin fraction. Elution of proteins from gels confirmed that only the slower migrating components bound T4 when tested on Sephadex G-25, and Tx animals lacked this binding component. The protein(s) responsible for most of the T4 binding appears to exist in low concentration. Limited comparative studies with human blood showed a similar binding activity on Sephadex G-25, but electrophoretic mobilities of binding proteins were distinct from those in the turtle. Evidence suggests that this binding protein is not prealbumin.(ABSTRACT TRUNCATED AT 400 WORDS)
The principal thyroxine (T4) binding proteins were measured in 8 septic patients and 8 controls to determine the extent to which a decrease in their concentration contributes to the decrease in serum T4 in sepsis. T4 binding globulin (TBG) evaluated by radioimmunoassay (RIA) and radial immunodiffusion (RID) was 61% and 66%, respectively, of the normal mean value in sera from septic patients. Decreases of albumin and transthyretin (TTR) to 55% and 29%, respectively, of the normal mean concentration contributed to the loss of T4 binding power in these sera. Total serum binding of T4, calculated from the normal contribution of each protein to T4 binding and the reduction of its concentration in septic patients, was 55% of that in the normal controls. This decrease in the estimated protein binding of T4 was proportional to the decrease of serum T4 from a mean of 8.4 microg/dL in the normal controls to 4.7 microg/dL (56% of the control) in the septic patients. Because TBG binds most of the serum T4, the decrease in the TBG concentration was the major factor in the decrease of total T4 binding power. Since the concentration of the major T4 binding proteins decreased sufficiently to account for the decrease in serum T4, it is unnecessary to postulate the effects of additional factors such as binding inhibitors or modification of T4 binding protein affinity.
The hydrolysis of lecithin by phospholipase produces equimolar amounts of nonesterified fatty acids (NEFAs) and lysolecithin. In this study, we have evaluated the effect of lysolecithins and NEFAs on thyroid hormone binding by examining their interactions with thyroxine-binding globulin (TBG)(serum 1:10,000 dilution) and purified transthyretin (TTR). Unsaturated NEFAs (palmitoleic, oleic, linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acid) inhibited [125I]T4 binding to TBG. Their affinities, relative to unlabeled T4, ranged from 0.005 to 0.0016%, except for oleic acid with relative affinity of < 0.0005%. Saturated NEFAs, lauric, myristic, palmitic, and stearic acid were inactive. After purification by high-performance liquid chromatography, 1-oleoyl and 2-oleoyl lysolecithin displaced [125I]T4 from TBG with an affinity of 0.0006 and 0.0005%, respectively. On a molar basis, this affinity was approximately 10-fold lower than arachidonic acid, the most potent NEFA in inhibiting T4 binding to TBG in this assay system. Of all the NEFAs tested, only arachidonic acid inhibited [125I]T4 binding to TTR, with an affinity relative to unlabeled T4 of 0.49%. 1-Oleoyl, 1-palmitoyl, and 1-stearoyl lysolecithin were without effect on TTR binding. The T4-displacing effects of NEFAs are markedly attenuated by their extensive binding to albumin. Using purified [14C]NEFA preparations and heptane partitioning, the mean unbound percentages of linoleic, eicosapentaenoic, and docosahexaenoic acid in undiluted normal human serum were 0.00099, 0.0050, and 0.0042%, respectively (n = 3). In view of the very high degree of albumin binding of NEFAs, studies in diluted serum will grossly overestimate their competitor potency. The affinities of lysolecithins for the T4 binding sites of TBG and TTR are lower than those of NEFAs and depend on the fatty acid component. Lysolecithins are unlikely to influence plasma protein binding of T4 during critical illness.
Carbamazepine (CBZ) decreases the serum concentration of thyroid hormones. It is proposed that CBZ increases the extra-thyroidal metabolism of thyroid hormones. In order to test this hypothesis CBZ was given to nine hypothyroid patients substituted with thyroxine (T4). A significant decrease in serum concentrations of T4, calculated free T4 (FT4), triiodothyronine (T3), and calculated free T3(FT3) was found after 3 weeks of CBZ medication. The serum concentrations of TSH and the T4:T3 ratios were unaltered, while the serum concentrations of T4-binding globulin (TBG) increased markedly in eight of the nine patients. These findings support the hypothesis of a CBZ induced increase in the extra-thyroidal metabolism of thyroid hormones.
Rates of hepatic uptake of thyroxine (T4) from dilute solutions of five different plasma T4-binding proteins were measured in the isolated perfused rat liver using an indicator dilution method. For each protein, this rate was compared with the rate of spontaneous dissociation of the T4-protein complex measured in vitro. Proteins studied were human T4-binding globulin (TBG), human T4-binding prealbumin (TBPA), human albumin, rat TBPA, and human albumin isolated from subjects with familial dysalbuminemic hyperthyroxinemia. For each of the five protein-hormone complexes studied, the rate of hepatic uptake of T4 (measured under conditions expected to result in dissociation-limited uptake) closely approximated the rate of spontaneous dissociation of the protein-hormone complex within the hepatic sinusoids. These findings indicate an absence of special cellular mechanisms that facilitate the hepatic uptake of T4 from its plasma binding proteins, and support the view that uptake occurs from the free T4 pool after spontaneous dissociation of T4 from its binding proteins.
The binding characteristics of T4 and T3 to dilute plasma were studied separately in five normal euthyroid subjects with normal levels of thyroxine-binding globulin (TBG). Scatchard analyses of these data revealed similar mean affinity constants for T4 [2.0 +/- 0.7 (SD) X 10(9) M-1] and T3 (2.0 +/- 0.7 X 10(9) M-1), but a 5-fold higher capacity for T4 (0.75 +/- 0.18 mol T4/mol TBG) than for T3 (0.14 +/- 0.06 mol T3/mol TBG). Similar results were obtained using various assay buffers, pH concentrations, or separation methods. This characteristic pattern of T4 and T3 binding was retained by thyroid hormone free plasma, with the only difference being a slight parallel shift to the left of the Scatchard plots for both T4 and T3. The calculated affinities (Ka) for T4 and T3 were 5.2 X 10(9) M-1 and 5.2 X 10(9) M-1, respectively. High affinity T4 and T3 binding was abolished in plasma selectively depleted of TBG, but was retained after selective depletion of either prealbumin or albumin. Highly purified TBG, prepared from normal serum, demonstrated binding characteristics for T3 and T4 similar to dilute plasma. Displacement of [125I]T4 from dilute plasma by unlabeled T3 or T4 revealed a binding potency of T3 relative to T4 of 9%. Binding affinities derived from analog displacement studies appear invalid as these calculations assume equal binding capacities of TBG for T4 and T3. It seems clear from these studies, that the binding characteristics of human TBG are inconsistent with a single competitive binding site for thyroid hormones.
The principal transport protein for T4 in human blood, thyroxine-binding globulin (TBG), binds T4 with an exceptionally high affinity (Ka = 10(10) M(-1)). Its homology to the superfamily of the serpins has recently been used in the design of chimeric proteins, providing experimental evidence that an eight-stranded beta-barrel domain encompasses the ligand-binding site. We have now characterized the T4 binding site by site-directed mutagenesis. Sequence alignment of TBG from several species revealed a phylogenetically highly conserved stretch of amino acids comprising strands 2B and 3B of the beta-barrel motif. Mutations within this region (Val228Glu, Cys234Trp, Thr235Trp, Thr235Gln, Lys253Ala, and Lys253Asp), designed to impose steric hindrance or restriction of its mobility, had no significant influence on T4 binding. However, binding affinity was 20-fold reduced by introduction of an N-linked glycosylation site at the turn between strands 2B and 3B (Leu246Thr) without compromising the proper folding of this mutant as assessed by immunological methods. In most other serpins, this glycosylation site is highly conserved and has been shown to be crucial for cortisol binding of corticosteroid-binding globulin, the only other member of the serpins with a transport function. The ligand-binding site could thus be located to a highly aromatic environment deep within the beta-barrel. The importance of the binding site's aromatic character was investigated by exchanging phenylalanines with alanines. Indeed, these experiments revealed that substitution of Phe249 in the middle of strand 3B completely abolished T4 binding, while the substitution of several other phenylalanines had no effect.
The effect of sialylated TBG and desialylated TBG on thyroxine (T4) uptake by human peripheral mononuclear cells was investigated in vitro. [125I]-T4 uptake was observed when the cells were incubated with free [125I]-T4. The uptake was inhibited in a concentration dependent manner when TBG was added. During the incubation, [125I]-T4 binding to TBG was observed. [125I]-T4 incorporation into cells was also observed when the cells were incubated with [125I]-T4-sialylated TBG or with [125I]-T4-desialylated TBG complex. The uptake was related to the temperature and length of time of the incubation. The amount of [125I]-T4 incorporated into the cells incubated with [125I]-T4-sialylated TBG was greater than that into the cells incubated with [125I]-T4-desialylated TBG during the early 0-20 min. incubation, whereas the amount of [125I]-T4 incorporated into the cells incubated with [125I]-T4-desialylated TBG became greater than that into the cells incubated with [125I]-T4-sialylated TBG after 20 min. of incubation. Pretreatment of the cells with methylamine blocked [125I]-T4 uptake in both cases, i.e. incubated with [125I]-T4-sialylated TBG and incubated with [125I]-T4-desialylated TBG. The results suggest that TBG plays a role not only as a carrier protein for T4 in circulation but also as a protein which can transport T4 from the extracellular into the intracellular space, so that the mechanism of T4 transport mediated by desialylated TBG is different from that mediated by sialylated TBG, and that the T4 transport system in both cases, mediated by sialylated TBG and by desialylated TBG, may be related to the internalization of T4-TBG-TBG receptor complex or of T4-T4 receptor complex if TBG receptors are present in the outer surface of the cell membrane.
Serum total thyroxine (T4), total triiodothyronine (T3), T4-binding globulin (TBG), free T4(FT4) and free T3(FT3) concentrations and the T3-uptake(T3-U) value were estimated in 11 patients with subacute thyroiditis, and compared with the same parameters in 11 patients with Graves' disease, whose serum T4 concentrations were similar to the former group. Seven patients with subacute thyroiditis, who were treated with dicrofenac sodium alone, were investigated as to the sequential changes in serum parameters during their clinical courses. The mean serum T3-U value and FT4, T3 and FT3 concentrations in patients with subacute thyroiditis were increased, but all were significantly lower than those in patients with Graves' disease (p less than 0.01, p less than 0.001, p less than 0.001 and p less than 0.001, respectively). Three patients with subacute thyroiditis, who showed shorter duration of symptoms than 10 days, had serum TBG excess. Thus the mean (+/- SD) serum TBG concentration (26.5 +/- 8.4 micrograms/ml) was significantly higher than that (18.3 +/- 2.9 micrograms/ml) in patients with Graves' disease (p less than 0.02). The ratios of serum T3 to T4 and FT3 to FT4 in patients with subacute thyroiditis were also significantly lower than those in patients with Graves' disease (p less than 0.001 and p less than 0.001, respectively). The serum FT4 in 7 patients treated with dicrofenac sodium alone decreased to the normal range after 3 to 8 weeks from the onset of the illness. In 3 patients with TBG excess and one patient (TBG; 29.0 micrograms/ml), serum TBG declined in consequence of the serum FT4 normalization.(ABSTRACT TRUNCATED AT 250 WORDS)
UNLABELLED: Some patients with non-thyroidal illness (NTI) have sera with characteristics suggesting decreased functional affinity of thyroxine-binding globulin (TBG) for T4: increased T4 free fraction, decreased total T4 to TBG ratio, and a fall in free T4 with serum dilution greater than theoretical predictions assuming normal affinity. These studies aimed to further characterize this phenomenon. According to the law of mass action binding protein affinity for T4 can be estimated from the response of free T4 to progressive serum dilution. Free T4 responses in 25 normal controls and in 7 congenital TBG deficient controls resembled the predictions from the law of mass action. Among 25 of 38 medical intensive care unit patients, responses were intermediate between normals and TBG deficiency. Responses in the other 13 NTI were consistent with the presence of a dissociable inhibitor. In this subgroup, total T4 was depressed, both free T4 and TSH were elevated, and there was a positive correlation between TSH and free T4 (r2 = 0.41, p < 0.02). CONCLUSIONS: (i) decreased affinities of serum proteins for T4 consistent with binding inhibitor(s) are found in some patients with NTI; (ii) there is an association of these severely altered affinities with reversal of the expected free T4-TSH relationship.