Familial hyperthyroxinemia due to abnormal thyroid hormone binding

A patient had an elevated serum total thyroxine (T4) free thyroxine (free T4), free T4 index, and T4/thyroxine-binding globulin ratio. The serum triiodothyronine (T3), as well as the thyrotrophin response to thyrotrophin-releasing hormone was normal and consistent with the clinical euthyroid status. The basis for the elevated serum total T4, free T4 index, and T4/thyroxine binding globulin is the abnormally enhanced binding of thyroid hormone by albumin, or by an anomalous protein migrating with a mobility similar to albumin as determined in paper electrophoretic systems. The abnormal T4 protein binding was also seen in several members of the patient's family indicating that the condition was familial. A new type of serum T4 protein binding abnormality that results in hyperthyroxinemia may falsely indicate thyrotoxicosis in clinically euthyroid subjects.     

Normal response to thyrotrophin releasing hormone (TRH) in familial thyroxine-binding globulin deficiency.

The response in serum thyrotrophin (TSH) to thyrotrophin releasing hormone (TRH) has been studied in 5 euthyroid patients with familial thyroxine-binding globulin (TBG) deficiency. Total serum thyroxine (T4), serum triiodothyronine (T3) and free T4 index and free T3 index were significantly and equally decreased, but in spite of these findings the serum TSH and response to TRH was normal. The TRH test seems to be a better indicator of the euthyroid state in familial TBG deficiency than the measurement of free T4 and free T3 in serum.     

Alterations in serum thyroid hormonal indices with colestipol-niacin therapy

A serial blood-lipid-lowering study at the University of Southern California yielded unexpected findings on routine thyroid function monitoring. After 1 year of combined colestipol and niacin therapy, patients had reduced total serum thyroxine (T4) levels and increased triiodothyronine uptake ratios, an indicator of apparent decreases in thyroxine-binding globulin levels. Calculation of the free T4 index partially but not completely corrected for the apparent decrease in thyroxine-binding globulin, as determined by a relatively small decrease in the free T4 index compared with a large decrease in T4. Sequential sampling, using three separate methods, showed reduced thyroxine-binding globulin levels. The mechanism for these changes is unknown, but the fact that these patients were essentially euthyroid needs emphasis because the use of combined colestipol and niacin therapy is becoming more widespread.     

Elevated thyroxine levels due to increased thyroxine-binding globulin in acute hepatitis

Two patients are presented who had unexpected increases in serum thyroxine concentration due to acquired thyroxine-binding globulin excess associated with asymptomatic hepatitis. Serum hormone concentrations were also analyzed retrospectively in 10 outpatients with viral hepatitis. Acute hepatitis is associated with an increase in serum thyroxine and thyroxine-binding globulin concentrations and a corresponding decrease in the triiodothyronine resin uptake. In five patients, serum thyroxine concentration (mean +/- SD) was elevated at 21.08 +/- 5.86 micrograms/dl during illness, and decreased to 10.18 +/- 2.96 micrograms/dl during full recovery (p less than 0.05); serum thyroxine-binding globulin concentration was elevated at 2.14 +/- 0.36 mg/dl during illness, and decreased to 1.18 +/- 0.16 mg/dl during recovery (p less than 0.01). Interpretation of thyroid function test results can be difficult in patients with hepatitis. When serum thyroxine is elevated, careful attention to a decrease in the triiodothyronine resin uptake is essential to avoid the incorrect diagnosis of hyperthyroidism. Occasionally, this change in the triiodothyronine resin uptake may be the first evidence of occult hepatic inflammation.     

Serum free thyroxine in patients with T3-toxicosis

The serum free thyroxine concentration was measured by direct radioimmunoassay in 38 untreated T3-thyrotoxic patients with elevated serum total and free triiodothyronine, normal serum thyroxine and free thyroxine index, no TSH response to TRH, and with clinical evidence of hyperthyroidism. An elevation of circulating free thyroxine values was observed in 58% of the patients, whereas total serum thyroxine concentration was within the normal range. It is suggested, therefore, that T3-thyrotoxicosis should be reserved for patients with elevated serum total T3 and free T3 concentrations and normal serum total T4 and free T4 concentrations. Serum thyroxine-binding globulin concentrations were significantly lower (P less than 0.025) in patients with an elevated serum free thyroxine (18.7 +/- 3.6 micrograms/ml: mean +/- SD) as compared with those in patients with a normal free thyroxine concentration (23.4 +/- 2.6 micrograms/ml). In addition, no daily fluctuations in total and free thyroxine concentration were observed in 6 patients over a 4-8 day period.     

Thyroid hormone antibodies and Hashimoto's thyroiditis in mongrel dogs

Abnormally elevated serum T3 concentrations measured by RIA were observed in 19 clinically euthyroid or hypothyroid mongrel dogs. The serum T4 concentrations in these sera were low, normal, or high. Measurement of the intensity of thyroid hormone binding to serum proteins was determined by equilibrium dialysis. A marked decrease in the percent free T3 was observed in these abnormal sera. Polyacrylamide gel electrophoresis, pH 7.4, of normal dog serum enriched with tracer 125I-labeled thyroid hormones demonstrated binding of [125I]T4 to transthyretin, thyroid hormone-binding globulin, and albumin and of [125I]T3 primarily to thyroid hormone-binding globulin. In all abnormal sera, polyacrylamide gel electrophoresis demonstrated strikingly higher binding of T3 to immunoglobulin (Ig). Eleven of 16 abnormal sera had minimal to moderate binding of T4 to Ig. The percent free T4 was lower only in dogs whose sera demonstrated markedly increased binding of T4 to Ig. All abnormal sera tested had positive antithyroglobulin antibodies, consistent with the diagnosis of autoimmune lymphocytic thyroiditis. As in humans, antibodies to thyroid hormones in dogs are more common in the presence of Hashimoto's thyroiditis and should be considered when elevated serum thyroid hormone concentrations are observed in the absence of clinical thyrotoxicosis. When an antibody to only one thyroid hormone is present, a marked discrepancy in the serum concentrations of T3 and T4 will be observed.     

Hyperthyroxinemia in patients receiving thyroid replacement therapy

Eleven patients, with a history of hypothyroidism, who had hyperthyroxinemia and an elevated free thyroxine index but normal serum triiodothyronine concentrations on levothyroxine replacement underwent levothyroxine dose reduction at three-month intervals until the free thyroxine index fell into the normal range. All were clinically euthyroid throughout. Normalization of the thyrotropin response to thyrotropin-releasing hormone occurred concomitantly, indicating correction of subtle hyperthyroidism. The mean thyroxine dose decreased from 161 micrograms/d (2.06 micrograms/kg) to 120 micrograms/d (1.51 micrograms/kg). The resting heart rate fell in eight of 11 patients (P less than .02). The left ventricular ejection fraction decreased in eight of 11 patients, although the decrease was not statistically significant. Considering the sensitivity of pituitary, cardiac, and bone tissue to even a small excess of thyroxine over time, hyperthyroxinemia associated with an elevated free thyroxine index should be corrected even in patients taking levothyroxine replacement who are clinically euthyroid and whose serum triiodothyronine concentrations are within normal limits.     

Thyroxine-binding globulin deficiency in a family

Partial thyroxine-binding globulin (TBG) deficiency in a family is described. A 43-year-old male was admitted because of the association of low thyroxine level but markedly elevated triiodothyronine resin-uptake despite his complaints of palpitation and excessive sweating. TBG was low (6 micrograms/ml) by radioimmunoassay. His free thyroxine level was normal. 123I uptake at 24 hours was normal and was suppressed following oral administration of triiodothyronine. Serum TSH level was normal and responded normally to TRH stimulation. Similar low level (6 micrograms/ml) in TBG was found in his elder brother who had no complaints. Another brother and 3 sisters had normal TBG levels. According to the classification of the TBG deficiency proposed by Barbosa et al., a family described here is considered to have the type II TBG deficiency which shows a much lower TBG level in male than in female with X-linked inheritance.     

Increase in thyroxine-binding globulin (TBG) in lysinuric protein intolerance

The common occurrence of increased serum PBI concentration in patients with lysinuric protein intolerance (LPI) was elucidated by further studies. The reason was found to be an increase in the concentration of thyroid binding globulin (TBG), concomitantly with an increase in the binding capacity of TBG. The concentrations of serum thyroxine and triiodothyronine were elevated, whereas the free thyroxine index remained normal. The free triiodothyronine index was slightly increased. The binding capacity of thyroid hormone binding pre-albumin (TBPA) was significantly decreased. The concentrations of reverse triiodothyronine (3,3',5'-T3) and of 3,3'-diiodothyronine were normal. In all patients serum lactic acid dehydrogenase activities and ferritin concentrations were elevated. The reason for the almost constant increase in TBG remains obscure. It may be related to the primary disorder of LPI, a defect in diaminoacid transport.     

Serum sex hormone-binding globulin in amiodarone-treated patients. A marker for tissue thyrotoxicosis

The lodinated antiarrhythmic drug amiodarone frequently causes an elevation of the serum thyroxine (T4) level in patients who remain clinically euthyroid. Less frequently, true iodine-induced hyperthyroidism may occur. The clinical and laboratory distinction between these two conditions is often difficult. Since the serum sex hormone-binding globulin (SHBG) concentration is elevated in hyperthyroidism, this study was carried out to evaluate the serum SHBG concentration as a possible marker of hyperthyroidism in patients receiving amiodarone. Patients treated with amiodarone were divided into three groups: clinically euthyroid with normal serum T4 and triiodothyronine (T3) concentrations, clinically euthyroid with elevated serum T4 and normal T3 concentrations, and clinically hyperthyroid with elevated serum T4 and T3 concentrations. The mean serum SHBG concentration was significantly elevated in amiodarone-induced hyperthyroid patients, while it was normal in euthyroid patients treated with amiodarone who had normal or elevated serum T4 concentrations. The results suggest that the hyperthyroxinemia induced by amiodarone is not associated with excess thyroid hormone action in the liver unless the serum T3 concentration is also elevated.     

Low serum free T3 concentrations in postobese patients previously treated with very-low-calorie diet

Thirteen postobese patients with stable body weights were studied and compared with obese patients and normal subjects. Six had previously been treated with a very-low-calorie diet (VLCD) whereas seven had been treated with gastroplasty (GP). The median observation time of post-obesity was 20 months for GP patients, but significantly (P less than 0.001) shorter by 2 months in VLCD patients. The median serum concentration of free triiodothyronine (T3) was significantly (P less than 0.005) reduced in the postobese VLCD patients (3.4 pmol/l) but normal in postobese GP patients (4.2 pmol/l) and obese patients (4.5 pmol/l). The serum level of total T3 was correspondingly lowered in the postobese VLCD patients. Also the postobese GP patients had a small, but significant (P less than 0.01) reduction in the median serum concentration of total T3 suggesting a slight decrease in the binding capacity. The serum levels of thyroxine-binding globulin and thyroxine-binding prealbumin were normal in both postobese and obese patients. Furthermore, the serum levels of thyroxine were normal showing that the postobese patients were euthyroid. The study shows that serum concentrations of T3 are not associated with body weights and low serum concentration may be seen in postobese patients after VLCD.     

Prevalence of abnormal thyroid function test results in patients with acute medical illnesses

We measured serum total and free thyroxine (T₄) and triiodothyronine (T₃) concentrations, free T₄ and T₃ indexes, thyroid-stimulating hormone (TSH), thyroxine-binding globulin (TBG) and thyroxinebinding prealbumin (TBPA) concentrations in 98 patients hospitalized for acute medical illnesses. The free thyroxine index (FT₄I) or TSH level was abnormal in 16 percent, but only 3 percent had thyroid disease. Serum free T₄ measurements by equilibrium dialysis were abnormal in 25 percent, but no additional patients who initially had abnormal concentrations of serum free T₄ were subsequently proved to have thyroid disease. Patients with supranormal serum free T₄ concentrations (21 percent) had higher serum T₄, lower serum T₃, and higher serum reverse T₃ (rT₃) concentrations than other patients, but the measured changes in serum T₄, TBG and TBPA levels could only partly account for the magnitude of the free T₄ elevation. In these acutely ill patients, an accurate diagnosis of thyroid disease could be achieved by determination of FT₄I and TSH level and a history of medication usage. We conclude that other tests are rarely necessary for this purpose in a patient population such as this.     

Artifactually elevated serum-free thyroxine levels measured by equilibrium dialysis in a pregnant woman with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by radioimmunoassay (RIA) but not when determined by RIA after ultrafiltration of sera. These results indicate an increased T4 binding to TBG during pregnancy in the patients with FDH. Furthermore, our results suggest that normal serum FT4 determined by equilibrium dialysis is not an ultimate standard for the diagnosis of FDH in the patients with the mutant albumin R218P.     

Impaired binding properties of thyroxine-binding globulin in hepatocellular carcinoma and chronic liver disease.

To determine the factors underlying the apparent reduction in binding ability of thyroxine-binding globulin in hepatocellular carcinoma, hormone-binding characteristics were further examined in patients with this disease and in control subjects. No differences in affinity constants with respect to triodothyronine or serum thyroxine-binding globulin from hepatocellular carcinoma, cirrhotic and normal subjects were found. The affinity for thyroxine was significantly reduced in hepatocellular carcinoma (0.41 +/- 0.13 x 10(10) mol-1) and cirrhotic (0.65 +/- 0.1 x 10(10) mol-1) patients compared with normal subjects (0.94 +/- 0.7 x 10(10) mol-1). Investigations carried out on liver tissue obtained from patients with hepatocellular carcinoma and chronic liver disease showed that thyroxine-binding globulin within tumor tissue was elevated and bound less exogenous tracer hormone compared with that obtained from nontumor tissue. Tumor-derived thyroxine-binding globulin with altered binding properties is, at least partly, responsible for the abnormal behavior of the serum protein in patients with hepatocellular carcinoma.     

Serum thyrotropin by ultrasensitive immunoradiometric assay and serum free thyroid hormones in pregnancy

Variations of serum TSH, measured by an ultrasensitive immunoradiometric assay, of serum total and free thyroid hormones and of thyroxine-binding globulin (TBG) and sex hormone-binding globulin (SHBG) were investigated in a group of 18 normal women before and during pregnancy. A gradual increase of total thyroid hormones, TBG and SHBG was observed, while mean serum free thyroxine and free triiodothyronine progressively decreased. Serum TSH concentrations were comprised within the normal range throughout pregnancy, although a small but significant increase was found in the 2nd and 3rd trimester. These changes may represent a compensatory mechanism to meet the increased demand for thyroid hormones in pregnancy and must be taken into account for a correct evaluation of thyroid function during gestation.     

SERUM TRIIODOTHYRONINE CONCENTRATION IN THE DIAGNOSIS OF HYPERTHYROIDISM

The serum triiodothyronine concentration is superior to the serum thyroxine concentration, the resin uptake test and the free thyroxine index in the diagnosis of hyperthyroidism. Over a 14 month period fifty-five patients attending an endocrine clinic with suspected thyrotoxicosis of all degrees of severity had blood taken on initial attendance and the serum was stored for routine thyroid function tests and triiodothyronine estimation. The patients were followed up and forty-six proved to be toxic and seven to be euthyroid; two could not be classified. Analysis of the initial serum showed that the serum triiodothyronine concentration was superior to the serum thyroxine concentration, the resin uptake test and the free thyroxine index in predicting the clinical outcome.     

Developmental profile of thyroid hormone distributor proteins in a marsupial, the tammar wallaby Macropus eugenii

The ontogeny of thyroxine distributor proteins in serum of the marsupial Macropus eugenii (tammar wallaby) was investigated from day 3 after birth until adulthood. The thyroxine distributor proteins in the serum of adult M. eugenii are transthyretin and albumin. Northern analysis of RNA prepared from liver showed that transthyretin mRNA levels were initially high (about adult levels at the earliest ages tested), reduced to about 60% adult levels (between days 50 and 150), and then steadily increased to adult levels (by days 200 to 250). Albumin mRNA levels were initially about 50% of adult levels (day 3) and steadily rose to 90% of adult levels by days 175 to 220. A globulin, "wallaby thyroxine-binding protein" (W-TBP), bound [(125)I]thyroxine from day 3 until about day 200. Of the protein-bound thyroxine, the proportion bound by transthyretin had a similar pattern to the transthyretin mRNA levels. From day 26 onward, about half of the protein-bound thyroxine was bound to albumin. On day 3, less than 10% was bound to W-TBP and the proportion steadily increased to a maximum of about 46% by about day 120 and then reduced to undetectable levels by around day 250. The developmentally regulated W-TBP was present throughout pouch life, when the pouch young is dependent on obtaining thyroxine required for normal growth and development from the mother. After the young tammar wallaby leaves its mother's pouch, a time when it has reached a level of physiological development approximately equivalent to that at the time of birth in precocious eutherian mammals such as cattle and sheep, W-TBP was no longer detected as a thyroxine distributor protein in serum.     

THYROID FUNCTION AND THYROID REGULATION IN EUTHYROID MEN WITH CHRONIC LIVER DISEASE: EVIDENCE OF MULTIPLE ABNORMALITIES

Total and free serum thyroxine (T4) and triiodothyronine (T3), basal serum thyrotrophin (TSH) and the serum TSH response to a standard intravenous dose of thyrotrophin releasing hormone (TRH) have been measured in fifteen men with liver cirrhosis and in eight alcoholic men with fatty liver change. All the patients studied were clinically euthyroid. In cirrhotics, total T4 and free T4 (FT4) concentrations were normal as were free T3 (FT3) concentrations but total T3 concentrations were significantly reduced and basal TSH concentrations were significantly higher than normal. Alcoholics with fatty liver change had normal basal TSH concentrations and normal total and free thyroid hormone concentrations apart from reduced FT4. Correlation of thyroid function tests with liver function (serum albumin concentration) showed significant positive correlations for serum albumin with both total T3 and FT3 and significant negative correlations with both FT4 and basal TSH. Nine of fifteen cirrhotics had an abnormal serum TSH response to TRH, the commonest abnormal pattern being a delayed response (seven patients). Three of eight alcoholics with fatty liver change also had an abnormal TSH response to TRH. These findings not only show complex disturbances in hypothalamic-pituitary-thyroid relationships in chronic liver disease but also provide indirect evidence of reduced extra-thyroidal conversion of T4 to T3.     

Changes in serum levels of thyroxine and thyroxine-binding proteins (TBG, TBPA, ALBUMIN) induced by venous stasis.

Serum concentrations of thyroxine (T4), thyroxine-binding globulin (TBG), thyroxine-binding pre-albumin (TBPA) and albumin were determined in 21 healthy, young subjects before and after a brief venous stasis in two experiments: 1) 3 min stasis induced by a sphygmomanometer with constant pressure 20 mmHg above the diastolic blood pressure and 2) 2 min stasis induced by an arm tourniquet of rubber. In both experiments the serum T4 level was significantly rised (mean 9%) after venous compression. Increases of the same magnitude were observed for serum TBG, serum TBPA and serum albumin. The serum concentrations of the free constituents--sodium and creatinine--remained unchanged, whereas the haemoglobin concentration increased (mean 8%). This haemoconcentrating effect of venous stasis seemed to be more pronounced in females than in males. Our data emphasize the need for protein correction procedures when total serum T4 is measured.     

Inherited abnormal thyroid hormone-binding protein causing selective increase of total serum thyroxine.

A 9-yr-old boy is described in whom increased serum T4 concentration, increased T3 uptake, and increased free T4 index were associated with a euthyroid clinical state with normal total serum T3. T4-binding globulin (TBG), measured by RIA, was decreased. Reverse flow paper electrophoresis of serum proteins after reaction with radioactively labeled T4 demonstrated increased binding of T4 to a protein with electrophoretic mobility corresponding to albumin. Displacement of serum protein-bo-nd [125I]T4 activity by increasing concentrations of T4 revealed the presence of a low affinity, high binding capacity system with an association constant similar to that of T4-binding prealbumin. This low affinity binding protein cochromatographed with TBG on a DEAE-Sephadex column which normally separates TBG from T4-binding prealbumin. At free T4 concentrations equivalent to those present in the plasma of normal individuals, the T4 bound to free ratio is higher in the patient than in normals and the total serum T4 level is increased in the presence of normal free T4 concentrations. The relative affinity of this abnormal T4-binding protein for T3 is low compared to that of TBG. The patient's father had the same abnormal binding protein, which was not found in his mother or fraternal twin brother. These data suggest an autosomal dominant mode of inheritance of an aberration leading to synthesis of a new protein instead of normal TBG. The new protein is different from TBG in electrophoretic mobility, T4 and T3 binding, and antigenic properties.