Thyroxine-binding Globulin Excess Research Articles

Thyroxine binding globulin excess detected by neonatal screening.

Inherited thyroxine binding globulin (TBG) disorder can be identified incidentally or through neonatal screening test. TBG excess is characterized by high levels of thyroxine (T4) but normal level of free T4 (fT4), while TBG deficiency presents with low T4 levels and normal fT4 levels. A 27-day-old newborn was brought to the hospital because of hyperthyroxinemia detected by neonatal screening. His T4 level was 18.83 µg/dL (normal range, 5.9–16.0 µg/dL). His mother had no history of any thyroid disease. His fT4 and thyroid stimulating hormone (TSH) levels were 1.99 ng/dL (normal range, 0.8–2.1 ng/dL) and 4.54 mIU/L (normal range, 0.5–6.5 mIU/L), respectively. His serum total triiodothyronine (T3) level was 322.5 ng/dL (normal range, 105.0–245.0 ng/dL). His TBG level was 68.27 mg/L (normal range, 16.0–36.0 mg/L) at the age of 3 months. At 6 months and 12 months of age, his TBG levels were 48.77 mg/L (normal range, 16.0–36.0 mg/L) and 50.20 mg/L (normal range, 14.0–28.0 mg/L), respectively, which were 2 to 3 times higher than normal values. Hormonal studies showed consistently elevated T3 and T4 levels and upper normal levels of fT4 and free T3 with normal TSH levels. His growth and development were normal. TBG excess should be considered as a potential differential diagnosis for hyperthyroxinemia and especially high T3 levels with normal TSH concentration.

Selected genetic aspects in the pathogenesis of the thyroid diseases

According to genetic ethiopathogenesis, thyroid diseases may be divided into monogenic and polygenic (multifactorial) thyroid diseases. Monogenic thyroid diseases are the following: 1. congenital defects of thyroid hormones biosynthesis as a result of dyshormonogenetic (majority goitrous) primary congenital hypothyroidism; 2. genetic familial defects of thyroid underdevelopment, including thyroid agenesis, thyroid hypoplasia and ectopia; 3. congenital protein-binding defects, including thyroxine-binding globulin (TBG) defects, albumin and prealbumin defects; 4. congenital resistance to thyroid hormone syndrome; 5. genetic non-autoimmune hyperthyroidism; 6. medullary thyroid carcinoma (MTC) (familial type of the MTC, and multiple endocrine neoplasia MEN 2 A and B), caused by RET gene mutations and inherited as the autosomal dominant mode. About 10-15% of all cases of primary congenital hypothyroidism (CH) are associated with either a goitre or a normal thyroid gland. This type of CH has been linked to a number of defects in thyroid hormonogenesis and is caused by mutations in the following thyroid-specific genes: hNIS, Tg, TPO, PDS, THOX2, DEHAL. It is inherited by the autosomal recessive mode. Only about 2% of primary congenital hypothyroidism cases (CH) due to the defects of the thyroid underdevelopment are familial with genetic background. This type of CH is associated with mutations in genes responsible for the growth or development of thyroid follicle cells such as TSHR, TTF1, TTF2, PAX 8, NKX2, or Hoxa3. Except for defect caused by a mutation of the TSHR gene, such inborn thyroid dysgenesis is associated with an increased incidence of birth defects (such as: respiratory distress, ataxia, muscle hypotomy, choreoathetosis, cleft palate, bilateral choanal atresia, hypoplastic epiglottis, spiky hair). In addition, mutations in the GNAS 1 gene may give congenital hypothyroidism associated with hypogonadisms and Albright’s osteodystrophy, which is the part of pseudohypoparathyroidism type IA and II (pseudopseudohypoparathyroidism). The next group of monogenetic thyroid diseases with less or more evident thyroid dysfunction form the following: 1. TBG partial or complete deficiency and TBG excess due to TBG gene defects with an X-linked inheritance pattern; 2. Generalized, peripheral and pituitary resistance to thyroid hormones mainly caused by TRbeta gene mutations, inherited by the autosomal recessive. The second group of thyroid diseases are the multifactorial (polygenic) ones. Among them the most frequent are: 1. Graves’ hyperthyroidism; 2. Autoimmune thyroiditis; 3. Thyroid carcinoma derived from thyroid follicle cells such as papillary and follicular thyroid carcinoma. Although autoimmune thyroid diseases (AITD), including autoimmune thyroiditis and Graves’ hyperthyroidism with thyroid ophthalmopathy (TAO), are still unclear, they are defined as polygenic diseases resulting from genetic and environmental factors. The environmental factors which play a role in the development of AITD include iodine excess (with amiodarone treatment), selenium deficiency, stress, interferon alpha, bacterial and viral infections and, in the case of Graves’ hyperthyroidism, and tobacco smoking. There are some genes whose polymorphisms have been confirmed in the development of and susceptibility to AITD. These are the following: 1. thyroid-specific genes such as the Tg gene and 2. genes modulating the immune system, such as HLA antigens, CTLA4, PTPN22, genes encoding proinflammatory cytokines, such as: IFN, TGF beta, IL 6, IL 4, IL1 beta, IL10, and others. On the other hand, among the many genes involved in the development of differentiated thyroid carcinoma derived from thyroid follicle thyroid cells (papillary and follicular one), BRAF and RET-PTC seem to be the most important.

Inherited thyroxine-binding globulin excess. Study in a kindred.

A three-generation family with hereditary high thyroxine-binding globulin (TBG) serum levels has been studied. All patients were clinically euthyroid and did not have a goiter. Four females of the eleven members of the kindred had elevated TBG (range: 34-56 micrograms/ml), total thyroxine (T4) and total triiodothyronine (T3) levels, but normal free T4 (fT4) and normal response of thyroid stimulating hormone (TSH) to intravenous application of thyrotropin-releasing hormone (TRH). Microheterogeneity of TBG studied by isoelectric focusing showed a normal pattern. No variations of the four main bands as seen in other causes of TBG excess like liver diseases, estrogen therapy or pregnancy could be measured. The changes in TBG concentration seem to be due to an abnormal gene expression controlling synthesis of TBG.

Follow-up of newborns with elevated screening T4 concentrations

ObjectiveTo determine the type and incidence of hyperthyroxinemic disorders detected by follow-up of infants with elevated screening total T4 (TT4) values. Study designInfants born in Oregon with a screening TT4 measurement >3 SD above the mean were offered enrollment. Serum TT4, free T4, total T3, free T3, and thyroid-stimulating hormone concentrations were measured in study infants and their mothers. ResultsOver a 20-month period, 101 infants (51 boys) and their mothers enrolled in the study (of 241 eligible infants), from a total screening population of 80,884; 17 infants were identified with persistent hyperthyroxinemia (TT4 >16 μg/dL). Ten had thyroxine-binding globulin excess (1:8088), 5 had evidence for increased T4 binding but not thyroxine-binding globulin excess (1:16,177), and 2 had findings compatible with thyroid hormone resistance (1:40,442); the other 84 infants had transient hyperthyroxinemia. Sequence analysis revealed a point mutation in the thyroid hormone receptor-β gene in one infant with thyroid hormone resistance; no mutation was identified in the other infant. ConclusionsAlthough neonatal Graves' disease occurs in approximately 1 in 25,000 newborn infants, we did not detect any case among 80,884 infants, most likely because their mothers were receiving antithyroid drugs. Although the other hyperthyroxinemic disorders in the aggregate occur frequently (1:4758) and may benefit from detection, in general they do not require treatment.

Thyroxine-binding globulin: organization of the gene and variants.

Thyroxine-binding globulin (TBG), the principal thyroid hormone transport protein in human serum, is synthesized by the liver and secreted into the bloodstream as a 54-kD acidic glycoprotein made up of a single polypeptide chain of 395 amino acids and four heterosaccharide units. The carbohydrate chains are important for the correct posttranslational folding, secretion and degradation of the molecule but are not required for hormone binding. TBG, encoded by a single gene copy located on Xq22, consists of five exons spanning 5.5 kbp. An upstream sequence of 218 nucleotides containing a hepatocyte nuclear factor 1 binding motif imparts to the gene a strong liver-specific transcriptional activity. Inherited TBG defects produce three phenotypes based on the level of TBG in serum of affected hemizygotes: complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). The molecular basis of the TBG defect has been identified in 12 of 16 known TBG variants. TBG-CD is caused by either premature termination of translation or an amino acid substitution resulting in failure of secretion. Point mutations resulting in single amino acid substitutions are responsible for the alteration of the properties and/or concentration of TBG-PD variants. Gene duplication and triplication has been recently identified in subjects with TBG-E.

Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families.

T4-binding globulin (TBG) is the major thyroid hormone transport protein in man. Inherited abnormalities in the level of serum TBG have been classified as partial deficiency, complete deficiency, and excess. Sequencing analysis of the TBG gene, located on Xq21-22, has uncovered the molecular defects causing partial and complete deficiency. However, the mechanism leading to inherited TBG excess remains unknown. In this study, two Japanese families, F-A and F-T, with inherited TBG excess were analyzed. Serum TBG levels in hemizygous males were 58 and 44 micrograms/mL, 3- and 2-fold the normal value, respectively. The molecule had normal properties in terms of heat stability and isoelectric focussing pattern. The sequence of the coding region and the promoter activity of the TBG gene were also indistinguishable between hemizygotes and normal subjects. The gene dosage of TBG relative to that of beta-globin, which is located on chromosome 11, and Duchenne muscular dystrophy, which is located on Xp, was evaluated by coamplification of these target genes using polymerase chain reaction and subsequent quantitation by HPLC. The TBG/beta-globin ratios of the affected male and female of F-A were 3.13 and 4.13 times, respectively, that in the normal males. The TBG/Duchenne muscular dystrophy ratios were 2.92 and 2.09 times the normal value, respectively. These results are compatible with three copies of TBG gene on the affected X-chromosome. Similarly, a 2-fold increase in gene dosage was demonstrated in the affected hemizygote of F-T. A 3-fold tandem amplification of the TBG gene was shown by in situ hybridization of prometaphase and interphase chromosomes from the affected male with a biotinylated genomic TBG probe, confirming the gene dosage results. Gene amplification of TBG is the cause of inherited TBG excess in these two families.

Gene amplification as a cause for inherited thyroxine-binding globulin excess?

Gene amplification as a cause for inherited thyroxine-binding globulin excess?

Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families

Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families

A case of familial thyroxine binding globulin excess associated with growth hormone deficiency

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (-2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 microU/mL, triiodothyronine (T3) 3.1 ng/mL, thyroxine (T4) 23.4 micrograms/dL and free T4 1.8 ng/dL. The serum TBG level was beyond 80.0 micrograms/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T3 levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.

Variations in thyroid hormone transport proteins and their clinical implications.

Variations in major thyroid hormone transport proteins may be inherited or acquired and may be associated with changes in serum concentration of the proteins or their affinity for thyroid hormones. These variations most frequently involve thyroxine-binding globulin (TBG), but changes in transthyretin and albumin are also observed. The consequent alteration of thyroid hormone-binding capacity in serum is associated with variations in total thyroid hormone concentration. Increased serum total thyroid hormone levels are found in subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia, and transthyretin-associated hyperthyroxinemia. Conversely, diminished serum thyroid hormone values are observed in subjects with TBG deficiency, and decreased concentration or affinity of transthyretin and albumin is not associated with variations in serum concentrations of thyroid hormones. The transport protein-associated variations in serum total thyroid hormone concentrations do not reflect a change in thyroid status. Euthyroidism can be easily established in subjects with transport protein abnormalities by the normal free thyroid hormone and TSH concentrations. It is, however, crucial to select methods for free thyroid hormone measurement that are not affected by abnormalities of transport proteins. Some assays, such as the analog method, often provide artifactual and misleading results, which may lead to inappropriate and even detrimental treatments. The evolutionary advantage of TBG (and albumin) in terms of thyroid homeostasis still remains to be elucidated.

Graves' disease and thyroxine-binding globulin excess

Tb the Editor .—We have read with interest the article in the June issue of theArchivesby Dall' Aglio et al 1 on incorrect treatment following the lack of recognition of the association of Graves' disease with thyroxine-binding globulin (TBG) deficiency (TBG-d). The Table summarizes the relevant data of a case of Graves' disease (in a 57-year-old man) associated with the opposite TBG variation, ie, TBG excess (TBG-e), an association not recognized until our observation. Such an association is more frequent than the association with TBG-d. In fact, no thyroid disease was found in 30 subjects with inherited TBG-d, 2 and only five cases of TBG-d were isolated in a series of 250 thyrotoxic patients (2%) 3 ; on the contrary, four patients with Graves' disease were found among 56 subjects (7%) with inherited TBG-e 2 and 11 cases of inherited TBG-e were found among 155 patients (7%) with Graves'

Hypothyroidism With Thyroxine-Binding Globulin Excess

We read the article by Alain and Zipf who reported a 4-year-old boy with elevated thyroxine-binding globulin (TBG) level, elevated serum concentrations of both tri-iodothyronine (T3) and thyroxine (T4), short stature, delayed bone age, and an exaggerated thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone stimulation. The child showed a marked improvement in growth with T3 therapy. In searching through the literature, we have come across a few more examples of TBG excess associated with hypothyroidism.

Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: a mechanism for estrogen-induced elevation of serum TBG concentration.

Hyperestrogenemic states, including pregnancy, cause an increase in serum T4-binding globulin (TBG) concentrations and an increase in the proportion of TBG molecules with greater anodal mobility on isoelectric focusing, indicating greater sialic acid content. The possible causal relationship between the degree of sialylation and accumulation of TBG in serum was explored by measuring the in vivo half-lives (t1/2) of TBGs with different isoelectric points. TBG in unfractionated serum and its major peaks, isolated by chromatofocusing and defined by their isoelectric points on isoelectric focusing were each injected iv into rats. The resulting TBG concentrations, measured by specific RIA in serum samples obtained at intervals after injection, were used for the calculation of the t1/2. TBG in serum from a pregnant woman had a significantly longer t1/2 of 17.2 +/- 1.2 h (mean +/- SD) compared to those of 13.3 +/- 1.5 and 12.9 +/- 0.9 h for TBG in serum from a man and a nonpregnant woman, respectively. TBG peaks II, III, IV, and V, with increasing anodal mobility, had progressively longer t1/2 values of 11, 13, 15, and 33 h, respectively. However, TBG peaks of the same mobility on IEF isolated from serum of pregnant or nonpregnant subjects had similar t1/2 values. Neither the TBG concentration nor estrogen had a direct effect on the rate of TBG clearance. Indeed, the t1/2 of TBG from a subject with inherited TBG excess was not different from that of TBG from a nonpregnant woman or a man. Chronic treatment of rats with estradiol did not alter the rate of clearance of injected human TBG. Finally, the more heavily sialylated anodal bands of purified but unfractionated serum TBG, analyzed by Western blots, survived longer in the circulation of a rat. These results indicate that the rate of in vivo metabolism of TBG is dependent on its sialic acid content. The increased proportion of TBG molecules with higher sialic acid content thus contributes to the increase in the serum TBG concentration in hyperestrogenemic states.

Role of serum carrier proteins in the peripheral metabolism and tissue distribution of thyroid hormones in familial dysalbuminemic hyperthyroxinemia and congenital elevation of thyroxine-binding globulin.

To investigate the role of thyroxine-binding globulin (TBG) and albumin in the availability of thyroid hormones to peripheral tissues, comprehensive kinetic studies of thyroxine (T4) and triiodothyronine (T3) were carried out in eight subjects with familial dysalbuminemic hyperthyroxinemia (FDH), in four subjects with inherited TBG excess, and in 15 normals. In high-TBG subjects, the reduction of T4 and T3 plasma clearance rates (by 51% and 54%, respectively) was associated with normal daily productions; T4 and T3 distribution volumes were significantly reduced. In FDH subjects T4 clearance was less reduced (by 31%) than in high TBG; consequently T4 production rate was significantly increased (by 42%); T4 and T3 distribution volumes and T3 clearance rate were unchanged. Increased T3 peripheral production in FDH (by 24%) indicates that T4 bound to abnormal albumin is more available to tissues than T4 carried by TBG, thus suggesting an important role of albumin in T4 availability to the periphery.

Serum free thyroxine concentrations in subjects with high circulating levels of thyroxine-binding globulin.

Serum free thyroxine (FT4) and thyroid hormone-binding protein concentrations were measured in pregnant women, stilboestrol-treated patients, and subjects with congenital thyroxine-binding-globulin (TBG) excess. In pregnant and stilboestrol-treated patients matched for TBG concentrations, serum FT4 concentrations measured by the Amerlex technique and by calculation, were reduced, as also was the total thyroxine (TT4)/TBG ratio. In congenital TBG excess Amerlex and calculated FT4 concentrations were normal whereas the TT4/TBG ratio was low. In contrast to the Amerlex method, FT4 concentrations by the Immophase procedure were normal in pregnant and stilboestrol-treated individuals and high in congenital TBG excess. We conclude that (i) reduced FT4 concentrations in pregnancy are related to an oestrogen effect rather than to some other pregnancy-associated factor, (ii) the TT4/TBG ratio gives a misleading indication of FT4 concentration in congenital TBG excess, and (iii) that when TBG concentrations are raised Immophase gives higher FT4 values than Amerlex or calculation when each is compared to FT4 values in their normal respective control group.

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 μg/dl during illness, and decreased to 10.18 ± 2.96 μg/dl during full recovery (p < 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 < 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.

Hereditary Abnormalities of Thyroxine-Binding Globulin Concentration&lt;subtitle&gt;A STUDY OF 19 KINDREDS WITH INHERITED INCREASE OR DECREASE OF THYROXINE-BINDING GLOBULIN&lt;/subtitle&gt;

Nineteen families with hereditary abnormalities of thyroxine-binding globulin (TBG) have been studied, comprising a total of 15 males with absent TBG, and 15 females heterozygotic for this condition, and 14 males with excess of TBG and 44 heterozygotic females. Hereditary TBG excess was associated with thyrotoxicosis in four instances, and with myxoedema in three. The typical biochemical features of TBG abnormality are described, with the clinical histories of patients in whom diagnostic and management problems occurred.

An autonomously functioning thyroid adenoma in a male with thyroxine-binding globulin excess

An autonomously functioning thyroid adenoma in a male with thyroxine-binding globulin excess

Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess.

It has been previously suggested that inherited thyroxine-binding globulin (TBG) abnormalities in man may be due to mutations at a single X-chromosome-linked locus controlling TBG synthesis. However, abnormalities in TBG degradation have not been excluded. The availability of purified human TBG and its successful labeling with radioiodide allowed us to examine such possibility. Human TBG was purified by affinity chromatography, labeled under sterile conditions with 131I or 125I,, and mixed with [125I]thyroxine (T4) or [131I]T4, respectively, before their intravenous injection. Blood and urine samples were collected over a 10-day period, and the turnover parameters were calculated. In eight normal volunteers mean values +/-SD for TBG and T4 respectively, were as follows: Half time (t1/2) 5.3 +/- 0.4 and 7.0 +/- 0.6 days; distribution space (DS) 7.2 +/- 1.0 and 10.8 +/- 1.2 liters; and total daily degradation (D) 0.211 +/- 0.053 and 0.088 +/- 0.011 mumol/day. In all subjects, t1/2 of TBG was shorter than that of T4; and the DS was smaller. 2.4 mol of TBG was degraded for each mole of T4. In five of six subjects from four families, comprising hemizygous and heterozygous carriers of TBG absence, decrease, and excess, the t1/2 and DS for TBG were within the normal range. The D of TBG was proportional to the serum concentration of the protein. Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration. A striking decrease in the t1/2 of TBG was found only in a patient with acquired diminution in TBG concentration and in patients with thyrotoxicosis or other conditions apparently unrelated to thyroid dysfunction. TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis. Decreased TBG t1/2 was also observed in three of six patients with nonthyroidal pathology and was associated with an increase in TBG D disproportionate to their level of serum TBG. These studies indicate that changes in TBG concentration in patients with X-chromosome-linked TBG abnormalities are due to alterations in its rate of synthesis. In other conditions, abnormalities of TBG degradation and/or rate of synthesis may be found.