eMedicine from WebMD
 

eMedicine Specialties > Endocrinology > Thyroid

Thyroxine-Binding Globulin Deficiency

Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Boaz Hirshberg, MD, Associate Director, CVMD, Pfizer

Updated: Dec 18, 2008

Introduction

Background

The thyroid hormones (THs) — thyroxine (T4) and 3,5,3'-triiodothyronine (T3) — circulate in blood by reversibly binding to carrier proteins. Although only 0.3% or less of T3 and T4 circulates unbound, it is this free hormone fraction that is metabolically active at the tissue and cellular level.

The 3 main proteins that carry the majority (>95%) of THs are thyroxine-binding globulin (TBG), transthyretin (TTR, or prealbumin), and albumin. A minor proportion of the THs is bound on serum lipoproteins. Very rarely, and in the context of anti-TH antibodies in autoimmune thyroid disease, immunoglobulins also may bind TH. TH binding to TBG is characterized by low capacity but high avidity; the converse is true, ie, high capacity but low avidity, for TH binding to TTR and albumin. Inherited or acquired variations in the concentration and/or affinity of these proteins may produce substantial changes in serum total TH levels measured by commercially available assays. Notably, these changes do not result in illness (ie, hypothyroidism or hyperthyroidism), because the concentration of the free TH does not change.

A deficiency in TH-binding proteins is suspected when abnormally low serum total TH concentrations are encountered in clinically euthyroid subjects in the presence of normal serum thyrotropin (ie, thyroid-stimulating hormone [TSH]). More specifically, low TBG is suggested because this protein carries the majority of the serum TH. Several states of deficiency of this protein have been described that are either inherited or acquired (see Thyroid binding protein deficiency states, below). Thyroid function tests (TFTs) in patients with TBG deficiency show normal TSH and free T4, but low total T4 and, occasionally, low total T3 serum concentrations. The most important clinical aspect of TBG deficiency states is to recognize these disorders and to avoid unnecessary and potentially harmful TH replacement therapy.

Thyroid binding protein deficiency states

Inherited causes include the following:

  • TBG gene defects - Partial deficiency (X linked) and complete deficiency (X linked)
  • Other genetic defects - Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1), which is autosomal recessive

Acquired causes include the following:

  • Hyperthyroidism
  • Nephrotic syndrome1
  • Chronic renal failure
  • Chronic liver disease
  • Severe systemic illness (except human immunodeficiency virus/acquired immune deficiency syndrome [HIV/AIDS] and acute intermittent porphyria)2
  • Malnutrition
  • Acromegaly (in very rare cases only)3,4
  • Cushing syndrome
  • Drugs (eg, androgens, glucocorticoids, L-asparaginase)

Pathophysiology

Thyroxine-binding globulin (TBG) is a 395–amino acid, 54-kd polypeptide that is synthesized in the liver and is encoded by a single gene copy.5 The gene locus in humans is on chromosome band Xq22.6,7 TBG is a member of the serine protease inhibitor (SERPIN) superfamily, to which cortisol-binding globulin (CBG), antithrombin III, and angiotensinogen also belong. Notably, however, neither TBG nor CBG has intrinsic antiprotease activity.

Cleavage of TBG by a serine protease causes a conformational change that reduces the affinity of TBG for T4. This allows large concentrations of thyroid hormone (TH) to exist at specific sites. Cleavage also may increase the clearance of TBG. TBG is a minor component of the alpha globulins and has a serum half-life of 5 days; it is glycosylated on 4 asparagine residues.8,9

The normal serum concentration of TBG ranges from 1.1-2.1 mg/dL in adults. Although TBG concentrations are far lower than those of the other 2 TH-binding proteins (ie, TTR, albumin), it carries approximately 75% of serum T4 and T3. TBG has a 10-fold greater affinity for T4 than for T3; its molecule has a single TH binding site. In normal serum, TBG usually is only 25% saturated with T4. Interestingly, TBG also binds numerous T4 and T3 analogs and drugs, such as phenytoin, diclofenac, fenclofenac, meclofenamate, mefenamate, diflunisal, diazepam, salicylates, and milrinone. Because some of these drugs also bind to TTR and may displace TH from the TTR binding site, it is at least theoretically possible that patients with either partial or complete TBG deficiency who are treated with these drugs may show some temporary increase in free TH levels.

The genetic basis of TBG deficiency pertains to point mutations resulting in amino acid substitutions in the mature protein or in truncations caused by stop codons.10,11,12,13 More rarely, TBG defects are caused by aberrant mRNA processing due to mutations in the acceptor splice site or by exon skipping, as well as a probable defect in TBG-specific transcription factors.14 Additionally, in the case of a single pedigree, partial TBG deficiency was found to be caused by a mutation in the signal peptide for that protein, ie, in the absence of mutation within the mature peptide.15

Finally, 2 pedigrees have been described in which, in the deoxyribonucleic acid (DNA) of members of the group who had complete TBG deficiency, no mutations were found in either the signal peptide or in the actual coding regions of the gene. In these 2 pedigrees, the deficiency is believed to be caused by an overactive silencer located a considerable distance from the TBG gene promoter.16 Research has revealed an increasingly complex variety of genetic mechanisms leading to TBG deficiency.

TBG deficiency does not cause thyroid disease. The homeostatic mechanism of equilibrium dynamics between TBG-bound and free TH is described as follows. First, any decrease in TBG levels initially increases the concentration of the free hormone. Subsequently, the tendency to cause hyperthyroidism is counterbalanced by the tendency to shut off TSH secretion and hence decrease the TH secretory rate from the thyroid gland. Finally, the total TH concentration in the serum decreases until the concentration of the free hormone is restored to normal.

This equilibrium is achieved extremely rapidly and on a physicochemical level. If chronic, the decreased extrathyroidal pool of TH may lead to small, transient declines in circulating free TH levels, thus resulting in transient TSH stimulation of the thyroid. The latter mechanism may explain the moderate elevation in serum thyroglobulin levels observed in up to one third of patients with TBG deficiency. Because TBG deficiency is not an acute process, a state of resultant hypothyroidism does not occur. Total T4 and T3 may be low in states of TBG deficiency, but the free T4, free T3, and TSH remain normal.

Familial TBG deficiency is X linked. In families with complete TBG deficiency, males have no detectable TBG, while carrier females have half the normal concentration. In families with partial deficiency, males have some measurable TBG concentration, while females tend to have TBG levels that are higher than half the normal concentration.17

Inherited TBG deficiency also has been described within the context of another genetic syndrome, congenital disorder of glycosylation type 1 (CDG1), or Jaeken syndrome. The features of this syndrome are psychomotor retardation, cerebellar ataxia, peripheral sensorimotor neuropathy, skeletal abnormalities, lipodystrophy, and retinitis pigmentosa.18 CDG1 is caused by mutations in phosphomannomutase 2 and shows autosomal recessive inheritance.19 The CDG1 gene locus is located on chromosomal band 16p13 in humans.

In addition to quantitative defects in TBG, qualitative defects resulting in lower T4 affinity or increased degradation due to improper intracellular processing have been described.

Acquired TBG deficiency, which can be caused by protein malnutrition, also is encountered frequently in chronic diseases and debilitative states, in liver failure, and in calorie malnutrition. In patients with the nephrotic syndrome, TBG is lost through the glomerular filtrate. The cause of the decrease in TBG concentration associated with glucocorticoid or androgen administration is not clear, but it is believed that the effect is transcriptionally mediated, although cleavage of the protein also may play a role in increasing its clearance.

Frequency

International

The prevalence of inherited complete thyroxine-binding globulin (TBG) deficiency is approximately 1 case per 15,000 male births, while the prevalence of inherited partial TBG deficiency is 1 case per 4000 newborns. In a study of thyroid hormone – binding protein abnormalities in patients with abnormal TFTs, ie, in a priori select population, the prevalence of complete and partial TBG deficiency was 1 in 2,500 and 1 in 200, respectively.20 The incidence and prevalence of secondary TBG deficiency is unknown.

Mortality/Morbidity

  • Thyroxine-binding globulin (TBG) deficiency does not lead to phenotypic features and is not usually associated with excess mortality. No morbidity or mortality is directly associated with TBG deficiency.
  • Morbidity may be associated with misinterpretation of the TFTs as representing a hypothyroid state, with resultant unnecessary and potentially harmful treatment.
  • Patients with acquired TBG deficiency may have morbidity and mortality secondary to their underlying illness (usually severe).

Race

  • Two variant thyroxine-binding globulins (TBGs) have been described with high frequency in certain populations. TBG-A, found in Australian Aborigines, presents with moderate TBG deficiency, with an allele frequency of 50%.21 TBG-S is associated with mild TBG deficiency and has an allele frequency of 4-12% in black African and Pacific Island populations.22
  • Notably, TBG gene polymorphisms that do not lead to abnormal serum thyroid hormone levels have been described in the black populations of Africa and America.

Sex

  • No sex differences in the incidence and prevalence of acquired thyroxine-binding globulin (TBG) deficiency have reported.
  • Complete TBG deficiency occurs only in males, because the gene for TBG is located on the X chromosome. Female carriers of the trait have 50% of the normal concentration of TBG.

Age

  • Thyroxine-binding globulin (TBG) deficiency occurs in all age groups.
  • Inherited TBG deficiency is identifiable at birth.

Clinical

History

Patients may have constitutional symptoms unrelated to thyroxine-binding globulin (TBG) deficiency (eg, fatigue, weight gain, constipation, drowsiness, somnolence, low energy, dry skin, edema) that prompt them to seek medical advice. These symptoms are highly common in the general population and usually lead to extensive investigations, including TFTs and the ultimate diagnosis of TBG deficiency.

  • Most individuals with TBG deficiency are expected to be asymptomatic.
  • Others present to their heath care provider because of conflicting findings from a thyroid function screening test (eg, low total thyroid hormone and normal thyroid-stimulating hormone levels).
  • Identifying medical and nutritional states that may be associated with a secondary deficiency of TBG is very important, because this may indicate important coexisting disease (see Thyroid binding protein deficiency states).
  • A family history of TBG deficiency is suggestive of an inherited state.

Physical

  • No specific findings are associated with inherited deficiency of thyroxine-binding globulin (TBG) upon physical examination.
  • In secondary deficiency of TBG, any clinical findings are attributable to the underlying illness.

Causes

In most cases, the cause of inherited thyroxine-binding globulin (TBG) deficiency (partial or complete) is a mutation of the coding region of the TBG gene, located on the long arm of chromosome X.7 Rarely, other germline genetic defects lead to a familial absence of or reduction in TBG expression. Secondary causes (acquired TBG deficiency) are lack of protein supply or synthesis, loss of urinary protein, and inducement via drugs.

  • States of protein malnutrition, observed in chronic liver or renal diseases, gastrointestinal malnutrition, anorexia, marasmus, and kwashiorkor, are associated with secondary TBG deficiency. These states also usually are associated with moderate to severe albumin and TTR deficiencies.
  • In nephrotic syndrome, TBG, like albumin, TTR, and immunoglobulins, is lost through the kidneys.1

    • Several endocrine conditions, such as Cushing syndrome, acromegaly, and poorly controlled diabetes mellitus, are associated with TBG deficiency. The etiologic basis for this association remains unclear.
    • Long-term treatment with glucocorticoids and androgenic steroids also can cause TBG deficiency.23,24

Differential Diagnoses

Euthyroid Sick Syndrome
Hypothyroidism

Workup

Laboratory Studies

  • Levels of thyroid-stimulating hormone, free T4, and free T3 are normal.
  • Total T4 and total T3 levels are low.
  • Thyroxine-binding globulin (TBG) levels vary, and can be interpreted, as follows:
    • They are decreased in patients with secondary TBG deficiency and incomplete acquired deficiency, but they are undetectable in complete TBG deficiency (males only).
    • The finding of undetectable TBG in female patients denotes laboratory error or the very rare occurrence of homozygosity for TBG gene mutations and TBG mutations in females with Turner syndrome (XO karyotype).25
    • In patients with qualitative defects, the TBG concentration may be normal.
  • Serum thyroglobulin levels are mildly to moderately elevated in one third of patients.

Imaging Studies

  • No imaging studies are necessary for the diagnosis of thyroxine-binding globulin deficiency. Occasionally, however, imaging studies are inappropriately performed for the investigation of possible thyroid function abnormalities, due to the "misleading" laboratory abnormalities. Hence, in selected patients, neck ultrasonography or iodine-123 radioiodine scans and percent-uptake measurements, or other thyroid imaging may have been ordered prior to the patient's referral and the establishment of the diagnosis.

Other Tests

  • In general, additional testing is not indicated except in cases in which secondary thyroxine-binding globulin deficiency is suggested. To further define a qualitative abnormality, procedures involving heat stability, isoelectric focusing, and perhaps gene sequencing may be indicated.

Procedures

  • No surgical or other interventional procedures are necessary to establish a diagnosis of thyroxine-binding globulin (TBG) deficiency.

Histologic Findings

No specific histologic findings are encountered in the pituitary, thyroid gland, or liver (site of thyroxine-binding globulin production).

Treatment

Medical Care

  • The most important aspect of dealing with thyroxine-binding globulin (TBG) deficiency is to recognize and correctly diagnose this condition in order to avoid unnecessary treatment for a mistaken diagnosis of hypothyroidism.26
  • A firm diagnosis of secondary TBG deficiency may be important when it indicates the coexistence of a previously unrecognized or underestimated serious general medical disease. Prompt evaluation of the possible causative conditions (see Thyroid binding protein deficiency states) is mandatory.

Surgical Care

No surgical care is indicated or necessary for patients with thyroxine-binding globulin deficiency.

Consultations

In cases of secondary thyroxine-binding globulin (TBG) deficiency, referral to consultants should be made as appropriate for the evaluation and treatment of the primary disorder.

A geneticist may be of value for selected cases of inherited TBG deficiency. Occasionally, referral to an endocrinologist is necessary because concomitant disease (eg, euthyroid sick syndrome, glucocorticoid therapy, concurrent thyroidopathy) may complicate the laboratory test picture in TBG deficiency, rendering the establishment of the diagnosis almost impossible without expert subspecialty input. Follow-up evaluations with the endocrinologist may be necessary until the concurrent illness subsides.

Diet

Dietary modification or other types of restrictions are not necessary for patients with thyroxine-binding globulin deficiency. In cases of malnutrition/malabsorption, protein supplementation may be necessary.

Activity

No changes in the intensity or frequency of physical activity or exercise patterns are recommended or necessary for patients with thyroxine-binding globulin deficiency.

Medication

Medications are not needed for patients with thyroxine-binding globulin (TBG) deficiency. The condition does not necessitate specific therapy, with the exception of cases of secondary TBG deficiency, in which treatment of the primary disorder is indicated.

Follow-up

Further Inpatient Care

  • No specific further inpatient care is recommended for individuals with thyroxine-binding globulin (TBG) deficiency, except, in cases of secondary TBG deficiency, as indicated for the treatment of the primary disorder.

Further Outpatient Care

  • No specific further outpatient care is recommended, except as indicated for the treatment of the primary disorder in cases of secondary thyroxine-binding globulin (TBG) deficiency. For primary TBG deficiency, family members should be made aware of this benign problem so that unnecessary testing is avoided.

Transfer

  • Usually, no specific transfer requirements exist.

Deterrence/Prevention

  • No deterrence or prevention measures are known for primary thyroxine-binding globulin (TBG) deficiency.
  • For a full discussion of the states or diseases associated with secondary TBG deficiency, refer to specific articles for these conditions.

Complications

  • No known complications from thyroxine-binding globulin deficiency are described. However, patients should be aware of their condition in order to notify their health care providers and avoid misdiagnosis, which could lead to complications from erroneously administered treatment.

Prognosis

  • Prognosis is excellent for patients with inherited thyroxine-binding globulin (TBG) deficiency.
  • The prognosis for patients with secondary forms of TBG deficiency is determined by the severity of the associated medical condition.

Patient Education

  • Patients with inherited forms of thyroxine-binding globulin deficiency should be aware of their condition in order to provide health care professionals with correct information.

Miscellaneous

Medicolegal Pitfalls

  • Failure to avoid unnecessary treatment and evaluation of patients with an inherited form of thyroxine-binding globulin (TBG) deficiency
  • Failure to investigate the cause of secondary forms of TBG deficiency, which may lead to omitting diagnoses of potentially serious medical conditions

References

  1. Chandurkar V, Shik J, Randell E. Exacerbation of underlying hypothyroidism caused by proteinuria and induction of urinary thyroxine loss: case report and subsequent investigation. Endocr Pract. Jan-Feb 2008;14(1):97-103. [Medline].

  2. Lambert M. Thyroid dysfunction in HIV infection. Baillieres Clin Endocrinol Metab. Oct 1994;8(4):825-35. [Medline].

  3. Corrigan DF, Wartofsky L, Dimond RC, et al. Parameters of thyroid function in patients with active acromegaly. Metabolism. Feb 1978;27(2):209-16. [Medline].

  4. Inada M, Sterling K. Thyroxine turnover and transport in active acromegaly. J Clin Endocrinol Metab. Jul 1967;27(7):1019-27. [Medline].

  5. Flink IL, Bailey TJ, Gustafson TA, et al. Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases. Proc Natl Acad Sci U S A. Oct 1986;83(20):7708-12. [Medline]. [Full Text].

  6. Mori Y, Miura Y, Oiso Y, et al. Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization. Hum Genet. Oct 1995;96(4):481-2. [Medline].

  7. Trent JM, Flink IL, Morkin E. Localization of the human thyroxine-binding globulin gene to the long arm of the X chromosome (Xq21-22). Am J Hum Genet. Sep 1987;41(3):428-35. [Medline]. [Full Text].

  8. Gershengorn MC, Lippoldt RE, Edelhoch H, et al. Structure and stability of human thyroxine-binding globulin. J Biol Chem. Dec 10 1977;252(23):8719-23. [Medline].

  9. Janssen OE, Chen B, Buttner C, et al. Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago. J Biol Chem. Nov 24 1995;270(47):28234-8. [Medline]. [Full Text].

  10. Lacka K, Nizankowska T, Ogrodowicz A, et al. A novel mutation (del 1711 G) in the TBG gene as a cause of complete TBG deficiency. Thyroid. Nov 2007;17(11):1143-6. [Medline].

  11. Carvalho GA, Weiss RE, Vladutiu AO, et al. Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene. Thyroid. Feb 1998;8(2):161-5. [Medline].

  12. Miura Y, Hershkovitz E, Inagaki A, et al. A novel mutation causing complete thyroxine-binding globulin deficiency (TBG-CD-Negev) among the Bedouins in southern Israel. J Clin Endocrinol Metab. Oct 2000;85(10):3687-9. [Medline]. [Full Text].

  13. Ueta Y, Mitani Y, Yoshida A, et al. A novel mutation causing complete deficiency of thyroxine binding globulin. Clin Endocrinol (Oxf). Jul 1997;47(1):1-5. [Medline].

  14. Carvalho GA, Weiss RE, Refetoff S. Complete thyroxine-binding globulin (TBG) deficiency produced by a mutation in acceptor splice site causing frameshift and early termination of translation (TBG-Kankakee). J Clin Endocrinol Metab. Oct 1998;83(10):3604-8. [Medline]. [Full Text].

  15. Fingerhut A, Reutrakul S, Knuedeler SD, et al. Partial deficiency of thyroxine-binding globulin-Allentown is due to a mutation in the signal peptide. J Clin Endocrinol Metab. May 2004;89(5):2477-83. [Medline]. [Full Text].

  16. Reutrakul S, Dumitrescu A, Macchia PE, et al. Complete thyroxine-binding globulin (TBG) deficiency in two families without mutations in coding or promoter regions of the TBG genes: in vitro demonstration of exon skipping. J Clin Endocrinol Metab. Mar 2002;87(3):1045-51. [Medline]. [Full Text].

  17. Bigazzi M, Ronga R, Olivotti AL, et al. Inherited X chromosome linked thyroxine-binding globulin (TBG) deficiency in a homozygous female. J Endocrinol Invest. Oct-Dec 1980;3(4):349-52. [Medline].

  18. Vermeer S, Kremer HP, Leijten QH, et al. Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening. J Neurol. Oct 2007;254(10):1356-8. [Medline].

  19. Quelhas D, Quental R, Vilarinho L, et al. Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2. Ann Hum Genet. May 2007;71:348-53. [Medline].

  20. Bhatkar SV, Rajan MG, Velumani A, et al. Thyroid hormone binding protein abnormalities in patients referred for thyroid disorders. Indian J Med Res. Sep 2004;120(3):160-5. [Medline]. [Full Text].

  21. Watson F, Dick M. Distribution and inheritance of low serum thyroxine-binding globulin levels in Australian Aborigines: a new genetic variation. Med J Aust. Oct 4 1980;2(7):385-7. [Medline].

  22. Waltz MR, Pullman TN, Takeda K, et al. Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks. J Endocrinol Invest. Apr 1990;13(4):343-9. [Medline].

  23. Alen M, Rahkila P, Reinila M, et al. Androgenic-anabolic steroid effects on serum thyroid, pituitary and steroid hormones in athletes. Am J Sports Med. Jul-Aug 1987;15(4):357-61. [Medline].

  24. Oppenheimer JH, Werner SC. Effect of prednisone on thyroxine-binding proteins. J Clin Endocrinol Metab. Jul 1966;26(7):715-21. [Medline].

  25. Refetoff S, Selenkow HA. Familial thyroxine-binding globulin deficiency in a patient with Turner's syndrome (XO). Genetic study of a kindred. N Engl J Med. May 16 1968;278(20):1081-7. [Medline].

  26. Gruters A, Krude H. Update on the management of congenital hypothyroidism. Horm Res. 2007;68 Suppl 5:107-11. [Medline].

  27. Bartalena L, Robbins J. Thyroid hormone transport proteins. Clin Lab Med. Sep 1993;13(3):583-98. [Medline].

  28. Bartalena L, Robbins J. Variations in thyroid hormone transport proteins and their clinical implications. Thyroid. Fall 1992;2(3):237-45. [Medline].

  29. Benvenga S, Robbins J. Lipoprotein-thyroid hormone interactions. Trends Endocrinol Metab. Aug 1993;4(6):194-8. [Medline].

  30. Benvenga S, Trimarchi F, Robbins J. Circulating thyroid hormone autoantibodies. J Endocrinol Invest. Dec 1987;10(6):605-19. [Medline].

  31. Bernstein RS, Robbins J, Rall JE. Polymorphism of monkey thyroxin-binding prealbumin (TBPA): mode of inheritance and hybridization. Endocrinology. Feb 1970;86(2):383-90. [Medline].

  32. Bertenshaw R, Takeda K, Refetoff S. Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotide substitutions. Am J Hum Genet. Apr 1991;48(4):741-4. [Medline].

  33. Blomstedt B, Einhorn J. Effect of cortisone on the PBI and the resin uptake I-131- triiodothyronine. Metabolism. Apr 1967;16(4):319-23. [Medline].

  34. Burr WA, Ramsden DB, Hoffenberg R. Hereditary abnormalities of thyroxine-binding globulin concentration. A study of 19 kindreds with inherited increase or decrease of thyroxine-binding globulin. Q J Med. 1980;49(195):295-313. [Medline].

  35. Charbonneau M, Dussault JH, Refetoff S. A study on the inheritance of thyroxine-binding globulin (TBG) deficiency from data obtained in 13 families detected by a neonatal screening program. Clin Invest Med. Feb 1988;11(1):34-9. [Medline].

  36. Domingues R, Bugalho MJ, Garrao A, et al. Two novel variants in the thyroxine-binding globulin (TBG) gene behind the diagnosis of TBG deficiency. Eur J Endocrinol. Apr 2002;146(4):485-90. [Medline]. [Full Text].

  37. Ekins RP, Sinha AK, Pickard MR, et al. Transport of thyroid hormones to target tissues. Acta Med Austriaca. 1994;21(2):26-34. [Medline].

  38. Emerson CH, Seiler CM, Alex S, et al. Gene expression and serum thyroxine-binding globulin are regulated by adrenal status and corticosterone in the rat. Endocrinology. Sep 1993;133(3):1192-6. [Medline]. [Full Text].

  39. Gamstedt A, Jarnerot G, Kagedal B, et al. Effects of betamethasone on serum iodothyronines and thyroid hormone-binding proteins in Graves' disease. Acta Med Scand. 1986;220(3):237-40. [Medline].

  40. Gershengorn MC, Larsen PR, Robbins J. Radioimmunoassay for serum thyroxine-binding globulin: results in normal subjects and in patients with hepatocellular carcinoma. J Clin Endocrinol Metab. May 1976;42(5):907-11. [Medline].

  41. Golden MH. Transport proteins as indices of protein status. Am J Clin Nutr. May 1982;35(5 Suppl):1159-65. [Medline].

  42. Grimaldi S, Bartalena L, Ramacciotti C, et al. Polymorphism of human thyroxine-binding globulin. J Clin Endocrinol Metab. Dec 1983;57(6):1186-92. [Medline].

  43. Hayashi Y, Mori Y, Janssen OE, et al. Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation. Mol Endocrinol. Aug 1993;7(8):1049-60. [Medline].

  44. Heidemann PH, Stubbe P, Beck W. Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: an effect of L- asparaginase. Eur J Pediatr. Jul 1981;136(3):291-5. [Medline].

  45. Herrick AL, McColl KE, Wallace AM, Moore MR, Goldberg A. Elevation of hormone-binding globulins in acute intermittent porphyria. Clin Chim Acta. Feb 28 1990;187(2):141-8. [Medline].

  46. Janssen OE, Astner ST, Grasberger H, et al. Identification of thyroxine-binding globulin-San Diego in a family from Houston and its characterization by in vitro expression using Xenopus oocytes. J Clin Endocrinol Metab. Jan 2000;85(1):368-72. [Medline]. [Full Text].

  47. Janssen OE, Takeda K, Refetoff S. Sequence of the variant thyroxine-binding globulin (TBG) in a Montreal family with partial TBG deficiency. Hum Genet. Jun 1991;87(2):119-22. [Medline].

  48. Kobayashi H, Sakurai A, Katai M, et al. Autosomally transmitted low concentration of thyroxine-binding globulin. Thyroid. Feb 1999;9(2):159-63. [Medline].

  49. Korcek L, Tabachnick M. Thyroxine-protein interactions. Interaction of thyroxine and triiodothyronine with human thyroxine-binding globulin. J Biol Chem. Jun 25 1976;251(12):3558-62. [Medline]. [Full Text].

  50. Langsteger W. Clinical aspects and diagnosis of thyroid hormone transport protein anomalies. Curr Top Pathol. 1997;91:129-61. [Medline].

  51. Li P, Janssen OE, Takeda K, et al. Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene. Metabolism. Nov 1991;40(11):1231-4. [Medline].

  52. Macchia PE, Harrison HH, Scherberg NH, et al. Thyroid function tests and characterization of thyroxine-binding globulin in the carbohydrate-deficient glycoprotein syndrome type I. J Clin Endocrinol Metab. Dec 1995;80(12):3744-9. [Medline]. [Full Text].

  53. Mandel S, Hanna C, Boston B, et al. Thyroxine-binding globulin deficiency detected by newborn screening. J Pediatr. Feb 1993;122(2):227-30. [Medline].

  54. Miura Y, Kambe F, Yamamori I, et al. A truncated thyroxine-binding globulin due to a frameshift mutation is retained within the rough endoplasmic reticulum: a possible mechanism of complete thyroxine-binding globulin deficiency in Japanese. J Clin Endocrinol Metab. Feb 1994;78(2):283-7. [Medline]. [Full Text].

  55. Mori Y, Refetoff S, Flink IL, et al. Detection of the thyroxine-binding globulin (TBG) gene in six unrelated families with complete TBG deficiency. J Clin Endocrinol Metab. Oct 1988;67(4):727-33. [Medline].

  56. Mulaisho C, Utiger RD. Serum thyroxine-binding globulin: determination by competitive ligand- binding assay in thyroid disease and pregnancy. Acta Endocrinol (Copenh). Jun 1977;85(2):314-24. [Medline].

  57. Munro SL, Lim CF, Hall JG. Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin. J Clin Endocrinol Metab. Jun 1989;68(6):1141-7. [Medline].

  58. Murata Y, Magner JA, Refetoff S. The role of glycosylation in the molecular conformation and secretion of thyroxine-binding globulin. Endocrinology. Apr 1986;118(4):1614-21. [Medline].

  59. Murata Y, Takamatsu J, Refetoff S. Inherited abnormality of thyroxine-binding globulin with no demonstrable thyroxine-binding activity and high serum levels of denatured thyroxine-binding globulin. N Engl J Med. Mar 13 1986;314(11):694-9. [Medline].

  60. Narendran P, Lado-Abeal J, Moeller LC, et al. Partial thyroxine-binding globulin (TBG) deficiency in a family with no detectable mutation of the TBG gene. Clin Endocrinol (Oxf). Dec 2003;59(6):824-5. [Medline].

  61. Okamoto H, Mori Y, Tani Y, et al. Molecular analysis of females manifesting thyroxine-binding globulin (TBG) deficiency: selective X-chromosome inactivation responsible for the difference between phenotype and genotype in TBG-deficient females. J Clin Endocrinol Metab. Jun 1996;81(6):2204-8. [Medline].

  62. Peters T Jr. Serum albumin. Adv Protein Chem. 1985;37:161-245. [Medline].

  63. Refetoff S. Thyroid hormone transport proteins: thyroxine-binding globulin, transthyretin, and albumin. In: Henry HL, Norman AW, eds. Encyclopedia of Hormones. 3rd ed. New York, NY: Academic Press; 2003:483-90.

  64. Refetoff S, Fang VS, Marshall JS. Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess. J Clin Invest. Feb 1976;57(2):485-95. [Medline]. [Full Text].

  65. Refetoff S, Murata Y, Mori Y. Thyroxine-binding globulin: organization of the gene and variants [published erratum appears in Horm Res 1996 Jul;46(1):37]. Horm Res. 1996;45(3-5):128-38. [Medline].

  66. Refetoff S, Robin NI, Alper CA. Study of four new kindreds with inherited thyroxine-binding globulin abnormalities. Possible mutations of a single gene locus. J Clin Invest. Apr 1972;51(4):848-67. [Medline]. [Full Text].

  67. Reutrakul S, Janssen OE, Refetoff S. Three novel mutations causing complete T(4)-binding globulin deficiency. J Clin Endocrinol Metab. Oct 2001;86(10):5039-44. [Medline]. [Full Text].

  68. Robbins J. Inherited variations in thyroxine transport. Mt Sinai J Med. May-Jun 1973;40(3):511-9. [Medline].

  69. Sarne D, Barokas K, Scherberg NH. Elevated serum thyroglobulin level in congenital thyroxine-binding globulin deficiency. J Clin Endocrinol Metab. Sep 1983;57(3):665-7. [Medline].

  70. Schollen E, Pardon E, Heykants L. Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. Hum Mol Genet. Feb 1998;7(2):157-64. [Medline]. [Full Text].

  71. Schussler GC. The thyroxine-binding proteins. Thyroid. Feb 2000;10(2):141-9. [Medline].

  72. Seo H. Mutations of the thyroxine-binding globulin gene in Japanese. Intern Med. Apr 1996;35(4):237. [Medline]. [Full Text].

  73. Snyder SM, Cavalieri RR, Goldfine ID. Binding of thyroid hormones and their analogues to thyroxine-binding globulin in human serum. J Biol Chem. Nov 10 1976;251(21):6489-94. [Medline]. [Full Text].

  74. Snyder SM, Cavalieri RR, Goldfine ID. The binding of thyroid hormone analogues to thyroxine binding globulin (TBG). In: Robbins J, Braverman LE, eds. Thyroid Research: Proceedings of the Seventh International Thyroid Conference, Boston, Massachusetts, June 9-13, 1975. New York, NY: Elsevier; 1976:297-9.

  75. Su CC, Wu YC, Chiu CY, et al. Two novel mutations in the gene encoding thyroxine-binding globulin (TBG) as a cause of complete TBG deficiency in Taiwan. Clin Endocrinol (Oxf). Apr 2003;58(4):409-14. [Medline]. [Full Text].

  76. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med. Dec 21 1995;333(25):1688-94. [Medline].

  77. Takamatsu J, Refetoff S, Charbonneau M. Two new inherited defects of the thyroxine-binding globulin (TBG) molecule presenting as partial TBG deficiency. J Clin Invest. Mar 1987;79(3):833-40. [Medline]. [Full Text].

  78. Tojo K, Miura Y, Mori Y, et al. Familial thyroxine-binding globulin deficiency associated with hyperthyroidism. Intern Med. May 1995;34(5):413-7. [Medline]. [Full Text].

  79. Vassart G, Dumont JE, Refetoff S. Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:2908-11.

  80. Zinn AB, Marshall JS, Carlson DM. Carbohydrate structures of thyroxine-binding globulin and their effects on hepatocyte membrane binding. J Biol Chem. Oct 10 1978;253(19):6768-73. [Medline]. [Full Text].

Keywords

thyroxine-binding globulin deficiency, thyroid, thyroid disease, thyroid gland, thyroid hormone, thyroxine, albumin, protein binding, thyroid levels, prealbumin, triiodothyronine, thyroid hormones, TH, T4, T3, thyroxine binding globulin, thyroxine-binding globulin, TBG, transthyretin, TTR, prealbumin, serum lipoproteins

Contributor Information and Disclosures

Author

Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Nicholas J Sarlis, MBBS, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Therapeutic Radiology and Oncology, American Society of Clinical Oncology, American Thyroid Association, Association for Psychological Science, Endocrine Society, European Society for Medical Oncology, New York Academy of Sciences, and Royal Society of Medicine
Disclosure: Sanofi-Aventis Salary Employment

Coauthor(s)

Boaz Hirshberg, MD, Associate Director, CVMD, Pfizer
Boaz Hirshberg, MD is a member of the following medical societies: American Dietetic Association
Disclosure: Nothing to disclose.

Medical Editor

Harris C Taylor, MD, Clinical Professor of Medicine, Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine
Harris C Taylor, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)