eMedicine Specialties > Endocrinology > Thyroid

Thyroxine-Binding Globulin Deficiency

Author: Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Coauthor(s): Boaz Hirshberg, MD, Associate Director, CVMD, Pfizer
Contributor Information and Disclosures

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

More on Thyroxine-Binding Globulin Deficiency

Overview: Thyroxine-Binding Globulin Deficiency
Differential Diagnoses & Workup: Thyroxine-Binding Globulin Deficiency
Treatment & Medication: Thyroxine-Binding Globulin Deficiency
Follow-up: Thyroxine-Binding Globulin Deficiency
References
[ CLOSE WINDOW ]

References

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Further Reading

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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

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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.

 
 
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