AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The thyroid hormones (TH), 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 TH are thyroxine-binding globulin (TBG), transthyretin (TTR, or prealbumin), and albumin. A minor proportion of TH 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). 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 syndrome

• Chronic renal failure

• Chronic liver disease

• Severe systemic illness (except HIV/AIDS and acute intermittent porphyria)

• Malnutrition

• Acromegaly (in very rare cases only)

• Cushing syndrome

• Drugs (eg, androgens, glucocorticoids, L-asparaginase)

Pathophysiology

TBG is a 395 amino acid, 54-kd polypeptide that is synthesized in the liver and is encoded by a single gene copy. The gene locus in humans is on chromosome band Xq22. TBG is a member of the serine protease inhibitor (SERPIN) superfamily, to which cortisol-binding globulin (CBG), antithrombin III, and angiotensinogen also belong. However, notably, 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 would allow large concentrations of TH 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.

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 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. 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. Additionally, in the case of a single pedigree, partial TBG deficiency was caused by a mutation in the signal peptide for that protein, ie, in the absence of mutation within the mature peptide. Finally, 2 pedigrees have been described where in the DNA of the affected members with complete TBG deficiency, no mutations are found in either the signal peptide or 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. Over the last few years, the genetic mechanisms leading to TBG deficiency have become increasingly complex in their variety.

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 counter-balanced 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 transient small 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 (Tg) 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.

Inherited TBG deficiency also has been described within the context of another genetic syndrome, CDG1 (ie, congenital disorder of glycosylation type 1) or Jaeken syndrome. The features of this syndrome are psychomotor retardation, cerebellar ataxia, peripheral sensorimotor neuropathy, skeletal abnormalities, lipodystrophy, and retinitis pigmentosa. CDG1 is caused by mutations in phosphomannomutase 2 and shows autosomal recessive inheritance. 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 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 recent 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 (Bhatkar, 2004). The incidence and prevalence of secondary TBG deficiency is unknown.

Mortality/Morbidity

• This disorder 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 TBGs have been described with high frequency in certain populations. TBG-A presents with moderate TBG deficiency in Australian Aborigines, with an allele frequency of 50%. TBG-S is associated with mild TBG deficiency and has an allele frequency of 4-12% in black African and Pacific Island populations.
• Notably, TBG gene polymorphisms that do not lead to abnormal serum TH levels have been described in both African and American black persons.

Sex

• No differences in the incidence and prevalence of acquired TBG deficiency are reported between men and women.
• 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

• TBG deficiency occurs in all age groups.
• Inherited TBG deficiency is identifiable at birth.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients may have constitutional symptoms unrelated to this disorder (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 TH and normal TSH 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 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 TBG deficiency (partial or complete) is a mutation of the coding region of the TBG gene, located on the long arm of chromosome X. Rarely, other germline genetic defects lead to 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, as are 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 the nephrotic syndrome, TBG, like albumin, TTR, and immunoglobulins, are lost through the kidneys.
  
  
  • 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• TSH, free T4, and free T3 levels are normal.
• Total T4 and total T3 levels are low.
• TBG levels are discussed 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 girls with Turner syndrome (XO karyotype).

  • In patients with qualitative defects, the TBG concentration may be normal.

• Serum Tg levels are mildly to moderately elevated in one third of patients.

Imaging Studies

• No imaging studies are necessary for the diagnosis of this disorder. Unfortunately, occasionally imaging studies are inappropriately performed for the investigation of possible thyroid functional 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 establishment of the diagnosis.

Other Tests

• In general, additional testing is not indicated except in cases in which secondary TBG 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 for the establishment of the diagnosis.

Histologic Findings

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The most important aspect of TBG deficiency is to recognize and correctly diagnose this condition in order to avoid unnecessary treatment for a mistaken diagnosis of hypothyroidism.
• 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.

Consultations

In cases of secondary 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 any type of restriction is not necessary for this disorder. 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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medications are not needed. 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

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• No specific further inpatient care is recommended, except as indicated for the treatment of the primary disorder in cases of secondary TBG deficiency only.

Further Outpatient Care

• No specific further outpatient care is recommended, except as indicated for the treatment of the primary disorder in case of secondary TBG deficiency only. For primary TBG deficiency, family members should be made aware of this benign problem to avoid unnecessary testing.

Transfer

• Usually, no specific transfer requirements exist.

Deterrence/Prevention

• No deterrence or prevention measures are known for primary TBG deficiency.
• For states or diseases associated with secondary TBG deficiency, refer to the specific article for full discussion of the topic.

Complications

• No known complications from TBG deficiency are described. However, patients should be aware of their condition in order to notify their health care providers and avoid complications of erroneously administered treatment in case of misdiagnosis of this condition.

Prognosis

• Prognosis is excellent for patients with inherited 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 TBG deficiency should be aware of their condition in order to provide future health care professionals with correct information.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to avoid unnecessary treatment and evaluation of patients with an inherited form of 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 12, 2006