Excerpt from Thyroxine-Binding Globulin Deficiency

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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.

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