Thyroxine-Binding Globulin Deficiency

Etiology

Thyroxine-binding globulin (TBG) is a serine protease inhibitor produced in the liver. It belongs to the SERPINA7 family. The encoding gene for this protein is on the long arm of the X chromosome and as such, inherited forms of TBG tend to follow an X-linked pattern. Approximately 27 different mutations have been identified to play a role in the etiology of the inherited form of complete TBG deficiency thus far. These mutations seem to be caused by a nucleotide substation or by a frameshift.  Missense mutations have been the only type identified so far in an inherited form of partial TBG deficiency.[1]

Acquired forms of TBG deficiency are attributable to degradation and altered synthesis of the molecule. Patients with hyperthyroidism have been found to have an increase in the rate of turnover of TBG.  In terminal illness, interleukin-6 seems to play a role in altering the levels of TBG. Levels of TBG have been found to vary with fluctuations in sex hormones as well.  For example, estrogen has been known to cause an increase in TBG, while androgens have been found to decrease levels TBG.[3]

Epidemiology

The most common inherited form of TBG deficiency is partial TBG deficiency with a prevalence of 1 in 4000 newborns.  Complete TBG deficiency has an incidence of 1 per 15000 male newborns. There has been no reported increase in the predilection of TBG deficiency in a particular race.[4]

Pathophysiology

The primary function of TBG is to help maintain the constant pool of thyroid hormone in the serum.  Research estimates that in the absence of new thyroid hormone production, the amount already present in the serum would be used within just a few hours.  However, in the presence of TBG, there would be only a 10% drop in T4 and a 40% drop in T3. As such, TBG can also be noted to play a role in preventing thyroid hormone fluctuations.[3]

When there is a decrease in TBG, the levels of free T4 increase and negatively inhibit TSH, resulting in a reduction of the total T4 produced. Thus, the total T4 decreases and the free T4 in serum returns to normal levels.[5]

History and Physical

Though there are no clinical signs and symptoms particular to TBG deficiency, there is usually a strong family history in inherited forms of TBG deficiency.  Patients with acquired TBG deficiency may present with symptoms consistent with an underlying illness such as severe liver disease or protein-wasting nephropathy.  The patient's history could also suggest the use of anabolic steroids or androgens. Physical examinations are within normal limits, in both acquired and inherited forms and any variation are usually be attributable to a secondary disease process.[6] For example, a female patient with complete TBG deficiency may present with features of Turner syndrome, including webbed neck and short stature.[7]

Evaluation

In cases of inherited thyroid binding globulin deficiency, the disorder is often picked up on the newborn screening during the evaluation of congenital hypothyroidism. The newborn screening often looks at either TSH, total T4, or both.   If the total T4 is below the serum cut off, the screen comes back as a positive result.[8] Confirmatory testing with TBG, free T4, and TSH help rule out congenital hypothyroidism and rule in the diagnosis of TBG deficiency.[9] Thyroxine-binding globulin has been found to be present in the serum of a fetus as early as at 12 weeks gestation. The level of TBG is approximately 1.5 times that of an adult until adolescence at which point it starts to decrease.[10] Affected boys have been found to have mild, moderate and severe changes in thyroid hormone levels; whereas girls have been rarely found to have critical changes in thyroid hormone levels except in the instance of Turner syndrome. The normal level TBG in an adult male is 1.1 to 2.1 mg/dl.[3] In a hemizygous male with complete TBG deficiency, TBG is found to be below 5 mg/L. In hemizygous females with partial TBG deficiency, serum levels of TBG are near normal.[1]  TBG deficiency can also present as an incidental finding.  In such cases, if other causes of TBG deficiency are ruled out, suspicion for inherited TBG deficiency should be high and should prompt genetic testing for confirmation.  

Treatment / Management

Management of secondary illness, causing acquired TBG deficiency, may improve levels of TBG.  However, replacement with l-thyroxine is not required, as there is no change in the levels of metabolically active free T4 levels. 

Differential Diagnosis

The differential diagnosis for TBG deficiency includes central hypothyroidism and euthyroid sick syndrome. Laboratory testing for patients with central hypothyroidism shows low FT4, low Total T4 along with low or inappropriately normal TSH levels. Central hypothyroidism may be congenital or acquired. Some critically ill euthyroid patients with non-thyroidal illness may also present with low FT4, low T4 along with low TSH. However, most of these patients present with high reverse T3 levels due to reduced clearance of Reverse T3. These abnormalities usually resolve with resolution of non-thyroid illness. 

Prognosis

TBG deficiency is a benign condition, and the prognosis is favorable. Patients with inherited forms need reassurance only and should receive education about the nature of the condition. 

Complications

Complications can arise from misinterpretation of total T4 levels. As such, iatrogenic symptoms and the manifestations of hyperthyroidism may occur as a result of inappropriate treatment with levothyroxine.