Thyroxine-binding globulin (TBG) isone of the three main proteins that carries thyroid hormones.
The thyroidhormones thyroxine (T4) and triiodothyronine (T3) circulate in the bloodstreamby binding to the carrier proteins TBG, transthyretin (TTR), or albumin. A smallportion of all T3 and T4 hormones remain unattached and are metabolicallyactive in tissues and cells.1 TBG is produced in the liver. Itfunctions to assist in controlling cell development and the body’s rate of metabolismby transporting thyroxine in the blood. It is a small molecule formed by thelinkage of two tyrosines which are iodinated to give alternative forms of the hormonethyroxine. TBG has retained the distinctive framework structure of theinhibitory members of its family, including ?1-antitrypsin, antithrombin, and antichymotrypsin,yet it’s not a protease inhibitor itself. It’s also reserved the reactive siteloop with the P1 reactive center, as well as the hinge of the loop 17 residuesbefore it.
Thyroxine is transported in a surface pocket present on the TBGmolecule. The ?-sheet of TBG is fully opened so that the reactive center loopmay easily move in and out of the sheet to attach to or let go ofthyroxine. An open ?-sheet is not a typical characteristicof serpins, the family of proteins to which TBG belongs.1It is important to monitor TBGconcentration because it can indicate whether a patient has a certain diseaseor disorder. There are several sources, including genetic and acquired, thatcan affect TBG concentration.
For example, TBG gene defects, X-linked partial orcomplete deficiency, and autosomal recessive carbohydrate-deficientglycoprotein syndrome type 1 (CDG1) can cause genetic TBG deficiency.2Chromosomal abnormalities of inherited origin correspond with the location ofthe TBG gene on the long arm of the X-chromosome, thus always resulting in anX-linked disorder. The partial deficiency of TBG is the most common form ofinherited TBG deficiencies. All partial deficiency cases are caused by missensemutations which result in the TBG molecule being unstable or having a lowbinding affinity to thyroxine. The complete deficiency of TBG may be caused bya single nucleotide substitution, a frameshift mutation due to the deletion ofone nucleotide, the deletion of 19 nucleotides, or mutations occurring inintrons close to splicing sites, which all lead to the early termination of thegene during translation.3 Chronic renal failure, nephroticsyndrome, acromegaly, chronic liver disease, severe systemic illness, Cushing’ssyndrome, malnutrition, or drug classes including glucocorticoids,L-asparaginase, and androgens can all cause an acquired deficiency of TBG.2Inherited abnormalities causing TBG excess are less common than those causinginsufficiencies. Grave’s disease is an autoimmune disorder, and is the mostcommon cause of hyperthyroidism.
4 They are caused by geneduplication or triplication, which were discovered by measuring PCR productswith high performance liquid chromatography. Other causes of hyperthyroidismand increased TBG include a toxic nodule or multinodular goiter (lumps in thethyroid gland), pregnancy in women, or the inflammation of the thyroid gland(thyroiditis).5Altercations of TBG levels lead tothe total T3 and T4 concentrations falling outside of the normal referenceranges, which may not represent the underlying thyroid dysfunction. Forexample, increased TBG may produce an increase in the total T3 and T4, but willnot necessarily increase their hormone activity.
6 There are,however, several procedures that can be implemented to determine the thyroid standingin a patient that has altered TBG levels. These tests should always beconducted on diabetic patients, and they include directly measuring serumconcentrations of T3, T4, or the thyroid stimulating hormone (TSH), indirectlymeasuring T3 resin uptake (T3RU) or the free T4 index (FT4I), or by assessingthe serum TBG. Measuring TSH is the test most often consulted when detectingthe presence of primary hyperthyroidism or to determine hyperthyroid states. Ithas been noted as the most useful test, especially when considering the thirdgeneration chemiluminometric assay because of its increased sensitivity andlower chance of giving false negative results. This type of test may alsodifferentiate between euthyroidism and hyperthyroidism.7 Serum TBGis a good indicator for disorders including hyperthyroidism and hypothyroidism.Serum T3 and T4 are often measured by a radioimmunoassay (RIA),chemiluminometric assay, or similar techniques.7 In the case of the 31-year-old manmentioned earlier, the patient experienced hyperthyroidism.
He was treated withdrugs that inhibit thyroid hormone synthesis and the conversion of T4 to T3,which resulted in symptoms caused by hypothyroidism. Based on the patient’s physicalexamination and lack of adenopathy, it is likely that the patient’shyperthyroidism was not caused by thyroiditis or nodular or multinodular goitersin the thyroid gland. Since TBG can sometimes affect the readings of thyroidfunction tests, the first assay that should be conducted is the serum TSH thirdgeneration chemiluminometric assay. It is highly sensitive and is often thefirst choice of testing due to its high accuracy and ability to differentiatebetween disorders. However, there are a few cases where normal results of TSHcan be misleading.
Under these circumstances, it is necessary to examine thevalues of total T4 or T3 as well. In the patient’s case, TSH was within thenormal range; however, total T4 and TBG were highly elevated. There are severalconditions in which this can happen. They are Grave’s disease, pituitarydisease, and thyroid hormone resistance. To determine the diagnosis, othertests that were previously discussed may be conducted.