Thyroxine-binding the blood. It is a small molecule formed

Thyroxine-binding globulin (TBG) is
one of the three main proteins that carries thyroid hormones. The thyroid
hormones thyroxine (T4) and triiodothyronine (T3) circulate in the bloodstream
by reversibly binding to the carrier proteins TBG, transthyretin (TTR), or
albumin. A small portion of all T3 and T4 hormones remain unbound and are
metabolically active in tissues and cells.1 TBG is produced in the
liver. It functions to assist in controlling cell development and the body’s rate
of metabolism by transporting thyroxine in the blood. It is a small molecule
formed by the linkage of two tyrosines which are iodinated to give alternative
forms of the hormone thyroxine. TBG has retained the distinctive framework
structure of the inhibitory members of its family, including ?1-antitrypsin, antithrombin,
and antichymotrypsin, though it is not a protease inhibitor itself. It’s
also reserved the reactive site loop with the P1 reactive center, as well as
the hinge of the loop 17 residues before it. Thyroxine is transported in a
surface pocket present on the TBG molecule. The ?-sheet of TBG is fully
opened so that the reactive center loop may easily move in and out of the sheet
to attach to or let go of thyroxine. An open
?-sheet is not a typical characteristic of serpins, the family
of proteins to which TBG belongs.1

It is important to monitor TBG
concentration because it can indicate whether a patient has a certain disease
or disorder. There are several sources, including genetic and acquired, that
can affect TBG concentration. For example, TBG gene defects, X-linked partial
deficiency and complete deficiency, and autosomal recessive carbohydrate-deficient
glycoprotein syndrome type 1 (CDG1) can cause genetic TBG deficiency.2
Chromosomal abnormalities of inherited origin correspond with the location of
the TBG gene on the long arm of the X-chromosome, thus always resulting in an
X-linked disorder. The partial deficiency of TBG is the most common form of
inherited TBG deficiencies. All partial deficiency cases are caused by missense
mutations which result in the TBG molecule being unstable or having a low
binding affinity to thyroxine. The complete deficiency of TBG may be caused by
a single nucleotide substitution, a frameshift mutation due to the deletion of
one nucleotide, the deletion of 19 nucleotides, or mutations occurring in
introns close to splicing sites, which all lead to the early termination of the
gene during translation.3

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Chronic renal failure, nephrotic
syndrome, acromegaly, chronic liver disease, severe systemic illness, Cushing’s
syndrome, malnutrition, or drug classes including glucocorticoids,
L-asparaginase, and androgens can all cause an acquired deficiency of TBG.2
Inherited abnormalities causing TBG excess are less common than those causing
insufficiencies. Grave’s disease is an autoimmune disorder, and is the most
common cause of hyperthyroidism.4 They are caused by gene
duplication or triplication, which were discovered by measuring PCR products
with high performance liquid chromatography. Other causes of hyperthyroidism
and increased TBG include a toxic nodule or multinodular goiter (lumps in the
thyroid gland), pregnancy in women, or the inflammation of the thyroid gland

Altercations of TBG levels lead to
the total T3 and T4 concentrations falling outside of the normal reference
ranges, which may not represent the underlying thyroid dysfunction. For
example, increased TBG may produce an increase in the total T3 and T4, but will
not necessarily increase their hormone activity.6 There are,
however, several tests that can be performed to determine the thyroid status in
a patient that has altered TBG levels. These tests should always be conducted
on diabetic patients, and they include directly measuring serum concentrations
of T3, T4, or the thyroid stimulating hormone (TSH), indirectly measuring T3
resin uptake (T3RU) or the free T4 index (FT4I), or by assessing the serum TBG.
Measuring TSH is the test most often consulted when detecting the presence of
primary hyperthyroidism or to determine hyperthyroid states. It has been noted
as the most useful test, especially when considering the third generation
chemiluminometric assay because of its increased sensitivity and lower chance
of giving false negative results. This type of test may also differentiate
between euthyroidism and hyperthyroidism.7 Serum TBG is 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 man
mentioned earlier, the patient experienced hyperthyroidism. He was treated with
drugs that inhibit thyroid hormone synthesis and the conversion of T4 to T3,
which resulted in symptoms caused by hypothyroidism. Based on the patient’s physical
examination and lack of adenopathy, it is likely that the patient’s
hyperthyroidism was not caused by thyroiditis or nodular or multinodular goiters
in the thyroid gland. Since TBG can sometimes affect the readings of thyroid
function tests, the first assay that should be conducted is the serum TSH third
generation chemiluminometric assay. It is highly sensitive and is often the
first choice of testing due to its high accuracy and ability to differentiate
between disorders. However, there are a few cases where normal results of TSH
can be misleading. Under these circumstances, it is necessary to examine the
values of total T4 or T3 as well. In the patient’s case, TSH was within the
normal range; however, total T4 and TBG were highly elevated. There are several
conditions in which this can happen. They are Grave’s disease, pituitary
disease, and thyroid hormone resistance. To determine the diagnosis, other
tests that were previously discussed may be conducted.