Thyroxine-binding on the TBG molecule. The ?-sheet

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 binding to the carrier proteins TBG, transthyretin (TTR), or albumin. A small
portion of all T3 and T4 hormones remain unattached 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,
yet it’s 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 or
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

We Will Write a Custom Essay about Thyroxine-binding on the TBG molecule. The ?-sheet
For You For Only $13.90/page!

order now

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 procedures that can be implemented to determine the thyroid standing
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 yielding false negative results. This type of test may also
differentiate between euthyroidism and hyperthyroidism.7 Serum TBG
is a favorable 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 syndromes. 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 circumstance, TSH
was within the standard 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.