CLINICAL CASES
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within the follicular cell that result in the secretion of the thyroid hormones
thyroxine (T4; 3,5,3',5'-tetraiodo-L-thyronine) and 3,5,3'a-triiodo-L-
thyronine (T3). These events include increases in
1.
The transport of iodide ions across the basolateral membrane into the
thyroid follicular cell via the Na/I cotransporter (NIS)
2.
Iodination of tyrosine residues on colloidal thyroglobulin in the lumen
of the follicle
3.
Conjugation of iodinated tyrosines to form T3 and T4 on thyroglobulin
4.
The endocytosis of thyroglobulin into the follicular cell from the lumen
5.
The hydrolysis of thyroglobulin in the lysosome to release T3 and T4
6.
The secretion of T3 and T4 into the bloodstream
Although the thyroid hormones are derived from amino acids, they act in
a fashion similar to that of the steroid hormones. In the circulation, almost
all of the thyroid hormones (99.98 percent of T4 and 99.5 percent of T3) are
tightly bound to the proteins thyroxine binding globulin (TBG), albumin, and
transthyretin. However, the free, or “unbound,” T3 and T4 are responsible for the
biological effects of the thyroid hormones. The thyroid hormones enter the cell
either by simple or carrier-mediated diffusion across the cell membrane.
Within the cytoplasm, approximately 50 percent of T4 is deiodinated to form T3.
The hormones enter the nucleus where they bind to the thyroid hormone
receptor (THR). The affinity of the THR is approximately 10 times greater
for T3 than it is for T4, one reason why T3 is more biologically active than T4.
When T3 or T4 bind to THR, the complex is able to bind to the thyroid response
element of specific genes. The net effect of increased thyroid hormones is an
increase in basal metabolic rate. This is accomplished by increasing the
expression of genes that code for enzymes in both the catabolic and anabolic
pathways of fats, carbohydrates and proteins, as well as the expression of
the Na-K pump. The careful regulation of thyroid hormone secretion is there-
fore important in the overall regulation of metabolism. Thus, T3 and T4 exert a
negative feedback inhibition on the synthesis of TRH by the hypothalamus and
the secretion of TSH by the anterior pituitary, so that the levels of T3 and T4
are tightly controlled.
Graves disease is an autoimmune disease in which the B lymphocytes syn-
thesize an immunoglobulin that binds to and activates the TSH receptor on
the thyroid follicular cell membrane. This thyroid-stimulating immunoglobulin
(TSIg) binds to and activates the TSH receptor in such a way that T3 and T4 do
not feedback inhibit the receptor-effector interaction. Thus, all of the processes
enumerated above that are sequelae of the TSH receptor binding hormone are
increased resulting in a hyperthyroid condition.
Nonsurgical treatments for Graves disease include administration of thion-
amide antithyroid drugs, which include propylthiouracil (PTU) and methi-
mazole, and/or treatment with radioactive iodine. The thionamides act by
inhibiting the enzyme thyroid peroxidase, an enzyme on the apical mem-
brane of the thyroid follicular cell that faces the lumen. This enzyme catalyzes
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