Ganong's Review of Medical Physiology, 23rd Edition

CLINICAL BOX 20–1
Reduced Thyroid Function
The syndrome of adult hypothyroidism is generally called myxedema,
although this term is also used to refer specifically to the
skin changes in the syndrome. Hypothyroidism may be the end
result of a number of diseases of the thyroid gland, or it may be
secondary to pituitary or hypothalamic failure. In the latter two
conditions, the thyroid remains able to respond to TSH. Thyroid
function may be reduced by a number of conditions (Table 20–
3). For example, when the dietary iodine intake falls below 50
μg/d, thyroid hormone synthesis is inadequate and secretion declines.
As a result of increased TSH secretion, the thyroid hypertrophies,
producing an iodine deficiency goiter that may become
very large. Such “endemic goiters” have been substantially
reduced by the practice of adding iodide to table salt. Drugs may
also inhibit thyroid function. Most do so either by interfering
with the iodide-trapping mechanism or by blocking the organic
binding of iodine. In either case, TSH secretion is stimulated by
the decline in circulating thyroid hormones, and a goiter is produced.
The thioureylenes, a group of compounds related to
thiourea, inhibit the iodination of monoiodotyrosine and block
the coupling reaction. The two used clinically are propylthiouracil
and methimazole (Figure 20–11). Iodination of tyrosine is inhibited
because propylthiouracil and methimazole compete
with tyrosine residues for iodine and become iodinated. In addition,
propylthiouracil but not methimazole inhibits D 2 deiodinase,
reducing the conversion of T 4 to T 3 in many extrathyroidal
tissues. Paradoxically, another substance that inhibits thyroid
function under certain conditions is iodide itself. In normal individuals,
large doses of iodide act directly on the thyroid to produce
a mild and transient inhibition of organic binding of iodide
and hence of hormone synthesis. This inhibition is known as the
Wolff–Chaikoff effect.
(RXR). The TR/RXR heterodimer does not bind 9-cis retinoic
acid, the usual ligand for RXR, but TR binding to DNA is
greatly enhanced in response to thyroid hormones when the
receptor is in the form of this heterodimer. There are also
coactivator and corepressor proteins that affect the actions of
TABLE 20–3 Causes of congenital hypothyroidism.
Maternal iodine deficiency
Fetal thyroid dysgenesis
Inborn errors of thyroid hormone synthesis
Maternal antithyroid antibodies that cross the placenta
Fetal hypopituitary hypothyroidism
CHAPTER 20 The Thyroid Gland 309
In completely athyreotic adults, the BMR falls to about 40%.
The hair is coarse and sparse, the skin is dry and yellowish
(carotenemia), and cold is poorly tolerated. Mentation is slow,
memory is poor, and in some patients there are severe mental
symptoms (“myxedema madness”). Plasma cholesterol is elevated.
Children who are hypothyroid from birth or before are
called cretins. They are dwarfed and mentally retarded.
Worldwide, congenital hypothyroidism is one of the most
common causes of preventable mental retardation. The main
causes are included in Table 20–3. They include not only maternal
iodine deficiency and various congenital abnormalities
of the fetal hypothalamo–pituitary–thyroid axis, but also maternal
antithyroid antibodies that cross the placenta and
damage the fetal thyroid. T 4 crosses the placenta, and unless
the mother is hypothyroid, growth and development are normal
until birth. If treatment is started at birth, the prognosis for
normal growth and development is good, and mental retardation
can generally be avoided; for this reason, screening tests
for congenital hypothyroidism are becoming routine. When
the mother is hypothyroid as well, as in the case of iodine deficiency,
the mental deficiency is more severe and less responsive
to treatment after birth. It has been estimated that 20 million
people in the world now have various degrees of brain
damage caused by iodine deficiency in utero.
Uptake of tracer doses of radioactive iodine can be used to
assess thyroid function (contrast this with the use of large
doses to ablate thyroid tissue in cases of hyperthyroidism
(Clinical Box 20–2). An analysis of the kinetics of iodine handling
also provides insights into the basic physiology of the
gland (Figure 20–12).
TRs. Presumably, this complexity underlies the ability of thyroid
hormones to produce many different effects in the body.
In most of its actions, T 3 acts more rapidly and is three to
five times more potent than T 4 (Figure 20–13). This is
because T 3 is less tightly bound to plasma proteins than is T 4 ,
but binds more avidly to thyroid hormone receptors. RT 3 is
inert (see Clinical Box 20–3).
H N C O
S
H
C C H
N
C C 3 H 7
Propylthiouracil
CH 3
FIGURE 20–11 Structure of commonly used thioureylenes.
HS
N
C
N
C
H
C H
Methimazole