774
chapter 33
Endocrine Metabolism IV: Thyroid Gland
of iodine. With lower iodine intake (e.g., 50-150 /zg/d),
T
4
production increases due to increased efficiency in io-
dide processing and to a greater response to TSH; in fact,
although plasma TSH levels are within the normal range,
a mild enlargement of the gland is not an uncommon con-
sequence (e.g., nontoxic goiter). On the other hand, with
a diet enriched in iodine (e.g.,
1 - 2
mg/d), the increase in
T4
production as a function of iodine consumption is sub-
normal, due to negative feedback of the organified iodide
pool on
T4
production and the thyroid response to TSH;
as a result, plasma TSH levels are maintained within the
normal range.
Abnormal thyroid function is seen at the extremes of
iodine intake: at the lower end, less than 50 /zg/d; at the
upper end, 5 mg/d or more. At the lower end, frank hy-
pothyroidism occurs because there is an insufficient supply
of iodine to meet the
T4
production demands despite the ef-
ficiency with which the limited iodide is used. In this con-
dition, the iodide deficiency creates an organified iodide
pool consisting of MITs and a paucity of DITs, and, con-
sequently, little or no coupling occurs because substrate
requirements are not met. Products of Tg digestion are
mainly MITs, small amounts of DITs, and possibly some
T
3
and T4. The decrease in thyroid hormone increases
output of TSH which, in its futile attempt to increase
T
4
production, creates glandular overgrowth due to thy-
rocyte hypertrophy and colloid accumulation (“hypothy-
roid goiter,” “colloid goiter,” or “endemic goiter”). At
the upper end, further increase in iodine intake causes
a shut-down of thyroid gland function and acutely re-
duces the thyroid response to TSH; consequently, there
is a paradoxical decline in
T4
production as a function
of iodine consumption accompanied by a dramatic reduc-
tion in vascular supply to the gland. This phenomenon is
called the Wolff-Chaikoff effect and is observed only in
thyroid glands that are stimulated (e.g., with TSH or in
hyperthyroidism).
33.3 Transport and Metabolism of
Thyroid Hormones
Thyroid hormones in blood are mainly bound to serum
proteins. The major thyroid hormone-binding protein in
blood is
thyroxine-binding globulin
(TBG), a glycopro-
tein (M.W. 63,000) of electrophoretic mobility between
that of cci- and «
2
-globulins. TBG exhibits a high affinity
for T
4
(K(i
= 50 pM) and a moderate affinity for T
3
(K(l =
500 pM). Approximately three-fourths of circulating
T4
is
firmly bound to TBG, while about one-half of circulating
T
3
is TBG-bound (Table 33-1).
Thyroxine-binding pre-
albumin
(TBPA), more properly known as
transthyretin,
which functions in the transport of retinol, has about
1% of the affinity of TBG for
T4,
but it accounts for
about 20% of circulating T
4
and does not bind T3. These
differences in binding can be partially explained, since T
4
is almost completely ionized at physiological pH, whereas
T
3
is not. The 4'-hydroxyl group of T
4
probably exists
as a 4'-phenoxide ion, which optimizes binding to serum
proteins. However, the 4'-hydroxyl group is required for
receptor binding. Binding to albumin accounts for much
of the circulating T
4
and T
3
that is not bound to TBG
and TBPA. About 0.03% of T
4
and about 0.3% of T
3
is
unbound, so that only a small fraction is accessible for
target cell uptake. The albumin-bound hormone disso-
ciates rapidly in the vicinity of target cells. The cellular
uptake of
T4
and
T3
is mediated by carrier-mediated
processes at stereospecific binding sites. At high-affinity
sites the uptake is energy, temperature, and often Na+-
dependent. T
3
is metabolized about six times more
TABLE 33-1
Source, Transport, and Metabolism o f the Thyroid Hormones
T
4
3,5, 3', 5 -Tetraiodo-L-thyronine
T3
3 ,5 ,3 -Triiodo-L-thyronine
Molecular weight
777
651
Production rate ( jug/day)
90
35
% Produced by thyroid gland
1 0 0
2 0
Half-life
7 days
0.75 day
Total plasma concentration
51-142 nmol/L (4-11 pg/dl)
1.2-3.4 nmol/L (75-220 ng/dl)
% Free
0
.
0 2
%
0.3%
% Bound to plasma proteins
99.98%
99.7%
% Bound to TBG
70-75
70-75
% Bound to albumin
5-10
20-25
% Bound to transthyretin
15-20
0-5
