+++
Metabolism of
Dietary Iodine
++
The thyroid gland concentrates iodide from the blood and returns
it to peripheral tissues in a hormonally active form. The major
substrates for thyroid hormone synthesis are iodide and the amino
acid tyrosine. Iodine is absorbed from the upper gastrointestinal
tract, where it is distributed within the extrathyroidal iodide
pool.1,2 The rate of thyroid iodide trapping is
inversely related to the rate of renal iodide excretion. Iodide
is excreted largely in urine through glomerular filtration; 1% to
2% may be excreted in sweat under basal conditions and
as much as 10% with severe sweating. There is continuous
secretion of iodide by the salivary and digestive glands, but this
is reabsorbed; there is no substantial fecal excretion.
+++
Biosynthesis
of Thyroid Hormone
++
Iodide is transported across the cell membrane into the thyroid
follicular cell by a sodium-iodide symporter (NIS). The symporter
normally generates a thyroid to a serum concentration gradient of
30- to 40-fold. This gradient can reach several hundredfold when
the thyroid gland is stimulated by a low iodine diet, by thyroid-stimulating
hormone (TSH), or by thyroid-stimulating immunoglobulins in Graves
disease. The iodide traverses the cell from the plasma membrane
to the apical membrane, where it is transported out of the cell
by a chloride-iodide transport protein referred to as Pendrin.1,2 Pendrin
is localized to the apical membrane near the complex of thyroid
peroxidase (TPO) and two nicotinamide adenosine dinucleotide phosphate
(NADPH) oxidases (THOX1 and THOX2), which catalyze iodine organification
(Fig. 526-1). Thyroglobulin is the essential
substrate for iodide organification. Iodide is oxidized to an active
intermediate followed by iodination of thyroglobulin-bound tyrosyl
residues to form monoiodinated and diiodinated tyrosine (MIT and
DIT). Both iodide oxidation and organification are catalyzed by
the TPO-THOX complex.
++
++
A normal thyroid gland contains 50 to 100 mg thyroglobulin for
every 1 g of gland. MIT, DIT, triiodothyronine (T3), and
thyroxine (T4) are present within thyroglobulin as iodoaminoacyl
residues that can be cleaved by proteolytic enzymes. Thyroglobulin
is a large 650,000-dalton glycoprotein composed of two monomeric
2767 amino acid polypeptide chains, each containing 67 tyrosine
residues.1,3-6 Approximately one third of the tyrosines
are spatially oriented to be susceptible to iodination, most at
the extreme ends of the monomers. TPO catalyzes the coupling of
iodotyrosines (MIT and DIT) within the thyroglobulin molecule to
form T3 and T4. DIT and MIT couple, with loss
of an alanine side chain, to form T3; DIT and DIT couple
to form T4. The relative proportions of T3 and
T4 formed depend on the amount of available iodide and
the extent of thyroglobulin iodination. With adequate iodine intake,
70% of the iodoprotein is iodotyrosine; the rest is iodothyronine
with a T4-to-T3 ratio ranging from 10:1 to 20:1.
++
An outer-ring iodothyronine monodeiodinase (MDI) in the follicular
cell catalyzes monodeiodination of T4 to T3. MDI
activity is stimulated by TSH, with the result that the ratio of
T3 to T4 secreted from the thyroid gland increases
with increasing TSH stimulation.
+++
Secretion of
Thyroid Hormones
++
Thyroglobulin is stored in colloid, and before thyroid hormones
are released, the colloid must be ingested by the follicular cell.1,3-6 Ingested
colloid droplets fuse with proteolytic enzyme-containing lysosomes
to form phagolysosomes, where thyroglobulin hydrolysis occurs. The
free monoiodinated tyrosine (MIT), diiodinated tyrosine (DIT), T3,
and T4 within the phagolysosomes are released into the
cytoplasm and diffuse into blood (Fig. 526-1).
The MIT and DIT released during hydrolysis of thyroglobulin are
largely deiodinated under the influence of an iodotyrosine deiodinase.1,3-5 Most
of the released iodide is reused for new hormone synthesis. The
loss from the thyroid gland of this normally recycled iodine, amounting
to 70% to 80% of the daily thyroidal iodine supply,
can cause iodine deficiency and variable degrees of hypothyroidism.
+++
Regulation of
Thyroid Function
++
Thyroid gland biosynthesis and secretion are regulated by thyroid-stimulating
hormone (TSH).1,7-9 TSH activates follicular cell adenylate
cyclase and stimulates production of intracellular cyclic adenosine
monophosphate (cAMP), which mediates iodide trapping, iodothyronine synthesis,
thyroglobulin synthesis, glucose oxidation, pinocytosis, hormone
release, and thyroid growth.1,7,8
++
The hypothalamus controls the secretion of TSH by the pituitary
gland. Removal of the pituitary gland causes thyroid atrophy, but
thyroid cell integrity and function are maintained at a basal level.
Secretion of TSH is regulated by thyrotropin-releasing hormone (TRH),
a tripeptide synthesized in the hypothalamus and secreted into the
pituitary portal vascular system for transport to the anterior pituitary
thyrotroph cell. TRH production is regulated by environmental temperature;
decreasing environmental and body temperatures increase TRH secretion
and increase the tonic level of TSH release. Somatostatin and dopamine
can inhibit TSH release by actions at the pituitary level. Norepinephrine,
glucocorticoids, and serotonin can also inhibit TSH release.
++
TSH secretion is characterized by centrally mediated pulsatile
and circadian variation. Low amplitude pulsatile peaks occur at
1- to 2-hour intervals. The diurnal variation in children is characterized
by a peak in serum TSH at 10 to 11 pm with nadir values at 2 to
6 pm. The absence of the nocturnal TSH surge in children is associated
with an approximate 30% reduction in serum T4,
T3, and FT4 levels.1,9Superimposed on
the central hypothalamic control is a negative feedback action of
thyroid hormones to maintain the normal resting levels of free thyroid
hormones within narrow limits. Hypothalamic and pituitary iodothyronine
monodeiodinase (MDI) deiodinates T4 to T3, which,
with circulating free T3 acts via thyroid hormone receptors
in the TRH neurons and pituitary thyrotroph cells to continually
modulate TRH, TSH, and thyroid hormone secretion to maintain free
hormone levels at or near the individual “set pointî” Fig. 526-2).
++
+++
Transport and
Distribution of Thyroid Hormones
++
Both T3 and T4 are present in blood in association
with plasma proteins. The thyroid gland is the sole source of T4,
but most of the T3 in blood is derived from nonglandular
sources through monodeiodination of T4 in peripheral tissues.1,3-5 The
concentration of T4 in human blood is 50 to 100 times greater
than that of T3. The concentrations of both are relatively
constant in the steady state. Average values for children relative
to age are shown in Table 526-1. The circulating
thyroid hormone-binding proteins include thyroxine-binding globulin
(TBG), thyroxine-binding prealbumin (transthyretin), and albumin.
The binding reactions are such that the euthyroid steady-state concentrations
of free T4 and free T3 approximate 0.03% and
0.30%, respectively, of the total hormone concentrations.
Absolute mean free T4 and T3 concentrations approximate
2.0 and 0.30 ng/dL, respectively (25.7 and 4.6 pmol/L).
++
+++
Metabolism of
Thyroid Hormones
++
Deiodination is the main pathway of thyroid hormone metabolism
mediated by iodothyronine monodeiodinase (MDI) enzymes.1,3,10,11Circulating
free T4 enters peripheral tissues where it is enzymatically
monodeiodinated (Fig. 526-3). Three iodothyronine
monodeiodinase enzymes (MDI-1, MDI-2, and MDI-3) are involved in
the progressive deiodination of T4:two hydroxyl
or outer-ring deiodinases (types 1 and 2), and one alanine side
chain or inner-ring deiodinase (type 3). The first step in T4 metabolism
is deiodination either to active T3 or to reverse T3 (rT3),
which is inactive metabolically. Under normal circumstances, T3 and
rT3 are produced at approximately similar rates. The alanine
side chain of the inner ring of the iodothyronines is subject to
degradative reactions, including transamination, deamination, and
decarboxylation. Sulfation at the outer-ring hydroxyl site produces
inactive iodothyronine sulfates (Fig. 526-3).
++
++
In most tissues, particularly liver, and excluding brain and
brown adipose tissue, T3 and rT3 generated through
T4 monodeiodination diffuse rapidly from tissue to interstitial
fluid to plasma. Thus, circulating levels of T3 and rT3 reflect
both secretion and peripheral production. From 70% to 90% of
circulating T3 is derived from peripheral conversion and
10% to 25% from the thyroid gland; respective
values for rT3 are 96% to 98% and 2% to
4%. Progressive tissue monodeiodination reactions degrade
T3 and rT3 to diiodo-, monoiodo-, and noniodinated
thyronine.
++
The acetic acid analogs in tissue, bile, and urine have some
activity, but are rapidly degraded. Pyruvic acid analogs and small
amounts of lactic acid analogs that have been observed in urine
and bile have minimal biologic activity. Thyroid hormones are excreted
in urine and stool in both free and conjugated forms. The conjugation
reactions involve both glucuronide and sulfoconjugation. Glucuronide
conjugation occurs mainly in liver through microsomal glycuronyl
transferase. Sulfoconjugation is also prominent in the liver and
may be an obligatory step for hepatic monodeiodination reactions.
Iodothyronine sulfation markedly augments outer-ring deiodination
in the liver. In the fetus, where outer-ring deiodinase activity
is developmentally low, the major thyroid hormone metabolites are
sulfate conjugates, which are biologically inactive.
+++
Actions of Thyroid
Hormones
++
The free thyroid hormones are transported into peripheral cells
via plasma membrane iodothyronine transporters.1,3,12-14 These
belong to several families of integrin, organic anion, amino acid,
and monocarboxylate solute carriers. The relative significance of
these transporter types is not yet clear. αVβ3
integrin binds T4 with high affinity, and this or similar
membrane receptors appear to trigger the reported nongenomic actions
of thyroid hormones, including solute transport, signal-transducing
kinase activation, posttranslational modifications of nucleoproteins,
actin polymerization, and mitochondrial activity; these effects
have been triggered by rT3 and T2, as well as
T4 and T3, so that several membrane transporters
may be involved. The regulation of actin polymerization by thyroid
hormone in developing brain provides a nongenomic mechanism to influence
neuronal migration.
++
Thyroid hormones influence brain maturation; growth and development;
oxygen consumption and heat production; nerve function; and metabolism
of lipids, carbohydrates, proteins, nucleic acids, vitamins, and
inorganic ions. They also have important effects on other hormone
actions. T3 is the active hormone and binds to nuclear
receptors with approximately 10 times the affinity of T4.
T3 also binds to plasma membrane and mitochondrial inner-membrane
receptors. The major effects of thyroid hormones are mediated by
the nuclear T3 receptors, which are members of the steroid
hormone-retinoic acid receptor superfamily and function as DNA transcription
factors. In humans, two genes code for thyroid hormone nuclear receptors:
one on chromosome 3, designated TRβ, and one on
chromosome 17, designated TRα. Alternative splicing
of expressed mRNA species leads to production of the major active
thyroid hormone-binding transcripts, TRα1, TRβ1,
TRβ2, and TRβ3. The TRs exist
as monomers, homodimers, and heterodimers with other nuclear receptor
family members such as the retinoid X receptors (Fig.
526-4).
++
++
Other receptor transcripts, including TRα2,
TRΔα1, and TRΔα2, have been characterized.
These do not bind T3 or DNA but can inhibit TR and retinoid
receptor activities. The TRα receptors are expressed
in most tissues. TRβ1 is expressed in liver, kidney,
heart, lung, brain, cochlea, and pituitary, and TRβ2
in the hypothalamus, pituitary gland, retina, and cochlea. The receptors
function redundantly, as indicated by knockout studies in mice,
but predominant effects of one or another TR have been described.
T3 binding by the TR leads to transcriptional regulation
of responsive gene activity, modulating synthesis of RNA and proteins
that mediate thyroid hormone actions in various tissues (Fig. 526-4). Thyroid hormone receptor inactivation
studies in mice have led to the view that TRβ receptors
are more involved with feedback regulation of thyroid hormone and
cochlear development, whereas energy metabolism and cardiac function
are more likely TRα regulated.