01-herzovich-thyroid hormone synthesis and physiology

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hyroid hormone synthesis and physiology

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Thyroid hormone synthesis and

physiology

Author

Douglas S Ross, MD

Section Editor

David S Cooper, MD

Deputy Editor

Kathryn A Martin, MD

Last literature review version 17.1: January 2009 | This topic last updated:

September 16, 2008 (More)

INTRODUCTION Thyroid hormones are critical determinants of brain and somatic

development in infants and of metabolic activity in adults; they also affect the function ofvirtually every organ system. Thyroid hormones must be constantly available to perform

these functions. To maintain their availability there are large stores of thyroid hormone in the

circulation and in the thyroid gland. Furthermore, thyroid hormone biosynthesis and secretion

are maintained within narrow limits by a regulatory mechanism that is very sensitive to smal

changes in circulating hormone concentrations.

The processes of thyroid hormone synthesis, transport, and metabolism, and the regulation

of thyroid secretion will be reviewed here. The actions of thyroid hormone are discussed

elsewhere. ( See "Thyroid hormone action").

ANATOMY The thyroid gland weighs 10 to 20 grams in normal adults in the United States

[ 1] . Thyroid volume measured by ultrasonography is slightly greater in men than women,

increases with age and body weight, and decreases with increasing iodine intake [ 2] .

Microscopically, the thyroid is composed of spherical follicles, each composed of a single laye

of follicular cells surrounding a lumen filled with colloid (mostly thyroglobulin). When

stimulated, the follicular cells become columnar and the lumen is depleted of colloid; when

suppressed, the follicular cells become flat and colloid accumulates in the lumen.

THYROID HORMONE BIOSYNTHESIS There are two biologically active thyroid

hormones: thyroxine (T4) and 3,5,3'-triiodothyronine (T3) ( show figure 1). They are

composed of a phenyl ring attached via an ether linkage to a tyrosine molecule. Both have

two iodine atoms on their tyrosine (inner) ring. They differ in that T4 has two iodine atoms on

its phenyl (outer) ring, whereas T3 has only one. The compound formed if an iodine atom is

removed from the inner ring of T4 is 3,3',5'-triiodothyronine (reverse T3, rT3), which has no

biological activity.

T4 is solely a product of the thyroid gland, whereas T3 is a product of the thyroid and of

many other tissues, in which it is produced by deiodination of T4. The thyroid gland contains

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large quantities of T4 and T3 incorporated in thyroglobulin, the protein within which the

hormones are both synthesized and stored. Being stored in this way, T4 and T3 can be

secreted more quickly than if they had to be synthesized.

Iodine economy Iodine is essential for normal thyroid function, and it can be obtained

only by consumption of foods that contain it or to which it is added.

q Foods rich in iodine include seafood, seaweed, kelp, dairy products, and some

vegetables. Sea salt contains some iodine, and iodized salt is widely available (iodized

salt in the US contains 45 to 80 mcg/g). Salt iodination is legally mandated in many

countries (although not in the US). ( See "Iodide and thyroid function").

q Dietary iodine is absorbed as iodide and rapidly distributed in the extracellular fluid,

which also contains iodide released from the thyroid and by extrathyroidal deiodination

of the iodothyronines. Iodide leaves this pool by transport into the thyroid and

excretion into the urine.

q The recommended daily iodine intake (Food and Nutrition Council, Institute of

Medicine) is: infants 0 to 6 months, 110 mcg; infants 7 to 12 months, 130 mcg;

children 1 to 8 years, 90 mcg; children 9 to 13 years, 120 mcg; adolescents and

adults, 150 mcg; pregnant women, 220 mcg; lactating women, 290 mcg.

q Iodine deficiency is defined by urinary iodine excretion, as follows: mild iodine

deficiency, 50 to 99 mcg/L; moderate iodine deficiency, 20 to 49 mcg/L, and severe

iodine deficiency,


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thyroglobulin. The oxidation of iodide is catalyzed by thyroid peroxidase in a reaction that

requires hydrogen peroxide. This enzyme catalyzes iodination of about 10 percent of the

tyrosine residues of thyroglobulin.

Coupling of iodotyrosyl residues of thyroglobulin T4 is formed by coupling of two

diiodotyrosine residues and T3 by coupling of one monoiodotyrosine and one diiodotyrosine

within a thyroglobulin molecule. These reactions also are catalyzed by thyroid peroxidase.

Thyroglobulin synthesis Thyroglobulin is a 660 kilodalton (kd) glycoprotein composed otwo identical noncovalently linked subunits. It is found mostly in the lumen of thyroid follicles

[ 5] . It is synthesized and glycosylated in the rough endoplasmic reticulum, and then

incorporated into exocytotic vesicles that fuse with the apical cell membrane. Only then are

tyrosine residues iodinated and coupled to form T4 and T3.

The coupling process is not random. T4 and T3 are formed in regions of the thyroglobulin

molecule with unique amino-acid sequences [ 6] . Normal thyroglobulin contains about six

molecules of monoiodotyrosine, four of diiodotyrosine, two of T4, and 0.2 of T3 per molecule

Endocytosis of colloid and hormone release To liberate T4 and T3, thyroglobulin is

resorbed into the thyroid follicular cells in the form of colloid droplets. The droplets fuse with

lysosomes to form phagolysosomes, in which the thyroglobulin is hydrolyzed to T4, T3, and

its other constituent amino acids, and some T4 is converted to T3. The hormones are then

secreted into the extracellular fluid and enter the circulation.

Recycling of iodide The iodotyrosines liberated from thyroglobulin are deiodinated by

iodotyrosine deiodinase. Most of the iodide is then recycled for thyroid hormone synthesis.

Homozygous mutations in DEHAL1, the gene that encodes iodotyrosine deiodinase [ 7] ,

results in iodotyrosine deiodinase deficiency with hereditary, and sometimes, severe

hypothyroidism and goiter [ 8] . ( See "Clinical features and detection of congenital

hypothyroidism", section on Disorders of thyroid hormone synthesis and secretion).

Thyroglobulin secretion About 100 g of thyroglobulin is released from the thyroid each

day. This is a tiny fraction of the 25 mg that must be hydrolyzed to yield the 100 g (130

nmoles) of T4 that is secreted each day [ 6] .

Extrathyroidal T3 production Approximately 80 percent of the T3 produced is formed by

5'-deiodination (outer-ring deiodination) of T4 in extrathyroidal tissue. This reaction is

catalyzed by two T4-5'-deiodinases (type I and type II), which are, respectively, plasma

membrane and microsomal enzymes that require reduced sulfhydryl groups as a cofactor.

The liver and kidney contain abundant deiodinase activity [ 9,10] . These organs are themajor sources of serum T3, but some T3 is produced in most if not all tissues.

The two types of T4-5'-deiodinase (types I and II) are distinguished by their location,

biochemical properties, and responses to physiologic stimuli [ 9] .

q Type I T4-5'-deiodinase is the predominant deiodinating enzyme in the liver, kidney,

and thyroid. It has a high Km for T4, is propylthiouracil (PTU)-sensitive, and

deiodinates in the following order: rT3>T4>T3.

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q Type II T4-5'-deiodinase is the predominant deiodinating enzyme in muscle, brain,

pituitary, skin, and placenta. It has a low Km for T4, is not inhibited by PTU, and

deiodinates T4>rT3.

Overall, in normal subjects, about 65 percent of the extrathyroidally produced T3 in serum is

probably contributed by type II deiodinase and 35 percent by type I deiodinase. The

proportion contributed by the type II enzyme is higher in hypothyroidism and lower inhyperthyroidism [ 11] .

Identification of polymorphisms in the deiodinase genes may ultimately prove to have clinica

importance. For example, a single nucleotide polymorphism in the type I deiodinase

(rs2235544) appears to increase deiodinase function, resulting in higher ratios of free T3/free

T4 in patients, including those taking levothyroxine [ 12] .

Reverse T3 is produced at extrathyroidal sites by 5-deiodination (inner ring deiodination) of

T4 (type III T4-5-deiodinase). This enzyme is widely distributed throughout the body, and its

properties are very similar to those of type I T4-5'-deiodinase.

THYROID HORMONE METABOLISM There are major differences in the production and

metabolism of T4 and T3, both quantitatively and qualitatively:

Thyroxine The production rate of T4 is 80 to 100 g (100 to 130 nmoles) per day, all of

which is produced in the thyroid [ 13] . The extrathyroidal pool of T4 contains 800 to 1,000

g (1000 to 1300 nmoles), most of which is extracellular.

T4 is degraded at a rate of about 10 percent per day. Approximately 80 percent is

deiodinated, 40 percent to form T3 and 40 percent to form rT3. The remaining 20 percent is

conjugated with glucuronide and sulfate, deaminated and decarboxylated to formtetraiodothyroacetic acid (tetrac), or cleaved between the two rings [ 13] .

Deiodination of T4 to T3 leads to increased biologic activity, but the other metabolites of T4

are biologically inactive. The conversion of T4 to T3 in extrathyroidal tissues is regulated (see

below), so that production of T3 may change independently of changes in pituitary-thyroid

function.

Triiodothyronine Most T3 (80 percent) is produced by extrathyroidal deiodination of T4

and the rest by the thyroid [ 13] . The total production rate is 30 to 40 g (45 to 60 nmoles)

per day. The extrathyroidal T3 pool contains about 50 g (75 nmoles), most of which is

intracellular. T3 is degraded, mostly by deiodination, much more rapidly than T4 (about 75

percent per day).

Reverse triiodothyronine The production rate of rT3 is 30 to 40 g (45 to 60 nmoles)

daily, nearly all by extrathyroidal deiodination of T4 [ 13] . rT3 is degraded even more rapidly

than is T3, mostly by deiodination.

SERUM BINDING PROTEINS More than 99.95 percent of the T4 and 99.5 percent of the

T3 in serum are bound to several serum proteins, thyroxine-binding globulin (TBG),

transthyretin (TTR, formerly called thyroxine-binding prealbumin [TBPA]), albumin, and

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lipoproteins ( show figure 3) [ 14,15] .

q For T4, approximately 75 percent is bound to TBG, 10 percent to TTR, 12 percent to

albumin and 3 percent to lipoproteins. Approximately 0.02 percent, or 2 ng/dL (25

pmol/L), of the T4 in serum is free.

q For T3, approximately 80 percent is bound to TBG, 5 percent to TTR, and 15 percent to

albumin and lipoproteins. Approximately 0.5 percent, or 0.4 ng/dL (6 pmol/L), is free.

Because nearly all of the T4 and T3 in serum is bound, changes in the serum concentrations

of binding proteins, especially TBG, have a large effect on serum total T4 and T3

concentrations and the fractional metabolism of T4 and T3. They do not, however, alter free

hormone concentrations or the absolute rates of metabolism of T4 and T3. ( See "Euthyroid

hyperthyroxinemia and hypothyroxinemia").

General functions It is the serum free T4 and T3 concentrations that determine the

hormones' biological activity. The binding proteins serve to maintain the serum free T4 andT3 concentrations within narrow limits, yet ensure that T4 and T3 are immediately and

continuously available to tissues. These proteins, therefore, have both storage and buffer

functions. The storage function also facilitates uniform distribution of T4 and T3 within

tissues, particularly large solid organs [ 16] .

In the longer term, if thyroid secretion ceases, the T4 stored in serum serves to delay the

onset of hypothyroidism. In contrast, the supply would be exhausted within hours if only free

T4 were available. The binding proteins also protect tissues from sudden increases in thyroid

secretion or extrathyroidal T3 production.

Thyroxine-binding globulin TBG is a 54-kd glycoprotein synthesized in the liver that has

one binding site for T4. The affinity of TBG for T4 is very high; that for T3 is lower [ 14,15] .

The serum TBG concentration in normal subjects is about 1.5 mg/dL (0.27 mol/L), an

amount capable of binding about 20 g of T4 (26 nmoles). Only about one-third of the TBG in

serum normally contains T4.

Transthyretin TTR is a 55-kd tetrameric protein composed of four identical subunits that

is synthesized in the liver. Each TTR molecule has two T4 binding sites; however, occupation

of one site decreases the affinity of the second site for T4. The affinity of TTR for T4 (and T3)

is less than that of TBG [ 14,15] . The serum TTR concentration is about 25 mg/dL (4.6 mol

L), an amount that can bind up to 200 g of T4 (260 nmoles).

Albumin Albumin has one strong and several weaker binding sites for T4. There are four

T4-binding albumin isoforms, with varying affinity for T4 and T3 [ 14,15] . Because only

about 12 percent of the T4 in serum is bound to albumin, changes in serum albumin

concentrations have little effect on serum T4 concentrations.

Lipoproteins Lipoproteins, primarily the apoprotein A-I component of high-density

lipoproteins, bind a small amount of the T4 and T3 in serum [ 14] .

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CELLULAR HORMONE ENTRY AND BINDING Serum free T4 and T3 are available for

cellular uptake at any instant in time. In addition, T4 and T3 dissociate from the binding

proteins so rapidly that more free T4 and T3 can become available almost instantaneously.

T4 and T3 enter the cells of most organs by carrier-mediated transport and perhaps also by

diffusion [ 17] .

T3 is also available to cells because it is produced from T4 within them. Some of the locally

produced T3 must leave the cells, as evidenced by the observation that serum free (and

total) T3 concentrations are normal in hypothyroid patients taking T4 in doses that raise theirserum T4 concentrations to normal. However, some of the T3 does not leave, and local

production of T3 provides much of the T3 that is bound to T3-nuclear receptors in many

tissues. Overall, approximately 90 percent of the extrathyroidal T3 pool of 50 g (75 nmoles)

is intracellular.

The fraction of T3 that is produced locally from T4 and the contribution of locally produced T3

to the amount of T3 bound to its receptors vary substantially from tissue to tissue. In rats, as

an example, locally produced T3 accounts for about 20 percent of the nuclear T3 in the liver,

50 percent in the pituitary, 80 percent in the cerebral cortex, and less than 10 percent in

other tissues [ 18] .

T3-nuclear receptors Nuclear receptors mediate most if not all of the physiologic actions

of thyroid hormone [ 19] . Cytosolic T3 diffuses or is transported into nuclei, and then binds

to the chromatin-localized receptors. Some characteristics of the receptors are:

q Affinity for T4 and T3 The nuclear receptors bind T3 much more avidly than T4, and

in vivo virtually all of the nuclear-bound hormone is T3. T4 is therefore largely a

prohormone, with little if any intrinsic biologic activity.

q Types of receptors There are two T3-nuclear receptors, alpha and beta, both of

which are linear proteins ( show figure 4). The mRNAs for each receptor can be spliced

in several ways, so that there are at least three forms of alpha receptors and two

forms of beta receptors. The receptors differ in the structure of their amino- and

carboxyl-terminal regions, but the DNA- and T3-binding regions are highly conserved,

and each receptor binds to DNA in the absence of T3.

q Tissue distribution of the receptors Beta-1 and beta-2 receptors are concentrated,

respectively, in brain, heart, liver, and kidney and in pituitary and hypothalamic tissue

[ 19] .

q Variability in tissue action There is a variable tissue response to occupation of the

nuclear receptors. In the pituitary and heart, there is a linear correlation between

increasing occupancy of nuclear sites by T3 and the response, while in other tissues

increasing receptor occupancy results in nonlinear, amplified responses. As an exampl

of the latter, an increase in T3-receptor occupancy from 50 to 100 percent in the liver

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results in a 10-fold increase in the rate of synthesis of some enzymes.

These differences can be explained by the diversity of the T3-nuclear receptors, the

variations in their distribution among different tissues, the fact that receptors containing T3

and not containing T3 are biologically active, and variations in the tissue content of other

transcription-regulating factors.

Those tissues most responsive to T3, such as the pituitary and liver, contain more T3-nuclear

receptors than do less responsive tissues, such as the spleen and testes. Furthermore, T3

regulates the production of the mRNAs for the different forms of the nuclear receptor in some

tissues. In animals, hepatic T3-nuclear receptor content is reduced by starvation, diabetes,

uremia, and partial hepatectomy [ 20,21] . Such changes, if they occurred in humans, would

limit the impact of T3 in patients with nonthyroidal illness.

REGULATION OF THYROID HORMONE PRODUCTION Thyroid hormone production is

regulated in two ways ( show figure 5):

q Regulation of thyroidal biosynthesis and secretion of T4 and T3 by thyrotropin (thyroid

stimulating hormone, TSH). The secretion of TSH is inhibited by T4 and T3 and is

stimulated by thyrotropin-releasing hormone (TRH).

q Regulation of extrathyroidal conversion of T4 to T3 by nutritional, hormonal, and

illness-related factors. The effect of these factors differs in different tissues.

The first mechanism provides a very sensitive defense against alterations in thyroid

secretion, and the second provides for rapid changes in tissue thyroid hormone availability in

response to nonthyroidal illness. ( See "Thyroid function in nonthyroidal illness").

Thyrotropin TSH is a 28-kd glycoprotein that is synthesized and secreted by the

thyrotrophs of the anterior pituitary. It is composed of noncovalently bound alpha and beta

subunits, and contains about 15 percent carbohydrate [ 22] . The alpha subunit is the same

as that of luteinizing hormone, follicle-stimulating hormone, and chorionic gonadotropin. In

contrast, the beta subunit is unique and therefore determines the hormone's biologic

specificity.

The TSH secretion rate in normal subjects ranges from 75 to 150 mU/day (15 to 30 g/day,

0.5 to 1 nmol/day). TSH secretion is pulsatile, and serum TSH concentrations are 50 to 100

percent higher in the late evening than during the day.

Thyroid hormone regulation of TSH secretion TSH secretion is inhibited by very small

increases in serum T4 and T3 concentrations, and it increases in response to very small

decreases in serum T4 and T3 concentrations. As a result of this very "tight" control of TSH

secretion, thyroid hormone secretion is maintained within very narrow limits. An important

exception is that the decrease in serum T3 concentrations that occurs in patients with

nonthyroidal illness has little effect on TSH secretion, probably because serum T4 contributes

more to the nuclear T3 content of the hypothalamus and pituitary than it does in many other

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tissues [ 9,18] .

T4 and T3 inhibit the synthesis and release of both TSH, and TRH [ 23,24] . The inhibition of

TSH synthesis is achieved primarily by inhibition of transcription of the TSH subunit genes.

The rate and extent of T4- and T3-induced inhibition of TSH secretion are dependent upon

the initial serum TSH concentration, the particular hormone given, and its dose. Serum TSH

concentrations decline within hours after administration of single 400 to 500 g doses of T3

or T4 to hypothyroid patients; the action of lower doses is considerably slower. The maximuminhibition of TSH secretion occurs later than the peak serum T4 or T3 concentrations. In usua

doses, T3 decreases serum TSH to normal in hypothyroid patients in approximately one

week, but the response to T4 is slower. When given chronically, the potency of T3 as an

inhibitor of TSH secretion is about three times greater than that of T4 [ 25] . Conversely,

serum TSH concentrations become supranormal in 10 to 14 days after cessation of T4 or T3

therapy in patients with hypthyroidism [ 26] .

Thyrotropin-releasing hormone TRH is the tripeptide pyroglutamyl-histidyl-

prolineamide. It is distributed throughout the hypothalamus, but its content is highest in the

median eminence and paraventricular nuclei [ 27] . Small amounts of TRH are foundelsewhere in the central nervous system and in the pituitary gland, gastrointestinal tract,

pancreatic islets, and reproductive tract. The function of TRH in these sites is unknown.

TRH is synthesized as a 26-kd protein (proTRH) containing five copies of the molecule. It is

formed from proTRH by the action of peptidases and then cyclization of the glutamine residue

to form a pyroglutamyl residue [ 28] . The production of proTRH mRNA and its translation in

the paraventricular nuclei are increased by hypothyroidism and decreased by local or

systemic injection of T4 or T3 [ 24] . TRH is metabolized very rapidly, its plasma half-life

being about three minutes.

TRH stimulates TSH secretion via receptor-mediated activation of the phospholipase C-

phosphoinositide pathway, which stimulates mobilization of calcium from intracellular storage

sites. Chronic TRH stimulation also increases the synthesis and glycosylation of TSH; the

latter action increases the biologic activity of TSH [ 22] . TRH secretion is probably pulsatile,

accounting for pulsatile TSH secretion. Hypothyroidism ensues when TRH is absent. ( See

"Disorders that cause hypothyroidism").

The physiologic role of TRH is to determine the set-point of thyroid hormone regulation of

TSH secretion. In animals or humans with hypothalamic lesions, thyroidectomy results in

smaller increases in TSH secretion and less T4 and T3 is needed to inhibit TSH secretion thanin normal subjects or animals.

Exogenous administration of TRH causes a dose-dependent increase in serum TSH

concentrations in normal subjects. The response is increased in hypothyroid patients and

decreased in hyperthyroid patients. Exogenous TRH administration also stimulates prolactin

release in normal subjects and most patients with hyperprolactinemia, and it stimulates

growth hormone secretion in normal elderly subjects and patients with acromegaly, chronic

liver disease, and diabetes mellitus.

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Other factors altering TSH secretion Other factors that affect TSH secretion include

somatostatin, dopamine, and glucocorticoids.

q Infusions of somatostatin and its long-acting analog octreotide reduce serum TSH

concentrations, but not as much as they reduce growth hormone secretion; patients

receiving long-term treatment with octreotide do not become hypothyroid [ 29] . In

animals with hypothalamic lesions that reduce somatostatin content, TSH secretion is

increased, suggesting that somatostatin may be a physiologically important inhibitor o

TSH secretion.

q Infusions of dopamine, in doses of 1 g/kg per min or more, cause a rapid decrease in

serum TSH concentrations; thus, serum TSH concentrations are often low in intensive

care-unit patients receiving dopamine. ( See "Drug interactions with thyroid

hormones"). Conversely, serum TSH concentrations rise after the administration of

dopamine antagonists such as metoclopramide. These actions are exerted on the

pituitary, not the hypothalamus [ 30] . Like somatostatin, dopamine may be a

physiologically important inhibitor of TSH secretion.

q Glucocorticoids also inhibit TSH secretion [ 31] . They mostly decrease pulsatile TSH

secretion, indicating that they inhibit TRH secretion. However, serum TSH responses to

exogenous TRH are also decreased, suggesting a direct effect on the pituitary. In

contrast, decreases in cortisol production result in a transient increase in serum TSH

concentrations.

The overall impact of the inhibitory actions of somatostatin, dopamine, and glucocorticoids onTSH secretion is probably small. While increases in endogenous dopamine, somatostatin, or

glucocorticoid secretion may transiently decrease TSH secretion, sustained increases in their

production do not lead to sustained decreases in TSH secretion (and hypothyroidism). Once

serum T4 and T3 concentrations fall, the ensuing stimulation of TSH secretion overcomes the

inhibition.

Mechanism of action of TSH TSH stimulates every step in thyroid hormone synthesis

and secretion by the thyroid ( show figure 2) [ 3,32] . It also stimulates intermediary

metabolism and the expression of many genes in thyroid tissue, and causes thyroid

hyperplasia and hypertrophy.

The actions of TSH are initiated by its binding to specific plasma membrane receptors. The

receptor is an 85-kd glycoprotein with an extracellular domain of approximately 400 amino

acids, seven transmembrane domains of about 250 amino acids, and an intracytoplasmic

domain of about 100 amino acids [ 32] . The binding of TSH to its receptors activates

adenylyl cyclase, increasing cyclic AMP formation, which then activates several protein

kinases. How these steps are linked to the specific steps of thyroid hormone synthesis and

secretion or to other thyroid metabolic processes is not known. TSH also stimulates

phospholipase C activity in thyroid tissue, via the same receptor, thereby increasing

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phosphoinositide turnover, intracellular calcium ion concentrations, and protein kinase C

activity.

Other thyroid-stimulating substances Other factors that may be involved in thyroid

growth (goiter formation) include insulin-like growth factor-I and epidermal growth factor.

Thyroid cells produce and have receptors for these substances.

Regulation of extrathyroidal T3 production The activity of the extrathyroidal T4-5'-

deiodinases that catalyze the conversion of T4 to T3 is altered by many factors.

The activity of type I T4-5'-deiodinase, the enzyme that predominates in liver and kidney, is

decreased in tissues from fetal animals and animals that are starved, hypothyroid, diabetic,

uremic, or have other nonthyroidal illnesses ( show table 1) [ 9,10,18,20,33] .

Propylthiouracil, glucocorticoids, beta blockers, and various iodothyronine analogues, notably

rT3, also decrease the activity of this enzyme. On the other hand, type I T4-5'-deiodinase

activity is increased by hyperthyroidism, glucose plus insulin, and a high caloric intake [ 34] .

The biochemical mechanisms that might cause alterations in tissue T4-5'-deiodinase activity

include alterations in substrate (T4) production, transport of T4 into cells, intracellular

distribution of T4, enzyme activity or mass, and cofactor availability. The drugs that reduce

T4-5'-deiodinase activity bind to the enzyme, whereas starvation may decrease hepatic T3

production by decreasing T4 uptake into the liver [ 35] . In other situations, alterations of

enzyme mass or activity are the likely cause(s) of decreased T3 production, but the specific

nutritional, hormonal, or toxic factors or cytokines that cause these changes are not known.

The regulation of the type II T4-5'-deiodinase that predominates in brain, pituitary, and

muscle is different ( show table 1). Its activity is increased by thyroid deficiency, little

affected by nutritional deficiency and PTU, and decreased by hyperthyroidism

[ 9,10,18,33,36] . Such regulation serves to reduce the impact of systemic thyroid deficiency

in these tissues by increasing the availability of T3 for maintenance of neural growth and

function and pituitary function. The increase in pituitary T4-5'-deiodinase activity that occurs

in thyroid deficiency and the decrease that occurs with thyroid hormone excess probably do

not include the thyrotrophs, because alterations in T3 production in these cells would blunt

the changes in TSH secretion needed to defend against changes in thyroidal T4 and T3

secretion.

Overall, these findings indicate that the production of T3 in different tissues is regulated in

different ways, and that changes in thyroidal or extrathyroidal thyroid hormone production,

as manifested by their circulating concentrations, are not the only, and perhaps not the

major, determinants of intracellular T3 availability. Local regulation of T3 production may be

particularly important in reducing the impact of thyroid deficiency in tissues such as the brain

and pituitary, and this local regulation undoubtedly leads to differences in T3 content in

different tissues in patients with nonthyroidal illness.

ACKNOWLEDGMENT The author and UpToDate would like to acknowledge Robert D

Utiger, MD, who contributed to an earlier version of this topic review.

Use ofUpToDate is subject to the Subscription and License Agreement.

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35. Van der Heyden, JTM, Docter, R, van Toor, H, et al. Effects of caloric deprivation on

thyroid hormone tissue uptake and generation of low-T3 syndrome. Am J Physiol

1986; 251:E156.

36. Silva, JE, Leonard, JL. Regulation of rat cerebrocortical and adenohypophyseal type II

5'-deiodinase by thyroxine, triiodothyronine and reverse triiodothyronine.

Endocrinology 1985; 116:1627.

GRAPHICS

Structures of the thyroid hormones

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Thyroid hormone biosynthesis

Thyroid hormone synthesis includes the following steps: (1) iodide (I -)

trapping by the thyroid follicular cells; (2) diffusion of iodide to the apex of

the cells; (3) transport of iodide into the colloid; (4) oxidation of inorganic

iodide to iodine and incorporation of iodine into tyrosine residues within

thyroglobulin molecules in the colloid; (5) combination of two diiodotyrosine

(DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of

monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3); (6) uptake

of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion

of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3,

DIT, and MIT; (7) release of T4 and T3 into the circulation; and (8)

deiodination of DIT and MIT to yield tyrosine. T3 is also formed from

monodeiodination of T4 in the thyroid and in peripheral tissues. Modified

from Scientific American Medicine, Scientific American, New York, 1995.



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Transport and metabolism of thyroid hormones

Forms of T4 (thyroxine) and T3 (triiodothyronine) in serum and

pathways of T4 and T3 production and degradation.

TBG: thyroxine-binding globulin; TTR: transthyretin.

Adapted from Utiger, RD. The Thyroid: Physiology, thyrotoxicosis,

hypothyroidism, and the painful thyroid. In: Endocrinology and

Metabolism, 3rd ed, Felig, R, Baxter, JD, Frohman, LA (Eds),

McGraw-Hill, 1995.



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Schematic representation of the structure of the T3(triiodothyronine) nuclear receptor

The region labeled DNA is the portion of the receptor that binds to

DNA, and the region labeled T3-binding is the region that binds T3.

NH2 denotes the amino-terminal end of the receptor and COOH the

carboxy-terminal end.Adapted from Utiger, RD. The thyroid:

Physiology thyrotoxicosis, hypothyroidism, and the painful thyroid. In:

Endocrinology and Metabolism, 3rd ed, Felig, R, Baxter, JD, Frohman,

LA (Eds), McGraw-Hill, NY 1995.

Pathways of thyroid hormone metabolism



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Thyrotropin-releasing hormone (TRH) increases the secretion of thyrotropin

(TSH), which stimulates the synthesis and secretion of trioiodothyronine (T3) andthyroxine (T4) by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both

directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in

the liver and many other tissues by the action of T4 monodeiodinases. Some T4

and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile,

and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine

may be reabsorbed. Drug interactions may occur at any of these sites.



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Conditions affecting thyroxine 5'-deiodinase activity

Condition

Enzyme type affected*

Type 1 Type 2

Fetus Decreased Decreased

Hypothyroidism Decreased Increased

Hyperthyroidism Increased Decreased

Starvation Decreased Normal

Diabetes mellitus Decreased Normal

Uremia Decreased Normal

Propylthiouracil Decreased Normal

Amiodarone Decreased Decreased

Propranolol Decreased ?

* Type 1 deiodinase predominates in the liver, kidneys, and thyroid; type 2deiodinase in the brain, pituitary, and skin.

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