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Phys Ch 76
Thyroid Metabolic Hormones
 Thyroid hormones profoundly increase metabolic rate of body; complete lack of thyroid secretion usually causes
basal metabolic rate to fall 40-50% below normal, and extreme excesses can increase basal metabolic rate to 60100% above normal
Synthesis and Secretion of Thyroid Metabolic Hormones
 93% of metabolically active hormones secreted by thyroid gland is thyroxine (T4), and 7% triiodothyronine (T3)
o Almost all T4 eventually converted to T3 in tissues, so both functionally important
o Functions of T4 and T3 qualitatively the same, but differ in rapidity and intensity
 T3 is 4x as potent as T4, but is present in blood in much smaller quantities and persists for much
shorter time than T4
 Thyroid gland composed of large numbers of closed follicles filled with colloid and lined with cuboidal epithelial
cells that secrete into interior of follicles
o Major constituent of colloid is thyroglobulin (glycoprotein that contains thyroid hormones)
o Once secretion enters follicles, it must be absorbed back through follicular epithelium into blood before
it can function in body
o Thyroid gland has blood flow 5x weight of itself each minute (blood supply as great as any other area of
body with exception of adrenal cortex)
 To form normal quantities of thyroxine, about 50 mg of ingested iodine required each year (1 mg/week)
o Iodides ingested orally absorbed from GI tract into blood in about same manner as chlorides
o Normally most iodides rapidly excreted by kidneys, but only after 1/5 selectively removed from
circulating blood by cells of thyroid gland and used for synthesis of thyroid hormones
 First stage in formation of thyroid hormones is transport of iodides from blood into thyroid glandular cells and
follicles
o Basal membrane of thyroid cells has sodium-iodide symporters (NIS) that actively pumps 1 I- with 2 Na+
across basolateral membrane into cell
o Energy for transporting I- against concentration gradient comes from Na/K-ATPase pump, which pumps
Na+ out of cell, establishing low intracellular Na+ concentration and gradient for facilitated diffusion of
Na+ into cell
o Iodide trapping – process of concentrating I- in cell; in normal gland, I- pump concentrates I- to 30x
serum concentration; when thyroid gland becomes maximally active, concentration ratio can rise to
250x serum concentration
 TSH stimulates and hypophysectomy greatly diminishes activity of I- pump in thyroid cells
o I- transported out of thyroid cells across apical membrane into follicle by Cl--I- counter-transporter
molecule (pendrin)
o Thyroid epithelial cells secrete into follicle thyroglobulin that contains tyrosine amino acids to which Iwill bind
 ER and Golgi apparatus of thyroid cells synthesize and secrete into follicles thyroglobulin (large glycoprotein
molecule); each molecule of thyroglobulin contains 70 tyrosine amino acids, and they are major substrates that
combine with I- to form thyroid hormones
o Thyroid hormones form within thyroglobulin molecule; T3 and T4 remain part of thyroglobulin molecule
during synthesis and as they are stored in follicular colloid
 First essential step in formation of thyroid hormones is conversion of I- to oxidized form of iodine (either nascent
iodine (I0) or I3-) that is then capable of combining directly with amino acid tyrosine
o Oxidation promoted by peroxidase and accompanying H2O2, which provide potent system capable of
oxidizing I-; peroxidase either located in apical membrane of cell or attached to it, providing oxidized
iodine at exactly point in cell where thyroglobulin molecule issues forth from Golgi apparatus through
PM into stored thyroid gland colloid
o When peroxidase system blocked or hereditarily absent, rate of formation of thyroid hormones falls to 0
 Binding of iodine with thyroglobulin called organification of thyroglobulin; oxidized iodine even in molecular
form will bind directly but slowly with tyrosine
o
In thyroid cells, oxidized iodine associated with thyroid peroxidase enzyme that causes process to occur
within seconds or minutes; almost as rapidly as thyroglobulin molecule released from Golgi apparatus or
as it is secreted through apical PM into follicle, iodine binds with 1/6 of tyrosine amino acids
 Tyrosine iodized to monoiodotyrosine (MIT) and then (possibly) diiodotyrosine (DIT); during next few minutes,
hours, or days, more and more iodotyrosine residues become coupled with one another
o Major hormonal product is T4, formed when 2 DITs joined together; T4 remains part of thyroglobulin
o When MIT couples with DIT, it forms T3 (1/15 of final hormones; 3,5,3’-triiodothyronine)
o Small amounts of reverse T3 (RT3) formed by coupling of DIT with MIT (3,3’,5’-triiodothyronine); doesn’t
have functional significance
 Thyroid gland is unusual among endocrine glands in ability to store large amounts of hormone; after synthesis of
thyroid hormones has run its course, each thyroglobulin molecule contains up to 30 T4 molecules and a few T3
o Thyroid hormones stored in this form in follicles in amount sufficient to supply body with normal
requirements for 2-3 months
 Thyroglobulin itself not released into circulating blood in measurable amounts; T3 and T4 cleaved from
thyroglobulin and free hormones released
o Apical surface of thyroid cells sends out pseudopod extensions that close around small portions of
colloid to form pinocytic vesicles that enter apex of thyroid cell
o Lysosomes in cell cytoplasm immediately fuse with pinocytic vesicles to form digestive vesicles
containing digestive enzymes from lysosomes mixed with colloid
o Multiple proteases among enzymes digest thyroglobulin molecules and release T4 and T3 in free form
o Free thyroid hormones diffuse through base of thyroid cells into surrounding capillaries
o About ¾ of iodinated tyrosine in thyroglobulin never become thyroid hormones but remain MIT and DIT
 During digestion of thyroglobulin molecule to cause release of T4 and T3, these iodinated
tyrosines also freed from thyroglobulin molecule but aren’t secreted into blood; iodine cleaved
from them by deiodinase enzyme that makes virtually all iodine available for recycling
 Congenital absence of deiodinase causes many people to become iodine deficient because of
failure of recycling process
 During ensuing days after T3 and T4 release, about ½ of T4 slowly deiodinated to form additional T3
o Hormone finally delivered to and used by tissues mainly T3
 On entering blood, more than 99% of T3 and T4 combines immediately with several plasma proteins (thyroxinebinding globulin, thyroxine-binding prealbumin, and albumin)
o Because of high affinity of plasma-binding proteins for thyroid hormones, T3 and T4 (T4 especially)
released to tissue cells slowly
o ½ of T4 in blood released to tissue cells every 6 days
o ½ of T3 (because of its lower affinity) released to cells in 1 day
o On entering tissue cells, both T4 and T3 bind with intracellular proteins, T4 binding more strongly, so they
are stored in target cells and used slowly over period of days or weeks
 After injection of large quantity of T4 into human, essentially no effect on metabolic rate discerned for 2-3 days,
demonstrating long latent period before T4 action begins
o Once activity begins, it increases progressively and reaches max in 10-12 days
o After that, it decreases with half-life of 15 days
o Some activity persists as long as 6 weeks to 2 months later
 Actions of T3 occur 4x as rapidly as those of T4, (latent period of 6-12 hours and max cellular activity in 2-3 days)
 Most of latency and prolonged period of action caused by binding with proteins in plasma and tissue cells,
followed by slow release
Physiological Functions of Thyroid Hormones
 General effect of thyroid hormone is to activate nuclear transcription of large numbers of genes
o In virtually all cells of body, great numbers of protein enzymes, structural proteins, transport proteins,
and other substances synthesized
o Net result is generalized increase in functional activity throughout body
 Before acting on genes to increase genetic transcription, one I- removed from almost all T4 (forming T3)
o Intracellular thyroid hormone receptors have high affinity for T3; consequently, more than 90% of
thyroid hormone molecules that bind with receptors is T3
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Thyroid hormone receptors either attached to DNA genetic strands or located in proximity to them
o Thyroid hormone receptor usually forms heterodimer with retinoid X receptor (RXR) at specific thyroid
hormone response elements on DNA
o On binding with thyroid hormone, receptors become activated and initiate transcription process
o Large numbers of different types of mRNA formed, followed within another few minutes to hours by
RNA translation on cytoplasmic ribosomes to form hundreds of new intracellular proteins
 Not all proteins increased by similar percentages
o Most actions of thyroid hormone result from subsequent enzymatic and other functions of new proteins
Thyroid hormones have non-genomic cellular effects independent of effects on gene transcription
o Some effects of thyroid hormones occur within minutes and aren’t affected by inhibitors of gene
transcription and translation; happens in heart, pituitary, and adipose tissue
o Site of non-genomic thyroid hormone action is PM, cytoplasm, and perhaps some organelles such as
mitochondria
o Non-genomic actions include regulation of ion channels and oxidative phosphorylation; involves
activation of intracellular secondary messengers such as cAMP or protein kinase signaling cascades
Thyroid hormones increase metabolic activities of almost all tissues of body
o Rate of utilization of foods for energy greatly accelerated
o Although rate of protein synthesis increased, at same time rate of protein catabolism also increased
o Growth rate of young people greatly accelerated
o Mental processes excited
o Activities of most endocrines glands increased
When T4 or T3 given to animal, mitochondria in most cells increase in size and number; total membrane surface
area of mitochondria increases almost directly in proportion to increased metabolic rate of whole animal
o One of principal functions of T4 might be to increase number and activity of mitochondria, which in turn
increases rate of formation of ATP to energize cellular function
o Increase in number and activity of mitochondria could be result of increased activity of cells as well as
cause of increase
Na-K-ATPase increases its activity in response to thyroid hormone; increases rate of transport of Na+ and K+
through PMs of some tissues
o Because process uses energy and increases amount of heat produced in body, this might be one of
mechanisms by which thyroid hormone increases body’s metabolic rate
o Thyroid hormone also causes PMs of most cells to become leaky to Na+, which further activates Na+
pump and further increases heat production
Effect of thyroid hormone on growth manifests mainly in growing children; in those with hypothyroidism, rate of
growth greatly retarded; in those with hyperthyroidism, excessive skeletal growth often occurs, causing child to
become considerably taller at early age
o Bones also mature more rapidly and epiphyses close at early age, so duration of growth and eventual
height of adult may actually be shortened
o Thyroid hormone promotes growth and development of brain during fetal life and for first few years of
postnatal life
 If fetus doesn’t secrete sufficient quantities of thyroid hormone, growth and maturation of brain
both before birth and afterward are greatly retarded and brain remains smaller than normal
 Without specific thyroid therapy within days or weeks of birth, child without thyroid gland will
remain mentally deficient throughout life
Thyroid hormone stimulates almost all aspects of carb metabolism, including rapid uptake of glucose by cells,
enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption from GI tract, and increased
insulin secretion with resultant secondary effects on carb metabolism
Essentially all aspects of fat metabolism enhanced under influence of thyroid hormone; lipids mobilized rapidly
from fat tissue, which decreases fat stores of body to greater extent than almost any other tissue element
o Increases free fatty acid concentration in plasma and greatly accelerates oxidation of free fatty acids by
cells
Increased thyroid hormone decreases concentrations of cholesterol, phospholipids, and triglycerides in plasma,
even though it increases free fatty acids
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Decreased thyroid secretion greatly increases plasma concentrations of cholesterol, phospholipids, and
triglycerides and almost always causes excessive deposition of fat in liver
o Large increase in circulating plasma cholesterol in prolonged hypothyroidism often associated with
severe atherosclerosis
o One of mechanisms by which thyroid hormone decreases plasma cholesterol concentration is to
increase significantly rate of cholesterol secretion in bile and consequent loss in feces
 Possible mechanism for increased cholesterol secretion is thyroid hormone induces increased
numbers of LDL receptors on liver cells, leading to rapid removal of LDLs from plasma by liver
and subsequent secretion of cholesterol in lipoproteins from liver cells
Because thyroid hormone increases metabolism in almost all cells of body, excessive quantities of hormone can
occasionally increase basal metabolic rate 60-100% above normal
o When no thyroid hormone produced, basal metabolic rate falls to almost ½ normal
o Extreme amounts of hormones required to cause high basal metabolic rates
Greatly increased thyroid hormone almost always decreases body weight, and greatly decreased thyroid
hormone almost always increases body weight; not always because thyroid hormone increases appetite, and
this may counterbalance change in metabolic rate
Increased metabolism in tissues causes more rapid utilization of oxygen than normal and release of greater than
normal quantities of metabolic end products from tissues
o Causes vasodilation in most body tissues, increasing blood flow; rate of blood flow in skin especially
increases because of increases need for heat elimination from body
o As consequence of increased blood flow, cardiac output increases, sometimes rising to 60% above
normal when excessive thyroid hormone present and falling to only 50% of normal in severe
hypothyroidism
Heart rate increases considerably more under influence of thyroid hormone than would be expected from
increase in cardiac output; thyroid hormone has direct effect on excitability of heart, which increases heart rate
o Heart rate is one of sensitive physical signs in determining whether patient has excessive or diminished
thyroid hormone production
Increased enzymatic activity caused by increased thyroid hormone production increases strength of heart when
only slight excess of thyroid hormone secreted
o When thyroid hormone increased markedly, heart muscle strength becomes depressed because of longterm excessive protein catabolism
o Some severely thyrotoxic patients die of cardiac decompensation secondary to myocardial failure and
increased cardiac load imposed by increase in cardiac output
Mean arterial pressure usually remains about normal after administration of thyroid hormone; because of
increased blood flow through tissues between heartbeats, pulse pressure often increased with systolic pressure
elevated in hyperthyroidism 10-15 mm Hg and diastolic pressure reduced corresponding amount
Increased rate of metabolism increases utilization of oxygen and formation of CO2; effects activate all
mechanisms that increase rate and depth of respiration
Thyroid hormone increases both rates of secretion of digestive juices and motility of GI tract
o Hyperthyroidism often results in diarrhea, and hypothyroidism can result in constipation
In general, thyroid hormone increases rapidity of cerebration but also often dissociates this
o Lack of hormone decreases cerebration
o Hyperthyroid individual likely to have extreme nervousness and many psychoneurotic tendencies, such
as anxiety complexes, extreme worry, and paranoia
Slight increase in thyroid hormone usually makes muscles react with vigor, but when quantity of hormone
becomes excessive, muscles become weakened because of excess protein catabolism
o Lack of thyroid hormone causes muscles to become sluggish and they relax slowly after contraction
One of most characteristic signs of hyperthyroidism is fine muscle tremor; can be observed by placing sheet of
paper on extended fingers and noting degree of vibration of paper
o Tremor caused by increased reactivity of neuronal synapses in areas of spinal cord that control muscle
tone; important means for assessing degree of thyroid hormone effect on CNS
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Because of exhausting effect of thyroid hormone on musculature and on CNS, hyperthyroid patients often have
feelings of constant tiredness, but because of excitable effects of thyroid hormone on synapses, it is difficult to
sleep; extreme somnolence characteristic of hypothyroidism (sleeping 12-14 hours/day)
 Increased thyroid hormone increases rates of secretion of other endocrine glands, but increases need of tissues
for hormones
o Increased T4 secretion increases rate of glucose metabolism everywhere in body and therefore cause
corresponding need for increased insulin secretion by pancreas
o Thyroid hormone increases many metabolic activities related to bone formation and, as consequence,
increases need for PTH
o Thyroid hormone increases rate at which adrenal glucocorticoids inactivated by liver; leads to feedback
increase in ACTH production by anterior pituitary and, therefore, increased rate of glucocorticoid
secretion by adrenal glands
 For normal sexual function, thyroid secretion needs to be approximately normal; in men, lack of thyroid
hormone likely to cause loss of libido; great excesses of hormone sometimes cause impotence
o In women, lack of thyroid hormone often causes menorrhagia (excessive menstrual bleeding) and
polymenorrhea (frequent menstrual bleeding); in other women, lack of thyroid hormone may cause
irregular periods and occasionally amenorrhea
o Woman with hypothyroidism likely to have greatly decreased libido
o In hyperthyroid women, oligomenorrhea (greatly reduced menstrual bleeding) common and
occasionally amenorrhea results
o Action of thyroid hormone on gonads probably results from combination of direct metabolic effects on
gonads, as well as excitatory and inhibitory feedback effects operating through anterior pituitary
hormones that control sexual functions
Regulation of Thyroid Hormone Secretion
 TSH (thyrotropin) – anterior pituitary hormone; glycoprotein; increases secretion of T4 and T3 by thyroid gland;
most important early effect after administration is to initiate proteolysis of thyroglobulin, which causes release
of T3 and T4 into blood within 30 minutes; other effects require hours to days; specific effects include
o Increased proteolysis of thyroglobulin that has already been stored in follicles, with resultant release of
thyroid hormones into circulating blood and diminishment of follicular substance itself
o Increased activity of I- pump, which increases rate of I- trapping in glandular cells
o Increased iodination of tyrosine to form thyroid hormones
o Increased size and increased secretory activity of thyroid cells
o Increased number of thyroid cells plus change from cuboidal to columnar cells and much infolding of
thyroid epithelium into follicles
 Most of effects of TSH on thyroid cells is from activation of second messenger cAMP system of cell
o TSH binds with specific TSH receptors on basal membrane surfaces of thyroid cell; this activates adenylyl
cyclase in PM, which increases formation of cAMP in cell
o cAMP acts as second messenger to activate protein kinase, which causes multiple phosphorylations
throughout cell
o Immediate increase in secretion of thyroid hormones and prolonged growth of thyroid glandular tissue
itself
 Anterior pituitary secretion of TSH controlled by hypothalamic hormone (thyrotropin-releasing hormone or
TRH), which is secreted by nerve endings in median eminence of hypothalamus
o TRH transported to anterior pituitary by way of hypothalamic-hypophyseal portal blood
o TRH directly affects anterior pituitary gland cells to increase output of TSH
o When blood portal system from hypothalamus to anterior pituitary gland becomes blocked, rate of
secretion of TSH by anterior pituitary decreases greatly but isn’t reduced to zero
o Molecular mechanism by which TRH causes cells to produce TSH is to bind with TRH receptors in
pituitary PM, which activates phospholipase second messenger system inside pituitary cells to produce
large amounts of phospholipase C, followed by cascade of other second messengers, including Ca2+ and
diacyl glycerol, which eventually leads to TSH release
 Exposure to cold increases rate of TRH secretion by hypothalamus (therefore TSH secretion and so on)
o Caused by excitation of hypothalamus centers for body temperature control
o People who move to arctic regions develop basal metabolic rates 15-20% above normal
 Various emotional reactions can affect output of TRH
o Excitement and anxiety greatly stimulate SNS and can cause acute decrease in secretion of TSH because
these states increase metabolic rate and body heat, and therefore exert inverse effect on heat control
 Emotional and external temperature effects on metabolism not observed if hypophyseal stalk cut
 Increased thyroid hormone in body fluids decreases secretion of TSH by anterior pituitary; almost all feedback
depressant effect occurs even when anterior pituitary separated from hypothalamus
o Increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by direct effect on anterior
pituitary gland itself
o Feedback mechanism maintains almost constant concentration of free thyroid hormones in circulating
body fluids
 Thiocyanate ions decrease iodide trapping – same active pump that transports I- into thyroid cells can also pump
thiocyanate ions, perchlorate ions, and nitrate ions; therefore administration of thiocyanate (or one of the other
ions) in high enough concentration can cause competitive inhibition of I- transport into cell (inhibition of iodidetrapping mechanism)
o Decreased availability of I- in glandular cells doesn’t stop formation of thyroglobulin, but prevents
thyroglobulin that is formed from becoming iodinated and therefore from forming thyroid hormones
o Deficiency of thyroid hormones leads to increased secretion of TSH by anterior pituitary gland, which
causes overgrowth of tyroid gland even though gland still doesn’t form adequate quantities of thyroid
hormones
o Use of thiocyanates and some other ions to block thyroid secretion can lead to development of goiter
 Propylthiouracil (and other similar compounds such as methimazole and carbimazole) prevent formation of
thyroid hormone from iodides and tyrosine
o Mechanisms partly to block peroxidase enzyme required for iodination of tyrosine and party to block
coupling of 2 iodinated tyrosines to form T4 and T3
o Doesn’t prevent formation of thyroglobulin
o Absence of T3 and T4 in thyroglobulin can lead to tremendous feedback enhancement of TSH secretion
by anterior pituitary gland, thus promoting growth of glandular tissue and forming goiter
 When iodides present in blood in high concentration (100x normal plasma level), most activities of thyroid gland
decreased, but often remain decreased for only a few weeks
o Effect is to reduce rate of iodide trapping so that rate of iodination of tyrosine to form thyroid hormones
also decreased
o Normal endocytosis of colloid from follicles by thyroid glandular cells paralyzed by high I- concentrations
o Results in almost immediate shutdown of thyroid hormone secretion into blood
o Because iodides in high concentrations decrease all phases of thyroid activity, they slightly decrease size
of thyroid gland and especially decrease its blood supply
o Iodides frequently administered to patients 2-3 weeks before surgical removal of thyroid gland to
decrease necessary amount of surgery, especially to decrease amount of bleeding
Hyperthyroidism
 Hyperthyroidism – in most patients, thyroid gland is 2-3x normal size with tremendous hyperplasia and infolding
of follicular cell lining into follicles so number of cells increased greatly
o Each cell increases rate of secretion several-fold
 Graves’ disease – most common form of hyperthyroidism; autoimmune disease in which thyroid-stimulating
immunoglobulins (TSIs) form against TSH receptor in thyroid gland
o Antibodies bind with same membrane receptors that bind TSH and induce continual activation of cAMP
system of cells, with resultant development of hyperthyroidism
o TSI antibodies have prolonged stimulating effect on thyroid gland, lasting 12x normal TSH binding
o High level of thyroid hormone secretion suppresses anterior pituitary formation of TSH (near 0)
o Possibly caused by history in patient of excess of thyroid cell antigens released from thyroid cells at
some point in time, resulting in formation of antibodies against thyroid gland itself
 Thyroid adenoma (tumor) can sometimes cause hyperthyroidism; develops in thyroid tissues and secretes large
quantities of thyroid hormones
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As long as it continues to secrete large quantities of thyroid hormone, secretory function of remainder
of thyroid gland almost totally inhibited because thyroid hormone from adenoma depresses production
of TSH by pituitary gland
 Symptoms include high state of excitability, intolerance to heat, increased sweating, mild to extreme weight
loss, varying degrees of diarrhea, muscle weakness, nervousness or other psychic disorders, extreme fatigue but
inability to sleep, and tremor of hands
o Most people with hyperthyroidism develop some degree of exophthalmos; major degree occurs in
about 1/3 of patients
o Condition sometimes becomes so severe that eyeball protrusion stretches optic nerve enough to
damage vision
o More often, eyes are damaged because eyelids don’t close completely when person blinks of falls
asleep; as result, epithelial surfaces of eyes become dry and irritated and often infected, resulting in
ulceration of cornea
o Cause of exophthalmos is edematous swelling of retro-orbital tissues and degenerative changes in
extraocular muscles
o In most patients, Ig’s that react with eye muscles can be found in blood; concentration of Ig’s usually
highest in patients who have high concentrations of TSIs
o Exophthalmos usually greatly ameliorated with treatment of hyperthyroidism
 For usual case of hyperthyroidism, most accurate diagnostic test is direct measurement of concentration of free
T4 (sometimes T3) in plasma, using radioimmunoassay procedures
 Other tests that can test for hyperthyroidism are
o Basal metabolic rate (increased +30-+60 in severe cases)
o Concentration of TSH in plasma measured; in usual type of thyrotoxicosis, anterior pituitary secretion of
TSH so completely suppressed by large amounts of circulating T4 and T3 that there is almost no TSH
o Concentration of TSI measured; usually high in thyrotoxicosis but low in thyroid adenoma
 Most direct treatment is surgical removal of most of thyroid gland; in general, desirable to prepare patient by
administering propylthiouracil (usually for several weeks) until basal metabolic rate of patient returned to
normal; then administration of high concentrations of iodides for 1-2 weeks immediately before operation
causes gland to recede in size and blood supply to diminish
 80-90% of injected dose of iodide absorbed by hyperplastic, toxic thyroid gland within 1 day after injection
o If injected iodine is radioactive, it can destroy most of secretory cells in thyroid gland
o Radioactive iodine administered until normal thyroid status reached
Hypothyroidism
 Often initiated by autoimmunity against thyroid gland (Hashimoto disease); thyroid glands of most patients first
have autoimmune thyroiditis (inflammation of thyroid) that progressively deteriorates and finally fibrosis of
gland results, with resultant diminished or absent secretion of thyroid hormones
 Other types of hypothyroidism often associated with goiter
o Endemic colloid goiter – in certain areas of world (Swiss Alps, Andes, and Great Lakes region of U.S.),
insufficient iodine present in soil for foodstuffs to contain even minute quantity needed
 Lack of iodine prevents production of T4 and T3; as result, no hormone available to inhibit
production of TSH by anterior pituitary, causing it to secrete excessively large quantities of TSH
 TSH stimulates thyroid cells to secrete tremendous amounts of thyroglobulin colloid into
follicles, and gland grows larger and larger
 Because of lack of iodine, T4 and T3 production doesn’t occur in thyroglobulin molecule and
therefore doesn’t cause normal suppression of TSH production
o Idiopathic nontoxic colloid goiter – thyroid may secrete normal quantities of thyroid hormones, but
more frequently, secretion depressed
 Exact cause not known, but most patients show signs of mild thyroiditis (possibly same
mechanism as endemic colloid goiter but far less thyroid hormone depression)
 Glands usually nodular, with some portions growing and other portions destroyed by thyroiditis
 In some patients, thyroid has abnormality in enzyme system required for formation of thyroid
hormones, such as
 Deficient iodide-trapping mechanism – iodine not pumped adequately into thyroid cells
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Deficient peroxidase system – iodides not oxidized to iodine state
Deficient coupling of iodinated tyrosines in thyroglobulin molecule so final thyroid
hormones can’t be formed
 Deficiency of deiodinase enzyme prevents recovery of iodine from iodinated tyrosines
that aren’t coupled to form thyroid hormones (2/3 of iodine) thus leading to iodine
deficiency
 Some foods contain goitrogenic substances that have propylthiouracil-type of antithyroid
activity, leading to TSH-stimulated enlargement of thyroid gland; goitrogenic substances found
in turnips and cabbages
Physiological effects of hypothyroidism the same, regardless of cause; include fatigue and extreme somnolence,
extreme muscular sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume,
sometimes increased body weight, constipation, mental sluggishness, failure of many trophic functions in body
evidenced by depressed growth of hair and scaliness of skin, development of frog-like husky voice, and in severe
cases development of edematous appearance (myxedema)
Myxedema develops in patient with almost total lack of thyroid hormone function; bagginess under eyes and
swelling of face
o Greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form
excessive tissue gel in interstitial spaces, causing total quantity of interstitial fluid to increase
o Because of gel nature of excess fluid, it is mainly immobile and edema is nonpitting
Diagnostic tests show FT4 low, basal metabolic rate -30 to -50, secretion of TSH by anterior pituitary when test
dose of TRH administered usually greatly increased (except in rare instances of hypothyroidism caused by
depressed response of pituitary gland to TRH)
Easy to maintain steady level of thyroid hormone activity in body by daily oral ingestion of tablet of T4
o Proper treatment of hypothyroid patient results in complete normality that formerly myxedematous
patients have lived into their 90s after treatment for more than 50 years
Cretinism caused by extreme hypothyroidism during fetal life, infancy, or childhood; characterized by failure of
body growth and mental retardation
o Results from congenital lack of thyroid gland (congenital cretinism), failure of thyroid gland to produce
thyroid hormone because of genetic defect, or from iodine lack in diet (endemic cretinism)
o Severity of endemic cretinism varies greatly, depending on amount of iodine in diet
o Neonate without thyroid gland may have normal appearance and function because it was supplied with
some (usually not enough) thyroid hormone by mother in utero; few weeks after birth, neonate’s
movements become sluggish and both physical and mental growth begin to be greatly retarded
o Treatment of neonate with cretinism with adequate iodine or thyroxine usually causes normal return of
physical growth, but unless cretinism treated within few weeks after birth, mental growth remains
permanently retarded
o Mental retardation caused by retardation of growth, branching, and myelination of neuronal cells of
CNS at critical time in normal development of mental powers
o Skeletal growth characteristically more inhibited than is soft tissue growth
 Soft tissues likely to enlarge excessively, giving child with cretinism an obese, stocky, and short
appearance
 Occasionally tongue becomes so large in relation to skeletal growth that it obstructs swallowing
and breathing, inducing characteristic guttural breathing that sometimes chokes child