Pathophysiology of The Thyroid Gland

M. Djauhari Widjajakusumah
Department of Physiology
Fakultas Kedokteran Universitas Indonesia
Figure 741
Anatomical loci of the principal
endocrine glands and tissues of
the body.
Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
 ORGANISASI FUNGSIONAL SISTEM ENDOKRIN
dan
KELENJAR-KELENJAR ENDOKRIN UTAMA SERTA HORMON YANG
DISEKRESIKAN
Hipotalamus

ADH TRH v
CRH GnRH GRH
PRH
Oksitosin (OT) v
GIH PIH

Neuro- Adeno-hipofisis
hipofisis
TSH ACTH FSH GH
PRL v
LH

Med. Langer- Para- v

Gin- Para- Tiroid Korteks Testis Ova
Hati
adr hans tiroid jal folik adrenal
Andr
v
ADH Insulin 1,25 T3 Aldos Estr
OT Glukagon DHC T4
Korti-
IGF-1
E PTH Kalsi- sol
IGF-2
tonin
NE Andr
Estr
 The Thyroid Gland

One of the largest endocrine gland

Consists of two lobes lie on either side of the
trachea
Highest blood flow rates of any tissue in the body
Tremendous capacity for growth: appropriate
stimulus greatly enlarged (goiter)
Greenspans Basic & Clinical
Endocrinology 8e, 2007
Figure 181.
Ganongs Review of
Med Physiol 22th ed,
2006
From Iodide To Thyroid Circulating Hormones

Trapping
Iodide Hormone Synthesis:
oxidation
iodination
coupling reaction (oxidative condensation)

Hormone Secretion
 Iodide oxidation
Iodination
trapping

Iodination

Oxidative
coupling

Outline of thyroid hormone biosynthesis. Iodination of tyrosine takes place at the

apical border of the thyroid cells while the molecules are bound in peptide linkage in
thyroglobulin.
 Thyroid
Plasma Thyro-globulin
cell
Colloid molecule

Oxidation
(Thyroid
Active Tyrosine
peroxidase)
transpor
I- t I- I
Iodide Iodine Monoiodotyrosine (MIT)

I- I- I Diiodotyrosine (DIT)

MIT +DIT Alanine Triiodothyronine (T3)

+

DIT +MIT Alanine Reverse Triiodothyronine

+ (RT3)

DIT +DIT Alanine + Thyroxine (T4)

 Iodide Trapping
o Iodide active transport from circulation to the
colloid
o Stimulated by Thyroid Stimulating Hormone (TSH)
o Iodide is pumped into the cells against the
electrical gradient (resting membrane potential -
50 mv) iodide pump (competitively
inhibited by perchlorate and other anions)
o Iodide then diffuses down the electrical gradient
into the colloid
 Hormone Synthesis
Oxidation (thyroid peroxidase):
Iodide is oxidized to iodine

Iodination (thyroid peroxidase; blocked by

propylthiouracil)
binding of iodine to thyrosine-thyroglobulin
Mono-iodotyrosine (MIT)
binding of iodine to MIT Di-iodotyrosine (DIT)

Coupling reaction / oxidative condensation (thyroid

peroxidase))
MIT + DIT Tri-iodothyronine (T3)
DIT + DIT Tetra-iodothyronine/Thyroxine (T4)
 Hormone Secretion

(1) Colloid (with all its contents) ingestion / endocytosis

reabsorption lacunae
(2) Endocytotic vacuoles of colloid merge with
lysosome (protease):
peptide bonds between iodinated tyrosine
and thyroglobulin are broken free T4, free
T3, free DIT and free MIT are liberated
 Hormone Secretion

(3) Iodinated tyrosine (DIT, MIT) are deiodinated by

iodotyrosine deiodinase
free iodine and tyrosine-thyroglobulin
compounds are liberated, and are reutilized.

(4) Free T3 and free T4 pass into the circulation

Secretion and interconversion of thyroid hormones in normal adult humans.
Figures are in micrograms per day. Note that most of the T3 and RT3 are formed
from T4 deiodination in the tissues, and only small amounts are secreted by the
thyroid.
 THE MAIN FUNCTIONS OF THYROID HORMONES

Maintain the level of metabolism in the tissues for

their normal function
Stimulate the O2 consumption of most cells in the
body
Help regulate lipid and carbohydrate metabolism
Necessary for normal growth and maturation
 Effects Of Thyroid Hormones
(1) Calorigenesis
(2) Increase cardiac output
(3) Increase oxygenation

(4) Effects on carbohydrate metabolism

(5) Effects on lipid metabolism cataboli
sm
(6) Effects on protein metabolism
(7) Promote normal growth
(8) Promote development and maturation of nervousanabolis
system m

cataboli ADP + Pi work

sm ATP
increase energy heat
oxygenation
 Thyroid Hormones Increase Cellular Metabolic
Activity
o The thyroid hormones increase the metabolic activities of
almost all the tissues of the body.
o The basal metabolic rate can increase to 60 to 100 % above
normal when large quantities of the hormones are secreted.
o The rate of utilization of foods for energy is greatly
accelerated.
o The rate of protein synthesis is increased, at the same time
the rate of protein catabolism is also increased.
o The growth rate of young people is greatly accelerated.
o The mental processes are excited
o The activities of most of the other endocrine glands are
increased Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
Abnormalities of thyroid function include both
hypothyroidism and hyperthyroidism.
 FIGURE 19-3
-- Regulation of thyroid hormone
secretion.

Sherwood Human
Physiology From Cells to
Systems 7e 2010
Sherwood Human Physiology From Cells To Systems 7e, 2010
 Goiter
A goiter is an enlarged thyroid gland.
A goiter develops when the thyroid gland is overstimulated.
Because the thyroid lies over the trachea, a goiter is readily
palpable and usually highly visible
A goiter occurs whenever either TSH or TSI excessively
stimulates the thyroid gland.
A goiter may accompany hypothyroidism or
hyperthyroidism, but it need not be present in either
condition.
Knowing the hypothalamus-pituitary-thyroid axis and
feedback control, we can predict which types of thyroid
Sherwood Human Physiology
dysfunction will produce a goiter. From Cells To Systems 7e,
2010
HYPOTHYROIDISM
 HYPOTHYROIDISM

o Hypothyroidism can result

(1) from primary failure of the thyroid gland itself;

(2) secondary to a defciency of TRH, TSH, or

both;
(3) from an inadequate dietary supply of iodine.

Sherwood Human Physiology From Cells To Systems 7e, 2010

 Temprature
Environmental regulatory Other brain
Influences centers centers

Hypothalamus
(-)
(-)
TRH

Anterior pituitary
(-)
TSH

Iodide
Thyroid gland

T3 & T4
Primary steps
Biological effects involved in
Heat production
regulating
thyroid
Metabolism of CH, proteins,
and fats hormone
production
 Hypothyroidism
o The symptoms of hypothyroidism are largely caused by a
reduction in overall metabolic activity
a reduced BMR (less energy expenditure at rest);

poor tolerance of cold (lack of the calorigenic effect);

tendency to gain excessive weight (not burning fuels at

a normal rate);

easily fatigued (lower energy production);

slow, weak pulse (caused by a reduction in the rate and

strength of cardiac contraction and a lowered cardiac
output);
Sherwood Human
exhibits slow reflexes and slow mental responsiveness
Physiology From Cells To
(because of the effect on the nervous system).Systems 7e, 2010

diminished alertness,

slow speech,
 Hypothyroidism
o Another notable characteristic is an edematous condition caused by
infltration of the skin with complex, water-retaining carbohydrate
molecules, presumably as a result of altered metabolism.
Puffy appearance, primarily of the face, hands, and feet, known as

myxedema.

o Adequate levels of thyroid hormone are essential for normal growth

and CNS development
Hypothyroidism from birth, develops a condition known as

cretinism
Cretinism is characterized by dwarfsm and mental retardation , and

other general symptoms of thyroid defciency.

o The mental retardation is preventable if replacement therapy is started

promptly, but it is not reversible once it has developed for a few
months after birth, even with later treatment with thyroid hormone.

Sherwood Human
Physiology From Cells To
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 Guyton and
Hall: Textbook
of Medical
Physiology 11th
ed. 2006
Figure 769
Patient with myxedema. (Courtesy Dr. Herbert Langford.)
PHYSIOLOGIC EFFECTS OF THYROID HORMONES

Effects on Growth
Essential for normal growth and skeletal maturation

Necessary for the normal growth hormone secretion

Potentiate the effect of growth hormone on the

tissue

In hypothyroid children, bone growth is slowed and

epiphysial closure is delayed.
 Effect On Growth And The Nervous System
Thyroid hormone is essential for normal growth because of its
effects on growth hormone (GH) and IGF-I.
Stimulates GH secretion and increases production of IGF-I by the
liver
Promotes the effects of GH and IGF-I on the synthesis of new
structural proteins and on skeletal growth.
Thyroid-defcient children have stunted growth that can be reversed
by thyroid replacement therapy.
Excess thyroid hormone does not produce excessive growth.
Thyroid hormone plays a crucial role in the normal development of
the nervous system, especially the CNS, an effect impeded in
children who have thyroid defciency from birth.
Thyroid hormone is also essential for normal CNS activity in adults.
Figure 18-13. Fraternal twins,
age 8 years. The boy has
congenital hypothyroidism.
(Reproduced, with permission,
from Wilkins L in: Clinical
Endocrinology I. Astwood EB,
Cassidy CE [editors]. Grune &
Stratton, 1960.)
Normal and abnormal growth. Hypothyroid dwarfs (cretins) retain
their infantile proportions whereas dwarfs of the constitutional type
and, to a lesser extent, of the hypopituitary type have proportions
 Hypothyroidism
o Treatment of hypothyroidism, with one exception, consists
of replacement therapy by administering exogenous thyroid
hormone.
o The exception is hypothyroidism caused by iodine
defciency, in which the remedy is adequate dietary iodine.

Sherwood Human
Physiology From Cells To
Systems 7e, 2010
Hyperthyroidism
In most patients with hyperthyroidism, the thyroid
gland is increased (struma, goiter) to two to three
times' normal size, with tremendous hyperplasia
and infolding of the follicular cell lining into the
follicles, so the number of cells is increased greatly.
Also, each cell increases its rate of secretion
severalfold; radioactive iodine uptake studies
indicate that some of these hyperplastic glands
secrete thyroid hormone at rates 5 to 15 times
normal.
Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
Causes Of Hyperthyroidism
(Toxic Goiter, Thyrotoxicosis,
Graves' Disease)
Graves' disease
o The most common form of hyperthyroidism
o An autoimmune disease in which antibodies called thyroid-
stimulating immunoglobulins (TSI) are formed against
thyroid tissue, and bind with TSH membrane receptors with
resultant development of hyperthyroidism.
o The high level of thyroid hormone secretion caused by TSI
in turn suppresses anterior pituitary formation of TSH
TSH concentrations are less than normal (often essentially
zero)
o Presumably, an excess of thyroid cell antigens was
released from the thyroid cellsGuyton
and this hasTextbook
& Hall: resulted in the
of Medical
formation of antibodies against the thyroid gland itself.
Physiology 12e, 2011
Causes Of Hyperthyroidism
(Toxic Goiter, Thyrotoxicosis,
Graves' Disease)
o The most common cause of hyperthyroidism is Graves
disease, an autoimmune disease in which the body
produces thyroid-stimulating immunoglobulin (TSI),
also known as long-acting thyroid stimulator (LATS),
an antibody whose target is the TSH receptors on the
thyroid cells.
o TSI stimulates both secretion and growth of the thyroid in a
manner similar to TSH.
o TSI is not subject to negative-feedback inhibition by thyroid
hormone, so thyroid secretion and growth continue
unchecked.
o Less frequently, hyperthyroidism occurs secondary to
Sherwood Human
excess TRH or TSH or in association with a Physiology
hypersecreting
From Cells To
thyroid tumor. Systems 7e, 2010
 Sherwood
Human
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 Graves disease
o A prominent feature of Graves disease but not of the other
types of hyperthyroidism is exophthalmos (bulging
eyes).
o Complex, water-retaining carbohydrates are deposited
behind the eyes, although why this happens is still unclear.
o The resulting fluid retention pushes the eyeballs forward so
they bulge from their bony orbit.
o The eyeballs may bulge so far that the lids cannot
completely close, in which case the eyes become dry,
irritated, and prone to corneal ulceration.
o Even after correction of the hyperthyroid condition, these
troublesome eye symptoms may persist.Sherwood Human Physiology
From Cells To Systems 7e,
2010
 Exophthalmos

o In about one third of hyperthyroid patients develop some

degree of protrusion of the eyeballs, exophthalmos.
o Sometimes the eyeball protrusion stretches the optic nerve
enough to damage vision.
o The eyelids do not close completely when the person blinks or is
asleep, the epithelial surfaces of the eyes become dry and
irritated and often infected, resulting in ulceration of the cornea.
o The cause of the protruding eyes is edematous swelling of the
retro-orbital tissues and degenerative changes in the
extraocular muscles.
o In most patients, immunoglobulins that react with the eye
muscles can be found in the blood.
o There is much reason to believe that exophthalmos, like
hyperthyroidism itself, is an autoimmune process.
Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
Sherwood Human Physiology
From Cells To Systems 7e,
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 The Symptoms of Hyperthyroidism
o The hyperthyroid patient has an elevated BMR.
o The resultant increase in heat production leads to excessive
perspiration and poor tolerance of heat.
o Increased appetite and food intake that occur in response
to increased metabolic demands
o Body weight typically falls because the body is burning fuel
at an abnormally rapid rate.
o Net degradation of carbohydrate, fat, and protein stores
occurs
Sherwood
o The resultant loss of skeletal muscle protein results in Human
Physiology
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 The Symptoms of Hyperthyroidism
o Various cardiovascular abnormalities are associated with
hyperthyroidism, caused both by the direct effects of
thyroid hormone and by its interactions with
catecholamines.
o Heart rate and strength of contraction may increase so
much that the individual has palpitations (an unpleasant
awareness of the hearts activity).
o In severe cases, the heart may fail to meet the bodys
metabolic demands despite increased cardiac output.
o The effects on the CNS are characterized by an excessive
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degree of mental alertness to the point where the patient is
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irritable, tense, anxious, and excessively emotional. Physiology
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 The Symptoms of Hyperthyroidism
(1) a high state of excitability,
(2) intolerance to heat,
(3) increased sweating,
(4) mild to extreme weight loss
(5) varying degrees of diarrhea,
(6) muscle weakness,
(7) nervousness or other psychic disorders,
(8) extreme fatigue but inability to sleep,
(9) tremor of the hands.
Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
Sherwood Human Physiology From Cells To Systems 7e, 2010
 FIGURE 19-3
-- Regulation of thyroid hormone
secretion.

Sherwood Human
Physiology From Cells to
Systems 7e 2010
 A Goiter May Or May Not Accompany Hypothyroidism:

o Hypothyroidism secondary to hypothalamic or anterior pituitary failure

will not be accompanied by a goiter, because the thyroid gland is not
being adequately stimulated, let alone excessively stimulated.
o With hypothyroidism caused by thyroid gland failure or lack of iodine, a
goiter does develop because the circulating level of thyroid hormone is
so low that there is little negative-feedback inhibition on the anterior
pituitary and hypothalamus, and TSH secretion is therefore elevated.
o TSH acts on the thyroid to increase the size and number of follicular
cells and to increase their rate of secretion. If the thyroid cells cannot
secrete hormone because of a lack of a critical enzyme or lack of iodine,
no amount of TSH will be able to induce these cells to secrete T3 and T4.
o TSH can still promote hypertrophy and hyperplasia of the thyroid, with a
paradoxical enlargement of the gland (that is, a goiter), even though the
gland is still underproducing.

Sherwood Human
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Figure 815.
The hypothalamic-hypophysial-
thyroidal axis. TRH produced in
the hypothalamus reaches the
thyrotrophs in the anterior
pituitary by the hypothalamic-
hypophysial-portal system and
stimulates the synthesis and
release of TSH. In both the
hypothalamus and the
pituitary, it is primarily T3 that
inhibits TRH and TSH
secretion, respectively. T4
undergoes monodeiodination
to T3 in neural and pituitary as
well as in peripheral
Greenspans tissues.
Basic & Clinical
Endocrinology 8e, 2007
 Temprature
Environmental regulatory Other brain
Influences centers centers

Hypothalamus
(-)
(-)
TRH

Anterior pituitary
(-)
TSH

Iodide
Thyroid gland

T3 & T4
Primary steps
Biological effects involved in
Heat production
regulating
thyroid
Metabolism of CH, proteins,
and fats hormone
production
 Sherwood Human
Physiology From Cells to
Systems 7e 2010
 A Goiter May Or May Not Accompany Hyperthyroidism:

o Excessive TSH secretion resulting from a hypothalamic or

anterior pituitary defect would be accompanied by a goiter
and excess T3 and T4 secretion because of overstimulation
of thyroid growth.
o Because the thyroid gland in this circumstance is capable of
responding to excess TSH with increased hormone
secretion, hyperthyroidism is present with this goiter.
o In Graves disease, a hypersecreting goiter occurs because
TSI promotes growth of the thyroid as well as enhancing
secretion of thyroid hormone.
o Because the high levels of circulating T3 and T4 inhibit the
anterior pituitary, TSH secretion is low.

Sherwood Human
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 Sherwood
Human
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 Thyroid Adenoma

o Hyperthyroidism occasionally results from a localized

adenoma (a tumor) in the thyroid tissue and secretes large
quantities of thyroid hormone.
o Different from the more usual type of hyperthyroidism, it is
usually not associated with evidence of any autoimmune
disease.
o As long as the adenoma continues to secrete large
quantities of thyroid hormone, secretory function in the
remainder of the thyroid gland is almost totally inhibited
because the thyroid hormone from the adenoma depresses
the production of TSH by the pituitary gland.
Guyton & Hall: Textbook of Medical
Physiology 12e, 2011
 Thyroid Tumor

o Hyperthyroidism resulting from over-activity of the thyroid

(an uncontrolled thyroid tumor) in the absence of
overstimulation, is not accompanied by a goiter.
o The spontaneous secretion of excessive amounts of T3 and
T4 inhibits TSH, so there is no stimulatory input to promote
growth of the thyroid.
o Even though a goiter does not develop, a tumor may cause
enlargement of the thyroid, depending on the nature or size
of the tumor.
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 Treatment
Three general methods of treatment can suppress excess
thyroid hormone secretion:
(1) Use anti-thyroid drugs that specifcally interfere with
thyroid hormone
synthesis (drugs that block symporter uptake of Iodide
or drugs that
inhibit thyro-peroxidase);
(2) surgical removal of a portion of the over-secreting
thyroid gland;
(3) administration of radioactive iodine, which, after being
concentrated in
the thyroid gland by the iodide pump, selectively
destroys thyroid
glandular tissue.
Thank You
 M. Djauhari
Widjajakusumah