Download CASE 34

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CASE 34
A 41-year-old woman presents to her primary care physician with weight and
hair loss, diarrhea, nervousness, and eye pressure. She has no medical problems, but some of her family members have similar symptoms and require
medication. On examination, she is noted to have exophthalmos, an enlarged
nontender goiter, hyperreflexia, and a tremor when her arms are outstretched.
The patient has a decreased thyroid-stimulating hormone (TSH) level and an
increased free thyroxine (T4) level and is diagnosed with Graves disease
(hyperthyroidism).
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What is the mechanism by which high levels of iodine inhibit
thyroid production?
How does propylthiouracil (PTU) inhibit thyroid synthesis?
What affect does pregnancy have on the free thyroid hormone
level?
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CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 34: THYROID DISEASE
Summary: A 41-year-old woman has weight and hair loss, diarrhea, nervousness, eye pressure, nontender goiter, exophthalmos, and laboratory evidence of
hyperthyroidism.
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High levels of iodine: Inhibit the iodine pump (Wolff-Chaikoff effect).
Mechanism of action of PTU: Inhibits peroxidase enzyme activity in
the follicular cell membrane, resulting in an inability to oxidize iodine.
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Effect of pregnancy on free thyroid levels: No change in free levels.
The total level would be elevated because of an increase in thyroxinebinding globulin. Because the free levels remain the same, the patient is
euthyroid.
CLINICAL CORRELATION
Patients with abnormalities of the thyroid may present with many different
clinical symptoms. Patients with hyperthyroidism may present with weight
loss, tremor, weakness, diarrhea, hair and nail changes, heat intolerance, goiters, exophthalmos, and/or tachycardia. The most common cause of hyperthyroidism is Graves disease. This disease results from stimulation of the thyroid
gland by the binding of antibodies to the TSH receptor. The normal negative
feedback mechanism does not stop the thyroid because antibody levels, unlike
TSH levels, are not modulated by T3 and T4 levels. Laboratory findings suggestive of hyperthyroidism include a decreased TSH and an elevated T4 or T3
count. Treatment is often with PTU (blocks peroxidase activity), iodine
(inhibits the iodine pump), radioactive iodine (ablates the thyroid), or surgery
(thyroidectomy). Beta-blocker medications often are used when tachycardia is
present.
APPROACH TO THYROID PHYSIOLOGY
Objectives
1.
2.
3.
Describe the synthesis of thyroid hormones.
Understand the regulation of thyroid synthesis and secretion.
Describe the various actions of thyroid hormones.
Definitions
Colloid: The material that fills the lumen of the thyroid follicles. It is comprised mostly of thyroglobulin, the storage form of thyroid hormone.
Thyroxin-binding globulin: The plasma protein to which most of the thyroid hormone in the circulation is bound.
CLINICAL CASES
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DISCUSSION
The thyroid gland is composed of many follicles that consist of epithelial (follicular) cells surrounding a lumen where thyroglobulin, the precursor of the
thyroid hormones T3 and T4, is synthesized and stored. Thus, thyroglobulin is
stored outside the apical membranes of the follicular cells and away from the
capillaries perfusing those cells’ basolateral membranes. Thyroglobulin is a
glycoprotein that is synthesized in the endoplasmic reticulum of the follicular cells and secreted across their apical membranes into the lumen by the
Golgi apparatus. The other hormone component, iodide, is taken up from the
blood on the cells’ basolateral membranes by a sodium-coupled active
transport process that can concentrate iodide 30 to 200 times. The iodide then
passes through the cell to be oxidized on the apical surface by H2O2 through
the action of the enzyme thyroperoxidase. The oxidized iodide then reacts
with a small number of the tyrosines of thyroglobulin to form mono- and
diiodotyrosine. Synthesis is completed by the coupling of two diiodotyrosines
to form T4, the major product, and by the coupling of monoiodotyrosines with
diiodotyrosines to form T3, the minor product. This coupling takes place while
the tyrosines are still part of the thyroglobulin molecule and is catalyzed by thyroperoxidase. Normally, this storage form of thyroid hormone is sufficient to
provide the body with adequate amounts of hormone for 1 to 3 months.
Secretion of thyroid hormones begins with the uptake of thyroglobulin
by the apical membrane of follicular cells by endocytosis. Lysosomal vesicles
then fuse with the endocytotic vesicles, and lysosomal enzymes hydrolyze the
thyroglobulin to form T4, T3, mono- and diiodotyrosine, free amino acids, and
peptides. The T4 and T3 diffuse across the follicular cell basolateral membrane to enter the circulation. The mono- and diiodotyrosines are deiodinated, and the iodide is recycled.
Synthesis and secretion of T3 and T4 will take place at low levels without
any stimulus. However, normally, thyroid function is enhanced to various levels by the pituitary hormone TSH. TSH binds to receptors on the basolateral surface of follicular cells and through a G protein-linked pathway
increases cyclic adenosine monophosphate (cAMP) levels in the cell. This
leads to stimulation of hormone synthesis and secretion, and, if TSH levels are
high enough for a long enough time, to an increase in size and number of follicular cells. In certain conditions, as in this case, antibodies to the TSH receptor can bind to and activate the receptor. This leads to a marked increase in the
synthesis and secretion of thyroid hormone and to growth of the thyroid gland.
Circulating thyroid hormones exert a negative feedback at the level of the pituitary, thus decreasing the release of TSH (see Case 33).
Once secreted, T3 and T4 are tightly bound to plasma proteins, primarily
thyroxin-binding globulin with lesser amounts bound to thyroxin-binding prealbumin and albumin. Less than 1% of these hormones is in free solution
and thus in equilibrium with the interstitial fluid. Because of the tight binding
to plasma proteins and the rather slow uptake of hormone by cells of the body,
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CASE FILES: PHYSIOLOGY
circulating T3 and T4 have plasma half-lives of around 1 and 6 days, respectively. Much of the T3 circulating in the blood arises not from secretion from the
thyroid but instead from the deiodination of T4 by deiodinases primarily in the liver
and kidney. Also, many cell types have deiodinases that convert T4 to T3 upon the
uptake of T4 into the cell. This is important because T3 seems to be the most active
hormone at the level of cellular receptors. T4 also can be degraded to an inactive
T3, called rT3 (reverse T3), by the removal of an iodide from the internal ring of T4
by deiodinase. The regulation and importance of this reaction are not clear.
The effects of thyroid hormones have a slow onset and a long duration and
do not bring about moment-to-moment regulation. T3 and T4 enter cells by simple diffusion. Most of the T4 is converted to T3, which then binds with nuclear
receptors to modulate the transcription of a number of proteins involved in
cellular metabolism. By upregulating the synthesis of these proteins, thyroid
hormones increase the oxygen consumption and adenosine triphosphate
(ATP) production of all tissues in the adult body except brain, testis, and spleen.
Much of the ATP produced is consumed to produce body heat. To support the
increased metabolism, there is an increase in carbohydrate absorption from the
intestine and in hepatic glycogenolysis and gluconeogenesis.
The effects of thyroid hormones on lipid and protein metabolism are somewhat complex. A certain hormone level is needed to provide the carbohydrate
for lipogenesis to take place. However, thyroid hormone also is needed for
fatty acid mobilization, and as hormone levels increase, mobilization predominates. Thyroid hormones affect protein metabolism in much the same way as
they affect lipid metabolism. Optimal synthesis and degradation of protein
require a certain low level of hormone. At high levels, although both synthesis
and degradation are increased, degradation predominates.
In general, thyroid hormone stimulates the metabolic activity of most cells
in the body. Because overall metabolism is enhanced by thyroid hormone, cardiac output and respiration are positively correlated with hormone levels.
More specifically, thyroid hormones are required for normal brain development during the perinatal period. In adults, the effects of thyroid hormone on the
central nervous system (CNS) are complex and are not completely understood.
Hypothyroidism is accompanied by slow thought processes and somnolence.
Hyperthyroidism is characterized by nervousness, anxiety, paranoia, and difficulty sleeping. Fine muscle tremor also is prominent in hyperthyroidism.
In many tissues innervated by the autonomic nervous system, especially the
sympathetic branch, thyroid hormones increase the number of adrenergic receptors, particularly β-adrenergic receptors, and/or the concentration of intracellular signaling mediators coupled to the receptors. Thus, heart rate and
myocardial contractility are increased in hyperthyroidism. Gastrointestinal
secretions and motility also are stimulated by thyroid hormone. This may be
due to an action on the enteric nervous system. T3 and T 4 play little role in
fetal growth but are essential for growth to adulthood. Thyroid hormones
appear to have few direct actions on skeletal growth by themselves; however,
they are essential for growth hormone and other growth factors to be effective.
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CLINICAL CASES
COMPREHENSION QUESTIONS
[34.1]
A 33-year-old woman is noted by her physician to have some fatigue
and some coarse skin. Her only medication is an oral contraceptive
agent. The following laboratories have been returned:
TSH
Free thyroxine
Total thyroxine
Thyroid-binding globulin (TBG)
1.0 mU/L (0.35-6.0 mU/L)
1.0 ng/dL (0.8-2.7 ng/dL)
13.0 μg/dL (4.5-12.0 μg/dL)
55 ng/mL (15-34 mg/L)
Which of the following is the most likely diagnosis?
A.
B.
C.
D.
[34.2]
Hyperthyroidism
Hypothyroidism
Normal thyroid status
Transient hyperthyroidism
A 33-year-old chemist takes L-thyroxine (Synthroid) 1 μg orally each
day. He asks how the thyroxine works on a cellular level. Which of
the following is the best explanation?
A. It binds onto membrane surface receptor and activates protein
synthesis.
B. It binds onto membrane surface receptor and activates a secondary
messenger.
C. It binds onto a cytoplasmic receptor, and the hormone–receptor
complex diffuses to the nucleus to affect transcription.
D. It has a direct effect on the hypothalamic nuclei affecting metabolism.
[34.3]
A 15-year-old adolescent is suspected of having anorexia nervosa.
Thyroid function tests are also drawn. Her TSH is in the normal
range, but the rT3 level is elevated. Which of the following is the most
accurate statement regarding her status?
A.
B.
C.
D.
Reverse T3 has little biological effect.
This patient probably has T3 thyroiditis.
The free rT3 would be the next step to assess possible hyperthyroidism.
This patient probably has hypothyroidism.
Answers
[34.1]
C. This patient has an elevated total thyroxine level because of
increased TBG. However, the free (active) thyroxine is normal, and
the TSH is in the normal range, both of which indicate a normal
euthyroid state. Women who are pregnant or on an oral contraceptive
agent may develop an increased TBG; hence, free T4 or TSH levels
are better tests to assess thyroid status.
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CASE FILES: PHYSIOLOGY
[34.2]
C. Thyroxine behaves similarly to steroid hormones in that it binds
onto cytoplasmic receptors, and the hormone–receptor complex then
diffuses to the nucleus to affect the transcription of DNA and ultimately protein synthesis. Most protein hormones bind to surface
membrane receptors; thyroid hormone is an exception.
[34.3]
A. Reverse T3 has no biological effect. Individuals with anorexia nervosa often have an increased rT3 level and a lower T3 level, reflecting
a lower metabolism rate as compensation for the markedly decreased
caloric intake. The fact that her TSH is in the normal range makes it
difficult to make a diagnosis of hypothyroidism.
PHYSIOLOGY PEARLS
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Iodide necessary for the synthesis of thyroid hormone is taken up by
thyroid follicular cells against an electrochemical gradient by
sodium-coupled secondary active transport.
The oxidative reaction steps linking iodide to tyrosine residues of
thyroglobulin take place extracellularly in the colloid stored
within thyroid follicles.
Thyroid hormone secretion requires the pinocytotic uptake and
breakdown of colloid by follicular cells.
TSH, which is secreted by the pituitary in response to thyrotropinreleasing hormone from the hypothalamus, simultaneously stimulates thyroid hormone synthesis and thyroid hormone secretion.
Thyroid hormone exists in two forms: triiodothyronine (T3) and
tetraiodothyronine (T4). Both circulate in the blood bound to
plasma proteins, but at the cellular level, T4 is converted to T3,
which then binds to thyroid hormone receptors.
Thyroid hormone is essential for normal brain development in the
perinatal period.
Thyroid hormone stimulates oxidative metabolism in all tissues
except brain, spleen, and testis. ATP utilization and heat production are increased.
Thyroid hormone binds to nuclear receptors to regulate the transcription of genes involved in metabolic events.
REFERENCES
Genuth SM. Thyroid gland. In: Levy MN, Koeppen BM, and Stanton BA, eds. Berne
& Levy, Principles of Physiology. 4th ed. Philadelphia, PA: Mosby; 2006:663-675.
Goodman HM. Thyroid gland. In: Johnson LR, ed. Essential Medical Physiology.
3rd ed. San Diego, CA: Elsevier Academic Press; 2003:587-605.