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Endocrinology: 9-10am
Friday, November 6, 2009
Scribe: Strudwick Louis Tutwiler
Dr. Weigent
Thyroid Endocrinology
Page 1 of 5
Dr Weigent skipped text in italics.
I. Thyroid Gland [S1]: This gland is one of the only endocrine glands that can be palpated. The thyroid gland has
been known about for a long time since pathology usually appears. With thyroid problems, there is a hypertrophy or
enlargement seen in the throat.
a. Assigned Reading: Physiology Text by L.S. Costanzo
b. Outline:
i. Anatomy of the thyroid gland
ii. Synthesis and release of thyroid hormones
iii. Regulation of thyroid gland activity
iv. Actions of thyroid hormones
v. Thyroid dysfunction = too much or too little hormone produced
c. They thyroid gland is a system unique in that not only can a problem be visually seen, but also it is a system
where the hormones are secreted and stored outside the cells. In most systems, hormones are made and
synthesized within cells. The body retrieves it from a space when needed and sends it back into the blood.
II. Diet [S2]: Do not have to recall these numbers. I = Iodine
a. 400ug (micrograms per day digested)  (Extracellular Fluid) 320 l + 80 l (20% reaches the thyroid gland)
i. The thyroid gland has a receptor with a high binding coefficient for Iodine.
b. 80 l (Thyroid)  20 l + 60 HI
i. 75% of Iodine taken into the thyroid gland is Iodinated, formed into hormone, and move into the tissues.
c. 60 HI (Tissues)  50 l + 10 HI
d. 50 l (Urine)  390 l (Majority of iodine finds its way into the urine)
e. 10 HI  (Stool) 10 HI (Small amount of Iodine passes through the stool)
f. There are places in the world where Iodine deficiencies cause problems in both adults and children.
III. Thyroid Anatomy [S3]
a. The Thyroid gland, bow tie shaped, is right below the Adam’s apple or Thyroid Cartilage.
b. Normally 20 grams in weight, but with hypertrophy it can increase ten times.
c. It has a Left and Right lobe, as well as a Pyramidal Lobe and Isthmus.
d. It surrounds the trachea and is well vascularized.
IV. Thyroid Follicle [S4]: microscopic view of thyroid gland
a. Normal Follicle is the main unit and is show under resting conditions. A layer of columnar epithelial cells has
capacity to synthesize hormone and are surrounded by blood vessels. Iodine traffics down capillaries and
captured. When the hormone is made, it is stored in the center.
b. Stimulated Hyperplastic Follicle: Colloid Undergoing Resorption = on the right shows what happens when the
cell is stimulated. It forms these scalloped scenarios on the apical side. This is the basolateral on the outside.
It sculpts it back into the cell. The colloid, thyroglobulin, or thyroid hormone itself is taken back into the cell.
V. T3 (Active) Formation [S5]: Chemistry of the thyroid hormone
a. Thyroid hormone is within a protein called thyroglobulin. There are tyrosine residues in the thyroglobulin, but
there is a low average of tyrosine in the protein. Tyrosines and Benzyl group become Iodinated.
b. Tyrosine  MIT (monoiodotyrosine) or DIT (diiodotyrosine); occurs via iodination process
c. By adding a Benzyl group and iodination, you get Thyroxine or T4. T3 = tri-iodo-thyronine
d. Tyrosine is now in the backbone of this protein called thyroglobulin, and in appropriate conditions, it becomes
iodinated.
e. 90% Thyroxine (T4) reverse T3 (inactive) or via deiodinase to T3 (active). T4 is the primary product from the
thyroid gland, but it is not as active as T3.
f. Need to appreciate the deiodinase enzyme, which converts T4 to T3. There are different kinds of this enzyme.
g. Their regulation and appearance is important the level of each hormone produced. When you are sick, you do
not produce as much T3 because the deiodinase changes. Deiodinase #1 removes iodine from thyroxine.
h. The regulation of the deiodinase in the tissue is important, and other things in the cell affect regulation. The
regulation of this system is controlled by the thyroid hormones (T3 and T4).
i. The pituitary has a deiodinase that converts T4 to T3, but it is a different deiodinase. It is involved in negative
feedback regulation.
j. The activity of the deiodinase is important for modulating activity in the tissue, for control in regulating, and for
salvage. In the process of synthesizing thyroid hormone, a lot of iodine is not used but is preserved and
salvaged in cells to be reutilized. If Iodine is not used, it is stored in the body.
k. Do not have to know structures.
l. Depending on which deiodinase is working, you can remove a different Iodine you can get Reverse T3 (inactive
and functions as an inhibitor) or T3 (active).
m. The type and amount of deiodinase will determine how much active thyroid hormone one has.
n. Bound to plasma proteins: TBG (means either thyroxine-binding globulin or thyroglobulin)
Endocrinology: 9-10am
Friday, November 6, 2009
Scribe: Strudwick Louis Tutwiler
Dr. Weigent
Thyroid Endocrinology
Page 2 of 5
VI. Thyroid Hormone Biosynthesis [S6-8]
a. Step I: Iodide Trapping by Na/I Pump – ATP dependent: The sodium/iodide transporter moves iodide into the
cell very efficiently and effectively. It is transported across the cell from the basolateral side to apical side to a
protein called pendrin.
b. Step 2: Thyroglobulin Synthesis
c. Step 3: Iodination (organification); I- (Iodide) to Io (Iodine) required H2O2; Organification: Io added to at
tyrosine’s of thyroglobulin. There is oxidation of the iodide to iodine.
i. In the process of transporting Iodide onto the surface where this is a TPX (thyroperoxidase), an oxidation of
the iodide occurs to Iodine. It is very reactive. TPX is the enzyme, and Iodide is very reactive. The
process of organification is where the iodine becomes attached to the tyrosine residues within the
thyroglobulin molecule. This is building the thyroid hormones (T1, T2, T3, or T4).
d. Step 4: Coupling reactions to form T4
i. MIT (monoiodotyrosine) + DIT (diiodotyrosine) to form T3
ii. 2 DIT form a thyroxine (T4). Tyrosine molecules in backbone of thyroglobulin with thyroperoxidase will
combine and form T4 shown early in pictures.
iii. Thyroperoxidase is used in Steps 3-4.
iv. This is the colloid, and it will reside function. The the thyroid hormone is stored in the body in a gushy
material. When the body needs thyroid hormone, Step 5 starts.
e. Step 5: Endocytosis: TG receptor called “megalin.” This receptor protein is in the scalloping portion or villi that
are stimulated by TSH. It encourages the sculpting out of the colloid and removal from space back into the cell
via megalin.
f. Step 6: Proteolysis: (~90% T4, ~10% T3). Once back in the cell, this “gunk” is taken into and acted upon by
lysosomes and proteases. Then, T3 (active tri-iodo-thyronine) & T4 (inactive thyroxine) are released in those
percentages. Most of the thyroid hormone found in the blood is T4, which binds to the receptor proteins.
g. Step 7: Secretion and Recycling: What does not make it to a mature T4 or T3 via deiodinase (ex. T2), will have
its Iodine rescued and reentered into the process.
i. Steps 5-7 are involved in Hormone Secretion.
VII. Compare T3 and T4 [S9]: Dr Weigent said there were common test questions.
a. T3 and T4 are the two main hormones produced by the thyroid gland.
b. T4 is the predominant form released by the thyroid gland.
c. T4 is bound more tightly by plasma proteins than T3.
d. Therefore, T4 half-life in serum is six times greater than T3. (due to being bound more tightly)
e. However, T3 has 3-5 times more biological activity than T4. (T3 has 10x the ability to bind receptors in cells)
f. T4 is prehormone for T3.
VIII. Autoregulation by Iodine [S10]:
a. There are several slides about how the synthesis of thyroid hormones is regulated by the neuroendocrine
system. The thyroid cell has the ability to monitor and respond to its environment.
b. Independent of TSH and is regulated by changes in Iodine levels
c. Iodine Deficiency: Increased Trapping; Low Iodine is sensed by the cell (independent of TSH) and will increase
the receptors and Na/I transporter. This is autoregulation of Iodine coming into the cell
d. Iodine Excess: Too much iodine in the diet will cause the cell to decrease Thyroperoxidase and Pinocytosis
(sculpting out of stored colloid hormones via the binding of Megalin back into the cell).
e. A number of hormones as well as autoregulation regulate the gland.
IX. Effects of TSH on Thyroid Gland [S11]
a. Major regulating factor is TSH (thyroid stimulating hormone) made by thyrotrophs in the pituitary. TSH is a
dimer (alpha and beta subunit) and acts at a receptor in the membrane of the thyroid cell. Via G-proteins and
increase of adenyl cyclase, it increases cyclic-AMP. This activates Protein Kinase A.
b. TSH (alpha + Beta) binds  AC (adenyl cyclase)  (+) cAMP  Protein Kinase A, which causes a multiple
stimulatory processes within the cell:
i. Increases growth from within the cell:
1. Increased DNA, RNA, and Protein Synthesis
2. Increased Cell Size, Cell Number, and Follicle Formation
ii. Increases hormone Synthesis from:
1. Increased Trapping of Iodine, Iodination, Endocytosis of Colloid, Thyroglobulin degradation,
Organification
2. Increased Glucose Oxidation, NADPH generation
c. TSH is the major player, but not the only factor. Under normal conditions and certainly under pathologic
conditions, other regulating factors come into play. Minor factors are IGF (insulin-like growth factor), GH (growth
hormone), and fibroblast growth factor.
Endocrinology: 9-10am
Friday, November 6, 2009
Scribe: Strudwick Louis Tutwiler
Dr. Weigent
Thyroid Endocrinology
Page 3 of 5
X. Axis of Thyroid Control [S12]
a. Third slide on regulation with the family feedback mechanism.
b. Thermal or Caloric  Signals  TRH (Hypothalamus)
c. Hypothalamus, Pituitary, and Thyroid Gland  undergoes long loop negative feedback that can act back at level
of pituitary and hypothalamus.
d. It is “long loop” due to T3 and T4 secreted by the thyroid gland that can act back at the level of the pituitary or
hypothalamus.
e. The hormones can decrease synthesis of TSH, decrease sensitivity of pituitary to TRH by down regulating TRH
receptors, or low the levels of TRH made in the hypothalamus. There are number of ways these thyroid
hormones can feedback and inhibit.
f. Importantly, the deiodinase (star) will allow for negative feedback inhibition of thyroid hormones. This is a
specific, different deiodinase than from the one in the tissues.
XI. Effects of Cytokines on the Hypothalamic-Pituitary-Thyroid Axis (Inhibit) [S13]
a. Dr Weigent says he likes this area, so possibly might be a test question.
b. The hormones are not only under the influence of TSH, autoregulation, and negative feedback. Cytokines can
influence hormone production, but mainly affect the immune system.
c. When you are sick, you interleukin 1 and TNF-alpha that have serious effects in neuroendocrine system at level
of hypothalamus and pituitary. Cytokines are used to explain our behavioral responses when we are sick.
d. IL-1 enhances the synthesis of somatostatin, a TSH release-inhibiting hormone, in cultured hypothalamic
neurons. Somatostatin is a negative regulator of TSH.
e. TNF-alpha decreases hypothalamic TRH content.
f. IL-1, TNF-alpha and IFN-gamma directly inhibit thyroid hormone biosynthesis, secretion, and cell growth
induced by TSH. Cytokines can also directly affect the thyroid gland, and not just the hormones.
g. Cytokines may play a role in triggering autoimmune disease.
XII. Flowchart [S14]
a. This explains and describes features of thyroid hormones.
b. T4(found in blood) T3 (in cytoplasm of target cells) + tissue deiodinase  T3 on TR (nucleus)  Increased
mRNA
i. T3 is 10 times more avid for the receptor than T4. Most of the alpha and beta thyroid receptors (TR) are
already nuclear bound or bound to DNA.
ii. TR cooperates with other receptors in the nucleus called the retinoid receptors, and as a result,
transcription is stimulated.
iii. It works through a thyroid response element, which is specific to bind this receptor and other transcription
factors that mediate the transcriptional response to these hormones.
c. Intracellular Effects
i. Increased Na/K-ATPase and ATP use by cell
ii. Increased Mitochondria and Respiratory enzymes
iii. Increase in other enzymes and proteins involved in metabolism
iv. Proteins for Growth and Maturation
d. Whole Body Effects (permissive)
i. Increased Cardiac Output and Ventilation
ii. Increase Food Intake, Mobilization of stored fat, carbohydrates, and proteins (to provide substrates for
needs of cell)
iii. Increased CO2, Urea, Ventilation, Renal Function, but a net decrease in muscle mass and adipose tissue;
Thyroid hormone can increase muscle production and lipogenesis, but it can also increase protein
degradation and lipolysis. Over production of thyroid hormone causes loss net loss of proteins and fats,
forming a catabolic situation.
iv. Increased Thermogenesis, Sweating, and Insensible Water Loss
e. Overall: Increased Metabolic Rate measured by O2 consumption or heat production
f. Thyroid hormone activity in cells is referred to as futile cycling. Sometimes they encourage synthesis of proteins
and sometimes they degrade proteins.
g. Heat is produced and ATP is consumed, all producing an increase in metabolic rate. This makes people
nervous, hyperactive, and sweaty.
XIII.
Thyroid Hormone & Cardiac Output [S15]
a. Indirect Effect: Increased Heat Production and CO2 in tissues  Decreased Peripheral Vascular Resistance 
Decreased Diastolic Blood Pressure  Reflex increased in Adrenergic Stimulation of the Heart
b. Direct Effect: Increase in Cardiac Muscle (Na/K-ATPase, B-adrenergic receptor density, Gs to Gi ratio,
Sarcoplasmic Reticulum Ca-ATPase, alpha-Myosin heavy chain isoform)  Increase in Ventricular Contractility
and Function
Endocrinology: 9-10am
Friday, November 6, 2009
Scribe: Strudwick Louis Tutwiler
Dr. Weigent
Thyroid Endocrinology
Page 4 of 5
c. Overall Effect: Increased Cardiac HR and Contractility
XIV.
Effects of Thyroid Hormone [S16
a. Nervous System
i. T3 is required for perinatal brain development.
1. Growth of cerebral and cerebellar cortex
2. Axon proliferation
3. Synaptogenesis
ii. In Adults, enhances:
1. Wakefulness and Responsiveness
2. Emotional Tone
3. Memory
b. Sympathetic Nervous System
i. Synergizes with Sympathetic Nervous System
1. Promotes Increases in B-adrenergic receptor and Gs proteins
2. Important for Metabolic and Cardiac Effects of Thyroid Hormone
XV. Autoimmune Thyroid Diseases (ATD) [S17]
a. Two main clinical entities: Graves’ disease (too much) and Hashimoto’s disease (too little)
b. Most common of all autoimmune disease (~1.0% of population, 5-10:1 (women: men), 40-60 yrs of age). 20%
of women will have thyroid problems in their lives.
c. Patients with ATD will have a mixture of antibodies to almost anything in thyroid gland, so clinical description of
patients can be overlapping.
d. Patients can have antibodies (immune-complex) to thyroglobulin, thyroperoxidase, or antibodies to the TSH
receptors (most important). Antibodies to TSH receptors cause Graves’ disease or hyperthyroidism and
Hashimoto’s disease or hypothyroidism.
e. The TSH receptor has a large extracellular portion. Scientists think a protease clips the receptor changing its
configuration in the membrane with the result being an antibody to the TSH receptor. Patients can develop
pretibial issues due to this antibody.
f. The receptor for this class is mainly on the thyroid gland, but it can also be found in muscle and adipose in low
amounts. These cause problems in other parts of the body.
g. Multifactorial pathogenesis: environmental and genetic component; The genetic part is supported by twin
studies: (familial, monozygotic 35%, dizygotic 3% risk). Immigrants moving into the US will adopt the
endogenous frequency of thyroid disease. Smoking is a particular hazard for developing the disease.
h. Important: Graves’ disease is a mild lymphocyte infiltration inducing antibodies to the TSH receptor (TH2,
hyperthyroidism). Thyrotoxicosis is toxic levels of thyroid hormone. Graves‘ disease has lymphocytes but is not
very bad. Key issue: The gland is stimulated by the antibody (acts like TSH) resulting in overproducing of
thyroid hormone.
i. Important: Hashimoto’s disease: more severe lymphocyte infiltration causes destruction of thyroid follicles.
Antigen – Antibody complex is more established. Site of inflammation develops with serious destruction of
tissue and ability to make the hormone. (hypothyroidism, TH1). Chronic thyroiditis.
XVI.
Primary Hyperthyroidism [S18]
a. Increased T4 and T3 in blood (due to stimulation of gland) and Decreased TSH (due to negative feedback
inhibition)  monitored by Elisa or IRA
b. Autoimmune Thyroiditis: Graves Disease
i. Autoantibodies bind and activate TSH receptors
ii. Other: Tumor of thyroid gland
c. Symptoms:
i. Large increases in BMR: Leads to weight loss despite increased food intake
ii. Increased heat production: heat intolerance and excessive sweating
iii. Increased SNS activity: Tachycardia, tremor, nervousness, wide-eyed stare
iv. Enlarged thyroid gland – Goiter; Why? TSH stimulates the hyperplasia of the cells.
v. Exopthalmos is protrusion of eyeballs with a stare effect.
1. Mechanism of this eye protrusion is debatable. Some people think antibody to TSH receptor
recognizes TSH receptor in fat or muscle cell in the orbit of the eye. Fibroblasts are stimulated.
2. The eye is a limited structure incased in a boney orbit. With fluid accumulation, the eye protrudes
resulting in problems like the inability to close the eyelid.
3. Fibroblasts produce glycosaminoglycans. They are stimulated by cytokines and accumulate. They
are hygroscopic, so they draw in water pushing the eye forward.
4. Man with exopthalmos is also suffering from protein degradation due to thyroid hormone, making him
look “cacatic”(not sure of spelling).
Endocrinology: 9-10am
Friday, November 6, 2009
Scribe: Strudwick Louis Tutwiler
Dr. Weigent
Thyroid Endocrinology
Page 5 of 5
d. Treatment: Skipped
i. Surgical Removal of Thyroid with Hormone Replacement
ii. Thiouracil: Blocks thyroperoxidase
iii. Thiocyanide: Blocks Iodide Trapping
XVII. American Thyroid Association Classification of Eye Changes in Graves’ Disease [S19]
a. Acronym: “No Specs”
b. Class 0: No physical signs or symptoms
c. Class 1: Only signs, no symptoms (signs limited to upper lid retraction, star, lid lag, and proptosis to 22mm)
d. Class 2: Soft tissue involvement (symptoms and signs)
e. Class 3: Proptosis > 22mm
f. Class 4: Extraocular muscle involvement
g. Class 5: Corneal Involvement
h. Class 6: Sight loss (optic nerve involvement)
XVIII.
Pretibial Myxedema [S20]
a. Uncommon complication of Graves’ disease (1-4%) (1-2 yrs post-Graves’)
b. Thyroid hormones normally inhibit synthesis of glycosaminoglycans. In the absence of inhibitor
(hypothyroidism), glycosaminoglycans accumulate and cause water retention.
c. Diffuse edema and thickening of skin usually on lower legs. Mechanical contribution with reduced return of
lymphatic fluid. In cases of hypothyroidism, you get myxedema or puffiness.
d. In Graves’ disease (hyperthyroidism), you get myxedema from action of cytokines on glycosaminoglycans.
e. One quarter of patients, have periosteal bone changes in the fingers causing clubbing.
f. Circulating factors stimulate fibroblasts to increase synthesis of glycosaminoglycans.
g. High titer of antibodies to TSH receptor (?); TSH receptors in the fibroblast of the skin appear to play a major
role in the pathogenesis.
h. Risk factors include smoking and obesity.
i. Treatment: Most cases go into remission. Normalize thyroid function and short-term corticosteroids.
j. Some people think the reason it is “pretibial” is due to gravity and the flow of fluid through the body.
XIX.
Lower Extremities of Pt with Severe Pretibial Dermopathy [S21]
a. Swelling that can occur on bottom of feet. Usually resolves on its own with treatment of the thyroid gland.
b. Mostly a cosmetic issue and putting on shoes is difficult
XX. Clubbing of a Digit in Thyroid Dermopathy associated with Acropachy [S22]
a. Can get bone problems causing clubbing
XXI.
Primary Hypothyroidism [S23]
a. Opposite case
b. Reduced T4 or T3 and Increased TSH (Lost ability of negative feedback)
c. Autoimmune Disease of Thyroid: Hashimoto’s Disease
i. Blocks Hormone Synthesis and Glandular Growth
d. Other Causes:
i. Genetic defect or autoantibody vs enzymes necessary for thyroid hormone synthesis or the conversion of
T4 or T3
ii. Severe Iodine Deficiency
e. Symptoms:
i. Myxedema: Accumulation of Mucopolysaccharides with resultant fluid accumulation; puffiness
ii. Decreased Thermogenesis: Cold Intolerance
iii. Lethargy, Sleepiness, Decreased Mentation
iv. Bradycardia (slowed heart rate)
v. Lowering of Upper Eyelid (ptosis)
vi. In utero or infancy and childhood:
1. Marked Retardation in Growth
2. Severe Mental Retardation due to poorly developed nervous system
3. Known as “cretins”
f. Treatment: Hormone Replacement
g. Why a Goiter?