Anatomy

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Anatomy
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Netter, F.H., The Ciba Collection of Medical
Illustrations 1983
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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Summary
? Thyroid is the largest endocrine
gland ? Located in anterior part of neck
Parathyroid glands posterior, recurrent laryngeal
nerve ? A goiter is an enlargement of thyroid
gland and can cause mechanical pressure on
trachea and esophagus
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Thyroid Histology and Thyroid Hormone Formation
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Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Proposed coupling scheme for intramolecular
formation of T4 within the thyroglobulin
molecule. The major hormone site at tyrosyl
residue 5 is indicated. The assistance of Dr.
H.J. Cahnmann in the early development of this
scheme is gratefully acknowledged.
Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Three Proteins that are Important (and specific)
for Thyroid Hormone Biosynthesis 1. The Iodide
Transporter a) A 618 aa protein with 12
predicted transmembrane domains b) Cotransports
Na and I-from the basal surface of thyroid
cellsdriven by Na/K ATPase c) Concentrates
Iodide 20- to 40-fold 2. Thyroglobulin a) A
660 kd homodimeric glycoprotein that constitutes
50 of thyroid protein b) Tyrosine residues in
Tg are iodinated to form thyroid hormone. Of 134
tyrosines, specific ones are
iodinated to give rise to thyroid hormone. 3 to
4 molecules of T4 are formed per Tg
molecule c) Is the major component of colloid
which is stored in the center of thyroid
follicles d) When all thyroid is removed,
measurement of serum Tg becomes a tumor marker
for thyroid cancer 3. Thyroid Peroxidase
a) Catalyzes organification of iodide (oxidation
and incorporation into tyrosine ring) and
coupling of iodinated tyrosine residues in
thyroglobulin b) Is the target for antithyroid
drugs which are competitive inhibitors of TPO c)
Measurement of antibodies against TPO is useful
in making the diagnosis of
autoimmune thyroiditis (Hashimotos disease)
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Summary

• Thyroid gland contains Thyroid follicles and C
  cells (Calcitonin)
• T4 and T3 is formed on the thyroglobulin (Tg)
  protein
• The amino acid tyrosine is mono and diiodinated
  and coupled to form T4 and T3 by thyroid
  peroxidase
• T4 and T3 is released from thyroglobulin by
  proteolytic cleavage
• The major proteins involved in T4/T3 formation
  are
• Na Iodine Symporter (NIS)
• for iodine transport
• Thyroglobulin with tyrosines
• for iodination and coupling
• Thyroid Peroxidase (TPO)
• executing iodination and coupling of tyrosine

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Regulation of Thyroid Hormone Formation

• Hypothalamic Pituitary Thyroid Axis
• Iodine (Iodide) Autoregulation

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Iodine Uptake into Thyroid Cell

• Mediated at basolateral side of cell by Na I
  symporter (NIS)
• Leads to 201 concentration gradient cell to
  plasma
• NIS has 13 membrane opening loops
• also expressed in salivary gland, mammary
  gland, gastric mucosa, choroid plexus
• NIS gene upregulated by TSH (CREB element)
• Only thyroid gland can form thyroid hormone
• no organification in other organs

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AutoregulationWolff Chaikoff effect

• High doses of I and I levels in thyroid cell
  inhibits organic binding of I,iodolipid
• Inhibition of thyroid hormone production
• TPO ?
• H2O2 generation ?
• Adenylate Cyclase
  inhibited
• Release of T4/T4 from Tg highly iodinated ?
• Escape from effect after 2 days
• NIS ?

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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Summary

• Thyroid gland takes up 20 of iodine intake
• 50 mcg/day uptake
• 10 mcg/day recycled iodine
• Total use 60 mcg/day
• Thyroid gland produces T4 80-100 mcg/day
• T3 daily production rate 30-40 mcg/day
• 6-8 mcg/day produced by thyroid gland (20)
• 80 of T3 derived from peripheral conversion

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Summary

• TSH major stimulator of T4/T3 formation
• Adequate Iodine supply needed for T4/T3 formation
• Autoregulation of thyroid cell by iodine levels

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Transport and Metabolism of Thyroid Hormone
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TransportT4/T3 in Serum

• T4 99.97 protein bound
• 0.03 free
• T3 99.7 protein bound
• 0.3 free
• Protein binding of T4 and T3 provides stability
  for system
• T3 is 5-10 times more biological active than T4
• 10 fold higher amount is free hormone

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T4/T3 Binding Proteins

• Thyroxine Binding Globulin (TBG) (70 T4 /T3)
• High affinity binding of T4 (1010 mol/L)
• Lower affinity binding of T3 (109 mol/L)
• Transthyretin (Prealbumin) (15 T4/T3)
• Binding affinity for T4 and T3 about equal
  (10 mol/L)
• Albumin (8 T4/T3)
• low affinity for T4 and T3 (106 mol/L)
• large capacity

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De Groot, et al. The Thyroid and its Diseases,
6th Edition 1996
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Changes in T4/T3 protein binding

• Change in amount of binding protein
• T4/T3 displacement by other agents

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Goldman, et al. Cecil Textbook of Medicine 21st
Edition 2000
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Summary

• T4/T3 in serum is over 99 protein bound, storage
  and buffering function
• Thyroxine binding globulin, transthyretin, and
  albumin are major binding proteins
• Changes in binding protein amount and drugs
  competing for T4/T3 binding can alter serum
  levels of T4/T3
• Alterations in binding proteins with intact
  pituitary thyroid axis does not lead to long term
  changes in free T4/T3

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Metabolism of T4/T3
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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Conclusion

• Deiodination is most important pathway for T4/T3
  metabolism
• Three Deiodinases exist (D1, D2, D3)
• All have selenocysteine in active center
• D1 Inner and outer Ring
• D2 Outer Ring
• D3 Inner Ring

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Metabolism

• Deiodination (80 of T4 metabolism)
• Alternate Routes
• Deamination
• Decarboxylation
• Ether link cleavage
• Conjugation
• Sulfate
• Glucuronidate

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Life History of Thyroid Gland

• Phylogenesis
• Invertebrates ? Vertebrates (e.g. larval
  lamprey)
• Frog, toad metamorphosis T4/T3 driven
• Embryogenesis
• HPT axis established at 12-16 weeks of
  gestation
• T3 receptor occurs before T3

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DeGroot, et al. Endocrinology 4th Edition 2001
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Study Design

• Elevated TSH during pregnancy (Group 1)
• (Some on T4, some not)
• Normal TSH during pregnancy (Group 2)
• Children 7-9 years old of Group 1 and Group 2
  underwent IQ and Neuropsychological testing

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• Neonatal screening for hypothyroidism
• State law
• Heel prick blood T4 or T.S.H.
• 1 in about 4500 children are hypothyroid
• Early replacement with Thyroxine
• Near normal IQ development

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Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Conclusion

• HPT axis is established at 12-16 weeks of
  gestation
• During early brain development (up to 12 weeks
  gest.)
• placental transfer of T4/T3 from mother may be
  important
• Neonatal screening for hypothyroidism identifies
  about 14500 children as hypothyroid
• Early T4 replacement markedly improves mental
  development ( IQ)

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Mechanism of Thyroid Hormone Action
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Larsen, et al. Williams Textbook of
Endocrinology, 10th Edition 2003
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Thyroid Hormone Receptor Isoforms
?2
?1
?1
?2
from Hodin, R.A. et al. Science 244 76-79 1989
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Mediation of T3 Action
T3 concentration
T3Ra1
Homodimer
T3Rß1
T3
T3R
Heterodimer
T3R x RXR
Direct repeat 4
AGGTCANNNNAGGTCA
TRE configuration
Palindrome
Inverted Palindrome
Co-activators
Co-repressors
Changes in chromatin structure (HAT)
Cell-type specific factors, e.g. MEF-2
Interaction with other signaling cascades (ß
sympathetic)
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Conclusion

• T3 mediates its action by binding to Thyroid
  Hormone receptors (TR)
• Two genes TRa and TRß code for thyroid hormone
  receptor
• TRs are ligand activated transcription factors
  acting in the nucleus
• T3 may also activate some MAPKinase at the cell
  membrane
• T3 enters cells by specific ATP-consuming
  carried-mediated transporters

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General Biological Effects of T3

• Development
• CNS
• linear growth

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General Biological Effects of T3

• Energy Metabolism
• Basal Metabolic rate ?
• Core body Temperature ?
• Organ Effects
• Heart - Rate ?
• Liver - Cholesterol ?
• Muscle - Proteins turnover ? strength ?
• GI tract - Motility ?

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Conclusion

• T3 stimulates growth, development, and energy
  metabolism
• T3 influences the function of most organs (low TR
  in spleen and testis)

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Laboratory Assessment of Thyroid Status

• T4
• Free T4
• T3 Thyroid Status Euthyroid,
  Hyperthyroid, Hypothyroid
• TSH

• Thyroglobulin Thyroid Cancer Follow up
• Antithyroid Antibodies Thyroid Autoimmune
  Disease
• Antiperoxidase
• Antithyroglobulin
• Radioactive Iodine Scan Cold Nodule, Graves
  Disease.
• I 131 I 123 99m Technetium
• Thyroid Ultrasound
• Aspiration of Thyroid Nodules - Cytology

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Braverman, et al. Werner Ingbars The Thyroid,
8th Edition 2000
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Conclusion

• For evaluation of Thyroid Status (Eu, Hyper,
  Hypothyroid)
• Free T4 and TSH is most frequently used
• For evaluation of thyroid nodules one uses
• Fine needle aspiration
• Thyroid Ultrasound
• Radioactive Iodine Scan (RAI)
• For thyroid cancer follow up
• Thyroglobulin
• RAI

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Thyroid Diseases and Therapy
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Treatment of Hypothyroidism

• T4 Replacement 0.1 0.15 mg (average 0.125
  mg)
• In patients with C.A.D. start at 0.025 mg
  increase dose every 2 - 4 weeks

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Hyperthyroidism

• Nutritional Weight loss despite increased
  appetite
• Temperature Heat intolerance, flushing, sweating
• Kinetics Hyperactive, irritable
• Gastrointestinal Hypermotility, frequent stools,
  diarrhea, vomiting
• Cardiac high output, heart failure, arrhythmias,
  tachycardia
• Muscular weakness, muscle wasting, myopathy
• Menstrual Amenorrhea, infertility

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Hyperthyroidism

• Ectodermal Velvety, moist skin, fine hair,
  onycholysis
• Bone Hypercalcaemia, osteoporosis
• Metabolism Relative carbohydrate
  intolerance, increased insulin
  requirement in existing diabetes
• Eyes Opthalmopathy (lid lag, stare, faulty
  convergence, infiltrative exophthalmos
  (occurs in absence of hyperthyroidism)
• Unusual
• symptomatology Gynecomastia, vomiting,
  myasthenia, gravis, periodic paralysis

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Actions of Thioureylenes (e.g. PTU, Methimazole)

• Inhibition of Peroxidase Enzyme
• - iodine organification
• - coupling
• PTU T4 ? T3
• 2. Mild Immunosuppressive Effect

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Antithyroid Drugs
Methimazole 30 40 mg/day
PTU 100 200 mg T.I.D. (400 600 mg/day)
General treatment time 1 2 years
Decrease dose as TFT normalizes
50 or less permanent remission
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Conclusion

• Hypo, Hyperthyroidism, Thyroid Nodules, Thyroid
  Cancer, and Thyroiditis are important Thyroid
  Diseases.
• Hypothyroidism is well treated by thyroid hormone
  replacement
• Hyperthyroidism is treated by Antithyroid Drugs,
  RAI or Surgery.
• Thyroid Cancer is treated by surgery and RAI and
  has frequently a good prognosis

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