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Thyroid Hormone Synthesis, Regulation and Diagnostics
Howard J. Sachs, MD
www.12daysinmarch.com
Thyroid follicular lumen filled with colloid
Colloid
TGB
Cuboidal
Thyroglobin
Tyrosine-rich protein
Initial Step: Thyroglobulin (TGB) synthesized in ER of follicular cell
Thyroid follicular lumen filled with colloid
TGB
The next slides will review the 3 critical steps in
thyroid hormone synthesis:
1. Oxidation
2. Organification
3. Coupling
Note: Each step is catalyzed by Thyroid Peroxidase
Autoantibodies:
Anti-TPO
Meds: PTU, MTZ
Oxidation (I- ® I2), Organification and Coupling
I2
TGB
I2
I2
I2
Thyroglobin
Capillary
2Na-I Transporter
Capillary
Step One: Iodide (I -) is absorbed in inverse proportion to serum concentration.
Oxidized to Iodine (I 2)
Oxidation (I- ® I2), Organification and Coupling
I2
TGB
I2
I2
I2
Thyroglobin
I-
Capillary
I-
2Na-I Transporter
I-
I-
I-
Stimulated by TSH
Capillary
Step One: Iodide (I -) is absorbed in inverse proportion to serum concentration.
Oxidized to Iodine (I 2)
Oxidation (I- ® I2), Organification and Coupling
TGB
I2
MIT
TGB
I2
TGB
I2
DIT
Thyroglobin
Capillary
Na-I Transporter
Capillary
Step Two: Organification. Iodine binds tyrosine residues on thyroglobulin
(TGB) to form mono- and di-iodotyrosine
Oxidation (I- ® I2), Organification and Coupling
TGB
I2
MIT
TGB
I2
TGB
I2
MIT
DIT
T3
DIT
DIT
T4
DIT
Thyroglobin
Capillary
Na-I Transporter
Capillary
Step Three: Coupling. Just as it sounds! MIT and DIT
couple to form T4 >>> T3
Oxidation (I- ® I2), Organification and Coupling
TGB
I2
MIT
TGB
I2
TGB
I2
MIT
DIT
T3
DIT
DIT
T4
DIT
All Three Steps Catalyzed by ~ Thyroid Peroxidase ~
Thyroglobin
Capillary
Na-I Transporter
Capillary
Thyroid hormone release
MIT
DIT
T3
DIT
DIT
T4
T3
T4
Na-I Transporter
Capillary
T4
T3
T4
Capillary
Capillary
I
T4
T4
I
T3
I
Capillary
I
5’-deiodinase
I
I
I
1. T4 is released in higher concentration than T3.
2. T4 is less active than T3 (i.e. behaves as a ‘prohormone’).
3. T4 is converted in the periphery by 5’-deiodinase to T3, the biologically active form
of thyroid hormone.
Thyroid Hormone Infomercial
Capillary
I
I
T4
T4
I
I
T3
I
Capillary
I
I
I
I
rT3 is elevated in ‘sick euthyroid syndrome’
I
1. During times of ‘abundance’, T4 may also be converted to reverse T3 (rT3).
2. rT3 has a different iodine molecule removed.
3. It is biologically inactive.
TBG = Thyroid Binding Globulin
(do not confuse with thyroglobulin!)
T4
T4
TBG
T3
•
•
•
T4
5’-deiodinase
T3
T4
T4
TBG
T3
TBG Trivia (synthesized in liver):
Once released into the circulation. thyroid hormone circulates bound to TBG
This serves as a ‘reservoir’ for hormone.
High affinity for T4
Only free circulating hormone (~1%) is biologically active!
TBG
TBG
Lots of bound T4 = ­­ TOTAL T4
TBG
TBG
TBG
TBG
TBG
•
•
Free T4
Bioavailable Form
Increased TBG (e.g. pregnancy, OCP)
Decreased TBG
Key Point:
•
•
TBG levels can increase (e.g. pregnancy) or decrease (e.g. cirrhosis).
The total amount of hormone (tT4) will increase or decrease with TBG levels BUT the
amount of free (bioavailable) hormone will NOT change.
Thyroid Hormone Regulation
Pituitary and TSH
are key players
Hypothalamus: TRH
Adenohypophysis: TSH
Hypothalamic-Pituitary-Thyroid,
TSH (Thyroid Stimulating Hormone)
A trophic hormone that can cause
hypertrophy and hyperplasia
Hypothalamus: TRH
Anterior Pituitary: TSH
T3
T4
Hypothalamus: TRH
(-)
Anterior Pituitary: TSH
(-)
T3
T4
Thyroid Diagnostics
Serology
TSH
Hormone
Free T4
Total T4 (tT4)
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Primary Thyroid Gland Dysfunction
Imaging
Pathology
Ultrasound
Nuclear
Radioactive Iodide
Uptake (RAIU)
Technetium
Cytopathology (FNA)
(Excisional) Biopsy
Thyroid Diagnostics
Serology
TSH
Hormone
Free T4
Total T4 (tT4)
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Imaging
Pathology
Patient is treated with T3 for
hypothyroidism. How do the
Cytopathology (FNA)
Ultrasound following respond?
(Excisional) Biopsy
Nuclear
Radioactive Iodide
Uptake (RAIU)
Technetium
¯ TSH
¯ T4
¯ rT3
Thyroid Diagnostics
Serology
TSH
Hormone
Free T4
Total T4 (tT4)
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Imaging
Pathology
Patient is treated with T3 for
hypothyroidism. How do the
Cytopathology (FNA)
Ultrasound following respond?
(Excisional) Biopsy
Nuclear
Radioactive Iodide
Uptake (RAIU)
Technetium
¯ TSH
¯ T4
¯ rT3
Question Hierarchy:
Data >> Physical Exam >> Language
Thyroid Diagnostics
Serology
TSH
Hormone
Free T4
Total T4 (tT4)
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Imaging
Pathology
Ultrasound
Cytopathology (FNA)
(Excisional) Biopsy
Nuclear
Radioactive Iodide
Graves Disease
Uptake (RAIU)
Technetium Hashimoto’s
Lymphocytic
Thyroid Diagnostics
Serology
TSH
Hormone
Free T4
Total T4 (tT4)
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Imaging
Pathology
Ultrasound
Cytopathology (FNA)
(Excisional) Biopsy
Nuclear
Radioactive Iodide
Uptake (RAIU)
Technetium
Granulomatous (Viral) Thyroiditis
Serial monitoring, Neoplasm
Hyperthyroidism, Inflammatory
Thyroid Diagnostics
Serology
Imaging
TSH
Hormone
Total T4 (tT4)
Free T4
T3
rT3
Pathology
Ultrasound
Nuclear
Radioactive Iodide
Uptake (RAIU)
Immune Markers
TSIg
Technetium
Anti-TPO
Anti-TGB
Anatomic
Miscellaneous:
ESR
TGB
Functional
Cystic v Solid
Cytopathology (FNA)
(Excisional) Biopsy
Increased v Decreased
Uptake
Thyroid Diagnostics
Serology
Imaging
Pathology
Ultrasound
FNA: Cytopathology
Nuclear
Radioactive Iodide
Uptake (RAIU)
(Excisional) Biopsy
TSH
Hormone
Total T4 (tT4)
Free T4
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Technetium
Anatomic
Functional
Tumors, 4
Hashimoto
Graves
Granulomatous
Riedel’s
Thyroid Diagnostics
Serology
Imaging
Pathology
TSH
FNA most useful
for
Ultrasound
Hormone
Total T4 (tT4)Papillary Carcinoma
Free T4
T3
rT3
Immune Markers
TSIg
Anti-TPO
Anti-TGB
Miscellaneous:
ESR
TGB
Nuclear
Radioactive Iodide
Uptake (RAIU)
FNA: Cytopathology
(Excisional) Biopsy
Technetium
Anatomic
Functional
Tumors, 4
Hashimoto
Graves
Granulomatous
Riedel’s
Thyroid Hormone Synthesis, Regulation and Diagnostics
Key Derivatives