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
2Na-I -
Transporter

Capillary
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
2Na-I -
Transporter

I- I- I- I- I-
Stimulated by TSH
Capillary
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

TGB MIT

I2 TGB I2

DIT

Thyroglobin
Na-I -
Transporter

Capillary
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 DIT T3
TGB MIT

I2 TGB I2 DIT DIT T4

DIT

Thyroglobin
Na-I -
Transporter

Capillary
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 DIT T3
TGB MIT

I2 TGB I2 DIT DIT T4

DIT

All Three Steps Catalyzed by ~ Thyroid Peroxidase ~

Thyroglobin
Na-I -
Transporter

Capillary
Capillary
 Thyroid hormone release

MIT DIT T3

DIT DIT T4

T3

T4
Na-I -
Transporter

Capillary T4 T3 T4 Capillary
 Capillary T4 T4 T3 Capillary

I I I 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 T4 T4 T3 Capillary

I I I I

I 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 T4 T4 T4

TBG TBG
5’-deiodinase

T3 T3 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 Primary Thyroid Gland Dysfunction

Imaging Pathology

Hormone
Free T4
Ultrasound Cytopathology (FNA)
Total T4 (tT4)
(Excisional) Biopsy
T3
rT3
Nuclear
Immune Markers Radioactive Iodide
TSIg Uptake (RAIU)

Anti-TPO Technetium
Anti-TGB

Miscellaneous:
ESR
TGB
 Thyroid Diagnostics

Serology

TSH Imaging Pathology

Hormone Patient is treated with T3 for

Free T4 hypothyroidism. How do the
Cytopathology (FNA)
Ultrasound following respond?
Total T4 (tT4)
(Excisional) Biopsy
T3
rT3 ¯ TSH
Nuclear ¯ T4
Immune Markers Radioactive Iodide ¯ rT3
TSIg Uptake (RAIU)

Anti-TPO Technetium
Anti-TGB

Miscellaneous:
ESR
TGB
 Thyroid Diagnostics

Serology

TSH Imaging Pathology

Hormone Patient is treated with T3 for

Free T4 hypothyroidism. How do the
Cytopathology (FNA)
Ultrasound following respond?
Total T4 (tT4)
(Excisional) Biopsy
T3
rT3 ¯ TSH
Nuclear ¯ T4
Immune Markers Radioactive Iodide ¯ rT3
TSIg Uptake (RAIU)

Anti-TPO Technetium
Anti-TGB Question Hierarchy:
Data >> Physical Exam >> Language
Miscellaneous:
ESR
TGB
 Thyroid Diagnostics

Serology

TSH Imaging Pathology

Hormone
Free T4
Ultrasound Cytopathology (FNA)
Total T4 (tT4)
(Excisional) Biopsy
T3
rT3
Nuclear
Immune Markers Radioactive Iodide
Uptake (RAIU)Graves Disease
TSIg

Anti-TPO Technetium Hashimoto’s

Anti-TGB Lymphocytic

Miscellaneous:
ESR
TGB
 Thyroid Diagnostics

Serology

TSH Imaging Pathology

Hormone
Free T4
Ultrasound Cytopathology (FNA)
Total T4 (tT4)
(Excisional) Biopsy
T3
rT3
Nuclear
Immune Markers Radioactive Iodide
TSIg Uptake (RAIU)

Anti-TPO Technetium
Anti-TGB

Granulomatous (Viral) Thyroiditis

Miscellaneous:
ESR
TGB Serial monitoring, Neoplasm
Hyperthyroidism, Inflammatory
 Thyroid Diagnostics

Serology Imaging

TSH Pathology
Ultrasound Cystic v Solid
Hormone
Total T4 (tT4)
Cytopathology (FNA)
Free T4
(Excisional) Biopsy
T3 Nuclear
rT3 Radioactive Iodide
Uptake (RAIU) Increased v Decreased
Uptake
Immune Markers
Technetium
TSIg

Anti-TPO
Anti-TGB Anatomic

Miscellaneous: Functional
ESR
TGB
 Thyroid Diagnostics

Serology Imaging Pathology

TSH

Ultrasound FNA: Cytopathology

Hormone
Total T4 (tT4)
Free T4
T3 Nuclear (Excisional) Biopsy
rT3 Radioactive Iodide
Uptake (RAIU)
Immune Markers
Technetium
TSIg
Tumors, 4
Anti-TPO Hashimoto
Anti-TGB Anatomic
Graves
Granulomatous
Miscellaneous: Functional Riedel’s
ESR
TGB
 Thyroid Diagnostics

Serology Imaging Pathology

TSH
FNA most useful
Ultrasound
for FNA: Cytopathology

Total T4 (tT4)Papillary Carcinoma

Hormone

Free T4
T3 Nuclear (Excisional) Biopsy
rT3 Radioactive Iodide
Uptake (RAIU)
Immune Markers
Technetium
TSIg
Tumors, 4
Anti-TPO Hashimoto
Anti-TGB Anatomic
Graves
Granulomatous
Miscellaneous: Functional Riedel’s
ESR
TGB
Thyroid Hormone Synthesis, Regulation and Diagnostics

Key Derivatives