1. Biochemical aspects of thyroid hormone metabolism
Reading material ; Clinical Chemistry. Principles techniques and correlations.
Chapter 23
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology

2. Overview
The thyroid gland, located immediately below the larynx on each side of and anterior to the trachea
Thyroid gland is one of the largest of the endocrine glands, normally weighing 15 to 20 grams in adults
The thyroid secretes two major hormones, thyroxine and triiodothyronine, commonly called T4 and T3, respectively
Calcitonin is secreted by para-follicular cells (Involved in calcium metabolism

3. Overview
About 93% of the metabolically active hormones secreted by the thyroid gland is thyroxine (T4).
7% is triiodothyronine.
Almost all the thyroxine is eventually converted to triiodothyronine in the tissues.

4. Differences between T4 and T3
They differ in rapidity and intensity of action. How?
Triiodothyronine is about four times as potent as thyroxine.
Triiodothyronine is present in the blood in much smaller quantities
T3 has a shorter half life than T4

5. Note
In tissues, most of the effect of T4 results from its conversion to T3.
This reaction is catalyzed by selenium-containing enzyme iodothyronine deiodinases.
Deiodination can also produce reverse triiodothyronine (rT3) (physiologically inactive)

6. Congenital Hypothyroidism
Thyroid hormone is critical to neurologic development of the fetus.
Congenital hypothyroidism occurs in 1 of 4,000 live births.
If the mother has normal thyroid function, the fetus is protected during development by maternal thyroid hormone crossing the placenta.
Postpartum, newborns require initiation of appropriate doses of thyroid hormone or neurologic development will be impaired
Screening tests are performed on all newborns to diagnose congenital hypothyroidism and prevent complications

7. Cretinism

9. Physiologic anatomy of the thyroid gland
The thyroid gland is composed of closed follicles filled with colloid.
Follicles are lined with cuboidal epithelial cells that secrete colloid
Colloid is mainly made from thyroglobulin (large glycoprotein)
Thyroid hormones are found within thyroglobulin.

10. Major Actions of thyroid hormones
Thyroid hormones are essential for normal growth and development and have many effects on metabolic processes
They stimulate the synthesis of a number of hormones and enzymes.
One of the key enzymes stimulated is cytochrome oxidase

11. Their overall effect on metabolism is to stimulate the basal metabolic rate, oxygen consumption and heat production.
Thyroid hormones increase net catabolism.
Weight loss, muscle wasting and heat intolerance are features of excessive secretion of thyroid hormones.

12. Thyroid hormones increase the sensitivity of the cardiovascular and nervous systems to catecholamines.
This leads to an increases in heart rate, cardiac output, and to increased arousal.

13. Synthesis of thyroid hormones
Thyroid hormone synthesis involves a number of specific enzyme-catalysed reactions.
Synthesis begins with the uptake of iodide by the gland and ends in the iodination of tyrosine residues in the protein thyroglobulin.
All of these reactions are stimulated by TSH

15. Synthesis: Detailed reactions 1. Iodide trapping
The first stage in the formation of thyroid hormones, is transport of iodides from the blood into the thyroid gland.
The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell.
The iodide pump concentrates the iodide to about 30 times its concentration in the blood.
The rate of iodide trapping by the thyroid is influenced by the concentration of TSH.

16. Radioactive iodine uptake (RAIU) can help diagnose thyroid disease

18. Thiocyanate Ions Decrease Iodide Trapping

19. A note about thyroglobulin
Each molecule of thyroglobulin contains about 70 tyrosine amino acid residues.
These tyrosine residues are the substrates that bind with iodine to form the thyroid hormones.
Thyroid hormones form within the thyroglobulin molecule.
Thyroid hormones remain part of thyroglobulin during synthesis and later on during storage of the colloid.

20. Synthesis: Detailed reactions 2. Oxidation of iodide ion.
This is conversion of the iodide ions to an oxidized form of iodine
Iodide ion is converted to I2 that is capable of combining directly with tyrosine.
Oxidation of iodine is catalyzed by peroxidase and its accompanying hydrogen peroxide, which provide a potent system capable of oxidizing iodides.
When the peroxidase system is blocked rate of synthesis falls down to zero.

22. Synthesis; Detailed reactions 3. Organification and coupling
The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin.
This process is catalyzed by the enzyme iodinase
Tyrosine is first iodized to monoiodotyrosine (MIT) and then to diiodotyrosine (DIT)
Iodotyrosine residues become coupled with one another and the coupling reactions result in the formation of thyroid hormones T4 and T3
Under normal condition 70% of tyrosine residues of thyreoglobulin are in the form MIT and DIT and 30% as thyroxine (with minor part of T3)

23. Organification and coupling

24. Organification and coupling

25. Propylthiouracil inhibit peroxidase enzyme as well as coupling of iodinated tyrosine residues

26. Storage of thyroglobulin
Thyroid gland can store large amounts of hormone (unlike other endocrine glands).
Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules.
The thyroid hormones stored in the follicles are sufficient to supply the body with thyroid hormones for 2 to 3 months.
When synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months.

27. Release and Secretion of thyroid hormones
Thyroglobulin itself is not released into the circulating blood.
Thyroxine and Triiodothyronine are cleaved from the thyroglobulin and then released.

28. Release and secretion of thyroid hormones
Thyroid cells sends out pseudopod extensions that close around portions of the colloid to form pinocytic vesicles.
Lysosomes in the cell cytoplasm immediately fuse with these vesicles.
3. Multiple proteases digest the thyroglobulin molecules and release thyroxine and triiodothyronine in free form.
4. T4 and T3 then diffuse through the base of the thyroid cell into the surrounding capillaries.

31. Figure 22.14 Cellular mechanisms for T3 and T4 release into bloodstream.
Redrawn from Berne, R. M., and Levy, M. L.(Eds.). Physiology, 2d ed. New York: Mosby, 1990, 938.
Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.

32. Recycling of iodine
During the digestion of the thyroglobulin molecule to release thyroxine and triiodothyronine, MIT and DIT released from thyroglobulin
MIT and DIT are not secreted into the blood in large amounts.
Instead, their iodine is cleaved by deiodinase enzyme that makes iodine available for making thyroid hormones.

33. Regulation of thyroid hormone secretion: 1. TSH
TSH (thyrotropin) an anterior pituitary hormone is chemically a glycoprotein.
This hormone, increases the secretion of thyroxine and triiodothyronine by the thyroid gland.
Specific effects on thyroid gland:
1. Increased proteolysis of the stored thyroglobulin.
2. Increased activity of the iodide pump.
3. Increased iodination of tyrosine to form the
thyroid hormones.
4. Increased size and increased secretory activity of
the thyroid cells (hypertrophy).
5. Increased number of thyroid cell (hyperplasia).

34. Note
The most important early effect after administration of TSH is to initiate proteolysis of thyroglobulin.
Thyroxine and triiodothyronine will get released into the blood within 30 minutes.
Most of the effects of TSH are mediated by cAMP second messenger system.

35. Regulation of thyroid hormone secretion 2
Regulation of thyroid hormone secretion 2. Thyrotropin-Releasing Hormone (TRH)
Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH).
TRH is secreted by nerve endings in the median eminence of hypothalamus.
TRH is transported to the anterior pituitary by hypothalamic hypophysial portal blood.
TRH causes an increase in the output of TSH by anterior pituitary.

36. Regulation of thyroid hormone secretion 3. Cold and Anxiety
Cold is a stimuli for increasing the rate of TRH secretion by the hypothalamus and therefore TSH secretion by the anterior pituitary gland.
Excitement and anxiety cause an acute decrease in the rate of secretion of TSH.

37. Feedback Effect of Thyroid Hormone to Decrease Anterior Pituitary Secretion of TSH

38. Transport of thyroid hormones
When released into the circulation, only 0.04% of T4 and 0.4% of T3 are unbound by proteins (physiologically active)
The three major binding proteins, in order of significance, are thyroxine-binding globulin (TBG), thyroxine-binding prealbumin, and albumin
The quantity of T4 and T3 in the circulation can be affected by the amount of binding protein available for carrying these hormones
High TBG levels result in higher levels of bound thyroid hormones, leading to high levels of total T3 and total T4
Measurement of free T4 and free T3 may be necessary to eliminate any confusion caused by abnormal binding protein levels

39. Mechanism of action of thyroid hormones

40. Mechanism of action of thyroid hormones
Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR)
Binding T3 to its receptor liberates co-repressor and recruits coactivator and RNA polymerase which drives mRNA transcription

42. Thyroid autoantibodies