8/12/2016. Biochemistry #2 Thyroid hormone. Mahmoud Al-Faqih Ahmad Abu-alloush

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1 8/12/2016 Biochemistry #2 Thyroid hormone Mahmoud Al-Faqih Ahmad Abu-alloush

Overview about the thyroid gland The thyroid gland is one of the largest endocrine glands in the body.it s located immediately below the larynx, anterior to the trachea at both sides.

2 Overview about the thyroid gland The thyroid gland is one of the largest endocrine glands in the body.it s located immediately below the larynx, anterior to the trachea at both sides. It consists of two lobes connected with each other by a bridge called Isthmus. Thyroid gland is a butterfly-shaped organ as you can see in the figure: Surgically, the anatomic location of the thyroid gland is very important for 2 reasons: 1. Posterior to the thyroid gland there is another type of glands called the Parathyroid glands which are responsible for secreting the parathyroid hormone (PTH). Function of PTH: It s important for mobilization (resorption) of calcium from the bone, so the secretion of PTH will increase when the calcium level in the blood goes down. 2. Posterior to the thyroid gland there is a nerve called the recurrent laryngeal nerve. Why we are focusing on these two things? Because when there is an enlargement of the thyroid gland, one of the treatments is removing the thyroid gland surgically. So, the surgeon should be very cautious in order not to injure the parathyroid glands or the recurrent laryngeal nerve. If the surgeon injures these structures by accident, the patient will end with: 1- Hypocalcaemia, as a result of the destruction of parathyroid gland. 2- Permanent hoarseness of the voice. يعني مثل صوت جورج وسوف 1 P a g e

Function of the thyroid gland The main function of thyroid gland is hormones secretion, which are actually two important hormones : - Thyroxin (T4) - Triiodothyronine (T3) Thyroid gland also secretes

3 Function of the thyroid gland The main function of thyroid gland is hormones secretion, which are actually two important hormones : - Thyroxin (T4) - Triiodothyronine (T3) Thyroid gland also secretes another hormone called the Calcitonin which is not very important. We will talk about it when we study the hormonal control of calcium metabolism Calcitonin [Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.] Wikipedia As we said, there are two major hormones that are secreted from the thyroid gland. But Are these hormones (T3 and T4) secreted in the same amount? Are there any differences between these two hormones other than being structurally different? - 93% of thyroid active secretions is Thyroxin (T4) while only 7% of secretion is Triiodothyronine. - Although T3 is secreted in fewer amounts, it s more potent than T4. - T3 has shorter half-life(t1/2). Actually, a lot of clinicians consider T4 as a Pro-hormone for the T3 because T4 is converted into T3 in peripheral tissues. 2 P a g e

If this cretinism is not treated, the patient will end up with immature growth and immature nervous system (will become mentally retarded).

4 Congenital Hypothyroidism The thyroid hormone is important for the growth or maturation of the nervous system. Sometimes, there is congenital hypothyroidism, where the gland or part of it is missed embryonically. So the baby is born with no thyroid gland. This case is called Cretinism. If this cretinism is not treated, the patient will end up with immature growth and immature nervous system (will become mentally retarded). So, the doctor should do a screening to the baby at the time of delivery to see if there is any deficiency of the thyroid hormone in order to avoid these complications. Cretinism is a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormone (congenital hypothyroidism) usually due to maternal hypothyroidism. Wikipedia The thyroid hormone is important for the nervous system and skeleton. The question then arises in this case, if the thyroid gland was missed in the embryonic development, How was the fetus protected? Simply, the thyroid hormone that is produced from the mother s intact thyroid gland can cross the placenta and protect the fetus from these complications during the development of the fetus s different organs. How can we diagnose the patient with cretinism? From the features of the neonate at the time of birth. [You are not required to know these features in slide # 7] 3 P a g e

the structure of tyrosine amino acid. Actually, they all are synthesized from tyrosine.

5 The structure of the thyroid hormones This figure shows the structure of the T4 and T3. There is another inactive hormone called reverse Triiodothyronine (rt3) If you look at the structure of these hormones you will notice that it resembles the structure of tyrosine amino acid. Actually, they all are synthesized from tyrosine. T3 and rt3 are both can be synthesized from T4 by an enzyme called Iodothyronine Deiodinase in peripheral tissues. As we said, the T4 is the Pro-hormone for both rt3 & T3, but due to different location of Iodine, one of them is active (T3) and the other one is inactive (rt3). 4 P a g e

Histology of the thyroid gland The thyroid gland is made from closed follicles and each one of these follicles is filled with a material called (colloid).

6 Histology of the thyroid gland The thyroid gland is made from closed follicles and each one of these follicles is filled with a material called (colloid). Follicle is actually made up from a single layer of cuboidal epithelial cells that secretes and encircles the colloid and is called the follicular cells. Colloid is mainly made from thyroglobulin (large glycoprotein). It s actually where the hormones are found. The thyroid hormones are built on glycoprotein called (thyroglobulin). Thyroglobulin - Thyroglobulin is not found in any other tissue in the body (just in the thyroid gland). -Thyroglobulin is a large glycoprotein molecule contains about 70 tyrosine amino acid residues. -The synthesis of thyroid hormones (T3 and T4) takes place on these residues. -Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules 5 P a g e

7 Thyroid gland - unlike other endocrine gland - can store large amounts of hormones. The amount of thyroid hormones stored in the follicles is large enough to sustain the thyroid hormone levels in the body up to 2 to 3 months after destruction of thyroid gland. So, in the case of hypothyroidism, it takes around 2-3 months of deficiency until symptoms start to appear. Synthesis of thyroid hormones: Synthesis of thyroid hormones happens in the colloid. It requires the trace element Iodine in addition to the thyroglobulin (which has many tyrosine residues). In very simple words, Thyroid cells uptake the Iodine from blood and move it across the cell to reach thyroglobulin in the follicles to make these hormones. The follicular cell has two membranes 1- Apical: toward colloid 2- Basal: toward plasma 6 P a g e

8 Look at the figure in the previous page for better understanding 1. Iodide trapping (Iodide uptake) : The first stage in the formation of thyroid hormones, is transport of iodides from the blood (plasma) 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. How? On the basal membrane there is Co- transporter will pump the Iodide inside the cell and pumps the sodium outside the cell [Active uptake of the Iodide]. - 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 Thyroid-stimulating hormone (TSH). Iodide ion is the ion I 2. Oxidation of Iodide ion: This is conversion of the iodide ions to an oxidized form of iodine. Iodide ion is converted to tyrosine. I2 that is capable of combining directly with Oxidation of iodide 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. 3. Organification of the Thyroglobulin: It s a biochemical process that takes place in thyroid glands. It is the incorporation of iodine into thyroglobulin for the production of the thyroid hormone, a step done after the Oxidation. - The binding of one Iodine molecule with tyrosine will result in a compound called MonoIodoTyrosin (MIT) - the binding of another Iodine with the MIT will result in result in a compound called DiIodoTyrosin (DIT) 7 P a g e

9 >> This process is catalyzed by the enzyme Iodinase. So, the process starts with Tyrosine, then an Iodine group is added to the tyrosine to get MIT. After that, another Iodine group is added to the MIT itself to end up with DIT compound Notes: - Not all MITs are converted to DITs - MIT and DIT are Not biologically active [And this leads us to the next step which is the coupling] 4. Coupling: It s the conversion of Iodotyrosine residues (MIT & DIT) - by coupling reactions- to the active forms of the thyroid hormones (T3 and T4). MIT (has 1 iodine molecule) +DIT (has 2 iodine molecules) = T3 DIT (has 2 iodine molecule) +DIT (has 2 iodine molecules) = T4 Note from the slides: Under f normal condition 70% of tyrosine residues of thyroglobulin are in the form MIT and DIT and 30% as thyroxine (T4) with minor part of (T3) Note: All these processes (uptake, oxidation, organification, coupling and which is the release ) require the Thyroid-stimulating hormone (TSH) secreted from the anterior pituitary gland. 8 P a g e

10 Clinical correlations: (1) Treatment of hyperthyroidism Uptake of Iodine by the gland (Iodide trapping ) can be inhibited by the Thiocyanate Ions, so they can be used in order to treat cases of hyperthyroidism. The peroxidase enzyme that catalyzes the oxidation is inhibited by a compound called Propylthiouracil (PTU) which is also can be used in the treatment of hyperthyroidism. So, the drugs PTU & Thiocyanate Ions can be used in the treatment of hyperthyroidism. (2) GOITER disease: As we said the thyroid gland requires Iodine to do its function. Nowadays, the Iodine is added to the salt but in the past the only source of Iodine was the soil. There were certain geographic areas - Swiss Alps & Great Lakes - where there wasn t Iodine in the soil. Those people were suffering from Goiter (simply, the enlargement of the gland). It could be a result of hyperthyroidism, hypothyroidism or cancer. The synthesis of hormones will stop because of insufficient Iodine in the body. There will be No release of T4 & T3 to the blood circulation. As a result of that, TSH level will increase (feedback mechanism) and cause hyperplasia of the gland and this will end up with Goiter. 9 P a g e

(3) Thyroid cancer The thyroid tissue is the only tissue in the body that makes thyroglobulin. In case of thyroid cancer, the cancer cells may get out from the gland to the plasma.

11 (3) Thyroid cancer The thyroid tissue is the only tissue in the body that makes thyroglobulin. In case of thyroid cancer, the cancer cells may get out from the gland to the plasma. If you can detect the presence of thyroglobulin, this could be an indication of the presence of thyroid tissue in the blood and that makes a good correlation with thyroid gland cancer. So, the thyroglobulin could be used as a biomarker for the presence of thyroid cancer. 5. Release and secretion of thyroid hormones: Thyroglobulin itself is not released into the blood. Thyroxine and Triiodothyronine are cleaved from the thyroglobulin and then released. (a) Again, as a result of TSH secretion, Thyroid cells sends out pseudopod extensions that close around portions of the colloid and pinch a part of thyroglobulin to form pinocytic vesicles in a process called (pinocytosis). (b) Lysosomes in the cell cytoplasm immediately fuse with these vesicles. (c) Lysosomes have hydrolytic enzymes (proteases) will digest the thyroglobulin molecules and give T3 and T4 in free forms in addition to amount of MITs and DITs. (d) T4 and T3 then diffuse through the base of the thyroid cell into the surrounding capillaries. 10 P a g e

12 During the digestion of the thyroglobulin, MIT and DIT released from thyroglobulin are not secreted into the blood in large amounts. Instead, their iodine is cleaved by deiodinase enzyme that recycles iodine to be used again in further thyroid hormones synthesis. Slides: 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. 11 P a g e

Major Actions of thyroid hormones Thyroid hormones are essential for normal growth and development and have many effects on

one of the key enzymes that is stimulated is Cytochrome c Oxidase which has an essential role in the Electron Transport Chain

Electron transport chain (ETC) is a series of compounds that transfer electrons from electron donors to electron acceptors via

Thyroid hormone secreting will increase the activity of mitochondria.

13 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 that is stimulated is Cytochrome c Oxidase which has an essential role in the Electron Transport Chain in the inner Mitochondria. Electron transport chain (ETC) is a series of compounds that transfer electrons from electron donors to electron acceptors via redox (both reduction and oxidation occurring simultaneously) reactions, and couples this ions) across a The increase of Thyroid hormone secreting will increase the activity of mitochondria. electron transfer with the transfer of protons (H + membrane. Chronically, there will be enlargement of the mitochondria and increase in their number. Wikipedia Biochemically: The increase in the cytochrome oxidase leads to Increase in the activity of Electron Transport Chain. So there will be more energy (ATP) production 12 P a g e

14 Mitochondria are the Power houses of the cell that produces energy. Any machine that gives energy will give heat and this is exactly what happens when there is Overactivity of the thyroid hormone. The mitochondria of patients with hyperthyroidism will generate more heat. As a result of the over activity of the Electron Transport Chain, whatever you eat, you will metabolize. So, those individuals with hyperthyroidism will lose weight. Although they have weight loss, they have a very high appetite. They will be hyperactive, hyper thermic, very excitable and irritated, active all the time, alert all the time and can t sleep. (The hyperthyroidism patients are predisposed to neuropsychiatric diseases) Their gastric motility will increase also. The terminal acceptor in the Electron Transport Chain is Oxygen. So the Electron Transport Chain needs O 2 to keep working and this will increase the Respiratory Rate. Thyroid hormones increase the sensitivity of the cardiovascular and nervous systems to Catecholamines (like Epinephrine and Dopamine). This leads to an increase in heart rate, cardiac output, and to increased arousal. So they will feel tired all the time. All of this can be explained by the increase of cytochrome oxidase activity due to the increased activity of thyroid hormone. In the case of hypothyroidism, the opposite will happen hypothyroidism patient will be very sluggish. He will be very cold and will gain weight. In addition to that, he will suffer from constipation because the gastric motility will decrease. 13 P a g e

If there is an increase in the activity of the thyroid gland, the Iodine uptake will be higher than normal.

15 Radioactive iodine uptake (RAIU) The thyroid gland is active in the uptake of Iodine. And this has 2 important clinical correlations: 1. Diagnosis of hyperthyroidism: thyroid gland using test called radioactive iodine uptake (RAIU) test. If there is an increase in the activity of the thyroid gland, the Iodine uptake will be higher than normal. So, you can give the patient a radioactive Iodine meal and measure the iodine uptake using the X-rays photo of the thyroid gland. RAIU test will tell you if the gland is active or not. It s good method for the Diagnosis You can probe the activity of 2. Treatment of hyperthyroidism: increased activity of the gland which results in increased uptake of the Iodine can be used to treat the hyperthyroidism. How? You can give a large amount of radioactive Iodine (higher than the diagnostic dose). The gland itself will take the radioactive Iodine and the radioactivity will kill the areas of high activity. So, one approach to treat the hyperthyroidism is to give Radioactive Iodine to kill the areas of high activity of the gland. Note: The thyroid gland is the only gland that uses iodine If the patient becomes hypothyroid after radioactive Iodine treatment, you give him a thyroid replacement therapy for lifetime. And he can live healthy normal life until their 90s if he know how to titer the dose of thyroid hormone. 14 P a g e

Mechanism of action of thyroid hormones Unlike other nuclear receptors which are found in the cytoplasm and translocated across the nucleus to do their effect, the thyroid receptors are already found

Thyroid receptors are inactive because of their binding to corepressor.

16 Mechanism of action of thyroid hormones Unlike other nuclear receptors which are found in the cytoplasm and translocated across the nucleus to do their effect, the thyroid receptors are already found in the DNA and they are sitting with another nuclear receptor called Retinoid x receptor (RXR) How the thyroid hormones do their effect? 1. Thyroid hormones pass through the nuclear envelop 2. Thyroid receptors are inactive because of their binding to corepressor. When the hormone enters the nucleus and bind with the receptor, coactivator will sit in place of the corepressor (Switch the receptor) and this will recruit the RNA polymerase which drives mrna transcription. Corepressor: a substance that inhibits the expression of genes. Coactivator: a protein that increases gene expression And this is how the thyroid hormone does its effect P a g e

Slides >> - Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR) - Binding T 3 to its receptor liberates co-repressor and

Fat metabolism (the doctor focused on this topic) when there is secretion of thyroid hormones into the blood, lipolysis will increase and this increases fatty acids concentration.

17 Slides >> - Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR) - Binding T 3 to its receptor liberates co-repressor and recruits coactivator and RNA polymerase which drives mrna transcription Effect of thyroid hormone on body metabolism 1. Fat metabolism (the doctor focused on this topic) when there is secretion of thyroid hormones into the blood, lipolysis will increase and this increases fatty acids concentration. Other lipids (cholesterol, phospholipids and triglycerides) concentration will decrease. The most important point is that the cholesterol levels in the blood will go down -unlike the fatty acids- as a result of thyroid hormones activity. As you know, cholesterol in the liver could be secreted in the bile unchanged or could be converted to bile acids. Lipolysis is the breakdown of lipids and involves hydrolysis of triglycerides into glycerol and free fatty ).acids As a result of thyroid hormone activity: 1-The rate of conversion of cholesterol into bile acids will increase 2-The rate of cholesterol secreting in the bile will increase So, the level of cholesterol will decrease in the case of hyperthyroidism In the case of hypothyroidism, triglyceride and cholesterol will be high This usually affects women in middle age (40 s and 50 s ). As a result of hypothyroidism, she is a little bit obese, sluggish and suffering from constipation (because of decreased gastric motility) 16 P a g e

This case is very hard to diagnose because almost the majority of women in this age fit the

So keep in your mind that hypothyroidism could result in higher cholesterol and triglycerides

Carbohydrate metabolism (slides) - Thyroid hormone stimulates almost all aspects of carbohydrate

gluconeogenesis. -Increased rate of absorption from the gastrointestinal tract.

18 This case is very hard to diagnose because almost the majority of women in this age fit the exact profile. So keep in your mind that hypothyroidism could result in higher cholesterol and triglycerides levels. And this was the cause that made Ronaldo (Brazilian football player) quit. 2. Carbohydrate metabolism (slides) - Thyroid hormone stimulates almost all aspects of carbohydrate metabolism - Increase uptake of glucose by the cells, enhanced glycolysis, and enhanced gluconeogenesis. -Increased rate of absorption from the gastrointestinal tract. >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> Effect of thyroid hormone on body metabolism (slides) - Increased requirement for vitamins - Increased basal metabolic rate - Decreased body weight despite increase in appetite 17 P a g e

Effect of thyroid hormone on the cardiovascular system (Slides) Increased Blood Flow and Cardiac Output. Increased Heart Rate. Increased Heart Strength (Acute Vs.

Increased rate of respiration Increased gastrointestinal motility Effect of thyroid hormones on the body (Slides) General excitatory effect on the CNS.

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> Regulation of thyroid hormone secretion by TSH TSH (thyrotropin) an anterior pituitary hormone is chemically a glycoprotein.

19 Effect of thyroid hormone on the cardiovascular system (Slides) Increased Blood Flow and Cardiac Output. Increased Heart Rate. Increased Heart Strength (Acute Vs. Chronic effects). The pulse pressure is increased. Increased rate of respiration Increased gastrointestinal motility Effect of thyroid hormones on the body (Slides) General excitatory effect on the CNS. Enhanced muscle function (Acute Vs. Chronic) Increased muscle tremor Difficulty in sleep despite tiredness. >>>>>>>>>>>>>>>>>>>>>>>>>>>>>> Regulation of thyroid hormone secretion by 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). 18 P a g e

Regulation of thyroid hormone secretion by Thyrotropin-Releasing Hormone (TRH) (Slides) Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone

TRH causes an increase in the output of TSH by anterior Pituitary.

20 Regulation of thyroid hormone secretion by Thyrotropin-Releasing Hormone (TRH) (Slides) 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. Regulation of thyroid hormone secretion by Cold and Anxiety (Slides) 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. Done Sorry for any possible mistake مالحظة : هذا التفريغ معتمد على تسجيل شعبة A و بعتذر على آخر ثالث صفحات في التفريغ يلي ما انشرحوا في المحاضرة بالتوفيق 19 P a g e

Thyroid Gland 甲状腺. Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel:

Thyroid Gland 甲状腺. Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel: Thyroid Gland 甲状腺 Huiping Wang ( 王会平 ), PhD Department of Physiology Rm C541, Block C, Research Building, School of Medicine Tel: 88208292 Outline Thyroid Hormones Types Biosynthesis Storage and Release