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Thyroid hormones

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4Physiology

البطاينة. حميد د

صاالح & بني الله عبد

20 / 12 / 2009

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الرحيم الرحمن الله بسمwe want you my colleagues to know that we've reorganized the lecture in a way

that we think it's better to study and understand.

The thyroid gland� Contents

- Introduction

- Anatomic considerations : you took it in anatomy.

- Formation and synthesis of thyroid hormone

- Physiologic function of the thyroid hormone

- diseases of thyroid gland.

What's important here is the synthesis and release of the thyroid hormone, metabolic effects of thyroid hormone, regulation of thyroid hormone production and concentration. And all of these have direct relation with the thyroid diseases.

Anatomic consideration

From your anatomy information what's the location of thyroid gland:

─ it's found in the neck region, below the larynx and anterior to the trachea.

─ it consists of 2 lopes connected by a bridge of tissue, called the thyroid isthmus.

►Endocrine thyroid gland is considered as one of the largest endocrine glands that weighs 15-20 g in adults.

►The thyroid gland is composed of a large number of closed follicles which are lined by cuboidal epithelial cells and filled inside by a material

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called colloid, and part of this colloid forms and gives what we call

thyroglobulin.

This slide shows to us the larynx, cartilage, thyroid gland and also shows the trachea.

-note the location of the thyroid gland.

Here is another picture showing the larynx, right and left lopes, thyroid isthmus , and also you can see the trachea.

■This is a back view of thyroid gland, look at the parathyroid glands which are attached to the thyroid gland.

■One of the complications of the surgical operations on the thyroid, especially if the surgeon is not professional and trained he may remove the whole thyroid and remove the parathyroid glands with it ( كل يمعط ممكن

جالند الباراثايرويد كل معاها ويمعط so the ,( الثايرويدsurgeon must be fine while removing the thyroid gland in order not to harm and affect the parathyroid glands, in order to bypass the severe complications of the damage or removal of the parathyroid glands such as hypocalcaemia and as you know calcium is very important.

This is a front view for thyroid gland

■This is a microscopic slide and in it we can see the follicles, cuboidal epithelial cells and also we can see colloid granules inside the follicles.

■ The thyroid gland is highly vascular, meaning that the blood flow to the thyroid gland is very high, the blood flow is higher than the weight of the thyroid gland by 5 times. – I don't know what the Dr means here !! - .

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The thyroid glands produce the thyroid hormone which regulates the chemical reactions and metabolic reactions in body tissue cells, and it also has a big role in the maturation process and growth of bones and membranes and muscles.

So we can notice that the thyroid gland affects all the tissues in the body because it's primarily responsible for metabolism.

Have you ever felt or palpated your thyroid glands ? the thyroid gland

This is also a microscopic slide and we also here can see the follicles ( note that they are lined with cuboidal cells ), follicular cells, colloid in the center.

From the Dr's slides

The thyroid gland maintains the level of metabolism in the tissues that is optimal for their normal function.

Its hormones stimulate the oxygen consumption of most of the cells in the body, help regulate lipid and carbohydrate metabolism, and are necessary for normal growth and maturation.

♦ This picture shows us the area of the hypothalamus and pituitary gland.♦ we know that the hypothalamus produces thyrotropin-releasing hormone(TRH) which is the hormone responsible for regulation process of thyroid hormone secretion.♦ the thyroid gland and the thyroid hormone is under control of the anterior pituitary hormone secretion which produces TSH(thyroid stimulating hormone).

Therefore, thyroid hormone production is under the control of TSH as well as TRH, so in all cases that lead to increase production rate of TRH from the hypothalamus and this will lead to increase production rate of TSH and as a result increase production of T3 & T4 , and also in all cases that lead to increase production rate of TSH will lead to

increase production of T3 & T4

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is normally not palpable and you can't touch it except when it is enlarged, so when someone has clinical disorder in the thyroid gland such as enlargement, one of the clinical application is to try to palpate the area where the thyroid gland is found, and ask the patient to sit in front of you , and then we put our fingers kindly and slightly and ask him to swallow, and during the swallowing there will be some kind of movement, so if the thyroid is enlarged then we will palpate and feel it by our fingers, otherwise, if it is normal then we cannot feel and palpate it.

The thyroid gland gives 3 hormones:

1- Thyroxine which is also called tetraiodothyronine(T4) 2- Triiodothyronine ( T3 ) .3- Calcitonin.

The tissues of thyroid gland have different types of cells, some of them are thyroid cells "follicular cells" which produce T3&T4, and there are different types of cells called C cells which give the calcitonin hormone.

The metabolic effects of calcitonin differs from the metabolic effects of the thyroid hormone; calcitonin is responsible for regulation process of calcium concentration in blood, calcium concentration is under control of 2 hormones :

a) Parathyroid hormone which increases calcium concentration.b) Calcitonin which reduce calcium concentration in blood, so in all

cases in which there is increase in calcium concentration above normal ( the normal concentration of calcium is 9.5 mg\dL( 8.4 - 10.2 mg/dL ) and this will increase production of calcitonin to enhance reduction in calcium levels in blood.

The thyroid hormones Let's talk about T3 & T4 :

▬ Most of the hormones that are produced and released and secreted from the thyroid gland are T4, that about 93% of the thyroid hormone that are released from thyroid gland are T4.

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▬ The release of T3 is very low ( not more than 7% ).

*so we conclude that the concentration is high for T4, and low for T3. But all the T4(thyroxine) is transformed into T3, so T3 is more active than T4.

▬ In all cases in which there is a decreased production of thyroid hormone T4 & T3 , this will cause reduction in basal metabolic rate (BMR) which in turn may reach 40%-50% below normal metabolism.

▬ On the other hand, if there is an increase in production of thyroid hormone as a result of increase in thyroid gland activity, this will increase metabolism and chemical reactions that will increase the BMR to 60%-100%.

How can we know that someone has increase in metabolism or a decrease in it? Always in all cases of increased metabolism there will be increase in heat production, so the patient who has increased metabolism you will find him overheating(increased temperature سخنان) and if you feel his hand for example you will find it warm. On the other hand, if the rate of metabolism is less than normal then the patient is always cold and suffers from coldness even in moderate weathers.

To summarize :

▬ The concentration of T4 is more than the concentration of T3, but T3 is more active than T4.

▬ In Target cells and in target organs the thyroid hormone T4 is transformed into T3 because T3 is more active. This note is very important as it might come in the exam –as the Dr said- .

From the Dr's slides

■ The function of these two hormones are the same, but they differ in rapidity and intensity of action.

■ Triiodothyronine T3 is about 4 times as potent as thyroxine T4 , but it is present in the blood in much smaller quantities, and persists for a much shorter time than thyroxine.

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Synthesis and secrection of Thyroid hormones

As we've said thyroid hormone is under the control of TRH as well as TSH and any increase in these 2 hormones will result in increasing thyroid hormones production.

*thyroid hormone is composed of tyrosine which is attached to iodine, and both are attached to thyroglobulin.

*Iodine (اليود) is very essential for synthesis and formation of thyroid hormones, so the people who are far away from the sea and don't eat marine foods are subjected to have hypothyroidism( which means that the thyroid hormone production is very low), because we can never produce enough production of thyroid hormone if there's deficiency in iodine. On the other hand, in areas close to the sea where people eat marine food and fish-which contain iodine in the shape of salts "not sure", so they rarely have deficiency in iodine.

*Weekly need for iodine is 1 mg\week, and if we compute it yearly it will be 48-50 mg\year, so when there's a deficiency in iodine intake and penetration this will lead to decrease in production rate of thyroid hormone in a condition called hypothyroidism.

Now my colleagues take these 2 pieces of information from the Dr's slides : - iodides ingested orally are absorbed from the gastrointestinal tract into the blood. - Most of them are rapidly excreted by the kidneys, but only 20% are selectively removed from the circulation by the cells of the thyroid gland and used for the synthesis of the thyroid hormones.

But when the Dr talked about them he explained them in a very strange way and this is what the Dr said :

While digesting iodine contained in the ingested food then there will be excretion of it in the feces and only 20% of iodine in the diet is absorbed to the blood and then to the thyroid gland, meaning that only 20% of the whole amount of iodine that you take in the diet is the only amount that undergoes reabsorbtion, so that it's the amount which used in formation of thyroid hormone.

حكا الدكتور هيك دخل، إلي وال

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The first step in the formation process of thyroid hormone is to transport iodine from the blood or from the extracellular space into the thyroid glandular cells and follicles.

Here one of our colleagues asked a question, but unfortunately his voice is not clear but the Dr's answer is: the excretion is done through the GI and through the kidneys.

The concentration of iodine inside the thyroid cells is higher than its concentration in the extracellular space, so the transport of iodine from the low concentration to the high concentration needs iodine pump; so it's an active transport process through iodine pump which will elevate the concentration of iodine inside the thyroid into about 30 times its concentration in the extracellular space or the blood.

And by this my part ends أحمد , والخالص

. له مهنة الطب اختار من كل إلى خاصة تحية

الجزار عمر إلى خاصة تحية

: معتصم ، الجنيدي رضوان مشتركة محاضرة معي كتب من كل إلى خاصة تحيةصالح . بني عبدالله بـ وانتهاء ، سوالمة خالد ، كيالني وسيم ، األمعري

خاصة . أسباب ولذلك ، أيضاً المحاضرة هذه في حواري نص تضمين عدم عن نعتذر

… in case of hyperthyroidism and very high production rate of thyroid hormones the concentration of iodide within the thyroid cells and follicles can reach 250 times that of the blood.

The rate of iodide trapping or increasing the concentration of iodide within the thyroid cells is under the control of TSH, the higher the production rate of TSH the more the transport of Iodide from the extracellular fluid or the blood to the thyroid cells.

This slide shows the hypothalamus- pituitary- thyroid axis. The hypothalamus secretes TRH that stimulates the

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anterior pituitary which in turn gives TSH. TSH affect directly increasing the iodide trapping, elevating the iodide concentration within the thyroid cells which is required to increase the production rate of the thyroid hormones T3 and T4.

The higher the concentration of Iodide in the thyroid cells the higher the production rate of T3 and T4.

When T3 and T4 concentration reache certain level a negative feedback process inhibits the secretion of both the hypothalamus (reducing TRH) and the anterior pituitary (reducing TSH). The blood levels of both T3 and T4 affect the metabolism and chemical reactions.

Thyroid cells are protein secreting glandular cells that synthesize the thyroglobulin, a single thyroglobulin molecule contains about 70 tyrosine amino acids, theses tyrosine residues are the major substrate that combine with iodine to form thyroid hormones.

The next step following iodide trapping is the oxidation of iodide to iodine, the oxidation is promoted by the enzyme peroxidase, if this enzyme is blocked or is hereditarily absent the rate of thyroid hormones formation falls down to ZERO. This shows how important the peroxidase enzyme is for the synthesis of thyroid hormones.

The next step is iodination of tyrosine and formation of the thyroid hormones—“Organification” of Thyroglobulin.Iodination means to add iodine to the tyrosine, this is under control of an enzyme called Iodinase that adds one molecule of iodine to the tyrosine forming monoiodotyrosine, if two molecules are added then it’s called Diiodotyrosine.

The last step is the coupling reaction where one monoiodotyrosine combines with a Diiodotyrosine forming Triiodothyronine, then a

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monoiodotyrosine combines with Triiodothyronine forming Tetraiodothyronine or Thyroxin.

• Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine.

• During the next few minutes, hours and even days, iodotyrosine residues become coupled with one another.

• The major hormonal product of coupling reaction is thyroxine that remains part of the thyroglubulin molecule.

To sum up… Steps of thyroid hormone synthesis

1 Transport of iodide “iodide trapping” Iodide pump2 Oxidation of iodide to iodine Peroxidase3 Iodination Iodinase4 Coupling

Transport of Thyroxin and Triiodothyronine to the TissuesThyroid hormones are released in the blood where we have three different types of protein carriers. They bind Mainly with thyroxine-binding globulin, and much less with thyroxine-binding prealbumin and albumin.

Releasing these hormones to the target tissues is slow due to the high affinity between the plasma protein carriers and the hormones.

Thyroid hormones have slow onset and long duration of action. We can notice a difference between T3 and T4,,

There is a long latent period of 2-3 days before the activity of

T4 begins, then it reaches maximum activity in 10-12 days.

However T3 takes only 6-12 hours to start its action and reach maximum activity in 2-3 days.

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So you need to differentiate between T3 and T4 in the production rate, activity and the onset of action.

Specific receptors for thyroid hormones are present in the nucleus of the cell, to increase metabolism and chemical reactions thyroid hormones stimulates more protein synthesis by enhancing mRNA transcription and translation.

PHYSIOLOGITIONS OF THE THYROID HORMONES

Thyroid hormones increase cellular metabolic activity by way of

1. Increasing the number and activity of mitochondria and thus increasing the production rate of ATP.

2. Increasing active transport of ions across the cell memberane (e.g. na/k pump that utilizes ATP ), this process uses energy and increase the amount of heat produced by the body.

3. By making the cell membranes more leaky to sodium ions, activating the sodium pump and further increasing heat production.

Effect of Thyroid Hormone on Growth

Normally, Thyroid hormone stimulates the growth rate so decreased amounts of thyroid hormone correlate with low growth rate and vice versa.

In children the growth rate is very high. If they have hypothyroidism the growth rate will be greatly retarded, in hyperthyroidism excessive skeletal growth occurs.

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Thyroid hormones affect the growth and development of the brain during fetal life and for the first few years of life, reduction in thyroid hormone during pregnancy, before or after birth results in reduction in the brain maturation and mental retardation.

Stimulation of carbohydrate metabolismThyroid hormones stimulate all aspects of carbohydrate metabolism which includes :• increase uptake of glucose by the cells (muscle cells liver

cells…) • Enhanced glycolysis and gluconeogenesis • Increase rate of absorption from the gastrointestinal tract • Increase insulin secretion

All these effects probably result from increase in cellular metabolic enzymes caused by thyroid hormone. Among the hormones that help in readjusting blood glucose level when glucose concentration is below normal is thyroid hormone by way of increasing glucose absorption from the GI tract.

Stimulation of fat metabolismIncreased levels of thyroid hormone increases lipid metabolism

and utilization, lipids include cholesterol, phospholipids and triglycerides.

So in cases of hyperthyroidism there will be low plasma levels of cholesterol, phospholipids and triglycerides, whereas in cases of hypothyroidism there will be increased concentration of lipids in the blood which eventually causes precipitation of lipids in arterioles and results in Atherosclerosis.

You can use the above distinction to differentiate hypothyroidism from hyperthyroidism in a blood test (low cholesterol-- hyperthyroidism) (high cholesterol-- hypothyroidism).

Thyroid hormones affect the body weight, the more the thyroid hormones the lesser the body weight and vice versa. Among the

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clinical signs of hyperthyroidism is weight loss because of increased fat catabolism, these patients will also exhibit increased appetite to replace the fat that is rapidly metabolized, a normal person needs about 2000-3000 calories per day, these patients need about 4000-5000 calories. On the other hand patients with hypothyroidism will gain more weight because of reduced metabolism, in those patients 1000 calories will be enough.

Also thyroid hormone increases the rate of chemical reactions which requires increased production of enzymes and coenzymes, and because vitamins are essential parts of some of these enzymes & coenzymes; thyroid hormone causes increased need for vitamins.

Effects of Thyroid hormone on the Cardiovascular system

Increased blood flow and cardiac outputIncreased metabolism in the tissues causes more rapid

utilization of oxygen than normal and release of greater quantities of metabolic end products from the tissues. These end products (e.g. CO2) cause vasodilation in most body tissues, thus increasing blood flow particularly in the skin because of the increased need for heat elimination from the body. As a consequence of the increased blood flow, cardiac output also increases and blood pressure increases as will.

Increased heart rate

An important clinical sign, patients with hyperthyroidism have tachycardia and patients with hypothyroidism have bradycardia.

Effects of thyroid hormone on Respiration

Thyroid hormones metabolism and metabolic end products CO2 exhalation respiratory rate.

Thyroid hormones increase GI motility and Secretions.

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This figure shows the activation of the target cell by T3 and T4 and some of there physiologic functions.

Excuse us for any mistakes…Best wishes…

Done by: Derar Domaidat & Abdullah B.Saleh.