Thyroid is a butterfly-shaped endocrine gland situated at the base of neck in front of trachea.

This gland plays a major role in metabolic activities, growth and development of body.

It also helps to regulate functions of many vital organs such as heart, brain, kidneys and liver.

Morphology of Thyroid Gland

Thyroid gland has two lobes, which are connected in the middle by an isthmus.

It weighs about 20 to 40 g in adults. Thyroid is larger in females than in males.

Structure and function of thyroid gland change in different stages of the sexual cycle in females.

Activity of thyroid gland increases slightly during pregnancy and lactation, and decreases during menopause.

Functional Histology of Thyroid Gland

Thyroid gland is composed of large number of closed follicles called thyroid follicles.

Each follicle is formed by cuboidal epithelial cells called follicular cells around the follicular cavity.

Follicular cavity is filled with a colloidal substance known as thyroglobulin, which is secreted by the follicular cells.

Follicular cells also secrete tetraiodothyronine (T4) or thyroxine and triiodothyronine (T3).

In between follicles, there are parafollicular cells or clear cells or C cells, which secrete calcitonin.

Blood Supply to Thyroid Gland

Thyroid gland receives arterial blood via three arteries:

1. Superior thyroid artery.
2. Inferior thyroid artery.
3. Small artery, arteria thyroidea (branch of brachiocephalic trunk).

Venous Drainage

Venous blood is drained from thyroid by three veins:

1. Superior thyroid vein.
2. Middle thyroid vein.
3. Inferior thyroid vein.

Nerve Supply to Thyroid Gland

Thyroid gland is innervated by postganglionic fibers arising from superior, middle and inferior cervical sympathetic ganglia.

Thyroid gland secretes three hormones:

1. Tetraiodothyronine (T4) or thyroxine.
2. Triiodothyronine (T3).
3. Calcitonin.

T4 is forms about 90% of the total secretion, whereas T3 is only 9 to 10%. Calcitonin is described separately.

Chemistry of Thyroid Hormones

Both T4 and T3 are iodine-containing derivatives of amino acid tyrosine.

Potency and Duration of Action

Potency of T3 is four times more than that of T4. T4 acts for longer period than T3.

Duration of T4 action is more than T3 because of difference in the affinity of these hormones to plasma proteins.

T3 has less affinity for plasma proteins and combines loosely with them, so that it is released quickly.

T4 has more affinity and binds strongly with plasma proteins, so that it is released slowly.

Therefore, T3 acts on the target cells immediately and T4 acts slowly.

Half-life of Thyroid Hormones

Thyroid hormones have long half-life. T4 has a half-life of 7 days. Half-life of T3 is varying between 10 and 24 hours.

Rate of Secretion

Plasma Level of Thyroid Hormones

Metabolism of Thyroid Hormones

Degradation of thyroid hormones occurs in muscles, liver and kidney.

Synthesis of thyroid hormones takes place in thyroglobulin present in follicular cavity.

Iodine and tyrosine are essential for synthesis of thyroid hormones.

Iodine which is consumed through diet is converted into iodide and absorbed from GI tract. Tyrosine is also consumed through diet and absorbed from GI tract.

For synthesis of normal quantities of thyroid hormones, approximately 1 mg of iodine is required per week, or about 50 mg per year.

To prevent iodine deficiency, common table salt is iodized with one part sodium iodide to every 100,000 parts of sodium chloride.

Stages of Synthesis of Thyroid Hormones

Synthesis of thyroid hormones takes place in five stages:

1. Thyroglobulin synthesis.
2. Iodide trapping or iodide pump.
3. Oxidation of iodide.
4. Iodination of tyrosine.
5. Coupling reactions.

1. Thyroglobulin Synthesis

Endoplasmic reticulum and Golgi apparatus in the follicular cells of thyroid gland synthesize thyroglobulin continuously.

Each thyroglobulin molecule contains 140 tyrosine molecules.

After synthesis, thyroglobulin is stored in the follicle.

2. Iodide Trapping or Iodide Pump

Iodide is transported actively from blood into follicular cell against electrochemical gradient by a process called iodide trapping.

Iodide is pumped with sodium into the follicular cell by sodium-iodide symport pump.

From the follicular cell, iodide is transported into follicular cavity by iodide-chloride pump.

3. Oxidation of Iodide

Iodide must be oxidized to elementary iodine because only iodine can combine with tyrosine to form thyroid hormones.

Oxidation of iodide into iodine occurs inside follicular cells in the presence of thyroid peroxidase.

4. Iodination of Tyrosine

Combination of iodine with tyrosine is known as iodination.

This process takes place in the follicle within thyroglobulin.

First, iodine is released from follicular cells into the follicular cavity where it binds with thyroglobulin. This process is called organification of thyroglobulin.

In organification, iodine combines with tyrosine which is already present in thyroglobulin.

Binding of iodine with tyrosine is accelerated by the enzyme iodinase, which is secreted by follicular cells.

Iodination of tyrosine occurs in several stages. Tyrosine is iodinated first into monoiodotyrosine (MIT) and later into diiodotyrosine (DIT). MIT and DIT are called iodotyrosine residues.

5. Coupling Reactions

Iodotyrosine residues get coupled with one another through coupling reactions. Coupling occurs in different configurations and gives rise to different thyroid hormones.

1. One molecule of DIT and one molecule of MIT combine to form triiodothyronine (T3).
2. Sometimes one molecule of MIT and one molecule of DIT combine to produce another form of T3, called reverse T3 or rT3. Reverse T3 is only 1% of thyroid secretion.
3. Two molecules of DIT combine to form tetraiodothyronine (T4), which is thyroxine.

After synthesis, thyroid hormones remain in the form of vesicles within thyroglobulin.

In combination with thyroglobulin, thyroid hormones can be stored for several months.

Thyroid gland is unique in this, as it is the only endocrine gland that can store its hormone for a long period of about 4 months.

So, when the synthesis of thyroid hormone stops, signs and symptoms of deficiency do not appear for about 4 months.

Thyroid hormones are first cleaved from thyroglobulin and then released into the blood.

Only T3 and T4 are released into the blood.

In peripheral tissues, T4 is converted into T3. A small amount of reverse T3 is also formed. Reverse T3 is biologically inactive.

MIT and DIT are not released into blood. The iodotyrosine residues are deiodinated by an enzyme called iodotyrosine deiodinase, resulting in release of iodine.

This iodine is reutilized by follicular cells for synthesis of thyroid hormones.

During congenital absence of iodotyrosine deiodinase, MIT and DIT are excreted in urine and the symptoms of iodine deficiency develop.

Thyroid hormones are transported in blood in combination with three types of plasma proteins:

1. Thyroxine-binding globulin (TBG).
2. Thyroxine-binding prealbumin (TBPA).
3. Albumin.

Thyroid hormones have two major functions:

1. Stimulation of overall metabolic rate in the body.
2. Stimulation of growth in children.

1. Action on Basal Metabolic Rate (BMR)

Basal metabolic rate is the minimum amount of energy (number of calories) required for body functions at rest.

Thyroxine increases metabolic activities in most of the body tissues, except brain, retina, spleen, testes and lungs.

It increases BMR by increasing oxygen consumption of the tissues. This action is called calorigenic action.

In hyperthyroidism, BMR increases by about 60 to 100% above normal level and in hypothyroidism falls by 20 to 40% below the normal level.

2. Action on Protein Metabolism

Thyroid hormones increase synthesis of proteins in cells by four ways:

i. By Increasing Translation of RNA

Because of increase in translation of RNA in cells, ribosomes are activated and more proteins are synthesized.

ii. By Increasing Transcription of DNA to RNA

Transcription of DNA to RNA accelerates the synthesis of proteins in cells.

iii. By Increasing Activity of Mitochondria

Thyroid hormone acts at mitochondrial level also. It increases the number and activity of mitochondria in most of the cells.

Thyroid hormone accelerates the synthesis of RNA and other substances from mitochondria by activating a series of enzymes.

In turn, mitochondria increase the production of ATP, which is utilized for the energy required by cellular activities.

iv. By Increasing Activity of Cellular Enzymes

Thyroid hormones also increase the activity of at least 100 or more intracellular enzymes such as alpha glycerophosphate dehydrogenase and oxidative enzymes.

These enzymes accelerate the metabolism of proteins and carbohydrates.

Though thyroxine increases synthesis of protein, it also causes catabolism of proteins.

3. Action on Carbohydrate Metabolism

Thyroxine stimulates almost all processes involved in metabolism of carbohydrate.

Thyroxine:

1. Increases the absorption of glucose from GI tract.
2. Enhances the glucose uptake by the cells, by accelerating the transport of glucose through the cell membrane.
3. Increases the breakdown of glycogen into glucose.
4. Accelerates gluconeogenesis.

4. Action on Fat Metabolism

Thyroxine mobilizes fat from fat depots and increases free fatty acids in the blood.

It also decreases the level of cholesterol and triglycerides in plasma.

Action on Fats in Plasma

Even though there is an increase in blood level of free fatty acids, thyroxine specifically decreases the cholesterol, phospholipids and triglyceride levels in plasma.

So, hypersecretion of thyroxine, cholesterol level in plasma increases, resulting in atherosclerosis.

Action on Fats in Liver

Thyroxine also increases deposition of fats in liver, leading to fatty liver.

Thyroxine decreases plasma cholesterol level by increasing excretion of cholesterol from liver cells into bile.

Cholesterol enters the intestine through bile and then it is excreted through the stool.

5. Action on Vitamin Metabolism

Thyroxine increases the formation of many enzymes. Since vitamins form parts of enzymes, vitamins may be utilized during formation of the enzymes.

Hence, vitamin deficiency is possible during hyperthyroidism.

6. Action on Body Temperature

Thyroxine increases heat production in the body by accelerating various cellular metabolic processes and increasing BMR.

It is called thyroid hormone-induced thermogenesis.

During hypersecretion of thyroxine, body temperature increases greatly, resulting in excessive sweating.

7. Action on Growth

Thyroid hormones have general and specific effects on growth.

Increase in thyroxine secretion accelerates the growth of the body, especially in growing children.

Lack of thyroxine arrests the growth. At the same time, thyroxine causes early closure of epiphysis. So, height of the individual may be slightly less in hypothyroidism.

8. Action on Body Weight

Thyroxine is essential for maintaining the body weight.

Increase in thyroxine secretion decreases the body weight and fat storage. Decrease in thyroxine secretion increases the body weight because of fat deposition.

9. Action on Blood

Thyroxine accelerates erythropoietic activity and increases blood volume.

It is one of the important general factors necessary for erythropoiesis.

Polycythemia is common in hyperthyroidism.

10. Action on Gastrointestinal Tract

Thyroxine increases appetite and food intake. It also increases the secretions and movements of GI tract.

Hypersecretion of thyroxine causes diarrhea and deficiency of thyroxine causes constipation.

11. Action on Other Endocrine Glands

Because of its metabolic effects, thyroxine increases the demand for secretion by other endocrine glands.

12. Action on Sexual Function

Thyroxine is necessary for normal sexual function.

In men, hypothyroidism leads to complete loss of libido and hyperthyroidism leads to impotence.

In women, hypothyroidism commonly causes menorrhagia. In some women, it causes irregular menstruation and occasionally amenorrhea.

Hyperthyroidism in women leads to oligomenorrhea and also sometimes amenorrhea.

13. Action on Cardiovascular System

Thyroxine increases overall activity of cardiovascular system.

i. Effect on Heart Rate

Thyroxine acts directly on heart and increases the heart rate. It is an important clinical investigation for diagnosis of hypothyroidism and hyperthyroidism.

ii. Effect on Force of Contraction of Heart

Thyroxine increases force of contraction of the heart.

But in hyperthyroidism or in thyrotoxicosis, heart may become weak due to excess activity and protein catabolism.

The patient may die of cardiac decompensation.

Cardiac decompensation refers to failure of heart to maintain adequate circulation associated with dyspnea, venous engorgement (veins overfilled with blood) and edema.

iii. Effect on Blood Vessels

Thyroxine causes vasodilatation by increasing metabolic activities. Increased metabolic activities produce a large quantity of metabolites which cause vasodilatation.

iv. Effect on Arterial Blood Pressure

Because of increase in heart rate, force of contraction of heart and blood volume by thyroxine, cardiac output increases.

This, in turn, increases systolic blood pressure. At the same time, thyroxine decreases diastolic pressure by its vasodilator effect.

Systolic pressure increases and diastolic pressure decreases. So, pulse pressure increases and the mean arterial pressure is not altered.

14. Action on Respiration

Thyroxine increases rate and force of respiration indirectly.

Increased metabolic rate caused by thyroxine increases the demand for oxygen and formation of excess carbon dioxide.

These two factors stimulate the respiratory centers to increase the rate and force of respiration.

15. Action on Central Nervous System

Thyroxine is very essential for development and maintenance of normal functioning of central nervous system (CNS).

i. Effect on Development of Central Nervous System

Thyroxine is essential for growth and development of brain during fetal life and first few years of postnatal life.

Deficiency of thyroid hormones during this period leads to mental retardation.

ii. Effect on Normal Function of Central Nervous System

Thyroxine is a stimulating factor for CNS, particularly brain. So, normal functioning of brain needs the presence of thyroxine.

Hypersecretion of thyroxine causes excess stimulation of CNS. The effect on person is likely to have extreme nervousness and may develop psychoneurotic problems such as anxiety complexes, excess worries that other people are plotting or conspiring against them or harming them.

Hyposecretion of thyroxine leads to lethargy and somnolence.

16. Action on Skeletal Muscle

Thyroxine is essential for normal activity of skeletal muscles. Slight increase in thyroxine level makes the muscles to work with more vigor.

But, hypersecretion of thyroxine causes weakness of muscles due to catabolism of proteins. This condition is called thyrotoxic myopathy.

Muscles relax very slowly after the contraction.

Hyperthyroidism also causes fine muscular tremor. Tremor occurs at the frequency of 10 to 15 times per second.

It is due to the thyroxine-induced excess neuronal activity, which causes muscle spasm. Lack of thyroxine makes the muscles more sluggish.

17. Action on Sleep

Normal thyroxine level is necessary to maintain normal sleep pattern.

Hypersecretion of thyroxine causes excessive stimulation of muscles and central nervous system.

So, the person feels tired, exhausted and feels like sleeping. But the person cannot sleep because of the stimulatory effect of thyroxine on neurons.

On the other hand, hyposecretion of thyroxine causes somnolence.

Mode of Action of Thyroid Hormones

Thyroid hormones act by activating the genes.

Regulation of Secretion of Thyroid Hormones

Secretion of thyroid hormones is controlled by anterior pituitary and hypothalamus through feedback mechanism.

Role of Pituitary Gland

Thyroid-Stimulating Hormone

Thyroid-stimulating hormone (TSH) secreted by anterior pituitary is the major factor regulating the synthesis and release of thyroid hormones.

TSH is a peptide hormone with one α-chain and one β-chain. Normal plasma level of TSH is approximately 2 U/mL.

Actions of TSH

Immediate effect of TSH is proteolysis of thyroglobulin, by which thyroxine is released within 30 minutes.

Effect of TSH on thyroxine synthesis takes place after some days or weeks.

TSH accelerates thyroxine synthesis by following ways:

1. Increases number of follicular cells of thyroid.
2. Accelerates development of thyroid follicles by converting cuboidal cells in thyroid gland into columnar cells.
3. Increases size and secretory activity of follicular cells.
4. Activates iodide pump and iodide trapping in follicular cells.
5. Increases thyroglobulin secretion into follicles.
6. Increases iodination of tyrosine and coupling to form the hormones.
7. Increases proteolysis of thyroglobulin, and release of hormones.

Mode of Action of TSH

TSH acts through cyclic AMP mechanism.

Role of Hypothalamus

Hypothalamus regulates thyroid secretion by inducing release of TSH by thyrotropin-releasing hormone (TRH).

TRH is transported from hypothalamus through the hypothalamo-hypophyseal portal circulation to anterior pituitary.

After reaching pituitary gland, TRH causes release of TSH.

Feedback Control

Thyroid hormones regulate their own secretion through negative feedback control by inhibiting the release of TRH from hypothalamus and TSH from anterior pituitary.

Role of Iodide

Iodide is an important factor regulating the synthesis of thyroid hormones.

When the dietary level of iodine is moderate, blood level of thyroid hormones is normal.

However, when iodine intake is high, the enzymes necessary for synthesis of thyroid hormones are inhibited by iodide itself, resulting in suppression of hormone synthesis.

Hyperthyroidism: Thyrotoxicosis

Hyperthyroidism refers to excess synthesis and release of thyroid hormones by thyroid gland resulting in increased level of hormones in blood.

Thyrotoxicosis is defined as high level of thyroid hormones in blood. It is the condition caused by not only excess secretion by thyroid glands, but also release of thyroid hormones from other sources.

Causes for Hyperthyroidism

Hyperthyroidism is caused by Graves’ disease and thyroid adenoma.

Graves’ Disease

Graves’ disease is an autoimmune disease characterized by hypersecretion of thyroid hormones.

Normally, thyroid-stimulating hormone (TSH) combines with surface receptors of thyroid cells and causes the synthesis of thyroid hormones.

In Graves’ disease, the B lymphocytes (plasma cells) produce autoimmune antibodies called thyroid-stimulating hormone receptor antibodies (TSHRAb).

TSHRAb antibodies act like TSH by binding with membrane receptors of TSH and activating cAMP system of the thyroid follicular cells.

This results in hypersecretion of thyroid hormones.

Thyroid Adenoma

Sometimes, a localized tumor develops in thyroid tissue. It is known as thyroid adenoma and it secretes large quantities of thyroid hormones.

Signs and Symptoms of Hyperthyroidism

1. Intolerance to heat because of production of more heat during increased basal metabolic rate caused by hyperthyroidism.
2. Increased sweating due to vasodilatation.
3. Decreased body weight due to fat mobilization.
4. Diarrhea due to increased motility of GI tract.
5. Muscular weakness due to excess protein catabolism.
6. Neuronal disturbances such as nervousness, extreme fatigue, inability to sleep, mild tremor in hands, and psychoneurotic symptoms such as hyperexcitability, extreme anxiety or worry.
7. Toxic goiter.
8. Oligomenorrhea or amenorrhea.
9. Exophthalmos.
10. Polycythemia.
11. Tachycardia and atrial fibrillation.
12. Systolic hypertension.
13. Cardiac failure.

Exophthalmos

Protrusion of eyeballs is called exophthalmos. Most, but not all hyperthyroid patients develop some degree of protrusion of eyeballs.

Causes for Exophthalmos

Exophthalmos in hyperthyroidism is due to edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles.

Effect of Exophthalmos on Vision

Severe exophthalmic conditions lead to blindness because of two reasons:

1. Protrusion of the eyeball stretches and damages the optic nerve resulting in blindness.
2. Due to protrusion of eyeballs, eyelids cannot be closed completely while blinking or during sleep. So, constant exposure of eyeball to atmosphere causes dryness of the cornea leading to irritation and infection. It finally results in corneal ulcers leading to blindness.

Decreased secretion of thyroid hormones is called hypothyroidism.

Hypothyroidism leads to myxedema in adults and cretinism in children.

Myxedema

It is the hypothyroidism in adults characterized by generalized edematous appearance.

Causes for Myxedema

1. Diseases of thyroid gland.
2. Genetic disorder.
3. Iodine deficiency.
4. Deficiency of thyroid-stimulating hormone or thyrotropin-releasing hormone.
5. Autoimmune disease called Hashimoto’s thyroiditis.

Signs and Symptoms of Myxedema

Typical feature of myxedema is an edematous appearance throughout the body.

Myxedema is associated with following symptoms:

1. Swelling of the face.
2. Bagginess under the eyes.
3. Non-pitting type of edema, i.e. when pressed, it does not make pits and the edema is hard.
4. Atherosclerosis: It is the hardening of the walls of arteries because of accumulation of fat. It occurs in myxedema because of increased plasma level of cholesterol which leads to deposition of cholesterol on walls of the arteries.

Atherosclerosis produces arteriosclerosis (thickening and stiffening of arterial wall). Atherosclerosis causes hypertension.

Other General Features of Hypothyroidism in Adults

1. Anemia.
2. Fatigue and muscular sluggishness.
3. Extreme somnolence with sleeping up to 14 to 16 hours per day.
4. Menorrhagia and polymenorrhea.
5. Decreased cardiovascular functions such as reduction in rate and force of contraction of the heart, cardiac output and blood volume.
6. Increase in body weight.
7. Constipation.
8. Mental sluggishness.
9. Depressed hair growth.
10. Scaliness of the skin.
11. Frog-like husky voice.
12. Intolerance to cold.

Cretinism

Cretinism is the hypothyroidism in children characterized by stunted growth.

Causes for Cretinism

Cretinism occurs due to congenital absence of thyroid gland, genetic disorder or lack of iodine in the diet.

Features of Cretinism

1. A newborn baby with thyroid deficiency may appear normal at the time of birth because thyroxine might have been supplied from mother. But a few weeks later, the baby starts developing the signs like sluggish movements and croaking sound while crying. Unless treated immediately, the baby will be mentally retarded permanently.
2. Skeletal growth is more affected than the soft tissues. So, there is stunted growth. Abdominal bloating is common in cretins. Tongue becomes so big that it hangs down with dripping saliva. The big tongue obstructs swallowing and breathing. The tongue produces characteristic guttural breathing that may sometimes cause death to the baby.

Cretin vs Dwarf

A cretin is different from pituitary dwarfism.

Goiter means enlargement of thyroid gland. It occurs both in hypothyroidism and hyperthyroidism.

Goiter in Hyperthyroidism: Toxic Goiter

Toxic goiter is the enlargement of thyroid gland with increased secretion of thyroid hormones caused by thyroid tumor.

Goiter in Hypothyroidism: Non-toxic Goiter

Non-toxic goiter is the enlargement of thyroid gland without increase in hormone secretion. It is also called hypothyroid goiter.

Types of Non-toxic Hypothyroid Goiter

Based on cause, nontoxic hypothyroid goiter is classified into two types:

1. Endemic colloid goiter.
2. Idiopathic non-toxic goiter.

1. Endemic Colloid Goiter

It is the non-toxic goiter caused by iodine deficiency. It is also called iodine deficiency goiter.

Iodine deficiency occurs when intake is less than 50 μg/day.

Lack of iodine leads to stoppage of formation of thyroid hormones.

By feedback mechanism, hypothalamus and anterior pituitary are stimulated. It increases the secretion of TRH and TSH.

Excess TSH causes thyroid cells to secrete tremendous amounts of thyroglobulin into the follicle.

As there are no hormones to be cleaved, the thyroglobulin remains as it is, and gets accumulated in the follicles of gland. This increases the size of gland.

2. Idiopathic Non-toxic Goiter

It is the goiter due to unknown cause. Enlargement of thyroid gland occurs even without iodine deficiency. The exact cause is not known.

Some foodstuffs contain goitrogens (goitrogenic substances) such as goitrin.

These food substances contain antithyroid substances like prothiouracil.

Goitrogens suppress the synthesis of thyroid hormones. Therefore, TSH secretion increases resulting in enlargement of the gland.

Such goitrogens are found in vegetables such as turnips and cabbages. Soybean also contains some amount of goitrogens.

Goitrogens become active only during low iodine intake.

Treatment for Hyperthyroidism

Hyperthyroidism is treated by two methods:

1. By antithyroid substances such as thiocyanate, thiouracil and high concentration of inorganic iodides.
2. By surgical removal (thyroidectomy) in advanced cases when treatment with antithyroid substances fails.

Treatment for Hypothyroidism

Only treatment for hypothyroidism is the administration of thyroid extract or ingestion of pure thyroxine in the form of tablets, orally.

Functional status of thyroid gland is assessed by following tests:

1. Measurement of Plasma Level of T3 and T4

For hyperthyroidism or hypothyroidism, the most accurate diagnostic test is direct measurement of concentration of free thyroid hormones, T3 and T4 in plasma.

2. Measurement of TRH and TSH

TRH and TSH are almost absent in hyperthyroidism because of negative feedback mechanism, by increased level of thyroid hormones.

3. Measurement of Basal Metabolic Rate

Basal metabolic rate is increased by about 30 to 60% in hyperthyroidism and decreased by 20 to 40% in hypothyroidism.