The thyroid gland is controlled by the hypothalamus and pituitary (to be specific, the anterior pituitary). The thyroid gland gets its name from the Greek word for "shield", after the shape of the related thyroid cartilage. The most common problems of the thyroid gland consist of an over-active thyroid gland, referred to as ' hyperthyroidism', and an under-active thyroid gland, referred to as ' hypothyroidism'.

The thyroid gland is a butterfly-shape organ and is composed of two cone-like lobes or wings, lobus dexter (right lobe) and lobus sinister (left lobe), connected via the isthmus . The organ is situated on the anterior side of the neck, lying against and around the larynx and trachea , reaching posteriorly the oesophagus and carotid sheath. It starts cranially at the oblique line on the thyroid cartilage (just below the laryngeal prominence, or ' Adam's Apple'), and extends inferiorly to approximately the fifth or sixth tracheal ring. It is difficult to demarcate the gland's upper and lower border with vertebral levels because it moves position in relation to these during swallowing.

The thyroid gland is covered by a fibrous sheath, the capsula glandulae thyroidea , composed of an internal and external layer. The external layer is anteriorly continuous with the lamina pretrachealis fasciae cervicalis and posteriorolaterally continuous with the carotid sheath. The gland is covered anteriorly with infrahyoid muscles and laterally with the sternocleidomastoid muscle also known as sternomastoid muscle. On the posterior side, the gland is fixed to the cricoid and tracheal cartilage and cricopharyngeus muscle by a thickening of the fascia to form the posterior suspensory ligament of Berry. The thyroid gland's firm attachment to the underlying trachea is the reason behind its movement with swallowing. In variable extent, Lalouette's Pyramid, a pyramidal extension of the thyroid lobe, is present at the most anterior side of the lobe. In this region, the recurrent laryngeal nerve and the inferior thyroid artery pass next to or in the ligament and tubercle.

Between the two layers of the capsule and on the posterior side of the lobes, there are on each side two parathyroid glands.

The thyroid isthmus is variable in presence and size, and can encompass a cranially extending pyramid lobe ( lobus pyramidalis or processus pyramidalis ), remnant of the thyroglossal duct. The thyroid is one of the larger endocrine glands, weighing 2-3 grams in neonates and 18-60 grams in adults, and is increased in pregnancy.

The thyroid is supplied with arterial blood from the superior thyroid artery, a branch of the external carotid artery, and the inferior thyroid artery, a branch of the thyrocervical trunk, and sometimes by the thyroid ima artery, branching directly from the brachiocephalic trunk. The venous blood is drained via superior thyroid veins, draining in the internal jugular vein, and via inferior thyroid veins, draining via the plexus thyroideus impar in the left brachiocephalic vein.

Lymphatic drainage passes frequently the lateral deep cervical lymph nodes and the pre- and parathracheal lymph nodes . The gland is supplied by parasympathetic nerve input from the superior laryngeal nerve and the recurrent laryngeal nerve.

Evolution

Thyroid cells phylogenetically derived from primitive iodide-concentrating gastroenteric cells ( endostyle) which, during evolution, migrated and specialized in uptake and storage of iodine in follicular cellular structures, also in order to adapt the organisms from iodine-rich sea to iodine-deficient land. Venturi et al.suggested that iodide has an ancestral antioxidant function in all iodide-concentrating cells from primitive Algae to more recent Vertebrates. In 2008, this ancestral antioxidant action of iodides has been experimentally confirmed by K??pper et al.. Since 700 million years ago thyroxine is present in fibrous exoskeletal scleroproteins of the lowest invertebrates (Porifera and Anthozoa), without showing any hormonal action. When some primitive marine Chordates started to emerge from the iodine-rich sea and transferred to iodine-deficient fresh water and finally land, their diet became iodine deficient. Therefore, during progressive slow adaptation to terrestrial life, the primitive vertebrates learned to use the primitive thyroxine in order to transport antioxidant iodide into the cells. So, the remaining triiodothyronine (T3), the real active hormone, became active in the metamorphosis and thermogenesis for a better adaptation of the organisms to terrestrial environment ( fresh water, atmosphere, gravity, temperature and diet ). In fact, the U.S. Food and Nutrition Board and Institute of Medicine recommended daily allowance of iodine ranges from 150 micrograms /day for adult

humans to 290 micrograms /day for lactating mothers. However, the thyroid gland needs no more than 70 micrograms /day to synthesize the requisite daily amounts of T4 and T3. These higher recommended daily allowance levels of iodine seem necessary for optimal function of a number of body systems, including lactating breast, gastric mucosa, salivary glands, oral mucosa, thymus, epidermis, choroid plexus and brain, etc..

Embryological development

In the fetus, at 3???4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue between the tuberculum impar and the copula linguae at a point latter indicated by the foramen cecum . The thyroid then descends in front of the pharyngeal gut as a bilobed diverticulum through the thyroglossal duct. Over the next few weeks, it migrates to the base of the neck. During migration, the thyroid remains connected to the tongue by a narrow canal, the thyroglossal duct.

Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) start being secreted from the fetal hypothalamus and pituitary at 18-20 weeks of gestation, and fetal production of thyroxine (T₄) reach a clinically significant level at 18???20 weeks. Fetal triiodothyronine (T₃) remains low (less than 15 ng/dL) until 30 weeks of gestation, and increases to 50 ng/dL at term. Fetal self-sufficiency of thyroid hormones protects the fetus against e.g. brain development abnormalities caused by maternal hypothyroidism. However, preterm births can suffer neurodevelopmental disorders due to lack of maternal thyroid hormones due their own thyroid being insufficiently developed to meet their postnatal needs.

The portion of the thyroid containing the parafollicular C cells, those responsible for the production of calcitonin, are derived from the 4th pharyngeal pouch endoderm. This is first seen as the ultimobranchial body, which joins the primordial thyroid gland during its descent to its final location in the anterior neck.

Histology

At the microscopic level, there are three primary features of the thyroid:| '''Feature''' || '''Description

	Follicles	The thyroid is composed of spherical follicles that selectively absorb iodine (as iodide ions, I-) from the blood for production of thyroid hormones, but also for storage iodine in thyroglobulin, in fact iodine is necessary for other important iodine-concentrating organs as breast, stomach, salivary glands, thymus etc. (see iodine in biology). Twenty-five percent of all the body's iodide ions are in the thyroid gland. Inside the follicles, colloid serve as a reservoir of materials for thyroid hormone production and, to a lesser extent, act as a reservoir for the hormones themselves. Colloid is rich in a protein called thyroglobulin.
Thyroid epithelial cell|Thyroid epithelial cells (or "follicular cells")	The follicles are surrounded by a single layer of thyroid epithelial cells, which secrete triiodothyronine|T3 and thyroxine|T4. When the gland is not secreting T3/T4 (inactive), the epithelial cells range from low columnar to cuboidal cells. When active, the epithelial cells become tall columnar cells.
Parafollicular cells (or "C cells")	Scattered among follicular cells and in spaces between the spherical follicles are another type of thyroid cell, parafollicular cells, which secrete calcitonin.

Disorders of the thyroid gland fall into the following categories:

Hyperthyroidism

Hyperthyroidism, or overactive thyroid, is the overproduction of the thyroid hormones T3 and T4, and is most commonly caused by the development of Graves' disease, an autoimmune disease in which antibodies are produced which stimulate the thyroid to secrete excessive quantities of thyroid hormones. The disease can result in the formation of a toxic goiter as a result of thyroid growth in response to a lack of negative feedback mechanisms. It presents with symptoms such as a thyroid goitre, protruding eyes ( exopthalmos), palpitations, excess sweating , diarrhea, weight loss, muscle weakness and unusual sensitivity to heat.

Beta blockers are used to decrease symptoms of hyperthyroidism such as increased heart rate , tremors, anxiety and heart palpitations, and anti thyroid drugs are used to decrease the effect of thyroid hormones, in particular, in the case of Graves' disease. These medications take several months to take full effect and have side-effects like skin rash or a drop in white blood cell count, which decreases the ability of the body to fight off infections. These drugs involve frequent dosing (often one pill every 8 hours) and often require frequent doctor visits and blood tests to monitor the treatment, and may sometimes lose effectiveness over time. Due to the side-effects and inconvenience of such drug regimens, some patients choose to undergo radioactive iodine 131 treatment. Radioactive iodine is administered in order to destroy a proportion of or the entire thyroid gland, since the radioactive iodine is selectively taken up by the gland and gradually destroys the cells of the gland. Alternatively, the gland may be partially or entirely removed surgically, though iodine treatment is usually preferred since the surgery is invasive and carries a risk of damage to the parathyroid glands or the nerves controlling the vocal cords . If the entire thyroid gland is removed, hypothyroidism results.

Hypothyroidism

Hypothyroidism is the underproduction of the thyroid hormones T3 and T4. Hypothyroid disorders may occur as a result of congenital thyroid abnormalities, autoimmune disorders such as Hashimoto's thyroiditis, iodine insufficiency, especially in poorer countries, or the removal of the thyroid following surgery to treat severe hyperthyroidism. Typical symptoms are abnormal weight gain, tiredness, baldness, temperature intolerance (both heat and cold), and palpitation. Individuals with thyroid gland underactivity may require hormone replacement therapy , which is typically required for the rest of the patient's life. Thyroid hormone treatment is given under the care of a physician and may take a few weeks to become effective.

Negative feedback mechanisms result in growth of the thyroid gland when thyroid hormones are being produced in sufficiently low quantities as a means of increasing the thyroid output; however, where the hypothyroidism is caused by iodine insufficiency, the thyroid is unable to produce T3 and T4 and as a result, the thyroid may continue to grow to form a non-toxic goiter. It is termed non-toxic as it does not produce toxic quantities of thyroid hormones, despite its size.

Initial hyperthyroidism followed by hypothyroidism

This is the overproduction of T3 and T4 followed by the underproduction of T3 and T4. There are two types: "Hashimoto's Thyroiditis" and "Postpartum Thyroiditis".

Hashimoto's thyroiditis is an autoimmune disorder whereby the body's own immune system reacts with the thyroid tissues . At the beginning, the gland is overactive, and then becomes underactive as the gland is destroyed resulting in too little thyroid hormone production or hypothyroidism. Hashimoto's is most common in middle-age females and tend to run in families. Also more common in individuals with hashimoto's thyroiditis are type 1 diabetes and celiac disease .

Postpartum thyroiditis occurs in some females following delivery. The gland gets inflamed and the condition initially presents with over activity of the gland followed by under activity. In some cases, the gland does recover with time and resume its functions.

Cancers

Cancers do occur in the thyroid gland and are more common in females. In most cases, the thyroid cancer presents as a painless mass in the neck. It is very unusual for the thyroid cancers to present with symptoms, unless it has been neglected. One may be able to feel a hard nodule in the neck. Diagnosis is made using a needle biopsy and various radiological studies.

Non-cancerous nodules

Many individuals may find the presence of small masses ( nodules ) in the neck. The majority of these thyroid nodules are benign (non cancerous). The presence of a thyroid nodule does not mean one has thyroid disease. Most thyroid nodules do not cause any symptoms, and most are discovered on an incidental exam. Doctors usually perform a needle aspiration biopsy of the thyroid to determine the status of the nodules. If the nodule is found to be non-cancerous, no other treatment is required. If the nodule is suspicious then surgery is recommended..

Seasonal Aggravation

Limited research shows that seasonal allergies may trigger episodes of hypo- or hyperthyroidism.

The primary function of the thyroid is production of the hormones triiodothyronine (T3), thyroxine (T4), and calcitonin. Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is several times more powerful than T4, which is largely a prohormone, perhaps four

T3 and T4 production and action

Thyroxine (T4) is synthesised by the follicular cells from free tyrosine and on the tyrosine residues of the protein called thyroglobulin (Tg). Iodine is captured with the "iodine trap" by the hydrogen peroxide generated by the enzyme thyroid peroxidase (TPO) Thyroid hormones that are secreted from the gland is about 80-90% T4 and about 10-20% T3.

Cells of the brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain maturation during fetal development. A second transport protein ( MCT8 ) is important for T3 transport across brain cell membranes.

Non-genomic actions of T4 are those that are not initiated by liganding of the hormone to intranuclear thyroid receptor. These may begin at the plasma membrane or within cytoplasm. Plasma membrane-initiated actions begin at a receptor on the integrin alphaV beta3 that activates ERK1/2. This binding culminates in local membrane actions on ion transport systems such as the Na(+)/H(+) exchanger or complex cellular events including cell proliferation. These integrins are concentrated on cells of the vasculature and on some types of tumor cells, which in part explains the proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on some cancers including gliomas. T4 also acts on the mitochondrial genome via imported isoforms of nuclear thyroid receptors to affect several mitochondrial transcription factors. Regulation of actin polymerization by T4 is critical to cell migration in neurons and glial cells and is important to brain development.

T3 can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alpha V beta3.

In the blood, T4 and T3 are partially bound to thyroxine-binding globulin (TBG), transthyretin, and albumin . Only a very small fraction of the circulating hormone is free (unbound) - T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. As with the steroid hormones and retinoic acid , thyroid hormones cross the cell membrane and bind to intracellular receptors (??₁, ??₂, ??₁ and ??₂), which act alone, in pairs or together with the retinoid X-receptor as transcription factors to modulate DNA transcription.

T3 and T4 regulation

The production of thyroxine and triiodothyronine is regulated by thyroid-stimulating hormone (TSH), released by the anterior pituitary. The thyroid and thyrotropes form a negative feedback loop : TSH production is suppressed when the T4 levels are high. The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones ( estrogen and testosterone), and excessively high blood iodide concentration.

An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cells produce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid ( thyroidectomy), but not the parathyroids.

Thyroid function laboratory tests - normal ranges

! Test || Abbreviation || Normal ranges

	'''Serum thyrotropin/thyroid-stimulating hormone'''	'''TSH'''	'''0.3???3.0 ??U/ml
'''Free thyroxine'''	'''FT4'''		'''7???18 ng/l = 0.7???1.8 ng/dl
'''Serum triiodothyronine'''	'''T3'''	'''0.8???1.8 ??g/l = 80???180 ng/dl
'''Radioactive iodine-123 uptake'''	'''RAIU'''	'''10???30%
Radioiodine scan (gamma camera)	N/A	N/A - thyroid contrasted images
Free thyroxine fraction	FT4F	0.03???0.005%
Serum thyroxine	T4	46???120 ??g/l = 4.6???12.0 ??g/dl
Thyroid hormone binding ratio	THBR	0.9???1.1
Free thyroxine index	FT4I	4???11
Free triiodothyronine l	FT3	230???619 pg/d
Free T3 Index	FT3I	80???180
Thyroxine-binding globulin	TBG	12???20 ug/dl T4 +1.8 ??g
TRH stimulation test	Peak TSH	9???30 ??IU/ml at 20???30 min.
Serum thyroglobulin l	Tg	0-30 ng/m
Thyroid microsomal antibody titer	TMAb	Varies with method
Thyroglobulin antibody titer	TgAb	Varies with method

• ??U/ml = mU/l, microunit per milliliter

• ng/dl, nanograms per deciliter

• ??g, micrograms

• pg/d, picograms per day

• ??IU/ml = mIU/l, micro-international unit per milliliter

• See for more information on medical units of measure

Significance of iodine

In areas of the world where iodine is lacking in the diet the thyroid gland can become considerably enlarged, a condition called 'endemic goitre'. Pregnant women on a diet that is severely deficient of iodine can give birth to infants who can present with thyroid hormone deficiency, manifesting in problems of physical growth and development as well as brain development (a condition referred to as 'endemic cretinism'), and is one cause of congenital hypothyroidism. In many developed countries, newborns are routinely tested for congenital hypothyroidism as part of newborn screening. Children with congenital hypothyroidism are treated supplementally with levothyroxine, which facilitates normal growth and development.

Thyroxine is critical to the regulation of metabolism and growth throughout the animal kingdom. Among amphibians, for example, administering a thyroid-blocking agent such as propylthiouracil (PTU) can prevent tadpoles from metamorphosing into frogs; in contrast, administering thyroxine will trigger metamorphosis.

Because the thyroid concentrates this element, it also concentrates various radioactive isotopes of iodine produced by nuclear fission. In the event of large accidental releases of such material into the environment, the uptake of radioactive iodine isotopes by the thyroid can, in theory, be blocked by saturating the uptake mechanism with a large surplus of non-radioactive iodine , taken in the form of potassium iodide tablets. One consequence of the Chernobyl disaster was an increase in thyroid cancers in children in the years following the accident.

The use of iodised salt is an efficient way to add iodine to the diet. It has eliminated endemic cretinism in most developed countries, and some governments have made the iodination of flour, cooking oil, and salt mandatory. Potassium iodide and sodium iodide are typically used forms of supplemental iodine.

As with most substances, either too much or too little can cause problems. Recent studies on some populations are showing that excess iodine intake could cause an inceased prevelence of autoimmune thyroid disease , resulting in permanent hypothyroidism.

There are several findings that evidence a great interest for thyroid disorders just in the Medieval Medical School of Salerno (12th century). Rogerius Salernitanus , the Salernitan surgeon and author of "Post mundi fabricam" (around 1180) was considered at that time the surgical text par excellence all over Europe. In the chapter "De bocio" of his magnum opus, he describes several pharmacological and surgical cures, some of which nowadays are reappraised quite scientifically effective.

In modern times, the thyroid was first identified by the anatomist Thomas Wharton (whose name is also eponymised in Wharton's duct of the submandibular gland) in 1656.

Thyroxin was identified only in the 19th century.

The thyroid gland is found in all vertebrates. In fish, it is, in general, located below the gills and is not always divided into distinct lobes. However, in some teleosts, patches of thyroid tissue are found elsewhere in the body, associated with the kidneys, spleen, heart, or eyes.

In tetrapods, the thyroid is always found somewhere in the neck region. In most tetrapod species, there are two paired thyroid glands - that is, the right and left lobes are not joined together. However, there is only ever a single thyroid gland in most mammals, and the shape found in humans is common to many other species.

In larval lampreys, the thyroid originates as an exocrine gland, secreting its hormones into the gut, and associated with the larva's filter-feeding apparatus. In the adult lamprey, the gland separates from the gut, and becomes endocrine, but this path of development may reflect the evolutionary origin of the thyroid. For instance, the closest living relatives of vertebrates, the tunicates and Amphioxus, have a structure very similar to that of larval lampreys, and this also secretes iodine-containing compounds (albeit not thyroxine).

Image:Illu endocrine system.jpg|Position of the Thyroid in Males and Females
Image:illu08_thyroid.jpg|
Image:Gray384.png|Section of the neck at about the level of the sixth cervical vertebra.
Image:Gray386.png|Muscles of the neck. Anterior view.
Image:Gray505.png|The arch of the aorta, and its branches.
Image:Gray507.png|Superficial dissection of the right side of the neck, showing the carotid and subclavian arteries.
Image:Gray561.png|Diagram showing common arrangement of thyroid veins.
Image:Gray994.png|Sagittal section of nose mouth, pharynx, and larynx.
Image:Gray1031.png|Muscles of the pharynx, viewed from behind, together with the associated vessels and nerves.
Image:Gray1032.png|The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
Image:Gray1176.png|Section of 
thyroid gland of sheep. X 160.
Image:Gray1178.png|The thymus of a full-term fetus, exposed in situ.
Image:Thyoid-histology.jpg|Thyoid histology

• Thyroid disease

• Academy of Clinical Thyroidologists

• EndocrineWeb.com for more information on thyroid disease, hormones, and surgery

• American Thyroid Association (Thyroid Information and professional organization)

• "Thyroid Gland"