Many homeostatic processes that occur within the body are dependent on various supporting hormonal systems for efficient functioning. The thyroid gland is an endocrine organ located in the neck that participates in a myriad of systemic processes. The effects of the hormones it produces can be seen throughout all systems in the body.
Thyroid hormones are able to diffuse freely across cell membranes. They can then enter the nucleus of the cell and bind to thyroid hormone receptors (which exist as a heterodimer that is attached to another receptor). The thyroid receptor hormone then activates a transcription pathway specific to the cell line it is located in. Consequently, the mRNA is translated and the synthesized protein will have its desired effect within that system.
|Function||Secretes thyroid hormones that regulate body metabolism (T3, T4) and calcium homeostasis (calcitonine)|
|Anatomy||Left lobe, right lobe, isthmus, pyramidal lobe (may be absent)|
Cells: thyrocytes (synthesize thyroglobulin from which T3 and T4 are released), parafollicular (C) cells (secrete calcitonine)
Functional unit: thyroid follicle - central lumen filled with colloid (storage of thyroglobuline) surrounded by thyrocytes and C-cells
|Endocrine control||Increased TRH (hypothalamus) -> increased TSH (pituitary gland) -> increased synthesis thyroid hormones (->decreased TRH - negative feedback loop)|
Arteries: superior and inferior thyroid arteries
Veins: superior, middle and inferior thyroid veins
|Innervation||Cervical ganglion (sympathetic), recurrent laryngeal nerve (parasympathetic)|
|Clinical relations||Ectopia, adult thyroid disease|
The goal of this article is to discuss the embryology, anatomy, brief histology, and neurovascular supply of the thyroid gland. Further details regarding thyroid hormone synthesis and the key functions of the gland will also be addressed. Discussion of disorders of the thyroid gland can be found in a subsequent article.
The pharyngeal apparatus is responsible for the formation of numerous parts of the head and neck region . During the 3rd gestational week, there is hypertrophy of the endoderm in the midline of the primitive pharynx, arising from the first pharyngeal arch between the tuberculum impar and copula; at a point later referred to as the foramen caecum. This thyroid primordium subsequently enlarges and is attached to the floor of the primitive pharynx by a hollow tube known as the thyroglossal duct. The duct communicates with the foramen caecum, which is caudal to the tuberculum impar (median tongue bud) and rostral to the copula (hypobranchial eminence). The thyroid primordium progresses to a thyroid placode located at the base of the tongue ; which subsequently forms the thyroid diverticulum near the apical pole of the aortic sac.
The thyroid diverticulum then begins its descent towards its final pretracheal destination, passing anterior to the laryngeal cartilages and hyoid bone . During this course, it maintains connection with the floor of the primitive pharynx via the thyroglossal duct. Under normal circumstances, the thyroglossal duct will degenerate and the diverticulum remains suspended in mesenchyme. The solid structure is invaded by vascular mesenchyme, which results in disruption of the solid cellular arrangement. Subsequently, the cells arrange themselves into a web of epithelial cords. The gland regains contact with the aortic sac and subsequently bifurcates. This process is associated with rapid, thyroid stimulating hormone (TSH)-independent, proliferation of the thyroid progenitor cells.
During the 5th week of gestation, the ultimobranchial body (arising from the 4th pharyngeal arch) fuses with the thyroid gland. Prior to this, the ultimobranchial body, which is an endodermal derivative, is invaded by neural crest cells. These cells give rise to the C-cells that participate in calcium homeostasis by producing calcitonin under hypocalcemic circumstances. A structure known as the tubercle of Zuckerkandl is the only remaining structure at the point where the two primitive structures merged. This tubercle can be seen in most adults at the posterior aspect of the gland. It is of clinical significance during thyroidectomies, as the nerve has a close relationship to the recurrent laryngeal nerve.
Around the 7th gestational week, the gland continues to enlarge and the left and right lobes begin to form on either side of the thyroid cartilage in the proximal trachea . They are attached to each other by the thyroid isthmus. In the 10th gestational week, the epithelial cords cluster together into smaller groups. The cells aggregate around a lumen in a single layer and form thyroid follicles. In the 11th week, cellular differentiation occurs that results in the onset of thyroglobulin production and colloid can be seen in the thyroid follicles. By the 20th week, TSH levels begin to rise, resulting in production of thyroid hormones. In the final trimester adult levels of thyroid hormone can be observed in the fetus and the cellular proliferation responds to TSH.
The thyroid gland is a butterfly shaped, vascular, red-brown endocrine gland situated in the midline of the anterior neck. Under normal circumstances, it extends from the level of the 5th cervical vertebra (C5) to the first thoracic vertebra (T1). On average, the gland weighs between 15 to 25 g, and is the largest of the endocrine glands.
The irregular structure is encased in the pretracheal part of the deep cervical fascia . It is made up of a central isthmus that connects the right and left lobes of the organ inferomedially. Between the ages of 8 months to 15 years, the thyroid gland appears the same in both males and females. However, the gland is slightly heavier in females over the age of 15 than in male counterparts of similar age.
Each lobe is roughly conical in shape, with each apex pointing superolaterally and their bases inferomedially (between the 4th and 5th tracheal rings). At their widest point, each lobe measures about 3 cm in the transverse plane, and 2 cm in the anteroposterior dimension. The lobes are roughly 5 cm long. The isthmus lies above the 2nd or 3rd tracheal cartilages and measures 1.25 cm in both the transverse and vertical planes. In some individuals, there may be a third lobe of the thyroid gland known as the pyramidal lobe. It is also a conical structure that extends from the isthmus up to the hyoid bone. In some cases, it may also arise from the inferomedial aspect of either left or right lobes; but it is more commonly seen arising from the left lobe.
The major laryngeal cartilages provide a scaffold for the thyroid gland. Posteromedially, the gland is attached by the lateral thyroid ligaments to the cricoid cartilage. Additionally, the levator glandulae thyroideae (levator of the thyroid gland), which is a fibromuscular structure, also anchors the isthmus or pyramidal lobe to the hyoid bone.
Recall that the neck can be subdivided into paired anterior and posterior triangles. The anterior triangles are formed in the midline by an imaginary line called the median line of the neck that transects the symphysis menti (mandibular symphysis), laterally by the medial border of sternocleidomastoid and superiorly by the inferior border of the mandible . The thyroid gland occupies the inferior part of both anterior triangles.
It is covered by the overlying skin and very little subcutaneous tissue. Beneath the skin is the superficial cervical fascia, which covers and blends with the aponeurosis of the platysma muscle . The investing cervical fascia covers the superficial muscles of the neck, while the pretracheal fascia invests the thyroid gland and other neck viscera.
There are several neck muscles that course over the anterior surface of the thyroid gland. The sternothyroid forms the immediate anterior relation and more anteriorly lie the superior belly of the omohyoid muscles and sternohyoideus; while fibres of the anterior border of sternocleidomastoid course over the anteroinferior region of the gland. They sternohyoid muscle also wraps around the lateral convexity of the gland as well, thus limiting the superior poles of the thyroid gland from projecting on the thyrohyoid muscle. The superior poles of the gland also come into close proximity with the inferior pharyngeal constrictors. Additionally, it is separated from the lamina of the thyroid cartilage as well as the cricoid cartilage by the posterior part of the cricothyroid muscle.
Medially, the gland is related with larynx and trachea and is fixed to the cricoid cartilage, along with the first two tracheal rings, by the suspensory ligament of Berry. The cricothyroid muscles and the inferior constrictors of the pharynx are the medial muscular relations. The external laryngeal nerve passes by the gland along this border as well. Both the recurrent laryngeal nerve and the trachea are posteroinferiorly related to the medial border of the thyroid gland.
The carotid sheath can be found near the posterolateral border of the gland. The anterior branch of the superior, and the inferior, thyroid arteries are related to the anterior and posterior borders of the thyroid gland, respectively. Another important structure that has a posteroinferior relationship to the left lobe of the thyroid gland is the thoracic duct . Additionally, the parathyroid glands are often embedded in the superior and inferior extents of the gland as well.
Unlike other endocrine glands that secrete their products directly into the bloodstream, the thyroid gland stores its products in follicles. The follicles are often clustered together to form numerous lobules that forms the parenchyma of each lobe of the thyroid. The lobules are also separated by septae, which are formed by invading parts of surrounding fibrous capsule. The septae also act as a conduit for neurovascular and lymphatic structures to traverse the gland. Each follicle is formed by either simple low columnar or cuboidal epithelium surrounding a central lumen. When the gland is in a dormant state, the epithelium may also be squamous.
Thyrocytes (follicular cells) are noted to have a rounded nucleus, and relatively large numbers of organelles (mitochondria, rough endoplasmic reticulum, Golgi bodies, etc.) in-keeping with its function (i.e. protein synthesis and secretion). The rough endoplasmic reticula are more abundant towards the base of the cells, while the Golgi bodies are found towards the apex.
Inadvertently, newly synthesized thyroglobulin, which is temporarily stored in the Golgi apparatus, to be exocytosed into the lumen once the vesicle reaches the cell apex. Apical pole of these cells contains several microvilli. Thyroglobulin is stored as a semi-solid entity known as colloid within the lumen of the follicle. It is one of the key histological features observed on light microscopy, as it stains bright pink with haematoxylin and eosin (H&E). Apically, thyrocytes have numerous zonula occludens (tight junctions), zonula adherens (anchoring junctions), and macula adherentes (spot desmosomes) that holds the cells together.
The basal lamina on which thymocytes reside also function as a scaffold for the parafollicular (C cells) that are also found in the thyroid gland. These endocrine cells are slightly larger, and appear paler (takes up less H&E), than the thyrocytes. They also have numerous organelles to support their function of synthesizing and secreting calcitonin, to assist in maintaining calcium homeostasis.
Although chiefly occupied by thymocytes and parafollicular cells, the stroma of the thyroid gland also contains sparse reticular connective tissue . Additionally, there is also a vast network of fenestrated capillaries that are available to carry thyroid hormones to their main circulation so that they can be distributed systemically.
The superior thyroid artery (arising from the external carotid artery) and the inferior thyroid artery (originating from the thyrocervical branch of the subclavian artery) bring oxygenated, nutrient rich blood to the thyroid gland. Inconsistently, there is also the arteria thyroidea ima that arises directly from the brachiocephalic trunk that also supplies the gland.
There are numerous points of intraglandular and periglandular anastomoses between the large vessels and their branches. The superior thyroid artery divides on the gland into an anterior branch that travels towards isthmus and posterior branch that goes down the back of the lobe. They anastomose with ascending branch of inferior thyroid artery. The inferior thyroid artery divides outside the pretracheal fascia into 4-5 branches that pierce the fascia and reach the lower pole of the gland to supply.
It is of great importance that the surgeon is aware of the very close relationship between the superior thyroid artery and the external laryngeal nerve. This nerve is very close to the artery at the superior pole. Additionally, the recurrent laryngeal nerve is most often related to the posterior branch of the inferior thyroid artery. Damage to the either nerve is associated with serious complications.
Bifurcation of the superior thyroid artery occurs after the vessel pierces the pretracheal fascia to enter the gland. It forms anterior and posterior branches that perfuse the anterior, and lateral and medial, surfaces, respectively. The inferior thyroid artery also bifurcates into ascending (superior) and inferior branches as it approaches the inferior pole of the thyroid gland. They supply the posterior and inferior surfaces.
The venous tributaries of this organ coalesce to form superior, middle and inferior thyroid veins. The first of the three vessels arise from the upper pole of the thyroid gland and travels alongside the similarly named artery. It courses towards the carotid sheath and subsequently drains into the internal jugular vein. The middle thyroid vein exits from the lateral side of the gland, bringing deoxygenated blood from the inferior part of the gland and also drains into the internal jugular vein.
There is a glandular venous plexus that allows communication between the superior and middle thyroid veins. This pretracheal plexus subsequently gives rise to the inferior thyroid vein. On the left side, the inferior thyroid vein drains to the left brachiocephalic vein . On the right, the inferior thyroid vein takes an oblique course, crosses over the right brachiocephalic artery and may either join the right brachiocephalic vein, or drain directly into the superior vena cava.
The sympathetic ganglion chain is a bilaterally paired series of autonomic nerve fibers and their associated cell bodies that is situated on either side of the vertebral column. It is subdivided into cervical, thoracic, lumbar and sacral parts. Both sympathetic ganglia terminate as the coccygeal ganglion at the coccyx.
The cervical sympathetic ganglion is further subdivided into superior, middle and inferior ganglia. The largest of the three ganglia is the superior ganglion; extending from C1 to C3. The middle ganglion most frequently occurs at C6, and the inferior ganglion can be found at the C7-T1 junction. While all three ganglia provide autonomic innervation to the thyroid gland and its vasculature, the inferior ganglion also forms a plexus around the inferior thyroid artery. This plexus also interacts with the both external and recurrent laryngeal nerves, which also provides parasympathetic innervation to the gland as well.
The lymphatic plexus that arises from the thyroid gland also communicates with the tracheal lymphatic plexus. They drain to the Delphian (prelaryngeal) lymph nodes that reside above the thyroid isthmus. There is also subsequent drainage to the paratracheal and pretracheal lymph nodes as well. There is also evidence supporting lymphatic drainage from the thyroid gland to the brachiocephalic lymph nodes near the thymus.
The deep cervical lymph nodes receive lymph from the lateral part of the gland. This fluid is carried by lymph channels that travel along the superior thyroid vein. There are also other lymph vessels arising from the thyroid that bypass all lymph nodes and drain directly into the thoracic duct .
Thyroid hormone synthesis is governed by the hypothalamus . When circulating levels of thyroid hormone is low, the hypothalamus releases thyrotropin releasing hormone (TRH). This hormone then travels to the anterior pituitary glan , where it promotes the release of thyroid stimulating hormone (TSH). TSH enters the bloodstream and travels to the thyroid gland, where it upregulates the transcription and translation of thyroglobulin. The thyroglobulin is packaged by the Golgi body in vesicles, which are exocytosed. The compound is then temporarily stored in the follicular lumen.
Iodine is also important for the production of thyroid hormones. Iodine is provided by dietary means and is concentrated within the cells via basolateral sodium-iodide (Na+-I-) symporters. Iodide within the thyrocytes are then pumped into the follicular lumen via pendrin pumps (apically located iodide-chloride (I--Cl-) pumps). Also, the excess sodium is pumped back into systemic circulation by Na+-K+ ATPase pumps.
At the luminal surface of the follicular cells, iodide is oxidized by peroxidase bound to the microvilli to iodine; which is then used for the organification of the tyrosine moiety of the thyroglobulin protein. The resulting monoiodotyrosine (MIT) can be further organified to diiodotyrosine (DIT). In the presence of thyroperoxidase, MIT and DIT, or two DIT molecules react to form triiodothyronine (T3) or thyroxine (T4), respectively.
The newly synthesized thyroid hormones are still bound to thyroglobulin. This allows the hormones to re-enter the cells by receptor mediated endocytosis. The thyroglobulin part of the molecule will bind to their respective apical receptors and are engulfed by the cells. Alternatively, colloid can be taken up by pinocytosis and re-enter the cell.
Once the vesicle is within the cell, they fuse with other lysosomal vesicles and the protein moiety is degraded by the lysosomal proteases. The remaining T3 and T4 are then released at the basolateral aspect of the cell to be taken up by the fenestrated capillaries. Within the blood, they are bound to albumin, thyroxine-binding globulin (TBG) or thyroxine-binding prealbumin (TBPA) and transported to their target sites. Note that the endocytotic processes may also take up MIT and DIT compounds as well. These can be recycled within the cell and secreted in the follicular lumen for further hormone synthesis.
When the serum levels of thyroid hormones increase, they act at the level of the pituitary gland and hypothalamus to inhibit release of TRH and TSH. Therefore, the hypothalamic-pituitary-thyroid axis operates under a negative feedback mechanism in order to maintain homeostasis. Majority of the hormone released from the gland is in the T4 form. However, at the level of the target cells almost all of the T4 is converted to T3, which is utilized for various metabolic processes.
At a cellular level, the hormones promote an increase in the total number of mitochondria within the cell, as well as the total surface area of the mitochondria as well. This increase in the quantity of mitochondria also corresponds directly to the increased metabolic rate observed in the organism.
Also at the cellular level, the thyroid hormones cause an increase in the rate of active transport of ions across cellular membranes. This is achieved by increasing the activity of the sodium-potassium adenosine triphosphatase (Na=-K+ ATPase) enzyme, which enhances the transportation rate of the respective ions. This energy dependent activity is also supported by the aforementioned increase in metabolic rate of the organism (i.e. increased ATP production).
It is interesting to note that the thyroid gland is one of the first endocrine organs to begin functioning in utero. The aforementioned cellular changes along with other tissue specific functions of the thyroid hormone have been shown to promote growth and development. It encourages the absorption and metabolism of carbohydrates, as evidenced by increased absorption of carbohydrates from the gastrointestinal tract, optimization of glycolysis and gluconeogenesis, and increased activity of insulin. Furthermore, there is mobilization of lipids from their fat stores resulting in a decrease in the amount of triglycerides, cholesterol, and phospholipids have also been observed with increased thyroid hormone levels. Majority of the cholesterol is excreted in feces (via bile). These events, as well as other tissue specific activities result in an increase in the basal metabolic rate of the organism.
In the cardiovascular system, the thyroid hormones have been shown to increase the rate and force of contraction of the heart , and by extension, the overall cardiac output. It has been proposed that this phenomenon is linked to the increased oxygen demand associated with the increased metabolic rate of the organism. The increased blood flow is also necessary to dissipate the excess heat generated from the metabolic reactions that are occurring. The organism’s respiratory function also increases as there is a need to excrete the excess carbon dioxide (as well as to obtain more oxygen) generated by the heightened metabolic processes.
Within the musculoskeletal system, the thyroid hormones promote the reaction of muscle fibres to the neurotransmitters. Consequently, the muscle fibres respond more vigorously with acceptable elevations in thyroid hormones. On the other hand, a decrease in the thyroid hormones would be associated with a reduced muscular response to the neurotransmitters. These hormones also have excitatory effects within the central nervous system ; promoting either anxiety or depression with elevated or depressed hormone levels, respectively.
The effects of the hormone also extends to sexual reproduction; such that patients may experience loss of libido, impotence (in men), or disorders of the menstrual cycle (menorrhagia, polymenorrhea, oligomenorrhea, or amenorrhea). Lastly, other endocrine glands are also affected by the activity of thyroid hormones. Thyroid hormones alter the negative feedback mechanisms of other endocrine glands by increasing the demand for other hormones at the target tissue level. For example, by enhancing the metabolism of glucocorticoid hormones at the liver result in lower circulating levels of the hormones. This is detected by the adrenal glands, which responds by increasing the production of glucocorticoids.
Developmental abnormalities of the thyroid gland arise from the pharyngeal pouch abnormalities. An ectopic thyroid is one of the most common anomalies.
This occurs when thyroid tissue is found anywhere along the path of migration from the foramen cecum and not with the thyroid as a whole in its final destination. It can often be the only tissue with follicular and parafollicular cells and the thyroid as a whole can be completely absent. These remnants are still susceptible to thyroid diseases. The most common locations listed in order from the greatest include:
- a lingual thyroid
- a sublingual thyroid
- a thyroglossal duct remnant
- a thyroid in the anterior mediastinum
- a prelaryngeal thyroid
- an intralingual thyroid
- an intratracheal thyroid
Adult Thyroid Diseases
Adult diseases of the thyroid include:
- Hashimoto’s thyroiditis