The parathyroid glands are a group of endocrine glands located on the posterior thyroid. These glands are responsible for the secretion of parathyroid hormone (PTH), and play a role in calcium homeostasis. Typically, there are four glands divided into pairs - the superior parathyroid glands and the inferior parathyroid glands. The superior parathyroids generally are located superior to the inferior thyroid artery and posterolaterally to the recurrent laryngeal nerve, bilaterally. The inferior parathyroids are most commonly near the inferior pole of the thyroid and anteromedially to the recurrent laryngeal nerve, bilaterally. Branches of the inferior thyroid artery deliver arterial blood supply. Venous drainage is via the thyroid veins (superior, middle, inferior). The number and location of the parathyroid glands can be variable, with patients presenting with anywhere from three to eight parathyroid glands. Ectopic glands generally appear along the path of embryologic descent, within the carotid sheath, inside the thyroid gland, or within the superior mediastinum.
Embryologically, the parathyroid glands derive from the endoderm of the third and fourth pharyngeal pouches. The third pharyngeal pouch gives rise to the inferior parathyroid glands, while the superior parathyroids arise from the fourth pharyngeal pouch. Due to their relatively long course of descent, the final location of the inferior glands is more variable.
Much of the human head/neck development derives from the framework of the pharyngeal arches, which appear during the fourth to fifth weeks of development. There are a total of six pharyngeal arches, and the spaces between the arches are the pharyngeal clefts. The pharyngeal pouches develop due to lateral migration of the endoderm and present as outpouchings of the primitive pharynx. The first pharyngeal pouch contributes to the formation of the middle ear and the mastoids, while the second pharyngeal pouch forms the epithelial lining of the palatine tonsil. The third and fourth pouches are responsible for the development of the parathyroids, the thymus, and a portion of the thyroid gland. The pharyngeal pouches are derived from the endoderm, while the pharyngeal arches are composed of mesoderm, and the clefts are ectoderm.
Third Pharyngeal Pouch - The third pharyngeal pouch divides into dorsal and ventral wings. The dorsal wing gives rise to the inferior parathyroid gland, while the ventral wing leads to the formation of the thymus. The thymus loses its connection with the pharyngeal wall and descends inferomedially to fuse with the contralateral portion in the anterior mediastinum. In the seventh week of gestation, the inferior parathyroid glands separate from the posterior pharyngeal wall and follow the path of the thymus, to reach their final destination on the posterior thyroid.
Fourth Pharyngeal Pouch - The fourth pharyngeal pouch divides into dorsal and ventral wings. The dorsal wing differentiates into the superior parathyroid gland, while the ventral wing differentiates into the ultimobranchial body. The ultimobranchial bodies fuse with the posterolateral thyroid and give rise to the parafollicular C-cells of the thyroid. In the seventh week of development, the parathyroid glands separate from the pharyngeal wall and attach to the posterior surface of the thyroid. Due to the comparatively longer course, the final location of the inferior parathyroid is more variable, and ectopic parathyroid tissue can be found anywhere along their pathway of descent.
The parathyroid glands are composed of two cell types - chief cells and oxyphil cells.
Chief Cells - Chief cells are the functional cells of the parathyroids, responsible for the synthesis and secretion of PTH. During low-calcium states, a calcium-sensitive receptor (CaSR) on the surface of the parathyroid gland activates a G-protein messenger pathway, leading to PTH synthesis/secretion. During hypercalcemic states, this pathway becomes inhibited, leading to decreased PTH synthesis/secretion.
Oxyphil Cells - Oxyphil cells are poorly understood, and their function is unclear. Research has suggested that they produce/secrete PTH in cases of secondary hyperparathyroidism. They are larger than chief cells microscopically and become more abundant with increasing age.
Primary hyperparathyroidism (PHPT), according to recent studies, could be caused by an alteration during the development of the semaphorin3d glycoprotein (Sema3d). The latter regulates the excessive formation of cells of the parathyroid gland. If Sema3d is ineffective, it could be an important cause of PHPT development; glycoprotein works by inhibiting the epidermal growth factor receptor (EGFR)/Erb-B2 (receptor tyrosine kinase 2 or also known as HER2/neu).
Isolated parathyroid aplasia is caused by a mutation in the Glial cells missing (Drosophila) homolog b (GCM2) gene or by a mutation in the SRY-Box Transcription Factor 3 (SOX3) protein.
DiGeorge syndrome comes from a 22q11 chromosome aberration (chromosome 22q11.2123), from a loss of the Tbox transcription factor gene 1 (TBX1), an alteration of chromosome 10p13 containing the nebulette gene (NEBL) gene.
Hypoparathyroidism comes from an alteration of chromosome 8q12.2 with a lack of the chromodomain helicase DNA binding protein type 7 (CDH7) gene and the aberration of the gene encoding the semaphorin 3E protein (SEMA3E). Other variations of hypothyroidism concern an anomaly of chromosome 10p14-15, which will cause a haploinsufficiency of the GATA binding protein-3 gene (GATA3); an anomaly of chromosome 1q42–43 which contains the gene for the tubulin-specific protein chaperone E (TBCE); an aberration of the family with sequence similarity 111, member A (FAM111A) gene for DNA replication. Mutation of chromosome 11p15.3-p15.1 alters the function of the parathyroid hormone, as well as in the chromosomal area p.S23P and p.S23X. Other causes result from a mutation of mitochondrial development.
Pharyngeal pouch formation begins with lateral migration of the endoderm, and this process becomes stimulated by several fibroblast-growth-factors (FGFs). The predominant factors vary based on the location within the pouches - FGF8 expresses in the anterior region of each pouch, bone-morphogenic-protein-7 (BMP7) expresses in the posterior region, and paired-box-protein-1 (PAX1) expresses in the dorsal area of each pouch. In the second and third pouches, SHH (sonic-hedgehog-signaling-molecule) expresses in the posterior endoderm. Endodermal tissue migration is a key step in the development of the pharyngeal arches, neural crest cell migration, and the differentiation of skeletal structures in the head/neck.
Parathyroid Gland Physiology 
The parathyroid glands play a vital role in calcium homeostasis. They contain calcium-sensitive-receptors (CaSRs) that sense the level of serum calcium. In states of hypocalcemia, the glands increase the secretion of PTH to increase serum calcium. Increased serum phosphate, decreased levels of activated Vitamin D, and cases of minor hypomagnesemia also stimulate PTH secretion. Elevated serum calcium, low levels of serum phosphate, and severe hypomagnesemia lead to decreased PTH secretion.
Parathyroid Hormone (PTH) Physiology 
The initial synthesis of parathyroid hormone takes place within the parathyroid gland as pre-pro-PTH (a 115-amino-acid polypeptide). It is then cleaved into pro-PTH (90-amino-acids). A second cleavage leads to an 84-amino-acid mature PTH, with a half-life of approximately 3 minutes, allowing for rapid control of serum calcium. PTH exerts its effects primarily through action in the kidneys, bones, and the GI tract.
Ultrasound - Can be used to identify the parathyroid glands on the posterior thyroid. The parathyroids appear as small, oval masses on the posterior thyroid. They are comparatively homogenous and hypoechoic when compared to the thyroid, allowing for the identification of intra-thyroid parathyroid tissue. It is useful to screen for parathyroid adenomas. Normal parathyroid glands are approximately 5 mm in size and weigh 30 to 50 mg, while parathyroid adenomas are 1 to 2 cm in size, and weigh 500 to 1000 mg. Ultrasound has poor sensitivity for the identification of parathyroid hyperplasia.
Technetium-99 (sestamibi) Scan - Technetium-99 (99mTc) is a radiotracer used in nuclear medicine studies. It is also useful for myocardial perfusion scans, detection of breast cancer, detection of multi-drug resistance proteins in certain cancers, and identification of parathyroid tissue. It is particularly useful in the localization of ectopic parathyroid tissue. Technetium-99 is taken up by tissues with high metabolic activity and blood flow. In cases of primary hyperparathyroidism, normal parathyroid tissue undergoes suppression by negative feedback and will have low metabolic activity, while parathyroid adenomas/hyperplasia will not be suppressed and will have high metabolic activity. Therefore, abnormal parathyroid tissue will be demonstrated radiographically. Of note, The thyroid is often suppressed before sestamibi scanning to decrease its metabolic activity and 99mTc uptake.
4D CT Scan - This is a specialized imaging technique with higher sensitivity/specificity for parathyroid adenomas than sestamibi scanning. It has utility in identifying smaller adenomas (as small as 1mm x 6mm) It is particularly useful in false-negative sestamibi scans (identifying the abnormal gland in 80% of cases) and in patients needing reoperation, (identifying 91% of abnormal glands as compared to 45% for sestamibi scanning). 4D CT is the combination of standard CT scanning while evaluating contrast changes over time (the fourth 'dimension'). Often three phases are used, with pre-contrast, arterial phase, and delayed phases. Parathyroid adenomas have low attenuation in the pre-contrast phase, intense/maximal enhancement in the arterial phase, and rapid washout during the delayed phase. One-or-two phase protocols have been developed to reduce radiation exposure.
Hypoparathyroidism  - This can occur secondary to a variety of causes, most commonly following head/neck surgery, but can also occur due to abnormal parathyroid development, severe hypomagnesemia, autoimmune destruction of the parathyroids and other causes. This condition most commonly presents with symptoms of hypocalcemia, including perioral paresthesias, tetany/muscle cramps, and Chvostek's sign (facial muscle spasm in response to mechanical stimulation). In patients receiving bilateral thyroidectomy, low intraoperative PTH levels can be a good predictor for postoperative hypocalcemia.
DiGeorge Syndrome  - a development defect caused by a microdeletion at 22q11, which can lead to a failure of the development of the third and fourth pharyngeal pouches, affecting the thymus and parathyroid glands. Poor thymic development leads to abnormal immune system development and deficiencies in T-cells. Improper parathyroid gland development leads to hypocalcemia. Patients with DiGeorge Syndrome can also present with congenital cardiac defects (particularly of the outflow tracts), abnormal facial development, and cleft palates.
Multiple Endocrine Neoplasia - a rare, genetically inherited syndrome, leading to proliferative lesions in various endocrine organs. There are several forms defined by the genes involved, but all have an autosomal dominant inheritance pattern.
Ectopic Parathyroid Glands - These result from abnormal embryologic development and migration of the parathyroid glands. They occur in approximately 15% of patients and are the most common etiology of persistent/recurrent disease following surgical parathyroidectomy.  The inferior parathyroids are more likely to be ectopic, secondary to their prolonged course of descent during development. Ectopic superior parathyroids are most common in the tracheoesophageal groove (approximately 45%), retro-esophageal area (approximately 20%), or posterior mediastinum (approximately 15%). Ectopic inferior parathyroid glands most commonly present within the thymus (approximately 30%), the anterior mediastinum (approximately 20%), within the thyroid (approximately 20%), or within the thyrothymic ligament (approximately 15%).  Mediastinal ectopic glands >6cm below the superior clavicle will likely require a thoracic approach, but those less than 6 cm can undergo successful resection through a cervical approach. Other locations for ectopic tissue have been described, including a case of an adenoma anterior to the pericardium or within the sternohyoid muscles in a patient with MEN1. Some patients present with more than four parathyroid glands, often as a result of fragmentation during development. In a case study of patients with parathyroid hyperplasia who underwent surgical resection, 46% of patients possessed ectopic glands, supernumerary glands, or both.
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