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Home , Parafollicular cell, Thyroid follicular cell

Thyroid gland The gland is located in the anterior neck region adjacent to the larynx and trachea.

* The thyroid gland is - A bilobate located in the anterior neck region, - consists of two large lateral lobes connected by an isthmus, a thin band of thyroid tissue. - The two lobes, each approximately Each lateral lobe is 2 to 2.5 cm wide, 5 to 6 cm long, and 2 cm deep and normal weight of the adult thyroid is 15 to 25 g, - A pyramidal lobe (a vestige of the thyroglossal duct, is found in about 40% of ) often extends upward from the isthmus. ). - In women, the thyroid volume is known to increase during the secretory phase of the menstrual cycle. - The color of the normal thyroid is red “brown. - A thin connective tissue capsule surrounds the gland. . It sends trabeculae into the parenchyma that partially divide it into lobules (so-called thyromeres). - Thyroid follicles constitute the functional units of the gland. Thyroid

2 to 2.5 cm wide, 5 to 6 cm long, and 2 cm deep. 15 to 25 g The thyroid gland develops from the endodermal lining of the floor of the primitive pharynx.

- The thyroid gland begins to develop during the fourth week of gestation from a primordium originating as an endodermal thickening of the floor of the primitive pharynx. -The primordium grows caudally and forms a duct like invagination known as the thyroglossal duct. - The thyroglossal duct descends through the tissue of the neck to its final destination in front of the trachea, where it divides into two lobes. - During this downward migration, the thyroglossal duct undergoes atrophy, leaving an embryologic remnant, the pyramidal lobe of the thyroid. - About the ninth week of gestation, endodermal cells differentiate into plates of follicular cells that become arranged into follicles. - By week 14, well-developed follicles lined by the follicular cells contain colloid in their lumen. - During week 7, epithelial cells lining the invagination of the fourth branchial pouches (sometimes called the fifth branchial pouches), known as the ultimobranchial bodies, start their migration toward the developing thyroid gland and become incorporated into the lateral lobes. - After fusing with the thyroid, ultimobranchial body cells disperse among the follicles, giving rise to parafollicular cells (C cells). . PAX8, a transcription factor is involved in the maintenance of functional differentiation in follicular cells. . Thyroid transcription factor-1 (TTF1), also is expressed in the median thyroid anlage. * C cells are thought to derive from the and to migrate to the ultimobranchial bodies (UBBs) before the incorporation of the latter in the thyroid.

Blood and nerve supply of the thyroid gland The blood supply of the thyroid gland derives primarily from: - The inferior thyroid artery (originates from the thyrocervical trunk of the subclavian artery) and - The superior thyroid artery (arises from the external carotid). - The superior and medial thyroid veins and the inferior vein drain (via a venous plexus in the thyroid capsule) into the . internal jugular and . brachiocephalic vein, respectively. * lymphatic network, encircling the follicles and connecting the two lateral lobes through the isthmus. - It empties into Subcapsular channels, which in turn give rise to collecting trunks within the thyroid capsule in close proximity to the veins. * Vasomotor nonmedullated postganglionic neural fibers originating from the - Superior and midline cervical sympathetic ganglia influence indirectly the secretory activity of the thyroid gland through their action on the blood vessels. . Adrenergic receptors in follicular cells and a network of adrenergic fibers ending near the follicular . * It has been hypothesized, therefore, that thyroid secretion is regulated both by direct neural signals and by indirect vascular nerve signals. The thyroid follicle is the structural and functional unit of the thyroid gland. A thyroid follicle is a - Roughly spherical cystlike compartment with a wall formed by a simple squamous to columnar , the follicular epithelium. - Hundreds of thousands of follicles, diameter from about 0.2 to 1.0 mm. - The follicles contain a gel-like mass called colloid; . The colloid, which is pale eosinophilic in the actively secreting gland, acquires a deeply eosinophilic staining quality. . In some follicles the colloid may have an amphophilic or basophilic staining, increase in the amount of( acidic groups) in the TGB molecule. . The glycoproteic material present within the follicles stains for periodic acid- Schiff (PAS) and alcian blue and is immunoreactive for TGB. - A row of small vacuoles is seen at the interface between follicular epithelium and the colloid in actively functioning glands; . Resorption vacuoles. - The epithelial glandular cells lining the follicle are known as follicular cells or thyrocytes; among them, there is a C cells. - The apical surfaces of the follicular cells are in contact with the colloid, and the basal surfaces rest on a typical basal lamina. Thyroid gland. A overview of the thyroid shows its relationship to surrounding structures. Also visible are tracheal rings composed of hyaline cartilage tissue.

The colloid accumulated in these follicles exhibits different densities and tintorial qualities, the latter ranging from acidophilic to basophilic. The basophilic colloid present in most of these follicles contrasts with the more typical red colloid present in the follicles on the right upper corner. Inset: Alcian blue-PAS highlights the mucinous character of the basophilic colloid. Thyroid gland (a) H&E (LP) (b) Immunohistochemical method for CD34 Thyroid C cell H&E (HP) A second type of endocrine cell with the ultrastructural characteristics of neuroendocrine cells, the C cell or C, is found in the thyroid gland as individual scattered cells in the follicle lining or as small clumps in the interstices between follicles. They are particularly prominent in dogs, where they are identifiable in H&E sections as pale-staining cells with granular cytoplasm. In humans they are much less prominent and can usually only be identified ultrastructurally (see Fig. 17.9) and by immunohistochemical methods. These cells secrete , which is a physiological antagonist to parathyroid hormone and therefore lowers blood calcium levels by suppressing the osteoclastic resorption of . The epithelium of one follicle is low cuboidal and relatively inactive. The adjacent follicle shows a taller epithelium and reabsorption vacuoles. B. The epithelium of the same follicle is flattened on one side and cuboidal on the other, as an expression of functional polarization. Thyroid follicle:(a) Inactive, H&E (HP) (b) Active, H&E Thyroid follicle, rat EM ×6800 EM of a . The cell has a spherical euchromatic nucleus and many tightly packed organelles. Its basal aspect is close to a fenestrated capillary. Short stubby microvilli (arrows) project from its apical surface into a colloid-filled follicular lumen. Intercellular junctions (circles) link lateral borders of the cells, whose basal surfaces rest on an inconspicuous basal lamina (arrowheads). 14,000×. Follicular epithelium contains two types of cells: Follicular and parafollicular cells. - The parenchyma of the thyroid gland is composed of epithelium containing two types of cells: Follicular Cells (principal cells) The cells lining the follicles ”follicular cells or thyrocytes, are responsible for production of the T4 and T3. - ”Show variations in their shape and size according to the functional status of the gland. - Three major types: . Flattened cells are relatively inactive. . Cuboidal cells are the most numerous and their major function is to secrete colloid. . Columnar cells resorb the TGB-containing colloid, liberate the active hormones, and excrete these hormones into blood vessels. Ultrastructurally; - The follicular cells are arranged in a single layer around the colloid and rest on a basement membrane, approximately 35 to 40 nm in thickness , that separate them from the interstitial stroma. - Microvilli emanate from the surface of the cells, their number being increased and their length greater in actively functioning cells. - Cell membranes of adjacent cells interdigitate in a complex fashion and are joined by junctional complexes toward the apex. - The cytoplasm contains variable amounts of endoplasmic reticulum, mitochondria of usually small size, and lysosomes. Electron micrograph of follicular cells in rat thyroid gland.

The apical surfaces with visible microvilli (Mv) are in contact with the colloid, whereas basal surfaces of follicular cells rest on the basal lamina (FBL). A narrow extracellular connective tissue space separates the follicular cells from the lumen of the capillary. Note that the fenestrated endothelial cells (En) lining capillary lumen rest on the basal lamina (EBL). Accumulation of lysosomes (L) and colloid resorption droplets (CRD), extensive Golgi apparatus (G), rough endoplasmic reticulum (rER), and presence of enlarged intercellular spaces are indicative of intensive activity of follicular cells. Physiology Thyroid gland function is essential to normal growth and development. The thyroid gland produces three hormones, each of which is essential to normal metabolism and - Thyroxine (3,3,5,5-tetraiodothyronine, T4) and 3,3,5- (T3) are synthesized and secreted by the follicular cells. . These hormones regulate cell and tissue basal metabolism; - increase protein synthesis in every tissue of the body, and

- increase O 2 consumption. . Thyroid hormones are particularly important for body development and normal maturation of the central and peripheral nervous system. - Calcitonin (thyrocalcitonin) is synthesized by the parafollicular cells (C cells) and is a physiologic antagonist to parathyroid hormone (PTH). The principal component of colloid

- The principal component of colloid is a large (660 kilodalton) iodinated glycoprotein called containing about 120 tyrosine residues. . Thyroglobulin is not a hormone. - It is an inactive storage form of the thyroid hormones. - Several enzymes and other glycoproteins. - Active thyroid hormones are liberated from thyroglobulin and released into the fenestrated blood capillaries that surround the follicles only after further cellular processing. - The thyroid is unique among endocrine glands because it stores large amounts of its secretory product extracellularly. Synthesis of thyroid hormone involves several steps The synthesis thyroxine (T4) and T3 takes place in the thyroid follicle in a series of discrete steps : 1. Synthesis of thyroglobulin, in the rER and posttranslationally glycosylated in the rER and the Golgi apparatus before it is packaged into vesicles and secreted by exocytosis into the lumen of the follicle. 2. Resorption, diffusion, and oxidation of iodide. - transport iodide from the blood using ATPase-dependent sodium/iodide symporters (NIS) in the basolateral membrane. . intracellular concentration of iodide that is 30 to 40 times greater than that of the serum. . Iodide ions then diffuse rapidly toward the apical cell membrane. . From here iodide ions are transported to the lumen of the follicle by iodide/chloride transporter called at the apical cell membrane. - Iodide oxidized to , the active form of iodide. . This process occurs in the colloid and is catalyzed by membrane- bound (TPO). 3. Iodination of thyroglobulin. - One or two iodine atoms are then added to the specific tyrosine residues of thyroglobulin. .This process occurs in the colloid at the microvillar surface by thyroid peroxidase (TPO) To forms monoiodotyrosine (MIT) and a (DIT) residue. 4. Formation of T3 and T4 by oxidative coupling reactions. - The thyroid hormones are formed by oxidative coupling reactions of two iodinated tyrosine residues in close proximity. . DIT and MIT residues undergo a coupling reaction, T3 is formed; . two DIT residues react with each other, T4 is formed. - After iodination, T4 and T3 as well as the DIT and MIT residues that are still linked to a thyroglobulin molecule are stored as the colloid within the lumen of the follicle. 5. Resorption of colloid. In response to TSH, thyroglobulin follows at least two different intracellular pathways: Lysosomal pathway, - - Resorption of TGB takes place through cytoplasmic pseudopodia (streamers) that engulf colloid in the form of membrane-bound colloid droplets. . . Thyreoglobulin is internalized and transported within endocytotic vesicles to early endosomes. - They eventually mature into lysosomes or fuse with existing lysosomes. . Thyroglobulin is then degraded by lysosomal proteases into constituent amino acids and carbohydrates, leaving free T4, T3, DIT, and MIT molecules. - Under physiological condition, this is a major pathway of colloid resorption. Transepithelial pathway, - Thyroglobulin is transported intact from the apical to the basolateral surface of follicular cells. . To enter this pathway thyroglobulin binds to its receptor megalin, ( 330- kilodalton member of the LDL endocytic receptor family). . Thyreoglobulin internalized by megalin avoids the lysosomal pathway and endocytic vesicles are delivered to the basolateral membrane of follicular cells. * In pathologic conditions of high TSH or TSH-like stimulation, megalin expression is increased and large amounts of thyroglobulin follow the transepithelial pathway. - This pathway may reduce the extent of T4 and T3 release by diverting thyroglobulin away from the lysosomal pathway. - Patients with Graves’ and other thyroid diseases have detectable amounts of circulating thyroglobulin that contains portion of megalin receptor. - If the levels of TSH remain high, the amount of colloid in the follicle is reduced because it is synthesized, secreted, iodinated, and resorbed too rapidly to accumulate. 6. Release of T4 and T3 into the circulation and recycling processes. - Majority of T4 and T3 are liberated from thyroglobulin in the lysosomal pathway in a T4 to T3 ratio of 20:1. - They enter the blood and lymphatic capillaries. - Most of the released hormones are immediately bound to either a specific plasma protein, thyroxinbinding protein (TBG)(70%), or a prealbumin fraction of serum protein called transthyretin (20%). - T4 has a stronger bond to the TBG, whereas T3 has a stronger bond to transthyretin. - Approximately less than 10% of released hormones are bound to a nonspecific fraction of albumin, leaving only small amounts (1%) of free circulating hormones that are metabolically active. * Only the follicular cells are capable of producing T4, whereas most T3, which is five times more active than T4, is produced through conversion from T4 by organs such as the kidney, liver, and heart. * The free circulating hormones also function in the feedback system that regulates the secretory activity of the thyroid. Diagram of steps in thyroid hormone synthesis

Transport across the cell membrane is essential for thyroid hormone action and metabolism. - Thyroid hormones can enter the cell by simple diffusion. - Thyroid hormones are transported across cell membranes by several thyroid hormone transporter molecules. . Within the CNS, T3 and T4 are transported via the blood–brain barrier to the nerve and glial cells by the monocarboxylate transporter 8 (MCT8) and MCT10, as well as a family of organic anion transporting polypeptide (OATPs). - For example, the OATP1C1 transporter is exclusively expressed on the endothelial cells forming the blood–brain barrier and is responsible for T4 uptake to the brain. - The MCT8 is also found in heart, kidney, liver, and skeletal muscle. . Mutations in the MCT8 gene cause severe psychomotor and intellectual disability associated with high serum T3 levels in affected male patients, a condition known as the Allan–Herndon–Dudley syndrome. . Defected MCT8 transporters are unable to transport T3 into nerve cells, which disrupt normal brain development. - BecauseT3 is not utilized by nerve cells, excessive amounts of this hormone continue to circulate in the blood, causing signs and symptoms of thyroid hormone toxicity. The triiodothyronine (T3) hormone is more biologically active than thyroxine (T4). - Once T3 and T4 molecules enter the cell, they interact with a specific thyroid nuclear receptor. . T3 binds to nuclear receptors much faster and with higher affinity than T4, thus T3 is more rapidly and biologically active than T4. . T3 binds to mitochondria, increasing the production of ATP. - biological activity and metabolic effect of the thyroid hormone is largely determined by the intracellular concentration of T3. - Several factors impact the intracellular concentration of T3 include: . the conversion rate of T4 to T3 in the peripheral organs; . transport of thyroid hormones across the cell membrane by specialized thyroid hormone transporters; and . presence of iodothyronine deiodinase enzymes, which activate or inactivate thyroid hormones. -Two deiodinase enzymes called D1 and D2 convert T4 to the more active T3, whereas the third enzyme called D3 degrades T4 to the inactive form of rT3 (reverse T3) and DIT. - Both T3 and T4 are deiodinated and deaminated in the target tissues, conjugated in the liver, and then passed into the bile, where they are excreted into the intestine. - Conjugated and free hormones are also excreted by the kidney. Production, transport, and regulation of thyroid hormones. Thyroid hormones play an essential role in normal fetal development. - In humans, thyroid hormones are essential to normal growth and development. - In normal pregnancy, both T3 and T4 cross the placental barrier and are critical in the early stages of brain development. - The fetal thyroid gland begins to function during the 14th week of gestation and also contributes additional thyroid hormones. - Thyroid hormone deficiency during fetal development results in irreversible damage to the central nervous system (CNS), causing reduced numbers of neurons, defective myelination, and mental retardation. - If maternal thyroid deficiency is present before the development of the fetal thyroid gland, the mental retardation is severe. - Thyroid hormones also stimulate gene expression for GH in the somatotropes. - Therefore, in addition to neural abnormalities, a generalized stunted body growth is typical. - The combination of these two abnormalities is called congenital hypothyroidism. Clinical Pointe - Iodine deficiency. Sea water is rich in iodine salts and in some countries supplements of iodine salts are added to table salt. - In some parts of the world, particularly those distant from a salty sea, there may be insufficient intake of iodine in the diet to provide adequate levels of thyroid hormones. . In such cases, TSH levels in blood increase, the thyroid undergoes hypertrophy and a swelling in the neck, known as a goitre, develops. Clinical Pointe - (toxic goiter/Graves disease): . Autoantibodies stimulate follicular cells to release excess amount of thyroid hormones resulting in thyroid hypertrophy (goiter), protrusion of the eyeballs, increased metabolism, weight loss, tachycardia, etc. - Hypothyroidism: Reduced thyroid hormone production due to . lack of iodine or autoantibodies that triggers apoptosis of follicular cells resulting in thyroid hypertrophy (goiter), weight gain, and mental and physical sluggishness. CLINICAL POINT The most frequent cause of primary hypothyroidism is; - the autoimmune disorder Hashimoto thyroiditis (chronic lymphocytic thyroiditis). - More common in women than in men and often associated with type 1 diabetes, celiac disease, and other autoimmune conditions, symptoms are painless enlargement of thyroid, reduced metabolic rate, and mental lethargy. - In genetically predisposed people, high iodine intake, deficiency, and certain pollutants are implicated in the pathogenesis. - Circulating antibodies against thyroid antigens (e.g., peroxidase, thyroglobulin, TSH receptors) lead to follicular cell apoptosis by infiltrating cytotoxic T cells, formation of lymphoid follicles, and gradual glandular destruction. - In response to chronic inflammation, many enlarged and metaplastic follicular cells (known as Hürthle cells) possess eosinophilic granular cytoplasm caused by accumulation of altered mitochondria. - Thyroid hormone replacement therapy helps alleviate symptoms. Parafollicular cells (C cells) Parafollicular cells (C cells) 0.1% of the glandular mass of the thyroid gland. - They have a neuroendocrine function . - C cells are located, individually or in small groups, within thyroid follicles. . within its basement membrane and without contact with the follicular lumen, produce of the peptide hormone CT (calcitonin), a hormone that regulates . - C cells are restricted to the midupper and upper thirds of the lateral lobes. - C cells appear polygonal and with a granular weakly eosinophilic cytoplasm that is larger and paler than that of follicular cells. . The nucleus is round to oval, pale, with a centrally located nucleolus. . C cells occupy an intrafollicular (rather than interfollicular) position, and that they are separated from the thyroid interstitium by the follicular basal lamina. . The parafollicular cells reveal numerous small secretory vesicles, 130 to 550 nm, and a prominent Golgi apparatus. * An extensive network of fenestrated capillaries derived from the superior and inferior thyroid arteries surrounds the follicles. * Blind-ended lymphatic capillaries provide a second route. Clusters of C cells in the thyroid of an elderly individual with no known clinical or laboratory evidence of calcium disturbance Immunoperoxidase stain for CT demonstrates C cells within follicles, arranged either individually or in small groups. Electron micrograph of thyroid showing 2 calcitonin producing parafollicular cells and part of a thyroid follicle. Note 2 blood capillaries at both sides of the parafollicular cells Electron micrograph of a calcitonin producing cell. Note the small secretory granules (SG) and the scarcity of rough endoplasmic reticulum (RER). G, Golgi region. x5000. Calcitonin (thyrocalcitonin) is synthesized by the parafollicular cells (C cells) and is a physiologic antagonist to parathyroid hormone (PTH). - CT is a 32 “amino acid peptide whose main function is the regulation of the level of calcium in the plasma by a feedback mechanism. - brought about by the inhibition of osteoclastic activity. - When calcium plasma levels are increased, CT is released from the thyroid. - CT also acts in the kidney to enhance the production of vitamin D. - Both gastrin and cholecystokinin induce the secretion of CT, as does the chronic administration of estrogenic hormones. - In normal male adults, basal CT levels range from 3 to 36 pg/ml (0.9 to 10.5 pmol/L) Plasma levels in females range from 3 to 17 pg/ml (0.9 to 5.0 pmol/L). * Normal values after stimulation are less than 106 pg/ml (30.9 pmol/L) for males and less than 29 pg/ml (8.5 pmol/L) for females. * Katacalcin, the C-terminal flanking peptide of CT, is a 21 “amino acid peptide that is cosecreted with CT in equimolar amounts. - Its function, (may be involved in both plasma calcium regulation and skeletal maintenance and thus may prove useful in the treatment of bone disease). * Calcitonin gene related peptide (CGRP) is a 37 “amino acid peptide that is an extremely potent vasodilator and can function in the transmission of pain (serves a neuromodulator or neurotransmitter function). Parathyroid glands The parathyroid glands; - are small endocrine glands closely associated with the thyroid. -They are ovoid, each adult gland measures 3 to 6 mm in length, 2 to 4 mm in width, and 0.5 to 2.0 mm in thickness and arranged in two pairs, - Constituting the superior and inferior parathyroid glands. - They are usually located in the connective tissue on the posterior surface of the lateral lobes of the thyroid gland. - (90%) to 97% of individuals, have four parathyroid glands. . the number has been reported to vary between two and 12 glands However, the number and location may vary. . In 2% to 10% of individuals, additional glands are associated with the thymus.

- Diagram demonstrating the location of the parathyroid glands. Parathyroid glands develop from the endodermal cells derived from the third and fourth branchial pouches. - Embryologically, the inferior parathyroid glands (and the thymus) are derived from the third branchial pouch; - the superior glands, from the fourth branchial pouch. - Normally, the inferior parathyroids separate from the thymus.. . Failure of these structures to separate results in the atypical association of the parathyroids with the thymus in the adult. - The principal (chief ) cells differentiate during embryonic development and are functionally active in regulating fetal calcium metabolism. - The oxyphil cells differentiate later at puberty. . By 17 to 20 weeks abundant parathyroid hormone is present in the glands. - Transcription factors, Hoxa3, Pax9, Tbx1, GATA3, Glial cell missing (Gcm) 2, and Eyes absent (Eya)1, found in the third pharyngeal pouch. Diagram of normal pharyngeal organ development. The superior parathyroid glands and ultimobranchil body derives from the 4th pharyngeal pouch. The inferior parathyroid glands originate from the 3rd pharyngeal pouch along with the thymus. Immunohistochemical stain demonstrating PTH in the gland of a 20-week fetus A fetal parathyroid (33 weeks' gestation) is seen between the thymus (top) and lower edge of the thyroid ( bottom ). A small amount of stroma surrounds the parathyroid vessels. The gland is composed of pure tightly packed chief cells. Histology of

- Each parathyroid gland is surrounded by a thin connective tissue capsule that separates it from the thyroid. - Septa extend from the capsule into the gland to divide it into poorly defined lobules and to separate the densely packed cords of cells. - The connective tissue is more evident in the adult, with the development of fat cells that increase with age and ultimately constitute as much as 60% to 70% of the glandular mass. - The glands receive their blood supply from the inferior thyroid arteries or from anastomosis between the superior and inferior thyroid arteries. . Typical of endocrine glands, rich networks of fenestrated blood capillaries and lymphatic capillaries surround the parenchyma of the parathyroids. - Nerve bundles in close proximity to chief cells suggest autonomic innervation. - With age, there is focally increasing collagenization of the perivascular stroma. Surrounding the capillaries and lymphatics are interstitial cells that consist of fibroblasts, pericytes, mast cells, and a few lymphocytes. - Adipocytes are sparse in the stroma of infants and children. - Adipocytes occupy an average of 50% of the stromal volume. - Women have a higher percentage of stromal fat than do men. - Each parenchymal cell is separated from the stroma by a prominent basement membrane. Parathyroid gland H&E LM of the parathyroid in the midsagittal plane. A delicate connective tissue capsule sends in trabeculae to penetrate the parenchyma and divide it into irregular lobules. Blood vessels are abundant. With age, numerous fat cells intermingle with parenchyma.20×. H&E.

LM of part of the parathyroid. Organization of the parenchyma and stroma is seen. Blood vessels (BV), nerves, and fat cells occupy the stroma. Parenchymal cells form irregular, poorly defined lobules. Chief cells predominate and are arranged in cords; nests of oxyphils either mingle with chief cells or are in separate lobules. 70×. H&E.

LM of the outer part of the parathyroid. A capsule surrounding the organ sends in a trabecula that conveys blood vessels (BV) to the interior. Most of the parenchyma consists of tightly packed chief cells (shown at higher Nephrolithiasis in hyperparathyroidism. magnification in the inset). 400×; inset: 650×. Plastic section, toluidine blue. Sheets of chief cells in a newborn. The stroma has little collagen and is outside the large sheet. The cell membranes are poorly demarcated. The cytoplasm is eosinophilic. parathyroid gland from a 7.5-month-old girl. The chief cells are the only cell type seen and are arranged in sheets, between the large vascular channels. The capillaries are present between individual chief cells. The chief cells show central regular nuclei and a clear amphophilic cytoplasm. A thin fibrous capsule separates the gland from the stroma A parathyroid gland from a 21-year-old male just below the thyroid gland capsule in the thyroid parenchyma. A large accumulation of adipocytes is present within the parathyroid. Only chief cells are seen within the parathyroid. Photomicrograph of a parathyroid from a 39-year-old man. There is abundant stromal fat separating the cords of chief cells. A parathyroid from a 76-year-old man. There is a moderate amount of stromal fat, largely in the center of the gland. Small oxyphil nodules are present A parathyroid from a 77-year-old man with abundant stromal fat. The parenchyma is composed entirely of chief cells. Nests and cords of oxyphil cells and chief cells among the adipocytes of the stroma Principal cells and oxyphil cells constitute the epithelial cells of the parathyroid gland. - There are two types of parenchymal cells recognized by light microscopy in the adult normal parathyroid gland. . Principal cells (chief cells) the more numerous of the parenchymal cells of the parathyroid, are responsible for regulating the synthesis, storage, and secretion of large amounts of PTH. in their active and inactive forms, and . the oxyphil cell . Principal (chief cells) are arranged in sheets, cords, trabeculae, small nodules and pseudofollicles. - They are small, polygonal cells, with a diameter of 7 to 10 µm. - The cytoplasm is amphophilic or faintly eosinophilic, with 70 to 80% of the chief cells containing large prominent fat droplets. 1. The resting phase, or inactive chief cell, is characterized by accumulation of glycogen and lipid bodies ( vacuolated clear appearance), lysosomes, sacs of granular endoplasmic reticulum are dispersed, free ribosomes partially aggregated into polysomes, small Golgi apparatus,, with few vacuoles and prosecretory granules. . The cell membranes are straight with few interdigitations. 2. The synthetic phase is marked by the parallel aggregation of the cistern of rough granular endoplasmic reticulum, and the granules correspond to the location of PTH, and chromogranin. . The cell cytoplasm in the synthetic and secretory phases becomes depleted of glycogen and lipid bodies. - The nuclei are round, centrally located, have small rare nucleoli. - The normal adult gland has 70 to 80% of the chief cells in the resting phase, and the normal prepubertal gland has 30 to 40% in the resting phase. - Proliferation of parathyroid chief cells is controlled by the ambient ionized [Ca 2+ ], and may be via depression of cyclins D1 and D2. Chief cells with intracytoplasmic lipid droplets (Oil-Red-O stain, hematoxylin Trabecula of parathyroid showing mixture of oxyphil and chief cells Numerous pseudofollicles in a normal parathyroid of a 58-year-old white man. Lining the pseudofollicles are chief cells. At the right of the micrograph is the edge of an oxyphil cell nodule Chief cells showing abundant PTH in the parathyroid gland. Note the variation in the amount of hormone in various chief cells. (Immunoperoxidase stain for PTH, hematoxylin counterstain.) Parathyroid gland showing abundant chromogranin in the chief cells. The chief cells have different amounts of chromogranin. The oxyphil cells are free of chromogranin Inactive chief cell in the parathyroid gland of a cat. The cytoplasm contains few secretory granules (S), a small Golgi apparatus (G), sparse endoplasmic reticulum (ER), scattered mitochondria (M), and glycogen particles (arrow). The extracellular perivascular space is bordered by the basement membranes of the capillary endothelial and chief cells and contains collagen fibers. Active chief cells in the parathyroid gland from a young (9-week-old) cat. By comparison, the cytoplasm of chief cells in the active stage of the secretory cycle contains numerous secretory granules (S), scattered profiles of rough endoplasmic reticulum (ER), numerous free ribosomes, Golgi apparatuses (Go associated with prosecretory granules and vacuoles, and scattered mitochondria (M). Scanning electron micrograph of the secretory surface of active chief cells in the parathyroid gland illustrating secretory granules (arrowheads) budding into the perivascular space. Chief cells are polyhedral, and distinct cell boundaries can be visualized (arrows). (original magnification x 3000) Subcellular compartmentalization, transport, and cleavage of precursors of parathyroid hormone (PTH). Preproparathyroid hormone (pre-proPTH) is the initial translation product from ribosomes of the rough endoplasmic reticulum, which is rapidly converted to pro-parathyroid hormone (proPTH). The hydrophobic sequence on the amino-terminal end of the pre-proPTH facilitates penetration of the leading portion of the nascent peptide into the lumen of the endoplasmic reticulum. ProPTH is transported to the Golgi apparatus where it is converted enzymatically by a carboxypeptidase (CPase) to biologically active PTH. A major portion of the biosynthetic precursors and active PTH is degraded by Iysosomal enzymes and is not secreted by chief cells under normal conditions. Parathyroid secretory protein (PSP) may function as a binding protein for PTH during intracellular storage in secretion granules and may be released with PTH into the extracellular space. (Habener JF, Potts JT Jr: Biosynthesis of parathyroid hormone. Diagram of the secretory cycle of the parathyroid chief cells (derived from electron microscopic studies * Oxyphil cell - Felt to be derived from the chief cells. - Beginning at puberty and increasing throughout life. - They are distributed among the chief cells as individual cells, sheets, and small or large nodules. - Continual transformation from the chief cells and clonal proliferation of the oxyphil cells. - contain only minimal PTH or chromogranin. - Mitochondropathy, which may lead to the proliferation of the mitochondria within the cells. - The oxyphil cell measures 12 to 20 µm in diameter and has a clearly demarcated cell membrane, a pyknotic nucleus, and abundant eosinophilic granular cytoplasm, rich in mitochondria and resembling the Hurthle cells of the thyroid or the oncocytes of other endocrine organs, occasional lysosomes and lipofuscin granules. Oxyphil cells of the parathyroid in an 80-year-old woman. The centrally located, variably sized , pyknotic nuclei are seen within the granular eosinophilic cytoplasm. The cell membranes and the vascular channels are easily visible. Oxyphil cell with large cytoplasmic area packed with numerous mitochondria and containing a small irregular nucleus (N). These metabolically altered parathyroid cells have a small Golgi apparatus (G) and few secretory granules (arrow), displaced to the periphery of the cell by the numerous mitochondria. (original magnification x 6000) Parathyroid hormone regulates calcium and phosphate levels in the blood. - The parathyroids function in the regulation of calcium and phosphate levels. - Parathyroid hormone (PTH) is essential for life. - Care must be taken during thyroidectomy to leave some parathyroid tissue. . If the glands are totally removed, death will ensue because muscles, including the laryngeal and other respiratory muscles, go into tetanic contraction as the blood calcium level falls. - PTH is an 84–amino acid linear peptide. . It binds to a specific PTH receptor on target cells that interacts with G protein to activate a second-messenger system. - PTH release causes: . increase the level of calcium in the blood to. . Simultaneously, it reduces the concentration of serum phosphate. - Secretion of PTH is regulated by the serum calcium level through a simple feedback system. . calcium-sensing receptors on principal cells detect low serum calcium levels, they stimulate secretion of PTH; high levels of serum calcium inhibit its secretion. PTH functions at several sites: Action on bone tissue. - The , the major effect of PTH action on bone. - PTH acts directly and indirectly on several cell types. - Receptors for PTH are found on osteoprogenitor cells, osteoblasts, osteocytes, and bone lining cells. . Surprisingly, the bone- resorbing do not have PTH receptors; . They are indirectly activated by the RANK RANKL signaling mechanism of osteoblasts. . The binding of PTH to its receptors on osteoblasts increases local RANKL Production and decreases osteoprotegerin (OPG). . These stimulate differentiation, which increased bone resorption and release of calcium and phosphates into the extracellular fluid. - PTH also has an anabolic effect on bone that leads to increased bone mass; therefore, it is utilized in the treatment of osteoporosis. - Kidney excretion of calcium is decreased by PTH stimulation of tubular reabsorption, thus conserving calcium. - Urinary phosphate excretion is increased by PTH secretion, thus lowering phosphate concentration in the blood and extracellular fluids. - Kidney conversion of 25-OH vitamin D3 to hormonally active 1,25-(OH)2 vitamin D3 is regulated primarily by PTH, which stimulates activity of 1-hydroxylase and increases the production of active hormone. - Intestinal absorption of calcium is increased under the influence of PTH. - Vitamin D3, has a greater effect than PTH on intestinal absorption of calcium.

Parathyroid Hormone PTH and calcitonin have reciprocal effects in the regulation of blood calcium levels. - Although PTH increases blood calcium levels, the peak increase after its release is not reached for several hours. . PTH appears to have a rather slow, long-term homeostatic action. - Calcitonin, however, rapidly lowers blood calcium levels and has its peak effect in about 1 hour; therefore, . It has a rapid, acute homeostatic action. Clinical pointe Parathyroid Hormone - A similar protein to PTH, PTH-related peptide (PTHrP), is chronically secreted in small amounts by cells in other locations (e.g., skin, atrial heart muscle, Epiphyseal cartilage, mammary glands, bone marrow). . The physiologic significance of the peptide in normal circumstances seems to be relatively small. . When tissues become cancerous, they often secrete excessive amounts of PTHrP that severely damage the skeleton. - This so-called malignant hypercalcemia can be found in as many as 20% of cancer patients and is a serious complication of cancer. Disorders of the parathyroid gland * The parathyroid glands may either overwork, producing excessive PTH (hyperparathyroidism) or underwork, producing little or no hormone (hypoparathyroidism). - The commonest cause of hyperparathyroidism is a benign tumour of one of the parathyroid glands () which constantly produces excessive PTH, unresponsive to normal feedback mechanisms related to the blood calcium levels. - The excess parathormone stimulates excessive osteoclastic erosion of bone, with the release of bone calcium into the blood to produce hypercalcaemia. - The results include bone pain with X-ray abnormalities and an increased risk of kidney stones. . This pattern is called primary hyperparathyroidism. - Secondary hyperparathyroidism is a secondary response of all the parathyroid glands to a persistent low serum calcium level in patients with kidney failure who are constantly losing calcium in their urine. . The feedback mechanism is triggered and all of the parathyroids become enlarged (parathyroid hyperplasia) and secrete excess PTH in an attempt to bring the serum calcium level back to normal. - Tertiary hyperparathyroidism occurs when the hyperplastic glands of secondary hyperparathyroidism cease to respond to serum calcium levels. . The glands secrete high levels of PTH autonomously. - Hypoparathyroidism is rare and is usually due to inadvertent surgical removal of all parathyroid glands during total thyroidectomy.

Electron micrograph of a follicle showing follicular cells (FC) , colloidal material (Co) and capillaries (Ca) Parathyroid gland: (a) H&E (MP) (b) H&E LM of part of the parathyroid at high magnification. Features of the two main types of parenchymal cells are seen. Chief cells are spherical and have pale cytoplasm with a central, round nucleus. Oxyphils are larger and more eosinophilic, each with a small dark nucleus. The stroma contains abundant blood vessels, most being sinusoidal capillaries that are in close contact with parenchymal cells and many being filled with erythrocytes. 300×. H&E.

Ultrastructure of parathyroid gland. A parathyroid from a 27-year-old woman showing only sheets of chief cells and no stromal fat. The vascular pole can be seen at the right margin of the micrograph. A thin fibrous capsule is seen A parathyroid gland of a 77-year-old man. The stroma is almost completely replaced by adipocytes. There is a large oxyphil cell nodule in the center of the gland. A parathyroid from a 69-year-old woman. There is a moderate amount of stromal fat, largely concentrated in the center of the gland. A few small oxyphil nodules can be seen in the parenchyma. A normal parathyroid from a 70-year-old woman showing almost no stromal fat or oxyphil cells Hypothalamic adenohypophyseal thyroid interaction