Parathyroid hormone

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Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates serum calcium and phosphate through its actions on the bone, kidneys, and small intestine. PTH increases serum calcium levels and is counteracted by calcitonin. Additionally, it promotes the synthesis of calcitriol, the active form of vitamin D.<ref>Template:Cite book</ref>

PTH influences bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time. PTH is secreted in response to low blood serum calcium (Ca²⁺) levels. PTH indirectly stimulates osteoclast activity within the bone matrix (osteon), in an effort to release more ionic calcium (Ca²⁺) into the blood to elevate a low serum calcium level. The bones store calcium from which the body can release into the blood as needed as needed to keep the amount of calcium in the blood at appropriate levels despite the ever-present challenges of metabolism, stress, and nutritional variations. PTH is the trigger for the bones to release the stored calcium into the blood.

PTH is secreted primarily by the chief cells of the parathyroid glands. The gene for PTH is located on chromosome 11. It is a polypeptide containing 84 amino acids, which is a prohormone. It has a molecular mass around 9500 Da.<ref name="pmid4509319">Template:Cite journal</ref>

There are two types of PTH receptors. Parathyroid hormone 1 receptors, activated by the 34 N-terminal amino acids of PTH, are present at high levels on the cells of bone and kidney. Parathyroid hormone 2 receptors are present at high levels on the cells of central nervous system, pancreas, testes, and placenta.<ref>Template:Cite book</ref> The half-life of PTH is about 4 minutes.<ref name="pmid12324490">Template:Cite journal</ref>

Disorders that yield too little or too much PTH, such as hypoparathyroidism, hyperparathyroidism, and paraneoplastic syndromes can cause bone disease, hypocalcemia, and hypercalcemia. Template:TOC limit

StructureEdit

hPTH-(1-84) crystallizes as a slightly bent, long, helical dimer. The extended helical conformation of hPTH-(1-84) is the likely bioactive conformation.<ref name="pmid10837469">Template:Cite journal</ref> The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

File:The ribbon cartoon structure.png

Helical dimer structure of hPTH-(1-34)<ref name="pmid10881197">Template:PDB; Template:Cite journal</ref>

FunctionEdit

Regulation of serum calciumEdit

File:Parathyroid Hormone Negative Feedback.svg

The parathyroid gland releases PTH which keeps calcium in homeostasis.

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File:Calcium balance 2.jpg

A diagrammatic representation of the movements of calcium ions into and out of the blood plasma (the central square labeled PLASMA Ca²⁺) in an adult in calcium balance:
The widths of the red arrows indicating movement into and out of the plasma are roughly in proportion to the daily amounts of calcium moved in the indicated directions.
The size of the central square in not in proportion to the size of the diagrammatic bone, which represents the calcium present in the skeleton, and contains about 25,000 mmol (or 1 kg) of calcium compared to the 9 mmol (360 mg) dissolved in the blood plasma.
The differently colored narrow arrows indicate where the specified hormones act, and their effects (“+” means stimulates; “-“ means inhibits) when their plasma levels are high.
PTH is parathyroid hormone, 1,25 OH VIT D₃ is calcitriol or 1,25 dihydroxyvitamin D₃, and calcitonin is a hormone secreted by the thyroid gland when the plasma ionized calcium level is high or rising.
The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.<ref name="pmid25287933" /><ref name="Brini">Template:Cite book</ref><ref name="Walter">Template:Cite book</ref><ref name="guyton">Guyton A (1976). ‘’Medical Physiology’’. p.1062; New York, Saunders and Co.</ref><ref name="ganong">Template:Cite book</ref>

Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the intestine:<ref name="pmid15180028">Template:Cite journal</ref>

In bone, PTH enhances the release of calcium from the large reservoir contained in the bones.<ref>Template:Cite journal</ref> Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of osteoprotegerin (OPG). Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates osteoclast precursors, which are of a monocyte lineage, to fuse. The resulting multinucleated cells are osteoclasts, which ultimately mediate bone resorption. Estrogen also regulates this pathway through its effects on PTH. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.<ref name="pmid12633785">Template:Cite journal</ref>

In the kidney, around 250 mmol of calcium ions are filtered into the glomerular filtrate per day. Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60–70%, of it in the proximal tubule), except in the thin segment of the loop of Henle.<ref name="pmid25287933">Template:Cite journal</ref> Circulating parathyroid hormone only influences the reabsorption that occurs in the distal tubules and the renal collecting ducts<ref name="pmid25287933" /> (but see Footnote<ref group="nb">This reduction in the rate of calcium excretion via the urine is a minor effect of high parathyroid hormone levels in the blood. The main determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration itself. The plasma parathyroid hormone (PTH) concentration only increases or decreases the amount of calcium excreted at any specified plasma ionized calcium concentration. Thus, in primary hyperparathyroidism, the quantity of calcium excreted in the urine per day is increased despite the high levels of PTH in the blood, because hyperparathyroidism results in hypercalcemia, which increases the urinary calcium concentration (hypercalcuria) despite the moderately increased rate of calcium reabsorption from the renal tubular fluid caused by PTH's direct effect on those tubules. Renal stones are, therefore, often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid "stones".<ref name="pmid25287933" /><ref name=Harrison>Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> </ref>). A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption of phosphate (HPO₄²⁻) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized.<ref name="pmid6623048">Template:Cite journal</ref><ref name="pmid8915965">Template:Cite journal</ref> A third important effect of PTH on the kidney is its stimulation of the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.<ref name=stryer>Template:Cite book</ref>

Via the kidney, PTH enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D₃ 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca²⁺ ions) by the intestine via calbindin.

PTH was one of the first hormones to be shown to use the G-protein adenylyl cyclase second messenger system.

Regulation of serum phosphateEdit

PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney,<ref>Template:Cite book</ref> which means more phosphate is excreted through the urine.

However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The result of PTH release is a small net drop in the serum concentration of phosphate.

Vitamin D synthesisEdit

PTH upregulates the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.

Interactive pathway mapEdit

Template:VitaminDSynthesis WP1531

Regulation of PTH secretionEdit

Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. Parathyroid cells express calcium-sensing receptors on the cell surface. PTH is secreted when [Ca²⁺] is decreased (calcitonin is secreted when serum calcium levels are elevated). The G-protein-coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengers IP3 and diacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space. Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration. In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.

In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the reabsorptive activity PTH has on the kidneys. Severe hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.<ref name="pmid10405219">Template:Cite journal</ref>

StimulatorsEdit

Decreased serum [Ca²⁺].
Mild decreases in serum [Mg²⁺].
An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).
Adrenaline
Histamine

InhibitorsEdit

Increased serum [Ca²⁺].
Severe decreases in serum [Mg²⁺], which also produces symptoms of hypoparathyroidism (such as hypocalcemia).<ref name=brs>Template:Cite book</ref>
Calcitriol
Increase in serum phosphate. Fibroblast growth factor-23 (FGF23) is produced in osteoblasts (from bone) in response to increases in serum phosphate (Pi). It binds to the fibroblast growth factor receptor of the parathyroid and suppresses PTH release. This may seem contradictory because PTH actually helps rid the blood of phosphates but it is also causes release of phosphate into the blood from bone resorption. FGF23 inhibits PTH and then takes its place helping inhibit re-absorption of phosphate in the kidney without the phosphate releasing effect on bones.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

DisordersEdit

Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcemia. A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.

There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including pseudohypoparathyroidism, familial hypocalciuric hypercalcemia, and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged in pseudopseudohypoparathyroidism. In osteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45–65%.<ref name="pmid11346808">Template:Cite journal</ref>

MeasurementEdit

PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations. The level may be stated in pg/dL or pmol/L (sometimes abbreviated mmol/L); multiply by 0.1060 to convert from pg/dL to pmol/L.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A US source states the average PTH level to be 8–51 pg/mL.<ref>Template:Cite book</ref> In the UK the biological reference range is considered to be 1.6–6.9 pmol/L.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Interpretive guideEdit

The intact PTH and calcium normal ranges are different for age; calcium is also different for sex.<ref>PTH, Intact and Calcium Test Detail. Quest Diagnostics Lab. Accessed 2019-06-29.</ref><ref>Parathyroid Hormone (PTH) Plus Calcium. LabCorp. Accessed 2019-07-02.</ref>

Condition	Intact PTH	Calcium
Normal Parathyroid	Normal	Normal
Hypoparathyroidism	Low or Low Normal <ref name=quest group=note>Low Normal or Normal only for Quest Lab, not LabCorp</ref>	Low
Hyperparathyroidism
- Primary	High or Normal <ref name=quest group=note/>	High
- Secondary	High	Normal or Low
- Tertiary<ref group=note>Both primary and tertiary hyperparathyroidism may have high PTH and high calcium. Tertiary is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism. </ref>\|\|High \|\|High
Non-Parathyroid Hypercalcemia	Low or Low Normal <ref name=quest group=note/>	High