Hyperparathyroidism pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief:
Overview
- The exact pathogenesis of [disease name] is not fully understood.
OR
- It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
- [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
- Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
- [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
- The progression to [disease name] usually involves the [molecular pathway].
- The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathohysiology
Parathyroid, Vitamin D, and mineral homeostasis
The effect of Parathyroid hormone on mineral metabolism is as follows:[1][2]
- Effect of parathyroid hormone on inorganic phosphate metabolism:
- Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
- Effect on parathyroid hormone on calcium metabolism:
- Direct effect:
- Increased resorption of bones.
- Decreases excretion from kidney.
- Indirect effect:
- Increases conversion of inactive 25-hydroyxvitamin D to the active 1,25-dihydroyxvitamin D which increases absorption of calcium from gut.Decreased phosphate concentration also increases this conversion process. Vitamin D also synergizes with parathyroid action on bone.
- Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
- Both these direct and indirect mechanism results in an increased serum calcium concentration.
- Direct effect:
- Effect of parathyroid hormone on magnesium concentration:
- Decreases excretion of magnesium resulting in increased serum magnesium concentretion.
Effect of minerals and vitamin D on parathyroid hormone:
- Decrease in serum calcium concentration stimulates parathyroid hormone.
- Calcium provides negative feedback on parathyroid hormone.
- Magnesium provides negative feedback on parathyroid hormone.
- Vitamin D decreases the concentration of parathyroid hormone.
The sequence of events is shown in the algorithm below:
| Parathyroid hormone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kidney | Bone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Decreased excretion of magnesium | Increasead conversion of inactive 25-hydroyxvitamin D to the active 1,25-dihydroyxvitamin D | Increase excretion of inorganic phosphate | Decrease excretion of calcium | Increased resorption of bone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of magnesium | Increased absorption of calcium from gut | Decreased serum concentration of inorganic phosphate | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prevents precipitation of calcium phosphate in bones | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of calcium | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Calcium-sensing receptors
- Calcium -ensing receptors are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.[3]
- Calcium-sensing receptors sense change in extracellular concentration of inonised calcium.[4]
- Calcium-sensing receptor expression in reduced in primary hyperparathyroidism (parathyroid adenomas) and secondary hyperparathyroidism.[5]
- This reduced expression of receptor causes an increases in calcium sensing set point.[6]
- This in turn leads to increase in secretion of parathyroid hormone in presence on normal serum concentration of extracellular ionized calcium.
Pathogenesis of primary hyperparathyroidism
- Primary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a primary process in parathyroid gland.
- Majority of times, increase in secretion of parathyroid hormone is the result of parathyroid adenoma. Other causes of increase in secretion of parathyroid hormone includes parathyroid hyperplasia and parathyroid carcinoma.
- Calcium sensing receptor expression in reduced in parathyroid adenomas resulting in an increase in calcium sensing set point.[5][6]
- In parathyroid hyperplasia, an increase in cell number causes increased secretion of parathyroid hormone.
Pathogenesis of secondary hyperparathyroidism
- Secondary hyperparathyroidism is due to increase in secretion of parathyroid hormone from a secondary process, most commonly due chronic renal failure. Other causes include vitamin D deficiency, severe calcium deficiency.[7]
- Chronic renal failure leads to high serum inorganic phosphate and low serum calcium and deficiency of active form of vitamin D(1,25-dihydroxy vitamin D, calcitirol)
- This leads to continuous stimulation of parathyroid glands resulting downregulation of parathyroid vitamin D receptors and calcium sensing receptors.
- Fibroblast growth factor 23 (FGF-23) concentration increases in chronic renal failure which plays a central role in regulation of phosphate vitamin D homeostasis.
- Elevated FGF-23 expression downregulates remaining 25(OH)-1-hydroxylase enzyme. 25(OH)-1-hydroxylase enzyme is responsible for conversion of inactive 1-hydroxy vitamin D into active 1,25-dihydroxy vitamin D(calcitirol). This leads to aggravates the deficiency of active vitamin D.
- These all factors leads to hyperplasia of parathyroid gland.
| Chronic renal failure | |||||||||||||||||||||||||||||||||||||
| Elevated serum inorganic phosphate concentration | |||||||||||||||||||||||||||||||||||||
| Elevated FGF-23 | |||||||||||||||||||||||||||||||||||||
| Decreased Calcitriol | |||||||||||||||||||||||||||||||||||||
| Decreaed serum calcium concentration | |||||||||||||||||||||||||||||||||||||
| Continuous stimulation of parathyroid gland | |||||||||||||||||||||||||||||||||||||
| Downregulation of parathyroid vitaminn D receptors and calcium-sensing receptors | |||||||||||||||||||||||||||||||||||||
| Parathyroid hyperplasia | |||||||||||||||||||||||||||||||||||||
| Increased secretion of parathyroid hormone | |||||||||||||||||||||||||||||||||||||
Mechanism of fibroblast growth factor 23 (FGF-23)[7]
- FGF-23 is a hormone produced in the osteocytes and osteoblasts.
- Its production is increased due to high serum phosphate and high calcitriol.
- FGF-23 binds and activates a receptor called fibroblast growth factor receptor 1 (FGFR1).
- FGFR1 is functional when coexpressed with the Klotho transmembrane protein, as a Klotho-FGF receptor complex.
- FGF-23 reduces the expression of type II sodium phosphate cotransporters (NaPi-2a and NaPi-2c) decreasing phosphate reabsorption in proximal tubules.
- In chronic renal failure, as a result, phosphate absorption is increased in proximal tubules due to effect of FGF-23 as well as increased parathyroid hormone. This is responsible for normal serum phosphate levels in majority of patients until the GFR falls below 20 ml/min.
- As chronic renal failure progresses, these negative feedback loops are impaired leading to deranged phosphate homeostasis.
- FGF-23 have direct and indirect effect on parathyroid hormone.
- Direct effect: In normal parathyroid gland,FGF-23 decreases synthesis of parathyroid hormone through the mitogen-activated protein kinase (MAPK) pathway.[8] FGF-23 increased expression of the parathyroid calcium-sensing receptor and the vitamin D receptor, and reducing cellular proliferation.[9]
- Indirect effect: Increased synthesis of parathyroid hormone by decreasing synthesis of calcitriol.
- FGF-23 fails to activate mitogen-activated protein kinase pathway in hyperplastic parathyroid gland secondary to chronic renal failure.[9]
Pathogenesis of tertiary hyperparathyroidism
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.
- ↑ Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.
- ↑ Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O; et al. (1993). "Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid". Nature. 366 (6455): 575–80. doi:10.1038/366575a0. PMID 8255296.
- ↑ Brown EM, Pollak M, Seidman CE, Seidman JG, Chou YH, Riccardi D; et al. (1995). "Calcium-ion-sensing cell-surface receptors". N Engl J Med. 333 (4): 234–40. doi:10.1056/NEJM199507273330407. PMID 7791841.
- ↑ 5.0 5.1 Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, Sarfati E; et al. (1997). "Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism". Kidney Int. 51 (1): 328–36. PMID 8995751.
- ↑ 6.0 6.1 Kifor O, Moore FD, Wang P, Goldstein M, Vassilev P, Kifor I; et al. (1996). "Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism". J Clin Endocrinol Metab. 81 (4): 1598–606. doi:10.1210/jcem.81.4.8636374. PMID 8636374.
- ↑ 7.0 7.1 Cunningham J, Locatelli F, Rodriguez M (2011). "Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options". Clin J Am Soc Nephrol. 6 (4): 913–21. doi:10.2215/CJN.06040710. PMID 21454719.
- ↑ Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007). "The parathyroid is a target organ for FGF23 in rats". J. Clin. Invest. 117 (12): 4003–8. doi:10.1172/JCI32409. PMC 2066196. PMID 17992255.
- ↑ 9.0 9.1 Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, Mendoza FJ, Munoz-Castaneda JR, Shalhoub V, Almaden Y, Rodriguez M (2010). "FGF23 fails to inhibit uremic parathyroid glands". J. Am. Soc. Nephrol. 21 (7): 1125–35. doi:10.1681/ASN.2009040427. PMC 3152229. PMID 20431039.