Hypoparathyroidism pathophysiology: Difference between revisions
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| colspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Kenny-Caffey syndrome type 2]]'''<ref name="pmid23996431">{{cite journal |vauthors=Isojima T, Doi K, Mitsui J, Oda Y, Tokuhiro E, Yasoda A, Yorifuji T, Horikawa R, Yoshimura J, Ishiura H, Morishita S, Tsuji S, Kitanaka S |title=A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2 |journal=J. Bone Miner. Res. |volume=29 |issue=4 |pages=992–8 |year=2014 |pmid=23996431 |doi=10.1002/jbmr.2091 |url=}}</ref> | | colspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Kenny-Caffey syndrome type 2]]'''<ref name="pmid23996431">{{cite journal |vauthors=Isojima T, Doi K, Mitsui J, Oda Y, Tokuhiro E, Yasoda A, Yorifuji T, Horikawa R, Yoshimura J, Ishiura H, Morishita S, Tsuji S, Kitanaka S |title=A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2 |journal=J. Bone Miner. Res. |volume=29 |issue=4 |pages=992–8 |year=2014 |pmid=23996431 |doi=10.1002/jbmr.2091 |url=}}</ref> | ||
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]] | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]] | ||
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1 | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Mutation of “family with sequence similarity 111, member A″ (FAM111A) [[gene]] located on chromosome locus 11q12.1 | ||
| style="padding: 5px 5px; background: #F5F5F5;" | | | style="padding: 5px 5px; background: #F5F5F5;" | | ||
*Similar clinical features as Kenny-Caffey syndrome type 1 | *Similar clinical features as Kenny-Caffey syndrome type 1 | ||
Revision as of 00:34, 27 October 2017
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Hypoparathyroidism Microchapters |
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Hypoparathyroidism pathophysiology On the Web |
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Risk calculators and risk factors for Hypoparathyroidism pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]
Overview
Hypoparathyroidism is a decrease in serum parathyroid hormone. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calcium. Parathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calcium. Calcium and magnesium provides a negative feedback for secretion of parathyroid hormone. Deficiency of parathyroid hormone causes body to decrease reabsorption of calcium from bone, excretion of phosphate, reabsorbtion of calcium from distal tubules, and vitamin D mediated absorption of calcium from intestine leading to hypocalcemia. Many genetic conditions are associated with hypoparathyroidism. Hypoparathyroidism associated with genetic defects may be either autoimmune hypoparathyroidism, isolated hypoparathyroidism, associated with congenital multisystem syndromes, or a part of metabolic disorders.
Pathophysiology
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-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone 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:
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 in Parathyroid, Vitamin D, and Mineral Homeostasis
| Parathyroid hormone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kidney | Bone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Decreased excretion of magnesium | Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin 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-sensing 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 ionized calcium.[4]
Pathogenesis
- There is deficiency of parathyroid hormone in hypoparathyroidism.
- Deficiency of parathyroid hormone causes body to decrease:
- Reabsorption of calcium from bone.
- Excretion of phosphate.
- Reabsorbtion of calcium from distal tubules.
- Vitamin D mediated absorption of calcium from intestine.
- This leads to hypocalcemia.
| Hypoparathyroidism | |||||||||||||||||||||||||||||||||||||||||||
| Deficiency of parathyroid hormone | |||||||||||||||||||||||||||||||||||||||||||
| Decrease reabsorption of calcium from bone | Decrease excretion of phosphate | Decrease reabsorbtion of calcium from distal tubules | Decrease vitamin D mediated absorption of calcium from intestine | ||||||||||||||||||||||||||||||||||||||||
Post-surgical Hypoparathyroidism
- Anterior neck surgery most commonly causes hypoparathyroidism. Majority of time this hypoparathyroidism is transient i.e. it resolves within 6 months.[5][6][7]
- The features of hypoparathyroidism should persist for atleast 6 month after surgery to be diagnosed as chronic hypoparathyroidism.
- 30–60% Patients undergoing total thyroidectomy develops hypocalcaemia within 24 hours as an initial manifestation of postoperative parathyroid failure. About 60%-70% of these cases resolve within 4–6 weeks after surgery. Remaining cases progress to develop protracted hypoparathyroidism requiring continuous treatment. Around 15–25% of patients with protracted hypoparathyroidism progress to chronic hypoparathyroidism.[8]
- Factors favorring recovery from protracted hypoparathyroidism include:
- Number of parathyroid glands remaining in situ.
- Serum calcium level at this stage : There is high rate of recovery in individuals whose calcium levels are normal to elevated one month postoperatively.
Genetics
| Genetics of Hypoparathyroidism | ||||||
|---|---|---|---|---|---|---|
| Hypoparathyroidism | Inheritance | Gene mutation | Clinical features | |||
| Autoimmune | Autoimmune polyglandular hypoparathyroidism | Autoimmune polyendocrine syndrome type 1[9] | Autosomal recessive | Mutation in AIRE gene |
| |
| Isolated | Familial Isolated hypoparathyroidism | Autosomal dominant | PTH gene[10] |
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| Glial cells missing GCM2 gene[11] |
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| Autosomal recessive | PTH gene[12] |
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| Glial cells missing 2 (GCM2) gene[11][13] |
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| X-linked | FHL1 gene (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27[14] |
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| Autosomal dominant hypercalcemia[15] | Autosomal dominant hypocalcemia type 1 | Autosomal dominant | Calcium-sensing receptor gene mutation |
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| Autosomal dominant hypocalcemia type 2 | Autosomal dominant | G protein G11 (GNA11) mutation |
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| Congenital multisystem syndromes | DiGeorge syndrome[18] | Autosomal dominant | 22q11.2 deletion |
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| CHARGE syndrome[19] | Autosomal dominant | CHD7 G744S missense mutation |
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| Kenny-Caffey syndrome type 1[20] | Autosomal recessive | Deletion of the TBCE gene |
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| Kenny-Caffey syndrome type 2[21] | Autosomal dominant | Mutation of “family with sequence similarity 111, member A″ (FAM111A) gene located on chromosome locus 11q12.1 |
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| Sanjad-Sakati syndrome[22] | Autosomal recessive | Mutation in TBCE gene |
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| Barakat syndrome[23][24] | Autosomal recessive | Mutations in the GATA3 gene | ||||
| Metabolic diseases | Mitochondiral polyneuropathies[25] | Kearns–Sayre syndrome | Mitochondrial inheritence | mtDNA deletion |
| |
| Maternally inherited diabetes and deafness (MIDD) | Mitochondrial inheritence | MT‑TL1 defect |
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| Mitochondrial enzyme deficiencies | Mitochondrial trifunctional protein deficiency (MTP deficiency)[26][27] | Autosomal recessive | HADHA or HADHB gene mutation |
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| Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)[28] | Autosomal recessive | G1528C gene mutation |
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| Heavy metal storage disorders | Hemochromatosis[29][30] | Autosomal recessive | HFE gene mutation |
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| Wilson's disease[31][32] | Autosomal recessive | ATP7B gene mutation |
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Associated Conditions
Conditions associated with hypoparathyroidism include:[9][15][16][17][18][19][20][21][22][23][24][25][26][28][29][31]
- Autoimmune polyendocrine syndrome type 1
- Autosomal dominant hypocalcemia type 1
- Autosomal dominant hypocalcemia type 2
- Bartter syndrome type 5
- DiGeorge syndrome
- CHARGE syndrome
- Kenny-Caffey syndrome type 1
- Kenny-Caffey syndrome type 2
- Sanjad-Sakati syndrome
- Barakat syndrome
- Kearns–Sayre syndrome
- Maternally inherited diabetes and deafness (MIDD)
- Mitochondrial trifunctional protein deficiency (MTP deficiency)
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
- Hemochromatosis
- Wilson's disease
Gross Pathology
- There is no gross pathology findings for hypoparathyroidism.
Microscopic Pathology
- There is no microscopic pathology findings for hypoparathyroidism.
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.
- ↑ Bilezikian JP, Khan A, Potts JT, Brandi ML, Clarke BL, Shoback D, Jüppner H, D'Amour P, Fox J, Rejnmark L, Mosekilde L, Rubin MR, Dempster D, Gafni R, Collins MT, Sliney J, Sanders J (2011). "Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research". J. Bone Miner. Res. 26 (10): 2317–37. doi:10.1002/jbmr.483. PMC 3405491. PMID 21812031.
- ↑ Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS (2015). "Hypoparathyroidism after total thyroidectomy: incidence and resolution". J. Surg. Res. 197 (2): 348–53. doi:10.1016/j.jss.2015.04.059. PMC 4466142. PMID 25982044.
- ↑ Sturniolo G, Lo Schiavo MG, Tonante A, D'Alia C, Bonanno L (2000). "Hypocalcemia and hypoparathyroidism after total thyroidectomy: a clinical biological study and surgical considerations". Int. J. Surg. Investig. 2 (2): 99–105. PMID 12678507.
- ↑ Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OM (2015). "European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults". Eur. J. Endocrinol. 173 (2): G1–20. doi:10.1530/EJE-15-0628. PMID 26160136.
- ↑ 9.0 9.1 Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J (1990). "Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients". N. Engl. J. Med. 322 (26): 1829–36. doi:10.1056/NEJM199006283222601. PMID 2348835.
- ↑ Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (1990). "Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism". J. Clin. Invest. 86 (4): 1084–7. doi:10.1172/JCI114811. PMC 296835. PMID 2212001.
- ↑ 11.0 11.1 Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN (2009). "Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism". Hum. Mutat. 30 (1): 85–92. doi:10.1002/humu.20827. PMID 18712808.
- ↑ Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S (1999). "A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism". J. Clin. Endocrinol. Metab. 84 (10): 3792–6. doi:10.1210/jcem.84.10.6070. PMID 10523031.
- ↑ Ding C, Buckingham B, Levine MA (2001). "Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB". J. Clin. Invest. 108 (8): 1215–20. doi:10.1172/JCI13180. PMC 209530. PMID 11602629.
- ↑ Pillar N, Pleniceanu O, Fang M, Ziv L, Lahav E, Botchan S, Cheng L, Dekel B, Shomron N (2017). "A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism". Hum. Genet. 136 (7): 835–845. doi:10.1007/s00439-017-1804-9. PMC 5487855. PMID 28444561.
- ↑ 15.0 15.1 Roszko KL, Bi RD, Mannstadt M (2016). "Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2". Front Physiol. 7: 458. doi:10.3389/fphys.2016.00458. PMC 5067375. PMID 27803672.
- ↑ 16.0 16.1 Vezzoli G, Arcidiacono T, Paloschi V, Terranegra A, Biasion R, Weber G, Mora S, Syren ML, Coviello D, Cusi D, Bianchi G, Soldati L (2006). "Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome". J. Nephrol. 19 (4): 525–8. PMID 17048213.
- ↑ 17.0 17.1 Choi KH, Shin CH, Yang SW, Cheong HI (2015). "Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C". Korean J Pediatr. 58 (4): 148–53. doi:10.3345/kjp.2015.58.4.148. PMC 4414630. PMID 25932037.
- ↑ 18.0 18.1 Fomin AB, Pastorino AC, Kim CA, Pereira CA, Carneiro-Sampaio M, Abe-Jacob CM (2010). "DiGeorge Syndrome: a not so rare disease". Clinics (Sao Paulo). 65 (9): 865–9. PMC 2954737. PMID 21049214.
- ↑ 19.0 19.1 Jain S, Kim HG, Lacbawan F, Meliciani I, Wenzel W, Kurth I, Sharma J, Schoeneman M, Ten S, Layman LC, Jacobson-Dickman E (2011). "Unique phenotype in a patient with CHARGE syndrome". Int J Pediatr Endocrinol. 2011: 11. doi:10.1186/1687-9856-2011-11. PMC 3216247. PMID 21995344.
- ↑ 20.0 20.1 Metwalley KA, Farghaly HS (2012). "Kenny-Caffey syndrome type 1 in an Egyptian girl". Indian J Endocrinol Metab. 16 (5): 827–9. doi:10.4103/2230-8210.100645. PMC 3475915. PMID 23087875.
- ↑ 21.0 21.1 Isojima T, Doi K, Mitsui J, Oda Y, Tokuhiro E, Yasoda A, Yorifuji T, Horikawa R, Yoshimura J, Ishiura H, Morishita S, Tsuji S, Kitanaka S (2014). "A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2". J. Bone Miner. Res. 29 (4): 992–8. doi:10.1002/jbmr.2091. PMID 23996431.
- ↑ 22.0 22.1 Rafique B, Al-Yaarubi S (2010). "Sanjad-Sakati Syndrome in Omani children". Oman Med J. 25 (3): 227–9. doi:10.5001/omj.2010.63. PMC 3191633. PMID 22043344.
- ↑ 23.0 23.1 Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T (2001). "GATA3 abnormalities and the phenotypic spectrum of HDR syndrome". J. Med. Genet. 38 (6): 374–80. PMC 1734904. PMID 11389161.
- ↑ 24.0 24.1 Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000). "GATA3 haplo-insufficiency causes human HDR syndrome". Nature. 406 (6794): 419–22. doi:10.1038/35019088. PMID 10935639.
- ↑ 25.0 25.1 Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S (2017). "Mitochondrial disease and endocrine dysfunction". Nat Rev Endocrinol. 13 (2): 92–104. doi:10.1038/nrendo.2016.151. PMID 27716753.
- ↑ 26.0 26.1 Labarthe F, Benoist JF, Brivet M, Vianey-Saban C, Despert F, de Baulny HO (2006). "Partial hypoparathyroidism associated with mitochondrial trifunctional protein deficiency". Eur. J. Pediatr. 165 (6): 389–91. doi:10.1007/s00431-005-0052-5. PMID 16523289.
- ↑ "mitochondrial trifunctional protein deficiency - Genetics Home Reference".
- ↑ 28.0 28.1 Tyni T, Rapola J, Palotie A, Pihko H (1997). "Hypoparathyroidism in a patient with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation". J. Pediatr. 131 (5): 766–8. PMID 9403664.
- ↑ 29.0 29.1 Jeong HK, An JH, Kim HS, Cho EA, Han MG, Moon JS, Kim HK, Kang HC (2014). "Hypoparathyroidism and subclinical hypothyroidism with secondary hemochromatosis". Endocrinol Metab (Seoul). 29 (1): 91–5. doi:10.3803/EnM.2014.29.1.91. PMC 3970271. PMID 24741460.
- ↑ "hereditary hemochromatosis - Genetics Home Reference".
- ↑ 31.0 31.1 Carpenter TO, Carnes DL, Anast CS (1983). "Hypoparathyroidism in Wilson's disease". N. Engl. J. Med. 309 (15): 873–7. doi:10.1056/NEJM198310133091501. PMID 6888480.
- ↑ "Wilson disease - Genetics Home Reference".