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*Parathyroid carcinoma
*Parathyroid carcinoma
*Familial isloated hyperparathyroidism
*Familial isloated hyperparathyroidism
*Radiation exposure (due to development of parathyroid adenoma or parathyroid hyperplasia)<ref name="pmid21848480">{{cite journal| author=Boehm BO, Rosinger S, Belyi D, Dietrich JW| title=The parathyroid as a target for radiation damage. | journal=N Engl J Med | year= 2011 | volume= 365 | issue= 7 | pages= 676-8 | pmid=21848480 | doi=10.1056/NEJMc1104982 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21848480  }} </ref><ref name="pmid18774659">{{cite journal| author=McMullen T, Bodie G, Gill A, Ihre-Lundgren C, Shun A, Bergin M et al.| title=Hyperparathyroidism after irradiation for childhood malignancy. | journal=Int J Radiat Oncol Biol Phys | year= 2009 | volume= 73 | issue= 4 | pages= 1164-8 | pmid=18774659 | doi=10.1016/j.ijrobp.2008.06.1487 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18774659  }} </ref><ref name="pmid890665">{{cite journal| author=Tisell LE, Hansson G, Lindberg S, Ragnhult I| title=Hyperparathyroidism in persons treated with X-rays for tuberculous cervical adenitis. | journal=Cancer | year= 1977 | volume= 40 | issue= 2 | pages= 846-54 | pmid=890665 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=890665  }} </ref>
*Radiation exposure (due to development of parathyroid adenoma or parathyroid hyperplasia)
*Celiac disease<ref name="pmid17148709">{{cite journal |vauthors=Maida MJ, Praveen E, Crimmins SR, Swift GL |title=Coeliac disease and primary hyperparathyroidism: an association? |journal=Postgrad Med J |volume=82 |issue=974 |pages=833–5 |year=2006 |pmid=17148709 |pmc=2653933 |doi=10.1136/pgmj.2006.045500 |url=}}</ref><ref name="pmid22238405">{{cite journal |vauthors=Ludvigsson JF, Kämpe O, Lebwohl B, Green PH, Silverberg SJ, Ekbom A |title=Primary hyperparathyroidism and celiac disease: a population-based cohort study |journal=J. Clin. Endocrinol. Metab. |volume=97 |issue=3 |pages=897–904 |year=2012 |pmid=22238405 |pmc=3319223 |doi=10.1210/jc.2011-2639 |url=}}</ref>
*Celiac disease


===Genetic causes===
===Genetic causes===
*HRPT2 gene mutations:<ref name="pmid14585940">{{cite journal| author=Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D et al.| title=Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 18 | pages= 1722-9 | pmid=14585940 | doi=10.1056/NEJMoa031237 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14585940  }} </ref>
*HRPT2 gene mutations:
**HRPT2 gene code for parafibromin protein.
**HRPT2 gene code for parafibromin protein.
**HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
**HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
**HRTP2 gene mutations increases risk of parathyroid carcinoma.
**HRTP2 gene mutations increases risk of parathyroid carcinoma.
*Cyclin D1 gene (CCND1)/PRAD1 gene:<ref name="pmid19373510">{{cite journal| author=Westin G, Björklund P, Akerström G| title=Molecular genetics of parathyroid disease. | journal=World J Surg | year= 2009 | volume= 33 | issue= 11 | pages= 2224-33 | pmid=19373510 | doi=10.1007/s00268-009-0022-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19373510  }} </ref><ref name="pmid8626826">{{cite journal| author=Hsi ED, Zukerberg LR, Yang WI, Arnold A| title=Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 5 | pages= 1736-9 | pmid=8626826 | doi=10.1210/jcem.81.5.8626826 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8626826  }} </ref>
*Cyclin D1 gene (CCND1)/PRAD1 gene:
**PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
**PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
**Cyclin D1 gene translocation and oncogene action observerd in 8% of adenomas
**Cyclin D1 gene translocation and oncogene action observerd in 8% of adenomas
**Cyclin D1 gene overexpression is pbserved in 20% to 40% of parathyroid adenomas
**Cyclin D1 gene overexpression is pbserved in 20% to 40% of parathyroid adenomas
*MEN1 gene:<ref name="pmid19373510">{{cite journal| author=Westin G, Björklund P, Akerström G| title=Molecular genetics of parathyroid disease. | journal=World J Surg | year= 2009 | volume= 33 | issue= 11 | pages= 2224-33 | pmid=19373510 | doi=10.1007/s00268-009-0022-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19373510 }} </ref><ref name="pmid9215689">{{cite journal| author=Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC et al.| title=Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. | journal=Hum Mol Genet | year= 1997 | volume= 6 | issue= 7 | pages= 1169-75 | pmid=9215689 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9215689 }} </ref>
*MEN1 gene:<ref name="pmid19373510">{{cite journal| author=Westin G, Björklund P, Akerström G| title=Molecular genetics of parathyroid disease. | journal=World J Surg | year= 2009 | volume= 33 | issue= 11 | pages= 2224-33 | pmid=19373510 | doi=10.1007/s00268-009-0022-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19373510  }} </ref>
**MEN1 is a tumor supressor gene on chronosome 11q13.
**MEN1 is a tumor supressor gene on chronosome 11q13.
**Somatic loss of single MEN1 allele is observed in  25% to 40% of sporadic parathyroid adenomas.
**Somatic loss of single MEN1 allele is observed in  25% to 40% of sporadic parathyroid adenomas.
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Causes of secondary hyperparathyroidism are as follows:
Causes of secondary hyperparathyroidism are as follows:
===Common causes===
===Common causes===
*Chronic renal failure (leading to parathyroid hyperplasia)<ref name="pmid15507543">{{cite journal| author=Rodriguez M, Nemeth E, Martin D| title=The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. | journal=Am J Physiol Renal Physiol | year= 2005 | volume= 288 | issue= 2 | pages= F253-64 | pmid=15507543 | doi=10.1152/ajprenal.00302.2004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15507543  }} </ref>
*Chronic renal failure (leading to parathyroid hyperplasia)
*Vitamin D deficiency<ref name="pmid11493580">{{cite journal| author=Lips P| title=Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. | journal=Endocr Rev | year= 2001 | volume= 22 | issue= 4 | pages= 477-501 | pmid=11493580 | doi=10.1210/edrv.22.4.0437 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11493580  }} </ref>
*Vitamin D deficiency


===Less common causes===
===Less common causes===
*Severe calcium deficiency<ref name="pmid16512945">{{cite journal| author=Mehrotra M, Gupta SK, Kumar K, Awasthi PK, Dubey M, Pandey CM et al.| title=Calcium deficiency-induced secondary hyperparathyroidism and osteopenia are rapidly reversible with calcium supplementation in growing rabbit pups. | journal=Br J Nutr | year= 2006 | volume= 95 | issue= 3 | pages= 582-90 | pmid=16512945 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16512945  }} </ref>
*Severe calcium deficiency
*Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)<ref name="pmid16633006">{{cite journal |vauthors=Johnson JM, Maher JW, DeMaria EJ, Downs RW, Wolfe LG, Kellum JM |title=The long-term effects of gastric bypass on vitamin D metabolism |journal=Ann. Surg. |volume=243 |issue=5 |pages=701–4; discussion 704–5 |year=2006 |pmid=16633006 |pmc=1570540 |doi=10.1097/01.sla.0000216773.47825.c1 |url=}}</ref>
*Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)
*Malabsorption syndrome<ref name="pmid19836494">{{cite journal |vauthors=Pitt SC, Sippel RS, Chen H |title=Secondary and tertiary hyperparathyroidism, state of the art surgical management |journal=Surg. Clin. North Am. |volume=89 |issue=5 |pages=1227–39 |year=2009 |pmid=19836494 |pmc=2905047 |doi=10.1016/j.suc.2009.06.011 |url=}}</ref>
*Malabsorption syndrome


==Causes of tertiary hyperparathyroidism==
==Causes of tertiary hyperparathyroidism==
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===Common causes===
===Common causes===
*Chronic renal failure (leading to parathyroid hyperplasia)
*Chronic renal failure (leading to parathyroid hyperplasia)
*Renal transplant patients<ref name="pmid9780988">{{cite journal |vauthors=Kilgo MS, Pirsch JD, Warner TF, Starling JR |title=Tertiary hyperparathyroidism after renal transplantation: surgical strategy |journal=Surgery |volume=124 |issue=4 |pages=677–83; discussion 683–4 |year=1998 |pmid=9780988 |doi=10.1067/msy.1998.91483 |url=}}</ref>
*Renal transplant patients


===Less common cause===
===Less common cause===
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*Familial hypocalciuric hypercalcemia
*Familial hypocalciuric hypercalcemia
*Hyperparathyroid-jaw tumor syndrome
*Hyperparathyroid-jaw tumor syndrome
*Pancreatitis<ref name="pmid22874807">{{cite journal |vauthors=Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ |title=The association of primary hyperparathyroidism with pancreatitis |journal=J. Clin. Gastroenterol. |volume=46 |issue=8 |pages=656–61 |year=2012 |pmid=22874807 |pmc=4428665 |doi=10.1097/MCG.0b013e31825c446c |url=}}</ref>
*Pancreatitis


=Natural history, Prognosis and Complications=
=Natural history, Prognosis and Complications=
==Natural history==
==Natural history==
*Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
*Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
*If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.<ref name="pmid12412783">{{cite journal |vauthors=Peacock M |title=Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum |journal=J. Bone Miner. Res. |volume=17 Suppl 2 |issue= |pages=N87–94 |year=2002 |pmid=12412783 |doi= |url=}}</ref><ref name="pmid2763869">{{cite journal |vauthors=Silverberg SJ, Shane E, de la Cruz L, Dempster DW, Feldman F, Seldin D, Jacobs TP, Siris ES, Cafferty M, Parisien MV |title=Skeletal disease in primary hyperparathyroidism |journal=J. Bone Miner. Res. |volume=4 |issue=3 |pages=283–91 |year=1989 |pmid=2763869 |doi=10.1002/jbmr.5650040302 |url=}}</ref>
*If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.


*Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable.<ref name="pmid21897756">{{cite journal |vauthors=Nikodimopoulou M, Liakos S |title=Secondary hyperparathyroidism and target organs in chronic kidney disease |journal=Hippokratia |volume=15 |issue=Suppl 1 |pages=33–8 |year=2011 |pmid=21897756 |pmc=3139677 |doi= |url=}}</ref>
*Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable.
*Secondary hyperparathyroidism leads to vascular calcification due to elevated calcium and phosphorus levels. This is strongly associated with increase in  morbidity and mortality.<ref name="pmid21454719">{{cite journal |vauthors=Cunningham J, Locatelli F, Rodriguez M |title=Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options |journal=Clin J Am Soc Nephrol |volume=6 |issue=4 |pages=913–21 |year=2011 |pmid=21454719 |doi=10.2215/CJN.06040710 |url=http://cjasn.asnjournals.org/content/6/4/913.full}}</ref>
*Secondary hyperparathyroidism leads to vascular calcification due to elevated calcium and phosphorus levels. This is strongly associated with increase in  morbidity and mortality.
*If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.
*If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.


*Tertiary hyperparathyroidism usually develops in post renal transplant patients.<ref name="pmid12714225">{{cite journal |vauthors=Jevtic V |title=Imaging of renal osteodystrophy |journal=Eur J Radiol |volume=46 |issue=2 |pages=85–95 |year=2003 |pmid=12714225 |doi= 10.1016/S0720-048X(03)00072-X|url=http://www.sciencedirect.com/science/article/pii/S0720048X0300072X?via%3Dihub}}</ref>
*Tertiary hyperparathyroidism usually develops in post renal transplant patients.
*If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.
*If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.


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===Primary hyperparathyroidism===
===Primary hyperparathyroidism===
Majority of complications of primary hyperparathyroidism are due to hypercalcemia. Common complications of primary hyperparathyroidism include:
Majority of complications of primary hyperparathyroidism are due to hypercalcemia. Common complications of primary hyperparathyroidism include:
*Bone related complication:<ref name="pmid25166047">{{cite journal |vauthors=Bandeira F, Cusano NE, Silva BC, Cassibba S, Almeida CB, Machado VC, Bilezikian JP |title=Bone disease in primary hyperparathyroidism |journal=Arq Bras Endocrinol Metabol |volume=58 |issue=5 |pages=553–61 |year=2014 |pmid=25166047 |pmc=4315357 |doi= |url=}}</ref><ref name="pmid9801732">{{cite journal |vauthors=Mazzuoli GF, D'Erasmo E, Pisani D |title=Primary hyperparathyroidism and osteoporosis |journal=Aging (Milano) |volume=10 |issue=3 |pages=225–31 |year=1998 |pmid=9801732 |doi= |url=}}</ref>
*Bone related complication:
**Brown tumor
**Brown tumor
**Osteitis fibrous cystica
**Osteitis fibrous cystica
**Osteoporosis
**Osteoporosis
*Cardiac complications:<ref name="pmid8989242">{{cite journal |vauthors=Stefenelli T, Abela C, Frank H, Koller-Strametz J, Globits S, Bergler-Klein J, Niederle B |title=Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue=1 |pages=106–12 |year=1997 |pmid=8989242 |doi=10.1210/jcem.82.1.3666 |url=}}</ref>
*Cardiac complications:
**Aortic and mitral valve calcification
**Aortic and mitral valve calcification
**Calcific deposits in the myocardium
**Calcific deposits in the myocardium
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*Endocrine complications:<ref name="pmid22874807">{{cite journal |vauthors=Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ |title=The association of primary hyperparathyroidism with pancreatitis |journal=J. Clin. Gastroenterol. |volume=46 |issue=8 |pages=656–61 |year=2012 |pmid=22874807 |pmc=4428665 |doi=10.1097/MCG.0b013e31825c446c |url=}}</ref>
*Endocrine complications:<ref name="pmid22874807">{{cite journal |vauthors=Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ |title=The association of primary hyperparathyroidism with pancreatitis |journal=J. Clin. Gastroenterol. |volume=46 |issue=8 |pages=656–61 |year=2012 |pmid=22874807 |pmc=4428665 |doi=10.1097/MCG.0b013e31825c446c |url=}}</ref>
**Pancreatitis
**Pancreatitis
*Gastrointestinal complications:<ref name="pmid3878002">{{cite journal |vauthors=Corlew DS, Bryda SL, Bradley EL, DiGirolamo M |title=Observations on the course of untreated primary hyperparathyroidism |journal=Surgery |volume=98 |issue=6 |pages=1064–71 |year=1985 |pmid=3878002 |doi= |url=}}</ref>
*Gastrointestinal complications:
**Peptic ulcer disease
**Peptic ulcer disease
*Metabolic complications:<ref name="pmid3812520">{{cite journal |vauthors=Fitzpatrick LA, Bilezikian JP |title=Acute primary hyperparathyroidism |journal=Am. J. Med. |volume=82 |issue=2 |pages=275–82 |year=1987 |pmid=3812520 |doi= |url=}}</ref><ref name="pmid25447624">{{cite journal |vauthors=Ahmad S, Kuraganti G, Steenkamp D |title=Hypercalcemic crisis: a clinical review |journal=Am. J. Med. |volume=128 |issue=3 |pages=239–45 |year=2015 |pmid=25447624 |doi=10.1016/j.amjmed.2014.09.030 |url=}}</ref><ref name="pmid3878002">{{cite journal |vauthors=Corlew DS, Bryda SL, Bradley EL, DiGirolamo M |title=Observations on the course of untreated primary hyperparathyroidism |journal=Surgery |volume=98 |issue=6 |pages=1064–71 |year=1985 |pmid=3878002 |doi= |url=}}</ref><ref name="pmid11493580">{{cite journal| author=Lips P| title=Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. | journal=Endocr Rev | year= 2001 | volume= 22 | issue= 4 | pages= 477-501 | pmid=11493580 | doi=10.1210/edrv.22.4.0437 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11493580  }} </ref>
*Metabolic complications:<ref name="pmid3878002">{{cite journal |vauthors=Corlew DS, Bryda SL, Bradley EL, DiGirolamo M |title=Observations on the course of untreated primary hyperparathyroidism |journal=Surgery |volume=98 |issue=6 |pages=1064–71 |year=1985 |pmid=3878002 |doi= |url=}}</ref><ref name="pmid11493580">{{cite journal| author=Lips P| title=Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. | journal=Endocr Rev | year= 2001 | volume= 22 | issue= 4 | pages= 477-501 | pmid=11493580 | doi=10.1210/edrv.22.4.0437 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11493580  }} </ref>
**Hypercalcemic crisis
**Hypercalcemic crisis
**Osteomalacia
**Osteomalacia
*Neuromuscular complications:
*Neuromuscular complications:
**Neuropathic muscle disease
**Neuropathic muscle disease
*Pregnancy related complications:<ref name="pmid17569990">{{cite journal |vauthors=Poomthavorn P, Ongphiphadhanakul B, Mahachoklertwattana P |title=Transient neonatal hypoparathyroidism in two siblings unmasking maternal normocalcemic hyperparathyroidism |journal=Eur. J. Pediatr. |volume=167 |issue=4 |pages=431–4 |year=2008 |pmid=17569990 |doi=10.1007/s00431-007-0528-6 |url=}}</ref>
*Pregnancy related complications:
**Neonatal hypoparathyroidism
**Neonatal hypoparathyroidism
*Psychiatric complications:<ref name="pmid19336505">{{cite journal |vauthors=Walker MD, McMahon DJ, Inabnet WB, Lazar RM, Brown I, Vardy S, Cosman F, Silverberg SJ |title=Neuropsychological features in primary hyperparathyroidism: a prospective study |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=6 |pages=1951–8 |year=2009 |pmid=19336505 |pmc=2690425 |doi=10.1210/jc.2008-2574 |url=}}</ref><ref name="pmid21917870">{{cite journal |vauthors=Espiritu RP, Kearns AE, Vickers KS, Grant C, Ryu E, Wermers RA |title=Depression in primary hyperparathyroidism: prevalence and benefit of surgery |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=11 |pages=E1737–45 |year=2011 |pmid=21917870 |doi=10.1210/jc.2011-1486 |url=}}</ref><ref name="pmid2608590">{{cite journal |vauthors=McAllion SJ, Paterson CR |title=Psychiatric morbidity in primary hyperparathyroidism |journal=Postgrad Med J |volume=65 |issue=767 |pages=628–31 |year=1989 |pmid=2608590 |pmc=2429194 |doi= |url=}}</ref>
*Psychiatric complications:
**Anxiety
**Anxiety
**Cognitive dysfunction including verbal memory and nonverbal abstraction
**Cognitive dysfunction including verbal memory and nonverbal abstraction
Line 153: Line 153:
**Lack of concentration
**Lack of concentration
**Sleep disturbances
**Sleep disturbances
*Renal complications:<ref name="pmid12412783">{{cite journal |vauthors=Peacock M |title=Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum |journal=J. Bone Miner. Res. |volume=17 Suppl 2 |issue= |pages=N87–94 |year=2002 |pmid=12412783 |doi= |url=}}</ref><ref name="pmid22470864">{{cite journal |vauthors=Lila AR, Sarathi V, Jagtap V, Bandgar T, Menon PS, Shah NS |title=Renal manifestations of primary hyperparathyroidism |journal=Indian J Endocrinol Metab |volume=16 |issue=2 |pages=258–62 |year=2012 |pmid=22470864 |pmc=3313745 |doi=10.4103/2230-8210.93745 |url=}}</ref><ref name="pmid19808852">{{cite journal |vauthors=Tassone F, Gianotti L, Emmolo I, Ghio M, Borretta G |title=Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism |journal=J. Clin. Endocrinol. Metab. |volume=94 |issue=11 |pages=4458–61 |year=2009 |pmid=19808852 |doi=10.1210/jc.2009-0587 |url=}}</ref>
*Renal complications:<ref name="pmid12412783">{{cite journal |vauthors=Peacock M |title=Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum |journal=J. Bone Miner. Res. |volume=17 Suppl 2 |issue= |pages=N87–94 |year=2002 |pmid=12412783 |doi= |url=}}</ref>
**Hypercalciuria
**Hypercalciuria
**Nephrolithiasis
**Nephrolithiasis
**Nephrocalcinosis
**Nephrocalcinosis
**Renal insufficiency (impairement of GFR)
**Renal insufficiency (impairement of GFR)
*Rheumatologic complications:<ref name="pmid20305774">{{cite journal |vauthors=Michael JW, Schlüter-Brust KU, Eysel P |title=The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee |journal=Dtsch Arztebl Int |volume=107 |issue=9 |pages=152–62 |year=2010 |pmid=20305774 |pmc=2841860 |doi=10.3238/arztebl.2010.0152 |url=}}</ref><ref>{{cite book | last = Hochberg | first = Marc | title = Rheumatology|chapter=204. Primary hyperparathyroidism: rheumatologic manifestations and bone disease |page=1668| publisher = Mosby/Elsevier | location = Philadelphia, PA | year = 2015 | isbn = 9780323091381}}</ref><ref name="pmid11890884">{{cite journal |vauthors=Rubin MR, Silverberg SJ |title=Rheumatic manifestations of primary hyperparathyroidism and parathyroid hormone therapy |journal=Curr Rheumatol Rep |volume=4 |issue=2 |pages=179–85 |year=2002 |pmid=11890884 |doi= |url=}}</ref>
*Rheumatologic complications:
**Gout
**Gout
**Osteoarthritis
**Osteoarthritis
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===Secondary hyperparathyroidism===
===Secondary hyperparathyroidism===
Complications of secondary hyperparathyroidism includes:
Complications of secondary hyperparathyroidism includes:
*Cardiovascular complications:<ref name="pmid11256521">{{cite journal |vauthors=Strózecki P, Adamowicz A, Nartowicz E, Odrowaz-Sypniewska G, Włodarczyk Z, Manitius J |title=Parathormon, calcium, phosphorus, and left ventricular structure and function in normotensive hemodialysis patients |journal=Ren Fail |volume=23 |issue=1 |pages=115–26 |year=2001 |pmid=11256521 |doi= |url=}}</ref>
*Cardiovascular complications:
**Impaired left ventricular diastolic function
**Impaired left ventricular diastolic function
**Left ventricular hypertrophy
**Left ventricular hypertrophy
*Hematologic complication:<ref name="pmid6118720">{{cite journal |vauthors=Remuzzi G, Benigni A, Dodesini P, Schieppati A, Livio M, Poletti E, Mecca G, de Gaetano G |title=Parathyroid hormone inhibits human platelet function |journal=Lancet |volume=2 |issue=8259 |pages=1321–3 |year=1981 |pmid=6118720 |doi= 10.1016/S0140-6736(81)91343-X |url=http://www.sciencedirect.com/science/article/pii/S014067368191343X?via%3Dihub}}</ref>
*Hematologic complication:
**Platlet function inhibition
**Platlet function inhibition
*Metabolic complicattions:<ref name="pmid22258399">{{cite journal |vauthors=Saab G, Whaley-Connell A, Bombeck A, Kurella Tamura M, Li S, Chen SC, McFarlane SI, Sowers JR, Norris K, Bakris GL, McCullough PA |title=The Association between Parathyroid Hormone Levels and the Cardiorenal Metabolic Syndrome in Non-Diabetic Chronic Kidney Disease |journal=Cardiorenal Med |volume=1 |issue=2 |pages=123–130 |year=2011 |pmid=22258399 |pmc=3101512 |doi=10.1159/000327149 |url=}}</ref><ref name="HjelmesæthHofsø2009">{{cite journal|last1=Hjelmesæth|first1=Jøran|last2=Hofsø|first2=Dag|last3=Aasheim|first3=Erlend T|last4=Jenssen|first4=Trond|last5=Moan|first5=Johan|last6=Hager|first6=Helle|last7=Røislien|first7=Jo|last8=Bollerslev|first8=Jens|title=Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study|journal=Cardiovascular Diabetology|volume=8|issue=1|year=2009|pages=7|issn=1475-2840|doi=10.1186/1475-2840-8-7}}</ref>
*Metabolic complicattions:


**Metabolic syndrome
**Metabolic syndrome
*Musculoskeletal complications:<ref name="pmid9158318">{{cite journal |vauthors=Spaulding CM, Young G |title=Osteitis fibrosa cystica and chronic renal failure |journal=J Am Podiatr Med Assoc |volume=87 |issue=5 |pages=238–40 |year=1997 |pmid=9158318 |doi=10.7547/87507315-87-5-238 |url=http://www.japmaonline.org/doi/10.7547/87507315-87-5-238?url_ver=Z39.88-2003&rfr_dat=cr_pub%3Dpubmed&rfr_id=ori:rid:crossref.org&code=pmas-site}}</ref><ref name="pmid328228">{{cite journal |vauthors=Eastwood JB |title=Renal osteodystrophy--a radiological review |journal=CRC Crit Rev Diagn Imaging |volume=9 |issue=1 |pages=77–104 |year=1977 |pmid=328228 |doi= |url=}}</ref><ref name="pmid10633462">{{cite journal |vauthors=Adams JE |title=Renal bone disease: radiological investigation |journal=Kidney Int. Suppl. |volume=73 |issue= |pages=S38–41 |year=1999 |pmid=10633462 |doi= |url=}}</ref>
*Musculoskeletal complications:
**Renal Osteodystrophy
**Renal Osteodystrophy
***Brown cysts
***Brown cysts
Line 179: Line 179:
***Osteoporosis
***Osteoporosis
***Osteosclerosis
***Osteosclerosis
*Neurologic complications:<ref name="pmid6892917">{{cite journal |vauthors=Goldstein DA, Feinstein EI, Chui LA, Pattabhiraman R, Massry SG |title=The relationship between the abnormalities in electroencephalogram and blood levels of parathyroid hormone in dialysis patients |journal=J. Clin. Endocrinol. Metab. |volume=51 |issue=1 |pages=130–4 |year=1980 |pmid=6892917 |doi=10.1210/jcem-51-1-130 |url=}}</ref><ref name="pmid205786">{{cite journal |vauthors=Avram MM, Feinfeld DA, Huatuco AH |title=Search for the uremic toxin. Decreased motor-nerve conduction velocity and elevated parathyroid hormone in uremia |journal=N. Engl. J. Med. |volume=298 |issue=18 |pages=1000–3 |year=1978 |pmid=205786 |doi=10.1056/NEJM197805042981805 |url=}}</ref>
*Neurologic complications:
**Electroencephalogram abnormalities
**Electroencephalogram abnormalities
**Uremic neuropathy
**Uremic neuropathy
*Neuromuscular complications:<ref name="pmid47234">{{cite journal |vauthors=Mallette LE, Patten BM, Engel WK |title=Neuromuscular disease in secondary hyperparathyroidism |journal=Ann. Intern. Med. |volume=82 |issue=4 |pages=474–83 |year=1975 |pmid=47234 |doi= |url=}}</ref>
*Neuromuscular complications:
**Neuropathic muscle disease
**Neuropathic muscle disease
*System non-specific complications:<ref name="pmid9531176">{{cite journal |vauthors=Block GA, Hulbert-Shearon TE, Levin NW, Port FK |title=Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study |journal=Am. J. Kidney Dis. |volume=31 |issue=4 |pages=607–17 |year=1998 |pmid=9531176 |doi= |url=}}</ref>
*System non-specific complications:
**Metastatic calcifications
**Metastatic calcifications


===Tertiary hyperparathyroidism===
===Tertiary hyperparathyroidism===
Complications of tertiary hyperparathyroidism post renal transplantation includes:<ref name="pmid12714225">{{cite journal |vauthors=Jevtic V |title=Imaging of renal osteodystrophy |journal=Eur J Radiol |volume=46 |issue=2 |pages=85–95 |year=2003 |pmid=12714225 |doi= 10.1016/S0720-048X(03)00072-X|url=http://www.sciencedirect.com/science/article/pii/S0720048X0300072X?via%3Dihub}}</ref>
Complications of tertiary hyperparathyroidism post renal transplantation includes:<ref name="pmid12714225">{{cite journal |vauthors=Jevtic V |title=Imaging of renal osteodystrophy |journal=Eur J Radiol |volume=46 |issue=2 |pages=85–95 |year=2003 |pmid=12714225 |doi= 10.1016/S0720-048X(03)00072-X|url=http://www.sciencedirect.com/science/article/pii/S0720048X0300072X?via%3Dihub}}</ref>
*Metabolic complications:<ref name="pmid9451734">{{cite journal |vauthors=Barbur MA, Kurjak M, Becker K |title=[Systematic calciphylaxis in chronic renal failure: fulminant course after kidney transplantation] |language=German |journal=Pathologe |volume=18 |issue=6 |pages=453–8 |year=1997 |pmid=9451734 |doi= |url=}}</ref>
*Metabolic complications:
**Calciphylaxis
**Calciphylaxis
*Musculoskeletal complications:
*Musculoskeletal complications:
**Musculoskeletal infections
**Musculoskeletal infections
**Osteonecrosis
**Osteonecrosis
*Neuromuscular complications:<ref name="pmid646555">{{cite journal |vauthors=Gerhardt RE, Zeitlin EL |title=Neuromuscular disease in tertiary hyperparathyroidism |journal=Arch. Intern. Med. |volume=138 |issue=6 |pages=1013–5 |year=1978 |pmid=646555 |doi= |url=}}</ref>
*Neuromuscular complications:
**Neuropathic muscle disease
**Neuropathic muscle disease
*Renal complications:<ref name="pmid11590898">{{cite journal |vauthors=Kim H, Cheigh JS, Ham HW |title=Urinary stones following renal transplantation |journal=Korean J. Intern. Med. |volume=16 |issue=2 |pages=118–22 |year=2001 |pmid=11590898 |pmc=4531707 |doi= |url=}}</ref>
*Renal complications:
**Nephrolithiasis
**Nephrolithiasis
*Rheumatologic complications:<ref name="pmid2712794">{{cite journal |vauthors=Adler JS, Cameron DC |title=Erosive spondylo-arthropathy and tertiary hyperparathyroidism |journal=Australas Radiol |volume=33 |issue=1 |pages=90–2 |year=1989 |pmid=2712794 |doi= |url=}}</ref>
*Rheumatologic complications:
**Destructive or erosive spondyloarthropathy
**Destructive or erosive spondyloarthropathy
*System non-specific complications:
*System non-specific complications:
Line 212: Line 212:
*Hyperphosphatemia and metastatic calcification results due elevated product of serum calcium and serum phosphorus. Both conditions are present in patients with secondary hyperparathyroidism in presence of end stage renal disease. This leads to a significant increase in morbidity and mortality. Aggressive control of hyperphosphatemia may improve prognosis<ref name="pmid9531176">{{cite journal |vauthors=Block GA, Hulbert-Shearon TE, Levin NW, Port FK |title=Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study |journal=Am. J. Kidney Dis. |volume=31 |issue=4 |pages=607–17 |year=1998 |pmid=9531176 |doi= |url=}}</ref>.
*Hyperphosphatemia and metastatic calcification results due elevated product of serum calcium and serum phosphorus. Both conditions are present in patients with secondary hyperparathyroidism in presence of end stage renal disease. This leads to a significant increase in morbidity and mortality. Aggressive control of hyperphosphatemia may improve prognosis<ref name="pmid9531176">{{cite journal |vauthors=Block GA, Hulbert-Shearon TE, Levin NW, Port FK |title=Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study |journal=Am. J. Kidney Dis. |volume=31 |issue=4 |pages=607–17 |year=1998 |pmid=9531176 |doi= |url=}}</ref>.


*Prognosis of tertiary hyperparathyroidism is generally good after resection of abnormal hyperplastic gland.<ref name="pmid11981213">{{cite journal |vauthors=Nichol PF, Starling JR, Mack E, Klovning JJ, Becker BN, Chen H |title=Long-term follow-up of patients with tertiary hyperparathyroidism treated by resection of a single or double adenoma |journal=Ann. Surg. |volume=235 |issue=5 |pages=673–8; discussion 678–80 |year=2002 |pmid=11981213 |pmc=1422493 |doi= |url=}}</ref>
*Prognosis of tertiary hyperparathyroidism is generally good after resection of abnormal hyperplastic gland.




=ECG=
=ECG=
There are no CT scan findings associated with hyperparathyroidism. However, a CT scan may be helpful in the diagnosis of cardiac complications of hyperparathyroidism.
There are no CT scan findings associated with hyperparathyroidism. However, a CT scan may be helpful in the diagnosis of cardiac complications of hyperparathyroidism.
Findings on ECG are due to hypercalcemia and includes:<ref name="pmid8201301">{{cite journal |vauthors=Lind L, Ljunghall S |title=Serum calcium and the ECG in patients with primary hyperparathyroidism |journal=J Electrocardiol |volume=27 |issue=2 |pages=99–103 |year=1994 |pmid=8201301 |doi= |url=}}</ref>
Findings on ECG are due to hypercalcemia and includes:
*ST segment - ST segment is short in patients with hyperparathyroidism when compared to normocalcemic patients. This represents a decrease in systolic interval.
*ST segment - ST segment is short in patients with hyperparathyroidism when compared to normocalcemic patients. This represents a decrease in systolic interval.
*QRS complex - QRS complex has an increased amplitudein patients with hyperparathyroidism when compared to normocalcemic patients. This represents an increase in ventricular muscle mass.
*QRS complex - QRS complex has an increased amplitudein patients with hyperparathyroidism when compared to normocalcemic patients. This represents an increase in ventricular muscle mass.
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|-
|-
|
|
Finding in primary hyperparathyroidism includes:<ref name="pmid24614783">{{cite journal |vauthors=Lachungpa T, Sarawagi R, Chakkalakkoombil SV, Jayamohan AE |title=Imaging features of primary hyperparathyroidism |journal=BMJ Case Rep |volume=2014 |issue= |pages= |year=2014 |pmid=24614783 |pmc=3962932 |doi=10.1136/bcr-2013-203521 |url=}}</ref>
Finding in primary hyperparathyroidism includes:
*Subperiosteal bone resorption
*Subperiosteal bone resorption
**Classically affects the radial aspects of the proximal and middle phalanges of the 2nd and 3rd fingers
**Classically affects the radial aspects of the proximal and middle phalanges of the 2nd and 3rd fingers
Line 251: Line 251:
*Chondrocalcinosis
*Chondrocalcinosis


X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological. <ref name="pmid7785573">{{cite journal |vauthors=Tigges S, Nance EP, Carpenter WA, Erb R |title=Renal osteodystrophy: imaging findings that mimic those of other diseases |journal=AJR Am J Roentgenol |volume=165 |issue=1 |pages=143–8 |year=1995 |pmid=7785573 |doi=10.2214/ajr.165.1.7785573 |url=http://www.ajronline.org/doi/pdf/10.2214/ajr.165.1.7785573}}</ref>
X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological.  
Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency:
Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency:
*Subperiosteal bone resorption
*Subperiosteal bone resorption
Line 283: Line 283:
=CT scan=
=CT scan=
*Good quality preoperative evaluation favors post operative results.
*Good quality preoperative evaluation favors post operative results.
*4-Dimentional CT scan is an investigation for preoperative localizing of hyperfunctioning pituitary gland.<ref name="pmid22798226">{{cite journal| author=Hunter GJ, Schellingerhout D, Vu TH, Perrier ND, Hamberg LM| title=Accuracy of four-dimensional CT for the localization of abnormal parathyroid glands in patients with primary hyperparathyroidism. | journal=Radiology | year= 2012 | volume= 264 | issue= 3 | pages= 789-95 | pmid=22798226 | doi=10.1148/radiol.12110852 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22798226  }} </ref>
*4-Dimentional CT scan is an investigation for preoperative localizing of hyperfunctioning pituitary gland.
*4D-CT may be used for preoperative localization of hyper-functioning parathyroid glands in hyperparathyroidism. 4D-CT is significantly more sensitive than sestamibi imaging and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands.<ref name="pmid17188140">{{cite journal| author=Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD et al.| title=Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. | journal=Surgery | year= 2006 | volume= 140 | issue= 6 | pages= 932-40; discussion 940-1 | pmid=17188140 | doi=10.1016/j.surg.2006.07.028 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17188140  }} </ref>
*4D-CT may be used for preoperative localization of hyper-functioning parathyroid glands in hyperparathyroidism. 4D-CT is significantly more sensitive than sestamibi imaging and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands.
*The name 4D-CT refers to  3-dimensional CT scanning plus additional dimension of changes observed with respect to time as perfusion of contrast occurs. The principle is similar to CT angiography.
*The name 4D-CT refers to  3-dimensional CT scanning plus additional dimension of changes observed with respect to time as perfusion of contrast occurs. The principle is similar to CT angiography.
*4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout).
*4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout).
*4D-CT has a sensitive of 88% in preoperative lateralizing hyper-functioning parathyroid glands to one side of neck when compared to sestamibi imaging (68% to 86% sensitive) and ultrasound (61% to 88% sensitive).<ref name="pmid21367374">{{cite journal| author=Eichhorn-Wharry LI, Carlin AM, Talpos GB| title=Mild hypercalcemia: an indication to select 4-dimensional computed tomography scan for preoperative localization of parathyroid adenomas. | journal=Am J Surg | year= 2011 | volume= 201 | issue= 3 | pages= 334-8; discussion 338 | pmid=21367374 | doi=10.1016/j.amjsurg.2010.08.033 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21367374  }} </ref>
*4D-CT has a sensitive of 88% in preoperative lateralizing hyper-functioning parathyroid glands to one side of neck when compared to sestamibi imaging (68% to 86% sensitive) and ultrasound (61% to 88% sensitive).
*4D-CT has a sensitive of 79-88% in preoperative localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior) when compared to sestamibi imaging (33% to 40% sensitive) and ultrasound (29% to 48% sensitive).<ref name="pmid26359149">{{cite journal| author=Griffith B, Chaudhary H, Mahmood G, Carlin AM, Peterson E, Singer M et al.| title=Accuracy of 2-Phase Parathyroid CT for the Preoperative Localization of Parathyroid Adenomas in Primary Hyperparathyroidism. | journal=AJNR Am J Neuroradiol | year= 2015 | volume= 36 | issue= 12 | pages= 2373-9 | pmid=26359149 | doi=10.3174/ajnr.A4473 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26359149  }} </ref>
*4D-CT has a sensitive of 79-88% in preoperative localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior) when compared to sestamibi imaging (33% to 40% sensitive) and ultrasound (29% to 48% sensitive).
*4D-CT has a specificity of 75-100% in preoperative localizing the hyper-functioning parathyroid gland.<ref name="pmid21178047">{{cite journal| author=Beland MD, Mayo-Smith WW, Grand DJ, Machan JT, Monchik JM| title=Dynamic MDCT for localization of occult parathyroid adenomas in 26 patients with primary hyperparathyroidism. | journal=AJR Am J Roentgenol | year= 2011 | volume= 196 | issue= 1 | pages= 61-5 | pmid=21178047 | doi=10.2214/AJR.10.4459 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21178047  }} </ref>
*4D-CT has a specificity of 75-100% in preoperative localizing the hyper-functioning parathyroid gland.
*4D-CT enables an improved planning preoperativively, particularly in case of reoperation.
*4D-CT enables an improved planning preoperativively, particularly in case of reoperation.
*A modified technique of 4D-CT/Ultrasound (Mod 4D-CT/US) has a sensitivity of 94% and specificity of 96% for lateralizing the hyperfunctioning parathyroid glands to one side of the neck. Mod 4D-CT/US has a sensitivity of 82% and specificity of 93% for localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior). Mod 4D-CT/US has a positive predictive vaue of 92% for single-gland disease and 75% for multi-gland disease.Mod 4D-CT/US has a negative predictive value of 73% for single-gland disease and 92% multi-gland disease.<ref name="pmid21557243">{{cite journal| author=Kutler DI, Moquete R, Kazam E, Kuhel WI| title=Parathyroid localization with modified 4D-computed tomography and ultrasonography for patients with primary hyperparathyroidism. | journal=Laryngoscope | year= 2011 | volume= 121 | issue= 6 | pages= 1219-24 | pmid=21557243 | doi=10.1002/lary.21783 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21557243  }} </ref>
*A modified technique of 4D-CT/Ultrasound (Mod 4D-CT/US) has a sensitivity of 94% and specificity of 96% for lateralizing the hyperfunctioning parathyroid glands to one side of the neck. Mod 4D-CT/US has a sensitivity of 82% and specificity of 93% for localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior). Mod 4D-CT/US has a positive predictive vaue of 92% for single-gland disease and 75% for multi-gland disease.Mod 4D-CT/US has a negative predictive value of 73% for single-gland disease and 92% multi-gland disease.
*The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.
*The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.
=MRI=
=MRI=
Line 299: Line 299:


=Sestamibi scintigraphy=
=Sestamibi scintigraphy=
*Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) scintigraphy is the most popular investigation for preoperative localization of hyper-functioning parathyroid glands.<ref name="pmid16150247">{{cite journal| author=Palestro CJ, Tomas MB, Tronco GG| title=Radionuclide imaging of the parathyroid glands. | journal=Semin Nucl Med | year= 2005 | volume= 35 | issue= 4 | pages= 266-76 | pmid=16150247 | doi=10.1053/j.semnuclmed.2005.06.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16150247  }} </ref>
*Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) scintigraphy is the most popular investigation for preoperative localization of hyper-functioning parathyroid glands.
*Most of the sestamibi is retained in mitochondria of thyroid and abnormal parathyroid tissue and is a function of mitochondrial activity.<ref name="pmid11742331">{{cite journal| author=Hetrakul N, Civelek AC, Stagg CA, Udelsman R| title=In vitro accumulation of technetium-99m-sestamibi in human parathyroid mitochondria. | journal=Surgery | year= 2001 | volume= 130 | issue= 6 | pages= 1011-8 | pmid=11742331 | doi=10.1067/msy.2001.118371 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11742331  }} </ref>
*Most of the sestamibi is retained in mitochondria of thyroid and abnormal parathyroid tissue and is a function of mitochondrial activity.
*The basis of this "single-isotope, double-phase technique" is that sestamibi washes out of the thyroid more rapidly than from abnormal parathyroid tissue.
*The basis of this "single-isotope, double-phase technique" is that sestamibi washes out of the thyroid more rapidly than from abnormal parathyroid tissue.
*As all parathyroid lesions does not retain sestamibi nor all thyroid tissue washes out quickly, subtraction imaging may be beneficial.<ref name="pmid8288719">{{cite journal| author=Thulé P, Thakore K, Vansant J, McGarity W, Weber C, Phillips LS| title=Preoperative localization of parathyroid tissue with technetium-99m sestamibi 123I subtraction scanning. | journal=J Clin Endocrinol Metab | year= 1994 | volume= 78 | issue= 1 | pages= 77-82 | pmid=8288719 | doi=10.1210/jcem.78.1.8288719 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8288719  }} </ref>
*As all parathyroid lesions does not retain sestamibi nor all thyroid tissue washes out quickly, subtraction imaging may be beneficial.
{| class="wikitable"
! colspan="4" |Factors influencing Sestamibi-SPECT scan
|-
| colspan="2" |Biological factors
|
|Sensitivity
|-
|Biochemical factors
|Serum calcium
|Higher calcium
|Increased
|-
|
|Serum Parathyroid hormone
|Higher
|Increased
|-
|
|Vitamin D
|
|
|-
|
|
|
|
|}
 
==References==
==References==
<references />

Revision as of 15:54, 31 August 2017

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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]

Classification

Classification of hyperparathyridism
Features Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism
Pathology Hyperfunction of parathyroid cells due to hyperplasia, adenoma or carcinoma. Physiological stimulation of parathyroid in response to hypocalcaemia. Following long term physiological stimulation leading to hyperplasia.
Cause
Associations May be associated with multiple endocrine neoplasia. Usually due to chronic renal failure or other causes of Vitamin D deficiency. Seen in chronic renal failure.
Serum calcium High Low/Normal High
Serum phosphate Low/Normal High High
Management Usually surgery if symptomatic. Cincacalcet can be considered in those not fit for surgery. Treatment of underlying cause. Usually cinacalcet or surgery in those that don't respond.

Causes

Overview

Hyperparathyroidism is caused by an increase in concentration of parathyroid hormone in serum. There are three type of hyperparathyroidism including primary, secondary and tertiary hyperparathyroidism. The are an array of different causes for all types of hyperparathyroidism.

Causes of Primary hyperparathyroidism

Causes of primary hyperparathyroidism are as follows:

Common causes

  • Parathyroid adenoma
    • Usually single gland affected
    • Sometimes multiple gland affected

Less common causes

  • Parathyroid hyperplasia
  • Parathyroid carcinoma
  • Familial isloated hyperparathyroidism
  • Radiation exposure (due to development of parathyroid adenoma or parathyroid hyperplasia)
  • Celiac disease

Genetic causes

  • HRPT2 gene mutations:
    • HRPT2 gene code for parafibromin protein.
    • HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
    • HRTP2 gene mutations increases risk of parathyroid carcinoma.
  • Cyclin D1 gene (CCND1)/PRAD1 gene:
    • PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
    • Cyclin D1 gene translocation and oncogene action observerd in 8% of adenomas
    • Cyclin D1 gene overexpression is pbserved in 20% to 40% of parathyroid adenomas
  • MEN1 gene:[1]
    • MEN1 is a tumor supressor gene on chronosome 11q13.
    • Somatic loss of single MEN1 allele is observed in 25% to 40% of sporadic parathyroid adenomas.

Causes of secondary hyperparathyroidism

Causes of secondary hyperparathyroidism are as follows:

Common causes

  • Chronic renal failure (leading to parathyroid hyperplasia)
  • Vitamin D deficiency

Less common causes

  • Severe calcium deficiency
  • Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)
  • Malabsorption syndrome

Causes of tertiary hyperparathyroidism

Causes of tertiary hyperparathyroidism are as follows:

Common causes

  • Chronic renal failure (leading to parathyroid hyperplasia)
  • Renal transplant patients

Less common cause

  • Long standing celiac disease[2]


Pathogenesis

Associated conditions

  • Hypercalcemia
  • Chronic renal failure
  • Osteitis fibrous cystica
  • Osteoporosis
  • Osteomalacia
  • Osteoarthritis
  • Brown tumor
  • Multiple endocrine neoplasia type 1, type 2A, and type 4
  • Familial isolated hyperparathyroidism
  • Neonatal severe hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
  • Hyperparathyroid-jaw tumor syndrome
  • Pancreatitis

Natural history, Prognosis and Complications

Natural history

  • Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
  • If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.
  • Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable.
  • Secondary hyperparathyroidism leads to vascular calcification due to elevated calcium and phosphorus levels. This is strongly associated with increase in morbidity and mortality.
  • If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.
  • Tertiary hyperparathyroidism usually develops in post renal transplant patients.
  • If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.

Complications

Primary hyperparathyroidism

Majority of complications of primary hyperparathyroidism are due to hypercalcemia. Common complications of primary hyperparathyroidism include:

  • Bone related complication:
    • Brown tumor
    • Osteitis fibrous cystica
    • Osteoporosis
  • Cardiac complications:
    • Aortic and mitral valve calcification
    • Calcific deposits in the myocardium
    • Left ventricular hypertrophy
  • Endocrine complications:[3]
    • Pancreatitis
  • Gastrointestinal complications:
    • Peptic ulcer disease
  • Metabolic complications:[4][5]
    • Hypercalcemic crisis
    • Osteomalacia
  • Neuromuscular complications:
    • Neuropathic muscle disease
  • Pregnancy related complications:
    • Neonatal hypoparathyroidism
  • Psychiatric complications:
    • Anxiety
    • Cognitive dysfunction including verbal memory and nonverbal abstraction
    • Depression
    • Irritability
    • Lack of concentration
    • Sleep disturbances
  • Renal complications:[6]
    • Hypercalciuria
    • Nephrolithiasis
    • Nephrocalcinosis
    • Renal insufficiency (impairement of GFR)
  • Rheumatologic complications:
    • Gout
    • Osteoarthritis
    • Pseudogout

Secondary hyperparathyroidism

Complications of secondary hyperparathyroidism includes:

  • Cardiovascular complications:
    • Impaired left ventricular diastolic function
    • Left ventricular hypertrophy
  • Hematologic complication:
    • Platlet function inhibition
  • Metabolic complicattions:
    • Metabolic syndrome
  • Musculoskeletal complications:
    • Renal Osteodystrophy
      • Brown cysts
      • Osteitis fibrosa cystica
      • Osteoporosis
      • Osteosclerosis
  • Neurologic complications:
    • Electroencephalogram abnormalities
    • Uremic neuropathy
  • Neuromuscular complications:
    • Neuropathic muscle disease
  • System non-specific complications:
    • Metastatic calcifications

Tertiary hyperparathyroidism

Complications of tertiary hyperparathyroidism post renal transplantation includes:[7]

  • Metabolic complications:
    • Calciphylaxis
  • Musculoskeletal complications:
    • Musculoskeletal infections
    • Osteonecrosis
  • Neuromuscular complications:
    • Neuropathic muscle disease
  • Renal complications:
    • Nephrolithiasis
  • Rheumatologic complications:
    • Destructive or erosive spondyloarthropathy
  • System non-specific complications:
    • Amyloid deposition
    • Metastatic calcifications

Prognosis

  • Prognosis of primary hyperparathyroidism is generally excellent after parathyroidectomy.
  • The complications of primary hyperparathyroidism resolves after the treatment.
  • Untreated complication of primary hyperparathyroidism may be fatal.[4]
  • Effective treatment can reduce morbidity and mortality associated with uncontrolled secondary hyperparathyroidism.[8]
  • Hyperphosphatemia and metastatic calcification results due elevated product of serum calcium and serum phosphorus. Both conditions are present in patients with secondary hyperparathyroidism in presence of end stage renal disease. This leads to a significant increase in morbidity and mortality. Aggressive control of hyperphosphatemia may improve prognosis[9].
  • Prognosis of tertiary hyperparathyroidism is generally good after resection of abnormal hyperplastic gland.


ECG

There are no CT scan findings associated with hyperparathyroidism. However, a CT scan may be helpful in the diagnosis of cardiac complications of hyperparathyroidism. Findings on ECG are due to hypercalcemia and includes:

  • ST segment - ST segment is short in patients with hyperparathyroidism when compared to normocalcemic patients. This represents a decrease in systolic interval.
  • QRS complex - QRS complex has an increased amplitudein patients with hyperparathyroidism when compared to normocalcemic patients. This represents an increase in ventricular muscle mass.
  • T wave - T wave is prolonged in patients with hyperparathyroidism when compared to normocalcemic patients.

X-ray

Finding in primary hyperparathyroidism includes:

  • Subperiosteal bone resorption
    • Classically affects the radial aspects of the proximal and middle phalanges of the 2nd and 3rd fingers
    • Medial aspect of tibia, femur, humerus
    • Phalyngeal tuft erosion (acro-osteolysis)
    • Lamina dura around teeth (floating teeth)
  • Endoosteal bone resorption
    • Widening of medullary cavity
    • Thinning of the inner cortex
  • Subchondral resorption
    • Lateral end of the clavicles
    • Symphysis pubis
    • Sacroiliac joints
  • Subligamentous resorption
    • Ischial tuberosity
    • Humeral tuberosity
    • Trochanters
    • Inferior surface of calcaneus
    • Inferior margin of lateral clavicle
  • Intracortical resorption: cigar/oval-shaped or tunnel-shaped radiolucency in the cortex
  • Osteopaenia
  • Brown tumours
  • Salt and pepper sign in the skull (pepper pot skull)
  • Chondrocalcinosis

X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological. Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency:

  • Subperiosteal bone resorption
    • Radial aspect of middle phalanges of index and long fingers are involved.
  • Subchondral resorption
    • Hands, hips, shoulders, patellofemoral and sacroiliac joints are involved.
    • Hands are involves in the ulnar side.
    • Distal interphalangeal and metacarpophalangeal joints are involved.
    • Subchondral resorption is very severe. It may lead to bony collapse.
  • Subligamentous resorption
    • Retrocalcaneal bursa and insertion of planter aponeurosis may be involved.
  • Severe osteopenia, may be complicated by pathologic fractures
  • Osteosclerosis, e.g. rugger-jersey spine
  • Brown tumor
  • Amyloid deposition
    • May be manifested as lytic bone lesion on radiograph
  • Soft tissue and vascular calcification
  • Superior and inferior rib notching
  • Osteonecrosis may be often observed in patients in whom steroid is administered for prevention of renal transplant rejection.
Subperiosteal bone resorption - Source:Radiopedia
Brown tumors - Source:Case courtesy of A.Prof Frank Gaillard, Radiopedia
Normal skull compared to Salt & pepper appearance of skull - Source:Radiopedia
Acro-osteolytis, terminal tufts erosion - Source:Case courtesy of Dr Andrew Dixon, Radiopedia

CT scan

  • Good quality preoperative evaluation favors post operative results.
  • 4-Dimentional CT scan is an investigation for preoperative localizing of hyperfunctioning pituitary gland.
  • 4D-CT may be used for preoperative localization of hyper-functioning parathyroid glands in hyperparathyroidism. 4D-CT is significantly more sensitive than sestamibi imaging and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands.
  • The name 4D-CT refers to 3-dimensional CT scanning plus additional dimension of changes observed with respect to time as perfusion of contrast occurs. The principle is similar to CT angiography.
  • 4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout).
  • 4D-CT has a sensitive of 88% in preoperative lateralizing hyper-functioning parathyroid glands to one side of neck when compared to sestamibi imaging (68% to 86% sensitive) and ultrasound (61% to 88% sensitive).
  • 4D-CT has a sensitive of 79-88% in preoperative localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior) when compared to sestamibi imaging (33% to 40% sensitive) and ultrasound (29% to 48% sensitive).
  • 4D-CT has a specificity of 75-100% in preoperative localizing the hyper-functioning parathyroid gland.
  • 4D-CT enables an improved planning preoperativively, particularly in case of reoperation.
  • A modified technique of 4D-CT/Ultrasound (Mod 4D-CT/US) has a sensitivity of 94% and specificity of 96% for lateralizing the hyperfunctioning parathyroid glands to one side of the neck. Mod 4D-CT/US has a sensitivity of 82% and specificity of 93% for localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior). Mod 4D-CT/US has a positive predictive vaue of 92% for single-gland disease and 75% for multi-gland disease.Mod 4D-CT/US has a negative predictive value of 73% for single-gland disease and 92% multi-gland disease.
  • The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.

MRI

MRI may be helpful in the preoperative evaluation of hype-functioning parathyroid glands.

SPECT

Sestamibi scintigraphy

  • Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) scintigraphy is the most popular investigation for preoperative localization of hyper-functioning parathyroid glands.
  • Most of the sestamibi is retained in mitochondria of thyroid and abnormal parathyroid tissue and is a function of mitochondrial activity.
  • The basis of this "single-isotope, double-phase technique" is that sestamibi washes out of the thyroid more rapidly than from abnormal parathyroid tissue.
  • As all parathyroid lesions does not retain sestamibi nor all thyroid tissue washes out quickly, subtraction imaging may be beneficial.
Factors influencing Sestamibi-SPECT scan
Biological factors Sensitivity
Biochemical factors Serum calcium Higher calcium Increased
Serum Parathyroid hormone Higher Increased
Vitamin D

References

  1. ↑ Westin G, Björklund P, Akerström G (2009). "Molecular genetics of parathyroid disease". World J Surg. 33 (11): 2224–33. doi:10.1007/s00268-009-0022-6. PMID 19373510.
  2. ↑ Maida MJ, Praveen E, Crimmins SR, Swift GL (2006). "Coeliac disease and primary hyperparathyroidism: an association?". Postgrad Med J. 82 (974): 833–5. doi:10.1136/pgmj.2006.045500. PMC 2653933. PMID 17148709.
  3. ↑ Bai HX, Giefer M, Patel M, Orabi AI, Husain SZ (2012). "The association of primary hyperparathyroidism with pancreatitis". J. Clin. Gastroenterol. 46 (8): 656–61. doi:10.1097/MCG.0b013e31825c446c. PMC 4428665. PMID 22874807.
  4. ↑ 4.0 4.1 Corlew DS, Bryda SL, Bradley EL, DiGirolamo M (1985). "Observations on the course of untreated primary hyperparathyroidism". Surgery. 98 (6): 1064–71. PMID 3878002.
  5. ↑ Lips P (2001). "Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications". Endocr Rev. 22 (4): 477–501. doi:10.1210/edrv.22.4.0437. PMID 11493580.
  6. ↑ Peacock M (2002). "Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum". J. Bone Miner. Res. 17 Suppl 2: N87–94. PMID 12412783.
  7. ↑ Jevtic V (2003). "Imaging of renal osteodystrophy". Eur J Radiol. 46 (2): 85–95. doi:10.1016/S0720-048X(03)00072-X. PMID 12714225.
  8. ↑ 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.
  9. ↑ Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998). "Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study". Am. J. Kidney Dis. 31 (4): 607–17. PMID 9531176.
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