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Hyperparathyroidism Microchapters

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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)[1][2][3]
  • Celiac disease[4][5]

Genetic causes

  • HRPT2 gene mutations:[6]
    • 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:[7][8]
    • 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:[7][9]
    • 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)[10]
  • Vitamin D deficiency[11]

Less common causes

  • Severe calcium deficiency[12]
  • Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)[13]
  • Malabsorption syndrome[14]

Causes of tertiary hyperparathyroidism

Causes of tertiary hyperparathyroidism are as follows:

Common causes

  • Chronic renal failure (leading to parathyroid hyperplasia)
  • Renal transplant patients[15]

Less common cause

  • Long standing celiac disease[4]


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[16]

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 hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.[17][18]

Complications

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

  • Bone related complication:[19][20]
    • Brown tumor
    • Osteitis fibrous cystica
    • Osteoporosis
  • Cardiac complications:[21]
    • Aortic and mitral valve calcification
    • Calcific deposits in the myocardium
    • Left ventricular hypertrophy
  • Endocrine complications:[16]
    • Pancreatitis
  • Gastrointestinal complications:[22]
    • Peptic ulcer disease
  • Metabolic complications:[23][24][22][11]
    • Hypercalcemic crisis
    • Osteomalacia
  • Pregnancy related complications:
    • Neonatal hypoparathyroidism
  • Psychiatric complications:[25][26][27]
    • Anxiety
    • Cognitive dysfunction including verbal memory and nonverbal abstraction
    • Depression
    • Irritability
    • Lack of concentration
    • Sleep disturbances
  • Renal complications:[17][28][29]
    • Hypercalciuria
    • Nephrolithiasis
    • Nephrocalcinosis
    • Renal insufficiency (impairement of GFR)
  • Rheumatologic complications:[30][31]
    • Gout
    • Osteoarthritis
    • Pseudogout

Prognosis

  • Prognosis is generally excellent after parathyroidectomy.
  • The complications resolves after the treatment.
  • Untreated complication may be fatal.[22]


References

  1. ↑ Boehm BO, Rosinger S, Belyi D, Dietrich JW (2011). "The parathyroid as a target for radiation damage". N Engl J Med. 365 (7): 676–8. doi:10.1056/NEJMc1104982. PMID 21848480.
  2. ↑ McMullen T, Bodie G, Gill A, Ihre-Lundgren C, Shun A, Bergin M; et al. (2009). "Hyperparathyroidism after irradiation for childhood malignancy". Int J Radiat Oncol Biol Phys. 73 (4): 1164–8. doi:10.1016/j.ijrobp.2008.06.1487. PMID 18774659.
  3. ↑ Tisell LE, Hansson G, Lindberg S, Ragnhult I (1977). "Hyperparathyroidism in persons treated with X-rays for tuberculous cervical adenitis". Cancer. 40 (2): 846–54. PMID 890665.
  4. ↑ 4.0 4.1 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.
  5. ↑ Ludvigsson JF, Kämpe O, Lebwohl B, Green PH, Silverberg SJ, Ekbom A (2012). "Primary hyperparathyroidism and celiac disease: a population-based cohort study". J. Clin. Endocrinol. Metab. 97 (3): 897–904. doi:10.1210/jc.2011-2639. PMC 3319223. PMID 22238405.
  6. ↑ Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D; et al. (2003). "Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma". N Engl J Med. 349 (18): 1722–9. doi:10.1056/NEJMoa031237. PMID 14585940.
  7. ↑ 7.0 7.1 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.
  8. ↑ Hsi ED, Zukerberg LR, Yang WI, Arnold A (1996). "Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study". J Clin Endocrinol Metab. 81 (5): 1736–9. doi:10.1210/jcem.81.5.8626826. PMID 8626826.
  9. ↑ Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC; et al. (1997). "Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states". Hum Mol Genet. 6 (7): 1169–75. PMID 9215689.
  10. ↑ Rodriguez M, Nemeth E, Martin D (2005). "The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism". Am J Physiol Renal Physiol. 288 (2): F253–64. doi:10.1152/ajprenal.00302.2004. PMID 15507543.
  11. ↑ 11.0 11.1 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.
  12. ↑ Mehrotra M, Gupta SK, Kumar K, Awasthi PK, Dubey M, Pandey CM; et al. (2006). "Calcium deficiency-induced secondary hyperparathyroidism and osteopenia are rapidly reversible with calcium supplementation in growing rabbit pups". Br J Nutr. 95 (3): 582–90. PMID 16512945.
  13. ↑ Johnson JM, Maher JW, DeMaria EJ, Downs RW, Wolfe LG, Kellum JM (2006). "The long-term effects of gastric bypass on vitamin D metabolism". Ann. Surg. 243 (5): 701–4, discussion 704–5. doi:10.1097/01.sla.0000216773.47825.c1. PMC 1570540. PMID 16633006.
  14. ↑ Pitt SC, Sippel RS, Chen H (2009). "Secondary and tertiary hyperparathyroidism, state of the art surgical management". Surg. Clin. North Am. 89 (5): 1227–39. doi:10.1016/j.suc.2009.06.011. PMC 2905047. PMID 19836494.
  15. ↑ Kilgo MS, Pirsch JD, Warner TF, Starling JR (1998). "Tertiary hyperparathyroidism after renal transplantation: surgical strategy". Surgery. 124 (4): 677–83, discussion 683–4. doi:10.1067/msy.1998.91483. PMID 9780988.
  16. ↑ 16.0 16.1 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.
  17. ↑ 17.0 17.1 Peacock M (2002). "Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum". J. Bone Miner. Res. 17 Suppl 2: N87–94. PMID 12412783.
  18. ↑ Silverberg SJ, Shane E, de la Cruz L, Dempster DW, Feldman F, Seldin D, Jacobs TP, Siris ES, Cafferty M, Parisien MV (1989). "Skeletal disease in primary hyperparathyroidism". J. Bone Miner. Res. 4 (3): 283–91. doi:10.1002/jbmr.5650040302. PMID 2763869.
  19. ↑ Bandeira F, Cusano NE, Silva BC, Cassibba S, Almeida CB, Machado VC, Bilezikian JP (2014). "Bone disease in primary hyperparathyroidism". Arq Bras Endocrinol Metabol. 58 (5): 553–61. PMC 4315357. PMID 25166047.
  20. ↑ Mazzuoli GF, D'Erasmo E, Pisani D (1998). "Primary hyperparathyroidism and osteoporosis". Aging (Milano). 10 (3): 225–31. PMID 9801732.
  21. ↑ Stefenelli T, Abela C, Frank H, Koller-Strametz J, Globits S, Bergler-Klein J, Niederle B (1997). "Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up". J. Clin. Endocrinol. Metab. 82 (1): 106–12. doi:10.1210/jcem.82.1.3666. PMID 8989242.
  22. ↑ 22.0 22.1 22.2 Corlew DS, Bryda SL, Bradley EL, DiGirolamo M (1985). "Observations on the course of untreated primary hyperparathyroidism". Surgery. 98 (6): 1064–71. PMID 3878002.
  23. ↑ Fitzpatrick LA, Bilezikian JP (1987). "Acute primary hyperparathyroidism". Am. J. Med. 82 (2): 275–82. PMID 3812520.
  24. ↑ Ahmad S, Kuraganti G, Steenkamp D (2015). "Hypercalcemic crisis: a clinical review". Am. J. Med. 128 (3): 239–45. doi:10.1016/j.amjmed.2014.09.030. PMID 25447624.
  25. ↑ Walker MD, McMahon DJ, Inabnet WB, Lazar RM, Brown I, Vardy S, Cosman F, Silverberg SJ (2009). "Neuropsychological features in primary hyperparathyroidism: a prospective study". J. Clin. Endocrinol. Metab. 94 (6): 1951–8. doi:10.1210/jc.2008-2574. PMC 2690425. PMID 19336505.
  26. ↑ Espiritu RP, Kearns AE, Vickers KS, Grant C, Ryu E, Wermers RA (2011). "Depression in primary hyperparathyroidism: prevalence and benefit of surgery". J. Clin. Endocrinol. Metab. 96 (11): E1737–45. doi:10.1210/jc.2011-1486. PMID 21917870.
  27. ↑ McAllion SJ, Paterson CR (1989). "Psychiatric morbidity in primary hyperparathyroidism". Postgrad Med J. 65 (767): 628–31. PMC 2429194. PMID 2608590.
  28. ↑ Lila AR, Sarathi V, Jagtap V, Bandgar T, Menon PS, Shah NS (2012). "Renal manifestations of primary hyperparathyroidism". Indian J Endocrinol Metab. 16 (2): 258–62. doi:10.4103/2230-8210.93745. PMC 3313745. PMID 22470864.
  29. ↑ Tassone F, Gianotti L, Emmolo I, Ghio M, Borretta G (2009). "Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism". J. Clin. Endocrinol. Metab. 94 (11): 4458–61. doi:10.1210/jc.2009-0587. PMID 19808852.
  30. ↑ Michael JW, Schlüter-Brust KU, Eysel P (2010). "The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee". Dtsch Arztebl Int. 107 (9): 152–62. doi:10.3238/arztebl.2010.0152. PMC 2841860. PMID 20305774.
  31. ↑ Hochberg, Marc (2015). "204. Primary hyperparathyroidism: rheumatologic manifestations and bone disease". Rheumatology. Philadelphia, PA: Mosby/Elsevier. p. 1668. ISBN 9780323091381.
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