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Primary hyperparathyroidism
Classification and external resources

Thyroid and parathyroid.
ICD-10 E21.0
ICD-9 252.01
DiseasesDB 6283
eMedicine radio/355
MeSH D049950

Primary hyperparathyroidism causes hypercalcemia (elevated blood calcium levels) through the excessive secretion of parathyroid hormone (PTH), usually by an adenoma (benign tumors) of the parathyroid glands. Its incidence is approximately 42 per 100,000 people. It is almost exactly three times as common in women as men.

Contents

Signs and Symptoms

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by the mnemonic "stones, bones, abdominal groans and psychic moans".

The German description of the same symptoms is "Stein-, Bein- und Magenpein", literally "stone, leg, and stomach-pain".

Other signs include proximal muscle weakness, itching, and band keratopathy of the eyes.

Diagnosis

The diagnosis of primary hyperparathyroidism is made by blood tests. Serum calcium levels are elevated.

The serum chloride phosphate ratio is 33 or more in most patients with primary hyperparathyroidism.[3][4][5] However, thiazide medications have been reported to causes ratios above 33.[6]

Urinary cAMP is occasionally measured; this is generally elevated..

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Parathyroid hormone activity

Intact PTH levels are also elevated.

Causes

The most common cause of primary hyperparathyroidism is a sporadic, single parathyroid adenoma[7] resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia[7] (~2.5%), parathyroid carcinoma (malignant tumor), and adenomas in more than one gland (together ~0.5%).

Primary hyperparathyroidism is also a feature of several familial endocrine disorders: Multiple endocrine neoplasia type 1 and type 2A (MEN type 1 and MEN type 2A), and familial hyperparathyroidism.

Genetic associations include:

OMIM Name Gene
145000 HRPT1 MEN1, HRPT2
145001 HRPT2 HRPT2
610071 HRPT3 unknown at 2p13.3-14[8]

In all cases, the disease is idiopathic, but is thought to involve inactivation of tumor suppressor genes (Menin gene in MEN1), or involve gain of function mutations (RET proto-oncogene MEN 2a).

Complications

The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.

Treatment

Treatment is usually surgical removal of the gland(s) containing adenomas.

Medications

Medications include estrogen replacement therapy in postmenopausal women and bisphosphonates. Bisphosphonates may improve bone turnover.[9] Newer medications termed "calcimimetics" used in secondary hyperparathyroidism are now being used in Primary hyperparathyroidism. Calcimimetics reduce the amount of parathyroid hormone released by the parathyroid glands. They are recommended in patients in whom surgery is inappropriate.

Surgery

The symptoms of the disease, listed above, are indications for surgery. Surgery reduces all cause mortality as well as resolving symptoms. However, cardiovascular mortality is not significantly reduced[10]

A consensus statement in 2002 recommended the following indications for surgery in asymptomatic hyperparathyroidism[11]:

  • Serum calcium (above upper limit of normal): 1.0 mg/dl
  • 24-h urinary calcium >400 mg
  • Creatinine clearance reduced by 30% compared with age-matched subjects.
  • Bone mineral density t-score <−2.5 at any site
  • Age <50

More recently, three randomized controlled trials have studied the role of surgery in patients with asymptomatic hyperparathyroidism. The largest study reported that surgery showed increase in bone mass, but no improvement in quality of life after one to two years among patients with[12]:

  • Untreated, asymptomatic primary hyperparathyroidism
  • Serum calcium between 2.60–2.85 mmol/liter (10.4–11.4 mg/dl)
  • Age between 50 and 80 yr
  • No medications interfering with Ca metabolism
  • No hyperparathyroid bone disease
  • No previous operation in the neck
  • Creatinine level < 130 µmol/liter (<1.47 mg/dl)

Two other trials reported improvements in bone density and some improvement in quality of life with surgery.[13][14]

Future therapies

Future developments such as calcimemetic agents (e.g. cinacalcet) which activate the parathyroid calcium-sensing receptor may offer a good alternative to surgery.

See also

References

  1. ^ Stefenelli T, Abela C, Frank H, et al. (1997). "Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up". J. Clin. Endocrinol. Metab. 82 (1): 106–12. doi:10.1210/jc.82.1.106. PMID 8989242. http://jcem.endojournals.org/cgi/content/full/82/1/106.  
  2. ^ Vestergaarde and Mosekilde, BMJ Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism.2003 Sep 6;327(7414):530-4.Click here to read
  3. ^ Reeves CD, Palmer F, Bacchus H, Longerbeam JK (1975). "Differential diagnosis of hypercalcemia by the chloride/phosphate ratio". Am. J. Surg. 130 (2): 166–71. doi:10.1016/0002-9610(75)90365-7. PMID 1155729.  

    This study found a ratio above 33 to have a sensitivity of 94% and a specificity of 96%.

  4. ^ Palmer FJ, Nelson JC, Bacchus H (1974). "The chloride-phosphate ratio in hypercalcemia". Ann. Intern. Med. 80 (2): 200–4. PMID 4405880.  
  5. ^ Broulík PD, Pacovský V (1979). "The chloride phosphate ratio as the screening test for primary hyperparathyroidism". Horm. Metab. Res. 11 (10): 577–9. doi:10.1055/s-0028-1092784. PMID 521012.  

    This study found a ratio above 33 to have a sensitivity of 95% and a specificity of 100%.

  6. ^ Lawler FH, Janssen HP (1983). "Chloride:phosphate ratio with hypercalcemia secondary to thiazide administration". The Journal of family practice 16 (1): 153–4. PMID 6848626.  
  7. ^ a b "Endocrine Pathology". http://library.med.utah.edu/WebPath/ENDOHTML/ENDO044.html. Retrieved 2009-05-08.  
  8. ^ Warner JV, Nyholt DR, Busfield F, et al. (March 2006). "Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3-14". J. Med. Genet. 43 (3): e12. doi:10.1136/jmg.2005.035766. PMID 16525030. PMC 2563254. http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=16525030.  
  9. ^ Khan AA, Bilezikian JP, Kung AW, et al. (2004). "Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial". J. Clin. Endocrinol. Metab. 89 (7): 3319–25. doi:10.1210/jc.2003-030908. PMID 15240609.  
  10. ^ Vestergaarde and Mosekilde, BMJ Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism.2003 Sep 6;327(7414):530-4
  11. ^ Bilezikian JP, Potts JT, Fuleihan Gel-H, et al. (2002). "Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century". J. Clin. Endocrinol. Metab. 87 (12): 5353–61. doi:10.1210/jc.2002-021370. PMID 12466320.  
  12. ^ Bollerslev J, Jansson S, Mollerup CL, et al. (2007). "Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial". J. Clin. Endocrinol. Metab. 92 (5): 1687–92. doi:10.1210/jc.2006-1836. PMID 17284629.  
  13. ^ Ambrogini E, Cetani F, Cianferotti L, et al. (2007). "Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial". J. Clin. Endocrinol. Metab. 92 (8): 3114–21. doi:10.1210/jc.2007-0219. PMID 17535997.  
  14. ^ Rao DS, Phillips ER, Divine GW, Talpos GB (2004). "Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism". J. Clin. Endocrinol. Metab. 89 (11): 5415–22. doi:10.1210/jc.2004-0028. PMID 15531491.  

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