Primary hyperparathyroidism

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Primary hyperparathyroidism
Classification and external resources
Illu thyroid parathyroid.jpg
Thyroid and parathyroid.
ICD-10 E21.0
ICD-9 252.01
DiseasesDB 6283
MedlinePlus 000384
eMedicine radio/355
MeSH D049950

Primary hyperparathyroidism It is usually caused by a tumour within the parathyroid gland. The symptoms of the condition relate to the elevated calcium levels, which can cause digestive symptoms, kidney stones, mental features and bone disease.

The diagnosis is initially made on blood tests; an elevated level of calcium together with a raised level of parathyroid hormone are typically found. To identify the source of the excessive hormone secretion, medical imaging may be performed. Parathyroidectomy, the surgical removal of one or more parathyroid glands, may be required to control symptoms.

Signs and Symptoms[edit]

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

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

When subjected to formal research, symptoms of depression, pain, and gastric dysfunction seem to correlate with mild cases of hypercalcemia.[3]

Diagnosis[edit]

The diagnosis of primary hyperparathyroidism is made by blood tests.

Serum calcium levels are elevated, and the parathyroid hormone level is abnormally high compared with an expected low level in response to the high calcium. A relatively elevated parathyroid hormone has been estimated to have a sensitivity of 60%-80% and a specificity of approximately 90% for primary hyperparathyroidism.[4]

A more powerful variant of comparing the balance between calcium and parathyroid hormone is to perform a 3 hour calcium infusion. After infusion, a parathyroid hormone level above a cutoff of 14 ng/l has a sensitivity of 100% and a specificity of 93% in detecting primary hyperparathyroidism, with a confidence interval of 80% to 100%.[5]

The serum chloride/phosphate ratio is 33 or more in most patients with primary hyperparathyroidism. However, usage of thiazide medications have been reported to causes ratios above 33.[6] Studies without any usage of thiazide diuretics have estimated a serum chloride/phosphate ratio to have a sensitivity of 94%[7] or 95%[8][9] and a specificity of 96%[7] or 100%.[8]

Urinary cAMP is occasionally measured; this is generally elevated.

Parathyroid hormone activity[edit]

Intact PTH levels are also elevated.

Causes[edit]

The most common cause of primary hyperparathyroidism is a sporadic, single parathyroid adenoma[10] resulting from a clonal mutation (~97%). Less common are parathyroid hyperplasia[10] (~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[11]

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).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.[12]

Primary hyperparathyroidism can also result from pregnancy. It is apparently very rare, with only about 110 cases have so far been reported in world literature, but this is probably a considerable underestimate of its actual prevalence in pregnant women.[13]

Treatment[edit]

Treatment is usually surgical removal of the gland(s) containing adenomas, but medication may also be required.

Surgery[edit]

The surgery on parathyroid is called "Parathyroidectomy"; it was first done in 1925.[14] 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.[15]

The 2002 NIH Workshop on Asymptomatic Primary Hyperparathyroidism developed criteria for surgical intervention . The criteria were revised at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism . These criteria were chosen on the basis of clinical experience and observational and clinical trial data as to which patients are more likely to have end-organ effects of primary hyperparathyroidism (nephrolithiasis, skeletal involvement), disease progression if surgery is deferred, and the most benefit from surgery. The panel emphasized the need for parathyroidectomy to be performed by surgeons who are highly experienced and skilled in the operation. The Third International Workshop guidelines concluded that surgery is indicated in asymptomatic patients who meet any one of the following conditions:

●Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal
●Creatinine clearance that is reduced to <60 mL/min
●Bone density at the hip, lumbar spine, or distal radius that is more than 2.5 standard deviations below peak bone mass (T score <-2.5) and/or previous fragility fracture
●Age less than 50 years

Operative intervention can be delayed in patients over 50 years of age who are asymptomatic or minimally symptomatic and who have serum calcium concentrations <1.0 mg/dL (0.2 mmol/L) above the upper limit of normal, and in patients who are medically unfit for surgery

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:[16]

  • 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.[17][18]

Medications[edit]

Medications that are sometimes required include estrogen replacement therapy in postmenopausal women and bisphosphonates. Bisphosphonates may improve bone turnover.[19]

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.[20]

Epidemiology[edit]

The incidence of primary hyperparathyroidism is approximately 1 per 1,000 people (0.1%),[21] while there are 25-30 new cases per 100,000 people per year in the United States.[22] The prevalence of primary hyperparathyroidism has been estimated to be 3 in 1000 in the general population and as high as 21 in 1000 in postmenopausal women.[23] It is almost exactly three times as common in women as men.

Primary hyperparathyroidism is associated with increased all-cause mortality.[15]

Research directions[edit]

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

See also[edit]

References[edit]

  1. ^ Barreras, R. F.; Donaldson, R. M. (1967). "Role of Calcium in Gastric Hypersecretion, Parathyroid Adenoma and Peptic Ulcer". New England Journal of Medicine 276 (20): 1122–1124. doi:10.1056/NEJM196705182762005. PMID 6024167.  edit
  2. ^ 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. 
  3. ^ Bargren AE, Repplinger D, Chen H, Sippel RS (2011). "Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism?". J Am Coll Surg 213 (3): 410–4. doi:10.1016/j.jamcollsurg.2011.06.401. PMID 21723154. 
  4. ^ [1] Lepage, R.; d'Amour, P.; Boucher, A.; Hamel, L.; Demontigny, C.; Labelle, F. (1988). "Clinical performance of a parathyrin immunoassay with dynamically determined reference values". Clinical chemistry 34 (12): 2439–2443. PMID 3058363.  edit
  5. ^ Titon, I.; Cailleux-Bounacer, A.; Basuyau, J. P.; Lefebvre, H.; Savoure, A.; Kuhn, J. M. (2007). "Evaluation of a standardized short-time calcium suppression test in healthy subjects: Interest for the diagnosis of primary hyperparathyroidism". European Journal of Endocrinology 157 (3): 351–357. doi:10.1530/EJE-07-0132. PMID 17766719.  edit
  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 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. 
  8. ^ a b Palmer FJ, Nelson JC, Bacchus H (1974). "The chloride-phosphate ratio in hypercalcemia". Ann. Intern. Med. 80 (2): 200–4. doi:10.7326/0003-4819-80-2-200. PMID 4405880. 
  9. ^ 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. 
  10. ^ a b "Endocrine Pathology". Retrieved 2009-05-08. 
  11. ^ 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. PMC 2563254. PMID 16525030. 
  12. ^ Boehm, Bernhard O.; Rosinger, Silke, Belyi, David, Dietrich, Johannes W. (August 2011). "The Parathyroid as a Target for Radiation Damage". New England Journal of Medicine 365 (7): 676–678. doi:10.1056/NEJMc1104982. PMID 21848480. Retrieved 19 August 2011. 
  13. ^ Primary Hyperparathyroidism in Pregnancy - a review at obgyn.net. By Sushanta Bhadra and John Fairbank. Retrieved April 2011
  14. ^ Weber T, Eberle J, Messelhäuser U,and et al. (2013). "Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study". JAMA Surg. 148 (2): 109–115. doi:10.1001/2013.jamasurg.316. 
  15. ^ a b Vestergaard, P.; Mosekilde, L. (2003). "Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism". BMJ 327 (7414): 530–534. doi:10.1136/bmj.327.7414.530. PMC 192894. PMID 12958111. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ http://pi.amgen.com/united_states/sensipar/sensipar_pi_hcp_english.pdf
  21. ^ Deshmukh, R. G.; Alsagoff, S. A. L.; Krishnan, S.; Dhillon, K. S.; Khir, A. S. M. (1998). "Primary hyperparathyroidism presenting with pathological fracture". Journal of the Royal College of Surgeons of Edinburgh 43 (6): 424–427. PMID 9990797. 
  22. ^ Bilezikian, John P.; Silverberg, Shonni J. (2002). "Primary hyperparathyroidism: Epidemiology and clinical consequences". Clinical Reviews in Bone and Mineral Metabolism 1 (1): 25–34. doi:10.1385/BMM:1:1:25. 
  23. ^ Bolland, M. J.; Grey, A. B.; Gamble, G. D.; Reid, I. R. (2004). "Association between Primary Hyperparathyroidism and Increased Body Weight: A Meta-Analysis". Journal of Clinical Endocrinology & Metabolism 90 (3): 1525. doi:10.1210/jc.2004-1891.  edit

Weber T, Eberle J, Messelhäuser U and et al.Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study. JAMA Surg. 2013 Feb;148(2):109-15.

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