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Hyperparathyroidism

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Hyperparathyroidism results when there is excessive secretion of parathyroid hormone (PTH).1 PTH is secreted by the 4 parathyroid glands, located in the neck behind the thyroid gland. It regulates serum calcium and phosphate levels and also plays a part in bone metabolism. High levels of PTH cause serum calcium levels to increase and serum phosphate levels to fall.

Hyperparathyroidism may be:

  • Primary - one, or more, parathyroid gland produces excess PTH.
  • Secondary - there is increased secretion of PTH in response to low calcium because of kidney, liver, or bowel disease.
  • Tertiary - there is autonomous secretion of PTH, usually because of chronic kidney disease.
A reminder of calcium and phosphate homeostasis
  • Maintenance of normal serum calcium levels involves the regulation of the flux of calcium between the intestinal tract, kidneys and bone.
  • Calcium itself, PTH and 1,25-dihydroxyvitamin D3 (calcitriol) all play a role in calcium regulation.
  • Calcitonin (produced by C cells of the thyroid) can also effect calcium homeostasis. It inhibits osteoclast activity and reduces the release of calcium and phosphate from bone.1
  • PTH:2
    • Increases the release of calcium from bone matrix.
    • Increases calcium reabsorption by the kidney.
    • Increases phosphate excretion.
    • Increases renal production of 1,25-dihydroxyvitamin D-3 (calcitriol), which increases intestinal absorption of calcium.
  • High concentrations of serum calcium inhibit PTH secretion, while low concentrations stimulate it.
Primary hyperparathyroidism

Epidemiology

  • Is the third most common endocrine disorder.1
  • Most common in post-menopausal women.1

Causes

  • Excess PTH is produced by one or more of the parathyroid glands due to:
    • A single parathyroid gland adenoma (75-85% of cases).1
    • Multigland adenoma or hyperplasia (14%).
    • Parathyroid carcinoma (less than 1%).1
  • The aetiology of adenomas or hyperplasia is largely unknown.
  • There may be an association with ionising radiation.1
  • Familial cases can occur as part of the multiple endocrine neoplasia syndromes (MEN 1 or MEN 2a), hyperparathyroid-jaw tumour (HPT-JT) syndrome, or familial isolated hyperparathyroidism (FIHPT).2

Presentation1,2

70-80% of people are asymptomatic and diagnosis is made after incidental hypercalcaemia is found. In those who are symptomatic, remember: "bones, stones, abdominal groans, and psychic moans."

Clinical features are due to:

  • Excessive calcium resorption from bone:
    • Osteopenia, presenting as bone pain and pathological fractures.
    • Osteitis fibrosa cystica presents with subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, salt-and-pepper appearance of the skull, and brown tumours of the long bones. It can occur in severe cases.
  • Excessive renal calcium excretion:
    • Renal calculi (the most common presentation).
  • Hypercalcaemia:

Differential diagnosis2

  • Familial benign (hypocalciuric) hypercalcaemia (FBHH) - presents with hypercalcaemia and modestly raised or normal PTH. Autosomal dominant inheritance. A gene defect leads to inappropriate secretion of PTH at high serum calcium levels. Parathyroidectomy will be ineffective.1
  • Lithium-induced hypercalcaemia
  • Tertiary hyperparathyroidism
  • Other causes of hypercalcaemia, especially malignancy; other causes include thyrotoxicosis, sarcoidosis, Paget's disease of bone and Addison's disease.

Investigations

Primary hyperparathyroidism is the most common cause of hypercalcaemia in many studies.1

If someone presents with hypercalcaemia:

  • Look for any obvious drug causes (e.g. lithium, thiazide diuretics).
  • Repeat plasma albumin-adjusted calcium levels.
  • Ensure renal function is normal.
  • Measure PTH, which will be raised in primary hyperparathyroidism.

There is:

  • Hypercalcaemia
  • Raised PTH
  • Hypophosphatemia
  • Mild-to-moderate increase in 24-hour urinary calcium excretion

Other tests:

  • Dual-energy X-ray absorptiometry (DEXA) can show any skeletal involvement in primary hyperparathyroidism.2
  • Pathognomonic X-ray changes include salt and pepper degranulation in the skull and subperiosteal bone resorption in the phalanges in severe cases.2
  • Imaging of renal tract (X-ray, ultrasound) can demonstrate renal calculi.
  • A biopsy may be performed if carcinoma is suspected.

Treatment

The management of acute hypercalcaemia is described in a separate article Hypercalcaemia.

  • Mild, asymptomatic disease:
    • Surveillance can be used in patients with mildly elevated calcium levels and close to normal renal and bone status.3
    • Such patients may continue for long periods without deterioration in bone mineral density.4,5
    • Monitor for overt signs and symptoms of primary hyperparathyroidism.
    • Check serum creatinine level and calcium levels every 6 months.
    • 3-site DEXA study should also be obtained on an annual basis.2,6
    • Avoid dehydration (advise a high fluid intake).
    • Avoid thiazide diuretics.
    • Patients should have a moderate calcium intake.
  • Surgical treatment:
    • Parathyroid surgery to remove abnormal parathyroid gland(s) is suggested in most symptomatic patients.1 In the case of 4-gland hyperplasia, a 3.5-gland (subtotal) parathyroidectomy is performed.2
    • Guidelines for whom surgery should be offered were produced by a National Institutes of Health (NIH) Workshop on Asymptomatic Primary Hyperparathyroidism in 2002:7
      • Serum albumin-adjusted calcium greater than 0.25 mmol/L above the upper limit of local laboratory reference range.
      • 24 hour total urinary calcium excretion greater than 10 mmol (400mg).
      • Creatinine clearance reduced by 30% or more.
      • Bone mineral density T score less than -2.5 (at any site).
      • Age younger than 50 years.
      • Patient request; adequate follow-up unlikely.
    • Experienced surgeons may be able to identify abnormal glands with full neck exploration.
    • Minimally invasive surgery in combination with pre-operative localisation investigations are increasingly being used. These investigations include ultrasound, MRI, computerised axial tomography and 99technetium-labelled sestamibi-single photon emission CT.1
    • When performed by expert surgeons, minimally invasive approaches to parathyroid surgery appear to be as effective as the classic bilateral cervical exploration approach.8
    • Intraoperative measurement of PTH may also help to see if the abnormal gland(s) has been removed.1
  • Medical treatment:
    • Medical management is used for those who opt against surgery or who do not meet the criteria for surgery.9
    • Treatment is aimed at improving bone mineral density and achieving calcium homeostasis.
    • HRT and raloxifene may be used in post-menopausal women. They have been shown to reduce calcium levels as well as improve bone density.1 However, because of the risks associated with oestrogen replacement, it should not be used purely to treat primary hyperparathyroidism.2
    • Bisphosphonates (particularly alendronate) may be a useful treatment.1
    • Cinacalcet reduces both serum calcium and PTH levels and raises serum phosphorus. Cinacalcet does not, however, reduce bone turnover or improve bone mineral density.9

Complications after surgery

These include:

  • Hypocalcaemia - due to 'hungry bone syndrome' Calcium and phosphorus are rapidly deposited in bone. There is hypoparathyroidism and transient, but sometimes severe, hypocalcaemia until the normal glands regain sensitivity.2 If hypoparathyroidism persists, calcium and vitamin D supplements are required.
  • Recurrent laryngeal nerve injury - suspect this if a patient develops new hoarseness post-operatively. Immediate laryngoscopy is indicated.2
  • Haematoma formation - if this occurs in the pretracheal space, urgent evacuation is required before airway obstruction occurs.

Outcome after surgery

  • Reduced bone density and increased fracture risk can be improved with parathyroidectomy.8,10,11,12
  • The effect of surgery on renal calculi formation is variable.13,14,15
  • Long-term control of hypertension may not be improved by surgery.16,17
Secondary hyperparathyroidism

Causes

Presentation

  • Almost all patients with chronic renal failure have secondary hyperparathyroidism to some degree, so the clinical presentation is often that of renal failure.
  • If secondary hyperparathyroidism is due to vitamin D deficiency, the symptoms are mainly due to the vitamin deficiency (e.g. osteomalacia with increased fracture risk, myopathy, etc.).
  • In severe secondary hyperparathyroidism, bone pain may be present.
  • Calcium levels are low-normal so there are not the symptoms related to hypercalcaemia as with primary hyperparathyroidism.

Investigations

  • There is:
    • Low-normal calcium
    • Raised PTH
    • Phosphate levels depend on aetiology (e.g. high in renal disease, low in vitamin D deficiency)
  • Radiology can show evidence of bone disease

Treatment

  • Medical management is the mainstay of treatment.2
  • The underlying condition needs to be treated; for example, correcting vitamin D deficiency.
  • Treatment in chronic kidney disease includes:2
    • Phosphate restriction ± phosphate binders.
    • Calcium supplementation.
    • Treatment with vitamin D and its analogues.
    • Calcimimetics such as cinacalcet, which may also be helpful.
  • The National Institute for Clinical Excellence (NICE) only recommends the use of cinacalcet for those people with end-stage renal disease whose secondary hyperparathyroidism is refractory to other treatment and in whom surgery is not suitable as a treatment.18
  • Recent trials indicate that early intervention in stages 3 and 4 of chronic kidney disease can correct parathyroid hormone levels and could prevent renal bone disease and prolong patient survival.
  • Parathyroidectomy may be considered in severe cases refractory to medical treatment.
  • There is a 10% risk of recurrent or persistent disease after parathyroidectomy.2
Tertiary hyperparathyroidism

Causes

  • Usually occurs after prolonged secondary hyperparathyroidism.
  • The glands become autonomous, producing excessive PTH even after the cause of hypocalcaemia has been corrected.2
  • This results in hypercalcaemia.
  • Longstanding kidney disease is the most common cause.1,2
  • It can persist after a renal transplant.2

Presentation

  • Symptoms and signs are due to hypercalcaemia so presentation can be similar to primary hyperparathyroidism.
  • There are important health risks, particularly concerning bone density and the cardiovascular system.

Investigations

  • Raised calcium
  • Raised PTH
  • Phosphate is often raised

Treatment

  • Total or subtotal parathyroidectomy is the recommended treatment.2,19
  • Autotransplantation of parathyroid tissue in an easily accessible site, such as the forearm, is also commonly carried out.1


Document references
  1. Fraser WD; Hyperparathyroidism. Lancet. 2009 Jul 11;374(9684):145-58. [abstract]
  2. Kim L, Makdissi A; Hyperparathyroidism. eMedicine. Updated: Sep 24, 2009.
  3. No authors listed; NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med. 1991 Apr 1;114(7):593-7. [abstract]
  4. Bollerslev J, Jansson S, Mollerup CL, et al; Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab. 2007 May;92(5):1687-92. Epub 2007 Feb 6. [abstract]
  5. Ambrogini E, Cetani F, Cianferotti L, et al; Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007 Aug;92(8):3114-21. Epub 2007 May 29. [abstract]
  6. Silverberg SJ, Lewiecki EM, Mosekilde L, et al; Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009 Feb;94(2):351-65. [abstract]
  7. Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al; Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a J Clin Endocrinol Metab. 2002 Dec;87(12):5353-61.
  8. Udelsman R, Pasieka JL, Sturgeon C, et al; Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009 Feb;94(2):366-72. [abstract]
  9. Khan A, Grey A, Shoback D; Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009 Feb;94(2):373-81. [abstract]
  10. Vestergaard P, Mosekilde L; Parathyroid surgery is associated with a decreased risk of hip and upper arm fractures in primary hyperparathyroidism: a controlled cohort study. J Intern Med. 2004 Jan;255(1):108-14. [abstract]
  11. VanderWalde LH, Liu IL, O'Connell TX, et al; The effect of parathyroidectomy on bone fracture risk in patients with primary hyperparathyroidism. Arch Surg. 2006 Sep;141(9):885-9; discussion 889-91. [abstract]
  12. Khosla S, Melton J 3rd; Fracture risk in primary hyperparathyroidism. J Bone Miner Res. 2002 Nov;17 Suppl 2:N103-7. [abstract]
  13. Parfitt AM, Rao DS, Kleerekoper M; Asymptomatic primary hyperparathyroidism discovered by multichannel biochemical screening: clinical course and considerations bearing on the need for surgical intervention. J Bone Miner Res. 1991 Oct;6 Suppl 2:S97-101; discssion S121-4. [abstract]
  14. Mollerup CL, Lindewald H; Renal stones and primary hyperparathyroidism: natural history of renal stone disease after successful parathyroidectomy. World J Surg. 1999 Feb;23(2):173-5; discussion 176. [abstract]
  15. Mollerup CL, Vestergaard P, Frokjaer VG, et al; Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ. 2002 Oct 12;325(7368):807. [abstract]
  16. Jones DB, Jones JH, Lloyd HJ, et al; Changes in blood pressure and renal function after parathyroidectomy in primary hyperparathyroidism. Postgrad Med J. 1983 Jun;59(692):350-3. [abstract]
  17. Salahudeen AK, Thomas TH, Sellars L, et al; Hypertension and renal dysfunction in primary hyperparathyroidism: effect of parathyroidectomy. Clin Sci (Lond). 1989 Mar;76(3):289-96. [abstract]
  18. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy, NICE Technology Appraisal (2007)
  19. Triponez F, Clark OH, Vanrenthergem Y, et al; Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg. 2008 Jul;248(1):18-30. [abstract]

Internet and further reading
Acknowledgements EMIS is grateful to Dr Michelle Wright for writing this article and to Dr Colin Tidy for earlier versions. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2009.
Document ID: 2286
Document Version: 21
Document Reference: bgp941
Last Updated: 16 Oct 2009
Planned Review: 16 Oct 2011

The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest. Find out more about updating.

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