Hyperparathyroidism

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Hyperparathyroidism results when there is excessive secretion of parathyroid hormone (PTH).[1] PTH is secreted by the four 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 parathyroid gland (or more) 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 (CKD).
  • 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:
    • Increases the release of calcium from bone matrix.
    • Increases calcium reabsorption by the kidney.
    • Increases phosphate excretion.
    • Increases renal production of 1,25-dihydroxyvitamin D3 (calcitriol), which increases intestinal absorption of calcium.
  • High concentrations of serum calcium inhibit PTH secretion, while low concentrations stimulate it.

Epidemiology

  • Is the third most common endocrine disorder.[1]
  • it is most common in postmenopausal women.[1]

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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).

Presentation[1]

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:
    • Muscle weakness, proximal myopathy, fatigue.
    • Anorexia; nausea and vomiting; constipation; abdominal pain; peptic ulcer disease (hypercalcaemia can increase gastric acid secretion); acute pancreatitis.
    • Polyuria, polydipsia, dehydration.
    • Renal colic, haematuria, hypertension.
    • Long-standing hypercalcaemia causes corneal calcification, which is usually asymptomatic.
    • Neuropsychiatric manifestations are particularly common and may include depression, dementia, confusion, inability to concentrate and memory problems.
    • Hypertension, shortened QT interval on ECG and cardiac arrhythmias (rare).
    • Severe cases may lead to coma and death.

Differential diagnosis

  • 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 (eg, 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
  • Hypophosphataemia
  • Mild-to-moderate increase in 24-hour urinary calcium excretion

Other tests:

  • Dual-energy X-ray absorptiometry (DEXA) scan can show any skeletal involvement in primary hyperparathyroidism.
  • Pathognomonic X-ray changes include salt and pepper degranulation in the skull and subperiosteal bone resorption in the phalanges in severe cases.
  • 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.[2] 
    • Such patients may continue for long periods without deterioration in bone mineral density.[3][4]
    • Monitor for overt signs and symptoms of primary hyperparathyroidism.
    • Check serum creatinine level and calcium levels every six months.
    • 3-site DEXA study should also be obtained on an annual basis.[5]
    • Avoid dehydration (advise a high fluid intake).
    • Avoid thiazide diuretics.
    • Patients should have a moderate calcium intake.
  • Surgical treatment:
    • One review found that surgery was more effective than medical follow-up for patients with asymptomatic primary hyperparathyroidism.[6] 
    • 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.
    • Guidelines for whom surgery should be offered were produced by a National Institutes of Health (NIH) Workshop on Asymptomatic Primary Hyperparathyroidism:[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 (400 mg).
      • 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 technetium 99m Tc-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 postmenopausal 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.
    • 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. If hypoparathyroidism persists, calcium and vitamin D supplements are required.
  • Recurrent laryngeal nerve injury - suspect this if a patient develops new hoarseness postoperatively. Immediate laryngoscopy is indicated.
  • Haematoma formation - if this occurs in the pre-tracheal 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]
  • The effect of surgery on renal calculi formation is variable.[11]

Causes

  • The parathyroid glands become hyperplastic after long-term stimulation in response to chronic hypocalcaemia.
  • Usually seen in renal disease and seen in almost all patients with dialysis-dependent chronic renal failure. Most patients with CKD stage 5 develop secondary hyperparathyroidism.[12] 
  • It can, however, occur in any condition with chronic hypocalcaemia such as deficiency in vitamin D or malabsorption.
  • (For specific details on vitamin D deficiency, CKD and its management and gastrointestinal malabsorption, see the separate articles Vitamin D Deficiency including Osteomalacia and Rickets, Chronic Kidney Disease (Chronic Renal Failure) and Gastrointestinal Malabsorption.)

Presentation

  • Almost all patients with chronic renal failure have secondary hyperparathyroidism to some degree, so the clinical presentation is often that of renal failure.
  • Secondary hyperparathyroidism causes skeletal and cardiovascular complications in CKD patients.[13] 
  • If secondary hyperparathyroidism is due to vitamin D deficiency, the symptoms are mainly due to the vitamin deficiency (eg, 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 (eg, high in renal disease, low in vitamin D deficiency)
  • Radiology can show evidence of bone disease

Treatment

  • Medical management is the mainstay of treatment.
  • The underlying condition needs to be treated - for example, correcting vitamin D deficiency.
  • Treatment in CKD includes:
    • Phosphate restriction ± phosphate binders.
    • Calcium supplementation.
    • Treatment with vitamin D and its analogues.
    • Calcimimetics (eg, cinacalcet) which may also be helpful.
  • The National Institute for Health and 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.[14]
  • Recent trials indicate that early intervention in stages 3 and 4 of CKD 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.

Causes

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

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

  • There is:
    • Raised calcium
    • Raised PTH
    • Phosphate often raised

Treatment

  • Cinacalcet may be used in tertiary hyperparathyroidism.[15] 
  • Total or subtotal parathyroidectomy is the recommended treatment.[16]
  • Autotransplantation of parathyroid tissue in an easily accessible site, such as the forearm, is also commonly carried out.[1]

Further reading & references

  • Bilezikian JP, Khan AA, Potts JT Jr; Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009 Feb;94(2):335-9.
  1. Fraser WD; Hyperparathyroidism. Lancet. 2009 Jul 11;374(9684):145-58.
  2. Rejnmark L, Amstrup AK, Mollerup CL, et al; Further insights into the pathogenesis of primary hyperparathyroidism: a nested case-control study. J Clin Endocrinol Metab. 2013 Jan;98(1):87-96. doi: 10.1210/jc.2012-2499. Epub 2012 Nov 12.
  3. 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.
  4. 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.
  5. 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.
  6. Sejean K, Calmus S, Durand-Zaleski I, et al; Surgery versus medical follow-up in patients with asymptomatic primary hyperparathyroidism: a decision analysis. Eur J Endocrinol. 2005 Dec;153(6):915-27.
  7. Lendel I, Horwith M; An update from the latest workshop on asymptomatic primary hyperparathyroidism. Otolaryngol Clin North Am. 2004 Aug;37(4):737-49, viii.
  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.
  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.
  10. 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.
  11. 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.
  12. de Francisco AL; Secondary hyperparathyroidism: review of the disease and its treatment. Clin Ther. 2004 Dec;26(12):1976-93.
  13. Joy MS, Karagiannis PC, Peyerl FW; Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J Manag Care Pharm. 2007 Jun;13(5):397-411.
  14. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy, NICE Technology Appraisal (2007)
  15. Vestergaard P, Thomsen Sv; Medical treatment of primary, secondary, and tertiary hyperparathyroidism. Curr Drug Saf. 2011 Apr;6(2):108-13.
  16. Triponez F, Clark OH, Vanrenthergem Y, et al; Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg. 2008 Jul;248(1):18-30.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Colin Tidy
Current Version:
Peer Reviewer:
Dr John Cox
Last Checked:
22/04/2013
Document ID:
2286 (v22)
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