Hyperparathyroidism

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.

• 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.

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

Presentation^1,2

• 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, bradycardia, QT interval prolongation, and left ventricular hypertrophy.
  • Severe cases may lead to coma and death.

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

• 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

• 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

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.
• But it can occur in any condition with chronic hypocalcaemia such as deficiency in vitamin D or malabsorption.
• (There are separate articles that address Osteomalacia and Rickets (Vitamin D Deficiency), Chronic Kidney Disease and its Management 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.
• 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

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

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]

• American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons; Position statement on the diagnosis and management of primary hyperparathyroidism. February 2005.
• 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. [abstract]