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Primary hyperparathyroidism


Primary hyperparathyroidism (PHPT) is the most common cause of an elevated calcium level in the outpatient setting.  PHPT is characterized by hypercalcemia and an elevated or non-suppressed (inappropriately normal) parathyroid hormone (PTH) level.

Clinical manifestations

In the modern era, most patients with PHPT are asymptomatic and are noted to have hypercalcemia on routine laboratory testing. In patients presenting symptomatically, the most common complaint is kidney stones.

Classically, patients with PHPT presented with “bones, stones, psychic moans, and abdominal groans” — overt bone disease (osteitis fibrosa cystic, osteoporosis, fractures), nephrolithiasis, neuropsychologic manifestations (fatigue, weakness, poor mood, and cognition), and abdominal discomfort.  This presentation is still common in the developing world.

Red flags

A persistently elevated calcium level should prompt a workup for hyperparathyroidism or other etiologies of hypercalcemia.

Low albumin levels cause an underestimation of total calcium; calcium levels should be “corrected” for albumin as follows:

Corrected calcium = Measured calcium + [0.8 x (4.0 – Albumin)]

Thiazide diuretics interfere with normal excretion of calcium. Patients with hypercalcemia on thiazide diuretics should be reassessed after the thiazide has been discontinued. In patients with multigland disease or a positive family history of PHPT, a hereditary endocrine disorder (such as multiple endocrine neoplasia (MEN) type 1, MEN type 2A, or hyperparathyroidism-jaw tumor syndrome) should be considered.


PHPT affects approximately 1 in 1,000 people, with peak incidence at age 60-70.  In an older population, the female:male ratio is 3:1, but is closer to 1:1 in persons younger than 45.

Pathology and physiology

PHPT results from a loss of normal feedback of PTH by calcium. The most common cause (approximately 85%) is a single gland parathyroid adenoma. Other etiologies include multigland hyperplasia, multiple adenomas, and, very rarely, parathyroid carcinoma.

The hypercalcemia in PHPT results in hypercalciuria and an increased risk of kidney stones.  PHPT also results in increased bone resorption, particularly at sites with primarily cortical bone (eg, distal radius).  Patients with PHPT may have an increased risk of hypertension, insulin resistance, and cardiovascular morbidity and mortality, although this remains controversial.

Differential diagnosis

Other than PHPT, there are few causes of hypercalcemia with elevated or “normal” PTH levels. They include tertiary hyperparathyroidism (seen in longstanding advanced renal disease) and familial hypocalciuric hypercalcemia (a genetic disorder seen in patients with low urinary calcium excretion).

In patients with hypercalcemia and a suppressed PTH, the major diagnostic concern is hypercalcemia of malignancy. The differential diagnosis also includes vitamin D disorders and mill-alkali syndrome.


Most patients with hyperparathyroidism have a solitary adenoma. It is not known why patients develop these lesions, although the clonal origin of most parathyroid adenomas suggests that oncogenes are involved. A small proportion of patients (less than 5%) with PHPT have a hereditable genetic disorder such as MEN type 1, MEN type 2A, or hyperparathyroidism jaw-tumor syndrome.

Radiographic and laboratory findings

An elevated serum calcium level with an elevated or inappropriately normal PTH level is highly suggestive of PHPT in patients with normal renal function. Phosphate levels can be variable but are usually low or low-normal.

Twenty-four-hour urine calcium excretion should be measured.  Familial hypocalciuric hypercalcemia should be considered in patients with low 24-hour calcium excretion.

Bone densitometry by DEXA should be measured at the hip, spine, and forearm.  PHPT has a particular propensity for reducing bone density in the 1/3 distal forearm. Radiologic tests are not needed for the diagnosis of PHPT. However, Sestamibi scanning and/or neck ultrasound may be useful for preoperative imaging in patients undergoing surgery.

Osteitis fibrosa cystica, the classic skeletal manifestation of PHPT, consists of generalized demineralization, subperiosteal bone resorption (most evident in the phalanges of the hand), bone cysts, and pathologic fractures. It is rarely seen in the modern era.

Risk factors and prevention

PHPT risk is increased with a history of head and neck irradiation in childhood or long-term lithium use, and in those with a family history of primary hyperparathyroidism. There are no known preventive measures, though maintaining normal levels of vitamin D may be helpful.

Treatment options

Surgical management is indicated in symptomatic patients (kidney stones, fractures) and in asymptomatic patients who meet any of the following criteria: age less than 50 years old, calcium level greater than 1 mg/dL above the upper limit of normal, creatinine clearance less than 60 mL/min, and T-score < - 2.5 at any site.

Although any patient may be considered for surgery, many patients who do not meet the above criteria can be considered for surveillance. Patients undergoing surveillance should have serum calcium and serum creatinine measured annually, and three-site bone densitometry performed every 1-2 years.

Patients who are surgical candidates but who refuse surgery, or those that are not surgical candidates, may be treated with bisphosphonates (to reduce fracture risk) and/or cinacalcet (to lower calcium levels).


For patients with a solitary adenoma, surgery is curative and restores eucalcemia.  Surgery is usually beneficial in patients with other etiologies of PHPT, although the results are less certain.

In patients cured by surgery, the risk of recurrent nephrolithiasis is markedly reduced and bone density improves significantly. Neuropsychological symptoms may improve, though the data are controversial and it is not possible to predict which patients will benefit.

Approximately 25% of asymptomatic patients undergoing surveillance develop an indication requiring surgical intervention over a 10-year period.  Bone density levels appear to remain stable for 10 years, after which bone density at cortical sites appears to decline.

Holistic medicine

Patients with aymptomatic PHPT undergoing surveillance should maintain adequate fluid intake and avoid dehydration and immobilization. Patients with PHPT should maintain normal intake of calcium by dietary means, with supplements if necessary, and normal levels of vitamin D.


Parathyroid surgery previously required four-gland exploration. At present, most parathyroid surgery is done in a minimally invasive manner with preoperative imaging and the use of intraoperative PTH monitoring.

Key terms

Primary hyperparathyroidism, osteitis fibrosa cystica

Skills and competencies

  • Understand the presentation and diagnosis of PHPT
  • Differentiate PHPT patients who require surgical intervention from those who may be candidates for surveillance

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