Primary hyperparathyroidism (PHP) is a disease caused by excessive production of parathyroid hormone (PTH). This can be due to a tumor of one or more of the parathyroid glands or to a condition called hyperplasia in which all four of the parathyroid glands are enlarged and overproduce PTH (about 10% of cases). PHP affects about 1 in 500 women and about 1 in 2000 men in the United States and becomes more common as people age. Risk factors include a family history of elevated calcium, a family history of PHP, and known genetic mutations that cluster into well recognized endocrine syndromes (MEN-1 and MEN-2). Exposure to radiation therapy is also a risk factor. Up until the 1960s, many young Americans were treated with radiotherapy for benign conditions such as acne, ringworm and enlarged tonsils. Also, patients treated with radiation for head and neck malignancies have an increased risk of developing PHP. Finally, environmental exposure to radiation such as being in close proximity to a nuclear reactor meltdown, increases the risk of PHP. PHP is often not seen for 20 to 40 years after the exposure to radiation.
Symptoms of elevated calcium include muscle and bone pain, fatigue and memory loss, constipation, irritability, and even depression. These symptoms are nonspecific and can be caused by many other conditions. Because of this, there is no guarantee that these nonspecific symptoms will resolve even when parathyroid surgery has been successful in returning the blood calcium level to the normal range. Despite this, many patients will report an improvement in their symptoms.
With the increased levels of blood calcium in patients with PHP, the kidneys attempt to normalize the blood levels. This results in a high amount of calcium filtered from the blood into the urine. High concentrations of urinary calcium can lead to the development of kidney stones. Once the PHP is corrected, the rate of stone formation is reduced, but any stones that are already formed can still pass from the kidney to bladder.
The most challenging problem for most patients with PHP is their bone health. Because of the abnormally high level of PTH, patients with PHP have a high circulating level of calcium in the blood. This excess calcium is cleared by the kidneys resulting in a slow but relentless loss of total body calcium. Because the vast majority of the calcium in the body is stored in the bones, slowly over time the bones are demineralized. This demineralization of the bones is often identified on bone density scans (DEXA) taken of the hip, wrist and lumbar spine. Bone loss can be mild to moderate (osteopenia) or more advanced (osteoporosis), and is associated with an increased risk of fracture. Bone loss associated with PHP can be corrected after successful parathyroid surgery with calcium supplementation.
The diagnosis of PHP is made based on blood tests. Normally, calcium and PTH levels should track in opposite directions. In PHP, the calcium level will be elevated and the PTH level will be inappropriately high. Because calcium and PTH levels should move in opposite directions, a patient with PHP who has an elevated calcium level, may have a PTH that is at the high end of normal. However, because a high calcium would normally suppress the PTH level to the low end of the normal range, such an individual likely does have PHP. Vitamin D deficiency can increase the PTH level in the blood and can lead to some confusion in the diagnosis of PHP. Often patients who are vitamin D deficient will need to be reassessed for PHP after their vitamin D stores have been replaced.
The majority of patients with PHP will have a benign enlargement of a single parathyroid gland (parathyroid adenoma). Preoperative localization of the diseased gland allows the surgeon to perform a focused exploration which can limit the invasiveness of the procedure. Patients with multigland disease will often need all four of their parathyroid glands identified at the time of surgery. The three most common and most accurate imaging studies employed for preoperative localization of abnormal parathyroid glands are ultrasound, CT scan, and Sestamibi scanning.
High resolution ultrasound of the neck is routinely performed on patients with PHP either in a radiology suite or by the surgeon. This noninvasive test does not involve the use of radiation and poses no risk to the patient. In about half of the patients with PHP, an enlarged parathyroid gland can be identified on ultrasound. Ultrasound will only identify abnormal glands that are positioned in the neck. Ultrasound will identify the parathyroid gland based on structure, but not function.
A 4D CT scan of the neck with dynamic bolus administration of intravenous contrast material can identify up to 95% of enlarged parathyroid glands. While sensitive and specific, this localization test does involve the use of x-rays and is only available at certain radiology suites. CT scan will identify the parathyroid gland based on structure but not function.
Sestamibi scan is a nuclear medicine test that is often used to identify diseased parathyroid glands. A small tracer dose of radioactivity is injected intravenously. This dye is taken up preferentially by the parathyroid glands which tend to retain the dye (as seen on delayed images) for longer than other tissues. While this test lacks the anatomic precision of ultrasound and CT scan, it is the only imaging modality available that identifies the abnormal gland based on function.
The only known cure for PHP is surgery to remove the diseased parathyroid gland or glands. This is a minimally invasive procedure that is done as an outpatient at most experienced centers. In the absence of surgery to correct the problem, the bones generally continue to demineralize resulting in an ongoing and increasing risk of fracture with time. Treatment with bisphosphonates or estrogen can temporize the bone loss in some patients, but these drugs do not treat the underlying cause of the problem. Calcimimetic drugs such as Cinacalcet and Sensipar are effective at lowering the blood level of calcium, but they have not been shown to improve the PTH level and most importantly, they do not restore bone strength.
However, not all patients with PHP require surgery. Patients who are symptomatic are generally offered surgery to relieve their symptoms. In the absence of symptoms, NIH consensus guidelines have been developed to determine which patients will benefit from surgery. These guidelines are mostly based on the calculated risk of fracture and include:
- Age < 50 years
- A blood calcium level greater than 1 mg/dL above the normal range (at most labs this means 11 to 11.5 mg/dL)
- Glomerular filtration rate < 60 mL/min (reduced kidney function)
- Recent fracture