Incidence and Risk Factors
In primary hyperparathyroidism, one or more of the parathyroid glands produces PTH in excess with some degree of autonomy from the regular negative feedback loop inhibition (i.e. the thermostat remains on despite the temperature being high). In[AH1] more than 80% of cases, a single gland is the source of excess PTH. These are termed single adenomas. In up to 20%, more than one gland may be abnormal. This might be due to multiple adenomas or hyperplasia of all four glands. Over time, this disease leads to detrimental effects on the bones and kidneys and may result in neurocognitive symptoms and poor cardiovascular health. Primary hyperparathyroidism is not the only cause of high calcium. Healthcare practitioners should consider and assess for other causes, including malignancy, medications, secondary hyperparathyroidism, and others.
Incidence and Risk Factors
Primary hyperparathyroidism is seen in 0.1–0.5% of the adult population. It is the most common cause of hypercalcemia in the general population. It is about three times more common in women than men. Patients are usually older, with an average age at presentation of 65 years (most cases are over 45 years).
Exposure to head and neck ionizing radiation may predispose patients to hyperparathyroidism. Lower doses commonly associated with medical imaging or background environmental radiation are felt to be insufficient to increase risk. A history of radiation exposure from medical treatment or nuclear fallout should be sought when investigating these patients.
While most (>95%) cases are sporadic, some patients develop primary hyperparathyroidism in the context of a genetic predisposition[AH2] . The possibility of a genetic syndrome should be considered in young patients (<45 years[EF3] ) and those with a history suggestive of a genetic syndrome. The potential of a genetic predisposition may affect surgical management, as four gland hyperplasia is more likely to be present in these individuals. Multiple endocrine neoplasia (MEN) type 1 and 2a are associated with the development of primary hyperparathyroidism. MEN1 may be associated with the development of pituitary and pancreatic tumors (functional or non-functional). Patients with MEN2a may develop medullary thyroid cancer and pheochromocytoma. Jaw tumor syndrome is associated with primary hyperparathyroidism and increased risk of parathyroid cancer as well as jaw tumors (ossifying fibromas). In addition, some patients may have an underlying familial cause limited to parathyroid disease alone.
A thorough medication history is also important. Some medications may result in hypercalcemia that is not PTH mediated. However, lithium (often used to treat bipolar/manic depressive disorder) can increase the risk of primary hyperparathyroidism.
An assessment of vitamin D status is important in patients being investigated for primary hyperparathyroidism. The human body can synthesize vitamin D through a process requiring sun exposure or absorb it through the intestine from dietary sources. Deficiency of vitamin D is common in the general population, particularly at northern latitudes where sun exposure may be more limited. Assessment of vitamin D status is important in these patients for two reasons:
- Patients with significant vitamin D deficiency, elevated PTH, and normal calcium may have secondary hyperparathyroidism. In this condition, vitamin deficiency leads to low serum calcium (reduced intestinal absorption), and the PTH is increased appropriately in order to bring the serum calcium into the normal range.
- Patients with primary hyperparathyroidism more commonly have vitamin D deficiency due to the effects of PTH on vitamin D metabolism.
Patients found to have secondary hyperparathyroidism should be treated with vitamin D. Patients with primary hyperparathyroidism can be given vitamin D supplements safely even prior to surgical parathyroidectomy.
Could This Be Parathyroid Cancer?
Fortunately, parathyroid cancer is very rare (approximately 1 in 2 million). Less than 1% of cases of primary hyperparathyroidism will be due to parathyroid cancer. The parathyroid surgeon will approach surgery with a higher suspicion of parathyroid cancer in patients that have very marked elevations in both calcium and PTH, those with a palpable neck mass, and patients with a pre-operative hoarse voice. The diagnosis is often made intraoperatively by the surgeon and requires a change in the operative plan with removal of the adjacent thyroid lobe. Pathology may be indeterminate, requiring long-term followup to monitor for recurrence. Chemotherapy and radiation are not very useful in the treatment of parathyroid cancer, so the best chance for cure is adequate surgical resection at the initial operation.
Patients will be monitored with clinical exam, calcium and PTH levels, and imaging for evidence of recurrence. If recurrence occurs, another surgery is the best option for treatment. In those patients in whom resection is not possible, calcimimetic agents (e.g. cinacalcet) may help palliate symptoms and potentially prolong life.