In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia.[3] A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of a parathyroid carcinoma.

Patients with primary hyperparathyroidism and other causes PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.[3]

List of tests for primary hyperparathyroidism: 

• Total calcium

• Albumin

• Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin) (calcium measured in mg/dL; albumin measured in g/dL)

• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium

• Parathyroid hormone

• Phosphorus

• BUN and creatinine

• Alkaline phosphatase

• 25-hydroxyvitamin D

• Urine calcium and creatinine

• Imaging to screen for renal calcifications or urolithiasis

• Bone densitometry (DXA) including measurement at the distal 1/3 radius

• EKG

• Genetic testing in selected individuals if there is suspicion of a genetic syndrome

• Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxyvitamins D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.[4]

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.[5]

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:[6]

• Serum calcium is more than 1 mg/dL greater than the upper limit of normal

• Age younger than 50 years

• Osteoporosis

• GFR less than 60 mL/min

• Urine calcium greater than 400 mg/24 hours

• Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or development of complications, then surgery should be recommended.[7]

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

• Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.

• Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.[8]

• Berylliosis

• Cancers producing parathyroid hormone-related protein

• Exogenous calcium intake 

• Histoplasmosis

• Immobilization

• Leprosy

• Lytic bone metastasis

• Milk-Alkali syndrome

• Multiple endocrine neoplasms

• Pheochromocytoma

Primary hyperparathyroidism preferentially reduces cortical bone density and increases fracture risk at sites where cortical bone predominates, such as the distal forearm, with relative sparing of trabecular bone. For this reason, those with hyperparathyroidism should have a dual-energy x-ray absorptiometry that includes the distal third radius, a site composed almost exclusively of cortical bone, in addition to measurements at the spine and hip.

Primary hyperparathyroidism is associated with some psychological complaints including depression, anxiety, fatigue, irritability, lassitude, and sleep disturbance. There is an inconsistent improvement in psychological parameters, and quality of life following parathyroidectomy and patient numbers in high-quality studies are small.[9]

When there is a family history of hyperparathyroidism consider the possibility of multiple endocrine neoplasia types 1 or 2a or familial hypocalciuric hypercalcemia (FHH), an autosomal dominant inactivating mutation of the calcium-sensing receptor. Urine calcium excretion with the calculation of the fractional excretion of calcium is the best initial test to differentiated familial hypocalciuric hypercalcemia from primary hyperparathyroidism. Patient with familial hypocalciuric hypercalcemia is typically asymptomatic without renal stones or osteoporosis. Subtotal parathyroidectomy does not cure this problem and total parathyroidectomy results in hypoparathyroidism.[10]

Primary hyperparathyoidism is a relatively common disorder. Because hypercalcemia can affect many organs, the condition is best managed by an interprofessional team that includes a radiologist, endocrinologist, surgeon, internist and a nephrologist. Patients who are asymptomatic can be observed but all symptomatic patients need surgery. Follow up can be by the primary care provider or nurse practitioner and should involve renal function, bone density, calcium levels and mood changes.

If hypercalcemia is left untreated it can have severe adverse effects on many organs. After surgery, most patients have a good outcome.