The most common presentation of primary hyperparathyroidism in developed countries is asymptomatic hypercalcemia often found on routine biochemical screening. Advanced clinical bone and renal disease that characterized initial presentation in the past has become rare with the availability of serum calcium (and subsequently) PTH measurement. As with all diseases, a thorough history is an important starting point. The history in patients with suspected primary hyperparathyroidism should include:
- Potential alternative causes of hypercalcemia (malignancy, medications, vitamins, other endocrine disorders)
- Symptoms/signs of hypercalcemia & hyperparathyroidism
- Potential genetic causes of hypercalcemia & hyperparathyroidism
Ultimately, the diagnosis of primary hyperparathyroidism is biochemical. Common labs ordered in the workup of these patients include a serum calcium (+/- ionized calcium), albumin (for correction of total serum calcium level), PTH, phosphate, creatinine, 25-hydroxy vitamin D, and a 24-hour urine calcium & creatinine. Evidence of hypercalcemia with an elevated PTH in a patient with normal renal function and without hypocalciuria clearly supports the diagnosis of primary hyperparathyroidism. However, some patients with this disease will have hypercalcemia with an “inappropriately normal” PTH. Still others may have a normal calcium with elevated PTH. This latter group may have normocalcemic hyperparathyroidism, but secondary hyperparathyroidism from renal dysfunction (serum creatinine) and vitamin D deficiency (25-hydroxy vitamin D level) should also be considered. A 24-hour urine calcium level is important to rule out hypocalciuria that might indicate the patient has a rare genetic disorder called familial hypocalciuric hypercalcemia (FHH). These patients tend to have mild elevations of both serum calcium and PTH, and surgery is not appropriate in this group.
Investigations in patients with probable primary hyperparathyroidism might also include a 3-site (hip, spine and distal radius) bone mineral density DEXA scan, renal ultrasound, and when appropriate, spine x-rays. While these investigations do not directly contribute to the diagnosis, they may inform the surgical decision-making process. Given that untreated primary hyperparathyroidism may, over time, lead to significant health problems, patients should be referred to a surgeon or endocrinologist experienced in the work-up and treatment of hyperparathyroidism to confirm the diagnosis and provide discussion about treatment (see section on treatment). As surgery is the only potential curative treatment, a large portion of these patients will be offered parathyroidectomy. Once the decision to proceed to surgery is made, localizing tests will likely be ordered. It is important to note that these tests are for surgical planning and not diagnosis. It is inappropriate to use these tests in an attempt to “confirm” an uncertain diagnosis.
Localizing tests may be ordered to facilitate surgical planning. Most patients with primary hyperparathyroidism (>80%) will have a single adenoma as the underlying cause. The remaining patients may have multiple adenomas or 4-gland hyperplasia. Localizing tests are utilized in an attempt to identify which parathyroid glands are overactive. Normal parathyroid glands are not seen on localizing studies. The accuracy of these studies is lower in patients with multi-gland disease, so a non-localizing result should increase the suspicion of this etiology. Localizing tests are mandatory for patients in whom a focused approach to parathyroid surgery is planned. Localizing studies are not required if a four-gland/bilateral exploration is planned. However, some surgeons may use them in this setting to inform the conduct of the operation.
Nuclear medicine parathyroid scan (sestamibi scan) and ultrasound are the most commonly employed localizing studies. Sestamibi scans involved the injection of Tc99-sestamibi followed by imaging with a gamma camera. There are a number of variations to how this is performed in different centers (e.g., subtraction scans with a second isotope or combined with SPECT [single photon emission CT]). Metanalyses suggest that the sensitivity of this test is around 80%. However, the range of sensitivities reported in the literature illustrate that the accuracy of this test may be influenced by patients and disease factors, as well as the experience of the practice.
The sensitivity of ultrasound is similar to that of sestamibi. However, ultrasound is less likely to find rare ectopic parathyroids located outside of the neck. Similar to sestamibi, the accuracy of ultrasound appears to vary among centers, suggesting that the performance of this test is user dependent. Many parathyroid surgeons perform their own ultrasounds, as the knowledge of hyperparathyroidism and the expected anatomic location of the glands may result in a more accurate exam. A number of surgeons will obtain both a sestamibi scan and an ultrasound prior to surgery. The combination of these two tests has potential advantages. Concordant imaging (i.e., sestamibi and ultrasound suggesting an abnormal gland in the same location) has a sensitivity higher than each single test on its own. In addition, ultrasound may demonstrate concomitant thyroid nodules that might require appropriate investigation to determine if surgery might be beneficial at the same time as a parathyroid procedure.
Traditional cross-sectional imaging with MRI and CT scanning have been used for localization. In general, these tests have lower sensitivities when compared to the more commonly used ultrasound and sestamibi scan. More recently, 4-dimensional CT scan (4D-CT) has been developed specifically for localization of enlarged parathyroid glands. This scan involves multiple series of scans before and at specific time points after contrast injection. The 4th dimension in the name of this study refers to time. 4D-CT has shown significant promise in parathyroid localization. While less experience with this technique exists than the more commonly utilized tests, the performance of 4D-CT appears to be at least comparable to the more traditional sestamibi and ultrasound scans.
In specific circumstances more invasive tests may be utilized for the localization of abnormal parathyroids. Fine needle aspiration of abnormal parathyroid glands is not routinely recommended in patients with primary hyperparathyroidism. This might rarely be used when an intrathyroidal parathyroid adenoma is suspected pre-operatively or in the operating room. When performed, a needle wash for PTH level (markedly elevated in parathyroid samples) should be added, as cytology is often unclear.
In addition, venous sampling can be used to facilitate localization in very specific clinical situations. Typically, these are used in difficult re-operative cases when non-invasive localization methods have been unsuccessful. Two techniques may be used: 1) Jugular venous sampling under ultrasound guidance to determine if PTH is higher on one side of the neck compared to the other; and 2) selective venous sampling in which a catheter is inserted into large veins in the groin and advanced to various locations in the neck and chest (multiple samples are taken to better localize the source of excess parathyroid hormone).