Laboratory Investigations

In patients with hypercalcemia, it is usually relatively easy to make the diagnosis of primary hyperparathyroidism by documenting an increased blood intact or two-site parathyroid hormone (PTH) level and normal or increased urinary calcium concentration. The two-site or intact PTH (iPTH) assays do not cross-react with PTHrP, the most common peptide secreted by nonparathyroid cancers.26 PTHrP cross-reacts with some mid- or C-terminal PTH assays and causes a falsely elevated PTH value. Some patients may have more than one reason for an increased calcium level, such as metastatic breast cancer and primary hyperparathyroidism. In these patients, an iPTH assay is most valuable for documenting that primary hyperparathyroidism is also present. In addition, the presence of a mild hypokalemic, hypochloremic alkalosis points to malignancy as the causative factor, whereas a mild hyperchloremic metabolic acidosis suggests hyperparathyroidism. A few patients have also been documented as having nonparathyroid tumors that make pure PTH.27 In these situations, selective venous catheterization for iPTH of the neck and mediastinal veins as well as veins draining the tumor is useful in documenting whether the hypercalcemia is caused by the tumor or by coexistent primary hyperparathyroidism. Open or fine-needle biopsy of the tumor and assay for iPTH are also of help in these rare situations.27

The only other metabolic condition that can mimic primary hyperparathyroidism from a laboratory point of view—that is, increased blood calcium and increased iPTH—is benign familial hypocalciuric hypercalcemia (BFHH).28,29 These patients, however, have low urinary calcium. It is important, therefore, to obtain a 24-hour urine sample for calcium and creatinine to determine the urinary calcium level, especially in patients who have never had documented normocalcemia. Patients with BFHH have urinary calcium levels less than 100 mg per 24 hours and have family members younger than 10 years with hypercalcemia, a situation that almost never occurs in patients with sporadic hyperparathyroidism or even in patients with familial hyperparathyroidism or hyperparathyroidism associated with multiple endocrine neoplasia (MEN) type 1 and MEN 2. Furthermore, the serum calcium-to-creatinine clearance ratio is usually less than 0.01 in patients with BFHH, whereas it is typically greater than 0.02 in patients with primary hyperparathyroidism.30 BFHH is inherited in an autosomal dominant fashion with nearly 100% penetrance but variable expression. The genetic locus for BFHH maps to the long arm of chromosome 3 and has been identified as the calcium-sensing receptor gene (CASR).31-32 Patients with BFHH are heterozygous for CASR mutations. When this is a homozygous mutation, the patient has neonatal hyperparathyroidism.31 The latter is often life threatening and warrants total parathyroidectomy with parathyroid autotransplantation and cryopreservation.31,33 Identifying patients with BFHH is crucial because these individuals do not benefit from parathyroidectomy.

Patients with primary hyperparathyroidism also often have a low (50%) or low-normal (40%) blood phosphorus level and an increased (>33) chloride-to-phosphorus ratio.34 As mentioned earlier, a mild hyperchloremic metabolic acidosis is often present. About 30% of patients with primary hyperparathyroidism have an increased uric acid level, and 15% have an elevated alkaline phosphatase level.34,35 Most patients with primary hyperparathyroidism also have an increased or high-normal 1,25-dihydroxyvitamin D3 level.36 It is also important to document the serum blood urea nitrogen and creatinine levels, and perform serum protein electrophoresis. The latter helps to eliminate the diagnosis of multiple myeloma. Patients with primary hyperparathyroidism who have increased bone alkaline phosphatase (with other normal liver enzymes) have high-turnover bone disease and are susceptible to postparathyroidectomy hypocalcemia. In patients with osteitis fibrosa cystica, the blood magnesium and potassium levels can be low, and hypomagnesemia can contribute to postoperative tetany.

Normocalcemic Hyperparathyroidism

Patients with primary hyperparathyroidism can also be normocalcemic. Most of these individuals are detected because of recurrent nephrolithiasis or osteoporosis.37 The reasons for normocalcemic hyperparathyroidism include (1) vitamin D deficiency, (2) low serum albumin, (3) pancreatitis, (4) increased phosphate intake, (5) excessive hydration, and (6) a low-normal blood calcium set point with an increase above the patient's normal calcium level but still within the normal range.37 The diagnosis of normocalcemic hyperparathyroidism is usually made by documenting an increased total PTH level with or without an increased blood ionized calcium level. However, patients with renal leak hypercalci-uria must be excluded. The increased PTH level in patients with renal leak is secondary to the excessive calcium loss in the urine; one can diagnose renal leak hypercalciuric patients by treating them with thiazide diuretics. With treatment, the urinary calcium level falls and the secondary increase in the blood PTH also decreases to normal. In patients with normocalcemic hyperparathyroidism, the urine calcium and blood PTH remain elevated.34 Normocalcemic hyperparathyroidism is discussed in more detail Chapter 45.

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