The biochemical diagnosis of primary hyperparathyroidism is made by documenting an elevated serum PTH in a patient with hypercalcemia (serum calcium > 10.5 mg/dL) without hypocalciuria. Patients with benign familial hypocalciuric hypercalcemia (BFHH) are also hypercalcemic and have an inappropriately high PTH. Virtually all patients with other causes of hypercalcemia have a suppressed serum PTH level. Patients with BFHH have elevated levels of PTH in the presence of hypercalcemia because of mutations in the gene encoding the extracellular calcium sensor protein, making the parathyroid cells less sensitive to hypercalcemia.12 BFHH can be suspected on the basis of a family history and identified by low urinary calcium excretion (calcium clearance less than 1% of creatinine clearance).
Cancer is the other most common cause of hypercalcemia.13 Patients with hypercalcemia of malignancy can be diagnosed by a thorough history and physical examination. Many solid tumors associated with hypercalcemia secrete parathyroid hormone-related protein (PTHrP); others cause hypercalcemia through cytokines or by direct bone destruction. With the exception of some very rare renal cell carcinomas and ovarian carcinomas that secrete PTH, none of these patients have elevated serum PTH levels.
Other laboratory findings consistent with primary hyperparathyroidism include a low serum phosphorus level (<2.5 mg/dL), elevated serum chloride level (>107 mmol/L), and elevated serum chloride-to-phosphate ratio (>33). Some patients have elevated serum levels of alkaline phosphatase and uric acid. Subperiosteal resorption can be demonstrated in hand radiographs of patients with elevated alkaline phosphatase levels. It is rare in other patients with primary hyperparathyroidism.
The symptoms and signs of mild primary hyperparathyroidism can be more subtle and less specific, such as fatigue, weakness, lethargy, depression, memory loss, personality changes, constipation, and decreased bone density. It is controversial whether to operate on patients with few or no symptoms or metabolic problems and minimal hypercalcemia. A prospective study of patients with primary hyperparathyroidism showed, however, that truly asymptomatic patients are uncommon: less than 5% of patients.14 Many patients with these nonspecific symptoms improved after a successful parathyroid operation compared with a control group of patients who underwent thyroidectomy. Ninety-five percent had improvement of one or more symptoms after parathyroidectomy, and 55% felt better overall (compared with 30% after thyroidectomy).15 The severity of hypercalcemia did not correlate with the presence of these symptoms before parathyroidectomy; neither did it correlate with the improvement in symptoms after successful surgery.15,16
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