Widespread use of biochemical screening in clinically healthy persons has led to an increase in the number of persons found to have hypercalcemia and subsequently diagnosed with primary hyperparathyroidism. However, only about 20 percent of them have systemic manifestations of parathyroid disease such as loss of bone mass or kidney stones. In 1990, the National Institutes of Health (NIH) issued a consensus statement on the diagnosis and management of asymptomatic primary hyperparathyroidism that specified limited criteria for the use of surgery in managing this disease. They noted in the report that there were limited data on the natural history of hyperparathyroidism in untreated patients and that future recommendations may need modification. Silverberg and associates followed two cohorts of patients with primary hyperparathyroidism for 10 years.

The study enrolled 121 patients during a seven-year period. The diagnosis of primary hyperparathyroidism was based on an elevated calcium level and confirmed by a serum parathyroid hormone assay. Patients who met the NIH–specified criteria for surgery were recommended for parathyroidectomy. These criteria included nephrolithiasis, osteitis fibrosa cystica, proximal muscle weakness, atrophy, hyperreflexia and gait disturbances. Patients were also recommended for surgery if they had at least one of the following: a serum calcium concentration of greater than 12 mg per dL (3 mmol per L), marked hypercalciuria (greater than 400 mg [10 mmol] per day), significant reduction in bone density or unexplained reduction in creatinine clearance, and were less than 50 years of age. Supplemental calcium was recommended for patients not undergoing surgery.

After a baseline clinical evaluation and laboratory assessment, patients had repeat biochemical studies every four months. Patients who underwent parathyroidectomy were evaluated every six months. Follow-up studies included measurements of serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels. Bone mineral density at the femoral neck, radius and lumbar spine (L2, L3 and L4) was measured at baseline and every year.

Among the cohort of 121 patients, 61 had surgery and 60 did not. The average age for the surgical and nonsurgical groups was 51 and 58 years, respectively. Ninety-one of the patients were women. Only 20 patients had symptoms (i.e., a history of nephrolithiasis) of hyperparathyroidism. Of the 61 patients who had surgery, 49 were asymptomatic and 12 had symptoms. All of the surgical patients had normalization of biochemical markers after surgery. None of the patients with kidney stones had recurrences during the 10-year follow-up. Increases in bone mineral density were noted at all sites, but after one year, only changes for the femoral neck were significant.

Among the 60 patients who did not have surgery, eight were symptomatic and either refused surgery or had undergone previous unsuccessful surgery. None of these 60 patients showed significant changes from baseline in the various biochemical markers. For example, the mean serum calcium level was 10.5 mg per dL (2.63 mmol per L) at baseline and 10.3 mg per dL (2.58 mmol per L) at the 10-year follow-up. There were also no significant changes in bone mineral density or urinary calcium excretion among the 52 who were originally asymptomatic.

During the 10-year follow-up, 14 of the 52 asymptomatic patients who did not undergo surgery showed signs of disease progression that became an indication for surgery. This included a serum calcium concentration of greater than 12 mg per dL in two patients, urinary calcium excretion greater than 400 mg per day in eight patients and a low cortical bone density in six patients. None of these patients had nephrolithiasis, fractures or change in creatinine clearance. Six of the 14 later elected to undergo surgery. Of the eight patients with nephrolithiasis who did not undergo surgery, six had a recurrence of kidney stones.

The authors conclude from the data that in patients with symptomatic primary hyperparathyroidism, surgical treatment results in normalization of biochemical markers and stabilization or increases in bone mineral density. Approximately 25 percent of the patients who were asymptomatic at the time of diagnosis did not have progression of symptoms or manifestations of hyperparathyroidism. Asymptomatic patients who do not have surgery should be followed with biannual measurements of serum calcium concentrations and annual measurements of urinary calcium excretion and bone mineral density.

editor's note: In an accompanying editorial, Utiger notes that most patients with primary hyperparathyroidism have at least some physical or neuropsychologic symptoms. Utiger believes that nearly all patients with hyperparathyroidism should have surgery. I believe more prospective data must be presented before changing the current NIH guidelines, as watchful waiting with regular follow-up still seems reasonable in most patients.—j.t.k.