Normocalcemic Primary Hyperparathyroidism: Evidence for a Generalized Target-Tissue Resistance to Parathyroid Hormone

Primary hyperparathyroidism (PHPT) is usually characterized by fasting hypercalcemia associated with inappropriately high PTH concentration. Nevertheless, cases of proven PHPT have been reported in normocalcemic patients. The purpose of the study was to investigate the mechanism(s) of persistent normocalcemia in PHPT. One hundred seventy-eight patients with PHPT were studied after exclusion of any evident cause of masked hypercalcemia. Patients were separated into normocalcemic (n = 34) and hypercalcemic (n = 144) subgroups on the basis of their fasting serum ionized calcium value. Patients with normocalcemic PHPT had, on average, a milder excess in PTH secretion assessed by a lower serum PTH concentration. Because of a clear overlap in PTH values between the two groups, normocalcemic and hypercalcemic patients were matched on the basis of serum PTH concentration, age, and sex. Patients with normocalcemic PHPT had lower fasting urine calcium excretion and renal tubular calcium reabsorption. In addition, normocalcemic patients differed from hypercalcemic patients by lower values of markers of bone turnover and plasma 1,25 dihydroxyvitamin D and higher values of renal phosphate threshold. In conclusion, a significant proportion of patients with PHPT are truly normocalcemic, and in addition to a milder increase in PTH secretion, the normocalcemic patients appear to display resistance to PTH action on bone and kidney.