Further Insights into the Pathogenesis of Primary Hyperparathyroidism: A Nested Case-Control Study

Context: The pathogenesis of primary hyperparathyroidism (PHPT) is largely unknown. Objective: The objective of the study was to ascertain the plasma levels of calcium, PTH, and 25-hydroxyvitamin D (25OHD) as measured prior to a clinical diagnosis of PHPT. Study Subjects: Within three population-based cohorts, we identified participants diagnosed with PHPT after their inclusion. Cases (n = 117) were compared with age, gender, and season-matched controls (n = 233). Results: Time from inclusion until a diagnosis of PHPT was median 5.6 yr. Parathyroidectomy was performed in 97%. At the cohort inclusion, undiagnosed PHPT was present in 63% of the cases. Among those without PHPT at inclusion (n = 43), 55% had normocalcemic hyperparathyroidism (vs. 21% in the matched controls, P < 0.01), and 31% had normoparathyroid hypercalcemia. Overall, 25OHD levels were lower in the cases. Compared with their matched controls, 25OHD levels were lower in normocalcemic hyperparathyroidism but not in normoparathyroid hypercalcemia. An adenoma was removed from 78% of the cases with normocalcemic hyperparathyroidism, whereas 39% of the cases with normoparathyroid hypercalcemia had parathyroid hyperplasia (P = 0.02). Overlap performance showed a positive predictive value for later PHPT of 95% for plasma calcium levels greater than 2.52 mmol/liter. Excluding cases with vitamin D insufficiency, the positive predictive value for later PHPT was 83% for PTH levels greater than 5.0 pmol/liter. Conclusion: Years prior to a clinical diagnosis of PHPT, calcium homeostasis shows signs of perturbations. Latent PHPT may be characterized by either normocalcemic hyperparathyroidism or normoparathyroid hypercalcemia. Such patients should be offered long-term follow-up to ascertain whether their biochemical profile represents an early state of PHPT. (J Clin Endocrinol Metab 98: 87-96, 2013)