Mechanism of Hypercalcemia in Sarcoidosis

Pathophysiological Mechanisms

Granulomatous macrophages in sarcoidosis produce excessive amounts of 1α-hydroxylase enzyme, which converts 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D (calcitriol), according to the American Thoracic Society 1, 3
Increased expression of parathyroid hormone-related protein (PTHrP) in sarcoidosis macrophages contributes to the hypercalcemia, as reported by the American College of Chest Physicians 1
Various cytokines and growth factors produced by granulomas further influence calcium metabolism, as noted by the American Journal of Respiratory and Critical Care Medicine 1

Hypercalcemia is detected in approximately 6% (95% CI, 4-8%) of patients with sarcoidosis, according to the American College of Chest Physicians 1, 2
Untreated hypercalcemia can lead to renal failure in 42% (95% CI, 33-52%) of patients, as reported by the American Thoracic Society 2

Most sarcoidosis patients (84%) have low 25-(OH) vitamin D levels, as noted by the American College of Chest Physicians 1, 2
Despite low 25-(OH) vitamin D, approximately 11% have high 1,25-(OH)2 vitamin D levels, according to the American Journal of Respiratory and Critical Care Medicine 1, 2
Patients with a history of hypercalcemia typically have relatively higher 1,25-(OH)2 vitamin D levels compared to their 25-(OH) vitamin D levels, as reported by the American Thoracic Society 2, 3

Baseline serum calcium testing is strongly recommended for all sarcoidosis patients, even without symptoms of hypercalcemia, as recommended by the American College of Chest Physicians 1, 5
If vitamin D assessment is needed, both 25-(OH) and 1,25-(OH)2 vitamin D levels should be measured before any supplementation, according to the American Journal of Respiratory and Critical Care Medicine 5