Hypercalcemia Associated with Wegener’s Granulomatosis and Hyperparathyroidism: Etiology and Management

Abstract

We report a case of hypercalcemia in a patient with coexisting hyperparathyroidism and Wegener’s granulomatosis. Parathyroidectomy with removal of an adenoma resulted in a low parathyroid hormone level but high calcitriol levels and hypercalcemia persisted. In various granulomatous diseases, hypercalcemia has been shown to be the result of overproduction of 1,25-dihydroxy-vitamin D by disease-activated macrophages. Chloroquine has been demonstrated to effectively reduce the extrarenal synthesis of 1,25-dihydroxyvitamin D and serum calcium concentration in hypercalcemic patients with sarcoidosis. Hypothesizing that a similar mechanism would explain hypercalcemia in Wegener’s granulomatosis as well, a therapeutic trial of chloroquine was initiated. The patient responded to chloroquine 500 mg twice daily with significant decreases in serum 1,25-dihydroxyvitamin D and calcium levels. This report extends previous observations of hypercalcemia associated with other granulomatous diseases to Wegener’s granulomatosis and demonstrates an effective reduction of serum calcitriol and calcium levels in response to chloroquine therapy.

Extrarenal 1α-Hydroxylase

“…The syndrome of extrarenal overproduction of 1,25 (OH) 2 D has also been documented in adult patients with widespread silicone-induced granulomata [60], eosinophilic granuloma [61], Wegener's granulomatosis [62], Langerhans cell histiocytosis [63], and the systemic granulomatous disease GCP [35]. Although the active vitamin D metabolite was not measured, dysregulated calcium balance in the granuloma-forming pulmonary disease berylliosis is also attributed to the extrarenal production of 1,25(OH) 2 D [64].…”

“…Silicone-induced granulomatosis [60] Langerhans cell histiocyosis [61,63] Wegener's granulomatosis [62,277,278] Berylliosis [279] Lipoid pneumonia [280,281] Talc granulomatosis [282] Infantile fat necrosis [66] Slack skin disease [283] Giant cell polymyositis [35] Crohn Plasma cell granuloma [284] Dysgerminoma [151,285] Seminoma [286] [1e5,13e17,19,39e41]. In the most expansive studies published on the topic, roughly 10% of patients with sarcoidosis develop hypercalcemia [41], and up to 50% suffer from hypercalciuria [41] at some time during the course of their disease.…”

Hypercalcemia Associated with Local and Ectopic Hormone Production

“…47 Additionally, any inflammatory process may be associated with 1,25(OH) 2 D-mediated hypercalcemia. Case reports include Crohn's disease, 48,49 Wegener's granulomatosis, [50][51][52] Langerhans' cell histiocytosis, 53 rheumatoid arthritis, 54 osteoarthritis, 55 neonatal subcutaneous fat necrosis, 56 lipoid pneumonia, 57 and hepatic granulomatosis in chronic dialysis. 58 Foreign bodies that cause a granulomatous reaction leading to hypercalcemia include talc, 59 silicone, 60 beryllium, 61 and paraffin.…”

Management of Wegener Granulomatosis

“…Published case reports cite successful treatment of WG with high-dose intravenous immunoglobulin, 86 -91 cyclosporin A, 92-95 chloroquine, 96 antithymocyte globulin, 97,98 15-deoxyspergualin, 99 antituberculosis medications, 100 immunoadsorption to remove ANCAs, 101 and etoposide, 102,103 but data are limited to uncontrolled trials and case reports. Chlorambucil, an alkylating agent related to CYC, has been used to treat WG with anecdotal successes 63,104 but is oncogenic and has myriad toxicities.…”