Background Hypercalcemia during flares of sarcoidosis is reported to occur with a 5-10% incidence. The underlying mechanism is thought to involve high circulating concentrations of 1,25-dihydroxyvitamin D3, produced by 1α-hydroxylation of vitamin D within sarcoid granulomas. Granulomatous production of parathyroid hormone-related protein (PTH-rp), important in humoral hypercalcemia of malignancy, may also play a role in abnormal calcium metabolism. We report a case of sarcoidosis that presented with significant hypercalcemia and simultaneous elevation of 1,25-dihydroxyvitamin D3 and PTH-rp.
Case Presentation A 39-year-old woman, with recently diagnosed Graves' disease, was admitted to our hospital with palpitations, fatigue, nausea, and abdominal pain. On admission, she had hypercalcemia (15.2 mg/dL), renal insufficiency (creatinine 1.5 mg/dL), and uncontrolled hyperthyroxinemia (TSH 0.1 uIU/mL, FT4 5.6 ng/dL, and TT3 483 ng/dL). The initial serum 1,25-dihydroxyvitamin D3 was inappropriately within the normal range (43 pg/mL), while intact PTH was appropriately suppressed (< 6 pg/mL) and PTH-rp elevated (11.6 pmol/L). Computed tomograms showed symmetric bilateral hylar adenopathy with diffuse interstitial lung disease and no evidence of malignancy. Transbronchial lung biopsy showed noncaseating granulomas, compatible with sarcoidosis. Treatment with saline infusion and prednisone 40 mg daily alleviated the hypercalcemia and renal insufficiency. Methimazole and beta-blockers were initiated for treatment of Graves' disease. Prednisone therapy was tapered to 10 mg/day and 1 month later, both the serum calcium, intact PTH, and TSH normalized while the PTH-rp was undetectable. The 1,25-dihydroxyvitamin D3 level was 47 pg/mL. Discussions: Corticosteroids are particularly effective for treating hypercalcemia in sarcoidosis because they inhibit the 1α-hydroxylase in macrophages, with a subsequent effect on vitamin D metabolism and decreases in gastrointestinal calcium absorption. Corticosteroids also bind to cytokine promoter regions in the macrophage nucleus, down-regulating IL-2 and IFN-γ expression and resulting in reduced PTH-rp production by macrophages. This case demonstrates several important physiological factors contributing to the onset of hypercalcemia, including that a patient with active sarcoid can have both a PTH-independent (1,25-dihydroxyvitamin D3) and PTH-dependent (PTH-rp) process. In this patient, corticosteroids rapidly restored normocalcemia by decreasing PTH-rp but had no effect in reducing the 1,25-dihydroxyvitamin D3.
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