Beyond Parathyroid: A Mystery of Refractory Hypercalcemia Requiring Hemodialysis

Introduction: About 90% hypercalcemia cases are from primary hyperparathyroidism or malignancy. Other causes are granulomatous diseases (sarcoidosis and tuberculosis), endocrinopathies (hyperthyroidism and adrenal insufficiency), medications, genetic disorders (familial hypocalciuric hypercalcemia) and immobilization. Treatment is tailored to acute management and addressing underlying cause. We report a case of a patient with refractory hypercalcemia despite multiple interventions, requiring transient dialysis and finally controlled on steroid therapy and off some medications. Case Description: A 61-year-old woman with CKD3, nephrolithiasis, gout (on probenecid-colchicine), and birdshot retinopathy (on methotrexate, prednisone), immunocompromise from chronic steroid and methotrexate use, presented with syncope, confusion and constipation. She was found to have severe hypercalcemia and pneumocystis jirovecii pneumonia (PJP). She had high Vitamin A, D levels with low PTH, but remainder of hypercalcemia workup was negative (Table 1). Her hypercalcemia did not respond to intravenous fluids, but improved transiently with calcitonin, zoledronic acid and antibiotics for PJP. She eventually responded to denosumab combined with transient hemodialysis and stabilized with steroids (Figure 1). Discussion: PJP is common in solid organ transplant or AIDS patients and rare in immunosuppressed patients. Our patient developed PJP infection causing an unusual complication of refractory hypercalcemia via hypervitaminosis D and granulomatous production of 1α-hydroxylase by macrophages, resulting in increased calcitriol formation. Extrarenal Vitamin D production by activated macrophages is autonomous and feedback-unresponsive (low PTH), seen in methotrexate-induced pneumonitis or PJP. Vitamin D is slow to decline due to fat-soluble sequestration in the body, making treatment response more challenging. Our patient was discharged on prednisone and dapsone, and off methotrexate and probenecid. She had subsequent improvement in hypercalcemia and chest X-ray findings, suggesting resolution due to PJP treatment and medication optimization.