A Case of 1,25-OH Vitamin D Mediated Hypercalcemia Due to Extrarenal 1-Hydroxylase Activity in a Patient with Disseminated Histoplasmosis: Challenges in Clinical Diagnosis and Management

Endogenous overproduction of 1,25-OH vitamin D is an uncommon cause PTH-independent hypercalcemia, and extra-renal 1-hydroxylase activity due to disseminated histoplasmosis in a non-endemic location an uncommon cause of 1,25-OH vitamin D mediated hypercalcemia. The case presented several diagnostic and therapeutic challenges. For example, corticosteroids specifically target the pathophysiology of absorptive hypercalcemia, but were contraindicated in disseminated fungal disease. Empiric use of anti-resorptive therapy was ineffective and likely contributed to the development of hypocalcemia subsequent to initiation of anti-fungal therapy.

Case Description:

The patient was a 71-year-old man with a history of chronic obstructive pulmonary disease, interstitial lung disease, and rheumatoid arthritis on chronic immunosuppressive therapy. He presented with night sweats, weight loss & pleuritic chest pain and treated with prednisone for presumed pericarditis. However, symptoms progressed over two weeks and his mental status deteriorated. Laboratory data included calcium 12.3 mg/d, albumin 3.6 g/dL, PO4 5.5 mg/dl, estimated GFR 23 ml/min/1.73m2. Hypercalcemia was refractory to iv normal saline, calcitonin, and denosumab (60 mg). Subsequent labs demonstrated suppressed parathyroid hormone < 4.2 pg/mL, elevated 1, 25-hydroxy vitamin D (94 pg/mL), and normal concentrations of 25-hydroxy vitamin D and PTHrP. CT imaging demonstrated extensive, bibasilar tree-in-bud pulmonary infiltrates and nodular opacities and infiltration of the upper abdominal omentum, concerning for metastatic disease. An incidental 1.6 cm adrenal nodule with indeterminate HU and stability since 2019 was also observed. Biopsy of the omental mass and other studies confirmed histoplasmosis. There was no clinical, laboratory, or radiological evidence of corticosteroid insufficiency or excess. Treatment with itraconazole promptly led to normalization of calcium and 1,25-OH vitamin D levels and clinical resolution of fungal disease.

Discussion:

Histoplasmosis is a rare cause of vitamin D-dependent hypercalcemia and should be considered as in the differential diagnosis of patients presenting with PTH-independent hypercalcemia, even in non-endemic areas of the world. Pharmacologic therapy directed to disseminated histoplasmosis rapidly resolved hypercalcemia and 1,25-OH vitamin D elevations, confirming the role of disseminated histoplasmosis and host response as the source of extra-renal 1-hydroxylase activity.