Case Presentation: Hypercalcemia can have adverse effects on the body. Rarely a sign in and of itself, its presence is characteristically associated with an underlying condition. There are usual suspects to consider in the differential but when workup for those return unremarkable, it becomes a challenge to find the underlying etiology.An 80-year-old female with a history of chronic hypercalcemia presented to the emergency department for hypercalcemia critically elevated at 15 mg/dL, with ionized calcium 1.84 mmol/L. Intact parathyroid hormone (PTH) was low at 7.7 pg/mL, and parathyroid hormone-related protein (PTHrP) < 2 pmol/L. Other pertinent medical history included chronic left lower extremity lymphedema and cellulitis, complicated by hematoma of the left calf. As the patient had reported more than 100 pounds of unintentional weight loss of over the past year, and given elevated beta-2 microglobulin, there was a concern for underlying malignancy, which is the prevailing cause of hypercalcemia in the hospital. Renal ultrasound confirmed bilateral pelvicaliectasis without visible stones. Urine protein/creatinine ratio, ACE levels, SPEP, UPEP, immunofixation, CT thorax, CT abdomen/pelvis, bone marrow biopsy, and flow cytometry were unremarkable. However, 1,25-dihydroxyvitamin D (calcitriol) was elevated.
Discussion: Hospitalization was complicated by a chronic non-healing pressure ulcer to the posterior aspect of the left lower extremity. NM dual-isotope scan was highly suspicious for cellulitis and osteomyelitis of the left lower extremity, left tibia, and tibiotalar articulation. MRI showed extensive marrow changes not typical of simple or disseminated osteomyelitis, but concerning for marrow infiltrative process like primary malignancy or metastatic disease. Due to the presence of innumerable subcutaneous intramuscular and intermuscular enhancing solid nodules without abscesses, a diagnosis of neoplastic/metastatic versus infectious process was favored. Soft tissue biopsy of the dominant subcutaneous nodule revealed CD positive B-cell lymphoma in favor of germinal center origin.With the determination of B-cell lymphoma as the underlying cause of this patient’s hypercalcemia, there are some potential processes behind this to consider. In the mechanism mediated by calcitriol, the enzyme 1α-hydroxylase is expressed by tumor cells and transforms inactive vitamin D (25-hydroxyvitamin D) into its active form, calcitriol. Hypercalcemia results from increased renal reabsorption and intestinal absorption of calcium. Contrastingly, in humoral hypercalcemia of malignancy, the production of PTHrP by tumors may lead to hypercalcemia by mimicking the effects of PTH, increasing bone resorption and renal calcium reabsorption. Less commonly, the osteolytic mechanism, aided by osteoclast activity, results from local cytokine release caused by bone infiltration by cancerous cells, stimulating bone resorption and calcium delivery into the blood. In the setting of this patient’s elevated 1,25-dihydroxyvitamin D, arising from increased production, with low PTH, the hypercalcemia was likely due to tumor expression of 1α-hydroxylase.
Conclusions: This case highlights the association of hypercalcemia with malignancy. Though PTHrP is often seen as the most common agent that mediates this process, other possible mechanisms and diagnostic clues should be explored, especially when PTHrP is normal.