Hypercalcemia
Summary of Key Points
Incidence
• Hypercalcemia is a major metabolic complication associated with malignant disease.
• Hypercalcemia occurs in approximately 10% of patients with cancer.
• Hypercalcemia has a specific predilection for squamous carcinoma of the bronchus, carcinoma of the breast, and multiple myeloma.
• Hypercalcemia is frequently recognized late and managed poorly.
Etiology of Complication
• Parathyroid hormone–related protein (PTHrP) produces hormonal and paracrine effects.
• Factors released by, or in response to, metastases in bone (receptor activator of nuclear factor–κB ligand [RANKL], PTHrP, transforming growth factor-α, tumor necrosis factor, interleukin-1 [IL-1], IL-6, and others) cause paracrine effects.
• The final common pathway is osteoclastic bone resorption.
• It is aggravated by renal functional abnormalities or renal effects of PTHrP, or both.
Evaluation of the Patient
• Determination of the stage of disease and subsequent antineoplastic options provides a logical approach to management.
• Patient symptomatology is more relevant than the absolute calcium level.
• The total calcium concentration must be corrected for serum albumin concentration.
• Close attention to volume status and renal function are mandatory.
• Causes of hypercalcemia other than malignancy should be considered.
Treatment
• Antitumor therapy should be implemented for best long-term results.
• Consideration should be given to active palliation in the face of advanced disease when antitumor options are exhausted.
• Extracellular fluid volume should be expanded to induce a calciuresis.
• Antiresorptive therapy (bisphosphonates with or without calcitonin) should be considered as first-line therapy.
1. A 57-year-old woman presents with a 6-week history of midthoracic pain, increasing lethargy, and somnolence. The family has noticed a reduced urine output during the past 2 days. Clinically she is rousable and protecting her airway. Her heart rate is 110 beats per minute and regular, and her blood pressure is 110/80 mm Hg with severe orthostatic symptoms on any attempt to sit her on the edge of the bed. Her jugular venous pressure is low and her axillae are dry. Laboratory values show hemoglobin, 9.5 g/dL (mean corpuscular volume 85 fL); leukocyte count, 3.5 × 109/L; platelet count, 118 × 109/L; sodium, 145 mEq/L; potassium, 5.7 mEq/L; chloride, 110 mEq/L; blood urea nitrogen, 10 mg/dL; creatinine, 3.9 mg/dL; albumin, 3.0 g/L; total protein, 9 g/L; calcium, 12.1 mg/dL; and phosphate, 6.0 mg/dL. Plain radiographs show diffuse osteopenia of the thoracic spine with no fracture or erosions. The likely diagnosis is:
A Breast cancer with thoracic metastases
B Multiple myeloma with thoracic involvement
2. For the patient described in Question 1, the most suitable initial management would be:
A Volume expansion with 0.9% saline solution
B Volume expansion with 0.9% saline solution plus furosemide, 40 mg administered intravenously (IV)
3. A 39-year-old man presents with asymptomatic hypercalcemia (calcium, 12.0 mg/dL) and a parathyroid hormone level of 40 pg/mL (reference range, 10-55 pg/mL). Which of the following medications is most likely to be associated with this picture?
4. Concerning the physiology of parathyroid hormone–related peptide (PTHrP), which associated biochemical finding would be unlikely?
5. A 65-year-old man with metastatic squamous carcinoma of the lung has evidence of disease progression in the lung, bone, and brain despite chemotherapy and radiation therapy. He presents comatose with a serum calcium level of 16.2 mg/dL. The most appropriate initial recommendation for therapy would be:
A Palliative care with no therapy for the hypercalcemia
B Admission to the intensive care unit to secure the airway followed by volume expansion with 0.9% saline solution
C Admission to the intensive care unit to secure the airway followed by administration of zoledronic acid, 4 mg IV, plus calcitonin 8 Medical Research Council units/kg administered intramuscularly every 6 hours
D Admission to the intensive care unit to secure the airway followed by volume expansion with 0.9% saline solution and 40 mg furosemide IV
1. Answer: B. The association of hypercalcemia, bone pain, and renal failure is a very common presentation for multiple myeloma. The diagnosis is supported by evidence of trilineage marrow suppression and a reversed albumin : globulin ratio (low albumin, high total protein), suggesting a high circulating globulin level.
2. Answer: A. The initial management of hypercalcemia is volume expansion with normal saline solution. Furosemide is not useful and is potentially dangerous in the volume-contracted state. Delaying bisphosphonates until renal function can be assessed after volume expansion is safer than administering those agents in the face of reduced renal function. Although dialysis could be used, it should be withheld until the patient is euvolemic because renal function may improve, obviating its use, and the introduction of dialysis in the volume-depleted state may be associated with worsening of hypotension and cardiovascular collapse.
3. Answer: D. Lithium carbonate is associated with an increase in the set point for PTH suppression. It therefore requires a higher calcium level to suppress parathyroid hormone (PTH). All other medications listed would be associated with a suppressed PTH.
4. Answer: B. Despite homology at the N-terminal end between PTHrP and PTH, PTHrP is not associated with stimulation of the renal 1α-hydroxylase. 1,25-(OH)2D3 levels tend to be low or in the low normal range in persons with humoral hypercalcemia of malignancy.
5. Answer: A. In this setting, the patient’s life expectancy is very short, even with aggressive correction of the hypercalcemia. Early involvement of palliative care personnel is important in patients who have no antitumor options available to them.
