A 60-year-old man is brought to the emergency department by his daughter due to a 2-day history of confusion and lethargy. According to the daughter, he has had a constant dry cough, fatigue, anorexia, polyuria, and constipation for several weeks. In addition, the patient has lost 9.1 kg (20 lb) over the past 3 months. He has no associated pain. The patient's medical history is significant for hypertension treated with chlorthalidone and for gastroesophageal reflux disease treated with over-the-counter antacids. He smokes 2 packs of cigarettes daily and consumes alcohol occasionally. Blood pressure is 130/90 mm Hg and pulse is 90/min. Temporal wasting is noted. Chest and abdominal examinations are normal. Mental status examination shows somnolence and disorientation to time. Neurologic examination shows decreased deep tendon reflexes. Laboratory results are as follows:
Serum chemistry Sodium 140 mEq/L Potassium 4 mEq/L Chloride 104 mEq/L Bicarbonate 24 mEq/L Creatinine 1.6 mg/dL Calcium 14.4 mg/dL Glucose 100 mg/dL Alkaline phosphatase, serum 130 U/L Phosphorus (inorganic), serum 2.2 mg/dL
Which of the following is the most likely cause of this patient's symptoms?
Hypercalcemia of malignancy | |||
Cause | Tumor type | Mechanism | Diagnostic |
PTHrP* |
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Bone metastases |
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1,25-dihydroxyvitamin D |
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*PTHrP causes ~80% of malignancy-associated hypercalcemia. PTH = parathyroid hormone; PTHrP = PTH-related protein. | |||
This patient has polyuria and neuropsychiatric symptoms consistent with hypercalcemia. Severe hypercalcemia can also cause impaired neuromuscular excitability, leading to weakness, diminished reflexes, and decreased gastrointestinal motility. In light of this patient's weight loss, temporal wasting, dry cough, and smoking history, he most likely has humoral hypercalcemia of malignancy (HHM) due to squamous cell carcinoma of the lung. HHM is a paraneoplastic syndrome due to the release of parathyroid hormone-related protein (PTHrP) by malignant cells, which is structurally similar to parathyroid hormone (PTH) and acts on the PTH-1 receptor. PTHrP causes increased bone resorption and reabsorption of calcium in the distal renal tubule. Increased phosphate excretion leads to hypophosphatemia.
HHM is characterized by severe (eg, >14 mg/dL) and rapid-onset hypercalcemia. The diagnosis is often suspected on clinical grounds and can be confirmed by an elevated PTHrP level and suppressed PTH level. HHM is usually seen in advanced malignancy and confers a poor prognosis.
(Choice A) Primary hyperparathyroidism causes gradual-onset, mild-to-moderate hypercalcemia (usually <14 mg/dL). Symptoms (eg, renal stones, osteoporosis, constipation), if present, are typically chronic and nonspecific.
(Choice C) Granulomatous diseases (eg, sarcoidosis) and lymphoma can cause hypercalcemia due to extrarenal production of 1,25-dihydroxyvitamin D. However, hypercalcemia due to excess 1,25-dihydroxyvitamin D would be associated with hyperphosphatemia rather than hypophosphatemia. Also, sarcoidosis is more common at age <40.
(Choices D and E) Osteolytic malignancies (eg, breast cancer, multiple myeloma) cause hypercalcemia due to stimulation of osteoclasts by local production of cytokines. This is significantly less common than HHM, and serum phosphorus levels are usually normal. In addition, most patients have significant associated bone pain.
(Choice F) Milk-alkali syndrome is caused by excessive intake of calcium and absorbable alkali. It is characterized by hypercalcemia, metabolic alkalosis, and acute kidney injury. Bicarbonate levels are elevated due to increased intake and decreased renal excretion of bicarbonate.
(Choice G) Thiazide diuretics cause increased reabsorption of calcium in the distal tubule. The resulting hypercalcemia is mild (usually <12 mg/dL) and rarely symptomatic.
Educational objective:
Humoral hypercalcemia of malignancy is characterized by severe, symptomatic hypercalcemia. It is due to the release of parathyroid hormone-related protein by tumor cells, leading to increased bone resorption and reabsorption of calcium in the distal renal tubule.