A 56-year-old man is admitted to the hospital with severe nausea and vomiting. He has also had fatigue, poor appetite, polyuria, polydipsia, and constipation for several weeks. The patient has a history of hypertension and type 2 diabetes mellitus. His home medications include metformin, lisinopril, and hydrochlorothiazide. He has a 40-pack-year smoking history and drinks alcohol occasionally. Temperature is 36.7 C (98 F), blood pressure is 110/70 mm Hg, pulse is 102/min, and respirations are 16/min. His mucous membranes are dry. The rest of the physical examination is unremarkable. Laboratory results are as follows:
Calcium 14.8 mg/dL Albumin 4.0 g/dL Parathyroid hormone, intact 5 pg/mL Creatinine 1.9 mg/dL Urea nitrogen 54 mg/dL Glucose 180 mg/dL 25-hydroxyvitamin D 50 ng/mL (normal, 20-60 ng/mL) 1,25-dihydroxyvitamin D 17 pg/mL (normal, 15-65 pg/mL)
Which of the following is the most likely cause of this patient's hypercalcemia?
Show Explanatory Sources
Hypercalcemia can be categorized as either parathyroid hormone (PTH) dependent (high-normal or increased PTH [eg, hyperparathyroidism]) or independent (low/suppressed PTH). Humoral hypercalcemia of malignancy (HHM) is the most common cause of PTH-independent hypercalcemia and frequently presents with very high (eg, >14 mg/dL), symptomatic (eg, polyuria, constipation, nausea) calcium levels. HHM should be strongly suspected in this patient in light of his smoking history, systemic symptoms (eg, fatigue, poor appetite), and markedly elevated calcium with low PTH.
HHM is due to secretion of PTH-related protein (PTHrP) by malignant cells and is associated with squamous cell (eg, lung, head and neck), renal, bladder, breast, or ovarian carcinomas. PTHrP causes increased bone resorption and increased reabsorption of calcium in the distal renal tubule. However, PTHrP does not induce the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D to the same extent as PTH does, and so 1,25-dihydroxyvitamin D levels will be low or low-normal.
Other causes of PTH-independent hypercalcemia in malignancy include bony destruction by osteolytic metastasis (eg, breast, non-small cell lung cancer, non-Hodgkin lymphoma, multiple myeloma), increased production of 1,25-dihydroxyvitamin D (eg, lymphoma), and increased interleukin-6 levels (eg, multiple myeloma).
(Choice A) Chronic kidney disease causes decreased renal production of vitamin D, leading to hypocalcemia, hyperphosphatemia, and a compensatory rise in PTH (secondary hyperparathyroidism).
(Choice B) Hydrochlorothiazide increases urinary calcium reabsorption, which can mildly increase serum calcium levels (usually <12 mg/dL). Severe hypercalcemia does not occur.
(Choice D) Rapid bony destruction due to skeletal metastasis may cause hypercalcemia, but the gradual bone loss seen in osteoporosis does not affect serum calcium levels.
(Choice E) Primary hyperparathyroidism rarely causes severe hypercalcemia (calcium is usually <12 mg/dL), and this patient's suppressed PTH level rules out this diagnosis.
(Choice F) Sarcoidosis and certain hematologic malignancies (eg, lymphoma) can cause hypercalcemia due to increased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. However, this patient's low-normal 1,25-dihydroxyvitamin D level makes this less likely.
Educational objective:
Humoral hypercalcemia of malignancy is the most common cause of parathyroid hormone (PTH)-independent hypercalcemia and frequently presents with very high, symptomatic calcium levels. It is due to secretion of PTH-related protein by malignant cells. Other mechanisms of tumor-related hypercalcemia include osteolytic bone metastasis, increased production of 1,25-dihydroxyvitamin D, and increased interleukin-6 levels.