The following cases and commentary, which focus on hypercalcemia, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 15).
Case 1: Pelvic fracture
A 20-year-old man is hospitalized after sustaining a pelvic fracture in an automobile accident. One month into his hospitalization, the patient notes nausea and anorexia. Before the injury, he was in good health and took no medications. Family history is unremarkable. Current medications are enoxaparin and hydromorphone.
Physical examination reveals an alert, oriented, and thin patient. Blood pressure is 128/78 mm Hg, pulse rate is 88/min, and respiration rate is 16/min. Thyroid examination reveals no goiter, and the lungs are clear to auscultation. The patient is immobilized in bed and a pelvic external fixation device is in place. Neurologic examination findings are unremarkable.
Laboratory studies show albumin 4.4 g/dL (44 g/L), calcium 12.6 mg/dL (3.15 mmol/L), creatinine 1.6 mg/dL (141.4 µmol/L), phosphorus 4.1 mg/dL (1.3 mmol/L), parathyroid hormone 7.1 pg/mL (7.1 ng/L), thyroid-stimulating hormone 0.3 µU/mL (0.3 mU/L), thyroxine (T4), free 1.1 ng/dL (14.2 pmol/L), 1,25-Dihydroxy vitamin D 35.2 pg/mL (84.5 pmol/L), 25-Hydroxy vitamin D 38 ng/mL (95 nmol/L).
Which of the following is the most likely cause of his hypercalcemia?
A. Acute kidney injury
B. Fracture-related hypercalcemia
C. Humoral hypercalcemia of malignancy
D. Hypercalcemia of immobilization
Case 2: Elderly man with high calcium
A 78-year-old man is evaluated in the emergency department for a 1-week history of weakness, fatigue, nausea, and anorexia. Medical history is remarkable for recurrent squamous cell carcinoma of the lung treated with surgery and chemotherapy.
On physical examination, temperature is 37.2°C (99.0°F), blood pressure is 90/60 mm Hg, pulse rate is 100/min, and respiration rate is 20/min. Confusion, skin tenting, and bitemporal wasting are noted.
Laboratory studies show blood urea nitrogen 30 mg/dL (10.7 mmol/L), calcium 13.5 mg/dL (3.38 mmol/L), creatinine 1.9 mg/dL (167.96 µmol/L), phosphorus 2.4 mg/dL (0.78 mmol/L).
Which of the following is the most appropriate next step in treatment for this patient?
A. 0.45% saline infusion
B. 0.45% saline infusion and furosemide
C. 0.9% saline infusion
D. 0.9% saline infusion and furosemide
Case 3: Alcoholic with abdominal pain
A 47-year-old man with a long-standing history of alcoholism is hospitalized for abdominal pain, nausea, and vomiting of 7 days' duration. His last drink was 6 days ago. He has lost approximately 10% of his body weight over the past 4 months; he states that his weight loss was caused by drinking alcohol and not eating.
On physical examination, he appears cachectic. Temperature is 37.1°C (98.8°F), blood pressure is 100/70 mm Hg, pulse rate is 110/min, and respiration rate is 18/min. BMI is 17. He is not confused or tremulous. There is midepigastric tenderness without rebound. Bowel sounds are present. Neurologic examination is normal.
Laboratory studies show amylase 300 U/L, lipase 150 U/L, sodium 130 meq/L (130 mmol/L), potassium 3.4 meq/L (3.4 mmol/L), chloride 90 meq/L (90 mmol/L), bicarbonate 20 meq/L (20 mmol/L), phosphorus 3.5 mg/dL (1.1 mmol/L), calcium 9.0 mg/dL (2.2 mmol/L), and urinalysis positive for ketones.
The patient receives immediate thiamine replacement, folic acid supplementation, and a multivitamin followed by vigorous intravenous fluid replacement with 5% dextrose and normal saline with aggressive potassium replacement. Morphine is used to control pain.
Eighteen hours later, the patient's abdominal pain has improved but he becomes restless, agitated, and extremely weak and is barely able to raise his extremities against gravity.
Which of the following is the most likely cause of this patient's new findings?
Case 4: Worsening fatigue and forgetfulness
A 59-year-old man is evaluated for a 4-day history of progressive worsening of fatigue, forgetfulness, constipation, excessive thirst, and increased urination. He has no pain. The patient has hypertension, treated with hydrochlorothiazide, and type 2 diabetes mellitus, controlled by diet. He developed right lower lobe streptococcal pneumonia 3 months ago.
On physical examination, he appears somnolent but is easily arousable. Temperature is 37.1°C (98.8°F), blood pressure is 110/70 mm Hg, pulse rate is 120/min, and respiration rate is 17/min. The oral mucosa is dry, and the conjunctivae are pale. The lungs are clear.
Laboratory studies show hemoglobin 8.9 g/dL (89 g/L), platelet count 150,000/µL (150 × 109/L), leukocyte count 2500/µL (2.5 × 109/L), calcium 13.6 mg/dL (3.4 mmol/L), creatinine 2.9 mg/dL (221.3 µmol/L), total protein 7.6 g/dL (76 g/L), albumin 3.3 g/dL (33 g/L), and urinalysis negative for protein.
A peripheral blood smear shows normochromic, normocytic erythrocytes with rouleaux formation, and no evidence of tear drop erythrocytes or immature myeloid and erythroid cells.
A chest radiograph shows osteopenia of all ribs. No pulmonary parenchymal infiltrates are seen.
The patient is hospitalized and responds to intravenous hydration with normal saline. He undergoes bone marrow aspiration while results of other laboratory tests are pending. Results are shown.
Which of the following is the most likely diagnosis?
A. Acute myeloid leukemia
B. Chronic lymphocytic leukemia
C. Metastatic small cell lung cancer
D. Multiple myeloma
Case 5: Bipolar disorder and weight loss
A 24-year-old woman is evaluated for a 6-month history of weakness, fatigue, diaphoresis, tremor, and oligomenorrhea. She has had an unintentional 6.8-kg (15-lb) weight loss during this same period. She has a history of bipolar affective disorder. Her only medication is lithium.
On physical examination, temperature is 37.2°C (99.0°F), blood pressure is 122/85 mm Hg, pulse rate is 118/min, respiration rate is 14/min, and BMI is 20. Bilateral proptosis is noted. Examination of the neck reveals a diffuse goiter. There is a tremor of both hands, and both palms are sweaty.
Laboratory studies show albumin 4.0 g/dL (40 g/L), calcium 11.1 mg/dL (2.78 mmol/L), phosphorus 4.5 mg/dL (1.5 mmol/L), parathyroid hormone 10 pg/mL (10 ng/L), thyroid-stimulating hormone <0.001 µU/mL (0.001 mU/L), thyroxine (T4), free 2.3 ng/dL (29.7 pmol/L), and triiodothyronine (T3), total 350 ng/dL (5.39 nmol/L).
Which of the following is the most likely cause of her hypercalcemia?
B. Primary hyperparathyroidism
C. Secondary hyperparathyroidism
Answers and commentary
Correct answer: D. Hypercalcemia of immobilization.
This patient has hypercalcemia most likely caused by his immobilization. Patients with high bone turnover, such as young patients and patients with Paget disease of bone, are more likely to develop hypercalcemia of immobilization, and serum calcium levels should be monitored in immobilized patients to check for the disease. Given this patient's young age and near-complete immobilization because of his pelvic fracture, he is at high risk for the disorder. Hypercalcemia associated with immobilization is most likely due to increased osteoclastic activity. Acute therapy includes saline infusion for volume repletion. Bisphosphonate therapy has also been used to decrease osteoclastic activity.
The patient's serum creatinine elevation is a result rather than the cause of his hypercalcemia and will resolve with volume resuscitation. Furthermore, acute kidney injury does not cause hypercalcemia.
Although the patient had sustained fractures, such trauma in itself is not generally associated with hypercalcemia.
No malignancy has been identified in this patient, and humoral hypercalcemia of malignancy is rarely due to an occult tumor.
- Serum calcium levels should be monitored in immobilized patients to check for the development of hypercalcemia of immobilization, which is more likely to occur in patients with high bone turnover, such as young patients and patients with Paget disease.
Correct answer: C. 0.9% saline infusion.
This patient should receive volume replacement with normal (0.9%) saline. Measures undertaken to treat hypercalcemia can be divided into four categories:
1. Nonspecific therapies aimed at increasing renal calcium excretion and decreasing intestinal absorption of calcium
2. Therapies specifically aimed at slowing bone resorption
3. Therapies that directly remove calcium from the circulation
4. Therapies aimed at controlling the underlying diseases causing hypercalcemia
Increased excretion of calcium can be achieved by inhibition of proximal tubular and loop sodium reabsorption, which is best achieved by aggressive volume expansion with intravenous normal saline infusion.
An infusion of 0.45% saline will be less effective than 0.9% saline in both restoring volume and delivering sodium to the proximal tubule, which is necessary for increased urinary excretion of calcium.
Furosemide therapy after aggressive intravenous saline infusion has been suggested as the next step in the emergency management of hypercalcemia. However, a review of the evidence for the use of furosemide in the medical management of hypercalcemia yielded only case reports published before the introduction of bisphosphonates, the use of which is supported by multiple randomized controlled trials. Therefore, furosemide should no longer be recommended as part of the management of hypercalcemia.
- In the treatment of acute hypercalcemia, the first step is aggressive volume expansion with intravenous normal saline.
Correct answer: D. Hypophosphatemia.
Severe hypophosphatemia rarely manifests as physiologic disturbances and most often develops in patients with chronic alcoholism who have poor oral intake, decreased intestinal absorption due to frequent vomiting and diarrhea, and increased kidney excretion due to the direct effect of ethanol on the tubule. Despite total body phosphorus depletion, these patients may have normal serum phosphorus levels on admission to the hospital.
Severe hypophosphatemia often develops over the first 12 to 24 hours after admission, usually because of intravenous glucose administration. This agent helps to release insulin and rapidly reverses alcoholic ketoacidosis, which causes phosphate to shift into cells.
The sudden development of hypophosphatemia may cause confusion, rhabdomyolysis, hemolytic anemia, and severe muscle weakness that can lead to respiratory failure. Treatment involves preventing the serum phosphorus level from decreasing below 1 mg/dL (0.32 mmol/L). Oral phosphate is the preferred treatment in this setting, but intravenous administration may be needed if oral therapy cannot be tolerated.
Hypercalcemia may manifest as decreased neuromuscular excitability that causes decreased muscular tone. Hypercalcemia is most commonly caused by alterations in calcium absorption from the gut and bone resorption due to primary hyperparathyroidism, malignancy, and granulomatous diseases. Primary hyperparathyroidism and thiazide diuretic use also may cause this condition. The development of hypercalcemia in this patient is unlikely.
Hypokalemia can cause diffuse muscle weakness, gastrointestinal tract atony, respiratory failure, and cardiac arrhythmias. In chronic hypokalemia, muscle weakness is unusual in patients with a serum potassium level above 2.5 meq/L (2.5 mmol/L) but may be precipitated by a sudden decrease in potassium. However, the risk of profound hypokalemia is low in a patient receiving potassium supplementation. Furthermore, hypokalemia would not explain this patient's mental status changes.
Early signs of hyponatremia typically include nausea, vomiting, and headaches; progressive manifestations include impaired mental status and seizures. These symptoms are not compatible with this patient's presentation.
- In the hospital setting, patients with chronic alcoholism may have normal serum phosphorus levels on admission to the hospital but often develop severe hypophosphatemia over the first 12 to 24 hours.
Correct answer: D. Multiple myeloma.
This patient has hypercalcemia, diffuse osteopenia, anemia, leukopenia, renal insufficiency, and a history of encapsulated organism-related pneumonia, which is a characteristic presentation of multiple myeloma. The diagnosis is supported by the bone marrow aspirate, which shows clusters of plasma cells. These cells can easily be distinguished from megaloblastoid erythrocytes by their dispersed chromatin pattern and perinuclear halo (Golgi apparatus).
Acute myeloid leukemia rarely causes hypercalcemia. In addition, more severe bone marrow failure and a decreased platelet count would be likely, and the bone marrow aspirate would not show leukemic blasts. Chronic lymphocytic leukemia (CLL) may rarely cause hypercalcemia along with renal insufficiency; an elevated leukocyte count is typical. Moreover, the morphologic findings of the bone marrow aspirate in this patient rule out a diagnosis of CLL.
Metastatic small cell lung cancer to the bone marrow may cause cytopenia. The peripheral blood smear would show leukoerythroblastic features with tear drop erythrocytes and immature myeloid and erythroid cells. Furthermore, the morphologic findings of the bone marrow aspirate in this patient, which shows a proliferation of plasma cells, is inconsistent with metastasis from any other cancer.
- Hypercalcemia is a common complication of multiple myeloma.
Correct answer: D. Thyrotoxicosis.
This patient's hypercalcemia is most likely caused by thyrotoxicosis. Mild hypercalcemia is found in approximately 10% of patients with thyrotoxicosis. As with this patient, the parathyroid hormone (PTH) level is below or in the low range of normal, and the serum phosphorus level is typically in the upper range of normal. Thyroid hormone has direct bone-resorbing properties that cause a high-turnover state; if left untreated, progression to osteoporosis often occurs. Therapy of the hypercalcemia should aim at attainment of biochemical euthyroidism, whether by antithyroid drug therapy, radioactive iodine therapy, or thyroidectomy.
Exposure to lithium shifts the set point for inhibition of PTH secretion to the right. Clinically, this results in hypercalcemia and an elevated level of PTH, which this patient does not have. Most patients with therapeutic lithium levels for bipolar affective disorder have a slight increase in the serum calcium level, and up to 10% become mildly hypercalcemic with PTH levels that are high normal or slightly elevated.
Primary hyperparathyroidism involves an elevated or inappropriately normal PTH level in the face of hypercalcemia. This patient's low-normal PTH level is not consistent with this condition.
Secondary hyperparathyroidism refers to an elevation of the PTH level that occurs in response to hypocalcemia or hyperphosphatemia, neither of which this patient has. This disorder is commonly seen in patients with chronic kidney disease or vitamin D deficiency.
- Mild hypercalcemia and suppressed parathyroid hormone levels are found in approximately 10% of patients with thyrotoxicosis.