Adverse Effects

Hydration ± loop diuretic

Acute (effect seen in hours)

Volume overload, electrolyte disturbances

Bisphosphonates

Subacute (1-2 days)

Hypophosphatemia, hypomag-nesemia, hypocalcemia, fever

Calcitonin

Acute (hours)

Efficacy short-lived (tachyphylaxis)

Glucocorticoids (effective in cancer-induced hypercalcemia)

Lengthy (days)

Hyperglycemia, osteoporosis, immune suppression

Dialysis (renal Acute (hours) Volume shifts, electrolyte dis-

insufficiency) orders, complicated procedure

Dialysis (renal Acute (hours) Volume shifts, electrolyte dis-

insufficiency) orders, complicated procedure intoxication with vitamin A, vitamin D. or calcium-containing antacids, or occur as a side effect of therapies with drugs such as lithium or thiazide diuretics. Genetic conditions such as familial hypocalciuric hypercalcemia and hyperparathyroidism as part of a multiple endocrine neoplasia syndrome are less common causes.

The differential diagnosis can be narrowed based on the chronicity of the patient's presentation and the presence or absence of other symptoms and signs. Primary hyperparathyroidism, usually caused by a solitary parathyroid adenoma, is the most likely cause when hypercalcemia is discovered in an otherwise asymptomatic patient on routine laboratory screening. Most patients have no symptoms with mild hypercalcemia <12 g/dL. except perhaps some polyuria and dehydration. With levels >13 mg/dL. patients begin developing increasingly severe symptoms, including central nervous system (CNS) symptoms (lethargy, stupor, coma, mental status changes, psychosis), gastrointestinal symptoms (anorexia, nausea, constipation, peptic ulcer disease), kidney problems (polyuria, nephrolithiasis, and prerenal azotemia), and musculoskeletal complaints (arthralgias, myalgias, weakness). The symptoms of hyperparathyroidism can be remembered as stones (kidney), moans (abdominal pain), groans (myalgias), bones (bone pain), and psychiatric overtones. Diagnosis can be established by finding hypercalcemia, hypophosphatemia, with inappropriately elevated PTH levels. Symptomatic patients can be treated with parathyroidectomy.

However, a patient presenting with acute onset of symptomatic hypercalcemia is more likely to have a malignancy. Multiple myeloma, lymphoma, and leukemia all can present with hypercalcemia, as can solid tumors such as breast, lung, and kidney cancers. Some of these cancers cause elevated calcium levels by stimulating osteoclast activity through direct bone marrow invasion (multiple myeloma, leukemia, and breast cancer). Others produce excess 1,25-vitamin I) (lymphomas), whereas others secrete a PTHrP parathyroid hormone-related protein that binds the PTH receptor (kidney and lung). Cancer-related hypercalcemia can be differentiated from primary hyperparathyroidism by a suppressed PTH level.

Electrolytes, to assess acid-base status, and renal function are important tests to consider. A normal complete blood count (CBC) and peripheral smear would make leukemia a less likely cause. Levels of PTH and specific assays for PTHrP are generally measured. If multiple myeloma is suspected, serum and urine electrophoresis for monoclonal antibody spikes should be examined. Radiographs showing lytic or blastic lesions may be helpful: finally, a bone marrow biopsy may be considered.

Multiple Myeloma

Multiple myeloma is a neoplastic proliferation of plasma cells that usually produce monoclonal immunoglobulin (Ig)A or IgG antibodies. Patients typically present with lytic bone lesions, hypercalcemia, renal insufficiency, anemia, and an elevated globulin fraction on serum chemistries, which, if separated by electrophoresis, shows a monoclonal proliferation (M-spike). The diagnosis of multiple myeloma requires laboratory and clinical criteria: a monoclonal antibody spike in the serum or light chains in the urine, and >10% atypical plasma cells in the bone marrow and lytic bone lesions.

Patients with increased IgA or IgG antibodies without the signs or symptoms of multiple myeloma have what is termed a monoclonal gammopathy of undetermined significance. Long-term studies demonstrate that approximately 16% of these patients will go on to develop multiple myeloma. It is impossible to predict which patients will progress. Risk factors include older age, male gender, black race, and a positive family history of multiple myeloma.

Therapy for multiple myeloma includes a combination of chemotherapy with melphalan and prednisone. Other chemotherapeutic regimens are used but have not been shown to increase survival. Some patients may be candidates for autologous bone marrow transplant.

Comprehension Questions

[36.1] On routine blood work performed for a life insurance application, a 53-year-old woman was found to have a calcium level of 12 mg/dL (normal = 8.8-10.4 mg/dL) and a phosphate level of 2 mg/dL (normal = 3.0^4.5 mg/dL). She is not anemic and has no symptoms. Her medical history is significant for osteoporosis, discovered on a dual-energy x-ray absorptiometry (DEXA) scan performed at the time of her menopause 1 year ago. What is the most likely cause of her hypercalcemia?

A. Multiple myeloma

B. Parathyroid adenoma

C. Familial hypocalciuric hypercalcemia

D. Lymphoma

E. Breast cancer

[36.2] A 62-year-old woman is noted to have multiple myeloma and an elevated calcium level. Which of the following therapies is useful for treating the hypercalcemia?

A. Bisphosphonates

B. Erythropoietin

C. Melphalan

D. Interferon-a

E. Parathyroid hormone replacement

[36.3[ A 22-year-old African-American woman presents with worsening cough and shortness of breath over 6 weeks, which did not improve with a course of antibiotics or antitussives. Her serum calcium level is found to be 12.5 mg/dL. and a chest x-ray reveals bilateral hilar lym-phadenopathy. Which of the following is the most likely diagnosis?

A. Sarcoidosis

B. Mycoplasma pneumonia

C. Leukemia

D. Diabetes mellitus

E. Pulmonary embolism

[36.4] A 66-year-old man with known metastatic squamous cell carcinoma of the esophagus is brought to the emergency room for increasing lethargy and confusion. He is clinically dehydrated, his serum calcium level is 14 mg/dL, and his creatinine level is 2.5 mg/dL but 1 month ago was 0.9 mg/dL. Which therapy for his hypercalcemia should be instituted first?

A. Intravenous bisphosphonate

B. Intravenous furosemide

C. Glucocorticoids

D. Intravenous normal saline

E. Chemotherapy for squamous cell carcinoma

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