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Mayo Clin Proc. 2009 December; 84(12): e9–e12.
PMCID: PMC2787399

54-Year-Old Woman With Fatigue, Back Pain, and Hypercalcemia

A 54-year-old woman with a medical history of hypothyroidism presented to her local physician with a 2-week history of fatigue and midback pain. The patient described the back pain as aching, worse in the morning, and aggravated by movement; she rated its severity as 6 out of 10 and noted that it was not relieved by ibuprofen. Her primary physician obtained laboratory studies that were remarkable for a serum calcium level of 16.7 mg/dL. Chest radiography revealed mild curvature of the thoracic spine but was otherwise unremarkable. Notably, findings on recent mammography and colonoscopy were both normal.

The patient was admitted to our hospital for pain control and further evaluation of back pain. She had no history of fever, chills, or night sweats but had intentionally lost 27.2 kg in 14 months. She also reported increased thirst during the past month. She had a strong family history of cancer, including multiple myeloma (mother), small cell lung cancer (sister), ovarian cancer (aunt), and testicular cancer (nephew). Her son had a history of common variable immunodeficiency. The patient was taking levothy-roxine, a multivitamin, fish oil, calcium, and glucosamine/chondroitin. On examination, her vital signs were as follows: blood pressure, 138/74 mm Hg; pulse, 85 beats/min; respiration, 12 breaths/min; and temperature, 37.6°. In general, she appeared in mild distress, having difficulty finding a comfortable position while lying in bed. Otherwise, the patient's physical examination was unremarkable and her neurologic examination revealed no localizing findings. Results of the initial blood tests performed at our institution were remarkable for the following: hemoglobin, 10.4 g/dL (reference ranges provided parenthetically) (12.0-15.5 g/dL), mean corpuscular volume, 90.4 fL (81.6-98.3 fL), leukocyte count, 9.2 × 109/L (3.5-10.5 × 109/L); platelet count, 233 × 109/L (150-450 × 109/L); calcium level, 15.9 mg/dL (8.9-10.1 mg/dL); creatinine level, 2.3 mg/dL (0.7-1.2 mg/dL); blood urea nitrogen level, 34 mg/dL (6-21 mg/dL); and erythrocyte sedimentation rate, 70 mm/1 h (0-29 mm/1 h).

  1. Which one of the following is the best initial treatment for this patient's hypercalcemia?
    1. Fluid resuscitation
    2. Furosemide
    3. Bisphosphonates
    4. Intranasal calcitonin
    5. Hemodialysis
    Fluid resuscitation is the most important initial step in treating patients with symptomatic hypercalcemia. An elevation in serum calcium level causes increased filtration across the glomerular membrane, interferes with urine concentration, and results in diuresis and hypovolemia. Indeed, most patients hospitalized with symptomatic hypercalcemia require aggressive fluid resuscitation. Although many textbooks recommend treatment with furosemide (ie, forced saline diuresis) for symptomatic hypercalcemia, this practice is controversial.1 Therefore, patients should be treated with intravenous saline, and loop diuretics should be restricted to patients with clinical evidence of intravascular volume excess.2-4 Although treatment with an intravenous bisphosphonate is standard for hypercalcemia in the setting of increased bone resorption, bisphosphonates would not be the best initial therapy because their effects are not immediate.5 Unlike bisphosphonate therapy, which requires up to 48 hours for clinical effect, calcitonin has a more rapid onset of action and would thus be better than bisphosphonates for the urgent management of severe symptoms3; nonetheless, it is not the first line of therapy. Hemodialysis should be reserved for refractory, life-threatening hypercalcemia.6
    We initiated aggressive intravenous fluid expansion with 0.9% normal saline. The patient's fatigue improved and her serum calcium level decreased to 13.7 mg/dL within 12 hours of hospital admission.
  2. Which one of the following is the most likely cause of this patient's hypercalcemia?
    1. Hyperparathyroidism
    2. Sarcoidosis
    3. Histoplasmosis
    4. Occult malignancy
    5. Vitamin A intoxication
    Hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting; with malignancy, it accounts for greater than 90% of all causes. An elevated parathyroid hormone (PTH) level usually results from a benign parathyroid neoplasm or adenoma but may rarely be caused by a parathyroid carcinoma. It is uncommon for hyperparathyroidism to cause serum calcium levels greater than 12 mg/dL. Sarcoidosis, like other granulomatous disorders, commonly causes hypercalcemia by increasing the synthesis of 1,25-dihydroxyvitamin D from macrophages within the granuloma. However, our patient did not have any indication of sarcoidosis, such as abnormal skin or chest radiographic findings. Hypercalcemia is uncommon in histoplasmosis, and the clinical findings may be similar to those of other granulomatous disorders.7
    Malignancy is the most frequent cause of symptomatic hypercalcemia in hospitalized patients. Elevated levels of serum calcium in solid tumors, particularly of the lung and kidney, are usually attributable to the paraneoplastic syndrome, resulting from the production of parathyroid-related peptide, which has the same biologic effect as PTH on the bone and kidney. Another mechanism, especially in lymphoma and multiple myeloma, presumably involves the increased synthesis of cytokines and lymphokines that promote osteoclastic activity and bone resorption. In both mechanisms, PTH is appropriately suppressed, which simplifies the diagnosis. Vitamin A intoxication is infrequently associated with hypercalcemia and appears to raise serum calcium levels by increasing bone resorption.8 Vitamin A intake of 50,000 to 100,000 IU (10-20 times the recommended daily allowance) has been shown to increase serum calcium levels to as high as 12 to 14 mg/dL.9 Screening for over-the-counter vitamin use is important, but our patient denied excessive vitamin use.
    Intravenous fluids were continued and the patient was treated with intravenous administration of a bisphosphonate. Her serum calcium level was monitored daily and eventually returned to the normal range. The patient also began receiving opioid analgesics, which reduced her back pain to an acceptable level.
  3. Which one of the following is the most appropriate next step in the diagnostic work-up of hypercalcemia?
    1. Skeletal survey
    2. Serum protein electrophoresis
    3. PTH assay
    4. Ionized calcium test
    5. Measurement of serum albumin level
    Skeletal survey, an inexpensive and sensitive method for visualizing the axial skeleton and proximal long bones in the setting of hypercalcemia secondary to increased bone resorption, can be beneficial as a screen for areas with a high potential for pathological fracture. Unlike bone scans, which measure osteoblastic activity, skeletal surveys reveal lytic bone lesions in disease states such as metastatic breast cancer and multiple myeloma. Serum protein electrophoresis is used to analyze the serum protein and shows the relative proportions of the α, β, and β fractions. The proteins are separated on the basis of size, charge, and immunoreactivity. Serum protein electrophoresis quantifies κ- and λ-containing immunoglobulins, which allows the identification of M-spikes, often characteristic of multiple myeloma, monoclonal gammopathy of undetermined significance, and Waldenström macroglobulinemia.10 However, before doing tests to evaluate for specific causes of hypercalcemia, it is important to determine whether the PTH is suppressed (as in malignancy or granulomatous disorders) or elevated (as in parathyroid adenoma). Hence, a PTH assay would be the preferred next test.
    It is also important to determine whether the serum calcium level is truly elevated. Serum calcium levels are susceptible to spurious fluctuations as a result of laboratory technique, hemoconcentration, and changes in serum pH balance. The serum albumin level can be used to “correct” for the protein-bound fraction of serum calcium. However, our patient's serum calcium was quite high, and her presentation, which included bone pain, normocytic anemia, renal insufficiency, and hypercalcemia, suggested the diagnosis of multiple myeloma. These symptoms made a spurious elevation in calcium level unlikely.
    Subsequent testing revealed a PTH that was suppressed to less than 6.0 pg/mL and a parathyroid-related peptide within normal limits. Skeletal survey showed multiple lytic-appearing lesions involving the skull. Serum and urine protein electrophoreses were obtained, both showing an M-spike in the γ region and a monoclonal IgG on immunofixation. A bone marrow biopsy revealed marked hypercellularity with 60% κ light chain—restricted plasma cells, yielding the diagnosis of multiple myeloma.
  4. Which one of the following tests is not an indicator of long-term prognosis in this patient?
    1. Serum creatinine level
    2. β2-Microglobuin level
    3. Hemoglobin level
    4. Bone marrow biopsy and flow cytometry
    5. Rouleaux formation on a peripheral blood smear
    Various staging criteria are used to classify myeloma as of high, intermediate, or low severity. Best known is the Durie-Salmon staging system, which uses biochemical, cytologic, and radiographic features to stage myelomatous disease. Specific criteria are cell mass, hemoglobin, IgG and IgA levels, serum calcium level, urine monoclonal excretion, and the presence of lytic bone lesions on skeletal survey. Patients are further subclassified according to renal function, with serum creatinine levels greater than 2 mg/dL indicating a worse prognosis.11 To more accurately predict prognosis, an alternative system was proposed that includes only 2 parameters: β2-microglobulin and serum albumin levels.12 Together, these systems include levels of serum creatinine, β2-microglobulin, and hemoglobin, as well as features of bone marrow biopsy and flow cytometry, all of which constitute the first 4 answers to this question. Rouleaux formation, which is the characteristic “stacked coin” appearance of red blood cells under microscopy, is caused by increased levels of fibrinogen that bind to red blood cells and cause them to clump. However, this has no prognostic relevance. Notably, recent advances in bone marrow immunophenotyping and cytogenetic analysis have improved the identification of patients likely to have a poor response to treatment. A recent study examining bone marrow samples from patients with newly diagnosed myeloma who had chromosome 13q deletions and β2-microglobulin levels greater than 2.5 g/L, showed that the presence of neither, one, or both characteristics gave median survival times of 111, 47, and 25 months, respectively.13
    Our patient was informed of her multiple myeloma diagnosis and was educated about this condition. We then consulted the Hematology Service for treatment recommendations.
  5. Which one of the following is the best choice for treating multiple myeloma in this patient?
    1. Melphalan, prednisone, and thalidomide
    2. Hematopoietic stem cell transplant (HCT)
    3. Vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD)
    4. Radiotherapy
    5. Plasmapheresis
    Therapeutic options in myeloma can be broadly defined as treatments for patients who are eligible for autologous HCT vs treatments for patients who are ineligible for HCT. Suggested exclusion criteria for HCT include 1 or more of the following: age greater than 77 years, direct bilirubin level greater than 2.0 mg/dL, serum creatinine level greater than 2.5 mg/dL (unless patient is receiving stable dialysis), Eastern Cooperative Oncology Group performance status of 3 or 4 (unless due to bone pain), and New York Heart Association grade III or IV.
    If a patient is deemed ineligible for autologous HCT, then the standard treatment regimen would be melphalan, prednisone, and thalidomide.14,15 Fortunately, however, our patient's age at presentation, healthy premorbid status, and lack of exclusion criteria qualified her for treatment with peripheral HCT.16,17
    Historically, VAD has been the induction therapy of choice before HCT. However, recent trials comparing induction with VAD vs dexamethasone alone showed no significant difference in overall and complete response after HCT.18 Therefore, given the considerable adverse effect profile and lack of additional benefit of vincristine and doxorubicin, VAD would not be the best option for this patient. Radiation therapy is often used for pain relief in patients with myeloma who have large symptomatic plasmacytomas of the bone, and plasmapheresis is sometimes used when patients with myeloma have a high serum viscosity or renal failure secondary to cast nephropathy; however, these would not be the best treatments for this patient.
    Our patient received lenalidomide and dexamethasone as induction therapy in preparation for HCT. At 3-month follow-up, the patient was feeling much better and had returned to work full-time; laboratory studies revealed normalization of her serum calcium level (9 mg/dL) and renal function (creatinine, 0.8 mg/dL).

DISCUSSION

Multiple myeloma is a monoclonal neoplasm resulting from abnormal maturation of plasma cells with a B-lymphocyte lineage. It often progresses from a premalignant proliferation of clonal plasma cells referred to as monoclonal gammopathy of undetermined significance. The exact cause is unknown; however, myeloma is associated with exposure to radiation and petroleum products and is also seen more frequently among farmers and those working with wood and leather. Additionally, translocations, errors of switch recombination, and overexpression of MYC and RAS genes have been implicated in the pathogenesis of plasma cell disorders, including multiple myeloma. The symptoms and organ dysfunction associated with multiple myeloma reflect physiologic responses to the plasmacytoma and its products. Therefore, clinical features of myeloma include bone pain, fractures, hypercalcemia, infections, renal failure, anemia, and neurologic symptoms.19

Multiple myeloma is typically diagnosed by a marrow plasmacytosis greater than 10%, lytic bone lesions, and the presence of M proteins in the serum and/or urine. The M-component level, quantifiable by serum electrophoresis, represents the clonal secretion of immunoglobulin and is an indicator of tumor burden. Immunoelectrophoresis confirms that the M component is monoclonal. However, presence of the M component is a nonspecific finding that is seen in various other conditions, including breast and colon cancer, autoimmune diseases, sarcoidosis, cirrhosis, and even parasitic diseases.19

Current treatment strategies involve determining whether the patient is a candidate for HCT.20 If HCT is not an option, the standard of care is 12 cycles of melphalan, prednisone, and thalidomide. If the patient meets criteria for HCT, then the combination of lenalidomide and dexamethasone (as for the current patient) or a bortezomib-based regimen may be used.20 Additionally, advances in supportive care, including bisphosphonates and antibiotics, have greatly increased the quality of life of patients with multiple myeloma. Yet it must be stressed that current therapy is not curative and that patients with myeloma survive only a median of 5 to 6 years.20 The most common causes of death are progressive myeloma, renal failure, and sepsis.19

Notes

See end of article for correct answers to questions.

Correct answers: 1. a, 2. d, 3. c, 4. e, 5. b

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