Hypercalcemia/Multiple Myeloma Case File

Hypercalcemia/Multiple Myeloma Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 50

A 63-year-old woman is brought to the emergency center for upper arm pain and swelling following a fall at home. The family has noted that for approximately the past 2 months, the patient has become progressively fatigued and absentminded, and she has developed loss of appetite and weight loss. She has been getting up to urinate several times per night and complains of thirst; a glucose test for diabetes mellitus in her doctor’s office was negative. This morning, she lost her balance because she felt “light-headed” and fell, landing on her left arm. Physical examination is notable for an older, thin woman in mild distress as a result of pain. She is afebrile, and her blood pressure is 110/70 mm Hg, and heart rate is 80 beats per minute (bpm). Her thyroid gland is normal to palpation. Her mucous membranes are dry and sticky. Heart and lung examinations are normal, and carotid auscultation reveals no bruits. Examination of her extremities is significant only for deformity of the left midhumerus with swelling. The left radial pulse is 2+ and symmetric. The radiologist calls you to confirm the fracture of the midleft humerus but also states that there is suspicion for some lytic lesions of the proximal humerus and recommends a skull film (Figure 50–1). Serum creatinine level is 2.1 mg/dL, with normal electrolyte and glucose concentrations, but serum calcium level is 13 mg/dL, and hemoglobin level is 9.2 g/dL.

Figure 50–1. X-ray of skull.

▶ What is the most likely diagnosis?

▶ What is the most likely underlying etiology in this patient?

▶ What is your next therapeutic step?

ANSWERS TO CASE 50:

Hypercalcemia/Multiple Myeloma

Summary: A 63-year-old woman presents with

• A humeral fracture sustained during a fall because of light-headedness
• A 2-month history of fatigue, absentmindedness, loss of appetite and weight, and nocturia
• Normal vital signs, but appearance of dehydration
• Lytic lesions of the skull, proximal humerus, renal insufficiency, anemia, and hypercalcemia

Most likely diagnosis: Hypercalcemia with pathologic fracture of the left humerus.

Most likely underlying etiology: Multiple myeloma.

Next therapeutic step: Initial therapy of the hypercalcemia with intravenous (IV) fluids could be started in the emergency department.

ANALYSIS

Objectives

1. Describe the clinical presentation and differential diagnosis of hypercalcemia. (EPA 1, 2)
2. Outline the treatment of symptomatic hypercalcemia. (EPA 4, 10)

Considerations

The patient presents with acute confusion, fatigue, and lethargy, all symptoms of hypercalcemia, consistent with the calcium level of 13 mg/dL. The first step in therapy should be IV saline to restore volume status and facilitate urinary calcium excretion. Given the rapidity of onset of symptoms, weight loss, age, and presence of lytic bone lesions, the first concern should be for malignancy, such as multiple myeloma or bony metastases from an undiagnosed cancer. Both serum and urine electrophoresis would help to identify the presence of a monoclonal gammopathy. Low serum parathyroid hormone (PTH) and absent PTH-related protein (PTHrP) levels would exclude other causes of hypercalcemia.

APPROACH TO:

Hypercalcemia and Multiple Myeloma

DEFINITIONS

CORRECTED CALCIUM LEVEL: Add 0.8 mg/dL to the serum total calcium for every 1 g/dL of albumin level below 4 g/dL. Example: If the serum calcium level is 9 mg/dL and the albumin level is 2 g/dL, the corrected calcium level is 10.6 mg/dL.

HYPERCALCEMIA: Elevated serum calcium levels after correction for albumin concentration (normal range approximately 8.8-10.4 mg/dL).

CLINICAL APPROACH TO HYPERCALCEMIA

Pathophysiology

The most common causes of hypercalcemia include malignancies or hyperparathyroidism, accounting for 90% of cases. Other causes include granulomatous disorders such as sarcoidosis and tuberculosis; less commonly, hypercalcemia may be the presentation of intoxication with vitamin A, vitamin D, or calcium-containing antacids or may occur as a side effect of 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. Causes of hypercalcemia are listed in Table 50–1.

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 (Figure 50–2). 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.

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 D (lymphomas), and still others secrete a PTHrP that binds the PTH receptor (kidney and lung). Cancer-related hypercalcemia can be differentiated from primary hyperparathyroidism by finding a suppressed PTH level.

Clinical Presentation

Most patients have no symptoms with mild hypercalcemia (less than 12 mg/dL), except perhaps some polyuria and dehydration. When calcium exceeds 13 mg/dL, patients begin developing increasingly severe symptoms, including central nervous system symptoms (lethargy, stupor, coma, mental status changes, psychosis), gastrointestinal symptoms (anorexia, nausea, constipation, peptic ulcer disease), kidney problems (polyuria, nephrolithiasis, 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 (mental status changes). Diagnosis can be established by finding hypercalcemia, hypophosphatemia, and inappropriately elevated PTH levels. Patients with primary hyperparathyroidism are generally treated surgically with parathyroidectomy if any of the following conditions are met: the patient is symptomatic, the calcium is greater than 1 mg/dL above upper limit of normal, the patient is less than 50 years old, or if there is significantly decreased bone mineral density (T score < –2.5). Patients younger than 50 tend to have a lower morbidity and mortality risk.

Abbreviations: ACE, angiotensin-converting enzyme; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein.

Laboratory Tests and Imaging. In this case scenario, checking 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 to confirm the diagnosis. Treatment then can be aimed at the underlying cause (Table 50–2).

Figure 50–2. Algorithm for evaluation of patients with hypercalcemia. FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine neoplasia; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein. (Reproduced with permission, from Braunwald E, Fauci AS, Kasper KL, et al.

Harrison’s Principles of Internal Medicine. 16th ed. 2005. Copyright © McGraw Hill LLC. All rights reserved.)

CLINICAL APPROACH TO MULTIPLE MYELOMA

Pathophysiology

Multiple myeloma is a neoplastic proliferation of plasma cells that usually produce monoclonal immunoglobulins. Patients typically present with lytic bone lesions, hypercalcemia, renal insufficiency, anemia, and an elevated globulin fraction on serum chemistries, which, if separated by electrophoresis and identified by immunofixation, 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; more than 10% clonal plasma cells in the bone marrow; and end-organ damage such as lytic bone lesions.

Patients with lower level monoclonal immunoglobulin (Ig) A or IgG antibody production without the signs or symptoms of multiple myeloma have what is termed a monoclonal gammopathy of undetermined significance (MGUS). MGUS is much more common than myeloma, affecting up to 1% of the population older than 50 years or up to 10% of people older than age 75. Long-term studies demonstrated that approximately 1% per year of these patients with MGUS will progress to develop multiple myeloma.

Treatment

Patients with MGUS typically require no therapy. Some patients with myeloma with no bone lesions or other end-organ damage have an indolent course (“smoldering myeloma”) and can be observed without treatment for many years if asymptomatic. Therapy for symptomatic multiple myeloma includes evaluation for autologous stem cell transplant and induction chemotherapy with high-dose pulsed dexamethasone, in combination with thalidomide or lenalidomide, and bortezomib.

CASE CORRELATION

• See also Case 31 (Osteoarthritis/Degenerative Joint Disease) and Case 32 (Low Back Pain).

COMPREHENSION QUESTIONS

50.1 On routine blood work performed for a life insurance application, a 48-year-old premenopausal 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, which was discovered on a dual-energy x-ray absorptiometry (DEXA) scan performed last year. Which of the following is the most likely cause of her hypercalcemia?

A. Multiple myeloma

B. Parathyroid adenoma

C. Familial hypocalciuric hypercalcemia

D. Sarcoidosis

E. Undiagnosed breast cancer

50.2 A 62-year-old asymptomatic woman is noted to have multiple myeloma and hypercalcemia but no bone lesions or end-organ damage. Which of the following therapies is useful for immediate treatment of the hypercalcemia?

A. Bisphosphonates

B. Erythropoietin

C. Dexamethasone plus thalidomide

D. Interferon-alpha

E. Observe without treatment since she is asymptomatic

50.3 A 22-year-old woman presents with a worsening cough over 6 weeks that 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 lymphadenopathy. She has erythema nodosum on her legs. Which of the following is the most likely diagnosis?

A. Sarcoidosis

B. Mycoplasma pneumonia

C. Acute lymphoblastic leukemia

D. Squamous cell carcinoma of the lung

E. Pulmonary embolism

50.4 A 66-year-old man with known metastatic squamous cell carcinoma of the esophagus is brought to the emergency department 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, though 1 month ago it 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

ANSWERS

50.1 B. This patient has an elevated serum calcium level and low phosphate level, which are likely due to an elevated parathyroid level. An asymptomatic and likely chronically elevated calcium level is most likely caused by primary hyperparathyroidism due to a parathyroid adenoma. The hypercalcemia is presumed to be chronic because she has osteoporosis and is premenopausal. Multiple myeloma (answer A) usually leads to elevated calcium and phosphate levels and lytic lesions of the bones. Familial hypocalciuric hypercalcemia (answer C) can also lead to elevated serum calcium and low serum phosphate levels, but it is usually asymptomatic and is far rarer than primary hyperparathyroidism. Sarcoidosis (answer D) is a granulomatous disease that is associated with an elevated calcitriol production leading to increased serum calcium and phosphate as well as increased 1,25(OH)2 vitamin D; osteoporosis is not seen. Undiagnosed breast cancer (answer E) with metastases to the bones can lead to elevated serum calcium and phosphate levels; this is less likely.

50.2 A. Bisphosphonates are helpful in controlling hypercalcemia through inhibition of osteoclastic bone reabsorption. Dexamethasone, in combination with thalidomide (answer C), is useful in treatment of the myeloma, with a slower effect on the calcium level. Erythropoietin (answer B) is inappropriate and is used to increase synthesis of red blood cells in those with renal failure. Interferon-alpha (answer D) is also not a treatment for hypercalcemia but is used for some cancers such as kidney, melanoma, carcinoid, and some lymphomas. Though the patient has no symptoms, observing alone (answer E) is not appropriate in presence of hypercalcemia.

50.3 A. Both sarcoidosis and lymphoma can present with cough, dyspnea, and hilar adenopathy on chest x-ray. In approximately 10% of cases, sarcoidosis can cause elevated calcium levels through the production of 1,25-vitamin D that occurs in the macrophages of the granulomas. This can also be seen in granulomas caused by tuberculosis and in lymphoma. Leukemia (answer C) usually does not present in this manner, although it can cause hypercalcemia. Squamous cell carcinoma of the lung (answer D) would be unusual in a patient of this age, and the radiographic presentation is atypical. The case scenario is consistent with Lofgren syndrome, an acute presentation of sarcoidosis, which includes hilar adenopathy, erythema nodosum, migratory polyarthralgia, and fever, seen most often in women. Neither pneumonia (answer B) nor pulmonary embolism (answer E) is associated with hypercalcemia.

50.4 D. Although all of the other therapies listed may be helpful in the treatment of hypercalcemia, given the clinical findings of dehydration and elevated creatinine level with a history of previously normal renal function, volume expansion with normal saline would correct the dehydration and presumed prerenal azotemia, allowing the kidneys to more efficiently excrete calcium. Other therapies (answers A, B, C, E) can be added if the response to normal saline alone is insufficient.

CLINICAL PEARLS

▶ Hypercalcemia that is acutely symptomatic is most likely caused by cancer.

▶ Asymptomatic hypercalcemia is most likely caused by primary hyperparathyroidism.

▶ In primary hyperparathyroidism, serum PTH and calcium levels are elevated, and phosphate levels are decreased. In malignancy-related hypercalcemia, the calcium level is high and PTH levels are suppressed.

▶ Symptoms of hyperparathyroidism can be remembered as “stones, moans, groans, bones, and psychiatric overtones.”

▶ MGUS and symptomatic multiple myeloma are on opposite ends of a spectrum of neoplastic disease of plasma cells.

▶ The classic triad of multiple myeloma consists of bone pain due to lytic lesions, anemia, and renal insufficiency.

REFERENCES

Bataille R, Harousseau J. Multiple myeloma. N Engl J Med. 1997;336:1657-1664. 

Deftos LJ. Hypercalcemia in malignant and inflammatory diseases. Endocrinol Metab Clin North Am. 2002;31:141-158. 

Munshi NC, Longo DL, Anderson KC. Plasma cell disorders. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill Education; 2015:710-719. 

Potts JT. Diseases of the parathyroid gland and calcium homeostasis. In: Kasper DL, Fauci AS, Hauser SL, et al, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:2466-2488.

HomeInternal Medicine Case FileHypercalcemia/Multiple Myeloma Case File