What are the differential diagnoses for a 60-year-old female with hypercalcemia, acute renal failure, and new-onset anemia, and a history of heavy smoking?

Differential Diagnoses for Hypercalcemia, Acute Renal Failure, and New-Onset Anemia in a 60-Year-Old Female with Heavy Smoking History

The most critical diagnosis to rule out immediately is multiple myeloma, followed closely by squamous cell lung cancer, as both commonly present with this exact triad and carry significant mortality if treatment is delayed. 1

Primary Differential Diagnoses

Multiple Myeloma (Most Likely)

Multiple myeloma is the leading diagnosis when hypercalcemia, renal failure, and anemia present together (the "CRAB" criteria: hypercalcemia, renal dysfunction, anemia, and bone lesions). 1

• This constellation occurs in symptomatic myeloma when serum M-protein ≥3 g/dL and/or bone marrow clonal plasma cells ≥10% are present with end-organ damage 1
• Hypercalcemia occurs through increased osteoclastic bone resorption mediated by the plasma cell clone 1
• Acute renal failure develops from light chain cast nephropathy, hypercalcemia-induced renal vasoconstriction, and volume depletion 1, 2
• Anemia results from bone marrow infiltration by plasma cells and suppression of normal hematopoiesis 1

Critical diagnostic workup includes:

• Serum and urine protein electrophoresis with immunofixation 3
• Serum free light chain assay 3
• Bone marrow biopsy to quantify plasma cells and confirm clonality 1
• Skeletal survey or whole-body CT to identify lytic lesions 1

Squamous Cell Lung Cancer (Second Most Likely)

Given the heavy smoking history, squamous cell lung cancer with hypercalcemia of malignancy must be considered, as it occurs in 10-25% of lung cancer patients and is most common with squamous cell histology. 1, 4

• Hypercalcemia develops through parathyroid hormone-related protein (PTHrP) production, characterized by suppressed intact PTH and low/normal calcitriol levels 1, 5
• Median survival after discovery of hypercalcemia in lung cancer is approximately 1 month, making urgent diagnosis essential 1, 5
• Anemia occurs as anemia of chronic disease from malignancy 6
• Renal failure results from hypercalcemia-induced volume depletion and decreased glomerular filtration 1, 7

Diagnostic approach:

• Chest CT to identify lung mass 1
• Measure serum intact PTH (should be suppressed), PTHrP (elevated), 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, calcium, albumin, phosphorus, and magnesium 1, 5

Diffuse Large B-Cell Lymphoma

Lymphoma can present with identical CRAB features to multiple myeloma, though it is less common. 3

• This diagnosis should be considered when serum/urine protein electrophoresis and free light chains are negative despite CRAB features 3
• Bone marrow biopsy is diagnostic 3
• Hypercalcemia may result from 1,25-dihydroxyvitamin D production by lymphoma cells or bone involvement 8, 6

Renal Cell Carcinoma

Renal cell carcinoma is associated with hypercalcemia in up to 20% of cases through PTHrP production 4, 9, 6

• The smoking history increases risk for this malignancy 9
• Anemia occurs from chronic disease and possible hematuria 9
• Renal failure may result from tumor involvement of the kidney or hypercalcemia 9
• Abdominal imaging (CT or MRI) is diagnostic 9

Primary Hyperparathyroidism (Less Likely but Must Exclude)

While less likely given the acute presentation with renal failure and anemia, primary hyperparathyroidism should be excluded, particularly if hypercalcemia is mild to moderate and stable rather than severe. 1

• Characterized by elevated intact PTH and elevated calcitriol levels, contrasting with malignancy-associated hypercalcemia 1
• Typically presents with more chronic, stable hypercalcemia rather than acute severe elevation 1
• Would not explain the acute renal failure and anemia unless longstanding 1

Critical Diagnostic Algorithm

Step 1: Immediate laboratory evaluation

• Measure corrected serum calcium or ionized calcium directly 8, 5
• Serum intact PTH, PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D 1, 8, 5
• Complete blood count with differential 1
• Comprehensive metabolic panel including calcium, albumin, phosphorus, magnesium, creatinine, BUN 1, 8, 5
• Serum and urine protein electrophoresis with immunofixation 3
• Serum free light chain assay 3

Step 2: Imaging studies

• Chest CT to evaluate for lung malignancy 1
• Skeletal survey or whole-body CT for lytic lesions 1
• Abdominal/pelvic CT if renal cell carcinoma suspected 9

Step 3: Tissue diagnosis

• Bone marrow biopsy if myeloma or lymphoma suspected 1, 3
• Biopsy of any identified mass lesions 1

Common Pitfalls to Avoid

Do not assume multiple myeloma without confirming monoclonal protein: Lymphoma can present identically with negative protein studies, requiring bone marrow biopsy for definitive diagnosis 3

Do not overlook coincidental causes of individual findings: In elderly patients, anemia may be from B12/folate deficiency or myelodysplasia, mild renal dysfunction from diabetes/hypertension, and osteoporosis from aging rather than malignancy 1

Do not delay treatment of severe hypercalcemia while awaiting diagnosis: Immediate IV hydration with normal saline and bisphosphonates (zoledronic acid 4 mg IV over 15 minutes) should be initiated for symptomatic or severe hypercalcemia (>14 mg/dL) regardless of underlying cause 8, 5, 4

Recognize that total serum calcium may underestimate severity: Hypoalbuminemia is common in malignancy, so corrected calcium or ionized calcium should be measured 4