What are the differential diagnoses for an elderly lady, a heavy smoker, presenting with hypercalcemia, anemia, acute renal failure, muscle pains, and fatigue?

Differential Diagnoses for Elderly Heavy Smoker with Hypercalcemia, Anemia, Acute Renal Failure, Muscle Pains, and Fatigue

Multiple myeloma is the most likely diagnosis given the constellation of hypercalcemia, renal failure, anemia, and bone/muscle pain (CRAB criteria), particularly in an elderly patient. 1, 2

Primary Differential: Multiple Myeloma

This clinical presentation strongly suggests multiple myeloma based on the CRAB criteria:

• Hypercalcemia (>11.5 mg/dL) causes muscle weakness, fatigue, and contributes to acute renal failure through volume depletion and direct nephrotoxicity 1, 2
• Renal failure (creatinine >2 mg/dL) occurs in 20-50% of myeloma patients, typically from light chain cast nephropathy and hypercalcemia 3
• Anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal) manifests as fatigue and weakness 1, 2
• Bone involvement presents as muscle/bone pain, though lytic lesions may not always be evident initially 1, 2

Required Diagnostic Workup for Multiple Myeloma

Immediate laboratory tests:

• Serum and urine protein electrophoresis with immunofixation 1
• 24-hour urine collection (not random sample) for protein electrophoresis 1
• Serum free light chain assay with kappa/lambda ratio 1
• Nephelometric quantification of IgG, IgA, and IgM 1
• Complete blood count, serum calcium, creatinine, and β2-microglobulin 2

Bone marrow examination:

• Bone marrow aspiration and biopsy with CD138 staining to quantify plasma cells (≥10% clonal plasma cells required for diagnosis) 1, 4
• Cytogenetic/FISH studies for risk stratification 1

Imaging studies:

• Complete skeletal survey including skull, spine, pelvis, and long bones 1
• MRI of spine if skeletal survey is negative, as it detects lesions not visible on plain radiographs 5

Critical Alternative Diagnoses to Exclude

Malignancy-Associated Hypercalcemia (Lung Cancer)

Given the heavy smoking history, lung cancer with hypercalcemia of malignancy must be excluded:

• Parathyroid hormone-related protein (PTHrP) secretion by squamous cell lung cancer causes hypercalcemia 6
• Can present with identical CRAB-like features without being myeloma 7, 6
• Requires chest imaging (CT chest) and PTHrP level measurement 6

Diffuse Large B-Cell Lymphoma

Lymphoma can mimic multiple myeloma with complete CRAB criteria:

• Case reports document lymphoma presenting with hypercalcemia, renal dysfunction, anemia, and lytic bone lesions 7, 6
• Critical distinction: serum/urine protein electrophoresis and free light chains are negative in lymphoma 7, 6
• Requires tissue biopsy (bone marrow or mass biopsy) for definitive diagnosis 7, 6
• Physical examination and imaging should evaluate for lymphadenopathy, though it may be absent 7, 6

Primary Hyperparathyroidism

• Can cause hypercalcemia with renal failure 8
• Measure intact parathyroid hormone (PTH) level—elevated in hyperparathyroidism, suppressed in malignancy 8
• Less likely to cause severe anemia unless chronic kidney disease is advanced 8

Other Plasma Cell Disorders

Solitary plasmacytoma:

• Single biopsy-proven plasma cell lesion without systemic disease 5
• Would not explain the constellation of CRAB features 5

Primary systemic (AL) amyloidosis:

• May present with renal failure, but typically shows substantial albuminuria, congestive heart failure, peripheral neuropathy, or hepatomegaly 2
• Requires Congo red staining of tissue biopsy 2

Diagnostic Algorithm

Step 1: Obtain serum/urine protein electrophoresis, immunofixation, and serum free light chains immediately 1

Step 2: If monoclonal protein or abnormal free light chain ratio is present:

• Proceed with bone marrow biopsy 1, 4
• Perform skeletal survey and/or MRI 5
• Diagnosis confirmed if ≥10% clonal plasma cells AND one or more CRAB criteria present 1, 4

Step 3: If protein studies are negative despite CRAB features:

• Measure PTHrP and intact PTH levels 6
• Obtain CT chest/abdomen/pelvis to evaluate for solid tumors or lymphoma 7, 6
• Consider bone marrow biopsy to exclude lymphoma 7, 6
• May require tissue biopsy of any identified masses 7, 6

Critical Pitfalls to Avoid

• Do not assume multiple myeloma without confirming monoclonal protein or abnormal free light chains—lymphoma can present identically with negative protein studies 7, 6
• Do not delay renal-protective measures while awaiting diagnostic confirmation—immediate hydration (>3 L/24h), hypercalcemia correction, and avoidance of nephrotoxins are essential 3
• Do not perform contrast studies without adequate hydration in patients with renal failure, though the actual risk is minimal with proper hydration 3
• Do not overlook lung cancer in a heavy smoker—obtain chest imaging regardless of other findings 6
• A negative skeletal survey does not exclude myeloma—MRI is more sensitive for detecting bone marrow involvement 5