What is the recommended workup for a patient over 60 years old with suspected cardiac amyloidosis and a history suggestive of plasma cell dyscrasias?

Workup for Cardiac Amyloidosis in Patients Over 60 with Suspected Plasma Cell Dyscrasia

In patients over 60 with suspected cardiac amyloidosis and history suggestive of plasma cell dyscrasia, immediately order comprehensive monoclonal protein screening (serum free light chains, serum immunofixation, and urine immunofixation) simultaneously, followed by tissue biopsy confirmation and bone marrow evaluation to establish AL amyloidosis diagnosis. 1

Initial Laboratory Screening

Monoclonal protein screening is mandatory and must include all three tests ordered simultaneously: 1, 2

• Serum free light chain assay (sFLC) with kappa/lambda ratio 1, 3, 2
• Serum immunofixation electrophoresis (SIFE) 1, 3, 2
• Urine immunofixation electrophoresis (UIFE) 1, 3, 2

Critical pitfall: Standard protein electrophoresis (SPEP/UPEP) alone has inadequate sensitivity and should never be used as the sole screening test. 3

Given the history suggestive of plasma cell dyscrasia, this patient requires immediate hematology consultation to interpret abnormal monoclonal protein results and distinguish between MGUS (present in ~5% of patients over 70), AL amyloidosis, or multiple myeloma. 1

Cardiac Imaging Workup

Echocardiography (First-Line)

Order transthoracic echocardiography immediately to assess: 2

• Left ventricular wall thickness ≥12-14 mm (key diagnostic threshold) 2
• Biatrial enlargement 2
• Restrictive transmitral Doppler filling pattern 2
• Speckle-tracking longitudinal strain with apical sparing pattern (apical-to-basal ratio >2.1 is highly specific for cardiac amyloidosis) 2

Electrocardiogram

Obtain 12-lead ECG looking for: 2

• Low QRS voltage despite increased wall thickness on echo (voltage-to-mass discordance is a red flag) 2
• Pseudoinfarct pattern 2

Cardiac Biomarkers

Measure cardiac biomarkers: 2

• NT-proBNP (disproportionately elevated relative to degree of heart failure; 93% sensitivity, 90% specificity for cardiac involvement) 2
• Troponin (T, I, or high-sensitivity; often elevated) 2

Cardiac MRI (If Echocardiography Equivocal)

Reserve cardiac MRI for cases where echocardiography shows suggestive but not definitive findings: 2

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) 1, 2
• Elevated native T1 values (>1020-1044 ms) 1, 2

Tissue Diagnosis Pathway for AL Amyloidosis

Since plasma cell dyscrasia is suspected, AL amyloidosis requires both demonstration of tissue amyloid deposits AND evidence of plasma cell dyscrasia. 1

Two Biopsy Approaches

Option 1 (Preferred for suspected AL): 1

1. Abdominal fat pad aspiration first (84% sensitivity for AL cardiac amyloidosis; simple office-based procedure) 1
2. If negative, proceed to cardiac biopsy to definitively exclude AL amyloidosis 1

Option 2: 1

• Direct cardiac biopsy (preferred when concomitant AL and ATTR amyloidosis suspected, such as MGUS with abnormal nuclear imaging) 1

Bone Marrow Evaluation

Bone marrow biopsy is required to: 1, 3

• Demonstrate clonal proliferation of lambda or kappa-producing plasma cells 3
• Exclude multiple myeloma or B-cell lymphoproliferative disorders 1

Important caveat: Bone marrow has 69% sensitivity for finding amyloid deposits in systemic AL amyloidosis, but over 10% of patients with monoclonal gammopathy can have ATTR deposits in bone marrow, making mass spectrometry typing essential. 1

Amyloid Typing

Once amyloid deposits are confirmed by Congo red staining showing apple-green birefringence under polarized light, determine the precursor protein: 1

• Mass spectrometry (LC-MS/MS) is the gold standard (88% sensitivity, 96% specificity) 1, 4
• Alternative methods include immunohistochemistry or immunogold immunoelectron microscopy in experienced centers 1

This step is absolutely mandatory before initiating therapy, as AL and ATTR amyloidosis require completely different treatments. 4

Nuclear Imaging (If Monoclonal Protein Negative)

If monoclonal protein screening is negative, pursue ATTR amyloidosis with bone scintigraphy: 2

• 99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP imaging 1, 2
• Grade 2-3 myocardial uptake in absence of monoclonal protein is diagnostic for ATTR cardiac amyloidosis without biopsy 1, 2

However, given this patient's history suggestive of plasma cell dyscrasia, nuclear imaging should only be pursued if monoclonal protein screening is definitively negative, as positive nuclear imaging with abnormal monoclonal proteins requires cardiac biopsy to distinguish AL from ATTR. 1

Critical Timing Considerations

Delays in monoclonal protein screening beyond 6 weeks are associated with increased early mortality. 2 Given that AL cardiac amyloidosis is rapidly fatal without treatment (median survival <6 months if untreated), urgent hematology-oncology consultation and expedited workup are essential. 4, 5, 6

Common Diagnostic Pitfalls

Spurious abnormal monoclonal protein results can occur with kidney dysfunction due to disproportionate urinary loss of lambda light chains, but immunofixation will not demonstrate monoclonal protein in these cases. 1

Approximately 10-15% of multiple myeloma patients also have AL amyloidosis, so any myeloma patient with restrictive cardiomyopathy, unexplained proteinuria, macroglossia, periorbital purpura, or peripheral neuropathy with autonomic features requires immediate AL amyloidosis evaluation. 3

Cardiac involvement drives prognosis and mortality in AL amyloidosis, making cardiac assessment the highest priority in the workup. 3, 4