AL Amyloidosis Workup
The workup for systemic AL amyloidosis requires three essential components: (1) demonstration of monoclonal protein through serum/urine immunofixation electrophoresis AND serum free light chain (FLC) assay, (2) tissue biopsy with Congo red staining showing apple-green birefringence, and (3) amyloid typing via mass spectrometry to confirm light chain composition 1, 2.
Initial Laboratory Screening
The first step is detecting the monoclonal protein, which is present in 98-100% of AL amyloidosis cases 3. You must order both tests simultaneously—never one alone:
- Serum and urine immunofixation electrophoresis
- Serum free light chain (FLC) assay with κ/λ ratio
Critical pitfall: Different FLC assays are not interchangeable and use different reference ranges 3. The Binding Site assay uses a normal κ/λ ratio of 0.26-1.65 (or 0.31-3.7 in renal failure), while Siemens uses 0.31-1.56 1. Always use the same assay and laboratory for the same patient to ensure consistency 3.
An abnormal FLC ratio is highly sensitive for AL amyloidosis and should immediately trigger further workup 1.
Cardiac Biomarkers for Risk Stratification
Once monoclonal protein is confirmed, obtain:
- NT-proBNP (≥332 ng/L indicates cardiac involvement with >99% sensitivity) 1
- Troponin T or I
These biomarkers are essential for staging and prognosis. The difference between involved and uninvolved FLC values, combined with NT-proBNP and troponin, classifies patients into four stages with 5-year survivals of 82%, 62%, 34%, and 20% respectively 2.
Tissue Biopsy and Typing
Biopsy is mandatory but does not always require organ biopsy 1, 2. The diagnostic approach:
Accessible site biopsy first (85% of patients don't need organ biopsy 2):
- Abdominal fat pad aspiration (75-80% sensitive) 4
- Bone marrow
- Minor salivary glands
Congo red staining demonstrating apple-green birefringence under polarized light 1
Amyloid typing is mandatory to differentiate AL from TTR amyloidosis—this distinction is critical because treatments are completely different (chemotherapy for AL vs. tafamidis for TTR cardiac amyloidosis) 5:
- Mass spectrometry (current gold standard) 5
- Alternative: immunohistochemistry, immunofluorescence, or immunogold electron microscopy
Major pitfall: 20% of patients with non-AL amyloidosis have a monoclonal component 4. This creates significant risk of misdiagnosis—you cannot assume AL amyloidosis based solely on finding a monoclonal protein. Definitive amyloid typing is essential 4.
Organ Involvement Assessment
After confirming AL amyloidosis, assess extent of organ damage:
- Cardiac: Echocardiography looking for LV wall thickness >12 mm with preserved ejection fraction 1
- Renal: Quantify proteinuria (nephrotic range common)
- Hepatic: Liver function tests, assess for hepatomegaly
- Neurologic: Evaluate for peripheral/autonomic neuropathy
- Other: Look for macroglossia, enlarged salivary glands
High-Risk Screening Populations
Patients with MGUS warrant regular screening with NT-proBNP and albuminuria monitoring, as these markers can rise before overt symptoms develop 5. This allows diagnosis before irreversible organ damage occurs—the main determinant of survival 5, 6.
Diagnostic Algorithm Summary
Suspect AL amyloidosis in patients with: heart failure with preserved ejection fraction, nephrotic proteinuria, unexplained peripheral neuropathy, hepatomegaly, macroglossia, or constitutional symptoms with organ dysfunction 5, 7
Screen for monoclonal protein: Serum/urine immunofixation + serum FLC assay (both required) 3
If positive, obtain cardiac biomarkers: NT-proBNP and troponin for staging 1, 2
Tissue biopsy: Start with accessible sites (fat pad, bone marrow, salivary gland) 1, 2, 4
Amyloid typing via mass spectrometry: Confirm light chain composition and exclude TTR amyloidosis 5, 4
Assess organ involvement: Comprehensive evaluation of cardiac, renal, hepatic, and neurologic systems 5
The key to improving outcomes is early recognition before irreversible organ damage occurs 5, 6. Patients with early-stage disease have approximately 80% 5-year survival with contemporary treatment, compared to less than 30% for advanced disease 6.