Serum Free Light Chains in Diagnosing AL Amyloidosis
Serum free light chains (sFLC) are essential for diagnosing AL amyloidosis but cannot be used alone—they must be combined with serum and urine immunofixation electrophoresis (IFE) to achieve optimal diagnostic sensitivity, and the diagnosis ultimately requires both tissue biopsy confirmation AND demonstration of a plasma cell dyscrasia. 1
Role of sFLC in the Diagnostic Algorithm
Primary Diagnostic Function
sFLC serves two critical roles in AL amyloidosis diagnosis:
- Screening tool to identify monoclonal protein and exclude AL amyloidosis before pursuing ATTR-specific testing (like Tc-PYP scanning) 1
- Confirmation of plasma cell dyscrasia after tissue biopsy demonstrates amyloid deposits 1
The key principle: AL amyloidosis diagnosis requires BOTH tissue amyloid deposits AND evidence of a plasma cell disorder—sFLC helps establish the latter. 1
Diagnostic Sensitivity
The diagnostic performance varies by testing approach:
- sFLC ratio alone: 76-81% sensitivity 2, 3
- Serum + urine IFE: 96% sensitivity 3
- sFLC + serum IFE: 96% sensitivity 3
- sFLC + serum IFE + urine IFE combined: 100% sensitivity 3
Critical caveat: An abnormal sFLC ratio is defined by kappa/lambda ratios outside reference ranges (0.26-1.65 for normal renal function; 0.31-3.7 for renal failure using Binding Site assay) 4. Kidney dysfunction can cause spuriously abnormal results due to disproportionate urinary lambda loss, so collaborate with hematology when results are abnormal 1.
The Complete Diagnostic Workup
Step 1: Monoclonal Protein Screen
When AL amyloidosis is suspected, order all three tests simultaneously:
- Serum free light chains (sFLC with kappa/lambda ratio)
- Serum immunofixation electrophoresis (SIFE)
- Urine immunofixation electrophoresis (UIFE)
Do NOT use serum/urine protein electrophoresis (SPEP/UPEP) alone—these have inadequate sensitivity for the low monoclonal protein levels typical in AL amyloidosis. 1
Step 2: Tissue Biopsy
After identifying abnormal monoclonal proteins, obtain tissue confirmation via:
Option A (Surrogate site first approach):
- Abdominal fat pad aspiration (84% sensitivity for AL-CM) AND/OR
- Bone marrow biopsy (69% sensitivity for systemic AL)
- If negative, proceed to affected organ biopsy 1
Option B (Direct approach):
- Biopsy the affected organ directly
Special situation: If MGUS coexists with positive nuclear scintigraphy suggesting ATTR, perform cardiac biopsy to definitively establish which amyloid type is causing cardiac disease 1
Step 3: Amyloid Typing
Once Congo red staining confirms amyloid deposits:
- Gold standard: Mass spectrometry (LC-MS/MS) with 88% sensitivity and 96% specificity 1
- Alternative: Immunohistochemistry (less reliable)
This step is non-negotiable—over 10% of patients with monoclonal gammopathy have ATTR (not AL) deposits, so Congo red staining alone is insufficient 1
Step 4: Exclude Multiple Myeloma
Complete the workup with bone marrow biopsy to:
- Assess plasma cell burden (<10% for AL amyloidosis vs ≥10% for myeloma)
- Confirm clonal proliferation of kappa or lambda-producing plasma cells
- Rule out B-cell lymphoproliferative disorders 1
Common Pitfalls to Avoid
Relying on sFLC alone: The combination approach is mandatory—single test sensitivity is inadequate 3
Misinterpreting abnormal sFLC in elderly patients: 5% of patients >70 years have MGUS, which can coexist with ATTR-CM. Always involve hematology to distinguish MGUS from true AL amyloidosis 1
Ignoring renal dysfunction: Kidney disease alters sFLC ratios through differential light chain clearance. Use adjusted reference ranges and confirm with IFE 4, 1
Skipping amyloid typing: Never assume AL based on monoclonal protein alone—mass spectrometry typing is essential because ATTR can coexist with MGUS 1
Using SPEP/UPEP for screening: These lack sensitivity for the low-level monoclonal proteins in AL amyloidosis 1
Additional Utility Beyond Diagnosis
While not the primary question, sFLC also serves critical roles in: