In amyloidosis, what are the typical laboratory findings for serum free kappa and lambda light chains, immunoglobulin G, A, and M levels, and immunofixation results?

Laboratory Findings in AL Amyloidosis

In AL amyloidosis, you should expect an abnormal serum free light chain (sFLC) kappa/lambda ratio in approximately 80-82% of patients, with monoclonal protein detected by serum immunofixation in 63-68% and urine immunofixation in 70-77% of cases, while immunoglobulin levels (IgG, IgA, IgM) are typically normal or only mildly elevated unless there is concurrent multiple myeloma. 1, 2

Serum Free Light Chains (sFLC)

The sFLC assay is the most sensitive single test for detecting the plasma cell dyscrasia in AL amyloidosis:

• Abnormal kappa/lambda ratio: Present in 79-82% of untreated patients 3, 4
• Lambda predominance: Approximately 75% of AL cases involve lambda light chains (versus 25% kappa) 5, 3
• Abnormal ratio defined as: κ/λ ratio < 0.26 or > 1.65 in patients with normal renal function
• Important caveat: Chronic kidney disease causes spuriously elevated both kappa and lambda levels with a preserved ratio, which can confound interpretation 2

The difference between involved and uninvolved free light chain (dFLC) is prognostically important, with dFLC ≥130 mg/L associated with worse survival 6.

Immunofixation Electrophoresis (IFE)

Serum IFE detects monoclonal protein in only 63-68% of AL patients 1, 3, while urine IFE is slightly more sensitive at 70-77% 3, 7. Neither test alone is sufficient.

Immunoglobulin Levels (IgG, IgA, IgM)

Immunoglobulin levels are typically normal or only minimally elevated in AL amyloidosis, distinguishing it from multiple myeloma. The plasma cell burden is low (median 3.5% in bone marrow) 5. If IgM is significantly elevated (>3,500 mg/L), consider AHL (heavy and light chain) amyloidosis or underlying lymphoproliferative disorder 8.

Optimal Diagnostic Strategy

You must use a combination approach - no single test is adequate 1, 2, 9:

1. First-line screening: Order all three tests simultaneously:

   • Serum immunofixation electrophoresis
   • Urine immunofixation electrophoresis
   • Serum free light chain assay with κ/λ ratio

2. Combined sensitivity:

   • Serum IFE + sFLC ratio: 96-99% 4
   • All three tests combined: 99-100% sensitivity 9, 7

3. If all tests are negative but clinical suspicion remains high, proceed to bone marrow biopsy with immunohistochemistry (85.7% sensitivity) and flow cytometry for aberrant plasma cells (92.9% sensitivity) 3

Critical Pitfalls to Avoid

• Never rely on serum or urine protein electrophoresis alone - they miss small monoclonal proteins and have sensitivities of only 35-45% 2, 3
• Do not skip urine testing - approximately 10-15% of patients have monoclonal protein detectable only in urine 9
• Interpret sFLC cautiously in renal dysfunction - both kappa and lambda are elevated with preserved ratio in chronic kidney disease, mimicking a negative result 2
• Remember that 15-20% of AL patients have normal sFLC ratios - this does not exclude the diagnosis 3, 4

Confirmation Requirements

Per ACC guidelines, diagnosis of AL amyloidosis requires BOTH 1:

1. Tissue biopsy showing amyloid deposits (Congo red positive with apple-green birefringence)
2. Evidence of plasma cell dyscrasia by the laboratory tests above

Mass spectrometry (LC-MS/MS) of tissue is the gold standard for confirming the amyloid is light chain-derived, with 88% sensitivity and 96% specificity 1.