What is the role of the immunoglobulin light chain (IGL) test in diagnosing cardiac involvement in immunoglobulin light chain amyloidosis?

Immunoglobulin Light Chain Testing in Cardiac Disease

Essential Role in Diagnosis

Immunoglobulin light chain testing is mandatory for all patients with suspected cardiac amyloidosis and must include the complete triad of serum free light chains (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) to achieve >99% sensitivity for detecting AL cardiac amyloidosis. 1, 2

The Critical Diagnostic Algorithm

Step 1: When to Suspect Cardiac Amyloidosis

Order light chain testing when patients present with:

• Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema 1, 3
• Voltage-mass discordance: thick walls on echo but low QRS voltage on ECG 1, 3
• Associated conditions: HFpEF, severe aortic stenosis, carpal tunnel syndrome, lumbar spinal stenosis, or autonomic/sensory polyneuropathy 1, 3
• Echocardiographic findings: apical sparing pattern on longitudinal strain imaging 3

Step 2: The Complete Light Chain Panel (Order All Three Simultaneously)

You must order all three tests together—never order them sequentially or individually: 1, 2, 4

1. Serum free light chain (sFLC) assay with kappa/lambda ratio 1, 2, 4
2. Serum immunofixation electrophoresis (SIFE) 1, 2, 4
3. Urine immunofixation electrophoresis (UIFE) 1, 2, 4

This triple combination achieves 100% sensitivity for identifying the amyloidogenic light chain, whereas SIFE and UIFE alone detect only 96% of cases, and sFLC ratio alone detects only 76-79.5%. 2

Step 3: Interpreting Results

If ANY monoclonal protein is detected:

• Urgent hematology-oncology referral is required 2, 4
• Consider tissue biopsy (cardiac, abdominal fat pad, or bone marrow) for amyloid typing 1, 4
• Do NOT proceed with nuclear scintigraphy alone, as >10% of AL amyloidosis cases show cardiac uptake mimicking ATTR amyloidosis 2

If NO monoclonal protein is detected:

• Proceed with bone scintigraphy (99mTc-PYP scan) to diagnose ATTR cardiac amyloidosis 1, 3
• Grade 2/3 cardiac uptake or H/CL ratio >1.5 confirms ATTR-CM in the absence of light chain abnormalities 1

Critical Pitfalls to Avoid

Never Use Serum Protein Electrophoresis (SPEP) Alone

SPEP fails to show a monoclonal spike in nearly 50% of AL amyloidosis cases because the monoclonal protein levels are too low. 2, 4 This is why immunofixation is mandatory—it is far more sensitive. 1, 4

Never Skip the Complete Light Chain Panel Before Nuclear Imaging

Ordering a 99mTc-PYP scan without first completing the monoclonal protein screen is a dangerous error. 2 More than 10% of AL amyloidosis cases show positive cardiac uptake on nuclear imaging, which can be misinterpreted as ATTR amyloidosis if light chains weren't checked first. 2

Account for Renal Impairment

In patients with severe renal impairment (CKD stage 5 or greater), the normal sFLC kappa/lambda ratio shifts to 0.34-3.10 (versus 0.26-1.65 in normal renal function). 2 Failure to account for this leads to false-positive interpretations.

Why This Matters for Mortality

Cardiac involvement is the single most important determinant of survival in AL amyloidosis, with approximately 30% of patients dying within the first year from diagnosis due to advanced cardiac disease. 1 Early detection through proper light chain testing enables timely hematology referral and treatment initiation before irreversible cardiac damage occurs. 5, 6

NT-proBNP has 100% sensitivity when elevated (>300 pg/mL) in patients with biopsy-proven cardiac AL amyloidosis, making it an excellent complementary test, though it cannot replace light chain testing for establishing the diagnosis. 7

Practical Implementation

Order the complete panel immediately when clinical suspicion arises—do not wait for echocardiography or other imaging results. 1, 2 The combination of clinical features, light chain testing, and cardiac biomarkers (NT-proBNP, troponin) can diagnose cardiac amyloidosis without requiring endomyocardial biopsy in most cases. 7

If monoclonal proteins are detected, even at low levels (including MGUS), endomyocardial biopsy may be required to definitively distinguish AL from ATTR cardiac amyloidosis, particularly if nuclear scintigraphy is also abnormal. 4