Laboratory Workup for Amyloidosis
The laboratory workup for amyloidosis must begin with screening for monoclonal proteins through serum and urine immunofixation electrophoresis and serum free light chain assay to distinguish between different types of amyloidosis, as this is critical for determining appropriate treatment. 1, 2
Initial Diagnostic Approach
Step 1: Monoclonal Protein Screening (Mandatory First Step)
- Serum protein electrophoresis (SPEP)
- Serum immunofixation electrophoresis (IFE)
- Serum free light chain (FLC) assay with kappa/lambda ratio
- Urine protein electrophoresis (UPEP)
- Urine immunofixation electrophoresis
Critical Note: Screening with serum electrophoresis alone is inadequate as it may miss nearly 50% of AL amyloidosis cases 1. The combination of serum/urine immunofixation with FLC assay provides 100% sensitivity for detecting amyloidogenic light chains 3.
Step 2: Basic Laboratory Tests
- Complete blood count (CBC) with differential and platelets
- Blood urea nitrogen (BUN)
- Serum creatinine
- Electrolytes
- Liver function tests
- Cardiac biomarkers (troponin, NT-proBNP)
Tissue Diagnosis
Step 3: Tissue Biopsy
- Abdominal subcutaneous fat aspiration (sensitivity ~80% for AL amyloidosis)
- Bone marrow biopsy (sensitivity ~69% for AL amyloidosis)
- Affected organ biopsy if necessary
Important: All biopsies should be stained with Congo red to identify amyloid deposits, which appear apple-green under polarized light 2, 4.
Amyloid Typing
Step 4: Amyloid Typing Methods
- Immunohistochemistry/immunofluorescence on tissue samples
- Mass spectrometry (gold standard for typing)
- Genetic testing for hereditary forms
Caution: Genetic testing must be performed in all patients with confirmed ATTR amyloidosis to distinguish wild-type from hereditary forms, regardless of age 1.
Cardiac Evaluation (For Suspected Cardiac Involvement)
Step 5: Cardiac Assessment
- Echocardiography (look for increased wall thickness)
- Electrocardiogram (assess for low voltage and conduction abnormalities)
- Cardiac MRI with gadolinium (if available)
- Bone scintigraphy for suspected ATTR cardiac amyloidosis
Critical Decision Point: For suspected cardiac amyloidosis, monoclonal protein screening must be performed before bone scintigraphy, as cardiac uptake consistent with ATTR-CM may be present in >10% of patients with AL-CM 1.
Diagnostic Algorithm for Cardiac Amyloidosis
If monoclonal protein screen is positive:
- Refer to hematologist for further evaluation
- Consider bone marrow biopsy
- Tissue biopsy required for definitive diagnosis of AL amyloidosis
If monoclonal protein screen is negative and clinical suspicion for cardiac amyloidosis remains high:
- Proceed with bone scintigraphy
- Grade 2 or 3 uptake without monoclonal protein confirms ATTR cardiac amyloidosis
- Perform TTR gene sequencing to differentiate hereditary variant from wild-type ATTR 1
Additional Considerations
- Renal Assessment: 24-hour urine protein quantification, estimated glomerular filtration rate
- Neurological Assessment: Nerve conduction studies and autonomic function testing if symptoms present
Common Pitfalls to Avoid
- Relying solely on serum electrophoresis - This can miss nearly 50% of AL amyloidosis cases 1
- Interpreting cardiac scintigraphy without monoclonal protein screening - This can lead to misdiagnosis of ATTR-CM when AL-CM is present 1
- Failing to perform genetic testing - Essential to distinguish hereditary from wild-type ATTR amyloidosis 1
- Missing concurrent conditions - Such as multiple myeloma in AL amyloidosis 2
- Using inadequate sensitivity tests - High-resolution techniques may be needed to detect small amyloidogenic clones 5
By following this systematic approach to laboratory workup for amyloidosis, clinicians can accurately diagnose and type this complex disease, which is essential for appropriate treatment selection and improving patient outcomes.