From the Guidelines
Diagnosing AL amyloidosis requires a combination of serum and urine protein electrophoresis with immunofixation, serum free light chain assay, and tissue biopsy with Congo red staining, while ATTR amyloidosis diagnosis involves technetium-labeled bone scintigraphy and genetic testing for TTR mutations. The diagnostic approach for AL and ATTR amyloidosis should prioritize the detection of monoclonal proteins and the identification of amyloid deposits in tissues. For AL amyloidosis, the process begins with:
- Serum and urine protein electrophoresis with immunofixation to detect monoclonal proteins
- Serum free light chain assay to identify abnormal kappa/lambda ratios
- Tissue biopsy (often abdominal fat pad, bone marrow, or affected organ) with Congo red staining to confirm amyloid deposits
- Mass spectrometry typing of the amyloid protein is the gold standard to confirm AL type 1
For ATTR amyloidosis, initial screening may include:
- Technetium-labeled bone scintigraphy (99mTc-PYP, DPD, or HMDP) to show cardiac uptake in ATTR cardiac amyloidosis
- Genetic testing for TTR mutations to distinguish hereditary from wild-type ATTR
- Tissue biopsy with immunohistochemistry for TTR protein to confirm the diagnosis
- Cardiac MRI with gadolinium enhancement showing late gadolinium enhancement and characteristic amyloid patterns can support diagnosis in both types 1
Complete evaluation should include assessment of organ involvement through biomarkers (NT-proBNP, troponin for cardiac involvement; proteinuria, creatinine for renal involvement) and functional studies (echocardiography, electrocardiogram for cardiac assessment). Early diagnosis is critical as newer treatments can slow disease progression if started before extensive organ damage occurs. The most recent and highest quality study 1 emphasizes the importance of a systematic approach to diagnosis, combining clinical evaluation, tissue biopsy, and specialized testing to accurately diagnose AL and ATTR amyloidosis.
From the Research
Diagnostic Approaches for AL and ATTR Amyloidosis
The diagnosis of AL (Amyloid Light-chain) amyloidosis and ATTR (Amyloid Transthyretin) amyloidosis involves different approaches.
- For AL amyloidosis, the diagnosis requires demonstration in a tissue biopsy of amyloid deposits formed by immunoglobulin light chains 2, 3.
- The workup of patients with AL amyloidosis requires adequate technology and expertise, and patients should be referred to specialized centers whenever possible 2.
- Stagings are based on cardiac and renal biomarkers and guide the choice of treatment 2.
- For ATTR amyloidosis, the standard of care includes agents capable of selectively stabilizing the precursor protein (e.g., tafamidis) 4.
- Novel treatments such as acoramidis and CRISPR-Cas9-based drugs (i.e., NTLA-2001) hold great potential in the setting of ATTR-CA 4.
- Monoclonal antibodies targeting misfolded ATTR (e.g., PRX004, NI301A) or AL (e.g., birtamimab, anselamib) have led to encouraging results 4.
Key Diagnostic Tests
- Tissue biopsy to demonstrate amyloid deposits formed by immunoglobulin light chains for AL amyloidosis 2, 3.
- Cardiac and renal biomarkers for staging and guiding treatment in AL amyloidosis 2.
- Screening biomarkers for early diagnosis of AL amyloidosis 3.
- Agents capable of selectively stabilizing the precursor protein (e.g., tafamidis) for ATTR amyloidosis 4.