Diagnosis and Treatment of Amyloidosis
Diagnostic Approach
Amyloidosis diagnosis requires tissue biopsy with Congo red staining showing apple-green birefringence under polarized microscopy, followed by mandatory amyloid typing using mass spectrometry (gold standard with 88% sensitivity and 96% specificity), and comprehensive organ assessment to determine extent of involvement. 1
Clinical Suspicion and Red Flags
Suspect amyloidosis when patients present with:
- Heart failure with preserved ejection fraction (HFpEF) with unexplained left ventricular wall thickness ≥12 mm 1
- Nephrotic-range proteinuria without other clear etiology 1
- Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma, or peripheral neuropathy with constitutional symptoms (weight loss, fatigue) 1
- Macroglossia (hallmark feature causing facial asymmetry) 2
- Periorbital purpura (pathognomonic for AL amyloidosis) 2
Initial Laboratory Screening
Perform all three monoclonal protein tests simultaneously—never rely on SPEP/UPEP alone: 1, 3
- Serum free light chain (sFLC) assay
- Serum immunofixation electrophoresis (SIFE)
- Urine immunofixation electrophoresis (UIFE)
Measure NT-proBNP or BNP levels (sensitivity 93%, specificity 90% for cardiac involvement; disproportionately elevated relative to degree of heart failure). 1
Tissue Biopsy and Typing
Biopsy is mandatory and cannot be bypassed. Choose the most accessible site: 1
- Abdominal fat pad aspiration (84% sensitivity for AL amyloidosis, least invasive)
- Bone marrow biopsy (required to demonstrate clonal proliferation of lambda or kappa-producing plasma cells) 2
- Affected organ biopsy (heart, liver, kidney)
Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity. 1, 2 Immunohistochemistry can be performed on tissue samples with antibodies against amyloid A, κ- and λ-light chains, and TTR amyloid. 4
Organ Involvement Assessment
Identify all affected organs: 1
- Cardiac evaluation: Echocardiography (mandatory in all suspected cases) and cardiac MRI when echocardiography is suggestive but not definitive
- Renal assessment: Function tests and urinalysis for proteinuria
- Liver function tests
- Neurological evaluation if peripheral neuropathy present
Treatment Strategy by Amyloid Type
AL (Light Chain) Amyloidosis Treatment
Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line treatment for both transplant-eligible and ineligible patients, achieving very good partial response or better in 78.5% of patients. 3 The goal is to eradicate pathological plasma cells and remove affected light chains from circulation. 2, 3
For Transplant-Eligible Patients (Age <60, ≤2 Organs Involved, No Severe Cardiac Involvement):
- High-dose melphalan followed by autologous stem cell transplantation (ASCT) is the standard of care 3
- Daratumumab-CyBorD may be considered as first-line therapy before ASCT 3
- For patients aged 60-65 years with serum creatinine ≥2 mg/dL: Reduce melphalan dose to 100 mg/m² and proceed with extreme caution 3
For Transplant-Ineligible Patients:
- Daratumumab-CyBorD as preferred first-line option 3
- Alternative: CyBorD (cyclophosphamide, bortezomib, and dexamethasone) 3
- Alternative: Melphalan 0.22 mg/kg plus high-dose dexamethasone 40 mg orally days 1-4 every 28 days (achieves 67% hematologic response, 33% complete remission) 3
Important: Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma, requiring close monitoring for cardiac decompensation during therapy. 3 There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status. 3
ATTR (Transthyretin) Amyloidosis Treatment
Tafamidis is FDA-approved for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 3, 5
- Dosing: Tafamidis meglumine 80 mg once daily OR tafamidis 61 mg once daily 5
- Both doses showed statistically significant results for all-cause mortality, frequency of cardiovascular hospitalization, 6-minute walk test, and quality of life measures 5
For Hereditary ATTR Amyloidosis:
Cardiac and liver transplantation may be considered in selected patients with TTR-related amyloidosis (5-year survival rate of 50% to 80%), as liver transplantation cures the disease process since TTR protein is synthesized in the liver. 4
AA (Secondary) Amyloidosis Treatment
Anti-inflammatory therapies, such as anti-tumor necrosis factor agents used for rheumatoid arthritis, suppress serum amyloid A production. 4 However, AA amyloidosis rarely affects the heart, with deposits primarily in liver, spleen, and kidney. 4
Supportive Cardiac Management
Judicious diuresis remains the mainstay of heart failure therapy in cardiac amyloidosis. 4, 3 Standard heart failure medications require extreme caution:
Medications to Use Cautiously:
- Diuretics and vasodilators: Use cautiously due to hypotension from underfilling of a stiff heart 4
- ACE inhibitors/ARBs: Should be used with caution and probably avoided due to hypotension 4
- β-blockers: Use cautiously if at all when cardiac output is low and there is severe restrictive physiology; probably should be avoided in AL amyloidosis, as cardiac output is heart rate dependent 4
Medications to AVOID:
- Digoxin should be avoided as it binds to amyloid fibrils and can cause toxicity even with normal serum digoxin levels 4
- Calcium channel antagonists (nifedipine or verapamil) should not be administered as they bind to amyloid fibrils and cause exaggerated hypotensive and negative inotropic responses 4
Anticoagulation:
Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score. 3 Risk of intracardiac thrombus is high even in sinus rhythm due to atrial mechanical "standstill" from amyloid infiltration. 4 Anticoagulation is indicated in patients with atrial fibrillation, history of embolic stroke or transient ischemic attacks, and probably in those with demonstrable intracardiac thrombus. 4
Cardiac Transplantation Considerations
Cardiac transplantation is generally not recommended for AL amyloidosis due to high risk of recurrence in the transplanted heart and progressive amyloid deposition in other organs, with 5-year survival of only 20% to 30%. 4 Survival appears to improve if cardiac transplantation is followed by bone marrow transplantation, reaching 5-year survival rate of 35% to 55%. 4
Post-cardiac transplantation survival for ATTR amyloidosis is better and similar to outcomes in cardiac transplantation performed for other conditions. 4
Multidisciplinary Care Requirements
Effective management requires close collaboration between specialists: 3
- Hematologist: Primary specialist directing anti-plasma cell therapies and coordinating overall care 3
- Cardiologist: Essential for managing cardiac involvement, which is the main driver of mortality 3
- Nephrologist: Manages kidney involvement, proteinuria, and renal dysfunction 3
- Neurologist: Required when peripheral or autonomic nervous system involvement is present 3
- Transplant specialists: Needed for evaluation of stem cell or organ transplantation 3
Critical Pitfalls to Avoid
- Do not assume facial droop is stroke—consider soft tissue infiltration with macroglossia or periorbital purpura 1, 2
- Do not diagnose based on monoclonal gammopathy alone—requires tissue confirmation and typing 1
- Do not use SPEP/UPEP alone—requires all three tests (sFLC, SIFE, UIFE) simultaneously 1, 2
- Do not skip amyloid typing—mass spectrometry is the gold standard 1, 2
- Differentiation between AL and ATTR amyloidosis is essential, as management differs significantly 3