Diagnostic and Treatment Approaches for Amyloidosis
Definitive Diagnosis Requires Tissue Biopsy with Mandatory Amyloid Typing
The diagnosis of amyloidosis mandates tissue biopsy demonstrating Congo red staining with apple-green birefringence under polarized microscopy, followed by mass spectrometry-based amyloid typing (LC-MS/MS: 88% sensitivity, 96% specificity)—this cannot be bypassed regardless of how suggestive clinical or imaging findings appear. 1, 2
Diagnostic Algorithm
Step 1: Recognize Clinical Red Flags
Suspect amyloidosis when encountering these specific presentations:
- Cardiac: Heart failure with preserved ejection fraction (HFpEF) with unexplained left ventricular wall thickness ≥12 mm 1, 2
- Electrocardiographic paradox: Low QRS voltage on ECG despite ventricular wall thickening on imaging (voltage-to-mass discordance) 3, 2
- Neurologic: Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma 1, 2
- Renal: Nephrotic-range proteinuria without clear alternative etiology 1
- Dermatologic: Periorbital purpura (pathognomonic for AL amyloidosis) or macroglossia causing facial asymmetry 4
Step 2: Perform Complete Monoclonal Protein Screening
Critical: All three tests must be performed simultaneously—never rely on serum/urine protein electrophoresis (SPEP/UPEP) alone 1:
- 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 clinical heart failure severity) 3, 1, 2
Step 3: Obtain Tissue Biopsy
Choose the most accessible site 1:
- Abdominal fat pad aspiration: 84% sensitivity for AL amyloidosis, least invasive, first-line approach 1
- Bone marrow biopsy: Alternative when fat pad negative
- Affected organ biopsy: Heart, liver, or kidney when other sites negative or when endomyocardial biopsy needed for equivocal cases 2
Organ biopsy is not required in 85% of patients 5
Step 4: Confirm Amyloid and Perform Typing
- Congo red staining demonstrating apple-green birefringence confirms amyloid presence 1, 2, 4
- Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1, 2, 4
- If transthyretin (TTR) amyloid detected, perform DNA mutational analysis to differentiate hereditary from wild-type (senile) amyloidosis 3
Step 5: Comprehensive Organ Assessment
Once amyloidosis confirmed, identify all affected organs 3, 1:
Cardiac evaluation (mandatory):
- Echocardiography: Must be performed in all patients with suspected cardiac amyloidosis or systemic amyloidosis with heart failure 3, 1, 2
- Look for: LV wall thickness >12 mm with small cavity size, biatrial enlargement, granular sparkling myocardial texture 2
- Cardiac MRI: When echocardiography suggestive but not definitive 1, 2
- Diagnostic features: LV wall thickness > upper limit of normal, global extracellular volume (ECV) >0.40, diffuse late gadolinium enhancement (LGE) in subendocardium 2
- Nuclear imaging: Technetium Tc 99m pyrophosphate or DPD scintigraphy can distinguish AL from TTR amyloidosis 3, 1
Other organ systems:
- Renal: Function tests, urinalysis for proteinuria 1
- Hepatic: Liver function tests 1
- Neurologic: Evaluation if peripheral neuropathy present 1
Step 6: Risk Stratification
Use cardiac biomarkers for staging (Mayo or European models) 1:
- Troponin T threshold <0.035 mcg/L
- NT-proBNP threshold <332 ng/L
Cardiac involvement is the primary driver of prognosis and mortality 4
Treatment Approaches
AL (Light Chain) Amyloidosis
First-line therapy: Daratumumab-CyBorD regimen (daratumumab + cyclophosphamide + bortezomib + dexamethasone) for both transplant-eligible and transplant-ineligible patients 4, 5
Treatment goal: Achieve ≥very good partial response (VGPR) 5
Consolidation options for patients failing to achieve VGPR 5:
- Pomalidomide
- Autologous stem cell transplantation
- Venetoclax
- Bendamustine
Prognosis: Median survival 13 months overall, but decreases to 4 months with onset of heart failure symptoms 3. Deep hematologic responses correlate with improved organ function and survival 4
ATTR (Transthyretin) Amyloidosis
For wild-type or hereditary ATTR cardiomyopathy:
Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved to reduce cardiovascular mortality and cardiovascular-related hospitalization 6:
- Dosing: Either VYNDAQEL 80 mg (four 20-mg capsules) orally once daily OR VYNDAMAX 61 mg (one capsule) orally once daily 6
- Not substitutable on per-mg basis between formulations 6
- Swallow capsules whole; do not crush or cut 6
Drug interaction: Tafamidis inhibits BCRP transporter—monitor for toxicity when coadministered with BCRP substrates (methotrexate, rosuvastatin, imatinib) 6
Prognosis: Median survival 70-75 months for hereditary and senile types 3
Critical Pitfalls to Avoid
- Never diagnose based on monoclonal gammopathy alone—requires tissue confirmation and typing 2
- Never assume ATTR diagnosis based on nuclear imaging alone—must confirm absence of monoclonal protein 2
- Never use digoxin or calcium channel blockers in suspected cardiac amyloidosis—these drugs bind to amyloid fibrils causing toxicity and exaggerated hypotensive responses even at therapeutic levels 2
- Never bypass biopsy even when imaging and clinical features highly suggestive—typing is mandatory for treatment decisions 1, 4
- Facial droop is not always stroke—consider soft tissue infiltration with macroglossia or periorbital purpura in amyloidosis 1
- Delayed diagnosis remains major obstacle—initiate workup immediately when red flags present to prevent end-stage organ failure 5
Multidisciplinary Management
Mandatory collaboration between hematology, cardiology, neurology, and dermatology for systemic AL amyloidosis management 4