What is the recommended evaluation, diagnostic workup, and management for systemic amyloidosis, including AL (light‑chain) and ATTR (transthyretin) types?

Systemic Amyloidosis: Evaluation, Diagnosis, and Management

Initial Clinical Recognition

Suspect systemic amyloidosis in patients presenting with heart failure with preserved ejection fraction (HFpEF), unexplained left ventricular wall thickening, nephrotic-range proteinuria, peripheral neuropathy, or the combination of these findings, particularly in older adults. 1

Red Flag Clinical Presentations

For ATTR Cardiac Amyloidosis:

• Heart failure symptoms (dyspnea, orthopnea, edema, fatigue) in patients over age 60, especially with elevated NT-proBNP out of proportion to clinical context 1
• Bilateral carpal tunnel syndrome (often preceding cardiac symptoms by years) 1
• Lumbar spinal stenosis 1
• Biceps tendon rupture 1
• Intolerance to ACE inhibitors, ARBs, or beta-blockers 1
• Hypertension that resolves over time 1
• Low-flow, low-gradient aortic stenosis 1
• Reduced QRS voltage on ECG despite ventricular wall thickening on imaging (present in ~50% of cases) 1
• African Americans over 60 with heart failure (10% carry the Val122Ile variant) 1

For AL Amyloidosis:

• Severe anasarca with nephrotic syndrome (proteinuria, hypoalbuminemia) 2
• Macroglossia, periorbital purpura, or organomegaly 1
• Unexplained weight loss and fatigue 1
• Peripheral neuropathy with autonomic dysfunction 1

Diagnostic Algorithm

Step 1: Monoclonal Protein Screening (Essential First Step)

Perform comprehensive monoclonal protein evaluation in all suspected cases to differentiate AL from ATTR amyloidosis: 1, 3

• Serum free light chain assay (SFLCA) with kappa/lambda ratio 4, 3
• Serum protein electrophoresis (SPEP) 4, 3
• Serum immunofixation electrophoresis (SIFE) 4, 3
• 24-hour urine collection with urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) 4, 3

Critical caveat: Standard protein electrophoresis alone misses monoclonal spikes in nearly 50% of AL amyloidosis cases. 3

Step 2: Cardiac Imaging for ATTR-CM

If monoclonal protein screening is negative and ATTR-CM is suspected, proceed directly to technetium pyrophosphate (Tc-99m PYP) scintigraphy: 1

• Positive uptake (grade 2 or 3) in the absence of monoclonal protein confirms ATTR-CM diagnosis without need for biopsy 1
• This non-invasive approach has revolutionized ATTR-CM diagnosis 5, 6

Echocardiographic findings suggestive of cardiac amyloidosis: 1

• Increased left ventricular wall thickness with normal or small cavity size 1
• Biatrial enlargement 1
• Granular sparkling appearance of myocardium 1
• Restrictive filling pattern 1

Step 3: Tissue Biopsy and Typing

If monoclonal protein is detected OR scintigraphy is equivocal, obtain tissue biopsy: 1, 3

Biopsy site selection:

• Abdominal fat pad aspiration first (sensitivity 69% for AL, ~45% for ATTRm, ~15% for ATTRwt) 1, 2
• If fat pad negative with high clinical suspicion: proceed to endomyocardial biopsy (100% sensitivity and specificity for cardiac involvement) or biopsy of clinically affected organ 1
• Kidney biopsy if nephrotic syndrome present 4, 2

Amyloid confirmation and typing (mandatory):

• Congo red staining showing apple-green birefringence under polarized light confirms amyloid 3, 2
• Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 3, 7
• Immunohistochemistry can produce false-positive results and should not be relied upon alone 7

Step 4: TTR Genotyping

Perform TTR gene sequencing in ALL confirmed ATTR cases, even without family history or neuropathy, as penetrance varies widely: 1

• Distinguishes hereditary (ATTRm) from wild-type (ATTRwt) disease 1
• Informs genetic counseling for family members 1
• Val122Ile variant occurs in 3-4% of African Americans 1

Organ Involvement Assessment and Staging

Cardiac Assessment

• NT-proBNP and cardiac troponin T levels 1, 3
• Echocardiography 3
• Cardiac MRI (if available) 3

ATTR-CM staging system (most recent): 1

• Stage 1: NT-proBNP <3000 pg/mL AND eGFR ≥45 mL/min
• Stage 2: One threshold met
• Stage 3: NT-proBNP >3000 pg/mL AND eGFR <45 mL/min

AL amyloidosis cardiac staging (Mayo 2004): 1

• Stage I: TnT <0.035 mcg/L AND NT-proBNP <332 ng/L
• Stage II: One elevated
• Stage III: Both elevated

Renal Assessment

• 24-hour urine protein collection 3
• Serum creatinine and eGFR 4, 3
• Electrolytes 4

Additional Organ Systems

• Peripheral neuropathy evaluation (nerve conduction studies if indicated) 1
• Liver function tests 1
• Autonomic function testing if symptoms present 1

Management by Type

AL Amyloidosis Treatment

Daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, 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

Alternative for highly selected patients: 3

• High-dose melphalan followed by autologous stem cell transplantation (ASCT) for patients meeting strict criteria: age <60 years, ≤2 organs involved, good performance status, troponin T <0.06 ng/mL, NT-proBNP <5000 ng/L 1, 3

For AL amyloidosis with renal involvement (light chain cast nephropathy): 4

• Initiate bortezomib-containing regimens immediately 4
• Bortezomib/dexamethasone can be administered without dose adjustment in severe renal impairment 4
• Add third agent that doesn't require dose adjustment (cyclophosphamide, thalidomide, or daratumumab) 4
• Goal: ≥50-60% reduction in free light chains by day 12 of treatment 4, 2

Supportive care: 4, 2

• Avoid nephrotoxic medications (NSAIDs) 4, 2
• Adequate hydration 4
• Treat hypercalcemia if present 4
• Dietary sodium restriction and diuretics for anasarca 2

Response monitoring: 3

• Assess response at 3-6 months using difference between involved and uninvolved free light chains (dFLC) 3
• Use same serum free light chain assay throughout treatment 4
• Monitor renal function regularly 4

Prognosis: Median survival in AL amyloidosis is approximately 13 months, but decreases to 4 months with heart failure symptoms; cardiac involvement is the main driver of mortality with ~30% dying within first year. 1, 3

ATTR Amyloidosis Treatment

For ATTR cardiac amyloidosis, tafamidis (TTR stabilizer) is the established therapy that slows disease progression, decreases hospitalizations, and improves survival. 1, 5, 6

For hereditary ATTR with polyneuropathy: 5

• RNA-interference agents: patisiran or inotersen 5
• TTR stabilizers: tafamidis 5

Supportive cardiac care: 1

• Standard heart failure management with caution regarding ACE inhibitors/ARBs (often poorly tolerated) 1
• Manage arrhythmias and conduction abnormalities 1
• Consider pacemaker for significant conduction disease 1

Prognosis: ATTR-CM has poor life expectancy of 2-6 years after diagnosis, but treatment earlier in disease course is more effective. 1

Critical Pitfalls to Avoid

• Do not rely on standard protein electrophoresis alone—it misses 50% of AL cases 3
• Do not skip TTR genotyping in confirmed ATTR—family history may be absent due to variable penetrance 1
• Do not accept negative fat pad biopsy as definitive—proceed to affected organ biopsy if clinical suspicion remains high 1
• Do not use immunohistochemistry alone for typing—mass spectrometry is mandatory to avoid false-positive light chain staining 3, 7
• Do not delay treatment initiation—early treatment is critical as outcomes worsen with advanced organ damage 1, 3
• Recognize that renal impairment alters free light chain concentrations due to impaired clearance, affecting interpretation 4