What are the diagnosis and management approaches for amyloidosis?

Diagnosis and Management of Amyloidosis

The definitive diagnosis of amyloidosis requires histological confirmation through tissue biopsy with typing to identify the specific amyloid protein, which is essential for determining treatment strategy and prognosis. 1

Diagnostic Approach

Initial Evaluation

• Suspect amyloidosis in patients with:
  • Restrictive cardiomyopathy or heart failure with preserved ejection fraction
  • Nondiabetic nephrotic syndrome
  • Unexplained hepatomegaly without imaging abnormalities
  • Peripheral neuropathy with distal sensory symptoms
  • Monoclonal gammopathy with atypical clinical features 1, 2

Diagnostic Testing

1. Tissue Biopsy (Gold Standard)

   • Abdominal fat aspiration is preferred initially (sensitivity: 84% for AL-CM, 45% for ATTRv-CM, 15% for ATTRwt-CM) 1
   • Endomyocardial biopsy for cardiac amyloidosis 3, 1
   • Congo red staining showing apple-green birefringence under polarized microscopy confirms amyloid deposits 3

2. Amyloid Typing

   • Mass spectrometry is the gold standard for typing 1
   • Immunohistochemistry can be performed with antibodies against amyloid A, κ- and λ-light chains, and TTR amyloid 3
   • DNA mutational analysis to differentiate between senile and hereditary amyloidosis if TTR amyloid is detected 3

3. Screening Tests

   • Monoclonal protein screening: serum free light chain assay, SPEP, IFE, UPEP 1
   • Cardiac biomarkers: BNP/NT-proBNP (sensitivity 93%, specificity 90%) and Troponin 1
   • Genetic testing for hereditary forms, especially in African-Americans and patients with peripheral neuropathy 1

4. Imaging

   • Echocardiography for suspected cardiac amyloidosis 3
   • Nuclear imaging with Technetium Tc 99m dicarboxypropane diphosphonate to distinguish between AL and TTR amyloidosis 3, 1
   • Cardiac MRI with late gadolinium enhancement showing global subendocardial pattern 1

Management Strategies

Treatment Based on Amyloid Type

1. AL Amyloidosis

   • First-line therapy: Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) 1
   • Alternative: CyBorD (cyclophosphamide, bortezomib, dexamethasone) for patients who cannot tolerate Dara-CyBorD 1
   • Goal: Achieve very good partial response or better 1

2. ATTR Cardiac Amyloidosis

   • FDA-approved treatment: Tafamidis (80 mg VYNDAQEL or 61 mg VYNDAMAX) to reduce cardiovascular mortality and cardiovascular-related hospitalization 1, 4
   • Emerging option: Acoramidis 1

3. Hereditary ATTR with Polyneuropathy

   • Patisiran for treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis 5

4. Advanced Disease Options

   • Heart transplantation for select patients with advanced/stage D heart failure (contraindicated with significant extracardiac manifestations) 1
   • Liver transplantation for hereditary TTR amyloidosis (5-year survival rate: 50-80% for combined heart and liver transplantation) 1

Supportive Care for Cardiac Amyloidosis

• Heart Failure Management:
  • Judicious diuresis is the mainstay of therapy 3
  • Use diuretics and vasodilators cautiously due to risk of hypotension 3
  • Avoid β-blockers as cardiac output is heart rate dependent 3
  • Avoid digoxin and calcium antagonists as they bind to amyloid fibrils 3
  • Use ACE inhibitors or ARBs with caution 3

Monitoring and Follow-up

• Monthly monitoring: CBC, basic biochemistry, NT-proBNP, troponin, and serum-free light chain quantification 1
• Every 6 months: Echocardiography with strain measurements and Holter ECG 1
• Regular assessment for treatment response using serum free light chain assays 1
• Monitor for cardiac toxicities, which are common with many treatments 1

Important Considerations and Pitfalls

• Diagnostic pitfalls:

  • 10-40% of patients with ATTR-CM have evidence of monoclonal gammopathy without AL amyloidosis, especially in older patients 1
  • Kidney dysfunction can cause disproportionate urinary loss of lambda light chains, potentially confusing diagnosis 1
  • Immunohistochemistry has limitations in sensitivity and specificity 6, 7

• Clinical challenges:

  • Many patients are underdiagnosed - 25% of AL amyloidosis patients die within 6 months of diagnosis 2
  • Early diagnosis is critical as treatment is ineffective if end-organ damage is severe 2
  • A multidisciplinary approach involving cardiologists, hematologists, nephrologists, and neurologists is essential 1

• Prognostic considerations:

  • Cardiac staging models (Mayo 2004, European 2015, Mayo 2012, Boston University) help determine prognosis 1
  • Early integration of palliative care improves symptom management and quality of life 1