What is the approach to diagnosing and treating amyloidosis?

Diagnosis and Management of Amyloidosis

Amyloidosis requires tissue biopsy with Congo red staining and mass spectrometry-based typing for definitive diagnosis, with treatment directed at the specific amyloid type: AL amyloidosis requires chemotherapy while ATTR amyloidosis is treated with targeted stabilizers like tafamidis. 1

Clinical Suspicion and Presentation

Amyloidosis should be suspected in patients with:

• Cardiac manifestations:

  • Restrictive cardiomyopathy
  • Heart failure with preserved ejection fraction (HFpEF)
  • Left ventricular wall thickness ≥14mm
  • Low QRS voltage with ventricular wall thickening 2
  • Arrhythmias, especially atrial fibrillation

• Extracardiac manifestations:

  • Unexplained proteinuria
  • Macroglossia and periorbital ecchymoses (highly specific for AL amyloidosis)
  • Peripheral neuropathy with autonomic features
  • Bilateral carpal tunnel syndrome
  • Hepatomegaly with elevated alkaline phosphatase
  • Acquired factor X deficiency with coagulopathy 1
  • Gastrointestinal symptoms (malabsorption, bloating, nausea, diarrhea) 2

Diagnostic Approach

Step 1: Initial Screening Tests

• Serum and urine monoclonal protein studies:

  • Serum free light chain assay
  • Serum protein electrophoresis (SPEP)
  • Serum immunofixation electrophoresis (IFE)
  • Urine protein electrophoresis (UPEP)
  • Urine immunofixation electrophoresis 1

• Cardiac biomarkers:

  • BNP/NT-proBNP (sensitivity 93%, specificity 90%)
  • Troponin 2, 1

Step 2: Imaging

• Echocardiography (for suspected cardiac involvement) 2
• Cardiac MRI (late gadolinium enhancement in subendocardium) 2
• Nuclear scintigraphy (Tc-PYP scan) for ATTR cardiac amyloidosis 1

Step 3: Tissue Diagnosis

• Biopsy sites:

  • Abdominal fat aspiration (sensitivity: 84% for AL-CM, 45% for ATTRv-CM, 15% for ATTRwt-CM) 1
  • Bone marrow (sensitivity 69% for systemic AL amyloidosis) 2
  • Affected organ (if surrogate site biopsy negative)
  • Endomyocardial biopsy (for cardiac amyloidosis) 2

• Tissue analysis:

  • Congo red staining (apple-green birefringence under polarized light)
  • Mass spectrometry (LC-MS/MS) for typing (gold standard, sensitivity 88%, specificity 96%)
  • Alternative typing: immunohistochemistry, immunogold electron microscopy, immunofluorescence 1

Step 4: Diagnostic Algorithm

1. For suspected AL amyloidosis:

   • Confirm monoclonal protein presence
   • Perform surrogate site biopsy (fat pad or bone marrow)
   • If negative, proceed to affected organ biopsy 2, 1

2. For suspected ATTR amyloidosis:

   • Nuclear scintigraphy (Tc-PYP scan) can diagnose ATTR cardiac amyloidosis without biopsy if monoclonal protein studies are negative 1
   • If TTR amyloid is detected, DNA mutational analysis should differentiate between senile (wild-type) and hereditary amyloidosis 2

Treatment Approach

AL Amyloidosis

• First-line therapy:

  • Bortezomib-based regimens (CyBorD: cyclophosphamide, bortezomib, dexamethasone)
  • Daratumumab-based regimens 1
  • High-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) for eligible patients 1

• Eligibility criteria for HDM/SCT:

  • Absence of advanced cardiac involvement
  • Good performance status
  • Limited organ involvement 2

ATTR Amyloidosis

• Pharmacological therapy:

  • Tafamidis (80 mg VYNDAQEL or 61 mg VYNDAMAX daily) - FDA approved for ATTR cardiac amyloidosis 1, 3
  • Acoramidis for ATTR cardiac amyloidosis 1

• Transplantation options:

  • Heart transplantation for select patients with advanced/stage D heart failure
  • Liver transplantation (for hereditary ATTR) as TTR protein is synthesized in liver
  • Combined heart and liver transplantation (5-year survival rate: 50-80%) 1

Disease Staging and Monitoring

Staging Models for AL Amyloidosis

• Mayo 2004 model:

  • Uses troponin T (TnT) and NT-proBNP
  • Stage I: Both TnT < 0.035 microg/L and NT-proBNP < 332 ng/L
  • Stage II: Either TnT or NT-proBNP above threshold
  • Stage III: Both TnT and NT-proBNP above threshold 2

• European 2015 modification:

  • Further classifies Stage III into:
    • Stage IIIA: NT-proBNP < 8500 ng/L
    • Stage IIIB: NT-proBNP ≥ 8500 ng/L 2

Monitoring Protocol

• Monthly monitoring:

  • Complete blood count
  • Basic biochemistry
  • NT-proBNP and troponin
  • Serum-free light chain quantification 1

• Every 6 months:

  • Echocardiography with strain measurements
  • Holter ECG 1

Important Clinical Considerations

• Diagnostic pitfalls:

  • Approximately 10-40% of patients with ATTR-CM may have evidence of a plasma cell dyscrasia without AL amyloidosis 2
  • The prevalence of monoclonal gammopathy of uncertain significance (MGUS) increases with age, affecting ~5% of patients older than 70 years 2
  • Kidney dysfunction can result in disproportionate urinary loss of lambda light chains, potentially causing false positives 2

• Prognosis:

  • 25% of patients with AL amyloidosis die within 6 months of diagnosis
  • 25% of patients with ATTR amyloidosis die within 24 months of diagnosis 4
  • Early diagnosis and treatment before irreversible organ damage is crucial 2

• Multidisciplinary approach:

  • Collaboration between hematologists, cardiologists, nephrologists, neurologists, and palliative care specialists is essential 1
  • Early integration of palliative care for symptom management and quality of life improvement 1