What is the recommended workup and treatment approach for a patient with suspected amyloidosis?

Workup and Treatment Approach for Suspected Amyloidosis

The comprehensive workup for suspected amyloidosis requires tissue diagnosis to identify amyloid deposits, followed by typing to determine the specific amyloid protein, which guides appropriate treatment selection. 1

Initial Diagnostic Workup

Clinical Assessment

• Look for specific organ involvement patterns:
  • Cardiac: Left ventricular wall thickness ≥14mm with fatigue, dyspnea, or edema; discordance between wall thickness on echocardiogram and QRS voltage on ECG 1
  • Renal: Proteinuria, nephrotic syndrome
  • Neurologic: Peripheral neuropathy, autonomic dysfunction
  • Associated conditions: Carpal tunnel syndrome, spinal stenosis 1

Laboratory Testing

1. Blood tests:

   • Complete blood count with differential and platelets
   • Renal function: BUN, serum creatinine, electrolytes
   • Monoclonal protein screening:
     • Serum and urine immunofixation electrophoresis
     • Serum free light chain assay 1

2. Urine tests:

   • 24-hour urine collection for total protein and electrophoresis
   • Random urine protein-to-creatinine ratio (cutoff >715 mg/g suggests renal involvement) 2

Tissue Diagnosis

• Required for definitive diagnosis: Identification of amyloid deposits in tissues 1
• Preferred biopsy sites:
  • Abdominal subcutaneous fat aspiration (safe, minimally invasive)
  • Organ-directed biopsy if clinically indicated (affected organ)
  • Bone marrow aspiration and biopsy 1, 3

Amyloid Typing

After confirming amyloid deposits:

1. For suspected AL amyloidosis:

   • Bone marrow examination with immunohistochemical staining to detect monoclonal plasma cell population 1

2. For suspected ATTR amyloidosis:

   • If no evidence of monoclonal light chains, perform bone scintigraphy (Tc-99m-PYP) to confirm transthyretin cardiac amyloidosis 1
   • If ATTR is confirmed, genetic testing with TTR gene sequencing to differentiate hereditary variant from wild-type transthyretin amyloidosis 1

3. Additional testing for organ involvement:

   • Cardiac: Echocardiogram, cardiac MRI, ECG
   • Renal: Proteinuria quantification, renal function tests
   • Neurologic: Nerve conduction studies

Treatment Approach

AL Amyloidosis

Treatment targets the underlying plasma cell dyscrasia:

1. First-line options:

   • Clinical trial participation when available 1
   • High-dose melphalan followed by autologous stem cell transplantation (for eligible patients) 1, 4
     • Achieves hematologic remission in 40% of patients
     • Associated with improved 5-year survival and reversal of amyloid-related disease

2. For transplant-ineligible patients:

   • Melphalan and high-dose dexamethasone 1
     • Hematologic response in 67% of patients
     • Complete remission in 33% of patients

3. Alternative regimens:

   • Lenalidomide and dexamethasone
   • Single-agent bortezomib
   • Dexamethasone and alpha-interferon 1

ATTR Amyloidosis

1. For wild-type or variant transthyretin cardiac amyloidosis:

   • Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg orally once daily) for NYHA class I-III heart failure symptoms 1, 5
     • Reduces cardiovascular mortality and cardiovascular-related hospitalization

2. For ATTR with neuropathy:

   • TTR silencer therapy 1

3. For cardiac amyloidosis with atrial fibrillation:

   • Anticoagulation regardless of CHA₂DS₂-VASc score 1

Monitoring Response to Treatment

AL Amyloidosis

• Hematologic response:

  • Serial serum and urine protein electrophoresis
  • Quantitative immunoglobulins
  • Serum free light chain assay for nonsecretory/oligosecretory disease 1

• Organ response:

  • Renal: 50% or greater reduction in proteinuria with less than 25% decline in renal function 4
  • Cardiac: Echocardiography, biomarkers (NT-proBNP, troponin)

ATTR Amyloidosis

• Regular cardiac assessment with echocardiography
• Functional capacity evaluation (6-minute walk test)
• Quality of life measures

Important Considerations and Pitfalls

1. Diagnostic pitfalls:

   • Serum protein electrophoresis alone is inadequate (misses nearly 50% of AL cases) 1
   • One patient may have two potential amyloid-forming proteins requiring direct tissue typing 6

2. Treatment considerations:

   • Avoid NSAIDs and intravenous contrast media in patients with renal impairment 1
   • Prophylactic anticoagulation should be considered with thalidomide-based therapy 1

3. Monitoring challenges:

   • Bone marrow examination not routinely needed to assess response unless establishing complete response 1
   • No need to repeat skeletal survey in responding patients unless new bone symptoms develop 1

By following this structured approach to diagnosis and treatment, patients with amyloidosis can receive timely, appropriate care that addresses their specific type of disease and organ involvement.