What are the diagnostic tests and treatment options for amyloidosis?

Diagnostic Tests and Treatment Options for Amyloidosis

The definitive diagnosis of amyloidosis requires tissue biopsy showing amyloid deposits with Congo red staining that produces apple-green birefringence under polarized light, followed by proper typing to determine the specific form of amyloidosis which is essential for appropriate treatment. 1

Diagnostic Algorithm for Amyloidosis

Step 1: Initial Screening and Clinical Suspicion

• Clinical suspicion indicators:
  • Cardiac: Left ventricular wall thickness ≥14mm with fatigue, dyspnea, or edema
  • Discordance between wall thickness on echocardiogram and QRS voltage on ECG
  • Associated conditions: HFpEF, aortic stenosis, carpal tunnel syndrome, spinal stenosis
  • Autonomic or sensory polyneuropathy
  • Proteinuria, hepatomegaly with mildly abnormal liver tests
  • Unexplained weight loss with GI symptoms 1, 2

Step 2: Laboratory Testing

• Mandatory screening tests:
  • Serum and urine immunofixation electrophoresis
  • Serum free light chain assay 1
  • BNP/NT-proBNP (sensitivity 93%, specificity 90% for cardiac involvement) 1
  • Troponin (prognostic value) 3

Step 3: Tissue Biopsy

• Preferred initial biopsy sites (less invasive):

  • Abdominal fat pad aspiration
  • Gingiva
  • Rectum
  • Bone marrow 1, 4

• Organ-specific biopsies (if non-invasive biopsies are negative):

  • Heart (endomyocardial biopsy)
  • Kidney
  • Liver (controversial safety profile)
  • Other affected organs 1, 2

Step 4: Amyloid Typing

• Immunohistochemistry/Immunofluorescence with antibodies against:

  • κ and λ light chains (AL amyloidosis)
  • Amyloid A (AA amyloidosis)
  • Transthyretin (ATTR amyloidosis) 1

• Advanced typing methods:

  • Laser microdissection followed by mass spectrometry (most accurate) 5
  • Proteomic typing 1

Step 5: Additional Testing Based on Amyloid Type

• For suspected ATTR amyloidosis:

  • Bone scintigraphy (technetium Tc 99m dicarboxypropane diphosphonate) 1
  • TTR gene sequencing to differentiate hereditary from wild-type 1

• For suspected AL amyloidosis:

  • Bone marrow biopsy to assess plasma cell percentage 3, 6
  • High-resolution immunofixation if standard tests are negative 6

Step 6: Organ Involvement Assessment

• Cardiac evaluation:

  • Echocardiography 1
  • Cardiac MRI with gadolinium 5
  • ECG (low QRS voltage with ventricular wall thickening) 1

• Other organ assessments:

  • Renal function tests
  • Liver function tests
  • GI evaluation if symptoms present 2

Treatment Options by Amyloid Type

AL Amyloidosis Treatment

1. First-line therapy:

   • Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) 3
   • Alternative: CyBorD if daratumumab unavailable 3

2. For eligible patients (approximately 25% of newly diagnosed):

   • High-dose melphalan followed by autologous stem cell transplantation 3

3. For advanced cardiac involvement (NT-proBNP >8,500 pg/mL):

   • Single-agent daratumumab with minimal dexamethasone 3

ATTR Amyloidosis Treatment

1. First-line therapy:

   • Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily) for wild-type or hereditary ATTR with NYHA class I-III HF symptoms 1, 7
   • Acoramidis (Attruby) - newer TTR stabilizer 3

2. For hereditary ATTR:

   • Consider liver transplantation (as TTR is synthesized in liver) 3
   • TTR silencer therapy if neuropathy is present 3

Supportive Care for All Types

1. Cardiac management:

   • Diuretics (used cautiously to prevent volume contraction) 3
   • Anticoagulation for atrial fibrillation regardless of CHA₂DS₂-VASc score 1
   • Avoid: Digoxin, calcium channel blockers, β-blockers in severe restrictive physiology 1, 3
   • Consider amiodarone and pacemaker for rhythm/conduction abnormalities 4

2. Advanced options for select patients:

   • Heart transplantation for advanced/stage D heart failure without significant extracardiac manifestations 3
   • Combined heart and liver transplantation for hereditary ATTR 3

Monitoring Response to Treatment

• Monthly: CBC, basic biochemistry, NT-proBNP, troponin, serum-free light chain quantification 3
• Every 6 months: Echocardiography with strain measurements and Holter ECG 3
• Cardiac response assessment: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline >650 ng/L) 3

Important Caveats and Pitfalls

• Small amyloidogenic clones may be missed by standard testing; pursue high-sensitivity techniques when clinical suspicion is high 6
• Misdiagnosis of amyloid type can lead to inappropriate treatment; ensure accurate typing before initiating therapy 5
• Heart failure medications that are standard in other conditions may worsen symptoms or be dangerous in cardiac amyloidosis 1, 3
• AL amyloidosis can present with normal free light chain ratios; bone marrow examination is essential when clinical suspicion is high 6
• Liver biopsy carries controversial safety profile in amyloidosis patients; consider less invasive alternatives first 2

The prognosis and treatment approach vary significantly based on amyloid type and organ involvement, with cardiac involvement being the most important prognostic factor, highlighting the importance of early and accurate diagnosis 4.