What are the recommended diagnostic tests for amyloidosis?

Recommended Diagnostic Tests for Amyloidosis

The definitive diagnosis of amyloidosis requires tissue biopsy showing amyloid deposits with Congo red staining demonstrating apple-green birefringence under polarized light, followed by typing to determine the specific amyloid protein. 1

Initial Diagnostic Approach

Step 1: Clinical Suspicion and Screening Tests

• Serum and urine testing for monoclonal proteins:

  • Serum and urine immunofixation electrophoresis
  • Serum free light chain assay 1

• Cardiac biomarkers:

  • NT-proBNP (elevated >332 ng/L has >99% sensitivity for cardiac involvement) 1
  • Troponin T/I/high-sensitivity troponin 1

Step 2: Imaging Studies

• Echocardiography - Look for:

  • LV wall thickness >12 mm
  • Relative apical sparing on longitudinal strain
  • Grade 2 or higher diastolic dysfunction
  • Granular sparkling appearance of myocardium
  • Biatrial enlargement 1

• Cardiac MRI - Look for:

  • Diffuse subendocardial or transmural late gadolinium enhancement
  • Global extracellular volume >0.40
  • Abnormal gadolinium kinetics (myocardial nulling prior to blood pool) 1

• Bone scintigraphy (if no monoclonal proteins detected):

  • 99mTc-PYP/DPD/HMDP nuclear imaging
  • Grade 2-3 myocardial uptake strongly suggests ATTR amyloidosis 1

Definitive Diagnosis

For ATTR Amyloidosis

• Non-biopsy diagnosis pathway (all criteria must be met):

  1. Grade 2-3 myocardial uptake on bone scintigraphy
  2. Absence of monoclonal protein on serum/urine testing
  3. Typical cardiac imaging features 1

• Genetic testing:

  • TTR gene sequencing to differentiate hereditary variant from wild-type ATTR 1

For AL Amyloidosis and Other Types

• Tissue biopsy from one of these sites (in order of preference):

  1. Affected organ (if accessible)
  2. Minor salivary gland (61.1% sensitivity, minimally invasive) 2
  3. Abdominal fat pad aspiration (simple, outpatient procedure)
  4. Bone marrow (especially if suspecting AL amyloidosis)
  5. Rectal mucosa 1, 3

• Amyloid typing methods:

  • Immunohistochemistry (less reliable)
  • Mass spectrometry (gold standard for typing) 4, 5

Special Considerations

• ECG findings to support diagnosis:

  • Low voltage QRS despite increased wall thickness
  • Pseudoinfarct pattern (Q waves without prior MI)
  • Conduction abnormalities 1

• Red flags for cardiac amyloidosis:

  • Heart failure with preserved ejection fraction, particularly in men
  • Intolerance to ACE inhibitors or beta blockers
  • Bilateral carpal tunnel syndrome
  • Lumbar spinal stenosis
  • Biceps tendon rupture
  • Unexplained peripheral neuropathy 1

Diagnostic Algorithm

1. Initial evaluation with serum/urine monoclonal protein studies and cardiac biomarkers

2. If monoclonal protein present → Proceed to tissue biopsy for confirmation and typing

3. If no monoclonal protein but cardiac suspicion → Bone scintigraphy

   • If Grade 2-3 uptake → Diagnosis of ATTR amyloidosis (proceed to TTR gene sequencing)
   • If negative/equivocal → Tissue biopsy needed

4. If tissue biopsy positive → Typing by immunohistochemistry and/or mass spectrometry

Pitfalls to Avoid

• Relying solely on echocardiography without confirmatory testing
• Failing to exclude monoclonal gammopathy before diagnosing ATTR by bone scan (up to 40% of ATTR patients can have concurrent MGUS) 1
• Misinterpreting low-grade uptake on bone scintigraphy (Grade 1 can occur in AL amyloidosis)
• Delaying diagnosis (early diagnosis is the major predictor of survival) 6
• Failing to perform genetic testing in confirmed ATTR cases to identify hereditary forms

By following this systematic approach, amyloidosis can be diagnosed efficiently with minimal invasive procedures in many cases, allowing for earlier treatment and improved outcomes.