What diagnostic tests are used to diagnose amyloidosis?

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 Workup

Laboratory Tests

• Serum and urine testing for monoclonal proteins:

  • Serum and urine immunofixation electrophoresis
  • Serum free light chain assay (abnormal kappa/lambda ratio)
  • These tests are essential to identify AL amyloidosis 1

• Cardiac biomarkers:

  • NT-proBNP (>332 ng/L has >99% sensitivity for cardiac involvement)
  • Troponin T/I/high-sensitivity troponin
  • These biomarkers predict prognosis and mortality 2

Tissue Biopsy

• Biopsy sites for diagnosis:

  • Abdominal fat pad aspiration (less invasive)
  • Minor salivary glands
  • Rectal mucosa
  • Bone marrow
  • Affected organs (heart, liver, kidney) 1, 2

• Histological examination:

  • Congo red staining (apple-green birefringence under polarized light)
  • Immunohistochemistry for amyloid typing (antibodies against amyloid A, κ- and λ-light chains, TTR)
  • Electron microscopy shows rigid, nonbranching 10-12 nm width fibrils 2

Advanced Diagnostic Methods

Imaging Studies

Cardiac Imaging

• Echocardiography:

  • LV wall thickness >12 mm with no other known cause
  • Relative apical sparing on longitudinal strain
  • Grade 2 or higher diastolic dysfunction
  • Granular sparkling appearance of myocardium
  • Biatrial enlargement 1, 2

• Cardiac MRI:

  • Diffuse subendocardial or transmural late gadolinium enhancement
  • Global extracellular volume >0.40
  • Abnormal gadolinium kinetics (myocardial nulling prior to blood pool) 1, 2

• Nuclear Imaging:

  • Bone scintigraphy using 99mTc-PYP/DPD/HMDP
  • Grade 2-3 myocardial uptake suggests ATTR amyloidosis
  • Can distinguish between AL and TTR amyloidosis 2

Specialized Testing

• Proteomic typing:

  • Laser microdissection followed by mass spectrometry
  • Most advanced technique for amyloid typing
  • Can directly identify proteins with or without mutations 3

• Genetic testing:

  • TTR gene sequencing to differentiate hereditary variant from wild-type ATTR
  • Essential when TTR amyloid is detected 2, 1

Non-Biopsy Diagnostic Pathway for ATTR Amyloidosis

A non-biopsy diagnosis pathway can be used if all criteria are 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

Red Flags for Amyloidosis

• Heart failure with preserved ejection fraction
• Intolerance to ACE inhibitors or beta blockers
• Bilateral carpal tunnel syndrome
• Lumbar spinal stenosis
• Biceps tendon rupture
• Unexplained peripheral neuropathy
• Alternating bowel pattern
• Unexplained atrial arrhythmias or conduction system disease 2, 1

Diagnostic Pitfalls to Avoid

• Relying solely on echocardiography without confirmatory testing
• Failing to exclude monoclonal gammopathy before diagnosing ATTR by bone scan
• Misinterpreting low-grade uptake on bone scintigraphy
• Delaying diagnosis due to nonspecific symptoms 1, 4
• Not performing typing after confirming amyloid deposits (treatment is type-specific) 3

The diagnostic approach to amyloidosis requires a high index of suspicion, appropriate tissue sampling, and accurate typing to guide treatment decisions that directly impact morbidity and mortality.