What is the diagnostic workup for amyloidosis?

Diagnostic Workup for Amyloidosis

The diagnostic workup for amyloidosis requires tissue biopsy for definitive diagnosis, followed by amyloid typing and comprehensive organ involvement assessment to guide treatment decisions. 1

Initial Evaluation

Clinical Suspicion

• Consider amyloidosis in patients with:
  • Unexplained heart failure with preserved ejection fraction
  • Restrictive cardiomyopathy
  • Unexplained proteinuria or nephrotic syndrome
  • Peripheral neuropathy with autonomic features
  • Bilateral carpal tunnel syndrome
  • Hepatomegaly
  • Acquired factor X deficiency with coagulopathy
  • Macroglossia or periorbital ecchymoses 2, 3

Laboratory Tests

• Complete blood count
• Blood urea nitrogen and serum creatinine
• Electrolytes
• Liver function tests
• Cardiac biomarkers (troponin T, NT-proBNP)
• Monoclonal protein studies:
  • Serum protein electrophoresis
  • Serum immunofixation electrophoresis (IFE)
  • Serum free light chain assay with kappa/lambda ratio
  • Urine protein electrophoresis and immunofixation 1, 2

Tissue Diagnosis

Biopsy Options

• Abdominal subcutaneous fat aspiration (sensitivity ~80% for AL amyloidosis)
• Bone marrow biopsy (sensitivity ~69% for AL amyloidosis)
• Rectal mucosa biopsy
• Affected organ biopsy (if other biopsies are negative) 2, 1

Biopsy Processing

• Congo red staining (amyloid appears red in normal light and apple-green in polarized light)
• Electron microscopy (to identify characteristic fibrils) 4

Amyloid Typing

Typing is critical as treatment differs significantly between types:

• Immunohistochemistry/immunofluorescence (limitations in specificity and sensitivity)
• Mass spectrometry (gold standard) - laser microdissection followed by mass spectrometry to directly identify proteins with or without mutations
• Genetic testing - essential for hereditary forms, especially in patients with peripheral neuropathy or family history 2, 4

Organ-Specific Evaluation

Cardiac Assessment

• Echocardiography (look for increased wall thickness)
• Electrocardiogram (assess for low voltage and conduction abnormalities)
• Cardiac MRI with gadolinium (characteristic late gadolinium enhancement pattern)
• Nuclear scintigraphy with bone-avid tracers (for ATTR amyloidosis) 2, 1

Renal Assessment

• 24-hour urine protein quantification
• Estimated glomerular filtration rate
• Kidney biopsy if diagnosis unclear 1

Neurologic Assessment

• Nerve conduction studies
• Electromyography
• Autonomic function testing if symptoms present 1

Gastrointestinal Assessment

• Endoscopy if GI symptoms present
• Assess for hepatomegaly and elevated alkaline phosphatase 5

Disease Staging

• Mayo 2004 staging system for AL amyloidosis:
  • Based on troponin T and NT-proBNP levels
  • Stage I (0 points), Stage II (1 point), and Stage III (2 points) 1

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific symptoms
• Inadequate typing leading to inappropriate treatment
• Missing concurrent conditions (e.g., multiple myeloma with AL amyloidosis)
• Relying solely on serum electrophoresis (can miss nearly 50% of AL amyloidosis cases)
• Overlooking hereditary forms by not performing genetic testing 1

For AL amyloidosis specifically, diagnosis requires both demonstration of tissue amyloid deposits AND evidence of a plasma cell dyscrasia, unlike ATTR-CM which can be diagnosed non-invasively 2.