What is the appropriate workup for amyloidosis?

Amyloidosis Workup

The appropriate workup for amyloidosis should include tissue biopsy for diagnosis, typing of the amyloid protein, and comprehensive evaluation of organ involvement to determine disease extent and guide treatment decisions. 1

Initial Diagnostic Evaluation

Clinical Assessment

• Evaluate for multi-system involvement:
  • Cardiac symptoms: heart failure, arrhythmias
  • Renal manifestations: proteinuria, renal insufficiency
  • Neurologic symptoms: peripheral/autonomic neuropathy
  • Gastrointestinal symptoms: diarrhea, constipation, pseudo-obstruction
  • Specific physical findings: macroglossia, periorbital purpura, hepatomegaly

Laboratory Studies

• Complete blood count (CBC) with differential and platelets
• Blood urea nitrogen (BUN), serum creatinine, electrolytes
• Liver function tests including albumin
• Cardiac biomarkers: troponin, NT-proBNP/BNP
• Serum and urine protein studies:
  • Serum protein electrophoresis (SPEP)
  • Serum immunofixation electrophoresis (SIFE)
  • Serum free light chain (FLC) assay with kappa/lambda ratio
  • 24-hour urine collection for total protein
  • Urine protein electrophoresis (UPEP)
  • Urine immunofixation electrophoresis (UIFE)

Tissue Diagnosis

• Tissue biopsy is mandatory for diagnosis - samples should be stained with Congo red to identify amyloid deposits (appears red in normal light and apple-green in polarized light)
• Biopsy sites:
  • Abdominal subcutaneous fat aspiration (least invasive, ~80% sensitivity)
  • Bone marrow biopsy
  • Rectal mucosa biopsy
  • Affected organ biopsy (kidney, heart, liver) when less invasive approaches are negative but clinical suspicion remains high

Amyloid Typing

• Essential for determining treatment approach
• Methods include:
  • Immunohistochemistry
  • Mass spectrometry (gold standard)
  • Genetic testing (for hereditary forms)

Organ-Specific Evaluation

Cardiac Assessment

• Echocardiography (look for increased wall thickness >12mm without other cause)
• Electrocardiogram (low voltage, conduction abnormalities)
• Cardiac MRI if available
• Nuclear scintigraphy with bone-avid tracers (particularly for ATTR amyloidosis)

Renal Assessment

• 24-hour urine protein quantification
• Estimated glomerular filtration rate (eGFR)
• Kidney biopsy if diagnosis unclear or to confirm renal involvement

Neurologic Assessment

• Nerve conduction studies/electromyography for peripheral neuropathy
• Autonomic function testing if symptoms present

Type-Specific Workup

AL Amyloidosis

• Bone marrow aspirate and biopsy with immunohistochemistry
• Cytogenetic studies including FISH for plasma cell abnormalities
• Skeletal survey to exclude multiple myeloma
• Serum β2-microglobulin (for staging)

ATTR Amyloidosis

• TTR gene sequencing to differentiate hereditary from wild-type ATTR
• Nuclear scintigraphy with bone tracers (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP)

AA Amyloidosis

• Evaluation for underlying chronic inflammatory conditions:
  • Rheumatologic diseases (rheumatoid arthritis, ankylosing spondylitis)
  • Chronic infections (tuberculosis, osteomyelitis, bronchiectasis)
  • Inflammatory bowel disease
  • Familial Mediterranean fever
  • Malignancies

Risk Stratification

Cardiac Staging

• Mayo 2004 staging system:
  • Troponin T >0.035 μg/L (1 point)
  • NT-proBNP >332 ng/L (1 point)
  • Stage I (0 points), Stage II (1 point), Stage III (2 points)

Renal Staging

• Based on proteinuria and eGFR

Common Pitfalls to Avoid

1. Delayed diagnosis - Consider amyloidosis in patients with unexplained heart failure with preserved ejection fraction, nephrotic syndrome, or peripheral neuropathy
2. Inadequate typing - Amyloid typing is crucial as treatment differs significantly between types
3. Missing concurrent conditions - AL amyloidosis can coexist with multiple myeloma
4. Relying solely on serum electrophoresis - May miss nearly 50% of AL amyloidosis cases; always include immunofixation and serum free light chain assay 1
5. Overlooking hereditary forms - Genetic testing is essential, especially in African Americans and patients with peripheral neuropathy 1

Follow-up Evaluation

• Regular monitoring of involved organ function
• For AL amyloidosis: serial measurement of involved free light chains
• Cardiac biomarkers (troponin, NT-proBNP/BNP) for cardiac involvement
• Proteinuria quantification for renal involvement
• Repeat imaging as clinically indicated

This comprehensive approach to amyloidosis workup enables accurate diagnosis, typing, and staging, which are essential for appropriate treatment selection and monitoring disease progression.