What tests should be ordered to rule out amyloidosis as a cause of neuropathy?

Diagnostic Tests for Amyloidosis as a Cause of Neuropathy

To rule out amyloidosis as a cause of neuropathy, tissue biopsy with Congo red staining is essential, along with serum and urine immunofixation electrophoresis and serum free light chain analysis to identify the type of amyloidosis. 1

Initial Diagnostic Approach

Laboratory Testing

• Serum studies:

  • Serum protein electrophoresis (SPEP) with immunofixation 1
  • Serum free light chain (FLC) assay 1
  • Complete blood count with differential
  • Renal function tests (BUN, creatinine)
  • Liver function tests
  • Calcium levels

• Urine studies:

  • 24-hour urine collection for protein electrophoresis and immunofixation 1
  • 24-hour urine for total protein

Tissue Sampling

• Abdominal fat aspiration - Simple, less-invasive procedure with excellent sensitivity (84% for AL amyloidosis) 1
• Bone marrow biopsy - Should include Congo red staining (sensitivity approximately 69% for systemic AL amyloidosis) 1
• Sural nerve biopsy - If peripheral neuropathy is the dominant feature 2
• Biopsy of affected organ - If surrogate site biopsies are negative but clinical suspicion remains high 1

Additional Testing Based on Amyloidosis Type

For AL Amyloidosis

• If monoclonal protein is detected, perform:
  • Bone marrow examination with immunohistochemical staining 1
  • Cardiac biomarkers (natriuretic peptide and troponin) 1
  • Echocardiogram with strain imaging 1

For ATTR Amyloidosis

• If no monoclonal protein is detected, perform:
  • Bone scintigraphy (99mTc-PYP/DPD/HMDP) 1
  • TTR gene sequencing to differentiate hereditary variant from wild-type transthyretin amyloidosis 1
  • Cardiac imaging (echocardiography or cardiac MRI) 1

For Neuropathy Evaluation

• Electromyography (EMG) with nerve conduction studies 1, 3
• Neurologic assessment for:
  • Small-fiber neuropathy (numbness, paresthesia, imbalance)
  • Autonomic dysfunction (orthostatic hypotension, GI symptoms)
  • Carpal tunnel syndrome 1, 3
• Anti-myelin-associated glycoprotein (anti-MAG) antibodies if motor neuropathy predominates 1

Diagnostic Algorithm

1. Step 1: Perform serum and urine immunofixation electrophoresis and serum free light chain analysis

   • If positive for monoclonal protein → Suspect AL amyloidosis
   • If negative for monoclonal protein → Consider ATTR amyloidosis

2. Step 2: Tissue sampling

   • Begin with abdominal fat aspiration and/or bone marrow biopsy with Congo red staining
   • If negative but high clinical suspicion remains, proceed to biopsy of affected organ or nerve

3. Step 3: If amyloid deposits are confirmed:

   • Determine amyloid type through mass spectrometry of tissue sample 1
   • For suspected ATTR without monoclonal protein, perform bone scintigraphy and TTR gene sequencing

Clinical Pitfalls and Caveats

• Screening with serum electrophoresis alone is inadequate, as it does not show a monoclonal spike in nearly 50% of cases 1
• Amyloid neuropathy can mimic chronic inflammatory demyelinating polyneuropathy (CIDP), especially when autonomic symptoms are subtle 4
• Patients with amyloid neuropathy often experience significant diagnostic delay (median 29 months from symptom onset to diagnosis) 2
• Genetic testing must be performed to identify specific mutations in hereditary forms, especially in African-Americans and patients with peripheral neuropathy 1
• Amyloid neuropathy should be considered in any patient over 40 years with idiopathic peripheral neuropathy, particularly with autonomic features 5

By following this comprehensive diagnostic approach, clinicians can effectively rule out amyloidosis as a cause of neuropathy or confirm the diagnosis to guide appropriate treatment, ultimately improving patient outcomes and quality of life.