Blood Tests for Amyloid Polyneuropathy
For suspected amyloid polyneuropathy, order serum protein immunofixation electrophoresis and serum free light chains as your primary amyloid-specific tests, alongside basic screening labs (CBC, comprehensive metabolic panel, HbA1c, TSH, vitamin B12), and confirm the diagnosis with genetic testing for TTR mutations and/or tissue biopsy with Congo red staining and amyloid typing 1, 2, 3.
Essential Laboratory Workup
First-Tier Screening Tests
Start with these basic tests that identify common polyneuropathy causes and provide baseline organ function assessment:
- Complete blood count (CBC)
- Comprehensive metabolic panel (glucose, renal function, liver function)
- HbA1c (diabetes is the most common polyneuropathy cause)
- Thyroid function tests (TSH)
- Serum vitamin B12 with metabolites (methylmalonic acid and homocysteine if B12 is 200-500 pg/dL)
- Serum protein immunofixation electrophoresis - this is critical as monoclonal proteins are found in approximately 9% of polyneuropathy patients 1
These screening tests have the highest diagnostic yield, with blood glucose abnormalities in ~11% of patients, serum protein abnormalities in 9%, and B12 deficiency in 3.6% 1, 4.
Amyloid-Specific Testing
When clinical suspicion for amyloid polyneuropathy exists (progressive sensory-motor neuropathy with autonomic dysfunction, unexplained weight loss, cardiac involvement, family history, bilateral carpal tunnel syndrome, or vitreous opacities), proceed immediately with:
Definitive Diagnostic Tests:
- Genetic testing for TTR mutations - this confirms hereditary ATTR (ATTRv) amyloidosis 2, 3
- Serum free light chains - essential for detecting AL amyloidosis 5
- Tissue biopsy (abdominal fat pad, nerve, or other affected tissue) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry - this definitively identifies the amyloid protein type 2, 3, 5
- Cardiac technetium-based scintigraphy (99mTc-PYP or DPD scan) - can diagnose ATTR cardiac amyloidosis non-invasively when combined with negative serum free light chains 2
Critical Clinical Pearls
Red Flags Requiring Amyloid Workup
Look specifically for these features that distinguish amyloid polyneuropathy from other causes 3:
- Progressive length-dependent small-fiber neuropathy with autonomic dysfunction
- Bilateral carpal tunnel syndrome preceding polyneuropathy
- Unexplained cardiac hypertrophy or heart rhythm disorders
- Unexplained weight loss (>10% body weight)
- Vitreous opacities or renal abnormalities
- Family history of similar symptoms (though 20-30% have no known family history)
- Rapidly progressive sensory-motor axonal neuropathy
- Atypical CIDP presentation that doesn't respond to immunotherapy
Common Diagnostic Pitfalls
Avoid these mistakes:
- Don't rely on serum protein electrophoresis alone - immunofixation is more sensitive for detecting monoclonal proteins 1
- Don't assume negative family history excludes hereditary amyloidosis - many patients have de novo mutations or incomplete penetrance 3
- Don't stop at biopsy showing amyloid - amyloid typing is mandatory to distinguish AL from ATTR from other types, as treatment differs completely 5
- Don't order B12 metabolites in patients with renal insufficiency or hypothyroidism without considering these cause false elevations 1
When Basic Tests Are Negative
If screening tests don't reveal an etiology and amyloid remains suspected based on clinical phenotype, do not delay genetic testing and tissue biopsy 2, 3. Early diagnosis is critical because disease-modifying treatments (TTR stabilizers and gene silencers) are most effective before significant end-organ damage occurs 6.
Algorithmic Approach
All patients with unexplained polyneuropathy: Basic screening panel (CBC, CMP, HbA1c, TSH, B12, immunofixation)
If red flags present: Add TTR genetic testing + serum free light chains + consider cardiac scintigraphy
If genetic testing positive: Confirms ATTRv - proceed to treatment evaluation
If free light chains abnormal: Pursue AL amyloidosis workup with hematology
If both negative but high suspicion: Tissue biopsy with Congo red staining and mass spectrometry typing
The evidence supporting this approach comes primarily from the 2009 American Academy of Neurology practice parameter 1 for general polyneuropathy screening, augmented by recent expert consensus specifically for ATTR amyloidosis 2, 3. The 2026 ISA guidelines emphasize that early diagnosis is essential given the availability of effective disease-modifying therapies 6.