Can blood mass spectrometry (BMS) detect localized light-chain amyloidosis?

Blood Mass Spectrometry for Detection of Localized Light-Chain Amyloidosis

Blood mass spectrometry alone cannot reliably detect localized light-chain amyloidosis, as this condition is characterized by the absence of circulating monoclonal proteins that would be detectable in blood. 1, 2

Understanding Localized vs. Systemic Amyloidosis

Localized Amyloidosis

• Characterized by amyloid deposition confined to a single organ or tissue, resulting from local synthesis of amyloid protein rather than deposition of proteins produced elsewhere 2
• Typically lacks detectable monoclonal proteins in serum or urine by conventional testing 2, 3
• Requires tissue biopsy with Congo red staining from the affected site showing characteristic apple-green birefringence under polarized light for diagnosis 2

Systemic AL Amyloidosis

• Features widespread amyloid deposition in multiple organs, particularly the heart and kidneys 1
• Associated with detectable monoclonal proteins in serum or urine and clonal plasma cells in bone marrow 1
• Serum free light chain (sFLC) assays, serum and urine immunofixation electrophoresis (SIFE/UIFE) are typically positive 1

Diagnostic Approach for Amyloidosis

Initial Testing

• Serum free light chain (sFLC) assay, serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) are the standard initial tests for detecting monoclonal proteins 1
• These tests have >99% sensitivity for systemic AL amyloidosis but will typically be negative in localized disease 1, 2
• Immunofixation is more sensitive than protein electrophoresis alone and should always be performed 1

Mass Spectrometry Applications in Amyloidosis

Blood-Based Mass Spectrometry

• Standard blood mass spectrometry techniques include:
  • Serum immunoglobulin free light chains mass spectrometry (FLC-MS) 4
  • Monoclonal immunoglobulin rapid accurate mass measurement (miRAMM) 5
• These techniques have increased sensitivity for detecting small monoclonal proteins in systemic disease 5, 4
• However, in truly localized amyloidosis, blood-based mass spectrometry will typically be negative due to absence of circulating monoclonal proteins 2, 3
• FLC-MS can detect persistent monoclonal light chains in patients with systemic AL amyloidosis who appear to be in complete remission by conventional testing 4

Tissue-Based Mass Spectrometry

• Liquid chromatography with tandem mass spectrometry (LC-MS/MS) of tissue samples is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1
• Can definitively identify the protein composition of amyloid deposits from formalin-fixed tissue samples 6
• Essential for accurate diagnosis of localized amyloidosis, as it can determine the precursor protein directly from the affected tissue 1, 2

Diagnostic Algorithm for Suspected Localized Amyloidosis

1. Tissue biopsy of affected organ/site

   • Congo red staining with apple-green birefringence under polarized light 2
   • LC-MS/MS for amyloid typing (gold standard) 1, 6

2. Exclude systemic involvement

   • Serum and urine studies (all should be negative in localized disease):
     • Serum free light chain assay 1, 2
     • Serum immunofixation electrophoresis 1
     • Urine immunofixation electrophoresis 1
   • Bone marrow biopsy to exclude plasma cell dyscrasia 2
   • Abdominal fat aspiration (should be negative in localized disease) 2

3. Comprehensive organ assessment

   • Cardiac evaluation (echocardiography) 1, 2
   • Renal function tests 2
   • Liver function tests 2
   • Neurological evaluation if clinically indicated 2

Common Pitfalls and Caveats

• Relying solely on blood tests (including mass spectrometry) for diagnosis of localized amyloidosis will lead to false negatives 2, 7
• Some patients with systemic AL amyloidosis may have normal serum free light chain ratios (up to 20%), requiring additional testing 8
• In cases of suspected localized disease, tissue biopsy with LC-MS/MS typing is essential for definitive diagnosis 1, 2
• Localized amyloidosis can potentially progress to systemic disease over time, requiring ongoing monitoring 3
• The presence of a monoclonal gammopathy does not automatically indicate AL amyloidosis, as over 10% of patients with monoclonal gammopathy can have ATTR deposits 1, 2