What is the next best step after an MRI suggests amyloidosis (a condition characterized by abnormal protein deposits)?

Next Steps After MRI Suggests Amyloidosis

The next best step is to screen for monoclonal protein with serum free light chains (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) to determine whether to pursue tissue biopsy or nuclear scintigraphy. 1

Immediate Diagnostic Algorithm

Step 1: Monoclonal Protein Screening

• Obtain sFLC assay, SIFE, and UIFE immediately to exclude AL amyloidosis before proceeding with other diagnostic tests 1
• Do not rely on serum/urine protein electrophoresis (SPEP/UPEP) alone, as these have lower sensitivity for detecting the typically low levels of monoclonal protein in AL amyloidosis 2
• If monoclonal protein is detected, collaborate with a hematologist to determine if findings represent spurious results from kidney dysfunction, monoclonal gammopathy of undetermined significance (MGUS), AL amyloidosis, or multiple myeloma 1

Step 2A: If Monoclonal Protein is Detected

• Proceed directly to tissue biopsy with Congo red staining from either a surrogate site or the clinically affected organ 1
• Two biopsy approaches are available:
  • Option 1: Biopsy the affected organ directly (e.g., endomyocardial biopsy if cardiac involvement is suspected) 1
  • Option 2: Start with bone marrow and/or abdominal fat aspiration (sensitivity 84% for AL-CM, 69% for bone marrow); if negative, proceed to affected organ biopsy 1
• Critical caveat: In the context of MGUS with suspected cardiac involvement, endomyocardial biopsy is necessary to definitively diagnose the amyloid type, as over 10% of patients with monoclonal gammopathy can have ATTR deposits 1, 2

Step 2B: If No Monoclonal Protein is Detected

• Proceed to nuclear scintigraphy with bone-avid tracers (99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP) 1
• If scintigraphy shows grade 2 or 3 myocardial uptake with typical cardiac imaging features and absence of monoclonal protein, ATTR cardiac amyloidosis can be diagnosed without tissue biopsy 1, 3
• If ATTR amyloidosis is identified, TTR gene sequencing must be performed to differentiate hereditary (ATTRv) from wild-type (ATTRwt) disease, even without family history 1, 2

Essential Tissue Confirmation Requirements

Biopsy Site Selection

• Abdominal fat aspiration: Simple, office-based procedure with 84% sensitivity for AL-CM but only 15% sensitivity for ATTRwt-CM 1
• Bone marrow biopsy: 69% sensitivity for systemic AL amyloidosis 1
• Endomyocardial biopsy: Gold standard with approximately 100% specificity and sensitivity for detecting amyloid deposits, but invasive with small risk of serious complications 1
• Critical pitfall: Given the high false-negative rate from surrogate sites (fat pad, bone marrow), further evaluation with affected organ biopsy is imperative if clinical suspicion remains elevated despite negative surrogate site biopsy 1

Amyloid Typing After Positive Congo Red Staining

• Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1, 2, 3
• If LC-MS/MS is not immediately available, transfer pathological samples with positive Congo red staining to an experienced reference laboratory 1, 2
• Immunohistochemistry or immunogold immunoelectron microscopy can be performed in experienced centers but are less reliable than mass spectrometry 1, 2
• Congo red staining alone is insufficient to determine amyloid type, particularly in the common scenario of MGUS with suspected ATTR cardiac amyloidosis 1

Confirmation of AL Amyloidosis Requires Both:

1. Demonstration of tissue amyloid deposits (Congo red positive with apple-green birefringence under polarized light) 1, 3
2. Evidence of plasma cell dyscrasia through bone marrow biopsy showing clonal proliferation of lambda or kappa-producing plasma cells 1, 2

Comprehensive Organ Assessment

• Perform systematic evaluation to identify all affected organs, as this is critical for determining treatment strategies and prognosis 2, 3
• Echocardiography should be performed in all patients with confirmed amyloidosis to assess cardiac involvement 2
• Assess renal function and proteinuria 2
• Evaluate for clinical red flags including bilateral carpal tunnel syndrome, peripheral neuropathy with autonomic features, macroglossia, hepatomegaly, or acquired factor X deficiency 1, 3

Common Pitfalls to Avoid

• Never assume AL amyloidosis based solely on monoclonal protein presence without proper tissue typing, as ATTR deposits can coexist with MGUS 1, 2
• Do not skip monoclonal protein screening before nuclear scintigraphy, as this can lead to misdiagnosis and inappropriate treatment 1
• Avoid relying on surrogate site biopsies alone when clinical suspicion is high; proceed to affected organ biopsy if initial biopsies are negative 1
• Misdiagnosing amyloid type leads to inappropriate treatment and patient harm, as AL and ATTR amyloidoses have fundamentally different treatment approaches 2, 3