What is the diagnostic workup for a patient suspected of having amyloidosis?

Amyloidosis Diagnostic Workup

Begin with immediate monoclonal protein screening (serum and urine immunofixation electrophoresis plus serum free light chains) in all patients with suspected amyloidosis, as this single step determines whether you pursue an AL versus ATTR diagnostic pathway and delays beyond 6 weeks are associated with increased early mortality. 1, 2, 3

Initial Clinical Recognition: Red Flags

Suspect amyloidosis when you encounter these specific clinical patterns:

Cardiac Clues

• Left ventricular wall thickness ≥12-14 mm with low QRS voltage on ECG (voltage-to-mass discordance) 1, 2, 4
• Heart failure with preserved ejection fraction (HFpEF) with unexplained LV hypertrophy 1, 2
• Restrictive cardiomyopathy pattern on echocardiography 1, 4
• Apical sparing pattern on longitudinal strain imaging (apical-to-basal strain ratio >2.1) 1, 4
• Concomitant aortic stenosis with right ventricular thickening 1, 2
• Unexplained atrial arrhythmias or need for pacemaker 1

Extracardiac Clues

• Bilateral carpal tunnel syndrome (especially without rheumatoid arthritis or trauma) 2, 4
• Lumbar spinal stenosis or spontaneous biceps tendon rupture 2, 4
• Autonomic or sensory polyneuropathy (unexplained) 2, 4
• Macroglossia or periorbital purpura (highly specific for AL amyloidosis) 1, 5
• Unexplained proteinuria or hepatomegaly 1

Step 1: Monoclonal Protein Screening (Do This First)

Order all three tests simultaneously—do not rely on SPEP/UPEP alone as they miss up to 50% of AL cases: 1

• Serum immunofixation electrophoresis (SIFE) 1, 2
• Urine immunofixation electrophoresis (UIFE) 1, 2
• Serum free light chain assay (sFLC) with kappa/lambda ratio 1, 2

Critical timing consideration: Delays >6 weeks between first cardiac amyloidosis suspicion and monoclonal protein testing correlate with higher Mayo stage IIIb presentation (65% vs 35%) and worse survival (median 3 vs 14 months). 3

Step 2: Divergent Pathways Based on Monoclonal Protein Results

If Monoclonal Protein IS Detected → Suspect AL Amyloidosis

This requires BOTH tissue confirmation AND demonstration of plasma cell dyscrasia: 1

Tissue Biopsy Options (Choose Based on Clinical Scenario):

1. Abdominal fat pad aspiration (first-line surrogate site): 84% sensitive for AL cardiac amyloidosis, office-based procedure 1
2. Bone marrow biopsy: 69% sensitive for systemic AL amyloidosis 1
3. Affected organ biopsy (cardiac, renal, etc.): Required if fat pad and bone marrow are negative but suspicion remains high 1

Biopsy must demonstrate:

• Congo red staining positive for amyloid deposits 1, 6
• Amyloid typing by liquid chromatography with tandem mass spectrometry (LC-MS/MS) (gold standard: 88% sensitivity, 96% specificity) 1, 6
  • Immunohistochemistry alone is insufficient, especially with concurrent MGUS 1

Confirm Plasma Cell Dyscrasia:

• Bone marrow biopsy showing clonal lambda or kappa-producing plasma cells 1
• Exclude multiple myeloma or B-cell lymphoproliferative disorders 1

Next step: Urgent hematology-oncology consultation—AL amyloidosis is rapidly fatal without treatment of the underlying plasma cell disorder 7

If Monoclonal Protein IS NOT Detected → Pursue ATTR Amyloidosis

Proceed directly to bone scintigraphy (nuclear imaging): 1, 2

Nuclear Imaging with Bone Tracers:

• 99mTc-PYP (USA), 99mTc-DPD or 99mTc-HMDP (outside USA) 1, 2
• Grade 2-3 myocardial uptake in the absence of monoclonal protein is diagnostic for ATTR cardiac amyloidosis without need for biopsy 2, 4
• Note: Some uptake can occur in AL amyloidosis (less than ATTR), which is why monoclonal protein screening must be negative 1

Genetic Testing for TTR Gene:

• Differentiates hereditary (ATTRv) from wild-type (ATTRwt) transthyretin amyloidosis 2
• Particularly important in African-Americans and patients with peripheral neuropathy 1

Step 3: Cardiac Imaging (Performed Concurrently)

Echocardiography (First-Line Cardiac Imaging)

Order transthoracic echocardiography in all suspected cases: 2, 4

Key findings include:

• LV wall thickness ≥12 mm with small cavity 4
• Biatrial enlargement disproportionate to ventricular dysfunction 4
• Thickened cardiac valves without significant stenosis 4
• Restrictive transmitral Doppler filling pattern 4
• Apical sparing pattern on speckle-tracking strain (apical-to-basal ratio >2.1) 1, 4
• Pericardial effusion 4

Important limitation: Echocardiography cannot distinguish AL from ATTR amyloidosis 4

Cardiac MRI (When Echo is Suggestive or Equivocal)

Reserve for cases where echocardiography shows suggestive but not definitive findings: 2, 4

Diagnostic features (80-92% sensitivity, 87-94% specificity):

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) distributed circumferentially 1, 2, 4
• Elevated native T1 values (>1020-1044 ms) 4
• Elevated extracellular volume (ECV >0.40) 4
• Abnormal gadolinium kinetics with difficulty nulling myocardium 4

Prognostic value: LGE presence and extent predict mortality (OR 2.73-19.84 depending on pattern) 4

Step 4: Additional Diagnostic Studies

Biomarkers

• NT-proBNP: Disproportionately elevated relative to degree of heart failure; sensitivity 93%, specificity 90% for cardiac involvement 2, 4
• Troponin (T, I, or high-sensitivity): Often elevated 4
• Used for Mayo staging in AL amyloidosis 7

ECG Findings

• Low QRS voltage (despite increased wall thickness on echo) 2, 4
• Pseudoinfarct pattern 4
• Conduction abnormalities 1

Common Pitfalls to Avoid

1. Do not rely on SPEP/UPEP alone—they miss nearly 50% of AL cases due to low monoclonal protein burden 1

2. Do not perform nuclear imaging before excluding monoclonal protein—some AL cases show bone tracer uptake, leading to misdiagnosis as ATTR 1

3. Do not accept immunohistochemistry alone for amyloid typing—over 10% of patients with monoclonal gammopathy can have ATTR deposits; use LC-MS/MS 1, 6

4. Do not delay monoclonal protein testing beyond 6 weeks from first suspicion—associated with worse Mayo staging and survival 3

5. In cases of MGUS with positive nuclear scintigraphy, perform cardiac biopsy—this is the only way to definitively establish whether cardiac pathology is AL or ATTR 1

6. Avoid 99mTc-MDP and 99mTc-aprotinin tracers—they are not recommended for cardiac amyloidosis imaging 1