Screening for Cardiac Amyloidosis
Begin screening with serum and urine monoclonal protein testing (immunofixation electrophoresis and free light chains), followed by bone scintigraphy if negative, in any patient with LV wall thickness ≥14 mm plus symptoms of fatigue, dyspnea, or edema. 1
Clinical Red Flags That Should Trigger Screening
Screen for cardiac amyloidosis when you identify these high-risk features:
- LV wall thickness ≥12-14 mm with discordance between wall thickness on echo and low QRS voltage on ECG 1, 2
- Heart failure with preserved ejection fraction (HFpEF) 1, 2
- Bilateral carpal tunnel syndrome (especially without rheumatoid arthritis or trauma) 1, 2
- Lumbar spinal stenosis or prior orthopedic procedures 1, 2
- Spontaneous biceps tendon rupture 1
- Autonomic or sensory polyneuropathy (unexplained) 1, 2
- Aortic stenosis with unexplained LV hypertrophy 1, 2
Step-by-Step Diagnostic Algorithm
Step 1: Initial Screening Tests
Always start with monoclonal protein screening - this is the critical first decision point that determines your entire diagnostic pathway 1:
Critical pitfall: Never interpret bone scintigraphy without first obtaining monoclonal protein screening, as >10% of AL amyloidosis patients can have positive cardiac uptake on bone scans, and up to 40% of ATTR patients have monoclonal gammopathy of unknown significance (MGUS) 1
Step 2: Cardiac Imaging for Suspicion
Obtain echocardiography as your initial cardiac imaging test 1:
- LV wall thickening (>12 mm) 1
- Apical sparing pattern on longitudinal strain (apical-to-basal ratio >2.1) 1, 2
- Grade ≥2 diastolic dysfunction 1
- Biatrial enlargement, thickened valves, granular sparkling appearance 1
- Small LV cavity, pericardial effusion 1
Cardiac MRI is appropriate when echo is suggestive 1:
- Diffuse subendocardial or transmural late gadolinium enhancement 1, 2
- Elevated native T1 and extracellular volume (ECV >0.40) 1
- Abnormal gadolinium kinetics with myocardial nulling before blood pool 1
Step 3: Definitive Diagnosis Based on Monoclonal Protein Results
If monoclonal protein screen is NEGATIVE:
- Proceed directly to bone scintigraphy (99mTc-PYP, DPD, or HMDP) 1, 2
- Grade 2 or 3 myocardial uptake plus typical cardiac imaging features confirms ATTR cardiac amyloidosis without need for biopsy 1
- Once ATTR is confirmed, obtain TTR gene sequencing to differentiate hereditary (ATTRv) from wild-type (ATTRwt) 1, 2
If monoclonal protein screen is POSITIVE or shows MGUS:
- Refer to hematologist-oncologist immediately 1, 2
- Bone scintigraphy alone is insufficient for diagnosis in this setting 1
- Endomyocardial or extracardiac biopsy is required to definitively distinguish AL from ATTR amyloidosis 1
- Biopsy tissue must be typed by immunohistochemistry and/or mass spectrometry 1
Additional Screening Tools
Biomarkers that support suspicion (but are not diagnostic):
- Disproportionately elevated NT-proBNP relative to degree of heart failure 1, 2
- Elevated troponin (T, I, or high-sensitivity) 1
- NT-proBNP elevates early in ATTR, even before cardiac symptoms in asymptomatic gene carriers 1
ECG findings (low sensitivity but useful when combined with echo):
- Low QRS voltage (seen in only ~25% of ATTR, ~50% of AL) 1, 3
- Pseudoinfarct pattern (Q waves without prior MI) - more common than low voltage 1
- Voltage-to-mass discordance (low QRS voltage relative to LV wall thickness) 1
Key Diagnostic Pitfalls to Avoid
Never rely on bone scintigraphy alone without monoclonal protein screening - this is the most common diagnostic error 1
Do not assume low voltage on ECG is required - it's present in only 25% of ATTR cases 1, 3
In patients with MGUS or positive monoclonal proteins, bone scan positivity does not confirm ATTR - biopsy is mandatory 1
Recognize that cardiac amyloidosis can present without heart failure symptoms - 37% of patients with echo evidence have no cardiac symptoms initially 4