How do I diagnose cardiac amyloidosis?

How to Diagnose Cardiac Amyloidosis

The diagnosis of cardiac amyloidosis requires a structured algorithmic approach: first, recognize clinical red flags; second, perform echocardiography to identify typical features; third, obtain monoclonal protein screening (serum free light chains, serum and urine immunofixation) to differentiate AL from ATTR subtypes; fourth, use nuclear scintigraphy (99mTc-PYP/DPD/HMDP) for non-invasive ATTR diagnosis when monoclonal proteins are absent, or proceed to tissue biopsy when monoclonal proteins are present or imaging is equivocal—with mass spectrometry being the gold standard for amyloid typing. 1, 2

Step 1: Recognize Clinical Red Flags

Suspect cardiac amyloidosis when patients present with specific cardiac and extracardiac features that should immediately trigger diagnostic evaluation:

Cardiac Red Flags

• Heart failure with preserved ejection fraction (HFpEF) with unexplained left ventricular wall thickness ≥12 mm is the most common presentation 1, 2
• Low QRS voltage on ECG despite ventricular wall thickening (voltage-to-mass discordance) occurs in approximately 50% of patients and is highly specific 1, 2, 3
• Pseudoinfarct pattern in precordial leads, atrial fibrillation, or atrioventricular conduction abnormalities 1
• Disproportionately elevated NT-proBNP or BNP relative to the degree of heart failure (sensitivity 93%, specificity 90%) 1, 2

Extracardiac Red Flags

• Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma is a critical clue, particularly for ATTR amyloidosis 1, 2, 3
• Unexplained biceps tendon rupture without trauma 1, 3
• Macroglossia or periorbital ecchymoses (periorbital purpura/"raccoon eyes") strongly suggest AL amyloidosis 1, 3
• Unexplained proteinuria or nephrotic syndrome 3
• Peripheral neuropathy with autonomic features 3
• Acquired factor X deficiency with coagulopathy 1, 3

Step 2: Perform Echocardiography as First-Line Imaging

Echocardiography must be performed in all patients with suspected cardiac amyloidosis or systemic amyloidosis with heart failure 1, 2. This is the initial imaging modality that guides subsequent diagnostic steps.

Key Echocardiographic Features

• LV wall thickness >12 mm with small cavity size and normal or preserved ejection fraction in early stages 1, 2
• Relative apical sparing of global longitudinal strain with ratio >1 (average apical LS/average of combined mid+basal LS) is highly specific 1, 3
• Grade 2 or higher diastolic dysfunction with restrictive filling pattern 1
• Biatrial enlargement due to elevated filling pressures 1
• Granular sparkling appearance of the myocardium (less specific, older finding) 1
• Pericardial effusion may be present 1

Step 3: Obtain Monoclonal Protein Screening

This step is critical to differentiate AL from ATTR amyloidosis and must be performed before proceeding with nuclear imaging 1, 4. The absence of monoclonal proteins is required for non-invasive ATTR diagnosis.

Required Tests (All Three Simultaneously)

• Serum free light chain (sFLC) assay with kappa/lambda ratio 1, 4, 3
• Serum immunofixation electrophoresis (SIFE) 1, 4, 3
• Urine immunofixation electrophoresis (UIFE) 1, 4, 3

Critical Pitfall: Never rely on serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) alone, as these have lower sensitivity for detecting the low levels of monoclonal protein typical in AL amyloidosis 1, 4. An abnormal free light chain ratio is defined as <0.26 or >1.65 (Binding Site assay) in patients with normal renal function 1.

Step 4: Proceed Based on Monoclonal Protein Results

If Monoclonal Proteins Are ABSENT: Nuclear Scintigraphy for ATTR Diagnosis

99mTc-PYP/DPD/HMDP bone scintigraphy allows non-invasive diagnosis of ATTR cardiac amyloidosis without biopsy when specific criteria are met 1, 2.

Diagnostic Criteria for ATTR (Non-Invasive)

ATTR cardiac amyloidosis is diagnosed when ALL three criteria are present:

1. Grade 2 or 3 myocardial uptake of radiotracer (visual score equal to or greater than bone uptake) 1, 3
2. Absence of monoclonal plasma cell process confirmed by negative sFLC, SIFE, and UIFE 1, 2
3. Typical cardiac imaging features on echo or cardiac MRI (as defined above) 1, 2

Critical Pitfall: A positive nuclear scan alone does not confirm ATTR—you must document absence of monoclonal proteins to avoid misdiagnosing AL amyloidosis as ATTR, which would lead to inappropriate treatment and patient harm 2, 3.

Next Step After ATTR Diagnosis

Perform TTR gene sequencing to differentiate hereditary (ATTRv) from wild-type (ATTRwt) amyloidosis, as this determines treatment strategy and family screening needs 1.

If Monoclonal Proteins Are PRESENT: Pursue AL Amyloidosis Diagnosis

The diagnosis of AL amyloidosis requires BOTH demonstration of tissue amyloid deposits AND evidence of plasma cell dyscrasia 1, 3.

Tissue Biopsy Options (Choose Most Accessible)

• Abdominal fat pad aspiration: Least invasive, 84% sensitivity for AL cardiac amyloidosis, can be performed in office 1, 3
• Bone marrow biopsy: 69% sensitivity for systemic AL amyloidosis, also evaluates plasma cell burden 1, 3
• Endomyocardial biopsy: Definitive for cardiac involvement, reserved for equivocal cases or when concomitant AL and ATTR suspected 1, 3
• Other affected organ biopsy (kidney, liver) if clinically indicated 1

If surrogate site biopsy (fat pad or bone marrow) is negative but clinical suspicion remains high, proceed to endomyocardial biopsy 1.

Confirm Amyloid Deposits

• Congo red staining showing apple-green birefringence under polarized light confirms amyloid presence 1, 3
• Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1, 4, 3

Critical Pitfall: Over 10% of patients with monoclonal gammopathy can have ATTR deposits, so mass spectrometry typing is mandatory—never rely on immunohistochemistry alone 1.

Confirm Plasma Cell Dyscrasia

• Bone marrow biopsy showing clonal proliferation of lambda or kappa-producing plasma cells 1
• Exclude multiple myeloma or B-cell lymphoproliferative disorders 1, 3

Step 5: Use Cardiac MRI for Additional Characterization

Cardiac MRI should be performed when echocardiography shows suggestive but not definitive findings, or to assess extent of cardiac involvement 1, 2.

Diagnostic Cardiac MRI Features

• LV wall thickness > upper limit of normal for sex on SSFP cine imaging 1, 3
• Global extracellular volume (ECV) >0.40 indicating extensive amyloid infiltration 1, 2, 3
• Diffuse late gadolinium enhancement (LGE), typically starting in subendocardium of basal LV wall with circumferential pattern 1, 3
• Abnormal gadolinium kinetics with myocardial nulling occurring before blood pool nulling 1

Contraindication: Gadolinium is contraindicated in patients with estimated GFR <30 mL/min/1.73 m² due to risk of nephrogenic systemic fibrosis 1, 3.

Step 6: Endomyocardial Biopsy When Needed

Endomyocardial biopsy remains the definitive diagnostic test and should be performed when:

• Non-invasive methods are equivocal 1, 2, 3
• Monoclonal gammopathy is present with positive nuclear scan (suggesting possible dual pathology) 1
• Precise tissue diagnosis is required for treatment decisions 1, 2

The biopsy provides Congo red staining confirmation and tissue for mass spectrometry typing 1, 3.

Common Diagnostic Pitfalls to Avoid

• Never assume ATTR based on nuclear imaging alone—must confirm absence of monoclonal proteins to avoid missing AL amyloidosis 2, 3
• Not all monoclonal gammopathies indicate AL amyloidosis—monoclonal gammopathy of undetermined significance (MGUS) is common in elderly patients and may coexist with ATTR 1, 3
• Do not use digoxin or calcium channel blockers in suspected cardiac amyloidosis, as these drugs bind to amyloid fibrils causing toxicity and exaggerated hypotensive responses even at therapeutic levels 2
• Facial droop may not be stroke—consider soft tissue infiltration with macroglossia or periorbital purpura in AL amyloidosis 4, 3
• Low sensitivity of surrogate site biopsies for ATTR: Fat pad aspiration has only 45% sensitivity for ATTRv and 15% for ATTRwt, so negative results do not exclude diagnosis 1, 3

Multidisciplinary Collaboration

Collaborate with hematology when monoclonal protein testing is abnormal to determine if findings represent spurious results, MGUS, AL amyloidosis, or multiple myeloma 3. This collaboration is essential for appropriate treatment planning and avoiding misdiagnosis 1, 3.