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

Workup for Cardiac Amyloidosis

Begin with echocardiography as first-line imaging, simultaneous monoclonal protein screening (serum and urine immunofixation plus free light chains), ECG, and cardiac biomarkers (NT-proBNP and troponin), then proceed to bone scintigraphy if monoclonal protein is negative or cardiac MRI if echocardiography is equivocal. 1, 2

Clinical Red Flags That Should Trigger Workup

Suspect cardiac amyloidosis when you encounter these specific patterns:

• LV wall thickness ≥12-14 mm with low QRS voltage on ECG (voltage-to-mass discordance) 1, 2
• Heart failure with preserved ejection fraction (HFpEF) with unexplained LV hypertrophy 1, 2
• Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma 1, 2
• Lumbar spinal stenosis or spontaneous biceps tendon rupture 1, 2
• Autonomic or sensory polyneuropathy (unexplained) 1, 2
• Aortic stenosis with unexplained LV hypertrophy 1
• Macroglossia or periorbital purpura (highly specific for AL amyloidosis) 2

Step 1: Initial Diagnostic Tests (Perform Simultaneously)

Monoclonal Protein Screening

Order all three tests together—do not wait for sequential results: 2

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

Critical timing: Delays beyond 6 weeks are associated with increased early mortality 2

Cardiac Biomarkers

• NT-proBNP (disproportionately elevated relative to heart failure severity; 93% sensitivity, 90% specificity) 2
• Troponin (T, I, or high-sensitivity) 1, 2

ECG Findings to Document

• Low QRS voltage despite increased wall thickness 1, 2
• Pseudoinfarct pattern 1, 2

Echocardiography (First-Line Cardiac Imaging)

Key structural findings: 1, 2

• LV wall thickness ≥12 mm with small cavity size 1
• Biatrial enlargement disproportionate to ventricular dysfunction 1
• Thickened cardiac valves without significant stenosis 1
• Increased atrial septal thickness 1
• Pericardial effusion (may be present) 1

Key functional findings: 1

• Restrictive transmitral Doppler filling pattern 1
• Apical sparing pattern on longitudinal strain (apical-to-basal strain ratio >2.1 is highly suggestive) 1, 2
• LV ejection fraction-to-strain ratio >4 1

Important limitation: Echocardiography cannot distinguish AL from ATTR amyloidosis 1

Step 2: Divergent Pathways Based on Monoclonal Protein Results

If Monoclonal Protein is DETECTED → Suspect AL Amyloidosis

Proceed with: 2

• Abdominal fat pad aspiration (first-line surrogate biopsy; 84% sensitivity for AL cardiac amyloidosis) 2
• Bone marrow biopsy (required to demonstrate clonal plasma cells and exclude multiple myeloma or B-cell lymphoproliferative disorders) 2

If Monoclonal Protein is NEGATIVE → Pursue ATTR Amyloidosis

Proceed immediately to bone scintigraphy: 1, 2

• Use 99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP tracers 1, 2
• Grade 2-3 myocardial uptake in the absence of monoclonal protein is diagnostic for ATTR cardiac amyloidosis without need for biopsy 1, 2

This noninvasive diagnostic pathway has transformed ATTR diagnosis and eliminated the need for endomyocardial biopsy in most cases 3

Step 3: Cardiac MRI (When Indicated)

Reserve cardiac MRI for cases where echocardiography shows suggestive but not definitive findings: 1, 2

Diagnostic MRI Features

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) distributed circumferentially (88% sensitivity, 100% specificity for AL amyloidosis) 1, 2
• Myocardial nulling before blood pool nulling on inversion recovery sequences (71-100% sensitivity, 70-100% specificity) 1
• Elevated native T1 values (>1020-1044 ms depending on technique) 1, 2
• Elevated extracellular volume (ECV >0.40) 1

When MRI Adds Most Value

• Tissue characterization to differentiate cardiac amyloidosis from hypertrophic cardiomyopathy or hypertensive heart disease 1
• Prognostication (LGE presence and extent predict mortality with OR 2.73-19.84 depending on pattern) 1

Caveat: The 2016 AHA statement notes uncertainty regarding the accuracy and utility of cardiac MRI for diagnosis, though it acknowledges MRI helps identify extent of cardiac involvement 1

Step 4: Genetic Testing (For All ATTR Cases)

Perform TTR gene sequencing for all patients with confirmed ATTR amyloidosis to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt): 4

Why This Matters

• Determines prognosis 4
• Guides liver transplantation eligibility 4
• Enables family screening and cascade testing 4
• Determines eligibility for specific therapies including tafamidis 4

High-Risk Populations Requiring Genetic Testing

• African-Americans (higher prevalence of specific TTR mutations) 4
• Patients with peripheral neuropathy 4

Family Screening Protocol

• All first-degree relatives of patients with confirmed ATTRv should undergo TTR gene sequencing 4
• Begin surveillance approximately 10 years before the age of disease onset in affected family members 4
• Annual assessments include ECG, echocardiogram with strain imaging, cardiac biomarkers, and neurologic examination 4

Common Pitfalls to Avoid

• Do not order monoclonal protein tests sequentially—order all three (SIFE, UIFE, sFLC) simultaneously to avoid diagnostic delays 2
• Do not skip bone scintigraphy in monoclonal protein-negative cases—this is now the diagnostic test of choice for ATTR and eliminates need for biopsy in most patients 1, 2
• Do not rely on echocardiography alone to distinguish AL from ATTR—further testing is always required 1
• Do not perform cardiac MRI first—echocardiography should always be the initial cardiac imaging modality 1
• Do not forget genetic testing in confirmed ATTR cases—this is essential for family counseling and treatment decisions 4