What diagnostic exams are used to diagnose cardiac amyloidosis?

Diagnostic Exams for Cardiac Amyloidosis

Cardiac amyloidosis diagnosis relies on a multimodality imaging approach combining echocardiography, cardiac magnetic resonance (CMR), and nuclear scintigraphy with bone-avid tracers, supplemented by tissue biopsy when needed and laboratory testing to determine amyloid subtype. 1

Histological Diagnosis (Gold Standard)

Endomyocardial Biopsy

• Endomyocardial biopsy with Congo red staining showing apple-green birefringence under polarized light remains the definitive diagnostic test for cardiac amyloidosis. 1, 2
• Amyloid typing must be performed via immunohistochemistry and/or mass spectrometry at specialized centers to differentiate AL, ATTR, and other subtypes. 1
• Mass spectrometry-based analysis (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity. 2

Extracardiac Biopsy Options

• Alternative biopsy sites include abdominal fat pad, gingiva, rectum, bone marrow, liver, and kidney. 1, 2
• Fine-needle aspiration of abdominal fat has 84% sensitivity for AL amyloidosis but only 45% for ATTRv and 15% for ATTRwt. 2
• Bone marrow biopsy has approximately 69% sensitivity for detecting amyloid deposits in systemic AL amyloidosis. 2

Non-Invasive Imaging Modalities

Echocardiography

• Echocardiography should be performed in all patients suspected of having cardiac amyloidosis or patients with systemic amyloidosis and heart failure. 1
• Typical echocardiographic features include: 1
  • LV wall thickness >12 mm
  • Relative apical sparing of global longitudinal strain ratio (average apical LS/average of combined mid+basal LS >1)
  • ≥Grade 2 diastolic dysfunction
• Low QRS voltage on ECG in the presence of ventricular wall thickening is suggestive but not diagnostic. 1, 2

Nuclear Scintigraphy (Bone-Avid Tracers)

• For ATTR cardiac amyloidosis, Grade 2 or 3 myocardial uptake on 99mTc-PYP, DPD, or HMDP scintigraphy combined with absence of a clonal plasma cell process and typical cardiac imaging features allows non-invasive diagnosis without biopsy. 1, 2
• This approach is specific for ATTR amyloidosis and cannot be used for AL amyloidosis diagnosis. 1
• Technetium Tc 99m bone tracers can help distinguish between AL and TTR amyloidosis. 1

Cardiac Magnetic Resonance (CMR)

• CMR provides detailed tissue characterization with typical features including: 1, 2
  • LV wall thickness > upper limit of normal for sex on SSFP cine CMR
  • Global extracellular volume (ECV) >0.40
  • Diffuse late gadolinium enhancement (LGE)
  • Abnormal gadolinium kinetics (myocardial nulling prior to blood pool nulling)
• Gadolinium use is contraindicated in patients with estimated GFR <30 ml/min/1.73 m² due to risk of nephrogenic systemic fibrosis. 1, 2

Laboratory Testing for Subtype Determination

For AL Amyloidosis

• Laboratory evaluation must include serum free light chain (sFLC) assay, serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE). 2
• The presence of serum or urine monoclonal gammopathy suggests AL amyloidosis but does not establish the diagnosis alone. 1
• AL cardiac amyloidosis requires both extracardiac biopsy-proven AL amyloidosis AND either typical cardiac imaging features OR abnormal cardiac biomarkers (abnormal age-adjusted NT-pro BNP or abnormal Troponin T/I/Hs-Troponin with all other causes excluded). 1

For ATTR Amyloidosis

• If TTR amyloid is detected from a biopsy specimen, DNA mutational analysis should be used to differentiate between wild-type (senile) and hereditary amyloidosis. 1
• ATTR cardiac amyloidosis requires extracardiac biopsy-proven ATTR amyloidosis AND typical cardiac imaging features. 1

Cardiac Biomarkers

• Natriuretic peptides (BNP/NT-proBNP) have 93% sensitivity and 90% specificity for cardiac involvement. 1
• Elevated BNP levels predict development of clinical cardiac involvement and correlate with prognosis and mortality. 1
• Troponin elevation (T/I/high-sensitivity) with all other causes excluded supports cardiac involvement in AL amyloidosis. 1

Clinical Red Flags That Should Prompt Diagnostic Workup

• Unexplained bilateral carpal tunnel syndrome (without rheumatoid arthritis or trauma). 1, 2
• Unexplained biceps tendon rupture (without trauma). 1, 2
• Unexplained peripheral sensorimotor neuropathy. 1, 2
• Known or suspected familial amyloidosis. 1
• Restrictive cardiomyopathy, macroglossia, unexplained proteinuria, hepatomegaly, peripheral neuropathy with autonomic features, and acquired factor X deficiency with coagulopathy. 2

Critical Diagnostic Algorithm

For suspected ATTR cardiac amyloidosis:

1. Obtain 99mTc-PYP/DPD/HMDP scintigraphy
2. If Grade 2 or 3 myocardial uptake present, perform serum FLCs and serum/urine immunofixation to exclude clonal plasma cell process
3. Confirm typical cardiac imaging features on echo or CMR
4. If all three criteria met, ATTR cardiac amyloidosis is diagnosed without biopsy 1

For suspected AL cardiac amyloidosis:

• Biopsy (cardiac or extracardiac) is required for definitive diagnosis
• Must demonstrate both amyloid deposits AND evidence of plasma cell dyscrasia 2
• Typical cardiac imaging features or abnormal cardiac biomarkers support diagnosis when extracardiac biopsy is positive 1

Common Pitfalls to Avoid

• Misdiagnosing amyloid type leads to inappropriate treatment and patient harm. 2
• Not all monoclonal gammopathies indicate AL amyloidosis; relying solely on clinical features without histological confirmation can lead to misdiagnosis. 2
• Collaboration with a hematologist is essential when monoclonal protein testing is abnormal to determine if findings represent spurious results, MGUS, AL amyloidosis, or multiple myeloma. 2