What are the diagnostic criteria for amyloidosis?

Diagnostic Criteria for Amyloidosis

The definitive diagnosis of amyloidosis requires tissue biopsy showing amyloid deposits with Congo red staining demonstrating apple-green birefringence under polarized light, followed by typing to determine the specific amyloid protein. 1

Histological Diagnosis

Endomyocardial Biopsy (Gold Standard)

• Positive for amyloidosis with Congo red staining showing apple-green birefringence under polarized light
• Typing by immunohistochemistry and/or mass spectrometry at specialized centers 2

Extracardiac Biopsy

For ATTR amyloidosis:

• Extracardiac biopsy proven ATTR amyloidosis AND
• Typical cardiac imaging features 2

For AL amyloidosis:

• Extracardiac biopsy proven AL amyloidosis AND
• Typical cardiac imaging features OR
• Abnormal cardiac biomarkers (abnormal age-adjusted NT-proBNP or abnormal Troponin) with other causes excluded 2

Non-Biopsy Diagnostic Pathway for ATTR Cardiac Amyloidosis

A non-invasive diagnosis of ATTR cardiac amyloidosis can be made when all of the following criteria are met:

1. Grade 2 or 3 myocardial uptake on 99mTc-PYP, DPD, or HMDP bone scintigraphy AND
2. Absence of a clonal plasma cell process (normal serum free light chains and negative serum/urine immunofixation) AND
3. Typical cardiac imaging features 2, 1

Typical Imaging Features of Cardiac Amyloidosis

Echocardiography

• LV wall thickness > 12 mm
• Relative apical sparing of global longitudinal strain ratio > 1
• ≥ Grade 2 diastolic dysfunction
• Granular sparkling appearance of myocardium
• Biatrial enlargement 2, 1

Cardiac MRI

• LV wall thickness > upper limit of normal for sex
• Global extracellular volume > 0.40
• Diffuse late gadolinium enhancement
• Abnormal gadolinium kinetics (myocardial nulling prior to blood pool nulling) 2, 1

PET Imaging

• Target to background (LV myocardium to blood pool) ratio >1.5
• Retention index >0.030 min-1 2

Laboratory Testing

For AL Amyloidosis

• Serum and urine immunofixation electrophoresis
• Serum free light chain assay
• Bone marrow biopsy with Congo red staining 1

For ATTR Amyloidosis

• TTR gene sequencing to differentiate hereditary variant from wild-type ATTR
• Negative serum and urine tests for monoclonal proteins 1

Cardiac Biomarkers

• NT-proBNP (elevated >332 ng/L has >99% sensitivity for cardiac involvement)
• Troponin T/I/high-sensitivity troponin 2, 1

Clinical Red Flags Suggesting Amyloidosis

• Heart failure with preserved ejection fraction
• Intolerance to ACE inhibitors or beta blockers
• Bilateral carpal tunnel syndrome
• Lumbar spinal stenosis
• Biceps tendon rupture
• Unexplained peripheral neuropathy 1
• Low-flow aortic stenosis 2

Common Diagnostic Pitfalls

1. Relying solely on echocardiography without confirmatory testing
2. Failing to exclude monoclonal gammopathy before diagnosing ATTR by bone scan
3. Misinterpreting low-grade uptake on bone scintigraphy
4. Delaying diagnosis due to non-specific symptoms 1
5. Not considering amyloidosis in patients with proteinuria, cardiomyopathy, hepatomegaly with mildly abnormal liver tests, peripheral/autonomic neuropathy, and GI symptoms 3

Tissue Sampling Sites

When amyloidosis is suspected, biopsies can be obtained from:

• Affected organ (most definitive)
• Minor salivary gland
• Abdominal fat pad aspiration (less invasive)
• Bone marrow
• Rectal mucosa
• GI tract (endoscopic biopsy of stomach, duodenum, or colon) 1, 4, 3

The diagnostic approach should be tailored based on the suspected type of amyloidosis and organ involvement, with the goal of obtaining a definitive diagnosis with the least invasive method possible.