Diagnostic Criteria for Amyloidosis

Histological Diagnosis

The American College of Cardiology recommends endomyocardial biopsy with Congo red staining showing apple-green birefringence under polarized light as the gold standard for diagnosing cardiac amyloidosis 1
Alternative biopsy sites include abdominal fat pad, gingiva, rectum, bone marrow, liver, and kidney, as suggested by the American Heart Association 2
Fine-needle aspiration of abdominal fat is a simple, less-invasive procedure with excellent sensitivity for AL amyloidosis (84%) but lower sensitivity for ATTR variants (45% for ATTRv-CM; 15% for ATTRwt-CM), according to the Journal of the American College of Cardiology 3, 4
Bone marrow biopsy has approximately 69% sensitivity for detecting amyloid deposits in systemic AL amyloidosis, as reported by the Journal of the American College of Cardiology 3

Mass spectrometry-based analysis (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity, as recommended by the Journal of the American College of Cardiology 3, 5
Immunohistochemistry or immunogold immunoelectron microscopy can be performed in experienced centers but are less reliable than mass spectrometry, according to the Journal of the American College of Cardiology 3, 5

Diagnosis of AL amyloidosis requires both demonstration of tissue amyloid deposits AND evidence of a plasma cell dyscrasia, as stated by the Journal of the American College of Cardiology 3
Laboratory evaluation for AL amyloidosis should include serum free light chain (sFLC) assay, serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE), as recommended by the Journal of the American College of Cardiology 3, 5
ATTR amyloidosis can be diagnosed non-invasively when specific criteria are met, including grade 2 or 3 myocardial uptake on 99mTc-PYP/DPD/HMDP scintigraphy, absence of a clonal plasma cell process, and typical cardiac imaging features, as suggested by the American Heart Association 1

Typical cardiac imaging features supporting amyloidosis diagnosis include LV wall thickness >12 mm, relative apical sparing of global longitudinal strain ratio >1, and ≥Grade 2 diastolic dysfunction on echocardiography, as recommended by the American Heart Association 1
Cardiac MRI criteria include LV wall thickness > upper limit of normal for sex, global extracellular volume (ECV) >0.40, diffuse late gadolinium enhancement (LGE), and abnormal gadolinium kinetics, as suggested by the American Heart Association 1

Unexplained bilateral carpal tunnel syndrome, unexplained biceps tendon rupture, restrictive cardiomyopathy, macroglossia, unexplained proteinuria, hepatomegaly, peripheral neuropathy with autonomic features, and acquired factor X deficiency with coagulopathy are clinical red flags for amyloidosis, as reported by the Journal of the American College of Cardiology 1, 3
Low QRS voltage on ECG in presence of ventricular wall thickening is also a clinical red flag for amyloidosis, as suggested by the American Heart Association 2

Misdiagnosing amyloid type can lead to inappropriate treatment and patient harm, as warned by the American College of Cardiology 5
Not all monoclonal gammopathies indicate AL amyloidosis, and relying solely on clinical features without histological confirmation can lead to misdiagnosis, as cautioned by the Journal of the American College of Cardiology 3, 5
Gadolinium-based contrast agents should be avoided in patients with estimated GFR <30 ml/min/1.73 m² due to risk of nephrogenic systemic fibrosis, as advised by the American Heart Association 1

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, as recommended by the Journal of the American College of Cardiology 3, 5
Systematic evaluation to identify all affected organs is critical for determining treatment strategies and prognosis, as suggested by the American College of Cardiology 5