What are the criteria for diagnosing amyloidosis (a condition characterized by the deposition of amyloid, a protein, in various tissues)?

Diagnostic Criteria for Amyloidosis

The definitive diagnosis of amyloidosis requires histological confirmation with Congo red staining showing characteristic apple-green birefringence under polarized light, followed by typing of the amyloid protein to determine the specific subtype. 1

Histological Diagnosis

Tissue Biopsy

• Endomyocardial biopsy with Congo red staining showing apple-green birefringence under polarized light is the gold standard for diagnosing cardiac amyloidosis 1
• Alternative biopsy sites include abdominal fat pad, gingiva, rectum, bone marrow, liver, and kidney 1
• 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) 1
• Bone marrow biopsy has approximately 69% sensitivity for detecting amyloid deposits in systemic AL amyloidosis 1

Amyloid Typing

• After confirming amyloid deposits, determining the precursor protein type is essential as it dictates treatment strategy and prognosis 2
• Mass spectrometry-based analysis (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1, 2
• Immunohistochemistry or immunogold immunoelectron microscopy can be performed in experienced centers but are less reliable than mass spectrometry 1, 2
• If LC-MS/MS is not immediately available, samples should be transferred to an experienced reference laboratory for definitive typing 2

Subtype-Specific Diagnostic Criteria

AL Amyloidosis

• Diagnosis requires both demonstration of tissue amyloid deposits AND evidence of a plasma cell dyscrasia 1
• Laboratory evaluation should include:
  • Serum free light chain (sFLC) assay 1, 2
  • Serum immunofixation electrophoresis (SIFE) 1, 2
  • Urine immunofixation electrophoresis (UIFE) 1, 2
  • Bone marrow biopsy to demonstrate clonal proliferation of plasma cells 2
• Serum/urine protein electrophoresis (SPEP/UPEP) alone is insufficient due to lower sensitivity 2

ATTR Amyloidosis

• Can be diagnosed non-invasively when the following criteria are met:
  1. Grade 2 or 3 myocardial uptake on 99mTc-PYP/DPD/HMDP scintigraphy AND
  2. Absence of a clonal plasma cell process (normal serum FLCs and negative serum/urine immunofixation) AND
  3. Typical cardiac imaging features 1
• DNA mutational analysis should be performed to differentiate between wild-type (senile) and hereditary (variant) ATTR amyloidosis 1, 2

Cardiac Imaging Criteria

Typical cardiac imaging features supporting amyloidosis diagnosis include:

Echocardiography

• LV wall thickness >12 mm 1
• Relative apical sparing of global longitudinal strain ratio >1 1
• ≥Grade 2 diastolic dysfunction 1

Cardiac MRI

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

Clinical Red Flags for Amyloidosis

• Unexplained bilateral carpal tunnel syndrome (in absence of rheumatoid arthritis or trauma) 1
• Unexplained biceps tendon rupture (in absence of trauma) 1
• Restrictive cardiomyopathy 1
• Macroglossia 1
• Unexplained proteinuria 1
• Hepatomegaly 1
• Peripheral neuropathy with autonomic features 1
• Acquired factor X deficiency with coagulopathy 1
• Low QRS voltage on ECG in presence of ventricular wall thickening 1

Common Pitfalls to Avoid

• Misdiagnosing amyloid type can lead to inappropriate treatment and patient harm 2
• Not all monoclonal gammopathies indicate AL amyloidosis - over 10% of patients with monoclonal gammopathy can have ATTR deposits 1, 2
• Relying solely on clinical features without histological confirmation can lead to misdiagnosis 2
• In cases of suspected concomitant AL and ATTR cardiac amyloidosis, cardiac biopsy is preferred to definitively establish cardiac pathology 1
• 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 1

Multidisciplinary Approach

• 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 1, 2
• Systematic evaluation to identify all affected organs is critical for determining treatment strategies and prognosis 2