Learning Objective
Describe the pathogenesis, organ-specific manifestations, diagnostic features, and major types of amyloidosis, and associate each amyloid protein with its clinical condition.
Definition & Pathogenesis
- Amyloidosis is characterized by extracellular deposition of misfolded proteins arranged in a β-pleated sheet configuration
- These insoluble fibrils disrupt normal tissue architecture, leading to cell injury and apoptosis
- Clinical manifestations depend on the organ involved
Organ-Specific Manifestations
- Renal: Nephrotic syndrome (most common presentation)
- Cardiac: Restrictive cardiomyopathy → diastolic dysfunction
- Gastrointestinal: Hepatosplenomegaly
- Neurologic: Peripheral neuropathy
- Musculoskeletal:
- Muscle enlargement (eg, macroglossia)
- Carpal tunnel syndrome
- Skin: Waxy thickening, easy bruising
Diagnosis
- Congo red stain:
- Red/orange on nonpolarized light
- Apple-green birefringence under polarized light (pathognomonic)
- Hematoxylin & eosin (H&E):
- Amorphous, eosinophilic (pink) extracellular deposits
USMLE Pearl: Apple-green birefringence on Congo red staining = amyloid
Common Types of Amyloidosis
Systemic Amyloidosis
| Type | Fibril Protein | Key Associations |
|---|---|---|
| Primary (AL) | Immunoglobulin light chains | Plasma cell dyscrasias (eg, multiple myeloma) |
| Secondary (AA) | Serum amyloid A | Chronic inflammatory conditions (eg, rheumatoid arthritis, IBD, familial Mediterranean fever, chronic infections) |
| Transthyretin (ATTR) | Transthyretin | Wild-type: aging, cardiomyopathy Mutated: familial amyloid polyneuropathy ± cardiomyopathy |
| Dialysis-related | β2-microglobulin | ESRD on long-term dialysis |
Localized Amyloidosis
| Condition | Amyloid Protein | Notes |
|---|---|---|
| Alzheimer disease | β-amyloid | Derived from the amyloid precursor protein (APP) |
| Isolated atrial amyloidosis | Atrial natriuretic peptide (ANP) | Common with aging, ↑ the risk of atrial fibrillation |
| Type 2 diabetes mellitus | Islet amyloid polypeptide (amylin) | Deposition in pancreatic islets |
| Medullary thyroid carcinoma | Calcitonin | Secreted by tumor cells |
High-Yield USMLE Step 1 Summary
- β-pleated sheets + Congo red = amyloid
- AL → plasma cell disorders
- AA → chronic inflammation
- ATTR → heart ± nerves
- β2-microglobulin → long-term dialysis
- Macroglossia + restrictive cardiomyopathy → think amyloidosis
