How amyloidosis is tested on Step 1
Vignettes give a protein source (a plasma-cell clone, chronic inflammation, dialysis, aging) and an organ problem, and ask for the amyloid type, the stain, or the precursor protein.
All amyloid looks the same under the microscope — the precursor protein is what defines the type, its cause, and its treatment.
What amyloid is
Normally, misfolded proteins are refolded or degraded. When production outpaces clearance, or a mutation makes a protein prone to misfolding, the proteins aggregate into rigid, non-branching fibrils that deposit between cells and compress or replace normal tissue.
Amyloid stains pink with Congo red on light microscopy and shows apple-green birefringence under polarized light. Biopsy of abdominal fat pad, rectum, or the affected organ confirms the diagnosis; mass spectrometry identifies the protein.
Types of amyloidosis
Classify amyloidosis as systemic or localized, then by the precursor protein.
| Type | Precursor protein | Cause | Main features |
|---|---|---|---|
| AL (primary) | Immunoglobulin light chains (λ more than κ) | Plasma-cell dyscrasia, multiple myeloma | Kidney, heart, macroglossia, periorbital purpura, neuropathy |
| AA (secondary) | Serum amyloid A (acute-phase reactant) | RA, IBD, chronic infections (TB, osteomyelitis), familial Mediterranean fever | Kidney most often; also liver and spleen |
| ATTR hereditary | Mutant transthyretin | Autosomal dominant | Peripheral and autonomic neuropathy, cardiomyopathy |
| ATTR wild-type (senile) | Normal transthyretin | Age (usually men > 70) | Restrictive cardiomyopathy; carpal tunnel syndrome |
| Aβ2M | β2-microglobulin | Long-term dialysis (not filtered) | Carpal tunnel, joint and bone deposits |
| Localized: Aβ | Amyloid β (from APP) | Alzheimer disease (APP gene on chromosome 21) | Senile plaques, cerebral amyloid angiopathy (lobar hemorrhage) |
| Localized: A-Cal | Calcitonin | Medullary thyroid carcinoma | Amyloid stroma in the tumor |
| Localized: IAPP | Islet amyloid polypeptide (amylin) | Type 2 diabetes | Deposits in pancreatic islets |
| Localized: ANP | Atrial natriuretic peptide | Aging | Isolated atrial amyloidosis |
People with Down syndrome develop Alzheimer pathology early because they carry an extra copy of the APP gene.
Organ involvement
Systemic amyloid can deposit almost anywhere; prognosis is set mainly by the heart and kidneys.
| Organ | Effect |
|---|---|
| Kidney (most common) | Nephrotic syndrome with massive proteinuria; enlarged kidneys; progression to renal failure |
| Heart | Restrictive cardiomyopathy: thick walls on echo with low voltage on ECG, diastolic dysfunction, arrhythmias |
| Nerves | Peripheral neuropathy, autonomic dysfunction (orthostatic hypotension), carpal tunnel syndrome |
| GI tract and tongue | Macroglossia (AL), malabsorption |
| Liver and spleen | Hepatosplenomegaly |
| Blood vessels and skin | Easy bruising; periorbital purpura ("raccoon eyes") in AL |
Thick ventricular walls with low ECG voltage is a classic clue — muscle hypertrophy would raise the voltage.
Putting it together
Name the precursor first, then the organ involvement follows.
A 62-year-old man has fatigue, heavy proteinuria, an enlarged tongue, and bruising around both eyes. Serum protein electrophoresis shows a monoclonal λ light-chain spike. A fat-pad biopsy shows Congo red–positive deposits. Which protein forms the amyloid?
- A monoclonal light-chain spike indicates a plasma-cell clone.
- Macroglossia and periorbital purpura are characteristic of AL amyloidosis.
- Nephrotic-range proteinuria reflects renal deposition.
Answer. Immunoglobulin λ light chains — AL (primary) amyloidosis from a plasma-cell dyscrasia. Treatment targets the clone (e.g., bortezomib-based therapy).
- Rheumatoid arthritis + new nephrotic syndrome → AA amyloid.
- Older man, heart failure with thick walls and low-voltage ECG, bilateral carpal tunnel → wild-type ATTR.
- Years of hemodialysis + carpal tunnel → Aβ2M.
- Dementia, plaques, lobar hemorrhage → Aβ (Alzheimer, cerebral amyloid angiopathy).