Amyloidosis
A board-focused Step 1 lesson on amyloidosis covering the unifying β-pleated-sheet/Congo-red concept, the clinically important types (AL, AA, ATTR, Aβ2M), and the classic next-best-step logic for diagnosing and typing systemic and cardiac amyloid.
What amyloidosis is
Amyloidosis is a family of diseases defined by extracellular deposition of misfolded proteins that aggregate into insoluble β-pleated sheet fibrils. Although the deposits arise from more than 20 different precursor proteins, all amyloid shares the same physical signature: it stains with Congo red and shows pathognomonic apple-green birefringence under polarized light, and appears as rigid, non-branching 7.5–10 nm fibrils on electron microscopy. On H&E it is amorphous, eosinophilic, and hyaline. A universal (non-fibrillar) companion, serum amyloid P component, coats every type of deposit.
Amyloid accumulates in organ interstitium and vessel walls, physically stiffening tissue and causing progressive dysfunction — most importantly nephrotic-range proteinuria and a restrictive (infiltrative) cardiomyopathy. The board task is always three steps: (1) recognize the clinical fingerprint, (2) confirm amyloid with tissue biopsy + Congo red, and (3) type the precursor protein — because treatment depends entirely on which protein is depositing.
- Congo red → apple-green birefringence under polarized light = the single most tested fact
- Fibrils are β-pleated sheet, non-branching, 7.5–10 nm on EM
- Kidney is the most commonly involved organ → nephrotic syndrome is the usual presenting feature
- Cardiac amyloid: thick ventricular walls on echo but LOW-voltage QRS on ECG — this voltage–mass discordance is the classic clue
- AL buzzwords: macroglossia, periorbital 'raccoon-eye' / pinch purpura, easy bruising (acquired factor X deficiency — X adsorbs to fibrils)
- Least-invasive diagnosis: abdominal subcutaneous fat pad aspirate + Congo red
- Amyloid heart is unusually digoxin- and calcium-channel-blocker–sensitive (drugs bind fibrils → toxicity) → avoid these agents
- Screen every patient for a plasma-cell clone: serum + urine immunofixation and serum free light chains
The tested types
| Type | Precursor protein | Setting / cause | Key organs |
|---|---|---|---|
| AL (primary) | Ig light chain (λ>κ) | Plasma-cell dyscrasia, multiple myeloma / MGUS | Heart, kidney, tongue, nerve, GI |
| AA (secondary) | Serum amyloid A (acute-phase) | Chronic inflammation — RA, IBD, chronic infection (TB, osteomyelitis), FMF | Kidney, liver, spleen |
| ATTR – hereditary | Mutant transthyretin | Autosomal dominant (V122I common in African-Americans) | Peripheral/autonomic nerve, heart |
| ATTR – wild-type | Normal transthyretin | Senile, elderly men | Heart (HFpEF), carpal tunnel |
| Aβ2M | β2-microglobulin | Long-term hemodialysis | Joints, carpal tunnel |
| Aβ | β-amyloid (from APP) | Alzheimer, cerebral amyloid angiopathy | Brain, vessels |
| IAPP (amylin) | Islet amyloid polypeptide | Type 2 diabetes | Pancreatic islets |
| ACal | Calcitonin | Medullary thyroid carcinoma | Thyroid |
Vignette: A 62-year-old man has 6 months of fatigue, leg edema, and frothy urine. Exam: an enlarged tongue with dental indentations (macroglossia) and bruising around both eyes that appeared after he strained. Labs: 6 g/day proteinuria, normal-sized kidneys; echo shows thickened ventricles with a speckled/granular myocardium and preserved EF; ECG shows low-voltage QRS.
Diagnosis: Systemic AL amyloidosis — macroglossia + periorbital purpura are essentially specific for AL and are not seen in AA.
Next best step: Abdominal fat pad aspiration with Congo red (least invasive) to confirm amyloid. Then type it and hunt the clone: serum + urine immunofixation electrophoresis and serum free light-chain assay, plus bone marrow biopsy. Do not rely on SPEP alone — it misses free light chains; immunofixation + free light chains are required.
Treatment: anti-plasma-cell therapy — current first-line is a daratumumab + bortezomib–based regimen (dara-VCd) ± autologous stem cell transplant.
Vignette: A 78-year-old man has HFpEF, bilateral carpal tunnel syndrome treated years earlier, and lumbar spinal stenosis. Echo: symmetric LV wall thickening; ECG: low voltage despite thick walls; serum/urine immunofixation and free light chains are normal.
Diagnosis: Wild-type ATTR (senile) cardiac amyloidosis — the negative light-chain workup points away from AL, and carpal tunnel + spinal stenosis are classic ATTR red flags.
Next best step: 99mTc-pyrophosphate (PYP) scintigraphy — strong cardiac uptake confirms ATTR without biopsy — but this is only valid once AL has been excluded by negative immunofixation + free light chains (AL can also take up tracer).
Treatment: TTR stabilizer tafamidis; supportive heart-failure care. Avoid digoxin and calcium-channel blockers — they concentrate in amyloid fibrils and are poorly tolerated.
Name = precursor (the letters give it away):
- AL = amyloid Light chain → pLasma cells / myeLoma
- AA = serum Amyloid A → chronic inflammation (an Acute-phase protein)
- ATTR = TransThyRetin (senile or hereditary → heart/nerve)
- Aβ2M = β2-microglobulin → dialysis
AA (secondary) causes — chronic inflammation: RA, IBD, chronic infection (TB, osteomyelitis, bronchiectasis), FMF.
Cardiac pearls: Thick walls + low ECG voltage = amyloid until proven otherwise — and never reflexively give digoxin.
Work-up order (know the sequence):
- Suspect amyloid → tissue biopsy (fat pad, rectum, or affected organ) → Congo red confirms deposits
- Type the amyloid — mass spectrometry is the gold standard and dictates therapy
- Screen everyone for an AL clone: serum + urine immunofixation and serum free light chains
- Cardiac: low-voltage ECG, echo (thick walls), cardiac MRI (diffuse late gadolinium enhancement), then PYP scan for ATTR after excluding AL
Management by type:
- AL → treat the plasma-cell clone (daratumumab-bortezomib–based, autologous SCT)
- AA → treat the underlying inflammatory disease; colchicine prevents AA in FMF
- ATTR → tafamidis (stabilizer); gene silencers (patisiran); liver transplant for hereditary disease
- Aβ2M → renal transplant / high-flux dialysis membranes
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