Step-by-step flowchart: Amyloidosis

Amyloidosis is one of those Step questions where pattern recognition wins: an “extracellular, eosinophilic, amorphous” deposit on H&E plus Congo red–positive “apple‑green birefringence” on polarized light. The trick is quickly identifying which amyloid, what organ is failing, and what underlying disease is driving it.

The 10-second definition (one-liner)

Amyloidosis = misfolded proteins deposited extracellularly as $\beta$ ‑pleated sheets → organ dysfunction + Congo red apple‑green birefringence.

Visual mnemonic: “APPLE-GREEN = AMYLOID” + the A table

Think: Amyloid → Apple‑green.
Then remember the big amyloid types as A‑words:

AL (light chains)
AA (acute-phase reactant)
A $\beta$ (Alzheimer)
ATTR (transthyretin)
A $\beta_2$ M (beta‑2 microglobulin; dialysis)

Step-by-step flowchart (USMLE-style)

Step 1: Suspect amyloid clinically/histologically

Clues:

Nephrotic syndrome (proteinuria, edema) with bland urine sediment
Restrictive cardiomyopathy or arrhythmias
Hepatosplenomegaly
Peripheral/autonomic neuropathy
Macroglossia, periorbital purpura (classic for AL)

Path clue (buzzwords): Extracellular, eosinophilic, amorphous deposits

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Step 2: Confirm it’s amyloid

Best initial tissue test (high-yield):

Congo red stain → apple‑green birefringence under polarized light
Due to $\beta$ ‑pleated sheet structure

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Step 3: Identify the amyloid type (this is where points are)

Use the clinical context:

A) Plasma cell dyscrasia?

Multiple myeloma, MGUS, unexplained macroglossia, nephrotic syndrome
✅ AL (Primary) amyloidosis
Protein: Ig light chains (often $\lambda$ )
Associated finding: Bence Jones proteins, M-spike, plasmacytosis

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B) Chronic inflammatory disease?

RA, ankylosing spondylitis, IBD, chronic osteomyelitis, TB/bronchiectasis
✅ AA (Secondary) amyloidosis
Protein: Serum amyloid A (SAA) (acute-phase reactant from liver; IL‑1/IL‑6 driven)

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C) Elderly with cardiomyopathy ± neuropathy?

✅ ATTR amyloidosis

Protein: Transthyretin
Two common testable forms:
- Wild-type ATTR (senile systemic amyloid) → restrictive cardiomyopathy in older adults
- Mutant ATTR → familial amyloid polyneuropathy/cardiomyopathy

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D) Long-term hemodialysis patient?

✅ A $\beta_2$ M amyloidosis

Protein: $\beta_2$ ‑microglobulin
Classically deposits in joints → arthralgias, carpal tunnel, shoulder pain
Mechanism: not cleared well by dialysis membranes (esp older ones)

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E) Dementia / Alzheimer disease?

✅ A $\beta$ amyloid

Protein: A $\beta$ derived from APP (amyloid precursor protein)
Location: neuritic plaques and cerebral vessels (cerebral amyloid angiopathy)

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Step 4: Predict organ findings (classic Step associations)

Organ	High-yield consequence	What you’ll see/test
Kidney	Nephrotic syndrome	Proteinuria, hypoalbuminemia, edema; amyloid in glomeruli
Heart	Restrictive cardiomyopathy → diastolic dysfunction	Thickened “stiff” ventricles; arrhythmias; low voltage on ECG can show up
Nerves	Peripheral + autonomic neuropathy	Orthostasis, gastroparesis, numbness/tingling (ATTR, AL)
Tongue/skin	Macroglossia, easy bruising	Strongly suggests AL
GI/Liver/Spleen	Malabsorption, hepatosplenomegaly	Elevated alk phos possible; enlarged organs

Micro + pathology essentials (rapid review)

What amyloid is

Misfolded proteins aggregate into insoluble fibrils
Fibrils share a $\beta$ ‑pleated sheet configuration → Congo red positivity

What it looks like

H&E: extracellular, pink (eosinophilic), “waxy”/amorphous material
Congo red: red-orange staining on light microscopy
Polarized light: apple‑green birefringence (classic board phrase)

The “AL vs AA” showdown (most commonly tested)

Feature	AL (Primary)	AA (Secondary)
Source	Ig light chains	Serum amyloid A (acute-phase)
Underlying condition	Plasma cell dyscrasia (MM/MGUS)	Chronic inflammation (RA, IBD, chronic infections)
Classic clue	Macroglossia, periorbital purpura, nephrotic syndrome	Longstanding inflammatory disease + renal findings
Mechanism	Monoclonal plasma cells produce excess light chains	Persistent cytokines (IL‑1/IL‑6) → liver makes SAA

High-yield pitfalls and “gotchas”

Amyloid is extracellular (contrast with many intracellular inclusion diseases).
Nephrotic syndrome from amyloid is typically due to glomerular deposition damaging filtration barrier.
Restrictive cardiomyopathy: think “stiff ventricle,” not dilated.
Dialysis-related amyloid = $\beta_2$ ‑microglobulin, and it loves joints.
Alzheimer’s A $\beta$ is from APP, and appears in plaques (plus cerebral amyloid angiopathy).

Quick self-check (2 vignettes)

RA for 15 years + new nephrotic syndrome → AA amyloidosis.
Multiple myeloma + macroglossia + nephrotic syndrome → AL amyloidosis.

“Shareable” recap (flow in one screen)

Suspect (nephrotic/restrictive/neuropathy) → Confirm (Congo red, apple‑green) → Classify:

AL = plasma cell dyscrasia (light chains)
AA = chronic inflammation (SAA)
ATTR = transthyretin (senile/familial; heart/nerve)
A $\beta_2$ M = dialysis (joints)
A $\beta$ = Alzheimer (plaques/angiopathy)