STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY | HIGH-YIELD REVIEW

Amyloidosis

Misfolded proteins stack into β-pleated sheets, deposit outside cells, and slowly crush organ function.

FOCUS ON
Every type looks the same on Congo red (apple-green birefringence). The question is which precursor protein is involved, and the clinical setting gives it away: plasma cell clone, chronic inflammation, old age, dialysis, Alzheimer, endocrine tumor.
TYPE
PRECURSOR · SETTING
MAIN ORGANS · FEATURES
CLASSIC CLUE
AL (primary)
systemic
Immunoglobulin light chains (λ > κ) from a plasma cell clone — multiple myeloma or a smaller clone.
Kidney (nephrotic), heart (restrictive), tongue, liver, nerves, skin
Macroglossia, periorbital purpura, M-protein
AA (secondary)
systemic
Serum amyloid A, an acute-phase protein made during chronic inflammation.
Kidney most often, then liver, spleen, adrenals
RA, IBD, TB, bronchiectasis, chronic osteomyelitis, familial Mediterranean fever
ATTR — wild-type
senile systemic
Normal transthyretin deposits with age, mostly in elderly men.
Heart (restrictive cardiomyopathy, HF), carpal tunnel
80-year-old with HF and thick walls
ATTR — hereditary
autosomal dominant
Mutant transthyretin (e.g., V122I in ~4% of African Americans).
Cardiomyopathy and/or peripheral + autonomic neuropathy
Familial amyloid polyneuropathy
Aβ₂-microglobulin
dialysis-related
β₂-microglobulin is not cleared by dialysis membranes and builds up.
Joints, tendon sheaths, bone
Carpal tunnel after years of hemodialysis
Aβ (amyloid-β)
localized — brain
Cleaved from amyloid precursor protein (APP, chromosome 21).
Senile plaques; vessel walls (cerebral amyloid angiopathy)
Alzheimer disease; lobar hemorrhage in elderly; early AD in Down syndrome
Endocrine-localized
hormone-derived
Calcitonin (medullary thyroid carcinoma) · amylin/IAPP (islets in type 2 DM) · ANP (isolated atrial amyloid)
Tumor stroma, islets, atria
Amyloid stroma in a thyroid tumor = medullary carcinoma

Mechanism — from fold to failure

Precursor excessor mutant protein
→
Misfoldingβ-pleated sheet
→
Extracellular depositresists proteolysis
→
Pressure atrophyorgan dysfunction

Diagnosis: tissue biopsy — abdominal fat pad aspirate or rectal biopsy for systemic disease. Congo red stains salmon-pink; under polarized light it shows apple-green birefringence.

Organ involvement

ORGAN
FINDING
Kidney (most common)
Nephrotic syndrome; glomerular deposits; kidneys may be enlarged
Heart
Restrictive cardiomyopathy; thick walls with low-voltage ECG; arrhythmia
Tongue, GI
Macroglossia (AL); malabsorption, GI bleeding
Liver, spleen
Hepatosplenomegaly; "sago" spleen with nodular deposits
Nerves
Carpal tunnel, peripheral neuropathy, orthostatic hypotension
Skin, vessels
Waxy papules; fragile vessels → periorbital purpura (AL)

How it's tested

COMMON CONFUSIONAL and AA both hit the kidney. The setting tells them apart: a plasma cell clone points to AL, a chronic inflammatory disease to AA. Treatment follows the cause.
THE TRAPThe echo shows thick ventricles but the ECG shows low voltage. That is infiltration (amyloid), not true hypertrophy.
YOUR APPROACHCongo red confirms amyloid. Then name the precursor from the setting, and expect nephrotic syndrome and restrictive cardiomyopathy as the big systemic complications.

If you see… think…

Apple-green birefringence on Congo red → amyloid
Macroglossia + nephrotic syndrome + raccoon-eye purpura → AL amyloidosis
Long-standing RA or Crohn disease, new proteinuria → AA amyloidosis
Elderly man, heart failure, thick walls, low-voltage ECG → wild-type ATTR
African-American with cardiomyopathy and neuropathy, family history → hereditary ATTR
Years on hemodialysis + carpal tunnel → β₂-microglobulin amyloid
Elderly patient with recurrent lobar hemorrhages → cerebral amyloid angiopathy (Aβ)
Thyroid tumor with amyloid stroma → medullary carcinoma (calcitonin)
Recurrent fevers and serositis, Mediterranean descent → FMF → AA risk (colchicine)