Amyloidosis · Medical Notes

Amyloid structure & staining

Amyloid deposits are extracellular, amorphous, eosinophilic on H&E.
Core molecular feature: β‑pleated sheet conformation of protein subunits.
Histochemical hallmark: Congo red stain → apple‑green birefringence under polarized light.
Non‑fibrillar components always present:
- Serum amyloid P (SAP) – pentraxin family, stabilizes fibrils.
- Glycosaminoglycans (heparan sulfate) – scaffold role.
Fibril protein varies by disease type (see table below).

            🔑 β‑pleated sheet confers resistance to proteolysis and permits Congo red binding.

          

Type	Fibril precursor	Typical context
Primary (AL)	Immunoglobulin light chains (κ or λ)	Plasma cell dyscrasias (MM, lymphoma) or idiopathic
Reactive (AA)	Serum amyloid A (SAA) – acute phase reactant	Chronic inflammation: RA, SLE, TB, IBD, cancer
Familial Mediterranean fever	SAA (AA type)	Autosomal recessive; pyrin gain‑of‑function; recurrent fever
Hemodialysis‑associated	β₂‑microglobulin (Aβ₂M)	Carpal tunnel syndrome, arthropathy
Senile cardiac/systemic	Transthyretin (ATTR) – TTR tetramer	Age >70; restrictive cardiomyopathy; African‑American V122I variant
Senile cerebral (Alzheimer)	β‑amyloid precursor protein (Aβ)	Senile plaques, cerebral vessels; chromosome 21
Endocrine	Procalcitonin (medullary thyroid), amylin (islet cells)	Medullary carcinoma, diabetes, islet tumors

Precursor protein → Partial unfolding → β‑sheet aggregation → Extracellular deposition → Organ dysfunction

Kidney – most common in systemic forms; manifests as nephrotic syndrome or progressive renal failure.
Heart – restrictive/infiltrative cardiomyopathy; conduction disturbances, diastolic dysfunction.
GI / tongue – macroglossia (especially AL), malabsorption, hepatosplenomegaly.
Nerves – peripheral/autonomic neuropathy (AL, ATTR).
Soft tissues – carpal tunnel syndrome (β₂M, ATTR).

⚠️ Cardiac involvement is a major prognostic factor; restrictive physiology leads to low‑output state.

AL amyloidosis – nephrotic syndrome, restrictive cardiomyopathy, macroglossia, periorbital purpura.
AA amyloidosis – proteinuria, renal insufficiency; underlying chronic infection/inflammation.
ATTR (wild‑type) – heart failure in elderly men; carpal tunnel often precedes cardiac symptoms.
Familial Mediterranean fever – recurrent serositis, fever, AA amyloidosis risk.
Hemodialysis‑associated – β₂M accumulates, causes destructive arthropathy and CTS.

🫀 ATTR V122I mutation: 4% of African Americans, 1% homozygous → increased cardiac risk.

Biopsy – abdominal fat pad, rectal mucosa, gingiva; sensitivity >80% for systemic disease.
Congo red stain with polarized microscopy: apple‑green birefringence (confirmatory).
AL typing – serum/urine protein electrophoresis + immunofixation; free light chain assay.
AA typing – immunohistochemistry or mass spectrometry (proteomic analysis).
ATTR – TTR gene sequencing; bone scintigraphy (DPD/PYP) can suggest cardiac ATTR.
Proteomic analysis (laser microdissection + MS) is the gold standard for fibril typing.

⚠️ Negative fat pad biopsy does not exclude amyloidosis; consider affected organ biopsy.

AL amyloidosis – anti‑plasma cell therapy (bortezomib, daratumumab, autologous SCT).
AA amyloidosis – treat underlying inflammatory disease (e.g., biologics for RA).
ATTR – TTR stabilizers (tafamidis); RNA silencers (patisiran, inotersen) for hereditary.
Supportive – heart failure management, dialysis, organ transplantation (selected cases).
Prognosis – systemic amyloidosis carries poor overall survival; cardiac involvement worsens outcome.

            🔹 Early diagnosis and precise fibril typing are essential for targeted therapy.

          

AL 5‑year survival ~30–50% with treatment; cardiac AL has median survival <1 year if untreated.
ATTR Survival improved with TTR stabilizers; liver transplantation for hereditary variants.