Amyloidosis

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 📘 Amyloidosis 

🔹 1. Definition & Pathogenesis

  • Amyloid: Insoluble misfolded proteins (or fragments) → aggregate into β-pleated sheet fibrils.

  • Amyloidosis: Extracellular deposition of amyloid fibrils → tissue compression, cellular apoptosis, fibrosis, and organ dysfunction.

  • Composition:

    • Fibrillar component (90–95%) → defines amyloid type.

    • Nonfibrillar proteins (5–10%) → common across types (amyloid P, glycosaminoglycans).

  • Naming: “A” (amyloidosis) + protein name (eg, AL, AA, ATTR).

🔹 2. Classification

  • By distribution:

    • Systemic amyloidosis (multiple organs).

    • Localized amyloidosis (single organ; eg, atrial amyloid, medullary thyroid carcinoma).

  • By origin:

    • Acquired (plasma cell dyscrasias, chronic inflammation).

    • Hereditary (mutant transthyretin).

🔹 3. Major Systemic Types (with Clinical Details)

A. AL Amyloidosis (Primary)

  • Protein: Immunoglobulin light chain.

  • Etiology: Plasma cell dyscrasias → multiple myeloma, Waldenström macroglobulinemia.

  • Epidemiology: Most common type in developed countries; median age ~64.

  • Organs affected:

    • Heart: restrictive cardiomyopathy, HFpEF, arrhythmias, AV block.

    • Kidney: nephrotic syndrome, CKD, type II RTA, nephrogenic DI.

    • Tongue: macroglossia (very characteristic).

    • Skin: periorbital purpura (“raccoon eyes”), yellow waxy papules.

    • Nervous system: peripheral neuropathy, autonomic neuropathy (orthostatic hypotension, diarrhea).

    • GI/liver: hepatomegaly, malabsorption.

    • Musculoskeletal: bilateral carpal tunnel, “shoulder pad sign.”

  • Classic triad: Macroglossia + raccoon eyes + shoulder pad sign (specific but rare ~10%).

  • Course: Rapidly progressive (1–2 years median survival untreated).

B. AA Amyloidosis (Secondary)

  • Protein: Serum amyloid-associated (SAA) → AA fibrils.

  • Etiology: Chronic inflammation, infection, or malignancy.

    • Inflammatory: RA, IBD, SLE, vasculitis, FMF.

    • Infectious: TB, leprosy, osteomyelitis, bronchiectasis.

    • Neoplastic: Renal cell carcinoma, lymphomas.

  • Epidemiology: Commonest type in children; can occur at any age.

  • Organs affected:

    • Kidneys (MC): nephrotic syndrome, CKD.

    • Liver & spleen: hepatosplenomegaly.

    • Adrenal glands: adrenal insufficiency.

    • GI: malabsorption, diarrhea.

    • Heart: rare but may cause thickened ventricles.

  • Course: Slower than AL; progression controlled if underlying disease treated (eg, colchicine in FMF, biologics in RA).

C. Aβ₂M Amyloidosis (Dialysis-Related)

  • Protein: β₂-microglobulin.

  • Etiology: Long-term hemodialysis (>10 yrs, due to inadequate clearance of β₂M).

  • Organs affected: Joints & tendons.

    • Carpal tunnel syndrome (bilateral).

    • Scapulohumeral periarthritis.

    • Bone cysts, spondyloarthropathy.

  • Clinical clue: Patient on dialysis for >10 years with joint pain + carpal tunnel.

D. ATTR Amyloidosis (Transthyretin-related)

Two forms:

1. ATTRmt (mutated, hereditary/variant)

  • Protein: Mutant transthyretin (TTR).

  • Inheritance: Autosomal dominant.

  • Subtypes:

    • Familial amyloid cardiomyopathy (FAC): Restrictive cardiomyopathy, arrhythmia.

    • Familial amyloid polyneuropathy (FAP): Peripheral/autonomic neuropathy.

  • Epidemiology: Common in African descent (FAC), Portugal/Sweden/Japan/Irish (FAP).

  • Management: Liver transplant (removes mutant TTR source), tafamidis (TTR stabilizer).

2. ATTRwt (wild-type, senile amyloidosis)

  • Protein: Normal (wild-type) transthyretin.

  • Etiology: Aging.

  • Epidemiology: Median age 75, 90% men.

  • Organs affected:

    • Heart: Restrictive cardiomyopathy, arrhythmia.

    • Musculoskeletal: carpal tunnel, spinal stenosis, tendon rupture.

  • Course: Slower than AL; less severe.

🔹 4. Localized Amyloidosis

  • Isolated atrial amyloidosis: ANP deposition → ↑ atrial fibrillation risk.

  • Type 2 diabetes: IAPP deposition in islets.

  • Injection-related: insulin amyloid at injection sites.

  • Medullary thyroid carcinoma: calcitonin amyloid.

  • Neurodegenerative:

    • Alzheimer’s: Aβ (APP-derived).

    • Prion disease: APrP (prion protein amyloid).

🔹 5. Diagnosis

  • Suspicion: Multisystem disease (heart + kidney + neuropathy) or nephrotic syndrome with unusual features.

  • Biopsy:

    • Abdominal fat pad or rectal mucosa: low risk, less sensitive.

    • Target organ (kidney, nerve, heart): more sensitive, higher risk.

  • Staining:

    • Congo red stain → pink/red under light microscopy.

    • Apple-green birefringence under polarized light = pathognomonic.

  • Additional workup:

    • SPEP/UPEP + immunofixation: detects monoclonal proteins (AL).

    • Serum free light chains.

    • Cardiac imaging: echo/CMR for restrictive cardiomyopathy.

🔹 6. Management

  • General: Focus on treating underlying cause.

  • AL amyloidosis:

    • Chemotherapy (melphalan + steroids, thalidomide, bortezomib).

    • Autologous HSCT if eligible.

  • AA amyloidosis:

    • Control underlying inflammatory disease.

    • Eg, colchicine for FMF, biologics for RA.

  • ATTRmt: Liver transplant; tafamidis/patisiran (stabilize or silence TTR).

  • ATTRwt: Supportive care; tafamidis in selected patients.

  • Dialysis-related: Improved dialysis techniques, transplantation.

  • Organ transplant: Renal or cardiac for end-stage disease.

🔹 7. High-Yield Pearls (Exam Essentials)

  • AL = most common in West, multiple myeloma, rapid course, macroglossia + raccoon eyes.

  • AA = chronic inflammation/infection, renal disease dominant, kids too.

  • Dialysis-related = carpal tunnel, scapulohumeral arthritis.

  • ATTRmt = hereditary; think African descent (cardiomyopathy), Portugal (polyneuropathy).

  • ATTRwt = elderly men, senile systemic amyloidosis, slower progression.

  • Congo red → apple-green birefringence = diagnostic.

  • Classic AL signs (rare but specific): macroglossia + raccoon eyes + shoulder pad sign.

Amyloidosis is a disease involving deposition of insoluble protein fibrils in various organs and tissues throughout the body.  Cardiac involvement is common, typically manifesting as restrictive cardiomyopathy that may later progress to dilated cardiomyopathy.  Other commonly affected organs include the liver, kidneys, skin, and nervous system.  The diagnosis is confirmed by tissue biopsy(eg, abdominal fat pad).

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