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PA9.1-2 | Amyloidosis — SDL Guide

Learning Objectives

• Define amyloid and describe its physical and chemical nature including the β-pleated sheet configuration
• Explain the pathogenesis of amyloid deposition — protein misfolding and impaired degradation
• Classify amyloidosis by precursor protein: AL, AA, Aβ2-microglobulin, ATTR, Aβ, and endocrine forms
• Distinguish systemic from localised amyloidosis and identify the clinical conditions associated with each type
• Describe the gross and microscopic morphology of amyloid deposits, including the Congo red staining reaction
• Enumerate the major organs affected in systemic amyloidosis and the clinical consequences of each

INSTRUCTIONS

Amyloidosis is a unifying concept in pathology — a single abnormal physical property (the β-pleated sheet) underlies diverse diseases ranging from plasma cell dyscrasia to Alzheimer disease. Mastering the classification logic and the diagnostic Congo red reaction will pay dividends in every system you study from Year 2 onward. This module links directly to haematology (AL type), chronic inflammation (AA type), and neuroscience (Aβ), and will recur in clinical postings whenever a patient presents with unexplained heavy proteinuria or restrictive cardiac disease.

References

• Robbins & Kumar: Basic Pathology, 11th ed., Ch 4 (Cellular Responses to Stress) and Ch 11 (Diseases of Immunity) (textbook)
• Harsh Mohan: Textbook of Pathology, 8th ed., Ch 4 (Amyloidosis) (textbook)

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Version 2.0 | NMC CBUC 2024

What Is Amyloid? Physical and Chemical Nature

Amyloid is a pathological extracellular deposit of insoluble fibrillar proteins that share a unique secondary structure regardless of the precursor protein involved.

Key physical and chemical properties:

Property	Detail
Structure	β-pleated sheet (cross-β) configuration — sheets stacked perpendicular to the fibril axis
Solubility	Insoluble in physiological salt solutions; resists proteolysis
Fibrils	7.5–10 nm diameter, non-branching, indefinite length
P component	Serum amyloid P (SAP) — a pentameric glycoprotein that binds all amyloid fibrils (used in scintigraphy)
Appearance	Waxy, homogeneous, eosinophilic on H&E

The β-pleated sheet is the unifying feature. Proteins that normally have α-helical or disordered conformations can misfold into this configuration under the right conditions — and once they do, they resist degradation and accumulate indefinitely.

Staining — the diagnostic signature:

Amyloid stains salmon-pink with Congo red on standard light microscopy. Under polarised light, the same section exhibits apple-green birefringence — this optical property is pathognomonic for amyloid and is caused by the parallel alignment of dye molecules along the β-pleated sheet.

Other stains: crystal violet (metachromatic purple), thioflavin T (fluorescence) — used in research.

Iodine reaction: amyloid stains brown with Lugol's iodine and turns violet-blue with dilute H₂SO₄ — historically used at autopsy (the "lardaceous" or "waxy" appearance that early pathologists described).

Amyloid: Physical and Chemical Nature

Pathogenesis — Misfolding and Impaired Degradation

Amyloid Pathogenesis: Misfolding, Impaired Degradation, and Seeding

Amyloid accumulation results from two converging mechanisms:

1. Protein misfolding (aggregation-prone precursors)

Normally, chaperone proteins (HSP70, HSP90) assist correct folding, and the ubiquitin-proteasome system degrades misfolded proteins. Amyloidogenic proteins escape this surveillance for one or more reasons:

• Overproduction overwhelms clearance — immunoglobulin light chains in myeloma
• Structural instability — mutant transthyretin (Val122Ile) misfolds spontaneously
• Proteolytic cleavage generates a fragment that is aggregation-prone — APP → Aβ in Alzheimer
• Normal-sequence protein released in excess — SAA in chronic inflammation

2. Impaired degradation

Once β-sheet oligomers and fibrils form, they are highly resistant to lysosomes and extracellular proteases. The serum amyloid P component actually protects fibrils from proteolysis, prolonging their survival.

Key concept — seeding: Preformed amyloid fibrils act as nucleation seeds, accelerating the addition of new monomers. This is why amyloid deposition is self-amplifying once initiated — a parallel to prion propagation.

Summary pathway:

Precursor protein overproduction or structural instability → misfolding → β-sheet oligomers → fibril nucleation (seeding) → fibril extension → extracellular accumulation → organ damage via pressure atrophy and ischaemia

Classification by Precursor Protein

Amyloidosis is classified by the precursor protein that forms the fibril. The letter designation follows: protein abbreviation + 'A' prefix (e.g., AL = Amyloid of Light chain origin).

Provided image

Systemic amyloidosis (generalised):

AL (Primary amyloidosis)
• Precursor: Immunoglobulin light chains (κ > λ, or λ > κ depending on clone)
• Association: Plasma cell dyscrasia — multiple myeloma (20%), monoclonal gammopathy (MGUS), Waldenström macroglobulinaemia
• Cross-reference: Cluster H11 (Plasma Cell Neoplasms)
• Organs affected: heart (restrictive), kidney (nephrotic), peripheral nerves, tongue (macroglossia), carpal tunnel
• Note: AL is the most common type of systemic amyloidosis in high-income countries

AA (Secondary / Reactive systemic amyloidosis)
• Precursor: Serum amyloid-associated (SAA) protein — an acute-phase reactant synthesised by the liver
• Association: Chronic inflammatory states — rheumatoid arthritis, ankylosing spondylitis, tuberculosis, bronchiectasis, chronic osteomyelitis, inflammatory bowel disease (Crohn > UC), leprosy
• Historically the commonest type worldwide (TB belt)
• Organs preferentially affected: kidney (most common and most devastating), liver, spleen, adrenals

Aβ2-microglobulin amyloidosis (Aβ2M)
• Precursor: β2-microglobulin (MHC class I light chain) — NOT cleared by dialysis membranes
• Association: Long-term haemodialysis (>10 years)
• Clinically: carpal tunnel syndrome, destructive arthropathy

ATTR (Transthyretin amyloidosis)
• Precursor: Transthyretin (formerly prealbumin) — a transport protein for thyroxine and retinol
• Familial (hereditary) ATTR: point mutations (Val30Met most common); autosomal dominant; peripheral neuropathy + cardiac involvement
• Senile/wild-type ATTR: normal-sequence transthyretin deposits in elderly men; restrictive cardiomyopathy is the dominant feature

Localised amyloidosis:

Aβ (Alzheimer-type)
• Precursor: Amyloid-β peptide — a 40–42 amino acid fragment of amyloid precursor protein (APP)
• Site: Brain — senile plaques (Aβ core) and amyloid angiopathy
• Down syndrome (trisomy 21): extra APP gene copy → early Alzheimer deposits by age 40

Endocrine amyloid (localised)
• Medullary thyroid carcinoma: calcitonin-derived amyloid in tumour stroma
• Islet amyloid (IAPP): amylin (islet amyloid polypeptide) in type 2 diabetes mellitus — deposits in islets of Langerhans