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Define amyloid. Classify amyloidosis and describe its staining, organ involvement and diagnosis.

Pathology · 2nd Professional — Para-Clinical

Definition

Amyloid is a pathological, extracellular deposit of protein in a beta-pleated sheet configuration, resistant to degradation, which progressively compresses and destroys the tissue in which it lies.

The name is a misnomer — Virchow believed it was starch-like
All amyloids share the same physical structure despite entirely different chemical composition, which is why a single stain identifies them all
Composed of 95% fibril protein and 5% P component and glycosaminoglycans

Staining and Identification

Method	Result
Haematoxylin and eosin	Amorphous, homogeneous, pink hyaline material
CONGO red	Red in ordinary light; apple-green birefringence in polarised light — the diagnostic test
Metachromatic stains	Methyl violet and crystal violet give a rose-pink colour
Thioflavin T or S	Yellow-green fluorescence
Electron microscopy	Non-branching fibrils, 7.5–10 nm in diameter
X-ray diffraction	Cross-beta-pleated sheet pattern

Classification

Type	Fibril protein	Precursor	Clinical association
AL (primary)	Amyloid Light chain	Immunoglobulin light chains (usually lambda)	Multiple myeloma and other plasma cell dyscrasias
AA (secondary, reactive)	Amyloid Associated	Serum Amyloid A, an acute phase protein	Chronic inflammation — tuberculosis, bronchiectasis, chronic osteomyelitis, rheumatoid arthritis, leprosy
A-beta2m	Beta-2 microglobulin	Beta-2 microglobulin	Long-term haemodialysis — carpal tunnel syndrome
ATTR	Transthyretin	Transthyretin	Familial amyloid polyneuropathy; senile cardiac amyloid
A-beta	Beta-amyloid	Amyloid precursor protein	Alzheimer disease — plaques and cerebral amyloid angiopathy
A Cal	Procalcitonin	Calcitonin	Medullary carcinoma of the thyroid
AIAPP	Islet amyloid polypeptide	Amylin	Type 2 diabetes mellitus
AANF	Atrial natriuretic factor	ANF	Isolated atrial amyloid

In India AA amyloid from tuberculosis and chronic infection remains the commonest form, whereas AL predominates in the West — a genuinely important regional difference that changes the investigation
Systemic forms are AL, AA and dialysis-associated; localised forms include those in the brain, thyroid and islets

Pathogenesis

An abnormal or excessive precursor protein is produced → It is incompletely degraded, or is inherently unstable → Intermediate fragments misfold into the beta-pleated sheet → The sheets aggregate into insoluble fibrils → Which resist proteolysis and are deposited extracellularly → Progressive pressure atrophy of the surrounding parenchyma

Organ Involvement

Organ	Effects
Kidney — the commonest and most serious	Deposits in the glomeruli → heavy proteinuria and nephrotic syndrome, then renal failure; the kidney is large, pale and firm
Spleen	"SAGO" spleen — deposits limited to the follicles; or "lardaceous" spleen — diffuse in the red pulp
Liver	Deposits in the space of Disse; massive hepatomegaly with relatively preserved function until late
Heart	Restrictive cardiomyopathy, arrhythmia and conduction defects; a low-voltage ECG with a thick ventricle on echocardiography — a characteristic and near-diagnostic mismatch
Tongue	Macroglossia
Nerves	Peripheral and autonomic neuropathy
Gut	Malabsorption, bleeding, obstruction
Skin	Periorbital purpura after minor pressure ("racoon eyes"), from vascular fragility

CLINICAL PEARL

Amyloid is deposited between cells and slowly strangles them. Because it is extracellular and inert, it provokes no inflammatory reaction at all — the tissue simply enlarges, hardens and fails. That is why the organs are big but underactive, and why the heart becomes stiff rather than weak.

Amyloid Compared with Hyaline Change

Feature	Amyloid	Hyaline change
Nature	A specific fibrillar protein	A descriptive term only, for any glassy pink material
Congo red	Positive with birefringence	Negative
Electron microscopy	Fibrils 7.5–10 nm	No fibrils
Examples	AL, AA and the rest	Hyaline arteriolosclerosis; Mallory bodies; Russell bodies; reabsorption droplets in the renal tubule

"Hyaline" says nothing about composition — it is a purely morphological word, and amyloid is one of the many things that look hyaline. This is a distinction examiners like, and students conflate

Diagnosis and Applied Aspects

Biopsy is essential — abdominal fat pad aspiration and rectal biopsy are safest; renal biopsy has the highest yield but carries a bleeding risk
Congo red with polarised light confirms it; immunohistochemistry then types it, and the type determines the treatment entirely
Serum and urine electrophoresis with immunofixation to detect a paraprotein in suspected AL
Treatment is of the underlying cause — chemotherapy for the plasma cell clone in AL, control of the chronic infection or inflammation in AA
Deposits regress slowly if the source is removed, so treating tuberculosis or rheumatoid arthritis effectively can reverse the proteinuria
Cardiac amyloid carries the worst prognosis, with a median survival of months if untreated
Avoid blind liver biopsy in suspected amyloid — the organ is friable and fatal haemorrhage is a recognised hazard
Digoxin and calcium channel blockers are avoided in cardiac amyloid, because the drug binds to the deposits and toxicity occurs at ordinary doses
Amyloid in Alzheimer disease is localised to the brain and causes no systemic disease, which is why one word covers such disparate conditions
Suspect amyloid in any patient with a chronic inflammatory disease who develops proteinuria — in Indian practice, most often long-standing tuberculosis, bronchiectasis or rheumatoid arthritis

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