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Amyloidosis - Pathology Notes (2nd Year MBBS)

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1. DEFINITION

• The term "amyloid" was coined because the deposits' staining resembled starch (amylose) - though the deposits are unrelated to starch.
• It is not a single disease but a group of diseases sharing the common feature of amyloid deposition.
• More than 40 different proteins can aggregate to form amyloid.

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2. PHYSICAL AND CHEMICAL NATURE OF AMYLOID

Physical Nature

• By electron microscopy: continuous, nonbranching fibrils, diameter ~8-10 nm
• Each fibril consists of stacks of protofilaments arranged in a β-pleated sheet conformation
• This β-pleated sheet configuration is responsible for the characteristic Congo red staining

Chemical Composition

The Three Major Forms of Amyloid

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3. PATHOGENESIS

1. Normal proteins that have an inherent tendency to self-associate and form fibrils, especially when produced in excess
2. Mutant proteins that are prone to misfolding and aggregation

• Intracellular misfolded proteins are normally degraded by proteasomes
• Extracellular protein aggregates are normally taken up and degraded by macrophages
• In amyloidosis, these quality control mechanisms fail → fibrillar proteins accumulate extracellularly

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4. CLASSIFICATION

A. Systemic (Generalized) Amyloidosis

1. AL Amyloidosis (Primary Amyloidosis)

• Made of immunoglobulin light chains (complete or amino-terminal fragments), predominantly λ light chains
• Associated with: Multiple myeloma, plasma cell dyscrasias, B-cell lymphomas
• Organs most affected: Heart, GI tract, respiratory tract, peripheral nerves, skin, tongue
• This is the most common systemic amyloidosis

2. AA Amyloidosis (Secondary/Reactive Amyloidosis)

• Protein: AA protein derived by proteolysis of Serum Amyloid A (SAA) - an acute-phase protein synthesized by the liver
• SAA levels rise in chronic inflammation → sustained overproduction → amyloid deposition
• Associated conditions:
  • Chronic inflammatory diseases: Rheumatoid arthritis (most common), ankylosing spondylitis, IBD
  • Chronic infections: Tuberculosis, bronchiectasis, osteomyelitis
  • Familial Mediterranean Fever (hereditary)
• Organs most affected: Kidneys, liver, spleen, lymph nodes, adrenals, thyroid

3. ATTR (Transthyretin) Amyloidosis

• Protein: Transthyretin (TTR) - a normal serum protein that transports thyroxine and retinol
• Two forms:
  • Wild-type ATTR (senile systemic amyloidosis): Deposits in heart of elderly individuals; affects ~25% of those >80 years
  • Variant ATTR (hereditary/familial): Mutant TTR deposited in peripheral nerves and heart; autosomal dominant; includes familial amyloid polyneuropathy (FAP)
• Most common form in cardiac involvement overall

4. Other Forms

• Aβ2M amyloid: β2-microglobulin in long-term dialysis patients (carpal tunnel syndrome, joint deposits)
• Aβ amyloid: In Alzheimer disease (senile plaques) and cerebral amyloid angiopathy
• AIAPP: Islet amyloid polypeptide (amylin) in type 2 diabetes mellitus - deposits in pancreatic islets
• ACal: Calcitonin-derived amyloid in medullary carcinoma of thyroid

B. Localized Amyloidosis

• Deposits in a single organ without systemic involvement
• Examples: Cutaneous amyloidosis, endocrine tumors (medullary thyroid carcinoma)

C. Hereditary/Familial Amyloidosis

• Familial Mediterranean Fever (FMF) - AA type; autosomal recessive
• Familial amyloid polyneuropathies - ATTR type (mutant transthyretin)

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5. MORPHOLOGY (Gross and Histological Features)

Gross Appearance

• Affected organ is frequently enlarged
• Tissue appears gray, waxy, and firm in consistency
• Amyloid deposition begins insidiously - may not be apparent macroscopically until advanced

Histological Appearance

• Amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance
• Deposition is always extracellular, beginning between cells closely adjacent to basement membranes
• As it accumulates, it encroaches on and eventually destroys surrounding cells
• No inflammatory reaction is evoked

• Under ordinary light: pink-red color to deposits
• Under polarized light: characteristic apple-green birefringence - the most diagnostic feature
• This reaction is shared by ALL forms of amyloid and is caused by the cross-β-pleated sheet configuration

Additional Confirmatory Tests

• Electron microscopy: Amorphous, non-oriented, thin nonbranching fibrils (~8-10 nm)
• Immunohistochemistry: Can identify AA, AL, and TTR types specifically
• Mass spectroscopy / protein sequencing: Definitive identification of AL amyloid

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6. ORGAN-SPECIFIC PATHOLOGY

Kidney (Most Common + Most Serious)

• Gross: Normal to enlarged; in advanced cases may be shrunken (ischemia from vascular narrowing)
• Histology:
  • Deposits first appear in the mesangium and along glomerular basement membranes
  • Causes thickening of GBM and mesangial matrix → capillary narrowing
  • Progressive obliteration of capillary lumens → obsolescent glomerulus replaced by confluent masses of amyloid
  • Interstitial peritubular tissue, arteries, and arterioles also affected
• Clinical: Proteinuria (nephrotic syndrome) → chronic renal failure

Spleen

• May be inapparent or cause marked splenomegaly (up to 800 g)
• Two patterns:
  1. Sago spleen: Deposits limited to splenic follicles → tapioca-like granules on gross inspection
  2. Lardaceous spleen: Deposits involve walls of splenic sinuses and red pulp connective tissue → large maplike areas

Liver

• Deposits may be inapparent or cause hepatomegaly
• Appears first in the space of Disse (between sinusoidal endothelium and hepatocytes)
• Progresses to compress and replace hepatocytes
• Rarely causes hepatic failure

Heart

• Especially in AL and ATTR amyloidosis
• Produces restrictive cardiomyopathy
• Deposits in interstitium between myofibers
• Subendocardial deposits and deposits in conducting system → arrhythmias
• Clinical: Congestive heart failure, diastolic dysfunction

Nervous System

• Peripheral neuropathy (especially in ATTR familial and AL forms)
• Autonomic neuropathy (postural hypotension, impotence, GI dysfunction)
• Carpal tunnel syndrome (AL and dialysis-associated Aβ2M)

Tongue (Macroglossia)

• Almost pathognomonic of AL amyloidosis
• Firm, rubbery enlargement of the tongue

Adrenals, Thyroid, Pituitary

• Typically in AA (secondary) amyloidosis
• May cause adrenal insufficiency

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7. CLINICAL FEATURES

Important: Amyloid deposits cause tissue injury without evoking an inflammatory response and impair function by causing pressure atrophy on cells and tissues.

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8. DIAGNOSIS

• Site of biopsy: Abdominal fat pad (most common, least invasive), rectal mucosa, gingiva, or affected organ
• Stain: Congo red - apple-green birefringence under polarized light = confirmatory
• Typing: Immunohistochemistry, mass spectroscopy, or genetic testing to determine amyloid type (essential before treatment)

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9. SUMMARY TABLE

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10. KEY MNEMONICS

• A - Ankylosing spondylitis
• M - Multiple myeloma (actually causes AL, but remember as separate)
• Y - (rheumatoid)
• L - Leprosy / Lupus
• O - Osteomyelitis
• I - IBD (Crohn's)
• D - Diabetes (AIAPP in type 2)

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11. HIGH-YIELD EXAM POINTS

1. Amyloid = β-pleated sheet conformation - this is the structural basis for Congo red staining
2. Congo red staining + apple-green birefringence under polarized light = gold standard diagnosis
3. AL amyloidosis = associated with plasma cell dyscrasias (myeloma)
4. AA amyloidosis = complication of chronic inflammatory conditions (RA, TB)
5. Kidney is the most commonly and seriously affected organ
6. Sago spleen = follicular deposits; Lardaceous spleen = red pulp/sinus deposits
7. Macroglossia = classic sign of AL amyloidosis
8. SAA protein synthesized in the liver (acute-phase reactant)
9. ATTR = transthyretin; wild-type causes senile cardiac amyloidosis in elderly
10. Amyloid deposits are always extracellular and cause NO inflammatory response

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