Amyloidosis
Pathology · General Pathology · lean revision notes
Amyloidosis
Amyloidosis is a group of disorders characterised by extracellular deposition of abnormally folded, insoluble fibrillar proteins (amyloid) that disrupt tissue architecture and organ function. The unifying feature is β-pleated sheet structure, Congo red positivity, and apple-green birefringence under polarised light — three facts that dominate NEET PG questions.
Definition and basic concept
Amyloid is not a single chemical entity but a physical/structural state. Over 30 biochemically distinct proteins can adopt the amyloid configuration. What makes them "amyloid" is the shared antiparallel β-pleated sheet conformation, which renders them:
- Insoluble and resistant to proteolysis (hence they accumulate)
- Birefringent with Congo red
- Fibrillar (8–10 nm rigid, non-branching fibrils) on electron microscopy
- Associated with a non-fibrillar glycoprotein component, serum amyloid P (SAP), derived from C-reactive protein family.
High-yield: Amyloid = β-pleated sheet + Congo red + apple-green birefringence + non-branching fibrils on EM + serum amyloid P component. These five points are repeatedly tested.
Composition of amyloid
| Component | Proportion | Nature |
|---|---|---|
| Fibril protein | ~95% | Type-specific (AL, AA, ATTR etc.) |
| Serum amyloid P (SAP) | ~5% | Non-fibrillar, common to ALL types, derived from CRP-related pentraxin |
| Glycosaminoglycans (heparan sulfate) | minor | Common component |
Classification of amyloidosis
The modern classification is biochemical (based on the precursor protein), prefixed by "A" for amyloid. The clinically/exam-relevant types:
| Type | Fibril protein | Precursor | Associated condition |
|---|---|---|---|
| AL (primary) | Amyloid light chain | Immunoglobulin light chains (λ > κ) | Plasma cell dyscrasia, multiple myeloma, MGUS |
| AA (secondary/reactive) | Amyloid-associated | Serum amyloid A (SAA) — an acute phase reactant | Chronic inflammation: RA, TB, osteomyelitis, IBD, bronchiectasis, leprosy, chronic infections |
| ATTR (wild-type) | Transthyretin (normal) | Normal transthyretin (prealbumin) | Senile systemic amyloidosis — elderly hearts |
| ATTR (mutant) | Mutant transthyretin | Mutated TTR | Familial amyloid polyneuropathy / cardiomyopathy (autosomal dominant) |
| Aβ2M | β2-microglobulin | β2-microglobulin (part of MHC I) | Long-term haemodialysis (not filtered by older membranes) → carpal tunnel |
| Aβ | Amyloid β protein | APP (amyloid precursor protein, chr 21) | Alzheimer disease, cerebral amyloid angiopathy, Down syndrome |
| AIAPP | Islet amyloid polypeptide (amylin) | IAPP, co-secreted with insulin | Type 2 diabetes mellitus (islets of Langerhans) |
| ACal | Calcitonin | Calcitonin | Medullary carcinoma thyroid |
| AANF | Atrial natriuretic factor | ANF | Isolated atrial amyloidosis (elderly) |
| APrP | Prion protein | PrP (misfolded) | Prion diseases (CJD, kuru) |
| Gelsolin / Lysozyme / Fibrinogen | Respective proteins | Mutant forms | Rare hereditary amyloidoses |
High-yield: AL = light chain (think L for Light and pLasma cell). AA = "A"ssociated with chronic inflammation, precursor is SAA (acute phase protein made in liver under IL-6). Memorise the precursor protein — that is the single most asked fact.
Clinical classification (older but still examined)
- Systemic (generalised):
- Primary = AL (plasma cell origin)
- Secondary/reactive = AA (chronic inflammation)
- Haemodialysis-associated = Aβ2M
- Heredofamilial = ATTR mutant, familial Mediterranean fever (AA type — periodic fever gene MEFV/pyrin)
- Localised: endocrine (medullary thyroid Ca, islet, ANF), cerebral (Alzheimer), senile.
High-yield: Familial Mediterranean fever produces AA amyloid (not a special type), due to recurrent inflammation; treated/prevented with colchicine.
Mnemonics
- "SAA in Secondary, light chAIn in primAry" — links AA→secondary, AL→primary.
- For AL causes — "Myeloma Makes Light" (multiple myeloma → light chains → AL).
- For Congo red colour shift — "CONGO turns green when POLARised" (apple-green birefringence under polarised light).
- Organ deposition triad classically — kidney, heart, liver, spleen ("the big four").
Pathophysiology
The common pathway is protein misfolding. Normally soluble proteins acquire a β-sheet–rich conformation, aggregate into oligomers, then mature into rigid fibrils that resist clearance.
Mechanisms differ by type:
- AL: A clone of plasma cells overproduces an unstable monoclonal light chain (especially λ), which misfolds and deposits.
- AA: Chronic inflammation → IL-1, IL-6, TNF → hepatic synthesis of SAA. Incomplete degradation of SAA by macrophage enzymes leaves the insoluble AA fragment.
- ATTR: Either a destabilising point mutation (familial) or age-related instability of normal transthyretin (senile) → tetramer dissociation → misfolding.
- Aβ2M: β2-microglobulin accumulates because old dialysis membranes fail to filter it.
Flow of reactive (AA) amyloidogenesis: Chronic inflammation → ↑ IL-6 → liver makes SAA (acute-phase reactant) → macrophage partial proteolysis → insoluble AA fibrils → tissue deposition → organ dysfunction.
High-yield: SAA is an acute-phase reactant produced by the liver under IL-6 stimulation; persistently elevated SAA is the substrate for AA amyloid. This is the favourite link for "chronic disease → amyloidosis" questions.
Morphology and staining (very high-yield)
| Stain / Method | Result with amyloid |
|---|---|
| H&E | Amorphous, eosinophilic, hyaline, extracellular |
| Congo red (light microscopy) | Pink/red (salmon) |
| Congo red + polarised light | Apple-green birefringence (pathognomonic) |
| Thioflavin T / S (fluorescence) | Yellow-green fluorescence |
| Electron microscopy | Non-branching fibrils, 7.5–10 nm |
| Crystal violet / methyl violet | Metachromasia (rose-pink) |
| Potassium permanganate pretreatment | Distinguishes AA (KMnO4-sensitive → loses Congo red) from AL (KMnO4-resistant) |
High-yield: Apple-green birefringence under polarised light after Congo red is the single most repeated MCQ answer for amyloidosis identification. The dye binds the β-pleated sheets.
High-yield: Potassium permanganate sensitivity differentiates AA (sensitive — staining abolished) from AL (resistant — staining retained).
Gross appearance
- Lardaceous spleen: diffuse deposition in red pulp → waxy, lardlike.
- Sago spleen: deposition limited to splenic follicles (white pulp) → tapioca-like granules.
- Amyloid kidney: enlarged, pale, waxy; later shrunken.
Organ involvement and clinical features
Amyloidosis is a great mimic; presentation depends on organs affected.
Kidney (most common and most serious in AA; major cause of death)
- Deposits in glomerular mesangium and basement membrane, vessel walls, interstitium.
- Nephrotic syndrome → heavy proteinuria → eventually renal failure.
- Most common cause of death in systemic amyloidosis (especially AA) is renal failure.
High-yield: Kidney is the most frequently and seriously involved organ in systemic (AA) amyloidosis; presents as nephrotic syndrome and is the leading cause of death.
Heart (dominant in AL and ATTR)
- Restrictive cardiomyopathy (most characteristic), conduction defects, arrhythmias.
- ECG: low voltage complexes despite ECHO showing thick walls ("voltage–mass mismatch").
- ECHO: thickened ventricular walls with a "granular sparkling" myocardial texture.
- Cardiac involvement is the chief cause of death in AL and ATTR amyloidosis.
High-yield: Low-voltage ECG + thick walls on ECHO + restrictive physiology = cardiac amyloidosis. The "sparkling/speckled" myocardium is a classic image.
Other systems
- Tongue: macroglossia (classic for AL).
- Skin: waxy papules, easy bruising, periorbital purpura ("raccoon eyes" after Valsalva/coughing) — characteristic of AL.
- GI tract: malabsorption, motility disturbance, bleeding; gingival/rectal biopsy for diagnosis.
- Nervous system: peripheral neuropathy, carpal tunnel syndrome (classic in Aβ2M dialysis amyloid and ATTR), autonomic neuropathy (postural hypotension).
- Liver: hepatomegaly, usually with preserved function until late.
- Spleen: sago/lardaceous; hyposplenism with Howell-Jolly bodies.
- Coagulation: acquired factor X deficiency (factor X adsorbed onto amyloid fibrils) → bleeding.
High-yield: Macroglossia + periorbital purpura + carpal tunnel + factor X deficiency = think AL amyloidosis.
Diagnosis and investigation of choice
Stepwise approach:
- Suspect clinically (nephrotic syndrome + restrictive cardiomyopathy + neuropathy + macroglossia).
- Tissue biopsy → the cornerstone of diagnosis.
- Abdominal subcutaneous fat pad aspiration = least invasive, safe screening biopsy (≈70–80% sensitive in systemic disease).
- Rectal/gingival biopsy are alternatives.
- Definitive: biopsy of the involved organ (kidney, heart) if fat pad negative but suspicion high.
- Congo red stain → apple-green birefringence confirms amyloid.
- Type the amyloid (essential because treatment differs):
- Immunohistochemistry / immunofixation
- Mass spectrometry (laser microdissection) — current gold standard for typing.
- Identify the precursor disorder:
- Serum/urine immunofixation + serum free light-chain assay (for AL).
- Bone marrow biopsy for plasma cell clone.
- Imaging for amyloid load: SAP scintigraphy (radiolabelled serum amyloid P) maps systemic deposits; cardiac MRI / technetium-pyrophosphate (PYP) scan for ATTR cardiac amyloid.
High-yield: Investigation of choice = tissue biopsy with Congo red staining; the safest screening biopsy is the subcutaneous abdominal fat pad aspirate. Typing the fibril (now by mass spectrometry) is mandatory before therapy.
Management / drug of choice
Treatment targets the underlying precursor, not the amyloid deposit itself (deposits clear slowly once production stops).
| Type | Principle | Specific therapy |
|---|---|---|
| AL | Suppress the plasma cell clone | Bortezomib-based regimens (CyBorD: cyclophosphamide + bortezomib + dexamethasone); autologous stem cell transplant with high-dose melphalan in eligible patients; daratumumab added in current regimens |
| AA | Treat the chronic inflammation | Control RA/TB/IBD; colchicine for FMF; anti-IL-1/anti-IL-6 biologics; tocilizumab |
| ATTR (familial/wild-type) | Stabilise/silence transthyretin | Tafamidis (TTR stabiliser); patisiran (siRNA), inotersen (antisense); liver transplant for familial |
| Aβ2M (dialysis) | Remove β2-microglobulin | High-flux dialysis membranes, renal transplantation (curative) |
High-yield: AL amyloid → bortezomib + autologous stem cell transplant (melphalan conditioning). ATTR cardiac amyloid → tafamidis. FMF/AA prevention → colchicine. Dialysis amyloid → high-flux membranes / transplant.
Supportive care: diuretics for cardiac/renal congestion (avoid digoxin and calcium channel blockers — they bind amyloid and cause toxicity), dialysis or transplant for renal failure.
High-yield: Digoxin and calcium-channel blockers are relatively contraindicated in cardiac amyloidosis because they bind avidly to amyloid fibrils → toxicity.
Prognosis
- AL has the worst prognosis, especially with cardiac involvement (median survival historically months to ~1–2 years untreated; greatly improved with modern regimens).
- AA prognosis depends on control of the underlying inflammation.
- Cardiac involvement is the strongest adverse prognostic factor across types.
Complications
- Progressive renal failure (commonest cause of death in AA).
- Restrictive cardiomyopathy, heart block, sudden cardiac death (commonest cause of death in AL).
- Bleeding diathesis (factor X deficiency, fragile vessels).
- Malabsorption and protein-losing enteropathy.
- Autonomic failure — postural hypotension, gastroparesis.
- Hyposplenism and infection susceptibility.
Key differentials
| Presentation | Amyloidosis mimics | Distinguishing clue |
|---|---|---|
| Nephrotic syndrome | Diabetic nephropathy, membranous GN | Congo red +ve biopsy; restrictive heart; macroglossia |
| Restrictive cardiomyopathy | Sarcoidosis, haemochromatosis, endomyocardial fibrosis | Low-voltage ECG + thick walls; PYP scan; biopsy |
| Hepatomegaly | Storage diseases, malignancy | Preserved LFTs; Congo red on biopsy |
| Macroglossia | Hypothyroidism, acromegaly | Periorbital purpura, monoclonal protein |
| Peripheral/carpal tunnel neuropathy | Diabetes, hypothyroidism | Dialysis history (Aβ2M), familial ATTR |
Histologically, amyloid must be distinguished from other hyaline deposits (collagen, fibrin, immune complexes) — only amyloid gives apple-green birefringence with Congo red.
Recently asked / exam angle
- Precursor protein matching: "Amyloid in medullary carcinoma thyroid is derived from?" → Calcitonin (ACal). "Dialysis-associated amyloid?" → β2-microglobulin. "Alzheimer plaque protein?" → Aβ (from APP). "Type 2 DM islet amyloid?" → IAPP/amylin.
- Staining: "Best stain / characteristic finding for amyloid?" → Congo red with apple-green birefringence under polarised light; alternative fluorescent stain → Thioflavin T/S.
- AA vs AL differentiation by potassium permanganate — AA loses staining (sensitive), AL resistant.
- Acute phase reactant precursor of AA → Serum amyloid A (SAA), IL-6 driven.
- Spleen patterns — sago (follicular) vs lardaceous (diffuse red pulp).
- Commonest organ involved / cause of death in systemic AA → kidney / renal failure.
- Drug of choice / treatment — AL → bortezomib + ASCT; ATTR → tafamidis; FMF → colchicine.
- Safest diagnostic biopsy → abdominal subcutaneous fat pad aspiration.
- ECG–ECHO mismatch (low voltage + thick walls) → cardiac amyloidosis.
- Image-based questions on apple-green birefringence and "speckled" myocardium are increasingly common.
Rapid revision
- Amyloid = misfolded protein in β-pleated sheet; Congo red → apple-green birefringence under polarised light.
- AL = immunoglobulin light chain (λ>κ); linked to multiple myeloma; worst prognosis; cardiac death.
- AA = from SAA (IL-6–driven acute phase protein); follows chronic inflammation (RA, TB, osteomyelitis); kidney → death.
- ATTR = transthyretin; familial polyneuropathy/cardiomyopathy (mutant) or senile cardiac (wild-type); Rx tafamidis.
- Aβ2M = β2-microglobulin in long-term dialysis; causes carpal tunnel.
- Aβ = Alzheimer; IAPP/amylin = type 2 DM islets; calcitonin = medullary thyroid Ca; ANF = atrial.
- Serum amyloid P (SAP) is the common non-fibrillar component of every amyloid type.
- Potassium permanganate: AA sensitive (loses stain), AL resistant.
- Spleen — sago (follicular) vs lardaceous (diffuse); EM shows non-branching 8–10 nm fibrils.
- Diagnosis = biopsy + Congo red; safest = abdominal fat pad aspirate; type by mass spectrometry.
- Cardiac amyloid = low-voltage ECG + thick sparkling walls + restrictive physiology; avoid digoxin & CCBs.
- AL treated with bortezomib + melphalan ASCT; FMF/AA prevented with colchicine; acquired factor X deficiency causes bleeding.