82 AMYLOID

# 83 AMYLOID

👩‍⚕️ One-line summary: Amyloid is a family of misfolded proteins that share a common β-pleated sheet structure, deposit extracellularly, resist degradation and damage organs by infiltration. Diagnosis is histological — Congo red stain + apple-green birefringence under polarised light. The protein subtype determines the clinical syndrome: AL (light chains, myeloma, heart) — AA (serum amyloid A, chronic inflammation, kidney) — ATTR (transthyretin, hereditary or senile, heart and nerves) — β2-microglobulin (dialysis, carpal tunnel).

Detailed notes

What is amyloid?

Amyloid is not a single substance but a structural pattern. Many unrelated proteins, when they misfold, can adopt the same configuration — long, antiparallel β-pleated sheets that aggregate into insoluble fibrils. These fibrils:

- Deposit in the extracellular space (between cells, in vessel walls, in basement membranes)

- Resist proteolytic degradation, so they accumulate progressively

- Physically distort tissue architecture and impair organ function

All amyloid fibrils share a common minor component — serum amyloid P (SAP), derived from the pentraxin family — which is exploited in SAP scintigraphy to image total body amyloid load.

➡ Amyloid is defined by structure, not by the protein of origin. That is why so many different diseases (myeloma, RA, Alzheimer's, type 2 diabetes) can all produce "amyloid."

Histology — the diagnostic gold standard

On H&E, amyloid appears as amorphous, eosinophilic (pink), waxy extracellular material. This is suggestive but not specific.

Confirmation requires:

- Congo red stain → amyloid appears salmon-pink/orange-red on standard light microscopy

- Polarised light → the same deposit shows apple-green birefringence — this is pathognomonic

- Thioflavin T → fluorescent alternative, sometimes used as a second-line stain

The β-pleated sheet structure is what causes the apple-green birefringence — the regular fibril orientation rotates polarised light in a characteristic way.

👩‍⚕️ Exam trap: Maltese-cross birefringence belongs to lipid crystals (fat emboli, cholesterol clefts), NOT amyloid. Examiners love this distractor.

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Classification — by precursor protein

The clinical syndrome depends entirely on which protein is misfolding and where it deposits.

Type	Precursor protein	Source / trigger	Main organs	Classic clue
AL (primary)	Immunoglobulin light chains (κ or λ)	Monoclonal plasma cell dyscrasia (myeloma, MGUS)	Heart, kidney, GI, nerves, soft tissue	Macroglossia, periorbital purpura, myeloma
AA (secondary)	Serum amyloid A (acute phase reactant)	Chronic inflammation: RA, IBD, TB, bronchiectasis, osteomyelitis, FMF	Kidney → nephrotic syndrome	Long-standing RA + new proteinuria
ATTR (transthyretin)	Transthyretin (prealbumin, made by liver)	Hereditary (autosomal dominant mutation) or senile (wild-type, age-related misfolding)	Heart + peripheral nerves	Elderly man with HFpEF + carpal tunnel
Aβ2M (dialysis)	β2-microglobulin	Long-term haemodialysis (poorly cleared by standard membranes)	Joints, bone, carpal tunnel	Dialysis patient with bilateral CTS
Aβ	Amyloid-β (from APP)	Cleavage of amyloid precursor protein	Brain (plaques)	Alzheimer's disease
AIAPP	Amylin / IAPP	Co-secreted with insulin	Pancreatic islets	Type 2 diabetes

➡ AL = "L for Light chain, Lambda, myeLoma, Left ventricle."

➡ AA = "A for Acute-phase reactant, Arthritis (RA), kidneys A-ffected."

Clinical features — recognise the system

#### Cardiac (mainly AL and ATTR)

- Restrictive cardiomyopathy — stiff, non-compliant ventricles → diastolic heart failure (HFpEF)

- Echo: symmetrical wall thickening with characteristic "sparkling" / granular myocardium, biatrial enlargement

- ECG paradox: low voltage QRS despite thick walls on echo. This combination is highly specific — myocytes are replaced by inert amyloid that doesn't generate voltage.

- Conduction disease, arrhythmias, syncope

#### Renal (mainly AA, also AL)

- Nephrotic syndrome — proteinuria >3 g/24h, hypoalbuminaemia, peripheral oedema

- Glomerular deposition is typical; eventually progresses to chronic kidney disease

#### Neurological (mainly AL and ATTR)

- Peripheral sensorimotor neuropathy, autonomic neuropathy (postural hypotension, erectile dysfunction)

- Carpal tunnel syndrome — classic in dialysis-related (Aβ2M) and ATTR; often bilateral; may precede systemic diagnosis by years

#### Soft tissue and skin (AL specific — these are exam gold)

- Macroglossia — enlarged tongue with lateral teeth indentations — virtually pathognomonic of AL

- Periorbital purpura ("raccoon eyes") — bleeding into eyelid skin after minor strain (coughing, Valsalva) due to vascular amyloid fragility

- Submandibular gland enlargement, shoulder pad sign

#### Hepatic / GI

- Hepatomegaly with cholestatic LFTs (raised ALP), splenomegaly

- GI dysmotility, malabsorption, bleeding

Investigation

Test	Role
Biopsy	Definitive. Abdominal subcutaneous fat pad or rectal biopsy are least invasive (sensitivity ~70–80% in systemic disease). Affected-organ biopsy for confirmation.
Congo red + immunohistochemistry / mass spec	Confirms amyloid AND identifies subtype (critical — treatment differs)
Serum free light chains + serum/urine electrophoresis	Screens for plasma cell dyscrasia (AL)
SAP scintigraphy	Whole-body amyloid burden, monitoring
ECG	Low voltage
Echo	Thick walls, sparkling myocardium, restrictive filling
Cardiac MRI	Late gadolinium enhancement in subendocardium
Genetic testing	If hereditary ATTR suspected

👩‍⚕️ Why fat pad biopsy? Amyloid is a systemic disease — fibrils are deposited in small vessels throughout the body, including subcutaneous fat. A fat pad aspirate avoids the morbidity of cardiac or renal biopsy.

Treatment — subtype-specific

- AL: treat the plasma cell clone — bortezomib + dexamethasone-based chemotherapy ± autologous stem cell transplant in fit patients. Goal: switch off light chain production.

- AA: treat the underlying inflammation (anti-TNF in RA, colchicine in FMF, antibiotics for chronic infection, surgery for bronchiectasis). Stopping the SAA driver allows existing deposits to slowly regress.

- ATTR: tafamidis (stabilises the transthyretin tetramer, preventing misfolding); patisiran / inotersen (RNAi or antisense oligonucleotide silencing hepatic TTR production); liver transplant historically used in hereditary forms.

- Aβ2M: consider renal transplantation; high-flux dialysis membranes clear β2M better.

Prognosis

- AL with cardiac involvement — historically the worst, median survival 6–12 months untreated, ~1–2 years even with chemotherapy. Cardiac biomarkers (NT-proBNP, troponin) stratify risk.

- AA — better; depends entirely on controlling the underlying inflammatory driver.

- ATTR — slower course; tafamidis significantly improves survival.

Test yourself

What is the stain used to confirm amyloid?

• ((H&E::Shows pink amorphous extracellular material — suggestive but not specific.))
• ((PAS::Highlights glycogen and basement membranes; not amyloid-specific.))
• ((Congo red::☑️ Apple-green birefringence under polarised light is pathognomonic.))
• ((Silver stain::Used for reticulin fibres and organisms (Pneumocystis, spirochaetes).))
• ((Masson's trichrome::Stains collagen blue-green — fibrosis, not amyloid.))

A Congo red stained biopsy is examined under polarised light. What is the characteristic finding?

• ((Maltese cross birefringence::Belongs to lipid crystals — classic distractor, not amyloid.))
• ((Apple-green birefringence::☑️ Pathognomonic of amyloid; caused by β-pleated sheet structure.))
• ((Blue birefringence::Not a recognised amyloid finding.))
• ((Red birefringence::Not a recognised amyloid finding.))

👩‍⚕️ Maltese cross = lipid. Apple-green = amyloid. Easy mark if memorised.

A patient with multiple myeloma develops nephrotic syndrome and a thickened tongue. Rectal biopsy shows pink amorphous deposits. What is the diagnosis?

• ((AA amyloidosis::Driven by chronic inflammation (RA, TB, IBD), not myeloma.))
• ((AL amyloidosis::☑️ Monoclonal light chains from myeloma misfold and deposit systemically.))
• ((ATTR amyloidosis::Transthyretin-derived; hereditary or senile, not myeloma-related.))
• ((β2-microglobulin amyloidosis::Long-term dialysis; presents with carpal tunnel and bone cysts.))

👩‍⚕️ Macroglossia and periorbital purpura are virtually pathognomonic of AL.

Which amyloid subtype most commonly causes restrictive cardiomyopathy in a patient with a plasma cell dyscrasia?

• ((AA::Predominantly renal; cardiac involvement uncommon.))
• ((AL::☑️ Light chains have high tropism for myocardium in myeloma patients.))
• ((ATTR::Causes cardiac amyloid but in elderly without paraproteinaemia.))
• ((β2-microglobulin::Dialysis-related; deposits in joints and synovium.))

An echo shows symmetrically thick ventricular walls with a sparkling myocardium. The ECG shows surprisingly low voltage QRS complexes. What is the diagnosis?

• ((Hypertensive heart disease::Voltage is typically high, not low.))
• ((Cardiac amyloidosis::☑️ Low-voltage ECG with thick walls on echo is the classic paradox.))
• ((Hypertrophic cardiomyopathy::Sarcomeric disorder; voltages are high, no deposition.))
• ((Cardiac sarcoidosis::Granulomatous infiltration; patchy LGE pattern, no birefringence.))

👩‍⚕️ Thick walls + low voltage = amyloid until proven otherwise — myocytes replaced by electrically inert protein.

A patient with 30-year rheumatoid arthritis develops proteinuria and oedema. Renal biopsy shows Congo-red positive deposits. Which precursor protein is responsible?

• ((Immunoglobulin light chains::AL — associated with plasma cell dyscrasia, not RA.))
• ((Serum amyloid A::☑️ AA amyloidosis; SAA is an acute-phase reactant chronically elevated in RA.))
• ((Transthyretin::ATTR — cardiac/neurological, not RA-driven.))
• ((β2-microglobulin::Dialysis amyloid; joint and bone deposition.))

An 82-year-old man has heart failure with preserved ejection fraction and bilateral carpal tunnel syndrome. Cardiac MRI suggests amyloid. Which precursor is most likely?

• ((AL::Would expect paraproteinaemia and rapid progression.))
• ((AA::Requires chronic inflammatory driver — not described.))
• ((Transthyretin (ATTR)::☑️ Wild-type ATTR is the classic cause of senile cardiac amyloidosis; bilateral CTS often precedes diagnosis.))
• ((β2-microglobulin::Requires long-term dialysis.))

👩‍⚕️ Tafamidis stabilises the TTR tetramer and is now first-line in ATTR cardiomyopathy.

A long-term haemodialysis patient develops bilateral carpal tunnel syndrome and cystic bone lesions. Which amyloid protein is responsible?

• ((AL::Light chain — associated with myeloma.))
• ((AA::Driven by chronic inflammation.))
• ((Transthyretin::Cardiac and neurological, not dialysis-specific.))
• ((β2-microglobulin::☑️ Poorly cleared by standard dialysis membranes; deposits in synovium and bone.))

What is the least invasive biopsy site to confirm systemic amyloidosis?

• ((Cardiac biopsy::Highest yield but invasive — reserved for confirmation.))
• ((Renal biopsy::Useful if renal involvement but carries bleeding risk.))
• ((Abdominal subcutaneous fat pad aspirate::☑️ Safe, sensitivity ~70–80% in systemic disease.))
• ((Liver biopsy::Risk of haemorrhage — amyloid-infiltrated liver is fragile.))

First-line treatment for AL amyloidosis is directed at:

• ((The amyloid deposits themselves::No drug currently dissolves established AL deposits.))
• ((The underlying plasma cell clone::☑️ Bortezomib + dexamethasone ± autologous stem cell transplant switches off light chain production.))
• ((Stabilising transthyretin::Tafamidis is used in ATTR, not AL.))
• ((Treating chronic inflammation::This is the strategy for AA, not AL.))

Revision summary

➡ Amyloid = misfolded proteins forming β-pleated sheets, deposited extracellularly, resistant to degradation.

➡ Diagnosis = Congo red stain + apple-green birefringence under polarised light.

➡ AL — Light chains from plasma cells (myeloma) → heart, kidney, macroglossia, periorbital purpura.

➡ AA — Acute-phase serum amyloid A from chronic inflammation (RA, TB, IBD, FMF) → kidney/nephrotic.

➡ ATTR — transthyretin; hereditary or senile → elderly HFpEF + bilateral carpal tunnel.

➡ Aβ2M — long-term dialysis → carpal tunnel, bone cysts.

➡ Cardiac amyloid paradox: thick walls on echo + low voltage ECG.

➡ Biopsy: abdominal fat pad or rectum first (least invasive); affected organ to confirm.

➡ Treatment: AL → chemo (bortezomib/dex) ± ASCT; AA → treat inflammation; ATTR → tafamidis, patisiran.

➡ Maltese cross = lipid. Apple-green = amyloid.