Overview
Amyloidosis
1. Overview
Amyloidosis is a group of rare but serious conditions caused by the extracellular deposition of misfolded protein fibrils (amyloid) in tissues and organs. These insoluble fibrils disrupt normal organ function, leading to progressive failure.
Key Classifications
The disease is classified by the precursor protein:
- AL Amyloidosis (Light Chain): Most common. Due to clonal plasma cell disorder producing toxic light chains. Medical emergency.
- ATTR Amyloidosis (Transthyretin):
- Wild-type (ATTRwt): Age-related (Senile). Common cause of HFpEF in elderly men.
- Hereditary (ATTRv): Genetic mutation. Neuropathy + Cardiomyopathy.
- AA Amyloidosis (Serum Amyloid A): Secondary to chronic inflammation (e.g., RA, IBD, chronic infections).
Why This Matters
- Underdiagnosed: Often missed cause of heart failure and nephrotic syndrome.
- Time-Critical: AL amyloidosis progresses rapidly; early chemotherapy is lifesaving.
- New Therapies: Game-changing treatments for ATTR (Tafamidis, Patisiran) now exist.
2. Pathophysiology
┌─────────────────────────────────────────────────────────────────────────────┐
│ AMYLOIDOSIS PATHOPHYSIOLOGY │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ PRECURSOR PROTEIN PRODUCTION │ │
│ │ • AL: Plasma cells produce unstable light chains (Kappa/Lambda) │ │
│ │ • ATTR: Liver produces Transthyretin (misfolded or unstable) │ │
│ │ • AA: Liver produces Serum Amyloid A (acute phase reactant) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ MISFOLDING & AGGREGATION │ │
│ │ • Protein loses native structure → Beta-pleated sheet │ │
│ │ • Protofilaments form insoluble AMYLOID FIBRILS │ │
│ │ • Resistant to normal proteolysis (cannot be cleared) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ TISSUE DEPOSITION │ │
│ │ • Fibrils deposit in extracellular space │ │
│ │ • Affinity for specific organs (Tropism) │ │
│ │ - AL: Heart, Kidney, Nerves, Soft tissue │ │
│ │ - ATTR: Heart, Nerves (Carpal tunnel) │ │
│ │ - AA: Kidney, Liver, Spleen │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ ORGAN DYSFUNCTION │ │
│ │ • Disruption of architecture (Mechanical) │ │
│ │ • Direct cellular toxicity (especially Light Chains on Heart) │ │
│ │ • Restrictive Cardiomyopathy │ │
│ │ • Nephrotic Syndrome │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
Apple-Green Birefringence
The defining histological feature of all amyloid types:
- Fibrils bind Congo Red stain.
- Under polarized light, they exhibit Apple-Green Birefringence.
3. Clinical Features
History Taking
Red Flag Symptoms (Think Amyloid if combined):
- Heart: Breathlessness, edema, syncope (Restrictive CM).
- Kidney: Frothy urine (Nephrotic syndrome).
- Nerves: Tingling/numbness (Peripheral neuropathy), dizziness (Autonomic).
- Soft Tissue: Tongue swelling (Macroglossia), easy bruising.
- History: Bilateral Carpal Tunnel Syndrome (often precedes ATTR cardiac diagnosis by 5-10 years).
Physical Examination
| System | Findings (Classic) |
|---|---|
| General | Cachexia, Purpura (especially periorbital "Raccoon Eyes" - AL) |
| Cardiac | Signs of Right HF (Raised JVP, Ascites, Edema), S3/S4 |
| Renal | Edema (Nephrotic), Orthostatic hypotension |
| Neurological | Stocking-glove neuropathy, Postural drop |
| Head/Neck | Macroglossia (Large tongue with tooth indentations - specific for AL) |
| Hands | Thenar wasting (Carpal tunnel) |
4. Diagnosis
Diagnostic Algorithm
Step 1: Screen for Monoclonal Protein (Rule out AL first - Emergency)
- Serum Free Light Chains (FLC)
- Serum Protein Electrophoresis (SPEP) + Immunofixation
- Urine Protein Electrophoresis (UPEP) + Immunofixation
Step 2: Tissue Diagnosis (Confirm Amyloid)
- Abdominal Fat Pad Biopsy: Simple, 70-80% sensitive for AL.
- Organ Biopsy: Kidney or Heart (if fat pad negative but high suspicion).
- Staining: Congo Red positive = Amyloid.
- Typing: Mass spectrometry or Immunohistochemistry (MANDATORY to differentiate AL from ATTR).
Step 3: Imaging
- Echo: "Granular sparkling" myocardium, Bi-atrial enlargement, LV hypertrophy despite low voltage ECG.
- Cardiac MRI: Diffuse Late Gadolinium Enhancement (LGE) - Gold standard imaging.
- DPD/PYP Scan (Bone Scintigraphy): Highly sensitive for ATTR cardiomyopathy. Can diagnose ATTR without biopsy if AL ruled out.
Differential Diagnosis (AL vs ATTR)
| Feature | AL Amyloidosis | ATTR Amyloidosis |
|---|---|---|
| Cause | Plasma cell clone | Ageing or Genetic |
| Progression | Rapid (Months) | Slow (Years) |
| Macroglossia | Common (15%) | Absent |
| Periorbital Purpura | Specific | Absent |
| Bone Scan (DPD) | Negative (Grade 0) | Strongly Positive (Grade 2/3) |
| Light Chains | Abnormal Ratio | Normal |
5. Management Algorithm
┌─────────────────────────────────────────────────────────────────────────────┐
│ AMYLOIDOSIS MANAGEMENT ALGORITHM │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ CONFIRMED AMYLOIDOSIS │
│ (Congo Red Positive) │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ DETERMINE TYPE (CRITICAL STEP) │ │
│ │ • Look for Light Chains (FLC, Immunofixation) │ │
│ │ • Look for TTR (DPD Scan, Genetic testing) │ │
│ │ • Tissue Typing (Mass Spec) if unsure │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ┌─────────────────────────┼──────────────────────────┐ │
│ ↓ ↓ ↓ │
│ ┌────────────────────┐ ┌───────────────────────┐ ┌──────────────────┐ │
│ │ AL AMYLOIDOSIS │ │ ATTR AMYLOIDOSIS │ │ AA AMYLOIDOSIS │ │
│ │ (Hematologic Emer- │ │ (Senile or Hereditary)│ │ (Inflammatory) │ │
│ │ gency) │ │ │ │ │ │
│ └────────────────────┘ └───────────────────────┘ └──────────────────┘ │
│ ↓ ↓ ↓ │
│ ┌────────────────────┐ ┌───────────────────────┐ ┌──────────────────┐ │
│ │ TREAT THE CLONE │ │ STABILIZE THE PROTEIN │ │ TREAT INFLAMMATION│ │
│ │ │ │ │ │ │ │
│ │ 1. CyBorD (First │ │ 1. Tafamidis │ │ 1. Treat RA/IBD │ │
│ │ Line) │ │ (Stabilizer) │ │ Aggressively │ │
│ │ - Cyclophos. │ │ - Reduces morta- │ │ │ │
│ │ - Bortezomib │ │ lity in CM │ │ 2. Anti-cytokines│ │
│ │ - Dexamethasone │ │ │ │ (IL-6, TNF) │ │
│ │ │ │ 2. Silencers (RNAi) │ │ │ │
│ │ 2. Autologous SCT │ │ - Patisiran │ │ 3. Antimicrobials│ │
│ │ (Use in fit │ │ - Inotersen │ │ (if infection) │ │
│ │ patients) │ │ (Neuropathy dominant)│ │ │
│ │ │ │ │ │ │ │
│ │ 3. Daratumumab │ │ 3. Supportive │ │ │ │
│ │ (Anti-CD38) │ │ - Diuretics (Loop) │ │ │ │
│ │ - Now standard │ │ - Beta-blockers │ │ │ │
│ │ frontline │ │ poorly toler- │ │ │ │
│ │ │ │ ated │ │ │ │
│ └────────────────────┘ └───────────────────────┘ └──────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
Management of AL Amyloidosis (Light Chain)
- Goal: Rapid hematologic response (suppress light chain production) to preserve organ function.
- Regimen: Dara-CyBorD (Daratumumab + Cyclophosphamide + Bortezomib + Dexamethasone) is the new standard of care (ANDROMEDA trial).
- Transplant: Autologous Stem Cell Transplant (ASCT) for younger, fitter patients with preserved cardiac function.
Management of ATTR Amyloidosis (Transthyretin)
- Tafamidis: Oral TTR stabilizer. Prevents tetramer dissociation. Approved for cardiomyopathy. (ATTR-ACT trial: 30% reduction in mortality).
- Patisiran / Inotersen: RNA interference (gene silencers). Reduce production of TTR by liver. Approved for polyneuropathy.
Supportive Care (Crucial)
- Heart Failure: Loop diuretics (Furosemide) mainstay. Caution with Beta-blockers and ACEi/ARBs (poorly tolerated due to hypotension/autonomic failure). Digoxin binds amyloid fibrils (toxicity risk).
- Nephrotic Syndrome: Salt restriction, diuretics.
- Hypotension: Midodrine, compression stockings.
6. Prognosis
- AL Amyloidosis: Traditionally poor (<1 year if cardiac), but significantly improved with Daratumumab/Bortezomib. Cardiac response is the main determinant of survival.
- ATTRwt (Senile): Slower progression (median survival 3-5 years from diagnosis).
- Biomarkers:
- Cardiac: NT-proBNP and Troponin (Mayo Staging).
- Hematologic: difference between involved and univolved Free Light Chains (dFLC).
7. Complications
- Sudden Cardiac Death: Common due to electromechanical dissociation.
- End-Stage Renal Disease: Requiring dialysis (amyloid doesn't clear).
- Severe Malnutrition: Gut amyloid causes malabsorption and motility issues.
- Embolic Events: Atrial thrombi common even in sinus rhythm (atrial standstill).
8. Special Considerations
Atrial Fibrillation in Amyloid
- High risk of thromboembolism.
- CHADS-VASc score underestimates risk.
- Anticoagulation recommended regardless of score if cardiac amyloid confirmed.
Carpal Tunnel Syndrome
- Bilateral CTS, especially in men >50 without occupational risk, is a strong red flag for ATTR amyloidosis.
- Refer for cardiac evaluation if red flags present.
9. Key Clinical Pearls
Exam-Focused Points
- Differentiate AL vs ATTR: AL is an emergency (Chemo); ATTR is slow (Stabilizers). AL has light chains; ATTR has positive Bone Scan.
- Macroglossia: Highly specific for AL (but only 15% sensitivity).
- "Granular Sparkling" Myocardium: Classic Echo description.
- Low Voltage ECG + LV Hypertrophy: The classic mismatch. LV is thick with amyloid (not muscle), so voltage is low.
- Periorbital Purpura: "Raccoon eyes" - induced by valsalva/endoscopy. Pathognomonic for AL.
- Avoid Beta-Blockers: In cardiac amyloid, stroke volume is fixed; heart rate is needed to maintain cardiac output. Beta-blockers can cause hemodynamic collapse.
Common Exam Scenarios
- Elderly man with HF, preserved EF, bilateral carpal tunnel. Dx? (ATTRwt). Test? (DPD Bone Scan).
- Patient with nephrotic syndrome, tongue swelling, and bruising. Dx? (AL). Test? (Fat pad biopsy/FLC).
10. Patient Explanation
What is Amyloidosis?
"Amyloidosis is a condition where an abnormal protein (amyloid) builds up in your tissues and organs. Think of it like a 'starch' that stiffens your organs.
- If it builds up in the heart, the heart becomes stiff and can't pump well.
- If it builds up in the kidneys, they leak protein."
Is it Cancer?
"AL amyloidosis is related to bone marrow cancer (myeloma) cells, and we treat it with similar chemotherapy, but it doesn't form solid tumors. Other types, like ATTR, are not cancer at all but related to aging or genetics."
What is the Treatment?
"It depends entirely on the protein type:
- For AL: We use chemotherapy to stop the factory (bone marrow) from making the protein.
- For ATTR: We use new tablets (Tafamidis) to stabilize the protein so it doesn't deposit."
11. Evidence & Guidelines
Key Guidelines
| Guideline | Organization | Year | Key Points |
|---|---|---|---|
| AL Amyloidosis | British Society for Haematology | 2021 | Daratumumab front line, ASCT criteria |
| Cardiac Amyloid | ESC / AHA | 2021 | Diagnostic algorithm (Bone scan vs biopsy) |
Landmark Trials
ANDROMEDA (2021):
- Daratumumab-CyBorD vs CyBorD in AL Amyloidosis.
- Major improvement in hematologic complete response (53% vs 18%).
- Standard of care established.
ATTR-ACT (2018):
- Tafamidis in ATTR Cardiomyopathy.
- 30% reduction in all-cause mortality.
- Reduced hospitalizations.
Evidence-Based Recommendations
| Recommendation | Evidence Level |
|---|---|
| Dara-CyBorD for AL | High (ANDROMEDA) |
| Tafamidis for ATTR-CM | High (ATTR-ACT) |
| Bone Scan for ATTR Dx | High |
| Anticoagulation in AF | Moderate |
12. References
- Kastritis E, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis (ANDROMEDA). N Engl J Med. 2021;385(1):46-58.
- Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-ACT). N Engl J Med. 2018;379(11):1007-1016.
- Palladini G, Merlini G. What is new in the diagnosis and management of light chain amyloidosis? Blood. 2016;128(2):159-168.
- Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis: A position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554-1568.
- Gillmore JD, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133(24):2404-2412.