Amyloidosis¶
Chapter 117 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Amyloidosis is a group of protein misfolding disorders characterized by extracellular deposition of insoluble fibrils, with AL, AA, ATTR, and A β M as the main types.
- Diagnosis relies on Congo red staining of tissue biopsies (e.g., abdominal fat) and mass spectrometry for precise amyloid typing.
- AL amyloidosis is the most common systemic form, associated with clonal plasma cell disorders, with treatment including HDM/SCT and novel agents like daratumumab.
- ATTR amyloidosis (familial or age-related) involves transthyretin misfolding, with TTR stabilizers (tafamidis, diflunisal) and liver transplantation as key therapies.
- AA amyloidosis is secondary to chronic inflammation, managed by treating the underlying condition and using TNF/IL-1 inhibitors to reduce SAA production.
1. DEFINITION & OVERVIEW¶
Amyloidosis is a group of protein misfolding disorders characterized by extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. The term was coined by Rudolf Virchow in 1854, describing deposits resembling starch under the microscope. Amyloid fibrils exhibit a unique β -sheet structure with green birefringence under polarized light when stained with Congo red. The disease is classified by systemic/localized, acquired/inherited nature, and clinical patterns.
Table 117-1 Amyloid Precursor Proteins and Their Clinical Syndromes¶
| DESIGNATION | PRECURSOR | CLINICAL SYNDROME | CLINICAL INVOLVEMENT |
|---|---|---|---|
| AL | Immunoglobulin light chain | Primary or myeloma-associated | Any |
| AH | Immunoglobulin heavy chain | Rare variant of primary or myeloma-associated | Any |
| AA | Serum amyloid A protein | Secondary; reactive | Renal, heart, other |
| AbM | b-Microglobulin | Hemodialysis-associated | Synovial tissue, bone |
| ATTR | Transthyretin | Familial (mutant)/Age-related (wild type) | Cardiac, peripheral and autonomic nerves, soft tissues, spine, bladder |
| AApoAI | Apolipoprotein AI | Familial | Hepatic, renal |
| AApoAII | Apolipoprotein AII | Familial | Renal |
| Agel | Gelsolin | Familial | Cornea, cranial nerves, skin, renal |
| DESIGNATION | PRECURSOR | CLINICAL SYNDROME | CLINICAL INVOLVEMENT |
|---|---|---|---|
| AFib | Fibrinogen Aa | Familial | Renal, vascular |
| ALys | Lysozyme | Familial | Renal, hepatic |
| ALECT2 | Leukocyte chemotactic factor 2 | Undefined | Renal |
| Ab | Amyloid b protein | Alzheimer’s disease; Down’s syndrome | Central nervous system |
| ACys | Cystatin C | Cerebral amyloid angiopathy | Central nervous system, vascular |
| APrP | Prion protein | Spongiform encephalopathies | Central nervous system |
| AIAPP | Islet amyloid polypeptide (amylin) | Diabetes-associated | Pancreas |
| Acal | Calcitonin | Medullary carcinoma of the thyroid | Thyroid |
| AANF | Atrial natriuretic factor | Atrial fibrillation | Cardiac atria |
| APro | Prolactin | Endocrinopathy | Pituitary |
| ASgl | Semenogelin I | Age-related; incidental autopsy or biopsy finding | Seminal vesicles |
1.1 Classification of Amyloidosis¶
Amyloidosis is categorized into systemic and localized forms based on protein precursor type and clinical involvement. Systemic amyloidoses include AL (light chains), AA (serum amyloid A), ATTR (transthyretin), A β M ( β -microglobulin), and others. Localized amyloidoses include Alzheimer’s (A β ), cerebral amyloid angiopathy (ACys), and prion-related diseases.
1.2 Diagnostic Approach¶
Diagnosis requires histopathologic identification of amyloid deposits via Congo red staining and immunohistochemistry. Mass spectrometry is the gold standard for amyloid typing with 88% sensitivity and 96% specificity. Abdominal fat biopsy is the most accessible tissue for initial screening.
2. EPIDEMIOLOGY¶
AL amyloidosis has an incidence of 8–12 per 100,000 population, with higher rates in older adults. ATTR amyloidosis (familial) is rare (<1/100,000), while age-related ATTR (ATTRwt) is more common in males >65 years. AA amyloidosis is secondary to chronic inflammation/infection, with prevalence decreasing in developed countries due to improved anti-inflammatory therapies. A β M amyloidosis is associated with long-term hemodialysis.
2.1 Risk Factors¶
Age >40, chronic inflammation/infection, hereditary periodic fever syndromes (e.g., familial Mediterranean fever), and genetic mutations in TTR, ApoAI, ApoAII, gelsolin, etc. Long-term dialysis increases risk of A β M amyloidosis.
2.2 Demographics¶
AL amyloidosis is most common in North America. ATTRv (familial) is prevalent in Portuguese, Swedish, and Japanese populations due to founder effects. ATTRwt (age-related) is common in males >65 years.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Amyloidosis arises from misfolding of precursor proteins (e.g., immunoglobulin light chains in AL, transthyretin in ATTR, SAA in AA). Misfolded proteins form oligomers, higher-order polymers, and fibrils that deposit in tissues. The amyloid hypothesis posits that oligomeric intermediates are the most toxic species, causing cellular dysfunction via reactive oxygen species and stress signaling.
3.1 Molecular Mechanisms¶
Misfolding of precursor proteins leads to aggregation into β -sheet-rich fibrils. Oligomers disrupt cell function by inducing oxidative stress and signaling pathways. Amyloidogenic proteins include immunoglobulin light chains, transthyretin, SAA, β -microglobulin, and others.
3.2 Genetic Factors¶
Familial amyloidoses are autosomal dominant with mutations in TTR, ApoAI, ApoAII, gelsolin, fibrinogen A α , lysozyme, etc. LECT2 mutations cause renal amyloidosis in Hispanic/Pakistani populations.
4. CLINICAL FEATURES¶
AL amyloidosis presents with multisystem involvement: nephrotic syndrome (proteinuria, hypoalbuminemia), cardiac dysfunction (concentric hypertrophy, diastolic dysfunction), peripheral neuropathy, and macroglossia. AA amyloidosis causes renal failure, cardiac involvement, and autonomic neuropathy. ATTR amyloidosis features cardiac hypertrophy, peripheral neuropathy, and gastrointestinal dysfunction.
4.1 AL Amyloidosis¶
Commonly affects kidneys (60–70%), heart (70–80%), and nerves. Renal involvement presents with nephrotic syndrome; cardiac involvement leads to diastolic dysfunction and elevated BNP. Macroglossia and raccoon-eye ecchymosis are pathognomonic signs.
4.2 AA Amyloidosis¶
Secondary to chronic inflammation, presents with renal failure, cardiac amyloidosis, and autonomic neuropathy. Symptoms include edema, hypoalbuminemia, and gastrointestinal motility disturbances.
4.3 ATTR Amyloidosis¶
Familial form (ATTRv) causes peripheral neuropathy and cardiac involvement. Age-related form (ATTRwt) presents with concentric cardiac hypertrophy and diastolic dysfunction.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include multiple myeloma, chronic kidney disease, cardiac amyloidosis, and other systemic diseases. Key differentiators include: AL vs. AA amyloidosis (based on precursor protein), ATTR vs. AL (cardiac vs. renal involvement), and localized vs. systemic forms.
5.1 Systemic vs. Localized¶
Systemic amyloidoses (AL, AA, ATTR) involve multiple organs, while localized forms (A β , ACys, APrP) are confined to specific tissues (e.g., brain, cornea).
5.2 Monoclonal Gammopathy¶
Monoclonal proteins in serum/urine (e.g., Bence-Jones proteins) are diagnostic for AL but not always present in AA or ATTR amyloidosis.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis combines clinical suspicion, Congo red staining of tissue biopsies, and mass spectrometry for precise typing. Biomarkers like NT-proBNP, troponin, and free light chains guide staging and prognosis.
6.1 Diagnostic Algorithm¶
Clinical suspicion (nephrotic syndrome, cardiomyopathy, neuropathy) → Congo red staining of abdominal fat or biopsy → Mass spectrometry for typing. Immunohistochemistry and genetic testing confirm specific amyloid types.
6.2 Laboratory Tests¶
Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), free light chain quantitation, NT-proBNP, troponin, and SAA levels are critical for diagnosis and staging.
7. MANAGEMENT & TREATMENT¶
Treatment varies by amyloid type: AL uses HDM/SCT, proteasome inhibitors, and novel agents (e.g., daratumumab); AA targets underlying inflammation; ATTR uses TTR stabilizers or liver transplantation. Supportive care includes diuretics, ACE inhibitors, and cardiac monitoring.
7.1 AL Amyloidosis¶
First-line: HDM/SCT (40% complete response), bortezomib-based regimens (MDex), and daratumumab. Supportive care includes diuretics for nephrotic syndrome and cardiac monitoring.
7.2 AA Amyloidosis¶
Treat underlying inflammation/infection. TNF/IL-1 inhibitors reduce SAA production. Dialysis cessation after renal transplant may improve symptoms.
7.3 ATTR Amyloidosis¶
TTR stabilizers (tafamidis, diflunisal) for ATTRv/ATTRwt. Liver transplantation for ATTRv. Gene silencing agents (patisiran, inotersen) are emerging therapies.
8. PROGNOSIS & COMPLICATIONS¶
AL amyloidosis has a median survival of 1–2 years without treatment but improves with modern therapies. Complications include renal failure, cardiac dysfunction, and thromboembolism. ATTR amyloidosis has a 4–15-year survival depending on organ involvement.
8.1 Survival Outcomes¶
AL: 1–2 years without treatment; 5–10 years with HDM/SCT. ATTR: 4–15 years depending on cardiac vs. neuropathic involvement.
8.2 Complications¶
Renal failure, cardiac amyloidosis, thromboembolism, and autonomic dysfunction. Amyloid cardiomyopathy leads to diastolic dysfunction and heart failure.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Amyloidosis may worsen due to increased proteinuria. Pediatrics: Rare, but possible in congenital forms (e.g., A β , ACys). Elderly: Higher risk for ATTRwt and AL due to age-related protein misfolding. Genetic counseling is essential for hereditary forms.
9.1 Pregnancy¶
Amyloidosis may progress due to increased renal burden. Monitor for proteinuria and cardiac dysfunction.
9.2 Genetic Counseling¶
Familial amyloidoses (ATTRv, LECT2 mutations) require genetic testing and counseling for at-risk relatives.
10. KEY POINTS & CLINICAL PEARLS¶
- Amyloidosis is diagnosed via Congo red staining and mass spectrometry. 2. AL amyloidosis is most common, with treatment including HDM/SCT and daratumumab. 3. ATTR amyloidosis uses TTR stabilizers or liver transplantation. 4. AA amyloidosis is secondary to chronic inflammation. 5. Macroglossia and raccoon-eye ecchymosis are pathognomonic for AL amyloidosis.