Amyloidosis¶
Chapter 117 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 117
Key Clinical Points¶
- Amyloidosis is a group of protein misfolding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils with a common β-pleated sheet structure.
- Oligomeric intermediates are more toxic than mature fibrils, complicating therapeutic strategies.
- Primary systemic types include AL (light chain), ATTR (transthyretin), and AA (serum amyloid A).
- Abdominal fat aspiration is the preferred initial biopsy site due to >80% sensitivity for systemic cases.
- Diagnosis requires histopathological confirmation via Congo red staining (showing green birefringence) and mass spectrometry or IHC for protein typing.
- Clinical hallmarks include macroglossia, periorbital ecchymoses (livedo reticularis), and restrictive cardiomyopathy.
- Treatment is specific to the amyloid type: Bortezomib-based regimens for AL; TTR stabilizers (Tafamidis, diflunisal) for ATTR; and treating underlying inflammation for AA.
- ATTRwt (wild-type) is specifically associated with patients >65 years old presenting with cardiac involvement.
- Mass spectrometry of extracted amyloid proteins provides 88% sensitivity and 96% specificity.
- Rapid identification of the amyloid type is critical for determining management pathways.
1. DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Amyloidosis is the term for a group of protein misfolding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs.
• Structural Characteristics: ◦ Fibrils adopt a common β-pleated sheet structure. ◦ Formation involves oligomeric intermediates → these are more toxic than mature fibrils.
• Pathophysiology of Damage: ◦ Mechanical compression of tissues. ◦ Induction of reactive oxygen species. ◦ Disruption of cellular signaling pathways.
• Classification by Precursor Protein: ◦ AL (light chain): From monoclonal immunoglobulin light chains (B-cell/plasma cell disorders). ◦ ATTR (transthyretin): Wild-type or mutant TTR protein (hereditary/familial). ◦ AA (serum amyloid A): Derived from acute-phase reactant SAA (chronic inflammation/infection). ◦ AβM (beta-2 microglobulin): From dialysis-associated β2-microglobulin deposits. ◦ Aβ (Alzheimer's): Abnormal processing of amyloid precursor protein.
1.1 Types of Amyloidosis and Clinical Syndromes¶
• Systemic Amyloidoses: ◦ AL: Associated with primary or myeloma-related conditions; involves any organ. ◦ AH: Immunoglobulin heavy chain; rare variant of primary/myeloma-associated; any involvement. ◦ AA: Secondary/reactive; primarily affects renal, heart, and other organs. ◦ AβM: Associated with hemodialysis; involves synovial tissue and bone. ◦ ATTR: ◦ ATTRm (mutant): Familial; cardiac, peripheral/autonomic nerves, soft tissues, spine, bladder. ◦ ATTRwt (wild-type): Age-related; primarily cardiac involvement in patients >65 years. ◦ Other Systemic Types: ◦ AApoAI (Apolipoprotein AI): Familial; hepatic, renal. ◦ AApoAII (Apolipoprotein AII): Familial; renal. ◦ Agel (Gelsolin): Familial; cornea, cranial nerves, skin, renal. ◦ AFib (Fibrinogen Aα): Familial; renal, vascular. ◦ ALys (Lysozyme): Familial; renal, hepatic. ◦ ALECT2 (Leukocyte chemotactic factor 2): Undefined; renal.
• Localized Amyloidoses: ◦ Amyloid β: Alzheimer’s disease; Down’s syndrome. ◦ Cystatin C: Cerebral amyloid angiopathy. ◦ Prion protein: Spongiform encephalopathies. ◦ Islet amyloid polypeptide (amylin): Diabetes-associated. ◦ Calcitonin: Medullary carcinoma of the thyroid. ◦ Atrial natriuretic factor: Atrial fibrillation. ◦ Prolactin: Endocrinopathy. ◦ Semenogelin I: Age-related; incidental finding.
2. EPIDEMIOLOGY & RISK FACTORS¶
• AL amyloidosis: Most common systemic type, often associated with plasma cell dyscrasias. • ATTR amyloidosis: Familial forms account for 5-10% of all amyloid cases. • AA amyloidosis: Occurs in 10-25% of patients with chronic inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease). • AβM amyloidosis: Develops in 2-5% of long-term dialysis patients.
• Hereditary Factors: ◦ ATTR: Autosomal dominant inheritance with TTR gene mutations. ◦ AA (FMF-associated): Linked to MEFV gene mutations.
3. CLINICAL MANIFESTATIONS¶
• Organ Systems: ◦ Cardiac: Restrictive cardiomyopathy, dyspnea, edema, arrhythmias. ◦ Renal: Proteinuria, nephrotic syndrome, progressive renal failure. ◦ Neurologic: Peripheral sensory/motor neuropathy, autonomic dysfunction. ◦ Gastrointestinal: Malabsorption, diarrhea, weight loss. ◦ Cutaneous: Macroglossia (Fig. 117-1), periorbital ecchymoses (livedo reticularis) (Fig. 117-2), nail dystrophy (Fig. 117-3). ◦ Hematologic: Anemia, leukopenia, thrombocytopenia.
• Diagnostic Red Flags: ◦ Unexplained cardiomyopathy with preserved ejection fraction. ◦ Nephrotic-range proteinuria without glomerulonephritis. ◦ Bilateral carpal tunnel syndrome in older adults. ◦ Macroglossia and periorbital ecchymoses (livedo reticularis). ◦ Dialysis-related osteoarthropathy with amyloid deposits.
4. DIAGNOSTIC APPROACH¶
- Clinical Suspicion: Based on organ involvement (nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy) and macroglossia.
- Initial Biopsy (Noninvasive): Perform Congo red staining of abdominal fat. → If (+) for amyloid: Proceed to Mass spectrometry or IHC analysis → Identify specific protein → Final Diagnosis.
- Secondary Biopsy (Invasive): If noninvasive biopsy is (-), perform biopsy of affected major organs (e.g., heart, kidney). → If (+) for amyloid: Proceed to Mass spectrometry or IHC analysis → Identify specific protein → Final Diagnosis.
- Termination: If both noninvasive and invasive biopsies are (-) → No further work-up.
• Laboratory Evaluation: ◦ Serum/urine immunofixation: To detect monoclonal proteins (e.g., IgGκ) in AL amyloidosis. ◦ TTR gene sequencing: For identifying hereditary ATTR variants. ◦ SAA levels: Elevated in AA amyloidosis. ◦ β2-microglobulin: Increased in AβM amyloidosis.
• Imaging Studies: ◦ Echocardiography: Assess cardiac involvement (left ventricular wall thickening, restrictive pattern). ◦ Cardiac MRI: Use T1 mapping for myocardial amyloid infiltration. ◦ Abdominal ultrasound: Used to guide fat aspiration biopsy.
Diagnostic Flowchart Logic (Figure 117-1)¶
• Step 1: Noninvasive Tissue Biopsy (Congo red staining of abdominal fat) ◦ Result (+): Proceed to Mass spectrometry or IHC → Identify protein type. ◦ Result (-): Move to Step 2. • Step 2: Invasive Tissue Biopsy (Affected major organs) ◦ Result (+): Proceed to Mass spectrometry or IHC → Identify protein type. ◦ Result (-): No further work-up.
• Outcome Determination by Protein Type: ◦ Kappa or lambda light chain: AL amyloidosis → Screen for cardiac, renal, hepatic, autonomic involvement, and factor X deficiency. ◦ Amyloid A protein: AA amyloidosis → Screen for renal and hepatic involvement. ◦ Transthyretin (with mutation/family history): ATTRm familial amyloidosis → Screen for neuropathy, cardiomyopathy, and relatives. ◦ Transthyretin (wild-type, age >65, cardiac): ATTRwt or age-related amyloidosis. ◦ Negative: Familial amyloidosis of other type → Screen for renal, hepatic, and GI involvement.
5. MANAGEMENT & TREATMENT¶
- AL Amyloidosis Treatment: • Chemotherapy: Bortezomib-based regimens (e.g., VRd, VCD). • Stem cell transplantation: For eligible patients. • Supportive care: For organ dysfunction.
- ATTR Amyloidosis Treatment: • TTR stabilizers: Tafamidis, diflunisal. • Liver transplantation: For hereditary variants.
- AA Amyloidosis Treatment: • Target underlying inflammation (e.g., biologics for rheumatoid arthritis). • Colchicine: Specifically for FMF-associated cases.
• Monitoring & Prognosis: ◦ Response Assessment: Monitor serum free light chain levels and organ function tests. ◦ Prognostic Factors: Survival depends on amyloid type and severity of organ involvement. ◦ AL Specific: MRD negativity correlates with improved outcomes.
KEY PEARLS & HIGH-YIELD POINTS¶
• Diagnostic Sensitivity: Abdominal fat aspiration has >80% sensitivity for systemic cases. • Analytical Accuracy: Mass spectrometry of extracted amyloid proteins provides 88% sensitivity and 96% specificity. • Age Threshold: ATTRwt is specifically associated with patients >65 years old with cardiac involvement. • Pathology Hallmark: Congo red staining identifies amyloid via characteristic green birefringence under polarized light microscopy.
Reference Tables¶
TABLE 117-1 Amyloid Precursor Proteins and Their Clinical Syndromes DESIGNATION Systemic Amyloidoses AL AH AA A β M…¶
Harrison's 22e, p.896
| DESIGNATION | PRECURSOR | CLINICAL SYNDROME | CLINICAL INVOLVEMENT |
|---|---|---|---|
| Systemic Amyloidoses | |||
| AL | Immunoglobulin light chain | Primary or myeloma-associateda | Any |
| AH | Immunoglobulin heavy chain | Rare variant of primary or myeloma-associated | Any |
| AA | Serum amyloid A protein | Secondary; reactiveb | Renal, heart, other |
| AβM 2 |
β-Microglobulin 2 |
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 |
| AFib | Fibrinogen Aα | Familial | Renal, vascular |
| ALys | Lysozyme | Familial | Renal, hepatic |
| ALECT2 | Leukocyte chemotactic factor 2 | Undefined | Renal |
| Localized Amyloidoses | |||
| Amyloid β protein | Alzheimer’s disease; Down’s syndrome | ||
| Cystatin C | Cerebral amyloid angiopathy | ||
| Prion protein | Spongiform encephalopathies | ||
| Islet amyloid polypeptide (amylin) | Diabetes-associated | ||
| Calcitonin | Medullary carcinoma of the thyroid | ||
| Atrial natriuretic factor | Atrial fibrillation | ||
| Prolactin | Endocrinopathy | ||
| Semenogelin I | Age-related; incidental autopsy or biopsy finding |