What is the pathophysiology and management of amyloidosis?

Comprehensive Overview of Amyloidosis

Definition and Classification

Amyloidosis is a heterogeneous group of protein misfolding disorders characterized by extracellular deposition of insoluble fibrillar protein aggregates in tissues and organs, leading to progressive organ dysfunction and, without treatment, death. 1

The major types of systemic amyloidosis include:

• AL (Light Chain) Amyloidosis: The most common form, affecting approximately 10 per million people annually, caused by clonal plasma cell proliferation producing unstable immunoglobulin light chains that misfold and deposit in tissues 1
• ATTR (Transthyretin) Amyloidosis: Divided into hereditary (variant) caused by TTR gene mutations, and wild-type (senile) occurring with aging 1, 2
• AA (Reactive) Amyloidosis: Secondary to chronic inflammatory conditions like rheumatoid arthritis or chronic infections, with deposition of serum amyloid A protein 1, 2
• Dialysis-related Amyloidosis: Caused by β2-microglobulin deposition in patients on long-term dialysis 1
• Isolated Atrial Amyloidosis: Limited to cardiac atria with atrial natriuretic factor deposition 1

Pathophysiology

Molecular Mechanisms

The fundamental pathologic process involves the transformation of normally soluble proteins into insoluble β-pleated sheet fibrils that aggregate and deposit extracellularly 3, 4. In AL amyloidosis specifically, a small bone marrow plasma cell clone (typically <10% plasma cells) secretes unstable free light chains (FLC) that circulate and infiltrate peripheral organs 1, 5.

Organ-Specific Pathology

Cardiac involvement occurs through multiple mechanisms 1:

• Amyloid deposits in the myocardial interstitium directly disrupt myocyte function, causing both diastolic and systolic dysfunction 1
• Direct myocyte necrosis occurs via oxidative stress from amyloid deposits 1
• Infiltration of the conduction system leads to arrhythmias and conduction abnormalities 1
• Deposition in coronary vessel walls (media and adventitia) can cause cardiac ischemia 1
• Valvular thickening occurs but rarely causes significant dysfunction 1
• Pericardial deposits can produce pericardial effusion 1

The disease typically progresses from restrictive cardiomyopathy with preserved ejection fraction and diastolic dysfunction to advanced systolic heart failure 1.

Renal involvement manifests as proteinuria, nephrotic syndrome, and progressive renal dysfunction due to glomerular and vascular amyloid deposition 1, 6.

Neurologic involvement includes peripheral neuropathy (often with autonomic features) and carpal tunnel syndrome from nerve infiltration 1, 6.

Gastrointestinal involvement causes malabsorption, weight loss, diarrhea, constipation, and GI bleeding 1, 6.

Clinical Presentation

AL Amyloidosis

The clinical presentation is notoriously vague and nonspecific, contributing to delayed diagnosis 1. Key manifestations include:

• Cardiac: Heart failure symptoms (dyspnea, edema, fatigue), arrhythmias, syncope 1
• Renal: Proteinuria (often nephrotic range), edema, renal insufficiency 1
• Neurologic: Peripheral neuropathy, autonomic dysfunction (orthostatic hypotension, early satiety, erectile dysfunction), bilateral carpal tunnel syndrome 1, 6
• Dermatologic: Periorbital purpura (periorbital ecchymoses), waxy skin thickening 6
• Macroglossia: Enlarged tongue with indentations from teeth 6
• Submandibular gland enlargement 6
• Hepatomegaly without significant liver dysfunction 1
• Coagulopathy: Acquired factor X deficiency causing bleeding diathesis 6

More than 69% of patients have multiple organ involvement at diagnosis 1.

ATTR Amyloidosis

Wild-type ATTR predominantly affects elderly men with cardiac involvement, while hereditary ATTR presents with variable cardiac and neurologic manifestations depending on the specific TTR mutation 1, 2.

Diagnostic Approach

When to Suspect Amyloidosis

High clinical suspicion is mandatory for early diagnosis. Consider amyloidosis in patients presenting with 1, 6, 7:

• Unexplained heart failure with preserved ejection fraction or restrictive cardiomyopathy, especially with increased wall thickness on echocardiography 1, 6
• Nephrotic-range proteinuria without diabetes or other obvious cause 6
• Peripheral neuropathy with autonomic features 6
• Bilateral carpal tunnel syndrome, especially if recurrent after surgical release 6
• Periorbital purpura or macroglossia 6
• Multisystem disease involving heart, kidney, liver, and nervous system 2
• Unexplained hepatomegaly 1
• Bleeding diathesis with prolonged PTT 6

Diagnostic Testing Algorithm

Step 1: Monoclonal Protein Screening (for AL Amyloidosis)

All three tests must be performed simultaneously 6, 2:

• Serum free light chain (sFLC) assay with kappa/lambda ratio 6
• Serum immunofixation electrophoresis (SIFE) 6
• Urine immunofixation electrophoresis (UIFE) on 24-hour collection 6

Critical pitfall: Standard protein electrophoresis (SPEP/UPEP) alone has insufficient sensitivity and should never be used as the sole screening test 6.

Step 2: Tissue Biopsy for Amyloid Confirmation

Biopsy with Congo Red staining is required to confirm amyloid deposition 2, 8. Under polarized light microscopy, amyloid displays characteristic apple-green birefringence 2, 8.

Biopsy site selection 8, 7:

• Abdominal fat pad aspiration: Least invasive, 70-80% sensitivity in AL amyloidosis 8
• Rectal biopsy: Higher sensitivity than fat pad 8
• Bone marrow biopsy: Necessary to demonstrate clonal plasma cell proliferation in AL amyloidosis 6
• Organ biopsy (kidney, heart, liver): Most definitive when clinically involved organ is biopsied 8

Exception: Cardiac ATTR amyloidosis may be diagnosed without biopsy if stringent criteria are met (positive nuclear scintigraphy with technetium-99m pyrophosphate and absence of monoclonal protein) 8.

Step 3: Amyloid Typing (Absolutely Mandatory)

Accurate identification of the amyloidogenic protein is absolutely crucial because AL and ATTR amyloidosis require completely different treatments 6, 2, 7.

• Mass spectrometry (LC-MS/MS): Gold standard with 88% sensitivity and 96% specificity 6, 2
• Immunohistochemistry: Less reliable than mass spectrometry, risk of mistyping 8, 7
• Immunofluorescence: Alternative antibody-based method 2

Critical pitfall: Mistyping amyloid leads to inappropriate and potentially harmful treatment 7.

Step 4: Organ Involvement Assessment

Cardiac evaluation 1, 6:

• Echocardiography: Increased wall thickness, "sparkling" granular appearance, biatrial enlargement, small pericardial effusion 1
• Cardiac MRI: Late gadolinium enhancement, elevated native T1 mapping 1
• Cardiac biomarkers: NT-proBNP, troponin (essential for staging) 1, 6
• ECG: Low voltage despite increased wall thickness (classic finding), pseudoinfarct pattern 1
• Nuclear scintigraphy (technetium-99m pyrophosphate): Highly specific for ATTR cardiac amyloidosis 8

Renal evaluation 6:

• 24-hour urine protein quantification 6
• Serum creatinine and eGFR 6

Neurologic evaluation 6:

• Nerve conduction studies if peripheral neuropathy suspected 6
• Autonomic function testing 6

Genetic testing: For all patients with ATTR amyloidosis to identify specific TTR mutations and enable family screening 2.

Risk Stratification and Prognosis

AL Amyloidosis Staging

Cardiac involvement is the primary driver of mortality 1, 6. The revised Mayo Clinic staging system uses cardiac biomarkers 1:

• Stage I: NT-proBNP <1800 ng/L and troponin T <0.025 ng/mL
• Stage II: Not meeting Stage I or III criteria
• Stage III: NT-proBNP ≥1800 ng/L and troponin T ≥0.025 ng/mL
• Stage IV: NT-proBNP >8500 ng/L and troponin T >0.05 ng/mL

Prognosis without treatment 1:

• Median survival in AL amyloidosis: 13 months 1
• With heart failure symptoms: 4 months 1
• Cardiac involvement drastically worsens prognosis 1, 6

ATTR Amyloidosis Prognosis

• Hereditary ATTR: Median survival approximately 70 months 1
• Wild-type ATTR: Median survival approximately 75 months 1

Treatment Strategies

AL Amyloidosis Treatment

The fundamental goal is to eradicate the pathologic plasma cell clone and eliminate amyloidogenic light chain production 6, 5.

Treatment Selection Algorithm

Step 1: Assess ASCT Eligibility 1, 6

ASCT-eligible criteria (approximately 20% of patients) 1, 6:

• Age <60-65 years 1, 6
• ≤2 organs involved 6
• Adequate cardiac function (no severe cardiac involvement) 6
• Good performance status 6
• Serum creatinine <2 mg/dL (if 60-65 years, reduce melphalan dose to 100 mg/m²) 6

Step 2: Select First-Line Therapy

For ASCT-eligible patients 6:

• Preferred: Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) as induction, followed by high-dose melphalan (140-200 mg/m²) with autologous stem cell transplantation 6
• Alternative: High-dose melphalan with ASCT without induction 6

For ASCT-ineligible patients (majority) 6:

• Preferred first-line: Daratumumab-CyBorD (cyclophosphamide, bortezomib, dexamethasone) 6
  • Achieves very good partial response or better in 78.5% of patients 6
• Alternative: CyBorD without daratumumab 6
• Alternative: Melphalan 0.22 mg/kg plus high-dose dexamethasone 40 mg days 1-4 every 28 days (achieves 67% hematologic response, 33% complete remission) 6

Medication Details and Toxicities

Daratumumab (anti-CD38 monoclonal antibody) 6:

• Recently FDA-approved for AL amyloidosis 6
• Cardiac toxicities: Heart failure (12%), arrhythmias (8%), atrial fibrillation (6%) 6
• Requires close cardiac monitoring during treatment 6

Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) 6:

• Risks: Grade 3 heart failure, decreased LVEF, pulmonary hypertension 6
• Peripheral neuropathy (especially bortezomib) 6

Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide) 6:

• Cardiac and renal concerns 6
• Thromboembolic risk requiring prophylaxis 5

Corticosteroids (dexamethasone, prednisone) 6:

• Monitor for peripheral edema, pulmonary edema, fluid overload 6
• Particularly problematic in patients with cardiac involvement 6

Critical principle: There are no absolute contraindications to plasma cell-directed therapies based solely on ejection fraction or cardiac status in AL cardiac amyloidosis 6. However, patients with AL amyloidosis are at higher risk for treatment-related toxicity than multiple myeloma patients 6.

Response Monitoring

Hematologic response assessment (primary endpoint) 1, 6:

• Serial sFLC measurements 6
• Goal: Achieve deep, durable hematologic responses 1
• Complete response: Normal FLC ratio and negative immunofixation 1

Organ response assessment 1, 6:

• Cardiac: NT-proBNP reduction, improved NYHA class 1
• Renal: Proteinuria reduction, improved creatinine 1
• Monitor every 3-6 months initially 1

Deep hematologic responses correlate with improved organ function and survival 6.

ATTR Amyloidosis Treatment

ATTR amyloidosis requires completely different disease-specific therapy targeting transthyretin stabilization, not plasma cell suppression 6, 2.

ATTR Cardiac Amyloidosis

Tafamidis (VYNDAQEL/VYNDAMAX) 9:

• FDA-approved indication: Treatment of cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization 9
• Dosing: Tafamidis meglumine 80 mg (four 20-mg capsules) once daily OR tafamidis 61 mg (one capsule) once daily 9
• Both doses demonstrated statistically significant reduction in all-cause mortality and cardiovascular hospitalizations 9
• Mechanism: Stabilizes TTR tetramers, preventing dissociation and amyloid fibril formation 9
• Storage: Room temperature 68-77°F (20-25°C) 9
• Pregnancy: May harm fetus; females should report pregnancy immediately 9
• Lactation: Do not breastfeed during treatment 9

Critical point: Tafamidis is ineffective for AL amyloidosis and should never be used without confirmed ATTR typing 6, 2.

Hereditary ATTR with Neuropathy

Additional options include 2:

• TTR gene silencers (patisiran, inotersen)
• Liver transplantation (eliminates source of mutant TTR)

Supportive Cardiac Management (All Types)

Heart failure management requires extreme caution 6:

Diuretics 6:

• Judicious diuresis is the cornerstone of symptomatic management 6
• Careful fluid balance essential; patients are preload-dependent 6

Medications to use with extreme caution or avoid 6:

• ACE inhibitors/ARBs: Often poorly tolerated due to hypotension 6
• Beta-blockers: May worsen heart failure due to negative inotropic effects 6
• Calcium channel blockers: Can bind to amyloid fibrils and worsen cardiac function 1
• Digoxin: Binds to amyloid fibrils, increasing toxicity risk 1

Anticoagulation 6:

• Reasonable in patients with atrial fibrillation regardless of CHA₂DS₂-VASc score due to high thromboembolic risk 6

Cardiac transplantation 6:

• May be considered in select AL amyloidosis patients without significant extracardiac involvement, followed by chemotherapy 6
• More commonly considered in hereditary ATTR 6

AA Amyloidosis Treatment

Treatment focuses on controlling the underlying inflammatory condition 1, 2:

• Aggressive management of rheumatoid arthritis, inflammatory bowel disease, or chronic infection 2
• Anti-inflammatory biologics (anti-TNF agents, anti-IL-6) 2
• Colchicine for familial Mediterranean fever 2

Renal Support

Supportive measures 6:

• Blood pressure control 6
• Avoid NSAIDs and IV contrast (nephrotoxic) 6
• Dialysis when indicated 6
• Renal transplantation may be considered in selected patients after achieving hematologic remission in AL amyloidosis 6

Multidisciplinary Management

Effective amyloidosis management requires close collaboration between multiple specialists 6, 2:

Core Team

• Hematologist: Primary specialist directing anti-plasma cell therapy in AL amyloidosis 6
• Cardiologist: Manages cardiac involvement (present in up to 50% of AL cases), the main driver of mortality 1, 6
• Nephrologist: Manages renal involvement, proteinuria, interprets sFLC in renal impairment 6

Additional Specialists as Needed

• Neurologist: Peripheral/autonomic neuropathy management 6
• Gastroenterologist: GI involvement, malabsorption 6
• Transplant specialists: ASCT evaluation, organ transplantation 6
• Palliative care: Symptom management, quality of life optimization 6
• Genetic counselor: For hereditary ATTR amyloidosis family screening 2

Critical pitfall: Fragmented care without specialist coordination leads to suboptimal outcomes 6.

Special Populations

AL Amyloidosis with Multiple Myeloma

Approximately 10-15% of multiple myeloma patients have concurrent AL amyloidosis, and 10% of AL amyloidosis cases are associated with multiple myeloma 6.

Red flags requiring amyloidosis evaluation in myeloma patients 6:

• Restrictive cardiomyopathy or unexplained heart failure 6
• Unexplained nephrotic syndrome 6
• Macroglossia 6
• Periorbital purpura 6
• Peripheral neuropathy with autonomic features 6
• Bilateral carpal tunnel syndrome 6
• Acquired factor X deficiency 6

Treatment considerations 6:

• Patients with both conditions are more fragile than myeloma alone due to severe organ dysfunction 6
• Treatment must target the plasma cell clone 6
• Consider ASCT for patients <60 years with ≤2 organs involved and no severe cardiac involvement 6
• Close cardiac monitoring mandatory during therapy 6

Localized AL Amyloidosis

Localized AL amyloidosis can progress to systemic disease 10:

Risk factors for progression 10:

• ≥10% bone marrow plasma cells AND ≥30 g/L monoclonal protein: 87% progression at 15 years 10
• ≥10% bone marrow plasma cells AND <30 g/L monoclonal protein: 70% progression at 15 years 10
• Abnormal FLC ratio: Independent additional risk factor 10

Progression risk timeline 10:

• Highest in first 5 years: 10% per year 10
• Years 5-10: 3% per year 10
• After 10 years: 1% per year 10

Monitoring recommendations 10:

• Intermediate/high-risk MGUS: SPEP, CBC, calcium, creatinine every 6 months initially, then annually if stable 10
• Smoldering myeloma: Every 4-6 months first year, then every 6-12 months if stable 10

Treatment: Not indicated for MGUS or localized AL amyloidosis unless progression to systemic disease occurs 10.

Common Pitfalls and How to Avoid Them

Diagnostic Pitfalls

1. Delayed diagnosis due to nonspecific symptoms 1

   • Maintain high clinical suspicion in multisystem disease 2
   • Consider amyloidosis in unexplained heart failure with preserved EF 6

2. Using SPEP/UPEP alone for screening 6

   • Always perform all three tests: sFLC, SIFE, UIFE simultaneously 6

3. Failure to type amyloid protein 6, 7

   • Never treat without definitive typing 7
   • Use mass spectrometry when available 6

4. Mistyping amyloid as AL when it is ATTR 6, 8

   • Leads to inappropriate chemotherapy instead of tafamidis 6
   • Always confirm with mass spectrometry in ambiguous cases 6

Treatment Pitfalls

1. Using standard heart failure medications without caution 6

   • ACE inhibitors, beta-blockers, calcium channel blockers, digoxin often poorly tolerated 1, 6
   • Prioritize diuretics for symptom management 6

2. Treating ATTR amyloidosis with chemotherapy 6, 2

   • ATTR requires tafamidis, not plasma cell-directed therapy 6, 9

3. Withholding treatment based on low ejection fraction 6

   • No absolute contraindications to plasma cell therapy based on cardiac status 6
   • Close monitoring essential but treatment should not be denied 6

4. Inadequate monitoring for treatment toxicity 6

   • AL amyloidosis patients have higher toxicity risk than myeloma patients 6
   • Monitor cardiac function closely during therapy 6

5. Overlooking cardiac involvement 1, 6

   • Cardiac involvement drives prognosis and mortality 1, 6
   • Always assess cardiac biomarkers and imaging 6