Pathophysiology of Amyloidosis
Amyloidosis is fundamentally a protein misfolding disorder characterized by the extracellular deposition of insoluble protein fibrils in various organs, causing architectural disruption, direct cytotoxicity, and progressive organ dysfunction that can lead to failure and death. 1
Core Pathophysiological Process
The pathogenesis of amyloidosis involves several key steps:
- Protein Misfolding: The process begins with the misfolding of amyloidogenic precursor proteins
- Self-Aggregation: These misfolded proteins self-aggregate in a highly ordered manner
- Fibril Formation: The aggregates generate protofilaments that interact to form characteristic amyloid fibrils
- Tissue Deposition: Fibrils deposit extracellularly in tissues
- Organ Dysfunction: The deposits cause progressive organ damage through:
- Direct disruption of tissue architecture
- Direct cytotoxicity to surrounding cells
- Interference with normal organ function
Types of Amyloidosis and Their Pathophysiology
Different types of amyloidosis are defined by their precursor proteins:
AL (Light Chain) Amyloidosis
- Source: Clonal plasma cells or B-cells in bone marrow
- Precursor Protein: Immunoglobulin light chains (lambda isotype in 75-80% of cases, kappa in the remainder)
- Mechanism:
- Indolent B-cell clones produce unstable light chains
- These light chains misfold and form amyloid fibrils
- The fibrils deposit in tissues causing both architectural disruption and direct cytotoxicity 1
- Key Distinction: Unlike multiple myeloma which has higher plasma cell burden, AL amyloidosis typically has a smaller clone but produces highly amyloidogenic light chains
ATTR (Transthyretin) Amyloidosis
- Forms:
- Hereditary: Caused by mutant transthyretin
- Senile/Wild-type: Caused by normal transthyretin that becomes unstable with aging
- Mechanism: Transthyretin protein becomes unstable, misfolds, and forms amyloid deposits
AA (Reactive) Amyloidosis
- Precursor Protein: Serum amyloid A protein (an acute phase reactant)
- Mechanism: Chronic inflammation leads to persistent elevation of serum amyloid A, which can misfold and form amyloid deposits
Other Types
- Isolated Atrial Amyloidosis: Derived from atrial natriuretic factor
- Dialysis-related Amyloidosis: Caused by β2-microglobulin accumulation
Organ Tropism and Damage
The mechanisms that determine which organs are affected (organ tropism) remain poorly understood 1. However:
- Heart and Kidneys: Most frequently affected in AL amyloidosis
- Cardiac Effects:
- Amyloid deposits in the myocardial interstitium disrupt myocyte function
- Early stages: Increased myocardial stiffness leading to diastolic dysfunction
- Later stages: Progressive systolic dysfunction
- Deposits in conduction tissue affect electrical conduction
- Deposits in coronary vessels can cause ischemia
- Pericardial deposits can cause effusions 1
- Renal Effects:
- Typically manifests as proteinuria and progressive renal dysfunction
- Can lead to nephrotic syndrome
Clinical Consequences of Pathophysiology
The pathophysiological processes translate to specific clinical manifestations:
AL Amyloidosis:
- Macroglossia and submandibular gland enlargement
- Periorbital purpura
- Coagulopathy from acquired factor X deficiency
- Restrictive cardiomyopathy
- Proteinuria 1
ATTR Amyloidosis:
- Musculoskeletal manifestations (biceps tendon rupture, spinal stenosis)
- Cardiomyopathy (especially in senile/wild-type)
- Neuropathy (especially in hereditary forms) 1
Prognostic Implications
The pathophysiology directly impacts prognosis:
- AL Amyloidosis: Median survival is approximately 13 months but decreases dramatically to 4 months with the onset of heart failure symptoms 1
- ATTR Amyloidosis: Generally has better prognosis (median survival 70-75 months) 1
Diagnostic Implications
The pathophysiology of amyloidosis necessitates specific diagnostic approaches:
- Histological Confirmation: Amyloid fibrils generate characteristic birefringence under polarized light when stained with Congo red dye
- Protein Typing: Critical for determining treatment approach, as therapies target the specific underlying protein pathology
Understanding the pathophysiology of amyloidosis is crucial for early diagnosis and appropriate treatment before irreversible organ damage occurs, which remains the cornerstone of effective management.