What is amyloidosis?

Amyloidosis: A Disorder of Protein Misfolding and Deposition

Amyloidosis is a disease complex characterized by the abnormal extracellular deposition of misfolded protein fibrils in various organs, leading to structural and functional damage that can result in organ failure and death. 1 This disorder represents a spectrum of conditions with diverse etiologies but similar pathological features.

Types of Amyloidosis

Several types of amyloidosis exist, classified based on the specific protein that forms the amyloid fibrils:

1. Amyloid Light Chain (AL) Amyloidosis

   • Previously called "primary" amyloidosis
   • Most common and severe form, affecting ~10 per million people annually 1
   • Caused by a small, slowly proliferating plasma cell clone in the bone marrow that secretes unstable immunoglobulin light chains
   • Can be associated with multiple myeloma or Waldenström's macroglobulinemia 1
   • Median survival of 13 months, decreasing to 4 months when heart failure develops 1

2. Transthyretin (ATTR) Amyloidosis

   • Two forms:
     • Hereditary ATTR: Caused by mutations in the TTR gene, resulting in abnormal "variant" TTR 1
     • Wild-type ATTR (formerly senile amyloidosis): Normal TTR protein misfolds due to aging 1
   • Median survival of approximately 75 months 1

3. Reactive (AA) Amyloidosis

   • Previously known as "secondary" amyloidosis
   • Results from chronic inflammatory or infectious diseases (e.g., rheumatoid arthritis, Crohn's disease)
   • Involves deposition of amyloid type A protein 1
   • Median survival of approximately 25 months 1

4. Other Types

   • Isolated atrial amyloidosis (atrial natriuretic factor)
   • Dialysis-related amyloidosis (β2-microglobulin)
   • Hereditary forms (various mutant proteins)

Organ Involvement and Clinical Presentation

Amyloid can deposit in virtually any organ system, with the most commonly affected organs including:

• Heart: Leads to restrictive cardiomyopathy, initially with diastolic dysfunction that can progress to systolic dysfunction 1
• Kidneys: Causes proteinuria, nephrotic syndrome, and eventual renal failure
• Nervous system: Results in peripheral neuropathy and autonomic dysfunction
• Liver: Leads to hepatomegaly and potential dysfunction
• Gastrointestinal tract: Causes various GI symptoms
• Skin: Can present with characteristic lesions or bruising

More than 69% of patients have multiple organ involvement at diagnosis 1, making early recognition critical to prevent irreversible damage.

Pathophysiology

The fundamental pathological process in all forms of amyloidosis involves:

1. Production of amyloidogenic proteins (e.g., light chains in AL amyloidosis)
2. Misfolding of these proteins
3. Aggregation into insoluble amyloid fibrils
4. Deposition in tissues and organs
5. Disruption of normal tissue architecture and function

In cardiac amyloidosis, deposits in the myocardial interstitium disrupt myocyte function, causing:

• Increased myocardial stiffness
• Impaired diastolic function
• Elevated filling pressures
• Potential direct myocyte necrosis through oxidative stress
• Conduction abnormalities when deposits affect the conduction system 1

Diagnosis

Diagnosis of amyloidosis requires:

1. Clinical suspicion based on multi-system involvement
2. Tissue biopsy showing Congo red-positive amyloid deposits with characteristic apple-green birefringence under polarized light
3. Amyloid typing to determine the specific protein (critical for treatment decisions)
   • Laser capture microdissection and tandem mass spectrometry (LCM-MS) is the most reliable method 2
   • Immunohistochemistry is also commonly used but less accurate

For cardiac ATTR amyloidosis specifically, non-biopsy diagnosis may be possible with stringent criteria 2.

Prognosis

Prognosis varies significantly by amyloid type and organ involvement:

• AL amyloidosis: Poorest prognosis, especially with cardiac involvement
  • Median survival: 13 months
  • With heart failure: 4 months 1
• ATTR amyloidosis: Better prognosis
  • Median survival: 70-75 months 1
• AA amyloidosis: Intermediate prognosis
  • Median survival: 25 months 1

Treatment Approaches

Treatment strategies depend on the type of amyloidosis:

1. AL Amyloidosis:

   • Target the underlying plasma cell clone
   • Autologous stem cell transplantation (ASCT) for eligible patients (~20%)
   • Bortezomib-based regimens for ASCT-ineligible patients
   • Daratumumab (anti-CD38 antibody) is a recent addition to treatment options 1

2. ATTR Amyloidosis:

   • Different management approach than AL amyloidosis
   • Liver transplantation may be considered for hereditary forms
   • Newer agents targeting TTR stabilization or production

3. AA Amyloidosis:

   • Treatment of the underlying inflammatory condition
   • Appropriate antibiotics for infectious causes

Key Clinical Considerations

• Early diagnosis is crucial before irreversible organ damage occurs
• Cardiac involvement is the main driver of prognosis and mortality
• Accurate typing of amyloid is essential for appropriate treatment selection
• Treatment should be initiated promptly to halt progression of organ damage
• Close monitoring for treatment response and early detection of relapse is vital

Amyloidosis remains a challenging diagnosis due to its nonspecific presentation and rarity. Increased awareness and advances in diagnostic techniques and treatments offer hope for improved outcomes in this complex group of disorders.