What is amyloidosis?

Amyloidosis: A Comprehensive Overview

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

Types of Amyloidosis

• Light Chain (AL) Amyloidosis

  • Most common form (~10 cases per million people annually)
  • Caused by plasma cell clones producing unstable immunoglobulin light chains
  • Can be associated with multiple myeloma or Waldenström's macroglobulinemia
  • Poorest prognosis among amyloidosis types, especially with cardiac involvement 1

• Transthyretin (ATTR) Amyloidosis

  • Two forms:
    • Hereditary ATTR: Caused by mutations in the TTR gene
    • Wild-type ATTR: Results from normal TTR protein misfolding due to aging
  • Better prognosis than AL amyloidosis (median survival ~75 months) 1

• Reactive (AA) Amyloidosis

  • Results from chronic inflammatory or infectious diseases
  • Involves deposition of amyloid type A protein
  • Median survival approximately 25 months 1

• Other Types

  • β2-microglobulin (Aβ2M): Associated with dialysis
  • Hereditary forms: AFib, apolipoproteins, AGel, ALys 2

Pathological Process

The fundamental process in all amyloidosis forms involves:

1. Production of amyloidogenic proteins
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 1

Organ Involvement

• Amyloid can deposit in virtually any organ system

• Most commonly affected organs:

  • Heart
  • Kidneys
  • Nervous system
  • Liver
  • Gastrointestinal tract
  • Skin 1

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

• AL amyloidosis rarely affects just one organ; median of 2 sites are typically involved 3

Clinical Presentation

• Symptoms often mimic other conditions, leading to delayed diagnosis
• Patients are frequently diagnosed after disease progression to advanced stages with organ damage already present 3
• Clinical presentation varies based on the organs involved:
  • Cardiac involvement: Heart failure, arrhythmias
  • Renal involvement: Proteinuria, kidney failure
  • Neurological involvement: Peripheral neuropathy, autonomic dysfunction
  • Gastrointestinal involvement: Malabsorption, dysmotility 1

Diagnosis

Diagnosis requires:

1. Clinical suspicion based on multi-system involvement
2. Tissue biopsy showing Congo red-positive amyloid deposits with characteristic yellow-green birefringence under polarized light
3. Amyloid typing to determine the specific protein (critical for treatment planning) 1

Prognosis

• Varies significantly by amyloid type and organ involvement:
  • AL amyloidosis: Median survival 13 months, decreasing to 4 months with heart failure
  • ATTR amyloidosis: Median survival approximately 75 months
  • AA amyloidosis: Median survival approximately 25 months 1

Treatment

Treatment strategies depend on the specific type of amyloidosis:

• AL Amyloidosis

  • Targets the underlying plasma cell clone
  • Options include:
    • Autologous stem cell transplantation (ASCT)
    • Bortezomib-based regimens
    • Recently approved: daratumumab (Darzalex®) in US and EU 3, 1

• ATTR Amyloidosis

  • Liver transplantation may be considered for hereditary forms 1

• AA Amyloidosis

  • Treatment of underlying inflammatory condition 1

Clinical Pitfalls and Caveats

1. Delayed Diagnosis: Symptoms often mimic other conditions, leading to delayed diagnosis and advanced disease at presentation 3

2. Mistyping: Determining the correct amyloid type is critical as treatment differs significantly between types. Incorrect typing can lead to inappropriate and potentially harmful treatment 2

3. Multi-organ Assessment: Given the high rate of multi-organ involvement, comprehensive evaluation of all potentially affected systems is essential 1

4. Treatment Monitoring: Well-planned monitoring during follow-up is crucial due to potential treatment toxicities and the need to assess response 4

5. Cardiac Involvement: Particularly in AL amyloidosis, cardiac involvement significantly worsens prognosis and requires special consideration in treatment planning 1