What is amyloidosis?

What is Amyloidosis?

Amyloidosis is a disorder characterized by the abnormal extracellular deposition of misfolded protein fibrils (amyloid) in various tissues and organs, leading to structural and functional damage that can result in organ failure and death. 1

Types of Amyloidosis

Amyloidosis encompasses several distinct types, each defined by the specific protein that forms the amyloid deposits:

1. AL (Amyloid Light Chain) Amyloidosis:

   • Most common and severe form, affecting approximately 10 per million people annually
   • Caused by plasma cell clones in bone marrow secreting unstable immunoglobulin light chains
   • Can be associated with multiple myeloma or Waldenström's macroglobulinemia 1

2. ATTR (Transthyretin) Amyloidosis:

   • Two subtypes:
     • Hereditary ATTR: Caused by mutations in the TTR gene
     • Wild-type ATTR: Results from normal TTR protein misfolding due to aging (formerly called senile amyloidosis) 2

3. AA (Reactive) Amyloidosis:

   • Results from chronic inflammatory or infectious diseases
   • Involves deposition of amyloid type A protein
   • Associated with conditions like rheumatoid arthritis, Crohn's disease, or ulcerative colitis 2, 1

4. Other types:

   • Hemodialysis-associated amyloidosis
   • Organ-specific amyloidosis (familial visceral amyloidosis, familial corneal amyloidosis) 2

Pathophysiology

The fundamental pathological process in all forms of amyloidosis 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

These fibrils share a common crystallographic beta-pleated sheet structure despite their heterogeneous origins 3.

Clinical Manifestations

Amyloidosis can affect virtually any organ system, with more than 69% of patients having multiple organ involvement at diagnosis 1. The most commonly affected organs include:

• Heart: Infiltrative cardiomyopathy, heart failure
• Kidneys: Proteinuria, renal failure
• Nervous system: Peripheral neuropathy, autonomic dysfunction
• Liver: Hepatomegaly
• Gastrointestinal tract: Malabsorption, dysmotility
• Skin: Purpura, papules 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 yellow-green birefringence under polarized light
3. Amyloid typing to determine the specific protein 1, 4

Advanced diagnostic techniques include:

• Immunofluorescence and immunohistochemistry
• Genetic mutational analysis for hereditary forms
• Laser microdissection followed by mass spectrometry (most advanced technique) 5
• Imaging studies such as cardiac MRI with gadolinium and (123)I-labeled SAP scintigraphy 5

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: Median survival approximately 75 months
• AA amyloidosis: Median survival approximately 25 months 1

Treatment Approaches

Treatment strategies depend on the specific type of amyloidosis:

• AL amyloidosis: Targeting the underlying plasma cell clone

  • Autologous stem cell transplantation (ASCT)
  • Bortezomib-based regimens 1

• Hereditary ATTR amyloidosis: Liver transplantation may be considered 1

• AA amyloidosis: Treatment of the underlying inflammatory condition 3

Early detection is critical for improving outcomes, as modern therapies can now achieve durable responses and long-term survival in many patients 6.

Clinical Pitfalls and Caveats

1. Delayed diagnosis: Clinical symptoms are largely nonspecific, leading to frequent misdiagnosis or late diagnosis, which significantly impacts treatment outcomes 6

2. Importance of typing: Determining the exact amyloid protein type is imperative before initiating therapy, as treatments are type-specific and inappropriate treatment can cause harm 4

3. Multisystem involvement: The widespread deposition of amyloid requires thorough evaluation of multiple organ systems, even when symptoms appear limited to one system 1

4. Genetic testing: Essential for ruling in or out hereditary forms of amyloidosis, particularly important for family screening 5