12. AMYLOIDOSIS

Amyloidosis is a group of disorders where abnormal proteins called amyloid fibrils get deposited in different tissues and organs. These fibrils are insoluble and accumulate in the extracellular space, disturbing normal structure and function of organs. Depending on the type of precursor protein and affected organ, amyloidosis can present in many forms.

Classification of Amyloidosis

Amyloidosis is classified based on the protein that forms amyloid and the pattern of its deposition:

1. Primary (AL) Amyloidosis

  • Caused by abnormal production of immunoglobulin light chains.
  • Associated with plasma cell disorders like multiple myeloma and MGUS.

2. Secondary (AA) Amyloidosis

  • Occurs due to chronic inflammatory diseases (RA, IBD, chronic infections).
  • Involves deposition of serum amyloid A (SAA), an acute-phase protein.

3. Hereditary (ATTR) Amyloidosis

  • Caused by genetic mutations leading to abnormal transthyretin (TTR) protein.
  • Affects the heart (ATTR-CM), nerves (ATTR-PN), or both.

4. Dialysis-Related Amyloidosis

  • Seen in long-term hemodialysis patients.
  • Due to accumulation of β2-microglobulin, especially affecting joints.

5. Localized Amyloidosis

  • Deposits limited to single organs.
  • Examples: Alzheimer’s disease (brain), senile cardiac amyloidosis (heart), cutaneous amyloidosis (skin).

Pathophysiology

The disease develops due to abnormal folding and accumulation of proteins. The main steps include:

1. Increased Production of Precursor Proteins

  • Proteins may be normal or mutated.
  • Mutations or inflammation stimulate excessive production.

2. Misfolding and Aggregation

  • Due to genetic defects, chronic inflammation or abnormal cell function.
  • Misfolded proteins form beta-sheet–rich structures resistant to breakdown.

3. Formation of Amyloid Fibrils

  • Misfolded proteins join to form stable, insoluble fibrils.
  • These fibrils further clump together to create large deposits.

4. Tissue Deposition

  • Amyloid accumulates in organs like kidneys, heart, liver, nerves, skin and GIT.
  • Deposits disrupt organ architecture and impair function.

5. Cellular Damage

  • Amyloid fibrils damage membranes, induce oxidative stress and trigger inflammation.
  • Chronic deposits reduce tissue repair and lead to organ failure.

Clinical Manifestations

The symptoms depend on which organs are affected. Common features include:

Renal Involvement

  • Proteinuria
  • Nephrotic syndrome
  • Renal insufficiency & progressive kidney failure

Cardiac Involvement

  • Restrictive cardiomyopathy
  • Arrhythmias
  • Heart failure
  • Risk of sudden cardiac death

Neurological Symptoms

  • Peripheral neuropathy
  • Autonomic dysfunction
  • Weakness and numbness
  • Cognitive decline (in some forms)

Gastrointestinal Symptoms

  • Chronic diarrhea
  • Malabsorption
  • GI bleeding
  • Hepatomegaly

Musculoskeletal Involvement

  • Arthralgia and arthritis
  • Carpal tunnel syndrome
  • Bone cysts (especially in dialysis-related amyloidosis)

Skin Manifestations

  • Petechiae and purpura
  • Ecchymoses
  • Waxy skin nodules
  • Macroglossia (enlarged tongue) – classic sign

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