Amyloidosis

Amyloidosis is a collective term for the extracellular deposition of abnormal proteins, either in a single organ (localized amyloidosis) or throughout the body (systemic amyloidosis). The different subtypes of amyloidosis are categorized according to the origin of the deposited proteins (e.g., AA, AL). These abnormal proteins are produced as a result of various diseases. The most common form of systemic amyloidosis in developed nations is light chain amyloidosis (AL deposition), which is caused by plasma cell dyscrasias such as multiple myeloma. The second most common systemic form – reactive amyloidosis (AA deposition) – is secondary to chronic inflammation and typically presents with nephrotic syndrome. Depending on which organs are affected, amyloidosis may also present with hepatomegaly, macroglossia, cardiac conduction abnormalities, and symptoms of restrictive cardiomyopathy. Abdominal fat or rectal mucosa biopsies are used to diagnose systemic amyloidosis. When stained with a Congo red dye, amyloid deposits exhibit an apple-green birefringence under polarized light. No definitive therapy for amyloidosis exists. Instead, the underlying disease should be treated. If amyloidosis progresses rapidly, melphalan and corticosteroids can be used to control the underlying disease.

• Definition: : Amyloidosis is the extracellular aggregation and subsequent deposition of different types of insoluble protein or protein fragments (amyloid) in various organs.
• Composition of amyloid
  • Fibrillar component (90–95% of amyloid): β-sheet fibrils
  • Nonfibrillar component (5–10% of amyloid): usually the same in all types of amyloid (e.g., amyloid P component, glycosaminoglycans)
• Pathogenesis: accumulation of amyloid → cellular injury and apoptosis ^[1]

Systemic amyloidosis

Light-chain amyloidosis (AL-amyloidosis) ^[2]

• Epidemiology: most common form of amyloidosis
• Etiology: associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenstrom macroglobulinemia)
• Pathophysiology: increased production of the light chains of immunoglobulins → deposition of amyloid light chain protein (AL protein) in various organs
• Clinical features: rapidly progressive clinical course
  • Heart: restrictive cardiomyopathy, atrioventricular block
  • Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
  • Tongue: macroglossia → obstructive sleep apnea
  • Autonomic nervous system: autonomic neuropathy
  • Gastrointestinal tract: malabsorption
  • Hematopoietic system: bleeding disorders, splenomegaly ^[3][4]
  • Musculoskeletal system: carpal tunnel syndrome ^[5]

Reactive amyloidosis (AA-amyloidosis)

• Etiology: secondary disease
  • Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)
  • Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)
  • Certain tumors (e.g., renal cell carcinoma, lymphomas)
• Pathophysiology: chronic inflammatory process → ↑ production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs
• Clinical features
  • Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
  • Adrenal glands: primary adrenal insufficiency
  • Liver and spleen: hepatomegaly, splenomegaly
  • Gastrointestinal tract: malabsorption
  • Musculoskeletal system: carpal tunnel syndrome ^[6]

Amyloidosis should always be considered in patients with a long-standing inflammatory and/or infectious disease who present with kidney, liver, or GI involvement.

Overview ^[2][7][8]

Overview of localized amyloidosis

Hereditary amyloidosis

• Biopsy of tissue sample with Congo red stain: The type of tissue sample depends on the extent of disease and organ involvement. ^[14]
  • Dysfunctional organ tissue (e.g., kidney, nerve) in case of single organ involvement
  • Abdominal fat or rectal mucosa are preferred in case of systemic amyloidosis (i.e., multiple organs and/or tissues involved).
  • Findings
    • Pink to red appearance under nonpolarized light
    • Apple-green birefringence under polarized light
    • Additional findings when kidney is affected may include deposits in glomerular mesangial areas visible in H&E stain and enlarged tubular basement membranes that can be identified via light microscopy.
    • See “Amyloid nephropathy.”
• Tests to diagnose the underlying disease ^[15]
  • Light chain amyloidosis
    • Serum electrophoresis: monoclonal gammopathy
    • Urine test for Bence-Jones proteins (see “Multiple myeloma”)
  • Reactive amyloidosis: ESR, CRP, chest x-ray

• No definitive therapy exists.
• Adequate treatment of the underlying disease may stall disease progression.
• Possibly surgery: e.g., liver transplantation in familial amyloid polyneuropathy (FAP)
• If amyloidosis progresses rapidly (e.g., light chain amyloidosis): corticosteroids, melphalan ^[7]
• Prevention of AA-amyloidosis and consequent renal failure in patients with FMF: colchicine ^[16]