• An uncommon disorder in which proteins change conformation, aggregate, and form fibrils that infiltrate tissues, leading to organ dysfunction and increased risk of mortality. Deposition of amyloid in organ-specific extracellular spaces organs leads to clinical manifestations. Diagnosis is often delayed because presenting features are subtle or mimic other more common conditions.
  • Classification based on the nature of precursor plasma proteins that form fibril deposits:
    • >30 precursor proteins are known to form amyloid fibrils; the most common are immunoglobulin light chains, mutant transthyretin (TTR), wild-type (nonmutant) TTR, mutant fibrinogen, and mutant apolipoprotein A1.
      • Primary amyloidosis (AL): plasma cell dyscrasia (including multiple myeloma and monoclonal gammopathy of undetermined significance [MGUS]) and other clonal lymphoid processes
        • Deposition of protein derived from immunoglobulin light chain fragments
        • The most common form of systemic amyloidosis
      • Secondary or reactive amyloidosis (AA): complicates chronic infections or inflammatory diseases; deposition of serum amyloid A (SAA) protein
        • Effective treatment of underlying inflammatory condition reduces incidence. Tuberculosis, chronic osteomyelitis, malaria, rheumatoid arthritis (RA), and leprosy are the most common precipitating diseases in undeveloped countries.
      • Heritable or familial amyloidosis (AF): Many different types of variant plasma proteins (most commonly formed from mutations of TTR) form amyloid deposits beginning in midlife; primarily involves (autonomic) nervous system
      • Dialysis-related amyloidosis: deposition of fibrils derived from β2-microglobulin; predilection for osteoarticular structures
      • Wild-type amyloidosis (wtTTR): formerly known as senile systemic amyloidosis: deposition of otherwise normal TTR in myocardium and other sites; typically in elderly men; indolent course, involves lungs and carpal ligaments
      • Localized or organ-specific amyloidosis: deposition isolated to one organ, resulting in specific syndromes; most common is cerebral amyloid angiopathy (CAA), which can cause Alzheimer dementia due to amyloid plaque development; also forms specific to endocrine, heart, bronchial tree, urinary tract, or skin



  • AL: 1,275 to 3,200 new cases annually in the United States
  • AA: rare in the United States; occurs in <5% of patients with chronic inflammatory diseases


  • AF: rare, <1/100,000 population
  • AL: most common type in North America, 4.5/100,000 population:
    • Predominant age: 60 to 70 years
  • AA: more prevalent in third-world countries; more prevalent in Middle East in association with familial Mediterranean fever (FMF)

Etiology and Pathophysiology

  • AL: fibril formation by monoclonal antibody light chains; secondary to multiple myeloma, monoclonal gammopathies, and light chain disease
  • AA: During inflammation, proinflammatory cytokines (e.g., interleukin [IL]-1, IL-6) stimulate liver synthesis of SAA.
  • AF: Mutant proteins, derived from TTR (amyloidogenic transthyretin [ATTR]), are present from birth.
  • Abnormal amyloid proteins are produced by different mechanisms, which all result in a change in protein conformation and fibril aggregation.


  • Only AF is inherited; usually autosomal dominant
  • FMF (risk factor for secondary or reactive amyloidosis) is autosomal-recessive disorder.

Risk Factors

Depends on type of systemic amyloidosis:

  • Age (SSA/Alzheimer)
  • Heredity (AF/AA)
  • Underlying plasma cell dyscrasia (AL)
  • Untreated chronic infections (AA)
  • Long-term hemodialysis

General Prevention

Early detection and treatment of underlying disorders (i.e., plasma cell dyscrasias, chronic inflammatory conditions, chronic infections)

Commonly Associated Conditions

  • AL
    • Plasma cell dyscrasias—MGUS/multiple myeloma
    • Non-Hodgkin lymphoma
    • Rarely, Waldenström macroglobulinemia
  • AA
    • Chronic inflammatory arthritides
      • Adult and juvenile RA
      • Spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis
      • Rarely in systemic lupus erythematosus (SLE), Sjögren syndrome, and vasculitides
    • Periodic fever syndromes:
      • FMF, tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS), Muckle-Wells syndrome
    • Chronic infections: bronchiectasis, tuberculosis, osteomyelitis
    • Crohn disease
    • Neoplasms, particularly renal cell cancer
    • Castleman disease

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