Description

• 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

Epidemiology

Incidence

• 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

Prevalence

• 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.

Genetics

• 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