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The New England Journal of MedicineSystemic Light Chain Amyloidosis

The article examines systemic light chain amyloidosis (AL amyloidosis), focusing on the pathogenesis of amyloid fibril formation, clinical manifestations, and advances in diagnostic and therapeutic strategies, with broader implications for related conditions like multiple myeloma.

Systemic light chain amyloidosis (AL amyloidosis) is a rare, progressive disease characterized by the misfolding of immunoglobulin light chains, leading to the formation of amyloid fibrils that deposit in various organs, causing dysfunction and failure. This comprehensive review covers recent advances in understanding the pathogenesis, risk factors, clinical presentations, and management of AL amyloidosis, highlighting the importance of early diagnosis and multidisciplinary treatment approaches to improve patient outcomes.

Key Points:

  • Pathogenesis:
    • AL amyloidosis results from abnormal folding of immunoglobulin light chains, leading to amyloid fibril formation.
    • Misfolded proteins aggregate and deposit in tissues, disrupting organ architecture and function.
    • Proteostasis mechanisms fail, promoting protein misfolding and aggregation.
  • Risk Factors:
    • Common in patients with monoclonal gammopathy and multiple myeloma.
    • Increased risk linked to preexisting monoclonal gammopathy of unknown significance (MGUS).
    • Agent Orange exposure may be associated, although evidence is limited.
  • Epidemiology:
    • Incidence and prevalence increase with age.
    • Recent data show significant increases in diagnosed cases, especially in older populations.
  • Clinical Presentations:
    • Symptoms vary widely; common signs include fatigue, weight loss, nephrotic-range proteinuria, cardiac involvement, and neuropathy.
    • Diagnostic delays are frequent due to nonspecific symptoms.
    • Cardiac involvement is the leading cause of death in AL amyloidosis.
  • Diagnosis:
    • Diagnosis requires tissue biopsy showing amyloid deposits and evidence of plasma cell dyscrasia.
    • Congo red staining and mass spectrometry are key diagnostic techniques.
    • High suspicion is necessary in patients with unexplained proteinuria, cardiomyopathy, neuropathy, or hepatomegaly.
  • Staging System and Risk Stratification:
    • Staging based on biomarkers of cardiac and kidney involvement.
    • Mayo Clinic staging systems (2004 and 2012) predict early death and late survival.
    • Advanced staging includes biomarkers like NT-proBNP, cardiac troponins, and dFLC.
  • Management:
    • Multidisciplinary approach tailored to organ involvement and disease extent.
    • Supportive care includes managing cardiac, renal, and neuropathic symptoms.
    • First-line therapy often includes CyBorD plus daratumumab; SCT considered for eligible patients.
    • Antifibril monoclonal antibodies like birtamimab and anselamimab are in clinical trials.
  • Future Directions:
    • Emphasis on early diagnosis, defining treatment standards for advanced cardiac disease, and developing new therapeutic strategies.
    • Continued research on clone-directed therapies and treatments targeting amyloid fibrils is crucial.

In a 2018 study, researchers claimed that the adjusted (unadjusted) prevalence of AL amyloidosis increased significantly from 20.1 (15.5) cases per million in 2007 to 50.1 (40.5) cases per million in 2015, an annual percentage change of 12% (11.9%).

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