Amyloidosis

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Overview

Historical Perspective

Classification

Primary amyloidosis
Secondary amyloidosis
Familial amyloidosis
Wild-type (senile) amyloidosis
Cardiac amyloidosis
Beta-2 microglobulin related amyloidosis
Gelsolin related amyloidosis
Lysozyme amyloid related amyloidosis
Leucocyte cell-derived chemotaxin 2 related amyloidosis
Fibrinogen A alpha-chain associated amyloidosis

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Differentiating Amyloidosis from other Diseases

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Case #1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Overview

Historical Perspective

  • In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess and splenomegaly and his report has been the first description of amyloidosis.[1]
  • In 1854, Rudolph Virchow introduced the term of amyloid as an macroscopic abnormality in some tissues.[2]
  • In 1867, Weber reported the first case of amyloidosis associated with multiple myeloma.[1]
  • In 1922, Bennhold introduced Congo red staining of amyloid that remains the gold standard for diagnosis.[3]
  • In 1959, Cohen and Calkins used ultrathin sections of amyloidotic tissues and assessed by electron microscopic examination, explained the presence of nonbranching fibrils with indeterminate length and variable width.[2][1]

Classification

Amyloidosis may be classified based on precursor of amyloidogenic protein into different subtypes, include:[4][5]

Type Amyloidogenic protein/ fibril Clinical syndrome
AL (primary amyloidosis) Light chains of immunoglobulines (most common type) Monoclonal gammopathy
AA (secondary amyloidosis) Serum amyloid A protein Chronic inflammatory diseases
AF Mutant transthyretin, A1-apolipoprotein, gelsolin, fibrinogen, etc. Familial polyneuropathy/cardiomyopathy/nephropathy
ATTRwt Wild-type transthyretin Senile restrictive cardiomyopathy _ Transthyretin-related amyloidosis wild-type
AH ß2-microglobulin Long-term hemodialysis

Amiloidosis also may classified by their organ involvement as below:

Systemic amyloidosis

  • Primary amyloidosis (AL)
  • Secondary amyloidosis (AA)
    • Most common causes of secondary amyloidosis include:
      • Tuberculosis (50%)
      • Familial Mediterranean fever (26-40%)
      • Rheumatoid arthritis (20-25%)
      • Multiple myeloma (10-15%)
  • Hereditary amyloidosis

Organ-specific amyloidosis

  • Renal amyloidosis
  • Cardiac amyloidosis
  • Hepatic amyloidosis
  • Pulmonary amyloidosis
  • Amyloid neuropathy 
  • Gastrointestinal amyloidosis

Pathophysiology

  • Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes.[6][7]
  • These abnormal amyloids derived from misfolding and aggregation of normally soluble proteins.[8]
  • Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.[9]

Systemic Amyloidosis

Primary Amyloidosis (AL)

  • Primary amyloidosis (AL amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones.
  • Change in the secondary or tertiary structure of a monoclonal light chain results in abnormal folding of the light chain that abnormally form amyloid fibrils.[10]
  • This type of amyloidosis most frequently involve the kidney (usually proteinuria with the nephrotic syndrome) and the heart.[11]

Secondary Amyloidosis (AA)

Hereditary Amyloidosis

Organ-specific Amyloidosis

  • In this type of amyloidoses, amyloid deposition occurs only in the origin organ or tissue of precursor protein.[14]
  • Some neurodegenerative disorders such as Parkinson disease, Alzheimer, and Huntington disease may occur in localized amyloidosis.
  • Localized amyloidoses can accure due to deposition of intracellular and/or extracellular amyloid.
    • Huntington's disease: intracellular protein deposition
    • Parkinson's disease: intracellular protein deposition
    • Alzheimer's disease: intracellular (Tau protein fibrils) and extracellular (amyloid β fibrils) deposition

Microscopic Pathology

In microscopy pathology of amyloidosis, amyloid is detectable as:[12][11]

  • Typical green birefringence under polarized light after Congo red staining (appears in red under normal light)
  • Linear non-branching fibrils (indefinite length with an approximately same diameter)
  • Distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril

Epidemiology and Demographics

Complications

In patients with amyloidosis the most frequent complications include:[15]

  • Heart failure
  • Nephrotic syndrome
  • Hepatomegaly
  • Peripheral neuropathy 

Prognosis

  • In primary (AL) amyloidosis survival rate depends on:[16]
    • Type of organ involvement (amyloid heart disease is the main prognostic factor)
    • The severity of different organs involvement
    • Haematological response to treatment
  • The median survival of patients with AL amyloidosis is aproximately 3.8 years.[17]
  • In primary (AL) amyloidosis 27% of patients dying within 1 year from diagnosis.
  • The major determinant of outcome in amyloidosis is the extent of cardiac involvement.
    • Cardiac amyloidosis is the cause of death in 75% of the patients who died, including sudden death in 25%

Case Studies

Case #1

Template:Metabolic pathology


Template:WikiDoc Sources

  1. 1.0 1.1 1.2 Kyle RA (June 2011). "Amyloidosis: a brief history". Amyloid. 18 Suppl 1: 6–7. doi:10.3109/13506129.2011.574354001. PMID 21838413.
  2. 2.0 2.1 Sipe JD, Cohen AS (June 2000). "Review: history of the amyloid fibril". J. Struct. Biol. 130 (2–3): 88–98. doi:10.1006/jsbi.2000.4221. PMID 10940217.
  3. Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  4. Real de Asúa D, Costa R, Galván JM, Filigheddu MT, Trujillo D, Cadiñanos J (2014). "Systemic AA amyloidosis: epidemiology, diagnosis, and management". Clin Epidemiol. 6: 369–77. doi:10.2147/CLEP.S39981. PMC 4218891. PMID 25378951.
  5. Misumi Y, Ando Y (July 2014). "[Classification of amyloidosis]". Brain Nerve (in Japanese). 66 (7): 731–7. PMID 24998818.
  6. Gillmore JD, Hawkins PN (October 2013). "Pathophysiology and treatment of systemic amyloidosis". Nat Rev Nephrol. 9 (10): 574–86. doi:10.1038/nrneph.2013.171. PMID 23979488.
  7. 7.0 7.1 Baker KR, Rice L (2012). "The amyloidoses: clinical features, diagnosis and treatment". Methodist Debakey Cardiovasc J. 8 (3): 3–7. PMC 3487569. PMID 23227278.
  8. 8.0 8.1 Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
  9. Jerzykowska S, Cymerys M, Gil LA, Balcerzak A, Pupek-Musialik D, Komarnicki MA (2014). "Primary systemic amyloidosis as a real diagnostic challenge - case study". Cent Eur J Immunol. 39 (1): 61–6. doi:10.5114/ceji.2014.42126. PMC 4439975. PMID 26155101.
  10. Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A (August 2012). "Al amyloidosis". Orphanet J Rare Dis. 7: 54. doi:10.1186/1750-1172-7-54. PMC 3495844. PMID 22909024.
  11. 11.0 11.1 11.2 11.3 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  12. 12.0 12.1 Röcken C, Shakespeare A (February 2002). "Pathology, diagnosis and pathogenesis of AA amyloidosis". Virchows Arch. 440 (2): 111–122. doi:10.1007/s00428-001-0582-9. PMID 11964039.
  13. Mahmood S, Palladini G, Sanchorawala V, Wechalekar A (February 2014). "Update on treatment of light chain amyloidosis". Haematologica. 99 (2): 209–21. doi:10.3324/haematol.2013.087619. PMC 3912950. PMID 24497558.
  14. Blancas-Mejía LM, Ramirez-Alvarado M (2013). "Systemic amyloidoses". Annu. Rev. Biochem. 82: 745–74. doi:10.1146/annurev-biochem-072611-130030. PMC 4044913. PMID 23451869.
  15. Jerzykowska S, Cymerys M, Gil LA, Balcerzak A, Pupek-Musialik D, Komarnicki MA (2014). "Primary systemic amyloidosis as a real diagnostic challenge - case study". Cent Eur J Immunol. 39 (1): 61–6. doi:10.5114/ceji.2014.42126. PMC 4439975. PMID 26155101.
  16. Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A (August 2012). "Al amyloidosis". Orphanet J Rare Dis. 7: 54. doi:10.1186/1750-1172-7-54. PMC 3495844. PMID 22909024.
  17. Merlini G, Seldin DC, Gertz MA (May 2011). "Amyloidosis: pathogenesis and new therapeutic options". J. Clin. Oncol. 29 (14): 1924–33. doi:10.1200/JCO.2010.32.2271. PMC 3138545. PMID 21483018.