Amyloidosis
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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%)
- Most common causes of secondary amyloidosis include:
- 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
- In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues.[7][8]
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)
- Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).[11]
- Secondary or reactive amyloidosis (AA) is approximately 45% of all systemic amyloidosis.[12]
- Pathogenesis of secondary or reactive amyloidosis is multifactorial that include:
- Primary structure of the precursor protein
- Acute phase response
- Nonfibril proteins (amyloid P component, apo E, GAGs, proteoglycans and basement membrane proteins)
- Receptors
- Lipid metabolism
- Proteases
Hereditary Amyloidosis
- Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils.[11]
- Hereditary amyloidosis are due to amyloidogenic mutations and subsequently deposition of amyloids, include:[13]
- Transthyretin (TTR) (most common inherited mutation)
- Fibrinogen
- Apolipoprotein A1
- Apolipoprotein A2
- Lysozyme
- Gelsolin genes
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
- ↑ 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.
- ↑ 2.0 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.
- ↑ Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ 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.
- ↑ Misumi Y, Ando Y (July 2014). "[Classification of amyloidosis]". Brain Nerve (in Japanese). 66 (7): 731–7. PMID 24998818.
- ↑ 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.
- ↑ 7.0 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.
- ↑ 8.0 8.1 Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
- ↑ 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.
- ↑ 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.
- ↑ 11.0 11.1 11.2 11.3 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ 12.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.