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
In 1639, Nicolaus Fontanus autopsied a young man who had ascitis, jaundice, liver abscess and splenomegaly and his report has been the first description of amyloidosis. and in 1959, Cohen and Calkins assessed an ultra-thin sections of amyloidotic tissues by electron microscopic examination. Amyloidosis may be classified based on precursor of amyloidogenic protein into different subtypes, include AL amyloidosis (Light chains of immunoglobulines), AA amyloidosis (Serum amyloid A protein), AF amyloidosis (Mutant transthyretin, A1-apolipoprotein, gelsolin, fibrinogen, etc.), ATTRwt amyloidosis (Wild-type transthyretin), and AH amyloidosis (ß2-microglobulin). Amyloidosis also may classified by their extension of organ involvement as systemic amyloidosis (primary amyloidosis, secondary amyloidosis, hereditary amyloidosis) and Organ-specific amyloidosis (cardiac amyloidosis, hepatic amyloidosis, renal amyloidosis, etc.). Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction. These abnormal amyloids derived from misfolding and aggregation of normally soluble proteins. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. In organ-specific amyloidoses, amyloid deposition occurs only in the origin organ or tissue of precursor protein. In microscopy pathology of amyloidosis, amyloid is detectable as typical green birefringence under polarized light after Congo red staining, linear non-branching fibrils, distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril.
Historical Perspective
- In 1639, Nicolaus Fontanus autopsied a young man who had ascitis, jaundice, liver abscess and splenomegaly and his report has been the first description of amyloidosis.
- In 1854, Rudolph Virchow introduced the term of amyloid as an macroscopic abnormality in some tissues.
- 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.
- In 1959, Cohen and Calkins used ultra-thin sections of amyloidotic tissues and assessed by electron microscopic examination, explained the presence of non-branching fibrils with indeterminate length and variable width.[2][1]
Classification
Amyloidosis may be classified based on precursor of amyloidogenic protein into different subtypes, include:
| 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 |
Amyloidosis also may classified by their extension of organ involvement as below:
| Classification | subtypes | Causes | Important clinical findings |
|---|---|---|---|
| Systemic amyloidosis | Primary amyloidosis (AL) |
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| Secondary amyloidosis (AA) |
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| Hereditary amyloidosis | |||
| Organ-specific amyloidosis | Renal amyloidosis |
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| Cardiac amyloidosis | |||
| Hepatic amyloidosis |
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| Amyloid neuropathy | |||
| Gastrointestinal amyloidosis |
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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.
- These abnormal amyloids derived from misfolding and aggregation of normally soluble proteins.
- Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.
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.[3][4]
Primary Amyloidosis (AL)
- Primary (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 structure or tertiary structure of a monoclonal light chain results in abnormal folding of the light chain that abnormally form amyloid fibrils.
- This type of amyloidosis most frequently involve the kidney (usually proteinuria with the nephrotic syndrome) and the heart.
- In primary (AL) amyloidosis survival rate depends on:
- 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.
For more information about primary amyloidosis click here.
Secondary Amyloidosis (AA)
- Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).[5]
- Secondary or reactive amyloidosis (AA) is approximately 45% of all systemic amyloidosis.
- Pathogenesis of secondary 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
For more information about secondary amyloidosis click here.
Hereditary Amyloidosis
- Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils.[5]
- Hereditary amyloidosis are due to amyloidogenic mutations and subsequently deposition of amyloids, include:
Organ-specific Amyloidosis
- In this type of amyloidoses, amyloid deposition occurs only in the origin organ or tissue of precursor protein.
- Some neurodegenerative disorders such as Parkinson's disease, Alzheimer, and Huntington's disease may occur in localised amyloidosis.
- Localised 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:[6][5]
- 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
Incidence
- The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide.[7]
Prevalence
- The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
- In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
- The prevalence of [disease/malignancy] is estimated to be [number] cases annually.
Mortality rate
- The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.[8]
Age
- In amyloidosis, the mean age of presentation is 55-60 years.[9]
Race
- Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the black population.[10]
- [Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
Gender
- Men are more commonly affected by amyloidosis than women.[11]
Case Studies
- ↑ 1.0 1.1 Kyle RA (June 2011). "Amyloidosis: a brief history". Amyloid. 18 Suppl 1: 6–7. doi:10.3109/13506129.2011.574354001. PMID 21838413.
- ↑ 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.
- ↑ Baker KR, Rice L (2012). "The amyloidoses: clinical features, diagnosis and treatment". Methodist Debakey Cardiovasc J. 8 (3): 3–7. PMC 3487569. PMID 23227278.
- ↑ Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
- ↑ 5.0 5.1 5.2 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ 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.
- ↑ Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
- ↑ Shin YM (March 2011). "Hepatic amyloidosis". Korean J Hepatol. 17 (1): 80–3. doi:10.3350/kjhep.2011.17.1.80. PMC 3304630. PMID 21494083.
- ↑ Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ Shin YM (March 2011). "Hepatic amyloidosis". Korean J Hepatol. 17 (1): 80–3. doi:10.3350/kjhep.2011.17.1.80. PMC 3304630. PMID 21494083.