Amyloidosis Pathophysiology

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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]Sabawoon Mirwais, M.B.B.S, M.D.[3]

## Overview[edit | edit source]

Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. 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. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils. Some neurodegenerative disorders such as Parkinson's disease, Alzheimer, and Huntington's disease may occur in localised amyloidosis. On microscopic pathology, typical green birefringence under polarized light after Congo red staining (appears in red under normal light).

## Pathophysiology[edit | edit source]

* Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes.[1]
* These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
* Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.[2]

### Systemic Amyloidosis[edit | edit source]

* 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)[edit | edit source]

* Primary (AL) amyloidosis) is the most common type of amyloidosis.[5]
* It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that are 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 (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 organ involvement
* Hematological response to treatment
* The median survival of patients with AL amyloidosis is approximately 3.8 years.

#### Secondary Amyloidosis (AA)[edit | edit source]

* Secondary amyloidosis occurs as a reaction to an existing illness.
* Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).[6]
* Secondary or reactive amyloidosis (AA) comprises approximately 45% of the systemic amyloidoses.
* Pathogenesis of secondary amyloidosis is multifactorial, including:
* 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[edit | edit source]

* Hereditary amyloidosis is an autosomal dominant disorder.[7]
* It can have a heterogeneous nature of presentation and can be complicated by significant disability and mortality.[8]
* Inherited variant proteins cause the production and deposition of amyloid fibrils.[6]
* Hereditary amyloidosis is due to amyloidogenic mutations and the subsequent deposition of amyloids which include:
* Transthyretin (TTR) (most common inherited mutation)
* Fibrinogen
* Apolipoprotein A1
* Apolipoprotein A2
* Lysozyme
* Gelsolin genes

### Organ-specific Amyloidosis[edit | edit source]

* In this type of amyloidosis, amyloid deposition occurs only in the organ of origin or tissue of precursor protein.
* Neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, may occur in localized amyloidosis.

* Localized amyloidoses can develop due to the 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

## Genetics[edit | edit source]

#### Hereditary Amyloidosis[edit | edit source]

* Hereditary amyloidosis involves mutations in the following genes:[9]
* LYZ gene
* Fibrinogen A alpha polypeptide gene
* FGA gene
* APOA1 gene
* Lysozyme gene
* B2M gene

#### Primary Localized Cutaneous Amyloidosis[edit | edit source]

* Primary localized cutaneous amyloidosis is inherited in autosomal dominant manner.[10]

* Primary localized cutaneous amyloidosis involves mutations in the following genes:[11]
* OSMR gene

## Associated Conditions[edit | edit source]

Conditions associated with amyloidosis include:[12]

* MEN2A

## Gross Pathology[edit | edit source]

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

* Porcelain like or waxy appearance
* Enlargement

### Images[edit | edit source]

Nodular deposits of amyloid on the pleural surfaces.[13] Cut section of an inguinal lymph node showing firm and waxy consistency.[14] A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.[15]

## Microscopic Pathology[edit | edit source]

On microscopic histopathological analysis, amyloidosis is characterized by:[6][16]

* Green birefringence under polarized light after Congo red staining (appears 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

### Images[edit | edit source]

Small bowel duodenum with amyloid deposition Congo red.[17] Amyloidosis (black arrows) in a lymph node after staining with Congo Red.[18] Green birefringence under polarized light.[19]

## References[edit | edit source]

1. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
2. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
3. ↑ Baker KR, Rice L (2012). "The amyloidoses: clinical features, diagnosis and treatment". Methodist Debakey Cardiovasc J. 8 (3): 3–7. PMC 3487569. PMID 23227278.
4. ↑ Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
5. ↑ Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
6. ↑ 6.0 6.1 6.2 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
7. ↑ Hund E, Linke RP, Willig F, Grau A (February 2001). "Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment". Neurology. 56 (4): 431–5. doi:10.1212/wnl.56.4.431. PMID 11261421.
8. ↑ Gertz MA (June 2017). "Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges". Am J Manag Care. 23 (7 Suppl): S107–S112. PMID 28978215.
9. ↑ Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ (April 1993). "Human lysozyme gene mutations cause hereditary systemic amyloidosis". Nature. 362 (6420): 553–7. doi:10.1038/362553a0. PMID 8464497.
10. ↑ Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA (January 2008). "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis". Am. J. Hum. Genet. 82 (1): 73–80. doi:10.1016/j.ajhg.2007.09.002. PMC 2253984. PMID 18179886.
11. ↑ Arita K, South AP, Hans-Filho G, Sakuma TH, Lai-Cheong J, Clements S, Odashiro M, Odashiro DN, Hans-Neto G, Hans NR, Holder MV, Bhogal BS, Hartshorne ST, Akiyama M, Shimizu H, McGrath JA (January 2008). "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis". Am. J. Hum. Genet. 82 (1): 73–80. doi:10.1016/j.ajhg.2007.09.002. PMC 2253984. PMID 18179886.
12. ↑ Hofstra RM, Sijmons RH, Stelwagen T, Stulp RP, Kousseff BG, Lips CJ, Steijlen PM, Van Voorst Vader PC, Buys CH (August 1996). "RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia". J. Invest. Dermatol. 107 (2): 215–8. doi:10.1111/1523-1747.ep12329651. PMID 8757765.
13. ↑ By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31127928
14. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377537238/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629764
15. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377538012/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629740
16. ↑ 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.
17. ↑ By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine - http://www.healcentral.org/healapp/showMetadata?metadataId=38717, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=870218
18. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559787/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629716
19. ↑ By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559955/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629705

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