Amyloid

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Amyloid is one of those things clinicians can put in many differential diagnoses. The pathologist can diagnose it.

Amyloid
Diagnosis in short

Cardiac amyloidosis. H&E stain.
LM typically extracellular, amorphous (no specific shape), acellular and pink (on H&E stain) -- cotton candy like, classically has a "cracked" appearance
Subtypes multiple subclassifications: Robbins (AL amyloidosis, AA amyloidosis, non-AA and non-AL), set of six subtypes (primary (AL amyloidosis), secondary (AA amyloidosis, hemodialysis-related, localized), hereditary, senile systemic amyloidosis)
LM DDx fibrin, collagen, smooth muscle
Stains Congo red +ve
EM non-branching fine fibrils - usually 8-12 nm in diameter (accepted range 8-15 nm)
Molecular beta sheet
Gross waxy appearance
Site pretty much anywhere, blood vessels
Associated Dx very many
Clinical history variable
Prevalence uncommon
Prognosis dependent on subtype

This article is a general overview of the topic. Links are provided to articles that deal with amyloidosis at specific sites, see site specific section below.

Overview

Definition

  • Disorder of protein folding - structure: beta sheet.[1]

Appearance

Light microscopy

Features:[2]

  • Pink (on H&E stain).
  • Extracellular location.
  • Amorphous - no specific shape.
  • May have a "cracked" appearance.[citation needed]

DDx - ABCs of pink:

  • Amyloid.
  • Blood (fibrin).
  • Collagen.
  • Smooth muscle.

Images

  • Amyloid - H&E stain. (WC)

  • Amyloid - congo red stain. (WC)

Electron microscopy

Features:[3]

  • Fine fibrils, non-branching.
    • Usually 8-12 nm in diameter; accepted range 8-15 nm.[4]

Images:

DDx

  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
    • Typically has basophilic granularity in the blood vessels.[5]

Stains

  • Congo red +ve.
    • Positive:[6]
      • Orange/light red (non-polarizaed light).
      • Apple green birefringence (polarized light).
    • Negative:
      • Blue birefringence (polarized light) = collagen fibers.[7]
  • Thioflavin T stain.[8]
  • Sodium sulphate-Alcian Blue stain +ve.[9]

Sign out

BONE LESION, RIGHT ILIAC, BIOPSY:
- AMYLOID ASSOCIATED WITH HISTOCYTES, GIANT CELLS AND A FEW LYMPHOCYTES
  AND PLASMA CELLS.

COMMENT:
The presence of amyloid is confirmed with congo red staining and polarization.

There are no histomorphologic findings suggestive of a plasma cell neoplasm
in this biopsy.

Clinical correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling is suggested.

Associations - DDx

Classification

Amyloidosis can be classified a number of different ways.

Six subtypes classification

Amyloid classified into six groups:[6]

  1. Primary (AL amyloidosis).
    • Monoclonal light chains in serum and/or urine, may be due to plasma cell dyscrasia.
  2. Secondary (AA amyloidosis).
  3. Hemodialysis-related.
    • Beta-2 microglobulin.[13]
  4. Localized.
  5. Hereditary.
  6. Senile systemic amyloidosis.

How to remember: Two As = secondary amyloidosis.

Three main types - Robbins classification

Amyloid classified into three groups:[1]

  1. AL amyloidosis - "AL" = Amyloid Light chain.[16]
    • Primary amyloidosis.[10]
    • Bence Jones protein (light chains -- kappa or lambda) +ve -- necessary for amyloidosis but not sufficient.[17]
  2. AA amyloidosis - "AA" = Amyloid Associated.[18]
    • Secondary amyloidosis.
  3. Abeta amyloid - found in Alzheimer's disease.[19]

Additional types:

  • ATTR = Amyloid Transthyretin (TTR)
    • Transthyretin - serum protein that transport thyroxine and retinol; transthyretin AKA prealbumin.

Treatment

The very short version:

  • AL - chemotherapy & stem cell transplant.[6]
  • AA - treat underlying cause.[6]

Classification of amyloid - differentiation

Biochemical techniques

  • Pre-treated with potassium permanganate, to obliterate congo red reactivity, was though be definitive for AA amyloidosis;[20] this is now generally considered to be unreliable.[21]

Immunohistochemistry

  • IHC may be useful for the subclassification of amyloidoses.[22]
    • The reliability of IHC for the subclassification of amyloidoses is thought to be low.[23][24]
      • Extreme caution is advised when interpreting IHC results.

Possibly useful immunostains:

  • Kappa.
  • Lambda.
  • Transthyretin.
    • The name transthyretin is from transports thyroxine and retinol (previous unknown as prealbumin).

Mass spectroscopy

  • Can be typed using mass spectroscopy.[25]
    • Considered to be the definitive test.[24][26]
      • High specificity and sensitivity vis-à-vis clinicopathologic correlation.[27]
    • May be done on formalin-fixed paraffin embedded (FFPE) material.[27]

Types

Secondary amyloidosis

  • AKA AA amyloidosis.
  • Pathophysiology: acute-phase reactant serum amyloid A (SAA) - degraded + deposits.[10][28]

Cerebral amyloid angiopathy

Main article: Cerebral amyloid angiopathy

A common cause of lobar hemorrhage (cerebral cortex, cerebellar cortex) in the elderly.

Senile systemic amyloidosis

  • Abbreviated SSA.

General

  • Previously known as senile cardiac amyloidosis.[29]
  • May be referred to as ATTR = amyloidosis TTR; in SSA the TTR is not mutated.
    • There is a hereditary form of amyloidosis with mutated TTR deposition known as ATTR type FAP = ATTR type Familial Amyloid Polyneuropathy.

Epidemiology:

  • Common in the elderly, as the word senile suggests.
  • Found in approx. 25% of elderly over 80 years old,[29] and in upto 65% of patients over 90 years old.[30]

Treatment:

  • No effective treatment.

Gross pathology

  • Grey/black "peppering" of left atrial endocardium - in fixed specimens.[31]
    • "Peppering" should be present if severe.

Microscopic

Features:

  • Heart most commonly involved, followed by lungs and then by kidney (renal papilla).
  • DDx of pink of H&E is important to remember: amyloid, muscle, collagen, clotted blood.
    • Amyloid vs. Fibrosis? Subendocardial fibrosis may have rim of (diffusion) preserved myocytes. (???)
  • Amyloid often present in the subepicardial tissue[30] - less commonly affected by ischemia.

Images

  • Senile systemic amyloidosis - H&E. (WC)

  • Senile systemic amyloidosis - congo red. (WC)

  • Senile systemic amyloidosis - Movat's. (WC)

Site specific

Abdomen

Abdominal fat pad biopsy redirects here.

General

  • Abdominal fat pad biopsy - common screen for amyloidosis.
    • May be done with FNA.
      • Suffers for poor sensitivity.[7]

Microscopic

Features:

  • Small-to-intermediate sized arteries with a thickened amorphous eosinophilic media.
    • Thickening classically nodular.
    • Apple green-birefringence -- with polarization.

Note:

  • Evaluation of at least 15 small blood vessels is recommended.[7]

Sign out

SOFT TISSUE, ABDOMEN, BIOPSY:
- AMYLOIDOSIS.

Negative

SOFT TISSUE, ABDOMEN, BIOPSY:
- BENIGN FIBROADIPOSE TISSUE.
- NEGATIVE FOR AMYLOIDOSIS WITH CONGO RED STAINING AND POLARIZED LIGHT.

COMMENT:
Correlation with serum protein electrophoresis, urine protein electrophoresis
and bone marrow sampling should be considered within the clinical context.

Cardiac amyloidosis

General

Cardiac amyloidosis - subtypes:

  1. AL amyloidosis - associated with plasma cell dyscrasia - most common cardiac amyloidosis.[30]
  2. Senile systemic amyloidosis - TTR-related amyloidosis (unmutated TTR).
  3. Hereditary amyloidosis.
  4. AA amyloidosis is uncommon.

Clinical:

  • CHF, conduction abnormalities.
  • Kidney disease (proteinuria) - associated with AL amyloidosis.

Pulmonary amyloidosis

Main article: Pulmonary amyloidosis
  • Very rare.

Renal amyloidosis

Main article: Medical kidney diseases

General

  • Both AL and AA amyloidosis can affect the kidney.[8]

Clinical:

Microscopic

Features:

  • Paucicellular mesangial expansion.
  • Fluffy hyaline material in medium-sized blood vessels.

DDx:

Images

  • Renal amyloidosis - high mag. (WC)

  • Renal amyloidosis - high mag. (WC)

  • Renal amyloidosis - very high mag. (WC)

www:

Urinary bladder amyloidosis

Main article: Urinary bladder amyloidosis

GI amyloidosis

  • GI amyloidosis can lead to obstruction and usually is greatest in the small bowel.[6]

Liver amyloidosis

Main article: Liver amyloidosis

Features:

  • Parenchymal deposition (common).
  • Portal triad deposition (less common).

Gastric amyloidosis

Main article: Amyloidosis of the stomach

Bone

Amyloid is reported in association with:

See also

References

  1. ↑ 1.0 1.1 Lachmann HJ, Hawkins PN (2006). "Amyloidosis and the lung". Chron Respir Dis 3 (4): 203-14. PMID 17190124. http://crd.sagepub.com/cgi/pmidlookup?view=long&pmid=17190124.
  2. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
  3. ↑ 3.0 3.1 URL: http://www.fondazionedamico.org/biopsiarenale_atlas/seco/amil/amil21.htm. Accessed on: 9 November 2010.
  4. ↑ Alpers, CE.; Kowalewska, J. (Jan 2008). "Fibrillary glomerulonephritis and immunotactoid glomerulopathy.". J Am Soc Nephrol 19 (1): 34-7. doi:10.1681/ASN.2007070757. PMID 18045849.
  5. ↑ Kleinschmidt-DeMasters BK, Prayson RA (November 2006). "An algorithmic approach to the brain biopsy--part I". Arch. Pathol. Lab. Med. 130 (11): 1630–8. PMID 17076524.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Ebert EC, Nagar M (March 2008). "Gastrointestinal manifestations of amyloidosis". Am. J. Gastroenterol. 103 (3): 776-87. doi:10.1111/j.1572-0241.2007.01669.x. PMID 18076735.
  7. ↑ 7.0 7.1 7.2 Devata, S.; Hari, P.; Markelova, N.; Li, R.; Komorowski, R.; Shidham, VB. (2011). "Detection of amyloid in abdominal fat pad aspirates in early amyloidosis: Role of electron microscopy and Congo red stained cell block sections.". Cytojournal 8: 11. doi:10.4103/1742-6413.82278. PMID 21760829.
  8. ↑ 8.0 8.1 Nishi S, Alchi B, Imai N, Gejyo F (April 2008). "New advances in renal amyloidosis". Clin. Exp. Nephrol. 12 (2): 93-101. doi:10.1007/s10157-007-0008-3. PMID 18175051.
  9. ↑ Pomerance, A.; Slavin, G.; McWatt, J. (Jan 1976). "Experience with the sodium sulphate-Alcian Blue stain for amyloid in cardiac pathology.". J Clin Pathol 29 (1): 22-6. PMID 55419.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Amyloidosis. Merck Manual. URL: http://www.merck.com/mmpe/sec12/ch160/ch160a.html. Accessed on: 3 December 2009.
  11. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 261. ISBN 0-7216-0187-1.
  12. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 261. ISBN 0-7216-0187-1.
  13. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 260. ISBN 0-7216-0187-1.
  14. ↑ URL: http://www.umm.edu/altmed/articles/amyloidosis-000007.htm. Accessed on: 23 October 2010.
  15. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/enfrm.html. Accessed on: 6 December 2010.
  16. ↑ Comenzo, RL.; Vosburgh, E.; Falk, RH.; Sanchorawala, V.; Reisinger, J.; Dubrey, S.; Dember, LM.; Berk, JL. et al. (May 1998). "Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients.". Blood 91 (10): 3662-70. PMID 9573002.
  17. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 261. ISBN 0-7216-0187-1.
  18. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
  19. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 259. ISBN 0-7216-0187-1.
  20. ↑ van Rijswijk MH, van Heusden CW (October 1979). "The potassium permanganate method. A reliable method for differentiating amyloid AA from other forms of amyloid in routine laboratory practice". Am. J. Pathol. 97 (1): 43–58. PMC 2042379. PMID 495695. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042379/.
  21. ↑ Picken, MM. (Apr 2010). "Amyloidosis-where are we now and where are we heading?". Arch Pathol Lab Med 134 (4): 545-51. doi:10.1043/1543-2165-134.4.545. PMID 20367306.
  22. ↑ Röcken C (December 2009). "[Update on immunohistological classification of amyloidoses]" (in German). Pathologe 30 Suppl 2: 121–3. doi:10.1007/s00292-009-1183-7. PMID 19756621.
  23. ↑ Solomon, A.; Murphy, CL.; Westermark, P. (Jan 2008). "Unreliability of immunohistochemistry for typing amyloid deposits.". Arch Pathol Lab Med 132 (1): 14; author reply 14-5. doi:10.1043/1543-2165(2008)132[14b:IR]2.0.CO;2. PMID 18181665. http://www.archivesofpathology.org/doi/pdf/10.1043/1543-2165%282008%29132%5B14b%3AIR%5D2.0.CO%3B2.
  24. ↑ 24.0 24.1 Murphy CL, Eulitz M, Hrncic R, et al. (July 2001). "Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens". Am. J. Clin. Pathol. 116 (1): 135–42. doi:10.1309/TWBM-8L4E-VK22-FRH5. PMID 11447744.
  25. ↑ Chee, CE.; Lacy, MQ.; Dogan, A.; Zeldenrust, SR.; Gertz, MA. (Jun 2010). "Pitfalls in the diagnosis of primary amyloidosis.". Clin Lymphoma Myeloma Leuk 10 (3): 177-80. doi:10.3816/CLML.2010.n.027. PMID 20511161.
  26. ↑ Murphy CL, Wang S, Williams T, Weiss DT, Solomon A (2006). "Characterization of systemic amyloid deposits by mass spectrometry". Meth. Enzymol. 412: 48–62. doi:10.1016/S0076-6879(06)12004-2. PMID 17046651.
  27. ↑ 27.0 27.1 Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR, Dogan A (December 2009). "Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens". Blood 114 (24): 4957–9. doi:10.1182/blood-2009-07-230722. PMID 19797517.
  28. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 260. ISBN 0-7216-0187-1.
  29. ↑ 29.0 29.1 Ikeda, S. (Dec 2004). "Cardiac amyloidosis: heterogenous pathogenic backgrounds.". Intern Med 43 (12): 1107-14. PMID 15645642.
  30. ↑ 30.0 30.1 30.2 Sharma, PP.; Payvar, S.; Litovsky, SH.. "Histomorphometric analysis of intramyocardial vessels in primary and senile amyloidosis: epicardium versus endocardium.". Cardiovasc Pathol 17 (2): 65-71. doi:10.1016/j.carpath.2007.05.008. PMID 18329550.
  31. ↑ Pomerance, A. (Sep 1965). "Senile cardiac amyloidosis.". Br Heart J 27 (5): 711-8. PMID 5829755. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC469777/pdf/brheartj00340-0085.pdf.
  32. ↑ Cardiac amyloidosis. Medlineplus.org. URL: http://www.nlm.nih.gov/medlineplus/ency/article/000193.htm. Accessed on: 3 December 2009.
  33. ↑ Satoskar, AA.; Burdge, K.; Cowden, DJ.; Nadasdy, GM.; Hebert, LA.; Nadasdy, T. (Jun 2007). "Typing of amyloidosis in renal biopsies: diagnostic pitfalls.". Arch Pathol Lab Med 131 (6): 917-22. doi:10.1043/1543-2165(2007)131[917:TOAIRB]2.0.CO;2. PMID 17550319. http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2007)131%5B917:TOAIRB%5D2.0.CO;2.
  34. ↑ Petruzziello, F.; Zeppa, P.; Catalano, L.; Cozzolino, I.; Gargiulo, G.; Musto, P.; D'Auria, F.; Liso, V. et al. (May 2010). "Amyloid in bone marrow smears of patients affected by multiple myeloma.". Ann Hematol 89 (5): 469-74. doi:10.1007/s00277-009-0857-9. PMID 19894050.
  35. ↑ Alabi, ZO.; Ojo, OS.; Odesanmi, WO. (1991). "Secondary amyloidosis in chronic osteomyelitis.". Int Orthop 15 (1): 21-2. PMID 2071276.
  36. ↑ Miossec, P.; Lormeau, B.; Valensi, P.; Arthuis, F.; Amouroux, J.; Attali, JR. (Sep 1999). "Bone amyloidoma in a diabetic patient with morbid obesity.". Diabetes Metab 25 (3): 261-3. PMID 10499196.


External links

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