Amyloid

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

Definition

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

Appearance

Features:[2]

  • Pink (on H&E stain).
  • Extracellular location.
  • Amorphous - no specific shape.

Stains:

  • Congo red stain - red (normal light), apple-green in polarized light.[3]
  • Thioflavin-T stain.[4]

Images:

Associations - DDx

  • Infections.[5][6]
    • Tuberculosis.
    • Leprosy.
    • Chronic osteomyelitis.
    • Bronchiectasis.
  • Idiopathic conditions:
    • Rheumatoid arthritis - relatively common (compared to others below).
    • Anklyosing spondylitis - renal amyloidosis.
    • Crohn's disease.[5]
    • Familial Mediterranean fever.[5]
  • Malignancy.
    • Plasmacytoma.
      • 5-15% of patients with multiple myeloma develop amyloidosis[7] - some say 10-20%.[5]
    • Medullary thyroid carcinoma.
    • Renal cell carcinoma.
  • Many other conditions...

Classification

Amyloidosis can be classified a number of different ways.

Six subtypes classification

Amyloid classified into six groups:[3]

  1. Primary (AL amyloidosis).
    • Monoclonal light chains in serum and/or urine, may be due to plasma cell dyscrasia.
  2. Secondary (AA amyloidosis).
    • Infections, neoplasia.
  3. Hemodialysis-related.
    • Beta-2 microglobulin.[8]
  4. Hereditary.
  5. Senile.
  6. Localized.

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.[9]
    • Primary amyloidosis.[5]
    • Bence Jones protein (light chains -- kappa or lambda) +ve -- necessary for amyloidosis but not sufficient.[10]
  2. AA amyloidosis - "AA" = Amyloid Associated.[11]
    • Secondary amyloidosis.
  3. Abeta amyloid - found in Alzheimer's disease.[12]

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.[3]
  • AA - treat underlying cause.[3]

Classification of amyloid - differentiation

If resistant to congo red with pre-treatment of potassium permanganate likely non-AA amyloidosis.[13]

References

  1. van Rijswijk MH and van Heusden CWGJ. The potassium permanganate method. A reliable method for differentiating amyloid AA from other forms of amyloid in routine laboratory practice. Am J Pathol 1979; 97: 43-58. PMID 495695.
  2. Murphy CL, Eulitz M, Hrncic R, Sletten K, Westermark P, Williams T, Macy SD, Wooliver C, Wall J, Weiss DT and Solomon A. Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens. Am J Clin Pathol 2001; 116: 135-142.
  3. Murphy CL, Wang S, Williams T, Weiss DT and Solomon A. Characterization of systemic amyloid deposits by mass spectroscopy. Methods Enzymol 2006; 412: 48-62.
  4. Vrana JA, Gamez JD, Madden BJ, Theis JD, Robert Bergen III H, and Dogan A. Classification of amyloidosis by laser microdissection and mass spectometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114: 4957-4959.

Secondary amyloidosis

  • AKA AA amyloidosis.
  • Pathophysiology: acute-phase reactant serum amyloid A (SAA) - degraded + deposits.[5][14]

Cardiac amyloidosis

General

  • Common cause of restrictive cardiomyopathy.[15]

Cardiac amyloidosis - subtypes:

  1. AL amyloidosis - associated with plasma cell dyscrasia - most common cardiac amyloidosis.[16]
  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.

Senile systemic amyloidosis

  • Abbreviated SSA.
  • Previously known as senile cardiac amyloidosis.[17]
  • 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 Polyneuropahty.

Epidemiology:

  • Common in the elderly, as the word senile suggests.
  • Found in approx. 25% of elderly over 80 years old,[17] and in upto 65% of patients over 90 years old.[16]

Gross pathology:

  • Grey/black "peppering" of left atrial endocardium - in fixed specimens.[18]
    • "Peppering" should be present if severe.

Histology:

  • 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[16] - less commonly affected by ischemia.

Treatment:

  • No effective treatment.

Images:

Renal amyloidosis

Both AL and AA amyloidosis can affect the kidney.[4]

GI amyloidosis

GI amyloidosis can lead to obstruction and usually is greatest in the small bowel.[3]

Liver amyloidosis

Features:

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


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. ↑ PBoD P.259.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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.
  4. ↑ 4.0 4.1 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.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Amyloidosis. Merck Manual. URL: http://www.merck.com/mmpe/sec12/ch160/ch160a.html. Accessed on: 3 December 2009.
  6. ↑ PBoD P.261.
  7. ↑ PBoD P.261.
  8. ↑ PBoD P.260.
  9. ↑ 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.
  10. ↑ PBoD P.261.
  11. ↑ PBoD P.259.
  12. ↑ PBoD P.259.
  13. ↑ 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/.
  14. ↑ PBoD P.260.
  15. ↑ Cardiac amyloidosis. Medlineplus.org. URL: http://www.nlm.nih.gov/medlineplus/ency/article/000193.htm. Accessed on: 3 December 2009.
  16. ↑ 16.0 16.1 16.2 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.
  17. ↑ 17.0 17.1 Ikeda, S. (Dec 2004). "Cardiac amyloidosis: heterogenous pathogenic backgrounds.". Intern Med 43 (12): 1107-14. PMID 15645642.
  18. ↑ 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.


External links

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