Contents

Search

amyloidosis

A condition characterized by the formation & accumulation of insoluble proteins (amyloid) in various organs of the body, compromising vital function. Etiology: 1) primary (idiopathic) a) senile systemic amyloidosis 1] transthyretin (wild-type) 2] atrial natriuretic peptide b) familial amyloidosis 1] transthyretin amyloidisis (amyloidosis VII) 2] familial Mediterranean fever (AA amyloidosis) c) Alzheimer's disease - beta amyloid peptide of senile plaques d) inclusion body myositis - intracellular accumulation of beta amyloid? 2) secondary a) chronic suppuration or tissue breakdown (AA amyloidosis) 1] rheumatoid arthritis 2] inflammatory bowel disease 3] familial Mediterranean fever (AA amyloidosis) 4] chronic infection - tuberculosis b) chronic renal failure - long-term dialysis (beta-2 microglobulin) 3) multiple myeloma a) amyloid light-chain (AL) amyloidosis (most common) b) overproduction of monoclonal light chains (80% lambda) c) a localized amyloidosis involving a single organ with deposition of light chains may occur Pathology: 1) serum amyloid P component (SAP) binds to all forms of amyloid fibrils & is present in all amyloid deposits including amyloid of Alzheimer's disease 2) senile systemic amyloidosis most frequently involves the heart 3) prealbumin is characteristic protein in familial amyloidosis 4) cardiac abnormalities are not a feature of secondary amyloidosis 5) increased risk of hemorrhage a) systemic fibrinolysis b) acquired factor X deficiency - absorption of factor X to amyloid fibrils c) increased vascular fragility 6) amyloidosis involving the kidney tends to present with nephrotic syndrome 7) progressive painful axonal polyneuropathy - preominant involvement of small fibers (pain & temperature Protein precursors of amyloidosis/amyloid deposits: - serum amyloid (SAA) - apolipoprotein A-I (ApoAI) - apolipoprotein A-II (ApoAII) - immunoglogulin light & heavy chains - beta-2-microglobulin - procalcitonin - islet amyloid peptide/amylin - atrial natriuretic peptide - prolactin - gelsolin - keratin (cutaneous amyloid) - keratoepithelin - transthyretin - amyloid precursor protein - prion protein - BRI gene product - cystatin-C - fibrinogen alpha chain - medin/lactadherin - lysozyme * histopathology images [7] Genetics: autosomal dominant (familial form) Clinical manifestations: depend on organ (systems) involved 1) asthenia 2) weight loss 3) progressive painful sensory polyneuropathy - pain & temperature dysethesia - paresthesias - bilateral carpal tunnel syndrome with recurrence after surgery [3] 4) macroglossia, smoothing of the tongue [2] 5) hypertension 6) lymphadenopathy 7) hepatomegaly 8) splenomegaly 9) petechiae, purpura, ecchymoses - 'pinch purpura' at sites of thin skin (periorbital) - easy bruising & bleeding after minor trauma 10) nephrotic syndrome 11) edema 12) arthralgia 13) myalgia 14) joint effusion 15) cardiomyopathy (cardiac amyloidosis) - restrictive cardiomyopathy 16) multiorgan autonomic dysfunction 17) case report of 84 year old woman with chest pain, dyspnea, nausea/vomiting (dry heaves) & rash [9] * images [8] Laboratory: 1) biopsy/tissue analysis a) biopsy of gingiva b) biopsy of rectum c) aspiration of abdominal fat pad d) yellow-green birefringence in polarized light - Congo red stain - thioflavin-T stain e) amyloid typing of biopsy/aspiration specimen - amyloid.prealbumin Ag in tissue - beta-2-microglobulin amyloid Ag in tissue f) amyloid in tissue by light microscopy 2) work up for multiple myeloma if indicated a) serum protein electrophoresis b) urine protein electrophoresis c) bone marrow aspirate & biopsy 3) PT & aPTT may be increased due to factor X deficiency 4) plasma fibrinogen may be diminished 5) serum beta-2 microglobulin 6) increased serum alkaline phosphatase is the 1st indication of liver involvement 7) negative findings: a) serum complement levels are normal b) antinuclear antibody (ANA) is negative c) rheumatoid factor (RF) is negative 8) urine protein: proteinuria or nephrotic syndrome if kidney involved [3] Special laboratory: - electrocardiogram: - low ECG voltage* - wide complex tachycardia (case report) [9] - echocardiogram - increased myocardial wall thickness* * association of low ECG voltage with increased myocardial wall thickness consistent with amyloidosis Radiology: - cardiac magnetic resonance imaging for restrictive cardiomyopathy - late gadolinium enhancement of papillary muscle [3] - not specific for amyloid type - 99m-technetium pyrophosphate cardiac scintigraphy (radionuclide ventriculography) - useful for differentiating amyloid subtypes - identifies misfolded transthyretin (ATR) with specificity > 99% Management: 1) treatment of underlying disease a) AL amyloidosis is treated with chemotherapy (see multiple myeloma) b) AA amyloid is treated by aggressively treating the inflammatory condition that generates the increased SAA levels 2) NO effective treatment for beta-2 microglobulin-related amyloidosis 3) a novel investigational approach is described [6] in which a small molecule binds serum amyloid followed with monoclonal antibody directed at amyloid deposits, stimulating macrophages to engulf the amyloid deposits

Related

amyloid multiple myeloma; plasmacytoma/plasma cell myeloma systemic fibrinolysis (fibrinolytic disorder)

Specific

AA amyloidosis AL amyloidosis amyloid polyneuropathy-nephropathy Iowa type; amyloidosis van Allen type; familial amyloid polyneuropathy type III (AMYLIOWA) amyloidosis type 8 (AMYL8); systemic non-neuropathic amyloidosis; Ostertag-type amyloidosis cardiac amyloidosis cerebral amyloid angiopathy (CAA) familial amyloid polyneuropathy familial amyloidosis familial Mediterranean fever (FMF, recurrent polyserositis) Finnish type amyloidosis; amyloidosis type 5; Meretoja type amyloidosis hemodialysis-related amyloidosis lattice dystrophy localized cutaneous amyloidosis oculoleptomeningeal type amyloidosis (amyloidosis VII) primary localized cutaneous amyloidosis; familial lichen amyloidosis renal amyloidosis; amyloid nephropathy senile systemic amyloidosis

General

chronic metabolic disease

References

  1. Stedman's Medical Dictionary 27th ed, Williams & Wilkins, Baltimore, 1999
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 54-55
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2015, 2018, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1307
  5. Merlini G & Bellotti V, Molecular Mechanisms of amylodosis. N Engl J Med 349:583, 2003 PMID: 12904524 - van der Hilst JC et al, Molecular Mechanisms of amylodosis. N Engl J Med 349:1872, 2003 PMID: 14606469 - Sungar CI, Molecular Mechanisms of amylodosis. N Engl J Med 349:1872, 2003 PMID: 14602890
  6. Bodin K et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature 2010 Nov 4; 468:93. PMID: 20962779
  7. Holmes RO, Diamond HS (histopathology images) Medscape: Amyloidosis http://emedicine.medscape.com/article/335414-overview
  8. DermNet NZ. Amyloidosis (images) http://www.dermnetnz.org/systemic/amyloidosis.html
  9. Roh EK, Ali M, Lu MT, Bradshaw SH. Case 2-2016. An 84-Year-Old Woman with Chest Pain, Dyspnea, and a Rash. N Engl J Med. 2016 Jan 21;374(3):264-74. PMID: 26789875
  10. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016 Jun 25;387(10038):2641-2654. Review. PMID: 26719234