MS4 Amyloidosis

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Author:
jknell
ID:
207118
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MS4 Amyloidosis
Updated:
2013-03-13 19:54:39
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Multisystem Disorders
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Multisystem Disorders
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  1. Amyloid Proteins
    • -resistant to proteolysis
    • -beta pleated sheet configuration
    • -homogenous protein

    • Main Components of Amyloid Deposits
    • 1. Fibrillary Protein (95%)
    • -each different type of amyloid has a separate protein precursor for its fibrillary protein
    • 2. Amyloid P component (5%)
    • 3. Glycosoamynoglycan
  2. Steps in Amyloidgenesis
    1. Misfolding of precursor protein to lower thermodynamic state

    2. Intermediate takes on more beta-sheet structures

    3. Enables aggregation and self-propagation secured by H-bonds

  3. Tissue Effects of Deposition
    • -Extracellular deposition
    • -Unusual stability
    • -Damages tissue structure and function
    • -Progressive and fatal without treatment

    • 1. Macroglossia (almost pathomnemonic)
    • 2. Violacious purpura around the eyes
    • 3. Amyloid deposits in the muscles
    • 4. Hepatomegaly
    • 5. Deposits in the lungs
    • 6. Submandibular gland enlargement

  4. Staining
    • Congo red
    • -Normal light: brick red
    • -Polarized light: apple green birefringence
    • **molecules align on the beta pleated sheet

  5. Clinical Subtypes of Amyloidosis
    • 1. Primary
    • -light chain amyloidosis (AL)
    • -underlying plasma cell proliferative disorder

    • 2. Secondary
    • -AA
    • -caused by abnormal deposition of acute phase reactant (increased during inflammation)
    • -serum amyloid A (SAA) protein

    • 3. Senile/Hereditary
    • -most commonly ATTR (transthyretin or prealbumin)
    • -sporadically in advanced age (senile)
    • -germline ATTR mutation (hereditary)

    • 4. Other Proteins (10-15%)
    • -more than 28 amyloidgenic proteins

    • 5. Localized amyloidosis
    • -abnormal accumulation of locally produced proteins in an organ
    • -ie: Alzheimer's (amyloid beta protein precursor)
    • -ie: Calcitonin in medullary thyroid cancer

  6. Mechanistic Categories
    • 1. Genetic mutations
    • -often AA substitutions
    • -ATTR, Afib, ALys, AI and AII (apolipoproteins)

    • 2. Wild Type Proteins
    • -senile amyloid of WT ATTR
    • -other senile from prolactin, calcitonin, amylin

    • 3. Acquired Structurally Abnormal Precursor
    • -monoclonal immunoglobulin light chain (AL)
    • -usually lambda

    • 4. Sustained elevated concentrations of inherently amyloidgenic precursor over a very long time
    • -increased production: AA in inflammatory syndromes
    • -decreased elimination: B2 microglobulin in end stage renal failure
    • -injected insulin (amyloidomas)

    • 5. Proteolytic Remodeling
    • -B-amyloid precursor protein in Alzheimer's

    • 6. Transmission by prions
    • -act as template for normal host prior protein PrPc to misfold into pathogenic PrPsc
  7. Possible Clinical Presentations
    • Visible Tissue Infiltration:
    • -bruising: periorbital, general
    • -macroglossia
    • -muscle pseudohypertrophy

    • Renal:
    • -proteinuria
    • -renal failure

    • Cardiac:
    • -restrictive cardiomyopathy
    • -ECG: low voltage, pseudoinfarct

    • Liver:
    • -hepatomegaly
    • -high ALP
    • -rarely liver failure

    • Peripheral Neuropathy:
    • -carpal tunnel syndrome
    • -symmetrical sensorimotor neuropathy

    • Autonomic Neuropathy:
    • -orthostatic hypotension/arrhythmias
    • -gut motility/bladder emptying

    • Gastrointestinal:
    • -weight loss/anorexia/bloating
    • -blood loss-constipation/diarrhea

    • Adrenal Axis:
    • -hypoadrenalism

    • Lymphoreticular System:
    • -hyposplenism/splenomegaly
    • -lymphadenopathy
  8. Presentations of Localized AL amyloidosis
    • -bladder
    • -bronchopulmonary tract
    • -prostate
    • -conjunctiva
    • -other

    • Good prognosis
    • Local Treatment
  9. Presentations of AL Amyloidosis
    • Precursor protein:
    • -usually lambda light chain

    • Clinical Presentations:
    • -cardiac
    • -renal
    • -hepatic/GI
    • -PNS
    • -soft tissues

    • Clinical Features:
    • -nephrotic syndrome
    • -renal failure
    • -cardiac failure
    • -peripheral or autonomic neuropathy (NOT CNS)
    • -Carpal Tunnel Syndrome
    • -Factor X deficiency
    • -periorbital bruising ("raccoon eyes")
    • -BM involvement
    • -Jaw claudication
    • -macroglossia
    • -lympadenopathy
  10. Presentations of ATTR Amyloidosis
    • Precursor Protein:
    • -mutant transthyretin

    • Clinical Presentations:
    • -Cardiac
    • -PNS
  11. Presentations of Senile Systemic Amyloidosis
    • Precursor Protein:
    • -wild-type transthyretin

    • Clinical Presentations:
    • -Cardiac
    • -Pulmonary
    • -PNS

    • Clinical Features:
    • -cardiac isolated disease
    • -thick walled LV
    • -diastolic dysfunction
    • -slowly progressive
    • -does NOT respond to chemo
    • -mostly elderly white men
    • -can be diagnosed as AL in the presence of MGUS/MM
  12. Presentations of AA Amyloidosis
    • -Rare in developed world
    • -cases still occur in associated with chronic infection, severe gout, UC, metastatic renal cancer

    • Precursor Protein:
    • -serum amyloid A

    • Clinical Presentations:
    • -renal

    • Clinical Features:
    • -primarily renal at presentation
    • -liver involvement (sign of advanced disease)
    • -adrenal involvement

    **almost never cardiac or neurologic
  13. Presentations of A Fib Amyloidosis
    • Precursor Protein:
    • -mutant fibrinogen A alpha

    • Clinical Presentation:
    • -Renal
    • -Hepatic
  14. Presentations of AApo-A1
    • Precursor Protein:
    • -Apolipoprotein A1

    • Clinical Presentation:
    • -Cardiac
    • -renal
    • -hepatic/GI
    • -PNS
    • -Skin
  15. Diagnosis of Amyloidoses
    • -can be difficult
    • -no blood test to diagnose or exclude
    • -usually depends on clinical suspicion

    • Supported by:
    • 1. underlying chronic inflammatory state (AA)
    • 2. underlying plasma cell dyscrasia (AL)
    • 3. FHx (hereditary)
    • 4. Evidence of organ dysfunction
  16. Bleeding in AL Amyloidosis
    • -acquired deficiency of Factor X
    • -postulated to occur due to absorption of factor X into amyloid fibril
  17. Biopsy
    • -screening biopsy
    • -rectal: more invasive but better for immunotyping
    • -abdominal fat FNA: highly variable sensitivity

    • Histology:
    • -apple green birefringence on congo red stain
    • -AA and hereditary are sensitive and specific
    • -AL not often easy (only 50%)
  18. Radiolabelled SAP Scintigraphy
    • -highly suggestive of AL amyloidosis
    • -bone uptake seen in 25%
    • -consistent with AA (but AA protects other amyloid proteins from degradation so it could be any type of systemic amyloidosis)
  19. Distinguishing different type of amyloidosis
    *essential for deciding treatment

    • 1. Spep/upep/IFE/FLC (???)
    • 2. bone marrow bx
    • 3. mutation analysis for hereditary
    • 4. tissue typing (gold standard)
    • 5. correlation with clinical features
  20. AL Amyloidosis vs MGUS
    • Typical Subtle monoclonal gammopathies:
    • -subtle monoclonal gammopathies (75-80%)
    • -myeloma (20%)
    • -clonal disease undetectable (2%)

    • MGUS is common in the elderly:
    • -monoclonal gammopathy of unknown significance

    The presence of clonal dyscracia does not confirm a diagnosis of AL amyloidosis

    The absence of detectable clone does NOT exclude AL amyloidosis
  21. Treatment of AL Amyloidosis
    • Chemotherapy
    • -Melphalan + dex +/- bortezomib
    • -plasma cell clone a little too hyperactive → use chemo to shut it down
    • -Difficulties: multi-organ involvement (poorly tolerated with high treatment related mortality)
    • -optimal treatment contentious

    • Autologous HSCT
    • -works best early in the course of the disease before too much amyloid has accumulated

    • Organ Transplantation:
    • 1. Liver: not recommended (poor survival in most)
    • 2. Heart: only if cardiac isolated disease, but be followed by ASCT
    • 3. Kidneys: viable if clonal disease under good control without significant cardiac disease
    • Serum free light chain assay:
    • -enables quantitative monitoring of plasma cell dyscracia and response to therapy
    • -more difficult in renal failure (retention)
    • -excess light chain demonstrable in 95% of patients with AL amyloidosis
  22. Prognosis of AL Amyloidosis
    • Better Prognosis:
    • -renal isolated disease
    • -peripheral neuropathy only
    • -soft tissue involvement only
    • -good response to chemotherapy

    • Biomarkers:
    • -BNP
    • -troponin
    • -markers of heart disease (poor prognosis)

    • Poorer Prognosis:
    • -poor response to chemo
    • -cardiac involvement
    • -ANS involvement
  23. Treatment of AA Amyloidosis
    Suppress underlying inflammation!

    • Control underlying inflammatory diseases:
    • -RA, JCA, chronic sepsis, crohn's etc

    • Immunosuppressants:
    • -anti-TNF

    Monitor response with serial SAA measurements

    Excellent results with kidney transplanation
  24. Treatment of Hereditary ATTR Amyloidosis
    • Hepato-renal transplant
    • -fibrinogen is synthesized in the liver
  25. Treatment of Senile Systemic Amyloidosis
    • Diuretics
    • -mainstay (cardiac involvement)

    • Diflunisal
    • -NSAID
    • -stabilizes variant TTRs and prevents unfolding and aggregation

    • Tafamidis
    • -stabilizing agent
    • -inhibits TTR aggregation by stabilizing monomers
    • -approved in Europe
  26. Future Therapies
    • Immunotherapy
    • -amyloid fibrils express unique epitopes
    • -try to develop antibodies against amyloid fibrils

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