Amyloidosis for the young ladies

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Amyloidosis for the young ladies
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Amyloidosis

• Definition In medicine, amyloidosis refers to a
  variety of conditions in which amyloid proteins
  are abnormally deposited in organs causing
  disease. A protein is amyloid if, due to an
  alteration in its secondary structure, it takes
  on a particular insoluble form, called the
  beta-pleated sheet.

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AMYLOIDOSIS

• Disease characterized by extracellular deposition
  of pathologic insoluble fibrillar proteins in
  organs and tissues.
• Term amyloid first coined by Virchow in mid 19th
  century (meaning starch or cellulose).
• Amyloid found to stain with congo red, appearing
  red microscopically in normal light but apple
  green when viewed in polarized light.
• Fibrillar nature and beta pleated sheet
  configuration described by electron microscopy in
  1959.

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Amyloidoses Are Protein Misfolding Diseases
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Amyloidoses Are Protein Misfolding Diseases
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Binding sites for Congo red
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• Protein Misfolding Diseases
• A specific protein may be unable to carry out its
  normal function because it is improperly folded
  or because it is not sufficiently stable due to
  misfolding.
• A protein may be unable to carry out its normal
  function because it is not trafficked to the
  proper location due to misfolding.
• A protein may fail to fold or to remain folded
  correctly and consequently aggregate (often with
  other components) leading to amyloid diseases.
  (Amyloidosis refers strictly to diseases in
  which extracellular deposits are formed, but the
  terms amyloid diseases or protein aggregation
  diseases are now being used to refer to diseases
  in which protein deposits are intra- or
  extracellular.)
• Some of the clinical symptoms of the
  non-neurological amyloidoses seem to be due to
  the accumulation of large deposits of aggregated
  proteins in vital organs
• In neurodegenerative diseases, cellular function
  appears to be impaired by the interaction of
  aggregated proteins with cellular components.
  This impairment is associate with evidence of
  elevated oxidative stress, but the mechanism is
  unknown.

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Pathogenesis of the major forms of amyloid fibrils
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Systemic amyloidoses are those which affect more
than one body organ or system. Localised
amyloidoses affect only one body organ or tissue
type. Primary amyloidoses arise from a disease
with disordered immune cell function such as
multiple myeloma and other immunocyte dyscrasias.
Secondary (reactive) amyloidoses are those
occurring as a complication of some other chronic
inflammatory or tissue destructive disease.
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• Imaging techniques Technetium Tc 99m
  pyrophosphate binds avidly to many types of
  amyloid. Quantitative assessment not possible and
  strongly positive results usually only occur in
  pts with severe disease. Technetium labeled
  aprotinin may be more sensitive.
• Quantitative scintigraphy can be done with
  iodine-123- labeled serum amyloid P component
  (sensitive for AL, ATTR and AA amyloid).

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Multiple Myeloma Incidence and Etiology

• 13,000 cases/year in USA
• Median age - 65 yrs.
• Incidence in African-Americans is two-fold other
  ethnic groups
• Familiar clusters are rare
• Environmental/occupational exposures have been
  implicated

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AL AMYLOIDOSIS

• Part of the spectrum of plasma cell dyscrasias.
• Cellular source of AL amyloid is always a single
  clone of the B-lymphocytic lineage, usually
  exhibiting the morphologic appearance of plasma
  cells.
• Underlying clonal proliferative disorder may be
  frankly neoplastic (iemultiple myeloma) or
  conversely a low grade proliferation of
  monoclonal plasma cells.

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Heart failure
Autonomic nervous system involvement
Macroglossia hoarsenes
Carpal tunnel sy
Peripheral nervous system involvement
Thrombocytosis
AL AMYLOID
Splenomegaly
Anemia
Hypofunction of adrenal glands hypothyreosis
Hepatomegaly
Nephrotic syndrome
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• Among MM patients, amyloidosis reported with
  variable frequency, but rarely exceeds 20.
• Majority of patients without myeloma associated
  AL, occurs in the setting of an apparently
  benign monoclonal gammopathy.
• Characterized by low concentrations of monoclonal
  Igs in serum/urine and an often occult low grade
  monoclonal plasma cell proliferation in BM.

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Bone marrow aspirate Plasma cell infiltrate
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AL Amyloidosis
Kidney (74)
Heart (58)
Bone marrow plasma cell clone synthesizing
amyloidogenic light chain
Liver (28)
No of organs involved 1 (31) gt1 (69)
GI (8)
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Primary Amyloidosis Histopathology
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Conditions Associated With AA Amyloidosis
Chronic Inflammatory Diseases Chronic Infections Neoplasia
Rheumatoid arthritis Psoriatic arthritis Chronic juvenile arthritis Ankylosing spondylitis Behcets syndrome Reiters syndrome Adult Still's disease Inflammatory bowel disease Hereditary periodic fevers Tuberculosis Osteomyelitis Bronchiectasis Leprosy Pyelonephritis Decubitus ulcers Whipples disease Acne conglobata Common variable immunodeficiency Hypo/agammaglobulinemia Cystic fibrosis Hepatoma Renal carcinoma Castleman's disease Hodgkin's disease Adult hairy cell leukemia Waldenström's disease
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Presenting Clinical Features in AA Amyloidosis

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• Macroglossia occurs in 10-20
• Amyloid can be found within any part of the GI
  tact and may infiltrate parenchyma, organs and
  nerves.
• Peripheral neuropathy may be presenting
  manifestation or develop subsequently during the
  course of the illness (history of carpal tunnel
  frequently elicited).
• Neuropathy usually distal, symmetric and
  progressive. Cranial nerve and autonomic nerve
  involvement also well described.
• Motor neuropathy rare.

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Macroglossia
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Purpura
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HEPATIC/SPLENIC

• Involvement of liver common.
• Hepatomegaly may be striking at presentation and
  usually disproportionate to extent of liver
  enzyme abnormalities (except alkaline phosphatase
  which is frequently elevated).
• Presence of jaundice is an adverse prognostic
  factor and MST from onset of jaundice is only 3
  months.
• Patients may present with severe intrahepatic
  cholestasis.
• Massive splenic deposition may result in
  functional hyposplenism.

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Extensive hypertrophy with yellow amyloid deposits
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CARDIAC

• May present with rapid and progressive onset of
  CHF.
• Characteristically, features are predominantly of
  right sided CHF.
• ECG low voltage and may have a pattern of MI in
  absence of CAD.
• ECHO concentrically thickened ventricles with
  normal-small cavity and diastolic dysfunction on
  doppler.
• Clinical clue is marked worsening of failure when
  CCB used.

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Echocardiogram revealing thickened walls with
small chambers
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RENAL

• Nephrotic syndrome present in 30-50 at
  diagnosis.
• Nephrotic syndrome and renal failure develop only
  rarely during course of the illness if not
  present at time of diagnosis.
• ? BJP have been associated with inferior survival
  as compared with ?BJP or no monoclonal protein,
  irrespective of serum creatinine.

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Lambda
Kappa
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• AL arthropathy may simulate RA. Most striking
  appearance is the shoulder pad sign secondary
  to swelling of the shoulder joints.
• Vascular infiltration may result in easy bruising
  especially in the eyelids and flexural regions.
  Purpuric lesions typically occur above the
  nipple.
• Factor X deficiency (acquired) can occur in up to
  10 of pts and over 2/3 of pts with acquired
  factor X deficiency have systemic Amyloidosis.

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B2 Microglobulin in Dialysis-related Amyloidosis
Dialysis-related amyloidosis requires an
increased concentration of free ?2-microglobulin
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AmyloidosisHeart
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This islet of Langerhans demonstrates pink
hyalinization (with deposition of amyloid) in
many of the islet cells. This change is common in
the islets of patients with type II diabetes
mellitus.
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PROGNOSIS

• Serious disease with high mortality.
• Overall median survival after diagnosis is lt
  2years in most series.
• Patients with co-existent MM have a poorer
  prognosis.
• Survival time largely dependent upon the organ
  system predominantly involved.
• Cardiac involvement is major determinant of
  prognosis and most common cause of death MST
  from onset of CHF is 7 months.

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• Results of a a large trial of 220 pts by Kyle et
  al in 1997 clarified the role of colchicine in AL
  Amyloidosis.
• Median duration of survival was 8months for the C
  group, 18 months for the MP group and 17 months
  for the MPC group.
• Median survival for pts with cardiac amyloid was
  5 months, 16 months for pts with renal
  involvement and 34 months for those with PN.
  Survival was best in those patients showing a 50
  reduction in serum or urine paraprotein levels.

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CONCLUSIONS

• Systemic, uncommon disease with poor long term
  survival.
• Symptoms often vague and recognition of syndromes
  associated with amyloidosis is key.
• In general, current therapy is suboptimal
  although new treatment options including
  thalidomide, proteosome inhibitors, antisense
  oligonucleotides and SCT hold promise for the
  future.

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