Transcript of Amyloidosis Definition : In medicine, amyloidosis refers to a variety of conditions in which amyloid...
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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.medicineamyloidproteinsorganssecondary
structureinsolublebeta-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 19 th 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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Misfolded proteins are normally detected and cleared from cell
(or stored in aggresomes)
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General mechanism of aggregation to form amyloid fibrils
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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.multiple myeloma 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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IgH chain translocations are also found in AL especially
t(11;14). Monosomy 18 is also frequently found as well as deletions
of chromosome 13. to ratio is approx 1:3 LCD Non amyloid Ig
deposition predominantly of and usually the constant region. Forms
granular rather than fibrillar deposits and mainly affects the
kidneys.
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CategoryAmyloid typePrecursor proteinAmyloidosis Systemic
acquiredAL Immunoglobin light chainsImmunoglobin light chains
(Bence Jones protein)Bence Jones protein AL amyloidosis AL
amyloidosis (primary amyloidosis) Systemic acquiredAASAA AA
amyloidosis AA amyloidosis (secondary amyloidosis) Systemic
acquired A2 mA2 m 2 microglobulin Haemodialysis associated Systemic
hereditaryAASAA Familial mediterranean fever Systemic
hereditaryATTRtransthyretin Familial amyloidotic polyneuropathies
Systemic hereditaryATTRtransthyretin Systemic senile
amyloidosis
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Primary Amyloidosis: Histopathology
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Primary Amyloidosis: Conventional Therapy General measures
Delay target organ failure Improve quality of life Specific
interventions Melphalan and Prednisone
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Experimental approaches for the treatment of Multiple Myeloma
Allogeneic transplantation (8 studies) Complete response rate26-51%
Median event free survival12-36 months Revimid (CC-5013)
Thalidomide derivative Phase II study PS-341 Proteosome inhibitor -
Cytotoxic to plasma cells Phase II study
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AA Amyloidogenesis IL-1, IL-6, TNF- SAA1 (>70%) and SAA2
HDL-SAA Specific receptors on macrophages (spleen, liver, kidney )
Plasma concentration changes from 310 mg/L 1001000 mg/L Tissue
injury, infections
Presenting Clinical Features in AA Amyloidosis Feature%
Proteinuria/renal insufficiency Diarrhea/malabsorption Goiter
Neuropathy/carpal tunnel syndrome Hepatomegaly Lymphadenopathy
Cardiac 91 22 9 3 5 2 1-2
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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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Plasma-cell-type Castlemans disease (H & E) Amyloid in the
lymph node, green birefringence in polarized light Plasma-cell-Type
Castlemans disease with IL-6 release and increased SAA
synthesis
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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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LambdaKappa
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PATHOLOGIC CALCIFICATION
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Objectives Define calcification Types of calcification Causes,
feature and effect of dystrophic calcification Causes, feature and
effect of metastatic calcification
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Pathologic calcification is a common process in a wide variety
of disease states it implies the abnormal deposition of calcium
salts with smaller amounts of iron, magnesium, and other
minerals.
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Types of Pathologic calcification Dystrophic calcification:
When the deposition occurs in dead or dying tissues it occurs with
normal serum levels of calcium Metastatic calcification: The
deposition of calcium salts in normal tissues It almost always
reflects some derangement in calcium metabolism
(hypercalcemia)
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INTRACELLULAR ACCUMULATIONS
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Objectives To study: Overview of intracellular accumulations
Accumulation of Lipids Accumulation of Cholesterol Accumulation of
Proteins Accumulation of Glycogen Accumulation of Pigments
Pathologic Calcification
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Lecture will include Overview of intracellular accumulations
Accumulation of Lipids Accumulation of Cholesterol Accumulation of
Proteins Accumulation of Glycogen Accumulation of Pigments
Pathologic Calcification
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Fatty Change (Steatosis)
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Fatty Change Fatty change refers to any abnormal accumulation
of triglycerides within parenchymal cells. Site: liver, most common
site it may also occur in heart, skeletal muscle, kidney, and other
organs.
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Causes of Fatty Change Toxins (most importantly: Alcohol abuse)
diabetes mellitus Protein malnutrition (starvation) Obesity
Anoxia
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Lecture will include Overview of intracellular accumulations
Accumulation of Lipids Accumulation of Cholesterol Accumulation of
Proteins Accumulation of Glycogen Accumulation of Pigments
Pathologic Calcification
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Cholesterol and Cholesteryl Esters
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Cellular cholesterol metabolism is tightly regulated to ensure
normal cell membrane synthesis without significant intracellular
accumulation
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Proteins
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Morphologically visible protein accumulations are much less
common than lipid accumulations They may occur because excesses are
presented to the cells or because the cells synthesize excessive
amounts
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Protein accumulations Example: 1. Nephrotic syndrome: In the
kidney trace amounts of albumin filtered through the glomerulus are
normally reabsorbed by pinocytosis in the proximal convoluted
tubules After heavy protein leakage, pinocytic vesicles containing
this protein fuse with lysosomes, resulting in the histologic
appearance of pink, hyaline cytoplasmic droplets
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The process is reversible; if the proteinuria abates, the
protein droplets are metabolized and disappear.
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Protein accumulations Example: 2. marked accumulation of newly
synthesized immunoglobulins that may occur in the RER of some
plasma cells, forming rounded, eosinophilic Russell bodies.
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Protein accumulations Example: 3. Mallory body, or "alcoholic
hyalin," is an eosinophilic cytoplasmic inclusion in liver cells
that is highly characteristic of alcoholic liver disease These
inclusions are composed predominantly of aggregated intermediate
filaments
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Protein accumulations Example: 4. The neurofibrillary tangle
found in the brain in Alzheimer disease is an aggregated protein
inclusion that contains microtubule-associated proteins
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Lecture will include Overview of intracellular accumulations
Accumulation of Lipids Accumulation of Cholesterol Accumulation of
Proteins Accumulation of Glycogen Accumulation of Pigments
Pathologic Calcification
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Pigments
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Pigments are colored substances that are either: exogenous,
coming from outside the body, or endogenous, synthesized within the
body itself.
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Exogenous pigment The most common is carbon When inhaled, it is
phagocytosed by alveolar macrophages and transported through
lymphatic channels to the regional tracheobronchial lymph
nodes.
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Exogenous pigment Aggregates of the pigment blacken the
draining lymph nodes and pulmonary parenchyma (anthracosis).
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Hemosiderosis is systemic overload of iron, hemosiderin is
deposited in many organs and tissues It is found at first in the
mononuclear phagocytes of the liver, bone marrow, spleen, and lymph
nodes and in scattered macrophages throughout other organs. With
progressive accumulation, parenchymal cells throughout the body
(principally the liver, pancreas, heart, and endocrine organs) will
be affected
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Hemosiderosis Hemosiderosis occurs in the setting of:
1.increased absorption of dietary iron 2.impaired utilization of
iron 3.hemolytic anemias 4.transfusions (the transfused red cells
constitute an exogenous load of iron)..