Cellular Accumulations Dr' Husni Maqboul M'D

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Cellular AccumulationsDr. Husni Maqboul M.D
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Intracellular Accumulations

• General Principles
• Transient or permanent
• Harmless or injurious
• Cytoplasm (lysosomes) or nucleus
• Synthesized by the affected cell or produced
  elsewhere

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Intracellular Accumulations

• General Principles
• Endogenous
• normal substance produced at normal or increased
  rate/rate of metabolism inadequate for removal
  (fatty liver)
• normal or abnormal substance cannot be
  metabolized (storage diseases)

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Intracellular Accumulations

• General Principles
• Exogenous
• cell cannot degrade substance (carbon)

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Intracellular Accumulations
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Intracellular Accumulations

• Fatty Change (Steatosis)
• Causes
• alcohol abuse, other toxins, anoxia, obesity,
  protein malnutrition, Reys ( defect in
  mitochondrial oxidation ).
• Pathogenesis
• various steps involved
• egress of hepatic triglycerides requires
  complexing with apoproteins to form lipoproteins

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Intracellular Accumulations

• Fatty Change (Steatosis)
• Liver
• increased weight, yellow color
• fat vacuoles within cytoplasm of hepatocytes

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Intracellular Accumulations

• Fatty Change (Steatosis)
• Heart
• focal fat deposits in myocardium (anemia) tigered
  heart
• diffuse fat deposits in myocardium (profound
  hypoxia, diphtheric myocarditis) the entire heart
  is affected.

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Intracellular Accumulations

• Cholesterol and Cholesterol Esters
• Atherosclerosis
• macrophages and smooth muscle cells filled with
  vacuoles
• Xanthomas
• macrophage accumulation/hereditary and acquired
  hyperlipidemias

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Intracellular Accumulations
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Intracellular Accumulations

• Proteins
• Renal tubular epithelium in proteinuria
• Plasma cells may accumulate immunoglobulins
  (Russel bodies)
• Alpha1-antitrypsin in liver.

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Intracellular Accumulations

• Glycogen in abnormal glucose or glycogen
  metabolism .
• Diabetes mellitus
• glycogen accumulation in renal tubular
  epithelium, hepatocytes, cardiac myocytes,
  pancreatic beta cells.

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Intracellular Accumulations

• Glycogen
• Glycogen storage diseases (glycogenoses)
• enzymatic defects in synthesis or breakdown of
  glycogen

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Intracellular Accumulations

• Exogenous Pigments
• Carbon (anthracosis)
• phagocytosed by alveolar macrophages and
  transported by lymphatics to lymph nodes
• mild accumulations usually are of no
  consequence--heavy accumulations may induce a
  fibroblastic response

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Intracellular Accumulations

• Exogenous Pigments
• Tattoos
• dyes phagocytosed by macrophages

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Intracellular Accumulations

• Endogenous Pigments
• Lipofuscin (wear and tear pigment)
• brownish yellow especially in heart, liver, and
  brain--function of age or atrophy (brown
  atrophy)
• represents complexes of lipid/protein
• derived from free radical peroxidation of
  subcellular membranes

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Intracellular Accumulations

• Endogenous Pigments
• Melanin
• brown-black pigment derived from tyrosine in
  melanocytes
• may also accumulate in basal keratinocytes and
  dermal macrophages

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Intracellular Accumulations

• Endogenous Pigments
• Hemosiderin
• hemoglobin derived iron containing golden-yellow
  pigment
• represents large aggregates of ferritin micelles
• small amounts normal in phagocytic cells of
  reticuloendothelial system

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Intracellular Accumulations

• Endogenous Pigments
• Hemosiderin
• local excesses in focal hemorrhage
• systemic iron overload (hemosiderosis)
• in macrophages and parenchyma mainly in liver,
  pancreas, heart, and endocrine organs

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Intracellular Accumulations

• Endogenous Pigments
• Hemosiderin
• systemic iron overload (hemosiderosis)
• increased absorption or impaired utilization of
  iron hemolytic anemias transfusions
• extensive accumulation--- hemochromatosis organ
  fibrosis

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Forms and Morphology of Cell Injury

• PATHOLOGIC CALCIFICATION

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Pathologic Calcification

• Dystrophic Calcification
• Normal serum calcium
• Areas of necrosis or injury
• Intracellular or extracellular
• In necrosis, aging or damaged heart
  valves,atheromas, tumors.
• May lead to heterotopic bone formation and
  psammomas

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Pathologic Calcification
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Pathologic Calcification
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Pathologic Calcification

• Metastatic Calcification
• Occurs in normal tissue
• Occurs with hypercalcemia
• hyperparathyroidism bone catabolism with tumors
  involving bone vitamin D intoxication
  sarcoidosis renal failure
• Primarily affects vessels, kidneys, lungs, and
  gastric mucosa

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Amyloidosis

• Nature Of Amyloid
• Abnormal proteinaceous substance
• Deposited between cells
• Not a single chemical entity
• Appears as a pink translucent material on HE
  stain

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Amyloidosis

• Physical Nature Of Amyloid
• EM-non branching fibrils
• Beta pleated sheet conformation 90
• Nonfibrillar pentagonal component 10 CRP like

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Amyloidosis

• Chemical Nature Of Amyloid
• AL (amyloid light chain)
• associated with B-cell dyscrasias
• produced by immunoglobulin-secreting cells

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Amyloidosis

• Chemical Nature Of Amyloid
• AA (amyloid associated)
• non-immunoglobulin
• derived from SAA (serum amyloid-associated
  precursor protein)
• associated with chronic inflammatory diseases
• Mostly in secondary amyloidosis

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Amyloidosis

• Chemical Nature Of Amyloid
• Transthyretin (a normal serum protein)
• mutant form deposited in familial amyloid
  polyneuropathies
• Beta-2-microglobulin (normal serum protein)
• Component of MHC1
• deposits in long-term hemodialysis

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Amyloidosis

• Chemical Nature Of Amyloid
• Beta-2-amyloid protein (derived from amyloid
  precursor protein -APP) , derived from normal
  transmembrane glycoprotiens.
• deposits in brain in Alzheimers disease
• Procalcitonin, proinsulin

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Immunocyte Dyscrasias With Amyloidosis

• Characteristics
• Complete immunoglobulin light chains (AL)
  produced by aberrant monoclonal B-cells, such as
  in multiple myeloma
• Serum M (myeloma) spike
• Bence Jones protein (either lambda or kappa light
  chains)

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Reactive Systemic Amyloidosis

• Characteristics
• AA protein deposits
• Occurs in setting of chronic inflammation

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Other Types Of Amyloidosis

• Heredofamilial Amyloidosis
• Familial Mediterranean fever
• AA protein-may be due to recurrent bouts of
  inflammation of joints and serosal surfaces
• Familial amyloid polyneuropathies
• mutant transthyretins deposited

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Other Types Of Amyloidosis

• Localized Amyloidosis
• Heterogeneous chemical composition and clinical
  presentation
• Often associated with local infiltration of
  plasma cells (AL type amyloid)
• Medullary carcinoma of thyroid (amyloid
  chemically related to calcitonin - a hormone
  secreted by the tumor cells

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Other Types Of Amyloidosis

• Amyloid Of Aging
• Senile cardiac amyloidosis
• transthyretin
• Senile cerebral amyloidosis (in Alzheimers
  disease)
• beta-2 amyloid protein

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Pathogenesis Of Amyloidosis
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Pathogenesis Of Amyloidosis

• Reactive Systemic Amyloidosis
• Elevated SAA (synthesized by liver in response to
  IL-6 IL-1)
• ??Abnormal breakdown of SAA??
• Immunocyte Dyscrasias
• AL synthesized by B-cells
• ??Abnormal degradation??

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Morphology Of Amyloidosis

• Generalizations
• Reactive systemic amyloidosis typically affects
  kidneys, liver, spleen, lymph nodes, adrenals,
  thyroid, and other tissues

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Morphology Of Amyloidosis

• Generalizations
• Immunocyte-associated amyloidosis more often
  involves heart, GI respiratory tracts,
  peripheral nerves, skin, and tongue.
• deposits may also occur in organs listed for
  reactive systemic amyloidosis

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Morphology Of Amyloidosis

• Histologic Appearance
• Pink staining intercellular substance with HE
  stain
• Red-orange staining with Congo red
• green birefringence under polarized light
• Often causes parenchymal cell atrophy or drop out

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Amyloidosis Of The Kidney

• Gross
• Unchanged or large and pale
• Microscopic
• Deposits mainly in glomeruli
• Also present in peritubular interstitium and
  walls of blood vessels

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Amyloidosis Of Other Organs

• Spleen
• Sago spleen-splenic follicles
• Lardaceous spleen-splenic sinuses pulp
• Liver, Heart, Endocrine glands
• Enlarged
• Interstitial deposits of amyloid
• Pressure atrophy

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Clinical Correlation

• Presentation
• Unsuspected to serious clinical dysfunction or
  death
• General Symptoms
• Weakness, fatigue, weight loss
• Organ Specific Symptoms
• Renal disease, hepatomegaly, splenomegaly,
  cardiac abnormalities

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Clinical Correlation

• Renal
• Nephrotic syndrome, renal failure
• Liver Spleen
• Hepatosplenomegaly rarely causes significant
  dysfunction
• Heart
• Conduction disturbances
• Cardiomyopathy

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Clinical Correlation

• Prognosis
• Poor
• Mean survival 1 to 3 years

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Lysosomal Storage Diseases
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Lysosomal Storage Diseases
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Sphingolipidoses Sulfatidoses

• Tay-Sachs, Gaucher and Neimann-Pick Diseases

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Tay-Sachs Disease
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Tay-Sachs Disease

• Characteristics
• Hexosaminidase A deficiency
• Accumulation of Gm2 gangliosides
• Involves neurons, axon cylinders of nerves, and
  glial cells throughout CNS
• Cells enlarged and foamy
• Mental retardation, blindness, neurologic
  dysfunctions-death 1-3 years

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Neimann-Pick Disease
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Neimann-Pick Disease

• Characteristics
• Sphingomyelinase deficiency
• Accumulation of sphingomyelin and cholesterol
• Involves phagocytic cells and neurons
• Spleen, liver, bone marrow, lymph nodes, lungs
  as well as CNS affected
• Enlarged vacuolated cells
• Visceromegaly neurologic defects

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Gaucher Disease
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Gaucher Disease

• Characteristics
• Glucocerebrosidase deficiency
• Accumulation of glucocerebrosides
• Involves phagocytic cells
• Predominantly affects liver, spleen and bone
  marrow CNS in types 2 and 3
• Phagocytes enlarged with a fibrillar wrinkled
  tissue paper cytoplasm
• Death within first 5 years of life in the
  infantile type A variant

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Gaucher Disease

• Types
• Type 1 (99) hepatosplenomegaly and absence of
  CNS involvement-longevity somewhat shortened
• Type 2 severe CNS involvement secondary
  involvement of spleen/liver--highly lethal
• Type 3 involves brain and viscera with a course
  intermediate to types 1 and 2

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Mucopolysaccharidoses
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Mucopolysaccharidoses

• General Principles
• Progressive disorders
• Multiple organ involvement, including liver,
  spleen, heart, and blood vessels
• Coarse facial features, clouding of the cornea,
  joint stiffness, mental retardation

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Hurler Syndrome--Gargoylism

• Characteristics
• Alpha-L-iduronidase deficiency
• Accumulation of dermatan sulfate
• Involves phagocytes, fibroblasts, vascular
  endothelium and smooth muscle, neurons
• Cells swollen with clear cytoplasm
• Life expectancy of 6 to 10 years

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Hurler Syndrome--Gargoylism

• Characteristics
• Death often due to cardiac complications--coronary
  artery and endocardial lesions

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Hunter Syndrome

• Characteristics
• L-iduronate sulfatase deficiency
• Accumulation of heparan sulfate and dermatan
  sulfate
• Absence of corneal clouding
• Milder clinical course than Hurler syndrome

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Glycogen Storage Disorders

• von Gierke, McArdle, and Pompe Diseases

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von Gierke Disease

• Characteristics
• Hepatic form, type I
• Glucose-6-phosphatase deficiency
• Accumulation of glycogen in cytoplasm
• Hypoglycemia, hyperlipidemia, hyperuricemia
• Hepatomegaly , renomegaly, failure to thrive
• Mortality about 50

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McArdle Disease

• Characteristics
• Myopathic type V
• Muscle phosphorylase deficiency
• Accumulation of glycogen in cytoplasm
• Muscle cramps after exercise and failure to
  induce elevation in lactate
• Normal longevity

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Pompe Disease

• Characteristics
• Generalized type II
• Lysosomal acid maltase deficiency
• Accumulation of glycogen in lysosomes
• Affects liver, skeletal muscle, heart
• Cardiomegaly, muscle hypotonia
• Cardiorespiratory failure within 2 years