General Pathology

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General Pathology

• Basic Principles of Cellular and Organ Pathology
• Steatosis.
• Mitochondrial
• and
• Peroxisomal
• Disorders.

Jaroslava Dušková Inst. Pathol. ,1st Med.
Faculty, Charles Univ. Prague
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Steatosis (Fatty Change)

• Definition
• acquired metabolic disorder with
  intracellular accumulation of lipid droplets
• (lipomatosis, adipositas - increase of fatty
  tissue amount)

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Steatosis - morphology

• Macroscopy
• yellowish - orange color of organs
• ( carotenoids - lipochrom)
• Microscopy
• microvacuolar cytoplasm - foamy cell
• macrovacuolar - unilocular

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LIVER - major organ of fat metabolism) abnormal
accumulations of TRIGLYCERIDES within
parenchymal cells Causes alcohol abuse, protein
malnutrition, diabetes mellitus, obesity,
toxins,drugs, anoxia Macro enlarged, yellow,
greasy, soft Micro small fatty, cytoplasmic
droplets OR large vacuoles
Steatosis hepatis
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Lipids accumulation in cells (sometimes
causing cellular injury)

• ? A normal cellular constituent accumulating
  in excess
• ? An abnormal substance, usually a product
  of abnormal metabolism
• ? A pigment

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Processes resulting in abnormal intracellular
accumulations

• ? Abnormal metabolism of a normal endogenous
  substance (e. g. fatty liver)
• ? Lack of an enzyme necessary for the
  metabolism of a normal or abnormal endogenous
  substance (e. g. lysosomal storage disease)

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Clear Intracellular Vacuoles adjunct
techniques

• accumulations of water neg.
• lipides SUDAN, OIL RED
• polysaccharides PAS, A-PAS

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Lipidosis (thesaurismosis, lipid
storage disease)

• Definition
• inborn metabolic disorder with intracellular
  accumulation of lipid droplets
• (lysosomal enzymopathies)

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Organelles Involved in Lipid Metabolism

• Granular Endoplasmic Reticulum GER
  Golgi app.
• mitochondria
• lysosomes

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GER - lipoprotein synthesis

• enterocytes Apo B48
• monoacylglycerols (fatty acids) triacylglycerols
  - chylomicrons
• hepatocytes Apo B100
• Very Low Density Lipoproteins

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GER - lipoprotein synthesisDISORDERS

• hepatocytes
• lack of Apo B100 synthesis - toxins

toxic steatosis
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Mitochondria - beta oxidation

• fatty acids - carnitinacyltranpherase 1
  coenzyme A - carnitinacyltranspherase 2
• beta oxidation

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Mitochondria - beta oxidation DISORDERS

• fatty acids - carnitinacyltranpherase 1
  coenzyme A - transport malfunction
• carnitinacyltranpherase 2
• beta oxidation defect - hypoxia, anoxia

hypoxic steatosis
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Mitochondria - semiautonomous organelles
(circular mtDNA, division)

• isolated
• network
• spiral chain
• Outer membrane
• Inner membrane
• Cristae
• Matrix

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Mitochondria - semiautonomous organelles
(circular mtDNA, division)

• Function
• beta oxidation,
• Krebs cycle,
• OXFOS
• protein sorting
• synthesis

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Mitochondria - life cycle

• division
• majority of proteins coded in the nucleus
• degradation in the autophagosomes

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Mitochondria - genetics

• circular mtDNA
• haploid (maternal origin)
• 2-20 mtDNA molecules in one mitochondrion
• 100 -10 000 mtDNA molecules in one cell
• variable amplification

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Mitochondria vs. Nucleus genetics

• linear - chromosomes
• diploid 23 pairs (maternalpaternal)
• 46 macromolecules per one nucleus
• 46 macromolecules per one cell
• synchronized replication

• circular mtDNA
• haploid (maternal origin)
• 2-20 mtDNA molecules in one mitochondrion
• 100 -10 000 mtDNA molecules in one cell
• asynchrone replication

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Mitochondria vs. Nucleus genetics

• homoplasmia
• heteroplasmia
• polyplasmia
• only some copies
• normal mutated mtDNA
• threshold effect

• homozygotic
• heterozygotic
• carriers

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Hürthle cell features Mitochondrial
proliferation Activation of HIF-1
Decreased apoptosis Tumourigenesis
Nuclear genes Ex. GRIM-19
Mt genes (Complex I, III, IV, V)
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Mitochondria - pathology

• acquired
• mitochondriosis
• oncocytic change
• inborn
• enzymopathies

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Mitochondria - pathology

• inborn - enzymopathies
• Synthesis defects (partly nucleus coded)
• urea and porphyrine
• transport proteins
• Krebs cycle enzymes succinate deh.
• OXFOS nucleus mitoch. coded

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Lysosomes - lipid hydrolysis

• enzymes - lipase, phospholipase,
  sphingomyelinase etc.
• membrane diffusion, reutilisation
• storage TAG, ChE
• transport from the cell - HDL, apo E

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Lysosomes - lipid hydrolysis DISORDERS

• acquired - intensive endocytosis of lipids
  - histiocytes
• hereditary - lipidoses , lipid storage dis.

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Storage Diseases

• Def.
• inborn errors of metabolism (mostly single gene
  abnormality) leading to an enzyme defect with
  subsequent accumulation of the substrate ( lack
  of the product) in tissues or organs
  thesaurismoses

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Lipid Storage Diseases -1.
Disease E- def Accum. Lipid Tissues Involved
Tay-Sachs Hexos aminidase A GM2 ganglioside Brain, retina
Gaucher ?- Glucosidase Gluco cerebrosid Liver, spleen, bone marrow, brain
Niemann-Pick Sphingo myelinase Sphingo myelin Brain, liver spleen
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Lipid Storage Diseases 2.
Disease E- def Accum. Lipid Tissues Involved
Metachromatic Leuco dystrophy Arylsulfat ase A Sulfatid Brain, kidney, liver, peripheral nerves
Fabrys ?-galactosid ase Ceramid trihexosid Skin, kidney
Krabbes Galactosyl ceramidase Galactol cerebroside Brain
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Extracellular Steatosis

• blood hyperlipemiae
• increased size of lipoprotein particles (rel.
  decrease of the apoprotein component)
• increased number of lipoprotein particles
• removed after oxidation via scavenger receptors
  resulting e.g. into aggravated accelerated
  atherosclerosis, pancreatic necrosis
• arcus senilis myringis, arcus senilis corneae

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Lipids in Cell Signaling - 1

• Many of the lipids involved as second messengers
  in cell signaling pathways arise from the
  arachidonic acid (AA) pathway.
• AA is an unsaturated fatty acid
• a normal constituent of membrane phospholipids
• released from the phospholipids by the actions
  of phospholipase A2 (PLA2).

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Lipids in Cell Signaling - 2

• Prostaglandins (PG) are generated by the
  cyclooxygenase (COX).
• There is a constitutive (COX-1) and an inducible
  cyclooxygenase (COX-2).
• The cyclic endoperoxide intermediate is also a
  precursor of prostacyclin (PGI2) and thromboxane
  (TXA3).

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Lipids in Cell Signaling - 3

• leukotrienes (LT) and lipoxins (LP), are derived
  directly from AA without the mediation of a
  cyclic endoperoxide.
• LT induce inflammation by their chemotactic and
  degranulating actions on polymorphonuclear
  leucocytes (PML)
• the amino acid containing LTs induce
  vasoconstriction and bronchoconstriction and are
  involved in asthma and anaphylaxis.

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Peroxisomes - microbodiesup to 2 microns -
catalase

• Function
• Degradation substrate oxidation (etanol)
• Anabolism synthesis of prostaglandin ,
  cholesterol, billiary acids, plasmalogens,
  gluconeogenesis, transamination

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Peroxisomes - microbodies DISORDERS

• Lack of
• Degradation substrate oxidation e.g. etanol...
• Anabolism synthesis of prostaglandin ,
  cholesterol, billiary acids, gluconeogenesis,
  transamination...