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General Pathology

General Pathology. Basic Principles of Cellular and Organ Pathology Steatosis. Mitochondrial and Peroxisomal Disorders. Jaroslava Dušková Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague. Steatosis (Fatty Change). Definition:

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General Pathology

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  1. General Pathology Basic Principles of Cellular and Organ Pathology Steatosis. Mitochondrial and Peroxisomal Disorders. Jaroslava Dušková Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague

  2. Steatosis (Fatty Change) Definition: acquired metabolic disorder with intracellular accumulation of lipid droplets (lipomatosis, adipositas - increase of fatty tissue amount)

  3. Steatosis - morphology Macroscopy: yellowish - orange color of organs (+ carotenoids - lipochrom) Microscopy: microvacuolar cytoplasm - foamy cell macrovacuolar - unilocular

  4. 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

  5. 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

  6. 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)

  7. Clear Intracellular Vacuoles& adjunct techniques • accumulations of water neg. • lipides SUDAN, OILRED • polysaccharides PAS, A-PAS

  8. Lipidosis (thesaurismosis, lipid storage disease) Definition: inborn metabolic disorder with intracellular accumulation of lipid droplets (lysosomal enzymopathies)

  9. Organelles Involved in Lipid Metabolism • Granular Endoplasmic Reticulum GER + Golgi app. • mitochondria • lysosomes

  10. GER- lipoprotein synthesis • enterocytes Apo B48 monoacylglycerols (fatty acids) triacylglycerols - chylomicrons • hepatocytes Apo B100 Very Low Density Lipoproteins

  11. GER- lipoprotein synthesisDISORDERS hepatocytes lack of Apo B100 synthesis - toxins toxic steatosis

  12. Mitochondria- beta oxidation • fatty acids - carnitinacyltranpherase 1 + coenzyme A - carnitinacyltranspherase 2 beta oxidation

  13. Mitochondria- beta oxidationDISORDERS • fatty acids - carnitinacyltranpherase 1 + coenzyme A - transport malfunction carnitinacyltranpherase 2 beta oxidation defect - hypoxia, anoxia hypoxic steatosis

  14. Mitochondria - semiautonomous organelles (circular mtDNA, division) • isolated • network • spiral chain Outer membrane Inner membrane Cristae Matrix

  15. Mitochondria - semiautonomous organelles (circular mtDNA, division) Function beta oxidation, Krebs cycle, OXFOS protein sorting & synthesis

  16. Mitochondria - life cycle • division • majority of proteins coded in the nucleus • degradation in the autophagosomes

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

  18. circular mtDNA haploid (maternal origin) 2-20 mtDNA molecules in one mitochondrion 100 -10 000 mtDNA molecules in one cell asynchrone replication linear - chromosomes diploid 23 pairs (maternal+paternal) 46 macromolecules per one nucleus 46 macromolecules per one cell synchronized replication Mitochondria vs.Nucleusgenetics

  19. homoplasmia heteroplasmia polyplasmia only some copies normal + mutated mtDNA threshold effect homozygotic heterozygotic carriers Mitochondria vs.Nucleusgenetics

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

  21. Mitochondria - pathology • acquired • mitochondriosis • oncocytic change • inborn • enzymopathies

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

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

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

  25. 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“

  26. Lipid Storage Diseases -1.

  27. Lipid Storage Diseases – 2.

  28. 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

  29. 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).

  30. 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).

  31. 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.

  32. Peroxisomes - microbodiesup to 2 microns - catalase Function Degradation: substrate oxidation (etanol) Anabolism: synthesis of prostaglandin , cholesterol, billiary acids, plasmalogens, gluconeogenesis, transamination

  33. Peroxisomes - microbodiesDISORDERS Lack of: Degradation: substrate oxidation e.g. etanol... Anabolism: synthesis of prostaglandin , cholesterol, billiary acids, gluconeogenesis, transamination...

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