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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. Steatosis (Fatty Change). Definition:

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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
Steatosis (Fatty Change)

Definition:

acquired metabolic disorder with intracellular accumulation of lipid droplets

(lipomatosis, adipositas - increase of fatty tissue amount)

steatosis morphology
Steatosis - morphology

Macroscopy:

yellowish - orange color of organs

(+ carotenoids - lipochrom)

Microscopy:

microvacuolar cytoplasm - foamy cell

macrovacuolar - unilocular

slide4

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

lipids accumulation in cells sometimes causing cellular injury
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

processes resulting in abnormal intracellular accumulations
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)

clear intracellular vacuoles adjunct techniques
Clear Intracellular Vacuoles& adjunct techniques
  • accumulations of water neg.
  • lipides SUDAN, OILRED
  • polysaccharides PAS, A-PAS
lipidosis thesaurismosis lipid storage disease
Lipidosis (thesaurismosis, lipid storage disease)

Definition:

inborn metabolic disorder with intracellular accumulation of lipid droplets

(lysosomal enzymopathies)

organelles involved in lipid metabolism
Organelles Involved in Lipid Metabolism
  • Granular Endoplasmic Reticulum GER + Golgi app.
  • mitochondria
  • lysosomes
ger l ipoprotein synthesis
GER- lipoprotein synthesis
  • enterocytes Apo B48

monoacylglycerols (fatty acids) triacylglycerols - chylomicrons

  • hepatocytes Apo B100

Very Low Density Lipoproteins

ger l ipoprotein synthesis disorders
GER- lipoprotein synthesisDISORDERS

hepatocytes

lack of Apo B100 synthesis - toxins

toxic steatosis

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

beta oxidation

mitochondria beta oxidation disorders
Mitochondria- beta oxidationDISORDERS
  • fatty acids - carnitinacyltranpherase 1 + coenzyme A - transport malfunction

carnitinacyltranpherase 2

beta oxidation defect - hypoxia, anoxia

hypoxic steatosis

mitochondria semiautonomous organelles circular mtdna division
Mitochondria - semiautonomous organelles (circular mtDNA, division)
  • isolated
  • network
  • spiral chain

Outer membrane

Inner membrane

Cristae

Matrix

mitochondria semiautonomous organelles circular mtdna division15
Mitochondria - semiautonomous organelles (circular mtDNA, division)

Function

beta oxidation,

Krebs cycle,

OXFOS

protein sorting

& synthesis

mitochondria life cycle
Mitochondria - life cycle
  • division
  • majority of proteins coded in the nucleus
  • degradation in the autophagosomes
mitochondria genetics
Mitochondria - genetics
  • circular mtDNA
  • haploid (maternal origin)
  • 2-20 mtDNA molecules in one mitochondrion
  • 100 -10 000 mtDNA molecules in one cell

variable amplification

mitochondria vs nucleus genetics
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
mitochondria vs nucleus genetics19
homoplasmia

heteroplasmia

polyplasmia

only some copies

normal + mutated mtDNA

threshold effect

homozygotic

heterozygotic

carriers

Mitochondria vs.Nucleusgenetics
slide20

Hürthle cell features

Mitochondrial proliferation

Activation of HIF-1

& Decreased

apoptosis

Tumourigenesis

Nuclear genes

Ex. GRIM-19

Mt genes

(Complex I, III, IV, V)

mitochondria pathology
Mitochondria - pathology
  • acquired
    • mitochondriosis
    • oncocytic change
  • inborn
    • enzymopathies
mitochondria pathology22
Mitochondria - pathology
  • inborn - enzymopathies

Synthesis defects (partly nucleus coded):

      • urea and porphyrine
      • transport proteins
      • Krebs cycle enzymes succinate deh.
      • OXFOS nucleus & mitoch. coded
lysosomes l ipid hydrolysis
Lysosomes- lipid hydrolysis
  • enzymes - lipase, phospholipase, sphingomyelinase etc….

membrane diffusion, reutilisation

storage TAG, ChE

transport from the cell - HDL, apo E

lysosomes l ipid hydrolysis disorders
Lysosomes- lipid hydrolysisDISORDERS
  • acquired - intensive endocytosis of lipids - histiocytes
  • hereditary - lipidoses , lipid storage dis.
storage diseases
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“

extracellular steatosis
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
lipids in cell signaling 1
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).
lipids in cell signaling 2
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).
lipids in cell signaling 3
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.
peroxisomes microbodies up to 2 microns catalase
Peroxisomes - microbodiesup to 2 microns - catalase

Function

Degradation: substrate oxidation (etanol)

Anabolism: synthesis of prostaglandin , cholesterol, billiary acids, plasmalogens, gluconeogenesis, transamination

peroxisomes microbodies disorders
Peroxisomes - microbodiesDISORDERS

Lack of:

Degradation: substrate oxidation e.g. etanol...

Anabolism: synthesis of prostaglandin , cholesterol, billiary acids, gluconeogenesis, transamination...