Introduction-to-Pathology

ChapterOneIntroductiontoPathologyDEFINITIONOFPATHOLOGYDefinitionofpathology•Pathologyistostudydiseasesbyscientificmethods.•Diseasemaybedefinedasanabnormalalterationofstructureorfunctioninanypartofthebody.Pathologyfocuseson4aspectsofdisease•ETIOLOGY:Causeofdisease.•PATHOGENESIS:Mechanismsofdevelopmentofdisease.•MORPHOLOGY:Thestructuralalterationsinducedincellandtissues.•FUNCTIONALCONSEQUENCES:Functionalconsequencesofthemorphologicchanges,asobservedclinically.Knowledgeofetiologyremainsthebackbone:DiseasediagnosesUnderstandingthenatureofdiseasesTreatmentofdiseases.Whilemuchstillneedstobeuncoveredtolinkabnormalgenesandtheexpressionofdisease,gonearethetimewhenthemechanismsofmostdiseaseswereunknown?orobscure?ormysterious?Oneetiologicagent—onedisease.Severaletiologicagents—onedisease.Oneetiologicagent—severaldiseases.Causesofcellinjuryanddisease•Oxygendeprivation(hypoxia,ischemia)•Nutritionalimbalances•Physicalagents•Chemicalagentsanddrugs•Infectiousagents•Immunologicreactions•GeneticderangementsHYPOXIAIschemia(lossofbloodsupply).Inadequateoxygenation(cardiorespiratoryfailure).Lossofoxygen-carryingcapacityoftheblood(anemiaorCOpoisoning).HYPOXICINJURY•LossofoxidativephosphorylationandATPgenerationbymitochondria.•DecreasedATP(withincreaseinAMP):stimulatingfructokinaseandphosphorylation,resultinginaerobicglycolysis.•Depletedglycogen.•ReducedintracellularpH:Lacticacidandinorganicphosphate.•Clumpingofnuclearchromatin.Fourbiochemicalthemes•Oxygen-derivedfreeradicals.•Lossofcalciumhomeostasisandincreasedintracellularcalcium.•ATPdepletion.•Defectsinmembranepermeability.PHYSICALAGENTS•Trauma•Heat•Cold•Radiation•ElectricshockCHEMICALAGENTSANDDRUGS•Endogenousproducts:urea•Exogenousagents:Therapeuticdrugs:hormonesNontherapeuticagents:leadoralcoholMECHANISMSOFCHEMICALINJURY•Directly:MercuryofmercuricchloridebindstoSHgroupsofcellmembraneproteins,causingincreasedpermeabilityandinhibitionofATPase-dependenttransport.•Byconversiontoreactivetoxicmetaboliteswhichinturncausecellinjuryeitherbydirectcovalentbindingtomembraneproteinandlipid,ormorecommonlybytheformationoffreeradicals.MECHANISMSOFCHEMICALINJURYCCl4inSERoflivercell(P-450)–CCl3.–lipidperoxidationandautocatalyticreactions–swellingandbreakdownofER,dissociationofribosome,anddecreasedhepaticproteinsynthesis(lossoflipidacceptorprotein–fattychangeoflivercell)–progressivecellularswelling,plasmamembranedamage,andcelldeath.FREERADICALINITIATION•Absorptionofenergy(UVlightandx-rays)•Oxidativemetabolicreactions•Enzymaticconversionofexogenouschemicalsordrugs(CCl4CCl3.)•Oxygen-derivedradicals•SuperoxideCellinjurycausedbyfreeradicalsthrough•Peroxidationoflipids.•Crosslinkingproteinsbytheformationofdisulfidebonds.•InductionofDNAdamagethathasbeenimplicatedbothincellkillingandmalignanttransformation.INFECTIOUSAGENTS•Viruses•Rickettsiae•Bacteria•Fungi•ParasitesMarfansyndromeFibrillin,ascaffoldingonwhichtropoelastinisdepositedtoformelasticfibers.FBN1,15q21,mutationsinMarfansyndrome.FBN2,5q3,mutationsincongenitalcontractualarachnodactyly.AdenomatouspolyposiscoliAPCloci,5q21Adenomatouspolyposisincolons(inteens).100%malignanttransformation(40ys).APCproteininthecytoplasm.Severalpartners,including-catenin.-cateninenteringthenucleusactivatingtranscriptionofgrowth-promotinggenes.Causingdegradationof-cateninmaintaininglowlevelof-catenininthecytoplasm.CELLSREACTTOADVERSEINFLUENCES•ADAPTING•SUSTAININGREVERSIBLEINJURY•SUFFERINGIRREVERSIBLEINJURYANDDYINGCELLINJURYANDNECROSISGeneralmechanisms:•Maintenanceoftheintegrityofcellmembranes.•AerobicrespirationandproductionofATP.•Synthesisofenzymesandstructureproteins.•Preservationoftheintegrityofthegeneticapparatus.Thecoreofthescienceofpathology—thestudythepathogenesisofthedisease.PathogenesisThesequenceeventsintheresponseofthecellsortissuestotheetiologicagent,fromtheinitialstimulustotheultimateexpressionofthedisease.PathogenesisImmunologic,cytogeneticandmolecularanalysesoftissuesandcellsareincreasinglybecomingguidestorenderdiagnoses,toassessprognosis,andtosuggesttherapy.•MorphologicchangeCharacteristicofthediseaseDiagnosticoftheetiologicproceess•Functionalderangements•ClinicalsignificanceMORPHOLOGYMorphologyremainsattheheartofdiagnosticpathology.DevelopmentofPathology•Organpathology•Cellpathology•Molecularpathology