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al a Glance

Second

PathologyataGlance

Pathology ataGlance

SecondEdition

BarryNewellBSc,MBBS,MRCP,FRCPath

CellularPathologyDepartment

StGeorge’sHospitalMedicalSchool London,UK

AsmaZ.FaruqiMBBS,FRCPath

DepartmentofCellularPathology

BartsHealthNHSTrust London,UK

CarolineFinlaysonMBBS,FRCPath

CellularPathologyDepartment(retired)

StGeorge’sHospitalMedicalSchool London,UK

Thiseditionfirstpublished2022

Š2022JohnWiley&SonsLtd

EditionHistory

JohnWiley&SonsLtd(1e,2009)

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TherightofBarryNewell,AsmaZ.FaruqiandCarolineFinlaysontobeidentifiedasthe authorsofthisworkhasbeenassertedinaccordancewithlaw.

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LibraryofCongressCataloging-in-PublicationDataappliedfor PBISBN:9781119472452

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CoverImage:ŠAsmaFaruqi

Setin9/11.5ptTimesNewRomanMTStdbyStraive,Chennai,India

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Wededicatethisbooktoourlovingandsupportivefamilies.

Contents

Preface, 8

Abbreviations, 9

Introduction

1Thenormalhumancell, 14

2Fluiddynamics, 18

Tissuedamage

3Tissuetypesandtheeffectoftissuedamage, 22

4Celldeath, 26

5Harmfulagentsintheenvironment, 28

6Theeffectsoftobacco,alcoholandotherdrugs, 32

7Nutritionaldisorders, 36

Inflammationandimmunity

8Thebody’snaturaldefences, 40

9Bcellsandimmunoglobulins, 44

10TcellsandtheTCR, 46

11Themajorhistocompatibilitycomplex, 50

12Primaryandsecondarylymphoidorgansandthe monocyte–macrophage(reticuloendothelial)system, 52

13Acuteinflammation, 56

14Chronicinflammation, 60

15Woundhealingandrepair, 62

16Infectionandimmunodeficiency, 64

17Shock, 68

18Toleranceandautoimmunedisease, 72

19Hypersensitivityreactions, 76

20Overviewofinflammationandimmunity, 80

Genetics

21Celldivision, 84

22Geneticdisease, 86

Neoplasia

23Disorderedcellgrowth, 92

24Basicconceptsinneoplasia, 96

25Tumorigenesisandoncogenesis, 100

26Oncogenesandtumoursuppressorgenes, 102

27Commoncarcinomahistologicalsubtypes, 106

28Tumourprognosisandtreatment, 108

Methodsinhistocytopathology

29Basictechniquesinhistopathology, 112

30Cytopathology, 116

31Molecularpathology, 118

Multisystemsdisease

32Sarcoidosisandsyphilis, 122

33Wilson’sdiseaseandhaemochromatosis, 124

34Systemicvasculitis, 126

Cardiovasculardisease

35Normalbloodvesselsandtypesofaneurysm, 130

36Congenitalheartdisease, 134

37Systemichypertension, 136

38Atherosclerosis, 138

39Coronaryheartdisease, 142

40Thrombosis, 146

41Embolismanddisseminatedintravascularcoagulation, 150

42Cardiacvalvulardisease, 154

43Myocardialandpericardialdisease, 156

Respiratorydisease

44Pulmonaryvasculardisorders, 160

45Pneumonia, 162

46Bronchiectasis, 164

47Tuberculosis, 166

48Chronicobstructivepulmonarydisease, 170

49Fibrosingalveolitis, 172

50Primarylungcarcinoma, 174

51Othertumoursofthelungandpleura, 176

Gastrointestinaltractdisease

52Malabsorption, 180

53Pepticulcerationand Helicobacterpylori, 184

54Oesophagealdisease, 188

55Tumoursofthestomachandsmallintestine, 192

56Mechanicaldiseaseofthegastrointestinaltract, 196

57Inflammatoryboweldisease:ulcerativecolitisandCrohn’s disease, 198

58Colorectalpolyps,colorectalcancerandanalcarcinoma, 202

Hepaticandpancreaticobiliarydisease

59Normalliverandtheeffectsofliverdamage, 208

60Jaundice,gallstonesandcarcinomaofthegallbladder, 210

61Fattyliverdisease:alcoholicandnon-alcoholic, 212

62Autoimmuneliverdisease:AIH,PBC,PSC, 216

63Viralhepatitis, 220

64Cirrhosis, 224

65Acuteandchronicpancreatitis, 228

66Tumoursoftheliver,biliarytreeandpancreas, 232

Genitourinarytractdisease

67Congenitalandinheritedabnormalitiesofthekidneyand urinarytract, 236

68Thenephronandrenalaspectsofhypertension, 240

69Glomerulonephritis, 242

70Importanttypesofglomerulonephritis, 244

71Tubulointerstitialdiseases, 248

72Renalneoplasms, 252

73Bladdertumours, 254

74Testicularcancer, 256

75Prostaticdisease, 258

Gynaecologicalandobstetricdisease

76Vulvalandvaginalpathology, 262

77Cervicalcancer, 266

78Benignuterineconditions, 270

79Uterinemalignancies, 272

80Ovarianneoplasia:partone, 274

81Ovarianneoplasia:parttwo, 278

82Obstetricpathology, 280

83Paediatrictumours, 284

Nervoussystemdisease

84Cerebrovascularaccidents, 288

85Cerebrovascularaccidentsyndromes, 290

86Raisedintracranialpressure, 292

87Traumaticinjuryandintracranialhaemorrhage, 294

88Centralnervoussystemtumours, 296

89Infectionsofthenervoussystem, 298

90Movementdisorders, 300

91Acquireddisordersofmyelination, 304

92Dementia, 306

Endocrinedisease

93Pituitarypathology, 310

94Non-neoplasticpathologyofthethyroid, 312

95Thyroidneoplasms, 314

96Parathyroidglandpathology, 316

97Adrenalpathology, 318

98Diabetesmellitus, 320

Headandneckpathology

99Headandneckpathology, 324

Lymphoreticulardisease

100Assortedhaematologicalconditions, 328 101Leukaemia, 330 102Lymphoma, 332

103Myeloma, 336

104Myeloproliferativedisorders, 338

Musculoskeletaldisease

105Muscledisorders, 342

106Arthritis, 344

107Miscellaneousnon-neoplasticosteoarticularpathology, 348 108Bonetumours, 352

Skindisease

109Inflammatorydermatoses, 356

110Benignskintumours, 358

111Malignantskintumours, 360

Breastdisease

112Benignbreastdisease, 364 113Breastcarcinoma, 366

Casestudiesandquestions, 368 Answers, 373 Glossary, 378 Referenceranges, 380 Index, 381

Preface

Wehavegreatlyappreciatedthefeedbackandcommentsreceived regardingthefirsteditionof PathologyataGlance.Itishearteningtoknowthatthisguidetopathology,whichaimstohighlight thefundamentalaspectsofparticulartopicsinthemannerofa low-scaleroadmap,hasbeenusefultohealthcareprofessionalsat allstagesoftheircareers.

Pathologyisfundamentaltomedicine,andagoodcoreknowledgehelpsimmenselytounitetheapparentlydisparatecollections ofsigns,symptomsandfactsencounteredinthestudyofothermedicalandsurgicaldisciplines.

Students,facedwithlimitlesslayersofinformationindetailed textbooksandonlinelearningplatforms,foundthisbookgave abalancedoverviewandaframeworkontowhichinformation gleanedfromothersourcescouldbeadded.Doctorsfromhouse officertoconsultanthavethankedusforsimplifyingtheirstarting pointforthepreparationofpresentations. PathologyataGlance is alsoapopularrevisionaid.

Acknowledgements

Weareindebtedtothosewhoseexpertisecontributedtothefirst editionandseveralpeoplewhokindlypointedouterrorsorareas

inwhichnewinformationhassupervened,inparticularDrJoe Houghton.

DrKateWheeler,ConsultantinPaediatricOncology,gaveus invaluablehelpwiththechapteronpaediatrictumoursinthesecondedition.MrColinJardine-Brown’smotivationalskillsand expertadvicearealsomuchappreciated(C.J.F.).

ThehelpgiveninthefirsteditionbyDrJenniferElse(renal overview),ProfessorNeilShepherd(Helicobacterpylori),DrDavid Bevan(haemostasis),ProfessorPhilipButcher(tuberculosis),ProfessorPeterMcCrorie(hypertension)andDrJonathanWilliams (breastdisease)continuestobegreatlyappreciatedinthesecond editionof PathologyataGlance

Ourthanksgoalsototheeditorialstafffortheirpatienceand encouragement.

BarryNewell
AsmaZ.Faruqi
CarolineFinlayson

Abbreviations

ACalternatingcurrent

ACEangiotensin-convertingenzyme

ACSacutecoronarysyndromes

ACTHadrenocorticotrophichormone

ADHantidiuretichormone

ADPKDautosomaldominantpolycystickidneydisease

AFPalpha-fetoprotein

AIDSacquiredimmunedeficiencysyndrome

AIHautoimmunehepatitis

AINanalintraepithelialneoplasia;acuteinterstitial nephritis

ALDalcoholicliverdisease

ALLacutelymphoblasticleukaemia

ALPalkalinephosphatase

ALTalanineaminotransferase

AMIacutemyocardialinfarction

AMLacutemyeloblasticleukaemia

ANCAantineutrophilcytoplasmicantibody

APCadenomatouspolyposiscoli

APTTactivatedpartialthromboplastintime

ARDSadultrespiratorydistresssyndrome

ASHalcoholicsteatohepatitis

ASTaspartateaminotransferase

ATNacutetubularnecrosis

ATPadenosinetriphosphate

AVatrioventricular

BALbronchoalveolarlavage

BCCbasalcellcarcinoma

BCGbacilleCalmette–Guérin

BCRBcellreceptor

BEBarrett’soesophagus

BMIbodymassindex

CAcoronaryartery

cAMPcyclicadenosinemonophosphate

CARScompensatoryanti-inflammatoryresponsesyndrome

CBDcommonbileduct

CCAcholangiocarcinoma

CCKcholecystokinin

CDclusterofdifferentiation;coeliacdisease

CFcysticfibrosis

CFAcryptogenicfibrosingalveolitis

CFTRcysticfibrosistransmembraneconductanceregulator

CFUcolonyformingunit

CGINcervicalglandularintraepithelialneoplasia

CHDcoronaryheartdisease

CINcervicalintraepithelialneoplasia

CJDCreutzfeldt–Jakobdisease

CLLchroniclymphocyticleukaemia

CMLchronicmyeloidleukaemia

CMVcytomegalovirus

CNScentralnervoussystem

COcarbonmonoxide

COPDchronicobstructivepulmonarydisease

CRCcolorectalcarcinoma

CrDCrohn’sdisease

CRPC-reactiveprotein

CSFcerebrospinalfluid

CTcomputedtomography

CVAcerebrovascularaccident

DADdiffusealveolardamage

DAIdiffuseaxonalinjury

DAMPdamage-associatedmolecularpattern

DCdirectcurrent

DCCdeletedincoloncancer

DCISductalcarcinomainsitu

DICdisseminatedintravascularcoagulation

DIPdesquamativeinterstitialpneumonia

DMdiabetesmellitus

DNAdeoxyribonucleicacid

DPASdiastasePAS

DUduodenalpepticulcer

dVINdifferentiatedvulvalintraepithelialneoplasia

DVTdeepvenousthrombosis

EATCLenteropathy-associatedT-celllymphoma

EBUSendobronchialultrasound

EBVEpstein–Barrvirus

EGFepidermalgrowthfactor

EGFRepidermalgrowthfactorreceptor

ENaCepithelialsodiumchannel

ENTear,noseandthroat

ERendoplasmicreticulum

ERCPendoscopicretrogradecholangiopancreatography

ESRerythrocytesedimentationrate

ESSendometrialstromalsarcoma

ETendothelin

FAPfamilialadenomatouspolyposis

FDCfollicledendriticcell

FEV1 forcedexpiratoryvolumein1second

FFAfreefattyacid

FFPEformalin-fixed,paraffin-embedded

FGFfibroblastgrowthfactor

FNAfineneedleaspiration

FOBfaecaloccultblood(test)

FSHfollicle-stimulatinghormone

FVCforcedvitalcapacity

G6PDglucose-6-phosphatedehydrogenase

GABAgamma-aminobutyricacid

GALTgut-associatedlymphoidtissue

GBMglomerularbasementmembrane

GCgastriccancer

GDPguanosinediphosphate

GFDgluten-freediet

GFRglomerularfiltrationrate

GGTgamma-glutamyltransferase

GHgrowthhormone

GIgastrointestinal

GNglomerulonephritis

GORDgastro-oesophagealrefluxdisease

GPgeneralpractitioner

GTNglyceryltrinitrate

GTPguanosinetriphosphate

HAARThighlyactiveantiretroviraltherapy

HAVhepatitisAvirus

Hbhaemoglobin

HBcAghepatitisBcoreantigen

HBeAghepatitisBeantigen

HBOChereditarybreastandovariancancer(syndrome)

HBsAghepatitisBsurfaceantigen

HBVhepatitisBvirus

HCChepatocellularcarcinoma

HCGhumanchorionicgonadotrophin

HCVhepatitisCvirus

HDLhighdensitylipoprotein

HDVhepatitisDvirus

H&Ehaematoxylinandeosin

HEVhepatitisEvirus;highendothelialvenules

HGOChigh-gradeovarianserouscarcinoma

HIAAhydroxyindoleaceticacid

HIVhumanimmunodeficiencyvirus

HLAhumanleucocyteantigen

HNPCChereditarynon-polyposiscolorectalcarcinoma

H2 O2 hydrogenperoxide

HP Helicobacterpylori;hydrostaticpressure

HPVhumanpapillomavirus

HRSCHodgkin–Reed–Sternbergcell

HSILhigh-gradesquamousintraepitheliallesion hspheatshockprotein

5HTserotonin/5-hydroxytryptamine

IBDinflammatoryboweldisease

ICAMintercellularadhesionmolecule

IDCinvasiveductalcarcinoma

IFNinterferon

Igimmunoglobulin

IHCimmunohistochemistry

ILinterleukin

INRinternationalnormalisedratio

ISLNin-situlobularneoplasia

IUDintrauterinedevice

IVCinferiorvenacava

JGAjuxtaglomerularapparatus

LAKlymphokine-activatedkiller

LDHlactatedehydrogenase

LDLlowdensitylipoprotein

LHluteinisinghormone

LSILlow-gradesquamousintraepitheliallesion

MALTmucosa-associatedlymphoidtissue

MCHCmeancorpuscularhaemoglobinconcentration

MCVmeancorpuscularvolume

MENmultipleendocrineneoplasia

MGUSmonoclonalgammopathyofuncertainsignificance

MHCmajorhistocompatibilitycomplex;mean haemoglobinconcentration

MImyocardialinfarction

MMRmismatchrepair(enzymes)

MPDmyeloproliferativedisease

MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRCPmagneticresonancecholangiopancreatography

mRNAmessengerRNA

MSImicrosatelliteinstability

NADPnicotinamide-adenine-dinucleotidephosphate

NADPHreducedNADP

NAFLDnon-alcoholicfattyliverdisease

NASHnon-alcoholicsteatohepatitis

NETneutrophilextracellulartrap

NHLnon-Hodgkinlymphoma

NKnaturalkiller(cell)

NLPHLnodularlymphocytepredominantHodgkin lymphoma

NMDA N-methyl-D-aspartate

NOnitricoxide

NOSnototherwisespecified

NSAIDnon-steroidalanti-inflammatorydrug

NSGCTnon-seminomatousgermcelltumour

NSTEMInon-ST-elevatedmyocardialinfarction

PAFplateletactivatingfactor

PAHpolycyclicaromatichydrocarbon

PAMPpathogen-associatedmolecularpattern

PANpolyarteritisnodosa

PASperiodicacid–Schiff

PBCprimarybiliarycholangitis

PEpulmonaryembolism

PEG-IFNpegylatedinterferon

PGEprostaglandinE

PHTportalhypertension

PKDpolycystickidneydisease

PMNpolymorphonuclearneutrophil

PNETprimitiveneuroectodermaltumour

POPplasmaoncoticpressure

PRRpatternrecognitionsensor

PSAprostate-specificantigen

PSCprimarysclerosingcholangitis

PTHparathyroidhormone

PVCpolyvinylchloride

RArheumatoidarthritis

RFrheumatoidfactor

RNAribonucleicacid

ROSreactiveoxygenspecies

SAsinoatrial

SAMEsyndromeofapparentmineralocorticoidexcess

SBPspontaneousbacterialperitonitis

SCCsquamouscellcarcinoma

SCFAshort-chainfattyacids

SCIDseverecombinedimmunodeficiency

SIADHsyndromeofinappropriateantidiuretichormone secretion

SIRSsystemicinflammatoryresponsesyndrome

SLEsystemiclupuserythematosus

SMAsuperiormesentericartery

SMCsmoothmusclecell

SRBCTsmallroundbluecelltumour

SSLsessileserratedlesion

STEMIST-elevatedmyocardialinfarction

T4thyroxine

TBtuberculosis

TcTcytotoxic(cell)

TCRTcellreceptor

T2DMtype2diabetesmellitus

TFtissuefactor

TDLUterminalductlobularunit

TGFtransforminggrowthfactor

ThThelper(cell)

TLRToll-likereceptor

TNFtumournecrosisfactor

TSAtraditionalserratedadenoma

TSGtumoursuppressorgene

TSHthyroid-stimulatinghormone

TTthrombintime

UCulcerativecolitis

UDCAursodeoxycholicacid

UIPusualinterstitialpneumonia

UTIurinarytractinfection

uVINusualvulvalintraepithelialneoplasia

VEGFvascularendothelialgrowthfactor

VLDLverylowdensitylipoprotein

VOCvolatileorganiccompound

VSDventricularseptaldefect

vWFvonWillebrandfactor

WCCwhitecellcount

WHOWorldHealthOrganisation

WHRwaist/hipratio

5YSRfive-yearsurvivalrate

Generalpathology

Introduction

• 1 Thenormalhumancell

Overview of the structure of normal human cells

Controlling the intracellular environment: cell membrane and ion pumps

Phospholipid bilayer: hydrophilic ends on outer and inner aspects. Hydrophobic ends inside membrane, stabilised by cholesterol

Na/Cl pump

Calcium channel

Receiving signals

Cell surface receptors and second messengers

Intracellular transport, cell movement and mitosis

Centriole: spindle formation (cell division)

Cytoskeletal components: microtubules and filaments

Degradation/destruction

Lysosome

Peroxisome

Cell membrane: a phospholipid bilayer,containing ion channels and receptor molecules

Receptor binding site

Signalling molecules transmit signal to nucleus

Protein production and secretion

Nucleus

Ribosome and newly producedpeptide

Rough (with ribosomes) and smooth endoplasmic reticulum

Golgi apparatus: protein modification (folding and addition of carbohydrate)

Secretory vesicle containing protein/glycoprotein product

Proteosome: degrades defective protein

Energy production

Mitochondrion

Cytosol

Theimportantfunctionsofthecellare:manufactureofproteins forlocalordistantuse,energygeneration,functionsappropriateto tissuetypeandreplication.

Themainelementsarethenucleus,thecytoplasm(cytosol),the cytoskeletonandthesubcellularorganelles,allboundbymembranes.

Nucleus

Thenuclearmembranecontainsporestopermitmetabolites,RNA andribosomalsubunitsinorout.Itcontains: •DNA,thenuclearchromatin,whichonlyformsabout20%ofthe nuclearmass.

•Nucleoli–ribosomalRNAsynthesisandribosomesubunit assembly.

•Nucleoprotein,e.g.syntheticenzymesforDNA,RNAandregulatoryproteins,allmadeinthecytoplasmandimportedintothe nucleus.

•Messenger,transferandribosomalRNAenrouteforthe cytoplasm.

Cytosol

Thenutritiousfluidmediumthatbathesandsupportsthe organelles,throughwhichthecytoskeletonramifies.Manyreactionstakeplacehere.

Cytoskeleton

•Microtubules:organellessuchassecretoryvesiclesorinternalised receptorscanbetransportedthroughthecellviathecytoskeleton.

•Microfilaments(actin,myosin):thesestabilisecellshapeandact ascontractileproteinsinmuscle.

•Intermediatefilaments,e.g.cytokeratin,desmin,neurofilament proteinsandglialfibrillaryacidicprotein(thetypesdifferbetween tissuesandallarestructural).

Organelles

Mitochondria

ThesearethemainATP/energy-generatingorganellesandhouse theKrebscycleandoxidativephosphorylation.Theyhavetheir ownssDNA(maternallyderived)whichcodesaminorityoftheir proteins.Aporousoutermembraneandfoldedinnermembraneare present.

Ribosomes

Nucleolus-producedribosomalsubunitsaggregateinthecytosol andattachtotheendoplasmicreticulumorlielooseinthecytosol, dependingonthedestinationoftheproteintobemade(freeribosomesmakeproteinsforinsidethecellitself).Ribosomestranslate RNAstrandsintoacorrectlyassembledaminoacidsequence(peptidemolecule).

Endoplasmicreticulum (ER)

TheERisanirregularmazeofmembrane-boundtubules,saccules andcisternswhichramifiesthroughthecell.

• RoughER isstuddedwithribosomes.Proteinsmadebytherough ERpassintotheroughERcisternaeandundergosecondaryfoldingandearlyglycosylationbeforebeingincorporatedintomembranesforexportfromthecell,receptormoleculesonthecell,or componentssuchaslysosomeswithinthecell.

• SmoothER:thereisafurtheradditionofcarbohydratemoieties toprotein,foldingtoachievetertiarystructure.

Golgi apparatus –seediagram.

Secretoryvesicles

Thesemembrane-boundpacketsaremovedviathecytoskeletonto fusewiththecellmembranetoexpeltheircontentsoutside.

Lysosomes

Theseareintracellularmembrane-boundvesicles,containing destructivechemicalsandenzymes,whichfusewithphagosomes toreleasetheircontentsintothephagolysosomeanddestroy pathogens.Lysosomesalsodegradeworn-outcellorganelles (autophagy).

Peroxisomes

Thesesmallmembrane-boundgranulescontainoxidativeenzymes whichmakehydrogenperoxideplusitsregulatorcatalase.

Proteasomes

Theseidentifydefectiveproteinsanddegradethemintotheircomponentpeptidesandaminoacidsforreusebythecell.Portionsof broken-downproteinareboundbyMHCclassImoleculesanddisplayedonthecellsurfacetoTccells.

Centrosome

Thiscontainsthetwolinkedcentrioles,fromwhichmicrotubules radiateintothecell.Thecentriolesduplicateandmigratetooppositeendsofthecellduringcelldivision,separatingtheduplicated chromosomes.

Membranes

Membranesarephospholipidbarrierssurroundingthecellitself andcertainorganelles.Theyisolateportionsofthecellandpermitseveral,oftenincompatible,metabolicprocessestotakeplace simultaneously.

Thecell membrane

Thisphospholipidbilayerinteractswiththeextracellularworldby assortedsurfacemolecules.Thecentreislipophilicandthesurfaces hydrophilic,withcholesterolasastabilising‘spacer’betweenthem. The‘rafttheory’suggeststhatintramembranestructurescanfloat andbecross-linkedaroundtheperimeterofthecell.

Membraneproteins:proteinsthatprojectthroughthemembrane outsidethecellusuallyhaveattachedcarbohydrates.Glycolipids arecarbohydratesattachedtothelipidmembraneandareimportantincellrecognition,cell–cellbondsandadsorbingmolecules. Sometissueshaveaprotectiveglycocalyx.

Transportthroughthecellmembrane:themainmechanismsareas follows.

•Passivediffusion(needsonlyaconcentrationgradient),e.g.lipids andlipid-solubleagentslikeethanol.

•Facilitateddiffusion:thebindingofamoleculetriggersaconformationalchangewhichmovesthemoleculeacrossthemembrane.

•Activetransport:againstaconcentrationgradienttomaintainionconcentrationswithinthecell,e.g.theNa+ /K+ -ATPase complex.

•Bulktransport: endocytosis, transcytosis and exocytosis.Endocytosisincludes receptor-mediatedendocytosis (ligandsorviral

particles)and phagocytosis (engulfingofparticles). Pinocytosis,the samplingofsmallquantitiesofextracellularfluid,isnotreceptor mediated.

Transmissionofmessagesacrossthecellmembrane

•Lipid-solubleagents(e.g.steroids)diffusedirectlyacrosscell membranes.

•Receptorbindingandactivationofsecondarymessengers: appliestoproteinmessengermolecules,whichbindtoaspecific

cellsurfacereceptor(ligand),resultinginactivetransportofthe moleculethroughthemembraneorthetriggeringofintracellular cascadereactions.

Neurotransmitters:thesearechemicalmessengersforneurones ormyocytesthatcauseanelectricalresponseinthetargetby receptor-mediatedopeningofanionchannel.

• 2 Fluiddynamics

Lymphatic drainage

Lymph exits via efferent lymphatic B

Thoracic duct returns lymph to venous system

Compartmentalisation within the body

Plasma protein

Fluid and electrolytes

Lymph carries fluid, cells, complement and other particles, e.g. bacteria to the lymph node

Fenestrated lymphatic endothelium lines blind-ended tubes which collect interstitial fluid

Vascular compartment

Fluid moves freely between the vascular and interstitial compartments, via the permeable capillary bed

Protein is retained within the vascular compartment by its large size and negative charge

Cell

Low Ca2+

High K+

Cell Interstitial compartment

High H2O and Na+

Cellular compartment

Cell membranes tightly regulate their electrolyte contents using Na/K exchange and calcium pumps

Normal fluid movement

Arterial side: hydrostatic pressure (HP) forces plasma out of fenestrated capillary endothelium

HP

Pre-capillary sphincter under sympathetic controlCapillary bed

Post-capillary venule reacts to vasoactive mediators

Venous side: hydrostatic pressure low

Valve

Plasma protein exerts oncotic pressure (POP) on fluid to remain in or return to vessel

Transudate

Normal specific gravity of <1.015

Excess plasma fluid without protein

Fluid accumulates in tissues, exceeding capacity of lymphatics to drain it, causing ‘pitting’ oedema caused when:

The plasma oncotic pressure drops, e.g. decreased protein production by the liver in chronic liver disease, or protein loss via the kidneys in nephrotic syndrome

Plasma protein retained in vessels, fluid is pressed out of vessels into the interstitium Oedema occurs if lymphatic drainage cannot meet demand

Fluid, without cells or plasma proteins

The hydrostatic pressure increases, e.g. back-pressure due to congestive cardiac failure

Specific gravity > 1.015

Lymphatics collect surplus interstitial fluid

Excess plasma fluid with protein

Example: inflammation, vascular response to inflammatory mediators:

Constriction of post-capillary venules increases hydrostatic pressure

Endothelial cells contract, enlarging the space between cells

Both fluid and plasma proteins move out of capillaries into the interstitium

Loss of plasma proteins reduces the osmotic pull on fluid to return to the blood vessels

Increased quantities of fluid, plus any cells, complement proteins or micro-organisms enter the lymph, but drainage cannot meet demand and fluid remains in the interstitium

Exudate

Approximately70%ofthebodyiscomposedofwater.Waterprovidestheessenceofthefluidmediumforthetransportofcells, nutrientsandwasteproductsbetweenorgans,providessubstance forcellularcytosolandisthesolventinwhichnumerouschemical reactionsoccur.Disruptionsofthequantityofwaterinthebody anditsdistributioncanhaveseriousconsequences.

Discussionsoffluidbalancetendtorevolvearoundacompartmentalmodeloffluiddistribution.Threemaincompartmentsare described:theintracellular(66%),interstitial/intercellular(25%) andintravascular(7%).Afourthcompartmentofspecialisedfluids (2%)canalsobeconsideredandincludessecretionsofthegastrointestinal(GI)tract,peritonealandpleuralfluids,cerebrospinalfluid, synovialfluid,intraocularfluidandthevestibulocochlearfluids. Thefourthcompartmentisoftenamalgamatedintotheinterstitial.

Fluidmovementisdynamicbetweenallofthecompartmentsand tendstofollowpassiveosmoticandhydrostaticgradients,provided thatthemembraneseparatingthecompartmentsiswaterpermeable.Ifwatermovementbetweenbodycompartmentsisrequired, manipulationofthesegradientsistypicallythemethodbywhich thisisaccomplished.Forexample,thesecretionofsweatinvolves thepumpingofsodiumandchlorideionsintothelumenofthe sweatduct.Waterthenfollowspassivelythroughmembranepores andintercellularjunctions.

Electrolytes

Electrolytesareoneofthemainclassesofsolutewithinbodywater. Thechiefintracellularcationispotassiumandtheprincipalextracellularcationissodium.Thisdifferentialdistributionofsodium andpotassiumismaintainedbytheNa+ /K+ -ATPasethatispresent oneffectivelyallcells.Itisthebasisfortheelectricalactivityof neurones,skeletalmuscleandcardiacmuscle.Alterationsinthe extracellularconcentrationofeitherpotassiumorsodiumcan destabilisetheelectricallyexcitablemembranesofthesecells,generatingaberrantelectricalactivitysuchasseizures,arrhythmiasor muscleweakness.

Electrolyteconcentrationsarealsovitalinmaintainingturgor withincells.Iftheosmolarityofextracellularfluidisdisturbed, waterwillmoveinoroutofcellsaccordingly,resultingincell swelling(andultimatelyrupture)orshrinkage.Sucharethepotentiallycatastrophiceffectsofthisinappropriatemovementofwater thatbodyosmolarityisextremelytightlyregulatedbytheantidiuretichormone(ADH)system.Inextremesituations,homeostaticmechanismswillstrivetopreservebloodosmolarity(which isinequilibriumwiththatoftheothercompartments)evenatthe expenseofelectrolytelevelsandotherparameters.

Bloodandbloodltration

Thevascularcompartmentcontains70mLofbloodperkilogram bodyweight(hence4900mLfora70-kgman).Cellularconstituents (erythrocytes,leucocytesandplatelets)comprise40%ofthisvolume,whiletheremaining60%isplasma.Plasmaiswaterinwhich electrolytes,numeroustypesofproteinsandlipoproteinsaredissolved.Bloodservesasatransportmediumtodelivernutrientsto thetissuesandtoremovewasteproductsfromthem.Thismovementofnutrientsandmetabolitesoccursatthecapillarylevel.

Whenbloodreachesthecapillaries,fluidandelectrolytescan passeasilythroughthegapsbetweenendothelialcells,butcells andlargermolecules(proteins)cannot.Thismovementisbidirectionalandthedirectionthatdominatesisregulatedbythebalance betweenthehydrostaticpressure(HP)exertedbythebloodpressure generatedbytheheartandtransmittedthroughthevasculartree andtheplasmaoncoticpressure(POP)generatedbyplasmaproteins.TheHPdriveswaterfromthebloodintothetissueswhereas thePOPprovidesagradientthatdrawsfluidbackintotheblood fromtheextracellularspace.

Intheproximalcapillarybed,HPexceedsPOPandthereisa netmovementoffluidfromthebloodintotheextracellularspace. Theinterstitialfluidisinequilibriumwiththeintercellularfluid andthereisreadymovementofnutrientsandmetabolitesbetween thesetwocompartments.However,theHPfallsacrossthecapillary bedandonthedistalsideisoverpoweredbytheoncoticpressure, causinganetmovementoffluidanditsaccompanyingsolutesback intotheblood.Nevertheless,theactionofthePOPisnotcomplete andasmallquantityoffluidremainsintheextracellularspace.This islymphandishandledbythelymphaticdrainagesystem.

Lymphaticsystem

Lymphaticvesselscommenceinthetissuesasblind-endedtubes linedbyfenestratedendothelium.Thelymphismassagedthrough progressivelylargerandmorevalve-bearing,muscularised(nonleaky)vesselstothethoracicduct,whichemptiesintothevenous systemviathesuperiorvenacava,returningthefluidtothecirculation.Enroute,lymphissievedthroughlymphnodesandthus lymphhasavitalroleinpresentingextracellularmaterialtothe immunesystem.

Transudates

Atransudateisanabnormalaccumulationoffluidthathasalow concentrationofprotein(typicallydefinedaslessthanbloodalbumin).Transudatesmayoccurinnumerouslocations,includingthe pleuralandperitonealcavities,andariseforoneoftworeasons.

1 Increasedhydrostaticpressure,typicallybackpressurewithinthe venoussystemduetoinadequatecardiacfunction.Fluidaccumulatesintheextracellularcompartmentandyields‘pitting’oedema oftheskin.Pleuraleffusionsmayalsobeseen.

2 The plasmaoncoticpressuredrops duetoeitherdecreasedhepatic proteinsynthesis(asincirrhosis)orexcessiveproteinlossviathe kidneys(nephroticsyndrome).Aswellaspittingoedema,ascites andpleuraleffusionsarecommon.

Exudate

Anexudateisanabnormalcollectionoffluidthathasahighprotein concentration,typicallygreaterthanplasmaalbumin.Exudatesare causedbyinflammatoryprocessesthatmarkedlyincreasetheleakinessofthecapillarybedsuchthatproteinsthatwouldnotnormally beabletoleavethecirculationarenowableto.Constrictionof post-capillaryvenulesraisesthehydrostaticpressureandalsocontributestoexudateformation.

Tissuedamage

• 3 Tissuetypesandtheeffectoftissuedamage

Tissue replacement by stem cells, e.g. colon

Epithelium

Mucosa with straight-sided crypts

Stem cell at crypt base divides to supply new cells for surface and self-renews

M. mucosae

Submucosa

M. propria

Subserosal fat

The effects of damage depends on the tissue type affected and the type of damaging agent

Labile cells

Constantly self-renewing, e.g. bone marrow derived cells, epithelium: generally have short lifespan, high turnover; are quick to regenerate following trauma. Liable to damage by radiation or chemotherapeutic drugs,which affect cells undergoing mitosis

Stable cells

Self-renew as required, from stem cells or mature cells. May divide in limited fashion. Long lifespan tissues, e.g. liver, regenerate effectively following injury if sufficient normal liver remains.

Fibroblast and endothelial cell proliferation is essential for healing and repair in many tissues

Permanent cells

Long lifespan, little or no capacity to self-renew, e.g. brain, cardiac muscle. Damage causes tissue loss: in the heart, scar tissue forms; in the brain the tissue liquefies

Cell types

Epithelium:

Covers surfaces, cells bind each other to form an impermeable barrier. Specialised to local needs

Neuroectoderm: Neurons, melanocytes and neuroendocrine cells

Connective (‘soft’) tissue:

Supporting tissues, e.g. fat, bone, fibrous tissue, nerve insulation, cartilage, muscle (smooth, striated, cardiac)

Endothelium lines vascular system

Haemopoeiticand lymphoreticular

Bone marrow-derived cells and their precursors. Mature cells are mobile, many circulate

Germ cells:

Haploid generative cells in testis and ovary

Placenta Trophoblast

Most damaging agents affect tissues directly, but watershed zone infarction can occur as an indirect consequence of diminished blood flow at the ‘watershed’ between zones supplied by end-arteries

The two main types of cell death, coagulative and liquefactive necrosis, and distinctive histological subtypes: fibrinoid, caseous and fat necrosis. The clinical observation of “gangrenous necrosis” refers to blackened, ischaemic extremities: dry gangrene is due to infarction (coagulative necrosis) and wet gangrene has superadded infection, causing liquefaction

Normal tissue:

Cells have nuclei and distinct cell outlines

Coagulative necrosis

Example, renal infarct: cell outline preserved but cell contents degenerate

Liquefactive necrosis

Necrotic material

liquefies, e.g. brain, abscess contents

Fibrinoid necrosis

Blood vessel destruction by eosinophilic ‘fibrinoid’ material, e.g. vasculitis.

Caseous necrosis

Tuberculosis –crumbly necrotic debris, combining coagulative and liquefactive features: granulomatous reaction

Fat necrosis

Follows trauma and forms hard nodule which can be mistaken for tumour (e.g. in breast)

Normaltissuetypes

Epithelium

Epithelium,derivedfromembryonalectoderm*,linesthebody’s surfaces.Itconstantlyregeneratesandhealsquickly.Thethreemain epithelialsubtypesare:

1Squamous:functionsasabarrierandprotectsagainstfriction.

a. Stratifiedsquamous:coversskin,pharynx,tongue,oesophagus,anus,vagina,externalauditorycanal;keratinisationisonly normallyseenintheskin.

b. Simplesquamous:formsmesotheliumliningthepleuraland peritonealcavities.Pathologistsregardendotheliumasaseparate entityfromsimplesquamousepithelium(SeeNotebelow).

2Glandular:linesallsecretoryorgans.Itsfunctionsinclude:

a. Secretion:

•Non-specialised,e.g.mucin,totrapbacteriainthenoseor assistfoodtransitingut.

•Specialised,e.g.hormoneoracidsecretion(gastricparietal) orabsorption(gut,renaltubules).

b. Iontransfer:renaltubules.

c. Clearance:ciliatedbronchialcellsremoveinhaledparticles stuckinmucin(mucociliaryescalator).

3Urothelial(formerly‘transitional’):this‘pseudostratified’epitheliumlinestheurinarytract.Itcontains umbrella cellsthatmaintain theintegrityofthesurfaceonstretchingtoaccommodateurine.

Note: Mesothelialcells,thesingle-layedsimpleepitheliumlining thepleuralandperitonealcavities,arederivedfrommesoderm, butcontainkeratins.Endothelium(seelater)isoftendescribedby non-pathologistsasasimplesquamousepithelium,butendothelial cellsdonotcontainkeratinfibres,adefiningfeatureofepithelium (theyaresupportedbyvimentinfibres).Notethatsynovialcavities arenotlinedbyepithelialcells,butbytwocelltypes,derivedfrom fibroblastsandmacrophages.

Neuroectodermal-derivedtissue

Thisformsthecentralandperipheralnervoussystem.Scatteredneuroendocrinecellspopulatevariousepitheliaandsecrete site-specificsubstances,e.g.skinmelanocytes,guthormonesecretingcellsandinthebronchus(wheretheyarethoughttogive risetopulmonarysmallcellcarcinoma).

Connectivetissue

Thisformsstructuraltissues.

• Fat (adipo-)storeslipid,canregenerateandmaysecreteor respondtocytokines.Adipokinescandriveinflammation.

• Bone (osteo-)consistsmainlyofmatrix-containingsparseosteocytesandisconstantlyremodelledbyosteoblasts,whichlaydown matrix,andosteoclasts,whichresorbit,inresponsetophysical stressesandhormones(e.g.parathyroidhormoneorcalcitonin).It healsexcellently.

• Fibroustissue (fibro-),suchastendon,whichconsistsmainlyof acellularandavascularcollagenoustissueandhealspoorly.

• Cartilage (chondro-)consistsmainlyofavascularmatrix,in whichafewchondrocytesareembedded;ithealspoorly.

• Nervesheath (neurofibro-)thereareseveralnervesheathcomponents,whichmayundergobenignproliferation,e.g.afteramputation,orformmalignanttumours.MyelinismadebySchwanncells, whichcanformschwannomas.

• Smoothmuscle (leio-)formsthewallsofmedium-sizedandlarge bloodvesselsandlymphatics,theuterinemyometrium,thevaginal wallandthemuscularlayersoftheGI,respiratoryandurological tracts.Itcanregeneratebutoftenhealsbyscarring.

• Striatedmuscle ((rhabdo)myo-)formsvoluntarymuscle.Regenerationislimited.

• Cardiacmuscle:myocardiumonly;doesnotregenerate.

• Endothelium arisesfrom‘bloodislands’oftheembryonalmesoderm.Differenttypeslinethebloodvessels,lymphaticsandthe hepaticandsplenicsinusoids.Endotheliumreadilyregenerates.

Haemopoietic andlymphoreticulartissue

Thesetissuesgeneratebloodcellsandformtheimmunesystem. TheyarediscussedinChapters8–12.

Germ cells

Thesearetheovarianandtesticularreproductivecells.Theyare constantlyproducedbythetestis;theovarycontainsafinitenumberfrombirth.

Proliferativeandregenerativecapacity

• Labiletissues readilyregenerateandconstantlyproliferateinlife, e.g.theepitheliaoftheskin,gastrointestinaltract,bronchus.

• Stabletissues includetheliverandkidney,andcan,ifnecessary,regeneratebutusuallyshowonlyverylimitedcellturnover. Theliverhashugeregenerativecapacity:overhalfcanberemoved yettheremaindercanundergocompensatoryregeneration.Renal tubulesarequicktoregeneratefollowingdamagesuchastransient ischaemia.

• Permanenttissues showlittletonoregenerationsocelldeathcan becatastrophic(e.g.cardiacmyocytes,neurones).

Stemcells areprogenitorcellsthatcanpotentiallyformanytissue butrespondtolocalhormonesandcytokinestoyieldcellsappropriatetotheplaceinwhichtheyaregenerated.Stemcellsdivide toformacopyofthemselves(andarethusimmortal)plusapopulationof‘committed’progenitorcells.Thesedivideinto‘transit amplifyingcells’andafterseveralcelldivisionsyieldterminallydifferentiatedcellswhichdieoncetheirlifespanisover,tobereplaced byfurtherstemcellprogeny.

Cellreplacementintissueswithahighturnoverisbystemcells. Intissuessuchasliver,withalowcellturnover,replacementof individuallydamagedcellsisbydivisionofadjacentcells,butlarger amountsofhepatocytelossrequiresstemcellsforreplacement. Eachtissuehasacompartmentcontainingitsownstemcell.

Tissuenecrosis

Necrosisisaformofunregulatedcelldeathwhichhasavarietyof causes,chieflyphysicaltrauma,infarction,infectionorchemicals. Theappearanceofnecrosisvariesaccordingtothestimulusandthe tissue.Themajortypesareasfollows.

• Coagulativenecrosis duetoischaemiaiscommonestandusually appearsasafirm,pale,wedge-shapedregionoftissuereflectingthe territorysuppliedbyanoccludedarteriole.Thecellsretaintheir shapebutlosetheirnucleiandareknownas‘ghostcells’.

• Liquefactivenecrosis typicallyaffectsthecentralnervoussystem (CNS),oftenafterastroke.Oncethedamagedtissuehasbeen clearedthereisnohealingandnoscar,andonlyacysticspace remains;themechanismisnotwellunderstood.Abscessesalso

showliquefactivenecrosis,duetoenzymicdigestionoftissuesby theinfectingorganism.

• Caseation isawhite,crumbly,cottagecheese-likeappearance foundintuberculosisandsomefungalinfections.Itisamixture ofcoagulativeandliquefactivenecrosis.

• Fatnecrosis:hard,brightyellownodulesoffatnecrosisoccur, possiblysecondarytotraumaandmaybecomecalcifiedandresembletumourclinically.Digestionoffatbypancreaticenzymeswith fatnecrosisandcalcificationiscommonlyseeninacuteandchronic pancreatitis.

Typesofinfarction

Infarctionisnecrosisofatissueororganduetodisruptionofits bloodsupply.In arterial infarctionthereisinadequateflowinto theorgan.In venous infarctiontheoutflowisobstructed,preventingflowthroughtheorganandcausingcongestionandstagnation.Arterialinfarctionistypicallyduetoocclusionofthevessel byathrombusorembolus;externalcompressionisrare.Venous infarctionoftenreflectscompressionoftheveins,asoccursinstrangulationofahernia. Watershedzone infarctionsareillustrated opposite.

• 4 Celldeath

Initiation of apoptosis may be via extrinsic or intrinsic pathways.

Caspases are central to apoptosis; so far 14 have been described

Effector caspases are enzymes which cleave proteins in membranes, the nucleus and the cytoskeleton and activate nuclear DNAase

Cytochrome-c release from mitochondrial membrane

Initiator caspases activate effectors

Mitochondrion

Anti-apoptosis

Bcl-2 blocks release of cytochrome-c, and may modulate Ca ion flux.

Bcl-xL stabilises the mitochondrial membrane and neutralises proapoptotic molecules by binding

Pro-apoptosis

Bad, Bax and Bim proteins activate apoptosis. They displace Bcl-2 and Bcl-xL

Bid, once activated, induces cytochrome-c release

Cascade of effector caspase activation

Extrinsic ‘death receptor’ pathway stimulated by cross-linking receptors, e.g. TNFR1, Fas. Example: TNF secretion by immune cells

Direct activation

Example: Granzyme B injected into cells by Tc cells through holes in membranes made by perforin

Intrinsic activation

Main pathway is by mitochondrial membrane release of cytochrome c and other pro-apoptotic molecules, influenced by Bcl-2 family members

Example: growth factor blockage/ withdrawal

Can be stimulated by autophagic or necrotic mechanisms which increase Ca++ levels in cytosol DNA damage via p53 stimulates caspases directly or through the synthesis of Bax and Bak

Fragments bud off the cell surface and express new ligands. The cell shrinks

Macrophages and some adjacent epithelial cells attach to the ligands and engulf the debris, digesting it in phagolysosomes.

There is no acute inflammation

Necrosis

Agents which cause necrosis fall into the following main categories:

Ischaemia, hypoxia or re-perfusion, e.g. myocardial infarction

Infection, e.g. bacterial, viral, fungal

Immune-mediated, e.g. cross-reacting antibodies

Physical agents, e.g. extreme heat or cold, electrocution, irradiation

Chemical agents, e.g. strong acid or alkali, drugs which bind DNA

Nutritional, e.g. folic acid/B12 deficiency

The generation of free radicals is a common effector pathway (oxidative stress occurs when there is more generation of reactive oxygen species (free radicals) than can be cleared by the available scavenging systems)

Surplus or worn-out material from intracellular protein production

Formation of autophagosome

Portion of cytoplasm enveloped in double lipid membrane Fusion with lysosome

Autophagolysosome

Storage of indigestible remnants

Degradation and recycling of protein and other elements

Na/K pump in the cell membrane fails, e.g. loss of ATP production by mitochondria. Lactic acid may accumulate

Na+ enters the cell, passively accompanied by water. The cell swells

Ca/Mg pump fails: excess cytosol Ca++ activates enzymes which deplete ATP

The membranes bleb and ribosomes dissociate from endoplasmic reticulum, cytoskeletal components clump

The situation is still reversible

Enzymes activated by Ca++ digest the cell membrane, cytoskeleton and the nuclear chromatin

The damage is irreversible

Various nuclear changes may occur: it may shrink and get darker (pyknosis), fade away (karyolysis) or fragment (karyorrhexis). Similar nuclear changes are seen in apoptosis, particularly karyorrhexis. Some claim that this appearance is unique to apoptosis but it is disputed

Release of cell contents stimulates acute inflammation. This adds to the damage by releasing further digestive enzymes and free radicals into the tissue

If proteolytic digestion predominates there is less inflammation and the result is coagulative necrosis

If hydrolytic enzyme digestion predominates, the tissue undergoes liquefaction

Inthelivingperson,celldeathoccursallthetimeandisoftena necessaryprocess.Thetwomechanismsthatproducecelldeathare apoptosisandnecrosis.Itisbecomingclearthattheseentitiesare notalwaysdistinct,butgeneralisationsaremadebelow.

Apoptosis

Apoptosis,oftencalled‘programmedcelldeath’,occursduringembryologicaldevelopment,asnewtissuesareformedand remodelled,orinphysiologicalcyclessuchasthemenstrualcycle. Apoptosisischaracterisedbytheorderlybreakdownofcellular constituents,whicharepackagedintomembrane-boundvesicles andtaggedforcollectionbyphagocytes.Thisrequiresenergy.

Theinitiationofapoptosisisasfollows.

1 Bindingofa‘deathligand’(e.g.TNFR1orFas)onthecell surface,e.g.directbindingbyTcellsorNKcells,ortumournecrosis factor(TNF)secretionbyimmunecells.

2 Membranedisruptionbyperforin,thenintracellularinjectionof granzymeBbyacytotoxicTcell(Chapter10).

3 Releaseofpro-apoptoticproteins,e.g.cytochrome c,fromleaky mitochondrialmembranes,aprocesslargelyregulatedbypro-and anti-apoptoticproteinsoftheBcl-2family.

4 TP53,a‘gatekeeper’geneinthecellcycle.p53proteininstigates apoptosisifthereisafailuretorepairDNAdamage(Chapter26).

Oncestarted,apoptosisisgenerallyirreversible,involvingafinal commonpathwayofanintracellularcascadeofcaspases.Proteolyticcleavageofcellcontentsandwaterlosscausescellshrinkage. Fragmentsbudoff,envelopedbycellmembrane,whichexpresses newligands.Apoptosisdoesnotstimulateanacuteinflammatory response;instead,macrophagesandadjacentcellsbindthenewligandsandphagocytosethefragments.

Necrosis

Thedeathofagroupofcellsduetoanoxiousstimulusisreferred toasnecrosis.Necrosisiscausedbymanyphysicalandchemical agents,amongstthemostcommonofwhichareischaemia,infectionanddrugs(e.g.chemotherapy).Necroticcellulardebrisstimulatesanacuteinflammatoryresponsewhichmayincreasethearea oftissuedamagedduetotheleakageoflysosomalenzymesfrom polymorphsandmacrophages.

Ithasbeensuggestedthatnecrosisiswhathappensaftercell death(i.e.irreversibledamage)andthatchangesuptothispoint, whichcanbereversed,shouldbeclassedascelldamage.Thepoint ofnoreturnisbestrecognisedwhenthereisalossofmembrane integrityandinfluxofcalciumintothecytosolfromtheinterstitial fluidorfromtheendoplasmicreticulum.

Factorsthatinfluencewhetherthedamageisreversibleinclude:

• Thedurationofthestimulus,e.g.ischaemiaduetocoronaryartery thrombosiswillcausemyocardialinfarction,butiftheocclusionis rapidlyclearedtheareaofcardiacmusclethatdieswillbereduced (Chapter36).Reperfusionmaycauseproblemsduetotherelease offreeradicalsinthereperfusedterritory.

• Thedoseofachemicalagent:whatcancausecelldeathinsome people,doesnotinothersduetogeneticpolymorphism(variation ininheritedgenesencodingtheliverenzymesthatmetabolisethe drugs).

• Thetissuetypeanditsmetabolicactivity:theneuronesofthebrain andcardiacmusclecellsarehighlymetabolicallyactive.Energyproductionfromglycolysisviaanaerobicpathwaysisavailableforliver

ormuscle(whichstorestarch)butproducestoxiclacticacidwithin thecell.Damagebeginswithinminutesinthebrain,butlimbstriatedmusclescanbedeprivedofoxygenforseveralhours.Cooling oftissuesreducestheirmetabolismandincreasessurvivaltime.

• Thestateofhealthoftheexistingtissue,e.g.ironoverloadin haemochromatosisrendersthelivermoresusceptibletodamageby othertoxins,likealcohol.

Autophagy

Thebodyattemptstopreservecellsthroughtimesofadversity byundergoingautophagy,aparticulartypeofcellularadaptation commonlyseeninstarvationandalsoininfection.Itisalsoinitiated bygrowthfactordeprivation.

Portionsofcytoplasmareboundbymembranestoformavesicle (autophagosome),whichfuseswithalysosomeanditscontents, oncedegradedbyhydrolaseenzymes,arethenrecycled.Theprocess islikehibernationandcanbereversedoncetheleantimespass,but iftakentoextremesbecausethestimuluspersists,thecelldieseither byapoptosisornecrosis.

Pathologicalexamplesofdiseasesinwhichautophagyplays animportantroleincludeneurodegenerativediseasessuchas Alzheimer’s,Parkinson’sandHuntington’sdiseases.Muchinterest hasrecentlydevelopedintheroleplayedbyautophagyincancer.

Freeradicals

Freeradicalsarehighlyreactiveanionswithanunpairedouter orbitalelectron.Theyreactwithinorganicororganicchemicalsto formfurtherfreeradicals.Importantexamplesare:

•Reactiveoxygenspecies(ROS):hydrogenperoxide(H2 O2 ),superoxideanionradical(O2 ⋅)andhydroxylradical(⋅OH).

•Nitricoxide(NO)madebyendothelium,macrophages,neurones andothercells.

Formation

•Duringnormalcellularenergygenerationbyoxygenreduction andelectrontransfer.

•Killingofpathogensbyphagocytes:ROSarepreformedina membranecomplex.

•Unwantedby-productofintracellularoxidasereactions.

•Radiation(generateshydroxylandhydrogenfreeradicalsbyionisingwater).

•Toxicby-productofdrug/chemicalmetabolismbycellular enzymes,e.g.intheliver.

Harmfuleffects

•Lipidmembranedamagebyperoxidation(affectsthecellmembraneandthemembranesoforganelles).

•Proteindamagebyaminoacidoxidation,cross-linkagesorproteinbreakdown,e.g.microtubuleaggregation.

•DNAdamagecancausemutationsandcancer.

Protection

•NaturaldecaytooxygenandH2 O2 .

•Antioxidants,e.g.glutathioneandvitaminsA,CandE.

•Bindingofcopperandirontotransportproteins.

•ScavengingenzymesthatbreakdownH2 O2 andsuperoxide anion,e.g.catalase,superoxidedismutasesorglutathione peroxidase.

• 5 Harmfulagentsintheenvironment

Environmental pollution

AIR

Air pollution alone is estimated to cause >6 million deaths annually in the world, a number similar to tobacco smoking. The effects on humans of air pollution include: asthma, COPD, lung cancer, MI, stroke, neurodegenerative and skin disorders.

Increased UV light penetration via stratospheric ozone (O3) deficiencies

Particulate matter, small worst (PM10, PM2.5): e.g. smog, soot, tobacco smoke

Organisms: bacteria and their spores, viruses

Dust: “atmospheric, heavy or settling,” e.g. derived from industry, incineration of waste, natural phenomena such as volcanic eruption

Gases:eg CO2 /CO, sulphates, nitrous compounds, PAH , VOC.

Increased O3 at ground level

Heavy metals, e.g. lead

Noise pollution

Radioactive waste

LAND

Chemical/radioactive waste e.g. heavy metals, hydrocarbons or pesticides

WATER

Chemical waste, soil waste, air pollution washed into water by rain, alteration in organisms (e.g. algal bloom in sea), plastics. Radioactive waste

Cold-induced damageHeat-induced damage

Hypothermia occurs when the core temperature is <35C. Frostbite is localised freezing of exposed peripheries, e.g. nose, fingers

The problems which affect resuscitation efforts are those of plasma volume depletion and alterations in ion concentration

A cold-induced diuresis increases plasma viscosity and the blood becomes hyper-coagulable, increasing the risk of myocardial infarction and stroke on resuscitation

Leakage of plasma occurs across damaged capillary endothelium. Hypovolaemia may cause shock if a patient is warmed suddenly, without careful monitoring and fluid and electrolyte correction

Plasma K+ levels rise because of the loss of integrity of the cellular Na+/K+ pump - this normally functions to keep intracellular K+ levels high and Na+ low, while the reverse is true in the extracellular fluid.

The high plasma K+ levels may cause cardiac arrhythmias

Radiation-associated disease

Exogenous: high ambient temperatures and excessive exercise may cause fluid and electrolyte loss and dehydration

Treatment is by cooling and fluid and electrolyte replacement

Mixed exogenous/endogenous: high ambient temperatures and impaired heat-losing mechanisms cause heat stroke

Example: athletes exercising in extremely hot environments

Infants, children and the elderly, especially those taking medication such as diuretics or tranquilisers

Treatment is with cooling, fluid and electrolyte replacement –antipyretics are ineffective

Many patients develop lactic acidosis, hypocalcaemia, muscle fibre damage and myoglobinuria, which may damage renal tubules

Endogenous:

Infections cause fever due to the release of cytokines, e.g. IL-1 and TNF, which affect the temperature control centre in the hypothalamus

Example: the drenching sweats and high fevers seen in tuberculosis and some lymphoma patients (though why this is typically at night is not clear)

Febrile convulsions are common in children with high temperatures

An aberrant response to anaesthetic may cause ‘malignant hyperthermia’

Radiation effects

Ionizing radiation causes DNA breakages and cross-linkage.

Rapidly dividing tissues (bone marrow, gut, skin, bronchus, urinary tract) are particularly susceptible

Effects vary depending on type (ι, β particles or γ , X-rays), depth of penetration, dose and host factors

Therapeutic deep X-ray radiotherapy (DXT) works because tumour cells tend to divide more rapidly than normal tissue

Radiation effects are cumulative.

Delivering divided doses (fractionating) and converging on tumour from different angles, DXT to tumour is maximised, but normal tissue damage is minimised

Immediate : High doses (e.g. 2000 rads) cause convulsion, coma and death within 1 day

Acute/subacute (hours /days-weeks)

Cerebral oedema, diarrhoea, dehydration, septicaemia (from gut breakdown), bone marrow failure

Long-term (months/years/decades) effects.

Fibrosis: strictures of small bowel, pericardial fibrosis, interstitial fibrosis of lung or kidney, spinal cord damage.

Mutation: Cancers: carcinoma (e.g. breast or thyroid), bone marrow derived cells (e.g. leukaemia, lymphoma), soft tissue (sarcomas)

Pregnancy:

In utero exposure: may cause fetal growth/mental retardation, microcephaly or hydrocephaly.

Future pregnancies in survivors: no radiation effects found

Environmentalpollution

Air,soilandwaterareallliabletocontamination(seediagram). Airpollutionisamajorcauseofmortalityandmorbiditydue toasthma,chronicobstructivepulmonarydisease(COPD),lung cancer,myocardialinfarction(MI),stroke,andneurodegenerative andskindisorders.Globally,morethan6millionannualdeathsare attributedtoairpollution.

Physicalagents

Electrocution

ElectrocutionbylightningorcontactwithDCorACcurrentsfrom thedomesticelectricitysupplyoftencausescharringoftheskinat theentry(e.g.handorhead)andexit(e.g.foot)points.Thedamage isrelatedtothetypeofshockandtheresistanceofthetissue.Muscle tetanymayrenderthesubjectunabletoletgoofafaultyelectrical wireorsocket.Electricalcurrentsareconductedthroughthebody bestbyfluidswithhighioncontent,i.e.blood,nervesandtissue fluids.Inelectricallyresistanttissue,suchasfat,boneortendon,the heatgeneratedcancausesevereburnsandjointsareoftendamaged. CNSinjuryislikelyiftheheadisstruckbylightningforexample,or currentpassingacrossthebodymaycausecardiacarrhythmiasand suddendeath.Electrocutioncancauserespiratoryarrest,seizures andrhabdomyolysis.Therapeutically,aDCshockappliedtothe praecordiumtotreatventricularfibrillationduringcardiacarrest mayshocktheheartbackintosinusrhythm.

Extremes oftemperature

Cellularhomeostasisdependsontemperature-sensitiveenzyme reactionsandthemaintenanceofionconcentrationswithinafairly narrowrangeofnormalvalues.Thenormalcoretemperatureis maintainedbythehypothalamusandisregulatedbyinterleukin (IL)-1releasefrommacrophagesandlocalprostaglandinproduction.Heatisgeneratedbymuscleandmetabolicactivitywithinthe bodyandislostthroughtheskin,sweatandbreath.

Excessheat:Heatexhaustion(coretemperature37–40∘ Cwith dizziness,headache,thirst,malaiseandnausea)requiresrehydrationandcooling.Leftuntreateditmayprogresstoamedical emergency, heatstroke (coretemperature40–42∘ Cwithsevereconfusion,problemswithcardiacfunctionandrespiration);42.5∘ C isvirtuallyalwaysfatal.Thecausemaybeincreasedheatgeneration(e.g.exercise),aninabilitytoloseheat(e.g.clothingor medication)oradisturbanceofhypothalamicthermalregulatory mechanisms.Thebodyrespondsbyprofoundvasodilatation.

Burns:Causedamagebycoagulatingtheskinandvariableamounts ofsubcutaneoustissue.Lipidmembranesmelt,enzymesdenature andproteinsprecipitate.Burnsareclassifiedasfirst,secondor thirddegreeaccordingtothedepthoftissuedamagedandthe surfaceareaofthebodyaffected.Plasmaandtissuefluidleak fromthesurfacesoftheburnedareasandmaycausehypovolaemic shockif >70%ofthebodysurfaceisinvolvedwiththird-degree burns.Thelossofvitalproteinmoleculesintheexudateimpairs theacuteinflammatoryresponseandhealing.Inhalationoffireand smokedamagestherespiratorytractmucosaandthealveolarwalls, causingacuterespiratorydistresssyndrome.Thedamagingeffectof heatisutilisedinradiofrequencyablation.

Cold:Hypothermiaoccurswhenthecoretemperaturedropsto 35∘ C.Ifshiveringandincreasedmuscleactivityfailtohaltthefall intemperature,respirationrate,pulse,bloodoxygenationandtissue perfusiondecreases.Bloodsludgesasplasmaislostbycold-induced diuresisandleakyendothelium.Thepatientbecomesconfused, thendeeplyunconscious.Deathisusualby28∘ C.

Suddenexposuretoextremecold,asseeninfrostbite,causes hypothermicdamagetoexposedorlesswell-perfusedparts,such asfingers,noseortoes.Thefluidinthecapillaries,cellsandtissues freezesandtherebyincreasesthevolumeofthecells.Theplasma membranesrupture,asdothoseoftheorganelles.Thereisgangrenousischaemicnecrosisoftheextremities.Treatmentisbygradualwarming.Oftentheextentofthedamageislessthaninitially feared,sodelayhastyamputation.

Perfusionwithcooledbloodreducesmetabolicdemandsand complicationsduringcardiactransplantsurgery.Thetransplanted heartwillhavebeentransportedtothedonor’shospitalinasupercooledstatetoreducetissuedeterioration.

Radiation

Radiationcausesionisationofmoleculesintissuefluid,forming freeoxygenradicals(reactiveoxygenspecies)whichdamagetissues. Risksarerelatedtothetype,extentandcumulativedoseofradiationandthetissuesexposedtoit(seediagram).

Chemicalagents

Exposuretostrongacidoralkalirupturescellmembranes,producingcellandtissuenecrosisandcapillarydamagewithleakageof bloodintotissues.Theeffectscanmimicburns.Healingofextensive woundsisoftenbyscarring.

Manyindustriesgenerateharmfulsubstancesasby-products. Somechemicalsreactwithcellularconstituentsorarealtered bynormalmetabolicpathwaystocreatetoxicmetabolites,for example:

•Conjugationwithglucuronidemayrenderamoleculesafeuntil itisexcretedbythekidney,whentheglucuronideisconservedand theurinaryepitheliumisexposedtothetoxicmetabolite.

•Volatileorganiccompounds(VOCs),e.g.polycyclicaromatic hydrocarbons(PAHs),aregeneratedbythepetrochemicalindustryorbycombustionoftars(e.g.soot)andalsofoundincigarette smoke.WhenconvertedtoepoxidesbycytochromeP450theycan bindandmutateDNA.SootwaslinkedtoscrotalcancerinchimneysweepsbyPercivalPottin1775.Smoking-relatedPAHsare stronglylinkedtothedevelopmentoflungcancer.

•Vinylchloridemonomers,producedduringPVCmanufacture, maygeneratechloracetaldehydewhenmetabolisedbyhepatic cytochromeP450;thiscanbindandmutateDNA.

CancertreatmentemploysdrugsthatinterferewithDNAreplicationtoattackdividingcells,workingonthepremisethatmore tumourthannormalcellsareusuallyproliferatingatanyone time,e.g.cyclophosphamidealkylatesDNAandcausesnonsense mutations.

Water

Deathbydrowningisduetoasphyxia.Diatomsfromthewater enterthebloodandtissues.Deathisfourtofivetimesfaster infreshwaterthansaltwaterbecausethehypotonicfresh-water

solutionthatentersthebloodviathepulmonarycapillarybed causeshaemodilution,withlowchlorideandpotassiumlevels,and laterhyperkalaemiaduetoredcelllysis.Seawatermaybealmost isotonic,althoughusuallyitishypertonicandthebloodchloride levelisincreased,buthaemolysisdoesnotoccur,andthusresuscitationeffortshavemorechanceofsuccessinpeoplerescuedfromthe

sea.Peoplewhosurvivenear-drowningmaydeveloppneumonitis fromorganismsindirtywater.

Infectiousagents

Inordertocausedamage,organismsmustevadethebody’sprimary defencesandenterthetissues(seeChapter16).

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