Review Article LactoseWord下载.docx
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Review Article LactoseWord下载.docx
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AlimentPharmacolTher.2008;
27
(2):
93-103.
Background:
Approximately70%oftheworldpopulationhashypolactasia,whichoftenremainsundiagnosedandhasthepotentialtocausesomemorbidity.However,noteveryonehaslactoseintolerance,asseveralnutritionalandgeneticfactorsinfluencetolerance.
Aims:
Toreviewcurrentclinicalpracticeandidentifypublishedliteratureonthemanagementoflactoseintolerance.
Methods:
PubMedwassearchedusingthetermslactose,lactaseanddiettofindoriginalresearchandreviews.Relevantarticlesandclinicalexperienceprovidedthebasisforthisreview.
Results:
Lactoseisfoundonlyinmammalianmilkandishydrolysedbylactaseinthesmallintestine.Thelactasegenehasrecentlybeenidentified.'
Wild-type'
ischaracterizedbylactasenonpersistence,oftenleadingtolactoseintolerance.Twogeneticpolymorphismsresponsibleforpersistencehavebeenidentified,withtheirdistributionconcentratedinnorthEuropeans.Symptomsoflactoseintoleranceincludeabdominalpain,bloating,flatulenceanddiarrhoea.Diagnosisismostcommonlybythelactosehydrogenbreathtest.However,mostpeoplewithhypolactasia,ifgivenappropriateadvice,cantoleratesomelactose-containingfoodswithoutsymptoms.
Conclusion:
Inclinicalpractice,somepeoplewithlactoseintolerancecanconsumemilkanddairyfoodswithoutdevelopingsymptoms,whereasotherswillneedlactoserestriction.
Lactoseintoleranceiswidespreadthroughouttheworldandsubjectsusuallyavoidmilkanddairyproductstoimprovesymptoms.Thedisaccharidelactoseisauniquecarbohydratepresentonlyinmammalianmilk,7.2g/100mLinmaturehumanmilk,4.7g/100mLincow'
smilkbutisnegligibleinthemilkofsomemarinemammals.[1]Foreffectiveutilization,lactoserequireshydrolysisbytheenzymelactaseand,duringinfancy,providesanexcellentsourceofenergyatatimeofrapidgrowthanddevelopment.Anenhancedunderstandingoflactaseanditsdeficiencyandwhythereisaspecialcarbohydrateinmilkisimportantforimprovedmanagementoflactoseintolerance.
Theenzymelactase-phlorizinhydrolase,morecommonlyknownaslactase,isaß
-galactosidaseresponsibleforthehydrolysisoflactosetothemonosaccharides,glucoseandgalactose.Theseareabsorbedbyintestinalenterocytesintothebloodstream(Figure1),glucoseisultimatelyutilizedasasourceofenergyandgalactosebecomesacomponentofglycolipidsandglycoproteins.Theenzymehastwoactivesites,onehydrolysinglactoseandtheotherphlorizin(anarylα-glucoside)andarangeofdietaryglycolipids.[2]Anumberofactionsofthephlorizinsiteareusefulinhumansandthisexplainswhysomeenzymeactivityisretainedfollowingtheusualdeclineinenzymeexpressionafterweaningfrombreastmilk(seebelow).
Inlactasepersistence,lactase-phlorizinhydrolaseinthebrushborderefficientlyhydrolyseslactoseintogalactose(Gal)andglucose(Glu)andisrapidlyabsorbedintothebloodstreamtakingluminalwaterwithit.Hydrolysistypicallyoccursinthejejunum,whichhaslowconcentrationsofbacteria101-4mL-1;
thus,littlelactoseisfermented.
Lactaseispresentontheapicalsurfaceofenterocytesinthesmallintestinalbrushborderwiththehighestexpressioninthemid-jejunum.ItissecuredbyitsC-terminalendwithmostofthemoleculeprotrudingintothegastrointestinallumen.Theenzymeisproducedasa220kDaprecursorpeptide,whichundergoesconsiderablepost-transcriptionalmodificationduringtransporttothecellsurfaceasthemature150kDaprotein.Luminalfactorsalsocontributetofinalmodificationoftheproteintoproducetheactiveenzymebycleavageoftwofurtheraminoacidsbypancreatictrypsin.[3]
Byweek8ofgestation,lactaseactivitycanbedetectedatthemucosalsurfaceinthehumanintestine.Activityincreasesuntilweek34andbybirth,lactaseexpressionisatitspeak.However,withinthefirstfewmonthsoflife,lactaseactivitystartstodecrease(lactasenonpersistence).Inmostmammals,itdeclinesatvariableratesfollowingweaningtoundetectablelevelsasaconsequenceofthenormalmaturationaldown-regulationoflactaseactivity.[4-6]Inhumans,approximately30%ofthepopulationhascontinuedlactaseactivitybeyondweaningandintoadulthood(lactasepersistence).[7]ThishappensmainlyinpeopleofnorthEuropeandescentandrelatesgeographicallytotheintroductionofdairyfarmingapproximately10000yearsago.[8]RecentanalysisofarchaeologicalDNAsuggeststhatgeneticlactasepersistencewasrareinNorthernEuropeanspriortodairyfarming.Theso-called'
culture-historicalhypothesis'
proposesthatthehighprevalenceoflactasepersistenceinNorthernEuropeansoccurredasaresultofamorerecentselectionprocessenablingpopulationstorelyonmammalianmilkasanimportantcomponentofthedietparticularlyattimeofpoorharvest.[9-11]Anopposinghypothesis'
reversecause'
proposedthatdairyfarmingandmilkconsumptionwasadoptedbythosewithpre-existinglactasepersistence[10,12,13]butevidencefromarchaeologicalDNAsuggeststhatthisislesslikely.[14]
Hypolactasia,orlactasedeficiency,existsinthreedistinctforms:
congenital,primaryandsecondary.Congenitallactasedeficiencyisassociatedwiththeleastlactaseactivity.Itisalifelongdisordercharacterizedbyfailuretothriveandinfantilediarrhoeafromthefirstexposuretobreastmilk.Congenitallactasedeficiencyisextremelyrare,withonlyaround40caseshavingbeenreported.Itisasingleautosomalrecessivedisorder,butverylittleisknownaboutthemolecularbasis.[15]Theonlytreatmentiscompleteavoidanceoflactosefrombirth.Lactasenonpersistence(primarylactasedeficiency),asdescribedabove,occursinthemajorityofhumans.Secondaryoracquiredlactasedeficiencyreferstothelossoflactaseactivityinpeoplewithlactasepersistence.Itoccursasaresultofgastrointestinalillnessthatdamagesthebrushborderofthesmallintestine,e.g.viralgastroenteritis,giardiasisorcoeliacdisease.[16,17]Thisisusuallyreversible.
Foreffectiveutilizationoflactosewithoutsymptomsofintolerance,only50%oflactaseactivityisnecessary[15]anditispresentonlyatthelevelthatitisrequired,asisthecaseforotherintestinaldisaccharides.[18]
Formanyyears,itwasthoughtthatlactasepersistenceinhumanswasthe'
wild-type'
pattern.[19]Asthelactasenonpersistencephenotypeisexpressedinothermammals,thisisnowconsideredtobetheancestraltypewhilstlactasepersistenceisbecauseofamutation.
Thelactasegeneisapproximately50kbinsize[20]andlocatedonchromosome2.[21,22]Wild-typeischaracterizedbylactasenonpersistencewhilsttwosinglenucleotidepolymorphisms(SNPs)inthelactasegenehavebeenassociatedwithlactasepersistence.TheseareC/T13910andG/A22018substitutionsoccurring14and22kbupstreamofthe5'
-endofthelactasegeneinaDNAregion,whichfunctionsasacis-actingelementinfluencingthelactasegenepromoter.[15,21,23]StudiessuggestthatC/T13910isthedominantpolymorphismwiththeCallelelinkedtoadeclineinlactasemRNAexpression.However,theexactmechanismofthisdeclineafterweaningisuncertain.[24]
IndividualsheterozygousforeitherSNPhaveintermediatelactaseactivityandaremoresusceptibletolactoseintoleranceattimesofstressorgastrointestinalinfection.[5]Thispolymorphismdoesnotprovideacompleteexplanationasindividualswithhomozygouslactasepersistence(genotypesTTandAA)mayoccasionallydeveloplactoseintolerance(i.e.acquiredlactasedeficiency.[25]Adulthomozygoteswithnonpersistence(CCandGG)havevirtuallyundetectablelevelsofintestinallactaseasaresultofdown-regulationofthebrushborderenzymefollowingweaning.[26]
Hippocratesfirstdescribedlactoseintolerancearound400yearsBC.buttheclinicalsymptomshavebecomerecognizedonlyinthelast50years.[5]Upto70%oftheworldpopulationhaslactasenonpersistence,[5]butnotallareintoleranttolactoseasmanynutritionalandgeneticfactorsinfluencetolerance.[8,27]
Ethnicoriginaffectsthefrequencyoflactoseintolerance.Inadults,whitenorthEuropeans,NorthAmericansandAustralasianshavethelowestratesrangingfrom5%inaBritishpopulationto17%inFinlandandnorthernFrance.InSouthAmerica,AfricaandAsia,over50%ofthepopulationhaslactasenonpersistenceandinsomeAsiancountriesthisrateisalmost100%.[1,4,15,23,28-36]Interestingly,insubjectsfrommixedethnicity,alowerprevalenceoflactasenonpersistenceisobservedwhereahighprevalenceisdetectedinthenativeethnicgroup.[30]
Thedeclineinlactaseexpressionisusuallycompleteduringchildhoodbutthedeclinehasalsobeenreportedtooccurlaterinadolescence.[33]Therateoflossoflactaseactivityalsovariesaccordingtoethnicitybutthephysiologicalexplanationforthisdifferenceintimingiscurrentlyunknown.ChineseandJapaneselose80-90%oflactaseactivitywithin3-4yearsafterweaning,JewsandAsianslose60-70%overseveralyearspostweaningandinwhiteNorthernEuropeansitmaytakeupto18-20yearsforlactaseactivitytoreachitslowestexpression.[5]
Earlystudiesoflactosedigestioninvolvedmeasuringbloodglucoselevelsfollowingalactoseloadof50g,asignificantincreaseinbloodglucoseafter30minindicatinghighlactaseactivity.[15,25]Inresearch,serummeasurementsof13C-labelledlactosefollowinganoraldosehavealsobeenused,butarenotappropriateforuseinclinicalpractice.[37]
Morerecently,lacta
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