Review Article Lactose.docx

Review Article Lactose.docx

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ReviewArticleLactose

ReviewArticle:

LactoseIntoleranceinClinicalPractice–MythsandRealities

M.C.E.Lomer,G.C.Parkes,J.D.Sanderson

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