epidemiologicalk12818.com

REVIEWOpenAccessH.
pyloriinfectionandextra-gastroduodenaldiseasesFeng-WoeiTsay1,2andPing-IHsu1*AbstractHelicobacterpyloriinfectionistheprincipalcauseofpepticulcerdisease,gastricadenocarcinomaandgastricmucosa-associatedlymphoidtissuelymphoma.
Recentstudieshaveshownthatitmayinterferewithmanybiologicalprocessesanddetermineorinfluencetheoccurrenceofmanydiseasesoutsidethestomach.
Currently,theroleofH.
pyloriinidiopathicthrombocytopenicpurpuraandirondeficiencyanemiaiswelldocumented.
EmergingevidencesuggeststhatitmayalsocontributetovitaminB12deficiency,insulinresistance,metabolicsyndrome,diabetesmellitusandnon-alcoholicliverdisease.
Additionally,itmayincreasetheriskofacutecoronarysyndrome,cerebrovasculardisease,neurodegenerativediseaseandothermiscellaneousdisorders.
Differentpathogenicmechanismshavebeenhypothesized,includingtheoccurrenceofmolecularmimicryandtheinductionofalow-gradeinflammation.
Thisreviewsummarizestheresultsofthemostrelevantstudiesontheextra-gastroduodenalmanifestationsofH.
pyloriinfection.
Keywords:Helicobacterpylori,Irondeficiencyanemia,IdiopathicthrombocytopenicpurpuraandvitaminB12deficiencyBackgroundHelicobacterpyloriinfectionistheprincipalcauseofchronicgastritis,gastriculcer,duodenalulcer,gastricadenocarcinomaandgastricmucosa-associatedlymphoidtissuelymphoma[1,2].
Inrecentdecades,manyarticleshavepublishedonthefascinatingtopicofextragastroduo-denalmanifestationsofH.
pyloriinfection,includinghematological,metabolic,cardiovascular,neurodegenera-tiveandallergicdisorders[3–13].
Differentpathogenicmechanismshavebeenhypothesized,includingtheoccur-renceofmolecularmimicryandtheinductionofalow-gradeinflammation.
Indeed,H.
pyloriinfectionisaverygoodmodelforstudyinghost-bacterialinteractionsandveryattractiveforthoseinterestedintheroleofgutmicrobiotainhealthanddiseases.
Here,wesummarizetheresultsofthemostrelevantstudiesontheextragastro-duodenalmanifestationsofH.
pyloriinfection.
IrondeficiencyanemiaThelinkbetweenIrondeficiencyanemia(IDA)andH.
pyloriinfectionwasreportedfirstlyin1991byBleckeretal.
,whocuredIDAofa15year-oldfemalepresentingwithanemia-relatedsyncopeandH.
pylori-inducedchronicactivehemorrhagicgastritisbyeradicationtherapywithoutironsupplements[14].
TheassociationofH.
pyloriinfectionwithunexplainedIDAhasbeenproveninadultandpediatricpopulations[15,16]thoughafewinvestigationsdidn'tshowthislink[17,18].
Recently,Quetal.
conductedameta-analysisof15case-controlstudiestoinvestigatetherelationbetweenH.
pyloriinfectionandIDA[19].
H.
pyloriinfectionwasdiagnosedbyendoscopyandhistologicalexaminationinfivestudies,inwhichpatientswithpepticulcerdiseaseandgastriccancerwerenotincluded.
Theother10studiesconfirmedH.
pyloriinfectionbyserologyorureabreathtest.
ThedatashowedanincreasedriskofIDAinpatientswithH.
pyloriinfectionwithanoddsratio(OR)of2.
2(95%confidenceinterval[CI]:1.
5–3.
2)[19].
SeveralworksalsodemonstratedrecoveryfromIDAbysuccessfuleradicationofH.
pyloriwithoutironsupplements[20].
Yuanetal.
performedameta-analysisof16randomizedcontrolledtrialsinvolving956patientstoassessthe*Correspondence:williamhsup@yahoo.
com.
tw1DivisionofGastroenterologyandHepatology,DepartmentofInternalMedicine,KaohsiungVeteransGeneralHospitalandNationalYang-MingUniversity,386TaChung1stRoad,Kaohsiung813,Taiwan,RepublicofChinaFulllistofauthorinformationisavailableattheendofthearticleTheAuthor(s).
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TsayandHsuJournalofBiomedicalScience(2018)25:65https://doi.
org/10.
1186/s12929-018-0469-6impactofH.
pylorieradicationtherapyonIDA[21].
Inthiswork,thediagnosisofH.
pyloriinfectionwasbasedonrapidureasetestorhistologyineightstudies,inwhichpatientswithpepticulcerdiseasewereexcluded.
TheothereightstudiesconfirmedH.
pyloriinfectionbyureabreathtest.
Thefollow-uptimeinthesestudiesrangedfrom1to3months.
Thedifferencefrombaselinetoend-pointofhemoglobin,serumiron,andserumferritininthemeta-analysiswasstatisticallysignificantlydifferentbe-tweenanti-H.
pyloritreatmentplusoralironandoralironalone(differences:Hb,1.
48g/dL;serumiron:1.
15mol/L;serumferritin,1.
84ng/mL)[21].
H.
pyloricausesIDAbyseveralmechanisms.
First,in-creasedironlosscanbeduetohemorrhagicgastritis,pepticulcerdiseaseandgastricadenocarcinoma[22].
Second,CagAproteinofH.
pylorihasbeenshowntoparticipateinironacquisitionfrominterstitialholotrans-ferrin[23].
IronuptakebyH.
pyloriisenhancedduringthegrowthofthebacteria[24].
Third,H.
pylori-relatedcorporalgastritismaydecreaseacidsecretionduetoglandatrophyandresultsinthereductionofironabsorptionfromdiet[25].
Insummary,theassociationofH.
pyloriandIDAhasbeenconclusivelyproveninnumerousstudies.
Currentinternationalandnationalguidelinesrecommenderadi-cationofH.
pyloriinfectioninpatientswithunexplainedIDA[26,27].
ImmunethrombocytopenicpurpuraGasbarrinietal.
reportedthefirstcaseofH.
pyloriinfec-tionassociatedwithimmunethrombocytopenicpurpura(ITP)in1998[28].
AnobservationstudyfromJapanalsofoundagoodplateletresponseinITPpatientstreatedbyH.
pylorieradication[29].
ArandomizedcontrolledtrialbyBritoetal.
revealedthatH.
pylorieradicationresultedinasignificantplateletresponseinchildrenandadolescentsaffectedbyITP[30].
TheroleofH.
pyloriinfectioninITPhasalsobeenconfirmedbyseveralotherstudies[31,32].
Nonetheless,somestudiesfromcountrieswithlowprevalenceofinfection,likeFranceandtheUnitedStates,didnotfindthelinkbetweenH.
pyloriinfectionandITP[33,34].
Recently,Stasietal.
conductedameta-analysisof25studiestoinvestigatetheimpactofanti-H.
pyloritherapyonITP[34].
Theassessingtimeforplateletresponserangedfromonetosixmonths.
Thedatashowedthattheratesofcompleteresponse(plateletcount≧100*109/L)andoverallre-sponse(plateletcount≧30*109/Landatleastdoublingofthebasalcount)aftersuccessfuleradicationofH.
pyloriwere42.
7and50.
3%,respectively[35].
ThepredictorsofagoodresponsetoeradicationtherapywerecountrieswithhigherprevalenceofH.
pyloriinfec-tion(suchasJapanandItaly)andpatientswithmilderdegreeofthrombocytopenia[35].
InthemajorityofITPpatientsrespondingtoanti-H.
pyloritherapy,thedur-abilityofplateletresponseismorethan7years,indicat-ingthediseaseiscured[36].
Anothermeta-analysisbyArnoldetal.
performedameta-analysistodeterminetheeffectofH.
pylorieradicationtherapyinpatientswithITPbycomparingtheplateletresponseinITPpatientswithandwithoutH.
pyloriinfection[37].
Theoddsofachievingaplateletcountresponsefollowingeradicationtherapywere14.
5higher(95%CI:4.
2to83.
0)inpatientswithH.
pyloriinfectionthaninthosewithoutinfection(responserate:51.
2%vs.
8.
8%).
ThesefindingsstrengthenthecausalassociationbetweenH.
pyloriinfectionandITP.
SeveralmechanismsregardingH.
pylori-associatedITPhavebeenproposed[38].
Oneintriguinghypothesisconcerningmolecularmimicryisthatcross-reactiveantibodiesareproducedthatreactbothH.
pyloricomponentsandplateletsurfaceantigens.
Takahashietal.
showedthatplateletelutesfromH.
pylori-infectedITPpatientsrecognizedCagAproteininimmunoblots,butthosefromH.
pylori-infectednon-ITPpatientsdidnot[39].
Baietal.
alsoreportedthatmono-clonalantibodiesgeneratedagainstH.
pyloriureaseBreactwithGPIIb/IIIaexpressedontheplateletsurface[40].
Whilethesefindingssuggestmolecularmimicrybe-tweenH.
pyloricomponentsandplateletsurfaceantigens,theexactpathogenicrolesofthesecross-reactiveanti-bodiesremainobscure.
Inanotherpotentialmechanism,H.
pyloriinfectionmayalterFcγreceptorbalanceofmon-cytes/macrophagesandinduceautoantibodyformation.
ArecentstudyshowedthattheFcγRIIBexpressiononcir-culatingmonocyteswasdown-regulatedinH.
pylori-in-fectedITPpatients[41].
Therefore,H.
pylorimayalterFcγreceptorbalanceofmoncytes/macrophagesthroughdownregulationoftheinhibitoryreceptorFcγRIIB.
Inconclusion,manystudiessupporttheassociationbetweenH.
pyloriinfectionandITP.
Currentinter-nationalandnationalguidelinesrecommendthatH.
pyloriinfectionshouldbesoughtandtreatedinpatientswithITP[27].
VitaminB12deficiencyThelinkbetweenvitaminB12deficiencyandH.
pyloriinfectionwasreportedfirstlyin1984byO'Connoretal.
whoshowedCampylobacter-likeorganismsinpatientswithtypeAgastritisandperniciousanemia[42].
StudieshavedemonstratedalinkbetweenchronicH.
pyloriin-fectionandmalabsorptionofvitaminB12[43].
Sararietal.
showedthatvitaminB12deficiencywaspresentin67.
4%(29/43)ofthepatientswithH.
pyloriinfection[44].
Shuval-Sudaietal.
foundahigherprevalenceofH.
pyloriinfectioninpatientsatthelowerendofthenor-malrangeofserumvitaminB12levels[45].
However,moststudiesregardingtheassociationbetweenvitaminB12andH.
pyloriinfectionfocusontestingH.
pyloriTsayandHsuJournalofBiomedicalScience(2018)25:65Page2of8statusandmeasuringserumlevelsofvitaminB12.
Noadequateinterventionalstudiesprovingtheeffectofanti-H.
pyloritherapyonvitaminB12deficiencyexist.
Metabolicsyndromeanddiabetesmellitus(DM)Manyepidemiologicalstudieshavesupportedalinkbetweeninsulinresistance,metabolicsyndromeandH.
pyloriinfection[46,47].
Chenetal.
demonstratedthatH.
pylori-infectedsubjectshadahigherprevalenceofmetabolicsyndromethanthosewithoutH.
pyloriinfec-tion[48].
Additionally,Yangetal.
showedasignificantassociationbetweenH.
pyloriinfectionandDM[49].
Similarresultswerealsoobservedbyotherinvestigators[50].
Furthermore,Horikawaetal.
revealedthatH.
pyloriinfectionworsenedglycemiacontrolindiabeticpatients[51].
Polyzosetal.
conductedasystemicreviewinclud-ingninestudiesandshowedatrendtowardapositiveassociationbetweenH.
pyloriinfectionandinsulinresistance[47].
Incontrast,severalstudiesdidnotfindthelinkbetweenH.
pyloriinfectionandinsulinresistanceormetabolicsyndrome[52].
Najaetal.
showednoassoci-ationbetweenH.
pyloriinfectionandmetabolicsyndromeinaLebanesepopulation[53].
Ameta-analysisof18stud-iesfoundnostrongcorrelationbetweenH.
pyloriinfectionandserumconcentrationsoftotalcholesterolandtrigly-ceride[54].
Wadaetal.
alsofoundthatsuccessfuleradica-tionofH.
pyloricouldnotimproveglucosecontrolofDMinJapanesepatients[55].
Furthermore,arecentrandom-izedcontrolledtrialinvolving49H.
pylori-infectedsubjectsinaprediabetesstageshowedthatH.
pylorieradi-cationresultedinanincreasedHomeostaticmodelassess-mentofinsulinresistance(HOMA-IR)[56].
SeveralstudiesreportedareverselinkbetweenH.
pyloriinfectionandobesity[57–60].
Acase-controlstudyfromTaiwandemonstratedaninverserelationshipbetweenmorbidobesityandH.
pyloriseropositivity[57].
AnecologicalstudyalsoshowedaninversecorrelationbetweenH.
pyloriprevalenceandrateofoverweight/obesityincountriesofthedevelopedworld[58].
However,alargecase-controlstudyincluding8820participantsfromChinashowedbodymassindexwassignificantlyandpositivelyassociatedwithH.
pyloriin-fection[59].
AninterventiontrialdemonstratedserumghrelinconcentrationswereinverselyrelatedtotheseverityofH.
pylori-associatedgastritisinprepubertalchildren[60].
EradicationofH.
pyloriinfectionresultedinasignificantincreaseinbodymassindexalongwithasignificantdecreaseincirculatingghrelinlevelsandanincreaseinleptinlevels[60].
Insummary,theissueoftheassociationbetweenH.
pyloriinfectionandmetabolicsyndromeorDMremainscontradictory.
Nonalcoholicfattyliverdisease(NAFLD)AcohortstudybyKimetal.
demonstratedthatthesub-jectswithH.
pyloriinfectionhadahigherincidenceofNAFLDthanthosewithoutinfection(hazardratio:1.
21[95%CI:1.
1–1.
3])[61].
Polyzosetal.
alsorevealedthatpatientswithNAFLDhadhigheranti-H.
pyloriIgGtiters,togetherwithlowercirculatingadiponectinandhighertumornecrosisfactor-αlevels,comparedtonon-NAFLDsubjects[62].
However,oppositeresultsfromKoreaandJapanshowednoassociationbetweenH.
pyloriinfectionandNAFLD[63,64].
Recently,ameta-analysisdemonstratedasignificantlyincreasedriskofNAFLDinpatientswithH.
pyloriinfection[65].
Nonetheless,themechanismunderlyingtheassociationbetweenH.
pyloriinfectionandNAFLDremainsunclear,andinterventionalstudiesprovingtheeffectofanti-H.
pyloritherapyonNAFLDarefairlylimited.
Insummary,theassociationbetweenH.
pyloriinfec-tionandNAFLDremainscontradictory.
Coronaryarterydisease(CAD)Mendalletal.
firstshowedalinkbetweenH.
pyloriandCADin1994[66].
SeveralstudiesreportedthatCagA-postivestrainsofH.
pyloriwereassociatedwithatherosclerosis[67–69].
Al-GhamdietalfoundthatH.
pyloriplaysanimportantroleinthedevelopmentofCADbyalteringthelipidprofileandenhancementofchronicinflammation[70].
Figuraetal.
alsorevealedthatCagA-postivestrainsofH.
pyloriwereassociatedwithhighserumlevelsofinterleukin-6andB-typenatri-ureticpeptideinpatientswithCAD[71].
AnationwideretrospectivecohortstudydemonstratedthatH.
pyloriinfectionincreasedtheriskofacutecoronarysyndrome[72].
Inaddition,ameta-analysisof26studiesinvolvingmorethan20,000patientsalsoshowedasignificantas-sociationbetweenH.
pyloriinfectionandtheriskofmyocardialinfarction(OR:2.
10;95%CI:1.
8–2.
5)[73].
HoweversomestudiesfromIndianandGermandidnotfindtheassociationbetweenH.
pyloriandCAD[74,75].
Additionally,therearestillnointerventionalstudiesprovingthebeneficialeffectofH.
pylorieradicationindecreasingtheincidenceofCAD.
ThereareseveralproposedmechanismsunderlyingtheassociationbetweenH.
pyloriinfectionandCAD.
H.
pylorihasbeendetectedinhumancarotidatheroscler-oticplaques[76].
Oshimaetal.
demonstratedtheassoci-ationofH.
pyloriinfectionwithsystemicinflammationandendothelialdysfunctioninhealthymalesubjects[77].
TheyproposedthatH.
pyloriinfectionmaycauseatherogenesisthroughpersistentlow-gradeinflamma-tion.
Recently,molecularmimicrybetweenCagAantigenofH.
pyloriandatheroscleroticplaquepeptideshasalsobeenproposedasapossiblemechanism[78].
TsayandHsuJournalofBiomedicalScience(2018)25:65Page3of8Inconclusion,thereiscontroversialevidencelinkingH.
pyloriinfectionandCAD.
NoadequateinterventionaltrialsdemonstratingalowerincidenceofCADasaresultofanti-H.
pyloritherapyexit.
CerebrovasculardiseaseWincupetal.
firstreportedalinkbetweenH.
pyloriinfectionandstrokein1996(OR=1.
57,95%CI0.
95to2.
60)[79].
AMexicanstudyfoundthatlevelsofantibodiestoH.
pyloripredictincidentstrokeinfullyadjustedmodels(OR:1.
58;95%CI:1.
1to2.
3)[80].
Recently,Wangetal.
performedameta-analysisof4041Chinesepatients,andfoundanassociationbetweenH.
pyloriinfectionandnon-cardioembolicstroke[81].
However,acohortstudyof9895casesfromtheUnitedStatesfoundareverselinkbetweenH.
pyloriinfectionandstrokemortality,andthisreverseassociationwasstrongerforH.
pyloricagApositivity[82].
Insummary,thereiscontroversialevidencelinkingH.
pyloriinfectionandcerebrovasculardisease.
OthermiscellaneousdisordersSomestudiesalsodisclosedtherelationshipofH.
pyloriwithdementiaandAlzheimer'sdisease(AD)[83,84].
AstudyinGreecebyKountourasetal.
foundhigherprevalenceofH.
pyloriinfectioninpatientswithADthaninthecontrolgroup[85].
Hungetal.
designedastudyfortherelationshipbetweenH.
pyloriinfectionandnon-Alzheimer'sdementia(non-AD)usinganation-widepopulation-baseddatasetinTaiwan,andfoundthatpatientswithH.
pyloriinfectionwere1.
6-foldmorelikelytodevelopnon-ADthanthosewithoutinfection[83].
AretrospectivecohortstudyusingnationwidedatabaseinTaiwanshowedthateradicationofH.
pyloriwasassociatedwithadecreasedprogressionofdementiaascomparedtonoeradicationofH.
pyloriinADpa-tientswithpepticulcers[86].
However,furtherprospect-iverandomizedcontroltrialsareneededtoclarifythesefindings.
TheinverserelationshipbetweenH.
pyloriinfectionandallergicasthmahasbeenreported.
Ameta-analysisbyZhouetal.
.
.
in2013foundlowerprevalencerateofH.
pyloriinfectioninpatientswithallergicasthma[87].
HigherprevalencerateofH.
pyloriinfectionhasbeenfoundincirrhoticpatientswithhepatoencephalopathythaninthosewithouthepatoencephalopathy[88].
JaingetalalsoshowedtheassociationofH.
pyloriinfectionwithelevatedbloodammonialevelsincirrhoticpatientsFig.
1ThepossiblemechanismfortheassociationbetweenH.
pyloriinfectionandextra-gasroduodenaldiseasesTsayandHsuJournalofBiomedicalScience(2018)25:65Page4of8Table1TherelevantstudiesontheassociationsbetweenH.
pyloriinfectionandextra-gastroduodenaldiseasesExtra-gastroduodenaldiseaseKeyevidencesConclusion1Irondeficiencyanemia(IDA)Pros:1.
Quetal.
[19]:anincreasedriskofIDAinpatientswithH.
pyloriinfection(meta-analysisofcase-controlstudies).
2.
Yuanetal.
[21]:EradicationofH.
pyloricouldimprovethelevelsofhemoglobinandserumferritininpatientswithIDA(meta-analysisofinterventiontrials).
Cons:1.
Sandstrometal.
[18]:noassociationbetweenH.
pyloriinfectionandIDAinfemaleadolescents(case-controlstudy).
EradicationofH.
pyloriinfectionisrecommendedforpatientswithunexplainedIDA.
2Immunethrombocytopenicpurpura(ITP)Pros:1.
Stasietal.
[35]:Theoverallresponserateofincreasedplateletcountwas50.
3%aftersuccessfuleradicationofH.
pyloriinITPpatients(meta-analysisofinterventiontrials).
2.
Arnoldetal.
[37]:Theoddsofachievingaplateletcountresponsefollowingeradicationtherapywere14.
5higherinITPpatientswithH.
pyloriinfectionthaninthosewithoutinfection(responserate:51.
2%vs.
8.
8%)(meta-analysisofinterventiontrials).
Cons:1.
Micheletal.
[34]:SeroprevalenceofH.
pyloriinpatientswithITPwasnotsignificantlydifferentfromthatincontrolsubjects(case-controlstudy).
H.
pyloriinfectionshouldbesoughtandtreatedinpatientswithITP.
3VitaminB12deficiencyPros:1.
Sararietal.
[44]:TherewassignificantassociationbetweenthepresenceofH.
pyloriinfectionandvitaminB12deficiency(case-controlstudy).
2.
Shuval-Sudaietal.
[45]:PrevalenceofH.
pyloriseropositivitywassignificantlyhigheramongsubjectswithborderline(>145–180pg/mL)orlownormal(>180–250pg/mL)vitaminB12levelsthanamongthosewithvitaminB12>250pg/mL(case-controlstudy).
H.
pyloriinfectionisassociatedwithvitaminB12deficiency.
4Metabolicsyndromeanddiabetesmellitus(DM)Pros:1.
Chenetal.
[48]:H.
pylori-infectedsubjectshadahigherprevalenceofmetabolicsyndromethanthosewithoutH.
pyloriinfection(case-controlstudy).
2.
Yangetal.
[49]:H.
pyloriinfectionwasassociatedwithriskofDM(case-controlstudy).
Cons:1.
Najaetal.
[53]:noassociationbetweenH.
pyloriinfectionandmetabolicsyndrome(case-controlstudy).
2.
Wadaetal.
[55]:TheeradicationofHelicobacterpyloridoesnotaffectglycemiccontrolinJapanesesubjectswithtype2diabetes(interventiontrial).
TheassociationbetweenH.
pyloriinfectionandmetabolicsyndromeorDMiscontradictory.
5Nonalcoholicfattyliverdisease(NAFLD)Pros:1.
Kimetal.
[61]:ThesubjectswithH.
pyloriinfectionhadahigherincidenceofNAFLDthanthosewithoutinfection(cohortstudy).
2.
Wijarnpreechaetal.
[65]:asignificantlyincreasedriskofNAFLDinpatientswithH.
pyloriinfection(meta-analysisofcase-controlstudies).
Cons:1.
Okushinetal.
[63]:noassociationbetweenH.
pyloriinfectionandNAFLD(case-controlstudy).
TheassociationbetweenH.
pyloriinfectionandNAFLDremainscontradictory.
6Coronaryarterydisease(CAD)Pros:1.
Yuetal.
[73]:significantassociationbetweenH.
pyloriinfectionandtheriskofmyocardialinfarction(meta-analysisofcase-controlstudies).
Cons:1.
Schottkeretal.
[75]:noassociationbetweenH.
pyloriinfectionandtheriskofCAD(cohortstudy).
TheassociationbetweenH.
pyloriinfectionandCADiscontradictory.
TsayandHsuJournalofBiomedicalScience(2018)25:65Page5of8[89].
SeveralstudieshavealsoreportedthatH.
pyloriinfectionincreasestheriskofcolonadenocarcinomaandadenoma[90–92].
Recently,anassociationbetweenH.
pyloriinfectionandchronicspontaneousurticariahasbeenreportedbutremainscontroversial.
Fukudaetal.
demonstratedasignificantimprovementofchronicspontaneousurticariabyanti-H.
pyloritherapyinJapa-nesepatients[93].
Thisworkwasconsistentwithasys-temicreviewof10studiesbyFedermanetal.
[94].
However,Moreiraetal.
didnotfindtheassociationbetweenH.
pyloriinfectionandchronicspontaneousurticaria[95].
Insummary,therearestillcontroversialevidenceslinkingH.
pyloriinfectionandaforementionedmiscel-laneousdisorders.
Adequateinterventionaltrialsareneededtoclarifytheseassociations.
ConclusionsRecentstudieshaveshownthatH.
pylorimayinterferewithmanybiologicalprocessesanddetermineorinflu-encetheoccurrenceofmanydiseasesoutsidethestom-ach(Table1andFig.
1).
Currently,itsroleinITPandIDAiswelldocumented.
EmergingevidencesuggeststhatitmayalsocontributetovitaminB12deficiency,in-sulinresistance,metabolicsyndrome,diabetesmellitusandnon-alcoholicliverdisease.
Additionally,itmayalsoincreasetheriskofacutecoronarysyndrome,cerebro-vasculardisease,andneurodegenerativedisease,H.
pyl-oriinfectionisaperfectmodelforthestudyofinterplaybetweenhumanbeingsandbacteria.
Furtherstudiesaremandatorytoclarifythepathogenesisofextragastroduo-denaldiseasesinducedbyH.
pyloriinfection.
AbbreviationsAD:Alzheimer'sdisease;CI:Confidenceinterval;DM:Diabetesmellitus;IDA:Irondeficiencyanemia;ITP:Immunethrombocytopenicpurpura;NAFLD:Nonalcoholicfattyliverdisease;OR:OddsratioAuthors'contributionsDrs.
PIHandFWTreviewedthearticlesandwrotethemanuscript.
Bothauthorsreadandapprovedthefinalmanuscript.
EthicsapprovalandconsenttoparticipateNotapplicable.
ConsentforpublicationNotapplicable.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Publisher'sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
Authordetails1DivisionofGastroenterologyandHepatology,DepartmentofInternalMedicine,KaohsiungVeteransGeneralHospitalandNationalYang-MingUniversity,386TaChung1stRoad,Kaohsiung813,Taiwan,RepublicofChina.
2ChengShiuUniversity,Kaohsiung,Taiwan,RepublicofChina.
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