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REVISTAROMNDEPEDIATRIE VOLUMULLXII, NR. 2, AN2013130

Adresa de coresponden:Dr. Valeriu V. Lupu, Universitatea de Medicini Farmacie Gr. T. Popa, Str. Universitii, Nr. 16, Iaie-mail: [email protected]

MANIFESTRI EXTRADIGESTIVE ASOCIATEINFECIEI CU HELICOBACTER PYLORI

Drd. Ancua Ignat, Prof. Dr. Marin Burlea, Dr. Valeriu V. Lupu,Drd. Nicoleta Gimiga, Dr. Gabriela Pduraru

Disciplina Pediatrie, Universitatea de Medicini Farmacie Gr. T. Popa, Iai

REZUMAT

Rolul bacteriei Helicobacter pylorin patogeneza bolilor digestive este foarte bine stabilit i cunoscut n prezent,nsultimele cercetri argumenteazimplicarea Helicobacter pylori n producerea unor afeciuni extradigestive.Prevalena infeciei diferde la o zongeograficla alta, fiind n declin n rile dezvoltate i meninndu-se

ncridicatla populaia din rile n curs de dezvoltare. H. pylori determindin partea gazdei un rspuns imuncare implic imunitatea umorali celular. Infecia este localizat la nivelul mucoasei gastrice, dar s-a de-monstrat canumite boli alergice sunt consecina, cel puin la o parte din bolnavi, a infeciei cronice cu H. pylori.Suferinele gastrointestinale manifestate prin greuri, vrsturi, inapeten, dureri epigastrice, pot fiasociate icu tulburri nutriionale. Infecia cu H. pylori se asociazcu anemie, scdere ponderali statural. Bacteria afost identificati la majoritatea pacienilor diabetici cu neuropatie autoimun producnd tulburri electricegastrice, ntrzierea evacurii stomacului, manifestri responsabile de simptomele dispeptice. Conduita tera-peutic corect realizat n cazul pacienilor cu afeciuni extradigestive i o eventual infecie cu H. pyloritrebuie svizeze att tratamentul bolii de bazct i eradicarea eficienta infeciei.

Cuvinte cheie: Helicobacter pylori,manifestri extradigestive, copil

REFERATE GENERALE

3

Helicobacter pylori, ca orice alt bacterie sauvirus, determindin partea gazdei un rspuns imuncare implicimunitatea celulari umoral. Infeciaeste localizatla nivelul stomacului, iar modificrileinflamatorii i imunologice sunt circumscrise aces-tui segment al tubului digestiv. n ultimii ani s-auadus dovezi privind implicarea bacteriei n suferineextragastrice. Manifestrile extradigestive ntlniten cazurile diagnosticate cu gastrite cu H. pyloridemonstreazcinfecia are rsunet nu numai lo-cal, ci i sistemic.

Rspunsul imun al gazdei n cursul infeciei cuH. pylori

Celulele sistemului imun gastric sunt adaptateunei interaciuni cu un numr mare de antigeni. ncondiii experimentale s-a demonstrat c sub in-fluenaH. pyloriagregatele foliculare din mucoasagastriccresc numeric (1).

n cursul infeciei cuH. pylori,celule mononu-cleare din mucoasa gastricproduc anticorpi cito-

toxici din clasa IgG, care, prin activarea leucocitelorpolimorfonucleare neutrofile de ctre complexeleimune, realizeazleziuni epiteliale acute. Celulelesistemului imun prezent n mucoas sunt repre-zentate de: Th, Ts i limfocite B prezente n laminaproprie a mucoasei. n cursul inflamaiei cronicecresc limfocitele intraepiteliale. n vitro,H. pyloriactiveazcelulele NK, induce activarea i maturareamonocitelor derivate din celule dendritice (2). Deifa de bacterie, organismul produce anticorpi,

aceasta nu poate fieliminatdatoritunor structurice-i asigursupravieuirea i i permite sevadezedin reeaua sistemului imun al tubului digestiv.

H. pyloriinduce sinteza localde interferon iTNF(3). n cursul inflamaiei se exprimmoleculede histocompatibilitate clasa II cu rolul n prezen-tarea locala antigenului.

Rspunsul imun celular local este cheia sintezeide anticorpi, generrii de citokine i inducerii lezi-unilor epiteliale. Cauza direct a leziunilor epite-

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REVISTAROMNDEPEDIATRIE VOLUMULLXII, NR. 2, AN2013 131

liului gastric sunt limfocitele T citotoxice i NKactivate. Un alt argument al rspunsului imun locall reprezintcreterea numrului foliculilor limfoizidin mucoasa gastricn cursul infeciei cronice.

n cursul infeciei cuH. pylori, IgA i IgG atingniveluri crescute la pacienii care dezvoltgastrit

bacterian. Anticorpii anti H. pylori ca rspunssistemic umoral al infeciei determin consecinelocale i extradigestive (cutanate, respiratorii, ne-urologice, cardiovasculare).

Implicarea H. pylorin tulburrile nutriionale idezvoltarea staturo-ponderalla vrsta pediatric

Suferinele gastrointestinale produse de infeciacuH. pylorimanifestate prin greuri, vrsturi, ina-peten, dureri epigastrice, pot fiasociate i cu tul-burri nutriionale cronice care sunt frecvente nrile n curs de dezvoltare.

Multe studii recente demonstreazcinfecia cuH. pylorise asociazcu anemie i hipotrofie staturo-ponderal.

Infecia cuH. pylorieste dobnditn copilrie.n rile dezvoltate prevalena la copii este de5-15%, iar n rile n curs de dezvoltare poateajunge la 70% (4). Sunt studii care demonstreazc

H. pylori influeneaz creterea copilului ncdinviaa intrauterin(3). S-a observat cnou-nscuiidin mame infectate au greutatea i talia la nateremai reduse dect cei nscui din mame H. pylorinegative (5). Unii autori aratcrata de cretere acopiilor infectai este mai redus cu aproximativ0,5 cm/an fade cei neinfectai (6).

Pe un lot de 1.170 de pacieni diagnosticai cudiferite forme de gastrite, s-a urmrit existenatulburrilor de nutriie la pacienii infectai cu H.

pyloricomparativ cu lotul de pacieni neinfectai.Protocolul de lucru a constat n studierea la loturile

H. pyloripozitiv/negativ a parametrilor biologici:

proteine totale, glicemie, teste de citolizhepatic,teste renale, colesterol, trigliceride, lipide. S-auobinut diferene semnificative doar la parametrulproteine serice totale. Modificrile dezvoltrii sta-turo-ponderale aprute ca o consecina tulburrilorde nutriie s-au corelat cu prezena infeciei bac-teriene care a avut un impact asupra creterii pon-derale, dar nu i asupra creterii staturale. (7)

Asocierea ntre infecia croniccuH. pyloriianumite sindroame de malabsorbie nu a putut fidemonstrat, concluzie ce poate fiexplicati prin

faptul cmuli copii din cei diagnosticai cu sindromde malabsorbie nu sunt investigai i pentru de-tectarea infeciei cuH. pylori (7).

n meninerea homeostaziei masei corporale unrol major l are leptina, o proteinprodusde gena

ob, sintetizat n esutul osos i care regleaz in-gestia de alimente. Leptina a fost gsiti n glan-dele gastrice din zona fundica stomacului i parea fiimplicatn medierea efectului CCK ce regleazingestia de alimente i senzaia de saietate. Infla-maia cronic i citokinele pot stimula sinteza de

leptince induce astfel anorexia n cadrul inflamaieicronice (8).Helicobacter pylorieste principala cauzde in-

flamaie cronic la nivelul stomacului, bacteriaproduce sintezde citokine, n mod special de IL-1. Duperadicarea bacteriei, leptina scade conco-mitent cu creterea indicelui de mascorporal. Nuse tie totui prin ce mecanism apar tulburri dedigestie i absorbie a proteinelor la copiii infectaicuH. pylori.

Apetitul este reglat i de un alt peptid format din

28 de aminoacizi cu o structurasemntoare mo-tilinei, produs n stomac, numit ghrelina. Ghrelinaeste sintetizatde celulele enteroendocrine situaten glandele oxintice. Are rolul de a crete apetitul ide a stimula eliberarea hormonului de cretere.Concentraia sanguina acestui peptid crete naintede prnz i scade postprandial (9).

S-a demonstrat cexisto relaie direct propor-ional ntre aciditatea gastric i ghrelina plas-matic. Se tie cduperadicarea infeciei cu H.

pylorisecreia de HCl crete, ceea ce ar explica i

faptul c ghrelina crete semnificativ dup eradi-care.

Mecanismul prin care bacteria reduce sinteza deghrelin nu este clar descifrat. Se discut douposibiliti pe lngimplicarea hipoclorhidriei dincadrul inflamaiei cronice: aciunea direct a H.

pyloriasupra glandelor gastrice oxintice i hiper-gastrinemia din cursul infeciei.

Aportul alimentar poate fi reglat de raportulghrelin/leptin. Ambele peptide sunt influenatede infecia cuH. pylori(9).

Tulburrile nutriionale datorate infeciei au osemnificaie importantla vrsta pediatricdeoarecen cursul creterii, copiii au nevoie de un aport pro-teic sporit.

Astfel, n cursul infeciei cu H. pylori apartulburri nutriionale cu scdere n greutate, urmndca duperadicare aceste tulburri sdisparcu re-venirea la normal a greutii.

Asocierea infeciei cu H. pyloricu anemia hipocrom

n practica pediatric, anemiile hipocrome feri-prive sunt cel mai frecvent ntlnite, iar stabilireadiagnosticului etiologic se realizeazde multe oricu dificultate deoarece existun segment de pacienila care etiologia nu poate fiprecizatcu exactitate.

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Factorul infecios ca verig patogenetic nanemia hipocromferipriva fost sugerat de maimuli ani. Gastrita, n general, poate fi nsoitdeanemie.

Din 1.170 de cazuri diagnosticate cu gastrit,338 (28,88%) de pacieni au prezentat i anemie

hipocrommicrocitarpersistent, neinfluenatdeterapii mariale anterioare. S-a pus n discuie attapariia unei gastrite acute postmedicamentoasedatorate efecului iritativ al fierului la nivelul mu-coasei gastrice, ct i urmrirea interaciunii cu in-fecia bacteriani dezvoltarea unei gastrite cronice.Analiza statistic a demonstrat o asociere semni-ficativntreinfeciaH. pylorii anemia feripriv.(7)

Nu exist date semnificative ntre loturile depacieni diagnosticai cu anemie feripriv, privind

simptomatologia acut sau cronic de gastrite.Acest rezultat se explic prin faptul c, pe de oparte, pacienii care prezintanemie hipocromiurmeaztratament cronic cu produse de fier, dez-volto gastritacutiritativ, iar pe de altpartepacienii la care are loc i suprainfecia bacteriandezvolt o gastrit cronic, care prin accentuareasimptomatologiei digestive i a leziunilor gastrice,ntreine i agraveazforma de anemie. (7)

Deficitul de fier apare ca o manifestare a uneibalane negative a fierului, determinatde mai mulifactori: depozite defier reduse la natere, alimentaiesracn fier, nevoi crescute de fier, malabsorbie,pierderi cronice de snge (10). Cu toate aceste cu-notine despre cauzele anemiei feriprive, existunnumr relativ crescut de copii la care etiologia boliirmne necunoscut, iar afeciunea este refractarla tratament.

Cercetrile din ultimii ani aduc dovezi prin caresusin cinfecia croniccuH. pylori ar putea ex-plica la copii rezistena la tratamentul cu preparate

orale defi

er a anemiei feriprive.Un studiu realizat pe un grup de 21 de adolescenicu anemie feripriva demonstrat prezena infecieicuH. pylorila 61% din subieci, iar la trei luni duperadicarea bacteriei prin tripl terapie, valoareahemoglobinei a crescut n medie cu 2 g% (10).

Se tie caproximativ 80% din fierul ingerat dinalimentaie este non-heminic (de origine vegetal)sub formde Fe3+i doar 20% este sub forma Fe2+(de origine animal), acesta din urmfiind inclus nstructura porfirinic a hemului. Conversia formei

trivalente n bivalent este facilitat la nivelulstomacului de acidul clorhidric i acidul ascorbic.Pacienii infectai cu H. pylori i care prezint nspecial forme de gastritcronicatroficcorporealau un pH gastric crescut, iar concentraia de acid

ascorbic este sczut. Bacteria are rolul de a mo-difica cei doi factori importani n absorbia fierului(10).

Hipoclorhidria indusde antisecretoarele utili-zate n tratamentul gastritelor este diferit de ceadin gastrita cronicatrofic, acest lucru fiind sus-

inut de studiile care aratcpH-ul gastric la bol-navii tratai cu antisecretoare n doze farmacologice,rmne sub 3 mai mult de opt ore.

Hipoclorhidria indusdeH. pylori este expresiagastritei cronice a corpului gastric. Nivelul secretorde HCl este constant, astfel nct hipoclorhidria semenine pe tot parcursul zilei (11).

Hipoclorhidria indusfarmacologic se nsoetede scderea acidului ascorbic numai la pacieniiinfectai cuH. pylori. Depleia de acid ascorbic sedatoreaz consumului n procesul de inactivare a

radicalilor liberi de oxigen eliberai n mucoasagastricinflamat. Acidul ascorbic este sczut i nplasmprobabil datoritcreterii secreiei active lanivelul mucoasei gastrice pentru meninerea nsucul gastric a unei concentraii adecvate (12).

S-a demonstrat cduptratamentul cu antibioticei eradicarea bacteriei, nivelul acidului ascorbic dinstomac se normalizeaz numai la pacienii cugastritcronicsuperficial, n timp ce la pacieniicu gastriccronicatrofic, duperadicarea infec-iei, acidul ascorbic nu mai revine la valorile nor-

male (13).

Impactul infeciei cu H. pyloriasupra pacienilordiabetici

Diabetul zaharat este cea mai frecvent boalmetabolic ce evolueazpe termen lung cu com-plicaii severe cum ar finefropatia, retinopatia, an-giopatia. n prezent se fac eforturi de a clasificadiabetul dupmecanismele patogenetice care suntparial elucidate, implicai fiind factorii genetici i

factorii de mediu. Infeciile intercurente, virale saubacteriene, imprimo evoluie mai severbolii, potduce la decompensare i creterea necesarului deinsulin(14). Rata reinfeciei anuale este de 38% ladiabetici i de numai 5% la populaia de control(15).

H. pyloriinduce o inflamaie cronicce ar puteainfluena controlul metabolic. S-a observat cpa-cienii obezi cu diabet zaharat i infectai cu H.

pyloriau glicemia bazalsemnificativ mai sczutdect la subiecii obezi H. pylori negativi (16).

Acest rezultat ar putea sugera cbacteria poteneazefectul hipoglicemiant al insulinei.

Unele studii arat c eradicarea infeciei lapacienii diabetici s-a realizat numai la 50% fade85% la non-diabetici (17). Rezultatele privind

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infecia cuH. pylorii controlul metabolic al dia-betului zaharat tip I sunt contradictorii, unele studiiartnd cnu s-au observat diferene semnificativeale prevalenei infeciei fade pacienii non-dia-betici (17), altele argumentnd cprevalena estecrescutla 80% fade 37,5% la persoanele sn-

toase.Halena neplcut este manifestarea clinic ce

dominla diabeticii infectai cuH. pylori. TulpinilecagA pozitive sunt mai virulente i se asociazcu oproducie crescut de cytokine (IL-1, IL-6, IL-8,TNF) (9). Este posibil ca la aceti pacieni, con-trolul metabolic sfie perturbat.

ntr-un alt studiu, H. pyloria fost identificat latoi pacienii diabetici cu neuropatie autoimun(18). Este posibil ca bacteria sjoace un rol n pato-geneza neuropatiei autoimune, cu producerea tul-burrilor gastrice, ntrzierea evacurii stomacului,manifestri responsabile de simptomele dispepticeprezente la pacientul diabetic.

La pacienii cu diabet zaharat tip I i infectai cuH. pylori, evacuarea gastric este mai prelungitdect la cei neinfectai (19). Duperadicarea infec-iei, evacuaurea gastricse normalizeaz. Aceastconstatare este foarte important, trebuie cunoscutpentru ca doza de insulin nainte de mas sfieadministrat n corelaie cu timpul de evacuare a

stomacului pentru a preveni hipoglicemia.

Infecia H. pylorii alergiile alimentare

Alergia alimentarreprezintun rspuns atipical sistemului imun de la nivelul mucoasei gastro-intestinale aprut n urma interaciunii acestuia cuantigenele ingerate. Prin alergie alimentar seneleg toate reaciile adverse la alimente declanatede mecanismul immunologic.

La bolnavii infectai cu H. pylori, proteinele

bacteriene au efect chemotactic pentru bazofi

le iastfel mucoasa gastric este infiltrat cu acestecelule (20).

Celulele dendritice sunt mediatori ntre sistemulimun nnscut i sistemul imun ctigat. Prin sti-mularea celulelor dendritice de ctreH. pylori, seelibereaz citokine ca IL-6, IL-8, IL-10 i IL-12.Aceste citokine sunt considerate astzi factori pato-genetici n diferite afeciuni, printre care i alergiilealimentare.

Majoritatea cercetrilor aduc numeroase argu-

mente care demonstreazcH. pylorieste un factorde risc n alergia alimentarla copil. Dintre acesteacele mai importante sunt: inflamaia mucoasei gas-trice prin care se realizeaz o cretere a permea-bilitii pentru alergenii alimentari, prevalena

nalta tulpinilor cagA pozitive, inducerea de ctrebacterie a unor substane proinflamatorii, cretereatitrului IgE la bolnavii infectai cuH. pyloricagApozitive (21).

Din 1.170 de pacieni diagnosticai cu diferiteforme de gastrit, 107 (9,14%) au asociat i afeciuni

alergice, frdiferene statistice pe grupe de vrste.Din analiza statistic rezult cpacienii infectaicuH. pyloriau prezentat alergii mult mai frecvent(14,58%) dect cei neinfectai (8,03%). (7)

Alte studii arat c prevalena infeciei cu H.pylori la copiii cu alergie alimentar nu este maimare dect n populaia general, dar se remarcocretere aproximativ de douori mai mare a frec-venei tulpinilor virulente cagA.

Prevalena infeciei cuH. pylorila un grup de 65de bolnavi cu angioedem ereditar nu a fost mai

ridicatdect n populaia general, aceasta fiind de30%, din care 84% au fost cagA pozitivi (15).

Rolul florei intestinale n tolerana digestivestedemonstratprin evoluia clinic favorabil a pa-cienilor cu boli alergice la care s-au administratprobiotice (22). Studii recente aratfaptul csugariialimentai natural de mame care primesc probioticedezvoltmult mai rar boli alergice, n special der-matitatopic.

Unii autori sugereaz cH. pylori poate fi unfactor patogenic n diverse boli dermatologice caurticaria, dermatita atopici angioedemul. Pentruexplicarea mecanismului de aciune s-a postulatipoteza cbacteria, prin potenialul proinflamatorpe care l are, constituie un trigger ce declaneazosuccesiune de evenimente imune prin care serealizeazdepleia inhibitorului C1-esterazei (23).

S-a demonstrat corelaia ntre urticaria cronici infecia cu H. pylori, n special cu tulpinile cagApozitive (24, 25). Seroprevalena anticorpilor anti-H. pyloria fost constatatla 75% din bolnavii cu

urticarie cronic idiopatic (24). La 88% din pa-cienii cu urticarie cronic infectai cu H. pylori,dup eradicarea infeciei, simptomele s-au remistotal sau parial. Densitatea celulelor din mucoasagastricce conin IgE a fost gsitsemnificativ maimare la bolnavii cu gastritcronicbacterianfade cei neinfectai i frboli cutanate (26).

Un studiu realizat pe un grup de pacieni cuangioedem aratcbolnavii infectai cuH. pyloriau avut n istoric episoade colicative abdominale,n timp ce bolnavii neinfectai au prezentat aceste

manifestri numai n procent de 23% (27). Duperadicarea infeciei, timp de peste doi ani nu au maiaprut episoadele dureroase abdominale.

Relaia H. pylori astm bronic este discutatcotradictoriu n literatur(28). La copii s-a observat

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o corelaie inversntre infecia gastrici astmulbronic. ntr-un alt studiu recent s-a observat oreducere cu 30% a riscului de astm bronic la copiiiinfectai cuH. pylori. SeroprevalenaH. pylorinudifersemnificativ la astmatici fade subiecii decontrol (20).

Helicobacter pylorieste cauza principala gas-tritei cronice la copil. Inflamaia cronicprodusnaceast patologie afecteaz drastic integritateabarierei mucoasei gastrice i astfel crete posi-bilitatea ca alergenii alimentari s traverseze mu-coasa. Prin creterea permeabilitii mucoaseitubului digestiv, antigenii alimentari traverseazcuuurini vin n contact cu sistemul imun (21).

La copiii alergici care au gastrit cronic iinfecie cuH. pylori, inflamaia mucoasei gastriceeste mult mai severdect la cei fralergie ali-

mentar. La pacienii infectai cu tulpini cagApozitive, leziunile de la nivelul mucoasei sunt maiimportante deoarece crete foarte mult permea-bilitatea epiteliului gastric i astfel este favorizatpasajul neselectiv al alergenilor cu stimulareadirecta rspunsului IgE. Unele studii aratc la

copiii cu alergie alimentars-a remarcat o creterea titrului anticorpilor anti-cag A. (25)

CONCLUZII

Infecia cu H. pylori poate induce tulburri n

creterea ponderal i anemie feripriv prin mo-dificarea mediului intragastric, creterea pH-ului lanivelul stomacului, scderea concentraiei aciduluiascorbic i sechestrarea fierului.

Pacienii cu diabet zaharat refractar la tratamenti cu manifestri digestive, trebuie investigaipentru infecia activcuH. pylori, inndu-se contde faptul crata de eradicare a infeciei cuH. pylorila diabetic este redus, rata de reinfecie este cres-cut, iar doza de insulinla pacienii infectai estemai mare.

Infecia cuH. pylori determindeclanarea sis-temului imun, fiind astfel asociat cu alergiilealimentare.

Manifestrile extradigestive ale infeciei cu H.pylori sunt determinate n special de tulpinile cagApozitive.

Extradigestive manifestations of Helicobacter pylori infection in children

Ancua Ignat, Marin Burlea, Valeriu V. Lupu, Nicoleta Gimiga,Gabriela Pduraru

Pediatrics Department, Gr. T. Popa University of Medicine and Pharmacy, Iasi

ABSTRACT

The role of Helicobacter pylori bacteria in the pathogenesis of the digestive diseases now, is very well established and

known, but recent research claims that Helicobacter pylori is involved in producing some extra-digestive diseases. Theprevalence of the infection differs from one geographical area to another, registering a descending trend in developed

countries and remaining at a constant level or even increasing in developing countries. Helicobacter pylori determines

an immune response of the host, which involves humor and cell immunity. The infection is located in the gastric mucosa,

but in recent years we have seen studies that try to explain some allergic diseases as the consequence, at least in some

patients, of the chronic infection with Helicobacter pylori. The gastro-intestinal sufferings caused by the infection with H.

pylorimanifested by nausea, vomiting, anorexia, epigastric pains can be associated with nutritional disorders. Many

recent studies prove that the infection withH. pylori is associated with anemia, and weight loss. Helicobacter pylori was

identified in most diabetic patients with autoimmune neuropathy, causing electric gastric disorders, the delay of the

stomach evacuation, manifestations responsible of the dyspeptic symptoms in diabetic patients. The appropriate

therapeutic behavior in the case of patients with extra-digestive affections and an eventual infection withH. pylorishould

concern both the basic disease treatment and the efficient eradication of the infection.

Key words: Helicobacter pylori,extradigestive manifestations, child.

Helicobacter pylori, like any other bacteria orvirus, causes an immune response from the host in-volving humoral and cellular immunity. The infec-

tion is localized in the stomach and inflammatoryand immunological changes are circumscribed tothis segment of the digestive tract. In the last few

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years, it has provided evidence on the involvementof bacteria in extragastric diseases. Extradigestivemanifestations encountered in cases diagnosed with

H. pylorigastritis demonstrates that infection hasecho not only local but also systemic.

The host immune response during infection withH. pylori

Cells of the gastric immune system are adaptedto an interaction with a large number of antigens. Inexperimental conditions, it has demonstrated thatunder the influence ofH. pylori, the follicular unitsof gastric mucosa numerically grow. (1).

DuringH. pyloriinfection, mononuclear cells ofgastric mucosa produce cytotoxic antibodies of theIgG class, which by activating polymorphonuclearneutrophil leukocytes by immune complexes, acute

epithelial damage its done. Immune system cellspresent in the mucosa are represented by: Th, Tsand B lymphocytes present in lamina propria ofmucosa. Intraepithelial lymphocytes increasedduring chronic inflammation. In vitro, H. pyloriactivates NK cells, inducing the activation andmaturation of monocytes derived from dendriticcells (2). In patients withH. pyloriinfection, gastricmucosa is infiltrated with macrophages.

Although, the body produces antibodies againstbacteria, it cannot be removed due to his structuresthat ensure survival and allows him to escape fromthe immune system of digestive tract.

H. pylori induces local synthesis of interferon and TNF(3). During the inflammation, it is expressclass II histocompatibility molecules with his rolein local presentation of the antigen.

Local cellular immune response is the key to thesynthesis of antibodies, the cytokines generationand the induce of epithelial lesions. The directcauses of gastric epithelial lesions are cytotoxic Tlymphocytes and activated NK cells. Anotherargument of the local immune response is theincrease of number of lymphoid follicles in thegastric mucosa during chronic infection.

During infection with H. pylori, IgA and IgGreached high levels in patients who developbacterial gastritis. Anti - H. pylori antibodies assystemic humoral response of infection cause localand extradigestive consequences (skin, respiratory,neurological, cardiovascular).

Involvement of H. pyloriin nutritional disorders andin the stature-weight development of pediatric

patients

Gastrointestinal sufferings caused by H. pyloriinfection manifested by nausea, vomiting, anorexia,

epigastric pain, may be associated with chronicnutritional disorders most common in developingcountries.

Many recent studies show that H. pylori infectionis associated with anemia and weakness stature-weight.

H. pylori infection is acquired in childhood. Indeveloped countries the prevalence in children is5-15%, and in developing countries can reach 70%(4). This studies are showing that H. pyloriinfluences the child from the womb (3). It wasobserved that newborns of infected mothers haveweight and size at birth lower than those born tomothers H. pylori negative (5). Some authors showthat the growth rate of infected children is lower byabout 0.5 cm / year to uninfected (6).

In a group of 1170 patients diagnosed with

various forms of gastritis, we have studied theexistence of eating disorders in patients infectedwith H. pylori compared with uninfected patientsgroup. The working protocol was to study in H.pylori positive/negative batches the biologicalparameters: total protein, glucose, hepatic cytolysistests, kidney tests, cholesterol, triglycerides, lipids.There were obtained significant differences only inthe parameter of total serum proteins. Changes instature-weight development occurred as a conse-quence of eating disorders correlate with the pre-sence of bacterial infection that had an impact onweight gain, but not on growth stature. (7)

The association between H. pylori infection andcertain chronic malabsorption could not bedemonstrated, this conclusion can be explained bythe fact that many children diagnosed with malab-sorption are not investigated for H. pylori infection(7).

In maintaining the body weight homeostasis,leptin plays a major role. Leptin is a protein

produced by the ob gene, synthesized in the bonetissue and she regulates food intake. Leptin wasfound in the gastric glands of fundus stomach andseems to be involved in mediating the effect ofCCK that regulates food intake and satiety. Chronicinflammation and cytokines can stimulate leptinsynthesis inducing anorexia inside of chronicinflammation (8).

Helicobacter pylori is the main cause of chronicinflammation of the stomach, the bacteria producesynthesis of cytokines, particularly IL-1. After

eradication of bacteria, leptin decreases while isincreasing body mass index. It is not known yet bywhat mechanism is occurring disorders of digestionand absorption of proteins from H. pylori-infectedchildren.

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Appetite is controlled by another peptideconsisting of 28 amino acids with a motilin-likestructure produced in the stomach, called ghrelin.Ghrelin is synthesized by enteroendocrine cellslocated in oxintice glands. His role is to increaseappetite and stimulate growth hormone release.

Blood levels of this peptide increase before lunchand are lowers after meals (9).It has been shown that there is a directly

proportional relationship between gastric acidityand plasma ghrelin. It is known that after theeradication of H. pylori infection increases thesecretion of HCl, which would explain the fact thatghrelin increases significantly after eradication.

The mechanism by which bacteria reduce ghrelinsynthesis is not clearly deciphered. We discuss twopossibilities besides hypochlorhydria involvement

in the chronic inflammation: direct action of H.pylori on gastric oxintice glands and hipergastrinemiaduring infection.

Food intake can be adjusted by the ratio ghrelin/ leptin. Both peptides are influenced by infectionwith H. pylori (9).

Nutritional disorders due to infection have animportant significance in pediatric age as duringgrowth, children need a high protein intake.

So, during H. pylori infection weight loss occurwith nutritional disorders, followed by eradicating

infection these problems to disappear with thereturn to normal weight.

The association of H. pylori infection with

hypochromic anemia

In pediatric practice, hypochromic iron defi-ciency anemia is the most common, and etiologicdiagnosis is often made difficult because there is asegment of patients whose etiology cannot bedetermined accurately.

Infectious factor like pathogenetic link inhypochromic iron deficiency anemia has beensuggested for many years. Gastritis generally maybe accompanied by anemia.

From 1170 cases diagnosed with gastritis, 338(28.88%) patients presented persistent microcytichypochromic anemia, influenced by previousmartial therapies. We discussed both the emergenceof acute gastritis due to drug reactions carriedirritation of the gastric mucosa by iron and trackinginteractions with bacterial infection and the

development of chronic gastritis. Statistical analysisdemonstrated a significant association between H.pylori infection and iron deficiency anemia. (7)

There are no significant data between groups ofpatients diagnosed with iron deficiency anemia, the

symptoms of acute or chronic gastritis. This resultis explained by the fact that on the one hand thehypochromic anemia patients who are chronicallyiron-treatment, developed a severe gastric irritation,and on the other hand, patients develop bacterialinfection occurs on chronic gastritis, which by

enhancing digestive symptoms and gastric lesions,maintain and worsens form of anemia. (7)Iron deficiency occurs as a manifestation of a

negative iron balance, driven by several factors:low iron stores at birth, poor nutrition iron increasediron needs, malabsorption, chronic blood loss (10).With all this knowledge about the causes of irondeficiency anemia, there is a relatively high numberof children whose etiology remains unknown andthe disease is refractory.

Recent research provides evidence that chronic

infection with H. pylori in children may explainresistance to treatment with oral preparations oniron deficiency anemia.

A study conducted on a group of 21 adolescentswith iron deficiency anemia, demonstrated thepresence of H. pylori infection in 61% of subjects,and three months after bacterial eradication bytriple therapy, the hemoglobin value has increasedby an average of 2 g% (10).

It is known that about 80% of ingested iron inthe diet is nonheminic (vegetable origin) as Fe 3 +and only 20% is in the form of Fe2 + (animal), thelatter being included in the structure of the hemeporphyrin. Trivalent to divalent form conversion isfacilitated in the stomach of hydrochloric acid andascorbic acid. Patients infected with H. pylori, andwhich in particular forms of chronic atrophicgastritis corporeal have increased gastric pH andthe concentration of ascorbic acid is reduced. Therole of bacteria is to change the two importantfactors in the absorption of iron (10).

Hypochlorhydria induced by antisecretory drugsused to treat gastritis is different from chronicatrophic gastritis, and this is supported by studiesshowing that gastric pH in patients treated withpharmacological doses of antisecretory remainsbelow 3 more than eight hours.

Hypochlorhydria induced by H. pylori is theexpression of chronic gastritis of gastric body. Thesecretion of HCl is constant, so that hypochlorhydriais maintained throughout the day (11).

Pharmacologically induced hypochlorhydria is

accompanied by decrease in ascorbic acid only inpatients infected with H. pylori. Ascorbic aciddepletion is due to inactivation of the consumptionof oxygen free radicals in inflamed gastric mucosa.Ascorbic acid is low probably due to an increase in

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the plasma discharge current from the gastric mu-cosa in order to maintain an appropriate concentra-tion of gastric juice (12).

It has been demonstrated that after treatmentwith antibiotic and elimination of bacteria, the levelof ascorbic acid in the stomach became normal only

in patients with chronic superficial gastritis, whilein patients with chronic gastric atrophy, after era-dication of the infection, ascorbic acid does notreturn to normal levels (13).

The impact of H. pyloriinfection on patients with

diabetes

Diabetes is the most common metabolic diseasethat develops severe long-term complications suchas nephropathy, retinopathy, angiopathy. Efforts are

currently made to classify diabetes as pathogeneticmechanisms which are partially understood, beinginvolved the genetic and environmental factors.Intercurrent infections, viral or bacterial, print amuch severe disease evolution which may lead todecompensation and increased of insulin require-ments (14). Annual re-infection rate is 38% in dia-betic patients and only 5% in the control population(15).

H. pylori induces a chronic inflammation thatcould influence metabolic control. It was observed

that obese diabetic patients infected with H. pylorihad significantly lower levels of glucose than obesesubjects H. pylori negative (16). This result maysuggest that bacteria potentiate the hypoglycemiceffect of insulin.

Some studies suggest that the eradication of theinfection in diabetic patients has been achievedonly at 50% to 85% in non-diabetic (17). The resultsfor H. pylori infection and metabolic control oftype I diabetes are contradictory, some studiesshowing that there were no significant differencesin the prevalence of infection compared to non-diabetic patients (17), and others arguing that theprevalence increased to 80% compared to 37.5% inhealthy individuals.

Unpleasant halitosis is dominating the clinicalmanifestation in diabetic patients infected with H.pylori. CagA positive strains are more virulent andare associated with increased production of cyto-kines (IL-1, IL-6, IL-8, TNF) (9). It is possible thatin these patients, metabolic control is disrupted.

In another study, H. pylori was found in alldiabetic patients with autoimmune neuropathy (18).It is possible that bacteria plays a role in thepathogenesis of autoimmune neuropathy producinggastric disorders, delayed gastric evacuation, events

responsible for dyspeptic symptoms present to thediabetic patient.

In patients with diabetes mellitus type I andinfected with H. pylori, gastric evacuation is moreprolonged than in uninfected (19). After eradicationof the infection, gastric evacuation normalized.

This finding is very important to be known becausethe insulin dose before meals should be taken inconjunction with stomach evacuation time toprevent hypoglycemia.

H. pylori infection and food allergies

Food allergy is an atypical immune systemresponse from the gastrointestinal mucosa appearedafter its interaction with ingested antigens. Thefood allergy means all adverse reactions to foodtriggered by immunological mechanism.

In patients infected with H. pylori, bacterial pro-teins have chemotactic effects for basophils and sothe gastric mucosa is infiltrated with this cells (20).

Dendritic cells are the mediators between theinnate immune system and the won immune system.Through the stimulation of dendritic cells by H.pylori, there are release cytokines such as IL-6,IL-8, IL-10 and IL-12. These cytokines are con-sidered today pathogenetic factor in various diseasesincluding food allergies.

Most of the researches bring many argumentsshowing that H. pylori is a risk factor in food allergyin children. Of all of these the most important are:inflammation of the gastric mucosa through whichincreased permeability of food allergens, highprevalence of cagA positive strains, the bacteria in-duce a proinflammatory substances, increased IgEtiters in patients infected with H. pylori cagA po-sitive (21).

Of 1170 patients diagnosed with various formsof gastritis, 107 (9.14%) had allergies associated,

with no statistical differences by age group. Astatistical analysis shows that patients infected withH. pylori had allergies more frequently (14.58%)than uninfected (8.03%). (7)

Other studies show that the prevalence of H.pylori infection in children with food allergy is nothigher than in the general population, but it is noteda grow approximately twice as large in the frequencyof virulent cagA strains.

The prevalence of H. pylori infection in a groupof 65 patients with hereditary angioedema was not

higher than in the general population, it was 30%,of which 84% were cagA positive (15).The role of the intestinal flora in the digestive

tolerance is demonstrated by favorable clinicalcourse of patients with allergic diseases which have

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been administered probiotics (22). Recent studiesshow that breast-fed infants of mothers receivingprobiotics develops more slowly allergic diseases,especially atopic dermatitis.

Some authors suggest that H. pylori may be apathogenic factor in various skin diseases like

urticaria, atopic dermatitis and angioedema. Inorder to explain the mechanism of action has beenpostulated the hypothesis that the bacteria byproinflammatory potential that it has, is a triggerthat starts a sequence of events by which it isperformed the immune depletion of C1-esteraseinhibitor (23).

Correlation between chronic rash and infectionwith H. pylori, has been demonstrated, especiallyin cagA positive strains (24, 25). Seroprevalence ofanti - H. pylori was found in 75% of patients with

chronic idiopathic rash (24). In 88% of patientswith chronic rash, infected with H. pylori after era-dication of the infection, the symptoms resolvedcompletely or partially. The density of cells in thegastric mucosa containing IgE was found signifi-cantly higher in patients with chronic gastritis fromthe bacterial infection and without skin disease(26).

A study on a group of patients with angioedemashows that H. pylori-infected patients had a historyof colicky abdominal episodes, while uninfectedpatients have experienced these symptoms only in23% (27). After eradication of the infection formore than two years have not appeared abdominalpain episodes.

Relationship H. pylori asthma is contradictorydiscussed in the literature (28). In children therewas an inverse correlation between gastric infectionand asthma. In another recent study showed a 30%reduction in the risk of asthma in children infectedwith H. pylori. H. pylori seroprevalence did not

differ signifi

cantly in asthmatics compared to con-trols. (20)

Helicobacter pylori is the main cause of chronicgastritis in children. Chronic inflammation in thispathology produced drastically affects on gastricmucosal barrier integrity and increase the possibilitythat food allergens to cross the mucosa. By increa-sing the permeability of the digestive tract, the food

antigens penetrate easily and come in contact withthe immune system (21).Allergic children with chronic gastritis and H.

pylori infection, the gastric inflammation is moresevere than in those without food allergies. Inpatients infected with cagA positive strains, mucosallesions are very important because it increasesgastric epithelial permeability and in this waypermits the selective passage of allergens withdirect stimulation of IgE response. Some studiesshow that children with food allergy noted an in-

crease in antibody titer cag A. (25)

CONCLUSIONS

Infection with H. pylori can induce disturbanceson iron deficiency anemia and weight gain byaltering intragastric environment, increasing thepH of the stomach, decreased concentrations ofascorbic acid and iron sequestration.

Patients with refractory diabetes and digestivesymptoms should be investigated for activeinfection with H. pylori, taking into account thefact that the rate of eradication of H. pylori infectionin diabetics is low, reinfection rate is high, and theinsulin dose is higher than patients infected.

Infection with H. pylori causes the trigger ofimmune system and this is associated with foodallergies.

Extradigestive manifestations of infection withH. pylori are determined mainly by cagA positivestrains.

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