Alimentary tract and pancreas

INTRODUCTION

Helicobacter pylori (Hp) colonizes gastric mucosa leading to the development of chronic gastritis in all of the individuals and in some it leads to complications such as peptic ulcer formation or even gastric cancer. Role of Hp in the pathogenesis of peptic ulcer disease (PUD) and gastric carcinoma was recognized soon after identification and cultivation of the bacterium by Warren and Marshall (1,2) However if the presence of the Hp infection plays a role in non ulcer dyspepsia (NUD) was not clear until the results of meta analysis (3,4,5).

Dyspepsia is, by the majority of authors, defined as a group of symptoms originating from proximal parts of gastrointestinal tract that are unrelated to the process of defecation. However there are substantial differences between various definitions. Some authors feel that even presence of abdominal pain alone could define patient as dyspeptic (6, 7), while others suggest more complex criteria for defining dyspepsia (8, 9). There is also no present agreement on the required period of time in which symptoms should persist, and criteria range from a single episode up to one year (7, 10). It is however clear that the dyspepsia is a common health problem, since the estimated prevalence of dyspepsia in general population varies, according to different studies, from 14-40%. (10, 11)

In this paper, we used the definition proposed by the international committee in Rome in 1999., that resulted in the Rome II classification of functional dyspepsia (7). According to this definition dyspepsia refers to pain or discomfort centered in the upper abdomen, while pain in the right or left hypochondrium is not considered to be representative of dyspepsia (7). Duration of symptoms was not specified by Rome II criteria, but it was advised that in research studies investigators may specify the duration of symptoms in order to improve the homogeneity of the patients studied. We therefore modified the definition as proposed by Knill Jones (9) stating that symptoms should persist at least for 4 weeks.

The aim of our study was to investigate if there are differences in the clinical presentation of dyspeptic patients related to the presence of Hp infection.

MATERIAL AND METHODS

Subjects: We conducted an outpatient-based prospective study at the Clinic for Gastroenterology and Hepatology (Clinical Center of Serbia, University of Belgrade). A total of 99 consecutive dyspeptic patients referred to endoscopy in the period August-December 2000 entered the study. In 72 Hp infection was diagnosed, while 25 were Hp negative. Mean age was 45 ± 3 years, 34 were males, 37 smokers and 31 had personal history of PUD.

Dyspepsia in patients was defined as pain or discomfort centered in the upper abdomen lasting for at least 4 weeks, while pain in the right or left hypochondrium was not considered to be representative of dyspepsia (7). Demographic factors including age, sex and smoking were analyzed.

Prior to esophagogastroduodenoscopy all patients filled a standardized questionnaire. The questionnaire contained the demographic characteristics of the patient (age, sex), information on the present risk factors for the peptic ulcer formation and detailed information on present dyspeptic symptoms and signs. The intensity of dyspeptic complaints was evaluated on a modified 5 grade Likert scale.

Hp infection was diagnosed by the simultaneous positivity for rapid urease test (RUT), histology and serology.

Standardized questionnaire: According to the recommendations of European Hp study group (1), the following parameters were recorded for each patient entering the study: age, sex, smoking, alcohol intake (more than 20g per day was considered relevant), present dyspeptic complaints (duration, intensity), pain localization, positive personal and family history of PUD, history of upper gastrointestinal hemorrhage (hemathemesis, melena); non-steroid anti-inflammatory drugs (NSAID) intake (more than 2 times a week); other concomitant diseases (diabetes mellitus, cardiovascular diseases, hypertension, chronic bronchitis, liver and renal disease, rheumatic disorders), previous cholecystectomy.

Assessment of the intensity of dyspeptic complaints: Five-grade Likert scale was used in order to assess the intensity of dyspeptic complaints. According to this scale intensity of the present complaint is graded from 1 to 5, as previously described in detail (12). Based on this scale we calculated the dyspeptic symptom score as a sum of all present dyspeptic complaints intensity. Absent symptoms were marked with 0.

Routine endoscopy and Hp status: Each patient underwent upper endoscopy and testing for the presence of Hp by RUT (Institute for virusology and immunology Torlak, Belgrade, Serbia and Montenegro) and histology. Biopsies from antral and corpus mucosa were stained using hematoxylin-eosin and modified Giemsa staining procedures. Biopsy specimens were assessed separately according to the Sydney System (13) by an experienced pathologist who was blinded to the clinical data.

Hp serology: Blood samples were taken from the patients after endoscopic examination and sera were separated by centrifugation and stored at -20 oC until analyzed. The concentration off anti-Hp IgG antibodies was analyzed using the Pyloriset EIA-G IIITM (Orion Diagnostica, Finland) according to the manufacturers’ instructions (14).

Statistical analysis: Results were analyzed using non parametric tests, Kruskall-Wallis test for independent samples, the chi-square or Fischer’s test to compare the demographic characteristics of the groups. P-values < 0.05 were considered significant.

DISCUSSION

Overall in 73% of dyspeptic patients included in this study Hp infection was diagnosed, that agrees with the results from other studies in European countries (15, 16), although some studies identified significantly lower prevalnece of the infection (17).

Alcohol was consumed by 92 % of unifected and only 66% of patients with Hp infection. These findings can arrive from the activation of the gastric mucosal defence mechanism called adaptive cytoprotection. Briefly, repeated administration of low doses of cytotoxic substances, such as ethanol, induces synthesis of different enzymes and cytoprotective substances leading to the adaptation of gastric mucosa against stress factors and preventing development of pathological changes. This was previously demonstrated in animal model by Konturek et al and could account for more frequent alcochol consumption in Hp negative patients (18). However, recent results from a large study by Treiber et al.(19), demonstrated that patients consuming alcohol or tobacco are more likely to show dyspeptic symptoms unrelated to the presence of the Hp infection implying that lifestyle modifications including psychological treatment should be considered in these subgroups of patients.

The antibacterial effects of bile on Hp, previously demonstrated in some (20), but not all studies (21), could explain the absence of the infection in the majority of patients with duodenogastric bile reflux, observed during endoscopy.

Lack of typical symptoms related to the Hp positive dyspepsia was seen by other authors in different populations (22, 23). However, we were able to identify higher intensity and longer duration of heartburn together with longer history of vomiting in the uninfected patients, as opposed to the results of others (22). Possible explanation for this finding would be more frequent presence of duodenogastric bile reflux observed in Hp negative patients, which agrees with results that we obtained using logistic regression analysis.

The usefulnnes of eradication therapy in dyspeptic patients with non ulcer dyspepsia is still a matter of debate between different authors. Some (24), but not all (25) suggest there is no clinical improvement and that dyspeptic symptoms in these patients derive from some other pathophisiological mechanism unrelated to the Hp infection.

The results of our study indicate that the presence of Hp infection can not be related specificly to any of the dyspeptic symptoms and that higher dyspeptic symptom score is found in unifected patients. Therefore further investigation in order to define underlying pathogenetic mechanism responsible for the upper dyspeptic syndrome is needed.

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20. Itoh M, Wada K, Tan S, Kitano Y, Kai J, Makino I. Antibacterial action of bile acids against Helicobacter pylori and changes in its ultrastructural morphology: effect of unconjugated dihydroxy bile acid. J Gastroenterol 1999;34:571-76.

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23. Bielanski W, Plonka M, Dobrzanska M, et al. Is Helicobacter pylori prevalence in asymptomatic Polish population different from symptomatic patients? Gut 1999; 45(Suppl 5):A42.

24. Sarnelli G, Cuomo R, Janssens J, Tack J. Symptom patterns and pathophysiological mechanisms in dyspeptic patients with and without Helicobacter pylori infection. Dig Dis Sci 2003; 48:2229-36.

25. Heikkinen M, Vonanen M, Hollmen S, Farkkila M. Prognostic significance of antrum-predominant gastritis in functional dyspepsia. Scand J Gastroenterol 2004;39:227-31.

SAŽETAK

Uvod/ciljevi: Helicobacter pylori dovodi do pojave ulkusa želuca i duodenuma i ima ulogu u nastanku karcinoma želuca. Ipak, da li prisustvo bakterije na želudačnoj sluznici utiče na kliničku sliku u ispitanika sa dispeptičkim tegobama nije do kraja razjašnjeno.

Materijal i metodologija: Prospektivna studija obuhvatila je 99 dispeptičnih ispitanika upućenih na peroralnu fiberpanendoskopiju (72 sa i 25 bez infekcije sa Helicobacter pylori). Prisustvo Helicobacter pylori infeckije utvrđivano je upotrebom brzog ureaza testa, patohistološkim pregledom sluzokože želuca i serološki. Svi ispitanici su pre endoskopskog pregleda popunili standardizovani upitnik koji je sadržao informacije o prisutnim poznatim faktorima rizika za nastanak ulkusne bolesti, kao i podatke o prisustvu, intenzitetu i trajanju dispeptičkih tegoba.

Rezultati: Dve grupe ispitanika nisu se razlikovale u pogledu demografskih karakteristika i prisutnih faktora rizika za nastanak ulkusa, izuzev unosa alkohola. Razlika nije uočena u pogledu prisustva dispeptičkih tegoba, ali su trajanje i intenzitet gorušice i povraćanja, kao i veće vrednosti skora dispeptičnih simptoma uočene u ispitanika bez prisutne infekcije sa Helicobacter pylori.

Zaključak: U ispitanika sa kliničkim sindromom dispepsije nije identifikovano postojanje simptoma “tipičnih” za prisustvo infekcije sa Helicobacter pylori. Ipak, uočene su razlike u intenzitetu i trajanju određenih dispeptičkih tegoba u odnosu na prisustvo infekcije.

Ključne reči: Helicobacter pylori, dispepsija, klinička slika

UVOD

Helicobacter pylori (Hp) kolonizuje želudačnu sluzokožu dovodeći do nastanka hroničnog gastritisa u svih inficiranih osoba, dok u nekih dolazi do pojave ulkusa želuca i duodenuma ili karcinoma želuca. Uloga Hp u procesu ulcerogeneze i karcinogeneze prepoznata je ubrzo nakon što su Voren i Maršal identifikovali i kultivisali bakteriju (1,2). Ipak, da li prisustvo Hp infekcije ima uticaja na nastanak neulkusne dispepsije nije bilo razjašnjeno sve dok nisu dobijeni rezultati meta analiza (3,4,5).

Većina autora dispepsiju definiše kao skup simptoma koji potiču iz gornjih delova gastrointestinalnog trakta, a nisu povezani sa procesom defekacije. Ipak, postoje suštinske razlike između različitih definicija dispepsije. Naime, neki autori smatraju da samo prisustvo bola u trbuhu može biti smatrano dispepsijom (6, 7), dok drugi predlažu složenije kriterijume za definiciju dispepsije (8, 9). Vremensko razdoblje u toku koga su tegobe prisutne, u različitim definicijama dispepsije, kreće se od jedne epizode do čak jedne godine (7, 10). Ipak je očigledno da je dispepsija prisutan i značajan zdravstveni problem. Naime prevalenca dispepsije u opštoj populaciji kreće se, po različtim autorima, od 14-40%. (10, 11)

U ovom radu koristili smo definiciju dispepsije koju je predložila Radna grupa za dispepsiju u Rimu 1999. godine, a koja je donela nove kriterijume za klasifikaciju funkcionalne dispepsije (Rim II klasifikacija) (7). Prema ovoj definiciji dispepsija podrazumeva bol ili nelagodnost u epigastrijumu, dok se bol lokalizovan u desnom i levom hipohondrijumu ne smatra reprezentativnim za dispepsiju. Potrebno trajanje tegoba nije precizirano Rim II kriterijumima, ali je preporučeno da se prilikom sprovođenja istraživanja definiše trajanje simptoma, a u cilju poboljšanja homogenosti karakteristika ispitanika obuhvaćenih studijom. Mi smo modifikovali definicju po predlogu Knill-Džonsa koji smatra da dispeptičke tegobe moraju biti prisutne bar 4 nedelje (9).

Cilj studije bio je da utvrdimo ima li razlike u kliničoj slici dispepsije u ispitanika u odnosu na prisustvo infekcije sa Hp.

MATERIJAL I METODE

Ispitanici: Studija je bila prospektivnog karaktera i obuhvatila je 99 dispeptičnih ispitanika upućenih na peroralnu fiberpanendoskopiju, u Institut za bolesti digestivnog sistema - Kliniku za gastroenterologiju i hepatologiju Kliničkog centra Srbije, u periodu od avgusta do decembra 2000. godine. Kod 72 ispitanika pokazano je prisustvo infekcije sa Hp, dok 25 nije bilo inficirano bakterijom. Prosečna starost ispitanika bila je 45 ± 3 godine, 34 ispitanika bila su muškog pola, 37 je bilo pušača, dok je u 31 ispitanika registrovana pozitivna lična anamneza za ulkusnu bolest.

Dispepsija je definisana kao prisustvo bola ili nelagodnosti u epigastrijumu u trajanju bar 4 nedelje, dok bol lokalizovan u desnom i levom hipohondrijumu nije smatran reprezentativnim za dispepsiju (7). Demografski faktori, starost, pol i pušenje su takođe analizirani.

Pre endoskopskog pregleda svi ispitanici su ispunili standardizovani upitnik. Upitnik je sadržao demografske podatke o ispitaniku (starost, pol), podatke o prisutnim faktorima rizika za nastanak ulkusa i detaljne informacije o postojanju, intenzitetu i trajanju dispeptičkih simptoma i znakova. Intenzitet dispeptičkih tegoba procenjivan je upotrebom modifikove petostepene Likertove skale.

Postojanje infekcije sa Hp dijagnostikovano je u slučaju da su rezultati brzog ureaza testa, patohistološkog pregleda i serologije bili pozitivni.

Standardizovani upitnik: U skladu sa preporukama Evropske grupe za proučavanje Hp infekcije (1), za svakog ispitanika uključenog u studiju zabeleženi su sledeći podaci: starost, pol, pušenje, unos alkohola (više od 20g/dan), prisutne dispeptičke tegobe (intenzitet, trajanje), lokalizacija bola, pozitivna lična ili porodična anamneza ulkusne bolesti, ranije epizode krvavljenja iz gornjih partija gastrointestinalnog trakta (hematemeza, melena); unos nesteroidnih antinflamatornih lekova (NSAIL) (češće nego 2 doze nedeljno); druga oboljenja (diabetes mellitus, kardiovaskularne bolesti, hipertenzija, hronični bronhitis, bolesti jetre i bubrega liver, reumatizam), prethodna operacija žučne kesice.

Procena intenziteta dispeptičkih tegoba: Petostepena Likertova skala korišćena je pri proceni intenziteta dispeptičkih tegoba. Prema ovoj skali intenzitet svake od tegoba se gradira od vrednosti 1 do 5, kao što je prethodno opisano u literaturi (12). Na osnovu ove skale izračunavali smo skor dispeptičnih tegoba kao zbir intenziteta svih prisutnih dispeptičkih tegoba.

Rutinski endoskopski pregled i prisustvo infekcije sa Hp: Svi ispitanici podvrgnuti su endoskopskom pregledu i testiranju radi utvrđivanja prisustva infekcije sa Hp upotrebom brzog ureaza testa (Institut za virusologiju i imunologiju Torlak, Beograd, Srbija i Crna Gora) i patohistološkim pregledom. Bojenje tkivnih preseka sluznice antruma i korpusa želuca vršeno je hematoksilin-eozin metodom i tkivnim bojenjem po Giemsa-i. U interpretaciji rezultata patohistološkog pregleda biopsiranih uzoraka korišćen je Sidnejski sistem za klasifikaciju gastritisa(13).

Hp serologija: Uzorci krvi uzeti su od ispitanika nakon endoskopskog pregleda, centrifugiranjem je izdvojen serum I sačuvan do upotrebe na -20 oC. Koncentracija anti-Hp IgG antitela određivana je upotrebom Pyloriset EIA-G IIITM testa (Orion Diagnostica, Finska) (14) prema uputstvu proizvođača.

Statistička obrada podataka: Prilikom analize rezultata korišćeni su neparametarski testovi, Kruskall-Wallis-ov test za nezavisne uzorke, hi-kvadrat i Fišerov test. Vrednosti p< 0.05 smatrane su statistički značajnim.

REZULTATI

Rezultati naše studije pokazali su da nema statistički značajne razlike u demografskim karakteristikama i poznatim faktorima rizika za nastanak ulkusa između ispitanika sa i bez prisutne infekcije sa Hp, izuzev u pogledu unosa alkohola (Tabela 1). Povremeni unos alkohola registrovan je u 92% ispitanika bez i svega 66% sa infekcijom sa Hp (p<0.05).

Takođe, prema rezultatima našeg istraživanja nema dispeptičke tegobe koja je tipična za ispitanike inficirane sa Hp, što je prikazano u Tabeli 2. Ipak, statistički značajna razlika između dve grupe ispitanika uočena je u intenzitetu i trajanju nekih dispeptičkih tegoba (Tabele 3 i 4). Gorušica je intenzivnija i prisutna u dužem vremenskom periodu u ispitanika koji nisu inficirani sa Hp (p<0.01 i p<0.05, respektivno). Isto tako, skor dispeptičkih tegoba bio je statistički značajno niži u ispitanika inficiranih sa Hp(p<0.01), dok je registrovano i statistički značajno kraće trajanje povraćanja u ovoj grupi ispitanika (p<0.01).

Rezultati logističke regresije identifikovali statistički značajnu razliku u prevalenci duodenogastričnog refluksa žuči i vrednosti skora dispeptičkih simptoma između dve grupe ispitanika. Naime, veća vrednost skora i prisustvo refluksa žuči u želudac češći su u ispitanika bez prisutne infekcije sa Hp (Tabela 5).

DISKUSIJA

Kod 73% ispitanika sa kliničkom slikom dispepsije uključenih u našu studiju utvrdjeno je postojanje infekcije sa Hp, što je u skladu sa rezultatima studija sprovedenih u drugim zemljama Evrope (15, 16), mada ima studija koje su pokazale i značajno nižu prevalencu infekcije (17).

Alkohol je konzumiralo 92 % ispitanika bez i svega 66% ispitanika sa prisutnom Hp infekcijom. Moguće objašnjenje za ovu pojavu uključuje aktivaciju lokalnih mehanizama odbrane želudačne sluzokože poznatih pod nazivom adaptivna citoprotekcija. Naime, ponavljano izlaganje želudačne sluzokože malim dozama citotoksičnih supstanci, poput etanola, indukuje sintezu većeg broja enzima i citoprotektivnih supstanci koje dovode do adaptacije na stres i sprečavaju oštećenje sluzokože želuca. Ovaj fenomen proučen je na animalnom modelu od strane Kontureka I saradnika i predstavlja moguće objašnjenje našeg rezultata (18). Sa druge strane, nedavno objavljeni rezultati grupe nemačkih autora (19), pokazali su da ispitanici koji uzimaju alkohol ili puše češće imaju dispeptičke tegobe koje nisu vezane za prisustvo infekcije sa Hp, što podražava tezu da bi promena načina života, uključujući i psihološko savetovanje, morala biti preporučena ovoj podgrupi ispitanika.

Antibakterijski efekat žuči na Hp, pokazan je u nekim (20), ali ne svim studijama (21), a predstavlja moguće opbjašnjenje odsustva infekcije u većine ispitanika sa duodenogastričnim refluksom žuči uočenim u toku endoskopije.

Odsustvo tipičnih simptoma u dispeptičnih iswpitanika inficiranih sa Hp uočen je od strane drugih autora u različitim populacijama (22, 23). Ipak, rezultati naše studije pokazali su da su veći intenzitet i duže trajanje gorušice i povraćanja u ispitanika bez prisutne infekcije sa Hp, suprotno rezultatioma drugih autora (22). Moguće objašnjenje je češće prisustvo duodenogastričnog refluksa žuči u ovoj grupi ispitanika, što je u skladu sa rezultatima koje smo dobili primenom logističke regresije.

Efekti eradikacione terapije u ispitanika sa neulkusnom dispepsijom još uvek su predmet rasprava između različitih autora. Neki (24), ali ne svi autori (25) smatraju da nema dokaza da eradikacija infekcije u ovih ispitanika dovodi do kliničkog poboljšanja i da je neki patofiziološki mehanizam nezavisan od prisustva infekcije sa Hp odgovoran za nastanak dispepsije u ovih ispitanika.

Rezultati naše studije pokazuju da prisustvo infekcije sa Hp ne može biti dovedeno u vezu ni sa jednim dispeptičkim simptomom i da se veče vrednosti skora dispeptičkih simptoma registruju u ispitanika bez prisutne infekcije. Smatramo da je dalje istraživanje neophodno u cilju jasnijeg definisanja patofiziološkog mehanizma odgovornog za nastanak sindroma gornje dispepsije.