Alimentary tract and pancreas
Alimentarni trakt i
pankreas
ARCH GASTROENTEROHEPATOL 2002; 21 ( No 1 – 2
):
( accepted February 20th, 2002 )
Section for Gastroenterology, Department of Internal Medicine,
Health Center of Leskovac, Leskovac.
Abrevations
used in this article:
H.
pylori, Helicobacter pylori;
GERD, gastroesophageal reflux disease;
IM, intestinal metaplasia.
Addres correspondence to:
Prim. dr sc. med. Saša Grgov
Department
of Medicine,
Health Center of Leskovac,
116 Svetozara Markovića St.,
Yu- 16000 Leskovac,
Serbia, Yugoslavia
FAX: + 381 16 247810
E-mail:
[email protected]
……………
………………………..
H.pylori,
carditis, gastroesophageal
reflux Gastroenteroloska sekcija
SLD-
01733, 2002.
GRGOV
The relationship between H. pylori, carditis with or without intestinal metaplasia of the cardia, and gastroesophageal reflux disease is not clear enough. There are two divergent opinions about the pathogenesis of carditis and intestinal metaplasia of the cardia. According to one, carditis is the consequence of gastroesophageal reflux disease and represents the histological indicator of reflux disease. According to another, carditis and intestinal metaplasia of the cardia are related with H. pylori infection and are a part of clinical manifestation of multifocal H. pylori gastritis. The latest studies showed that in patients with normally located Z-line, without Barrett's esophagus, intestinal metaplasia of the cardiac mucosa is possibly the consequence of the multifocal atrophic H. pylori gastritis and significantly associated with gastric intestinal metaplasia. By contrast, in the case of endoscopic presence of Barrett's esophagus, intestinal metaplasia of cardiac mucosa is related to gastroesophageal reflux disease, but not with H. pylori infection, and more frequently contains dysplasia. However, further studies are neccessary to prove the low risk of H. pylori-associated cardiac intestinal metaplasia for the development of cardiac carcinoma.
Key words: Helicobacter pylori, gastroesophageal reflux disease, cardia,
intestinal metaplasia.
GRGOV
Odnosi
između H. pylori, karditisa sa ili
bez intestinalne metaplazije kardije i gastroezofagusne refluksne bolesti nisu
dovoljno jasni. Postoje dva divergentna mišljenja o tome šta je u osnovi
karditisa i intestinalne metaplazije kardije. Prema jednom, karditis je
posledica gastroezofagusne refluksne
bolesti i predstavlja histološki indikator refluksne bolesti. Prema drugom,
karditis i intestinalna metaplazija kardije su u vezi sa H. pylori infekcijom i deo su kliničke manifestacije multifokalnog H. pylori gastritisa. Nedavna
ispitivanja su pokazala da u
pacijenata sa normalno lokalizovanom Z-linijom, bez Barrett-ovog ezofagusa,
intestinalna metaplazija mukoze kardije bi bila posledica multifokalnog
atrofičnog H. pylori gastritisa i
signifikantno je bila udružena sa gastričnom intestinalnom metaplazijom.
Nasuprot tome, u slučaju endoskopskog prisustva Barrett-ovog ezofagusa,
intestinalna metaplazija mukoze kardije je u vezi sa refluksnom bolešću, ali ne
i sa H. pylori infekcijom i sadrži
mnogo češće displaziju. Ipak, dalja istraživanja su potrebna da bi se potvrdio
nizak rizik od razvoja karcinoma kardije kod pacijenata sa intestinalnom
metaplazijom kardije povezanom sa H.
pylori infekcijom.
Ključne reči: Helicobacter pylori, gastroezofagusna refluksna bolest, kardija, intestinalna metaplazija.
GRGOV
In the last twenty years, in the developed countries, the prevalence and incidence of the gastroesophageal reflux disease (GERD), esophageal and cardiac adenocarcinomas increased, while the prevalence of duodenal ulcer and gastric cancer as well as the prevalence of Helicobacter pylori (H. pylori) infection have been decreasing. This observation has imposed many studies about the possible relationship between GERD and H. pylori, as well as researches about the possible role of H. pylori and/or GERD in the pathogenesis of carditis and intestinal metaplasia of the cardia.
In GERD patients, the pH of gastric refluxate is the main cause of esophageal mucosal injury. Therefore, the development of GERD is likely to depend on the pattern and severity of H. pylori-associated gastritis. Patients with antral predominant gastritis, such as duodenal ulcer patients, have normal or increased gastric acid secretion and in these people H. pylori can lead to GERD deterioration. If it is a more difficult stage of pangastritis or corpus predominant gastritis, gastric pH is above 3 or 3.5, so in this form of gastritis H. pylori protects from the further development of GERD (1). However, definite conclusions about this matter need further prospective researches.
In the
majority of patients with GERD, the biggest number of reflux episodes occurs
during the transitory relaxations of lower esophageal sphincter. Some studies
have shown that GERD patients show increased relaxation of the proximal part of
the stomach during meals. This phenomenon can be the starter of transitory
relaxation of lower esophageal sphincter and reflux. However, although there is
currently no evidence that H. pylori
infection can alter gastric wall compliance or postprandial fundic relaxation
in dyspeptic subjects, no data are available in GERD patients as yet (2-4). Therefore, according to the recent
researches by Zerbib and associates, the frequency of transitory relaxations of
lower esophageal sphincter caused by gastric distension, does not differ
significantly between H. pylori
positive people and the control group of H.
pylori negative people (5).
Some authors suggested that H. pylori infection might sensitize the gastroesophageal junction to acid, especially in the subgroup of patients with non-erosive GERD. Manes and associates have found an increased prevalence of H. pylori infection in patients with non-erosive GERD (62%) in comparison to healthy persons (40%) and patients with erosive GERD (36%) (6). Dilated intercellular spaces, as the consequence of separation of intercellular junction of epithelium, estimated by electron microscopy, can represent the earliest event in the course of esophageal damage by acid. Latest studies by Villanacci and associates have shown that the dilated intercellular spaces, as the earliest marker of reflux esophageal damage, can be diagnosed histologically and evaluated semiquantitatively (7).
The results of a number of clinical examinations of the relationships between H. pylori and GERD are controversial. Many studies in countries with low H. pylori incidence report little or no difference of H. pylori prevalence in GERD patients versus controls. Thus, for example, the American study by Oberg and his associates, has not established relationship between antral H. pylori presence and the clinical, endoscopical and histological manifestations of GERD (8). Also, in the big Finish study, the relationship between H. pylori and GERD has not been found (9).
As opposed to the previous studies, Wu and associates have found, on the population from Hong Kong, that the prevalence of H. pylori is significantly lower (31%) in 106 GERD patients than in 120 controls (61%) (10). Their further researches have shown that H. pylori positive patients with GERD have a milder form of GERD in comparison to H. pylori negative cases (11). Koike and associates reported H. pylori positivity in 33.7% of patients with reflux esophagitis, as compared with 72% in controls. The atrophy score in antrum and body was lower in reflux patients than in controls, and among H. pylori positive patients, atrophic gastritis was milder in patients with reflux esophagitis than in patients without it (12).
The virulent strains of H. pylori (cagA positive/iceA1) are significantly less present in GERD patients than non-virulent, and thus, it is believed that these strains can protect from the development of GERD (13). Vicari and associates have found the inverse relation between cagA prevalence and GERD complications: cagA-positive H. pylori prevalence was 42.3% in the control group, 41.2% in non-erosive GERD, 30.8% in erosive GERD, 13.3% in Barrett's esophagus, and 0% in Barrett's esophagus with adenocarcinoma or dysplasia (14).
The gastric cardia represents an area of a few centimetres directly under normally located squamocolumnar junction or the so-called Z-line. Under normal circumstances squamocolumnar junction coincides with the esophagogastric junction. Barrett’s esophagus is defined as the presence of columnar type mucosa with specialized intestinal metaplasoa (IM), proximally from esophagogastric junction, 2 (3) cm long (a short segment Barrett’s esophagus) or more than 2 (3) cm long (a long segment Barrett’s esophagus). Apart from that, IM can exist also in the level of normally located squamocolumnar junction without Barrett’s esophagus (15-17).
The techniques of colouring esophagus in methylene blue should increase the possibility of the esophagogastric junction IM and dysplasia detection, with reducing of the so-called sampling error existing in the conventional biopsy techniques. According to certain authors, the sensitivity and specificity of these colouring techniques is 95% and 97%, respectively (18,19). The latest studies by Sharma and associates have shown that the use of colouring esophagus in methylene blue significantly increases the possibility of IM detection with a smaller number of biopsies, in comparison to the randomly taken biopsies, in patients with suspected short segment Barrett’s esophagus. However, in patients with irregular Z-lines (< 1 cm of columnar mucosa) the advantage of this method has not been proved (20). According to the results of Wo and associates, methylene blue chromoendoscopy gives exactly the same results as the conventional biopsy in the detection of IM and dysplasia. This method has not shown any advantage in the diagnosis of the short segment Barrett’s esophagus (17). The results show that further researches are needed with the aim of standardising the technique of colouring in methylene blue and determining the adequate protocol of taking biopsy samples.
The scientific studies of chronic inflammatory changes of cardia (carditis) and IM of the cardia and esophagogastric junction since recently have aroused great interest, because of the hypothesis that these changes can represent precursor lesions for the development of esophageal and cardiac adenocarcinomas.
There are two divergent opinions about what is in the basis of carditis and IM of the cardia. According to one, carditis is the consequence of GERD and represents the histological indicator of GERD. According to another, carditis and IM of the cardia are in relation with H. pylori infection and are a part of clinical manifestation of multifocal H. pylori gastritis (21-24).
Csendes and associates have examined 500 patients with the aim to establish the relation between carditis and GERD. The prevalence of carditis in patients with reflux disease was 50% whereas in patients without reflux disease was less than 10%. IM was found in over 10% of patients with reflux disease and in only 2% of controls. According to this study, presence of GERD significantly correlates with finding of carditis and/or IM of the cardia, so that carditis represents an objective histological marker for GERD (25). Goldstein and associates have examined 150 patients by endoscopic biopsies from the cardia. Forty-two of these patients were infected with H. pylori. In the H. pylori negative patients cardia inflammation was correlated with the presence of squamous inflammation of the esophagus or GERD. In those infected with H. pylori, cardia inflammation was correlated with antral inflammation and the presence of H. pylori in the cardia. This study has shown that GERD is responsible for carditis in the absence of H. pylori infection (26).
Voutilainen and associates have examined the prevalence of carditis in a large population of more than 1000 patients undergoing upper gastrointestinal endoscopy for dyspepsia. In patients with normally located Z-line, carditis was present in 75% of cases, associated in 69% with chronic inflammation in the stomach. In multivariate analyses, only H. pylori infection was associated with carditis in patients with chronic gastritis. By contrast, in patients without chronic gastritis, carditis was significantly associated with erosive esophagitis. These results have shown that carditis may be the consequence of either H. pylori infection when chronic gastritis is present or GERD when inflammation is absent in the stomach (27).
Genta and associates have examined the degree of inflammation in the cardia of 42 patients with H. pylori infection. Forty of the 42 (95%) had H. pylori in the cardia. The inflammation in the cardia paralleled that of the antrum, with both being more severe than the gastric body. However, there were fewer lymphoid aggregates in the cardia (28). Golblium and associates found H. pylori infection in 97% of patients with carditis (29). Also, the researches by Pieramico and Zanetti, on 122 patients with GERD and 49 controls, have shown that the inflammation and IM of cardia are in relation with H. pylori infection, and not in relation with GERD (30). Sharma and associates have examined 31 patients with carditis and H. pylori infection. The patients have been monitored after the eradication of H. pylori on average 23.2 months (range: 6-48 months). In patients with successful eradication of H. pylori there was a significant reduction of the degree of inflammation and the inflammatory activity of the cardiac mucosa. The effects of H. pylori eradication on IM and atrophy was not evaluated because of the small number of patients with these lesions. The results indicate that H. pylori is the direct aetiologic factor for carditis, but they do not exclude the presence of other causes of carditis, such as gastric acid (31).
IM is commonly found in biopsy specimens obtained from the cardiac mucosa, but the relationships between IM, H. pylori infection and GERD are unclear, especially when erosive esophagitis or Barrett’s esophagus are present. Hackelsberger and associates have examined the prevalence of IM in the cardia in relation to the endoscopic aspect of the squamocolumnar junction in 423 patients. In patients with normal squamocolumnar junction, cardiac IM was found with a prevalence of 13.4% and was significantly associated with gastric IM and H. pylori infection. As opposed to this, IM was found in 34.3% of patients with endoscopic features of Barrett’s esophagus (including short segments), and associated with erosive esophagitis and male sex, but not with gastric IM and H. pylori infection (32).
According to the results of Voutilainen and associates, prevalence of IM at the gastroesophageal junction was 22.2%, in a large cohort of patients without endoscopic signs of Barrett’s esophagus. Complete junctional IM was significantly associated with multifocal atrophic H. pylori gastritis, while incomplete IM was associated with enoscopically detected erosive esophagitis, carditis, but not with H. pylori infection (33). Their further researches have shown that the incomplete IM most likely is not the direct precursor of Barrett’s esophagus. In comparison to Barrett’s esophagus, dysplasia in incomplete IM without Barrett’s esophagus is a rare finding, so that endoscopic monitoring with the aim to prevent junctional adenocarcinoma in these patients is not recommended (15).
According to the large study by Hirota and associates, on 889 patients, similar prevalence of short segment Barrett’s esophagus (6%) and IM of the esophagogastric junction with normally located Z-line (5.6%) was established, but each entity was 3.5 times more prevalent than the long segment Barrett’s esophagus (1.6%). The prevalence of dysplasia was two times larger in the long segment Barrett’s esophagus (15%) in comparison to the short segment Barrett’s esophagus (8%), and four times larger in comparison to IM of the esophagogastric junction without Barrett’s esophagus (4.3%). H. pylori on esophagogastric junction was detected in 21.3% of patients with IM without Barrett’s esophagus, and in 4.7% of patients with short segment Barrett’s esophagus and in 2.5% of patients with long segment Barrett’s esophagus. If monitoring of these patients is applied with the aim of early discovery of junctional adenocarcinoma, the monitoring interval should be shorter in patients with long segment Barrett’s esophagus, in comparison to the patients with short segment Barrett’s esophagus, but in the patients with IM of the esophagogastric junction without Barrett’s esophagus the period should be the longest or the monitoring is even not recommended (16).
Based on the results of the up-to-now researches, a conclusion can be drawn that, in patients with normally located Z-line, IM at the esophagogastric junction may be different from IM associated with Barrett’s esophagus. In patients with normally located Z-line (without Barrett's), IM of the cardiac mucosa would be the consequence of the multifocal atrophic gastritis related to H. pylori infection. By contrast, when endoscopic features suggestive of Barrett's esophagus are present, IM in cardiac mucosa is related to GERD independently of H. pylori infection, it is predominant in male sex, more frequently contains dysplasia and represents precursor lesion for the development of junctional and esophageal adenocarcinoma. However, further researches are needed to prove the low risk of H. pylori-associated cardiac IM (21).
The relationships between H. pylori eradication and the development of either GERD symptoms or endoscopic esophagitis are controversial. According to Hamada and associates, eradication of H. pylori increases the frequency of reflux esophagitis in patients with corpus gastritis - incidence of reflux eshophagitis, after three years of monitoring, was 18% in eradicated patients and 0.3% in not treated H. pylori positive patients. The patients who developed reflux esophagitis had significantly higher prevalence of hiatal hernia and severe corpus gastritis before treatment (34).
Labenz and associates have shown that the treatment of H. pylori infection can provoke reflux esophagitis, in patients with duodenal ulcer - incidence of reflux esophagitis in three years was 25.8% in eradicated patients and 12.9% in patients with not-treated H. pylori infection. The patients who developed reflux esophagitis after the treatment of H. pylori infection had much more severe corpus gastritis before the treatment, gained in weight, after the treatment, more frequently than others and were predominantly male (35). Also, Fallone and associates have found that reflux esophagitis was significantly more prevalent in eradicated patients with duodenal ulcer (37%) than in non-eradicated (13%), one year after the eradication therapy (36).
As opposed to these results, Vakil and associates have not found a significant difference in the frequency of new GERD symptoms, between eradicated (22%) and non-eradicated (15%) duodenal ulcer patients, six months after the eradication therapy (37). Mc Coll and associates, by observing in period from one to three years, 97 patients with duodenal ulcer and/or gastric ulcer, have not found that eradication of H. pylori infection provokes significantly more frequent newly aroused GERD symptoms (38). Also, our prospective study showed that there was not a significant difference in the frequency of the newly occurred reflux esophagitis, one year after the eradication therapy of H. pylori, between eradicated (8.2%) and non-eradicated duodenal ulcer patients (5.9%) (39).
The reason for discrepancy in results of the above mentioned studies is not clear. Since ulcer disease and GERD are commonly associated, it has been suggested that reflux symptoms could be unmasked by either withdrawal of acid inhibitory therapy or disappearance of ulcer-associated symptoms (37).
In GERD patients, most likely the eradication of H. pylori infection does not have influence on the course of GERD. Tefera and associates have established, by 24-hour esophageal pH-monitoring, that eradication of H. pylori does not cause any kind of changes in gastroesophageal reflux (40). Axon and associates have included in rendomised double-blind study over 250 H. pylori positive patients with a mild form of GERD. As compared with the control group, H. pylori eradication did not significantly change the course of the disease evaluated by the relapse rate at 1 year and the time to first relapse (41).
However, some studies have pointed to the reduction in the efficiency of antisecretory drugs after the eradication of H. pylori, which would point to the mechanism of possible deterioration of GERD after the eradication of H. pylori. Van Herwarrden and associates showed that nocturnal acid breakthrough during proton pump inhibitors treatment occurred more frequently after eradication of H. pylori (42). Katsube and associates showed that nocturnal acid breakthrough occurred more often in H. pylori negative than in H. pylori positive volunteers (43). However, the prevailing attitude is that the minimal fall of the efficiency of the proton pump inhibitors after the eradication of H. pylori, without the practical implications, should not be an argument against the decision of treating the infection in patients with GERD (21).
Does the prolonged antisecretory therapy with the proton pump inhibitors in the presence of H. pylori infection in GERD patients favour the development of atrophic gastritis, is the topic of many debates (44). Kuipers and associates examined H. pylori positive patents with GERD, treated with 20-40 mg omeprazole (105 patients) or with fundoplication (72 patients), in the period of 3-8 years. Their examinations showed that treatment with omeprazole increases the risk of development of glandular corpus atrophy in H. pylori positive patients (45).
As opposed to this, a three-year long, prospective rendomised study by Lundell and associates, on 155 GERD patients (40 H. pylori positive) treated with omeprazole and 155 GERD patents (53 H. pylori positive) treated with antireflux surgery, showed that in both groups of patients there was a mild progression of inflammation, atrophy and IM, but the incidence of atrophic gastritis was not different in patients treated with omeprazole or treated surgically (46). These examinations by Lundell and associates were criticised by some European experts. Considering the fact that not much is known about kinetics of atrophic changes during antisecretory therapy, the period of three years of monitoring patients would be too short to see the real effects of therapy, implying that a beta-type statistical error cannot be excluded (47-50).
The imposed question is if the eradication therapy of H. pylori can prevent eventual development of atrophic gastritis, during a long-term therapy with proton pump inhibitors, in GERD patients. Some studies show that by eradicating of H. pylori can prevent the development of corpus gastritis during therapy with omeprazole (51), but in order to make definite conclusions large multicentric studies are needed (52, 53).
It seems that H. pylori does not have an important role in the pathogenesis of GERD. In the presence of H. pylori infection a short-term increase of the efficiency of antisecretory drugs was noticed, but there are not any proof about a long-term influence of H. pylori on the therapeutic effect of these drugs. Recent data firmly show that a in a certain group of patients long-term use of the proton pump inhibitors may impose an increased risk for the development of hypochlorhydria and gastric cancer. In these cases the benefit of H. pylori eradication can surpass the potential risk of the development of de novo gastroesophageal reflux or the unmasking pre-existing reflux symptoms (21). The latest Maastricht 2 consensus agreed that H. pylori eradication is not associated with the development of GERD and does not exacerbate existing GERD. It considers eradication of H. pylori as advisable in patients who require long-term profound acid suppression with proton pump inhibitors (54).
GRGOV
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