Drugs 44 (6): 921-927. 1992 00 12-6667/92/00 12-0921/$03 .50/0 © Adis International Limited . All rights reserved . DRU1217

Role of Helicobacter pylori in Duodenal Ulcer E.A.J. Rauws Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef, Amsterdam, The Netherlands

Numerous studies have demonstrated the association between antral gastritis and Helicobacter pylori infection (Buck et al. 1986; Marshall & Warren 1984; Warren & Marshall 1983). Human volunteer studies (Marshall et al. 1985; Morris & Nicholson 1987) and accidental inoculations (Graham et al. 1988; Langenberg et al. 1990; Wiersinga & Tytgat 1977) with H. pylori have confirmed the pathogenetic role of this microorganism in active chronic gastritis. However, the pathogenetic role of H. pylori infection in duodenal ulcer disease is less clear. Duodenal ulcer disease has a multifactorial aetiology and is believed to be the end-point of an imbalance between various aggressive and defensive mechanisms. Many aggressive factors have been identified , including acid and pepsin, duodenogastric reflux, and recently also H. pylori colonisation. The relative importance of each individual factor is still not clear. H. pylori is not found in association with intestinal-type epithelium. In the presence of gastric mucin cell metaplasia in the duodenum, considered to be a response to hyperacidity, H. pylori is able to colonise the duodenal mucosa (Wyatt et al. 1987, 1990). Subsequently, impairment of the mucosal defence mechanism leads to active duodenitis and renders the mucosa susceptible to ulceration. This sequence of events ultimately leading to duodenal ulceration is not proven , but eradication of H. pylori with bismuth compounds, with or without additional antibiotics, enhances ulcer healing (Graham et al. 1991 b) and greatly reduces the

ulcer relapse rate (Borody et al. 1989; Borsch et al. 1988; Coghlan et al. 1987; George et al. 1990; Lambert et al. 1987; Marshall et al. 1988; Rauws & Tytgat 1990; Smith et al. 1988), strongly suggestingan important aetiological role for H. pylori infection in duodenal ulcer disease.

1. Epidemiology In 1983 was suggested that H. pylori is strongly involved in the aetiology of duodenal ulcers (Warren & Marshall 1983). H. pylori is found in almost all patients with endoscopically proven duodenal ulcers, but about 50% of patients with nonulcer dyspepsia and about 20% of asymptomatic volunteers are also colonised by H. pylori, but without ulceration (Rauws et al. 1988). The peak incidence of duodenal ulcer disease is around 45 to 55 years of age, but the prevalence of H. pylori infection increases with age reaching 60 to 70%at the age of 70 years (Dooley et al. 1989; Graham et al. 1988). Remarkably, a relatively isolated group of Australian Aboriginals showed a seroprevalence of H. pylori infection of only 0.7% (Dwyer et al. 1988) and have virtually no peptic ulcer disease (Bateson 1976). 20 to 50% of patients with duodenal ulcer have a positive family history, with first-degree relatives having a 2- to 3-fold increased risk to develop an ulcer (McConnell 1966). Duodenal ulcers are also more common in


patients with bloodgroup 0, nonsecretors and those with hyperpepsinogenaemia, all suggesting that inherited factors are also involved in ulcer pathogenesis (Rotter 1980; Samloff et al. 1986). From these epidemiological data it can be concluded that duodenal ulcer disease is strongly associated with H. pylori infection. H. pylori infection is also a marker for antral gastritis which is known to be associated with duodenal ulceration, or H. pylori plays a direct role in causing ulceration.

2. Pathogenesis of Duodenal Ulcers As well as many aggressive factors, defensive mechanisms such as an intact mucus barrier, bicarbonate secretion and mucosal blood flow, also play an important role in the pathogenesis of duodenal ulcers (Peterson 1991; Soli 1990). For example, because only 30 to 40% of patients with duodenal ulcer disease have acid secretion rates above the normal range, it had already been previously suggested that other factors apart from acid and pepsin must be important as well. The isolation of H. pylori from the human stomach generated much excitement, especially when it was shown that this microorganism was the cause of gastritis and probably played a dominant role in the pathogenesis of peptic ulcer disease. H. pylori displays potent urease activity (Eaton et al. 1990; Marshall et al. 1990; Smoot et al. 1990), a property that may have important pathogenetic implications. Bacterial hydrolysis of urea to ammonium ions may produce an alkaline environment around the microorganisms. In parietal cells, excess ammonia combines with hydrogen ions to form ammonium ions which are secreted in preference to hydrogen ions, probably leading to parietal cell failure and hypo- or even achlorhydria. Hypochlorhydria, usually temporarily, has indeed been reported during the initial phase of H. pylori colonisation (Graham et al. 1988; Morris & Nicholson 1987; Ramsey et al. 1979). Also as a consequence of generating ammonia, H. pylori may disturb the normal negative feedback of acid to the antral G-cells (granular enter-

Drugs 44 (6) 1992

ochromaffin cells which secrete gastrin) [Levi et al. 1989]. This group reported that patients with active duodenal ulcers and H. pylori infection secreted more acid and released more gastrin in response to a test meal than uncolonised patients. The mechanism by which H. pylori infection of the gastric antrum increases basal and meal-stimulated plasma gastrin levels is unclear. It has been suggested that it might be the result of the ammonia produced by the microorganisms raising antral surface pH and thus prevents acid inhibition of the gastrin release by the gastrin-producing G-cells. Other investigators have confirmed this , and also shown that the exaggerated gastrin response to a meal is reversed after H. pylori has been eradicated (Graham et al. 1990, 1991a; McColl et al. 1991). These data strongly support the view that chronic infection with H. pylori is the cause of this increased circulating levels of gastrin . However, eradication of H. pylori and a decrease in gastrin levels does not change the overall acid output, and casts some doubt on the importance of the elevated gastrin levels in the pathogenesis of duodenal ulceration. In addition, H. pylori produces catalases , lipases, phospholipases, proteolytic enzymes, adhesins and toxins. After attaching to the epithelial cell, these enzymes, metabolic products and toxins may reach the epithelial cell membrane. Proteases, lipases and phospholipases may reduce the important mucosal defence by degrading the mucous layer and damaging the lipid-containing epithelial cell membrane. Figura et al. (1989) demonstrated that cytotoxin-producing strains of H. pylori were isolated more frequently from patients with peptic ulcer disease (66.6%) than from patients with chronic gastritis only (30.1%; p < 0.01). Finally, H. pylori antigens elicit an immune response. Crabtree et al. (1991) studied mucosal IgA response to H. pylori using immunoblotting techniques. Of 19 patients with chronic gastritis who did not recognise a 120kD protein none had peptic ulcers, whereas 25 of 57 with positive recognition had peptic ulcers (p < 0.001), suggesting virulence differences between the various H. pylori isolates.


Helicobacter pylori in Duodenal Ulcer

3. H. pylori and Gastritis H. pylori is the most common cause of acute and chronic gastritis. Most information about acute H. pylori infection comes from volunteer studies (Marshall et al. 1985; Morris & Nicholson 1987) and accidental inoculation during acid secretion studies (Gledhill et al. 1985; Graham et al. 1988; Ramsey et al. 1979). In both volunteer studies, the subjects had normal gastric mucosa before they swallowed the H. pylori isolate . Repeat endoscopy and biopsy revealed active chronic gastritis, and spiral bacilli were seen adhering to the surface epithelium. Successful eradication of the organism, especially by an antibiotic with no known intrinsic effect towards the gastric mucosa, leads to normalisation of the gastric mucosa, thus supporting the evidence for the pathogenetic role of H. pylori in causing inflammation. H. pylori is highly adapted to the mucus that covers gastric-type epithelial cells. Patients with duodenal ulceration are known to have chronic antral gastritis characterised by a chronic inflammatory infiltrate associated with lymphoid follicles. The body mucosa is usually normal or shows only minimal inflammation. This type of gastritis does not progress proximally into the body mucosa (Jonsson et al. 1988; Kekki et al. 1984), so there is no loss of acid secretory capacity. Grading of gastritis and the extent of its presence (antrum or corpus or both) correlates with the function of the gastric mucosa (Sipponen et al. 1989). Gastritic and atrophic alterations markedly affect the function of gastric mucosa, for instance with regard to the release of gastrin from the antral glands or the secretion of acid and pepsin from the oxyntic body mucosa (Siurala et al. 1985; Varis et al. 1979). The classification of atrophy as slight, moderate, or severe (total) , correlates nearly linearly with a decrease in the output of acid, pepsins and gastrin. Gastritis may also impair mucosal resistance. Atrophic gastritis affects synthesis, composition, and thickness of the mucous layer at the gastric surface (Domschke et al. 1981). These effects may

influence the physiological homeostasis of the stomach and may also modulate the risk and likelihood of an individual developing a peptic ulcer. The relative risk of duodenal ulcer is approximately 20-fold in subjects with antral gastritis and nearly normal corpus mucosa, compared with those who have an endoscopically and histologically normal antrum (Sipponen et al. 1989).

4. H. pylori and Duodenitis H. pylori is only found in inflamed duodenal mucosa, and only in association with gastric epithelium (gastric metaplasia) in the duodenum. Gastric metaplasia is common and, as small foci, has been found in 64% of normal subjects (Kreuning et al. 1978). The condition is considered to be either a defence mechanism or change in response to damage, i.e. acid entering the duodenum (Rhodes 1964). Wyatt et al. (1987) investigated the strength of the association between the presence of H. pylori, gastric metaplasia and duodenitis. In general the more extensive the metaplasia, the more likely there was to be duodenitis, and active duodenitis was rarely present if only small foci of gastric metaplasia exist. This study showed that duodenitis is present in those patients with H. pylori-induced gastritis and gastric metaplasia in the duodenum. These results are consistent with the hypothesis that duodenitis is the result of duodenal colonisation by H. pylori. Gastric metaplasia is found in the margins of duodenal ulcers and scars of healed ulcers. Furthermore, if the acid secretion is diminished, for instance after highly selective vagotomy, then gastric metaplasia is reversed.

5. H. pylori and Duodenal Ulcer Acid suppressive therapy with H2-receptor antagonists or proton pump inhibitors, which have no effect on the presence of H. pylori, leads to ulcer healing. On the other hand, sucralfate and bismuth compounds, which lack any effect on gastric acid secretion, also heal ulcers at .the same rate as acid

Drugs 44 (6) 1992


suppressive agents. However, sucralfate and bismuth compounds have many modes of action. One of the intriguing effects of tripotassium dicitrato bismuthate (colloidal bismuth subcitrate) is its bactericidal effect against H. pylori, an effect absent in all other conventional ulcer healing agents (Marshall et al. 1984, 1987). It has been suggested that the lower duodenal ulcer relapse rate after healing with bismuth compounds might be caused by its anti-Helicobacter bactericidal effect (Hamilton et al. 1986; Lane & Lee 1988; Lee et al. 1985; Martin et al. 1981). This is, however, difficult to prove, since colloidal bismuth has several effects other than its antimicrobial activity (Konturek et al. 1987; Lavy et al. 1976; Lee 1982), including stimulation of prostaglandin E2 production with subsequent secretion of alkali into the mucus layer, reduction of pepsin production, and formation of a glycoprotein-bismuth complex in the gastric mucus layer. The strongest evidence that H. pylori infection is important in duodenal ulcer comes from studies of regimens containing a bismuth compound with or without additional antibiotics, in which the ulcer recurrence correlates with eradication of H. pylori (table I). A bismuth compound as monotherapy eradicates H. pylori in about 10 to 20% of patients after 4 to 6 weeks of therapy; combination with I or 2

antibiotics produces eradication in up to 90%. Effective elimination of H. pylori appears to require this combination antibiotic therapy, although the optimal therapeutic regimen, dosage, duration of treatment, formulat ion, etc., are still not known. Various antibiotics are effective in vitro, but in vitro efficacydoes not correlate well with the clinical eradication rates (Goodwin et al. 1986; McNulty et al. 1985). Eradication of H. pylori is not necessary for duodenal ulcer healing, but these ulcers rapidly recur after stopping therapy (Dobrilla et al. 1988; Graham 1989; Lane & Lee 1988). Several studies have shown that eradicating of H. pylori alters the natural history of duodenal ulcer disease. Patients in whom H. pylori was not successfully eradicated were more likely to experience the well-known ulcer recurrence, comparable with ulcer relapse after initial successful ulcer healing with H2-receptor antagonists. In an extension of this concept, Graham et al. (1991b) studied whether antimicrobial therapy to eradicate H. pylori infection actually accelerates duodenal ulcer healing. They randomised 105 patients with active duodenal ulcer to receive daily either ranitidine 300mg alone or plus tetracycline 2g, metronidazole 750mg, and 5 or 8 tablets ofbismuth salicylate per day. The antimicrobials were

Table I. Duodenal ulcer (DU) relapse rate during follow-up in relation to H. pylori status


Sorody et al. (1989) Coghlan et al. (1987) George et al. (1990) Lambert et al. (1987) Marshall et al. (1988) Rauws & Tytgat (1990)

Smith et al. (1988)


Sis + Tet + Met Cim or Sis Sis + Tet + Met Sis Cim ± Tin or Sis ± TIn Sis or Sis + Amx + Met Ran or Sis

No. of patients

Follow-up (months)

H. pylori status (n) [% with DU relapse]



3 [75] 29 [76]

58 39 62 45 70

9-37 12 12-48 6 12

33 [76] 47 [81]

54 [0] 10 [10] 62 [0] 12 [0] 23 [22]



21 [81]

17 [0]



35 [80]

9 [0]

Abbreviations and symbols: Amx = amoxicillin; Sis = tripotassium dicitrato bismuthate; Cim Ran = ranitidine; Tet = tetracycline; Tin = tinidazole; - indicates that results were not stated.

= clmetidine;


= metronidazole;

Helicoba cter pylori in Duodenal Ulcer

only given during the first 2 weeks of treatment. Repeat endoscopy was performed after 2, 4, 8, 12 and 16 weeks. In this study, combined therapy with antimicrobials and ranitidine resulted in a significantly superior ulcer healing rate compared with ranitidine monotherapy. The cumulative percentages of patients with healed ulcers in the group receiving ranitidine plus antibiotics versus ranitidine monotherapy recipients were 37 vs 18% after 2 weeks; 74 vs 53% at week 4; 84 vs 68% at week 8; 96 vs 80% at week 12; and 98 vs 84% at week 16. These data again indicate that H. pylori infection is important in duodenal ulcer disease.

6. Conclusion Duodenal ulceration is a multifactorial disease. Neither gastric acid and pepsin secretion, nor H. pylori infection alone can explain why only some people develop ulcers but the majority do not. Other factors must also be involved in the pathogenesis of duodenal ulceration. Most recent data suggest, however, that although other poorly delineated factors may modify the risk of ulceration, acid and pepsin secretion synergistically with H. pylori infection are by far the most important factors in ulcer pathogenesis. Treatment with acid-suppressive therapy or bismuth-antibiotic combinations heals ulcers at an equivalent rate. However, treatment with bismuth compounds with or without antibiotics leads to remission of the mucosal inflammation and reduces the duodenal ulcer relapse rate, but only if H. pylori has been successfully eradicated. The optimal regimen to eradicate H. pylori is not yet known, but probably in the near future short courses of triple therapy or antibiotic combinations with acid-suppressive drugs may prove to be effective, free from significant side effects, and free from inducing microbial resistance. One should carefully assess the possible risks versus potential benefits of anti-Helicobacter therap y for the individual patient. It has been suggested that therapy aimed at eradicating H. pylori should only be considered if


duodenal ulcer is a serious management problem requiring either continuous medication or before considering surgery, or if complications like bleeding or perforation have occurred (Tytgat et al. 1990). If anti-H. pylori medication is prescribed, the most effective regimen should be given. Triple therapy , i.e a combination oftripotassium dicitrato bismuthate or bismuth subsalicylate I tablet 4 times daily, tetracycline 500mg 4 times daily, and metronidazole 400mg 3 times daily for 2 weeks has been recommended.

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Helicobacter pylori in Duodenal Ulcer

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Role of Helicobacter pylori in duodenal ulcer.

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