DUODENAL ULCER, CAMPYLOBACTER PYLORI, AND THE "LEAKING ROOF" CONCEPT

1467 the autoimmune type A gastritis of pernicious anaemia. There is now irrefutable evidence that C pylori infection Some causes chronic active non-specific gastritis.16,17 gastroenterologists and histopathologists think that C pylori should, if aetiologically important in DU, be expected to flourish in an ulcerated duodenum; but C pylori is fastidious, and is found only in the presence of intact, though usually damaged, mucus-secreting epithelial cells.18 A duodenal ulcer crater is thus an inhospitable place for C pylori, but it should be no surprise to find C pylori in duodenums healed with cimetidine19 even though the study that revealed this finding was not reliably controlled. If C pylori were irrelevant in the cause and relapse of DU, then the relapse rate after treatment for DU should be the same for patients whether C pylori has been eliminated by antibacterial treatment or not. However, studies in Irelandzo and Australia2l have shown that among patients in whom C pylori was eliminated the relapse rate of duodenal ulceration after 12 months was only 25%, compared with a relapse rate of 75 % in patients in whom C pylori was not eliminated. to

Occasional

Surveys

DUODENAL ULCER, CAMPYLOBACTER PYLORI, AND THE "LEAKING ROOF" CONCEPT C. STEWART GOODWIN

Microbiology Department, Royal Perth Hospital, Box X 2213 GPO Perth, Western Australia 6001 THE Hz-receptor antagonists have proved to be very useful in the treatment of duodenal ulcers (DU), so why should doctors be thinking again about ulcer therapy? Firstly, because these drugs suppress but do not cure duodenal ulcers. Among patients from whom treatment was withdrawn after 8 weeks, a high proportion experienced re-ulceration, the relapse rate as determined by endoscopy being 80% at 1 year and 100% at 2 years.1 Even in patients continuing to receive ranitidine 150 mg at night, the cumulative recurrence rate after 1 year of maintenance treatment was 48%. A course of Hz-receptor therapy is usually 1 year, but some patients need permanent treatment. Secondly, although Hz-receptor antagonists reduce acid promptly, pain relief occurs before the ulcer is healed, which indicates that their therapeutic effects are complex, not merely the reduction of acid production. Their action could be due to relief of pain originating from paracrine neurotransmitters, stimulated by inflammation in the antrum and duodenum.4,5 The importance of inflammation in the duodenum has been studied only intermittently in relation to the aetiology of DU, although several workers have concluded that duodenitis and DU are part of the same spectrum.6,7 Duodenitis has been found to be resistant to treatment aimed at reducing acidity8 and healed duodenal ulcers have been described as histologically ill,9 which could account for the high relapse rate for DU. The dictum "no acid, no ulcer" offers no assistance for the treatment of duodenitis, and so may be hampering productive thought and obscuring the value of measures that might offer a cure for a DU after a short course of

therapy. An important

factor has emerged in the pathogenesis of duodenitis and DU-namely, Campylobacter pylori. In some surveys this organism has been found in all patients with DU after exclusion of individuals with ulcers due to

analgesics or other drugs, or those following partial gastrectomy.10,11 Even in Suva, Fiji, where peptic ulcer disease is common, 93 % of the ulcer patients had C pylori infection in the stomach.’2 In contrast, DU is apparently absent among Australian aborigines living in desert areas; this group had low titres of antibody to C pylori, similar to those found in white Australian dyspeptic patients without microbiological evidence of infection with C pylori, and lower titres than those in white Australians with C pylori. 13

My acquaintance with C pylori dates from the early 1980s when Dr Marshall asked my department to culture spiral bacteria seen in gastric biopsy specimens.14 Cultures of the first 34 specimens from DU patients were negative after 48 hours’ incubation, but the next batch of specimens underwent a longer incubation period because of the Easter holidays, and the cultures yielded campylobacter-like organisms.15 Since then C pylori has been found worldwide in association with the common type B gastritis, as opposed

GASTRIC METAPLASIA, DUODENITIS, AND THE "LEAKING ROOF" CONCEPT

This section is an account of how C pylori contributes to the pathogenesis of duodenal ulcer. Patients with DU often have areas of gastric mucosa in the duodenum-ie, gastric metaplasia* "—which may also occur in the absence of DU. Gastric metaplasia predates ulcer formation, and C pylori infects only the areas of gastric metaplasia.22,24-26 Most DUs occur at the site of gastric metaplasia and it has been pointed out that perhaps the original pathology is eroded by the ulcer itself.24 The aetiology of gastric metaplasia is discussed below, but at this point I wish simply to emphasise the relevance of duodenitis for DU and the close association of C pylori with this lesion. The effect of these bacteria on gastric mucosal epithelial cells is to produce damage to microvilli and the cytoskeletal web, disruption of intercellular junctions with bulging of cells, and severe associated mucus depletion.18,27 Similar effects have been seen in duodenal biopsy specimens Z8 Furthermore, incubation of a filtrate of C pylori with gastric mucus for 48 h leads to a 35% loss of mucus viscosityz9 because C pylori elaborates a protease and a lipase.3o When the protective mucus layer is thus impaired, stomach acid and pepsin can precipitate the epithelial erosions and ulceration. C pylori duodenitis would then be the major predisposing cause of DU. A simple analogy for the part that C pylori plays in the pathogenesis of DU would be a leaking roof. Such a roof predisposes to rain entering the house. A puddle forms on the floor only when it rains; rain is thus the precipitating cause of the puddle. A puddle can be prevented by either repairing the roof or ensuring that it does not rain. With modern therapy normal stomach acid (the rain) can be inhibited by H2-receptor blocking drugs. Drugs such as colloidal bismuth subcitrate (CBS) do not affect stomach acid, but they do lead to healing of DU; ulcers that have healed with CBS have a lower relapse rate than those that have healed after a short course of acid-reducing drugS.20213132 Bismuth is active against C pylori,33 and after treatment with CBS there is a great reduction in the inflammation in the duodenum.34 Thus bismuth "repairs the roof", so that even in the presence of normal stomach acid a DU does not generally recur.

1468

Other factors can be important in the pathogenesis and relapse of DU. In a recent study of DU, treatment with CBS and tinidazole resulted in the elimination of C pylori from 75% of patients.21 Among 25 in whom C pylori remained absent for 12 months, there were 5 who had a relapse, which suggests that other factors were at work. For example, stress can cause changes in mucus synthesis and release.35 Normal prostaglandin synthesis in response to exposure of duodenal mucosa to acid is depressed in DU patients.36 Smoking can inhibit prostaglandin synthesis in the gastric mucosa.3’ In some patients, DU may heal and remain healed after a short of cimetidine or ranitidine,8 even though these drugs usually have no effect on inflammation in the antrum and duodenum.9,22 These factors seem to be operative in only a minority of DU patients, and leave C pylori duodenitis as the major predisposing cause of DU. Thus a new dictum, which applies to 95% of patients, could be: "Cure the duodenitis, and the ulcer will look after itself’. The cause of gastric metaplasia in the duodenum is not entirely clear; although the condition may be a random occurrence (even in parts of the gut without acid), it has been linked in man23,2538 and animals39 to the acidity of the duodenal contents. Some DU patients hypersecrete gastric acid,40 but nearly all have increased sensitivity to gastric’" and an increased rate of gastric emptying;40 both these features result in material of low pH entering the duodenums1 Gastric metaplasia is especially extensive in patients with Zollinger-Ellison syndrome and DU is virtually unknown in patients with very low acid output.42 The possibility that gastric metaplasia is a response to high duodenal acidity has been supported by findings that the prevalence of gastric metaplasia is lower among patients who have undergone highly selective vagotomy than among course

pre-operative DU patients.25 The accompanying figure outlines the pathogenesis of duodenal ulcer. C pylori, spreading from the gastric antrum readily infects areas of gastric metaplasia, and the areas of duodenitis thus produced ulcerate when acted on by acid and pepsin. When hypochlorhydria is present, gastric metaplasia should be rare and C pylori gastritis would not lead

to

DU.

BENEFICIAL EFFECTS OF STOMACH ACID

Many intestinal pathogens are killed by normal gastric juice, including Vibrio cholerae, Salrnonella, Shigella, and enterotoxigenic Escherichia coli (so anyone travelling to developing countries should do so with acid in their stomachs) and, among the elderly, reduced stomach acid after gastrectomy is a risk factor for haemorrhagic colitis due to enterohaemorrhagic E coli.43. Thus if DU can be healed, and relapse prevented, by a method other than by neutralising gastric acid, not only might healing be permanent, but the beneficial effects of stomach acid might also be retained. Long-term cimetidine treatment can give rise to serious conditions such as hypergastrinaemia, enterochromaffin-like cell proliferation, and possible neoplastic change..14 Furthermore, one of the most effective treatments for C pylori gastritis probably depends in part for its efficacy on the presence of stomach acid. One study has shown that 75 min after the ingestion of liquid CBS, C pylori had become detached from the stomach mucosa and had degenerated ;45 a similar degeneration was seen in vitro after exposure of C pylori to pH 3-5 plus CBS, but not to CBS alone.46

Another

example of the value of stomach acid is a study showing that in vitro 20% of C pylori isolates exposed to tinidazole became resistant to it, but in vivo, when cimetidine was given with tinidazole, 70% of isolates showed resistance

to

tinidazole 21

SUGGESTIONS FOR MANAGEMENT OF DUODENAL ULCERS

The impact of these new discoveries on the economic burden of DU may stimulate research into short courses of treatment leading to low relapse rates. While the patient with dyspepsia awaits an appointment for endoscopy or radiology, it may be worth checking for the presence of C pylori by a breath test and a test for antibodies. If it is present, then antibacterial treatment can be prescribed, but doctors must be aware that C pylori are not only sequestered in the mucus layer and thus inaccessible to systemic antibiotics such as amoxycillin, but they also lodge between adjacent mucosal cells and in the mucus glands, protected from the topical action of bismuth.18,46 If I had a DU, diagnosed by endoscopy, an antral biopsy specimen should have been cultured for C pylori, and its sensitivities to antibiotics determined. If diagnosed by radiology, I would have a blood test for C pylori antibodies/1 and a [14C]urea breath test.4’ If C pylori were detected, I would undergo a repeat breath test four weeks after completion of antibacterial treatment, because C pylori is hard to eradicate. I would take CBS (De-Nol) 1 tablet four times a day, for 8 weeks; during the last 2 weeks I would also take oral phenoxymethylpenicillin 500 mg 6 hourly, plus tinidazole 500 mg twice daily. Metronidazole and amoxycillin with CBS have been reported to have the highest eradication rate of C pylori;48,49 but C pylori is sensitive to penicillin,33 which has fewer side-effects than amoxycillin. In Perth, children with C pylori5O have been successfully treated with a long course of penicillin and one or two courses of CBS. Antibiotic diarrhoea may be less common than expected because CBS may inhibit Clostridium difficile. For my DU I would accept investigation for possible psychosocial factors but I would not submit to hypnotherapy ;51 the relapse rate after the hypnotherapy (53%) may be preferable to that following ranitidine (100%), but it is higher than the 25% relapse rate after CBS plus tinidazole.21

1469 Severe epigastric pain due to DU may be more rapidly relieved by an Hz-receptor blocking drug than by CBS, and so a short course of the former might be given but it should be withdrawn before antibacterial treatment for C pylori. Patients may comply better with a regimen of ranitidine at night than with CBS therapy, but continuous therapy may be more unattractive than a short course of treatment. My experience is that patients who opt for antibacterial therapy not only remain pain-free but can also eat spicy foods and curry, which caused pain while they were on ranitidine. The question "Will antibacterial chemotherapy be efficacious for gastritis and peptic ulcer?" was asked in 1986.52 The answer now seems to be in the affirmative. Whether after C pylori is eradicated reinfection and re-ulceration will occur has yet to be seen, but C pylori has remained absent for up to 18 months after eradication.48 So the challenge for doctors now is to repair the leaking roof of duodenitis, while strongly advising their patients against smoking and undue stress. I thank many people for information, especially Dr Barry Rathbone, Dr Judith Wyatt, Dr Jane Carrick, and Dr Richard Hill; Dr John Annstrong for reviewing the paper; and Mrs Lorraine Roberts for typing it.

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"Why are there dilemmas of choice in modern health care systems? A significant cause lies in the ever-expanding range of things that can be done, which pose problems of two kinds. The first problem is whether some therapies or techniques are on balance beneficial. The second problem is one of making choices within the range of activities that are of positive benefit. There are too few nursing staff to manage dialysis or there is a shift of money from one hospital district to another. In general there are more worthwhile activities to be undertaken than there are human, material and organisational resources to support them. It follows from this fact that there are some worthwhile activities that simply cannot be accomplished. Resources put to one use will be taken away from another and the clash of priorities may be so strong that it may be impossible even to undertake some worthwhile activities. Ethical considerations emerge when it is a question of determining priorities."-ALBERT WEALE (editor). Cost and choice in health care: the ethical dimension. London: King Edward’s Hospital Fund for London, 1988. Pp 85. C6.95. ISBN 1-870551850.