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Possible absence of Helicobacter pylori in the early stages of duodenal ulceration

P.B. Boulos, A. Botha, M. Hobsley, J. Holton, A.O. Oshowo, F.I. Tovey
DOI: http://dx.doi.org/10.1093/qjmed/95.11.749 749-752 First published online: 1 November 2002

Abstract

Background: Helicobacter pylori is thought to be a cause of duodenal ulceration, but there is some evidence that it is found less often in early than in later disease.

Aim: To assess the presence of H. pylori in patients undergoing endoscopy for dyspepsia, with respect to their duration of symptoms.

Design: Retrospective case note review.

Methods: Patients were categorized as having a history greater or less than 6 months, and as H. pylori‐positive or ‐negative, using biopsy rapid urease, culture and PCR tests.

Results: Thirty‐two duodenal ulcer patients with a history >6 months were all H. pylori‐positive according to the PCR test; the five with a shorter history were H. pylori‐negative. No patient H. pylori‐negative by PCR was positive by the other tests.

Discussion: H. pylori was (at least) less commonly present before 6 months. It is possible that H. pylori, although nearly always present after 6 months, is not present at the onset of the disease. Confirmation of this finding would imply that infection with the organism is not the cause of duodenal ulceration, but a factor producing recurrence and chronicity.

Introduction

It is generally accepted that Helicobacter pylori (H. pylori) is, in the absence of other known causes such as NSAIDs, the cause of duodenal ulcer. However, doubt has been cast on this conclusion in several review articles.1–,4 The report5 that patients with a short history of duodenal ulcer (endoscopic diagnosis made in a first episode and lack of endoscopic stigmata of chronicity) often have no gastric infection with H. pylori, unlike those with a longer history, is also difficult to understand if the organism is the cause, and has stimulated us to report our own experience.

Methods

We reviewed the records of 208 patients who had undergone diagnostic endoscopy for dyspepsia,6 defined here as any clinical picture which led the attending doctor to ask for upper gastrointestinal endoscopy. Patients with a history of treatment with NSAIDs, steroids, antibiotics, bismuth, H2 receptor blockers or proton pump inhibitors during the previous 3 months were excluded, as were patients who had undergone gastric surgery, and those who had bleeding disorders or where there was a particular risk of infection, e.g. hepatitis. For inclusion, it was necessary that the patient's consent included endoscopic biopsy. There were no private patients in the group, and all patients lived in metropolitan London. Most (164) were White Caucasians, but 8 were of African, 26 of Indian and 10 of Chinese origin.

Age, smoking habits and gender were recorded. The duration of the dyspeptic symptoms was assessed by taking a history, making every effort not to overlook earlier bouts of dyspepsia. Durations were recorded as <1 month, 1–3 months, 3–6 months, 6–12 months, 1–5 years and >5 years. The protocol followed by the endoscopist(s) defined a duodenal ulcer as areas of mucosal loss that were larger than could be described as erosions (erosions would have been classified as duodenitis).

Tests were performed at the time of endoscopy on all these patients to determine whether gastric H. pylori infection was present. The tests were the biopsy‐rapid urease7 and polymerase chain reaction (PCR),8 and (in 187 patients) biopsy‐culture. Biopsy samples were taken from the gastric antrum, the number of samples in each patient varying between three and five, depending on clinical indications and practical exigencies. Transport of specimens was in normal saline and each specimen was processed within 4 h by homogenization and plating on Colombia agar containing 5% horse blood and 12 µg/ml amphotericin. This was incubated at 37 °C under micro‐aerobic conditions for 5 days; H. pylori was identified by colonial morphology, oxidase reaction and rapid urease reaction, and confirmed by a Gram stain.

PCR used the Puregene DNA isolation kits (Gentra Systems). Two 20‐based commercially synthesized primers, HP1 and HP2 (Oswell DNA Service, UK, sequence numbers V1777 and V1778, respectively) were used:

  • HP1 – 5′ CTG GAG AGA CTA AGC CCT CC 3′

  • HP2 – 5′ ATT ACT GAC GCT GAT TGT GC 3′

The two together amplified a 109‐bp PCR product. For full details, see reference 6.

Fisher's exact test was used to assess the likelihood of chance accounting for differences in proportions.

Results

Of the 208 patients, the endoscopic diagnosis was duodenal ulcer in 37. Five of the 37 gave a history of <6 months, while the other 32 had had symptoms for >6 months.

None of the five with a short history showed evidence of infection with H. pylori by any of the tests, including PCR. All 32 patients with a longer history were H. pylori‐positive by PCR and 26 were also positive by either the biopsy‐rapid urease test or culture or both.

The mean age of the five H. pylori‐negative patients was 46 years; that of the 35 H. pylori‐positive patients was 49 years. The negative patients comprised three men and two women; the positive, 27 men and 5 women. All negative patients were Caucasian. The negative group contained one non‐smoker and four smokers, while the positive group contained 23 smokers and 9 non‐smokers. Socio‐economic status was not specifically recorded. There were no private patients.

Discussion

This investigation supports the result reported by Dres Pest et al.5 that in the early stages of the disease, a patient with duodenal ulcer is likely to show no evidence of intragastric infection with H. pylori. Various explanations of this phenomenon are possible.

Firstly, the link could be fortuitous. It is known that at least 5% of patients with duodenal ulcer are H. pylori‐negative, and it might be coincidence that our 5 H. pylori‐negative patients were all early cases. This seems unlikely as the link between negativity and a short history has now become manifest in two studies, geographically widely separated, and because the statistical chance of getting the result obtained in our series is (Fisher's exact test) p<0.0001.

Secondly, could observer bias have contributed? This seems unlikely, because the study was not originally designed to investigate length of history; the relevant data were kept because previous researchers in our group had maintained such records, and the association we describe in this paper only became manifest when we reviewed our results in the light of reference 5.

Thirdly, the diagnosis of H. pylori in the early case might be more difficult to make than when the infection is longer established. It is well‐known that in the early stages the infection is patchy, and therefore it is feasible that biopsy samples can miss the infected areas9 and result in false‐negative decisions by rapid urease test and culture. On the other hand, PCR as used in our study is very sensitive; it requires only one molecule to trigger a positive result, and has shown evidence of H. pylori in acid gastric juice in which the organism cannot survive, so that it is probably the partially broken down remnants of dead organisms that are being demonstrated.10 It follows that PCR is also very specific. In direct comparisons,11 not only does PCR perform as accurately as breath testing in regard to both sensitivity and specificity, but PCR results can be used to determine the most effective cut‐off point for the breath test. This suggests that PCR should be regarded as the gold standard for the breath test. Using PCR as our gold standard in the endoscopic results, it seems that H. pylori was not present in our early patients, but was present in all our patients with a history longer than 6 months.

Fourthly, the explanation might be a cohort phenomenon. There is evidence that in Western communities infection rates with H. pylori are diminishing,12 and so young patients developing duodenal ulceration are less likely to have an infective aetiology for their condition than are old patients. There was no evidence of a cohort effect: there was no age‐difference between the <6 month and the >6 month groups (46 and 49 years, respectively), although the numbers in this study are small.

Fifthly, was there any other characteristic that differed between the positive and negative patients? There was no difference with regard to gender: (Fisher's exact p=0.2330). There was no difference in smoking (Fisher's exact p>0.9999). The fact that all five in the early group were White was not significant (Fisher's exact p=0.5859). Socio‐economic status was not specifically recorded, but there were no private patients. Could the negative cases have been milder, having perhaps only small superficial single ulcers compared with the positive patients? The protocol followed by the endoscopists can probably be relied upon to have avoided this possibility. Moreover, non‐NSAID non‐H.pylori‐duodenal ulcer patients have been claimed to have more, rather than less, severe symptoms and signs.13

The only other explanation we can think of is that H. pylori is not the cause of duodenal ulcer. The simplest explanation of absence of evidence of the organism in recent sufferers of duodenal ulcer is that the organism is not present at the onset of the disease. This suggestion seems to be at odds with the mass of evidence that H. pylori is present in most patients with duodenal ulcer and that the disease responds rapidly to, and recurs only at much longer intervals after, treatment eradicating the disease, either with, or even without, proton‐pump inhibitors.14 If it is not itself the cause, it might be that the role of H. pylori, an opportunistic infection in the first instance, is to promote the chronicity of an ulcer that would otherwise heal completely and stay healed. Such a role is well recognized for infection with micro‐organisms in ulcers at other sites. However, in the present circumstances the connection is possibly through the effect of the organism in increasing the gastric acid secretory response to gastrin.15,,16

This viewpoint raises the question why H. pylori is virtually always present after 6 months. Treatment of symptoms in these patients included inhibiting hydrogen ion secretion. We speculate that hypochlorhydria may encourage infection; moreover hypochlorhydria increases gastrin secretion and human gastrin is a growth factor for H pylori.17

We appreciate that the numbers involved in our study are small and unlikely to carry conviction, despite the results of the statistical tests. What is clear is that patients with duodenal ulcers that have been present less than 6 months certainly have a lesser prevalence of infection with H. pylori than those with a longer history, and it is even possible that they are free of the organism, which therefore cannot be the cause of ulceration. This last point is important, not because it affects management—it remains important to eradicate the organism from infected patients with ulceration, so as to promote stable healing without a tendency to early recurrence—but because it would mean that we still do not know the cause of duodenal ulceration.

This phenomenon of a link between length of history of duodenal ulcer and infection with H. pylori deserves further study. We publish these limited data in the hope of stimulating others to increase the number of observations.

Acknowledgments

We gratefully acknowledge two grants of support from The Stanley Thomas Johnson Foundation, Basel, Switzerland.

Footnotes

  • Address correspondence to Professor M. Hobsley, Fieldside, Barnet Lane, London N20 8AS. e‐mail: m.hobsley{at}ucl.ac.uk

References

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