1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References



There is little evidence that treatment of patients with Barrett's oesophagus with proton pump inhibitors over periods up to 6 years results in major regression of Barrett's oesophagus.


To determine if longer periods of treatment with proton pump inhibitors lead to significant regression of Barrett's oesophagus, and to determine the incidence of oesophageal adenocarcinoma in the proton pump inhibitor-treated patients.


We analysed prospectively-collected data on Barrett's oesophagus patients treated with proton pump inhibitors for 1–13 years.


188 patients with Barrett's oesophagus and intestinal metaplasia, were treated for 1–13 years with a proton pump inhibitor (966 years of treatment; mean 5.1 years). No change in length was seen during treatment but 48% of patients developed squamous islands (25% after 1–3 years; 100% at 12–13 years). Squamous islands correlated with treatment duration and male sex but not with proton pump inhibitor dose or patient age. Six patients developed dysplasia and three males developed adenocarcinoma during treatment (cancer incidence 0.31%).


Proton-pump inhibitor treatment over 1–13 years does not shorten the Barrett's oesophagus segment but squamous islands appear in many patients. The incidence of oesophageal adenocarcinoma was low in these proton pump inhibitor-treated patients compared with published series.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Barrett's oesophagus (BO) is a consequence of long-standing gastro-oesophageal reflux.1–3 In individuals with BO, the normal squamous epithelium of the distal oesophagus is replaced by a columnar epithelium. Most, but not all patients with BO have partially intestinalized metaplastic epithelium (IM) in their distal oesophagus4, 5 and this epithelium is at risk of transforming into dysplasia or adenocarcinoma.6–9

The aims of treatment in the patient with BO are to control reflux symptoms, to treat and prevent complications such as ulcer and stricture, and to prevent dysplasia and adenocarcinoma. It seems logical that the last two aims would be achieved if BO could be made to regress and disappear. There have been three approaches to inducing regression of BO: medical treatment with acid suppression, antireflux surgery and endoscopic ablation therapy. The results of antireflux surgery have been mixed with successful regression being claimed for a few patients; overall results are disappointing.10–13 Endoscopic destruction of BO using Nd YAG laser,14 argon plasma coagulation,15 multipolar electrocoagulation16 or photodynamic ablation17 followed by acid suppression with high-dose proton pump inhibitor (PPI) therapy, allows the regrowth of squamous epithelium in place of BO18 but these therapies are not practical for most patients and there is evidence that intestinal metaplasia persists in glands beneath the newly regenerated squamous epithelium.19

Regression of BO during medical treatment has been assessed by recording whether the treatment leads to reduction in length of the Barrett's segment and whether the treatment leads to partial re-epithelialization in the Barrett's segment as shown by the appearance of squamous islands (SIs). Acid suppression with H2-receptor antagonists does not cause any regression of BO.20–22 Many published studies have shown that PPI therapy at any dose does not reduce the length of BO23–26 but others have shown some shortening of BO with higher dose PPI therapy for up to 5 years.22, 27–30 Squamous islands occur in 55–60% patients after 6 years treatment.24, 26 A meta-analysis showed no evidence of regression during 1–3 years of PPI therapy.31 Complete regression (disappearance), if it occurs, is a very rare event. There are no studies of PPI therapy for longer than 6 years.

The main aim of the present study was to determine whether long-term PPI therapy up to 13 years causes BO to regress. A secondary aim was to determine the incidence of dysplasia and oesophageal adenocarcinoma in BO patients on long-term PPI treatment.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

At City Hospital Birmingham, an inner city teaching hospital serving an ethnically diverse population, data on patients with BO for the 18-year period from January 1987 to December 2004 were prospectively collected and entered on a computerized database. The database holds information such as patient demographics, medication, endoscopic findings, histology, concurrent illnesses, follow-up details and reasons for discontinuing follow-up. Patients who had been actively followed up in the oesophagus clinic and been taking continuous PPI therapy for at least 1 year, were identified. Patients who did not have repeat endoscopies and those without intestinal metaplasia on oesophageal biopsy were excluded. Also excluded were two patients requiring antireflux surgery for poorly controlled symptoms. The treatment period was determined as being from the start of PPI therapy to the date of the latest endoscopy. Symptoms were recorded at each clinic attendance. At endoscopy, length of BO was recorded and the presence or absence of SIs was noted. Biopsies were taken at least every 1 cm along the oesophageal body and from any abnormal or unusual looking areas.

Barrett's oesophagus was diagnosed at endoscopy when columnar epithelium was visible above the gastro-oesophageal junction. The distances between the incisor teeth and the proximal and distal ends of the Barrett's segment were recorded. The extent of the Barrett's segment was the distance between the gastro-oesophageal junction and the most proximal extent of columnar epithelium. The oesophageal junction was identified as the level at which there was a clear junction between stomach and oesophagus, where gastric folds ceased. In long segment BO, there was 3 cm or more between the squamo-columnar junction and the observed oesophago-gastric junction and in short segment BO, <3 cm.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The database contained information on 501 patients with BO diagnosed over the 18-year period 1987–2004; 188 of the 501 patients fulfilled the entry criteria for the study. One hundred and sixty-six patients had long segment BO and 22 had short segment disease. All had endoscopically identifiable BO (1–19 cm in length) with intestinal metaplasia present on oesophageal biopsies. There were 76 females [aged 42–85 (mean 65) years]; 75 were white Caucasians and one was south Asian. There were 112 males [aged 31–79 (mean 57) years]; 101 were white Caucasians, eight were south Asians and three were Afro-Caribbeans. The patients had undergone 966 years of treatment (mean 5.1 years) and had 539 repeat endoscopies (mean 2.9/patient). Numbers treated were: 76 patients for 1–3 years, 35 patients for 4–5 years, 31 for 6–7 years, 27 for 8–9 years, 12 for 10–11 years, seven for 12–13 years.

Proton-pump inhibitor therapy

One hundred and forty patients were taking a lower dose of PPI (either omeprazole 20 mg daily or lansoprazole 30 mg daily) and 48 patients were taking a higher dose (either omeprazole 40 mg daily or lansoprazole 60 mg daily) (Table 1). On these doses, patients’ symptoms were either completely or largely controlled. No significant side-effects were reported. There were no late withdrawals because of adverse events.

Table 1.  Proton pump inhibitor (PPI) treatment in 188 patients
PPIDose/day (mg)Patients treated

Length of BO during PPI therapy

Table 2 shows the length of BO on treatment. The same data are shown graphically in Figure 1. There was no significant change in length during treatment over 1–13 years in any cohort. BO did not disappear endoscopically in any patient. The initial mean length of BO was 6.1 cm and after treatment was 5.8 cm. If the 48 patients on higher dose PPI therapy are considered separately (Figure 2), there was still no significant shortening of BO length during treatment over 1–13 years. There were no significant differences in BO length after treatment between males and females or between patients ≤60 and >60 years of age at the start of treatment.

Table 2.  Length of Barrett's oesophagus (BO) during proton pump inhibitor (PPI) therapy
Years on PPI01–34–56–78–910–1112–13
Number of patients18876353127127
Length of BO (cm)

Figure 1. Length of Barrett's oesophagus (BO) during proton pump inhibitor (PPI) therapy in 188 patients.

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Figure 2. Length of Barrett's oesophagus (BO) in 48 patients during high-dose proton pump inhibitor (PPI) therapy.

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Squamous islands

Partial re-epithelialization in the form of SIs was seen in many of the treated patients (Figure 3). Overall, 48% patients developed SIs during treatment. After 1–3 years of PPI therapy, 25% of patients had developed SIs but after 12–13 years, 100% had developed SIs. The presence of SIs was significantly related to the duration of PPI therapy (relative risk: 0.43; 95% CI: 0.35–0.65) but not to PPI dose. Men were more likely to develop SIs than women (relative risk: 1.4; 95% CI: 1.1–1.8), but younger patients (≤60 years at start of treatment) were just as likely to develop SIs as older patients (>60 years).


Figure 3. Squamous islands during proton pump inhibitor (PPI) treatment.

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No patient had dysplasia detected at their index endoscopy. Six of the 188 treated patients (3%) subsequently developed dysplasia on biopsy; Five (three males) developed low-grade dysplasia after 2–7 years of PPI treatment; three were taking omeprazole 20 mg daily, one omeprazole 40 mg daily and one lansoprazole 60 mg daily. One male, who was taking omeprazole 40 mg daily, developed high-grade dysplasia after 3 years. The dysplasia incidence was 0.62%.


Three males from amongst the 188 treated patients (1.6%) developed oesophageal adenocarcinoma, after 3, 6.5 and 9.5 years of PPI therapy; one was taking omeprazole 20 mg daily, one omeprazole 40 mg daily and one lansoprazole 60 mg daily. No females developed adenocarcinoma. This male:female difference was not statistically significant. For males the cancer incidence was 0.52%. However, when all patients were considered, there was one case of oesophageal adenocarcinoma per 322 years of PPI treatment, i.e. a carcinoma incidence of 0.31%. These data were compared with the data on incidence of adenocarcinoma in British BO patients analysed by Jankowski et al.32 Our incidence of adenocarcinoma was significantly lower than that of the pooled British data (0.98%); standardized incidence ratio 0.33 (95% CI: 0.07–0.97).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Our retrospective review of prospectively collected data showed that patients tolerated long-term PPI therapy well and there were no late withdrawals because of side-effects. Reflux symptoms were well controlled. Our results showed that there was no significant shortening of the length of the BO segment during PPI therapy for up to 13 years. In contrast with some of the studies,22, 27–30 we found no evidence that significant shortening occurred with higher dose PPI therapy. We confirmed that patients develop partial squamous re-epithelialization in the form of SIs during long-term PPI therapy. By 13 years, all patients (admittedly a small number) had developed SIs in their BO segments. The development of SIs was significantly related to length of treatment and male sex but not to PPI dose or age. The development of SIs might suggest that the area of Barrett's metaplastic epithelium within the oesophagus was reduced. This may not be the case. The SIs can overlie and hide metaplastic Barrett's epithelium rather than replace it,33 so the dysplasia/cancer risk may not be lessened.

A secondary aim of our study was to determine oesophageal adenocarcinoma incidence in our PPI-treated patients. This was 0.31%, which is the lowest incidence recorded in BO patients undergoing endoscopic surveillance. The incidence of adenocarcinoma in BO was thought to be 1%34 but in 2000, Shaheen et al. reviewed the world literature and concluded that there was an inverse relationship between study size and cancer incidence.35 They calculated that the real risk was nearer 0.5%.35 Jankowski et al. reviewed the British data and concluded that the British incidence was 0.98%.32 Because of this analysis of 3788 patient follow-up years, there is a widely promulgated view that the Britain is a high risk region for BO cancer.36 However, more recent studies of endoscopically surveyed BO patients in the UK has shown a lower incidence (0.37% and 0.5%).37, 38 Two community-based epidemiological studies in the UK have shown a BO cancer incidence of 0.25%.39, 40 Therefore, it seems likely that incidence of BO cancer in the UK is no greater than elsewhere. Our study supports the view that males are at particular risk; the cancer incidence for males was 0.5% and for females was zero.

There is a tendency for more recent studies to have a lower cancer incidence. The main difference between older studies and recent ones is that the latter contain a lot of patients on PPI treatment. Our cancer incidence in PPI-treated patients was significantly lower than in British patients whose follow-up was reported between 1988 and 2001.32 Most endoscopic follow-up studies of BO patients give little or no data about the treatment that the patients are receiving. The present study is the first to be limited to PPI-treated patients. These observations raise questions about the role of PPI therapy in reducing the risk of cancer in BO. Obviously this question can only be answered by a prospective long-term controlled trial. This might be difficult to perform because PPI therapy is the most effective non-surgical means of controlling reflux symptoms in BO patients. It is of interest that in our PPI-treated patients, the progression to low-grade and high-grade dysplasia was low, compared to older studies.41, 42 None of our patients had dysplasia detected at diagnosis; Vieth and Stolte found low-grade dysplasia in only 1.1% of 5749 cases of BO.43

Is there evidence that acid induces malignant change and that prevention of acid reflux reduces cancer risk? Fitzgerald44 has recently reviewed this topic. Intermittent exposure of BO epithelial cells to acid in vitro and in vivo induces cellular hyperproliferation,45, 46 which is suspected but not proven to be a contributing factor to dysplasia.44 Cyclo-oxygenase (COX)-2 expression, which is involved in carcinogenesis, is increased in Barrett's adenocarcinoma47 and is upregulated in ex vivo Barrett's epithelial biopsies by exposure to acid as well as bile.48 Complete abolition of acid reflux by PPI therapy over 6 months reduced markers for hyperproliferation and increased those for cell differentiation.49 These changes were not seen if the acid suppression was incomplete. Another study showed similar benefits to the cell cycle in Barrett's epithelial cells in patients treated with PPIs but not in those treated with H2-receptor antagonists and antacids.50 The combination of COX-2 antagonist and high-dose PPI caused marked reduction in cell proliferation in Barrett's epithelium after short-term treatment.51

Is there any clinical evidence that might support the hypothesis that abolition of acid reflux reduces cancer risk? Although the data in the past have been conflicting, recent studies suggest that reduction in reflux by antireflux surgery does not reduce the risk of oesophageal adenocarcinoma in BO patients.52, 53 This might be seen as evidence against the hypothesis that abolition of acid reflux protects against cancer development. However, the barrier to reflux formed by antireflux surgery becomes less effective with time and patients may have asymptomatic reflux after surgery.54 Therefore, antireflux operations may not lead to an acid-free oesophageal environment over a long period of time.

Proton pump inhibitors decrease gastric acid output and therefore modify the refluxate in patients with gastro-oesophageal reflux disease and BO. In contrast to the surgical data, a retrospective analysis of prospectively collected endoscopic follow-up data on 350 Australian BO patients (median follow-up 4.7 years) showed that BO patients who delayed starting PPIs for 2 or more years after BO diagnosis had an increased risk of developing dysplasia and oesophageal adenocarcinoma compared with BO patients who started PPIs at diagnosis.55 A problem with this study is that some patients may have been taking other drugs, e.g. aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors; epidemiological studies suggest that these drugs may reduce the risk of oesophageal carcinoma.56, 57

Our study has a few problems. Our data were not controlled; we had too few BO patients under follow-up who were not taking PPIs, to act as a control group. The completeness of acid suppression in our patients was not known. Complete control of reflux symptoms on PPIs does not mean complete acid suppression.58, 59 Some of our patients will have been taking aspirin, NSAIDs or COX-2 antagonists for variable periods of time, which may be confounding factors. Our data do not prove that PPI therapy reduces the risk of oesophageal dysplasia and adenocarcinoma in BO patients. However, our cancer incidence in BO patients treated with PPIs for up to 13 years was very low compared with other published series.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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