Gastro‐oesophageal reflux disease and ulcer disease

Gastro-oesophageal reflux disease (GERD) was recognized as a clinical entity in the mid-1930s. It is the commonest disorder of the gastro-intestinal tract, resulting from failure of the gastro-oesophageal sphincter. It is a chronic condition and often requires life-long treatment with proton pump inhibitors in up to 25–50% of patients. The most common reported symptoms are heartburn and acid regurgitation, often exacerbated by eating. Heartburn alone occurs in 20–40% of the adult population in European countries. This disorder is associated with considerable long-term morbidity and mortality. Symptoms of GERD can have a major effect on a patient's lifestyle. In one survey conducted in the USA, 46% of patients were found to have moderate to extreme difficulty in eating certain foods that they wanted to include in their diet, and 30% also had difficulty eating the quantity of food they wanted. Half of respondents claimed that they did not have enough energy for activities they wanted to do, and 21–25% said that they felt tired or worn out almost all of the time. There has been a dramatic increase in the number of people suffering from GERD and fortunately, effective but costly medications are now available. These factors in combination have exponentially increased the cost of reflux management to health services. The estimation of the prevalence of GERD is difficult because of the lack of an accepted definition and of gold standard diagnostic criteria. European epidemiological data is lacking, however according to the available European data, the prevalence of GERD symptoms, mainly heartburn, has been reported to range from 10 to 40%. Hiatus hernia, which occurs when the upper part of the stomach moves up into the chest through a small opening in the diaphragm, resulting in retention of acid as well as other contents that reflux easily into the oesophagus, may cause some people to suffer from GERD. Certain foods, smoking and pregnancy may all trigger GERD. It is believed that genetics play a role. A recent study indicated that a family member of someone with GERD is four times more likely to experience the disorder. Obesity is an independent risk factor for GERD and may explain the recent increasing incidence. The concomitant use of drugs for treating blood pressure, angina and arthritis, together with stress, has also been found to be associated with GERD. In a recent Belgian study, 28.4% of participants experienced heartburn during the previous 12 months. This symptom was present at least once a week in 42% of sufferers. Heartburn was more frequent in women (31%) than men (25%), which is in accordance with a published French epidemiological study. In Finland, 9% had experienced heartburn on the day of response and 15%, 21% and 27% during the preceding week, month and year, respectively. The corresponding figures for regurgitation were 5, 15, 29 and 45%. Medication, most commonly antacids, was used by only 16% of symptomatic people, and only 5.5% had sought medical advice for symptoms during the past year. Thus, despite regular symptoms suggestive of GERD, only a minority of individuals use medication or seek medical consultation. In France, the annual incidence of epigastric pain and/or regurgitation was 35.2%. In Sweden, symptoms suggestive of GERD were found among 25% of the population, which may or may not include other dyspeptic symptoms. In the UK, GERD symptoms occurred in 28.7% of one large sample population. Fewer than 25% of reflux patients consulted a practitioner during the previous year. In Denmark, one study reported results of a 5-year follow-up of reflux and abdominal symptoms in an age- and sex-stratified random sample of 4581 Danes. Prevalence of both heartburn and acid regurgitation were significantly higher among men (38%) than women (30%). Approximately 20% of adults in the USA experience GERD symptoms such as heartburn, acid regurgitation and subxiphoid pain at least once a week. In populations undergoing gastroscopy for investigation of symptoms, oesophagitis (mucosal damage seen in patients who have acid regurgitation) may occur in 5–10% of people (Figure 1). Prevalence of gastro-oesophageal reflux disease symptoms in adult Europeans. Subjects with chronic GERD are at risk of developing Barrett's oesophagus, a condition manifested by a change in the lining of the oesophagus. The normal squamous lining of the oesophagus becomes replaced with columnar epithelium. The presence of specialized intestinal metaplasia is characteristic of Barrett's oesophagus. Approximately 12% of subjects who undergo endoscopy for GERD evaluation are found to have Barrett's oesophagus. Current research suggests patients with Barrett's oesophagus are at greater risk of developing oesophageal cancer. Some studies have revealed that Barrett's oesophagus predisposes to the development of adenocarcinoma in up to 40%. However, the degree of risk is not clearly defined, as many individuals with Barrett's oesophagus remain undiagnosed. Lifestyle modifications associated with symptom relief include the following: nocturnal elevation of the head of the bed by 4–6 inches, cessation of smoking, frequent small and low-fat meals, avoiding a recumbent position for 3 h after eating, and avoidance of foods that tend to aggravate symptoms. Patients should also be advised to reduce their alcohol and caffeine consumption, as both agents are associated with an increased number of reflux episodes. The mainstay of medical treatment is to reduce the amount of acid refluxing into the oesophagus. Several different medications are available, which achieve varying degrees of acid control. H2-receptor antagonists: H2-receptor antagonists block histamine receptors and so reduce acid secretion into the stomach. These drugs can decrease acid secretions by 50–70% in any 24-h period, but are unable to effectively suppress meal-stimulated acid secretion. This is now available to patients directly from pharmacists. The cost of over-the-counter medications for GERD is over €5 million in Ireland alone. Proton pump inhibitors: Proton pump inhibitors are the drugs of choice in achieving and sustaining a neutral gastric pH. They block the final pathway for acid production and so are often considered more effective than H2-receptor antagonists. These drugs have revolutionized the medical approach to GERD management. If the patient stops using proton pump inhibitor therapy, reflux symptoms reoccur rapidly and often with greater severity than before. The cost of proton pump inhibitors in Ireland has increased from €3.24 million in 1993 to €28 million in 2001. The cost of medical management of GERD in the USA is approximately $10 billion/annum. The most common anti-reflux procedure is a Nissen fundoplication, which provides relief of reflux symptoms in 90% of patients. In this procedure, the upper portion of the stomach is wrapped around the oesophagus. The operation, however, is not without risk and is associated with significant post-operative morbidity. These complications may also contribute to additional healthcare costs. Presently, a number of endoscopic anti-reflux techniques, including Endocinch, Radiofrequency Stretta and Enteryx, and expandable prostheses such as the Gatekeeper and NDO endoscopic full-thickness plicator, are being evaluated and may represent a significant advancement in the future treatment of GERD. Peptic ulcer disease is a common clinical problem. Today the lifetime risk of peptic ulcer disease in industrialized countries is 5–10%. The factors influencing this trend, such as increasing age, changes in smoking prevalence and the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs), have all impacted on the changing epidemiology of peptic ulcer disease. The two principal, independent risk factors of gastric ulcer and duodenal ulcer disease are pre-existing Helicobacter pylori infection and the regular intake of NSAIDs. H. pylori infection and related digestive diseases will be discussed in a separate paper in this supplement. NSAID-induced adverse events are among the most frequently reported world-wide. Gastrointestinal pathology associated with the use of NSAIDs is common and may be considered a public health issue. NSAID-related conditions are associated with significant morbidity and mortality. It has been estimated that over 30 million individuals regularly consume NSAIDs and that this figure is rapidly increasing. NSAIDs remain the mainstay of treatment for myriad inflammatory conditions, and are frequently employed as analgesics. In particular the use of aspirin has risen dramatically since its efficacy in preventing both coronary artery and cerebral vascular disease has been proven. The decreasing prevalence of H. pylori infection in the developed world coupled with the increased consumption of NSAIDs has meant that these drugs are now the most important cause of gastroduodenal ulceration in many countries. Our understanding of the mechanisms involved in NSAID-induced gastrointestinal damage has expanded over recent times and led to the development of preventative strategies and novel therapeutic agents. The relative contributions of different pathophysiological processes described to date in the development of mucosal damage as a result of any particular NSAID is still a matter for discussion (Table 1). Similarly, there is disagreement on whether data from endoscopic studies can be extrapolated to wider populations. Although there is significant consensus in the literature regarding these issues, the presence of conflicting laboratory and clinical data has naturally resulted in some debate among the diverse groups of individuals who prescribe and manage complications of NSAIDs. The consumption of NSAIDs induces acute gastric mucosal injury hours after ingestion, which is characterized by the presence of submucosal haemorrhage and the production of superficial mucosal erosions. Further ingestion may result in abrogation of these acute injuries via adaptation. Long-term consumption is associated classically with Type C gastritis, and a paucity of inflammatory response. The characteristic findings are epithelial, endothelial and muscular hyperplasia. Whether NSAID-induced gastritis is associated with symptoms such as dyspepsia is unclear. An observational study performed in England reported no increased prevalence of dyspepsia among NSAID users compared with controls over a 1-year follow-up. Conversely, a population-based study from the USA estimated that NSAID use was associated with a two-fold increased risk of gastrointestinal symptoms. Differences in the definition of dyspepsia and both the formulation and doses of NSAIDs employed may account for these disparate results. A recent meta-analysis of 92 studies reporting gastrointestinal complications of NSAIDs attempted to address this issue. Their analysis showed that epigastric pain-related symptoms are increased in NSAID users by 36% compared with controls.1 In many users, ongoing tissue damage results in the development of deep excavated gastric or duodenal ulcers, partly as a direct tesult of mucosal injury but also due to impairment of mucosal healing mechanisms. The effects of NSAIDs are not confined to the gastric or duodenal mucosa. Consumption has been implicated in the development of oesophagitis, oesophageal strictures, acute intestinal ulceration, perforation, and rarely, colonic ulceration. Frequently, NSAID-related ulcers are large, more commonly found in the stomach than in the duodenum and paradoxically less painful than other peptic ulcers. It has been suggested that NSAID-associated peptic ulcers cause less pain because of their effect on the production of prostaglandins, which are known to contribute to the sensation of somatic and possibly visceral pain. It has been demonstrated that patiets using NSAIDs are at an increased risk of development of both ulcers and associated complications (haemorrhage or perforation). It has been established that the consumption of NSAIDs is associated with a 3–4-fold increased risk of peptic ulcer development. The attributable risk of ulcer complications among NSAID users is 25–35%. Pooled data from several case control studies have reported that NSAID consumption is associated with relative risks of 3, 6 and 7.6 for gastrointestinal haemorrhage, perforation and mortality, respectively.2 Large-scale cohort studies have confirmed these findings.3-5 In addition, there are now more data available on the gastrointestinal effects of prophylactic low-dose aspirin. Case–control studies performed in the UK have shown that the use of low-dose aspirin confers an increased relative risk of bleeding compared with other patients and the community of between 2 and 6, depending on the dose employed (75–1200 mg per day).6 Further evidence from the UK Transient Ischaemic Attack Trial confirms previous data that showed the risk of bleeding to be greater for duodenal rather that gastric ulcers and that bleeding may occur from other sites of the gastrointestinal tract.7 Moreover, the risk of duodenal perforation is also increased and has been reported to be six times that of nonusers but less than that of other NSAIDs.8 It is worth noting that the concomitant use of low-dose aspirin and other NSAIDs has an additive effect, and has been reported to be associated with twice the risk of perforation and bleeding. There are a number of possible risk modifiers that may affect the rates of peptic ulceration and their complications regionally. The strength of available evidence for different risk modifiers varies. It has, however, been clearly established that age, past history of peptic ulceration, high doses, and concomitant use of anticoagulants or corticosteroids magnifies the risk of bleeding peptic ulceration (Table 2). Dosage and type of NSAID: It has been shown that patients with rheumatoid arthritis are more likely to develop complications of NSAIDs than individuals with osteoarthritis. Although some reports do suggest that disease entities confer differing risks, it is more likely that the variation in risk reflects both the dosages and formulations regularly employed in different conditions. There are many reports available in the literature that demonstrate a linear association between the dose of NSAIDs employed and the development of ulcer complications.5, 9, 10 Likewise, a meta-analysis of 12 studies that investigated the effect of different NSAIDs on rates of ulcer complications demonstrated that different formulations did confer different tisks. However, despite there being a safety advantage for some formulations such as ibuprofen compared with piroxicam or azapropazone, this was not consistent at higher doses.11 Other pharmacokinetic properties are also likely to alter the relative risk of varying formulations. Age, peptic ulcer disease, anti-coagulants and corticosteroids: It has been clearly established that older age predisposes to peptic ulcer development. Studies have estimated the relative risk in subjects over 60 years compared with controls to be in the order of 3.5. The effect of NSAIDs on this risk appears to be additive rather than synergistic, that is, both are associated with inherent risks but there does not appear to be any specific mechanism whereby the effect of one enhances the deleterious effect of the other. The combined risk of ulcer disease in elderly individuals prescribed NSAIDs is approximately 13.12 Furthermore, a previous history of peptic ulcer is a risk factor for subsequent ulcer development, and again the addition of NSAIDs appears to add to this risk, with estimates of a combined relative risk of 17. This effect is independent of H. pylori status, and tends to be site-specific. It is therefore plausible that abnormal healing as a result of disordered repair mechanisms may play a role in the interaction of these two risk factors. As with the aforementioned risk modifiers, the effect of combined usage of NSAIDs and anticoagulants reflects the additive risks inherent to both agents,13 although it is possible that different NSAIDs will interact to greater or lesser degrees. It would be logical to presume that aspirin would further enhance the effect because of its ability to interfere with platelet aggregation. The role of corticosteroids is not quite as clear-cut. Whether these agents are themselves ulcerogenic or merely enhance the effects of other noxious stimuli continues to be debated. There is evidence to show that regular usage of at least 10 mg per day is associated, in combination with NSAIDs, with a three-fold increased risk of ulcer bleeding compared with subjects taking NSAIDs alone.14 The effect of concomitant H. pylori infection on the risk of developing NSAID-related conditions is complex, with evidence both for an additive effect and for an apparently contradictory protective role. It is likely that bacterial and host differences account for this disparity. Management of NSAID-associated gastrointestinal toxicity: Awareness of the possible risks inherent in the use of NSAIDs enables prescribing physicians to rationalize treatment according to simple basic principles. In particular, the dose and type of NSAID employed should be considered carefully before initiating therapy. Increased doses are associated with an increased risk of complications without necessarily improving their clinical efficacy. Patient characteristics, such as past history of peptic ulcer disease either related to NSAIDs or not, comorbidity including maintenance therapies, age and H. pylori status if indicated, should also be taken into consideration. In patients at an increased risk it is reasonable to try alternative treatments such as cyclooxygenase-2 inhibitors or if necessary to use NSAIDs with primary prophylaxis against complications. Similarly, patients who have previously developed NSAID-related gastroduodenal complications should receive secondary prophylaxis while continuing to use these agents even after successful eradication of H. pylori infection. Profound acid suppression remains the mainstay of treatment for active NSAID-related peptic ulcers (Table 3). The substantial part of the total workload of gastroenterologist is attributed to dyspepsia, a significant proportion of which is a result of either GERD or peptic ulcer disease. Fewer than half the individuals with these problems will ever seek medical advice, yet these disorders are very costly as many buy medications such as antacids and H2 blockers over the counter. It is difficult to analyse separately the economic burden of GERD or peptic ulcer disease, as most studies have used the broader term ‘dyspepsia’ in their calculations. For the purpose of this analysis, to make a gross assessment of the burden of cost, dyspepsia has been employed as a surrogate marker. The available appropriate data on cost analysis is sparse. Using the Swedish model of cost analysis recently published in Pharmacoeconomics 2002, we applied the same model to assess the cost of these disorders in different countries throughout Europe. However, we are aware that this can certainly vary with different disease definitions, regional variations in population trends, family size, income, occupational category and other socio-economic variables, from country to country. We estimated the overall cost of these disorders as €253 per person. As with the previous study we can also assume that 61% would be accounted for by direct costs and 39% indirect costs. The direct costs include: visits to GPs and specialists, in-patient care with and without surgery, and investigations. Indirect costs include sick leave, disability pension, early retirement, and time off work. In all, drugs and sick leave (37% vs. 34%) were considered to be the two main expenses, constituting almost 70% of the total cost. The proportion of the cost for drugs increased from 7% to 37% from 1985 to 1997, while sick leave seemed to have decreased from at least 66% to 34% in the same time period. The gross assessment of cost analysis for different countries in Europe is shown in Table 4. The cost of managing the side-effects of NSAIDs has been studied separately throughout Europe. In one study examining the costs in Belgium, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland and the UK, the total cost of managing gastrointestinal related events was €62–962 for discomfort, €130–1200 for anaemia, €175–1470 for ulcers, and €2300–6500 for serious events requiring hospitalization.15 In summary, the cost of dyspepsia has exponentially increased in the last decade, mainly as a result of a marked increase in the cost of drugs, due to the introduction of proton pump inhibitors. The cost of sick leave has decreased, possibly due to better drugs and a general reduction in the financial benefits from sick leave. It is likely that these figures may represent an overestimation, but they do certainly suggest that a significant amount is being spent annually on these disorders throughout Europe. Costs associated with NSAIDs vary from region to region as a result of different resources consumed and price policies, but are substantial everywhere. H. pylori infection and NSAIDs are by far the commonest cause of gastroduodenal pathology worldwide. The discovery of H. pylori colonization of the gastric mucosa and its causal association with peptic ulcer disease has offered a new and lasting treatment for these previously chronic and often complicated conditions. In addition, the development of novel diagnostic tests and management strategies has revolutionized our approach of these diseases, enabling accurate diagnosis and subsequent treatment without recourse to invasive procedures and indeed often to hospital facilities. NSAID-induced gastroduodenal toxicity is a common clinical problem associated with serious consequences. It remains the most frequently reported drug-related adverse event worldwide. Advances in recent years have led to a better understanding of the pathophysiological processes involved in mediating mucosal injury and to the development of selective cyclooxygenase inhibitors, which may protect patients from these sequelae. The precise role of these agents in a variety of clinical settings is still under investigation and studies examining their costeffectiveness are ongoing.