Peptic-ulcer disease

doi:10.1016/S0140-6736(02)11030-0

The Lancet

Volume 360, Issue 9337, 21 September 2002, Pages 933-941

https://doi.org/10.1016/S0140-6736(02)11030-0 Get rights and content

Summary

The discovery of Hellcobacter pylori has greatly changed our approach to peptic ulcer disease. Bacterial, host, and environmental factors all have a role in peptic-ulcer disease. Although the prevalence of uncomplicated peptic ulcers is falling, hospital admissions for ulcer complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) are rising. Evidence suggests that coprescription of NSAIDs with potent antiulcer agents and the use of highly selective cyclo-oxygenase-2 inhibitors reduce gastroduodenal ulceration. Whether these therapeutic advances will translate into clinical benefits remains to be seen. The interaction between H pylori and NSAIDs is one of the most controversial issues in peptic ulcer disease. With the fall in rates of H pylori infection, the proportion of ulcers not related to this organism and NSAIDs has risen, which will affect the management of peptic ulcer.

Introduction

For more than a century, peptic ulcer disease has been a major cause of morbidity and mortality. The pathophysiology of peptic ulcer disease has centred on an imbalance between aggressive and protective factors in the stomach. 20 years have elapsed since Marshall and Warren's discovery of the link between a bacterium called at that time Campylobacter pylori and peptic ulcer disease.¹ This finding was initially received with scepticism and disbelief. Now there is much evidence to support the idea that Helicobacter pylori infection is a prerequisite for duodenal and gastric ulcers.2, 3 Nevertheless, much about the relation between H pylori and peptic ulcer remains to be learned. The rapid emergence of antimicrobial resistance has important implications for management of these ulcers.

Although hospital admissions for uncomplicated peptic ulcers in developed countries had begun to decrease by the 1950s,4, 5 there was a striking rise in admissions for ulcer haemorrhage and perforation among elderly people.4, 5, 6 This increase has been attributed to the increased use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin.4, 6 The widespread use of NSAIDs has led to an epidemic of ulcer complications. In the USA, prescribed NSAIDs account for about 25% of all reported adverse drug reactions. An estimated 16 500 patients with arthritis die from the gastrointestinal toxicity of NSAIDs every year.⁷ A better understanding of the mechanisms by which NSAIDs damage the stomach has led to the development of potent anti-ulcer agents and, recently, highly selective cyclo-oxygenase (COX)-2 inhibitors. Although there is evidence from large-scale clinical trials that these agents reduce the gastrointestinal toxicity of NSAIDs, whether these findings will translate into clinical benefits is unclear.

Researchers have previously identified several risk factors for the development of NSAID-associated ulcers.⁸ However, whether H pylori infection modifies the risk of ulcer in patients taking NSAIDs has generated many conflicting data.⁹ With the reduction in frequency of uncomplicated peptic ulcers, the proportion of ulcers not related to H pylori or NSAIDs has increased. Recent data from the USA suggest that the association between H pylori and ulcer disease is not as strong as previously reported.¹⁰ The pendulum seems to swing from enthusiasm for the idea that peptic-ulcer disease is an infectious disease, to a more cautious view that H pylori has a causative role in peptic-ulcer disease. Ulcers not associated with H pylori or NSAIDs–ie, non-NSAID non-H pylori ulcers–have attracted considerable attention.

Section snippets

Duodenal ulcers

Although there is much evidence to implicate H pylori in the development of duodenal ulcer, the underlying mechanisms remain unclear. The fact that duodenal ulcer can be effectively treated by acid suppression strongly suggests that duodenal ulcer is largely a disease of acid hypersecretion. However, the general view is that acid hypersecretion is only part of the equation in pathogenesis of duodenal ulcer; it is the imbalance between duodenal acid load and the buffering capacity of the

Gastric ulcers

Long before the discovery of H pylori, patterns of gastritis associated with duodenal ulcers were known to be different from those associated with gastric ulcers.³³ Duodenal ulcer is associated with an antrum-predominant gastritis, whereas gastric ulcer is associated with a diffuse or a corpus-predominant gastritis.³⁴ This last gastric phenotype is linked with low acid output, gastric atrophy, and adenocarcinoma. This pattern is consistent with the negative association between duodenal ulcer

NSAID-induced gastric injury

For the past three decades, investigators have been working on how NSAIDs damage the gastrointestinal tract. Some of these mechanisms have helped our understanding of the development of NSAIDs with lower ulcerogenic risk or prophylactic agents that reduce the toxicity of existing NSAIDs.

Current issues in prevention of NSAID ulcers

Various prophylactic strategies to reduce the gastric toxicity of NSAIDs have been investigated. These strategies include concurrent treatment with histamine-2 receptor antagonists (H2RA), misoprostol, PPIs, and recently, substitution of conventional NSAIDs by selective COX-2 inhibitors. Although there are data showing that these agents reduce gastroduodenal ulceration, whether these findings would translate into clinical benefits deserves careful consideration (panel 2).

Non-NSAID, non-H pylori ulcers

The decline in prevalence of H pylori infection in developed countries has changed the pattern of peptic ulcer disease. In one retrospective study from the USA in ulcer patients who did not use NSAIDs, H pylori-negative ulcers were found in 47% of white patients and 22% of non-white patients.¹⁰² In a meta-analysis of duodenal ulcer trials in the USA, 20% of patients had ulcer recurrence within 6 months after the eradication of H pylori.¹⁰ This finding contrasts with results from Asia where the

Selection criteria and search strategy

We reviewed international publications printed in English before April, 2002. The pathophysiology of peptic ulcer is based on research work published in major scientific journals such as Cell, Nature, Science, Gastroenterology, and Proc Natl Acad Sci USA. The efficacy of eradication therapies is based on results of large-scale randomised trials. The recommended treatments for H pylori infection is based on the Maastricht-2 2000 Consensus Report. The management of NSAID-associated ulcers is

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Association of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis
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The role of antisecretory drugs for the prevention of upper gastrointestinal bleeding in patients using anticoagulants is unclear. We investigated this question in a systematic review and meta-analysis.
We searched Embase, PubMed, Web of Science, Scopus, the Cochrane Library, and clinicaltrials.gov thru April 2021 for controlled randomized trials and observational studies evaluating the association of proton pump inhibitors (PPIs) or H2-receptor antagonists with overt upper gastrointestinal bleeding in patients using anticoagulants. Independent duplicate review, data extraction, and risk of bias assessment were performed. Observational studies were included only if they provided results controlled for at least 2 variables. Meta-analyses were performed using random effects models.
Six observational studies and 1 randomized trial were included. All but 1 study had low risk of bias. None of the studies excluded patients with concomitant aspirin or nonsteroidal anti-inflammatory drug use. For PPIs, the pooled relative risk of upper gastrointestinal bleeding was 0.67 (95% confidence interval 0.61, 0.74) with low statistical heterogeneity (I² = 15%). Individual studies showed greater treatment effect in patients with higher risk for upper gastrointestinal bleeding (eg, nonsteroidal anti-inflammatory drug or aspirin use, elevated bleeding risk score). A single observational study evaluating the association of H2-receptor antagonists with upper gastrointestinal bleeding found a relative risk of 0.69 (95% confidence interval 0.24-2.02).
Evidence drawn mostly from observational studies with low risk of bias demonstrate that PPIs reduce upper gastrointestinal bleeding in patients prescribed oral anticoagulants. The benefit appears to be most clearcut and substantial in patients with elevated risk of upper gastrointestinal bleeding.
An insight into the anti-ulcerogenic potentials of medicinal herbs and their bioactive metabolites
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Peptic ulcer disease (PUD) ranks top among the most prominent gastrointestinal problems prevalent around the world. Long-term use of non-steroidal anti-inflammatory drugs, pathogenic infection by Helicobacter pylori, imbalances between gastrointestinal regulatory factors and pathological hyperacidity are major contributors towards the development of peptic ulcers. Although synthetic drugs of multiple pharmacological classes are abundantly available, inadequacy of such agents in ensuring complete recovery in not uncommon. Therefore, pharmacological explorations of herbal products including plant extracts and their respective isolated phytoconstituents, for potential gastroprotective and antiulcer properties, are regular practice among the scientific community. Moreover, the historical preferences of a significant share of world population towards herbal-based medication over modern synthetic drugs also contribute significantly to such endeavors.
This review has endeavored to present ethnomedicinal and pharmacological prospects of a significant number of authenticated plant species in terms of their capacity to exert gastroprotection and antiulcer activities both in vitro and in vivo. The information delineated along the way was further subjected to critical analysis to ascertain the possible future prospects of such findings into designing plant-derived products in future for the treatment of peptic ulcer.
Electronic version of prominent bibliographic databases, including Google Scholar, PubMed, Scopus, ScienceDirect, Wiley Online Library, SpringerLink, Web of Science, and MEDLINE were explored extensively for the identification and compilation of relevant information. The plant names and respective family names were verified through the Plant List (version 1.1) and World Flora Online 2021. All relevant chemical structures were verified through PubChem and SciFinder databases and illustrated with ChemDraw Ultra 12.0.
A colossal number of 97 plant species categorized under 58 diverse plant families have been discussed in the review for their gastroprotective and antiulcer properties. In vivo illustrations of the pharmacological properties were achieved for almost all the species under consideration. 29 individual phytoconstituents from these sources were also characterized with similar pharmacological potentials. Majority of the plant extracts as well as their constituents were found to exert their gastroprotective effects through antioxidative pathway featuring both enzymatic and nonenzymatic mechanism. Moreover, active inhibition of acid secretion, upregulation of gastroprotective mediators and downregulation of pro-inflammatory cytokines, were also associated with a prominent number of plants or products thereof.
Comparative evaluations of the plant sources for their antiulcer activities, both as individual and as combination formulations, are necessary to be conducted in human subjects under properly regulated clinical conditions. Moreover, the efficacy and safety of such products should also be evaluated against those of the currently available treatment options. This will further facilitate in ascertaining their suitability and superiority, if any, in the treatment of peptic ulcer diseases. Implementation of these endeavors may eventually lead to development of more efficient treatment options in the future.
Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases
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Helicobacter pylori is a significant human pathogen of the stomach's epithelial lining. This type of carcinogen is associated with gastric cancer, indigestion, peptic ulcers, and upper digestive diseases. Therefore, successful treatment and eradication of this bacterium are required to reduce the prevalence of these diseases, especially in high-risk individuals. Moreover, some concerns exist regarding the extensive use of elimination therapy, such as anti-microbial resistance and rising H. pylori-associated diseases. Since there is still no effective vaccine, finding alternative therapies would appear to be a worthwhile pursuit. In this regard, curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.
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Citation Excerpt :
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Systematic review and meta-analysis, level III.
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SeminarPeptic-ulcer disease

Summary

Introduction

Section snippets

Duodenal ulcers

Gastric ulcers

NSAID-induced gastric injury

Current issues in prevention of NSAID ulcers

Non-NSAID, non-H pylori ulcers

Selection criteria and search strategy

Lancet

Clin Gastroenterol

Gastroenterol Clin North Am

Am J Gastroenterol

Gastroenterology

Lancet

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Gastroenterology

Lancet

Gastroenterology

Gastroenterology

Cell

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Gastroenterology

Lancet

Lancet

Lancet

NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease

JAMA

Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. European Helicobacter pylori Study Group

Gut

Time trends of physician visits and treatment patterns of peptic ulcer disease in the United States

Arch Intern Med

Recent trends in admissions and mortality due to peptic ulcer in England: increasing frequency of haemorrhage among older subjects

Gut

Epidemiology of NSAID-induced GI complications

J Rheumatol

Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs

N Engl J Med

Perturbations in gastric physiology in Helicobacter pylori duodenal ulcer: are they all epiphenomena?

Helicobacter

Campylobacter pyloridis and acid induced gastric metaplasia in the pathogenesis of duodenitis

J Clin Pathol

Impaired proximal duodenal mucosal bicarbonate secretion in patients with duodenal ulcer

N Engl J Med

Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer

Proc Natl Acad Sci USA

Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors

Proc Natl Acad Sci USA

Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori.

Proc Natl Acad Sci USA

Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion

Science

Seminar
Peptic-ulcer disease