Elsevier

The Lancet

Volume 374, Issue 9699, 24–30 October 2009, Pages 1449-1461
The Lancet

Seminar
Peptic ulcer disease

https://doi.org/10.1016/S0140-6736(09)60938-7Get rights and content

Summary

Peptic ulcer disease had a tremendous effect on morbidity and mortality until the last decades of the 20th century, when epidemiological trends started to point to an impressive fall in its incidence. Two important developments are associated with the decrease in rates of peptic ulcer disease: the discovery of effective and potent acid suppressants, and of Helicobacter pylori. With the discovery of H pylori infection, the causes, pathogenesis, and treatment of peptic ulcer disease have been rewritten. We focus on this revolution of understanding and management of peptic ulcer disease over the past 25 years. Despite substantial advances, this disease remains an important clinical problem, largely because of the increasingly widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin. We discuss the role of these agents in the causes of ulcer disease and therapeutic and preventive strategies for drug-induced ulcers. The rare but increasingly problematic H pylori-negative NSAID-negative ulcer is also examined.

Introduction

Peptic ulcer disease embraces both gastric and duodenal ulcers and has been a major threat to the world's population over the past two centuries, with a high morbidity and substantial mortality. Epidemiological data for this disease and its complications have shown striking geographical variations in incidence and prevalence. Development of ulcer disease and death from it has been associated with the birth of urbanisation and was interpreted as a birth-cohort event with the peak of disease in those born during the late 19th century.1, 2 Our understanding of the disease changed greatly with the discovery of Campylobacter pyloridis (renamed Helicobacter pylori in 1989 because of a revised taxonomic classification) in 1982 by Warren and Marshall.3, 4 This discovery switched the notion from an acid-driven disease to an infectious disease, opening a huge area for intensive research that resulted in the reconciliation of previously suggested mechanisms of pathogenesis.

The fall of the acid dogma in peptic ulcer disease, which had found its undisputed acceptance during and after the introduction of histamine H2-receptor antagonists, led to the present therapeutic principle. Maintenance acid-suppressive therapy for duodenal ulcer, which followed decades of dominance of surgical interventions (subtotal gastric resections, several forms of vagotomy), was replaced with a short-term antibiotic regimen targeting eradication of H pylori infection.5, 6 H pylori eradication as cure of peptic ulcer received its full recognition when the Nobel Prize for Medicine and Physiology was awarded to Warren and Marshall in 2005. This recognition has not, however, closed the chapter on peptic ulcers. The management of ulcer disease and its complications remains a clinical challenge. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin are an increasingly important cause of ulcers and their complications even in H pylori-negative patients.7, 8 Other rare causes of ulcer disease in the absence of H pylori, NSAIDs, and aspirin also exist.

Section snippets

Clinical manifestations and diagnosis

The predominant symptom of uncomplicated peptic ulcer is epigastric pain, which can be accompanied by other dyspeptic symptoms such as fullness, bloating, early satiety, and nausea. In patients with duodenal ulcer, epigastric pain occurs typically during the fasting state or even during the night and is usually relieved by food intake or acid-neutralising agents. Roughly a third of these patients also have heartburn, mostly without erosive oesophagitis.9 Chronic ulcers can be asymptomatic.10 In

Pathogenesis

Panel 1 shows an aetiological classification of peptic ulcers. The complex and multifactorial pathogenesis of peptic ulcer has been studied over several decades, and results from an imbalance of aggressive gastric luminal factors acid and pepsin and defensive mucosal barrier function. Several environmental and host factors contribute to ulcer formation by increasing gastric acid secretion or weakening the mucosal barrier.18, 19, 20 Among environmental factors, smoking, excessive alcohol use,

H pylori-positive ulcer

Epidemiological studies revealed a very strong association between H pylori infection and duodenal and gastric ulcers. The ultimate proof of H pylori as the main cause of ulcer disease was the permanent cure of peptic ulcers by eradication of the infection.30, 31 More than 50% of the world's population has a chronic H pylori infection of the gastric mucosa, yet only 5–10% of those infected develop ulcers. Factors determining whether the infection will produce disease are the pattern of

NSAID-induced ulcer

Topical injury by ion trapping78 and reduction of mucus gel hydrophobicity79 was once thought to be an important mechanism of NSAID-induced gastric damage. Later, NSAIDs were shown to damage the stomach mainly by suppression of gastric prostaglandin synthesis.80 The discovery of two isoforms of cyclo-oxygenase (COX), COX-1 and COX-2, sparked an enormous drive by the pharmaceutical industry to develop COX-2-selective NSAIDs as gastric-sparing anti-inflammatory analgesics. Now, good evidence

Management

Since Karl Schwarz's109 dictum of no acid, no ulcer, development of medical therapies has targeted gastric acid secretion and mucosal defence mechanisms. Many drugs have been used to treat ulcers, but few early treatments stood the test of time (table 1). The most successful classes of drugs were those inhibiting gastric acid secretion. H2-receptor antagonists revolutionised treatment of peptic ulcer, healing ulcers and keeping them in remission when given as maintenance therapy.110, 111 They

Treatment for H pylori-positive ulcer

Treatment for H pylori-associated ulcer disease is mainly directed at eradication of infection. Eradication is usually achieved with a combination of acid-inhibiting therapy and antibiotics. Antibacterial therapy alone does result in healing, but the process is accelerated by addition of acid suppressants (ie, PPIs).74 The Maastricht Consensus Report provides recommendations on management of H pylori infection (panel 2).6

H pylori eradication is equally effective in both duodenal and gastric

Treatment for NSAID-induced ulcer

NSAIDs, including low-dose aspirin, are the most important cause of ulcer complications in developed countries where prevalence of H pylori infection is falling. In patients who develop uncomplicated peptic ulcers while on NSAIDs, more than 90% of gastric or duodenal ulcers heal with 8 weeks of standard-dose H2-receptor antagonists (eg, ranitidine 150 mg twice a day), provided that NSAIDs are discontinued.129 However, healing of gastric ulcers will be greatly impaired if patients continue to

H pylori-negative NSAID-negative ulcer

Ulceration of the gastric or duodenal mucosa in the absence of H pylori infection and NSAID or aspirin usage is rare.149, 150, 151, 152, 153, 154 However, because of the falling prevalence of H pylori infection and resulting ulcers, the proportion of ulcers that are unrelated to this infection is likely to increase and several rare causes need specific attention. The most important consideration in a patient with gastric or duodenal ulcer, negative H pylori test, and negative NSAID or aspirin

Search strategy and selection criteria

Because of the complexity of the topic and change in dogma after H pylori discovery, reference search pre-1990 was mainly through book chapters, monographs, and review articles, including selective search of original publications. For 1990–2008, the PubMed database was used to retrieve key articles on various and specific aspects of peptic ulcer disease. Search terms were “ulcer”, “peptic ulcer”, “gastric ulcer”, “duodenal ulcer”, “epidemiology”, “ulcer pathogenesis”, “H pylori”, “H pylori

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