Editor: Joseph Sung
6. Gastritis and peptic ulcer disease: H. pylori infection and NSAIDs
Peter Malfertheiner & Deirdre McNamara
Gastritis is a diagnosis based on histological criteria; its aetiology is diverse. Helicobacter pylori colonization and non-steroidal
anti-inflammatory drug consumption are among the most frequent and important. Most patients remain asymptomatic in the absence
of complications (peptic ulcer disease). The major health implications associated with gastritis are attributable to longstanding
disease, in particular gastric atrophy and related achlorhydria as well as gastric carcinogenesis. It remains a challenge
to identify individuals in whom the disease will progress, enabling early intervention and disease prevention.
Damage to the gastroduodenal mucosa, with and without the induction of circumscribed lesions, can be the result of bacterial
infection, exogenous toxic factors, and/or autoimmune processes.
H. pylori infection and non-steroidal anti-inflammatory drugs (NSAIDS) are by far the two most prevalent aetiologies inducing gastroduodenal
pathology. In the following, we discuss basic and clinical features related to these factors (Fig. 1).
Gastritis is a commonly described endoscopic finding, but accurate diagnosis and differentiation requires histological assessment.
The currently accepted method of describing gastritis is the Sydney classification. Developed in 1996 and updated in 2001,
it includes assessment of mucosal morphology, grade of atrophy, and the distribution of abnormalities (Fig. 2). Histological grading includes the activity of inflammation, grade of atrophy, presence of intestinal metaplasia, H. pylori infection and other particular aetiological agents. In addition the distribution of inflammatory changes can be defined as:
- antrum predominant;
- corpus predominant;
The phenotypes described should be considered as a gradual interconnecting spectrum rather than clear-cut distinct entities.
Gastritis can be defined as either acute or chronic.
Acute gastritis may be induced by a variety of noxious agents, including alcohol, foods, medications, and infections. Acute gastritis often
appears macroscopically as edema and reddening of the mucosa. Aspirin-induced forms are often described with characteristic
punctate hemorrhages or fibrin-covered lesions in the antrum or duodenum. NSAID-induced lesions are often recognized as florid
lesions in the prepyloric antrum. The histological findings include edema with capillary exudation of leucocytes (Figs 35).
Chronic gastritis may be classified into two major forms (1) H. pylori-associated and (2) H. pylori-unrelated forms. H. pylori-induced gastritis accounts for 90% of all forms of chronic gastritis (Fig. 6). Although typical endoscopic features have been described for individual forms of chronic gastritis, classification is frequently
difficult by endoscopic appearance alone. In addition the often multifocal distribution of changes within the mucosa requires
that multiple biopsies be obtained from different sites (Fig. 7). At least two biopsies should be taken from the antrum/pylorus region and two from the fundus/corpus region to enable accurate histological differentiation. Additional biopsies from the incisura are often not clinically
relevant (although proposed in the last Sydney classification update). In addition, biopsies should be obtained from any visible
H. pylori infection is usually acquired in childhood by fecaloral or oraloral transmission. Humans represent the natural hosts for infection. The clinical manifestations usually occur later in life
when patients present with symptoms (gastritis, peptic ulcer, or gastric cancer) and undergo investigation. H. pylori infection is associated with the development of a chronic active gastritis.
Common macroscopic appearances include spotty or streaky reddening of the mucosal folds in the antrum, with or without chronic
erosions. Florid exudative erosions are uncommon in H. pylori infection. Following H. pylori colonization, the superficial gastric epithelium becomes infiltrated with neutrophils, lymphocytes, and plasma cells. With
ongoing inflammation, mucosal epithelial regeneration occurs with mucus depletion and the development of focal intestinal
metaplasia. Whether these latter abnormalities develop or not is dependent both on the virulence of the infecting strains
and the host's genetic predisposition. This is clinically relevant as the type of underlying gastritis predisposes to the
development of different disease entities (ulcers or carcinoma).
Gastritis: clinical manifestations and symptoms
The majority of individuals (80%) with H. pylori infection and gastritis remain asymptomatic in the long term. It is not clear whether the presence of gastritis alone is
sufficient to induce symptoms. The majority of patients will present with dyspepsia. Dyspepsia is a symptom complex referable
to the upper gastrointestinal tract and includes epigastric pain, nausea, vomiting, and bloating. Despite several attempts
at classifying dyspepsia there is still no clear way of predicting underlying endoscopic or histological findings based on
any predominant symptom complex.
However, alarm symptoms may suggest the presence of serious underlying conditions (Fig. 8). It is important to note that gastritis refers to a histological entity and is not a symptom, although many patients and
doctors use the term interchangeably. Many patients with gastritis will be asymptomatic and in addition some individuals may
have symptoms without undergoing pathology. 'Gastritis' is an umbrella term for a variety of disease entities, and should be categorized based on histological and aetiological criteria.
H.pylori and ulcers
H. pylori is the predominant pathogen in peptic ulcer disease. Supportive evidence comes from epidemiological data as well as from
a change of pathogenetic events initiated by H. pylori in gastroduodenal mucosa and a complex puzzle of inflammatory events with repercussions in gastric physiology. The definitive
proof for the causal role of H. pylori in peptic ulcer is that successful eradication results both in ulcer healing and prevention of disease relapse . Epidemiological studies have attributed a fourfold increased risk of developing an ulcer for H. pylori-infected vs.-non-infected persons; this risk is estimated to be 25 times higher if the degree of inflammatory activity is
high and antrum predominant [2,3]. Approximately 90% of patients with duodenal ulcer and 70% with gastric ulcers harbour H. pylori infection [4,5].
The difference in prevalence of H. pylori among duodenal and gastric ulcers is due to the higher frequency of NSAIDs, the other well-established aetiological agents
frequently involved in gastric ulcers. The other side of the coin is that only about 10% of H. pylori-infected subjects in Western industrialized countries will eventually develop an ulcer; others develop symptoms without ulcers
or, much more rarely, gastric neoplasia. Approximately 80% of H. pylori-infected persons will live with a persistent chronic gastric inflammation without symptoms and without any further progression
to relevant clinical disease. The complexity of H. pylori as an ulcerogenic condition clearly suggests that additional factors are required for completion of the pathogenetic cascade
towards ulcer formation.
H.pylori: the pathogenetic pathway
The following factors are relevant in the pathogenetic cascade leading to peptic ulceration:
- pattern and phenotype of gastritis;
- alterations in the homeostasis of gastric hormones and acid secretion;
- gastric metaplasia in the duodenum as a prerequisite for H. pylori colonization;
- the interaction of H. pylori with the mucosal barrier and 'ulcerogenic' strains;
- therapeutic proof of causality;
- genetic factors.
Pattern and phenotype of gastritis in association with H. pylori
Generally H. pylori colonizes the epithelium from the prepyloric antrum to the cardia, and the outcomes of H. pylori infection are significantly influenced by the topographical predominance of the chronic inflammation. The characteristic
pattern of gastritis in patients with duodenal ulcer (DU) is the antrum-predominant distribution of H. pylori, with a high density of the bacteria and a high degree of inflammatory activity in this location . Following eradication therapy, gastric mucosal alterations are usually fully reversible in DU .
In gastric ulcer (GU), the topographical expression of chronic gastritis is such that the body mucosa and antral mucosa are
equally affected. Unlike DU, acid secretion is decreased in patients with GU, because of the more severe involvement of the
body mucosa. Acid-inhibitory drugs, in particular protein pump inhibitors (PPIs), always lead to changes in the pattern of
gastritis, with a reduction of bacteria and inflammatory activity in the antrum and an increase of both these conditions in
Alterations in the homeostasis of gastric hormones and acid secretion related to H. pylori
Antrum-predominant chronic H. pylori infection is accompanied by an increase in both basal and stimulated gastric acid output, the effect being most pronounced
in patients with DU . The link between H. pylori infection and acid hypersecretion appears to be hormonal in nature and driven by hypergastrinemia. The hypergastrinemia is
a consequence of a reduction in gastric somatostatin synthesis and release, which normally exerts an inhibitory control on
gastrin release [15,16]. More recent work has shown that, in addition to gastric hormones, neural pathways are also influenced by H. pylori infection, with functional disruption of antralfundic neural connections . The impairment of the inhibitory neural control of gastrin and acid secretion elicited by a test meal in patients with H. pylori-positive DU was recently demonstrated . These abnormal responses, which in association with increased gastric emptying induce a higher duodenal acid load, are all
reversed following H. pylori eradication. Eradication of H. pylori infection rapidly resolves the accompanying hypergastrinemia and is associated with normalization of antral somatostatin
levels, whereas it may take several months before acid hypersecretion returns to normal [16,19,20]. Hypergastrinemia not only stimulates gastric acid secretion but also exerts a trophic effect on the parietal cell mass,
which may explain the sustained acid secretion following H. pylori eradication.
Gastric metaplasia in the duodenum is a prerequisite for H. pylori colonization
Gastric acid hypersecretion, and more specifically the acid overload in the duodenum, leads to the development of gastric
metaplasia in the duodenal bulb. H. pylori is adapted to colonize gastric epithelial cells; as such, gastric metaplasia in the epithelium of the duodenal bulb is crucial
and essential for the organisms to colonize the duodenum. Most likely this happens by migration from the antrum. The risk
of developing a DU in the presence of gastric metaplasia and H. pylori appears to be 50 times that of controls .
Interaction of H. pylori with the mucosal barrier
Colonization of the gastric mucosa by H. pylori evokes a local inflammatory response, which results in mucosal injury of varying degrees . The acute inflammatory response starts with the release of epithelium-derived cytokines, predominantly interleukin-8 (IL-8)
[23,24]. Bacterial products and cytokines orchestrate the acute inflammatory response, promoting an influx of neutrophils and macrophages
into the gastric mucosa, which subsequently release lysosomal enzymes, leukotrienes, and oxygen-free radicals [23,25]. The next step in the inflammatory cascade is the activation of T and B lymphocytes by bacterial antigens with the release
of further proinflammatory cytokines, including IL-1, IL-2, IL-6, and tumour necrosis factor-a (TNF-a), as well as the generation of specific antibodies (IgA and IgG) directed against H. pylori[26,27]. All these factors contribute to mucosal damage by promoting the release of factors with ulcerogenetic potential, such as
platelet activating factor (PAF) and components of the complement pathway 
Ulcerogenic strains of H. pylori
Pathogenetic properties (virulence factors) vary among strains. H. pylori isolated from patients with peptic ulcer disease appear to be more virulent, with some evidence that they exert a stronger
adhesive property and produce greater amounts of enzymes with toxic potential. Among them, urease and phospholipases A2 and
C are of particular interest. H. pylori strains from ulcer patients produce greater amounts of urease; this enzyme catalyzes the production of ammonia, which in
high concentrations is followed by the formation of toxic complexes such as NH4Cl . Phospholipases A and C disrupt a defensive element of the mucosal barrier surfactant composed of a phospholipid-rich layer
responsible for maintaining mucosal hydrophobicity, a key component in maintaining the integrity of the gastric epithelium
[30,31]. The released phospholipids appear to be ingested by H. pylori.
Several other bacterial products are released in close proximity to the epithelial cells, exerting a direct harmful effect.
Infection with certain H. pylori genotypes is linked to more severe morbidity. The most important genotypes are vacA- and cagA-positive, present in almost
all patients with peptic ulceration. The H. pylori-derived vacuolating cytotoxin (vacA), an 87 kDa protein, causes vacuolar degeneration in cultured gastric cell preparations
and gastric ulceration in experimental animals . Although present in all H. pylori strains, the vacA gene, depending on its allelic form, is expressed in only 60%, lending strong support to the hypothesis of strain-dependent
virulence. The cytotoxin-associated gene A (cagA), which is restricted to cytotoxin-producing strains of H. pylori, encodes for an 120160 kDa immunodominant protein that is now recognized as a marker of greater virulence, leading to an enhanced local inflammatory
Among H. pylori-infected individuals, bacterial strains expressing cagA protein are closely associated with peptic ulcer (present in 92%
of cases) and, to a lesser extent, with chronic gastritis (~60% in Western populations) [38,39]. The cagA gene is now known to be part of a larger cag pathogenicity island, which embraces other genes. These and a series of other
genes (NAP, oiPA, iceA) have been characterized, and their function is to enhance mucosal inflammation through induction of cytokines [40,41].
Genetic factors and H. pylori
Twin studies confirm a genetic predisposition for infection with increased susceptibility in monozygotes vs. dizygotes . Lewis antigen association studies also support a genetic predisposition for peptic ulcer disease [43,44]. A Japanese working group contributed a new finding to this issue of genetic predisposition by reporting that subjects with
human lymphocyte antigen (HLA) type DQA 1301 have an increased prevalence of ulcer disease .
The therapeutic proof of causality: H. pylori and ulcers
The list of therapeutic studies is long, and all studies unequivocally report that H. pylori eradication leads to cure of gastric as well as duodenal ulcer [1,4,5]. The effect is lasting, as shown in long-term follow-up studies . In addition, ulcer healing is accelerated if antibiotics are added to acid-secretory inhibitors . Finally, complications of peptic ulcer disease can also be presented following H. pylori eradication, and this is superior to acid-inhibitory therapy alone (Fig. 9). All these facts taken together led to the NIH consensus statement in 1994 that antibiotic treatment in addition to antisecretory
therapy is required for all patients with H. pylori-positive peptic ulcers .
Ulcers: clinical features and diagnosis
Abdominal pain is the key presenting symptom in patients with either gastric or duodenal ulcers. A detailed description of
the pain and its related features (intensity, site, radiation, relationship to meals, diurnal variation, aggravating and relieving
factors, and associated symptoms such as nausea, vomiting, or weight loss) may assist differentiation between the types of
peptic ulcer disease and also distinguish them from other gastric conditions such as gastric cancer.
It is particularly important to ascertain if there are any alarm symptoms, suggestive of sinister underlying pathology and
indicating the need for rapid thorough investigation (Fig. 8). Typically, duodenal ulcers are characterized by pain at night, hunger pain, and pain which is relieved by eating. It is
important however, to note that ulcers may be symptom free. Asymptomatic ulcers are more frequent in elderly subjects and
those taking NSAIDs. Similarly, in patients on immunosuppressive therapy, such as corticosteroids, symptoms may be reduced
or even masked completely.
Individuals with symptoms for four or more weeks require investigation. The use of radiological imaging techniques is now
obsolete. The gold standard investigative tool is gastroscopy. Performing a gastroscopy facilitates accurate assessment of
the lesion, including site, size, presence or absence of complications, and to distinguish between benign and malignant disease
by performing biopsies (Figs 1012).
Several successful management strategies have been proposed.
Test and treat
The most accepted non-invasive management strategy is a so-called test and treat strategy. In this strategy non-invasive H. pylori testing (C13 urea breath test, stool antigen assay, or serology) is undertaken as the first-line investigation in young people
(<40 years) who present with dyspepsia (without alarm symptoms). Those who are H. pylori positive subsequently receive an accepted eradication therapy while those who are not infected receive empirical symptomatic
treatment. Such a strategy has advantages in reducing the endoscopy workload but also in enabling rapid assessment and treatment
of dyspeptic patients.
Diagnosis of H. pylori at the time of gastroscopy requires both antral and corpus samples for histological assessment in combination with an additional
antral sample for either rapid urease testing or culture. It is inadequate to perform only one diagnostic test. Again it should
be stressed that histological samples from gastric ulcers should be obtained to detect malignancy. Following treatment (eradication
therapy) a repeat gastroscopy is not indicated in the majority of patients, as a non-invasive H. pylori test performed at least 4 weeks after treatment has been shown to be effective. However, in the case of gastric ulcers, or
complicated duodenal ulcers, a follow-up gastroscopy 68 weeks after instigating treatment is warranted both to ensure healing of the lesions and, in the case of gastric ulcers,
to check again for malignancy.
Treatment of peptic ulcers
Acid suppression has been used for the management of patients with peptic lesions for over a hundred years. An historical
breakthrough was the development of histamine 2 receptor antagonists (H2RAs), which had a greater effect on ulcer healing
than any other modalities available up to then. The ability to suppress gastric acid secretion more profoundly became available
with the development of omeprazole, a PPI, in 1989. PPIs dramatically enhanced ulcer healing rates: at 4 weeks 90% of ulcers
could be healed compared to approximately 70% with H2RAs.
The scientific rationale behind employing acid suppression to induce ulcer healing is to attempt to maintain the gastric pH
above 3.5, at which level pepsinogen enzymatic activation to pepsin, the injurious gastric factor, is inhibited. The need
for long-term acid-suppressant therapy has been made redundant following the recognition that eradication of H. pylori infection results in a rapid and sustained healing of ulcer lesions with only a 5% risk of future relapse. H. pylori eradication therapy is now the principal treatment for both gastric and duodenal ulcers. A 7-day course of acid suppression
combined with antibiotics is sufficient therapy in the case of uncomplicated ulcers. In those with a gastric ulcer or duodenal
lesions >2 cm, signs of complications, or H. pylori-negative lesions, acid suppression therapy should continue until ulcer healing has been documented.
The currently recommended therapy for eradication is a short, 7 day combination of a PPI (standard dose bd) with clarithromycin
and either amoxicillin or metronidazole, known as triple therapy . Intention to treat analyses have confirmed that triple therapy induces ulcer healing in up to 80% of cases with successful
eradication. The choice between combining clarithromycin (C) with either amoxicillin (CA) or metronidazole (CM) is difficult.
Gastrointestinal side-effects, particularly diarrhoea, are more frequent when a CA combination is used (20 vs. 10%). CA would
appear to be the treatment of choice in regions with high levels of primary metronidazole resistance (Fig. 13).
Treatment failure is frequently a result of either poor patient compliance (improved with the advent of shorter treatment
duration) or antibiotic or PPI resistance. The issue of antimicrobial primary resistance has become increasingly important
. It has been estimated that the world-wide prevalence of primary resistance to metronidazole and clarithromycin is in the
order of 2070% and 112%, respectively. These figures vary dramatically by region. Amoxicillin resistance appears extremely uncommon. Secondary
resistance to metronidazole has been demonstrated in 6070% of individuals and to clarithromycin in 3050%. Despite this, second-line treatments have been developed which offer eradication rates of 7080% and which may be employed without necessitating culture and antibiotic sensitivity testing. If second-line therapy fails
it is advisable to repeat a gastroscopy and to obtain mucosal samples for culture and sensitivity analysis, as retreatment
is unlikely to be successful with empirical (blind] therapy (Fig. 14).
NSAIDs and gastrointestinal pathology
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 increasing rapidly. NSAIDs remain the mainstay of treatment for a myriad
of inflammatory conditions and are frequently employed as analgesics; in particular the use of aspirin has risen dramatically
since its efficacy in prevention of 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 in 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 (Fig. 15). Similarly, whether data from endoscopic studies can be extrapolated to the wider population is not agreed. 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.
Clinical and histological characteristics of NSAID-related injury
The consumption of NSAIDs induces acute gastric mucosal injury hours after ingestion, which is characterized by the presence
of submucosal hemorrhage 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, which is a relative
misnomer as one of the key histological findings is 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 to controls over a 1 year follow-up. Conversely,
a population-based study from America estimated that NSAID use was associated with a twofold 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 which reported gastrointestinal complications of NSAIDs attempted
to address this issue. This showed that epigastric pain and related symptoms are increased in NSAID users by 36% compared
to controls .
In many patients, ongoing tissue damage results in the development of deep excavated gastric or duodenal ulcers, partly as
a direct result 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 esophagitis, esophageal
strictures, acute intestinal ulceration, perforation, and, rarely, colonic ulceration. Often NSAID-related ulcers are large,
more commonly found in the stomach than in the duodenum, and paradoxically frequently 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.
Epidemiology of NSAIDs and gastric injury
It has been clearly demonstrated that patients using NSAIDs are at an increased risk of developing both ulcers and associated
complications (hemorrhage or perforation). Consumption of NSAIDs is associated with a three- to fourfold increased risk of
peptic ulcer development. The attributable risk of ulcer complications among NSAID users is 2535%. 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 hemorrhage, perforation, and mortality, respectively .
Large-scale cohort studies have confirmed these findings . In addition, there are now more data available on the gastrointestinal effects of prophylactic low-dose aspirin. Case control
studies performed in the United Kingdom have shown that the use of low-dose aspirin confers an increased relative risk of
bleeding compared to other patients and to the community of 26 depending on the dose employed (751200 mg/day) .
Further evidence from the UK Transient Ischaemic Attack Trial confirms previous data which showed that the risk of bleeding
is greater for duodenal than gastric ulcers and that bleeding may occur from other sites of the gastrointestinal tract . Moreover, the risk of duodenal perforation is also increased and has been reported to be six times that of non-users, but
less than that for other NSAIDs . 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.
Risk modifiers of injury with NSAIDs
There are a number of possible risk modifiers that may affect the rates of peptic ulceration and their complications regionally
(Fig. 16). The strength of available evidence for different risk modifiers varies. It has been clearly established that age, past
history of peptic ulceration, high doses, and concomitant use of anticoagulants or corticosteroids magnify the risk of bleeding
Dosage and type of NSAID
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 which demonstrate a linear association between the dose of NSAID and the development of ulcer complications
[63,67,68]. A meta-analysis of 12 studies which investigated the effect of different NSAIDs on rates of ulcer complications demonstrated
that different formulations did confer different risks (Fig. 17). However, despite there being a safety advantage for some formulations such as ibuprofen compared to piroxicam or azapropazone,
this was not consistent at higher doses . Other pharmacokinetic properties are also likely to alter the relative risk of varying formulations.
It has been clearly established that older age predisposes to peptic ulcer development. Studies have estimated the relative
risk in subjects over 60 compared to 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 to say, both are associated with inherent risks but there does not appear to be any specific
mechanism whereby the effect of one increases the deleterious effect of the other. The relative risk of ulcer disease in elderly
individuals prescribed NSAIDs is approximately 13 .
A previous history of peptic ulcer is a risk factor for subsequent ulcer development; 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 . 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 of prednisone per day is associated, in combination with NSAIDs, with a threefold increased risk of ulcer bleeding compared
to subjects taking NSAIDs alone .
H.pylori infection and NSAIDs combined
There is conflicting evidence available in the medical literature regarding the nature of the relationship between H. pylori infection and NSAID-induced gastric toxicity. H. pylori infection is causally associated with the development of peptic ulcers, gastric cancer, and mucosal associated lymphoid tissue
lymphoma. Contrary to the previously mentioned risk modifiers, there is evidence to show that concomitant infection may protect
in some individuals and be deleterious in others using NSAIDs.
This apparent paradox can be explained partially by the diverse outcomes associated with infection itself. It is known that
environmental, bacterial, and host factors combine to determine the long-term consequences of infection. Therefore similar
factors are likely to interact in the relationship between H. pylori infection, NSAIDs, and the risk of disease development.
Evidence to support this theory comes from studies which have reported that H. pylori infection in patients at low risk of ulcer development and naive to NSAIDs appears to be at increased risk of ulceration
compared to H. pylori-negative counterparts, whereas individuals with a past history of ulcers and on long-term NSAIDs appear to be protected by
A plausible explanation for this apparent dichotomy is that H. pylori-produced cyclo-oxygenase (COX)-2 may promote the healing of NSAID-related ulcers, possibly by offsetting the systemic effects
of NSAIDs on prostaglandin synthesis. Studies have also reported that the efficacy of PPIs is enhanced by the presence of
Whether to screen for and eradicate H. pylori in subjects taking long-term NSAIDs remains a controversial issue. However, there is growing consensus among medical practitioners
that individuals with or without additional risk factors such as age and previous history of ulcer, who are likely to require
treatment in the long term, should undergo testing for H. pylori, and eradication if positive [76,77]. Supporting evidence for such a strategy comes from studies which have reported an increased risk in such patients of early
ulcer development and associated complications. Following successful eradication, patients with complicated NSAID-related
ulceration or a past history will require maintenance therapy with other cytoprotectants. This may not be the case for patients
taking low-dose aspirin, in whom recent evidence has shown that H. pylori eradication alone is sufficient to prevent ulcer relapse.
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
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 according to previously stated criteria), should also be taken into consideration. In patients at an
increased risk it is reasonable to try alternative treatments such as COX-2 inhibitors, or if necessary to use NSAIDs with
primary pharmacological 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 Helicobacter infection.
The mainstay of treatment for active NSAID-related peptic ulcers remains profound acid suppression (Fig. 18).
Selective COX-2 inhibitors
Recognition that COX occurred in two forms (a constitutive form, COX-1, responsible for many beneficial physiological functions,
and an inducible form, COX-2, thought to mediate pathology) led to the production of selective COX-2 inhibitors with the aim
of maintaining efficacy while reducing or eliminating adverse events.
The initial hypothesis has subsequently been shown to be anything but simple following further analysis. It is apparent from
animal studies that COX-1 knockout mice do not develop spontaneous gastric pathology . In addition, in patients with H. pylori infection, causally associated with the development of peptic ulcers, the predominant source of prostaglandin production
is COX-1 despite COX-2 being an inducible form and increased in other forms of gastric inflammation. Conversely, COX-2 knockout
mice have only minor changes in inflammatory processes and develop renal abnormalities .
It is also clear from additional research that inhibition of one isoform results in a corresponding increase in the other,
suggesting that the two are not acting in isolation. Further supportive evidence comes from animal studies which have shown
that inhibition of both COX-1 and -2 are required to induce ulceration .
Despite the fact that we are still a long way from fully understanding the functions of these isoforms and their interactions
with each other and the gastric mucosa, there is good evidence to show that their use is associated with a reduced risk of
both peptic ulcer development and associated complications. Even at supratherapeutic dosages, the available selective COX-2
inhibitors do not appear to induce acute mucosal injury or to interfere with gastric prostaglandin synthesis . This is presumably the mechanism through which protection is conferred.
The therapeutic role of these various agents in inflammatory conditions continues to be evaluated. Their use has been associated
with other reported NSAID-related side-effects such as salt and water retention, liver toxicity, and their efficacy and cost-benefit
remain to be clarified. Furthermore there are data to show that these agents, by inhibiting COX-2, hinder the repair mechanisms
involved in ulcer healing; although similar to other NSAIDs, this implies that they are not immune to gastrointestinal adverse
Similarly, whether administration of selective COX-2 inhibitors in patients with ulcerative colitis will result in disease
exacerbation or relapse, as seen with other NSAIDs, is unknown. Although these issues remain to be clarified it is clear from
the comparative studies undertaken to date that COX-2 inhibitors represent a significant advance in the area of gastrointestinal
Prophylaxis against NSAID injury
Available prophylactic agents include PPIs, the prostaglandin analogue misoprostol, and H2RAs. There is growing evidence to
show that H2RAs are as effective as other available agents at preventing the development of duodenal ulcers, but less effective
for gastric lesions . For this reason it would appear that these agents would not be the preferred treatment modality. However, there are data
to show that, at an increased dose, effectiveness is similar to that of omeprazole.
Misoprostol has been shown in a number of studies to reduce the risk of ulcer development in patients taking NSAIDs; the effect
appears to be dose dependant. Unfortunately, significant side-effects are frequent in higher doses, in particular diarrhoea
and abdominal pain. These effects appear to be reduced by the combination of misoprostol with diclofenac in a single tablet
PPIs have been shown to reduce the occurrence of ulcers in patients on NSAIDs by 7580% compared to placebo. In addition, comparative studies with H2RAs and misoprostol have revealed that omeprazole leads to
a higher rate of ulcer healing and is also superior as a secondary prophylactic agent [87,88]. There is some evidence to suggest that misoprostol may be as effective as PPIs in a subgroup of H. pylori-negative patients. To date PPIs have the best established record for healing NSAID ulcers. Whether healing rates are quickest
if the offending drug is stopped is not clear. NSAIDs are known to impair ulcer healing and it would therefore appear logical
that improved quality and rates of healing would occur if they were discontinued.
H. pylori infection and NSAIDs are by far the commonest cause of gastroduodenal pathology.
The discovery of H. pylori colonization of the gastric mucosa and its causal association with peptic ulcer disease has opened the way for a new and
lasting treatment for these previously chronic and often complicated conditions. In addition the development of novel diagnostic
tests and management strategies have revolutionized our approach to these diseases, enabling accurate diagnosis and subsequent
treatment without recourse to invasive procedures, and often in the clinic environment.
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 COX 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 cost effectiveness are ongoing.
Both primary and secondary prophylaxis trials have been reported, which have shown that, in high-risk groups, gastrointestinal
complications can be reduced dramatically by a number of agents. H. pylori infection is not implicated in the development of NSAID-associated peptic ulceration, but data assessing its status as a
risk modifier have reported contradictory results. Furthermore, although there is a growing consensus regarding the role of
eradication therapy, both to prevent and manage these ulcers, it is far from unanimous, and will require additional investigation.
Outstanding issues and future trends
The discovery of H. pylori and its subsequent association with both peptic ulcer disease and gastric cancer in the 1980s profoundly altered the clinical
management of these conditions. In particular surgical intervention for peptic ulcer disease has become a rare event, the
majority of peptic ulcers being treated medically with eradication therapy. The development of powerful acid-suppressing medications
facilitated the conservative treatment of peptic ulceration not induced by H. pylori, especially that related to NSAIDs.
More recently it has become medically accepted practice in geographical areas with a low prevalence of gastric cancer in young
individuals to look for infection in people who have symptoms attributable to peptic ulcer disease by non-invasive means,
thereby reducing the necessity for upper endoscopy, while providing appropriate treatment for infected individualsthe so-called 'test and treat strategy'. In addition to providing rapid, effective treatment for peptic ulcer disease and some patients with functional dyspepsia,
there is a large body of evidence for this strategy having an excellent cost-benefit. This management strategy will, according
to all available circumstantial evidence, reduce the incidence of long-term sequelae of infection, namely peptic ulcer and
Development of search and treat management strategies for H. pylori infection would appear to be the most logical progression from current practice. A search and treat strategy can be retrospective,
involving individuals with a history of peptic ulcer, and prospective, in that asymptomatic individuals at high risk of being
infected and suffering complications would be screened for infection, especially those with a strong family history of distal
gastric cancer. The widespread implementation of effective non-invasive diagnostic tests for H. pylori will facilitate such a development.
The future with regard to NSAID-related gastroduodenal pathology appears to be almost upon us. The development of new anti-inflammatory
agents such as COX-2 inhibitors and their clinical application in a myriad of conditions should significantly reduce the incidence
of serious gastrointestinal complications. It has also become apparent that novel antiplatelet agents offer a viable alternative
for patients with ischemic heart disease and gastric side-effects from aspirin use, thereby alleviating a significant proportion
of the burden of gastrointestinal disease associated with its widespread usage. Future challenges do exist. Firstly, the cost
of these agents is substantial, and there is still need to optimize the strategies for the long-term use of PPIs as cytoprotectants.
It is necessary to identify cost-benefit models for clearly defined patient groups.
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