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Peptic ulcer disease had a tremendous eect on morbidity and mortality until the last decades of the 20th century, Lancet 2009; 374: 144961
when epidemiological trends started to point to an impressive fall in its incidence. Two important developments are Published Online
associated with the decrease in rates of peptic ulcer disease: the discovery of eective and potent acid suppressants, August 14, 2009
DOI:10.1016/S0140-
and of Helicobacter pylori. With the discovery of H pylori infection, the causes, pathogenesis, and treatment of peptic
6736(09)60938-7
ulcer disease have been rewritten. We focus on this revolution of understanding and management of peptic ulcer
Department of
disease over the past 25 years. Despite substantial advances, this disease remains an important clinical problem, Gastroenterology, Hepatology,
largely because of the increasingly widespread use of non-steroidal anti-inammatory drugs (NSAIDs) and low- and Infectious Diseases,
dose aspirin. We discuss the role of these agents in the causes of ulcer disease and therapeutic and preventive Otto-von-Guericke University,
Magdeburg, Germany
strategies for drug-induced ulcers. The rare but increasingly problematic H pylori-negative NSAID-negative ulcer is
(P Malfertheiner MD);
also examined. Institute of Digestive Disease,
Chinese University of Hong
Introduction introduction of histamine H2-receptor antagonists, led to Kong, Hong Kong SAR, China
(F K L Chan MD); and Medical
Peptic ulcer disease embraces both gastric and duodenal the present therapeutic principle. Maintenance acid-
Sciences, Western Inrmary,
ulcers and has been a major threat to the worlds suppressive therapy for duodenal ulcer, which followed Glasgow, UK (K E L McColl MD)
population over the past two centuries, with a high decades of dominance of surgical interventions (subtotal Correspondence to:
morbidity and substantial mortality. Epidemiological gastric resections, several forms of vagotomy), was Prof Peter Malfertheiner,
data for this disease and its complications have shown replaced with a short-term antibiotic regimen targeting Otto-von-Guericke University,
Department of Gastroenterology,
striking geographical variations in incidence and eradication of H pylori infection.5,6 H pylori eradication as
Hepatology, and Infectious
prevalence. Development of ulcer disease and death cure of peptic ulcer received its full recognition when the Diseases, 39120 Magdeburg,
from it has been associated with the birth of urbanisation Nobel Prize for Medicine and Physiology was awarded to Germany
and was interpreted as a birth-cohort event with the Warren and Marshall in 2005. This recognition has not, peter.malfertheiner@med.
ovgu.de
peak of disease in those born during the late however, closed the chapter on peptic ulcers. The
19th century.1,2 Our understanding of the disease management of ulcer disease and its complications
changed greatly with the discovery of Campylobacter remains a clinical challenge. Additionally, non-steroidal
pyloridis (renamed Helicobacter pylori in 1989 because of anti-inammatory drugs (NSAIDs) and low-dose aspirin
a revised taxonomic classication) in 1982 by Warren are an increasingly important cause of ulcers and their
and Marshall.3,4 This discovery switched the notion from complications even in H pylori-negative patients.7,8 Other
an acid-driven disease to an infectious disease, opening rare causes of ulcer disease in the absence of H pylori,
a huge area for intensive research that resulted in the NSAIDs, and aspirin also exist.
reconciliation of previously suggested mechanisms of
pathogenesis. Clinical manifestations and diagnosis
The fall of the acid dogma in peptic ulcer disease, which The predominant symptom of uncomplicated peptic
had found its undisputed acceptance during and after the 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,
Search strategy and selection criteria epigastric pain occurs typically during the fasting state or
Because of the complexity of the topic and change in dogma even during the night and is usually relieved by food
after H pylori discovery, reference search pre-1990 was mainly intake or acid-neutralising agents. Roughly a third of
through book chapters, monographs, and review articles, these patients also have heartburn, mostly without
including selective search of original publications. For erosive oesophagitis.9 Chronic ulcers can be
19902008, the PubMed database was used to retrieve key asymptomatic.10 In particular, this absence of symptoms
articles on various and specic aspects of peptic ulcer disease. is seen in NSAID-induced ulcers, for which upper
Search terms were ulcer, peptic ulcer, gastric ulcer, gastrointestinal bleeding or perforation might be the rst
duodenal ulcer, epidemiology, ulcer pathogenesis, clinical manifestation of disease. The most frequent and
H pylori, H pylori eradication, non-steroidal severe complication of peptic ulcers is bleeding, which is
anti-inammatory drugs, aspirin, cyclo-oxygenase-2, reported in 50170 per 100 000, with the highest risk in
ulcer complications, bleeding, proton-pump inhibitor, people aged older than 60 years.1113 Perforation is less
misoprostol, histamine-2-receptor antagonist, and frequent than is bleeding, with an incidence of around
myocardial infarction. Selection of articles was based on seven to ten per 100 000.14,15 Penetration of retroperitoneal
individual and personal experience of the investigators with organs is characterised by constant severe pain but
the intention to cover all major aspects of this specialty; only fortunately is rare.15 Gastric outlet obstruction due to
English language publications were included. ulcer-induced brosis is also rare, and should raise
suspicion of underlying malignant disease.15
however, NSAID gastropathy in man is characterised by asymptomatic (hazard ratio 53, 95% CI 26108).101
an absence of inammatory cells unless H pylori Thus, high-risk patients who develop breakthrough
infection is present. Whether neutrophils initiate NSAID dyspepsia should have treatment withheld and undergo
injury in man is unknown. endoscopic assessment.
Acid suppression has been the mainstay of management Use of low-dose aspirin increases risk of ulcer bleeding
of NSAID-associated ulcer disease. Gastric acid probably by two-fold to three-fold compared with risk in non-
exacerbates NSAID injury by converting supercial users.102,103 Even use of very low-dose aspirin in people
mucosal lesions to produce deeper injury,84 interfering with low gastrointestinal risk is not risk free.104 Growing
with platelet aggregation,85 and impairing ulcer healing.86 evidence suggests that low-dose aspirin is not the same
Patients taking NSAIDs have about a four-fold increase as non-aspirin NSAIDs in several important aspects.
in risk of ulcer complications such as bleeding compared First, data from a large-scale randomised trial suggested
with non-users. Several risk factors have been identied that endoscopic ulcer is not a good predictor for upper
in these patients, such as history of ulcer or ulcer gastrointestinal bleeding with low-dose aspirin.105 The
complications, old age, comorbidities, use of high-dose antiplatelet action of low-dose aspirin might be more
NSAIDs, concomitant use of corticosteroids, aspirin, or important than its ulcerogenic eect in provoking upper
anticoagulants, and H pylori infection.8790 gastrointestinal bleeding. Second, increasing age per se
A history of ulcer complications is the most important is not a risk factor for upper gastrointestinal bleeding
predictor of future ulcer complications associated with with low-dose aspirin.106 Third, research has consistently
NSAID use.88 How past history increases risk is unclear. shown that H pylori infection is a risk factor for ulcer
Indirect evidence exists that ulcers tend to recur at bleeding with low-dose aspirin.107 In our opinion, low-
previous sites,91,92 suggesting that local factors determining dose aspirin may provoke bleeding from pre-existing
mucosal defence might play an important part in H pylori ulcers. Eradication of H pylori heals ulcers and
ulcerogenesis. Contrary to general belief, use of therefore reduces the risk of recurrent ulcer bleeding
corticosteroids per se is not ulcerogenic.93 However, both with low-dose aspirin.108
corticosteroids and anticoagulants substantially increase
risk of ulcer bleeding when used concomitantly with Management
NSAIDS.88,93,94 Anticoagulants probably provoke bleeding Since Karl Schwarzs109 dictum of no acid, no ulcer,
from ulcers induced by NSAIDs in addition to causing development of medical therapies has targeted gastric
generalised mucosal bleeding. acid secretion and mucosal defence mechanisms. Many
Does any interaction exist between H pylori and drugs have been used to treat ulcers, but few early
NSAIDs? There are data to suggest that H pylori increases, treatments stood the test of time (table 1). The most
have no eect on, or decrease ulcer risk in NSAID users. successful classes of drugs were those inhibiting gastric
Two systematic reviews have shown that H pylori infection acid secretion. H2-receptor antagonists revolutionised
substantially increases risk of peptic ulcer and ulcer treatment of peptic ulcer, healing ulcers and keeping
bleeding in chronic NSAID users.89,90 In one study, risk of them in remission when given as maintenance
ulcer bleeding was increased by a factor of 179 with therapy.110,111 They were gradually replaced with the more
H pylori infection, by 485 with NSAID usage, and by potent class of acid-inhibitory drugs, the PPIs, which
613 in the presence of both NSAID use and H pylori became available in 1989. PPIs selectively block the H+K+
infection.90 In patients who are about to start NSAIDs, ATPase of the parietal cell.112 On the basis that speed of
eradication of H pylori substantially reduces subsequent ulcer healing is associated with degree of acid suppression,
risk of endoscopic and complicated ulcers.95,96 Two PPIs became the hallmark in ulcer therapy. However,
systematic reviews have shown that H pylori eradication after the healing phase ulcers were usually seen to recur,
was more eective than was placebo in primary prevention and for years standard practice was to keep patients on
of peptic ulcers in regular NSAID users (relative risk maintenance acid suppression until the revolutionary
035, 95% CI 020061).97,98 Additionally, no dierence is introduction of H pylori eradication therapy.
reported between H pylori eradication and co-therapy with A second group of drugs is directed at reinforcement of
a PPI in primary prevention of ulcers in regular NSAID the mucosal barrier, and has found its major application
users with average gastrointestinal risk.99 However, in protection against NSAIDs and aspirin. Misoprostol, a
eradication of H pylori alone is not sucient to prevent prostaglandin analogue, has been the most widely used
ulcer bleeding in NSAID users with high gastrointestinal but its application is limited by abdominal side-eects,
risk, such as a history of ulcer bleeding.100 especially at higher doses.113 Sucralfate and bismuth salts
Whether dyspepsia is a risk factor for ulcers in NSAID also promote ulcer healing by improving mucosal
users is controversial.88,94 However, in patients with a past repair.110 Sucralfate might also act partly by reducing acid
history of ulcer bleeding, those who had breakthrough secretion and suppressing H pylori infection.114 Bismuth
dyspepsia while on a COX-2 inhibitor or prophylaxis salts with some intrinsic anti-H pylori activity are used in
with a PPI had a signicantly higher likelihood of ulcer therapy only in combination with antibiotics.110
recurrent ulcer than did those who remained Cytoprotective drugs have been outdated by more
Mechanisms Use
H2-receptor antagonists (cimetidine, Acid inhibition H pylori-negative peptic ulcer; replaced by PPI because of inferiority in acid
ranitidine, famotidine, nizatidine, suppression
roxatidine)
PPI (omeprazole, pantoprazole, Most potent acid inhibition Standard treatment for all H pylori-negative peptic ulcers; prevention of
lansoprazole, rabeprazole, esomeprazole) NSAID or aspirin ulcers; essential component in eradication regimen; given
intravenously in bleeding ulcers
Prostaglandin analogues* (misoprostol) Increase mucosal resistance; weak H pylori-negative gastric ulcer; prevention of NSAID ulcers
acid inhibition
H pylori eradication regimens (PPI plus two Cure of H pylori infection Standard therapy in all H pylori-positive ulcers
antibiotics)
Bismuth salts (subcitrate, subsalicylate) Weak antibacterial eect; increase In quadruple therapy for H pylori eradication
of mucosal prostaglandin synthesis
Several mucosal protectives used in some countries (ie, sucralfate, rebamipide, and others) do not have sucient trial documentation to be included in the ecacy
comparison with the listed standard therapies. PPI=proton-pump inhibitor. NSAID=non-steroidal anti-inammatory drug. *Contraindicated in pregnancy.
eective therapies. Current ulcer therapy consists of resistant to either of these drugs, causing reduced
H pylori eradication in H pylori-positive peptic ulcer and eradication rates. Checking for antimicrobial sensitivity
PPI for healing and preventing peptic ulcers induced by before treatment of H pylori is not routine. However, if a
gastrotoxic drugs. A small role exists for drugs enhancing patient has previous exposure to these antimicrobials or
mucosal resistance. lives in a region where these drugs are frequently
prescribed, they are more likely to have a resistant strain
Treatment for H pylori-positive ulcer and alternative antimicrobials should be given.
Treatment for H pylori-associated ulcer disease is mainly Monitoring of eradication rates is important to detect
directed at eradication of infection. Eradication is usually emergence of resistant strains and alert to the need to
achieved with a combination of acid-inhibiting therapy modify the regimen. One should aim to maintain rst-
and antibiotics. Antibacterial therapy alone does result in line eradication rates greater than 80%.6
healing, but the process is accelerated by addition of acid The duration of eradication therapy remains
suppressants (ie, PPIs).74 The Maastricht Consensus controversial. In Europe, 1-week triple regimens are used,
Report provides recommendations on management of whereas US guidelines recommend 10 or even 14 days of
H pylori infection (panel 2).6 therapy.117 A meta-analysis showed that increasing the
H pylori eradication is equally eective in both duration of triple therapy from 7 days to 10 days increased
duodenal and gastric ulcers.73,115 In duodenal ulcer, the eradication rate by 4% and from 7 days to 14 days by
testing by non-invasive methods (13C-UBT, stool antigen 5%.118 Although these dierences were statistically
testing) is a validated surrogate marker to conrm signicant, the investigators questioned their clinical
healing.6 However, in gastric ulcer, healing should be signicance.118 Quadruple therapiesPPI, tetracycline,
conrmed endoscopically and biopsies are mandatory metronidazole, and a bismuth saltare alternative rst-
to exclude malignant disease, even when the ulcer line therapies in areas of high prevalence of antibiotic
appears healed. For uncomplicated duodenal ulcer a resistance, and achieve excellent eradication rates as rst-
714 day eradication therapy does not need to be line treatment.6,119 A rst-line 10-day sequential therapy
followed by PPIs, whereas for gastric ulcer PPIs should was better than was standard triple therapy in several
be continued beyond the eradication phase for studies done in Italy.120 An intention-to-treat result of 84%
48 weeks.116 If complications arise (ie, bleeding), PPI for sequential therapy in one study from Spain121 suggests
therapy should be continued until healing is conrmed that the greater ecacy achieved with this promising
endoscopically. In this circumstance, conrmation of therapy than with triple therapies should be tested further
eradication relies on histological examination of biopsy before general recommendation.
samples taken from both antral and body regions of the The most eective treatment regimens fail in about
stomach, because PPI therapy can produce false- 1020% of patients. Bismuth-based quadruple therapy is
positive urease test results. the main option for second-line therapy if these
Eradication rates depend on several factors: (i) drug compounds were not used as rst-line treatment, with
regimen; (ii) resistance rate to the antimicrobiotic used; eradication rates of 5795%.122 However, since bismuth is
(iii) compliance with the drug; (iv) duration of therapy; not available in some countries because of putative toxic
and (v) genetic variations in drug-metabolising enzymes. eects, triple therapies of various combinations have
Two antimicrobials often used in eradication regimens been tested as second-line options. PPI combined with
are clarithromycin and metronidazole. H pylori can be amoxicillin and metronidazole are recommended as
No gastrointestinal risk factors One or two gastrointestinal risk factors Many gastrointestinal risk factors or previous
ulcer bleed
Low cardiovascular risk NSAID NSAID plus PPI or misoprostol, or COX-2 COX-2 inhibitor plus PPI or misoprostol
(low-dose aspirin not needed) inhibitor alone
High cardiovascular risk Naproxen plus PPI or misoprostol Naproxen plus PPI or misoprostol Avoid NSAIDs and COX-2 inhibitors if possible*
(low-dose aspirin needed)
NSAID=non-steroidal anti-inammatory drug. PPI=proton-pump inhibitor. COX=cyclo-oxygenase. *Combination of low-dose aspirin, PPI or misoprostol, and naproxen or
low-dose COX-2 inhibitor in selected cases (see text).
Table 2: Recommendations on non-steroidal anti-inammatory use according to gastrointestinal and cardiovascular risks
over misoprostol in reducing the risk of gastric ulcers.98 A and cardiovascular risks of individual patients. If a
note of caution is that eectiveness of PPIs for prevention patients cardiovascular risk is more serious (eg, recent
of NSAID-associated ulcers was largely established by myocardial infarction) than the gastrointestinal risk (eg,
endoscopic and observational studies.133135 Only full-dose remote history of peptic ulcer), combination of a PPI or
misoprostol (200 g four times a day) prevented NSAID- misoprostol, low-dose aspirin, and naproxen is preferred
associated ulcer complications in a large-scale trial.113 to keep cardiovascular toxic eects to a minumum. If
In a systematic review, COX-2 inhibitors induced gastrointestinal risk is more serious (eg, recent ulcer
signicantly fewer gastroduodenal ulcers (relative bleeding) than cardiovascular risk (eg, coronary heart
risk 026, 95% Cl 023030), ulcer complications disease well controlled with medical therapy),
(relative risk 039, 95% Cl 031050), and treatment combination of a PPI or misoprostol, low-dose aspirin,
withdrawals due to gastrointestinal symptoms than did and low-dose COX-2 inhibitor is preferred. This
non-selective NSAIDs. Concomitant use of aspirin, combination is based on the observation that the
however, negates the gastric-sparing eect of COX-2 cardiovascular hazard of COX-2 inhibitors is dose
inhibitors.136 COX-2 inhibitors and non-selective dependent.139 Furthermore, in patients receiving low-
NSAIDs both increase cardiothrombotic risk. The only dose aspirin, COX-2 inhibitors probably carry a lower
probable exception is full-dose naproxen (500 mg twice risk of gastrointestinal bleeding than do NSAIDs.140
daily).137,138 The cardiovascular hazard of COX-2 For many years, the American Heart Association and
inhibitors might be dose-dependent. In a pooled the American College of Cardiology recommended the
analysis of trials of celecoxib, there was a dose- use of clopidogrel as an alternative to aspirin in patients
dependent increase in cardiovascular hazard of this with major gastrointestinal intolerance.142 Whether
drug in patients with high baseline cardiovascular clopidogrel has a lower risk of gastrointestinal bleeding
risk.139 In another pooled analysis of observational than that of aspirin has yielded conicting results in
studies, the excess cardiothrombotic risk associated observational studies,103,143 but in head-to-head randomised
with most NSAIDs and COX-2 inhibitors was not seen trials of patients with high gastroinestinal risk combination
in patients receiving concomitant low-dose aspirin.140 of aspirin and a PPI is better than is clopidogrel alone at
Large-scale, head-to-head randomised trials are prevention of ulcer bleeding.92,144 An updated consensus
underway to assess cardiothrombotic risk of NSAIDs report issued jointly by US cardiology and gastroenterology
and COX-2 inhibitors. societies recommends co-therapy with a PPI instead of
Because of the potential cardiovascular hazard of switching to clopidogrel in aspirin users with high
COX-2 inhibitors and non-selective NSAIDs, physicians gastrointestinal risk.145 Additionally, the consensus
should assess gastrointestinal and cardiovascular risk of recommends prophylactic PPI in patients receiving dual
individual patients before prescribing anti-inammatory antiplatelet therapy. However, according to in-vitro studies
analgesics. In patients with low cardiovascular risk some PPIs reduce the antiplatelet activity of clopidogrel by
(absence of established or multiple risk factors for inhibiting CYP2C19, a hepatic cytochrome P450 enzyme.146
coronary artery disease), NSAIDs can be prescribed The results of two observational studies showed a
according to the number and nature of gastrointestinal substantial increase in the risk of myocardial infarction in
risk factors (table 2). Patients with one or two users of clopidogrel and PPIs.147,148 So far, prospective data
gastrointestinal factors should receive a COX-2 inhibitor are not available. Patients with high gastrointestinal risk
or an NSAID plus a PPI. This recommendation is based who receive dual antiplatelet therapy should not
on randomised and observational studies that showed discontinue PPI cotherapy.
that a COX-2 inhibitor was similar to a non-selective
NSAID plus a PPI in prevention of recurrent ulcer H pylori-negative NSAID-negative ulcer
bleeding.91,133 In patients with several gastrointestinal risk Ulceration of the gastric or duodenal mucosa in the
factors or a history of ulcer complications, neither of absence of H pylori infection and NSAID or aspirin usage
these treatments is adequate.101 Combination of a PPI and is rare.149154 However, because of the falling prevalence of
a COX-2 inhibitor oers the best protection.133,141 H pylori infection and resulting ulcers, the proportion of
Patients with high cardiovascular risk should start or ulcers that are unrelated to this infection is likely to
continue to receive prophylactic low-dose aspirin, and increase and several rare causes need specic attention.
full-dose naproxen is the preferred NSAID. Co-therapy The most important consideration in a patient with
with a PPI or misoprostol is recommended since gastric or duodenal ulcer, negative H pylori test, and
naproxen plus low-dose aspirin will substantially negative NSAID or aspirin history is to check the validity
increase risk of ulcer complications even without other of the test and history.149 Furthermore, the sensitivity of
gastrointestinal risk factors. Patients with high any H pylori test is less than 100% and can lead to
cardiovascular and gastrointestinal risk should avoid underdiagnosis of infection. Detection of H pylori
taking NSAIDs or COX-2 inhibitors. If anti-inamma- infection is very important so that patients presenting
tory analgesic therapy is judged necessary, the choice of with ulcers are not deprived of a permanent cure of this
therapy requires a trade-o between gastrointestinal disease, especially since false-negative tests can result
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