REVISO / REVIEW ARQGA/1719

ETIOPATHOGENESIS OF PEPTIC ULCER:

back to the past?
Mariana Barbosa ARAJO1, Paulo BORINI2 and Romeu Cardoso GUIMARES3

ABSTRACT - Objective - To review some aspects of the etiopathogenesis of peptic ulcerous disease especially on the basis of studies
on its correlation with Helicobacter pylori (H. pylori). Methods - A search was made in the data bases MEDLINE, LILACS and
PubMed, and in Brazilian and foreign books, referring to the incidence and prevalence of infection by H. pylori and of peptic
ulcerous disease in various populations of different countries. Results - It was observed that the prevalence of H. pylori infection is
similar in individuals with peptic ulcerous disease and the general population. There are differences between countries with respect
to the prevalence of infection and of gastric or duodenal peptic ulcers. In many countries the prevalence of infection by H. pylori
shows stability while the prevalence of peptic ulcerous disease is declining. The prevalence of peptic ulcerous disease without H.
pylori infection varies between 20% and 56% in occidental countries. Discussion - The observations might be suggestive of H. pylori
being only one more factor to be summed together with other aggressive components in the genesis of peptic ulcerous disease. We
would therewith be returning to the classic concept that peptic gastric and duodenal ulcers have multifactorial etiology and would
result from imbalance between aggressive and defensive factors. The focus of studies should be enriched with the identification of
the defensive factors and of other aggressive factors besides the well known H. pylori and non-steroidal anti-inflammatory drugs,
since these two aggressors do not exhaust the full causal spectrum.
HEADINGS - Peptic ulcer. Stomach Ulcer. Duodenal ulcer. Helicobacter infections.

INTRODUCTION from the predominance of aggressive factors while

gastric ulcer would result mainly from the failure of
Peptic ulcers are sites of loss of continuity of part defensive factors(57).
of the wall of organs of the gastrointestinal tract Some authors even hypothesized that they would
exposed to the gastric chloridopeptic secretion. The be different diseases. Duodenal ulcer is usually dia
organs affected are more frequently the stomach and gnosed in younger age, typically with higher acid
the duodenum. Under some conditions it is also pos- secretion and affecting mainly males. Gastric ulcer
sible to observe peptic lesions in the esophagus and occurs more frequently in older patients, acid secre-
jejunum among other less common sites(40). Lesions tion is near-normal or reduced and the sex-ratio is
are chronic and single in the majority of cases but can not skewed(57).
be multiple in about 5% to 20% of cases, simultane- In Brazil, epidemiological surveys revealed that
ously affecting the stomach and the duodenum or duodenal peptic ulcers are more prevalent than
even other segments, as occurs in the Zollinger and the gastric in a 3:1 proportion, besides being more
Ellison Syndrome(13, 40). prevalent in males(13, 53). In the UK, the incidence of
The etiology of the peptic ulcerous disease peptic ulcer was 12% higher in men than in women(9),
(PUD), gastric or duodenal, is becoming one of the although the prevalence of infection by Helicobacter
most intriguing problems of gastroenterology. Up pylori (H. pylori) is not associated with sex(50, 58, 64).
to some time before the last two decades of the past After Marshall and Warren(43) presented studies
century it was considered a disease of multifactorial on the correlation between gastritis and peptic ul-
origin. It was assumed that it would be installed in cer, and on the pathogenic action of H. pylori plus
constitutionally predisposed individuals, in con- the fast evolution of knowledge on the theme, this
sequence of disequilibrium between the action of association became established and is universally
aggressive and defensive factors upon the gastro- accepted. In 1994, the US National Institutes of
duodenal mucosa. Duodenal ulcer would develop Health recognized that H. pylori was directly involved

Declared conflict of interest of all authors: none

Research performed at: Disciplina de Clnica Mdica, Faculdade de Medicina e Enfermagem de Marlia. Marlia, SP, Brasil.
1
Faculdade de Medicina de Marlia; 2 Departamento de Gastroenterologia, Faculdade de Medicina de Marlia, Marlia, SP, Brasil; 3 Laboratrio de Biodiversidade e
Evoluo Molecular, Departamento de Biologia Geral, Instituto de Cincias Biolgicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
Correspondence: Paulo Borini. Rua Gabriel Monteiro da Silva, 40, Marlia, SP, Brasil. E-mail: [email protected]

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Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

in peptic ulcer pathogenesis(18). On the bases of the facts RESULTS

that the majority of peptic ulcers were associated with the
presence of H. pylori and that eradication of the bacteria Infection by H. pylori is detected worldwide. Incidence
lead to significant reduction of reinstallation of the ulcers, and prevalence of the infection vary according to age of
the microorganism became considered a decisive etiologic individuals and to socioeconomic conditions of each region.
factor in the genesis of PUD, besides the non-steroidal anti- There is no reported difference between sexes(50, 58). Studies
inflammatory drugs (NSAID)(12). Recurrence of the disease in different countries reveal prevalence of infection between
is higher in patients infected by the bacterium (13.4% per 11% and 69% in the general population (7) and between
year), relative to the patients submitted to therapy for 8.9% and 72.8% in children, respectively in developed and
eradication of H. pylori (2.5% per year)(45). Since then, PUD developing countries(42). Along recent years a reduction of
became considered either an infectious(26) or an iatrogenic the infection rates was observed, most evident in occiden-
(NSAID-induced) disease; it would be a rare disease in the tal industrialized countries and in some oriental emergent
absence of these two factors. It became valid to affirm that economies(5, 6, 7). Various studies indicate that the incidence
in peptic ulcer the treatment of H. pylori means the cure of and prevalence of colonization by H. pylori have declined
the disease(17). More recently, to the classic aphorism No progressively with industrialization in different countries(4,34).
acid no ulcer(56) the dictum No Helicobacter pylori no While the prevalence of infection is higher in underdeveloped
ulcer was associated(10, 29). and developing countries, there is also a reduction of the
This work discusses the etiopathogenesis of PUD based infection in them, attributed to the eradication therapy and
on a review of medical bibliography on the correlation and to the improvement of sanitary conditions observed in the
association between PUD and H. pylori. last two decades(7).
Brazilian studies on the prevalence of infection by
METHODS H. pylori were conducted in limited population samples
of some states. It was found high, from 59.5% in Rio de
A search was made on the databases MEDLINE, LI- Janeiro (RJ) to 96% in So Luis (MA)(35). High prevalence
LACS and PubMed using the following keywords: Peptic was also reported in a low income community of Fortaleza
ulcerous disease or PUD, Helicobacter pylori-negative or (CE): 73.3% in the age range from 11 to 20 years and above
H. pylori-negative or Hp-negative and peptic ulcerous 87% at 60 years of age or more(52). In the city of So Paulo,
disease or peptic gastric ulcer or GUP or peptic duo- prevalence of infection was below 65.6% in the population
denal ulcer or DUP, as well as on Brazilian and foreign of high income(50); among blood donors the infection was
books on the theme. Searches were restricted to publications of 66.5% of 746 males and of 63.2% in 247 females(64). An
in English, Portuguese or Spanish. overall decline in prevalence of H. pylori was noted in both
The searches, including the supplementations, yielded high and low socioeconomic status countries(7).
56 original or review articles and 8 books. Some studies The duodenum is the major location of peptic ulcers in
were discarded due to the inclusion of patients under 18 the western population; the gastric location is more frequent
years of age, of patients in use of any NSAID (including in oriental countries, particularly Japan(46). The relevance of
aspirin) or with concomitant diseases that could lead to H. pylori for the genesis of the mucosal ulceration is well sup-
lower prevalence of infection by H. pylori (such as atrophic ported by the identification of the bacterium in 90%-95% of
gastritis, malignant ulcerous disease, cirrhosis with portal duodenal ulcer patients and 60%-80% of patients with gastric
hypertension and hepatic insufficiency), as well as those ulcer, as compared to 25%-30% in symptomatic controls(46).
bearing diseases that could cause gastric or duodenal ulcers In developing countries, all studies up to now are consistent
(Crohn disease, cytomegalovirus infection, stress-related in detecting the bacterium in over 90% of bearers of peptic
ulcer, Behcet disease). In the studies involving peptic ulcer ulcers(17). Otherwise, the decline in the incidence of PUD
patients, infection by H. pylori was diagnosed by direct dem- cannot be explained by population or demographic changes(9)
onstration of the bacteria in biopsy specimens(19) combined while the increase in the frequency of non-H. pylori ulcers
with another diagnostic test, usually the Rapid Urease Test. cannot be explained solely by the declining rates of infec-
The only exceptions to this rule were the epidemiologic stud- tion(23). In Brazil, the prevalence of duodenal ulcer decreased
ies of the infection that employed other tests (e.g., urease from 8.6% in 1996 to 3.3% in 2005(54).
test on biopsies, 13Curea breath test, seroprevalence of The review of Blaser(5) showed that the rate of PUD,
antibodies, culture and stool antigen test). Patients were especially at the duodenum, was increasing in the USA and
classified as having H. pylori-negative ulcer if no test was in Europe during the last decade, while there was evidence
positive and at least two tests were negative; an exception that the rate of H. pylori colonization was declining for a
was a Brazilian study of PUD(42), included due to the scar- long time. Another review of Sung et al.(61) encompassing
city of studies in the country. various countries reported reduction of both the rates of

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 Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

PUD and of the proportion of ulcerous patients infected by ten years, totaling 16,080 patients, the average prevalence
the bacterium, especially in occidental countries. A variety of H. pylori infection in duodenal peptic ulcer was of 81%;
of studies referring to diverse world regions have been point- the rate declined to 77% when only the last five years of the
ing to an increase throughout recent time of the prevalence sample were considered(25). In New York, among non-users
of H. pylori-negative duodenal ulcer or idiopathic peptic of NSAID, only 61% of peptic ulcer patients presented the
ulcer(8, 16, 29, 31-33, 37, 38, 47, 51, 55, 59, 63) (Table 1). A meta-analysis H. pylori infection (conversely, 39% of PUD patients were
of seven double blind, randomized trials in North America H. pylori-negative); among 2,900 patients bearers of duode-
found that 20% of patients with H. pylori-associated ulcers nal ulcer, 27% did not report usage of NSAID and were H.
had ulcer recurrence within 6 months despite successful H. pylori-negative(14).
pylori eradication and no reported NSAID use(37-39). In the USA the hospitalization rate due to PUD experi-
No role could be proposed for the smoking habit on the enced an average reduction of 21% between 1998 and 2005,
basis of two studies, either on non-H. pylori and non-NSAID more pronounced among women with gastric ulcer. Among
duodenal ulcers or on H. pylori-associated ulcers(49, 63). hospitalized individuals, 47% did not present H. pylori infec-
In developed countries there was wide variation in the tion. Higher rates of H. pylori-negative PUD patients were
rates of DUP and of infection by H. pylori. In Scotland the found at ages equal or above 65 years (54%) and among white
prevalence of infection was 65%, and 95% of the ulcers were skin color (56%)(22).
associated with infection(45). Results from the USA suggest The incidence of not further complicated PUD in the UK
that the proportion of H. pylori-negative ulcer, while varying decreased to little more than half between the years 1997 and
somewhat, appears to be rising(60); the prevalence of infection 2005, the reduction of duodenal ulcer being greater than that
in some regions may be of only 30%, and about 20% of the of gastric ulcer. The number of confirmed H. pylori-negative
PUD patients are not infected(45). Quan and Talley(49) system- cases increased from 5% to 12% from the first to the last year
atically reviewed the prevalence of unexplained ulceration in in the study(9).
the period between 1995 and 2001, finding that a relevant In Japan and Hong Kong, the rates of PUD not associ-
proportion of PUD patients were not infected by H. pylori. ated with usage of NSAID or with H. pylori infection were
Other studies in the USA showed that 20% to 50% of the of only 1.3% and 4.1%, respectively(15, 30). Both of these
peptic ulcers were not related to H. pylori infection or to the studies highlighted that the proportions of idiopathic PUD
use of NSAID(14, 15, 23, 25). In studies published along the last were increasing. In Korea, the prevalence of H. pylori infec-

TABLE 1. Prevalence of Helicobacter pylori-negative peptic ulcer among non-NSAID users

Year of Method of H. pylori Number % non-NSAID
Reference (Country) Ulcer type
publication detection of patients H. pylori-negative
McColl et al.(44) (Scotland) 1993 Histology and CLO test 12 DU 50
Graham et al. (USA)
(26)
1995 Histology and CLO test 139 DU 33
62 DU 18
Bakkevold (Norway)
(3)
1995 - 1996 Histology and CLO test
25 GU 12
Lanza et al.(38) (USA) 1996 Histology and CLO test 183 DU 30
Peterson et al.(47) (USA) 1996 Histology and CLO test 128 DU 27
Sprung et al.(60) (USA) 1997 Histology and CLO test 59 DU 52
Kemppainem et al.(32) (Finland) 1997 Histology and CLO test 125 PUD 30
160 DU 39
Jyotheeswaran et al.(31) (USA) 1998 Histology and CLO test
145 GU 39
Laine et al. (37) (USA) 1998 Histology and CLO test 619 DU 20
41 DU 39
Schubert et al.(55) (USA) 1999 Histology and CLO test
43 GU 47
Ciocola et al. (16) (USA) 1999 Histology and CLO test 2394 DU 27
14 DU 43
Xia et al.(63) (Australia) 1999 Histology and CLO test
33 GU 58
Bytzer et al.(8) (Denmark) 2001 Histology and CLO test 276 DU 19
47 DU 43
Bakkevold(3) (Norway) 2007 - 2008 Histology and CLO test
28 GU 57
770 DU 50
Feinstein et al.(22) (USA) 2010 Histology and CLO test
548 GU 40
2011 391 DU 36
Marques et al. (Brazil)
(42)
CLO test
103 GU 43
NSAID: non-steroidal anti-inflammatory drug; CLO: rapid urease test; DU: duodenal ulcer; GU: gastric ulcer; PUD: peptic ulcer disease, location unspecified

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Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

tion in association with gastric ulcer was increasing in more mucosal atrophy(62). About 30% of patients with idiopathic
recent years, whereas H. pylori infection in duodenal ulcer ulcers show histological characteristics suggestive of previous
was decreasing (30). infection, indicating that eradication of the infection does
The prevalence of PUD has not been adequately evalu- not protect against recurrence of the peptic ulcer(15). About
ated in Brazil, while the prevalence of H. pylori infection is 20% or more of the cured of H. pylori infection may develop
high. A report on patients in the southern states revealed subsequent H. pylori-negative ulcer(36).
low prevalence of duodenal peptic ulcer(54). Marques et al.(42) Elevation of gastric pH in consequence of the utilization
studied 1478 consecutive higher digestive organ endoscopic of some antibiotics, high doses of H2 antagonists or of pro-
examinations realized in a tertiary care hospital in the city ton pump inhibitors would strongly reduce urease activity,
of So Paulo, finding peptic ulcers in 494 (33.4%). Infection therewith leading to false-negative results with respect to H.
with H. pylori was diagnosed in 252 (64%) patients with pylori infection through the urease or respiratory tests(1, 28, 36).
duodenal ulcer, 59 (57%) of bearers of gastric ulcer and Furthermore, these medications reduce bacterial density in
143 (53%) patients with normal endoscopy. The rates of H. the organ(27).
pylori-negative patients were moderately high, 36% of the Gastric alkalinization and the use of some antibiotics
duodenal and 43% of the gastric ulcerous. could be causes of false-negative urease or respiratory tests.
Otherwise, these queries might not apply to the studies re-
DISCUSSION viewed here, which were all based on histologic search for
the bacteria in biopsy materials.
It seems significant that, more recently, there has been an The rise in the number of idiopathic peptic ulcers has been
accumulation of medical studies coming from different regions attributed to diagnostic errors. Gisbert et al.(24) observed that
indicating that an appreciable proportion of gastric and duo- the rate of diagnostic sensitivity from biopsies with urease
denal peptic ulcers is not related to H. pylori infection or to test and histological examination was of 83% in analyses of
the use of NSAID. An appraisal of the data compiled above samples from corpus and antrum concomitantly, decreasing
indicates that about 20% to 56% of PUD did not find a defined to 78% with material collected from only one of the regions.
etiology, being included in the idiopathic PUD category. In order to be sure of the absence of the infectious cause of
The review of Blaser(5) showed that the rate of PUD, espe- the peptic ulcer, it is also recommended that samples should
cially of duodenal localization, started an increasing trend in be examined from both antrum and corpus, and utilizing
the USA and Europe, while there was evidence that the rate two different tests, with negative results for both(62). A lower
of H. pylori colonization was starting to fall. In industrial- bacterial density in the antrum can lead to false-negative
ized countries, after a peak in the early decades of the last urea respiratory tests(1, 20, 28, 36).
century, the incidence of PUD and the prevalence H. pylori It is general to endoscopic procedures that samples be
colonization started a declining trend. It has been questioned taken from both antrum, where the majority of the ulcers
why the occurrence of PUD is increasing at the same time reside, and corpus, where bacterial populations are higher.
when the prevalence of H. pylori infection declines(6). It is also general knowledge of specialists that in biopsies of
It has been observed that the prevalence of PUD did not areas immediately adjacent to peptic ulcers the finding of
change in concomitance with the regimes of H. pylori eradica- bacteria is not highly probable, the results being negative even
tion in the countries with low prevalence of the infection(6). in cases with intense colonization density. If these facts are as-
The increase in the rate of eradication of the bacterium in sumed well known to endoscopists it should be wise to accept
the USA did not result in reduction of the rates of hospital that the biopsies are good representatives of reality, being
admissions related to complications from PUD(41). also improbable that the pathologists would have recently
Varied argumentation has been presented attempting to lost the ability to identify the bacteria. Examination of the
justify the occurrence of PUD in the absence of H. pylori biopsy fragments through the usual Giemsa staining allows
infection but we consider that the great majority, if not the demonstration of the bacteria in 80% to 97% of cases(21).
totality of the justifications do not resist criticisms. The diagnosis of infection by H. pylori is impaired in
Patients without present evidence of colonization by H. cases of peptic ulcers with acute complications (bleeding,
pylori would have had a previous infection responsible for obstruction, perforation)(11, 24).
permanent alterations in the gastro-duodenal mucosa that Studies compiled in this review did not include patients
facilitated development of the PUD(45). with obstruction or perforation installed upon PUD. In all
It remains controversial whether gastric mucosal atrophy patients with acute bleeding, the search for H. pylori was
and duodenal metaplasia are reversible or not after eradica- conducted in gastric biopsies obtained after the bleeding
tion of the infection(62). Furthermore, such possible mucosal was controlled, with repetition of the procedure whenever
alterations are difficult to confirm in consequence of not necessary. It is also not likely that false-negative results
being possible, in the majority of cases, to obtain data on would occur repetitively, especially after the complication is
the previous conditions with respect to the presence of H. circumvented. In such circumstances, Bakkevold(3) repeated
pylori in the population included in the studies(20, 62). Anato- the gastric biopsy and found that, when the bacteria are
mopathological studies on peptic ulcers refer signs of inflam- present, both histopathological and rapid urease tests were
mation in the regions surrounding the ulcer but not signs of positive for diagnosis of the infection.

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 Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

Gastric biopsies might not reveal the presence of bacteria similar in males and females, other factors should be ad-
in cases where the colonization and the ulcerous disease are vocated to explain the reasons for the higher prevalence of
restricted to the duodenum(48). duodenal PUD in males and for the finding in some coun-
The study of Pietroiusti et al.(48) refers to 608 PUD pa- tries, including Brazil, of the 3:1 ratio of prevalence between
tients of which 6,9% (42 patients) did not present gastric duodenal and gastric ulcers. There are differences between
infection. Among the latter, H. pylori was not detected in the countries with respect to the prevalence of infection and of
duodenum in 24 (57%), whereas 18 patients had a positive gastric and duodenal peptic ulcers. In various countries, the
duodenal culture for Helicobacter that is 2.9% from the total prevalence of infection is stable while that of PUD is decreas-
sample. The authors informed that duodenal colonization ing. Occurrence of H. pylori-negative PUD is being detected
by species of Helicobacter other than H. pylori cannot be in significant proportions and these are higher than would
excluded since the cagA-negative genotype was higher in be expected according to the etiologic conception of being
patients with isolated duodenal colonization, when compared an infectious disease.
with patients presenting the usual pattern of colonization. These considerations might be taken in support of the
While there are no explanations for the exclusive duodenal conception that H. pylori would be only one more of the
location, its prevalence is so scanty that would not justify the strong aggressive factors known to cause peptic ulcers, aside
rise of H. pylori-negative PUD. with the NSAID. Under this panorama, we would be turning
The finding of H. pylori-negative cases could derive back to the concept that peptic gastric and duodenal ulcers
from the extensive use of antibiotics starting from the last have a multifactorial etiology and result, as it was assumed
decades of the past century. Such usage could contribute in in the past, from disequilibrium between aggressive and de-
a short term basis to negative results in bacterial detection fensive factors acting in the mucosa. A consequence of the
tests(21, 24, 61). recognition of this conception would be the reinforcement of
This possibility might be relevant but with some ponder- the focus on the search for the possible other factors.
ing. The large majority of antibiotics do not affect specifi- At present there is little doubt that eradication of H.
cally H. pylori. In case a temporary eradication is obtained, pylori is mandatory to ensure successful treatment of gastric
clinical symptoms should also disappear from the temporary and duodenal ulceration(46). The 1994 National Institutes
cure of the disease and consequently the patients would not of Health Consensus Conference concluded that ulcer
have the need for looking after medical assistance and would disease was an infectious disease that could be cured by
not be submitted to the endoscopic examination. Even when bacterial eradication(2). However, the more recent reports
this examination is conducted at least the scar of the lesion suggesting that a considerable proportion of peptic ulcer
should be observed. may be non-infectious in origin would indicate a change
in the management strategies since non-infectious ulcer
CONCLUSION cannot be cured with antibiotics. A call for concern would
spring from the report of Bytzer et al.(8) indicating that
The prevalence of H. pylori infection is similar in indi- H. pylori-negative duodenal ulcers were associated with a
viduals with PUD and in the general population. Since the poorer prognosis mainly because of a higher rate of ulcer
incidence and prevalence of the infection by the bacteria is and symptom relapse.

Araujo MB, Borini P, Guimares RC. Etiopatogenia da lcera pptica: de volta ao passado? Arq Gastroenterol. 2014,51(2):155-61.
RESUMO - Objetivo - Revisar a etiopatogenia da doena ulcerosa pptica com base em reviso de estudos sobre a correlao entre Helicobacter pylori
(H. pylori) e doena ulcerosa pptica. Mtodos - Foi realizada busca nas bases de dados MEDLINE, LILACS e PubMed, e em livros brasileiros e
estrangeiros referentes incidncia e prevalncia de infeco pelo H. pylori e de doena ulcerosa pptica em vrias populaes de diferentes pases.
Resultados - Observamos que a prevalncia da infeco pelo H. pylori semelhante em indivduos com doena ulcerosa pptica e a populao geral;
que existem diferenas entre pases no que tange as prevalncias de infeco e a de lceras pptica gstrica e duodenal e que, em muitos pases, a
prevalncia de infeco pelo H. pylori se mantm estvel, enquanto a prevalncia de doena ulcerosa pptica est em queda. A prevalncia de doena
ulcerosa pptica na ausncia de infeco pelo H. pylori varia de 20% a 56% nos pases ocidentais. Discusso - As observaes sugerem que o H. py-
lori constituiria somente mais um fator a ser somado ao rol dos agressores na gnese da doena ulcerosa pptica. Assim, estaramos retornando ao
conceito de que as lceras ppticas, gstrica e duodenal, tm etiologia multifatorial e decorreriam, como era admitido no passado, do desequilbrio
entre fatores agressivos e defensivos da mucosa. O foco dos estudos deveria ser redirecionado identificao dos fatores defensivos e de outros fatores
agressivos alm dos bem conhecidos H. pylori e medicamentos anti-inflamatrios no-esterides, desde que esses dois agentes no cobrem todo o
espectro de causas.
DESCRITORES - lcera pptica. lcera gstrica. lcera duodenal. Infeces por Helicobacter.

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Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

REFERENCES 29. Graham DY. Campylobacter pylori and peptic ulcer disease. Gastroenterology.
1989;96:615- 25.
30. Jang HJ, Choi MH, Shin WG, KimKH, Chung YW, Kim KO, et al. Has peptic
1. Adachi K, Fujishiro H, Mihara T, Komazawa Y, Kinoshita Y. Influence of lanso- ulcer disease changed during the past ten years in Korea? A prospective multi-cen-
prazole, famotidine, roxatidine and rebamipide administration on the urea breath ter study. Dig Dis Sci. 2008;53:1527-31.
test for the diagnosis of Helicobacter pylori infection. J Gastroenterol Hepatol. 31. Jyotheeswaran S, Shah N, Jin HO, Potter GD, Ona FV, et al. Prevalence of
2003;18:168-71 Helicobacter pylori in peptic ulcer patients in greater Rochester, NY: is empirical
2. Anonymous. Helicobacter pylori in peptic ulcer disease. JAMA. 1994;272:65-9. triple therapy justified? Am J Gastroenterol. 1998;93:574-8.
3. Bakkevold KE. Time trends in incidence of peptic ulcer bleeding and associated 32. Kemppainem H, Raiha I, Sourander L. Clinical presentation of ulcer peptic in
risk factors in Norway 1985-2008. Clin Exp Gastroenterol. 2010;3:71-7. the elderly. Gerontology. 1997;43:283-8.
4. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The 33. Konturek SJ, Bielanski W, Plonka M, Pawlik T, Pepera J, Konturek PC, et al.
cohort effect and Helicobacter pylori. J Infect Dis. 1993;168:219-21. Helicobacter pylori, non-steroidal anti-inflammatory drugs and smoking in risk
5. Blaser MJ. Helicobacters are indigenous to the human stomach: duodenal pattern of gastroduodenal ulcers. Scand J Gastroenterol. 2003;38:923-30.
ulceration is due to changes in gastric microecology in the modern era. Gut. 34. Kosunen TU, Aromaa A, Knekt P, Salomaa A, Rautelin H, Lohi P, et al. Helico-
1998;43:721-7. bacter antibodies in 1973 and 1974 in the adult population of Vammala, Finland.
6. Blaser MJ. Hypothesis: the changing relationships of Helicobacter pylori and Epidemiol Infect. 1997;119:29-34.
humans: implications for health and disease. JID. 1999;179:1523-30. 35. Ladeira MSP, Salvadori DMF, Rodrigues MAM. Biopatologia do Helicobacter
7. Bruce MG, Maaroos HI. Epidemiology of Helicobacter pylori infection. Helico- pylori. J Bras Patol Med Lab. 2003;39:335-42.
bacter. 2008;13(Suppl. 1):1-6. 36. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton pump
8. Bytzer P, Teglbjaerg PS, Danish Ulcer Study Group. Helicobacter pylori-negative inhibitors therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med.
duodenal ulcer: prevalence, clinical characteristics, and prognosis results from a 1998;129:547-50.
randomized trial with 2 year follow-up. Am J Gastroenterol. 2001;96:1409-16. 37. Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy
9. Cai S, Rodrguez LAG, Mass-Gonzlez EL, Hernndez-Daz S. Uncomplicated on ulcer recurrence in the United States been overstated? A meta-analysis of
peptic ulcer in the UK: trends from 1997 to 2005. Aliment Pharmacol Ther. rigorously designed trials. Am J Gastroenterol. 1998;93:1409-15.
2009;30:1039-48. 38. Lanza F, Ciociola AA, Sykes DL, Sontag SJ, Heath A, McSortey DJ. Ranitidine
10. Castro LP, Coelho LGV. Helicobacter pylori: importncia e tratamento. In Clnica bismuth citrate plus Claritomicin is effective in eradicating H. pylori, healing
Mdica Contempornea II, Lopes AC, Cardoso Filho MC (eds). So Paulo: duodenal ulcer, and preventing ulcer relapse. Gastroenterology. 1996;110:A172.
Sarvier. 1995. p.415-6. 39. Lanza F, Goff J, Silvers D, Winters J, Jhala N, Jennings D, et al. Prevention of
11. Chan HL, Wu JC, Chan FK, Choi CL, Ching JY, Lee YT, et al. Is non Helico- duodenal ulcer recurrence with 15 mg lanzoprazole: a double-blind placebo-con-
bacter pylori, non NSAID peptic ulcer a common cause of upper GI bleeding? trolled study. The Lansoprazole Study Group. Dig Dis Sci. 1997;42:2529-36.
A prospective study of 977 patients. Gastrointest Endosc. 2001;53:438-42. 40. Liu C, Crawford JM. O trato gastrointestinal. Robbins e Cotran: patologia
12. Chehter L. lcera pptica gastroduodenal (no complicada). In: Manual de bases patolgicas das doenas. In: Kumar V, Abbas A, Fausto N, editores. Rio
Gastroenterologia. Forones NM, Miszputen SJ (coordenadores). So Paulo: de Janeiro: Elsevier. 2005. p. 837-918.
EPM Editora de Projetos Mdicos. 2000. p. 26-36. 41. Manuel D, Cuttler A, Goldstein J, Fennerthy MB, Brown K. Decreasing preva-
13. Chinzon D, Eisig JN, Cury M, Zaterka S. lcera pptica. In: Coelho JCU, editor. lence combined with increasing eradication of Helicobacter pylori in the United
Aparelho digestivo: clnica e cirurgia. So Paulo: Ateneu. 2006; p. 522-43. States has not resulted in fewer hospital admissions for peptic ulcer disease-related
14. Chow DKL, Sung JJY. Is the prevalence of idiopathic ulcers really on the increase? complications. Aliment Pharmacol Ther. 2007;25:1423-7.
Nature Clinical Practice. 2007;4:176-7. 42. Marques SB, Mattar R, Artifon ELA, Sakai P, Carrilho FJ. High prevalence of
15. Chow DKL, Sung JJY. Non NSAID non H. pylori ulcer disease. Best Pract Res duodenal ulcer in a tertiary care hospital in the city of So Paulo, SP, Brazil. Arq.
Clin Gastroenterol. 2009;23:3-9. Gastroenterol. 2011;48:171-4.
16. Ciociola AA, McSorley DJ, Turner K, Syke D, Palmer JB. Helicobacter pylori 43. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients
infection rates in duodenal ulcer patients in the United State may be lower than
with gastritis and ulcer disease. Lancet. 1984;1:1311-5.
previously estimated. Am J Gastroenterol. 1999;94:1834-40.
44. McColl K, El-Nujumi AM, Chittajallu RS, Dahill SW, Dorrian CA, E-Omar E, et
17. Coelho LGV, Castro LP. Helicobacter pylori desafios para a sua erradicao
al. A study of the pathogenesis of Helicobacter pylori-negative chronic duodenal
em pases desenvolvidos. In: Teraputica em Gastroenterologia Temas de At-
ulceration. Gut. 1993;34:762-8.
ualizao do Curso pr congresso; Congresso Brasileiro de Gastroenterologia.
Rosa H, Dani R, Alves JG (eds). So Paulo: Lemos Editorial. 2002. p. 51-9. 45. McColl KEL. Helicobacter pylori-negative nonsteroidal anti-inflamatory drug
18. Coelho LGV. Helicobacter pylori e doenas gastroduodenais. In: Gastroenter- negative ulcer. Gastroenterol Clin North Am. 2009;38:353-61.
ologia & Hepatologia Diagnstico e tratamento. Mincis M (ed). So Paulo: 46. Modlin IM, Sachs G Gastric and duodenal ulcer disease. In: Modlin IM, Sachs G
Lemos-Editorial. 1997. p. 313-32. eds. Acid related diseases biology and treatment. Konstanz: Druckerei Konstanz
19. Cutler AF. Testing for Helicobacter pylori in clinical practice. Am J Med. GmbH. 1998. p. 199-236.
1996;100:355-9 S. 47. Peterson WL, Ciociola AA, Sykes DL, McSorley DJ, Webb DD. Ranitidine
20. Desai JC, Goo T, Fukata M, Sanyal S, Dikman A, Miller K, et al. NSAID-induced bismuth citrate plus claritrommicin is effective for healing duodenal ulcers, eradi-
antral ulcers are associated with distinct changes in mucosal gene expression. cating H. pylori and reducing ulcer recurrence. Gastroenterology. 1996;110:A172.
Aliment Pharmacol Ther. 2009;30:71-81. 48. Pietroiusti A, Forlini A, Magrini A, Galante A, Bergamaschi A. Isolated H. py-
21. El- Zimaity HM, Graham DY, Al-Assi MT, Malaty H, Kartunnen TJ, Graham DP, lori duodenal colonization and idiopathic duodenal ulcers. Am J Gastroenterol.
et al. Interobserver variation in the histopathological assesment of Helicobacter 2008;103:55-61.
pylori gastritis. Hum Pathol. 1996;27:35-41. 49. Quan C, Talley NJ. Management of peptic ulcer disease not related to Helicobacter
22. Feinstein LB, Holman RC, Christensen KLY, Steiner CA, Swerdlow DL. Trends pylori or NSAIDS. Am J Gastroenterol. 2002;97:2950-61.
in hospitalizations for peptic ulcer disease, United States, 1998-2005. Research. 50. Queiroz DMM, Luzza F. Epidemiology of Helicobacter pylori infection. Helico-
2010;16:1410-8. bacter. 2006;11:1-5.
23. Freston SW. Review article: role of proton pump in non-H. pylori-related ulcers. 51. Ramirez-Ramos A, Chinga Alayo E, Mendoza Requena D, Leey Casela J, Segovia
Aliment Pharmacol Ther. 2001;15(Suppl. 2):2-5. Castro MC, Otoya C. Changes in the prevalence of H. pylori in Peru; during the
24. Gisbert JP, Abraira V. Accuracy of Helicobacter pylori diagnostic tests in patients 1985-2002 period in medium and upper socio-economic strata. Rev Gastroenterol
with bleeding peptic ulcer: a systematic review and meta-analysis. Am J Gastro- Peru. 2003;23:92-8.
enterol. 2006;101:848-63. 52. Rodrigues MN, Queiroz DMM, Rodrigues RT, Rocha AMC, Luz CRL, Braga
25. Gisbert JP, Calvet X. Helicobacter pylori-negative duodenal ulcer disease. Aliment LLBC. Prevalncia da infeco pelo Helicobacter pylori em Fortaleza, Cear. Rev.
Pharmacol Ther. 2009;30:791-815. Sade Pblica, 2005;39:847-9.
26. Graham D. Foreword. In: Lee A, Mgraud F, editors. Helicobacter pylori: tech- 53. Romero JMC, Rodrguez EML. Tratamiento de la lcera pptica. Medifam.
niques for clinical diagnosis & basic research. London: Saunders; 1996. 2002;12:314-8.
27. Graham DY, Genta R, Evans D, Reddy R, Clarridge JE, Olson CA, et al. He- 54. Saul C, Teixeira CR, Pereira-Lima JC, Torresini RJS. Reduo da prevalncia de
licobacter pylori does not migrate from the antrum to the corpus in response to lcera duodenal: um estudo brasileiro (anlise retrospectiva na ltima dcada:
omeprazole. Am J Gastroenterol. 1996, 91:2120-4. 1996-2005) .Arq Gastroenterol. 2007;44:320-6.
28. Graham DY, Opekun AR, Hammoud F, Yamaoka Y, Reddy R, Osato MS, et al. 55. Schuber M, DeWitt JM, Taylor CA. Prospective evaluation of the prevalence of
Studies regarding the mechanism of false negative urea breath tests with proton H.pylori in duodenal and gastric ulcer: is its role overstated? Gastroenterology.
pump inhibitors. Am J Gastroenterol. 2003;98:1005-9. 1999;16:A305.

160 Arq Gastroenterol v. 51 no. 2 - abr./jun. 2014

 Arajo MB, Borini P, Guimares RC. Etiopathogenesis of peptic ulcer: back to the past?

56. Schwartz K. ber penetrierende magen und jejunal geschwure. Beitrge zur 61. Sung JJY, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and
klinische Chirurgie. 1910;67:95. prevalence of peptic ulcer disease. Aliment Pharmacol Ther. 2009;29:938-46.
57. Shay H, Sun DCH. Etiologia y anatomia patolgica de la lcera gstrica y duo- 62. Toyokawa T, Suwaki K, Miyake Y, Nakatsu M, Ando M. Eradication of Heli-
denal. In: Bockus HL. Gastroenterologia. Barcelona: Salvat. 1971. p. 443-90. cobacter pylori infection improved gastric mucosal atrophy and prevented pro-
58. Shi R, Xu S, Zang H, Ding Y, Sun G, Huang X, et al. Prevalence and risk factors for gression of intestinal metaplasia, especially in the elderly population: a long-term
Helicobacter pylori infection in Chinese populations. Helicobacter. 2008;13:157-65. prospective cohort study. J Gastroenterol Hepatol. 2010;25:544-7.
59. Sprung DJ, Apter MN, Allen B. The prevalence of Helicobacter pylori in duodenal 63. Xia H, Phung N, Kalantar J, Talley NJ. Characteristics of Helicobacter pylori
ulcer disease a community based study. Am J Gastroenterol. 1996;91:1926. positive and negative peptic ulcer disease. Gastroenterology. 1999;116:A359.
60. Sprung DJ, Gano B. The natural history of duodenal ulcer disease and how it 64. Zaterka S, Eisig JN, Chinzon D, Rothstein W. Factors related to Helicobacter
relates to H. pylori a community study. Am J Gastroenterol. 1997;92:1655-A pylori prevalence in an adult population in Brazil. Helicobacter. 2007;12:82-8.
286.
Received 26/8/2013.
Accepted 19/12/2013.

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