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Kari Toljam
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OULU 2012
D 1152
Kari Toljamo
GASTRIC EROSIONS – CLINICAL SIGNIFICANCE AND PATHOLOGYA LONG-TERM FOLLOW-UP STUDY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU, FACULTY OF MEDICINE,INSTITUTE OF CLINICAL MEDICINE, DEPARTMENT OF INTERNAL MEDICINE;INSTITUTE OF DIAGNOSTICS, DEPARTMENT OF PATHOLOGY
A C T A U N I V E R S I T A T I S O U L U E N S I SD M e d i c a 1 1 5 2
KARI TOLJAMO
GASTRIC EROSIONS – CLINICAL SIGNIFICANCE AND PATHOLOGYA long-term follow-up study
Academic dissertation to be presented with the assent ofthe Doctora l Train ing Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 7 of Oulu University Hospital, on 25 May2012, at 12 noon
UNIVERSITY OF OULU, OULU 2012
Copyright © 2012Acta Univ. Oul. D 1152, 2012
Supervised byDocent Seppo NiemeläProfessor Tuomo Karttunen
Reviewed byDocent Johanna ArolaDocent Perttu Arkkila
ISBN 978-951-42-9803-5 (Paperback)ISBN 978-951-42-9804-2 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2012
Toljamo, Kari, Gastric erosions – clinical significance and pathology. A long-termfollow-up studyUniversity of Oulu Graduate School; University of Oulu, Faculty of Medicine, Institute ofClinical Medicine, Department of Internal Medicine; University of Oulu, Faculty of Medicine,Institute of Diagnostics, Department of Pathology, P.O. Box 5000, FI-90014 University of Oulu,FinlandActa Univ. Oul. D 1152, 2012Oulu, Finland
Abstract
Gastric erosions are superficial mucosal breaks. With the exception of bleeding, they areconsidered harmless, but their aetiology, histopathology and long-term course have remainedunknown and even the evolution of gastritis in patients with gastric erosions is unclear. Thepresent study aimed to solve clinical significance and pathology of gastric erosions in a long-termfollow-up study.
Initially, 117 patients and 117 controls were studied in 1974–1981, and a follow-up study wasperformed in 1996. We evaluated the presence of Helicobacter pylori and Herpes simplex virus(HSV) infections, use of NSAIDs and alcohol, smoking, and assessed features of gastrichistopathology. For follow-up, 52 patients and 66 controls were available.
In the follow-up visit, 39% patients still had gastric erosions while 11% of the controls haddeveloped erosions (p = 0.001). In H. pylori-positive subjects, peptic ulcer or a scar was morecommon in patients (17%) than in controls (4%, p = 0.006), but otherwise no increased morbidityor mortality was seen. High antibody titres against HSV predicted the persistence of erosions(p = 0.000), but H. pylori infection, use of NSAIDs, alcohol or smoking were not associated.Initially, inflammation was more active in the region of erosions than elsewhere in the antralmucosa, and more active inflammation in the erosion was associated with HSV seropositivity, H.pylori infection and the recent use of NSAIDs. Initially, H. pylori-positive subjects with chronicor recurrent erosions had higher scores of neutrophils compared to those with non-chronic/non-recurrent erosions. In H. pylori-positive subjects, body gastritis was initially less active in thepatient group. With time, antral gastritis worsened only in the patient group. In H. pylori-negativesubjects, there was no evolution of gastritis.
These results show that a significant proportion of gastric erosions are chronic/recurrent butmostly without serious complications. However, H. pylori-positive patients have a significant riskto develop a peptic ulcer. A significant proportion of chronic gastric erosions is related to HSVinfection. Focally enhanced inflammation modified by HSV or NSAID may be important in thepathogenesis of gastric antral erosions. Active inflammation in the erosions seems to predict theirchronicity/recurrency. Patients with erosions share the characteristics of gastritis of the duodenalulcer phenotype.
Keywords: follow-up studies, gastric mucosal erosion, gastritis, H. pylori, Herpessimplex virus, NSAID, peptic ulcer
Toljamo, Kari, Mahaeroosiot – kliininen merkitys ja patologia. Pitkäaikainenseurantatutkimus Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta, Kliinisenlääketieteen laitos, Sisätaudit; Oulun yliopisto, Lääketieteellinen tiedekunta, Diagnostiikanlaitos, Patologia, PL 5000, 90014 Oulun yliopistoActa Univ. Oul. D 1152, 2012Oulu
Tiivistelmä
Eroosiot ovat mahalaukun pinnallisia limakalvovaurioita. Niitä pidetään vaarattomina lukuunottamatta niihin liittyvää verenvuototaipumusta. Niiden etiologiaa, histopatologiaa ja taudinkul-kua ei tunneta. Ei myöskään tiedetä eroosiopotilaiden mahan limakalvon tulehduksen kulkua.Tämän tutkimuksen tavoitteena oli selvittää mahalaukun eroosioiden kliininen merkitys ja pato-logia pitkäkestoisena seurantatutkimuksena.
Alkujaan 117 potilasta ja 117 kontrollihenkilöä tutkittiin vuosina 1974 - 1981, ja seurantatut-kimus tehtiin vuonna 1996. Selvitimme helikobakteerin ja Herpes simplex -viruksen (HSV) ai-heuttamien infektioiden, tulehduskipulääkkeiden (NSAID) ja alkoholin käytön, sekä tupakoin-nin esiintymistä. Lisäksi tutkimme histopatologisesti mahalaukun limakalvoa. Lopulta oli 52potilaan ja 66 kontrollihenkilön aineisto käytettävissä.
Seurantakäynnillä 39 prosentilla potilaista oli yhä mahalaukun eroosioita, kun taas kontrolli-ryhmästä 11 prosentille oli kehittynyt eroosioita. Helikobakteeri-infektoituneilla maha- tai poh-jukaissuolen haava/arpi oli yleisempää eroosioryhmässä (17 %) kuin kontrolleilla (4 %), muttamuuten ei esiintynyt lisääntynyttä sairastuvuutta tai kuolleisuutta. Tulehdus oli aktiivisempaaeroosioissa kuin viereisellä limakalvolla, ja tämä tulehdus liittyi korkeisiin HSV-vasta-ainetasoi-hin, helikobakteeri-infektioon ja NSAID:n käyttöön. Korkeat HSV-vasta-ainetasot ennustivateroosioiden pysyvyyttä. Ensimmäisellä käynnillä aktiivinen tulehdus eroosioissa oli voimak-kaampaa niillä helikobakteeri-infektoituneilla, joilla eroosiot olivat pysyviä kuin niillä, joillaeroosiot eivät uusineet. Helikobakteeri-infektoituneilla eroosiopotilailla mahalaukun runko-osanlimakalvon tulehdus oli aluksi vähemmän aktiivista kuin vastaavilla kontrolliryhmän henkilöil-lä, mutta ajan myötä mahalaukun corpusosan limakalvon tulehdus voimistui vain eroosioryh-mällä. Limakalvotulehdus ei edennyt helikobakteeri-infektoitumattomilla henkilöillä.
Tulokset osoittavat, että merkittävä osa mahalaukun eroosioista on kroonisia/toistuvia, muttaenimmäkseen ilman vakavia komplikaatioita. Kuitenkin helikobakteeri-infektoituneilla eroosio-potilailla on merkittävä riski saada maha- tai pohjakaissuolen haava. HSV-infektio liittyy merkit-tävään osaan kroonisia mahalaukun eroosioita. Paikallisella tulehdusaktiivisuudella, jota HSV jaNSAID:n käyttö muokkaavat, saattaa olla tärkeä rooli eroosioiden synnyssä ja niiden kroonistu-misessa. Eroosiopotilailla on samanlainen mahalaukun limakalvon tulehduksen jakauma kuinpohjukaissuolihaavaa sairastavilla.
Asiasanat: helikobakteeri, Herpes simplex virus, mahalaukun eroosiot, mahalaukunlimakalvon tulehdus, NSAID, seurantatutkimukset
To Anja, Pirkka and Samu
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Acknowledgements
This study was carried out in the Department of Internal Medicine and Pathology,
University of Oulu, during the years 1995–2012.
I wish to express my deepest gratitude to my supervisors, Docent Seppo
Niemelä, M.D., Ph.D., and Professor Tuomo Karttunen, M.D., Ph.D. It was Seppo
who proposed this topic for my thesis. He has kindly guided me innumerable
times during these years, or actually decades. His expertise in gastroenterology
has been invaluable in providing a critical view on how to fit our observations
into the more recent scientific literature. Tuomo re-examined all histological
samples from both visits. He also has always arranged time to discuss with me
problems that I have encountered – and I have encountered many. He has an
inexhaustible supply of theories to explain the observations made during the study;
these theories were invariably based on the most up-to-date scientific literature
about the topic. Seppo and Tuomo formed a pleasant and very balanced
supervisory team.
I want to express my gratitude to Professor Juhani Lehtola, M.D., Ph.D., for
participating in this study by performing so many of the endoscopies during both
visits. Juhani was the Head of the Unit of Gastroenterology during my sub-
specialization in gastroenterology, and he is one of the most warm-hearted
colleagues I ever have met.
I am grateful to co-author Docent Anna-Liisa Karvonen, M.D., Ph.D., who
completed her dissertation “Gastric mucosal erosions in elective gastroscopic
patients” in 1983, and the subjects in the initial visit of my thesis consist of her
study subjects. Anna-Liisa reviewed the erosion classifications of the initial visit
findings in addition to co-authoring our publications. I am also grateful to co-
author Docent Riitta Karttunen, M.D., Ph.D., who participated in the work with
the Herpes simplex virus antibodies. I acknowledge the help of co-author Heli
Piiparinen, Ph.D., who participated in our study concerning detection of Herpes
simplex virus of histological samples; In this respect, I also wish to thank to
Docent Irmeli Lautenschlager, M.D., Ph.D.
I express my gratitude to the official referees, Docent Johanna Arola, M.D.,
Ph.D., and Docent Perttu Arkkila, M.D., Ph.D., for their valuable advice and
suggestions, which substantially improved this thesis.
I owe my warm thanks to the entire staff of the Division of Gastroenterology,
Department of Internal Medicine for their excellent co-operation during my sub-
specialization in gastroenterology, during the time when the follow-up monitoring
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was performed. I also owe my warm thanks to entire Department of Internal
Medicine. I am also grateful to Ritva Koskela, M.D., for the practical information
about how to complete a dissertation. I am grateful to laboratory technician
Hannu Wäänänen for helping with the graphic work. In addition, I owe my warm
thanks to staff in Department of Clinical Chemistry for analyzing and conserving
of the blood samples. I express my warm thanks to staff of Medical Library for
their friendly assistance in obtaining publications.
I am grateful to Ewen MacDonald, Doctor of Pharmacy, for prompt and
careful revision of the English language of this thesis and some of the
publications. I owe my gratitude for Kaija-Riitta Kiiskilä for her help in the
arrangement of doctoral celebration.
I am also grateful to Martti Lampinen, M.D., the former Head of Internal
Medicine in Salo District Hospital. Martti who granted me leave of absence from
my hospital position, which often occurred in the middle of hectic patient work.
I express my warm gratitude to my parents Karin and Onni for “everything”.
Finally, I want to express my warmest gratitude to my wife Anja and my
children Pirkka and Samu for their patience and support during this long process
of dissertation – not forgetting the times of absence of home life, during which
my loveable mother-in-law, Tora, provided invaluable help to my family.
Oulu March 23th 2012 Kari Toljamo
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Abbreviations
ASA Acetylsalicylic Acid
CagA cytotoxin associated gene A
CI confidence interval
DNA deoxyribonucleic acid
H. pylori Helicobacter pylori HSV Herpes simplex virus
GI gastrointestinal
MALToma mucosa-associated lymphoid tissue lymphoma
NSAID non-steroidal anti-inflammatory drug
PCR polymerase chain reaction
TNF tumour necrosis factor
χ2 test chi-square test
UACL ulcer associated cell lineage
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List of original publications
This thesis is based on the following publications, which are referred to in the text
by their Roman numerals:
I Toljamo K, Niemelä S, Karttunen TJ, Karttunen R, Karvonen A-L, Piiparinen H & Lehtola J (2002) The role of Herpes simplex and Helicobacter pylori infection in the etiology of persistent or recurrent gastric erosions: a follow-up study. Dig Dis Sci 47(4): 818–822.
II Toljamo K, Niemelä S, Karvonen A-L, Karttunen R & Karttunen TJ (2011) Histopathology of gastric erosions. Association with etiological factors and chronicity. Helicobacter 16(6): 444–451.
III Toljamo K, Niemelä S, Karvonen A-L & Karttunen TJ (2005) Evolution of gastritis in patients with gastric erosions. Scand J Gastroenterol 40(11): 1275–1283.
IV Toljamo K, Niemelä S, Karttunen TJ, Karvonen A-L & Lehtola J (2006) Clinical significance and outcome of gastric mucosal erosions: a long-term follow-up study. Dig Dis Sci 51(3): 543–547.
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Contents
Abstract
Tiivistelmä
Acknowledgements 9 Abbreviations 11 List of original publications 13 Contents 15 1 Introduction 19 2 Review of the literature 21
2.1 Orientating figures to the topic ............................................................... 21 2.2 Definition of gastric erosion .................................................................... 23 2.3 Classification ........................................................................................... 24
2.3.1 Endoscopic classification of gastric erosions ............................... 24 2.3.2 Acute and chronic erosions .......................................................... 26
2.4 Incidence and prevalence of gastric erosions .......................................... 27 2.4.1 Prevalence of erosions in asymptomatic subjects ......................... 27 2.4.2 Prevalence in clinical series .......................................................... 27
2.5 Aetiology of gastric erosions .................................................................. 28 2.5.1 Herpes simplex virus .................................................................... 28 2.5.2 Helicobacter pylori ....................................................................... 29 2.5.3 Non-steroidal anti-inflammatory drug .......................................... 30 2.5.4 Gastric acid ................................................................................... 30 2.5.5 Other factors ................................................................................. 31 2.5.6 Factors affecting chronicity .......................................................... 33
2.6 Pathogenesis of gastric erosions .............................................................. 33 2.7 Histopathology of gastric erosions .......................................................... 34 2.8 Gastritis in patients with erosion ............................................................. 35
2.8.1 Definition of gastritis and classification ....................................... 35 2.8.2 Phenotypes and dynamics of gastritis ........................................... 36 2.8.3 Gastritis in erosion patients .......................................................... 37 2.8.4 Dynamics of gastritis in erosion patients ...................................... 37
2.9 Follow-up studies in gastric erosion ....................................................... 37 2.10 Clinical significance of gastric erosions .................................................. 37
2.10.1 Symptoms ..................................................................................... 38 2.10.2 Bleeding ....................................................................................... 38 2.10.3 Ulcer risk ...................................................................................... 38
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2.10.4 Malignancy ................................................................................... 38 3 Aims of the study 39 4 Materials and Methods 41
4.1 Patients .................................................................................................... 41 4.2 Controls ................................................................................................... 41 4.3 Endoscopy and biopsies .......................................................................... 41 4.4 Histological assessment of gastritis ......................................................... 42 4.5 Evaluation of Helicobacter pylori infection and Herpes simplex
virus infection.......................................................................................... 43 4.6 Symptoms and other clinical data ........................................................... 43 4.7 Blood chemistry ...................................................................................... 44 4.8 Occurrence of Malignancies, Mortality and Causes of Death ................. 44 4.9 Statistical analysis ................................................................................... 44 4.10 Ethical consideration ............................................................................... 45
5 Results 47 5.1 Final study groups ................................................................................... 47 5.2 Types of erosion ...................................................................................... 50 5.3 Etiological factors (I) .............................................................................. 50
5.3.1 Herpes simplex virus .................................................................... 50 5.3.2 Helicobacter pylori ....................................................................... 51 5.3.3 Non-steroidal anti-inflammatory drug .......................................... 52 5.3.4 Simultaneous effects of Herpes simplex virus,
Helicobacter pylori and non-steroidal anti-inflammatory
drug ............................................................................................... 53 5.3.5 Other factors and the erosion rate ................................................. 54
5.4 Histopathology of gastric antral erosions (II) .......................................... 54 5.4.1 Comparison of inflammatory changes in the erosion and
in the background antral mucosa .................................................. 54 5.4.2 Role of Helicobacter pylori on histopathology of erosions .......... 57 5.4.3 Role of non-steroidal anti-inflammatory drugs on the
histopathology of erosions ............................................................ 57 5.4.4 Role of Herpes simplex seropositivity on the
histopathology of erosions ............................................................ 58 5.4.5 Relationship of histopathological features in erosions and
the chronicity/recurrence of the erosions ...................................... 59 5.4.6 Histopathological features in erosions and the risk for the
development of peptic ulcer or gastric malignancy ...................... 59
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5.5 Progression of gastritis in patients with gastric erosions (III) ................. 60 5.5.1 Severity of chronic gastritis .......................................................... 61 5.5.2 Activity of gastritis ....................................................................... 62 5.5.3 Atrophic changes, intestinal metaplasia and dysplasia ................. 63 5.5.4 Microscopic erosions and epithelial reactive changes .................. 64 5.5.5 Non-steroidal anti-inflammatory drug use and features of
gastritis ......................................................................................... 65 5.5.6 Parietal cell antibodies .................................................................. 66 5.5.7 Ulcer development during the follow-up ...................................... 66
5.6 Clinical features, ulcer and malignancy .................................................. 66 5.6.1 Endoscopical findings .................................................................. 66 5.6.2 Symptoms and other clinical data ................................................. 66 5.6.3 Surgical operations and other diseases ......................................... 67 5.6.4 Occurrence of malignancies, mortality, and causes of
death ............................................................................................. 68 6 Discussion 69
6.1 Methodological aspects ........................................................................... 69 6.2 Aetiology and pathogenesis of chronic/recurrent gastric erosions .......... 70 6.3 Histopathology of chronic/recurrent gastric erosions ............................. 73 6.4 Progression of gastritis in patients with chronic or recurrent
gastric erosions ........................................................................................ 74 6.5 Clinical outcome of patients with gastric erosion ................................... 77 6.6 Future aspects .......................................................................................... 79
7 Conclusions 81 References 83 Original publications 93
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1 Introduction
Gastric erosions have been defined as endoscopically detectable mucosal breaks
that do not penetrate the muscularis mucosae (Yardley & Hendrix 1995). The
duration of erosion can be short-term, chronic or recurrent (Karvonen & Lehtola
1984, Yardley & Hendrix 1995). Erosions are a frequent finding in 3–12%
asymptomatic volunteers and in 4–49% of clinical series (Tables 2 and 3).
The aetiology of gastric erosions of indeterminate duration has been
postulated to involve Herpes simplex virus (HSV), Helicobacter pylori (H. pylori), the use of nonsteroidal anti-inflammatory drugs (NSAIDs), hyperacidity,
use of alcohol and cigarette smoking (Bernersen et al. 1992, Karvonen & Lehtola
1983, Karvonen et al. 1987, Lehtola et al. 1988, O'Laughlin et al. 1981).
There are only a few reports describing the histopathology of gastric erosions.
Nesland et al. (1986) studied erosive prepyloric changes, and found that a feature
of acute inflammation always followed those erosions, which were diagnosed also
by histological techniques, and fibrosis was found in all cases.
Erosions can be found in gastric mucosa that is either histologically inflamed
or non-inflamed and this suggests that there is the existence of different
phenotypes of gastric erosion disease (Karvonen & Lehtola 1983). The peptic
ulcer risk associates with antrum predominant H. pylori gastritis, while risk of
gastric cancer is linked with multifocal or body predominant atrophic gastritis.
Finally body predominant gastritis exhibits a low peptic ulcer risk (Sipponen
2001, Uemura et al. 2001). The progression patterns of gastritis are related to both
phenotype and associated complications, such as peptic ulcer as has been reported
in follow-up studies (Maaroos et al. 1985, Niemelä et al. 1995a, Niemelä et al. 1995b, Valle et al. 1996). Currently, studies of evolution of gastritis in patients
with gastric erosions are lacking, confirming the need for the current study.
The clinical importance of gastric erosions is that they may bleed; this
symptom occurs up to 23% of cases (Laine 1998). Otherwise, gastric erosions are
considered as harmless. However, erosions in gastric mucosa could be associated
with clinically important local, distant, or systemic complications, and this was
another reason for undertaking the current study.
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2 Review of the literature
2.1 Orientating figures to the topic
Orientation of a scientific article can be difficult individuals not having special
knowledge of the topic. To overcome this problem, here three figures will be
shown to provide an basis for the remainder of this thesis (Figures 1–3).
Fig. 1. Schematic figure of different gastric anatomical regions.
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Fig. 2. Examples of erosion findings as photographs. Type I (A), type IIa (B), type IIb (C)
and type III (D) erosions are shown.
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Fig. 3. Schematic figure of the cross-sectional structure of gastric wall. Examples of
(A) normal structure, (B) superficial erosion, (C) deep erosion, (D) an acute gastric
ulcer and (E) a chronic gastric ulcer are shown.
2.2 Definition of gastric erosion
Already in 1761, Morgagni utilized the term “erosion” in describing gastritis
(Morgagni 1761). In 1950, a gastric erosion was defined as a superficial defect in
the mucosa that did not penetrate through the muscularis mucosae layer (Ivy et al. 1950). In 1986, a workshop on the “Aggression to the Gastric Mucosa” was held
at the World Congresses in Sao Paulo, Brazil, and there erosion was defined as a
visible break in the mucosa (Laine & Weinstein 1988). The usual finding is a
white base of erosion, although occasionally a blackened base may be seen as a
mark of recent haemorrhage; the lesions are flat or minimally depressed and
usually are surrounded by a narrow rim of erythema (Laine & Weinstein 1988).
Erosion has also been described as a defect in the mucosa with a necrotic base
that is less than 3–5 mm in diameter (Yardley & Hendrix 1995).
Microerosions are defects in epithelium, which can be revealed only by the
microscope. They have been graded as follows: Grade 1, single cell dropouts are
present; Grade 2, dropouts consisting of multiple cells are present. In addition,
this grading extends to grade 3, in which there are real, endoscopically visible
erosions, which are too large to be classified as microerosions (Leung et al. 1992).
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The distinction of an erosion from an ulcer is based on the depth of the
mucosal break. By definition, the ulcer penetrates the muscularis mucosae
whereas an erosion does not. Endoscopically this is assessed in that the erosion
does not interrupt the passage of the peristaltic wave in contrast with an ulcer.
Another distinction can be seen when the margin of the erosion is grabbed with
biopsy forceps, it can be lifted outwards because the floor of the erosion is not
fixed to the gastric wall, as is in the case of an ulcer. During endoscopy, the
estimation of depth of the mucosal break can only be an estimate. (Laine &
Weinstein 1988, Roesch 1978).
Erosion should also be distinguished from other macroscopic changes visible
in endoscopy. Erythema is defined as an area of redness. The mucosa is
considered to be friable, if the endoscope induces subepithelial haemorrhages or
oozing of blood. Subepithelial haemorrhage can be defined as petechiae or bright
red areas, even though there is no visible break in the mucosa. (Laine &
Weinstein 1988).
2.3 Classification
Gastric erosions has been classified according to chronicity, their endoscopical
characteristics and scored by their severity. However, there is no agreement of the
definition of acute and chronic gastric erosion. In this review, the term
“chronic/recurrent erosion” refers to erosions found in both visits, which were
nearly two decades separated from each other.
2.3.1 Endoscopic classification of gastric erosions
The classification is summarized in Table 1. Gastric erosions are divided into
three categories: complete erosion, incomplete erosion and hemorrhagic-erosive gastritis (Roesch & Ottenjann 1970). The last of these three consists of numerous,
pinpoint-sized haemorrhages on the mucosa and in addition within the mucosa
and submucosa, erythrodiapedesis and engorged blood vessels. These may be
diffuse or localized to the fundal or antral region.
Incomplete erosion has also been termed as a flat erosion and it is defined as
a defect of the mucosa without any reaction of the surrounding mucosa (Kawai et al. 1970). A hematin-covered floor surrounded by an elevated border
characterizes a complete erosion in the acute phase and it is usually followed
within 48 hours by a whitish, gray-yellow coat (Roesch & Ottenjann 1970).
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Incomplete erosions can further be divided into two subgroups: those located on
the prominent folds of the prepyloric region (type IIb) and those located on flat
mucosa (type IIa) (Karvonen et al. 1983). Nesland & Berstad (1985) defined
erosive prepyloric changes (EPC) and divided these into three grades. EPC grade
1 was defined as a standing mucosal prepyloric fold, which is independent of
peristalsis and runs transverse or parallel in relation to the antral lumen. EPC
grade 2 was defined as red spots and/or streaks, which are situated on the top of
the folds, in addition to the presence of grade 1 changes. EPC grade 3 was defined
as former, and in addition, presence of macroscopic erosion. EPC grade 3 seems
to correspond to type IIb erosions, which have been defined by Karvonen et al. (1983).
Kawai et al. (1970) subdivided complete erosions into two categories: a)
mature type, in which the surrounding circular prominence is irreversible due to
fibrosis and b) immature type, where it is due to oedema. Histology reveals that
the latter may appear as foveolar pseudo-hyperplasia due to elongation of the
cristae. When re-epithelisation does take place, these changes disappear within a
few days. (Roesch & Ottenjann 1970).
Varioliform gastritis is a rare condition in which there are multiple erosions
(Laine & Weinstein 1988). They are typified by < 10 mm mucosal elevation with
a central pale depression, and lesions are usually multiple at the crests of the folds
of the antrum, body or both (Elta et al. 1983, Franzin et al. 1984, Freise et al. 1979, Green et al. 1982, Lambert et al. 1978). Lymphocyte gastritis can be
manifested as this type of gastritis, mostly in the presence of normal antral
mucosa (Stolte & Meining 2001).
Portal hypertensive gastropathy can resemble a gastric erosion finding, but in
this case the histological findings are dilated superficial vessels without erosions
or inflammation (Pique 1997). Similar haemorrhagic gastropathy have been
detected during endoscopical examination in epidemic nephropathy (Nuutinen et al. 1992).
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Table 1. Endoscopical classification of gastric erosions and gastric conditions with
erosions as a predominant change.
Main class Subclass Characteristic features Publication
I Complete Innumerable, pinpoint-sized hemorrhages on the
mucosal surface
Roesch &
Ottenjann (1970)
Ia Mature type The surrounding mucosal elevation is irreversible
due to fibrosis
Kawai et al.
(1970)
Ib Immature
type
The bulging border is due to oedema Kawai et al.
(1970)
II Incomplete A simple defect of the mucosal layer without
reaction to surroundings
Roesch &
Ottenjann (1970)
IIa Erosion located on flat mucosa Karvonen et al.
(1983)
IIb Erosion located on the prominent folds of the
prepyloric region
Karvonen et al.
(1983)
III Haemorrhagic-
erosive gastritis
Innumerable, pinpoint-sized hemorrhages on the
mucosal surface with erythrodiapedesis and
engorged blood vessels within mucosa and
submucosa
Roesch &
Ottenjann (1970)
Erosive prepyloric
changes (EPC)
EPC grade 1 Standing mucosal prepyloric fold, independent of
peristalsis and running transverse or parallel into
relation of antral lumen
Nesland &
Berstad (1985)
EPC grade 2 EPC grade 1 plus red spots and/or streaks
situated on the top of the folds
Nesland &
Berstad (1985)
EPC grade 3
(equals
Incomplete type
IIb erosions)
EPC grade 2 plus the presence of macroscopic
erosions
Nesland &
Berstad (1985)
2.3.2 Acute and chronic erosions
Gastric erosions can be found recurrently in the same subject, but it is not known,
if these erosions are the same as seen before, or new ones. Thus these erosions
can either be chronic or recurrent. There is no commonly accepted definition of
what constitutes acute and chronic erosions.
27
2.4 Incidence and prevalence of gastric erosions
The exact incidence of gastric erosion is not known, but for example after
ingesting 2.6 g of aspirin, all subjects were found to have submucosal
haemorrhages or focal erosions within 24 hours (Graham et al. 1983).
2.4.1 Prevalence of erosions in asymptomatic subjects
In asymptomatic volunteers, the prevalence of gastric erosion has ranged from 3%
to 12% (mean 7%; Table 2).
Table 2. Reports of the prevalence of gastric erosions in asymptomatic subjects. The
mean prevalence and cumulative N are shown in the last row.
Prevalence % Erosion N Total N Publication
3 9 358 Ihamäki et al. (1979)
12 43 355 Akdamar et al. (1986)
9 10 113 Dooley et al. (1989)
4 13 310 Bernersen et al. (1992)
8 14 175 Lehmann et al. (2000)
7 89 1311
2.4.2 Prevalence in clinical series
In clinical series, the prevalence of gastric erosion has ranged from 4% to 49%
(mean 15%; Table 3).
Table 3. Reports of the prevalence of gastric erosions in clinical series. The mean
prevalence and cumulative N are shown in the last row.
Prevalence % Erosion N Total N Publication
4 79 1859 Roesch & Ottenjann (1970)
11 404 3837 Karvonen et al. (1983)
14 90 651 Nesland & Berstad (1985)
7 21 309 Bernersen et al. (1992)
9 35 400 Heikkinen et al. (1997)
30 19 64 Auroux et al. (2003)
27 88 331 Duck et al. (2004)
23 198 869 Cheung et al. (2010)
49 502 1022 Ma et al. (2010)
15 1436 9342
28
In autopsy series, the prevalence of hemorrhagic gastric erosion has been reported
to be 5% (546/11352) (Martinoli & Gantner 1970).
2.5 Aetiology of gastric erosions
An erosion is formed either as a consequence of epithelial cell death or of
epithelial detachment, resulting in loss of epithelial cells that exceeds the
epithelial regeneration capacity. Secondly, the loss of epithelial cells evokes
luminal factors e.g. gastric acid release which can start to destroy subepithelial
structures. This kind of loss of mucosal integrity can be induced by several
chemicals, diseases and mechanical or physical factors. Table 4 lists presumed
etiological factors.
Table 4. Presumed etiological factors of gastric erosions. See text for references.
Chemicals Diseases Mechanical/Physical factors
Alcohol Crohn’s disease Endoscopic haemostasis
Gastric acid Diabetes mellitus type II Gastric band
Iron preparations Duodenogastric reflux of bile acid Nasogastric tube
NSAID H. pylori infection
Osteoporosis treatment Herpes simplex infection
Potassium chloride
Smoking
Mini early carcinoma and lymphoma
Rare infections (Syphilis, CMV, Tuberculous)
2.5.1 Herpes simplex virus
Animal studies
Oral inoculation with HSV-1 evoked gastric ulcers in mice, and one of the 40
ulcers contained viral Ag. However, the remaining ulcers were situated adjacent
to virus-infected ganglia (Gesser et al. 1995). After placement of HSV-1 into the
oesophageal lumen of mice, the HSV-1 virus could spread via internodal strands
of the enteric nervous system, leading to infection of the neurons of plexuses of
the stomach. HSV-1 labelled terminal nerve fibres penetrate into the lamina
propria of the gastric mucosa allowing a direct interaction with surface epithelial
cells (Gesser & Koo 1996).
29
Human studies
Latent HSV-1 have been found in humans in the ganglia innervating the
gastrointestinal (GI) tract and these viruses have also been found in gastric ulcers
or in their immediate proximity in 9%-32% of cases. However, it is not certain
whether this is an etiologic factor, a cofactor or an opportunistic factor (Kemker et al. 1992, Tsamakidis et al. 2005, Warren et al. 1978). Herpes related lesions
recur when the latent virus in the ganglia travels along the nerve causing a
recurrent lesion (Docherty & Chopan 1974). It has been claimed that it is possible
to interrupt this migratory pathway by severing the nerve (Kemker et al. 1992).
However, there are no reported trials on the effects of anti-HSV treatment in
therapy of gastric erosions or ulcers.
2.5.2 Helicobacter pylori
The role of H. pylori infection as an etiological factor for gastric erosion is
controversial and the conclusions seem to depend on that how erosions and ulcers
have been differentiated.
Ulcers and erosions have been reported to disappear after eradication of H. pylori (Chan et al. 2001). In a histological analysis, H. pylori gastritis was present
in 99% of patients with complete erosions of the antral mucosa (Stolte & Eidt
1992). Erosive prepyloric changes grade 3 findings were observed more
frequently in H. pylori-infected than in non-infected subjects, although the
difference was not statistically significant (Berstad et al. 1988). It has been
reported that there is an increased H. pylori density in erosions, and also it has
been claimed that there are differences in the genotype distribution compared to
unaffected regions (Molnar et al. 2008).
There are some observations opposing a role for H. pylori as a causative
agent in gastric erosions. Gastroduodenal erosions in asymptomatic volunteers
have been found with equal frequencies in H. pylori-positive and -negative
subjects, and in another study with asymptomatic volunteers, only 4 of 14
subjects with gastric erosions were found to be infected with H. pylori (Dooley et al. 1989, Lehmann et al. 2000). In contrast, nearly half of 34 EPC grade 3
subjects were infected with H. pylori (Bernersen et al. 1992). Two more recent
studies also failed to detect any clear relationship between macroscopic erosions
and H. pylori infection (Ma et al. 2010, Szoke et al. 2008). It has even been
30
suggested that a H. pylori infection may protect from gastric erosions in patients
with end-stage renal failure (Moriyama et al. 2010).
2.5.3 Non-steroidal anti-inflammatory drug
Volunteers treated with acetosalicylic acid (ASA) can develop erosive lesions
within 24 hour (Graham et al. 1983, O'Laughlin et al. 1981). Incomplete type IIa
erosions have been associated with the use of analgesics (Karvonen & Lehtola
1983). It has been reported that there are similar numbers of gastric erosions after
the use of Cox-2 selective drugs and non-selective NSAID preparations (Cheung et al. 2010). After 12 weeks’ use of celecoxib and diclofenac, at the endpoint
almost the same number of subjects had developed gastric erosions; 21% (85 of
434) in the celecoxib group and 23% (91 of 435) of those receiving diclofenac. In
fact, there are even reports that fail to show relation between gastric erosions and
the use of NSAIDs (Dooley et al. 1989, Gallagher et al. 1987, Lehmann et al. 2000, Pazzi et al. 1994).
The mechanism of NSAID/ASA-induced erosions is proposed to be mainly
inhibition of prostaglandin synthesis and oxidative phosphorylation, but also
disturbances in the local microcirculation, resulting in ischemic necrosis, have
been proposed (Bjarnason et al. 1993, Kitahora & Guth 1987, Sanchez et al. 2002,
Vane 1971). It is postulated that an acid independent component in NSAID
gastropathy causes microscopic erosions that are related to the inhibition of
prostaglandin synthesis (Whittle 1981).
Long-term NSAID users infected with H. pylori develop significantly more
erosions as compared to patients not infected with H. pylori, but this is a matter of
controversy (Graham et al. 1991, Taha et al. 1995). Low-dose ASA users not
infected with H. pylori had more frequently gastric erosions compared to H. pylori infected; hence a H. pylori infection may possess some protective effect
against low-dose ASA-induced gastric erosions (Hart et al. 2010). The speculative
mechanism for this phenomenon can be damage to the parietal cells having a
putative lower production of acid. The risk of erosions did not increase with aging
(Hart et al. 2010).
2.5.4 Gastric acid
Roesch & Ottenjann (1970) reported that most patients with gastric erosions
displayed hyperacidity and this correlated well with their observation that
31
atrophic gastritis was uncommon in patients with erosions. However, another
study in EPC patients reported that the mean acid output values did not differ
from values of healthy subjects (Nesland & Berstad 1985). In addition, another
study showed that in patients with prepyloric erosions the body mucosa was well
preserved despite aging and this observation is similar to the situation in patients
with duodenal ulcers. The authors proposed that there would be a common acid-
related pathogenesis (Karvonen et al. 1987).
Studies which have taken into account H. pylori infection, have demonstrated
that too much gastric acid can lead to peptic ulcers and stress-related
erosions/ulcers (Schubert 2010).
Recovery of acid secretion capacity after H. pylori eradication has been
believed to be involved in the development of gastric erosions. Miyake et al. (2005) observed that the development of gastric erosions after eradication
depended on whether there was less severe corpus atrophy or more severe corpus
gastritis. On the other hand, treatment with H2 blocker has been claimed to
decrease the rate of erosions (Miyake et al. 2002).
2.5.5 Other factors
Although there are believed to be several genetical risk factors for peptic ulcer
such as polymorphisms in immunoregularatory genes, only a few studies have
addressed genetic factors in gastric erosion (Shiotani et al. 2010). The G-308A
polymorphism of TNF-alpha, which causes elevated expression of the TNF-α
protein (G/G genotype), has been associated with erosive gastritis (Szoke et al. 2008). In contrast, CD14 genetic polymorphism showed no association with the
risk of gastric erosions (Karhukorpi et al. 2002).
Chemicals
Alcohol. Gastric erosions are a common finding in patients with chronic
alcoholism (Segawa et al. 1987, Uppal et al. 1991). Erosive prepyloric changes
have been reported to be common in women using alcohol (Bernersen et al. 1992).
Iron containing preparations. In a study with 14 healthy volunteers that
ingested ferrous sulphate for two weeks, two subjects developed solitary antral
erosion (Laine et al. 1988).
32
Osteoporosis treatment. Alendronate 10 mg daily was reported to cause
gastric erosions in a minority of subjects during 2 weeks (Graham & Malaty
1999).
Potassium chloride. It has been reported that potassium chloride can induce
gastric erosions (McMahon et al. 1982).
Smoking. Smoking has been claimed to be common in erosion patients
(Karvonen & Lehtola 1983). Erosive prepyloric changes have been reported to
associate with cigarette smoking (Bernersen et al. 1992).
Diseases
Crohn’s disease. In patients with Crohn’s disease, endoscopically observed
erosions have been reported to be a usual finding, and these can be of predictive
value for the presence of granulomas (Schmitz-Moormann et al. 1985). The
histologic features, which are suggestive of Crohn’s disease, include focal active
gastritis and granulomatous gastritis (Parente et al. 2000, Yardley & Hendrix
1995).
One study of patients with diabetes mellitus type II, which is characterized by
high risk of vascular disease, found that their 21 out of 72 patients suffered gastric
erosions (Boehme et al. 2007).
Duodenogastric reflux of bile acids. Intragastric administration of bile into
the rat was shown to produce gastric erosions (Mann 1976)
Early carcinoma & early lymphoma. Early gastric cancer can appear
endoscopically as an erosion (Misumi et al. 1989). Patients with low-grade gastric
B-cell lymphoma of mucosa-associated lymphoid tissue type (MALToma) when
examined endoscopically can show evidence of gastric incomplete erosions
(Chiang et al. 1996).
Rare infections. Syphilitic gastritis has been reported in over 100 patients in
the literature. A typical syphilitic gastritis patient is a young adult with gastric
pain, in whom syphilis should be suspected if endoscopy reveals gastric erosion
or shallow gastric ulcer with extensive gastritis in histology (Kim et al. 2009). A
case of cytomegalovirus infection appearing as acute gastroduodenitis including
gastric erosions has been reported with the diagnosis being confirmed with
positive anti-cytomegalovirus antibody staining (Shirakami et al. 2007). A case of
tuberculosis with gastric erosion accompanied by bleeding has also been reported
(Rathnaraj et al. 1997).
33
Mechanical and physical factors
Gastric Band. Although a gastric band has been reported to erode only in a
minority, it may require the removal of the gastric band (Yoon et al. 2012).
Nasogastric tube and endoscopic haemostasis. Nasogastric tubes commonly
cause gastric erosions, and different endoscopic haemostasis techniques have also
been reported to cause gastric erosion in the areas being treated (Weinstein 1998).
2.5.6 Factors affecting chronicity
Many of the studies that have discussed factors affecting the chronicity of gastric
erosion predate the awareness of H. pylori, which is an important factor in
chronic gastritis. An elevated gastric acid secretion capacity has shown to be
associated with erosion chronicity, although this was statistically significant only
in the incomplete type of erosions (Karvonen & Lehtola 1984).
2.6 Pathogenesis of gastric erosions
As the aetiology of gastric erosion is multifactorial, so too the pathogenesis also
seems to be multifactorial. Erosions are a result of an imbalance between
protective and destructive factors. Erosion and ulcers can be considered to be the
same process and it is likely that they share common factors evoking mucosal
damage. The factors that participate in the pathogenesis of gastric ulcer can be
divided into luminal, epithelial cell, apoptotic and regenerative factors.
Luminal factors. Gastric acid is most important luminal factor. It is well
known that there is hyperacidity in stress ulcers (Fenoglio-Preiser et al. 2008).
Secondly, there is elevated pepsin formation (Feldman et al. 1988). Thirdly,
increased retrograde peristaltic waves with low pyloric tone and reduced local
motility can lead to more intensified biliary and pancreatic duodenogastric reflux
(Flint & Grech 1970). The levels of endothelins are increased in saliva in peptic
ulcer patients and this may contribute to the pathogenic process (Lam et al. 2004).
Saliva itself can be considered to participate in offering protection against peptic
ulcers (Malhotra 1970). In erosions patients, the mucoprotective index (the ratio
of neutral to total mucoproteins) has been reported to be decreased, and
weakening of mucosal defences has been speculated to be a major factor in the
pathogenesis of gastric erosions (Guslandi et al. 1989).
34
Epithelial cells and mucus. Protection against gastric acid is provided by
epithelial cells which secrete mucus and bicarbonate (Soll 1990). When gastric
protective mechanisms are activated then epithelial production of mucus and
bicarbonate increases (Holle 2010). Mucosal cells possess a membrane that resists
acid from returning into the cell (Soll 1990). Mucosal protection becomes
weakened when there is a decline in mucus secretion, mucosal blood flow, the
synthesis of DNA and prostaglandins. This changes the mucus composition and
low molecular glycoprotein production increases, leading to conditions favouring
proteolysis and rediffusion of H+-ion, which then enhance ulcer formation (Holle
2010, Younan et al. 1982). Damage to the mucosal barrier results in tissue
acidosis, congestion of mucosa and necrosis (Fenoglio-Preiser et al. 2008).
Increased apoptosis leading to loss of mucosal integrity is one factor in the
development of ulcers ((Leung et al. 2000). When reperfusion takes place, then
neutrophils can produce toxic oxygen free radicals (Fenoglio-Preiser et al. 2008).
Ischemic stress related erosions are encountered mainly in intensive care patients.
It has been reported that brain ischemia in rats can produce gastric hemorrhagic
erosions through gastric oxidative stress and activation of the arginine-nitric oxide
pathway (Hung 2006).
Epidermal growth factor has been reported to stimulate mucosal cell
proliferation and also inhibit acid secretion (Holle 2010).
Regeneration. Ulcer associated cell lineage (UACL) has been found at sites
of chronic gastric ulcers. Gastric stem cells induce UACL and this assists in the
healing of the ulcer. This involves coordinated localisation of mucins and trefoil
peptides, which are potent mitogens of GI epithelium in conjunction with
epidermal growth factor (Longman et al. 2000, Patel et al. 1994). In addition,
healing can be assisted also by an increased mucosal blood flow (Fenoglio-Preiser et al. 2008).
2.7 Histopathology of gastric erosions
Erosions are histopathologially characterized by epithelial defects extending into
the deeper layers of the mucosa. An erosion is formed either as a consequence of
epithelial cell death (necrosis or apoptosis) or of epithelial detachment, i.e. the
level of apoptosis or detachment is in excess of the magnitude of epithelial
regeneration. Detached epithelium alone defined as erosion can be misleading
because of biopsy induced artefacts, and the definition of erosion should always
include other features of erosion, for example fibrinoid necrosis or granulated
35
tissue (Laine & Weinstein 1988). There is no acknowledged histopathological
classification for gastric erosions, except for the classification of microerosions.
Furthermore, previously little was known about the prognostic value of
histological findings of the erosion.
In addition to the abovementioned factors, there are many reports of scattered
histological findings in erosion. Erosions have been noted to contain fibrin
deposition, neutrophilic infiltration and there may be regenerative changes in the
adjacent epithelium (Dixon et al. 1996). It has also been reported that
NSAID/ASA erosions consist of a homogeneous eosinophilic ischemic necrosis
blending into the adjacent lamina propria, whereas in H. pylori-induced erosions,
the erosive defects are covered with inhomogeneous fibroid necrosis that does not
blend into the adjacent lamina propria and they also contain cell debris and
granulocytes (Stolte et al. 1999). Stress induced erosions are characterized
histologically by epithelial necrosis, with a fibrin exudate and the presence of
neutrophils (Czaja et al. 1975). Foveolar hyperplasia has also been described
(Pazzi et al. 1994). EPC grades 2 and 3 have been reported to manifest with
infiltration of neutrophils, fibrosis, lymphocytes and plasma cells (Nesland et al. 1986). Kawai et al. (1970) reported that a subset of erosions displays signs of
fibrosis.
2.8 Gastritis in patients with erosion
2.8.1 Definition of gastritis and classification
Gastritis is defined as a microscopic inflammation of the stomach, and it is a
histological, but not a clinical, entity.
The most widely used classification of gastritis is the updated Sydney system,
which classifies gastritis according to the topography, morphology and aetiology.
Chronic gastritis is divided in nonatrophic, atrophic (autoimmune and multifocal)
and special forms of gastritis (i.e. chemical, radiation, lymphocytic, non-
infectious granulomatous, eosinophilic and other infectious gastritides); also other
forms differing from chronic gastritis have been defined. (Dixon et al. 1996).
36
2.8.2 Phenotypes and dynamics of gastritis
Apart from normal gastric mucosa, even without H. pylori infection, topographic
phenotypes of H. pylori gastritis and atrophic gastritis are classified as follows
(Sipponen 2001, Stolte & Meining 2001):
Ulcer phenotype H. pylori gastritis consist of two forms. Gastritis in patients with duodenal ulcer, in which the corpus mucosa is nonatrophic and especially in
the antrum there is evidence of gastritis (antrum predominant gastritis), and the
surface epithelium displays lesions, which are degenerative and regenerative,
especially in the antrum and in one fifth of cases there is also intestinal metaplasia
and atrophy. In this pattern of gastritis, there is a high level of acid secretion.
Gastritis in patients with gastric ulcer gastritis (corpus predominant gastritis)
differs from the above-mentioned type and tends to be diffuse, possibly with
multifocal atrophy and intestinal metaplasia (multifocal atrophic gastritis). The
stomach may also show hypochlorhydria and it may resemble the gastric cancer
phenotype gastritis. However, even the antral gastritis seems to advance in
patients with gastric ulcer (Niemelä et al. 1995a).
Gastric cancer phenotype of gastritis, where advanced atrophic gastritis and
intestinal metaplasia occur multifocally (multifocal atrophic gastritis), there can
be low production of gastric acid and the risk of gastric neoplasia is increased. In
some cases, despite positive serology, the histological search for H. pylori may be
negative. Lymphocytic gastritis has also been shown to associate with gastric
cancer and lymphoma, possibly due to its tendency to progress in severity and due
the presence of metaplastic changes in the body mucosa (Miettinen et al. 1995).
The dynamics of gastritis seems to modify the risk of complications. Corpus
predominant gastritis tends to lead to atrophy and cancer, and antrum
predominant gastritis in turn, tends to predispose to peptic ulcer.
The reasons for the individual different outcomes of H. pylori infection are
largely unclear. The different topographic distribution of gastritis in H. pylori infection has been explained by differences in bacterial factors, such as virulence
factors (e.g. cagA status) and the extent of colonization, host factors e.g. genetic
factors such as interleukin-1 gene cluster polymorphism, and the interaction
between these two factors. In addition, host-microbial interaction and
environmental factors have been postulated, and the final outcome may be multi-
staged (Blaser et al. 1995, El-Omar et al. 2000, Garcia-Gonzalez et al. 2001,
Maaroos et al. 1994, Nomura et al. 2002, Peek & Blaser 2002).
37
2.8.3 Gastritis in erosion patients
Atrophic antral gastritis is reported to be rare in erosion patients (Karvonen et al. 1983). However gastritis in chronic erosion patients is strongly dependent on the
presence of H. pylori infection, but few studies have taken into account the H. pylori status. Patients with EPC grade 3 are reported to experience more chronic
atrophic gastritis and more subacute gastritis than those without EPC (Bernersen et al. 1992).
2.8.4 Dynamics of gastritis in erosion patients
The dynamics of gastritis in erosion patients is largely unknown. A slow
progression of antral gastritis in gastric erosion patients has been reported, with
increasing body gastritis with age. However, prepyloric erosions, similar to those
encountered in duodenal ulcer patients, did not show this progression of body
gastritis. Unfortunately this study was mainly done before the era of awareness of
H. pylori (Karvonen et al. 1987).
2.9 Follow-up studies in gastric erosion
There are only a few follow-up studies examining gastric erosions. One study had
follow-up of six years; two thirds of erosions healed and two patients developed
new hyperplastic polyps, and there was no correlation between symptoms and
erosion findings. In that study, type IIb erosions only healed in 38% of cases
(Karvonen & Lehtola 1984). After a mean of 45 months of follow-up of grade 3
erosive prepyloric changes, most patients still had dyspeptic symptoms (92%;
21/23), and grade of EPC (61%; 14/23) remained unchanged, and patients were
also without complications such as ulcers (Stene-Larsen et al. 1989).
2.10 Clinical significance of gastric erosions
The clinical significance of gastric erosion has been only examined to a limited
extent and those studies have largely focused on gastritis and ulcers. To a lesser
degree, erosions have been evaluated and the distinction between erosion and
ulcer might well be blurred. These considerations further emphasize the need for
studies focusing on the clinical importance and course of gastric erosions.
38
2.10.1 Symptoms
There are some publications, which suggest that gastric erosions associate with
dyspeptic symptoms (Nesland & Berstad 1985, Stene-Larsen et al. 1989). On the
other hand, it has been proposed that in the majority of cases, gastric erosions
seem to evoke no symptoms (Larkai et al. 1987, Lehmann et al. 2000). The
mechanisms behind what symptoms do appear are not clear. Since there are no
sensory nerves in the gastric mucosa, simple mucosal destruction does not explain
the symptoms. Since erosions obviously do not correlate with symptoms, ulcers
also do not correlate well with symptoms (Aro et al. 2006). In population living
in northern Sweden, peptic ulcers have been reported to be asymptomatic in 20%
of cases (Aro et al. 2006).
2.10.2 Bleeding
In one study a total of 12,392 gastroscopies were performed for evaluation of
nonvariceal hematemesis, melaena or suspected upper GI bleeding and the most
common finding was ulcer (33%) followed by erosion in 19% of subjects
(Enestvedt et al. 2008). Among 2097 patients endoscoped for upper GI bleeding,
30% (620 patients) displayed gastric erosions and of these, active bleeding was
reported in 27% (166/613). (Gilbert et al. 1981).
2.10.3 Ulcer risk
In a study with a follow-up of up to 6 years monitoring gastric erosion patients,
only 4% (4 of 105) had acquired gastric ulcer (Karvonen & Lehtola 1984). In
another study with a mean of nearly 4 years of follow-up of 60 patients with EPC,
none of the subjects developed peptic ulcer (Stene-Larsen et al. 1989). Finally, it
has been reported that long-term NSAID users with gastric erosions develop more
often peptic ulcer than those without erosions (Taha et al. 1995).
2.10.4 Malignancy
There are no follow-up studies with adequate follow-up times investigating
malignancy risk in patients with gastric erosions.
39
3 Aims of the study
Gastric erosions are one of the most prevalent gastroscopic abnormalities, and
among the most important causes of GI bleeding. Rather incomplete information
about the long-term course of gastric erosions is available, and in addition,
nothing is known about the pathogenetic factors leading to delay of healing or
chronicity of erosions as well as the clinical significance of chronic erosions. The
purpose of this study was to focus on these aspects of gastric erosions by using a
long-term follow-up study setting. The detailed aims are as follows:
1. To determine the rate of chronic/recurrence of gastric erosions in a long-term
follow-up setting.
2. To investigate the aetiology of chronic/recurrent gastric erosions, including
HSV infection, H. pylori infection, and the use of NSAIDs.
3. To characterize the histopathology of gastric erosion and gastritis in patients
with gastric erosion, and to determine features related with prognosis of
erosions.
4. To define clinical significance of chronic/recurrent and non-recurrent gastric
erosion.
40
41
4 Materials and Methods
Numerals (I-IV) are referring to scientific articles belonging to this thesis:
4.1 Patients
The patients and controls were recruited from those referred for elective
gastroscopy in the Gastroenterologic Unit of the Department of Internal Medicine,
University Central Hospital of Oulu, during a period of five years (Sept. 1 1974 -
Aug. 31 1979). The series consisted of 3837 patients (2080 males). Gastric
erosions were diagnosed in 404 subjects. Those subjects with erosions concurrent
with peptic ulcer disease (N = 129), any GI disease requiring specific or urgent
treatment (N = 16) or some serious disease (N = 21) were excluded. In addition,
121 patients were also excluded because of inadequate co-operation, poor
tolerance of gastroscopy, difficulties in attending the follow-up examination, or
refusal to attend further examinations. Altogether 287 patients were excluded
from the original series. Thus a final total of 117 patients (63 males) with erosion
as the predominant finding were included and invited to a re-examination in 1996.
4.2 Controls
For each patient, a control of the same age (± 5 years) and sex (except one woman
instead of a man) was drawn prospectively from subjects gastroscopied electively
in the same department during 1979 - 1981 and not diagnosed as having gastric
erosions, peptic ulcer disease or any other severe disease of the GI tract or other
organs requiring immediate treatment. The control group consisted of 117 patients
(62 males).
4.3 Endoscopy and biopsies
Upper GI endoscopy was performed both at the initial visit (years 1974–1981)
and at the follow-up visit (1996). In the initial and follow-up visit, two biopsies
were taken from the greater curvature of the antrum and the corpus, avoiding
areas of macroscopical erosions. In the follow-up visit, two additional biopsies
were taken from the lesser curvature of the antrum and corpus. Furthermore,
separate biopsies were taken from macroscopically visible erosions. All biopsies
42
were fixed in neutral buffered formalin and embedded in paraffin. The sections
were stained with modified Giemsa and Hematoxylin-Eosin.
The erosions were diagnosed and classified according to established criteria
by the dominant type as follows (Roesch & Ottenjann 1970). Type I (complete
erosion): erosion elevated above the surrounding mucosa and surrounded by a
marginal wall. Type II (incomplete erosion): erosion located on even mucosa and
often surrounded by a reddish margin. Type III (haemorrhagic-erosive gastritis):
several small haemorrhagic erosions on even mucosa. Erosions were classified as
chronic/recurrent if they were endoscopically visible on both visits. Also all other
endoscopic findings were recorded according to the protocol.
4.4 Histological assessment of gastritis
According to the histological criteria of the updated Sydney-system, activity and
severity of gastritis were scored by using a scale from normal or absent (score 0),
to slight (score 1), moderate (score 2) and severe (score 3) change or increase
(Dixon et al. 1996). Atrophy was scored as absent (score 0), slight (score 1),
moderate (score 2) and severe (score 3). The presence of eosinophils,
vasodilatation, lymphoid follicles, germinal centres, fibrosis and foveolar
hyperplasia was scored as absent (score 0), slight (score 1), moderate (score 2)
and severe (score 3). Lymphocytic gastritis was diagnosed (score 2), if the count
of intraepithelial lymphocytes was at least 25/100 epithelial cells. The extent of
intestinal metaplasia was expressed as the percentage of mucosa showing
intestinal metaplastic epithelium. The presence and severity of intraepithelial
neoplasia (dysplasia) were assessed as absent (score 0), mild (score 1), moderate
(score 2) and severe (score 3), and they were recoded as low-grade (scores 1 and
2) or high-grade (score 3) (Fenoglio-Preiser et al. 2000). Metaplastic and
nonmetaplastic intraepithelial neoplasias (dysplasia) were evaluated separately.
Microscopic erosions were scored by using a scale as absent (score 0), mild
(single cell dropouts present; score 1), moderate (dropouts of several cells; score
2) or true erosions (score 3) (Leung et al. 1992). The percentage of surface
epithelial cells showing tufting was estimated (Chan et al. 1991). The reactive
gastritis score was calculated (Dixon et al. 1986). In addition, biopsies from
erosions were assessed separately from the other biopsies with the assessor being
blinded to the observations made from the non-eroded mucosa. One investigator
(TJK) performed all histological analyses and he was blinded to the clinical data.
43
Specimens of the initial and follow-up endoscopy were evaluated separately, with
the investigator being blinded to the results of the corresponding analyses.
4.5 Evaluation of Helicobacter pylori infection and Herpes simplex virus infection
H. pylori infection was diagnosed at both visits from the biopsy specimens taken
from the antral and body mucosa using Giemsa and Hematoxylin-eosin staining.
Antibodies to HSV at both visits were measured of sera by using the
complement fixation method with a commercial antigen (Bio Whittaker,
Walkersville, USA). Titres of one to ≥ 32 in the initial and ≥ 16 in the follow-up
visit were designated as “high titre”, based on values of all the samples and their
normal distribution.
Formalin fixed, paraffin embedded biopsy specimens representing erosions
taken at the follow-up visit were used for HSV immunohistochemistry and
polymerase chain reaction (PCR). The sections were deparaffinised and stained
with specific rabbit antibodies against HSV-1 and HSV-2 (BioGenex, San Ramon,
Ca, USA) using avidin-biotin detection system and diaminobenzidine as a
chromogen (Dako ABC kit, Dako, Copenhagen, Denmark). No antigen retrieval
system was used. The dilution of primary antibody was 1:400 with an incubation
time at room temperature of one hour. A specimen from herpetic esophagitis was
used as a positive control. Phosphate buffered saline was used instead of primary
antiserum as a negative control.
For HSV PCR, the paraffin in the biopsy specimens was removed with xylene,
and DNA was isolated using proteinase K digestion following phenol extraction
and ethanol precipitation. The primer pair used in PCR was chosen from the
polymerase gene for HSV-1 and HSV-2 (Piiparinen & Vaheri 1991). In each run,
positive and negative controls were included. The amplified products were
detected by microplate hybridization using specific probes for HSV-1 and HSV-2
(Vesanen et al. 1996).
4.6 Symptoms and other clinical data
On both visits, the investigators interviewed the subjects and pertinent anamnestic
and clinical data from the local hospital were recorded using a questionnaire. A
routine clinical abdominal status was also conducted.
44
On both visits, the type and duration of abdominal pain were evaluated and
inquired as described earlier (Karvonen & Lehtola 1983). During the follow-up
visit, the type of dyspepsia (reflux/ ulcer/ motility/ non-specific) was specified
(Drossman et al. 1990). A patient history of diseases was recorded on each visit.
In particular, clinically identified GI diseases, including GI bleeding during the
follow-up period, and gastric or other abdominal surgery were recorded.
The use of all medication for abdominal diseases or symptoms was asked at
both visits. The most recent use of NSAID was registered (< 24 hours, 1–3, 4–7
or > 7 days before endoscopy). Any use of an NSAID within the past 7 days was
designated as recent use. Drugs for other diseases and the possible use of H. pylori eradication treatments were inquired. Smoking habits and the use of
alcohol were recorded. Family history in first-degree relatives of gastric cancer,
gastric or duodenal ulcers and other GI diseases was registered.
4.7 Blood chemistry
Erythrocyte sedimentation rate, leukocyte count, serum C-reactive protein,
haemoglobin, creatinine, alanine aminotransferase, and alkaline phosphatase were
measured at both visits by routine methods. (I-IV)
In the initial visit, serum parietal cell antibodies were examined using the
polyvalent antihuman immunoglobulin fluorescein conjugate (Roboz®). (III)
4.8 Occurrence of Malignancies, Mortality and Causes of Death
The Finnish Cancer Registry (Helsinki, Finland) was contacted to obtain data on
the occurrence of malignant diseases (II, IV). Statistics Finland (Helsinki,
Finland.) provided data of mortality and causes of death (IV).
4.9 Statistical analysis
The statistical analysis was carried out using a statistical program (SPSS for
Windows Release 8.0–14.0, and SPSS 16.0 for Macintosh, SPSS Inc., Chicago,
Illinois, USA). The analysis of categorized variables was carried out by the χ2
and Fischer’s two-sided exact tests. Differences were considered as significant at
p values < 0.05 in two-tailed tests. Mann-Whitney U-test was used for the
analysis between groups of the scored variables and Wilcoxon paired rank sum
test was used for the analysis of temporal changes in the scored variables. The
45
nonparametric Spearman rho test was used for estimation of correlations. The
estimations of the relative risk of erosion association with HSV infection, the
recent use of NSAIDs and existence of H. pylori infection were carried out with
logistic regression analysis. Kaplan-Meier Log Rank test was utilized to calculate
mortality and malignancy data.
4.10 Ethical consideration
The study was approved by the Ethical Committee of the Medical Faculty of the
University of Oulu. All subjects who participated in the study signed an informed
consent.
46
47
5 Results
5.1 Final study groups
The characteristics of the final study groups are summarized in Figures 4 and 5.
All of the 117 patients and 117 controls of the original series studied in 1974–
1981 were included after 16 years of follow-up in the analysis of mortality and
the occurrence of malignant tumours.
The follow-up visit was arranged in 1996 and 54 (46% of the original series)
of the 117 patients agreed to take part in an interview, a clinical assessment and
routine blood tests. Of the controls, 70 (60% of the original series) were available
for follow-up analyses in 1996 (IV).
From H. pylori-positive subjects in the initial visit, 16% (5 of 32) of patients
and 31% (14 of 45; 33% 15 of 46 in III) of controls had changed to being
negative in the follow-up endoscopy. From H. pylori-negative subjects in the
initial visit, 12% (2 of 17) of patients and 11% (2 of 18; 12% 2 of 17 in III) of
controls had changed to being positive in the follow-up endoscopy. Subjects with
a changed H. pylori status were excluded from the analysis of the effect of H. pylori infection. (I-III).
After the exclusions, the final study group consisted of 42 patients and 47
controls (I, 46 controls in III, IV). The mean follow-up was 19 years (range 16.7–
21.4 years) in the patient group and 16 years (range 15.1–19.0 years) in the
control group (I,III).
It was possible to evaluate the histopathology from erosions and background
antral mucosa in 52 H. pylori-positive and in 31 H. pylori-negative patients at the
initial visit, but at the follow-up visit, there were only 7 H. pylori-positive and 3
H. pylori-negative patients with erosion, making it impossible to make
comparisons within H. pylori-positive or negative groups. Comparison analysis of
chronic/recurrent and non-chronic/non-recurrent erosions was possible in 28
patients; of those, 10 were patients with chronic/recurrent erosions and 18 were
patients with non-chronic/non-recurrent erosions. (II; Figure 5).
48
Fig
. 4. S
um
ma
ry o
f p
ati
en
ts a
nd
co
ntr
ols
in
th
e i
nit
ial
vis
it 1
974
–7
9 a
nd
in
th
e f
oll
ow
-up
vis
it 1
99
6 (
I, I
II-I
V).
Re
vis
ed
H.
pylo
ri
sta
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lis
ted
in
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ua
re b
rac
kets
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nce
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g p
ub
lic
ati
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s I
II-I
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49
Fig. 5. Summary of patients examined in the initial visit in 1974–79 and in the follow-up
visit in 1996 (II).
50
5.2 Types of erosion
In the follow-up endoscopy, 38% (20/52) of the patients and 11% (7/66) of the
controls had gastric erosions (p = 0.001; IV). The type of erosion was most often
similar in both visits, but in a remarkable proportion (30%) the type had changed.
(Table 5; IV). There was no significant difference in age or sex with the respect to
the occurrence of erosions. (III)
Table 5. Evolution of gastric erosion types in erosion patients and controls. (IV:
Table 1).
Initial visit erosion status Follow-up visit erosion status
Erosion any
type N (%)
Type I
N (%)
Type II
N (%)
Type III
N (%)
No erosion
N (%)
Total N
Patients (any type erosion) 20 (38) 6 (12) 11 (21) 3 (6) 32 (62) 52
Type I 6 (60) 4 (40) 1 (10) 1 (10) 4 (40) 10
Type II 14 (35) 2 (5) 10 (25) 2 (5) 26 (65) 40
Type III 0 (0) 0 (0) 0 (0) 0 (0) 2 (100) 2
Controls (no erosion) 7 (11) 2 (3) 5 (8) 0 (0) 59 (89) 66
Erosion patients have been grouped according to the dominant type of erosion.
5.3 Etiological factors (I)
5.3.1 Herpes simplex virus
At the initial visit and at the follow-up, erosion patients and controls had a similar
prevalence of increased antibody titres to HSV (36% vs. 23%). Erosion patients
with high HSV antibody titres significantly more commonly had erosions at the
follow-up endoscopy than those with low HSV antibody titres (Figure 6).
Based on this serological evidence pointing to an association between HSV
and chronic/recurrent erosions, we sought evidence of an actual local HSV
infection by immunohistochemical staining and PCR. Specimens from erosions
taken at the follow-up visit were analysed, but no evidence for HSV was found
with either immunohistochemistry or PCR, all specimens being negative.
51
Fig. 6. Results of Herpes simplex virus (HSV) antibody test in the initial and the follow-
up visit with respect to occurrence of erosions in the follow-up visit. Total numbers of
cases and those with erosion (percentages in brackets) at the follow-up are indicated
in each column.
5.3.2 Helicobacter pylori
Erosion frequency rate was not related to the presence or absence of H. pylori infection. At the initial visit, the H. pylori-positivity rate was similar in the whole
erosion group (60%) and in the controls (65%; p = NS), and also among those
subjects available for follow-up studies (erosion group 65%; controls 73%;
p = NS; Figure 3). At the follow-up visit, H. pylori-positive were 59% of the
patients and 52% of the controls (p = NS; Figure 4).
The proportion subjects with erosions at the follow-up visit were similar in H. pylori-positive (41%, 11/27) and -negative patients (33%, 5/15; p = NS; Figure 7).
Similarly, in the control group, the erosion rate at follow-up was not related to the
presence (15%, 5/31) or absence of H. pylori (0%, 0/15; p = NS). There was no
significant difference between the erosion type and H. pylori infection at the
follow-up visit. (III).
52
Fig. 7. Distribution of the erosion types at the follow-up visit in patient and control
groups in subjects with unchanged H. pylori status.
5.3.3 Non-steroidal anti-inflammatory drug
The use of NSAIDs within one week before the initial visit was more common in
the erosion group than in the control group, but at the follow-up, the rate of use
was similar in both groups (Figure 8). Furthermore, there was no correlation with
concurrent erosions at the follow-up visit. The use of NSAID was not related with
the type of erosion. (I).
53
Fig. 8. Recent NSAID use in patient and control groups.
5.3.4 Simultaneous effects of Herpes simplex virus, Helicobacter pylori and non-steroidal anti-inflammatory drug
Some patients presented with several potential risk factors for the
chronic/recurrent erosions. The significance of simultaneous high HSV antibody
titres at the initial visit, H. pylori infection or usage of NSAID at the follow-up
visit was analysed in a pair-wise manner. However, there was no evidence for a
cumulative effect on the presence of erosions at follow-up.
We compared the influence of age, sex, HSV antibody titres (initial visit), H. pylori infection and NSAID use (preceding the follow-up visit) with the
occurrence of erosions in the follow-up endoscopy in the patient group. Using
logistic regression analysis, high HSV antibody titres proved to be the only
statistically significant factor predicting erosions at follow-up (Table 6).
54
Table 6. Occurrence of erosions at the follow-up visit in patient group analysed with
logistic regression (I: Table 2).
Variable p Odds ratio 95% CI
Age at the follow-up visit 0.7502 0.9812 0.87–1.10
Sex (M vs F) 0.8920 0.8884 0.16–4.90
Antibody titers (logarithmic value) against HSV at the initial visit 0.0038 4.8397 1.66–14.1
H. pylori in biopsy 0.4297 2.0765 0.34–12.6
NSAID used or not used within one week before the follow-up visit 0.6062 0.6516 0.13–3.32
Constant 0.1883
5.3.5 Other factors and the erosion rate
There were no major changes in the erosion rate or other factors. In the patient
group, gastric erosions were less frequent in those that had used sucralphate
recently (0/7) before the follow-up visit compared to those not using this drug
(16/35; p = 0.033). The use of alcohol, the smoking habits or the use of drugs
other than NSAIDs or sucralphate did not influence the occurrence of erosions at
follow-up in the patient group.
5.4 Histopathology of gastric antral erosions (II)
5.4.1 Comparison of inflammatory changes in the erosion and in the background antral mucosa
Table 7 shows a summary of the comparisons of the severity of main
histopathological features in the erosion samples and in the background antral
mucosa on the initial visit. An example of histopathological findings in or
adjacent to the erosion and in the background antral mucosa is shown in Figure 9.
In H. pylori-positive subjects, erosion samples exhibited more epithelial
degeneration (epithelial tufting) in the initial visit; an example case is presented in
Figure 10. The erosion samples were awarded higher scores for numbers of
neutrophils and eosinophils. On the contrary, the number of germinal centres was
lower in the erosion samples than in the antral mucosa. Erosion samples showed
more prominent vasodilatation on the initial visit. In H. pylori-negative subjects
in the initial visit, erosion samples had higher scores for neutrophils, eosinophils,
vasodilatation, foveolar hyperplasia and microscopic erosion than the antral
samples. (Table 7).
55
Table 7. Main histological features in the initial visit samples of endoscopically visible
erosion and in intact antral mucosa in H. pylori-positive (N = 52, except in glandular
atrophy N = 28) and negative (N = 31, except in glandular atrophy N = 26).
Histological feature H. pylori-positive subjects H. pylori-negative subjects
Erosion Antrum p Erosion Antrum p
Mean SD Mean SD Mean SD Mean SD
Epithelial alterations
Tufting 19 25 10 20 0.002 0.8 2.3 0.2 0.9 NS
Foveolar score 1.1 0.6 1.2 0.6 NS 1.3 0.6 0.8 0.6 0.007
Glandular atrophy 0.9 0.7 1.0 0.7 NS 0.2 0.5 0.2 0.4 NS
Intestinal metaplasia 3.9 14 4.0 12 NS 0.7 2.5 0.2 0.9 NS
Inflammatory cell reaction
Neutrophils 1.9 1.0 1.2 0.9 0.000 0.3 0.8 0.1 0.3 0.023
Eosinophils 1.6 0.8 1.1 0.8 0.000 1.0 1.0 0.3 0.6 0.005
Monon. infl. cells 2.1 0.7 2.0 0.7 NS 0.6 0.9 0.5 0.6 NS
Germinal centres 0.00 0.0 0.04 0.1 0.038 0.00 0.0 0.00 0.0 NS
Stromal changes
Fibrosis 0.8 0.7 0.7 0.6 NS 1.5 0.7 1.3 0.7 NS
Vasodilatation 0.6 0.5 0.2 0.5 0.008 1.0 0.8 0.4 0.6 0.001
Figures indicate mean scores except for epithelial tufting and intestinal metaplasia where mean extent
(%) is indicated. Differences between erosion and antral samples were compared with Wilcoxon Signed
Rank Test. Statistical comparison of H. pylori-negative and -positive subjects is described in the text.
56
Fig. 9. Photomicrographs of antral mucosa immediately adjacent to chronic/recurrent
erosion (A) and non-eroded antral mucosa (B) of the same H. pylori-positive patient,
who had recently used an NSAID. Infiltration of neutrophilic leukocytes is more
abundant in the erosion sample (A) than in non-eroded antral mucosa (B). Reference
line is 0.1 millimeters. Hematoxylin-Eosin staining. (II:Fig 2).
Fig. 10. Photomicrograph of epithelial tufting in antral mucosa of a H. pylori-positive
patient (A). Another H. pylori-positive patient, but without evidence of epithelial tufting
(B). Reference line is 0.1 millimetres. Hematoxylin-Eosin staining.
At the initial visit, there was a correlation between the erosion and the
background mucosa samples in the intensity of inflammation and in the severity
57
of epithelial degeneration in both H. pylori-negative and positive patients.
(Spearman rank correlation, data not shown).
5.4.2 Role of Helicobacter pylori on histopathology of erosions
On both visits, the erosions of the H. pylori-positive subjects showed significantly
stronger intensity of inflammation compared to H. pylori-negative subjects, and
on the initial visit, they also had significantly more severe epithelial degeneration,
while H. pylori-negative subjects displayed significantly clearer stromal changes
(Table 7).
5.4.3 Role of non-steroidal anti-inflammatory drugs on the histopathology of erosions
Those H. pylori-positive patients that had recently used NSAIDs, had a
significantly higher score of neutrophils in their erosion samples compared to
those who had not used these drugs at the initial visit (Figure 11).
At the initial visit, those H. pylori-negative patients that had recently used
NSAIDs had a lower score (0.8; N = 12) of foveolar hyperplasia in the erosion
samples compared to non-NSAID users (1.5; N = 16; p = 0.015). At the initial
visit, H. pylori-positive subjects that had recently used NSAIDs, displayed a
greater difference (-0.7; N = 10) in the grade of atrophy between the erosion
sample and antral mucosa than those who had not recently used NSAIDs (-0.2; N
= 18; p = 0.010).
58
Fig. 11. Comparison of neutrophil scores in the erosion samples and in the
background antral mucosa with respect to recent use of NSAID in H. pylori-infected
patients at the initial visit. Mean score (box) and standard deviation (thin bar) are
shown.
5.4.4 Role of Herpes simplex seropositivity on the histopathology of erosions
At the initial visit among H. pylori-positives, patients with high levels of HSV
antibodies exhibited a higher score of neutrophils in the erosion samples than
those patients with a low titre of these antibodies (Figure 12). A similar trend was
seen in the background mucosa (Figure 12). No such difference emerged at the
follow-up visit, probably due to the small number of cases (data not shown).
59
Fig. 12. Comparison of neutrophil scores in the erosion samples and in the
background antral mucosa with respect to antibody titres to H. simplex virus in
Helicobacter pylori infected patients at the initial visit. Mean score (box) and standard
deviation (thin bar) are shown.
5.4.5 Relationship of histopathological features in erosions and the chronicity/recurrence of the erosions
In the H. pylori-positive patients, a high degree of active inflammation in the
erosion sample predicted chronicity/recurrence of the erosions (Figure 13). In H. pylori-negative subjects, histopathological features did not display any predictive
value.
5.4.6 Histopathological features in erosions and the risk for the development of peptic ulcer or gastric malignancy
At the initial visit, no single significant difference emerged in the histopathology
that would have identified those patients who would develop peptic ulcer.
No intraepithelial neoplastic changes were present in the initial visit erosion
biopsies.
60
Fig. 13. Neutrophil scores in the erosion samples and in the background antral
mucosa in patients with non-chronic/non-recurrent (erosion in the initial visit only)
and chronic/recurrent (erosion at both visits) erosions in Helicobacter pylori-infected
patients. Mean score (box) and standard deviation (thin bar) are shown. (II: Fig. 3).
5.5 Progression of gastritis in patients with gastric erosions (III)
Main features of gastritis and their evolution in the erosion group and in the
controls are summarized in Tables 8 and 9.
61
Table 8. Main histological features in the antral mucosa in erosion patients and
controls in the initial and the follow-up visit about 17 years later. Statistical
comparison is described in detail in the text. (III: Table I).
Histological feature Helicobacter pylori positive Helicobacter pylori negative
Patients Controls Patients Controls
Initial
visit
N = 27
Follow-
up visit
N = 26
Initial
visit
N = 29
Follow-
up visit
N = 31
Initial
visit
N = 14
Follow-
up visit
N = 15
Initial
visit
N = 14
Follow-
up visit
N = 15
Atrophy† 0.8(0.8) 1.1(0.6) 1.0(0.6) 1.2(0.5) 0.3(0.5) 0.2(0.4) 0.1(0.3) 0.1(0.3)
Gastritis† 1.9(0.7) 2.4(0.8) 2.0(0.8) 2.2(0.7) 0.6(0.6) 0.4(6) 0.4(0.9) 0.3(0.6)
Activity† 1.3(0.9) 1.6(0.8) 1.5(0.8) 1.2(0.8) 0.0(0.0) 0.0(0.0) 0.1(0.3) 0.1(0.3)
Intestinal metaplasia‡ 3(11) 6(23) 1(3) 10(32) 2(14) 2(13) 0(0) 0(0)
Microscopic erosion‡ 5(19) 7(27) 7(24) 3(10) 0(0) 1(7) 0(0) 0(0)
Tufting‡ 11(41) 8(31) 11(38) 12(39) 1(7) 1(7) 0(0) 1(7)
† Mean and standard deviation (in parentheses)
‡ The number of cases showing the abnormality (percent in parentheses)
Table 9. Main histological features in the body mucosa in erosion patients and
controls in the initial and the follow-up visit about 17 years later. Statistical
comparison is described in detail in the text. (III: Table II).
Histological feature Helicobacter pylori positive Helicobacter pylori negative
Patients Controls Patients Controls
Initial
visit
N = 27
Follow-
up visit
N = 26
Initial
visit
N = 29
Follow-
up visit
N = 31
Initial
visit
N = 14
Follow-
up visit
N = 15
Initial
visit
N = 14
Follow-up
visit
N = 15
Atrophy† 0.1(0.3) 0.4(0.6) 0.2(0.4) 0.7(0.8) 0.6(1.3) 0.6(1.2) 0.3(0.8) 0.2(0.8)
Gastritis† 1.8(0.6) 1.9(0.8) 1.9(0.6) 2.3(0.6) 0.8(0.9) 0.5(0.8) 0.7(1.0) 0.4(0.9)
Activity† 0.6(0.7) 0.7(0.8) 1.1(0.9) 1.1(0.9) 0.1(0.3) 0.0(0.0) 0.3(0.6) 0.1(0.3)
Intestinal metaplasia‡ 0(0) 1(4) 1(3) 9(29) 2(14) 3(20) 0(0) 1(7)
Microscopic erosion‡ 1(4) 1(4) 6(20) 9(29) 1(7) 0(0) 0(0) 0(0)
Tufting‡ 7(29) 5(9) 9(30) 17(55) 0(0) 0(0) 0(0) 0(0) † Mean and standard deviation (in parentheses) ‡ The number of cases showing the abnormality (percent in parentheses)
5.5.1 Severity of chronic gastritis
In the H. pylori-positive subjects, the severity of gastritis (scores of mononuclear
cells) was similar in erosion patients and controls in the initial visit (Tables 8 and
9). At the follow-up visit, the severity had increased in the antral mucosa in the
patient group (erosion at the initial visit) and in the body in the controls, but no
62
significant differences were detected between the groups. In H. pylori-negative
subjects, the amount of mononuclear cells of gastric mucosa was low on both
visits. (Figure 14).
Fig. 14. Evolution of chronic gastritis in erosion patients (double lines) and controls
(single lines). Mean degree of chronic gastritis at the initial visit and after nearly 20
years’ of follow-up. (III: Fig. 2).
5.5.2 Activity of gastritis
In the body mucosa, no dynamic activity changes developed, but in the antrum
there was a trend towards more neutrophils in patients compared to controls,
among H. pylori-infected subjects.
On the initial visit if one considered only the H. pylori-positive subjects, then
the patients showed a lower score (0.56 ± 0.65) for neutrophilic leucocytes in the
body mucosa than controls (1.07 ± 0.91; p = 0.035). Initially, there were no
significant differences in the antral mucosa. At the follow-up visit, activity
displayed a non-significant increase in the patient group, while the controls
showed a non-significant decrease. These changes resulted in a trend toward
patients having more neutrophils in the antrum (1.58 ± 0.76) compared to controls
(1.19 ± 0.83; p = 0.060). In H. pylori-negative subjects, the gastric mucosal
neutrophils were largely absent and displayed no temporal changes. (Table 8 and
9; Figure 15).
63
Fig. 15. Evolution of active gastritis in erosion patients (double lines) and controls
(single lines). Mean degree of activity of gastritis at the initial visit and after nearly 20
years’ of follow-up. (III: Fig. 3).
5.5.3 Atrophic changes, intestinal metaplasia and dysplasia
H. pylori-infected patients showed less inflammation in body mucosa compared
to controls, and a trend toward less atrophy in the body. Some intestinal
metaplasia appeared only in H. pylori-infected controls, but not in patients.
Intraepithelial neoplasia – all mild and of the intestinal metaplasia type – was a
rarity.
On the initial visit, the grade of atrophy in H. pylori infected subjects did not
show any significant differences between patients and controls. Different erosion
types did not reveal any significant differences in any histological parameters of
gastritis (data not shown). At the follow-up visit, antral mucosa showed no
significant changes in the degree of atrophy, but body mucosa displayed an
increase, which was more evident in the control group (p = 0.002). Accordingly,
at the follow-up visit, controls showed more severe atrophy than patients
(p = 0.079). In H. pylori-negative subjects, the atrophic changes in the antrum
had been almost absent in the initial visit and remained low during follow-up.
However, even in the H. pylori-negative group, occasional subjects showed
atrophic changes in the corpus mucosa. (Tables 8 and 9; Figure 16).
64
Fig. 16. Evolution of atrophic changes in erosion patients (double lines) and controls
(single lines). Mean degree of atrophy at the initial visit and after nearly 20 years’ of
follow-up. (III: Fig. 1).
At the initial visit, there were no significant differences in prevalence of intestinal
metaplasia between patients and controls. At follow-up, H. pylori-positive
controls showed an increase in the extent of intestinal metaplasia both in the
antrum (mean % +/-SD from 1.4 % ± 7.4 to 7.4 % ± 15.4; p = 0.005) and the
body (from 0.7 % ± 3.7 to 4.5 % ± 10.3; p = 0.007). In the patient group, no
significant changes were seen. At the follow-up visit, H. pylori-positive controls
showed more prevalent intestinal metaplasia in the body mucosa than patients
(p = 0.014). In H. pylori-negative subjects, no significant differences emerged.
(Tables 8 and 9).
At the initial visit, only one patient showed intraepithelial neoplasia in the
intestinal metaplastic epithelium, but none of controls. At the follow-up visit,
intraepithelial neoplasia was found in two patients and in one control (p = NS). In
all cases, intraepithelial neoplasia was graded as being mild.
5.5.4 Microscopic erosions and epithelial reactive changes
The presence of microscopic erosions was assessed in both antral and body
biopsies taken outwith endoscopically visible erosions.
At the initial visit, the presence or score of microscopic erosions did not
differ significantly between the groups. In addition, there was no significant
65
evolution in either group. However, in the follow-up visit, H. pylori-positive
controls showed a higher prevalence and higher score for microscopic erosions in
the body mucosa (p = 0.012; Figure 17), while patients showed higher figures
than controls in the antral mucosa (score 0.42 ± 0.86 vs. 0.10 ± 0.30; p = 0.079).
Epithelial tufting exhibited a similar pattern, a significant difference between
patients and controls, emerging at the follow-up visit in the body mucosa. Among
H. pylori-positive subjects, patients showed a lower prevalence (p = 0.007) and
less extensive epithelial tufting (1.7 ± 4.4 vs. 10.5 ± 14.6; p = 0.002) than
controls. At both visits, both microscopic erosions and epithelial tufting were rare
and there were no significant differences between the groups in H. pylori-negative
subjects. (Tables 8 and 9).
Fig. 17. Evolution of microscopic erosions in the corpus mucosa in patients (double
lines) and controls (single lines). Mean degree of microscopic erosions at the initial
visit and after nearly 20 years’ of follow-up. (III: Fig. 4).
5.5.5 Non-steroidal anti-inflammatory drug use and features of gastritis
Recent use of NSAID before the initial visit had no effect on any severity
parameters assessing gastritis, in H. pylori-positive or negative subjects in either
of the groups.
66
5.5.6 Parietal cell antibodies
Among the H. pylori-positives, controls possessed more often parietal cell
antibodies (23 %; 7/31) than patients (0%; 0/26; p = 0.01). In H. pylori-negatives,
parietal cell antibodies were detected in 31% (4/13) of controls and in 7 % (1/15,
p = NS) of patients.
5.5.7 Ulcer development during the follow-up
In patients with an ulcer or scar, the activity of gastritis in the antrum increased
from 1.33 to 1.88 (p = 0.034), and also chronic gastritis showed a trend towards
an increase (from 1.78 to 2.50; p = 0.063).
5.6 Clinical features, ulcer and malignancy
5.6.1 Endoscopical findings
At the follow-up visit, the patients were more likely to show signs of an active
peptic ulcer or the scar of a healed peptic ulcer (17%; 9/52) than the controls (5%;
3/66; p = 0.031). Among the H. pylori-positive subjects, the risk was significantly
higher in the patient group than in the controls (Figure 18). Patients and controls
exhibited no other significant differences concerning other endoscopic findings
(IV: Table 2). At the follow-up visit, most patients with concurrent ulcer or scar
had recently used NSAIDs (67%, 6/9), whereas for those controls with concurrent
ulcer or scar, two of three were H. pylori-positive and one of three had recently
used NSAID.
5.6.2 Symptoms and other clinical data
At the initial visit, the patients showed more common upper abdominal pain
(100%; 54/54) than the controls (91%; 64/70; p = 0.035). At the follow-up visit,
the patients and the controls showed equal frequencies (70%) of dyspepsia or
upper abdominal pain (patients 37/53; controls 49/70). At the follow-up, the
presence or type of erosions showed no relationship with symptoms.
67
Among the H. pylori-infected patients, those who recently had used an
NSAID before follow-up visit, 54% (7/13) had motility type dyspepsia, while
only 8% (1/12) of those who had not recently used an NSAID, showed this type
of dyspepsia (p = 0.03).
Fig. 18. Ulcer risk at follow-up visit in the patient and the control groups in originally H. pylori-negatives and -positives.
On both visits no significant differences emerged between the patients and the
controls in laboratory parameters, or between the subjects with or without current
erosion at the follow-up-visit.
5.6.3 Surgical operations and other diseases
In all, showed 6% (3/54) of the patient group had undergone gastric surgery,
whereas only one individual (1%; 1 of 69) in the control group had required this
kind of surgical treatment (p = NS). One fatal haemorrhage due to a gastric ulcer
68
occurred in the control group, but none in the patient group. The patient group
suffered less often from rheumatoid arthritis (0%; 0/54) than the control group
(10%; 7/69; p = 0.018), but none of these individuals showed sings of erosions at
the follow-up visit. No other significant differences were noted in the incidence of
other diseases. No significant differences emerged between the groups regarding
diseases in close relatives.
5.6.4 Occurrence of malignancies, mortality, and causes of death
The patient group showed a significantly lower incidence of malignancy (5%;
6/117) than the controls (15%; 17/117) during the 16 years of follow-up
(p = 0.0247). During the follow-up, in the patient group there were three cases of
lung cancer, one of kidney cancer and one of prostate cancer, and a simultaneous
case with a gastric carcinoid tumour and an oesophageal cancer. In the control
group, there were four cases of breast cancer, three rectal, two uterine, one gastric,
one lung, one ovarian, one prostate, one kidney, one skin and one central nervous
system cancer, and one unspecified carcinoma. The incidence of malignancy was
not influenced by smoking habits.
During the 16 years of follow-up, no significant differences emerged in the
mortality (19%; 22 of 117 of the patients and 22%; 26 of 117 of the controls;
p = NS). Two deaths in the patient group (9%) and six deaths (23%) in the control
group were caused by malignancy (p = NS). One death occurred due to GI
haemorrhage in the control group.
69
6 Discussion
This is the first long-term follow-up study addressing the clinical significance and
pathology of gastric erosions. Nearly twenty years of follow-up revealed that the
erosions are chronic or recurrent in more than one third of the cases. The current
study also demonstrates that there is a significant association between increased
HSV antibody titres and gastric erosions - especially with chronic or recurrent
erosions. This suggests that a significant proportion of chronic gastric erosions is
related to HSV infection. In H. pylori-positive patients, this study also supports
the importance of H. pylori and gastric acid in the pathogenesis of
chronic/recurrent gastric erosions. In addition, focally enhanced inflammation,
perhaps evoked by HSV infection or NSAID use, may be important in the
pathogenesis. Active inflammation in the erosions predicted their chronicity or
recurrence, as did the high HSV antibody titres. In addition, in H. pylori-positive
subjects with gastric erosions, this study observed that gastritis shows an
evolution towards antral predominance, whereas a body predominance, including
the development of atrophic changes, is rare. Accordingly, H. pylori-positive
patients with erosions display the characteristics of gastritis of the duodenal ulcer
phenotype. Finally, chronic or recurrent erosions are mostly without serious
complications. However, H. pylori-positive patients with erosions are at a
significant risk of developing peptic ulcer, highlighting the benefits of eradication
therapy.
6.1 Methodological aspects
We succeeded, despite the very long follow-up time, to persuade half of the
subjects to come to the follow-up visit. Such a long follow-up time in originally
middle-aged subjects results in a high amount of diseases and marked mortality
rate.
Patients may not remember past symptoms over such a long time and this
may influence the results. For example, the use of medications, eradication
treatment against H. pylori – may be forgotten during the long follow-up period.
Only a few experienced endoscopists participated in this study. The same
endoscopist examined a marked proportion of the same patients on both visits.
The endoscopy systems have also developed substantially from fiberoptic systems
to video based systems, and a more precise description can now be done. It
70
remains undecided, whether these kinds of methological development have
affected the erosion detection rate.
The histological samples were not similarly representative in the late
seventies as compared with the nineties. The number of sampling containers,
specimen size, and the preparation of samples have changed during that time.
However, with re-examination of samples, it was possible to use modern criteria
of examination for both visits. The reproducibility of histological grading of the
inflammation between pathologists is not excellent (Talebkhan et al. 2009).
Furthermore,κvalues between pathologists classifying gastric mucosa atrophy
have been reported to vary from poor (0.37) to excellent (Rugge et al. 2002). To
avoid this bias, the same experienced pathologist reanalysed all samples.
If erosions were detected again after 19 years either they are chronic – that is
they are present all the time – or recurrent, i.e. they exist now and then. It is not
possible to draw any conclusions about this by assessing the location of erosions
due to their small size and multiplicity. Peptic ulcer is recurrent disease and the
same is the case with erosions. Perhaps erosions should be perceived as a
condition, in which there is an underlying predisposition towards having erosions.
Thus erosions may not always be present at any given moment, but because of
some underlying predisposition, they may reappear at other times.
It was possible to re-endoscope 44% (52 of 117) patients and 57% (67 of 117)
controls. Aging and chronic diseases in the study persons were probably major
reasons to explain why some subjects were unable to attend the study, and in
addition, there were several deaths prior to the planned follow-up visit. Patients,
who had changed their H. pylori status between visits, would have complicated
the study, and in addition, there were some persons receiving anticoagulation
therapy, which were two other reasons, which reduced the final study groups to
36% (42 of 117) and 39% (46 of 117) respectively.
6.2 Aetiology and pathogenesis of chronic/recurrent gastric erosions
The aetiology of gastric erosions seems to be multifactorial and a complete
understanding of the various contributing factors as well as their interactions and
mechanisms are largely unknown. Both chemicals, such as use of NSAIDs or
alcohol or cigarette smoking, and diseases, including H. pylori and HSV
infections and diseases leading to hyperacidity, might be involved in the
pathogenesis of this disorder (Bernersen et al. 1992, Karvonen & Lehtola 1983,
71
Lehtola et al. 1988, O'Laughlin et al. 1981). Long lasting follow-up studies,
which would evaluate the relationship of these factors with chronic/recurrent
gastric erosions, are lacking. One of the strengths of this study is that half of 234
subjects from the original cohort could be examined after a mean follow-up of
almost 20 years.
Exclusively high titres of antibodies against HSV exhibited a significant
association with chronic/recurrent gastric erosions. This suggests that HSV may
be at least part of the reason for a subset of gastric erosions and furthermore that
these erosions may, as a consequence, become chronic or recurrent. However,
immunohistochemistry and PCR of erosion biopsies failed to reveal any HSV
antigen or DNA. One must ask the question, what is the reason for this
contradiction? The most obvious explanation is that HSV is not present in the
erosion itself, as demonstrated here, but may reside in the submucosal ganglia but
still cause mucosal defects (Gesser et al. 1995). Therefore, specimens
representing the entire thickness of the gastric wall might be necessary to further
analyse the relationship between HSV and gastric erosions.
The role of HSV in the pathogenesis of gastroduodenal ulcers is still unclear.
Molecular biological methods have detected HSV DNA in a minority (less than
10%) of gastroduodenal ulcers (Kemker et al. 1992). The results of HSV serology
in peptic ulcer are not convincing (Archimandritis et al. 1992, Kottaridis et al. 1989). Oral inoculation with HSV-1 induced multiple gastric ulcers in about half
of animals in an immunodeficient mice model. In this study, the viral antigen was
rarely found in the ulcer, but in all ulcers located near to the virus-infected ganglia,
suggesting that the mucosal defects are related to the HSV infection (Gesser et al. 1995). HSV-1 is commonly first encountered during childhood as an oral
infection, but after this primary infection has resolved, the virus usually stays in a
latent form within the neural ganglia, to be activated later in some patients
(Gesser & Koo 1996).
H. pylori-positive patients with high HSV antibody titres had higher
neutrophil scores in the erosion samples than patients with low titres. However,
the high HSV antibody titres were not significantly associated with the intensity
of inflammation in the background antral mucosa. This suggests that HSV
infection associates with focally enhanced inflammation in the antral mucosa.
In the follow-up examination, the presence of H. pylori infection was not
significantly associated with the presence of gastric erosions. The current study
does not support the theory that H. pylori plays a crucial role in the pathogenesis
72
of chronic gastric erosions. However, the exclusion of the ulcer patients from the
study may have caused exclusions of some erosions possibly caused by H. pylori. Another important factor in the pathogenesis of gastric erosions is thought to
be the use of NSAIDs (O'Laughlin et al. 1981). Erosions were to some extent
associated with the use of NSAIDs. Recent use of NSAIDs was significantly
more common in patients with erosions than in controls at the initial visit, but at
the follow-up visit, the use of NSAIDs did not associate with erosions. NSAIDs
may cause acute or subacute erosions, even symptomatic erosions, leading to a
need for a diagnostic gastroscopy, as was the case in patients before the initial
gastroscopy in the current study (O'Laughlin et al. 1981). This injurious effect
might diminish after long-term use of NSAID (Graham et al. 1983).
The results of the current study do not support the hypothesis that H. pylori or
HSV infection can influence the occurrence of NSAID associated gastric erosions.
In patients using NSAIDs, the significance of H. pylori infection is controversial.
It has been reported that H. pylori-positive patients using NSAID may develop
erosions and ulcers more often than H. pylori-negative patients (Taha et al. 1995).
However, in other studies examining patients using NSAIDs, erosive lesions in
the gastric mucosa were less common in H. pylori-positive patients than in H. pylori-negative individuals (Graham et al. 1991, Hart et al. 2010). One possible
protective mechanism is the induction of prostaglandin synthesis in response to H. pylori infection. In addition, H. pylori infection can lead to loss of parietal cells
and the stomach will become less acidic. Gastric acid itself has been reported to
be an essential factor in NSAID induced gastric erosions. (Elliott et al. 1996, Hart et al. 2010, Hudson et al. 1993).
In the current study, significantly less foveolar hyperplasia was observed in
the erosions of NSAID users in H. pylori-negative patients, i.e. the regenerative
capacity of the epithelium might have been suppressed by these drugs (Leung et al. 2000). This is supported by another finding in which NSAID associated gastric
ulcer patients had more often moderate/severe foveolar hyperplasia than H. pylori-infected controls without ulcers (Haber & Lopez 1999).
In conclusion, a significant association was found between the increase in the
HSV antibody titres and gastric erosions, and with chronic or recurrent erosions.
In contrast, H. pylori infection, use of NSAID or alcohol did not show any
apparent associations with chronicity. According to these observations, HSV
infection may be responsible for a substantial proportion of chronic/recurrent
gastric erosions. In order to clarify the role of local HSV infection, further studies
should be performed to confirm the topographical association of mucosal defects
73
and HSV virus in the nervous ganglia of the gastric wall. Antiviral treatment trials
may also provide useful information.
6.3 Histopathology of chronic/recurrent gastric erosions
The observations in the current study indicate that in H. pylori-positive subjects
there is more active inflammation in the biopsies of erosions than in the
background antral mucosa. In H. pylori-positive subjects, both a high antibody
level to HSV and the use of NSAIDs were linked with this focally enhanced
inflammation. Stromal changes were a characteristic found in the erosion samples
from H. pylori-negative patients. In H. pylori-positive subjects, the presence of
highly active inflammation in erosions seemed to pose a risk of chronicity or
recurrence of erosions after 19 years. These findings may help in understanding
the pathogenesis of gastric erosions and in identifying factors affecting their
prognosis.
A positive correlation in the intensity of inflammation was observed between
erosion and the surrounding mucosa. This suggests that well-known factors
affecting the intensity of gastritis, such as polymorphisms in the host genes
regulating the mucosal immune system and the virulence of H. pylori strain, can
similarly influence the extent of inflammation in the erosions and the surrounding
mucosa (Koivurova et al. 2003, Suerbaum & Josenhans 2007). These factors still
do not explain the observation that there was a difference between the
inflammation activity at the erosion and in the surrounding mucosa. Two potential
mechanisms exist that could explain why more severe inflammation occurred in
the mucosa of erosion samples than in the surrounding mucosa. First, during the
development of the erosion, the local inflammatory response is secondarily
enhanced by the response to tissue destruction (Tarnawski 2005). Second, there
could be pre-existing structural or functional abnormalities present at the site of
erosion, even before the development of the erosion, which either evoke intense
local inflammation or become manifest in their own right.
In the erosion samples of H. pylori-positive patients, high HSV antibody
titres were associated with higher neutrophil scores than patients with low titres,
but no such difference was seen in the background antral mucosa. Accordingly,
HSV infection seems to associate with focally enhanced inflammation in the
antral mucosa. One possible explanation is that infection of autonomic ganglia
interferes with the mucosal innervation, and, then due to insufficient anti-
inflammatory neural signalling, this evokes intense focal inflammation and then
74
erosion (Borovikova et al. 2000, Croen et al. 1987, Gallowitsch-Puerta & Pavlov
2007, Gesser & Koo 1997). This is speculative, as the presence of a ganglial HSV
infection was not studied in the current study.
In the erosion samples in H. pylori-positive patients, NSAID users had more
intensive infiltration of neutrophils compared to nonusers. This indicates that the
use of an NSAID may worsen pre-existent inflammation and supports the
importance of neutrophils in the development NSAID related gastric lesions
(Wallace et al. 1990). In H. pylori-negative patients, NSAID users showed
significantly less foveolar hyperplasia in the erosions than nonusers, i.e. these
drugs might suppress the regenerative capacity of the epithelium (Leung et al. 2000).
At the initial visit, H. pylori-positive patients, chronic/recurrent antral
erosions showed higher scores of neutrophils compared to non-chronic/non-
recurrent erosions. This suggests that highly active inflammation in the erosion
either predisposes an individual to recurrence or impedes healing of the erosions.
In conclusion, antral erosions with strong neutrophilic reaction associate with
a tendency for chronicity/recurrence. This study revealed that the use of NSAIDs
and seropositivity for HSV are associated with focally highly active inflammation
in the region of erosion in H. pylori-positive subjects. This supports the role of
these factors in the pathogenesis of gastric erosions, emphasizing the importance
of local regulation of inflammation and the role of neutrophils in the pathogenetic
cascade leading to erosions.
6.4 Progression of gastritis in patients with chronic or recurrent
gastric erosions
In patients with and without gastric erosions, the cross-sectional and longitudinal
results indicate that the features and evolution of gastritis are different. The main
factor affecting gastric histology in both the cross-sectional and dynamic respects
was H. pylori infection. In H. pylori-negative subjects chronic gastritis was absent
in most cases regardless of the erosion status, and there was no association with
NSAID use or histological reactive gastritis.
In H. pylori-positive erosion patients, the body mucosa initially showed some
features indicative of less intensive inflammation than controls. These patients
showed a trend towards a lower degree of atrophy and significantly fewer
neutrophilic leucocytes in the body than controls. Miyake et al. (2005) found that
the mean activity score of the corpus was significantly higher in those ulcer
75
patients that developed gastric erosion after H. pylori eradication compared to
those who did not develop erosion. In the current study, patients with erosion and
controls exhibited no significant differences in activity score of the corpus in
those, which developed gastric erosion at the follow-up visit (data not shown).
Stolte et al. (1999) examined H. pylori-infected subjects and noted that patients
with complete erosion show more active and severe antral gastritis than subjects
without erosions, while no differences were seen in the body mucosa. These
findings in subjects with gastric erosions are in agreement with the results of
Stolte et al. in pointing to the importance of antral predominance of H. pylori gastritis, although the current study did not detect significant differences in the
antral mucosa.
The evolution of gastritis revealed differences, with the severity of antral
gastritis increasing in the erosion patients, and body gastritis with atrophic
changes in the controls. In subjects with erosions, these differences could be
related to the low prevalence of autoimmune-mediated gastric body destruction,
as shown by the infrequent occurrence of parietal cell antibodies.
The clinical importance of the topographic types of gastritis lies in the pattern
of complications associated with each type as shown by previous studies
(Sipponen 2001). Atrophy and other features of inflammation are associated with
each pattern and this may have prognostic significance. Accordingly, antrum
predominant gastritis is associated with the risk of peptic ulcer disease and antral
atrophy, and in addition, intestinal metaplasia and more severe activity in the
antrum compared to body mucosa (Sipponen 2001). This pattern of antral gastritis
reveals marked degenerative and regenerative alterations in the surface epithelium
(Sipponen 2001). In patients with duodenal ulcer, follow-up studies have shown
that this antral predominant pattern can remain stable for up to 32 years without
the development of body atrophy (Valle et al. 1996). On the other hand, patients
with gastric ulcer are suffering from a more progressive form of body gastritis
than non-ulcer subjects (Valle et al. 1996). It has been estimated that the
prevalence of body atrophic gastritis shows an annual increase of about 1 to 3%
(Correa et al. 1990, Ihamäki et al. 1985, Kuipers et al. 1995, Villako et al. 1991).
In H. pylori-positive patients with gastric erosions, the pattern and dynamics
of gastritis share several features in common with the antrum predominant
gastritis associated with the peptic ulcer risk described in other studies (Sipponen
2001, Valle et al. 1996). At follow-up, 17% of the subjects in the erosion group
had peptic ulcer or scar, all being H. pylori-positive. Originally, the features of
gastritis in this subgroup that developed ulcer did not differ from other patients
76
with erosions, but during the follow-up, an increase in the activity of antrum
gastritis was seen. This suggests that in this subgroup the evolution of gastritis is
even more antrum predominant than in erosion patients that do not develop ulcer.
The reasons for the variation in outcomes of H. pylori infection are not clear.
Differences in the genetically determined host response, such as interleukin-1
polymorphism, and virulence of H. pylori strain might be factors that determine
why some individuals infected with H. pylori develop gastric cancer or duodenal
ulcer, while others do not (Blaser et al. 1995, El-Omar et al. 2000, Garcia-
Gonzalez et al. 2001, Nomura et al. 2002). Based on morphological and
immunological observations of gastritis in H. pylori-positive patients observed in
this study, those genotypes that associate with body-predominant gastritis might
protect from erosions. Since erosive oesophagitis in H. pylori-negative subjects
has been associated with the same pro-inflammatory genotypes as those
associated with body predominant gastritis, similar genotypes might be involved
in promoting erosions in H. pylori-negative subjects (Koivurova et al. 2003).
The detailed pathogenesis of endoscopically visible erosions has not been
clarified. Evidence for epithelial defects and degeneration outside of endoscopic
erosions, such as microscopic erosions seen as single-cell dropouts in biopsy
specimen and epithelial cell tufting, could associate with the endoscopically
visible erosions in the same gastric region (Chan et al. 1991, Leung et al. 1992).
Most macroscopic erosions were located in the antral mucosa, but the occurrence
and extent of microscopic erosions or epithelial tufting did not associate with the
presence of endoscopically visible erosions. In addition, both epithelial tufting
and microerosions in the body mucosa were more abundant in the controls than in
patients with erosions. Altogether, this suggests that microerosions and epithelial
tufting are more related to the topographic type of H. pylori gastritis than to the
development of erosions.
This study provides evidence for the importance of the topographic
phenotype of H. pylori-associated gastritis in the development of gastric erosions.
In addition, the development of an autoimmune reaction against body mucosa and
the development of atrophic changes associate with a low prevalence of erosions.
These findings pointing to the importance of gastric acid secretion are in
agreement with reports indicating that after eradication of H. pylori, the increased
risk of gastric erosions can be controlled by acid suppression therapy (Miyake et al. 2002).
In conclusion, the current study indicates that H. pylori-positive subjects with
gastric erosion exhibit dynamic characteristics of gastritis of duodenal ulcer
77
phenotype and that the development of body predominant gastritis is rare. This
highlights the importance of H. pylori infection and acid in the pathogenesis of
gastric erosions in H. pylori-positive patients. Histological gastritis was virtually
absent in H. pylori-negative patients with gastric erosions, and other pathogenetic
factors need to be considered.
6.5 Clinical outcome of patients with gastric erosion
The results of nearly twenty years of follow-up show that in more than one third
of the cases, erosions are chronic or recurrent, and peptic ulcers develop in about
every sixth patient with erosions. Apart from the increased peptic ulcer risk in
erosion patients infected with H. pylori, gastric erosions do not seem to be
associated with an increased risk of local complications or other types of
morbidity as compared to dyspeptic patients without erosions. Therefore, these
results support the view that gastric erosions are often chronic or recurrent, but
nonetheless a clinically harmless condition, except for the significantly elevated
risk of peptic ulcer disease.
The finding of the high prevalence of persistent or recurrent erosions is in
agreement with previous follow-up studies of shorter duration. One publication
with about a six-year follow-up stated that erosions were detectable in 34% of
cases (Karvonen & Lehtola 1984).
Bleeding is an important complication of gastric erosions (Laine & Weinstein
1988, Silverstein et al. 1981). In this study, erosion patients reported no clinical
history of GI bleeding during the follow-up. In addition, no differences between
the groups, or between patients with and without concurrent erosion were seen in
blood haemoglobin concentrations at the follow-up visit, indicating that clinically
significant bleeding is rare. However, no subjects with haemorrhagic erosions
(type III) were available for follow-up, and these individuals are possibly more
prone to bleed significantly, and the long-term outcome of these types of lesions
remains unknown. Furthermore, without constant monitoring for occult faecal
blood, the occurrence of slight or temporary bleeding cannot be excluded.
The type of erosion seems to be rather stable, as about 70% of erosions
presented with the original type erosion. The erosion type had changed in about
30% of the cases, but the number of cases is too small to allow a proper analysis
of evolutionary sequences. The type of erosions changed in only about 5% of
cases in an earlier follow-up for a maximum of six years (Karvonen & Lehtola
1984).
78
None of subjects in this study had peptic ulcer at the initial visit; this was one
of the exclusion criteria. At the follow-up, 17% (9/52) of patients in the erosion
group had developed an active ulcer or scar. They were all H. pylori-positive and
most (67%; 6/9) had recently used NSAID medications. This suggests that
erosions, especially in H. pylori-positive patients or in patients using NSAIDs, are
associated with a significant risk of peptic ulcer. The presence of erosions showed
no significant association with H. pylori infection, and this seemed to indicate that
H. pylori does not play any major role in the pathogenesis of chronic or recurrent
gastric erosions. However, erosion patients presenting with concurrent peptic
ulcer disease were initially excluded and this may have caused exclusion of the
kinds of erosions which are with more evidently associated etiologically with H. pylori. Another factor explaining the absence of any association with H. pylori might be the high prevalence of this infection and in this respect there was no
difference between the groups, which is likely related to the high prevalence of
infection in the Finnish population almost 30 years ago (Kosunen et al. 1997). As
the prevalence of H. pylori ulcers has become less common, the NSAID-induced
ulcers have become proportionally more common. Nonetheless, the results of the
current study favour eradication of H. pylori in patients with gastric erosions.
Four subjects (two patients and two controls) that originally were categorised
as H. pylori-negative, converted to being positive during the follow-up. This H. pylori finding may have been a false negative in the initial visit, or new, true
infection finding in the follow-up visit. A false negative finding can be due to acid
suppression therapy, use of antibiotics, atrophy of gastric mucosa or possibly
from poorly preserved histological samples. At the time of the initial visit, there
were only limited possibilities to receive acid suppression therapy; according to
study protocol two of these 4 subjects had used an antacid within one month
before the initial visit but none had used any antibiotics in that time period. One
control subject showed atrophy in both antral and corpus mucosa, but
interestingly, all the four subjects were suffering from chronic gastritis, which in
turn may point to the possibility of false negative finding. H. pylori is commonly
acquired in childhood (Rowland et al. 2006). A finding of an H. pylori infection
that has been apparently first acquired in adulthood, should be interpreted with
caution as has been proposed in the literature (Weck & Brenner 2011). Re-
infection with H. pylori in adulthood occurs in a minority of subjects after
eradication of H. pylori; one potential re-infection mechanism is that H. pylori spreads from the oral cavity where H. pylori have been detected (Rasmussen et al. 2010). At the time of initial endoscopy, disinfection of the endoscope was done
79
manually, and endoscopic transmission cannot be excluded (Wu et al. 1996).
Overall, the suspicion must be that these were false negative findings.
It is not known for sure whether gastric erosions are related to symptoms.
Originally in this study, all patients and controls were examined for dyspeptic
symptoms or upper abdominal pain. At the initial visit, upper abdominal pain was
slightly more often experienced by the patients than the controls. However at the
follow-up visit, the prevalence of symptoms was similar (70% in both groups).
Furthermore at the follow-up visit, no differences in the pattern of symptoms
between the groups or any relationship to concurrent erosions could be seen.
Lehmann et al. (2000) examined asymptomatic volunteers and detected an 8%
gastric erosion prevalence. These observations indicate that the gastric erosions
may be asymptomatic or related with dyspeptic symptoms or pain, but the
symptom pattern does not help in the identification of the subject with erosions or
erosions with a tendency towards chronicity or recurrence.
No difference in overall mortality was seen between the patients in the
erosion group and controls after 16 years of follow-up. No deaths were related to
gastric erosions. However, significantly fewer erosion patients had diagnosed
malignancies than the controls. In both groups there were different types of
malignancies without there being any characteristic pattern. No conclusions about
the clinical significance or mechanisms of the observed negative association
between erosions and malignancy may be drawn, because of the low number of
patients, although one factor may be a protective effect of NSAID use.
In conclusion, this long-term follow-up study found that a significant
proportion of gastric erosions are chronic or recurrent. The occurrence of chronic
or recurrent gastric erosions is a condition, which is mainly without any major
local or systemic consequences as revealed by the clinical history of the subjects.
However, nearly 20% of patients with erosions will develop a peptic ulcer, and
patients with erosions should be examined for potential causes, such as H. pylori infection or use of NSAIDs, and treated accordingly.
6.6 Future aspects
One future challenge will be to confirm that an HSV infection is indeed
responsible for chronic/recurrent gastric erosions. If samples from the deep nerve
ganglia could be taken, culturing HSV or assaying it by PCR or immunological
methods might permit identification. These results need to be validated, for
example, by examining the occurrence of HSV in subjects known to either have
80
or not have ulcers as well as individuals without previously any known upper
gastric diseases.
From a pathogenetic point of view, it would be beneficial to understand how
the presence of H. simplex can enhance the formation of erosions. Possible
mechanisms might include a modification of mucosal immune activity or acid
secretion.
The necessity of treatment and if need, what is optimal treatment of erosions
are unresolved issues. In cases where the role of HSV is confirmed, studies of the
efficiency of antiviral treatment are warranted.
Erosions are etiologically heterogeneous. New knowledge of etiological
factors should be incorporated into the erosion classification. In addition, the
endoscopical and pathological criteria for diagnosis and classification should be
renewed to include relevant etiological and prognostic aspects. Furthermore, the
differential diagnosis of ulcers and erosions should be emphasized. It is probable
that some lesions classified as ulcers probably are erosions. New endoscopical
methods like high definition endoscopy and endoscopical ultrasound might well
provide useful information to enable a more precise differentiation between ulcers
and erosions. Simply magnifying endoscope is unlikely to be valuable in
distinguishing erosions from ulcers, as in the present study, the criteria for
distinguishing erosions from ulcers is based on the known fact that when the
lesion is pinched, an erosion can be lifted outwards, but not an ulcer. In addition,
it also based on the fact that an erosion does not interrupt the passage of the
peristaltic wave.
Non-invasive markers should be developed. Initially they would be used for
research purposes, but subsequently they might be able to separate ulcers and
erosions correctly without the need for biopsy.
Finally, the clinical value of erosion is that it is benign, and it must be
distinguished from ulcers, and also an erosion finding be an indication for
eradication of infection in H. pylori-positive subjects.
81
7 Conclusions
1. Gastric erosions are chronic/recurrent in one third of cases after nearly twenty
years of follow-up.
2. The association of high titres of HSV antibodies with chronic/recurrent
erosions suggests that a significant proportion of chronic/recurrent gastric
erosions are related to HSV infection, but not to H. pylori infection or to the
use of NSAIDs.
3. Focally enhanced inflammation is a characteristic of gastric erosions. Its
association with high HSV titres or use of NSAID suggests that these factors
could participate in the pathogenesis of gastric antral erosions. Active
inflammation in the erosions predicts their chronicity or recurrency, as do
high HSV antibody titres. Gastritis in H. pylori-positive subjects with gastric
erosions shows an evolution towards antral predominance. In contrast, body
predominance, including the development of atrophic changes, is rare.
Accordingly, patients with erosions share the characteristics of the gastritis
encountered in the duodenal ulcer phenotype. These findings emphasize the
importance of H. pylori and gastric acid in the pathogenesis of
chronic/recurrent gastric erosions in H. pylori-positive patients.
4. Chronic or recurrent erosions are mostly without serious complications.
However, H. pylori-positive patients exhibiting erosions do seem to exhibit a
significantly elevated risk to develop a peptic ulcer.
82
83
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Original publications
This thesis is based on the following original articles, which are referred to in the
text by their Roman numerals.
I Toljamo K, Niemelä S, Karttunen TJ, Karttunen R, Karvonen A-L, Piiparinen H & Lehtola J (2002) The role of Herpes simplex and Helicobacter pylori infection in the etiology of persistent or recurrent gastric erosions: a follow-up study. Dig Dis Sci 47(4): 818–822.
II Toljamo K, Niemelä S, Karvonen A-L, Karttunen R & Karttunen TJ (2011) Histopathology of gastric erosions. Association with etiological factors and chronicity. Helicobacter 16(6): 444–451.
III Toljamo K, Niemelä S, Karvonen A-L & Karttunen TJ (2005) Evolution of gastritis in patients with gastric erosions. Scand J Gastroenterol 40(11): 1275–1283.
IV Toljamo K, Niemelä S, Karttunen TJ, Karvonen A-L & Lehtola J (2006) Clinical significance and outcome of gastric mucosal erosions: a long-term follow-up study. Dig Dis Sci 51(3): 543–547.
The original articles have been reprinted with the permission from the copyright
holders: Springer Science + Business Media, license number 2781251140036 (I)
and 2781250718516 (IV), John Wiley & Sons Singapore Pte. Ltd (II) and Informa
Healthcare (III).
Original publications are not included in the electronic version of the dissertation.
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1150. Murtomaa-Hautala, Mari (2012) Species-specific effects of dioxin exposure onxenobiotic metabolism and hard tissue in voles
1151. Jauhola, Outi (2012) Henoch-Schönlein purpura in children
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OULU 2012
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Kari Toljamo
GASTRIC EROSIONS – CLINICAL SIGNIFICANCE AND PATHOLOGYA LONG-TERM FOLLOW-UP STUDY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU, FACULTY OF MEDICINE,INSTITUTE OF CLINICAL MEDICINE, DEPARTMENT OF INTERNAL MEDICINE;INSTITUTE OF DIAGNOSTICS, DEPARTMENT OF PATHOLOGY