Division of Gastroenterology, Department of Medicine

Helsinki University Central Hospital

Helsinki, Finland

HELICOBACTER PYLORI AND

FUNCTIONAL DYSPEPSIA

by

Jari Koskenpato

Academic Dissertation

To be publicly discussed, by permission of the Medical Faculty of the

University of Helsinki, in Auditorium 3 of the Biomedicum,

Haartmaninkatu 8, on October 26, 2001, at 12 noon.

HELSINKI 2001

CONTENTS

LIST OF ABBREVIATIONS................................................................................................... 7

LIST OF ORIGINAL CONTRIBUTIONS.............................................................................. 8

ABSTRACT.............................................................................................................................. 9

1. INTRODUCTION............................................................................................................... 11

2. REVIEW OF THE LITERATURE.................................................................................... 13

2.1. Functional dyspepsia..................................................................................................... 13

2.1.1 Definition.............................................................................................................. 13

2.1.2 Epidemiology and natural history......................................................................... 14

2.2. Helicobacter pylori infection......................................................................................... 15

2.2.1 Epidemiology........................................................................................................ 15

2.2.2 H.pylori and pathogenesis of gastroduodenal disease.......................................... 15

2.2.3 Diagnosis.............................................................................................................. 17

2.2.4 Clinical use of diagnostic tests............................................................................. 18

2.2.5 Aspects of 13C-urea breath test............................................................................ 18

2.2.6 Treatment regimens for H.pylori infection........................................................... 19

2.3. Gastric motility............................................................................................................... 20

2.3.1 Physiology........................................................................................................... 20

2.3.2 Measurement of gastric emptying........................................................................ 21

2.3.3 H.pylori and gastric motility............................................................................... 23

2.4 .Etiologic aspects and treatment of functional dyspepsia ............................................. 23

2.4.1 H.pylori eradication............................................................................................ 23

2.4.2 Motility disorders and treatment with prokinetic agents.................................... 24

2.4.3 Disturbances in acid secretion and treatment with acid-suppression.................. 26

2.4.4 Other aspects of treatment.................................................................................. 26

3. AIMS OF THE STUDY..................................................................................................... 28

4. MATERIALS AND METHODS....................................................................................... 29

4.1 Study population.................................................................................................... 29

4.2 Endoscopic and histological examination.............................................................. 31

4.3 Questionnaires....................................................................................................... 32

4.4 13C-urea breath test............................................................................................... 33

4.5 Scintigraphic measurement of gastric emptying................................................... 33

4.6 Medication............................................................................................................. 34

4.7 Statistical analysis................................................................................................. 34

5. RESULTS........................................................................................................................... 37

5.1 Gastric emptying.................................................................................................... 37

5.2 Treatment effect on dyspeptic symptoms and quality of life................................. 39

5.3 Gastritis and dyspeptic symptoms......................................................................... 43

5.4. Urease activity...................................................................................................... 47

6. DISCUSSION.................................................................................................................... 50

6.1. Gastric emptying.................................................................................................. 50

6.2. Symptoms and quality of life after H.pylori eradication..................................... 53

6.3. Subtypes of gastritis and urease activity of the stomach..................................... 56

6.4. Clinical applications and suggestion for management

of functional dyspepsia........................................................................................ 57

7. CONCLUSIONS................................................................................................................ 61

8. ACKNOWLEDGEMENTS................................................................................................ 62

9. LIST OF REFERENCES................................................................................................... 64

7

LIST OF ABBREVIATIONS

FD Functional dyspepsia

Hp Helicobacter pylori

MALT Mucosa associated lymphoid tissue

DOB Delta-over-baseline value

MMC Migrating motor complex

13C-UBT Carbon-13 urea breath test

14C-UBT Carbon-14 urea breath test

ROI Region of interest

In Indium

Tc Technetium

PPI Proton-pump inhibitor

PCR Polymerase chain reaction

ELISA Enzyme linked immunoabsorbent assay

NERD Non-erosive reflux-disease

DU Duodenal ulcer

GI Gastrointestinal

NSAID Non-steroidal anti-inflammatory drug

IBS Irritable bowel syndrome

PP Per protocol

ITT Intention to treat

8

LIST OF ORIGINAL CONTRIBUTIONS

I

Kairemo KJA, Koskenpato J, Korppi-Tommola ET, Färkkilä M. A dual-tracer method for

studying intragastric distribution and gastric emptying of solids and liquids in functional

dyspepsia. Nucl Med Comm 1998;19:143-47

II

Koskenpato J, Kairemo K, Korppi-Tommola T, Färkkilä M. Role of gastric emptying in

functional dyspepsia - a scintigraphic study of 94 subjects. Dig Dis Sci 1998;43:1154-1158.

III

Koskenpato J, Korppi-Tommola T, Kairemo K, Färkkilä M. Long-term follow-up study of

gastric emptying and Helicobacter pylori eradication among patients with functional dyspepsia.

Dig Dis Sci 2000; 9:1763-1768

IV

Koskenpato J, Färkkilä M, Sipponen P. Helicobacter pylori eradication and standardized 3-

month omeprazole therapy in functional dyspepsia. Am J Gastroenterol, in press

V

Koskenpato J, Färkkilä M, Sipponen P. Helicobacter pylori and different topographic types of

gastritis - treatment response after successful eradication therapy in functional dyspepsia.

Submitted for publication

9

ABSTRACT

Background: Functional dyspepsia (FD) has been defined as persistent or recurrent abdominal

pain or discomfort centred in the upper abdomen without any evidence of organic or

biochemical abnormality. The etiology of FD remains unknown, with inconclusive evidence for

several pathophysiologic factors including Helicobacter pylori (Hp) infection, gastric motility

disorders, altered gastric sensitivity or disturbances in acid secretion. Although Hp is associated

with peptic ulcer disease, treatment studies of Hp eradication in functional dyspepsia have

shown inconclusive results. This study evaluates the effect of Hp eradication on symptoms and

quality of life in FD, the role of gastric emptying (motility) in Hp positive FD, and the impact of

specific properties of Hp gastritis in FD.

Patients and methods: 151 Hp positive patients with functional dyspepsia were enrolled from

the basic population of outpatients sent for gastroscopy by primary care physicians. 2150

patients were screened. In addition, 11 healthy volunteers and 11 FD patients without Hp

infection were included in the scintigraphic examination as controls. Biopsy samples from

antrum, corpus and duodenum were taken from the patients and the gastritis was scored

according to the Sydney System. Different topographical elements of the gastritis were

evaluated from 143 patients and the urease activity of the stomach was determined from 36

patients by DOB-value of 13C-urea breath test. Hp infection was also confirmed by rapid urease

test and culture. Gastric emptying was measured by a dynamic dual-tracer scintigraphic

examination in 72 patients and again in 29 after one year. Solid meal was labelled with In-111

and liquid meal with Tc-99m and simultaneous anterior and posterior projections were imaged.

The symptoms and the quality of life were evaluated by separate questionnaires. Dyspeptic

symptoms were evaluated by a unique numeric scale questionnaire after every 3 months during

the one-year follow-up and the quality of life was measured by a validated RAND 36-item

health survey 1.0 questionnaire at the baseline and after 12 months. Of the 151 patients 77

received eradication therapy for the first 2 weeks with amoxycillin 500mg q.i.d, metronidazole

400mg t.i.d, and omeprazole 20mg b.i.d; 74 patients received omeprazole 20mg b.i.d and

placebo antibiotics. In addition, every patient received an open 3-month initial medication by

omeprazole 20mg daily to standardize the acid-suppression.

Main results: In gastric emptying parameters, a tendency for slower gastric emptying and more

distal gastric content distribution was seen among patients with functional dyspepsia. After

10

multivariate analysis, the use of NSAIDs was the only statistically significant factor associated

with prolonged solid lag-time (p<0.05). Habitual smoking caused alterations in intragastric

distribution and emptying of solids. Delayed liquid emptying (T1/2) was associated with

increasing age (p<0.025). After placebo-controlled eradication therapy and 12-month follow-up,

no differences were revealed in gastric emptying parameters between patients who had received

a successful Hp eradication therapy and patients with ongoing infection. This long-term

prospective study showed, however, the reproducibility of a scintigraphic gastric emptying

study. In the patient population, the association between the first examination and the one after

12 months was significant for both solid gastric emptying (T50, p=0.20, R=0.43) and liquid

emptying (T1/2, p=0.018, R=0.43). After one year, the dyspepsia score was 7.4±3.0 in the

treatment group with a mean symptom reduction of 28.8 % compared to baseline. In the control

group the dyspepsia score was 7.6±3.1 with the mean symptom reduction of 21.7 % (p=ns). In

addition, quality of life showed no difference between treatment group and controls after this

follow-up. In a multivariate model, female gender was the only factor independently related to

dyspeptic symptoms (p=0.02). However, heartburn (p<0.01) and regurgitation (p<0.001) were

improved during the 3-month omeprazole treatment despite the Hp status. The urease activity of

the stomach was associated with the subtype of chronic gastritis. The mean DOB-value in

patients with antrum-predominant gastritis or pangastritis was 46.8 ± 20.5, whereas patients with

corpus-predominant gastritis had a mean DOB-value of 28.6 ± 20.0 (p<0.05). There was no

statistical difference in dyspepsia scores between different types of gastritis prior to the

medication. As well, the severity of gastritis was not associated with the dyspeptic symptoms.

However, in patients with antrum-predominant gastritis, the reduction of dyspepsia was

significantly more profound among successfully Hp eradicated patients than among those with

ongoing infection.

Conclusions: Hp-positive patients with functional dyspepsia did not get benefit for their

symptoms by eradicating Hp. However, reflux-like symptoms were improved with omeprazole

treatment in these patients. Dual-tracer scintigraphic examination of gastric emptying revealed

no major alterations in gastric motility among Hp infected patients, and Hp eradication had no

effect on gastric emptying parameters during 12 months. Reproducibility of this scintigraphic

examination was good. In patients with FD, Hp positive antrum-predominant gastritis was

associated with positive treatment effect by eradicating Hp, and increased urease activity of the

stomach was associated with favourable treatment effect.

11

1. INTRODUCTION

Functional dyspepsia (FD) and Helicobacter pylori (Hp) infection are among the most common

clinical issues in gastroenterology but the association of these two entities is still unclear.

Functional dyspepsia has been determined as chronic or recurrent upper abdominal pain or

discomfort for a period of at least one month, with symptoms present more than 25 percent of

the time, and an absence of clinical, biochemical, endoscopic, and ultrasonographic evidence of

any organic disease that would account for the symptoms (Talley et al. 1991 and (a)1999). Hp

infection is one of the most common bacterial infections of humans in the world. Among

Finnish subjects, the prevalence of Hp varies between 6-10% in children and 50-70% in subjects

born from 1915 to 1935 (Sipponen 1997, Ashorn et al. 1995, Rehnberg-Laiho et al. 1998). Hp

infection is strongly associated with chronic gastritis, peptic ulcer disease, gastric MALT-

lymphoma, and gastric cancer (Sipponen and Marshall 2000, Stolte and Edit 1993). However,

whether this infection can cause upper abdominal symptoms in the absence of peptic ulceration

remains unclear, and treatment studies with Hp eradication therapy in FD have reached unclear

conclusions ((b)Moayyedi et al. 2000, Danesh et al. 2000, Laine et al. 2000, Jaakkimainen et al.

1999). Chronic active Hp gastritis affecting the distal part of the stomach (antrum) is associated

with duodenal ulcer disease, whereas corpus-predominant gastritis mainly leads to loss of acid

secretory capacity and atrophy ( Sipponen and Hyvärinen 1993, Sipponen et al. 1989 and 1990,

McColl et al. 2000). The association between different types of Hp gastritis and treatment

response of FD has not been studied.

Gastric motility includes the motor functions of the stomach which are the result of a complex

interaction of muscular and neural activity. Motor functions of the stomach and the gastric

emptying are connected together (Camilleri et al.1986, Datz 1991, Horowitz et al. 1994). Most

of the studies about functional dyspepsia and gastric motility, show a tendency to prolonged

gastric emptying in these patients (Klauser et al. 1993, Malagelada 1991), although the

relationship is not exactly clear. In addition, the role of Hp infection in gastric motility disorders

is unclear and there are only few studies about Hp eradication therapy and alterations in gastric

motility (Miyaji et al. 1999, Goh et al. 1997, Parente et al. 1998). Scintigraphic techniques are

currently considered the method of choice for the accurate and non-invasive measurement of

gastric emptying under relatively physiological conditions (Datz 1991, Horowitz et al. 1994). In

addition, because solid and liquid contents empty stomach by separate mechanisms, it is

12

possible to use different markers in isotope-based examinations to obtain the optimal

information.

This study was planned to investigate the gastric motility in Hp positive functional dyspepsia

by creating a scintigraphic system for measuring different gastric emptying parameters and to

evaluate the role of Hp eradication therapy in gastric emptying after a long-term follow-up. In

addition, the main aims were to investigate the long-term effect of Hp eradication therapy on

symptoms and quality of life in patients with FD, and to assess the impact of spesific properties

of HP gastritis in FD.

13

2. REVIEW OF THE LITERATURE

2.1. Functional dyspepsia

2.1.1 Definition

The definition of dyspepsia has changed over time. The term ’dyspepsia’ derived from the

Greek words ’dys’ (bad) and ’pepsis’ (digestion), refers to symptoms thought to originate in the

upper gastrointestinal tract. Dyspepsia is divided to organic dyspepsia and functional dyspepsia

(FD) depending from the etiology of the symptoms. A widely accepted definition of functional

dyspepsia has been presented in a working-group report by Talley et al. (1991). According to

that report, functional dyspepsia (nonulcer dyspepsia) means chronic or recurrent upper

abdominal pain or discomfort for a period of at least one month, with symptoms present more

than 25 percent of the time, and an absence of clinical, biochemical, endoscopic, and

ultrasonographic evidence of any organic disease that would account for the symptoms.

Functional dyspepsia has been further classified to reflux-like dyspepsia (heartburn,

regurgitation), ulcer-like dyspepsia (epigastric pain), dysmotility-like dyspepsia (nausea,

vomiting, early satiety) and nonspesific dyspepsia (Talley 1991). However, the usefulness of

this subclassification based on symptoms has proved to be of minor importance ((a)Talley

1993). In clinical practice, FD is a digestive syndrome different from, although freguently

overlapping with, gastroesophageal reflux disease and irritable bowel syndrome. Some studies

have shown that analysis of the predominant (most bothersome) symptom may identify

subgroups of FD characterized by different responses to treatment (Stanghellini et al. 1996,

Meineche-Schmidt and Christensen 1998). Therefore more detailed criteria for functional

gastroduodenal disorders (Rome II criteria) based on predominant symptoms instead of

symptom clusters have been published ((a)Talley et al 1999). Symptoms of IBS occur

commonly in patients with functional dyspepsia, but if strict definitions are applied, these two

entities can usually be separated to distinct syndromes (Talley et al.1991, (a)Talley et al. 1999).

It is known that heartburn and acid regurgitation predict reflux disease extremely well (Klauser

et al. 1990). Patients with mucosal erosions in the distal esophagus are easily diagnosed having

a reflux-disease, but the objective diagnosis of reflux disease is difficult in patients with normal

14

endoscopy (Dent et al. 1999). Twenty-four-hour ambulatory esophageal pH monitoring is

frequently considered to be a diagnostic golden standard (Joelsson and Johnsson 1989, Shi et al.

1995, Small et al. 1995), but it has still significant limitations and even severe reflux esophagitis

may have negative result (Dent 1998). Analysis of symptoms or a 2-week treatment-test by PPI

are probably the most useful methods for diagnosis (Dent 1998). Therefore, patients with

predominant reflux-like symptoms are usually not classified as functional dyspepsia-patients, as

is the case in our studies.

2.1.2 Epidemiology and natural history

General population studies have shown dyspepsia to be a very common phenomenon. In

separate studies the prevalence of dyspepsia has been shown to be 54 % in Sweden within a 3-

month period (Agreus et al. 1994), and 50 % in Denmark within 1 year (Kay and Jorgensen

1994). Approximately 15-40 % experience dyspepsia, at least once a year, depending on the

definition of dyspepsia and on the time frame of the prevalence (Locke 1998). Although

between 0.5 % and 1% of the population annually develop new dyspepsia or reflux symptoms,

the prevalence in the population is stable as the rate of loss of symptoms and the rate of

development of symptoms in new subjects balance each other out (Agreus et al.1998). Several

studies have addressed symptom turnover and repeated the findings that dyspeptic symptoms are

persistent and recurrent. Jones and Lydeard (1992) revealed that during 2 years only 26 % of the

patients had become symptom-free. In addition, 86 % of those with frequent dyspepsia reported

the same symptoms during the next 12-20 months (Talley et al. 1992), and only 25 % of

dyspeptics have shown to be symptom-free after five years (Kay and Jorgensen 1994). However,

only 25 % of patients with dyspepsia seek medical advice (Jones et al. 1990). Sociodemographic

and environmental factors have not been shown unequivocally to be predictors of dyspepsia in

the literature, while psychosocial factors have been shown to contribute to the morbidity

(Wiklund and Butler-Wheelhouse1996). For all visits at primary health care, dyspepsia covers

2-6 % in western countries (Brown and Rees 1990, Heikkinen et al. 1996). Approximately one

half of subjects with dyspepsia have an underlying organic lesion (Kagevi et al 1989, Klauser et

al 1993). In a population-based study in Finland by Heikkinen et al. (1995), 400 consecutive

unselected patients with dyspepsia were thoroughly investigated. The final diagnosis was

functional dyspepsia for 34 % of these patients. Most common organic causes were oesophagitis

15 %, peptic ulcer 13 %, and lactose intolerance 9 %.

15

2.2. Helicobacter pylori infection

Hp is a gram-negative bacteria first described by Warren and Marshall (1983). It colonises

human stomach which is the only known natural reservoir of this microbe. The discovery of HP

has revolutionized the pathophysiological and clinical approach to diseases of the upper GI-

tract, especially peptic ulcer disease.

2.2.1 Epidemiology

Hp infection is one of the commonest bacterial infections of humans in the world. It is generally

acquired during childhood (Broutet et al. 1999, Sipponen et al. 1995), and in practical view,

persists indefinitely if left untreated. The annual spontaneous elimination of the bacteria is only

0.5-2 % (Xia and Talley 1997). The prevalence of Hp infection is associated with low socio-

economic status and it is increased in developing countries (Broutet et al. 1999). In Finland, the

prevalence of Hp infection in children is 6-10 % (Ashorn et al. 1995, Rehnberg-Laiho et al.

1998), and the infection is acquired mainly before the age of seven. The overall prevalence is

dependent on so called cohort-phenomenon (Roosendaal et al. 1997). Among finnish subjects

born between 1915-35 the prevalence of Hp infection is 50-70 % and in subjects born between

1955-75, 15-35% of cases are Hp positive (Sipponen 1997).

2.2.2 H.pylori and pathogenesis of gastroduodenal disease

Colonisation of the gastric mucosa by Hp evokes a local inflammatory response, resulting in

further mucosal injury (Go and Crowe 2000, Blaser 1992). This inflammation is usually a

lifelong, stabile or slowly progressive disease, which may cause divergent effects on acid

secretion depending on the “stage” or type of the gastritis (Sipponen and Hyvärinen 1993,

Blaser 1992, El-Omar et al. 1993, McColl and El-Omar 1996, Anand and Graham 1999, Villako

et al. 1991).

In patients with duodenal ulcer disease, the infection is accompanied by an increase in both

basal and stimulated acid output (El-Omar et al. 1993, 1995). Hypergastrinaemia and reduction

in gastric somatostatin levels are associated with that phenomenon (Larsson and Houggaard

1994). In addition, gastric hypersecretion contributes to the development of gastric metaplasia

in the proximal part of the duodenum and the duodenal mucosa becomes increasingly vulnerable

16

to peptic acid attack and subsequent ulceration (Wyatt et al. 1990, Malfertheiner and Bode 1993,

Tytgat et al. 1993). The risk of developing gastric or duodenal ulceration during a 10-year

follow-up has been shown to be 11% in patients with Hp infection compared to less than 1% in

subjects without Hp gastritis (Sipponen et al. 1990).

It is frequently considered that chronic active gastritis affecting the antrum is associated with

duodenal ulcer disease, whereas corpus-predominant gastritis mainly leads to loss of acid

secretory capacity and atrophy increasing the risk of gastric carcinoma (McColl et al. 2000,

Anand and Graham 1999, Sipponen and Hyvärinen 1993, Sipponen et al. 1989 and 1990,

Cederberg et al. 1991, McColl and El-Omar 1996). In some cases, Hp gastritis is progressing

towards gastric mucosal atrophy after years or decades with chronic infection (Genta 1997), and

it seems that the grade of atrophy plays a major role in carcinogenesis whether the infection is

antrum-predominant or corpus-predominant (Sipponen and Marshall 2000). If there is a severe

atrophy in antrum and corpus, the risk for gastric cancer is approximately 90 times higher than

in subjects with a healthy gastric mucosa (Sipponen and Marshall 2000). In addition of

increased risk to develop gastric carcinoma, chronic Hp infection is associated with

development of primary gastric lymphoma (MALT) (Stolte and Edit 1993).

Whether chronic Hp infection can cause dyspeptic symptoms in the absence of any organic

causes mentioned earlier remains unclear ((b)Moayyedi et al. 2000, Laine et al. 2000,

Armstrong 1996, Labenz and Rokkas 1997, (b)Talley 1993, Lambert 1993). Assessing the

symptoms of FD and Hp is a difficult task. Some studies have been able to connect ’ulcus-like’

symptoms (mainly pain in the epigastrium) and Hp infection (Hovelius et al. 1994, Thurmer et

al. 1996, Lai et al. 1996). Burping and bloating have been associated with Hp infection, but

mainly, no clear symptom profile differences between HP positive and negative FD patients

have been found (Armstrong 1996). Hp is common in asymptomatic healthy subjects. In most

epidemiological studies (Lambert 1993), as well as in meta-analysis by Armstrong (1996), the

Hp prevalence among patients with FD is still higher than in asymptomatic subjects.

Considering the possible pathophysiologic mechanisms of FD, no difference in acid output was

found between Hp positive and Hp negative FD patients (Tucci et al. 1992). In addition, studies

about gastric motility and Hp, as discussed in chapter 2.3.3, have given controversial results.

Likewise, gastric sensitivity to mucosal irritation (George et al 1991) or distension to luminal

dilatation (Saslow et al. 1998) are not altered by Hp infection.

17

2.2.3 Diagnosis

Hp infection can be diagnosed by invasive tests in gastroscopy or by non-invasive tests. Today,

several excellent tests for clinical use are available but no single test is optimal. Hp protects

itself from the bactericidical effects of gastric acid by producing urease, which, by hydrolysing

urea to ammonia, neutralises the acid in the immediate microenvironment of the bacterium

(Marshall et al. 1990). Based to this urease reaction, several diagnostic approaches have been

developed.

Histological examination of the biopsy samples from gastric mucosa has widely been considered

as the golden-standard of diagnosis of Hp infection. Of course, the accuracy of histology for the

detection of Hp is dependent of the experience of the pathologist (Maconi et al. 1999). Usually

routine haematoxylin and eosin stain or Giemsa stain are used for histological examination. At

least two biopsies from the antrum and corpus should be taken (Niemelä et al. 2000). The

amount and site of biopsy samples is especially important in patients with partial atrophic

changes in the gastric mucosa (Satoh et al. 1998). The rapid urease test is available in different

commercial forms (Hirschl and Glupczynski 1999). Sensitivity of the rapid urease test depends

upon the number of bacteria present in the biopsy sample (Midolo and Marshall 2000).

Sensitivity of the test is in the range of 75-98 % (Midolo and Marshall 2000, Marshall et al.

1987, Borromeo et al. 1987). In addition, PCR methods to detect Hp in gastric biopsy samples

are available and various assays have been developed. However, PCR techniques are not yet

useful as routine tools for the diagnosis of Hp (Hirschl and Glupczynski 1999).

Several ELISA-based serological tests are available and the accuracy of these tests is acceptable.

The sensitivity and specificity of these tests are usually between 90-95 % (Feldman et al. 1995).

Hp can also be detected from stool samples by PCR, by spesific IgA-antibodies and by detection

of Hp antigen, but so far the antigen detection method is the only test based on stool samples

which has a role in routine diagnostic use (Watanabe et al. 1998, Hirschl and Glupczynski

1999). In a large multicentre study of 500 patients the sensitivity and specificity were reported

as 94% and 91% (Vaira et al. 1998). After treatment, however, the usefulness of this method for

confirming the absence of Hp is controversial (Ishihara et al. 2000, Caselli et al. 1999).

18

2.2.4 Clinical use of diagnostic tests

In the recommendation for Hp diagnosis and treatment by the Finnish Society of

Gastroenterology, the 13C-UBT, quantitative serology and antigen detection from stool are

listed as the most suitable non-invasive tests for Hp diagnosis. Treatment effect after eradication

therapy should be confirmed by C13-UBT at least four weeks after medication (Niemelä et al.

2000). In situations with low bacterial load in gastric mucosa (treatment with acid-suppression

or antibiotics, atrophic gastritis), tests based to the urease reaction or histological examination

may give wrong negative results and quantitative serology is needed. Rapid qualitative

serological tests using whole blood are not recommended for diagnosing Hp because of the

varying diagnostic accuracy (The European Helicobacter pylori study group 1997, Niemelä et

al. 2000).

2.2.5 Aspects of 13C-urea breath test

Principle of the diagnostic breath tests is based on the high urease activity of Hp. A minimal

dosage of isotope-labelled urea is given to the patient, and if Hp is present, the urea is

hydrolysed to isotope-labelled CO2, which circulates to the lungs and is expired in the breath

where it can be detected. The use of 14C-UBT is limited by the radioactivity of the isotope. It

can not be used in children or woman of child-bearing age, and the use of 14C-UBT is difficult

outside hospitals. 13C-UBT is a non-radioactive test, and the breath samples are analysed by gas

chromatography or isotope ratio mass spectrometry. Sensitivity and specificity of this test are

significantly over 90 % (Logan 1998). Many different protocols using 13C-urea are available for

detection of Hp (Graham and Klein 1991). A single breath sample collected at least 30 min after

administration of the substrate, and a delta-over-baseline value (DOB; i.e., an increase in the

13CO2/12CO2 isotope ratio) of 6 ‰ seems to be a suitable method for determining Hp infective

status (Klein and Graham 1993, (a,b)Logan et al. 1991) In its classical form, a test meal and a

waiting time of approximately 30 minutes are needed in 13C-UBT, but a new modification of

this test has been published. In this tablet-based 13C-UBT the time of the procedure has been

reduced to 10 minutes, no test meal is needed and the test can be performed also during an acid-

suppression therapy (Hamlet et al. 1999).

19

13C-UBT is known to be a sensitive method specific for Hp infection ((a,b)Logan 1991), but it

is unclear to what extent it is quantitative (Graham and Klein 2000, Atherton and Spiller 1994).

In some reports, UBT values have been associated with the results of bacterial counts contained

in biopsy specimens (Peura et al. 1996), but other studies have not confirmed these findings

((b)Logan 1991). Urease concentrations differing by as much as eightfold have been detected for

different Hp strains (Dunn et al. 1990). 13C-UBT values, however, have been shown to correlate

with the severity of gastritis ((b)Logan et al. 1991, (a)Perri et al. 1998)

2.2.6 Treatment regimens for H.pylori infection

The acidity of the human stomach and the increasing antibiotic-resistance of the bacteria make

it difficult to achieve an optimal treatment for Hp infection. A large number of studies have been

carried out to evaluate different therapies. The mechanisms behind the efficacy, or lack of

efficacy, in separate treatment regimens are not fully understood. It is widely accepted that acid-

suppression and antibiotics are both needed, and most recommended regimens consist of two

antibiotics (Laheij et al. 1999, Niemelä et al. 2000, The European Helicobacter pylori study

group 1997, Unge 1996, Montague et al. 1999, Buckley and Deltenre 1997). Usually the

antimicrobial agents used are amoxycillin, tetracycline, metronidazole or tinidazole,

clarithromycin and bismuth subcitrate or ranitidine bismuth citrate. The dosages and the

duration of the different treatment protocols show variation in different nations. However, the

treatment regimens should be simple, well tolerated and achieve an eradication rate of over 80

% (The European Helicobacter pylori study group 1997). The current Finnish primary treatment

recommendations for Hp are shown in Table 1. After two treatment failures a gastroscopy

should be performed and Hp culture for resistance analysis should be obtained (Niemelä et al.

2000).

So far no optimal treatment is available for metronidazole and clarithromycin resistant Hp

strains, although high-dose amoxycillin-omeprazole dual-therapy (Peitz et al 1999) has shown

promising results. In addition, rifabutin-based eradication therapy has been reported to be

effective in treating “non-responders” after repeatedly failed conventional therapies (Perri et al.

2000). At the moment, the metronidazole resistance is over 30 % and the clarithromycin

resistance is approximately 5 % in Finland (Glupczynski et al. 1999, unpublished data from

Helsinki University Central Hospital).

20

Table 1.

Finnish recommendation for Hp treatment in adults (Niemelä et al. 2000)

Primary treatment (1 or 2) Treatment after one failure

1) PPIx2 + Clarithromycin 500mgx2 +

Amoxycillin 1gx2,

for one week

Ranitidine bismuth citrate 400mgx2 +

Metronidazole 400mgx3 + Tetracycline

500mgx4,

for one week

2) Ranitidine bismuth citrate 400mgx2 +

Clarithromycin 500mgx2 + Amoxycillin

1gx2,

for one week

2.3. Gastric motility

2.3.1 Physiology

Gastric motility or gastric emptying is a physiologic phenomenon, which is still not fully

understood. The motor functions of the stomach are the result of a complex interaction of

muscular and neural activity. It includes the spontaneous electrical and contractile activity of the

gastric cells, which starts from a “pace-maker” region located in the upper part of the greater

curvature of the stomach (Minami and McCallum 1984). In general, it is widely accepted that

the motor functions of the stomach and the gastric emptying are connected together (Camilleri

et al. 1985 and1986, Datz 1991, Horowitz et al. 1994). When solid food or liquids are

swallowed, subsequent entry into the stomach is accompanied by relaxation of the fundus

(receptive relaxation). The role of the proximal stomach is mainly controlling the

accommodation and the intragastric tonic pressure after ingested food (Datz 1991, Horowitz et

al. 1994). Antrum or distal part of the stomach fragmentates the ingested food by coordinated

contraction of the stomach walls (Datz 1991, Horowitz et al. 1994). Thus, antrum is mainly

21

responsible for the emptying of solid contents, and liquids empty because of the tonic pressure

of the stomach and by the influence of gravity. Liquid emptying rate can even be normal in

gastroparesis (Datz 1991). However, solids, especially nondigestible, can also empty the

stomach via powerful phase III interdigestive migrating motor complex (MMC) contractions

that occur between meals (Datz 1991, Horowitz et al. 1994).

Many physiological factors can alter gastric emptying. A large fatty meal with high caloric

content delays gastric emptying as well as alcohol intake (Moore et al. 1984). Also, the gastric

emptying rates differ depending on the posture of the subject (Moore et al. 1988). Acute

physical or mental stress may delay gastric emptying (Datz et al. 1990), and the emptying rate

of stomach is lower in the evening than in the morning (Goo et al. 1987). However, during

physical exercise the gastric emptying may be fast (Moore et al 1990). Sex hormones (Datz et

al. 1987) and age (Moore et al. 1983) are also associated with alterations in gastric emptying.

Cigarette smoking seems both to alter the intragastric distribution of solids and liquids and to

delay gastric emptying ((a)Scott et al. 1993). Considering these observations listed above, it is

logical to study gastric motility disorders in functional dyspepsia.

2.3.2 Measurement of gastric emptying

A number of approaches have been devised to evaluate gastroduodenal motility and gastric

emptying (Table 2). Scintigraphic techniques are currently considered the method of choice for

the accurate and non-invasive measurement of gastric emptying under relatively physiological

conditions (Datz 1991, Horowitz et al. 1994, Akkermans and van Isselt 1994). Solid and liquid

contents empty stomach by separate mechanisms, and for that reason different markers are

needed to obtain the optimal information. Liquid markers currently used are in a nonabsorbable

chelated form, such as Tc99m, In113m or 111InDTPA. Digestible solid markers with a high

labelling efficiency are: in vivo 99mTc-labelled chicken liver; in vitro 99mTc-labelled egg

white, potato puree, liver pate, and pancake (Akkermans and van Isselt 1994). The rate of

emptying of small indigestible solid particles mixed with a solid digestible meal, is similar to

that of digestible solids (van der Sijp et al. 1993). Scintigraphy can measure total stomach

emptying, as well as the intragastric distribution of ingesta and even smaller regions of interest

(fundus for example) in the stomach can be examined. However, scintigraphic techniques do not

have sufficient temporal resolution to quantify transpyloric flow accurately (Horowitz et al.

1994). Gastric emptying of solids is a biphasic process in which the emptying phase is preceded

22

by a lag period, which probably presents the time taken for redistribution of food from the

proximal to the distal stomach and for grinding solid food into small particles for transpyloric

emptying (Horowitz et al. 1994).

In analysing the scintigraphic data, a power exponential function is usually applied to fit the

emptying curve and to obtain gastric emptying half-times, which is the commonest method for

describing the whole emptying process (Tosetti et al. 1998). Thus, parameters which quantify

solid gastric emptying are the duration of the lag phase in minutes and the postlag emptying rate

in percentage emptied per time unit (Akkermans and van Isselt 1994). If dual-isotope method is

used with two nuclides of different energies, such as 111In and 99mTc in the same meal, the

Compton scatter occurs. Magnitude of this error is somewhere between 20 and 30 %, and each

frame of the time-activity curve needs to be corrected (Akkermans and van Isselt 1994). Another

measurement error with underestimation of emptying rates occurs if scintigraphic detection is

made unilaterally alone (Tothill et al. 1978).

Table 2.

Techniques for measurement of gastric emptying and motility (modified from Horowitz et al.

1994)

Invasive techniques Noninvasive techniques

endoscopy scintigraphy

aspiration of gastric contents radiology

manometry ultrasound

barostat magnetic resonance imaging

applied potential tomography

electrogastrography

radioisotopic breath testing

absorption kinetics of orally administered

drugs

23

2.3.3 H.pylori and gastric motility

The role of Hp in gastric motility disorders is still obscure. Some studies show, that Hp positive

subjects have prolonged gastric emptying compared to Hp negative subjects. These include the

observation by Mearin et al. (1995) that the postprandial antral motor activity is decreased in Hp

positive subjects compared to other dyspeptic patients. Gastric emptying alterations in Hp-

positive subjects compared to controls have been described in few studies (Tucci et al. 1992,

(b)Scott et al.1993, Fock et al. 1997, Testoni et al. 1996), whereas most publications have shown

no difference between Hp-positive and negative subjects (Caballero-Plasencia et al.1995,

Parente et al. 1998, Perri et al. 1998, Chang et al. 1996, Saslow et al. 1998, Chiloiro et al. 2001,

Rhee et al. 1999). In a scintigraphic study by Scott et al.((b)1993), a prolonged gastric emptying

and an altered intragastric distribution of food was demonstrated in functional dyspepsia

patients, but the solid lag time was prolonged in Hp negative patients. Chang et al. (1996) found,

in 60 patients with functional dyspepsia, that delayed gastric emptying of solids was present in

about 60% of cases, and this feature was a slightly more common phenomenon among Hp

positive subjects.

There are only few studies about the effect of Hp eradication therapy on gastric motility. In few

studies an association between Hp eradication and changes in gastric emptying have been

demonstrated (Konturek et al. 1997, Thor et al. 1996). In a studies by Goh et al. (1997) and

Parente et al. (1998), no effect on gastric emptying was found after eradication therapy. As well,

in a breath-test based study by Peitz et al.(1996) the delayed gastric emptying in dyspeptic

patients was stable after Hp eradication.

2.4. Etiologic aspects and treatment of functional dyspepsia

2.4.1 H.pylori eradication

The results of studies with Hp eradication therapy in FD are controversial. In uninvestigated

dyspepsia, substantial cost benefits and reduction of endoscopy workload can be achieved if all

young patients with dyspepsia in primary care are tested for Hp and positive subjects are treated

(Patel et al. 1995, Heaney et al. 1999, (a)Moayyedi et al. 2000). Therefore the “test and treat”

policy for treating dyspepsia has been widely accepted in dyspepsia management

24

recommendations (The European Helicobacter pylori study Group 1997, Finnish Society of

Gastroenterology 2000). However, treatment studies of Hp positive functional dyspepsia have

given conflicting results. Different follow-up times, separate symptom questionnaires,

uneffective eradication therapies and well known placebo effect of treating functional dyspepsia

have made the results of these studies difficult to analyse. In addition, functional dyspepsia may

not be equally determined. There exist six randomised, placebo-controlled studies of Hp positive

functional dyspepsia with at least 12 month follow-up after eradication therapy and patient

number at least one hundred. In five of them ((b)Talley et al. 1999, (c)Talley et al. 1999,

Greenberg and Cello 1999, Blum et al. 1998, Froechlich et al. 2001) no differences in symptoms

between treatment group or placebo-group were detected, although in the study by (c)Talley et

al. (1999) healing of gastritis was associated with resolution of symptoms. One of these studies

(McColl et al. 1998) demonstrated a resolution of symptoms associated with eradication

therapy. In a study with smaller number of patients (n=90), Miwa et al. (2000) found no

significant improvement in symptoms of non ulcer dyspepsia in the treatment group compared

to placebo. In addition to these original publications, few abstracts considering placebo

controlled eradication therapy studies have been presented. Malfertheiner et al. (2000)

documented a statistically significant 9 % difference in dyspeptic symptoms after one year in

favour of the eradication group in a large patient material (n=860). In a recent abstract, complete

symptom relief was associated with H.pylori eradication, although there was no significant

difference in symptom scores (Bruley des Varannes et al. 2000).

In a systematic review evaluating nine studies of Hp eradication in functional dyspepsia,

(b)Moayyedi et al. (2000) concluded a benefit of eradication therapy in symptoms with risk

reduction of 9 %. In the same review, quality of life showed no improvement in meta-analysis

with three separate studies. However, two systematic analyses found no clear confirmation of

functional dyspepsia symptom relief by eradication therapy (Danesh et al. 2000, Laine et al.

2000) but a meta-analysis by Jaakkimainen et al.(1999) observed an improvement in dyspeptic

symptoms with odds ratio of 1.9 in patients whose Hp was eradicated.

2.4.2 Motility disorders and treatment with prokinetic agents

Several clinical conditions, such as diabetes mellitus and postoperative problems, are clearly

associated with disorders in gastric motility. Many studies about functional dyspepsia and

gastric motility, shows a tendency to prolonged gastric emptying of solids in these patients

25

(Quartero et al. 1998, Urbain et al. 1995, Duan et al. 1993, Rees et al. 1980, Caballero-Plasencia

et al. 1995), although the relationship is not exactly clear. In general, gastric motor dysfunction

demonstrated by scintigraphic studies, electrogastrography, or manometrical studies has been

reported in 25-60% of patients with functional dyspepsia (Malagelada 1996, Wilmer et al.

1998). However, the relationship between these findings and dyspeptic symptoms is

controversial (Caballero-Plasencia et al. 1995, Talley et al 1989, Vantrappen 1994, Wilmer et al.

1998). The association between chronic idiopathic gastric stasis and FD has been reported by

Narducci et al. (1986), patients were examined by scintigraphy and manometry. Prolonged solid

lagtime and 40 % prevalence of gastroparesis in FD patients were observed in a dynamic antral

scintigraphic study by Urbain et al. (1995). Scintigraphic study by Scott et al. ((b)1993) showed

disturbances in intragastric distribution of contents in addition to delayed emptying of solids and

prolonged solid lagtime in FD patients. Also, in a scintigraphic study with 50 patients and 50

control subjects, delayed gastric emptying of a solid meal or of indigestible solids were reported

in 78 % and 68 % of FD patients (Caballero-Plasencia et al. 1995). However, in this study, there

was no correlation between symptoms and gastroparesis. Usually, the gastric emptying of solids

is delayed in scintigraphic studies, and the role of antral contractions in solid food emptying has

been considered to be essential (Camilleri et al. 1986, Horowitz et al. 1994). Therefore, it is

obvious that antral hypomotility, measured by ultrasonography or scintigraphy, has been

reported in FD patients (Urbain et al. 1995, Narducci et al. 1986, Stanghellini et al 1992,

Hausken et al 1993). Myoelectric function of the stomach is characterized by a cyclic electrical

pacemaker activity, so called slow waves. Gastric slow-wave disturbances can include

tachygastria, tachybradyarrhytmia or absence of the normal increase in slow wave amplitude

after ingestion of a meal (Minami and McCallum 1984, Chen and McCallum 1993).

Prokinetic agents have been widely used for treating dyspeptic symptoms. In patients with

uninvestigated dyspepsia and a negative Hp serology, no difference in the severity of symptoms

was found in patients receiving cisapride as compared to placebo (Kearney et al. 2000).

However, cisapride provides symptomatic relief in functional dyspepsia associated with gastric

myoelectrical abnormality (Chen et al. 2000). In a systematic analysis by van Zanten et al.

(1996), cisapride has shown to be effective in 7/9 placebo-controlled studies in functional

dyspepsia, domperidone in all 7 studies reported and metoclopramide in both two studies

published. In a review article by Fisher et al. (1998), prokinetic agents were shown to be more

effective than placebo in 16/21 studies and the overall improvement of symptoms was

suggested to be 40 to 45 percentage points greater than with placebo. In a meta-analysis by Soo

26

et al. (2001), prokinetic drugs were the most effective agents in FD, but most of the published

trials were small and studies of poor quality studies were included.

2.4.3 Disturbances in acid secretion and treatment with acid-suppression

Functional dyspepsia patients with Hp gastritis are shown to have an acid output comparable to

that of healthy controls (Tucci et al. 1992), but a higher acid response to gastrin-releasing

peptide (El-Omar et al. 1995). However, as mentioned earlier Hp infection has also been linked

to increased basal and stimulated acid output, the effect being most pronounced in patients with

duodenal ulceration. Because the long-term risk of getting gastric atrophy is increased in Hp

positive patients, it is likely that the role of acid secretion disturbances is dependent on the

“stage” of the current infection.

In clinical practice, acid-suppressive agents appear to be the most widely used medication in

FD, and even long-term treatment without specific diagnosis is very common (Meineche-

Schmidt et al. 1999, Ryder et al. 1994). It seems that treatment with antacids provides no clear

benefit and H2-blockers may offer only limited improvement of symptoms in treating functional

dyspepsia (Van Zanten et al. 1996, Nyren et al. 1986, Fisher and Parkman 1998, Soo et al.

2001). Recent studies have confirmed the positive role of proton pump inhibitors, at least in

some subgroups, of treating functional dyspepsia. Meinache-Schmidt et al. (1999) have

reported a 3-month lasting symptom-resolution after a 4-week omeprazole treatment. In a report

by Talley et al. (1998), omeprazole appeared to be superior to placebo only in a subgroup of

patients with ’ulcer-like’ or ’reflux-like’ functional dyspepsia . In a study by Farup et al. (1999),

the patients with functional dyspepsia who responded to omeprazole treatment had a

characteristic gastro-esophageal reflux pattern. In general, the treatment response to proton

pump inhibitors is well documented but marginal. In a meta-analysis with 1225 patients, H2RA

therapy was superior to placebo and the efficacy was surprisingly even more pronounced than

that of PPI therapy (Soo et al. 2001). It should be born in mind that evaluation of treatment

responses by different pharmacological agents is difficult due to the marked, approximately 30

%, placebo-effect of treating FD (Van Zanten et al.1996, Grant Thompson 2000).

2.4.4 Other aspects of treatment

Many authors have considered functional dyspepsia as a symptom complex with a multiple

27

origin. The criteria for functional dyspepsia requires that the etiology of the symptom is not

known (Talley et al. 1991). However, hypotheses and treatment surveys have been performed.

There are only limited data from controlled studies of psychotropic medication for the treatment

of FD (Fisher and Parkman 1998), but there is evidence that psychotherapy may have positive

effects in patients with FD (Hamilton et al. 2000). In one placebo-controlled study with

mianserin, a positive effect on symptoms has been achieved (Tanum and Malt 1996).

Furthermore, psychological stress and psychiatric disease have been found to be notable risk

factors for the occurrence of upper GI symptoms (Stanghellini 1999). Also alterations in

autonomic nervous system activity (Muth et al.2000) and impaired relaxation of the proximal

stomach after meal (Tack et al. 1998) have been described in patients with functional dyspepsia.

Symptoms of irritable bowel syndrome are usually linked to dyspeptic symptoms and often

make it difficult to distinguish these two entities (Talley et al. 1991, (a)Talley et al. 1999). So far

treatment surveys of dyspepsia by fibre-products have not been published. In patients with IBS,

the presence of dyspepsia has been shown to be associated with Hp infection (Su et al. 2000).

The roles of various manners of living (tobacco, alcohol, coffee) have only minor impact on

dyspeptic symptoms (Elta et al.1990, Kay et al. 1994). Bismuth salts have shown to be

marginally more effective than placebo in FD, but there is no clear evidence that antacids,

sucralfate or misoprostol are superior to placebo (Soo et al. 2001)

28

3. AIMS OF THE STUDY

The main aims and the specific aims of the present study were:

1. To evaluate the effect of treatment on Hp positive FD

A. To investigate the long-term effect of Hp eradication therapy on symptoms of FD.

B. To examine whether acid-suppression therapy has impact on treatment of Hp positive FD

C. To examine, if a subgroup of patients, who clearly get benefit from Hp eradication for their

symptoms, can be found.

2. To investigate the role of gastric motility in Hp positive FD.

A. To create a scintigraphic system for measuring gastric emptying and to estimate the gastric

emptying parameters in Hp positive FD.

B. To investigate the role of Hp eradication therapy in gastric emptying after long-term follow-

up.

3. To assess the impact of specific properties of Hp gastritis in FD

A. To study whether topografic subtypes of Hp gastritis have different symptoms or treatment

response in FD.

B. To evaluate the role of the density of Hp in gastric mucosa and the role of the urease activity

in FD.

29

4. MATERIALS AND METHODS

4.1 Study population

The original study population consisted of 151 HP positive patients with functional dyspepsia.

Patients were enrolled from the basic population of outpatients sent for gastroscopy by primary

care physicians or gastroenterologists during a 24-month period between October 1995 to

November 1997. The study was carried out at the Department of Gastroenterology in the

Helsinki University Central Hospital. 2150 patients were screened. In addition, 11 healthy

volunteers and 11 FD patients without Hp infection were included in the scintigraphic

examination as controls. A flowchart covering the patient flow during the12-month follow-up is

in Figure 1. The clinical characteristics of the study population are shown in Table 3. Prior to

the inclusion of the study patients, organic causes of dyspepsia were thoroughly ruled out by

normal physical examination, gastroscopy, upper abdominal ultrasound examination, lactose

absorption test, and appropriate haematological and biochemical tests. Patients with

predominant reflux symptoms or a history of previous gastrointestinal surgery were excluded.

None had evidence of any systemic disease or medication known to cause dyspepsia symptoms.

Prior to the study, every patient suffering from lactose intolerance remained for at least 3

months on a lactose-free diet. Before participation in the study, an informed consent was given

by every patient.

31

Table 3.

Clinical characteristics of the study population

Eradication therapy

and

Omeprazole-treatment

Placebo

and

Omeprazole-treatment

N 77 74

Men 23 (30%) 29 (39%)

Mean age 51.5±9.5 51.8±11.8

Habitual smokers 40 (54%) 44 (59%)

NSAID use 1-3 tbl/week 17 (22%) 22 (30%)

NSAID use > 3tbl/week 11 (14%) 13 (17%)

Lactose intolerance 13 (17%) 13 (18%)

Irritable bowel syndrome 34 (44%) 36 (49%)

Chronic gastritis score 3.9±1.3 3.8±1.1

Dyspepsia score 10.4±3.3 10.2±2.9

4.2 Endoscopic and histological examination

The endoscopies were performed in the Helsinki University Central Hospital, at the Department

of Gastroenterology. In the study population, gastroscopy findings were either normal or

showed only minor inflammatory features (no ulcers, no erosions, no macroscopic oesophagitis

or duodenitis). At the endoscopy, two biopsies from lower duodenum, corpus and antrum were

taken as well as from any specific findings. In addition, Hp infection was confirmed by rapid

urease test and bacterial culture. Histology was considered the golden standard because the

patient was defined as Hp positive if either histology only, or two other tests without histology

were positive. Gastritis was graded according to the Sydney System (Price 1991). From the

randomized 151 patients, paired biopsy samples were insufficient in eight subjects, and

therefore different topographical elements of the gastritis were evaluated from 143 patients.

32

Activity of gastritis was graded by the neutrophilic infiltration in gastric mucosa. Scores of the

activity of antrum gastritis (0-3) and corpus gastritis (0-3) were evaluated separately and the

sum score (0-6) stood for “total activity of gastritis”. As well, the severity of the chronic gastritis

was determined by the amount of mononuclear cell infiltration and inflammation was graded

separately for antrum (0-3) and for corpus (0-3). Thus, the “total chronic gastritis score” varied

between 0 and 6. Similar scores (antrum, corpus and total) were determined for atrophy and

intestinal metaplasia, and for the Hp load in gastric mucosa. Furthermore, the topografic type of

gastritis was named according to the mononuclear cell distribution. If the chronic gastritis score

for antrum was higher than the score for corpus, the subject was classified having an “antrum

predominant” gastritis. If the scores were equal, the patient was classified having a

“pangastritis”, and the rest of the cases were classified as “corpus predominant”. After one year

follow-up, endoscopy and histological evaluation were repeated.

4.3 Questionnaires

The symptoms and the quality of life were evaluated by separate questionnaires. Dyspeptic

symptoms were evaluated by a unique numeric scale questionnaire after every 3 months during

the one-year follow-up. The questionnaire was a modified version from the questionnaire used

in a Finnish patient population by Heikkinen et al. (Heikkinen et al. 1995, Heikkinen et al.1998).

Symptoms evaluated were pain in the upper abdomen (score 1-4), bloating (1-2), heartburn (1-

6), early satiety (1-2), nausea (1-6), vomiting (1-6), night-time pain (1-2), regurgitation (1-6),

and hunger pain (1-2). A total dyspepsia score was determined based on ’ulcer-like’ symptoms

(pain, night-time pain, and hunger pain; 0-8) plus ’dysmotility-like’ symptoms (nausea and

bloating; 0-8). In study I, patients were divided into two subgroups (ulcer-like and dysmotility-

like) based on the most predominant symptom-scores. Diagnosis of irritable bowel syndrome

was made according to the criteria of Thompson et al. (1989).

At baseline and 12 months later, quality of life was measured by a validated RAND 36-item

health survey 1.0 questionnaire, which is a cross-translated version of the SF-36 questionnaire

(Hays et al. 1993, Ware and Sherbourne 1992). It has been validated in a Finnish patient

population (Aalto et al. 1999). Quality of life was evaluated in eight different aspects. In

addition, change in general health was determined by one question.

33

4.4 13C-urea breath test

13C-UBT was carried out in 36 patients according to the method described by Logan et al.

(1991). A single point breath sample was taken 30 min after ingestion of the 13C-urea. The

sampling procedure was identical to that followed the collecting the baseline sample. All

samples were taken in duplicate. The 13C-enrichment in the expired breath was measured by

automated breath 13C- analysis, by means of continuous flow-isotope ratio mass spectrometry.

A DOB over 4‰ was considered positive, values between 2‰ and 4‰ were considered

inconclusive, and values below 2 ‰ were considered negative.

4.5 Scintigraphic measurement of gastric emptying

Gastric emptying was measured by a dynamic dual-tracer scintigraphic examination in 72

patients and again in 29 after one year. In addition, 11 healthy control subjects and 11 FD

patients without Hp infection were examined. After an overnight fast lasting at least 12 hr, the

subjects ate a warm 200g standard test meal within 5 min (lactose-free meat-cabbage casserole;

Ruoka-Saarioinen Oy, Sahalahti, Finland) labelled with 111-In (9.25 MBq). The energy content

of the meal was 220 kcal. After consuming the meal, the study subjects drank 150 ml 99mTc-

labelled (75 MBq) water just prior to the study. After the 5-min eating period, the patient was

placed in a supine imaging position. The dynamic double isotope examination with its 30-sec

acquisition time included images of the gastric area in anterior and posterior projections for a

total of 90 minutes. The regions of interest (ROIs) were drawn, including the areas of the entire

stomach, proximal (corpus) and distal (antrum) parts of the stomach and the distal part of the

oesophagus. The oesophageal ROI was drawn in order to detect any reflux that occurred during

the study. The background area was drawn outside, near the medial side of the stomach. The

time-activity curves were calculated as geometric means of the total counts of the anterior and

posterior ROIs. The mirrored ROIs were used for posterior-anterior images to produce

geometric mean values. The background subtraction was made by use of the information from

the background curve generated by the 111-In and 99m-Tc Compton scatter. The 50% post-lag

retention time (T50) for solid substance and the gastric emptying half-time (T1/2) for liquid

substance were determined separately from the dynamic curves. The lagtime in solid emptying

was determined at the turning point of the descending part of the time-activity curve of the

entire stomach. The intragastric distribution of solids was chosen to be calculated at 10 min as

a percentage ratio of the geometric means for the anterior and posterior ROI counts between the

antrum and the entire stomach. A scintigraphic image of a liquid emptying with the

34

demonstration of ROIs is shown in Figure 2.

4.6 Medication

At baseline, patients received omeprazole 20mg daily for the first three months and thereafter

placebo during the follow up. In addition to the omeprazole treatment the patients were

randomised either for Hp eradication therapy or for placebo antibiotics. Of the 151 patients 77

received eradication therapy for the first 2 weeks with amoxycillin 500mg q.i.d, metronidazole

400mg t.i.d, and omeprazole 20mg b.i.d; 74 patients received omeprazole 20mg b.i.d and

placebo antibiotics. Randomisation was done in blocks of four and the randomisation list was

generated by the manufacturer of the treatment medicines by a computer-based method.

Investigators (pathologist, gastroenterologists, and other personnel) and patients were blinded

to all data until the study was fully completed. The only exception was the 3-month omeprazole

treatment, which was only single-blinded and was known to the investigators but not to the

patients. In addition, the patients were told not to use any other medication for dyspepsia, but

merely contact the study personnel if their symptoms worsened markedly. During the follow-up,

patients visited research assistants after each 3-month period for controlling the use of study-

medication and to return the symptom questionnaires.

4.7 Statistical analysis

In study III, the patient population whose Hp eradication was successful was termed as a

successful eradication group, and patients whose Hp eradication failed or who received placebo

and remained Hp positive stood for controls. In studies I, II, III and V paired t-tests and

nonparametric tests (Mann-Whitney rank sum test and Kruskall-Wallis tests) were used for

comparing groups and linear regression analysis was used for analysing association between

continuous variables. In study IV, patients who received Hp eradication therapy and omeprazole

were named as treatment group, and patients who were treated with placebo-antibiotics and

omeprazole stood for controls. The changes in scores of various aspects of quality of life and the

changes in dyspepsia scores were compared between the treatment group and controls by means

of Mann-Whitney rank sum test. Patients with symptom score reduction of 50 % or more were

considered as responders, and Chi-square-test was used to evaluate the amount of responders

between treatment group and controls. Multiple regression analysis controlling for age, sex,

36

smoking habits, use of NSAIDs, Hp status, and irritable bowel syndrome was used in

multivariate analysis separately for total dyspepsia score and heartburn at the end of the 12-

month follow-up. Two-tailed p-values # 0.05 were considered statistically significant. Data was

analyzed by BMDB for windows system. All results are expressed as means ± SD.

37

5. RESULTS

5.1 Gastric emptying

In study I, eleven healthy subjects were compared to twenty-five patients with functional

dyspepsia divided to either ulcus-like or dysmotility-like symptoms to create a standardized

double-tracer scintigraphic method. Gastric emptying half-time in patients with dysmotility-like

symptoms was 79.8±34.7 min for solids and 35.4±9.4 for liquids. Gastric emptying half-time in

patients with ulcer-like dyspepsia was 100.0±64.2 for solids and 35.2±8.8 for liquids. There was

no statistical difference in any of these parameters between patients and control subjects.

However, solid lag-time was prolonged in patients with dysmotility like dyspepsia compared to

controls (6.7±4.4 vs 2.5±3.1; p<0.05). Among patients with dysmotility-like symptoms

13.5±9.1% of the solid content was located in the antrum after 10 minutes of ingestion whereas

this proportion was 5.2±2.3% for controls (p<0.01). As well, the intragastric distribution for

liquids was more distal in patients with dysmotility-like symptoms (p<0.05). In study II, these

eleven healthy controls were compared to 83 patients with functional dyspepsia. In addition, the

anatomical settings (ROIs) for graphic evaluation of the data were reassessed and therefore the

“normal values” changed slightly. The values of gastric emptying parameters for healthy control

subjects are demonstrated in Table 4.

In study II, 94 subjects were examined and the gastric emptying parameters were compared

between patients with functional dyspepsia and healthy controls. In this larger patient population,

the prolonged solid lag time for dyspeptic patients (4.5±4.9 min vs 1.0±2.0; p<0.05), was the

only statistically significant difference in these parameters. However, the tendency for slower

gastric emptying and more distal gastric content distribution was seen among patients with

functional dyspepsia. The gastric emptying parameters for the 83 patients with functional

dyspepsia are seen in Table 4.

38

Table 4. Gastric emptying parameters for 83 patients with functional dyspepsia compared to

eleven healthy control subjects (normal values).

Parameter Value Normal values P

Gastric emptying for solids T50

(min)

94.8 ± 57.6 77.4± 29.9 ns

Gastric emptying for liquids T1/2

(min)

34.6 ± 10.8 35.9 ± 11.2 ns

Intragastric distribution for solids

(% in antrum after 10 minutes)

7.1 ± 5.8 6.1 ± 3.2 ns

Solid lag-time

(min)

4.5 ± 4.9 1.0 ± 2.0 Prolonged in

patients with

NSAID-use

(P<0.05)

The roles of various factors in gastric emptying parameters were tested in this population of 94

subjects. Parameters tested were sex, age, dyspeptic symptoms, Hp status, irritable bowel

symptoms, lactase deficiency, habitual smoking and use of NSAIDs. Hp gastritis and NSAID-use

were associated with prolonged solid lag-time (p<0.05) as well as dyspeptic symptoms (p<0.05).

However, after multivariate analysis the use of NSAIDs was the only statistically significant

factor. Delayed liquid emptying (T1/2) was associated with increasing age (p<0.025). Habitual

smoking was linked to more distally distributed gastric content in the stomach. Among males,

smokers had more rapid solid emptying (T50) (p<0.05).

The role of successful Hp eradication in gastric emptying after 12 months (study III) is

demonstrated in Table 5.

39

Table 5. Gastric emptying parameters between H.pylori-eradicated and placebo-treated

functional dyspepsia patients at the beginning of the study and one year after eradication therapy

(n=29).

Before H.pylori eradication At one-year follow-up

Treatment

group

Placebo

group

p Treatment

group

Plecebo

group

p

T50/solids (min) 110.0+74.5 104.1+87.9 ns 104.3+61.0 86.1+44.3 ns

T1/2/liquids (min) 35.2+11.1 33.2+10.6 ns 33.2+9.6 33.7+9.9 ns

solid lagtime (min) 3.6+3.5 3.1+3.5 ns 4.1+3.1 4.9+2.9 ns

intragastric distribution

(% in antrum)

3.3+1.1 7.8+5.5 <0.05 5.6+3.2 * 8.4+4.0 ns

* p<0.05 compared with the baseline value

In this follow-up study, no differences were revealed between patients who had received a

successful Hp eradication therapy and patients with ongoing infection after one year. However,

this long-term prospective study showed the reproducibility of a scintigraphic gastric emptying

study. In the patient population, the association between the first examination and the one after

12 months follow-up was significant for both, solid gastric emptying (T50, p=0.20, R=0.43) and

liquid emptying (T1/2, p=0.018, R=0.43).

5.2 Treatment effect on dyspeptic symptoms and quality of life

The dyspepsia symptom scores at the beginning of the study, after cessation of omeprazole

treatment (3 months) and after the follow-up (12 months) are demonstrated in Figure 3. 136

patients completed the one year follow-up. After 3-month omeprazole treatment, the total

dyspepsia symptom score diminished from 10.4±3.3 to 7.6±2.9 in the treatment group and from

10.2±2.9 to 7.5±2.7 in the control group. No statistical difference was revealed in the changes of

dyspepsia scores between these groups. After the 12-month follow-up, the dyspepsia score was

7.4±3.0 in the treatment group with a mean symptom reduction of 28.8% compared to baseline.

In the control group the dyspepsia score was 7.6±3.1 with the mean symptom reduction of 21.7%

41

(p=ns). In a multivariate model, female gender was the only factor independently related to

dyspeptic symptoms (p=0.02). The whole model accounted for 9% of dyspeptic symptoms. No

factor tested (Hp status, age, sex, use of NSAIDs, smoking habits, or irritable bowel) was related

to heartburn. In treatment group, 16 (20.8%) patients were considered as “responders” to the

treatment (symptom reduction at least 50%), whereas 11 (14.9%) “responders” were found in

the control group (p=0.32). In analysis by Hp status after 12-month (per protocol analysis), the

symptom reduction was 30.4% in patients with successful Hp eradication and 22.2% among

those who remained Hp positive after 12-month follow-up (p=ns) (Table 6).

Table 6.

Outcomes of the symptom-evaluation at one year.

Treatment Placebo

Change in

scores

95% CI Average

symptom

reduction

Change in

scores

95% CI Average

symptom

reduction

p

ITT

(by treatment

groups)

-3.1±3.4 -3.9- -2.2 28.8 % -2.2±3.0 - 3.0- -1.4 21.7 % 0.3

PP

(by Hp status)-3.2±3.5 -4.1– -2.4 30.4 % -2.1±3.0 -2.8– -1.4 22.2 % 0.1

In separate dyspeptic symptoms, a statistically significant reduction in nausea, vomiting,

bloating, heartburn, regurgitation, abdominal pain, and night-time pain was established in both

patient groups. Improvement in early satiety was seen only in the Hp eradicated patients. After

12 months’ follow-up, the statistically significant reduction in these seven symptoms was still

evident. However, heartburn (p<0.01) and regurgitation (p<0.001) revealed a relapse after

cessation of the 3-month omeprazole treatment in both patient groups (Figure 4). Statistically

significant relapse of bloating (p<0.05) was seen in the Hp eradicated patients, and relapse of

nausea (p<0.05) occurred among the Hp positive, after this 3-month period with acid-

suppression therapy.

43

In analysis of quality of life, the changes in the nine aspects are illustrated in Figure 5. In the

treatment group, the bodily pain reduced (p<0.05), and in the control group the mental health

improved (p<0.05). General health improved in both patient groups (p<0.001), but this aspect

was evaluated only by one question. Although all the aspects of quality of life showed a clear

tendency to improve during the study, there was no difference between treatment group and

controls after the 12-month follow-up.

5.3 Gastritis and dyspeptic symptoms

From the total of 143 patients 52% (74) had antrum-predominant gastritis, 38% (55) had

pangastritis and 10% (14) had corpus-predominant gastritis. The dyspepsia symptom scores in

separate types of chronic gastritis are shown in Table 7. There was no statistical difference in

any of the dyspepsia scores (total dyspepsia score, ulcuslike dyspepsia score, dysmotilitylike

dyspepsia score) between different types of gastritis prior to the medication. As well, the

severity of gastritis was not associated with the dyspeptic symptoms. Hp eradication rate was

100 % in patients with corpus-predominant gastritis compared to the 71% rate in antrum-

predominant gastritis and 88 % in pangastritis. However, there were only five patients in

eradication therapy group with corpus-predominant gastritis.

45

Table 7.

Properties of different gastritis subtypes at baseline.

Antrum-

predominant

Pangastritis Corpus-

predominant

Total

N 74 (52 %) 55 (38 %) 14 (10 %) 143

H.pylori

density score

3.7±1.3 3.8±1.3 2.5±1.2 3.6±1.4

Total gastritis

activity score

1.8±1.0 2.2±1.0 2.2±1.1 1.9±1.1

Total chronic

gastritis score

3.6±1.0 4.4±1.1 4.4±0.9 3.9±1.2

H.pylori

eradication

rate ITT (%)

25/35 (71) 24/27 (88) 5/5 (100 ) 54/67 (81)

Total

dyspepsia

score

10.4±3.2 10.0±3.2 10.0±3.4 10.2±3.2

Ulcuslike

dyspepsia

score

5.1±1.5 4.9±1.5 4.8±1.3 5.0±1.4

Heartburn

score

4.0±2.0 4.1±2.1 3.7±1.8 4.0±2.0

Among subtypes of chronic gastritis, dyspepsia symptom score reduced significantly after the 3-

month omeprazole treatment in patients with successfully Hp eradicated corpus-predominant

gastritis compared to controls with corpus-predominant gastritis. However, the difference was

not seen after the whole 12-month follow-up. In patients with antrum-predominant gastritis, the

reduction of dyspepsia was more profound among successfully Hp eradicated, and the difference

increased significantly after the 12-month follow-up (Table 8., Figure 6.). In different subtypes

47

of gastritis, no differences in ulcus-like dyspepsia or heartburn were seen between successfully

Hp eradicated patients and controls with ongoing infection during the follow-up.

5.4. Urease activity

Among the 36 patients whose urease activity was measured, the mean DOB-value was 43.3 ±

21.1. There was no association between the urease activity of the stomach and the total chronic

gastritis score (Figure 7.) or gastritis activity score. In addition, no association between Hp load

in gastric mucosa and the DOB-value of UBT was seen. However, the urease activity of the

stomach was associated with the subtype of chronic gastritis (Figure 7.). The mean DOB-value

in patients with antrum-predominant gastritis or pangastritis was 46.8 ± 20.5, whereas patients

with corpus-predominant gastritis had a mean DOB-value of 28.6 ± 20.0 (p<0.05). Furthermore,

the urease activity of the stomach was higher in patients with moderate or severe chronic

gastritis in antrum than in patients with mild or absent chronic antrumgastritis (Figure 7).

Patients with mild chronic gastritis in antrum (score 0-1) had a mean DOB-value of 14.2 ± 15.4,

and patients with moderate or severe antrumgastritis had a mean DOB-value of 45.9 ± 19.9

(p<0.05).

49

Table 8.

Change in dyspepsia scores in separate types of chronic gastritis among Hp eradicated patients

and patients who remained Hp positive after treatment.

After 3-month After 12-month

omeprazole treatment follow-up

H.pylori

eradicated

H.pylori

positive

p H.pylori

eradicated

H.pylori

positive

p

All patients -3.2 ± 2.9

(-4.0- -2.5)

-2.3 ± 3.0

(-3.0- -1.6)

0.07 -3.2 ± 3.5

(-4.2- -2.4)

-2.1 ± 3.0

(-2.9- -1.4)

0.13

Antrum-

predominant

gastritis

-3.7 ±2.7

(-4.8- -2.5)

-2.8 ± 3.0

(-3.9- -1.7)

0.12 -3.6 ± 2.9

(-4.8- -2.3)

-1.7 ± 2.9

(-2.7- -0.6)

0.05

Pangastritis -2.9 ± 3.3

(-4.4- -1.5)

-2.0 ± 3.2

(-3.2- -0.7)

0.32 -2.8 ± 3.4

(-4.3- -1.3)

-3.1 ± 3.2

(-4.5- -1.8)

0.88

Corpus-

predominant

gastritis

-4.8 ± 3.0

(-8.6- -1.0)

-0.9 ± 2.0

(-2.6- 0.8)

0.03 -5.2 ± 6.4

(-13.2-2.8)

0.0 ± 1.6

(-1.3-1.3)

0.15

50

6. DISCUSSION

6.1. Gastric emptying

We demonstrated a dual-tracer method to analyze the gastric emptying simultaneously for liquid

and solid contents. As is the problem with many other isotope-based gastric emptying tests,

many physiologic factors should be standardized to obtain a reliable result (Akkermans and Van

Isselt 1994). We used a standardazided test meal and a supine position, timing of the

imagination was equal (between 8 and 10 am) and the use of medication affecting gastric

emptying was not allowed prior to the examination. Gastric emptying parameters used (solid lag

time, solid postlag emptying rate and 50% emptying time for liquids) are generally accepted

(Akkermans and Van Isselt 1994). The shortcoming of our method was that cigarette smoking

was permitted before the imaging. Cigarette smoking has previously been shown to affect

gastric motility ((a)Scott et al. 1993, Hausken and Berstadt 1992). The number of control

subjects was limited and the range of normal values in the gastric emptying parameters remained

quite wide. This variability and the poor correlation between symptoms and altered gastric

emptying have previously been documented (Klauser et al 1993, Vantrappen 1994, Talley et al.

1989). Although, the follow-up study (III) was mainly planned to assess the effect of treatment

on gastric emptying, and not the reproducibility of our scintigraphic method, the data showed

gastric emptying rate to be stable after 12-months, whether Hp was eradicated or not. To our

knowledge, the long-term reproducibility of isotope-based gastric emptying measurement has

not been previously documented. We consider our method to be a reliable tool for evaluating

gastric emptying also in selected clinical settings, for example diagnosing gastroparesis in

complicated cases or using this method in clinical research.

Theoretically, Hp may affect gastric emptying through several hypothetical mechanisms:

cytokines, inflammatory cell infiltration of the mucosa and changes in the secretion of some

gastrointestinal hormones (Go and Crowe 2000). However, studies on gastric emptying in

relationship to H.pylori infection have showed inconclusive results (Table 9)

51

Table 9.

Studies on gastric emptying and H.pylori including present study.

Reference Patients Method Main results

Tucci et al. 45 FD (27 Hp+, 18 Hp-) Scintigraphy, solid

meal

Delayed in FD

Delayed for Hp-

Miyaji et al. 46 FD (31 Hp+, 15 Hp-) scintigraphy, EGG,

eradication therapy, 2

month follow-up

Eradication therapy

normalized altered

(delayed or rapid)

gastric emptying

Chiloiro et al. 27 FD, 30 controls ultrasound, solid-

liquid meal

No differences between

groups, alterations in

gastric hormones in Hp+

Goh et al. 39 FD (20Hp+, 19Hp-),

20 controls

Scintigraphy, solid

meal, eradication

therapy

No difference between

FD and controls or after

eradication therapy

Rhee et al. 34 FD Scintigraphy, gastric

barostat

No differences in gastric

emptying or gastric

sensitivity between Hp+

and Hp-

Testoni et al. 38 FD (20 Hp+, 18 Hp-) Scintigraphy,

manometry

No difference in gastric

emptying gastritis+ or

gastritis-, reduction of

MMC of gastric phase

III in Hp+

Scott et al. 75 FD (25 Hp+, 50 Hp-) Dual-tracer

scintigraphy, solid

and liquid meal

Longer solid lagtime for

Hp-, altered intragastric

distribution in FD

Caballero-

Plasencia et al.

50 FD, 10 controls Scintigraphy, solid

meal

Delayed in FD, no

difference in Hp+ and

Hp-

52

Reference Patients Method Main results

Parente et al. 38 FD, Hp+ Eradication therapy or

ranitidine, 6 month

follow-up, solid meal

No difference in gastric

emptying or acid

secretion, reduced

gastrin and PGI after

eradication

Perri et al. 304 FD (208 Hp+) 13C-octanoic acid

breath test, solid meal

No difference between

Hp+ and Hp-, delayed

emptying associated

with postprandial

fullness and nausea

Chang et al. 60 FD (38 Hp+, 22 Hp-) Scintigraphy, solid

meal

Delayed in FD, no

difference in Hp+ and

Hp-

Saslow et al. 16 controls (8 Hp+, 8 Hp-) Scintigraphy, solid

meal

No difference in Hp+

and Hp-

Fock et al. 72 FD, (23 Hp+, 49 Hp-),

32 controls

Gastric emptying of

radio-opaque markers

Delayed in FD, delayed

in Hp+

Present study

(II)

83 FD (72 Hp+, 11 Hp-),

11 controls

Dual-tracer

scintigraphy, solid

and liquid meal

Prolonged solid lagtime

in NSAID users,

alterations in smokers,

delayed liquid emptying

in older subjects

Present study

(III)

29 Hp+ FD and 11 controls Dual-tracer

scintigraphy, solid

and liquid meal, 12

month follow-up after

Hpylori eradication

No difference between

Hp+ and Hp eradicated

after 12-months, stable

individual gastric

emptying rate

53

We found a trend of delayed gastric emptying among FD patients but the finding was not

statistically significant. In overall, delayed gastric emptying in FD patients seems to vary

between 30% to 80% in published studies (Klauser et al. 1993, Malagelada 1991, Quartero et al.

1998), and the significance of this weak association between FD and prolonged gastric emptying

may have only minor clinical impact. We demonstrated prolonged solid lag time especially in

Hp positive subjects. Scott et al. ((b)1993) have reported an opposite finding but they have

excluded patients with ulcerlike dyspepsia. This is an interesting finding because antral part of

the stomach with peristaltic contractions is associated with gastric emptying rate of solids

(Minami and McCallum 1984). In our study considering the treatment response of FD by

eradicating Hp, patients with antrum-predominant gastritis got benefit from the eradication

therapy. In addition, antral hypomotility has been demonstrated among Hp positive FD patients

(Mearin et al. 1995), and improvement of gastric hypomotility has been documented after

successful Hp eradication (Thor et al. 1996). Conversely, Pieramico et al. (1993), did not find

differences in postprandial antral motility between Hp positive and negative patients. Studies on

gastric motility between different subtypes of Hp gastritis have not been performed. Severe

antrum-predominant chronic gastritis may have a role in altered gastric emptying, especially of

solid contents.

6.2. Symptoms and quality of life after H.pylori eradication

Although in general, the aspects of quality of life showed a clear tendency for improvement in

both treatment groups (Figure 5.), the reduction in bodily pain (p<0.05) in treatment group and

the improvement of mental health (p<0.05) were the only statistically significant changes. After

12-months, no clear difference in quality of life was demonstrated between groups. The quality

of life outcome in our study was very similar to the one in the study by Blum et al. (1998).

Therefore, we can conclude that this measurement tool can not demonstrate any treatment effect

favouring H.pylori eradication in functional dyspepsia. However, the role of placebo effect was

clearly observed.

Adequately performed H.pylori eradication studies in functional dyspepsia, including the

present study, are demonstrated in Table 10.

54

Table 10.

Studies of H.pylori eradication treatment in functional dyspepsia

Study N Symptom

assessing

Medication Control of

extra acid-

suppression

Follow-

up time

Study

design

Other Result / Conclusion

Present

study

151 Numeric scale

questionnaire and

RAND-36 (quality

of life)

Eradication

therapy vs

placebo

antibiotics and

3kk omeprazole

for all patients

3 kk omeprazole

treatment for all

patients, no extra

medication

12 months Single-

center

No differences in changes of

symptom or quality of life

scores

Talley -

99

(BMJ)

278 Gastrointestinal

symptom rating

scale and the

Psychological

general well being

index

ome+amo+cla (1

week) vs placebo

A weak antacid was

dispensed to patients

and extra medication

was monitored

12 months Multi-

center (40

centres)

Moderate or

severe gastritis

was associated

to impaired

treatment

success

No difference in treatment

success between groups

Greenbe

rg -99

(ArchInt

ernMed)

100 visual analog

symptom scale

ome+cla (2

weeks) vs

placebo

no extra medication 12 months Single-

center

HP eradication

only 71%

No difference in change of

symptom score

Talley -

99

(NenglJ

Med)

293 Gastrointestinal

Symptom Rating

Scale and diary

cards and SF-36

(quality of life)

ome+amo+cla (2

weeks) vs

placebo

A weak antacid was

dispensed to patients

12 months Multicenter No differences between groups

in symptoms or quality of life

Blum-

98

(NEnglJ

Med)

348 Likert scale diary

cards and

Gastrointestinal

symptom rating

scale and

psychological ell

being index

ome+amo+cla

(one week) vs

ome+placebo

Not known 12 months Multicenter Hp eradication

rate only 79%

No differences between groups

in symptoms or quality of life

McColl

-98

(NEnglJ

Med

330 Glasgow

dyspepsia severity

score and SF-36

(quality of life)

ome+amo/tetra+

metro (2 weeks)

vs placebo+ome

Use of extra

medication included

in the score system

12 months Single-

center

No endoscopy at

the end of the

follow-up

Resolution of symptoms

associated with eradication

therapy, no differences in

dyspepsia scores, long history

of dyspepsia associated to poor

treatment success

Froechli

ch -01

(Am J

Gastroe

nterol)

144 SF-12

Questionnaire

lan+amo+kla (1

week) vs

lan+placebo

Use of extra

medication was

monitored

12 months Multicenter No difference between groups

55

The common problem in these studies is the different outcome measure of dyspeptic symptoms.

Other problem is the extra medication used, which is in general poorly controlled. Acid-

suppressing therapy, especially with PPIs, is nowadays the most used treatment in FD (Ryder et

al. 1994), and recent studies have shown a positive effect on symptoms of FD by PPI treatment

(Meinache-Schmidt et al. 1999, Talley et al. 1998). In our study, the acid suppression was

standardized by using an initial 3-month omeprazole treatment for all patients. However,

shortcoming of our study is the questionnaire. Although, it has previously been used in Finnish

patient population (Heikkinen et al.1995 and 1998), it has not been planned for scoring

dyspeptic symptoms. In contrast, our SF-36-questionnaire measuring quality of life, has been

cross-translated and validated. In general, direct translations from different questionnaires can

not be used. For example, the terms “heartburn”, “halsbränna” and “närästys” may have very

different meanings among dyspeptic patients. In addition, the Glascow dyspepsia severity score

(McColl et al. 1998) including home visits by doctors can not be used in Finnish health-care

system.

As is the case in most studies published, the patient selection is based on past medical history

and gastroscopy findings. It is impossible by these means to totally rule out patients with reflux

disease, although the symptom analysis has been considered as the most useful method for

diagnosing reflux disease (Dent 1998). In the present study, improvement in pain, heartburn,

regurgitation, and nausea after the omeprazole treatment of three months was clear, although

patients with predominant reflux symptoms had been excluded. This positive effect was

maintained during the rest of the follow-up and it was obvious whether the Hp was eradicated

or not. Treatment with PPIs has shown positive effect in patients with ulcerlike or refluxlike

dyspeptic symptoms (Farup et al. 1999, Talley et al. 1998). However, no treatment studies in Hp

positive FD with previous oesophageal pH monitoring exist. Also in our data, the reflux-like

symptoms showed a clear relapse after cessation of omeprazole therapy in both patient groups,

and it points to the conclusion that the effect of omeprazole treatment disappeared and patients

with NERD may have been included. However, we demonstrated a sustained resolution of other

dyspeptic symptoms. In our opinion, we can not be sure whether this long-term symptom

improvement was due to omeprazole treatment or to placebo effect. Also in follow-up studies

without prolonged acid-suppressing therapy ((b)(c)(Talley et al. 1999, McColl et al.1998, Blum

et al. 1998), a clear improvement of dyspeptic symptoms has been achieved in treatment group

and controls. This points to the conclusion that the placebo-effect on treatment of Hp-positive

56

FD is marked (vanZanten et al. 1996, Grant Thompson 2000). Two recent meta-analyses

handling treatment of Hp positive FD have reached opposite conclusions (Laine et al. 2000,

(b)Moayyedi et al. 2000). Four of five treatment studies, including present study, have shown no

effect on treatment of Hp in symptoms of FD (Table 10). However, all studies have shown a

mild tendency favouring Hp eradication. More detailed studies with careful patient inclusions

(oesophageal pH-monitoring, controlling extra-medications, evaluating different subtypes of

gastritis) are needed to verify the real association between Hp infection and FD. So far in

clinical practice, the benefit from eradicating Hp from patients with FD seems to have a minor

impact on symptom reduction.

6.3. Subtypes of gastritis and urease activity of the stomach

Chronic active gastritis affecting the antrum is associated with duodenal ulcer disease, whereas

fundus-predominant gastritis mainly leads to loss of acid secretory capacity and atrophy

(Sipponen et al.1989, 1990, 1993, McColl et al. 2000). As discussed earlier, the role of Hp

gastritis on dyspeptic symptoms, without ulcer-disease, is still unclear. However, the role of

different topographic types of gastritis on functional dyspepsia has been documented

insufficiently. There is evidence that antral gastritis is associated with ulcus-like symptoms in

FD (Trespi et al. 1994). In addition, improvement of dyspeptic symptoms has been associated to

healing of chronic gastritis in the study by Talley et al.(c)(1999). On the other hand, no

difference has been shown between FD and DU patients in the severity of corpus gastritis in Hp-

positive subjects (Khulusi et al. 1995). In the present study, no difference in symptom reduction

between successfully Hp eradicated patients and controls was seen, but the subgroup with

antrum-predominant chronic gastritis showed a clear benefit from this therapy. Chronic antrum-

predominant gastritis subsides slowly, and there is evidence that12 months after eradication

almost half of the patients still have persistent chronic antrumgastritis (Valle et al. 1991).

Probably, a more profound effect on the symptoms in patients with antrum-predominant Hp

positive gastritis would have been seen, if we had had a longer follow-up period. Interestingly,

prolonged acid-suppression therapy improves Hp induced gastritis in antrum but aggravates

gastritis parameters in corpus, and it may even suppress Hp load in gastric mucosa (Stolte et al.

1998, Meining et al. 1998). This may partly clarify our positive treatment result in this antrum-

predominant gastritis subtype. Is the antrum-predominant Hp positive active gastritis only a

subtype of chronic peptic ulcer disease? The finding in our study concerning the best long-term

treatment response after successful Hp eradication in patients with antrum-predominant gastritis

57

has similarities to peptic ulcer disease. Previously, antrumgastritis has been strongly linked to

peptic ulcer disease, and as discussed earlier, ulcer-like symptoms have been linked to Hp

positive functional dyspepsia.

It is known that urease is a virulence factor and it is essential for Hp colonisation (Tsuda et al.

1994). There is also evidence that ammonia generated by the action of urease causes histological

damage in epithelial cells, and therefore it plays an important role in the inflammation process

(Eaton et al. 1991). In addition, DU patients have shown to have higher gastric biopsy urease

activity than FD patients with Hp infection (Khulusi et al. 1995). In clinical practice, 13C-UBT

is used to detect the Hp status non-invasively. In our study, it was used to detect the quantity of

total urease activity in the stomach at the moment the biopsies were taken. We noticed that the

urease activity of patients with antrum-predominant gastritis or pangastritis is higher than in

patients with corpus-predominant gastritis. Furthermore, the urease activity increased with the

increasing severity of chronic antrumgastritis. This may have some implications in clinical

practice to evaluate patients who will get benefit for their symptoms with Hp eradication.

6.4. Clinical applications and suggestion for management of functional dyspepsia

Dyspeptic patients are very common in clinical practice and it is not possible or reasonable to

profoundly investigate each dyspeptic patient. Missing gastric or esophageal malignancy is the

shortcoming of the strategy to investigate dyspeptic patients noninvasively only. If population

over 40 years with dyspeptic symptoms is endoscopied, 70% of gastric cancers were diagnosed

by investigating just 1% of population (Mollmann 1981 ). In other studies (O'Hanlon et al.

1996, Hallisey et al. 1990, Christie et al. 1997), the age-recommendation for endoscopying

dyspeptic patients varies between 40 to 55 years. By previous patient history, an evaluation of

other possible diseases causing dyspeptic symptoms should be done. These conditions are for

example inferior ischaemic heart disease causing dyspepsia-like symptoms, biliary-tract

problems, connective tissue diseases causing GI-motility problems and few endocrinologic

diseases. Use of NSAIDs should be asked but most important is the evaluation of classical

“alarm symptoms”. These include problems in swallowing, weight-loss, fever or suspicion of

bleeding from GI-tract (anaemia, haematemesis, melena). Patients having these symptoms

should be carefully investigated. Patients having reflux-like symptoms, heartburn and

regurgitation, very likely have reflux-disease, because a typical anamnesis is known to be

specific for this condition (Klauser et al. 1990). Therefore, patients with predominantly reflux-

58

like symptoms should be treated according to reflux-disease.

Hp eradication therapy is reasonable based on the knowledge that at least patients with ulcer-

disease, and according to present study, patients with antrum-predominant gastritis get benefit

for their symptoms after successful Hp eradication. In “functional dyspepsia”, antrum-

predominant Hp gastritis may even represent a subtype of chronic peptic ulcer disease, because

if a subject with Hp gastritis is endoscopied only once, the signs of ulcer may not be present at

the moment. In addition, the long-term risks of Hp gastritis are marked (chapter 2.2.2) and

colonisation of gastric mucosa by Hp can not be considered as normal flora. Therefore, it is

questionable to classify Hp positive subjects in “functional dyspepsia”. In clinical practice, it is

logical to give eradication therapy to Hp positive patients with upper abdominal symptoms and

no contraindications for the medication. As a non-invasive test to detect Hp, 13C-UBT,

quantitative serology or antigen detection from a stool sample are recommended (Niemelä et al.

2000). As it was shown in present study, the quantitative result of 13C-UBT may detect patients

with favourable eradication treatment effect in Hp positive gastritis without ulcer-disease.

Optimal symptomatic treatment of FD patients is not easy. Treatment responses with PPIs, H2-

blockers or prokinetics are best documented, although the treatment effect may be marginal (Soo

et al. 2001, van Zanten et al. 1996). As it is shown in the present study, the placebo-effect of

treatment is marked, but at least, patients with reflux-like symptoms will get benefit from PPI

therapy. Cisapride has been associated with serious arythmogenic side-effects (Napolitano et al.

2000, McMullin et al. 1999) and therefore using it in the treatment of “benign” dyspeptic

symptoms is not justifiable. As it is shown in this study, the delayed gastric emptying may have

only minor impact on symptoms of functional dyspepsia. However, cisapride still has an

important role in the treatment of GI-tract motility disorders including diabetic gastroparesis.

Scintigraphic gastric emptying study can be helpful in patients with problematic symptoms

suggesting gastroparesis but no evidence of gastric retention in endoscopy. Colon irritable-

symptoms are often linked with functional dyspepsia, and treatment with fibre-products or with

anticholinergic agents may be useful in some cases. In the future, agents targeted to 5-HT-

receptors will probably be helpful in the treatment of irritable bowel syndrome. There are only

limited data considering the treatment of dyspepsia with psychiatric medication. In functional

chest-pain, treatment with anti-depressive agents has been useful and it could be worth trying in

some patients with functional dyspepsia (Fisher and Parkman 1998).

59

In conclusion, the most important part in treating dyspepsia, is to rule out a possible organic

disease. Thereafter the treatment is planned based on patients’ Hp status, age and symptom

pattern. Each patient should be treated individually but general treatment strategies are useful

tools in practice. Based on these facts, an algorithm (modified from The European Helicobacter

pylori study group 1997) for investigating dyspeptic patients is expressed in Figure 8.

61

7. CONCLUSIONS

1. In general, Hp positive patients with functional dyspepsia did not get benefit for their

symptoms by eradication therapy, but at least refluxlike symptoms were improved with

omeprazole treatment. Placebo effect on treatment was marked.

2. Dual-tracer scintigraphic examination of gastric emptying was reproducible and revealed that

the individual gastric emptying rate in patients with FD was stable during one year. Although

FD symptoms and Hp infection were associated with prolonged solid lagtime, no major

alterations in gastric emptying were seen between FD patients and controls. Hp eradication had

no effect on gastric emptying parameters during 12 months.

3. Hp positive antrum-predominant gastritis in patients with FD was associated with positive

treatment effect by eradicating Hp. High urease activity detected by 13C-UBT of the stomach

was associated with antrum-predominant gastritis or pangastritis in these patients. Hp density in

gastric mucosa did not correlate with the severity of symptoms of FD.

62

8. ACKNOWLEDGEMENTS

I have had the privilege to work under the superb supervision of Docent Martti Färkkilä, the

present Head of the Division of Gastroenterology at Helsinki University Central Hospital. His

intelligence and skills in clinical gastroenterology have provided me with continuous

encouragement during this study. I also appreciate his great sense of humour, which has been

important for me in daily work.

I am greatly indebted to Professor Kari Seppälä and Professor Tatu Miettinen for the

opportunity to work at their Departments and for their support in teaching me gastroenterology

in the beginning of my career.

I wish to extend my gratitude to Docent Seppo Niemelä and Docent Pekka Pikkarainen, the

official reviewers of this thesis, for their valuable advice concerning the final manuscript.

I owe my sincerest thanks to Professor Kalevi Kairemo, Chief Medical Officer of the

Department of Oncology, Radiology and Clinical Immunology at Uppsala University Hospital,

for his endless enthusiasm and important advice to measure gastric motility by scintigraphic

imaging. His contribution has been absolutely crucial for this study.

I am grateful to Professor Pentti Sipponen, the Head of the Divison of Pathology at Jorvi

Hospital for performing the histological analyses of the gastric biopsy samples. His fabulous

expertise in the scientific field of Helicobacter pylori is greatly appreciated.

I like to thank Tapani Korppi-Tommola, PhD for his practical help and patience in teaching me

scintigraphic examinations. It has been a pleasure to work with him. I have been honoured to

work with several colleagues who have helped me to screen the study population and treat our

patients after the follow-up studies. I wish to thank Perttu Arkkila, MD, PhD, Markku Hillilä,

MD, Kati Jantunen, MD, Airi Jussila, MD, Tarmo Koivisto MD, Jukka Korpela, MD, PhD, Juha

Kuisma, MD, Urpo Nieminen, MD, PhD, Hannu Nuutinen, MD, PhD, Henna Rautiainen, MD,

Ulla Turunen, MD and Matti Vauhkonen, MD, PhD.

I want to thank the staff of the Division of Gastroenterology, especially the study assistants, for

their help in performing the gastroscopies and other clinical examinations. Without them, it

64

9. LIST OF REFERENCES

Aalto AM, Aro A, Teperi J. RAND 36 Item. Finnish version. STAKES 101. (National Research

and Development Centre for Welfare and Health). Helsinki, 1999

Agreus L, Svärdsudd K, Nyren O, Tibblin G. Prevalence of dyspepsia and demographic

characteristies in a Swedish adult population. Scand J Gastroenterol 1994;29:102-9.

Agreus L, Talley NJ, Svärsudd K, Nyren O, Tibblin G, Jones MP. Natural history of reflux,

dyspepsia and irritable bowel over 7 years in the general population. Gastroenterolgy

1998;114:A2

Akkermans LMA, van Isselt JW. Gastric motility and emptying studies with radionuclides in

research and clinical settings. Dig Dis Sci 1994;39:95S-96S.

Anand BS, Graham DY. Ulcer and Gastritis. Endoscopy 1999;31:215-225

Armstrong D. Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol 1996;31

(suppl 215):38-47.

Ashorn M, Mäki M, Hallstrom M, Uhari M, Akerblom HK, Viikari J, Miettinen A. Helicobacter

pylori infection in Finnish children and adolescents: A serologic cross-sectional and follow-up

study. Scand J Gastroenterol 1995;30:876-879

Atherton JC, Spiller RC. Leading article:The urea breath test for Helicobacter pylori. GUT

1994;35:723-725

Blaser MJ. Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced

inflammation. Gastroenterology 1992;102:720-727

Blum AL, Talley NJ, O'Morain C, van Zanten SV, Labenz J, Stolte M, Louw JA, Stubberod A,

Theodors A, Sundin M, Bolling-Sternevald E, Junghard O. Lack of effect of treating

Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1875-

81.

65

Borromeo M, Lambert JR, Pinkard KJ. Evaluation of CLO-test to detect Campylobacter

pyloridis in gastric mucosa. J Clin Pathol 1987;40:462-463

Brown C, Rees WDW. Dyspepsia in general practice. BMJ 1990;300:829-830

Broutet N, Gisbert JP, Pajares JM. Epidemiology. Curr Opin Gastroenterol 1999;15(suppl 1):

S43-S47

Caballero-Plasencia AM, Muros-Navarro MC, Martin-Ruiz JL, Valenzuela-Barranco M, de los

Reyes-Garcia MC, Casado-Caballero FJ, Rodriguez-Tellez M, Lopez-Manas JG. Dyspeptic

symptoms and gastric emptying of solids in patients with functional dyspepsia. Role of

Helicobacter pylori infection. Scand J Gastroenterol 1995;30:745-51

Camilleri M, Malagelada JR, Brown ML, Becker G, Zinsmeister AR. Relation between antral

motility and gastric emptying of solids and liquids in humans. Am J Physiol 1985;G580-G585

Camilleri M, Brown M, Malagelada JR. Relationship between impaired gastric emptying and

abnormal gastrointestinal motility. Gastroenterology 1986;91:94-9

Caselli M, Zaffoni E, Trevisani L, Sartori S, Avisi V. Diagnosis of Helicobacter pylori infection

by HpSA test (correspondence). Lancet 1999;354:1209-1211

Cederberg A, Varis K, Salmi HA, Sipponen P, Härkönen M, Sarna S. Young onset peptic ulcer

disease and non-ulcer dyspepsia are separate entities. Scand J Gastroenterol 1991;186:33-44.

Chang CS, Chen GH, Kao CH, Wang SJ, Peng SN, Huang CK. The effect of Helicobacter pylori

infection on gastric emptying of digestible and indigestible solids in patients with nonulcer

dyspepsia. Am J Gastroenterol 1996;91:474-9

Chen JD, McCallum RW. Clinical applications of electrogastrography. Am J Gastroenterol

1993;88:1324-1336.

Chen JD, Ke MY, Lin XM, Wang Z, Zhang M. Cisapride provides symptomatic relief in

functional dyspepsia associated with gastric myoelectrical abnormality. Aliment Pharmacol

66

Ther 2000;14:1041-7.

Chiloiro M, Russo F, Riezzo G, Leoci C, Clemente C, Messa C, Di Leo A. Effect of

Helicobacter pylori infection on gastric emptying and gastrointestinal hormones in dyspeptic

and healthy subjects. Dig Dis Sci 2001;46:46-53

Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of

55:implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-517

Danesh J, Lawrence M, Murphy M, Roberst S, Collins R. Systematic review of the

epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated

dyspepsia. Arch Intern Med 2000;160:1192-1198

Datz FL. Considerations for accurately measuring gastric emptying. J Nucl Med 1991;32:881-

884

Datz FL, Christian PE, Huston WR, Moore JG, Morton KA. The effect of physical and

psychologic stress on gastric emptying. J Nucl Med 1990;31:800-801

Datz FL, Christian PE, Moore JG. Differences in gastric emptying rates between menstruating

and post-menopausal women. J Nucl Med 1987;28:604-605

Dent J. Gastro-oesophageal reflux disease. Digestion 1998;59:433-445

Dent J, Brun J, Fendrick AM, Fennerty MB, Janssens J, Kahrilas PJ, Lauritsen K, Reynolds JC,

Shaw M, Talley NJ. An evidence-based appraisal of reflux-disease management - the Genval

workshop report. Gut 1999;44(suppl 2):S1-S16

Des Varannes S, Flojou J-F, Colin R, Zaom M, Meunier A, Chu G, Laennec R. Helicobacter

pylori eradication in non-ulcer dyspepsia: a randomized double-blind, placebo-controlled study

with a 12-month follow-up. Gastroenterology 2000;118:A468

Duan LP, Zheng ZT, Li YN. A study of gastric emptying in nonulcer dyspepsia using a new

ultrasonographic method. Scand J Gastroenterol 1993;28:355-360

67

Dunn BE, Campbell GP, Perez-Perez GI, Blaser MJ. Purification and characterization of urease

from Helicobacter pylori. J Biol Chem 1990;265:9460-9

Eaton KA, Brooks CL, Morgan DR, Krakowka S. Essential role of urease in pathogenesis of

gastritis induced by Helicobacter pylori in gnotobiotic piglets. Infect Immun 1991;59:2470-

2475.

El-Omar E, Penman I, Dorrian CA, Ardhill JES, McColl KEL. Eradicating Helicobacter pylori

infection lowers gastrin mediated acid secretion by two-thirds in patients with duodenal ulcer.

Gut 1993;34:1060-1065

El-Omar E, Penman I, Ardill JES, McColl KEL. A substantial proportion of non-ulcer dyspepsia

patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut

1995;36:534-538.

Elta GH, Behler EM, Colturi T. Comparison of coffee intake and coffee-induced symptoms in

patients with duodenal ulcer, nonulcer dyspepsia, and normal controls. Am J Gastroenterol

1990;85:1339-1342.

Farup PG, Hovde O, Torp R, Wetterhus S. Patients with functional dyspepsia responding to

omeprazole have a characteristic gastro-oesophageal reflux pattern. Scand J Gastroenterol

1999;34:575-579.

Feldman RA, Deeks JJ, Evans SJ. Multi-laboratory comparison of eight commercially available

Helicobacter pylori serology kits. Eur J Clin Microbiol Infect Dis 1995;14:428-433

Fisher R, Parkman H. Current concepts:management of nonulcer dyspepsia.N Engl J Med

1998;19:1376-1381

Fock KM, Khoo TK, Chia KS, Sim CS. Helicobacter pylori infection and gastric emptying of

indigestible solids in patients with dysmotility-like dyspepsia. Scand J Gastroenterol

1997;32:676-80

Froehlich F, Gonvers J-J, Wietlisbach V, Burnand B, Hildebrand P, Schneider C, Saraga E,

68

Beglinger C, Vader J-P. Helicobacter pylori eradication does not benefit patients with non-ulcer

dyspepsia. Am J Gatroenterol 2001;96:2329-2336

Genta RM. Helicobacter pylori, inflammation, mucosal damage and apoptosis: pathogenesis and

definition of gastric atrophy. Gastroenterology 1997;113:S51-S55

George AA, Tsuchiyose M, Dooley CP. Sensitivity of the gastric mucosa to acid and duodenal

contents in patients with non-ulcer dyspepsia. Gastroenterology 1991;101:3-6.

Glupczynski Y, Megraud F, Andersen LP, Lopez-Brea M. Antibiotic susceptibility of H.pylori

in Europe in 1998: results of the third multicenter study. Gut 1999;45(Suppl III):A 105

Go M, Crowe S. Virulence and pathogenicity of Helicobacter pylori. Gastroenterol Clin North

Am 2000;29:649-670

Goh K, Paramsothy M, Azian M, Parasakthi N, Peh SC, Bux S, Lo YL, Ong KK. Does

Helicobacter pylori infection affect gastric emptying in patients with functional dyspepsia? J

Gastroenterol Hepatol 1997;12:790-794

Goo RH, Moore JG, Greenberg E, Alazraki NP. Circadian variation in gastric emptying of meals

in humans. Gastroenterology 1987;93:515-518

Graham DY, Klein PD. What you should know about the methods, problems, interpretations,

and use of urea breath tests. Am J Gastroenterol 1991;86:1118-1122

Graham DY, Klein PD. Accurate diagnosis of Helicobacter pylori. 13C-urea breath test.

Gastroenterol Clin North Am 2000;29:885-893

Grant Thompson W. Placebos: A Review of the placebo response. Am J Gastroenterol

2000;95:1637-1643

Greenberg P, Cello J. Lack of effect of treatment for Helicobacter pylori on symptoms of

nonulcer dyspepsia. Arch Intern Med 1999;159:2283-88

69

Hallissey MT, Allum WH, Jewkes AJ, Ellis DJ, Fielding JWL. Early detection of gastric cancer.

BMJ 1990;301:513-515

Hamilton J, Guthrie E, Creed F, Thompson D, Tomenson B, Bennett R, Moriarty K, Stephens

W, Liston R, A randomized controlled trial of psychotherapy in patients with chronic functional

dyspepsia. Gastroenterology 2000:119:661-669

Hamlet A, Stage L, Lönroth H, Nyström C, Pettersson A. A novel tablet-based C-13 urea breath

test for Helicobacter pylori with enhanced performance during acid suppression therapy. Scand

J Gastroenterol 1999;34:367-374

Hausken T, Berstad A: Wide gastric antrum in patients with nonulcer dyspepsia. Effect of

cisapride. Scand J Gastroenterol 1992;27:427-432

Hausken T, Svebak S, Wilhelmsen I, Haug TT, Olafsen K, Petterson E, Hveem K, Berstad A.

Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom Med

1993;55:12-22

Hays RD, Sherbourne CD, Mazel R. The RAND 36-item Health Survey 1.0. Health Economics

1993;2:217-277

Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC. A prospective

randomised trial of a “test and treat” policy versus endoscopy based management in young

Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. GUT

1999;45:186-90

Heikkinen M, Pikkarainen P, Takala J, Räsänen H, Julkunen R. Etiology of dyspepsia: four

hundred unselected consecutive patients in general practice. Scand J Gastroenterol 1995;

30:519-523.

Heikkinen M, Pikkarainen P, Takala J, Julkunen R. General practitioners, approach to

dyspepsia. Survey of consultation frequencies, treatment, and investigations. Scand J

Gastroenterol 1996; 31:648-653.

Heikkinen M, Mayo K, Megraud F, Vornanen M, Marin S, Pikkarainen P, Julkunen R.

70

Association of CagA-positive and CagA-negative Helicobacter pylori strains with patients’

symptoms and gastritis in primary care patients with functional upper abdominal complaints.

Scand J Gastroenterol 1998;33:31-8

Hirschl A, Glupczynski Y. Diagnosis. Curr Opin Gastroenterol 1999;15 (suppl 1):S5-S9

Horowitz M, Dent J, Fraser R, Sun W, Hebbard G. Role and integration of mechanisms

controlling gastric emptying. Dig Dis Sci 1994;39(suppl):S7-S13

Hovelius B, Andersson SI, Hagander B, Molstad S, Reimers P, Sperlich E, Wadstrom T.

Dyspepsia in general practice: history and symptoms in relation to Helicobacter pylori serum

antibodies. Scand J Gastroenterol 1994;29:506-10.

Ishihara S, Kaji T, Kawamura A, Rumi MA, Sato H, Okuyama T, Adachi K, Fukuda R,

Watanabe M, Hashimoto T, Hirakawa K, Matsushima Y, Chiba T, Kinoshita Y. Diagnostic

accuracy of a new non-invasive enzyme immunoassay for detecting Helicobacter pylori in stools

after eradication therapy. Aliment Pharmacol Ther 2000;14:611-614

Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer

dyspepsia and will eradication improve symptoms? A meta-analysis. BMJ 1999;319:1040-1044

Joelsson B, Johnsson F. Heartburn-the acid test. Gut 1989;30:1523-1525

Jones RH, Lydeard SE, Hobbs FD, Kenkre JE, Williams EI, Jones SJ, Repper JA, Caldow JL,

Dunwoodie WM, Bottomley JM. Dyspepsia in England and Scotland. Gut 1990;31:401-405.

Jones R, Lydeard SE. Dyspepsia in the community: a follow-up study. British Journal of

Clinical Practice 1992;46:95-97

Kagevi I, Löfstedt S, Persson L-G. Endoscopic findings and diagnoses in unselected dyspeptic

patients at a primary health care center. Scand J Gastroenterol 1989;24:145-150.

Kay L, Jorgensen T. Epidemiology of upper dyspepsia in a random population. Prevalence,

incidence, natural history, and risk factors. Scand J Gastroenterol 1994;29:1-6.

71

Kearney DJ, Avins AL, McQuaid KR. Treatment of uninvestigated dyspepsia with cisapride for

patients with negative Helicobacter pylori serologies. Am J Gastroenterol 2000;95:2212-7.

Khulusi S, Mendall MA, Patel P, Levy J, Badve S, Northfield TC. Helicobacter pylori infection

density and gastric inflammation in duodenal ulcer and non-ulcer subjects. Gut 1995;37:319-324

Klauser AG, Schindlebeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux

disease. Lancet 1990;335:205-208

Klauser AG, Voderholzer WA, Knesewitsch PA, Schindlbeck NE, Muller-Lissner SA. What is

behind dyspepsia? Dig Dis Sci 1993;38:147-154.

Klein PD, Graham DY. Minimum Analysis Requirements for the Detection of Helicobacter

pylori Infection by the 13C-Urea Breath Test. Am J Gastroenterol 1993;88:1865-9

Konturek JW, Fischer H, Riemann B, Domschke W. Effects of eradication of Helicobacter

pylori on gastric secretory and motor function in patients with non-ulcer dyspepsia.

Gastroenterology 1997;112:A181

Labenz J, Rokkas T. Helicobacter pylori and dyspepsia. Curr Opin Gastroenterol 1997; 13:48-

51.

Laheij RJF, van Rossum LGM, Jansen JBMJ, Straatman H, Verbeek ALM. Evaluation of

treatment regimens to cure Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol

Ther 1999;13:857-864

Lai ST, Fung KP, Ng FH, Lee KC. A Quantitative analysis of symptoms of non-ulcer dyspepsia

as related to age, pathology, and Helicobacter infection. Scand J Gastroenterol 1996;31:1078-

1082.

Laine L, Schoenfeld P, Brian Fennerty M. H.pylori therapy is not effective for treatment of non-

ulcer dyspepsia: meta-analysis of randomized controlled trials. Gastroenterology 2000;4:A440

72

Lambert JR. The role of Helicobacter pylori in nonulcer dyspepsia: a debate-for. Gastroenterol

Clin North Am 1993;22:141-151.

Larsson L, Houggaard D. Evidence for paracrine somatostatinergic regulation of gastrin gene

expression by double-staining cytochemistry and quantitation. J Histochem Cytochem

1994;42:37-40

Locke GR. Prevalence, incidence and natural history of dyspepsia and functional dyspepsia.

Bailliere’s Clin Gastroenterol 1998;12:435-442

(a)Logan RPH, Dill S, Bauer FE, Walker MM, Hirschl AM, Gummett PA, Good D, Mossi M.

The European 13C-urea breth test for the detection of Helicobacter pylori. Eur J Gastroenterol

Hepatol 1991;3:915-921

(b)Logan RP, Polson RJ, Misiewicz JJ, Rao G, Karim NQ, Newell D, Johnson P, Wadsworth J,

Walker MM, Baron JH. Simplified single sample 13Carbon urea breath test for Helicobacter

pylori:comparison with histology, culture, and ELISA serology. GUT 1991;32:1461-1464

Logan RPH. Urea breath tests in the management of Helicobacter pylori. Gut 1998;43:S47-S50

Maconi G, Vago L, Galletta G, Imbesi V, Sangaletti O, Parente F, Cucino C, Bonetto S, Porro

GB. Is routine histological evaluation an accurate test for Helicobacter pylori infection? Aliment

Pharmacol Ther 1999;13:327-331

Malagelada JR. Gastrointestinal motor disturbances in idiopathic dyspepsia. Scand J

Gastroenterol 1991;26(suppl.182):29-32

Malagelada JR. Functional dyspepsia. Insights on mechanisms and management strategies.

Gastroenterol Clin North Am 1996;25:103-112

Malfertheiner P, Bode G. Helicobacter pylori and the pathogenesis of duodenal ulcer disease.

Eur J Gastroenterol Hepatol 1993;5 (suppl 1):S1-S8

Malfertheiner P, Fischbach W, Layer P, Moessner J, Stolte M, Leodolter A, Demleitner K,

73

Fuchs WA. Elan study proves symptomatic benefit of helicobacter pylori eradication in

functional dyspepsia. Gastroenterology 2000;118:A440

Marshall BJ, Warren JR, Graham JF, Langton SR, Goodwin CS, Blincow ED. Rapid urease test

in the management of Campylobacter pyloridis-associated gastritis. Am J Gastroenterol

1987;82:200-210

Marshall BJ, Barrett L, Prackash C, McCallum RW, Guerrant RL. Urea protects C.pylori from

the bactericidial effects of acid. Gastroenterology 1990;99:697-702

McColl KEL, El-Omar E. Helicobacter pylori and disturbance of gastric function associated

with duodenal ulcer disease and gastric cancer. Scand J Gastroenterol 1996;31(suppl 215):32-7

McColl KEL, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, Kelman A, Penny C,

Knill-Jones R, Hilditch T. Symptomatic benefit from eradicating Helicobacter pylori infection

in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1869-1874.

McColl KEL, El-Omar E, Gillen D. Helicobacter pylori gastritis and gastric physiology.

Gastroenterol Clin North Am 2000;29:687-703

McMullin ST, Reichley R, Watson L, Steib S, Frisse M, Bailey T. Impact of a web-based

clinical information system on cisapride drug interactions and patient safety Arch Intern Med

1999;159:2077-2082

Mearin F, de Ribot X, Balboa A, Salas A, Varas MJ, Cucala M, Bartolome R, Armengol JR,

Malagelada J-R. Does Helicobacter pylori infection increase gastric sensitivity in functional

dyspepsia? Gut 1995;37:47-51

Meineche-Schmidt V, Christensen E. Classification of dyspepsia. Identification of independent

symptom components in 7270 consecutive, unselected dyspepsia patients from general practice.

Scand J Gastroenterol 1998;33:1262-1272

Meineche-Schmidt V, Talley NJ, Pap A, Kordecki H, Schmid V, Ohlsson L, Wahlqvist P,

Wiklund I, Bolling-Sternevald E. Impact of functional dyspepsia on quality of life and health

74

care consumption after cessation of antisecretory treatment. A multicentre 3-month follow-up

study. Scand J Gastroenterol 1999;34:566-574.

Meining A, Kiel G, Stolte M. Changes in Helicobacter pylori-induced gastritis in the antrum and

corpus under 12 months of treatment with ranitidine and lansoprazole in patients with duodenal

ulcer disease. Gastroenterology 1998; 114: A224

Midolo P, Marshall BJ. Accurate diagnosis of Helicobacter pylori.Urease tests. Gastroenterol

Clin North Am 2000;29:871-878

Minami H, McCallum RW. The physiology and pathophysiology of gastric emptying in humans.

Gastroenterology 1984:86:1592-1610

Miwa H, Hirai S, Nagahara A, Murai T, Nishira T, Kikuchi S, Takei Y, Watanabe S, Sato N.

Cure of Helicobacter pylori infection does not improve symptoms in non-ulcer dyspepsia

patients-a double-blind-placebo-controlled study. Aliment Pharmacol Ther 2000;14:317-24

Miyaji H, Azuma T, Ito S, Abe Y, Ono H, Suto H, Ito Y, Yamazaki Y, Kohli Y, Kuriyama M.

The effect of helicobacter pylori eradication therapy on gastric antral myoelectrical activity and

gastric emptying in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther

1999;13:1473-80

(a)Moayyedi P, Feltbower R, Brown J, Mason S, Mason J, Nathan J, Richards IDG, Dowell A,

Axon A. Effect of population screening and treatment for helicobacter pylori on dyspepsia and

quality of life in the community: a randomised controlled trial. Lancet 2000;355:1665-1669.

(b)Moayyedi P, Soo S, Deeks J, Forman D, Mason J, Innes M, Delaney B. Systematic review

and economic evaluation at Helicobacter pylori eradication treatment for non ulcer dyspepsia.

BMJ 2000;321:659-64.

Mollmann K. Early diagnosis of gastric cancer. The possibility of de-limiting high risk groups.

Danish Medical Bulletin 1981;28:89-92

Montague S, Buckley M, O’Morain C. Treatment of Helicobacter pylori. Curr Opin

75

Gastroenterol 1999; 15 (suppl 1):S35-S41

Moore JG, Christian PE, Brown JA, Brophy C, Datz F, Taylor A, Alazraki N. Influence of meal

weight and caloric content on gastric emptying of meals in man. Dig Dis Sci 1984;29:513-519

Moore JG, Datz FL, Christian PE, Greenberg E, Alazraki N. Effect of body posture on

radionuclide measurements of gastric emptying. Dig Dis Sci 1988;33:1592-1595

Moore JG, Tweedy C, Christian PE, Datz FL. Effect of age on gastric emptying of liquid-solid

meals in man. Dig Dis Sci 1983;28:340-344

Moore JG, Datz FL, Christian PE. Exercise increases solid meal gastric emptying rates in men.

Dig Dis Sci 1990;35:428-432

Muth E, Koch K, Stern R. Significance of autonomic nervous system activity in functional

dyspepsia. Dig Dis Sci 2000;45:854-63.

Napolitano C, Schwarz P, Brown A, Ronchetti E, Bianchi L, Pinnavaia A, Acquaro G, Priori S.

Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-

threatening arrhythmias. J Cardiovasc Electrophysiol 2000;11:691-6.

Narducci F, Bassotti G, Granata MT, Gaburri M, Barroni F, Palumbo R, Morelli A. Functional

dyspepsia and chronic idiopathic gastric stasis, role of endogenous opiates. Arch Intern Med

1986;146:716-721

Niemelä S, Ashorn M, Färkkilä M, Kujala P, Kunnamo I, Pikkarainen P. Suomen

Gastroenterologiayhdistys ry. Helikobakteeri-infektion diagnostiikka ja hoito. Duodecim

2000;116:548-60.

Nyren O, Adami HO, Bates S, Bergstrom R, Gustavsson S, Loof L, Nyberg A. Absence of

therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. N Engl J Med

1986;314:339-343

O'Hanlon D, Karat D, Hayes N, Scott D, Raimes SA, Griffin SM. Open access endoscopy is

76

important in the early diagnosis of malignant lesions of the upper gastrointestinal tract. Br J

Surg 1996:83:29

Parente F, Imbesi V, Maconi G, Cucino C, Manzionna G, Vago L, Bianchi Porro G. Effects of

Helicobacter pylori eradication on gastric function indices in functional dyspepsia. A

prospective controlled study. Scand J Gastroenterol 1998; 33:461-467

Patel P, Khulusi S, Mendall MA, Lloyd R, Jazrawi R, Maxwell JD, Northfield TC. Prospective

screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995;346:1315-8.

Peitz U, Blaudszun S, Aygen S, Hennemann O, Stolte M, Boersch G. Non significant change of

delayed gastric emptying in functionally dyspeptic patients after cure of Helicobacter pylori.

Gastroenterology 1996;112:A181

Peitz U, Glasbrenner B, Ellenrieder V, Sulliga M, von Arnim U, Leodolter A, Kahl S, Labenz

J, Stolte M, Malfertheiner P. Re-treatment of H.pylori infection with high-dose omeprazole -

amoxicillin after failure with metronidazole -clarithromycin combination. GUT 1999;45(suppl

3):A111

(a) Perri F, Clemente R, Pastore M, Quitadamo M, Festa V, Bisceglia M, Bergoli M, Lauriola

G, Leandro G, Ghoos Y, Rutgeerts P, Andriulli A. The 13C-urea breath test as a predictor of

intragastric bacterial load and severity of Helicobacter pylori gastritis. Scand J Clin Lab Inv

1998;58:19-27

(b)Perri F, Clemente R, Festa V, Annese V, Quitadamo M, Rutgeerts P, Andriulli A. Patterns of

symptoms in functional dyspepsia: role of Helicobacter pylori infection and delayed gastric

emptying. Am J Gastroenterol 1998; 93:2082-8

Perri F, Festa V, Clemente R, Quitadamo M, Andriulli A. Rifabutin-based “rescue therapy” for

Helicobacter pylori infected patients after failure of standard regimens. Aliment Pharmacol Ther

2000;14:311-316

Peura DA, Pambianco DJ, Dye KR, Lind C, Frierson HF, Hoffman SR, Combs MJ, Guilfoyle E,

Marshall BJ. Microdose 14C-Urea Breath Test Offers Diagnosis of Helicobacter pylori in 10

77

Minutes. Am J Gastroenterol 1996;91:233-238

Pieramico O, Ditschunheit H, Malfertheiner P. Gastrointestinal motility in patients with non-

ulcer dyspepsia: a role of Helicobacter pylori infection? Am J Gastroenterol 1993;88:364-368

Price AB. The Sydney system:Histological division. J Gastroenterol Hepatol 1991; 6:209-22

Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJ, Hoes AW. Disturbed solid-phase

gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33

Rees WDW, Miller LJ, Malagelada JR. Dyspepsia, antral motor dysfunction and gastric stasis

of solids. Gastroenterology 1980;78:360-365

Rehnberg-Laiho L, Rautelin H, Valle M, Kosunen TU. Persisting Helicobacter antibodies in

Finnish children and adolescents between two and twenty years of age. Pediatr Infect Dis J

1998;17:796-799

Rhee PL, Kim YH, Son HJ, Kim JJ, Koh KC, Paik SW, Rhee JC, Choi KW. Lack of association

of Helicobacter pylori infection with gastric hypersensitivity or delayed gastric emptying in

functional dyspepsia. Am J Gastroenterol 1999; 94:3165-9

Roosendaal R, Kuipers EJ, Buitenwerf J, van Uffelen C, Meuwissen SG, van Kamp GJ,

Vandenbroucke-Grauls CM. Helicobacter pylori and the birth cohort effect: evidence of a

continuous decrease of infection rates in childhood. Am J Gastroenterol 1997;92:1480-1482

Ryder S, O’Reilly S, Miller R, Ross J, Jacyna M, Levi A. Long term acid suppressing treatment

in general practice. BMJ1994;308:827-830

Saslow SB. Thumshirn M. Camilleri M. Locke GR 3rd. Thomforde GM. Burton DD. Hanson

RB. Influence of H.pylori infection on gastric motor and sensory function in asymptomatic

volunteers. Dig Dis Sci 1998; 43:258-64

Satoh K, Kimura K, Taniguchi Y, Kihira K, Takimoto T, Saifuku K, Kawata H, Tokumaru K,

Kojima T, Seki M, Ido K, Fujioka T. Biopsy sites suitable for the diagnosis of Helicobacter

78

pylori infection and the assessment of the extent of atrophic gastritis. Am J Gastroenterol

1998;93:569-573

(a)Scott AM, Kellow JE, Shuter B, Nolan JM, Hischl R, Jones MP. Effects of cigarette smoking

on solid and liquid intragastric distribution and gastric emptying. Gastroenterology

1993;104:410-416

(b)Scott AM, Kellow JE, Shuter B, Cowan H, Corbett AM, Riley JW, Lunzer MR, Eckstein RP,

Höschl R, Lam SK, Jones MP. Intragastric distribution and gastric emptying of solids and

liquids in functional dyspepsia. Dig Dis Sci 1993;38:2247-2254

Shi G, Bruley des Varannes S, Scarpignato C, LeRhun M, Galmiche JP. Reflux related

symptoms in patients with normaloesophageal exposure to acid. Gut 1995;37:457-464

Sijp van der JRM, Kamm MA, Nightingale JMD, Britton KE, Granowska M, Akkermans LMA,

Lennard-Jones JE. Disturbed gastric and small bowel transit in severe idiopathic constipation.

Dig Dis Sci 1993;38:873-844

Sipponen P, Seppälä K, Äärynen M, Helske T, Kettunen P. Chronic gastritis and duodenal ulcer:

a case control study on risk of coexisting duodenal or gastric ulcer in patients with gastritis. Gut

1989;30:922-929.

Sipponen P, Varis K, Fräki O, Korri UM, Seppälä K, Siurala M. Cumulative 10-year risk of

symptomatic duodenal and gastric ulcer in patients with or without chronic gastritis. A clinical

follow-up study of 454 outpatients. Scand J Gastroenterol 1990;25:966-973

Sipponen P, Hyvärinen H. Role of Helicobacter pylori in the pathogenesis of gastritis, peptic

ulcer and gastric cancer. Scand J Gastroenterol 1993; 28 (suppl 196):3-6

Sipponen P, Kosunen TU, Heinonen OP, Samloff IM, Siurala M. Rate of H.pylori infection in

different birth cohorts. Gut 1995; 37(suppl 1):A11

Sipponen P. Helicobacter pylori gastritis-epidemiology. J Gastroenterol 1997;32:273-277

79

Sipponen P and Marshall BJ. Gastritis and gastric cancer. Gastroenterol Clin North Am

2000;29:579-592

Small PK, Loudon MA, Waldron B, Smith D, Campbell FC. Importance of reflux symptoms in

functional dyspepsia. Gut 1995;36:189-192

Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for

non-ulcer dyspepsia. The Cochrane Library 2001, Volume (Issue2)

Stanghellini V, Ghidini C, Ricci Maccarini M, Paparo GF, Corinaldesi R, Barbara L. Fasting

and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia. Gut 1992;33:184-

190

Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, Marengo

M, Corinaldesi R. Risk indicators of delayed gastric emptying of solids in patients with

functional dyspepsia. Gastroenterology 1996;110:1036-42

Stanghellini V. Relationship between upper gastrointestinal symptoms and lifestyle,

psychosocial factors and comorbidity in the general population: results from the

domestic/international gastroenterology surveillance study (DIGEST). Scand J Gastroenterol

1999;231:29-37.

Stolte M, Edit S. Healing gastric MALT lymphoma by eradication of H.pylori? Lancet

1993;342:568.

Stolte M, Meining A, Schmitz JM, Alexandridis T, Seifert E. Changes in Helicobacter pylori-

induced gastritis in the antrum and corpus during 12-months of treatment with omeprazole and

lansoprazole in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther

1998;12:247-53.

Su Y, Wang W, Wang S, Lu S, Chen L, Wu D, Chen C, Jan C, Horowitz M. The association

between Helicobacter pylori infection and functional dyspepsia in patients with irritable bowel

syndrome. Am J Gastroenterol 2000;95:1900-5.

80

Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric

accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115:1346-52.

Talley NJ, Shuter B, McCrudden G, Jones M, Hoschl R, Piper DW. Lack of association between

gastric emptying of solids and symptoms in nonulcer dyspepsia. J Clin Gastroenterol 1989;

11:625-630

Talley NJ, Colin-Jones D, Koch KL, Koch M, Nyren O, Stanghellini V. Functional dyspepsia:

a classification with guidelines for diagnosis and management. Gastroenterol Int 1991; 4:145-

160.

Talley NJ, Weaver AL, Zinmeister AR, Melton LJ. Onset and disappearence of gastrointestinal

symptoms and functional gastrointestinal disorders. Am J Epidem 1992; 136:165-177

(a)Talley NJ, Weaver AL, Tesmer DL, Zinsmeister AR. Lack of discriminant value of dyspepsia

subgroups in patients referred for upper endoscopy. Gastroenterology 1993;105:1378-1386.

(b)Talley NJ. The role of Helicobacter pylori in nonulcer dyspepsia: a debate-against.

Gastroenterol Clin North Am 1993;22:153-167.

Talley NJ, Meineche-Schmidt V, Pare P, Duckworth M, Raisanen P, Pap A, Kordecki H,

Schmid V. Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-

controlled trials (the Bond and Opera studies). Aliment Pharmacol Ther 1998;12:1055-65

(a)Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GNJ. Functional

gastroduodenal disorders. Gut 1999;45(Suppl II):II37-II42

(b)Talley NJ, Vakil N, Ballard ED. Absence of benefit of eradicating Helicobacter pylori in

patients with nonulcer dyspepsia. N Engl J Med 1999;341:1106-1111.

(c)Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter

pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months’

follow up. BMJ 1999;318:833-837

81

Tanum L, Malt UF. A new pharmacologic treatment of functional gastrointestinal disorder. A

double-blind placebo-controlled study with mianserin. Scand J Gastroenterol 1996;31:318-325

Testoni PA, Bagnolo F, Colombo E, Bonassi U, Tosi T. The correlation in dyspeptic patients of

Helicobacter pylori infection with changes in interdigestive gastroduodenal motility patterns but

not in gastric emptying. Helicobacter 1996;1:229-37

The European Helicobacter pylori study Group. Leading article. Current European concepts in

the management of Helicobacter pylori infection. The Maastricht consensus report. GUT

1997;41:8-13.

Thompson WG, Dotevall G, Drossman DA, Heaton KW, Kruis W. Irritable bowel syndrome:

guidelines for the diagnosis. Gastroenterology Int 1989;2:92-95.

Thor P, Lorens K, Tabor S, Herman R, Konturek JW, Konturek SJ. Dysfunction in gastric

myoelectric and motor activity in Helicobacter pylori positive gastritis patients with non-ulcer

dyspepsia. J Physiol Pharmacol 1996;47:469-476.

Thurmer HL, Flaaten B, Erichsen KE, Lid NO. Helicobacter pylori infection in non-ulcer

dyspeptic and ulcer patients - determinants and consequences in “real life”. Scand J

Gastroenterol 1996; 31:744-748.

Tosetti C, Paternico A, Stanghellini V, Barbara G, Corbelli C, Marengo M, Levorato M, Monetti

N, Corinaldesi R. Reproducibility of a solid and of a liquid caloric meal for gastric emptying

studies. Nucl Med Comm 1998;19:581-586

Tothill P, McLoughlin GP, Heading RC. Techniques and errors in scintigraphic measurements

of gastric emptying. J Nucl Med 1978;19:256-261

Trespi E, Broglia F, Villani L, Luinetti O, Fiocca R, Solcia E. Distinct profiles of gastritis in

dyspepsia subgroups. Their different clinical responses to gastritis healing after Helicobacter

pylori eradication.

Scand J Gastroenterol 1994;29:884-888

Tsuda M, Karita M, Morshed MG, Okita K, Nakazawa T. A urease-negative mutant of

82

Helicobacter pylori constructed by allelic exchange mutagenesis lacks the ability to colonize the

nude mouse stomach. Infect Immun 1994;62:3586-3589.

Tucci A, Corinaldesi R, Stanghellini V, Tosetti C, Di Febo G, Paparo GF, Varoli O, Paganelli

GM, Labate AM, Masci C. Helicobacter pylori infection and gastric function in patients with

chronic idiopathic dyspepsia. Gastroenterology 1992;103:768-74.

Tytgat GNJ, Noach L, Rauws EAJ. Helicobacter pylori infection and duodenal ulcer disease.

Gastroenterol Clin North Am 1993;22:127-139

Unge P. Review of Helicobacter pylori eradication regimens. Scand J Gastroenterol

1996;31(suppl 215):74-81

Urbain JLC, Vekemans MC, Parkman H, Van Cauteren J, Mayeur SM, Van Den Maegdenbergh

V, Charkes ND, Fisher RS, Malmud LS, De RooM. Dynamic antral scintigraphy to characterize

gastric antral motility in functional dyspepsia. J Nucl Med 1995;36:1579-1586

Vaira D, Malfertheiner P, Megraud F et al. A novel antigen assay based on a stool specimen for

Helicobacter pylori:European multicentre study. Gut 1998;43(suppl 2):A47

Valle J, Seppälä K, Sipponen P, Kosunen T. Disappearance of gastritis after eradication of

Helicobacter pylori. A morphometric study. Scand J Gastroenterol 1991;26:1057-1065.

Vantrappen G. Methods to study gastric emptying. Dig Dis Sci 1994;39:91-94.

Van Zanten SJOV, Cleary C, Talley NJ, Peterson TC, Nyren O, Bradley LA, Verlinden M,

Tytgat GN. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology

with recommendations for design of future trials. Am J Gastroenterol 1996;91:660-673

Villako K, Kekki M, Maaroos HI, Sipponen P, Uibo R, Tammur R, Tamm A. Chronic gastritis:

progression of inflammation and atrophy in a six-year endoscopic follow-up of a random sample

of 142 Estonian urban subjects. Scand J Gastroenterol 1991;186:135-141.

Ware JE, Sherbourne CD. The MOS-36-item Short-Form Health Survey (SF-36). Medical Care

83

1992;30:473-481.

Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic

gastritis. Lancet 1983;i:1273-1275

Watanabe T, Tomita S, Kudo M, Kurokawa M, Orino A, Todo A, Chiba T. Detection of

Helicobacter pylori gene by means of immunomagnetic separation-based polymerase chain

reaction in feces. Scand J Gastroenterol 1998;33:1140-1143

Wiklund I, Butler-Wheelhouse P. Psychosocial factors and their role in symptomatic

gastroesophageal reflux disease and functional dyspepsia. Scand J Gastroenterol 1996;220:94-

100

WilmerA, van Cutsem E, Andrioli A, Tack J, Coremans G, Janssens J. Ambulatory gastrojejunal

manometry in severe motility-like dyspepsia: lack of correlation between dysmotility,

symptoms, and gastric emptying. Gut 1998;42:235-242.

Wyatt JI, Rathbone BJ, Sobala GM, Shallcross T, Heatley RV, Axon AT, Dixon MF. Gastric

epithelium in the duodenum and its relationship to Helicobacter pylori and inflammation. J Clin

Pathol 1990;43:981-986

Xia HH-X, Talley NJ. Natural acquisition and spontaneous elimination of Helicobacter pylori

infection: clinical implications. Am J Gastroenterol 1997;92:1780-1787.