ABSTRACT
Aim: to obtain the proportion of dyspepsia symptom in non-ulcerative dyspepsia patient after eradication treatment of H. pylori, and recent status of H. pylori after eradication therapy.
Methods: cross-sectional study in patients with history symptoms of dyspepsia in non ulcer dyspepsia with positive H. pylori and had been administered eradication treatment of H. pylori for 1 week in 2002-2007 period. Conditions that influence the result of urea breath test such as proton pump inhibitor, antibiotic treatment, and gastric malignancy have been excluded. Patients were invited to be interviewed about current symptoms of dyspepsia and then underwent urea breath test (UBT) examination to identify H. pylori. Global overall symptom of dyspepsia scale was used to assess the symptoms of dyspepsia.
Results: twenty one patients (14 male and 11 female) fulfilled the eligibility criteria for this study, 9 patients with eradication treatment history less than 1 year, and 12 patients more than 1 year. The symptoms of dyspepsia were evaluated and as many as 17 patients (81%) dyspepsia symptoms’ were subsided and 4 patients had persistent symptoms after eradication. After eradication treatment, 17 patients (81%) resulted with negative Helicobacter pylori findings, and 4 patients remained positive. One patient of the positive group was reinfected by H. pylori, proved by previous negative result of UBT. In the negative group, 13 patients (76,4%) dyspepsia symptoms’ were free from dyspepsia symptoms, and 4 patients had persistent symptoms. All the symptoms of the patients in the positive group were relieved.
Conclusion: majority of patients had improvement of dyspepsia symptoms after eradication treatment, and 81% of patients had negative H. pylori findings, proved by UBT after eradication . The percentage of symptomatic improvement on H. pylori negative patients after eradication is 76, 4%.
Key words: Helicobacter pylori, dyspepsia, improvement.
Clinical Evaluation of Dyspepsia in Patients with Functional Dyspepsia, with The History of Helicobacter pylori Eradication Therapy in Cipto Mangunkusumo Hospital, Jakarta
Khaira Utia, Ari F. Syam, Marcellus Simadibrata, Siti Setiati, Chudahman Manan
Department of Internal Medicine Faculty of Medicine, University of Indonesia - dr. Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia.
Correspondence mail to: [email protected]
INTRODUCTION
Helicobacter pylori is the main cause of peptic ulcer, and many studies have proved the strong relation- ship between H. pylori infection with gastric lymphoma and corpus adenocarcinoma and gastric antrum.
Eradication therapy for H. pylori is strongly thought to decrease the risk of cancer.1-3
Result of a clinical study in Indonesia showed that the prevalence of Helicobacter pylori in peptic ulcer patients was around 90-100%.4 In non-ulcerative dyspepsia patients, the prevalence of H. pylori infection was reported to be 20-40% with different diagnostic methods: serology, culture, and histopathology.4 On the other hand, the prevalence of H. pylori in dyspepsia patients undergoing endoscopy in a multicenter study in 5 large cities in Indonesia in 2003-2004 was 10.2%, with the highest prevalence in Jogjakarta (30.6%) and the lowest in Jakarta (8%).5 This number was lower compared to a previous study in M. Djamil Hospital Padang which found the H. pylori prevalence in dyspepsia patients to be 60% with serologic assay and 45% with histopathologic assay.6 Temporary report from an epidemiological study currently enrolled in Jakarta by the Gastroenterology Division on H. pylori prevalence in DKI Jakarta shows that the prevalence of H. Pylori infection was 52.3% out of 310 patients.7
From a number of studies, H.pylori eradication results in several different effects, especially the symp- toms related to the the increased acidity. An increase in oesophageal reflux incidence after eradication therapy was first reported in 1991. However, several studies later gave different results.8 Success of eradicaton with triple therapy ranges between 80 and 100%. Unlike the response in patients with ulcer, post-therapeutic clinic
response in non-ulcerative patients vary around 21- 58%.9,10 Study by Jaakkimainen reported relationship between H.pylori and non-ulcerative dyspepsia symptom.11-13 Dyspepsia problem is essential to the researchers, because most patients with positive H .pylori status presented with dyspepsia symptom, however until now in Indonesia there are no study exist about percentage of reduction in dyspepsia symptom after eradication therapy and relationship between this symptom relieve with H. pylori status. A study by Ford AC et al supported that dyspepsia symptom should be reevaluated after eradication therapy, where this study concluded the low quality of life in patients with dyspepsia symptom.14
The objective of this study is to identify the improvement of dyspepsia symptom in patients with the history of non-ulcerative dyspepsia after H. pylori eradication therapy in Cipto Mangunkusumo Hospital, and in particular to study the proportion of dyspepsia symptom improvement in non-ulcerative dyspepsia patient after H. Pylori eradication therapy, to know the H. pylori status after eradication therapy, to study the proportion of dyspepsia symptom improvement in non- ulcerative patients with currently negative H. pylori status.
METHODS
A descriptive cross-sectional study was carried out in March to June 2007 at the Gastroenterology Clinic and Procedure Room, Department of Internal Medicine, Cipto Mangunkusumo Hospital, Jakarta.
The source population of this study is patients with history of non-ulcer dyspepsia with H. pylori infection at the Gastroenterology Clinic, Cipto Mangunkusumo Hospital, who have obtained triple eradication therapy during February 2002-February 2007. The sample consisted of members of the source population who fulfilled inclusion criteria.
Study subjects were all patients with non-ulcer dyspepsia who have had eradication therapy during February 2002-February 2007. However, the minimum sample size to determine the proportion of non-ulcer dyspepsia patients with improvement of symptoms post- eradication therapy was calculated using the sample size formula for proportion testing and the minimum sample size required was 49 subjects.
Study subjects were recruited from all patients with history of non-ulcer dyspepsia who have obtained eradication therapy at the Gastroenterology Clinic of Cipto Mangunkusumo Hospital during February 2002- February 2007 who fulfilled inclusion criteria.
Patients who have obtained H. pylori eradication therapy during the aforementioned period were invited back to the clinic. Those who consented to enroll in the study and fulfilled inclusion criteria were subjected to anamnesis on current dyspepsia complaints and urea breath test to evaluate the patient’s current H. pylori status.
Inclusion criteria were patients with history of non- ulcer dyspepsia with positive H. pylori test prior to therapy and having completed triple eradication therapy for at least 1 week. Exclusion criteria were patients obtaining eradication therapy or proton pump inhibitor at the time of study, gastrointestinal malignancy, and refusal to participate.
Measurements included urea breath test, which was performed after the following preparations: The subject was asked to fast for 8 hours prior to testing. Upon arrival at the place of examination, the patient was asked to rest for 5 minutes, then to ingest a urea tablet labeled with 14C. After resting for 10 minutes, the subject was asked to blow repeatedly into a device until the color of a balloon turned entirely from orange to yellow. The balloon was then measured on the UBT device and the results were noted as positive (2) or negative (0).
Other measurements were done through anamnesis of medication history, smoking, alcohol use, presence of anxiety or depression, and current complaints of dyspepsia by the Global Overall Symptoms of Dyspepsia Scale (GOS).
Study results were processed using SPSS 10.0 to obtain subject characteristics, proportions of dyspepsia complaints in conjunction with various risk factors, proportions of successful H. pylori eradication in patients who obtained therapy for less than and more than 1 year, respectively, and proportion of dyspepsia complaints in conjunction with the patient’s current H. pylori status.
All study subjects were given oral and written information on the study objectives and procedures, prior to being asked for written consent to participate in the study.
RESULTS
In the medical record data, we obtained 62 patients with dyspepsia symptom who have been receiving complete triple eradication therapy for 1 week within February 2002-2007. Among the 62 people with history of dyspepsia who had completed eradication therapy for H. pylori in RSCM, only 25 people could be invited to the outpatient clinic and gastroenterology procedure room, because 12 people were living out of town, 6 people
had gastrointestinal cancer, 5 geriatric patients passed away, 11 people with unclear address and phone number could not be contacted, and 3 people refused to participate in the study. From February to July 2007, there were 25 people willing to be re-invited to the outpatient clinic and Gastroenterology procedure room at Cipto Mangunkusumo Hospital. From the 25 patients we found 21 subjects with non-ulcerative appearance in the previous endoscopy, which consisted of 11 males and 10 females.
From Table 1 it is seen that most subjects were between 41-60 years of age (52,4%) with mean age 48,4 years, Bataknese, non-smoker, non-alcoholic, not suffering from anxiety nor depression, and also not consuming NSAIDs. From 21 subjects, there were 17 people whose dyspepsia symptoms resolved, and 4 people with constant dyspepsia symptoms. On further workup 17 people were found to have Helicobacter pylori – negative with urea breath test (UBT) examination, and positive result was found in 4 people.
One of the 4 patients had previously had negative result from the UBT test the previous year, and thus this result is thought to be H. pylori reinfection.
Of all the patients receiving H pylori eradication therapy for 1 week, omeprazole therapy was continued until 1 month after the end of eradication therapy.
Dyspepsia Symptom in Study Subjects
As mentioned in Table 1, from 21 study subjects 17 people (81%) no longer had dyspepsia symptom or only minimally insignificant dyspepsia symptom which spontaneously resolved without efforts such as taking medications. On the other hand, 4 people still had persistent dyspepsia symptom after eradication therapy, or only slightly better than previous symptom.
Several risk factors found from the 4 patients are: 1 patient with anxiety problem, 2 patients were mild smoker (6 cigarettes/day), and 1 patient was a long-term aspirin user (Table 2).
Dyspepsia symptoms felt in the 4 patients with persistent dyspepsia were bloating, epigastric pain, and nausea. From the 4 patients, 4 had bloating, 3 had epigastric pain, and 3 had nausea.
Table 1. Characteristics of study subjects
Characteristics Number of subjects (n=21) Age (year)
20 – 40 41 – 60
> 60
6 11 4 Sex
Male Female
11 10 Ethnicity
Bataknese Javanese Ambonese Manadonese Betawinese Dayaknese
16 1 1 1 1 1 Smoking
Nonsmoker
Previous history of smoking Mild smoker
12 7 2 Alcohol consumption
Never
Previous history of alcohol consumption Mild alcohol drinker
14 6 1 Anxiety-Depression
Positive Negative
2 19 Antiinflammatory agents
None NSAIDs Aspirin
15 3 3 Eradication time
< 1 year
> 1 year
9 12 Dyspepsia
Resolved (score 1-2) Persisted (score 3-7)
17 4 Result of UBT test
Positive Negative
17 4
Table 2. Proportion of dyspepsia symptom in various risk factors
Risk factor
Dyspepsia resolved
(n=17)
Dyspepsia persisted
(n=4) Age (year)
20 – 40 41 – 60
> 60
5 8 4
1 3 0 Sex
Male Female
9 8
2 2 Ethnicity
Bataknese Non-bataknese
14 3
2 2 Smoking
Nonsmoker
Previous history of smoking Mild smoker
11 6 0
1 1 2 Alcohol consumption
Never
Previous history of alcohol consumption
Mild alcohol drinker
12 4 1
2 2 0 Anxiety-Depression
Positive Negative
1 16
1 3 Antiinflammatory agents
None NSAIDs Aspirin
12 3 2
3 0 1 H. Pylori
Positive Negative
4 13
0 4
Urea Breath Test Result
From 21 study subjects, 17 patients (81%) showed negative H pylori result on UBT test, and 4 were shown to be positive. Based on anamnesis from the patients, only 7 subjects (33%) have underwent previous H. pylori test after eradication therapy. Six among them had negative result after eradication therapy, and 1 subject had positive result. Among the 4 subjects who currently showed positive result, 1 subject was known to have previous negative result on UBT test..
Proportion of Negative Dyspepsia at Present in Patients with Eradication < 1 Year and > 1 Year ago From 21 subjects, 9 of them received eradication therapy less than 1 year from the time of sample collection, and in the other 12 sampling was performed after more than 1 year of eradication. In the less than 1 year group, only 1 patient had persistent dyspepsia symptom, while in the more than 1 year group 3 patients still complained of dyspepsia (Table 3).
subjects) compared to the H. pylori-positive group whose all subjects no longer felt dyspepsia symptoms.
Proportion of Negative Helicobacter pylori at Present in Patients with Eradication Phase < 1 Year and > 1 Year Ago
From 9 subjects in the less than 1 year group, 1 patient still had positive H. pylori, while from 12 subjects in the more than 1 year group, 3 patients still had positive results (Table 4).
Proportion of Dyspepsia and Helicobacter pylori Status
From 17 patients with resolved dyspepsia, 5 subjects had positive H. pylori result. On the other hand, in the dyspepsia group, all 4 patients had negative H. pylori status (Table 5). Table 5 also illustrates that the percentage of improved dyspepsia symptom was lower in H. pylori-negative group, only 76.4% (13/17
DISCUSSION
Picture of Dyspepsia Symptoms
This study performed an assessment of dyspepsia symptoms using global overall symptoms of dyspepsia (GOS) scale, and obtained 81% of subjects with resolved dyspepsia symptoms (score 1-2). Several factors thought to be related with improvement of dyspepsia symptoms in both negative and positive for H. pylori group are relieved of gastritis as a result of long-term omeprazole therapy after eradication therapy.
From all the subjects, omeprazole/PPI therapy was continued for 1 month after eradication therapy.
Several studies reported recovery of gastric lesion in patients with positive H. pylori result after long-term omeprazole therapy for 1 month. Some of those studies were reported by Bayerdorfer and colleagues in 1992 who found ulcer healing in 25 out of 26 patients, and Sung and colleagues in 1994 who found ulcer healing in 61 of 77 patients receiving omeprazole therapy without triple therapy. Although the studies did not find good eradication level (0% in the study by Bayerdorfer and colleagues, and 6.9% in the study by Sung and colleagues), but they found relatively high ulcer reccurency within the first year after therapy, 12 out of 25 patients (48%) in Bayerdorfer and colleagues study, and 22 out of 61 patients (36%) in Sung and colleagues study.58
Most patients had avoided risk factors of dyspepsia such as smoking, alcohol consumption, anti-inflamma- tory agents, and prolonged stress. From the 21 subjects, only 2 patients (9,5%) were mild smoker, 1 patient (4,7%) was still consuming a small amount of alcohol, and 2 patients (9,5%) had anxiety, 2 patients consumed NSAIDs although not routinely (9,5%), and 3 others (14,3%) regularly consumed aspirin.
In persistent dyspepsia, the dyspepsia symptoms felt were bloating, nausea, and epigastric pain.
Length of Evaluation Time with Dyspepsia Episode In 21 subjects, proportion of eradication time with improvement of dyspepsia symptom was different
Table 3. Proportion of negative dyspepsia at present in patients with eradication phase < 1 year and > 1 year ago
Dyspepsia resolved
Dyspepsia
persisted Total
< 1 year
> 1 year Total
8 9 17
1 3 4
9 12 21
Table 4. Proportion of negativeHelicobacter pylori at present in patients with eradication phase < 1 year and > 1 year ago
H. pylori negative H pylori positive Total
< 1 year
> 1 year Total
8 9 17
1 3 4
9 12 21
Table 5. Proportion of dyspepsia andH. pylori status Dispepsia
resolved
Dispepsia
persisted Total
H. pylori-negative 13 4 17
H. pylori-positive 4 0 4
Total 17 4 21
between eradication group less than 1 year (88.8% or 8/
9), and with eradication group more than 1 year (75% or 9/12). Similar to the study by Rosengren and Polson who found dyspepsia improvement in 88.2% after 1 month of therapy, but 4 months after the therapy 2 patients felt the dyspepsia symptom again, and although the other 2 did not feel any more dyspepsia, once in a while they still consumed antacids or anti H2-receptor, thus the percentage of dyspepsia improvement decreased at the fourth month to 76.5%.42 The study by Rosengren and Polson proved that as the time advanced, a decrease of dyspepsia improvement occurred in the patients, as seen by re-consumption of medications to relieve dyspepsia.
Length of Evaluation Time with H. pylori Status Length of H. pylori status evaluation after eradication therapy was influenced by the possibility of reinfection during that time period. In this study, from 4 people with positive H. pylori status, 1 was known to have reinfection, proved by previously negative UBT test on evaluation after eradication therapy. Reinfection in adults was reported to be only 0.3-0.7% each year, and Cullen DJ and colleagues who performed long-term cohort study for 21 years from 1969 to 1990 only found 7% of reinfection in 86 previously seronegative patients after therapy.1,13 In this study, we could not conclude the prevalence of reinfection in patients after H. pylori eradication therapy only from this 1 patient, because the sample size did not meet requirements for calculation of proportion and statistical analysis. However, these data show that reinfection could occur in adults within 5 years’
time.
Dyspepsia Symptom and H. pylori Status
Looking at the proportion of dyspepsia resolution and negative H. pylori status, we found lower proportion symptom improvement in the H. pylori-negative group compared with the H. pylori-positive group, 76.4 % and 100% respectively. This result is different from previ- ous meta-analysis by Laheij and colleagues, who found better improvement of dyspepsia symptom in the negative group (73%) compared to the positive group (45%).48
Talley had previously reported no significant relationship in the improvement of dyspepsia symptom with H. pylori eradication, in patients with functional dyspepsia infected with H. pylori, and concluded that H. pylori eradication was not proved to improve symptoms of functional dyspepsia after 12 months of therapy. In that particular study they obtained 85%
H. pylori eradication rate, however, after 12 months of follow up, no significant difference in the improvement
of dyspepsia symptom was found in the therapeutic group, 24% compared to 22% in the control group.50
On the other hand, Chiba and colleagues who evaluated improvement in dyspepsia symptom after eradication therapy in patients with functional and organic dyspepsia found the improvement up to 54%51
The difference in symptom improvement found in several studies above might be because of the differences in study population. Laheij and Talley studies were performed in the non-ulcerative patients, while Chiba did not differentiate between the two groups.
Failure of Triple Therapy
After eradication therapy was performed, evaluation on the 25 subjects with different evaluation time found 4 patients with positive H. pylori infection, and 1 among them was thought to be caused by H.
pylori reinfection, since the patient had previously undergone UBT test after eradication therapy which
|revealed negative result. In all 4 subjects (19%), positive H. pylori status could result from failure of previous eradication therapy or reinfection. Thus, success of eradication therapy in 21 subjects was reported to be 81% of all samples. This figure is slightly lower than several previous studies. Wu and colleagues had up to 98% success rate after eradication with triple therapy in patients with reflux esophagitis symptoms, and in another study Manes G reported 94% eradication success in patients with dyspepsia symptoms.40,41 Rosengren and Polson performed an evaluation 1 month after eradication using triple therapy, and found 100%
eradication rate with 13C UBT.42
Therapeutic failure in patients after eradication therapy could have several causes, among them are antibiotic resistance, adherence to antibiotics due to adverse events, and reinfection. However in this study the failure was thought to be due to antibiotics resistance and reinfection, since all of the patients had completed triple therapy. Resistance was thought to be due to previous irrational antibiotics use. This was reported by Mc Mahon BJ and colleagues, that history of consuming the same type of antibiotics within the last 10 years were related with resistance, where 92% of clarythromycin-resistant patients had previously received clarythromycin, and 60% of metronidazole-resistant patients have received metronidazole within the last 6-8 years.32 Microbial resistance test to antibiotics is not routinely performed in Cipto Mangunkusumo Hospital nor in other hospitals in Jakarta, since this resistance test is exclusive, expensive, and is only used for research purposes.
Limitations of Study
In this study, the number of subjects fulfilling the study criteria were only 21 subjects, while on the minimal sample size calculation at least 49 subjects were required for statistical analysis. This inadequate sample size was due to the low prevalence of H. pylori in Cipto Mangunkusumo Hospital. A multicenter study in 5 large cities in Indonesia in 2003-2004 found H. pylori prevalence in patients with ulcerative and non-ulcerative dyspepsia symptom to be 10.2%, with the lowest prevalence in Jakarta, only 8%.5 Within 5 years in 2002- 2007, 62 H. pylori-positive cases with dyspepsia as early symptom were found in Cipto Mangunkusumo Hospital.
From the 62 cases, only 21 patients were able to participate in this study, since 12 people were living out of town (some of them in Medan, Kalimantan, and Central Java), 6 people had gastrointestinal cancer, 4 people with ulcerative appearance on previous endoscopy, 5 geriatric patients passed away, 11 people with unclear address and phone number could not be contacted, and 3 people refused to participate in the study because they did not feel any symptoms anymore and previous test were found to be negative. The limited sample size and unbalanced proportion between risk factors for H. pylori and the incidence of dyspepsia in patients with history of H. pylori eradication had caused difficulties in performing statistical relationship in this study. Therefore, our initial plan at the beginning of the study to proof hypotheses using statistical analysis was not able to put into realization.
Several issues that also turned to be the limitation of our study were sample collection that required 5 years to complete due to the low prevalence of H. pylori in Cipto Mangunkusumo Hospital each year, i.e. only between 10-12 cases annually. Thus, many other factors possibly have their influence in the incidence of dyspepsia in study subjects. However, in this study, other risk factors related to the incidence of dyspepsia found relatively similar proportion to patients with and without risk factors, with persistent dyspepsia symptoms.
CONCLUSION
Improvement of dyspepsia symptom after eradication therapy was found in most subjects and symptoms found in persistent dyspepsia were bloating, epigastric pain, and nausea. There were 81% of subjects with negative H. pylori status after eradication therapy through urea breath test (UBT) evaluation.
Proportion of dyspepsia symptom improvement in H. pylori who are currently negative were 76.4%.
Assessment of H. pylori status using urea breath test (UBT) should be performed 1 month after eradication therapy, considering failure of eradication using triple therapy was found. Efforts are needed for availability of H. pylori culture and resistance in CMH, so that whenever therapeutic failure occurs, right choice of antibiotics could be given to the patient. This is a pilot study, further study is required with representative sample size, in order to be able to perform statistical analysis to evaluate the success of eradication therapy and improvement of dyspepsia symptom
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