Aim: Establish long-term outcome and relate this to the initial H.pylori status (CagA- positive or negative).
Patients and Methods: In 1994/1995 a study on presence of H.pylori was done. IgG antibodies against cagA were determined. Three groups of patients were made: group 1: H.pylori + and CagA+; group 2: H.pylori + and CagA-; and group 3: H.pylori -patients. An extensive chart review and several questionnaires were used (a general questionnaire, the GerdQ, theSAI, and, the GSRS). Use of acid suppressive drugs was assessed.
Results: 411 patients were included. New upper GI-endoscopies were significantly more often done in patients of group 1 (p< 0.001). Reflux disease was significantly more often diagnosed in group 1 patients (p=0.02). After exclusions 239 patients (58.2%) received the questionnaires, 101 respondents were evaluable. Patients in group 1 reported significantly more often complaints. There was no significant difference in the overall presentation when patients of group 1 were compared with patients of group 2. However, there was a significant difference between the scores in H.pylori+ patients when compared with patients of group 3. Patients of group 1 significantly used more often acid suppressive therapy.
Conclusion: functional dyspeptics with H.pylori CagA+strain, may develop more often complaints in the future necessitating a new endoscopic investigations. Signs of reflux disease are more often present.
Key-words: Dyspepsia; H.pylori; Cag-A; Follow-up; Upper Gastrointestinal Endoscopy0>
An important virulence factor of H.pylori is the so-called Cag-pathogenicity island, containing the cytotoxin associated gene (cagA). The product of this gene is the immunodominant antigen CagA [3,4]. Patients with H.pylori positive ulcer disease are almost invariably cagA-positive [5,6]. Patients with CagA positivity also have an increased risk of gastric cancer [7].
Obviously, nowadays, all patients diagnosed with H.pylori infection are treated with anti-Helicobacter therapy. It is not known what the clinical sequelis in functional dyspeptics treated for H.pylori positive gastritis on the long-term. Most studies have a follow-up of six months till one year [1]. Another important point is the hypothesis that H.pylori might be protective against the development of gastroesophageal reflux disease [8].
A study was done in order to establish long-term out come in the sense of upper abdominal complaints, reflux complaints, and consultations for upper gastrointestinal complaints and relate this to the initial H.pylori status (CagApositive or negative).
In the present study only patients in whom no macroscopic abnormalities were seen during the endoscopy were included. These patients were diagnosed with functional dyspepsia (non-ulcer dyspepsia). During the procedure biopsy specimens were taken from the gastric antrum for haematoxilin/ eosin and immunoperoxidase stain (n=2), rapid urease test (n=1), and Gram stain with culture (n=1) according to previously described methods [10]. A patient was considered H.pyloripositive if one or more of the detection methods was positive. A patient was H.pylori-negative if all methods were negative. A serum sample was taken and frozen at minus 70 degrees Celsius. Specific IgG antibodies against the H.pylori cagA were determined as described earlier [9,11].
For the present follow-up study, the dyspeptic patients were grouped in three groups. Group 1:H.pylori positive and CagA positive; Group 2: H.pylori positive and CagA negative; and finally Group 3: patients negative for H.pylori.
Part of the patients diagnosed with functional dyspepsia participated in a trial with so-called reversed randomisation [12]. These patients were treated with the combination of omeprazole and amoxicillin. The trial did not include standard biopsies after completion of the study. Non-participants in this study were treated with the classic triple therapy or the classic quadruple therapy with bismuth, amoxicilline, metronidazole and protonpump inhibition. The majority of patients did not undergo follow-up endoscopy after treatment. The present study consists of two parts: first a chart review of all patients, and, second, the application of a number of questionnaires sent to all patients still alive at the date of evaluation.
A general questionnaire consisted of 20 questions [13,14]. The first question in the general questionnaire was: “Do you experience any upper abdominal complaint?” Severity and frequency of complaints were scored on a five and six point Likert scale respectively. Severity was scored as: 0 none; 1 light; 2: moderate; 3: serious; 4: serious complaint interfering with daily life. The minimum overall mean score for severity was 1, the maximum score 40. Severity score was calculated per patient. The overall mean frequency was scored as: 6: several times a day; 5: once daily; 4: several times a week; 3: once a week; 2: several times a month; 1: once a month. The minimum score on frequency was 1, the maximum score 60.
The GerdQ is a validated questionnaire that reveals a scoring on reflux symptomatology on the 7 days prior to receiving the list [15]. It calculates the probability that a patient has gastrointestinal reflux disease using six questions.
The SAI (symptom activity scale), which is a modified functional bowel disorder severity index, takes into account a subjective evaluation of the patients complaints, whether or not they have been present for over 6 months (chronic complaints) and how many times a patient consulted a general practitioner because of these complaints. A score of 36 or lower indicates mild complaints, a score between 37 and 110 is consistent with average complaints and a score of 111 or higher indicates severe complaints [16,17]. The gastrointestinal symptom rating scale (GSRS) ranges from 0 points when a patient has no complaints up to 18 points when a patient has all of six specified symptoms on a regular basis [18]. Use of acid suppressive drugs was assessed with the questions whether or not a patient used acid suppressive therapy. Statistical analysis was done with chi-square test for contingency tables and t-test. A value below 0.05 was considered statistical significant.
Only a minority of the patients in group 1 were not in the hospital system anymore, implying that they either moved out of the region or never went for any consultation again. This number was significantly higher in groups 2 and 3 (p=0.03). Table 2 shows the yield of the new endoscopies in the three groups of patients. In follow-up, reflux disease was significantly more often diagnosed in patients of group 1 (p=0.02). If biopsies were obtained during the endoscopy, these mostly were negative for H.pylori, indicating successful prior treatment. In all groups ulcers were detected.
The main reason was use of NSAID’s. Stomach cancerdiagnosis of functional dyspepsia. Oesophageal cancer was seen in one patient of group 2 already one year after the initial study.
Group 1 |
Group 2 |
Group 3 |
||
Number |
130 |
91 |
190 |
|
Men |
51(60.7) |
42(46.2) |
78(40) |
|
Women |
79(53.8) |
49(53.8) |
112(58.9) |
P = ns |
Not in the hospital system anymore |
12(9.3) |
20(21.9) |
31(16.3) |
|
Deceased |
29(22.3) |
34(38) |
36(19) |
|
No consultations in 2015 |
89(68.4) |
37(40.1) |
123(64.7) |
|
No pre-mortal consultations |
12 |
12 |
14 |
|
New endoscopy |
72(55) |
37(41) |
57(30) |
P < 0.001 |
Number of new endoscopies |
||||
1 |
33(45.8) |
20(54) |
35(61.4) |
|
2 |
17(23.6) |
8(21.6) |
10(17.5) |
|
3 |
12(16.6) |
4(10.8) |
7(12.3) |
|
>3 |
10(14) |
5(13.6) |
2(8.8) |
Group 1 |
Group 2 |
Group 3 |
|
No abnormalities |
59(82) |
24(65) |
38(67) |
Signs of reflux disease |
11(15) |
6(16) |
14(25) |
Ulcer |
1(15) |
6(16) |
4(7) |
Unknown |
- |
- |
1(1) |
H.pylori positive |
1 |
2 |
– |
H.pylori negative |
25 |
3 |
14 |
Patients in group 1 reported significantly more often complaints compared with those in groups 2 and 3 (Table 3).
|
Hp+ Cag+ |
Hp+ Cag- |
Hp- |
Complaints |
19(67.8) |
7(36.8) |
18(33.3) |
No complaints |
9(32.2) |
12(63.2) |
36(66.7) |
Hp+ Cag+ versus Hp+Cag- p<0.001 |
Table 5 shows the use of acid suppressive therapy in the three groups of patients. As can be seen the patients who were H.pylori+ and CagA+ used significantly more often acid suppression when compared with the other two groups..
The present study shows follow-up of more than 20 years in patients with functional dyspepsia especially related to H.pylori status. The majority of patients still visited their community hospital for all kinds of reasons. Some are treated in the out patients clinics of Internal Medicine or Gastroenterology, many visit other departments. Patients show great loyalty towards their community hospital. Hence, it can be assumed that if a patient had upper abdominal complaints, he/she again will visit his/her hospital and will undergo endoscopy if the general practitioner or the medical specialist feels the procedure is indicated.
General questionnaire |
Frequency |
GerdQ |
SAI |
GSRS |
|
Hp+ Cag+ |
|||||
Mean |
10.37 |
20.68 |
6.05 |
36.53 |
6.58 |
SD |
6.21 |
13.23 |
4.39 |
32.25 |
2.78 |
Median |
9 |
17 |
5 |
42 |
7 |
Range |
3-26 |
3-53 |
0-14 |
0-101 |
1-10 |
Hp+ Cag- |
|||||
Mean |
13.67 |
27.67 |
7.17 |
45.17 |
7.33 |
SD |
7.79 |
14.38 |
3.76 |
29.4 |
3.72 |
Median |
10 |
23.5 |
7 |
53.5 |
7.5 |
Range |
6-24 |
10-50 |
2-13 |
5-72 |
3-11 |
Hp- |
|||||
Mean |
6.72 |
12.06 |
2.67 |
18 |
4.33 |
SD |
4.79 |
9.4 |
2.25 |
19.67 |
2.85 |
Median |
7 |
13 |
0.53 |
21.9 |
0.67 |
Range |
0-19 |
0-39 |
0-7 |
0-54 |
0-12 |
General questionnaire |
|||||
Hp+ Cag+ versus Hp+ Cag- |
p = ns |
||||
Hp+ Cag+ versus Hp- |
p = 0.05 |
||||
Hp+ Cag- versus Hp- |
p = 0.01 |
||||
Frequency |
|||||
Hp+ Cag+ versus Hp+ Cag- |
p = ns |
||||
Hp+ Cag+ versus Hp- |
p = 0.02 |
||||
Hp+ Cag- versus Hp- |
p = .005 |
||||
GerdQ |
|||||
Hp+ Cag+ versus Hp+ Cag- |
p = ns |
||||
Hp+ Cag+ versus Hp- |
p = 0.07 |
||||
Hp+ Cag- versus Hp- |
p = 0.03 |
||||
SAI |
|||||
Hp+ Cag+ versus Hp+ Cag- |
p = ns |
||||
Hp+ Cag+ versus Hp- |
p = 0.04 |
||||
Hp+ Cag- versus Hp- |
p = 0.03 |
||||
GSRS |
|||||
Hp+ Cag+ versus Hp+ Cag- |
p = ns |
||||
Hp+ Cag+ versus Hp- |
p = 0.02 |
||||
Hp+ Cag- versus Hp- |
p = 0.05 |
Hp+ Cag+ |
Hp+ Cag- |
Hp- |
||
Medication+/complaints+ |
16 |
5 |
13 |
|
Medication+/complaints- |
4 |
2 |
5 |
|
Medication -/complaints + |
3 |
2 |
5 |
|
Medication -/complaints - |
5 |
10 |
31 |
|
Total |
||||
Medication + |
20(71.4) |
7(36.8) |
18(33.3) |
|
Medication - |
8(28.6) |
12(63.2) |
36(66.7) |
|
Hp+ Cag+ versus Hp+ Cag- |
p = 0.04 |
|||
Hp+ Cag+ versus Hp- |
p =0.001 |
|||
Hp+ Cag- versus Hp- |
p = ns |
An important finding in the present study is the fact that patients initially diagnosed with an H.pylori Cag-positive strain reported significantly more often that they still experienced upper abdominal complaints when compared with the Cagnegative strains or the H.pylori-negative patients. However, on the long-term patients who was H.pylori negative experienced significantly less often complaints or had a lower score in the different questionnaires. Harvey et al. studied the long-term effect of Helicobacter eradication. After 2 years, a 35% reduction in consultations for dyspepsia occurred. An extension of this study showed an ongoing trent in reduction of consultations in the next 2 and 7 years [22]. In another study it was shown that only 36% of functional dyspeptics were without any complaint seven years after treatment with anti-Helicobacter treatment [23]. Hansen et al. studied a very large population of individuals screened for presence of H.pylori after five years of follow-up. The response rate in Hansen’s study was very high, 94%. A modest effect on dyspepsia, and a modest, but significant effect on the consultation rate and sick leave days for dyspepsia were noted [24].
Another finding in the present study, although largely as indirect evidence, is the fact that patients who initially were infected with CagA-positive bacteria had the highest number of new endoscopies in the years to follow. Implicating more consultations because of complaints. Also these patients had a higher prevalence of reflux disease.
Also the fact that higher number patients in groups 2 and 3 were not in active the hospital system anymore is indirect evidence that they did rather well after being treated for their dyspepsia. Of course, it is always possible that they were referred to another hospital. But on the other hand why would a larger percentage of patients from group 1 still visit their hospital?
Patients received different anti-Helicobacter treatments. Triple therapy or even quadruple therapy is the most effective. However, anti-Helicobacter dual therapy with high dose proton pump inhibition can be as effective [25]. In the initial study biopsy specimens after therapy were not done routinely. But, if a patient underwent a new endoscopic investigation, biopsy specimens were often taken and proved to be H.pylori- negative in many cases implying successful prior anti-Helicobacter therapy (Table 2).
On the long-term the prognosis of functional dyspepsia is rather fair. The scores in the general questionnaire are lower than reported in a previous study in patients with active disease [22]. It can be concluded that patients with functional dyspepsia and H.pylori gastritise infected with a more virulentH.pylori strain (this is CagA-positive), may develop more often complaints in the future necessitating a new endoscopic investigations and treatment. Signs of reflux disease are more often present. H.pylori possibly seems to be protective against development of reflux disease [8].
- Zhao B, Zhao J, Cheng WF, Shi WJ, Liu W, Pan XL, et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia: a meta-analysis of randomized controlled studies with 12-month follow-up. J Clin Gastroenterol. 2014;48(3):241-247. doi: 10.1097/MCG.0b013e31829f2e25
- Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006;19(2):CD002096.
- Covacci A, Lange N, Censini S. The cag pathogenicity island of Helicobacter pylori. In: Hunt RH, Tytgat GNJ eds, Helicobacter pylori Basic mechanism to clinical cure. Kluwer Dordrecht. 1996:40-49.
- Censini S, Lange C, Xiang ZY, Crabtree JF, Ghiara P, Borodovsky, et al. Cag, a pathogenicity island of Helicobacter pylori encodes type I-specific and disease associated virulence factors. Proc Natl Acad Sci. 1996;93(25):14648-14653.
- Weel JF, van der Hulst RWM, Gerrits Y, Roorda P, Feller M, Dankert J, et al. The interrelationship between cytotoxin associated gene-A and vacuolating cytotoxin and Helicobacter pylori related diseases. J Infect Dis. 1996;173(5):1171-1175.
- Crabtree JE, Taylor JD, Wyatt Jl, Heatley RV, Shalcross TM, Tomkins DS, et al. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet. 1991;338(8763):332-335.
- Matos JI, de Sousa HA, Marcos-Pinto R, Dinis-Ribeiro M. Helicobacter pylori CagA and VacA genotypes and gastric phenotype: a meta-analysis. Eur J Gastroenterol Hepatol. 2013;25(12):1431-1441. doi: 10.1097/MEG.0b013e328364b53e
- Loffeld RJ, van der Hulst RW. Helicobacter pylori and gastro-oesophageal reflux disease: association and clinical implications. To treat or not to treat with anti-H. pylori therapy? Scand J Gastroenterol Suppl. 2002;236:15-18.
- Loffeld RJ, Werdmuller BF, Kusters JG, Kuipers EJ. Functional dyspepsia is associated with cagA-positive Helicobacter pylori strains. Scand J Gastroenterol. 2001;36(4):351-355.
- Loffeld RJLF, Stobberingh E, Arends JW. A review of diagnostic techniques for diagnosing Helicobacter pylori infection. Digestive Diseases. 1993;11(3):173-180.
- Pena AS, Endtz HPH, Offerhaus GJ, Hoogenboom-Verdegaal A, van Duijn W, de Vargas N, et al. Value of serology (ELISA and immunoblotting) for the diagnosis of Campylobacter pylori infection. Digestion. 1989;44(3):131-141.
- Werdmuller BF, van der Putten AB, Veenendaal RA, Lamers CB, Balk AG, Loffeld RJ. Functional dyspepsia has a good prognosis irrespective of H. pylori status. Long-term follow-up of symptoms after anti H. pylori treatment. Neth J Med. 1999;55(2):64-70.
- Dackus GH, Loffeld SM, Loffeld RJ. Use of acid suppressive therapy more than 10 years after the endoscopic diagnosis of reflux esophagitis with specific emphasis to trademark and generic proton pump inhibitors. J Gastroenterol Hepatol. 2012;27(2):368-371. doi: 10.1111/j.1440-1746.2011.06855.x
- Loffeld SM, Dackus GM, Loffeld RJ. The long-term follow-up of patients with endoscopically diagnosed reflux oesophagitis with specific emphasis to complaints. Eur J Gastroenterol Hepatol. 2011;23(12):1122-1126. doi: 10.1097/MEG.0b013e32834b8d18
- Jones R, Junghard O, Dent J, Vakil N, Halling K, Wernersson B, et al. Development of the GerdQ, a tool for the diagnosis and management of gastro-esophageal reflux disease in primary care. Aliment Pharmacol Ther. 2009;30(10):1030-1038. doi: 10.1111/j.1365-2036.2009.04142.x
- Drossman DA. Do psychosocial factors define symptom severity and patient status in irritable bowel syndrome? Am J Med. 1999;107(5A):41–50.
- Drossman DA, Li Z, Toner BB, Diamant NE, Creed FH, Thompson D, et al. Functional bowel disorders. A multicenter comparison of health statusand development of illness severity index. Dig Dis Sci. 1995;40(5):986–995.
- Kulich KR, Madisch A, Pacini F, Piqué JM, Regula J, Van Rensburg CJ, et al. Health Qual Life Outcomes. 2008;6:12. doi:10.1186/1477-7525-6-12
- Tally JN, Janssens J, Lauritzen 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(7187):833-837.
- Talley NJ, Vakil N, Ballard ED, Fennerty MB. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med. 1999;341:1106-1111.
- Werdmuller BFM, van der Putten ABMM, Veenendaal RA, Lamers CBHW, Balk AG, Loffeld RJLF. Functional dyspepsia has a good prognosis irrespective of H.pylori status. Neth J Med. 1999;55(2):64-70.
- Werdmuller BFM, van der Putten ABMM, Loffeld RJLF. The presentation of reflux oesophagitis, hiatal hernia, Barrett’s oesophagus and “reflux-like” dyspepsia: a prospective clinical and endoscopical study. Dis of the Esophagus. 1996;9:285-289.
- Harvey RF, Lane JA, Nair P, Egger M, Harvey I, Donovan J, et al. Clinical trial: prolonged beneficial effect of Helicobacter pylori eradication on dyspepsia consultations - the Bristol Helicobacter Project. Aliment Pharmacol Ther. 2010;32(3):394-400. doi: 10.1111/j.1365-2036.2010.04363.x
- Maconi G, Sainaghi M, Molteni M, Bosani M, Gallus S, Ricci G, et al. Predictors of long-term outcome of functional dyspepsia and duodenal ulcer after successful Helicobacter pylori eradication--a 7-year follow-up study. Eur J Gastroenterol Hepatol. 2009;21(4):387-393.
- Hansen JM, Wildner-Christensen M, Hallas J, Schaffalitzky de Muckadell OB. Effect of a community screening for Helicobacter pylori: a 5-Yr follow-up study. Am J Gastroenterol. 2008;103(5):1106-1113. doi: 10.1111/j.1572-0241.2007.01770.x
- Ince AT, Tozlu M, Baysal B, Şentürk H, Arıcı S, Özden A. Yields of dual therapy containing high-dose proton pump inhibitor in eradication of H. pylori positive dyspeptic patients. Hepatogastroenterology. 2014;61(133):1454-1458.