Materials and methods

We studied 1120 children who were diagnosed as having recurrent abdominal pain and who presented to the department of paediatrics, paediatric gastroenterology, and oncology at the Medical University of Gdañsk from 1993 to 1996 inclusive. All children had an endoscopic examination of their upper gastrointestinal tract by Olympus GIF-PQ 20 or GIF-PQ 10 endoscope. We examined the oesophagus, stomach, and duodenal cup and the severity of inflammation in the stomach mucosa was assessed visually according to the Sydney scale.22 The following features were considered: the presence of normal blood vessels, the presence of oedema, erythema, exudate, erosion, hypertrophy, or atrophy of gastric mucosal fold. We graded the degree of progression according to a scale from I to IV (grade I, no changes; grade II, mild changes; grade III, moderate changes; grade IV, severe changes). In the duodenum we evaluated the degree of visual inflammation as mild, moderate, or severe. The presence of oedema, erythema, exudate, erosion, and duodenal mucosa hypertrophy were considered. We performed the urease test (CLO-test) in all patients to exclude or confirm Helicobacter pyloriinfection. We took two biopsy specimens from the stomach (the body and the antrum) and one from the duodenal cap for morphological assessment from all children. In the stomach specimens we assessed histological inflammation according to the Sydney scale. We considered the following features: the intensivity and activity of inflammation, the degree of gastric gland atrophy, and the presence of metaplasia. We graded the degree of progression according to a scale from I to IV (as above). In the duodenum we considered the following features: the intensivity and activity of inflammation and the presence of metaplasia. We assessed the degree of progression as mild, moderate, and severe.

In children with endoscopic suspicion of bile reflux, we performed dynamic cholescintigraphy to confirm the diagnosis of bile reflux.

According to the result of endoscopic examination, we initially diagnosed bile reflux in 92 children. Children were fasted before cholescintigraphy. We administered the radiopharmaceutical agent (technetium-99m; HEPIDA) intravenously, at 3–4 mCi (111–148 MBq)/dose and acquisitions were carried out every five minutes, each lasting one minute. After the fifth measurement, we gave the children 150–200 ml of condensed cows’ milk to drink. After the 12th measurement, we gave 2 mCi (74 MBq) ^99mTc orally to detect the gastric field.

Evaluation of the results of cholescintigraphy was based on: morphological features (time–activity curves over the gastric field), and the reflux index calculated by dividing the number of gastric counts obtained during the exposure by the sum of the gastric and intestinal counts.

We randomly selected a control group of 50 from the group of children without endoscopic features of bile reflux. Some patients with bile reflux, confirmed by scintigraphy, received the prokinetic drug (cisapride) in addition to anti-inflammatory drugs (tripotassium dicitratobismuthate and amoxicillin and metronidazole in children withH pylori). To assess the efficacy of cisapride, we divided patients randomly into two groups: a group of children treated with cisapride and those who did not receive cisapride. Figure 1 gives a summary of the allocation of children to various groups. We gave cisapride for six weeks, tripotassium dicitratobismuthate for four weeks, amoxicillin for seven days, and metronidazole for 14 days. We performed the repeat scintigraphy three weeks after the end of treatment.

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Figure 1

Criteria for including children with chronic abdominal pain in our study on duodenogastric reflux.

We analysed results with the χ² test and Mann-Whitney test.

Our study was approved by the research advisory committee of the Medical University of Gdañsk.

Results

Among 1120 children, 92 (8.21%) were found to have bile reflux on endoscopy. The presence of reflux was confirmed by scintigraphy (group A) in 59 patients comprising 5.27% of the children who had abdominal pain. The range of the reflux index was 2–20% (median, 5.6%).

Group B consisted of 50 patients chosen at random from patients who did not have bile reflux at endoscopy. In group A there were 43 girls and 16 boys and in group B there were 22 girls and 28 boys. In group A the children’s ages ranged from 4 to 17 years, with a mean (SD) of 12.25 (2.58) years. In group B the children’s ages ranged from 5 to 17 years (mean, 11.58 years; SD, 3.08). No symptoms were found to be characteristic enough to identify those with bile reflux from the group of patients with recurrent abdominal pain.

Table 1 gives the results of endoscopic and histological examination of the stomach. More severe lesions were observed endoscopically in the body of the stomach in patients in group A than in group B (p < 0.01). However, the frequency of severe lesions in the antrum was similar in the two groups. The severity of histological inflammation was also similar in the two groups (table 1).Helicobacter pylori infection was detected in 15 children from group A and 27 from group B. Children who did not have bile reflux were significantly more often infected withH pylori compared with children who had bile reflux (p < 0.005). Table 2 gives the results of endoscopic and histological evaluation of the duodenum. There was no significant difference in the distribution of the severity of lesions between the two groups. In group A (children with reflux) we also analysed scintigraphic images. There were three types of distribution of the radiopharmaceutical agent: (1) the isotope was distributed evenly in the stomach; (2) the isotope accumulated in the antrum; and (3) the isotope accumulated in the cardiac region.

Statistic analysis (χ² test) showed no correlation between regions of accumulation of radiopharmaceutical agent and localisation of histologically assessed inflammatory lesions in the stomach (table 3).

We found that intensity of inflammation in the stomach and duodenum did not depend on the grade of reflux (table 4).

In our study, there was a lack of correlation between areas of the isotope accumulation and localisation of histologically assessed inflammatory lesions in the stomach. To explain this phenomenon, we carried out the following experiment. We performed cholescintigraphy on three male adult volunteers in the same way that it was performed on the children in our study. The contents of the stomach, containing 200 ml condensed cows’ milk as a test meal and the radiopharmaceutical agent, were evacuated and placed in a glass distortion dish. The distortion dishes were examined by means of a γ-camera. The pictures taken immediately after placing into the glass distortion dish and those taken later show the tendency of the radiopharmaceutical agent to gather at the top. Analysis of the isotope distribution revealed that the isotope particles, bound to digested milk, accumulated in the upper part of the dish (fig 2). This phenomenon is an artefact of the scintigraphic examination and is caused by using milk as the test meal.

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Figure 2

Distribution of radiopharmaceutical agent in the distortion dish filled with gastric contents and reflux material. (A) Immediately after gastric contents intake, (B) 15 minutes after gastric contents intake. Red, low radioactivity; yellow, high radioactivity.

Children from group A, who had gastritis and bile reflux, had anti-inflammatory drugs administered. Initially, 36 of the 59 were treated additionally with cisapride, but six were lost at follow up and so only 30 are reported here.

The evaluation of treatment with cisapride was based on two indices: the clinical improvement and alterations of reflux index. Because most of the patients did not consent to a further endoscopy, an analysis of changes in the mucosa of the stomach and duodenum during the course of treatment was not possible.

In those receiving cisapride, the initial reflux index ranged from 2% to 20% (median, 5.9%) and the corresponding results in those not receiving cisapride ranged from 2.2% to 18% (median, 6.4%). After cisapride treatment 18 children did not have any features of bile reflux (median, 0%). In five children, who were not treated with cisapride, there was no bile reflux (median, 6%). Statistic analysis (Mann-Whitney test) showed that treatment with cisapride reduces the incidence of bile reflux (U = 192.5; p < 0.01).

Clinical improvement was seen in 28 children who were treated with cisapride and in 18 children who were not treated with cisapride.

Cisapride was well tolerated by most of the patients; only two children complained of a worsening of abdominal pain, which made us decide to eliminate the drug from the treatment scheme in these patients. Other side effects were not noted.

Discussion

Endoscopic criteria of bile reflux in children are the same as in adults. As has been shown in other papers, they are not sufficient to establish the diagnosis. Other methods allow verification of the endoscopic diagnosis in 30–40% of cases.4 Similar results were obtained in our study (verification of endoscopic diagnosis in 64.1% cases).

Of special interest is the influence of bile reflux on the gastric mucosa. Although many authors have observed the correlation between the presence of bile reflux and intensity of inflammatory lesions,1-4 6 there are also many papers in which such correlations have not been found.12 23 24 It has been mentioned before that the concentration of bile acids in patients with bile reflux is very rarely as high as in experimental conditions.4 High concentrations of bile acids and lysolecithine are seen mainly in patients who have had surgery of distal parts of the stomach, and there were no such cases included in our study. The reflux index was also quite low in the children that we examined. In some studies, reflux indexes as high as 1–70% have been reported,4 and they are definitely higher in patients who have undergone partial gastrectomy (usually reflux index > 20%).25 In children, the reflux grade is comparatively low and this is probably why it does not have a crucial influence on inducing mucosal lesions. Hence, there must be some other factors that are responsible for inflammatory lesions in the stomach and duodenum in children. Some of them are widely known, such as genetic predisposition, psychological factors, andH pylori infection. In our study, the first two factors seem to dominate. A family history of upper gastrointestinal tract disorders was very common. In as many as 42.4% of the families, we found a history of gastric or duodenal ulceration. Our paper confirms the importance of psychological factors in the development of gastritis and duodenitis.

Helicobacter pylori infection has considerably less influence on the development of inflammatory lesions in children with bile reflux. These patients were significantly less often infected with the bacterium than children without reflux. This is probably because of the alkalisation of gastric contents in children with bile reflux, which may make colonisation by H pylori more difficult. Other authors have also noted this phenomenon in adults.5 26

During the scintigraphic verification of bile reflux in children we noted that regions of isotope accumulation did not correspond to the regions of the most severe inflammation diagnosed endoscopically and morphologically. It has been shown that Mackie’s modification18 of cholescintigraphy results in producing artefacts, which makes interpretation more difficult. Further research is needed to find a different test meal, so that this useful diagnostic method could be applied more widely. Treatment regimens for children with bile reflux have not been established yet. In our study we have added a prokinetic drug to the anti-inflammatory agent in the treatment. Cisapride was chosen because it has very few side effects and it is effective in improving gastroduodenal coordination.20 27 28 The drug was well tolerated, as has been noted in other reports. Our study proved its efficacy in eliminating bile reflux.

There is still one question that remains to be answered: whether or not, and in what situations, a prokinetic drug should be given. Our study does not enable us to draw conclusions of clinical importance, which would help the physician to make decisions about treatment. The fact that these drugs are also used in so called functional dyspepsia and in gastritis or gastric ulceration makes the problem even more complex. Usually, in these cases, the cause of the disorder is an impairment of evacuation of gastric contents, and the prokinetic drugs help to maintain proper evacuation of the retained food. Because of this, many authors suggest administering prokinetic preparations in the treatment of gastritis and/or gastric ulceration and in so called functional dyspepsia.29-32 This problem undoubtedly requires further evaluation.

CONCLUSIONS

• Gastroduodenal reflux was diagnosed endoscopically in 92 of 1120 children with recurrent abdominal pain, and cholescintigraphy confirmed its presence in 59 of these children. This suggests the need to verify the endoscopic diagnosis with other methods

• There was no significant difference in the intensity of inflammatory lesions in the mucosa of the stomach and duodenum between children with bile reflux and children without this disorder. This suggests that there might be other factors that are important in children, such as genetic predisposition and psychogenic factors

• The isotope method applied to verify the endoscopic diagnosis carries a potential error because of the use of milk as the test meal. It causes lack of correlation between the areas of the most intensive accumulation of the isotope and the localisation of inflammatory lesions in the stomach

• Administration of a prokinetic drug (cisapride) has a major influence on decreasing reflux index.