Peptic ulcer is an uncommon disease in childhood with low incidence worldwide (1–3). A Canadian study has estimated an incidence of 1 case per 2500 hospital admissions to a university hospital (2). Peptic ulcers in children can be classified into primary and secondary ulcers (2). Secondary peptic ulcer disease develops as a result of the acute stress of a severe systemic illness such as head trauma or overwhelming sepsis, or as sequelae to ingestion of ulcerogenic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids. Excluding those secondary peptic ulcers, primary peptic ulcers are even less commonly seen in pediatric practice. Single-center series from different parts of the world showed that primary peptic ulcer disease was diagnosed in only 1.8% to 3.6% of the total number of upper endoscopies performed to investigate gastrointestinal (GI) symptoms in children (4–7).
The discovery of the association of Helicobacter pylori with primary peptic ulcer disease has revolutionized the management of this disease in children (8). H pylori infection is considered to be the most important cause of primary duodenal ulcers in children, and eradication of the bacteria is effective in preventing ulcer relapse (9,10). However, because the prevalence of H pylori infection is expected to decline in newer generations, particularly in developed countries, with the improvement of socioeconomic conditions, there has been a concern about the potential increasing significance of H pylori–negative primary ulcers in both pediatric and adult population (4,11). To date, the characteristics and long-term outcome of H pylori–negative primary ulcers in children have yet to be adequately evaluated. The purpose of our study was to conduct a retrospective review to investigate the differences between H pylori–positive and H pylori–negative idiopathic peptic ulcers. We also arbitrarily divided our study period into 2 to evaluate for any difference in the prevalence of H pylori in our children with primary peptic ulcers.
PATIENTS AND METHODS
In our center from January 1998 to January 2006, we conducted a retrospective analysis of children age 16 or younger who were diagnosed endoscopically to have peptic ulcers. We searched through the data retrieval function of our hospital's computerized record system for patients with the diagnosis of gastric or duodenal ulcers after upper endoscopy. Exclusion criteria included the following: patients with documented intake of steroids, NSAIDs, or Chinese herbal medicine within 4 weeks of their first presentation, and patients with preexisting acute critical illnesses or subsequent diagnosis of Crohn disease. The demographic data, presenting symptoms, endoscopic findings, treatment, and subsequent recurrence were reviewed from hospitals notes and computer records.
Upper Endoscopy, Diagnosis of Ulcers and H pylori Infection, Histological Examination
Upper endoscopy for our children was performed either under sedation with intravenous pethidine and diazepam or under general anesthesia. In general, the majority of our children age 8 years or older had upper endoscopy done under sedation. At least 3 biopsies were routinely taken at the antrum, of which 2 were sent for histological examination and 1 was sent for rapid urease test, regardless of the endoscopic findings. Antral biopsy specimens were examined under hematoxylin and eosin and Giemsa stain. Ulcer was diagnosed endoscopically by the presence of a lesion bigger than 3 mm with complete mucosal breaching and a base with depth. H pylori infection was defined by either a positive rapid urease test or a positive antral biopsy for the bacteria. For this study, all of the antral biopsy specimens were retrospectively reviewed by a single pediatric pathologist (K.F.T.) and gastritis was defined according to established criteria using the Sydney system (12).
Treatment and Follow-up
Over the review period, H pylori infection was eradicated by a 1-week course of proton pump inhibitor (PPI)–based triple therapy using a combination of amoxycillin and clarithromycin. Depending on the protocols in use at the time of diagnosis, H pylori–positive ulcers were treated by a 1-week course of eradication therapy alone or eradication therapy followed by 3 more weeks of PPI. All H pylori–negative ulcers were treated by a standard 4-week course of PPI or H2-blockers in early years. Further continuation of treatment with PPI would be given only for cases with endoscopic proof of incomplete healing of ulcers. Follow-up endoscopy was performed on an individual case basis in early patients of our series. In recent years, we routinely repeated upper endoscopy in our newly diagnosed patients to allow better evaluation of ulcer healing and success of H pylori eradication. Successful H pylori eradication was defined by a negative rapid urease test and negative histology in antral biopsy specimens. According to our clinical protocol for children diagnosed with peptic ulcers, the patients were reassessed at 6 weeks, 3 months, and then every 6 to 9 months in an outpatient clinic. Upper endoscopy would be arranged at any time during the follow-up period should the patient become symptomatic again. Recurrent ulcers were defined in this study by new occurrence of ulcers after the endoscopic proof of complete healing of previous ulcers or new ulcers developed after the patient remained asymptomatic for more than 3 months after completion of treatment.
Descriptive statistics were used to review the overall characteristics of our patients regarding sex distribution, ulcer locations, clinical presentations, and H pylori prevalence. The study period was also arbitrarily divided into 2 with similar length, that is, 1998 to 2001 and 2002 to January 2006, to compare the prevalence of H pylori infection. Differences between H pylori–positive and H pylori–negative idiopathic ulcers were assessed using the χ 2 test for categorical data and Mann-Whitney U test to compare medians. Analysis of ulcer recurrence included only those patients who had been followed up for more than 6 months after diagnosis. Kaplan-Meier's method and log-rank test were used to estimate the annual recurrence rate and compare the 2 groups. Multivariate logistic regression was used to identify independent risk factors for ulcer recurrence. Results were expressed as relative risks with 95% confidence interval. A P value of less than 0.05 was considered statistically significant.
A total of 51 children were identified with the diagnosis of gastric or duodenal ulcers within the study period, of which 8 were excluded from this study according to the exclusion criteria and 43 were suitable for the retrospective review, and they were Chinese. These 43 children were out of 619 patients (6.9%) who had undergone upper endoscopy for investigation of upper gastrointestinal (GI) symptoms during the review period. There were 31 boys and 12 girls (M:F = 2.6:1, median age at diagnosis 12 years, range 3–16 years). Thirty-seven and 6 patients had duodenal and gastric ulcers, respectively, and there were no multiple ulcers in our patients. In 32 patients, the ulcer was 1 cm or less in size, whereas in 11 patients, the ulcers were bigger than 1 cm (Table 1).
Thirty children (70%) presented with acute GI bleeding and the diagnosis was made by emergency endoscopy. Other primary presentations included perforated peptic ulcers (n = 3), acute epigastric pain (n = 3), chronic iron deficiency anemia (n = 2), and chronic epigastric pain (n = 2). Overall, only 19 children (44.2%) had a history of epigastric pain (Table 2).
Twenty-three (53.5%) patients were found to be positive for H pylori infection, whereas 20 (46.5%) were negative. Among the 23 positive patients, 22 had both positive rapid urease test and positive histology of antral biopsies, whereas 1 had a positive biopsy but a negative rapid urease test. There were 18 and 25 patients from the periods of 1998 to 2001 and 2002 to January 2006, respectively. During the first period, there were 7 (39%) H pylori–positive ulcers compared with 16 (64%) during the latter period (P > 0.05).
The median age of the H pylori–positive group was significantly higher than that of the negative group (12 vs 10 years, P < 0.05). Twenty-one of the 23 H pylori–positive patients were boys (91.3%) compared with only 10 (50%) in the H pylori–negative group (P < 0.01). There were no differences between the 2 groups in duodenal/gastric ulcer ratio, ulcer size, prevalence of acute GI bleeding, chronic epigastric pain, and requirement for blood transfusion. The H pylori–infected group was associated with chronic iron deficiency anemia (P < 0.05) (Table 3).
A retrospective review of the antral biopsy specimens showed that all H pylori–positive children had chronic active gastritis characterized by infiltration of plasma cells, lymphocytes, and neutrophils. Only 1 had intestinal metaplasia and gastric glandular atrophy. Among the 20 H pylori–negative patients, 15 had features of chronic inflammation characterized by the increase in plasma cells and lymphocytes. Two of these 15 children also had evidence of neutrophils infiltration in addition to plasma cells and lymphocytes and were diagnosed as having chronic active inflammation. Four out of 20 had normal histology. One had histological features of reactive gastritis characterized by foveolar hyperplasia and proliferation of smooth muscle strands but without significant inflammatory cells infiltrate (Table 4).
The 20 H pylori–negative patients were treated by H2 blocker (n = 2) and PPI (n = 18), respectively. Eleven of them had undergone follow-up endoscopy and complete healing of the ulcers was seen in 8 children after 4 weeks of treatment. The remaining 3 found to have incomplete healing required continuation of PPI for an additional 4 weeks (n = 1) and 8 weeks (n = 2) before complete healing of the ulcers was confirmed eventually by endoscopy. Among the 23 H pylori–positive patients, 6 were treated by 1-week PPI-based triple eradication therapy alone, whereas 17 received 1-week eradication therapy with additional 3 more weeks of PPI. Eleven of the 23 positive patients had follow-up endoscopy. Complete healing of ulcer and successful eradication were confirmed in all of them.
Two patients had a follow-up of less than 6 months at the time of this study and thus were excluded from analysis in ulcer recurrence. These included 1 patient from each group. Both of them had remained asymptomatic by the time this study was completed. This left 41 patients for analysis of long-term outcome (H pylori–positive group n = 22, H pylori–negative group n = 19). The median follow-up periods were 31 months (range 6–72 months) and 42 months (range 10–60 months) for H pylori–positive and H pylori–negative groups, respectively. A total of 7 patients developed ulcer recurrences, and they all were patients with duodenal ulcers. None of them were taking NSAIDs or Chinese herbal medicines before their recurrences. One patient from the H pylori–positive group developed recurrent duodenal ulcers 10 months after endoscopic proof of successful eradication and complete healing of the ulcers. He remained H pylori negative when duodenal ulcer recurred. He was treated with a 4-week course of PPI and complete ulcer healing was confirmed by endoscopy. The remaining 6 patients were from the negative group and recurrences developed within 15 months after withdrawal of treatment. Four of them had undergone follow-up endoscopy that confirmed complete ulcer healing before they developed recurrence. The other 2 without follow-up endoscopy had remained asymptomatic for 12 and 15 months, respectively, before their presentation of recurrent ulcers. Four children had only 1 recurrence and were successfully treated by another 4-week course of PPI and had remained asymptomatic since then. Two of these 6 children had developed more than 1 recurrence and were put on long-term PPI. Both of them had normal gastrin levels. Duodenal biopsies taken from both patients showed only moderate inflammatory cells infiltrate without granuloma, viral inclusions, parasites, or any microorganisms on special stains. They had remained asymptomatic and ulcer-free endoscopically while receiving long-term PPI. There was a significant difference in the crude recurrence rates between the 2 groups (4.5% vs 31.6%, P < 0.05). Using the Kaplan-Meier method, the annual recurrence rates were estimated to be 5.2% (95% CI 4.2–6.3) and 11.4% (95% CI 9.1–13.6) for H pylori–positive and H pylori–negative peptic ulcers, respectively (P < 0.05 by log rank test) (Table 5).
Univariate analysis also demonstrated that ulcers bigger than 1 cm in size had a higher recurrence rate regardless of the H pylori status (P < 0.01). Multivariate logistic regression controlling for age and sex showed that H pylori–negative status and ulcer size >1 cm were independent risk factors for recurrence (P < 0.05, relative risk of H pylori–negative status = 20.8, 95% CI 1.1–500, relative risk of ulcer size >1 cm = 23.2, 95% CI 1.8–292).
Our results showed that primary peptic ulcer disease in our Chinese children had male preponderance, affected older children, and duodenal ulcers were more common than gastric ulcers. These findings were consistent with those previously reported by others (2,4,6,13–15). However, contrary to most of the previous reports that abdominal pain was the most common presentation (2,6,13), acute GI bleeding occurred as the primary presentation in 70% of our patients, and a history of epigastric pain actually was found in less than half of our patients. An earlier study conducted in our locality, reviewing patients from 1975 to 1988, also found acute GI bleeding to be the most common presentation (16). The reason for this was not apparent in this study. However, it is possible that our study population was biased because the study was conducted in a tertiary referral center with emergency service. Because the incidence of primary peptic ulcer disease in childhood is so low, children with recurrent epigastric pain may easily be presumed to suffer from nonulcer dyspepsia and may be given empirical treatment of PPI or H2 blockers by general practitioners. Noninvasive investigations for H pylori infection are also available in many private laboratories in Hong Kong; children with less acute GI symptoms may undergo those investigations and receive empirical eradication therapy without referral for endoscopic examination. Whether other environmental or genetic factors may influence the presentation of peptic ulcers in children remain mysterious and require further investigations.
The discovery of H pylori by Marshall and Warren (17) more than 20 years ago has radically changed the management for peptic ulcers. H pylori infection is now considered to be the most important cause for primary peptic ulcers in both adults and children, and eradication of the bacteria is effective in decreasing the ulcer relapse (9,10,18,19). However, recently there have been concerns about the significance of the role of H pylori in peptic ulcer disease in the adult population (20,21). Ciociola et al (21) reported 27% of duodenal ulcers were not associated with H pylori infection or NSAIDs in a pooled analysis of a population approximating 3000. An increasing proportion of H pylori–negative, non–NSAIDs-related peptic ulcers is believed to be related to the decreasing prevalence of H pylori infection, particularly in developed countries, as a result of improvement of economy. A recent study conducted in our hospital reported an increased incidence of H pylori–negative idiopathic bleeding duodenal ulcers in our local adult population in 2000 compared with that in 1997 to 1998 (11). It was also found that idiopathic H pylori–negative duodenal ulcers were more prone to develop recurrence and complications. Another study in our locality also demonstrated a decreasing trend of H pylori infection in adult patients referred for investigation of dyspepsia from 1997 to 2003 (22). There have been no pediatric series published in the literature to investigate the trend of H pylori prevalence in primary peptic ulcer disease. We arbitrarily divided our study period into 2 and did not come up with any significant difference in the prevalence of H pylori infection in our children with primary peptic ulcer disease between the period 1998 to 2001 and after 2002. Actually, we encountered a bigger proportion of H pylori–positive primary ulcers in the latter period (64% vs 39%), although no statistical difference was reached. The small number of cases, however, may not support a reliable investigation in the single-center study.
The overall prevalence of H pylori in our patients was 56.8% and 33.3% in duodenal and gastric ulcers, respectively. Our figure for primary duodenal ulcers is lower than most of the previous reports (5,7,13,14,23). A pooled analysis of early reports demonstrated that H pylori was associated with 33% to 100% of primary duodenal ulcers in children, with median being 92% (23). Kato et al (14) recently reported the prevalence of 83% in 100 cases of primary duodenal ulcers in a multicenter series in Japan. The significance of H pylori–negative idiopathic primary peptic ulcers in children was recently reported by Elitsur and Lawrence (4), who described 7 cases of H pylori–negative idiopathic ulcers among 10 children with primary duodenal ulcers. To our knowledge, our report is the first one with the aim of characterizing the differences between H pylori–positive and H pylori–negative idiopathic primary peptic ulcers in children with long-term outcomes. Our report showed that children with H pylori–positive ulcers were significantly older than the H pylori–negative group (median age 12 vs 10 years, P < 0.05). This was in agreement with another study from Greece (6). A recent longitudinal cohort study in Ireland has shown that H pylori infection was predominantly acquired at the age of 2 to 3 years, with the infection rate being 5.05/100 person-years (24). Although the exact role of H pylori in the pathogenesis of peptic ulcers is not fully understood, the fact that H pylori–positive peptic ulcers predominantly occur in adults and rarely in older children suggests that the bacteria take years or decades to induce the pathological formation of ulcers or it may require the presence of some unknown coetiological factors that are attained in adulthood or in a minority of older children. It has been believed that peptic ulcers in children younger than 10 years are almost always secondary in nature, not associated with H pylori, and tend not to recur as long as the predisposing causes are removed (2,9,25). In this study, however, we found that young children could have primary peptic ulcers that were not associated with H pylori infection but had a substantial risk of recurrence as will be discussed below. If future studies from other centers can confirm our finding of increasing significance of H pylori–negative idiopathic ulcer and its age characteristics, then the current concept that primary peptic ulcer disease predominantly occurs in older children and is always associated with H pylori infection may need to be changed.
The sex difference between the H pylori–positive and the H pylori–negative group is also of great interest. Studies have unanimously shown a male preponderance in peptic ulcer disease in children. Epidemiological studies do not suggest any sex predilection in H pylori infection (26). We found that male preponderance was only observed in the H pylori–positive group. The longstanding feature of male preponderance in primary peptic ulcer disease in children may simply reflect the overwhelming contribution of H pylori–positive ulcers. It remains unknown why primary peptic ulcers predominantly develop in infected male children. Our finding of symmetrical distribution of H pylori–negative idiopathic ulcers by sex suggests that both sexes have similar risk exposure to the unknown etiology. The sex and age differences between the 2 groups strongly suggest that they constitute 2 separate entities with different etiology and pathogenesis resulting in a similar outcome of ulcer formation. No differences were found between the 2 groups in their presenting features including prevalence of acute GI bleeding, history of epigastric pain, requirement for blood transfusion, and endoscopic appearance except that chronic iron deficiency anemia was significantly associated with the H pylori–positive group as reported by others (14,27,28).
Another important observation in our study was that ulcer recurrence occurred more commonly in H pylori–negative than the H pylori–positive group after eradication therapy. The recurrence rate in H pylori–positive peptic ulcers obviously varies with the effectiveness of eradication therapy. In a study of 4940 adult patients with H pylori–positive peptic ulcers after successful eradication, the rate of H pylori–negative relapse of duodenal ulcers was estimated to be only 1.5%/year after excluding all who took NSAIDs (29). In a pediatric series of an Irish study, no recurrence was seen after a median follow-up of 37 months in 15 children with H pylori–positive duodenal ulcers following successful eradication (13). Our report confirmed that H pylori–negative ulcer relapse could occur after successful eradication of H pylori in children. The cause of it is not clearly understood. Logistic regression analysis in our study suggested that both H pylori–negative status and ulcer size greater than 1 cm were independent risk factors for recurrent ulcers in children. Little is known in the literature about the ulcer size in relation to the etiology and long-term outcome of primary peptic ulcer disease in children. The only H pylori–positive patient in our series who developed recurrent ulcer had an initial ulcer size of 1.5 cm. We speculate that H pylori is a primary cofactor in the etiology of primary peptic ulcer disease in children, but ulcer recurrence also depends on other less important host factors that may determine the size of ulcers as well.
The etiology of H pylori–negative ulcers remains unknown. It has been postulated that in adults H pylori–negative idiopathic ulcers may be related to acid hypersecretion as a result of exaggerated integrated gastrin response (30,31). No similar studies have been done in children. It is interesting that 75% of our children in the H pylori–negative group were found to have chronic inflammation in their antral biopsy specimens because of unknown reasons. It is uncertain whether some mysterious factors other than H pylori could induce pathological changes resulting in gastritis followed by mucosal ulcerations in children. Nonspecific gastritis is also a common finding in children with functional dyspepsia, although its role in causing symptoms remains uncertain (32,33). One child in the H pylori–negative group had histological evidence of reactive gastritis, which was present in around one quarter of our local adult patients with H pylori–negative idiopathic ulcers (11). Reactive gastritis can result from chemical injury because of drugs or bile reflux. It is uncertain whether this patient had unreliable drug history in the hospital record.
We observed more ulcer recurrences in the H pylori–negative group, with an estimated annual recurrence rate of 11.4%. This suggests that children can be constantly or repeatedly exposed to the same causative factors whether they are exogenous or endogenous. The 2 patients who are PPI dependent showed complete healing of their ulcers while receiving PPI but relapsed soon after withdrawal of treatment. It is possible that these 2 children are persistently exposed to the same unknown etiology, which results in persistent imbalance between the acid and the mucosal defensive factors and can only be corrected by continuous and adequate acid suppression. This group of patients may represent the few children for whom ulcer surgery would be considered as an option in the era of H pylori. However, the issue whether surgery has advantage over long-term PPI in this particular group of children remains contentious, when long-term data concerning the clinical course of such condition are still lacking.
The retrospective nature of the analysis constituted the major limitation of our study. All of the data were gathered from hospital notes and computer records. The endoscopic procedures were done by different people at different time periods. History of drug intake before presentation may not be reliable. Although reviewing the hospital records of all of our 43 patients did not reveal that any one of them had chronic illness requiring regular analgesics or steroids, transient intake of NSAIDs or herbal medicine could not be completely excluded in this retrospective review, and our 20 cases of idiopathic ulcers may include some drug-induced cases. However, it is unlikely that the 6 patients, who had recurrent H pylori–negative idiopathic ulcers, were related to drugs, as wrong information collected repeatedly in the same patient is rare. It would be ideal if all our H pylori–negative patients had undergone other diagnostic tests for H pylori infection such as urea breath test to minimize the possibility of underdiagnosis of this infection in our series. Despite being one of the largest single-center series of primary ulcer disease in childhood, the intrinsic limitation by the relatively small number of cases has significant impact on our analysis. Nevertheless, our study supports the findings of the others that non–H pylori idiopathic peptic ulcers exist in children and pose a great challenge to clinicians, because little is known about its etiology, and it has a tendency to relapse after withdrawal of acid-suppression treatment.
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