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Is a Citric Acid Meal Useful for Increasing Accuracy of the 13C-Urea Breath Test in Asian Populations?

Tests for Helicobacter pylori infection are divided into invasive and noninvasive methods. Among them, C-urea breath test (C-UBT) is one of the noninvasive tests used to diagnose H. pylori infection and verify eradication after treatment. In 1987, C-UBT was reported as a method to detect H. pylori infection. The method of UBT is as follows: The patient blows before and after administering a tablet of urea labeled with the nonradioactive stable isotope C. Urea is hydrolyzed by H. pylori urease, thus if the patient is infected H. pylori, labeled carbon dioxide (CO2) is detected in breath samples. Additionally, it has been shown that sensitivity and specificity of C-UBT are higher than 90% for identifying H. pylori infection. Thus, C-UBT is simple as well as highly accurate, and this test is regarded as an established test in detecting H. pylori. However, there are considerable limitations to C-UBT, such as being cautious with interpretation of results. Recently used proton pump inhibitors, antibiotics, and bismuth salts may reduce the number of gastric bacteria which may affect the C-UBT results as false negative. Bleeding peptic ulcer and atrophic gastritis (AG) with or without intestinal metaplasia (IM) may also decrease sensitivity of C-UBT. On the contrary, other urease-producing bacteria (Streptococcus, Staphylococcus, Gardnerella, Lactococcus, and Enterococcus) reside in the stomach, and may represent false positive results of C-UBT. Additionally, interpretation of the gray zone, of which the exact range is not defined, remains a controversial issue. Various attempts have been suggested to overcome these limitations and to improve diagnostic accuracy. These modifications have contained dosage of labeled urea used, the collection time of breath samples, testing with or without fasting, type of test meal, cutoff value and equipment for measuring isotope enrichment. Numerous studies associated with the UBT technique and its methodology have been revealed. However, no standardized method of UBT has been confirmed. In terms of the test meal, it remains debatable if a test meal is required for C-UBT, or which test meal is superior. Theoretically, test meals were introduced to increase accuracy of UBT by delaying gastric emptying and maximizing distribution of the substrate within the stomach thereby enhancing the contact area and time between the bacteria and the substrate. Various nutrient meals containing carbohydrates, protein, and fats have been applied, and citric acid is a preferred test meal because it decreases antral motility and relaxes gastric fundus by reducing duodenal pH. Thus, protocols in the United States and Europe incorporate citric acid meal in C-UBT. However, the Asian protocol does not necessarily recommend use of citric acid meal. In this regard, this article investigated the effect of citric acid meal on diagnostic accuracy of C-UBT in Asian populations. In this issue of Gut and Liver, Kwon et al. reported that the rate of false positivity of the citric acid group is higher than the control group in C-UBT in Korea where there exists high prevalence of AG or IM. This prospective study conducted C-UBT for patients who received H. pylori eradication therapy, with one group administrating a citric acid solution (citric acid 4 g in 200 mL of water with 50 g glucose polymer, n=562) and the other group administrating a glucose meal without citric acid (n=645). In terms of C-UBT value, mean C-UBT value of the citric acid group was significantly higher than the control group (p<0.001). However, when compared with the histology, accuracy (83.3% vs 87.7%), specificity (81.3% vs 88.2%), and positive predictive

Tests for Helicobacter pylori infection are divided into invasive and noninvasive methods. Among them, 13 C-urea breath test ( 13 C-UBT) is one of the noninvasive tests used to diagnose H. pylori infection and verify eradication after treatment. 1 In 1987, 13 C-UBT was reported as a method to detect H. pylori infection. 1 The method of UBT is as follows: The patient blows before and after administering a tablet of urea labeled with the nonradioactive stable isotope 13 C. 1 Urea is hydrolyzed by H. pylori urease, thus if the patient is infected H. pylori, labeled carbon dioxide ( 13 CO 2 ) is detected in breath samples. Additionally, it has been shown that sensitivity and specificity of 13 C-UBT are higher than 90% for identifying H. pylori infection. 2 Thus, 13 C-UBT is simple as well as highly accurate, and this test is regarded as an established test in detecting H. pylori.
However, there are considerable limitations to 13 C-UBT, such as being cautious with interpretation of results. Recently used proton pump inhibitors, antibiotics, and bismuth salts may reduce the number of gastric bacteria which may affect the 13 C-UBT results as false negative. 3 Bleeding peptic ulcer and atrophic gastritis (AG) with or without intestinal metaplasia (IM) may also decrease sensitivity of 13 C-UBT. 3 On the contrary, other urease-producing bacteria (Streptococcus, Staphylococcus, Gardnerella, Lactococcus, and Enterococcus) reside in the stomach, and may represent false positive results of 13 C-UBT. 4 Additionally, interpretation of the gray zone, of which the exact range is not defined, remains a controversial issue.
Various attempts have been suggested to overcome these limitations and to improve diagnostic accuracy. These modifications have contained dosage of labeled urea used, the collection time of breath samples, testing with or without fasting, type of test meal, cutoff value and equipment for measuring isotope enrichment. 2 Numerous studies associated with the UBT technique and its methodology have been revealed. However, no standardized method of UBT has been confirmed.
In terms of the test meal, it remains debatable if a test meal is required for 13 C-UBT, or which test meal is superior. Theoretically, test meals were introduced to increase accuracy of UBT by delaying gastric emptying and maximizing distribution of the substrate within the stomach thereby enhancing the contact area and time between the bacteria and the substrate. 1 Various nutrient meals containing carbohydrates, protein, and fats have been applied, 2 and citric acid is a preferred test meal because it decreases antral motility and relaxes gastric fundus by reducing duodenal pH. 5 Thus, protocols in the United States and Europe incorporate citric acid meal in 13 C-UBT. 6 However, the Asian protocol does not necessarily recommend use of citric acid meal. In this regard, this article investigated the effect of citric acid meal on diagnostic accuracy of 13 C-UBT in Asian populations.
In this issue of Gut and Liver, Kwon et al. 7 reported that the rate of false positivity of the citric acid group is higher than the control group in 13 C-UBT in Korea where there exists high prevalence of AG or IM. This prospective study conducted 13 C-UBT for patients who received H. pylori eradication therapy, with one group administrating a citric acid solution (citric acid 4 g in 200 mL of water with 50 g glucose polymer, n=562) and the other group administrating a glucose meal without citric acid (n=645). In terms of 13 C-UBT value, mean 13 C-UBT value of the citric acid group was significantly higher than the control group (p<0.001). However, when compared with the histology, accuracy (83.3% vs 87.7%), specificity (81.3% vs 88.2%), and positive predictive value (55.0% vs 62.5%) of 13 C-UBT for the citric acid group were lower than those of the control group, and sensitivity (91.7% vs 90.9%) and negative predictive value (97.5% vs 97.8%) of 13 C-UBT were similar between the two groups.
Several studies have investigated the efficacy of citric acid meal in UBT by a direct comparison with or without citric acid. Most of the studies have been published on the Western population. Graham et al., 8 one of the representative studies, revealed that citric acid at 1, 2, or 4 g developed significant increases in breath 13 CO 2 activity in comparison with commercial pudding (p<0.05). However, few studies have been conducted assessing citric acid in 13 C-UBT on Asian populations. Interestingly, in accordance with this study, Wong et al. 9 also reported that 13 C-UBT protocol without citric acid demonstrated highly reliable data similar to 13 C-UBT protocol with citric acid in the Chinese population. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 90% or more in both groups. Reasons for debatable results are unclear. However, it may be associated with difference in distribution, delivery and emptying of 13 C-urea, 9 and ethnic differences in gastric emptying according to race. 10 Additionally, although this study could not demonstrate it, it is considered that moderate and severe AG and IM also influenced the difference in results.
There are several limitations in this study. First, there was no validation study of 13 C-UBT using citric acid meal for the Korean population. Although the authors used the U.S. Standard Protocol, the standard may not be suitable for Koreans. Second, the gold standard method compared to 13 C-UBT was only histology, and it is well-known that histology is susceptible to sampling error due to inconsistent H. pylori colonization in the gastric mucosa. Thus, some studies have conducted more than one H. pylori test and have defined H. pylori positive if both tests are positive. 9 Finally, the number of patients accepted histology is only 9.9% of all enrolled patients, which may have affected the relatively low accuracy of 13 C-UBT. Studies such as this study have not been conducted in recent years, and it is of academic value in that this is the first study to examine the efficacy of citric acid meal on 13 C-UBT in Korean populations. Further welldesigned prospective studies are required to elevate diagnostic accuracy of 13 C-UBT in countries with high prevalence of AG or IM.

CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.