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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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Is a Citric Acid Meal Useful for Increasing Accuracy of the 13C-Urea Breath Test in Asian Populations?

Sung Eun Kim

Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea

Correspondence to:Sung Eun Kim
Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea
Tel: +82-51-990-5205, Fax: +82-51-990-5055, E-mail: solefide@hanmail.net

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2019; 13(5): 479-480

Published online September 15, 2019 https://doi.org/10.5009/gnl19262

Copyright © Gut and Liver.

Tests for Helicobacter pylori infection are divided into invasive and noninvasive methods. Among them, 13C-urea breath test (13C-UBT) is one of the noninvasive tests used to diagnose H. pylori infection and verify eradication after treatment.1 In 1987, 13C-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 13C.1 Urea is hydrolyzed by H. pylori urease, thus if the patient is infected H. pylori, labeled carbon dioxide (13CO2) is detected in breath samples. Additionally, it has been shown that sensitivity and specificity of 13C-UBT are higher than 90% for identifying H. pylori infection.2 Thus, 13C-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 13C-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 13C-UBT results as false negative.3 Bleeding peptic ulcer and atrophic gastritis (AG) with or without intestinal metaplasia (IM) may also decrease sensitivity of 13C-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 13C-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 13C-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 13C-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 13C-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 13C-UBT in Korea where there exists high prevalence of AG or IM. This prospective study conducted 13C-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 13C-UBT value, mean 13C-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 13C-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 13C-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 13CO2 activity in comparison with commercial pudding (p<0.05). However, few studies have been conducted assessing citric acid in 13C-UBT on Asian populations. Interestingly, in accordance with this study, Wong et al.9 also reported that 13C-UBT protocol without citric acid demonstrated highly reliable data similar to 13C-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 13C-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 13C-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 13C-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 13C-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 13C-UBT in Korean populations. Further well-designed prospective studies are required to elevate diagnostic accuracy of 13C-UBT in countries with high prevalence of AG or IM.

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

  1. Graham DY, Klein PD, Evans DJ Jr, et al. Campylobacter pylori detected noninvasively by the 13C-urea breath test. Lancet 1987;1:1174-1177.
    Pubmed CrossRef
  2. Gisbert JP, Pajares JM. Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection: a critical review. Aliment Pharmacol Ther 2004;20:1001-1017.
    Pubmed CrossRef
  3. Graham DY, Klein PD. Accurate diagnosis of Helicobacter pylori. 13C-urea breath test. Gastroenterol Clin North Am 2000;29:885-893.
    Pubmed CrossRef
  4. Mégraud F. Advantages and disadvantages of current diagnostic tests for the detection of Helicobacter pylori. Scand J Gastroenterol Suppl 1996;215:57-62.
    Pubmed CrossRef
  5. Gisbert JP, Vazquez MA, Jimenez I, et al. 13C-urea breath test for the diagnosis of Helicobacter pylori infection before treatment: is citric acid necessary? Dig Liver Dis 2000;32:20-24.
    Pubmed CrossRef
  6. Domínguez-Muñoz JE, Leodolter A, Sauerbruch T, Malfertheiner P. A citric acid solution is an optimal test drink in the 13C-urea breath test for the diagnosis of Helicobacter pylori infection. Gut 1997;40:459-462.
    Pubmed KoreaMed CrossRef
  7. Kwon YH, Kim N, Yoon H, Shin CM, Park YS, Lee DH. Effect of citric acid on accuracy of 13C-urea breath test after helicobacter pylori eradication therapy in a region with a high prevalence of atrophic gastritis. Gut Liver 2019;13:506-514.
    Pubmed CrossRef
  8. Graham DY, Runke D, Anderson SY, Malaty HM, Klein PD. Citric acid as the test meal for the 13C-urea breath test. Am J Gastroenterol 1999;94:1214-1217.
    Pubmed CrossRef
  9. Wong WM, Wong BC, Wong KW, et al. (13)C-urea breath test without a test meal is highly accurate for the detection of Helicobacter pylori infection in Chinese. Aliment Pharmacol Ther 2000;14:1353-1358.
    Pubmed CrossRef
  10. Schwartz JG, Salman UA, McMahan CA, Phillips WT. Gastric emptying of beer in Mexican-Americans compared with non-Hispanic whites. Metabolism 1996;45:1174-1178.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2019; 13(5): 479-480

Published online September 15, 2019 https://doi.org/10.5009/gnl19262

Copyright © Gut and Liver.

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

Sung Eun Kim

Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea

Correspondence to:Sung Eun Kim
Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea
Tel: +82-51-990-5205, Fax: +82-51-990-5055, E-mail: solefide@hanmail.net

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

Tests for Helicobacter pylori infection are divided into invasive and noninvasive methods. Among them, 13C-urea breath test (13C-UBT) is one of the noninvasive tests used to diagnose H. pylori infection and verify eradication after treatment.1 In 1987, 13C-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 13C.1 Urea is hydrolyzed by H. pylori urease, thus if the patient is infected H. pylori, labeled carbon dioxide (13CO2) is detected in breath samples. Additionally, it has been shown that sensitivity and specificity of 13C-UBT are higher than 90% for identifying H. pylori infection.2 Thus, 13C-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 13C-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 13C-UBT results as false negative.3 Bleeding peptic ulcer and atrophic gastritis (AG) with or without intestinal metaplasia (IM) may also decrease sensitivity of 13C-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 13C-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 13C-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 13C-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 13C-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 13C-UBT in Korea where there exists high prevalence of AG or IM. This prospective study conducted 13C-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 13C-UBT value, mean 13C-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 13C-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 13C-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 13CO2 activity in comparison with commercial pudding (p<0.05). However, few studies have been conducted assessing citric acid in 13C-UBT on Asian populations. Interestingly, in accordance with this study, Wong et al.9 also reported that 13C-UBT protocol without citric acid demonstrated highly reliable data similar to 13C-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 13C-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 13C-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 13C-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 13C-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 13C-UBT in Korean populations. Further well-designed prospective studies are required to elevate diagnostic accuracy of 13C-UBT in countries with high prevalence of AG or IM.

CONFLICTS OF INTEREST

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

References

  1. Graham DY, Klein PD, Evans DJ Jr, et al. Campylobacter pylori detected noninvasively by the 13C-urea breath test. Lancet 1987;1:1174-1177.
    Pubmed CrossRef
  2. Gisbert JP, Pajares JM. Review article: 13C-urea breath test in the diagnosis of Helicobacter pylori infection: a critical review. Aliment Pharmacol Ther 2004;20:1001-1017.
    Pubmed CrossRef
  3. Graham DY, Klein PD. Accurate diagnosis of Helicobacter pylori. 13C-urea breath test. Gastroenterol Clin North Am 2000;29:885-893.
    Pubmed CrossRef
  4. Mégraud F. Advantages and disadvantages of current diagnostic tests for the detection of Helicobacter pylori. Scand J Gastroenterol Suppl 1996;215:57-62.
    Pubmed CrossRef
  5. Gisbert JP, Vazquez MA, Jimenez I, et al. 13C-urea breath test for the diagnosis of Helicobacter pylori infection before treatment: is citric acid necessary? Dig Liver Dis 2000;32:20-24.
    Pubmed CrossRef
  6. Domínguez-Muñoz JE, Leodolter A, Sauerbruch T, Malfertheiner P. A citric acid solution is an optimal test drink in the 13C-urea breath test for the diagnosis of Helicobacter pylori infection. Gut 1997;40:459-462.
    Pubmed KoreaMed CrossRef
  7. Kwon YH, Kim N, Yoon H, Shin CM, Park YS, Lee DH. Effect of citric acid on accuracy of 13C-urea breath test after helicobacter pylori eradication therapy in a region with a high prevalence of atrophic gastritis. Gut Liver 2019;13:506-514.
    Pubmed CrossRef
  8. Graham DY, Runke D, Anderson SY, Malaty HM, Klein PD. Citric acid as the test meal for the 13C-urea breath test. Am J Gastroenterol 1999;94:1214-1217.
    Pubmed CrossRef
  9. Wong WM, Wong BC, Wong KW, et al. (13)C-urea breath test without a test meal is highly accurate for the detection of Helicobacter pylori infection in Chinese. Aliment Pharmacol Ther 2000;14:1353-1358.
    Pubmed CrossRef
  10. Schwartz JG, Salman UA, McMahan CA, Phillips WT. Gastric emptying of beer in Mexican-Americans compared with non-Hispanic whites. Metabolism 1996;45:1174-1178.
    Pubmed CrossRef
Gut and Liver

Vol.15 No.6
November, 2021

pISSN 1976-2283
eISSN 2005-1212

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