Urea Breath Test

Helicobacter pylori (H.pylori) is a ubiquitous, microaerophilic, gram negative, bacillus.(1) H. pylori has strong associations with many non-neoplastic (peptic ulcer disease, chronic atrophic gastritis) and neoplastic (adenocarcinoma of the stomach, gastric lymphoma MALT) conditions of the gastrointestinal tract.(2) Therefore, the WHO categorized H. pylori as a class I carcinogen in 1994. (3) Early diagnosis and successful eradication of H. pylori infection cures chronic gastritis and can reduce the progression to the long-term complications. (2)

Diagnostic tests for H pylori can be divided into invasive and non-invasive methods. (4) UBT is the most accurate testing among the non-invasive tests. The test (UBT) detects active H. pylori infection and is useful for making the primary diagnosis and for documenting successful treatment.(5) UBT has been used for almost 30 years. There are two carbon isotopes used for UBT: 13C non-radioactive and14C- radioactive. (6)

Mechanism

13C or 14C labelled urea is fed to the patient and it is broken down by urease enzyme produces by H. pylori if present in the stomach. The released radioactive 13CO2 or 14CO2 diffuse into the blood and is released into the lungs. Finally, the expired air is collected to measure the activity of labelled Carbon. (6)

The radiation dose with the 14C test is 1μCi, equivalent to 1day of background radiation exposure. The 13C test is best for children and pregnant women because it uses a naturally occurring, stable non-radioactive isotope.The diagnostic accuracy between 13C-UBT and14C-UBT is not different and both tests can be considered to be the gold standardamong the various non-invasive tests for the diagnosis of H. pylori infection. (7)

The performance of both UBTs is almost similar, with sensitivities above 95% and specificities above 93%. (8)

Procedures

Before the test, antibiotics, and bismuth compounds should be discontinued for at least four weeks and proton pump inhibitors (PPIs) and sucralfate for at least two weeks.(9) These medications can reduce the urease activity of H. pylori and can generate a false negative result. Histamine 2-receptor antagonists should be ideally discontinued 24 to 48 hours before the test. These medications can reduce the urease activity of H. pylori and can generate a false negative result. Antacids can be continued. Also following H.pylori treatment, UBT should be performed to evaluate eradication only four weeks after the completion of the treatment. (10)

14C-UBT: The labeled urea with 14C is in the form of an oral capsule. The patient takes it with lukewarm water after fasting for 6 hours. The capsule should not be opened or crushed in the mouth to avoid contamination with oral flora. Ten minutes after ingesting the capsule, the patient is required to blow through a straw, and the breath sample gets collected in a balloon. Measurement of the labeled 14CO2 in the collected sample is by scintillation technique. In the presence of H. pylori, an increase in 14CO2 is noted. In the absence of H. pylori, there will be no hydrolysis of 14C-urea. The unhydrolyzed 14C-urea is absorbed in the stomach, enters the bloodstream and excreted by the kidneys. Appropriate safety precautions are necessary for the storage, handling, and disposal of the radioactive test ingredients. The overall cost of 14C-UBT is cheaper when compared to 13C-UBT. Hence 14C-UBT is more popular in resource-limited settings.(9)

13C-UBT: currently, 13C isotope is preferred as it is non-radioactive, especially in children, women of childbearing age and during pregnancy. (11) 13C-UBTs can be administered in children as young as three years of age. Since 13C is natural and present everywhere, a baseline breath sample of 13CO2 is noted before the administration of labeled 13C-urea. Unlike in 14C-UBT, a test meal is required to delay the gastric emptying, and citric acid is the most commonly used test meal given with 13C-urea.(9) 13C-urea with the citric acid mixture is ingested using a straw to minimize contamination with oral bacteria. Fifteen minutes later, breath is collected again for analysis. An increase in the 13CO2 value from the baseline indicates urease activity and the presence of H. pylori. (10) Unlike 14C isotope, the advantage of 13C isotope is that the breath samples can be sent safely to the laboratory for breath analysis.(9)

Indications

The urea breath test is useful for both initial diagnosis and eradication of infection. (9) In the absence of alarm symptoms for gastric malignancy (GI bleeding, anemia, significant weight loss, loss of appetite, dysphagia, significant emesis, family history of GI malignancy, and history of GI cancer), UBT could be used to diagnose H. pylori.(12)

H. pylori infections are also associated with unexplained iron-deficiency anemia (after a thorough negative evaluation), and immune thrombocytopenia in adults. Therefore, testing for H. pylori can be a consideration. (12)

It is necessary to rule out H. pylori which increases the chances of development of PUD and its complications before the initiation or continuation of long-term NSAIDs or aspirin. (12)

For eradication testing, UBT should be performed after 4 to 8 weeks of completion of the eradication treatment. (13)

Limitations of UBT

a. False positive test results can be found in the following conditions

1. Patients with achlorhydria can have false-positive UBT results.In patients with achlorhydria, other urease producing bacteria such as Proteus mirabilis, Citrobacter freunii, and Staphylococcus aureus has been reported to cause false positive UBT. (2)
2. Some oral flora have urease activity, and contamination with them could also result in false positive results.This can be prevented or minimized by swallowing the 14C-urea in a gelatin capsule or using a straw in 13C-UBT method. (10)

b. False negative test results can be found in the following conditions

1. Recent use of medications such as antibiotics, bismuth compounds, and, PPIs. (13)
2. Similarly, following the H. pylori eradication, the UBT should be done at least four weeks after the completion of treatment. If done earlier, the result could be falsely negative. (13)

c. Recent history of upper GI bleeding could affect the accuracy of UBT. (7)

d. Low sensitivity in patients with a history of gastric surgery. (7)

Advantages of UBT:

1. Noninvasive, safer, and cost-effective when compared to endoscopic evaluation. (2)
2. UBT is convenient and preferred by many patients when compared to stool collection for SAT.(11)
3. UBT is more accurate than the SAT and serological tests.(1)
4. UBT is useful for initial diagnosis (test-and-treat strategy) and also to confirm the eradication of infection. (10)
5. 13C-UBT can be easily repeated and also could be administered safely in children (above three years of age), and in pregnant women.(10)

Key points

1. UBT is the most accurate testing among the non-invasive tests.
2. UBTs (both 13C and 14C) have high sensitivities above 95% and high specificities above 93%
3. UBT can be usednot only for initial diagnosis but also for confirmation the eradication of infection.
4. 13C-UBT can be used safely in children (above three years of age), and in pregnant women

References

1. Kalali B, Formichella L, Gerhard M. (2015) Diagnosis of Helicobacter pylori: Changes towards the Future. Diseases. 29;3(3):122-135
2. Osaki T, Mabe K, Hanawa T, Kamiya S. (2008) Urease-positive bacteria in the stomach induce a false-positive reaction in a urea breath test for diagnosis of Helicobacter pylori infection. J Med Microbiol. 57(Pt 7):814-819.
3. Houghton J, Wang TC. (2005) Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology. 128(6):1567-78.
4. Kanna, S., Romero, C. M. &Fass R. (2013) Diagnostic tests for Helicobacter pylori.Gastroenterology and Endoscopy. News Special Edition, 51-58.
5. Skrebinska S, Mégraud F, Bessède E. (2018) Diagnosis of Helicobacter pylori infection. Helicobacter. 23 Suppl 1
6. Ohnmar-Nyunt-Tin (2021)EFFECT OF SACCHAROMYCES BOULARDII IN CONCOMITANT THERAPY IN ERADICATION OF HELICOBACTER PYLORI INFECTION.A thesis submitted to the postgraduate Academic Board of Studies, University of Medicine 1, Yangon, for the Degree of Dr.Med.Sc (Gastroenterology)
7. Wang YK, Kuo FC, Liu CJ, Wu MC, Shih HY, Wang SS, Wu JY, Kuo CH, Huang YK, Wu DC. (2015) Diagnosis of Helicobacter pylori infection: Current options and developments. World J Gastroenterol. 21(40):11221-35.
8. Ferwana M, Abdulmajeed I, Alhajiahmed A, Madani W, Firwana B, Hasan R, Altayar O, Limburg PJ, Murad MH, Knawy B. (2015) Accuracy of urea breath test in Helicobacter pylori infection: meta-analysis. World J Gastroenterol. 21(4):1305-14
9. Savarino V, Vigneri S, Celle G. (1999) The 13C urea breath test in the diagnosis of Helicobacter pylori infection. Gut. 45 Suppl 1:18-22
10. Sankararaman S, Moosavi L. (2021) Urea Breath Test. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.
11. Chey, W.D. & Wong, B.C. (2007) American College of Gastroenterology guidelineon the management of Helicobacter pylori infection. Am J Gastroenterol. 102(8), 1808-1825.
12. Chey WD, Leontiadis GI, Howden CW, Moss SF. (2017) ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 112(2):212-239.
13. Malfertheiner P, Megraud F, O’Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Hunt R, Moayyedi P, Rokkas T, Rugge M, Selgrad M, Suerbaum S, Sugano K, El-Omar EM. (2017) European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut.66(1):6-30.

Author Information

Thein Myint¹, Tin Moe Wai ², Swe Mon Mya ³, Mya Thet Nwe³, Sandar Win ², Nang Khin Phone Tint ⁴

1. Professor, Department of Gastroenterology (Retd), Yangon General Hospital
2. Associate Professor, Department of Gastroenterology, Yangon General Hospital
3. Senior Consultant Gastroenterologist, Department of Gastroenterology, Yangon General Hospital
4. Consultant Gastroenterologist, Department of Gastroenterology, Yangon General Hospital