I18 Gut 1999;45(Suppl I):I18–I22 The 13C breath test in the diagnosis of

Helicobacter pylori Gut: first published as 10.1136/gut.45.2008.i18 on 1 July 1999. Downloaded from

V Savarino, S Vigneri, G Celle

Summary simplify and optimise it, including changes to The urea breath test (UBT) is one of the most the dose of urea used, sample timing, test meal, important non-invasive methods for detecting and cut oV values to distinguish infected from infection. The test exploits uninfected subjects. Despite these modifica- the hydrolysis of orally administered urea by tions, the accuracy of the test has remained the , which H pylori produces in high and this is the best confirmation of its large quantities. Urea is hydrolysed to ammo- robustness. nia and , which diVuses into the The test exploits the large amount of urease blood and is excreted by the lungs. Isotopically produced by H pylori, as this enzyme hydro-

labelled CO2 can be detected in breath using lyses the orally administered, labelled urea into

various methods. ammonia and labelled CO2, which is absorbed Labelling urea with 13C is becoming increas- through the mucus layer of the and ingly popular because this non-radioactive iso- then transported to the lungs via the blood- tope is innocuous and can be safely used in stream for excretion. Isotope enrichment can children and women of childbearing age. be measured by various methods in breath Breath samples can also be sent by post or cou- samples collected at appropriate times. rier to remote analysis centres. The test is easy Urea can be labelled with two diVerent carbon to perform and can be repeated as often as isotopes: 14C and 13C. The main diVerence required in the same patient. A meal must be between them is that the former is radioactive, given to increase the contact time between the whereas the latter is stable. The advantages of tracer and the H pylori urease inside the stom- using 14C-urea are that it is cheap, so rapid that ach. The test has been simplified to the point administering 14C-urea in a gelatin capsule that two breath samples collected before and allows an accurate response to be obtained from 30 minutes after the ingestion of urea in a liq- a single 10 minute breath sample,23 and does uid form suYce to provide reliable diagnostic not require any test meal. However, although the information. The cost of producing 13C-urea is dose of 14C has become progressively smaller high, but it may be possible to reduce the dos- and the test can now be performed with 1 µCi,3 http://gut.bmj.com/ age further by administering it in capsule form. which is equal to the natural background radia- An isotope ratio mass spectrometer (IRMS) tion received in one day,34 the main problems is generally used to measure 13C enrichment in are still the availability of a nuclear medicine breath samples, but this machine is expensive. department or centres licensed for storage and In order to reduce this cost, new and cheaper disposal of radioactive substrates, shipping diY- equipment based on non-dispersive, isotope culties, and the copious amounts of labelled

selective, infrared spectroscopy (NDIRS) and tracer needed to perform large scale epidemio- on September 23, 2021 by guest. Protected copyright. laser assisted ratio analysis (LARA) have logical studies. The use of this unstable tracer recently been developed. These are valid alter- can be recommended when the number of natives to IRMS although they cannot process UBTs per annum in a given gastroenterological the same large number of breath samples centre is less than 2500 and 14C facilities are simultaneously. available on site.5 These promising advances will certainly In contrast, 13C is a non-radioactive isotope Dipartimento di 13 Medicina Interna e promote the wider use of the C-UBT, which is that can be used safely for repeated testing, Specialità Mediche, especially useful for epidemiological studies in which is frequently required in clinical practice, Cattedra di children and adults, for screening patients and for detecting H pylori infection in children Gastroenterologia, before , and for assessing the efficacy and women of childbearing age. Furthermore, Università di Genova, of eradication regimens. 13C-urea has been the most widely used Italy V Savarino substrate in methodological studies performed G Celle Introduction to validate this kind of diagnostic test. Another Many diagnostic methods have been developed relevant advantage of using the stable isotope is Istituto di Medicina over the past 15 years to detect Helicobacter that breath samples can be sent by post or cou- Interna e Geriatria, pylori infection—some invasive (rapid urease rier to remote analysis centres, thus promoting Università di Palermo, test, histology, culture, and polymerase chain the distribution of the test, which can even be Italy S Vigneri reaction) because they cannot be performed performed at home if the patients are adequately without endoscopy, and others non-invasive selected and instructed.6 The major drawbacks Correspondence to: (serology, urea breath test (UBT) and, more of 13C-urea are the higher cost compared with Professor V Savarino, recently, H pylori antigen determination on Dipartimento di Medicina Interna e Specialità faeces). Of the latter, the UBT is being increas- Abbreviations used in this paper: UBT, urea breath Mediche, Cattedra di ingly used both in pretreatment and post- Gastroenterologia, Università test; IRMS, isotope ratio mass spectrometer; NDIRS, treatment phases. non-dispersive, isotope selective, infrared spectroscopy; di Genova, Viale Benedetto 1 XV, n. 6, 16132 Genova, Since it was first described by Graham et al, LARA, laser assisted ratio analysis; PPI, proton pump Italy. the test has been modified extensively to inhibitor; ROC, receiver operator characteristic. Urea breath test in the diagnosis of H pylori infection I19

13 12 Table 1 Comparison of the main characteristics of three diVerent types of equipment for measuring the CO2 to CO2 ratio in breath samples

Characteristics of Mass spectrometer Infrared spectrometer Laser assisted ratio Gut: first published as 10.1136/gut.45.2008.i18 on 1 July 1999. Downloaded from the instruments (IRMS) (NDIRS) analyser (LARA)

Weight 90 kg 12 kg 350 kg Reference gas Necessary Enclosed Necessary Carrier gas Helium supply None None Analysis time 120 seconds 90 seconds 60 seconds Automation For 220 samples For 16 samples For 60 samples Breath sample 10 ml glass tube 1200 breath bag 12 ml plastic tube Sample mailing Favourable Not practicable Favourable Multitasking software Commonly available Unnecessary Planned Technical expertise Easy to operate Easy to operate Easy to operate After sales support Often required Low maintenance Low maintenance Reported reliability 90–100% 90–98% Limited experience Approximate price 75 000 Euros 40 000 Euros 60 000 Euros

14C-urea, and the need for expensive mass spec- time. NDIRS does not require helium as the trometry, which is the most preferable device for carrier gas and has the lowest weight and price, measuring 13C enrichment in breath samples of but it can analyse only a small number of sam- subjects infected with H pylori. ples and so does not need multitasking This review focuses on the most recent software. The LARA system has the quickest advances in the machines used to measure the analysis time; the other characteristics are aver- 13C isotope and on the most important aspects age compared with the other two machines, regarding the main UBT variables. especially with regard to the number of samples it can process and the cost. Integrated bar code Measuring equipment readers and the use of multitasking programs 13 13 12 have made running IRMS instruments much C is measured as the CO2: CO2 isotope ratio and is expressed as delta over baseline easier; however, they do require more mainte- (DOB) per mil (‰) with respect to the nance than NDIRS and LARA systems. IRMS international reference standard represented and LARA are more suitable for gastroentero- by the Pee Dee Belemnite limestone. The logical centres requiring large quantity, auto- diVerence in isotope masses (45:44) is detected mated analysis, whereas NDIRS is more with extreme accuracy by the sector magnet suitable for small laboratories in which the contained in the mass spectrometer (IRMS). daily number of assays is not high. In this light, This equipment also requires a gas chromato- a small, new, cheap, infrared device for examination of only two breath samples has graph because CO2 has to be carefully purified from the whole breath prior to introduction been developed to be used exclusively in the into the mass spectrometer. The precision of doctor’s oYce.16 In the endless attempt to http://gut.bmj.com/ measurements made by conventional IRMS render the test cheaper and to increase the can be as high as 0.01‰7 and this allows very number of laboratories where it can be low isotopic enrichments to be detected. As 13C performed, other investigators have shown that 13 12 a gas chromatograph coupled with a mass is measured as the ratio of CO2 to CO2, there is no need for a large volume of expired air and selective detector, which is available in many a 10 ml sample is enough to obtain reliable analytical and biomedical settings, can also be 5 13 17 18 diagnostic information. Furthermore, the ex- reliably used for C-UBT. on September 23, 2021 by guest. Protected copyright. amination results do not depend on the body mass, so it is not necessary to take this variable Concomitant medication into account.8 The 13C-UBT is a simple and innocuous assay If a mass spectrometer is the most preferable which requires only few precautions in order to machine for detecting 13C excess in breath obtain accurate results. Besides having to avoid samples, its high price has limited the spread of several dietary constituents with a natural the test and has prompted the biomedical abundance of 13C,19 such as maize, cane, and industry to develop new instruments that are cornflour, there is still some debate concerning capable of measuring the stable isotope at a both the type of antisecretory drugs that may lower cost. Over the past few years, analytical influence the test and the optimal timing of devices besides IRMS have been developed to breath testing after their discontinuation in 13 12 perform CO2 and CO2 analysis, such as order to exclude false negative results. This is a infrared spectrometry910and laser optogalvanic relevant point because many patients request- spectroscopy.11 Several comparative studies12–15 ing UBT are dyspeptic and thus reluctant to have shown the reliability of these new, cheaper discontinue their antisecretory drugs. Al- machines in measuring 13C enrichment, thus though there is general consensus20–25 regarding allowing them to be considered as valid the adverse eVect of proton pump inhibitors alternatives to IRMS. (PPIs) on the UBT (false negative results range Table 1 presents the main characteristics of from 17 to 61%), the timing of their cessation IRMS, non-dispersive, isotope selective, infra- prior to testing is not so clear. In many clinical red spectroscopy (NDIRS), and laser assisted trials aimed at assessing the eYcacy of eradica- ratio analyser (LARA) equipment. The advan- tion regimens, for instance, it is generally tage of IRMS is that it processes the highest reported that patients must not have taken number of breath samples and works in an PPIs for at least one month before the UBT, automated manner. However, it is the most but it has been shown that five to seven days is expensive and requires the longest analysis suYcient to reverse their adverse eVect.21–23 I20 Savarino, Vigneri, Celle

Laine et al,24 however, suggest that patients delay gastric emptying. Recently, citric acid, should remain oV PPIs for 14 days in order to which acts by lowering duodenal pH, which in be sure of avoiding false negative results. turn reduces antral motility and relaxes the 38 Gut: first published as 10.1136/gut.45.2008.i18 on 1 July 1999. Downloaded from Although H2 blockers are regarded as antise- gastric fundus, has been shown to be an opti- cretory drugs with no eVect on UBT,26 some mal test meal.34 In this study citric acid, which recent investigations have shown that even was compared with two other frequently used standard and high dose ranitidine can cause up semiliquid meals, Meritene and Ensure/ to 20% of false negative breath tests.22 25 These Calogen, provided the highest and earliest ä studies have shown that the reversal of this peaks; however, data from uninfected patients negative eVect occurs within five to seven days were not shown in the published paper and the 13 of drug cessation and therefore withdrawal for extent of the excess ä CO2 excreted because of one week suYces to rule out any adverse influ- the citric acid was only reported as the ratio 13 ence the drugs may have on the UBT. above the baseline excess ä CO2 values, mak- Antibiotics, particularly those with anti- ing it diYcult to judge.4 One advantage of using helicobacter action, and bismuth preparations citric acid is that the liklihood of contamination should be withdrawn at least one month prior by urease produced by bacterial flora in the to UBT, as is usually suggested. mouth is reduced greatly.29

Amount and formulation of 13C-urea Is pretest fasting necessary? The urea dose has been progressively reduced Many protocols recommend that patients fast from the 350 mg (5 mg/kg) dose initially used in for at least four hours before testing in order to the study by Graham et al,1 thus decreasing the avoid any interference from food. Some recent cost of the substrate needed to perform the test. studies, however, have addressed the question At present three diVerent dosages are utilised. A of whether fasting is really necessary in patients dose of 125 mg has been validated in the United undergoing UBT. Perri and colleagues31 and States by Klein et al,27 who showed that a sensi- Moayyedi and colleagues39 found that there is tivity and specificity as high as 100% can be no statistical diVerence between tests per- reached with this dosage. Logan et al used 100 formed in fasting and non-fasting conditions mg in their proposal of a standard diagnostic and therefore do not recommend fasting before protocol28 and this dosage has received the UBT. On the contrary, Epple and colleagues33 greatest amount of attention in Europe. Finally, and Savarino and colleagues13 observed that 75 mg (approximately 1 mg/kg) has been shown feeding causes a significant decrease in the 30 to be as reliable as the higher doses29 and is used minute ä values compared with the fasting ones satisfactorily in an increasing number of re- and an increase in false negative results. They search studies.13 15 17 30–34 This low dosage is also suggest that fasting before testing should be included in many commercial kits for 13C-UBT,4 mandatory. These contradictory findings prob- as it limits the cost of the test. However, it may ably result from the diVerent meals used in the http://gut.bmj.com/ be possible to reduce the dosage of 13C-urea fur- various studies, but at present there are no clear ther by administering the tracer in capsules. It guidelines in this area. has been shown that a dose of either 38 mg35 or 45 mg,36 given in rapidly dissolving gelatin cap- Time of breath collection sules, maintains the high sensitivity and specifi- The test has been progressively simplified since city of the test and also reduces its duration to the first report by Graham et al,1 who took

15–20 minutes. In fact, this peculiar formulation breath samples every 10 minutes for three on September 23, 2021 by guest. Protected copyright. bypasses the problem of contact of the substrate hours. At present, there is universal consensus with the urease producing present in the on the use of a two point examination—that is, oropharynx, thus avoiding false positive results if a basal sample collected before and another breath samples are taken too soon. Obviously, sample collected 30 minutes after ingestion of there is no need to delay gastric emptying by an the tracer, using whatever dosage of 13C-urea is appropriate meal, which is fundamental in tests chosen.5 20 29–34 40 As already mentioned, the use performed with the liquid form of 13C-urea. of citric acid as test meal has been shown to be better than other semiliquid fatty meals in the 13 Test meal maximal recovery of CO2 at this sampling One of the most important advantages of the time.34 UBT is that it samples the whole stomach and Reducing the number of breath samples to is not prone to sampling error as are only one by omitting the baseline collection in based tests, which can be influenced by the order to decrease cost and duration of the test patchy distribution of H pylori infection within further has also been proposed.30 40 Lastly, the gastric mucosa. This global test can be shortening the sampling time to 20 minutes improved if prolonged contact of the substrate and omitting the meal has been shown to with the urease enzyme is promoted. The use maintain the excellent sensitivity and specifi- of test meals capable of increasing the resi- city of the test41; however, this study was dence time of 13C-urea in the stomach is performed using 125 mg of 13C-urea, which is recommended in most protocols. The useful- the usual dose in the USA but not in Europe. ness of turning the patient instead of leaving him/her seated, in order to favour the contact Cut oV values between labelled substrate and urease activity, Discrimination between infected and unin- has recently been disproved.37 fected subjects is based on a strict cut oV value Test meals containing fat are usually chosen which has been validated in many studies. The due to the well known ability of this nutrient to most widely used value is 5‰, which has been Urea breath test in the diagnosis of H pylori infection I21

proposed by Logan and colleagues28 in their The other non-invasive test, serology, has European standard protocol. Later, by using relevant limits in assessing the success of anti- receiver operator characteristic (ROC) curves, helicobacter regimens due to the considerable Johnston and colleagues42 showed that this cut amount of time (at least six months) needed to Gut: first published as 10.1136/gut.45.2008.i18 on 1 July 1999. Downloaded from oV value can be lowered to 3.5‰ without com- show a consistent decrease in serum antibody promising the sensitivity and specificity of the levels. Lastly, 13C-UBT is the ideal test for chil- test. Cluster analysis was used by Mion et al,43 dren, using a lower dose of urea (50 mg); pro- who also suggested adopting 3.0‰ as the opti- vided that a mask is used, breath samples can mal cut oV point with the need, however, for a be collected from those under three years of grey zone in which the results of UBT are age.4 inconclusive; there was no reference to a gold standard in their study. However, there is no Conclusions universal agreement on the use of a lower than Currently, the UBT is considered to be one of usual cut o value. Zagari and colleagues44 also V the most important and reliable non-invasive used ROC analysis on a large sample of methods for the diagnosis of H pylori infection. patients and were not able to decrease the cut The examination is simple, innocuous when o level below the value of 4.5‰ with either 75 V 13C is used, easy to repeat, highly accurate, and mg or 100 mg doses of 13C-urea. It must be requires a low number of precautions in order stressed, however, that the 5‰ value remains a to obtain reliable results. It is particularly suit- strong index for distinguishing infected sub- able for epidemiological studies in children and jects from uninfected ones and therefore this adults, in all clinical conditions where endos- cut o value is still widely used. V copy is not strictly necessary, and to check the success of eradication regimens. The new and Diagnostic accuracy and clinical cheaper measuring equipment, the possibility applications of using a lower urea dose in capsules, thus The 13C-UBT can be used in many clinical set- omitting the meal, as well as shorter than usual tings because of its non-invasiveness, simplic- sampling times, will certainly promote an ity, and safety. Furthermore, the sensitivity and increasingly broader application of this test. specificity in untreated subjects are very high and range from 90 to 98% and from 92 to 5132839404546 1 Graham DY, Klein PD, Evans DJ Jr, et al. Campylobacter 100%, respectively. Accuracy in pylori detected noninvasively by 13C-urea breath test. Lan- the assessment of eradicating eYcacy is more cet 1987;i:1174–7. 47–50 2 Hamlet AK, Erlandsson KIM, Olbe L, et al. A simple, rapid, controversial because some investigators and highly specific reliable capsule-based 14C urea breath found excellent reliability even in the post- test for diagnosis of Helicobacter pylori infection. Scand J 51 Gastroenterol 1995;30:1058–63. treatment phase, whereas others did not con- 3 Peura DA, Pambianco DJ, Dye KR, et al. Microdose firm these good results. Accordingly, it has 14C-urea breath test oVers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233–8. http://gut.bmj.com/ been recommended recently that two UBTs, 4 Logan RPH. Urea breath tests in the management of performed at separate post-treatment time Helicobacter pylori infection. Gut 1998;43(suppl 1):S47– 50. points (for example, two months apart), can 5 Goddard AF, Logan RPH. Review article: urea breath tests equate to two diVerent tests52 when assessing for detecting Helicobacter pylori. Aliment Pharmacol Ther 1997;11:641–9. the success of anti-helicobacter treatments. 6 Thijs WJ, Thijs JC, Kleibeuker JH, et al. Evaluation of clini- Obviously, this applies to research trials on cal and home performance of the 13C-urea breath test for the detection of Helicobacter pylori. Eur J Gastroenterol eradication treatments rather than to routine Hepatol 1995;7:603–7.

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