Digestive and Liver Disease
Volume 39, Issue 9 , Pages 795-805, September 2007

13C-breath tests: Current state of the art and future directions

  • B. Braden

      Affiliations

    • John Radcliffe Hospital, Headley Way, OX3 9DU Oxford, UK
    • Department of Medicine I, University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany
    • Corresponding Author InformationCorresponding author at: Department of Gastroenterology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK. Tel.: +44 1865 221466.
    • ,
  • B. Lembcke

      Affiliations

    • Department of Medicine, St. Barbara Hospital Gladbeck, Barbara Str. 1, Gladbeck, Germany
    • ,
  • W. Kuker

      Affiliations

    • John Radcliffe Hospital, Headley Way, OX3 9DU Oxford, UK
    • ,
  • W.F. Caspary

      Affiliations

    • Department of Medicine I, University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany

Received 27 January 2007; accepted 28 June 2007.

Article Outline

Abstract 

13C-breath tests provide a non-invasive diagnostic method with high patient acceptance. In vivo, human and also bacterial enzyme activities, organ functions and transport processes can be assessed semiquantitatively using breath tests. As the samples can directly be analysed using non-dispersive isotope selective infrared spectrometers or sent to analytical centres by normal mail breath tests can be easily performed also in primary care settings.

The 13C-urea breath test which detects a Helicobacter pylori infection of the stomach is the most prominent application of stable isotopes. Determination of gastric emptying using test meals labelled with 13C-octanoic or 13C-acetic acid provide reliable results compared to scintigraphy. The clinical use of 13C-breath tests for the diagnosis of exocrine pancreatic insufficiency is still limited due to expensive substrates and long test periods with many samples. However, the quantification of liver function using hepatically metabolised 13C-substrates is clinically helpful in special indications. The stable isotope technique presents an elegant, non-invasive diagnostic tool promising further options of clinical applications.

This review is aimed at providing an overview on the relevant clinical applications of 13C-breath tests.

Keywords: Gastric emptying, Helicobacter pylori, Liver function, Stable isotopes

 

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1. Sources of information 

We selected articles from the PubMed database by using the search words “13C” and “breath test”. Inclusion criteria were articles published in English, in peer-reviewed journals, between 1966 and March 2007. This review is also based on our experience in introducing breath tests into medical research and clinical diagnostic routine.

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2. History of 13C-breath tests 

Advanced tracer technology with application of stable isotopes in humans has enabled the non-invasive observation of metabolic processes and the assessment of enzyme activities and organic functions in vivo. The stable isotope technique, mainly the use of 13C-labelled human substances for diagnostic purposes has remarkably enriched the gastroenterological diagnostic spectrum.

Breath tests using the radioactive carbon isotope 14C have been developed three to four decades ago for testing the exocrine pancreatic function, intestinal absorption and liver function. With increasing awareness of radiation hazard 14C has been replaced by the stable, non-radiating carbon isotope 13C in these breath tests. For studies in children and pregnant women, and for repeated studies in adults, the use of stable isotopically labelled substrates are preferable and safe. Due to its long half life (5730 years) the use of 14C for diagnostic tests in humans is disputable. New 13C-breath tests have been developed for further clinical indications (assessment of gastric emptying or the orocaecal transit time, bacterial overgrowth in the small intestine or malassimilation).

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3. Principle of 13C-breath tests 

The breath test concept is based on a 13C-labelled tracer probe. This is a specifically designed substrate of a “gateway” enzyme in a discrete metabolic pathway. The turnover of the substrate can be measured by monitoring the unidirectional decomposition to labelled carbon dioxide. Breath samples are collected in certain time intervals. The time limiting step from the intake of the tracer substance to the appearance of 13CO2 in breath is determined by the cleavage of the substrate in the gastrointestinal lumen, the transport processes, or the enzymatic degradation. Finally, 13CO2 is released as the end product of metabolism and is exhaled. Breath tests depend on the hypothesis, that the process in question determines the excretion rate of 13CO2, because all other metabolic processes are much faster or not variable.

The choice of the 13C-labelled substrate determines whether the 13C-breath test investigates transport, digestion, absorption, oxidation processes or enzymatic activities. Today, a multitude of test substrates are available for different diagnostic purposes (Table 1).

Table 1. 13C-labelled substrates in 13C-breath tests
IndicationSubstrateDiagnostic alternativeClinical importanceSubstrate costsReferences
Detection of Helicobacter pylori infection13C-ureaFecal antigen test, histology, rapid urease test, cultureHighLow[6], [7], [8], [9], [10], [11], [12], [108], [109], [110], [111], [112]
Gastric emptying
Solid phases13C-octanoate (13C-spirulina)ScintigraphyHighLow (high)[15], [16], [17], [18], [19], [20], [21], [22], [23], [113], [114]
Liquid phases13C-acetate, 13C-glycineScintigraphy (ultrasound)ModerateLow, low[16], [24], [25], [115], [116], [117]
Liver function13C-aminopyrineClinical scores (e.g. Child-Pugh-Score), MEGX-test, galactose elimination capacityModerateModerate[1], [3], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135]
13C-methacetinModerate
13C-galactoseHigh
13C-phenacetinModerate
13C-phenylalanineModerate
13C-erythromycineHigh
13C-caffeinHigh
13C-methionineHigh
13C-ketoiso-caproic acidModerate

Exocrine pancreatic function13C-mixed triglyceridesSecretin pancreozymin test, faecal fat analysis, faecal elastaseLowModerate[48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [136], [137]
13C-trioleinHigh
13C-trioctanoinModerate
13C-tripalmitinHigh
13C-hioleinHigh
13C-cholesterol-octanoateHigh
13C-proteinHigh
13C-starchLow

Absorption13C-palmitic acidFaecal fatVery lowHigh[99], [100], [101], [102], [103], [104], [105], [138]
13C-oleinHigh
13C-proteinHigh

Orocoecal transit time13C-lactoseureideLactulose hydrogen breath test, scintigraphyLowHigh[82], [83], [84], [85], [139]

Carbohydrate assimilation13C-lactoseHydrogen breath tests, measurement of enzyme activity in the duodenal biopsyVery lowHigh[87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [140], [141]
13C-fructoseModerate
13C-glucoseModerate
13C-starch(Low)
13C-saccharoseHigh

Bacterial overgrowth13C-glycocholateGlucose hydrogen breath test, microbiological culture from jejunal aspirateLowHigh[76], [77], [78], [142]
13C-xylose High

The non-invasiveness of the breath test method with simple, almost playful collection of the breath samples explains its high patients acceptance—not only in paediatrics (Fig. 1).

  • View full-size image.
  • Fig. 1. 

    For isotope ratio mass spectrometry analysis, breath samples for the 13C-breath tests are collected by exhaling into glass tubes using a straw. The glass tubes are immediately capped thereafter.

The element carbon has three naturally occurring isotopes, thereof 12C and 13C are stable, i.e. they do not undergo radioactive decay. The carbon isotope 13C naturally occurs in 1.11% of all carbon atoms. Thus, application of 13C-labelled substrates only means an increase of the physiologic present enrichment of the stable carbon isotope in the human body. According to this, the 13C-enrichment in breath samples must be related to the baseline enrichment before tracer ingestion in all breath tests (Delta over baseline-value, Table 2; Fig. 2).

Table 2. Measured and calculated parameters of the 13C-breath tests
ParameterSymbolCalculation
Isotope ratio in the breath sampleRP
Isotope ratio of a standard gas (usually PeeDeeBelmnite with RPDB=0.0112372)RSTD
Delta permille-valueΔ
Delta over baseline-valueaDOBδSample−δbasal value before tracer application

Recovery rate per hourb% dosage/h
APE: 13C-enrichment of the substrate in atom percent excess
n: number of 13C atoms in the substrate molecule
MW: molecular weight of the substrate

Cumulative percentage recovery% dosageIntegration of percentage recovery over time

aDue to the natural variations of 13C-isotopes sources in the human body, all 13CO2-enrichments measured in breath samples are related to the basal 13C-enrichment in breath before ingestion of the tracer substance (Delta over baseline-value DOB).

bFor quantification of breath test results, the recovery rate per hour gives how much of the amount 13C administered with the tracer substance has been exhaled as 13CO2. Therefore, the total carbon dioxide production must be measured or estimated (300mmol CO2/m2 body surface area/h).

  • View full-size image.
  • Fig. 2. 

    13C-methacetin breath test: average Delta over baseline-values (DOB, continuous lines) and average cumulative recovery (dotted lines) in healthy controls (n=60, black lines) and patients with histologically proven liver cirrhosis (n=40, black lines with triangles).

For the calculation of the 13C tracer recovery in breath the total carbon dioxide production must be measured or estimated. Usually it is approximated with 300mmol CO2/m2 body surface area/h. Therefore, it is necessary to be aware, that factors influencing the endogenous carbon dioxide production or excretion such as food ingestion, physical activity, respiratory diseases, thyroid dysfunctions and fever will affect breath test results.

Tracer recovery in breath is never complete as a substantial amount of tracer is retained in the carbon pool of the body. Therefore, 13C-breath test analysis is a semiquantitative diagnostic tool.

Because the amount, quality, or content of the test meal might alter gastrointestinal functions, a standardised meal application is mandatory.

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4. Analysis of breath samples 

High-resolution mass spectrometers are able to measure the slight mass difference of one neutron between 13C-labelled carbon dioxide and the naturally most common carbon dioxide with the carbon isotope 12C. Further automatisation and the development of user-friendly software programs for the isotope ratio mass spectrometry increased the analytical capacity and the spread of this technique.

The development of non-dispersive isotope selective infrared spectrometers (NDIRS) opened up a lower-priced analytical alternative with adequate precision [1], [2], [3], [4]. Operating and handling of NDIRS is easy, even for non-experienced users. At the push of a button breath samples can be analysed within about 60s. This enables not only the performance, but now also the analysis of 13C-breath tests in primary care settings.

Continuous analysing of 13C-enrichment in breath has also become possible and can shorten testing time in the 13C-urea breath test.

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5. Applications 

5.1. 13C-urea breath test for diagnosis of Helicobacter pylori infection 

The 13C-urea breath test [5] detecting gastric Helicobacter pylori infection is probably the best known, best standardised and most widely used breath test. 13C-urea is hydrolysed by the bacterial urease activity to 13C-labelled carbon dioxide and ammonia. An increase of 13CO2 in breath appearing 30min after drinking a test solution containing 75mg 13C-urea reliably detects H. pylori infection [6], [7], [8], [9], [10], [11].

The non-invasiveness of the breath test results in a high acceptance in patients. Multiple studies and a meta-analysis including more than 3500 patients showed excellent sensitivity (95%) and specificity (>95%) compared to histology [12]. Therefore, the 13C-urea breath test is best suited for therapy control, epidemiologic investigations and pharmacological therapy trials. It is also applicable for primary testing in paediatrics and in young patients below 45 years of age (“test and treat strategy” according to the Maastricht consensus [13].

As in biopsy dependent detection methods, the intake of proton pump inhibitors, H2-antagonists, and antibiotics might cause false negative results.

The detection of H. pylori antigens in faecal samples has turned out to be an also non-invasive, also reliable diagnostic alternative for the diagnosis of H. pylori infection. Stool tests can be used for therapy control [14], but sensitivities and specificities of the 13C-urea breath test are superior after eradication treatment. Patients often show ressentiments towards collecting stool samples. But physicians prefer the faecal antigen detection which is performed in conventional laboratories, as they are not as familiar with the (although very simple) collection of breath samples and their analysis.

5.2. Measurement of gastric emptying 

Golden standard for determining gastric emptying of solid and liquid meals is the radioscintigraphy using testmeals labelled by radioactive isotopes. However, the clinical use of scintigraphy is limited due to the anti-radiation precautions required and the occupation of a gamma camera for several hours. In contrast to scintigraphy, 13C-breath tests can be performed anywhere even as bedside test in critically ill patients. Other diagnostic methods for the assessment of gastric emptying using ultrasound, aspiration techniques or resorption measurements are disappointing because of inaccuracy, invasivity or the exhausting number of blood samples required.

The functional dyspepsia and the autonomic diabetic neuropathy are the main indications for the investigation of gastric emptying disorders. 13C-breath tests provide a practicable alternative for determining gastric emptying.

Measuring the gastric emptying of solid testmeals is in most diseases more sensitive than testing the liquid phase. 13C-octanoic acid is mixed into egg yolk and baken as it sticks firmly to the solid phase of this testmeal [15]. When the 13C-octanoic acid has passed the pylorus together with the ingested food, the labelled middle chain fatty acid will be fastly absorbed in the upper part of the small bowel and oxidised to 13C-labelled carbon dioxide. Collecting breath samples for more than 4h gives reproducible 13CO2-kinetics in breath which reflect gastric emptying [16], [17], [18], [19], [20], [21], [22], [23]. Curve fitting using non-linear regression leads to the calculation of half emptying times and lag phase, i.e. the time period from ingestion to the beginning of the gastric emptying process. 13C-glycine and 13C-acetic acid have been used for labelling liquid testmeals [24], [25]. Both 13C-breath tests, with 13C-octanoic acid for solid and with 13C-acetic acid for liquid phases, have been evaluated against scintigraphy using testmeals labelled by radioactive (99mTc) and stable isotopes (13C) [15], [24].

Simultaneous labelling of solid and liquid phases in the same testmeal can be done in nuclear medicine, e.g. using 99mTc for the liquid phase and 111In for the solid phase. The breath test-technique only enables doubly labelling by additionally using the radioactive isotope 14C [25]. However, the clinical use of 14C is obsolete in many European countries due to its long half time.

5.3. Quantitative liver function tests 

13C-breath tests for the study of liver function have been developed in order to non-invasively quantitate the residual liver function in patients with various degrees of liver fibrosis, from minimal stages up to liver cirrhosis. Multitudinous different substrates have been proposed (Table 1). The highest experience so far exists for the aminopyrine breath test [26], [27], [28], [29]. Most hepatic breath tests measure the microsomal dealcylation of 13C-labelled substrates and therefore the cytochrome P450 dependent enzymatic system. The cleaved methyl group is oxidised to formic acid, which enters the C1-pool, and is finally exhaled as carbon dioxide. Due to its lack of toxicity in low doses many groups nowadays prefer the use of methacetin [30], [31], [32]. In addition, the fast metabolism of 13C-methacetin enables a more practicable modification of the liver function test as a two-point-measurement with breath samples at baseline and 15min after substrate ingestion [32]. However, the hepatic metabolism of methacetin (also of phenacetin and erythromycin) is depending on the hepatic blood flow which might be altered in cirrhotic patients with portosystemic shunts. The metabolism of aminopyrine, diazepam or coffeine is independent from hepatic blood flow and almost exclusively reflects the enzymatic activity of different cytochromes P450.

As the knowledge in this field evolved substrates for specific hepatocyte functions were sought: The metabolisation of 13C-galactose reflects the activity of a cytosolic enzyme [33], [34], [35]. Ketoisocaproic acid and methionine are the best-studied carbon-labelled substrates for the investigation of mitochondrial functional damages [36], [37], [38], [39], [40], [41], [42], [43].

Sequential studies that were performed over the years using various 13C-breath test substrates showed that increasing degrees of liver fibrosis are paralleled by concomitant modifications in 13C-BT results [30], [33]. Promising results that breath tests might be able to replace percutaneous liver biopsy in certain patients with chronic hepatitis C infection before interferon therapy need further confirmation [31], [33]. Breath tests seem to be superior to the Child-Pugh-classification in predicting long-term prognosis [42], [44]. In some cases, breath tests could indicate enzyme inductions or inhibitions [45], [46]. Further studies should evaluate the diagnostic yield of 13C-breath test in particular clinical situations, such as in patients with normal static parameters of liver function, in following the effects of therapeutic regimen, the decision of optimal transplant timing, or to test the residual organ function before planning a resection of the liver.

5.4. Exocrine pancreatic function 

The reference method for an early diagnosis and quantification of exocrine pancreatic insufficiency is the invasive secretin–pancreocymin test. However, placing an duodenal tube, stimulating the pancreas by hormones, aspiration and analysis of the pancreatic enzymes secreted is a big expenditure of costs, time and manpower. Therefore, the secretin-pancreocymin test is seldomly performed even in specialised centres.

In contrast to this, 13C-breath tests with 13C-labelled triglycerides, cholesterol esters, proteins or carbohydrates as substrates non-invasively reflect the intraduodenal activities of pancreatic enzymes under physiological conditions. Several 13C-labelled triglycerides (1,3-distearyl-2-octanoylglycerol, the so-called mixed triglyceride [47], [48], [49], [50], [51], [52], trioctanoine [53], [54], [55], [56], [57], [58], trioleine [57], [59], [60] or tripalmitine [61], [62]) serve as substrate for the lipase. The triglycerides are 13C-labelled at the carboxy group of the fatty acids. Only if the intraluminal lipolysis has taken place the free fatty acids or monoglycerides can be absorbed and oxidised to 13CO2. 13C-hiolein is a very expensive, uniformly labelled mixture of triglycerides which is grown by algae. It also serves as a substrate of the lipase [63], [64].

The increase of the 13C-enrichment in breath after ingestion of 13C-cholesteroloctanoate [65], [66], [67] reflects the intraluminal activity of the cholesterol esterase.

(Naturally) 13C-labelled starch provides a substrate for the amylase. But the 13C-starch breath test is not very sensitive as the intraluminal activity of amylase becomes insufficient not before the pancreatic disease has reached advanced stages [68], [69], [70], [71], [72]. Recently, a 13C-protein breath test based on chicken egg white has been described for testing the activity of trypsine [73], [74].

These 13C-breath tests are indirect, non-invasive tests of exocrine pancreatic function. Particularly in paediatrics, they suit not only for diagnosis of exocrine pancreatic disorder, but also for therapy control under pancreatic enzyme substitution [59], [62], [75]. Currently, the immense costs of the substrates, the high time expenditure (breath collection periods of more than 6h), and the lack of standardisation still limit the clinical utilisation of these breath tests.

5.5. Bacterial overgrowth 

Bacterial overgrowth is defined by finding more than 105germs/ml in jejunal aspirate. However, the aspiration of jejunal content and its culture under aerobic and anaerobic atmosphere is cumbersome and unpractical. The glycocholic acid breath test can indirectly reflect bacterial overgrowth by the bacterial deconjugation of the orally ingested 13C-labelled bile acid [76]. 13C-glycine is cleaved by the bacteria, rapidly absorbed, and metabolised to 13CO2. However, a relatively low sensitivity of this breath test might indicate that not all patients with bacterial overgrowth harbour a flora which deconjugates the substrate. Additionally, disorders in bile acid absorption in the terminal ileum can result in false positive results. Otherwise, if bacterial overgrowth can be excluded, the 13C-gylcocholic breath might be used for testing the enterohepatic circulation of bile acids [76], [77].

The 13C-xylose breath test also offers a diagnostic alternative to the microbiological analysis of jejunal fluid for the diagnosis of small bowel bacterial overgrowth [78], although most studies used the radioactive 14C-xylose [79], [80].

Both breath tests provide a practical way of serial testing a condition that is often persistent/recurrent throughout life. But the substrates are still expensive, the tests are not yet standardised. The good old glucose hydrogen breath test offers a practicable and low-priced alternative. While the glucose hydrogen breath test depends on the exposure to mainly anaerobic bacteria, the bile acid breath test requires the presence of bacteria with deconjugating enzymes. Therefore, the results might not be directly comparable.

5.6. Orocoecal transit time 

Lactose [13-C]-ureide has proven to be a reliable marker to follow orocoecal transit time [81], [82], [83], [84]. The tracer resists the action of brushborder enzymes and is not metabolised until reaching the colonic bacteria. The low tracer dosage required for the lactose-ureide breath test avoids an osmotic diarrhoea which can shorten the small bowel passage. The long testing time in orocaecal transit measurements (about 10h) is a major drawback for the practicability in diagnostic routine.

The lactulose hydrogen breath test is cheaper, but shows lower sensitivity and specificity due to dose dependent accelerations of the transit time and the prevalence of H2-non-producers [83], [85]. The high dose of lactulose required influences the osmotic balance in the intestinal lumen and thereby the transit time.

5.7. Carbohydrate assimilation 

If the appropriate 13C-labelled carbohydrate substrate for the breath tests is chosen several intestinal digestive enzyme activities can be tested (13C-lactose: lactase [86], [87], [88], [89], 13C-starch: amylase [70], [72], [89], [90], [91], [92], [93], 13C-saccharose: saccharase [94]) or transport functions (e.g. 13C-fructose [95]). In contrast to the hydrogen breath tests, 13C-breath tests can also be reliably applied in non-hydrogen-producers, and the substrate dosage required is substantially less. However, the costs of the substrates and the analysis still limit the wide spread use of 13C-carbohydrate breath tests in clinical diagnosis. The recommended method for the diagnosis of lactose malabsorption is still the lactose hydrogen breath test combined with the lactose tolerance test (blood glucose measurements and monitoring of symptoms).

5.8. Other tests for malabsorption 

In general, all substances which are rapidly metabolised in the body to carbon dioxide can be used as 13C-labelled substrates to study the processes of absorption in the gastrointestinal tract. But so far, these breath test techniques have been rarely applied for solving clinical problems of transport and malabsorption (e.g. carbohydrates [95], [96], [97], [98], fatty acids [57], [99], [100], [101], [102], proteins [74], [103], [104], [105].

5.9. Outlook 

The stable isotope technique presents an elegant, non-invasive diagnostic tool promising further options of clinical applications. In the future, 13C-breath tests should be able to indicate, in vivo, the activity of various specific enzyme systems in the body and their response to stress or infection as well as to treatment regimes.

For instance, pre-treatment screening with a novel 13C-uracil breath test might help to detect dihydropyrimidine dehydrogenase (DPD)-deficient cancer patients and to prevent the potentially lethal side effects of 5-fluoruracil treatment in these patients [106]. Or, 5-oxoprolinase is an enzyme of the glutathione catabolism. It can generate intracellular cysteine, which is beneficial to the cell, from the substrate l-2-oxothiazolidone-4-carboxylate (OTC). Therefore, a breath test using 13C-labelled OTC as substrate would yield cysteine and 13CO2, and could thus reflect the state and capacity of glutathione metabolism [107].

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Practice points 


•13C-breath tests provide a non-invasive diagnostic tool to monitor in vivo the activity of various specific enzyme systems or transport processes. Thereby, the already naturally existing 13C concentration in the body is only slightly enriched.

•The 13C-urea breath test is the most sensitive diagnostic method to detect a present Helicobacter pylori infection of the stomach.

•Solid testmeals labelled by 13C-octanoic acid and liquid testmeals labelled by 13C-acetate enable the determination of gastric emptying processes and provide reliable non-radiating alternatives to scintigraphy.

•Several 13C-labelled hepatically metabolised substrates are used to evaluate the hepatic functional mass in acute and chronic liver disease, and before and after transplantation.

•The exocrine pancreatic function can non-invasively be tested by 13C-breath tests measuring the intraluminal activity of pancreatic enzymes.

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Research agenda 


•Agreement on standard protocols and the assessment of normal ranges would ease the comparability of breath test results from different centres.

•Factors influencing the recovery of the tracer need to be investigated.

•Prospective evaluation whether liver function tests using 13C-labelled hepatically metabolised substrates are prognostic, can predict liver resectability, are helpful to determine the best time point for transplantation, and can help to avoid liver biopsies in chronic hepatitis virus infections.

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Conflict of interest statement 

None declared.

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PII: S1590-8658(07)00275-7

doi:10.1016/j.dld.2007.06.012

Digestive and Liver Disease
Volume 39, Issue 9 , Pages 795-805, September 2007

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