Hydrogen and methane breath testing has become an increasingly common investigative tool for assessing carbohydrate mal-absorption, small intestinal bacterial overgrowth and gut dysbiosis. Despite hundreds of hospitals and several commercial laboratories offering breath testing services in the UK, there is little consensus as to how to perform and interpret these tests.
This situation is not peculiar to the UK. A recent review of 13 clinical trials showed that 13 different methodologies were used to acquire and interpret breath test data. In science, one needs to develop models that can be tested by experiment in order to control for known variables with as much certainty as is possible. To develop a model, parameters need to be agreed upon as a starting point so that new discoveries can be made disease understanding improved and more effective treatments developed.
In order to address this in the US, an expert panel of clinicians and scientists with experience in the use of breath testing was recently assembled to review existing practices and to try to construct and initial consensus document for the use of breath testing in gastrointestinal disease. The group developed a series of 28 questions based on existing data and voted independently on whether they agreed or not with the statements. The domains covered were clinical indications, preparation, performance, interpretation of results, and knowledge gaps.
The consensus findings were first presented at DDW in 2016 and the subsequent paper has just been accepted for publication in the American Journal of Gastroenterology. I was recently lucky enough to spend a few days at the GI Motility laboratory of two of the main authors of the document. Dr Mark Pimentel and Dr Ali Rezaie at the Cedar Sinai Hospital in Los Angeles have published extensively on breath testing in recent years and made several leaps in our understanding of its utility. The lab has performed over 50,000 breath tests and this was a great opportunity discuss some of the nuances and scientific reasoning around generation of consensus document, assess the impact on how my own service at The Functional Gut Clinic is delivered and look to disseminate these finding to the UK community.
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Breath testing can be an evocative subject with investigators at different ends of the spectrum both extoling and refuting its usefulness. Two of the main controversies exist around the type of substrate that should be used and the relationship between the timing of peaks in breath gases and location of the substrate within the bowel. There are few 100% accurate tests available to physiologists and thus a pragmatic approach has to be taken which incorporates knowledge of the physiological processes and clinical conditions under which a test is performed in order to both maximise and restrain interpretation.
The controversy of whether to use glucose or lactulose to assess SIBO is somewhat of a moot point. Glucose is absorbed within the first few feet of the small bowel and therefore if the overgrowth is distal to this then a false negative result is obtained. Lactulose travels all the way through the entire small bowel and a major criticism has been that a peak observed with lactulose may represent fermentation in the caecum (i.e. a false positive response). Data from imaging studies have not really helped answer these questions due to disconnect between imaging parameters and fermentation characteristics such as the lag time between the substrate reaching the bacteria and the onset of the fermentation process.
What was agreed was that 75g of glucose should be used and 10g of lactulose with a positive test for both being considered as a rise in gas levels of 20ppm above baseline at 90-minutes. My concern with this value and time-point is that it may be too sensitive at one end (i.e. at 90-minutes in some patients the substrate may be in the caecum) and not sensitive enough at the other end (i.e. a rise of 10-19 prior to 90-minutes could easily be positive for SIBO but would be determined negative using these parameters).
In discussion with Dr’s Pimentel and Rezaie, they explained that difference in the sensitivity of equipment across centres meant that lesser values were felt to be not easily attainable and that the time-point was chosen based on scintigraphic data and consideration of the time-lag involved in the fermentation process. From a personal perspective, I would still like to introduce caveats into our reporting process which would classify an earlier rise between 10-19ppm as ‘borderline’ positive especially in the presence of typical symptoms and a rise of 20ppm at 90-minute in the absence of symptoms as a potential false positive.
Clinical judgement is always required when interpreting physiological test results and perhaps the most valuable data to help guide this will come from outcome studies which look at whether these cut-off values can help to predict the efficacy of treatment. For example, Rifaxamin is supposed to work predominantly within the small bowel and therefore if a higher proportion of patients did not respond to Rifaxamin when their peak occurred at 90-minutes compared to 60-minutes (at values between 10-19ppm) then this would provide valuable information about ‘re-drawing’ the boundaries for a positive test.
We have always considered breath testing as a provocation test and carefully map symptoms during each test. However, symptoms did not play much of a role in the consensus document. This is because previous studies have shown that there is a fairly poor correlation between gas levels and symptoms (with the exception of methane and constipation). I think this slightly misses the point as symptoms may be influenced by other factors such as visceral hypersensitivity and if you can reproduce most of a patient’s typical symptoms with a small amount of carbohydrate then it provides greater confidence in the clinical translation of the physiological findings. We have previously shown that patients with SIBO have a higher incidence of nausea compared to those with colonic mal-fermentation whose provoked symptoms tend to be more bloating and distension. These data have only been published in abstract form and I think this is another area which can be developed to enrich the breath test model.
Methane is somewhat of an enigma in that baseline levels can be very high despite days of fasting, no one is completely certain of where the archaea are in the gut (i.e. colon and / or small bowel) and because the fermentation characteristics of methanogens are different to hydrogen producing bacteria then the timing of peaks is also difficult to interpret. In addition, methane sensors can be somewhat unstable and therefore less sensitive at the lower end of the detectable range. Therefore a pragmatic approach to methane was that a value of ≥10ppm should be considered abnormal and that the mere presence of methane was enough to be abnormal as opposed to trying to quantify levels and changes, although methane levels have been shown to correlate with constipation. What has also been suggested is that a single fasting spot breath test can be used to assess methane eradication after treatment with Rifaxamin and Neomycin or statins.
With regard to fructose and lactose there was good evidence that 25g of each substrate was adequate and that both tests should be extended out to 3-hours post ingestion to ensure full coverage of the physiological curve as opposed to 2-hours for SIBO.
At The Functional Gut Clinic, we also like to consider values >60ppm generated in the latter parts of a lactulose study as evidence of excessive fermentation in the caecum (caecal mal-fermentation) most likely caused by colonic dysbiosis. We feel this is an important factor as the differences in the levels of hydrogen produced can only be due to difference in the types of bacteria producing the gas as the amount and type of substrate remains constant (i.e. 10g of lactulose). In our practice, patients with this type of profile tend to head down a low fermentable / low fibre dietetic pathway as opposed to antibiotic therapy, with good success. We have recently completed a clinical trial which will look at this in more detail and we hope this will add to future consensus statements.
The consensus group identified several areas where further work is required to enhance the breath test model. These included the development of a sensor that detect hydrogen sulphide (the gas which provide the mal-odorous content of flatulence and sequesters large amounts of hydrogen to potentially cause ‘flat-line’ responses), examination of the influence of pre and probiotics, assessment of treatment efficacy and several other areas. We would certainly like to be contributing to this development and hope that the UK can play an important role in helping to drive this process further.
Implications for the UK
The UK currently finds itself between a rock and a hard place in terms of breath testing and in particular with regard to SIBO. On the one hand it is great that we may be able to improve the technical quality and scientific understanding of breath testing methodology and interpretation for UK patients but, on the other hand we don’t have ready access to treatments such as Rifaxamin when a positive SIBO test is identified.
Without larger scale trials of rifaxamin in the UK it is going to be difficult to convince the medical community and regulatory bodies that this can be an effective treatment. Anecdotally, a secondary care US physician told me that their IBS-D referrals had declined by 60-70% since rifaxamin was licensed and being used in primary care which could have potentially huge savings in healthcare cost in terms of inpatient, outpatient and colonscopy costs which total over £250-million in the UK at present.
So for now, what we will do is to continue to acquire high quality data, look to perform some comparative analysis looking at different time points and thresholds, look to develop outcome studies with our clinical partners and contribute to the scientific literature through our clinical trials data. Next steps should be a review of existing UK breath testing and establishment of a consensus group of our own would be beneficial so that we can begin to close the gap that exists between ourselves and the US.
Written by Dr Anthony R. Hobson PhD – Clinical Director – The Functional Gut Clinic, London, UK.