Interpreting the Lactulose Breath Test for the Diagnosis ...

CLINICAL INVESTIGATION

Interpreting the Lactulose Breath Test for the Diagnosis of Small Intestinal Bacterial Overgrowth

Joseph K. Sunny Jr., MD, Cesar J. Garcia, MD and Richard W. McCallum, MD

ABSTRACT

Introduction: Based on literature review, a positive lactulose breath test (LBT) for small intestinal bacterial overgrowth requires an initial peak value of hydrogen within 100 minutes of lactulose ingestion with a second peak before 180 minutes. However, using scintigraphic monitoring of lactulose transit time, mean oral-cecal arrival time has been reported as 73 minutes. The goal was to propose new criteria for analysing the LBT to overcome false positive interpretations.

Methods: LBTs from our referral center were interpreted as positive after ingestion of 10 g of lactulose using the following approach for hydrogen concentrations: (1) The literature guidelines: greater than 20 ppm from a baseline less than 10 ppm achieved within 100 minutes followed by a further rise of greater than 15 ppm within 180 minutes. (2) The proposed criteria: greater than 20 ppm from a baseline less than 10 ppm within either 60 or 80 minutes followed by a further rise of greater than 15 ppm during the 180-minute test.

Results: A total of 153 patients with symptoms suspicious for small-bowel bacterial overgrowth underwent testing. Of all, 26.1% patients tested positive by 100 minutes, 11.8% patients tested positive by 60 minutes and 18.3% patients tested positive by 80 minutes. The percentage of positive LBTs at 60 and 80 minutes was significantly lesser than for the 100 minutes criteria (P o 0.05).

Conclusions: The first hydrogen peak increase should occur by either 60 or 80 minutes to increase the specificity of LBT for small intestinal bacterial overgrowth based on the reality of lactulose cecal arrival times.

Key Indexing Terms: Lactulose breath test; Small intestinal bacterial overgrowth; Bloating; Diarrhea. [Am J Med Sci 2016;351(3):229?232.]

INTRODUCTION

The gastrointestinal tract has a complex population of symbiotic microbes called microbiota. Variable quantities exist along the tract from 101-103 bacteria per gram of luminal secretions in the stomach and duodenum to 1011-1012 bacteria per gram in the colon. Small intestinal bacterial overgrowth (SIBO) is defined as greater than 105 colony forming units of bacteria per milliliter of luminal fluid from the proximal jejunum, including anaerobic and aerobic cultures.1 More recently, a study investigated both the culturing of jejunal aspirates and polymerase chain reaction (PCR) analysis. The sensitivity and specificity of the breath test using PCR as a measure of bacterial counts was 55.00% and 0.0%, respectively with a positive predictive value of 100%. The sensitivity and specificity of the breath test using bacterial culture of jejunal aspirate was 45.45% and 33.33%, respectively with a positive predictive value of 44.45%. Clearly many bacteria are not able to be cultured by standard aerobic and anaerobic techniques and based on PCR of jejunal aspirates, essentially all patients with gas, bloating and abdominal bloating had 4105 organisms/mL of bacteria.2

As collecting aspirates from the jejunum requires an endoscopic procedure and culture methods, which are not available in most medical centers, breath tests have

been developed as a more available and practical approach to determine SIBO. Patients drink solutions with glucose or lactulose and provide breath samples that are collected over the next 2-3 hours and analyzed for hydrogen and methane concentrations.3 The sensitivity of these tests has been called into question and different guidelines have been proposed to define a positive breath test.

The lactulose breath test (LBT) is defined as a positive test in the literature in different ways. The initial focus in LBT was in 2 peaks and no specific time frame recommended for the first peak, specifically that a test was regarded as positive if the hydrogen exceeded 20 ppm at least 15 minutes before the colonic peak occurred. A range of 45?120 minutes was noted as the time of the initial hydrogen peak in controls signaling cecal arrival.4 The first peak is thought to result from encountering bacteria in the small intestine. A second peak occurs later when lactulose reaches the colon. More recently, a review article suggested a first hydrogen peak before 90 minutes as a positive test.5 Therefore, based on the literature available we decided a positive test was defined as whether the hydrogen concentration exceeded 20 ppm by 100 minutes. This was based on "middle ground" from the different opinions that were published.2,4,5

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Sunny et al

Previously conducted simultaneous hydrogen breath testing (HBT) and scintigraphic studies of isotope-labeled lactulose to investigate small-bowel transit concluded that the mean cecal arrival time was 73 minutes and individual arrival times ranged from 30?139 minutes. A total of 69% of patients had arrival times that were less than 90 minutes by both HBT and scintigraphy. The median arrival time by scintigraphy was 64 minutes and by HBT was 74 minutes.6 In another report, patients with irritable bowel syndrome also received isotope-labeled lactulose and their cecal arrival times ranged from 10?220 minutes and the mean was 71 minutes.7

Breath testing provides a more readily available, safe, inexpensive and noninvasive alternative to jejunal aspiration and culture for the diagnosis of SIBO. A rationale for LBT is that it could detect cases of distal small-bowel (ileal) bacterial overgrowth and pathologic bacterial strains not identified by culturing techniques of the more proximal small bowel (jejunum).8

Breath testing is unable to distinguish metabolism of lactulose from small-bowel or colonic flora as it is not absorbed in the small bowel and is therefore a nonabsorbed sugar when it arrives in the colon. Another consideration is that lactulose actually accelerates small-bowel intestinal transit9 and this would further impair the diagnostic accuracy of breath testing. There is also evidence that low-dose lactulose actually induces increased contractions of the colon smooth muscle and therefore increases cecal and colonic motility; all factors which can conceivably confound interpretation of changes in hydrogen concentration during the LBT.10

METHODS

Subjects This was a retrospective study analyzing the breath

test findings of 153 patients who were referred for LBT testing at a single academic tertiary referral center from 2011-2013 for suspected SIBO based on such symptoms as gas, bloating, abdominal distension, diarrhea, constipation, abdominal pain, nausea and vomiting.

Measurements

Lactulose Hydrogen Breath Testing LBT was performed using a Quintron BreathTracker SC

Digital Microlyzer with carbon dioxide calibration. Patients ingested 10 g of lactulose in 120 cc of water after 2 baseline breath samples were collected followed by breath samples obtained every 20 minutes for 180 minutes. Test results were analyzed based on 2 guidelines. (1) The literature guidelines: a hydrogen concentration of greater than 20 ppm from a baseline less than 10 ppm achieved within a 100 minutes after ingestion of 10 g of lactulose in 100 cc of water, followed by a further rise of greater than 15 ppm within 180 minutes was interpreted as a positive test for SIBO. (2) Our new proposed criteria for a positive result: a hydrogen concentration of greater than 20 ppm from a

230

baseline less than 10 ppm by either 60 or 80 minutes after ingestion of 10 g lactulose followed by a further rise of greater than 15 ppm during the 180 minutes of sampling. All patients who had a baseline hydrogen or methane greater than or equal to 10 ppm at baseline were excluded. All breath tests were evaluated by a single, experienced reader (RWM).

Patients adhered to the following instructions for the breath test. On the day before the test, their diet was limited to baked or broiled chicken, white bread, plain steamed white rice, eggs and clear chicken or beef broth with no vegetables. The patients had to fast for 12 hours before the test. For 1 hour before and during the test, patients could not fall asleep, perform vigorous exercise or smoke. Patients were to wait more than 14 days after having received colonoscopy, barium studies or antibiotic therapy. Patients remained fasting throughout the 3 hours study. For breath hydrogen samples greater than 10 ppm at baseline, patients were asked to brush their teeth and take mouthwash to gargle to see if hydrogen concentrations fell to less than 10 ppm. If so, breath sampling continued for 3 hours. If breath H2 and CH4 remained 410 ppm, then this data were not included in our analysis.

Statistical Analysis The 2 methods of diagnosis were compared using

McNemar's test. The performance of a new procedure in relation with the existing 1 was assessed using positive proportion (PPA) and negative proportion (NPA) agreements. The estimate of PPA and NPA and their 95% CI were reported. P o 5% was considered significant. Statistical analysis was carried out using STAT 12.1. Overall, raw agreement between procedures was estimated as 92%.

RESULTS

A total of 153 LBTs were analyzed from a University Motility Center from 2011-2013 for the indication of suspected SIBO based on symptoms such as gas, bloating, abdominal distension, diarrhea, constipation, abdominal pain, nausea and vomiting. Mean age was 54.6 years (range: 23-86) and 84.3% were women. Using the Current Guidelines, the 153 LBT results were scrutinized. Overall, 40 (26.1%) patients tested positive by 100 minutes (Table 1). Based on the proposed criteria, 18 (11.8%) patients tested positive by 60 minutes and 28 (18.3%) patients tested positive by 80 minutes (Table 1).

TABLE 1. Cumulative data of positive lactulose breath test results identified at time intervals over the 180 minutes duration of the breath sampling.

Time (minutes)

Percentage of patients with hydrogen concentration 420 ppm (%)

60

11.8

80

18.3

100

26.1

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Re-evaluating Interpretation of the LBT

TABLE 2. Summary of the specific time intervals yielding positive results for the lactulose breath based on hydrogen elevations.

Time (min)

Average hydrogen concentration (ppm)

Percentage of patients with hydrogen 420 ppm

(%)

Baseline

9.4

NA

20

11.1

1.3

40

14.6

5.2

60

18.5

4.5

80

24.6

5.9

100

29.7

7.8

120

37.6

9.8

All patients who tested positive had a subsequent second peak of greater than 15 ppm above the first noted peak within the 180 minutes time limit of the breath sampling. The percentage of positive LBTs at 60 and 80 minutes was significantly less than for the 100 minutes criteria (P o 0.05) (Tables 1 and 2).

The NPA result was found to be 100%. In other words, all the negative cases diagnosed by the existing criteria were also diagnosed as negative by the new criteria. PPA result was estimated as 70%. This indicates that in 30% of the cases the 2 procedures did not agree. In these 30%, they were diagnosed as positive by existing criteria and negative by the new criteria. This result demonstrates that there is a significant difference in the 2 approaches (P o 0.0001, McNemar's test).

Overall, 20 of the patients who were positive by 80 min criteria, were treated by Dr. McCallum using the antibiotic Rifaxamin 800 mg/day for 4 weeks followed by a probiotic. Overall symptomatic response was 450% in 14 patients, between 25% and 50% in 4 patients and 2 patients had responses of o10%. Repeat breath tests were also able to be obtained in 12 of the 20 patients at least 2 weeks after completing their antibiotics. A total of 50% were subsequently negative by the 60 and 80 minutes criteria. In the remainder, there was a reduction in the peak concentrations of hydrogen achieved compared to before treatment.

The 12 patients, who had a positive LBT at 100 minutes but negative at 60 and 80 minutes, underwent a subsequent fructose breath test for fructose intolerance and malabsorption. Of the 12 patients, 5 were positive based on elevated breath hydrogen criteria. They received instructions and information on how to follow a low fructose diet and subsequent symptomatic improvement was noted. The remaining 7 patients were advised to follow a low-fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet and specific information was provided. A variable improvement in their symptoms was observed over time.

DISCUSSION

HBT is based on the principle that bacterial metabolism of nonabsorbed carbohydrates is the sole source

of hydrogen and methane in exhaled breath.11,12 After oral ingestion of a substrate, gas chromatography can report concentrations in ppm for hydrogen and methane.13 Lactulose is a synthetic, nonabsorbable disaccharide consisting of fructose and galactose, and it is often prescribed as an osmotic laxative. It is a mainstay of hepatic encephalopathy treatment.14 Lactulose passes through the normal small intestine without absorption. In the cecum, it is metabolized by colonic bacteria to short-chain fatty acids and gases including hydrogen or methane (or both), which are absorbed systemically and ultimately excreted in exhaled breath.

The LBT was initially developed to determine smallbowel transit time.15 In SIBO, the colonic bacteria that have migrated proximally into the small bowel theoretically should lead to an early increase in breath hydrogen excretion. In this situation, a second increase in breath hydrogen excretion should also occur after lactulose reaches the cecum and further enhanced fermentation continues. More commonly, a single broad plateaued peak is observed further complicating the ability to differentiate contacting small-bowel bacteria from actual cecal arrival time. Multiple endpoints have been used to define a positive test, leading to significant confusion. The original definition of a positive test was a hydrogen peak of greater than 20 ppm attributed to small intestinal bacteria occurring at least 15 minutes before a subsequent prolonged peak thought to correspond to lactulose entering the colon. These authors also identified the cecal arrival time in normal subjects as ranging from 45120 minutes postlactulose ingestion.4

The main concern with a positive LBT is whether the first increase in hydrogen or methane above an agreed upon concentration, usually 20 ppm, could represent the patient's orocecal transit time instead of SIBO. Such early arrival times in the cecum for lactulose have been noted on previous scintigraphy and breath testing studies. Our previous research investigated small-bowel transit time for isotope-labeled lactulose and showed mean cecal arrival time was 73 minutes with a range of 31?139 minutes. A total of 69% of patients had arrival times of lactulose of under 90 minutes by both HBT and scintigraphy.6 Other scintigraphic studies have shown orocecal transit times ranging from 10?220 minutes with a mean of 71 minutes.7 Additionally, lactulose can accelerate orocecal transit time.9 LBT sensitivity in clinical research ranged from 17?68%, and specificity ranged from 44?86% when culture of upper gut aspirates was utilized as the gold standard.16-19

As glucose is absorbed in the jejunum, there are really no false-positives to explain a marked increase in breath hydrogen. It has been speculated that relying on the glucose breath test result may underestimate bacterial overgrowth in a very small subset of patients where bacterial overgrowth is limited to the ileum. On the other hand, by relying on lactulose as the substrate, there is the very real risk of overdiagnosis explained by colonic bacteria fermentation inducing hydrogen production in patients without SIBO.

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Sunny et al

A total of 40 (26.1%) of our patients tested positive by 100 minutes based on the Literature Guidelines. Of all, 18 (11.8%) patients tested positive by 60 minutes and 28 (18.3%) by 80 minutes based on our proposed criteria. All patients who tested positive had a subsequent second peak of greater than 15 ppm above the first noted peak. The percentage of positive LBTs at 60 and 80 minutes was significantly less than for the 100 minutes criteria (P o 0.05). Therefore, to increase the specificity of the LBT, we propose that the first hydrogen peak occur either by 60 or 80 minutes. This would minimize false positives explained by lactulose already reaching the colon.

The positive aspects of our research are that the test was always conducted in a standardized manner by the same personnel and interpreted by 1 physician, an expert in research on gastrointestinal motility. Some limitations of our study are the following: enrolling a greater number of patients would have been preferable; having more extensive clinical outcome data as far as treatment and symptom follow-up and including methane criteria in breath test analyses. Also, the role of predisposing systemic and gastrointestinal factors for a positive SIBO result was not the focus of this report.

CONCLUSION

When interpreting the LBT for diagnosing SIBO, the first peak increase in hydrogen should occur within the first 60 or 80 minutes to increase the specificity of LBT for SIBO based on the reality of lactulose cecal arrival times. Our data and conclusions also suggest the need for further research comparing LBT with jejunal aspirate studied by PCR methodology to provide more insight for further refining the interpretation of a LBT or concluding that it has no role in diagnosing SIBO.

REFERENCES

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2. Mendoza-Ladd A, Cooper CJ, Antony N, et al. Role of PCR amplification of jejunal aspirates in relation to culture and breath test in the diagnosis of small intestinal bacterial overgrowth. DDW Abstract 2015.

3. Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference. Aliment Pharmacol Ther 2009;29(suppl 1):1?49.

4. Rhodes JM, Middleton P, Jewell DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol 1979;14(3):333?6 [Previously 14].

5. Saad RJ, Chey WD. Breath testing for small intestinal bacterial overgrowth: maximizing test accuracy. Clin Gastroenterol Hepatol 2014; 12(12):1964?72.

6. Caride VJ, Prokop EK, Troncale FJ, et al. Scintigraphic determination of small intestinal transit time: comparison with the hydrogen breath technique. Gastroenterology 1984;86(4):714?20.

7. Yu D, Cheeseman F, Vanner S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects

oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS. Gut 2011;60:334?40. 8. Schiller LR. Evaluation of small bowel bacterial overgrowth. Curr Gastroenterol Rep 2007;9:373?7. 9. Miller MA, Parkman HP, Urbain JL, et al. Comparison of scintigraphy and lactulose breath hydrogen test for assessment of orocecal transit: lactulose accelerates small bowel transit. Dig Dis Sci 1997;42(1): 10?8. 10. Jou?t P, Sabat? JM, Cuillerier E, et al. Low-dose lactulose produces a tonic contraction in the human colon. Neurogastroenterol Motil 2006; 18(1):45?52. 11. Levitt MD. Volume and composition of human intestinal gas determined by means of an intestinal washout technic. N Engl J Med 1971;284: 1394?8. 12. Levitt MD, Bond JH Jr. Volume, composition, and source of intestinal gas. Gastroenterology 1970;59:921?9. 13. Christman NT, Hamilton LH. A new chromatographic instrument for measuring trace concentrations of breath-hydrogen. J Chromatogr 1982; 229:259?65. 14. Leise MD, Poterucha JJ, Kamath PS, et al. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc 2014;89(2):241?53. 15. Bond JH Jr, Levitt MD, Prentiss R. Investigation of small bowel transit time in man utilizing pulmonary hydrogen (H2) measurements. J Lab Clin Med 1975;85(4):546?55. 16. Riordan SM, McIver CJ, Walker BM, et al. The lactulose breath hydrogen test and small intestinal bacterial overgrowth. Am J Gastroenterol 1996;91:1795?803. 17. Ghoshal UC, Ghoshal U, Das K, et al. Utility of hydrogen breath tests in diagnosis of small intestinal bacterial overgrowth in malabsorption syndrome and its relationship with oro-cecal transit time. Indian J Gastroenterol 2006;25:6?10. 18. Corazza GR, Menozzi MG, Strocchi A, et al. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology 1990;98:302?9. 19. King CE, Toskes PP. Comparison of the 1-gram [14C]xylose, 10-gram lactulose-H2, and 80-gram glucose-H2 breath tests in patients with small intestine bacterial overgrowth. Gastroenterology 1986;91: 1447?51.

From the Division of Gastroenterology (JS, CJG), Hepatology and Nutrition, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas; Department of Internal Medicine (RWM), Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas; Center for Neurogastroenterology and GI Motility (RWM), Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas.

Submitted April 16, 2015; accepted September 30, 2015.

Abstract presented at Digestive Disease Week 2014 Chicago on May 4, 2014.

RWM has been on the Advisory Board of Smart Pill Corporation and Prostrakan Pharma. He has been a consultant for Tranzyme, Inc, Evoke, Rhythm and Medtronic Corporation, and has received research funding from Tranzyme, Takada, Salix, Novartis, Red Hill Pharma and Rhythm as well as current NIH funding from NIDDK--Gastroparesis Consortium. JS and CG have no declaration of personal interests. This research project had no specific source of funding.

Correspondence: Richard W. McCallum, MD, Department of Internal Medicine, Center for Neurogastroenterology and GI Motility, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 4800 Alberta Avenue, El Paso, TX 79905. (E-mail: richard. mccallum@ttuhsc.edu).

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