Breath Testing to Evaluate Lactose Intolerance inIrritable Bowel Syndrome Correlates With LactuloseTesting and May Not Reflect TrueLactose MalabsorptionMark Pimentel, M.D., F.R.C.P.(C.), Yuthana Kong, M.P.H., and Sandy Park, B.A.GI Motility Program, Department of Medicine, CSMC Burns and Allen Research Institute, Cedars-SinaiMedical Center, Los Angeles; and School of Medicine, University of California, Los Angeles, Los Angeles,California

OBJECTIVES: An increased prevalence of lactose intoleranceis seen in irritable bowel syndrome (IBS). Recently, wedemonstrated a high prevalence of abnormal lactulosebreath test results in IBS suggesting bacterial overgrowth.Because symptoms of lactose intolerance result frombacterial fermentation, the purpose of this study was todetermine whether an abnormal lactose breath test isreflective of malabsorption or early presentation to bac-teria.

METHODS: Subjects with diarrhea-predominant IBS wereenrolled. On day 1, subjects underwent a lactulose breathtest after an overnight fast. Within 1 wk, subjects returnedafter fasting for a lactose breath test with simultaneousblood glucose measurements every 15 min to complete alactose tolerance test (LTT). Symptoms were evaluated 3 hafter lactose administration.

RESULTS: Twenty subjects completed the study. One subjectinadvertently received dextrose through the intravenous andwas excluded. Of the remaining 19 subjects, three (16%)had an abnormal LTT suggesting malabsorption. In all, 10subjects (53%) had an abnormal lactose breath test, 14(74%) had an abnormal lactulose breath test, and 11 (58%)had symptoms after lactose administration. The agreementwith symptoms was moderate (� � 0.47) and fair (� � 0.24)when compared to the lactose breath test and LTT, respec-tively. There was a fair correlation between lactose breathtest and LTT (� � 0.29). However, lactose breath testhydrogen levels �166 ppm were universally predictive ofabnormal LTT. Finally, a significant correlation was seenbetween the hydrogen production on lactose and lactulosebreath test (r � 0.56, p � 0.01).

CONCLUSIONS: Lactose breath testing in IBS subjects doesnot seem to reflect malabsorption; it may be an indicator ofabnormal lactulose breath test, suggesting bacterialovergrowth. (Am J Gastroenterol 2003;98:2700�2704. ©2003 by Am. Coll. of Gastroenterology)

INTRODUCTION

Irritable bowel syndrome (IBS) is a chronic condition asso-ciated with alterations in bowel frequency and with abdom-inal pain. Although the etiology remains unknown, IBSpatients have characteristic complaints, many of which arerelated to food ingestion (1–4). These food intoleranceshave received much attention.

Lactose intolerance is one of the most prevalent forms offood intolerance. Because lactose intolerance and IBS areboth common, investigators have tried to establish a rela-tionship between these two problems. In fact, the prevalenceof lactose intolerance in IBS is reported to be between 17%and 86% (2, 5–14). However, these results seem to be highlydependent on the method of testing, with the highest prev-alence of abnormality seen if lactose breath test is used (2,6, 8–10, 12–14).

Evaluating lactose intolerance can therefore be complex.As mentioned above, one problem may be that studiesevaluating the role of lactose intolerance in IBS rely on thelactose breath hydrogen test. In both controlled (15) anduncontrolled studies (16), we have shown that �80% ofsubjects with IBS have an abnormal lactulose breath test tosuggest the presence of bacterial overgrowth (15). Becausethe milk sugar lactose is inherently difficult to digest, somelactose is expected to reach the distal small intestine beforesuccessful digestion and absorption. In fact, studies demon-strate that up to 8% of ingested lactose reaches the ileum innormal subjects (17). If bacterial overgrowth is present inthe distal small intestine, this residual lactose will becomefermented, resulting in gaseous byproducts, symptoms, anda falsely abnormal lactose breath test. Essentially, the pa-tient might experience intolerance of the milk lactose in theabsence of any true incapacity to absorb the carbohydrate.

The purpose of this study was to determine whether thehigh prevalence of abnormal lactose breath test in IBSrepresents true malabsorption or is instead a function ofabnormalities on lactulose breath test suggesting the pres-ence of bacterial overgrowth.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 12, 2003© 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00Published by Elsevier Inc. doi:10.1016/S0002-9270(03)01703-9

MATERIALS AND METHODS

Study PopulationFor this study, subjects with diarrhea-predominant IBS wererecruited based on Rome II criteria (18). Subjects wererecruited through advertising in Los Angeles area newsprintand were excluded if they had either a history of or riskfactors for bacterial overgrowth. These factors includedprevious bowel resection, known adhesions, narcotic use,cirrhosis, connective tissue disease, diabetes, proton pumpinhibitor use, and inflammatory bowel disease. The agerange was restricted to 18–65 yr. Subjects were not requiredto have a known history of milk intolerance. The study wasapproved by the Cedars-Sinai Medical Center InstitutionalReview Board, and all patients were required to providesigned consent for participation.

Lactulose Breath TestingOn the first day of the study, subjects were asked to presentto the GI Motility Program at Cedars-Sinai Medical Centerhaving fasted from 7 PM the previous evening. Subjectswere also asked to avoid a meal with legumes or heavyprotein and fat on the previous evening meal. On the day oftesting, subjects were asked to brush their teeth and to avoidsmoking (19). Before undergoing the lactulose breath test, aquestionnaire was administered. This questionnaire was de-signed to acquire demographic and general health informa-tion. Subjects then had an initial breath sample taken. Breathsamples were collected using a Quintron breath collectionbag (Quintron Instrument Company, Milwaukee, WI) de-signed to trap dead space air and to maximize alveolarsampling. After this initial breath sample, subjects weregiven 10 g of lactulose (Constulose, Alpharma USPD, Bal-timore, MD), after which repeat breath samples were col-lected every 15 min for 3 h. Samples were analyzed imme-diately to ensure quality measurements. Samples wereevaluated for hydrogen and methane using a model SCQuintron Gas Chromatograph (Quintron Instrument Com-pany). The results were recorded and blinded to both theinvestigator and patient so as not to influence the results ofother testing.

Evaluation of Lactose IntoleranceThe ability of subjects to tolerate lactose was evaluated.This involved a simultaneous lactose breath test and lactosetolerance test (LTT). To accomplish this, subjects wereasked to return to the GI Motility Program, again havingfasted, and underwent preparation in a fashion identical tothat described above for the lactulose breath test. This sec-ond visit was timed such that it was within 7 days of theinitial lactulose breath test. An i.v. was then placed into alarge antecubital vein and a blood sample was drawn. Theserum was sent to the Reference Laboratory (Cedars-SinaiMedical Center, Los Angeles, CA) for evaluation of glucoseby the hexokinase method. Subjects then had a baselinebreath sample. Subsequently, subjects were asked to ingest50 g of lactose (Spectrum Chemical Manufacturing, Gar-

dena, CA) dissolved in 250 ml of sterile water. After inges-tion of the lactose, breath and serum samples were obtainedevery 15 min for 3 h. After 3 h, subjects were asked to reporttheir symptoms related to the lactose ingestion includingbloating, distension, or diarrhea.

Definition of Abnormal TestingAn abnormal lactulose breath test was defined as a rise of�20 ppm in hydrogen or methane within 90 min of lactuloseingestion (16, 20). This was considered as suspicious for thepresence of bacterial overgrowth.

An abnormal LTT was defined as a rise in blood glucoseof �20 mg/dl within the 3 h of measurement. This lack ofadequate rise was considered to be representative of failedabsorption of the carbohydrate (21). An abnormal lactosebreath test result was defined as a rise in hydrogen ormethane of �20 ppm in the first 3 h of testing (22).

Symptoms during testing were also taken into account. Atthe conclusion of the lactose tolerance test/breath test, sub-jects were asked to disclose whether they experienced ex-cessive bloating, distension, or diarrhea. Any combinationof these symptoms constituted symptomatic intolerance tolactose.

Data AnalysisThe prevalence of abnormal lactulose breath test, lactosebreath test, LTT, and symptomatic intolerance was firstdetermined. Subsequently, agreement between lactose test-ing and symptoms of intolerance were undertaken usingCohen’s �. The rise in blood glucose was then comparedbetween symptomatic and nonsymptomatic subjects usingStudent’s t test. Student’s t test was also used to compare themaximal breath hydrogen production after lactose adminis-tration between subjects with normal versus those withabnormal lactose tolerance tests. Linear regression was thenused to compare the peak hydrogen production between thelactose and lactulose breath tests.

RESULTS

Subject DemographicsA total of 25 subjects with diarrhea-predominant IBS whomet the inclusion criteria were enrolled in this study. Five ofthese individuals withdrew from the study after completingthe lactulose breath test only. Of the 20 subjects completingall components of the study, one was excluded because ofextreme blood glucose levels throughout the lactose study,which were caused by the inadvertent infusion of dextrose tomaintain the i.v. used for blood drawing. This left 19 sub-jects for evaluation. Of the 19 subjects, 10 (53%) werewomen. The mean age of the subjects was 36.7 � 9.1 yr.

Agreement Between Lactose Testing and SymptomsAmong the 19 IBS subjects, 10 (53%) had an abnormallactose breath test suggesting the presence of lactose mal-digestion. Of these 10 subjects, eight (80%) had symptomsduring lactose administration. However, three of the nine

2701AJG – December, 2003 Breath Testing for Lactose Intolerance in IBD

subjects (33%) with no abnormality on lactose breath testalso had symptoms during lactose administration. Theagreement between lactose breath test results and symptomswas moderate (� � 0.47).

Among the same initial 19 IBS subjects, only three (16%)had an abnormal LTT with glucose failing to rise �20 mg/dlafter lactose ingestion. All three subjects were symptomaticafter lactose administration. The agreement between LTTand symptoms was only fair (� � 0.24).

Glucose Rise and Lactose ParametersThe rise in blood glucose after lactose was not differentbetween subjects symptomatic with lactose and those thatwere not. Symptomatic subjects were found to have a rise inglucose of 30.4 � 8.7 mg/dl compared to the rise of 26.9 �12.1 mg/dl that was observed in asymptomatic subjects (p �0.51). Likewise, when data for subjects with positive lactosebreath test results were compared to those with a negativebreath test results, no difference in glucose response wasseen.

Lactose Breath Test in Predicting LactoseMalabsorption on Lactose Tolerance TestThe agreement between the LTT and the lactose breath testwas also only fair (� � 0.29). However, subjects with anabnormal LTT had a significantly higher level of hydrogenon their lactose breath test (Fig. 1) than those with normalLTT results. The maximal hydrogen production seen onbreath test in subjects with normal LTT was 37 � 43 ppm(CI � 0–123 ppm). This was compared to 202 � 18 ppm(CI � 166–238 ppm) for subjects with abnormal LTT,suggesting malabsorption (p � 0.00001). Based on the highdegree of separation between the groups, any subject withmaximal hydrogen production of �166 ppm would be ex-pected to show malabsorption of lactose based on the tol-erance test (Fig. 2). In addition, there was an inverse cor-relation between the maximal hydrogen production on thelactose breath test and the rise in glucose (Fig. 3).

Relationship Between Lactose and Lactulose Breath TestLactulose breath test results were noted to be abnormal in 14of 19 subjects (74%). On comparing the maximum hydro-gen production between the lactose and lactulose breath test,there was a significant correlation between these two tests,suggesting that the abnormality seen on lactose breath testcould represent bacterial overgrowth rather than lactoseintolerance (Fig. 4).

Figure 1. The average lactose breath hydrogen profile in subjectswith and without abnormal lactose tolerance test results. “Lactoseintolerance” (indicated by solid lines) implied that the subjects hadan abnormal lactose tolerance test (n � 3). “Normal” (indicated bybroken lines) implied that the subjects had normal lactose tolerancetest results (n � 16). *p � 0.05, ¶p � 0.001, †p � 0.0001

Figure 2. Comparison of peak hydrogen on lactose breath test inIBS subjects with and without abnormal lactose tolerance testresults.

Figure 3. Correlation between height of hydrogen on lactose breathtest and change in serum glucose after lactose challenge.

Figure 4. Correlation between peak hydrogen production seen onlactose and lactulose breath test.

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DISCUSSION

In this article, we report data to support the contention thatlactose breath testing in IBS subjects may be misleading inthe diagnosis of lactose malabsorption. In the case of IBS, afalse positive lactose breath test may indicate bacterial over-growth, as a high degree of correlation was seen betweenhydrogen production on lactose and lactulose breath testresults. In addition, most subjects with abnormal lactosebreath test did not have abnormal lactose tolerance tests.

Lactose is a carbohydrate that is principally found in dairyproducts. Because of a relative paucity of the enzyme lac-tase in humans, studies show that digestion of lactose re-quires the full length of the intestine. Even in normal sub-jects, up to 8% of a lactose load may reaches the ileum,leading to a risk of exposure to colonic bacteria and toproduction of symptoms (17).

An important issue in the evaluation of lactose intoler-ance is its definition. Lactose intolerance implies that apatient experiences symptoms after ingestion of lactose con-taining food products. These symptoms include bloating,distension, and even diarrhea and are produced when unab-sorbed lactose sugar encounters bacteria, leading to fermen-tation. By association, this would imply lactose malabsorp-tion or a relative reduction of lactase in these subjects.However, the production of symptoms relates to the presen-tation of lactose to intestinal bacteria; and theoretically,bacterial expansion into the small intestine would result insymptoms without a reduction in lactase enzyme.

In the case of IBS, a high prevalence of lactose intoler-ance is not altogether intuitive. First, IBS consists of sub-groups including diarrhea predominant and constipationpredominant forms (18). In contrast, lactose intolerancemore often results in diarrhea. Nevertheless, studies dem-onstrate that in IBS subjects, a positive lactose breath testcan be seen in up to 86% of subjects (14). The issue that hasbeen incompletely addressed to date is whether this abnor-mal breath test finding truly represents a deficiency in lac-tase, hence malabsorption. This question is important, inas-much as some studies even suggest that lactose intolerancehas pathophysiological implications in IBS (2). There isevidence to suggest that an abnormal lactose breath test maynot represent malabsorption. When actual absorption istested by means of an LTT, the prevalence rates for abnor-mality are much lower, ranging from 17% to 24% (5, 7, 11).

The role of lactose intolerance in IBS can also be eval-uated through symptom improvement after elimination oflactose from the diet. In studies in which subjects with IBSare asked to cease consumption of all foods containinglactose, results are varied. Among IBS subjects who arepreselected with an abnormal lactose tolerance, responses of87.5% are seen (7). When general IBS subjects are lactoserestricted only 39% of subjects report improvement (9).However, subjects often continue to have the same IBSsymptoms, although with perhaps a lower severity. Anotherdifficulty with interpreting this finding is that symptom

improvement with dietary elimination of lactose does notconfirm malabsorption.

Recently we reported that the lactulose breath test isabnormal in up to 84% of IBS subjects (15), suggesting thepresence of bacterial overgrowth. Antibiotic treatment ofIBS subjects results in significantly greater improvementthan with placebo, with clinical response rates as high as88% with successful normalization of the lactulose breathtest. The current study demonstrates a similar high preva-lence of abnormal breath test at 74%. If the lactulose breathtest reflects true small intestinal bacterial overgrowth, thiswould result in nutrients being prematurely exposed to lu-minal bacteria. Because lactose requires most of the smallintestine to facilitate absorption (17), significant quantitiesof lactose could be exposed to the bacterial colonization,leading to symptom consequences. These symptom conse-quences might be caused by proximal bacteria rather than achange in capacity to absorb lactose. Theoretically, in sucha circumstance, elimination of lactose might improve symp-toms.

In the current study, a lactose tolerance test only identi-fied three IBS subjects (of 19 subjects) with true malabsorp-tion. This is in contrast to the 10 (53%) with a positivelactose breath test. Most importantly, as shown in Figure 4,the peak hydrogen on lactose breath testing correlates wellwith the lactulose breath test hydrogen rise. This impliesthat the lactose breath test may be representative more ofwhat the bacterial exposure is than true malabsorption.However, the lactose breath test seems not to be useless.Subjects with true malabsorption (based on lactose tolerancetest) had significantly higher concentrations of hydrogen onlactose breath test compared to subjects with normal lactosetolerance test (Fig. 2). These were so different as to have nooverlap at the 95% confidence limits. Therefore, breathhydrogen measurements �166 ppm seem to be diagnosticof malabsorption in IBS subjects.

One consideration that cannot be excluded in this study israpid transit. If these IBS subjects had rapid transit, bothlactose and lactulose breath tests might be abnormal becauseof premature presentation of lactose to the colon. Furtherstudies to evaluate this possibility are needed.

In conclusion, the lactose breath test likely is not reflec-tive of lactose malabsorption in IBS unless hydrogen pro-duction �166 ppm is seen. The abnormal lactose breath testin IBS may be more suggestive of bacterial overgrowth orrapid transit based on the lactulose breath test findings.More work is needed to characterize the lactase enzymelevels in IBS subjects to validate the lactose breath test andtolerance test if these tests are to be used in IBS subjects. Atthis point, the lactose tolerance test may be the preferredmethod.

ACKNOWLEDGMENT

This work was supported in part by the Beatrice and SamuelA. Seaver Foundation.

2703AJG – December, 2003 Breath Testing for Lactose Intolerance in IBD

Reprint requests and correspondence: Mark Pimentel, M.D.,8635 W. 3rd Street, Suite 770, Los Angeles, CA 90048.

Received Mar. 24, 2003; accepted July 18, 2003.

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