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Home , Fructose malabsorption

ORIGINAL ARTICLE

Fructose Intolerance in IBS and Utility of -Restricted Young K. Choi, MD,* Nancy Kraft, RD, LD,w Bridget Zimmerman, PhD,z Michelle Jackson,w and Satish S. C. Rao, MD, PhD, FRCPw

ructose is naturally present in fruits and vegetables, Introduction: Whether dietary fructose intolerance causes Fbut today it is avidly consumed in beverages and symptoms of (IBS) is unclear. We canned products as high fructose .1 In the examined the prevalence of fructose intolerance in IBS and long- United States, the consumption of fructose has increased term outcome of fructose-restricted diet. several fold during the last 2 decades. A United States Methods: Two hundred and nine patients with suspected IBS Department of Agriculture study estimated that the annual consumption of fructose has risen from less than were retrospectively evaluated for organic illnesses. Patients 2 with IBS (Rome II) and positive fructose breath test received a ton in 1966 to 8.8 million tons in 2003. Unlike other instructions regarding fructose-restricted diet. One year later, sugars such as or lactose which are digested by their symptoms, compliance with, and effects of dietary sucrase or lactase produced by the intestinal brush border, the gut does not appear to have a specific modification on lifestyle were assessed using a structured 3,4 interview. for digesting or transporting fructose. Recent studies have shown that GLUT-5 and GLUT-2 which Results: Eighty patients (m/f = 26/54) fulfilled Rome II criteria. actively transport across the mucosa may also Of 80 patients, 31 (38%) had positive breath test. Of 31 patients, play a role in facilitating absorption of fructose.4 26 (84%) participated in follow-up (mean = 13 mo) evaluation. Consequently, if fructose is ingested in large quantities, Of 26 patients, 14 (53%) were compliant with diet; mean the capacity of the gut to absorb fructose can be easily compliance = 71%. In this group, pain, belching, , overwhelmed leading to fructose and fullness, , and improved (P<0.02). Of 26 symptoms.5–9 patients, 12 (46%) were noncompliant, and their symptoms were Dietary fructose intolerance is associated with many unchanged, except belching. The mean impact on lifestyle, common symptoms such as abdominal bloating, pain, compliant versus noncompliant groups was 2.93 versus 2.57 flatulence, and diarrhea.5,8 These symptoms are also (P>0.05). similar to those described by patients with lactose10 or 6,7,11 12 Conclusions: About one-third of patients with suspected IBS had intolerance or bacterial overgrowth. Pre- 8 5 fructose intolerance. When compliant, symptoms improved on viously, we and others have reported a higher pre- fructose-restricted diet despite moderate impact on lifestyle; valence of fructose intolerance in patients with noncompliance was associated with persistent symptoms. unexplained gastrointestinal symptoms and dyspepsia. Fructose intolerance is another jigsaw piece of the IBS puzzle In contrast, a controlled study showed that the frequency that may respond to dietary modification. of gastrointestinal symptoms and the occurrence of fructose malabsorption were similar between Key Words: IBS, fructose intolerance, diet, breath test controls and patients with functional bowel disorder.13 (J Clin Gastroenterol 2008;42:233–238) Furthermore, the prevalence of fructose intolerance in patients with irritable bowel syndrome (IBS) is not clearly known. IBS affects 10% to 15% of the population in the 14 Received for publication August 23, 2006; accepted October 20, 2006. United States. The prevalence of fructose intolerance From the *Immanuel St Joseph’s, Mayo Health System, Mankato, MN; in patients with suspected IBS has not been systematically wDepartment of Internal Medicine; and zClinical Research Center, examined. Furthermore, whether IBS patients with University of Iowa Carver College of Medicine, Iowa City, IA. fructose intolerance benefit from a fructose-restricted diet The authors declare no conflict of interest. Supported in part by NIH RO1 grant DK 57100-05 and grant RR00059 is not known. from the General Clinical Research Centers program, National The aims of our study were to examine: (1) the Center for Research Resources. prevalence of fructose intolerance in patients with Reprints: Satish S.C. Rao, MD, PhD, FRCP, Department of Internal suspected IBS and to assess their symptom profiles and Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive/4612 JCP, Iowa City, IA 52242-1009 (e-mail: satish-rao@ (2) the effects of fructose-restricted diet on symptom uiowa.edu). patterns and lifestyle in patients with IBS and fructose Copyright r 2008 by Lippincott Williams & Wilkins intolerance.

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METHODS From these data, a mean score was calculated for each Patients referred to our tertiary care center with symptom. suspected IBS or with persistent, unexplained, nonspecific Patients with a positive fructose breath test received gastrointestinal complaints between January 2001 and both written and verbal dietary instructions by a dietician January 2002 were evaluated with appropriate diagnostic regarding a fructose exclusion or restricted diet. The tests to identify organic illnesses including fructose breath written instructions comprised of a fructose-restriction test. Subsequently, case records were reviewed to identify diet manual that was developed by our dietician. This those patients who fulfilled the Rome II criteria for IBS patient-directed, self-guide informs the patient about the and/or functional abdominal bloating,15 together with an fructose content of common foods and how to avoid food absence of alarm symptoms. In particular, we excluded items such as fruit , cola products, carbonated patients with abnormal findings on a barium study, beverages, corn products, chocolates, and foods contain- computed tomography/ultrasound scan of abdomen, ing high fructose corn syrup. One year later, fructose upper or lower gastrointestinal endoscopy, hematologic intolerant patients were invited to participate in a follow- or biochemical studies or stool tests. Patients were also up telephone survey. Through a structured interview excluded if they had any coexisting active or inactive conducted by one of the investigators (Y.C.), we enquired gastrointestinal problems such as previous abdominal about their current symptoms, their compliance with the surgery (except appendectomy or hysterectomy), lactose fructose-restricted diet, and the effects of dietary restric- intolerance (negative lactose breath test), bacterial over- tion on their lifestyle. The patient’s symptoms at 1 year growth (negative glucose breath test), , were compared with those obtained at baseline. The , , pancreatic disorders, compliance with a fructose-restricted diet was designated biliary disease, , any malignancy, celiac as compliant, if the patient reported that they had disease, inflammatory bowel disease, gastrointestinal modified their diet substantially to reduce consumption reflux disease, eosinophilic , or lymphocytic of fructose products by Z50% of the amount consumed . before testing and as noncompliant if it was <50%. The The following protocol was used to test dietary effect of dietary restriction on lifestyle was scored on a fructose intolerance. Patients were asked to refrain from modified Likert-like scale as follows: 0 (none), 1 (mini- taking high fat, lactose, or fructose containing foods for 1 mal), 2 (mild), 3 (moderate), 4 (significant), and 5 day before the test. Patients were also asked to fast from (extreme). midnight and refrain from smoking. After arrival in the The extra amount of time spent per week to comply motility laboratory, the patient was instructed to blow with the diet was assessed during the follow-up interview into a modified Haldane-Priestley bag (QuinTron, Mil- using the following scale: 1 = no extra time spent per waulkee, WI), and an end-expiratory breath sample was week; 2 = spending 1 extra hour; 3 = spending 3 extra collected. A 50 cm3 sample of air was taken from the bag hours; 4 = spending 4 extra hours; and 5 = spending and injected into a gas chromatography analyzer (Quin- more than 5 extra hours. tron Microlyzer Self Correcting Model SC, QuinTron, To assess the test-retest reliability of the bowel Milwaukee, WI), and baseline values for (H2) symptom questionnaire, we administered the symptom and (CH4) were measured. These values were questionnaire twice, at 1-week interval to 25 additional corrected for CO2. Next, the patients were asked to drink participants that included 8 healthy volunteers and 17 a solution containing 25 g of fructose dissolved in 250 mL patients who were undergoing breath tests for either of water (10% solution). This dose was chosen on dose research or clinical purposes. During this period of response studies of fructose absorption in healthy hu- assessment, these participants were advised to continue mans.16 Thereafter, breath samples were collected at 30- with their usual diet and were unaware of the results of minute intervals for 5 hours, and analyzed for H2 and the breath test. CH4. During the test, any symptoms experienced by the The study was approved by the University of Iowa patient were recorded. An incremental rise in breath H2 Institutional Review Board. and/or CH4 of Z5 ppm in 3 or more consecutive breath samples, over and above the baseline value or a value Statistics Z20 ppm above the baseline value in 2 consecutive The differences in symptom profiles in IBS patients samples was interpreted as a positive breath test.8,16,17 We who tested positive or negative to the fructose breath test used a stricter definition of incremental rise over 2 or was compared using the Wilcoxon signed-rank test. The more samples to minimize false positive test.16,17 symptom scores reported by our patients during the Before the test, patients were asked to fill out a fructose breath test were compared using the student t symptom questionnaire that assessed the presence of 9 test. After the fructose-restricted diet, the difference in common bowel symptoms8; abdominal discomfort or symptom profiles between the compliant and the non- pain, belching, bloating, postprandial fullness, indiges- compliant groups was compared, using the Wilcoxon tion, nausea, diarrhea, vomiting, and flatulence. The signed-rank test. severity of each symptom was rated in terms of frequency, The bowel symptom questionnaire was validated duration, and intensity on a scale of 0-3, and the using the weighted k statistic. For each symptom, the maximum possible total core for any 1 symptom was 9. individual scores for frequency, intensity, and duration

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TABLE 1. The Distribution of Symptom Scores, and the Proportion of Patients Who did not Report a Particular Symptom During Their First and Second Symptom Assessment Observed Score Range = Min-Max Freq (%) With no Symptom Distribution of Score Difference Symptom First Study Second Study Equal Differ by 1 Differ by 2 or Greater Weighted j (95% CI) Abdominal pain 0-9 0-9 11 6 6 0.68 7 (30.4%) 5 (26.1%) (Max diff = 6) (0.49, 0.87) Belching 0-9 0-9 11 7 5 0.68 8 (34.8%) 6 (26.1%) (Max diff = 5) (0.49, 0.86) Bloating 0-9 0-9 13 5 2 0.78 6 (26.1%) 7 (30.4%) (Max diff = 6) (0.63, 0.93) Diarrhea 0-9 0-8 13 2 8 0.51 15 (65.2%) 13 (56.5%) (Max diff = 7) (0.24, 0.78) 0-9 0-9 10 3 10 0.49 5 (21.7%) 7 (30.4%) (Max diff = 7) (0.24, 0.74) Fullness 0-9 0-9 6 8 9 0.40 7 (30.4%) 7 (30.4%) (Max diff = 7) (0.13, 0.68) Indigestion 0-9 0-9 13 2 8 0.61 9 (39.1%) 11 (47.8%) (Max diff = 6) (0.39, 0.84) Nausea 0-9 0-9 16 2 5 0.81 13 (56.5%) 13 (56.5%) (Max diff = 3) (0.71, 0.91) Vomiting 0-4 0-4 22 0 1 0.82 21 (91.3%) 21 (91.3%) (Max diff = 2) (0.50, 1.0) were summated to develop a total symptom score and Reproducibility of Symptoms During this was compared. We assessed the agreement for the the Breath Test patient’s total symptom score and for each of the 9 Among those who tested positive (fructose intoler- symptoms. ant), 28/31 (91%) patients reported that the breath test reproduced their typical symptom(s) such as bloating, RESULTS diarrhea, gas, or abdominal pain (Fig. 1). Similar symptoms were also reproduced in 40% of the patients Demographics who had a negative breath test (fructose tolerant). Two hundred and nine patients with suspected IBS Fructose intolerant patients were more likely or unexplained gastrointestinal symptoms were evaluated. (P = 0.006) to experience symptoms during the breath Of these, 129 patients were excluded, because of organic test when compared with those who were fructose gastrointestinal illness or coexisting disorder(s), and 80 tolerant (Fig. 1). patients who fulfilled the Rome II criteria for IBS and functional abdominal bloating were included. Data from Symptom Profiles these 80 patients [m/f = 26/54; mean age of 42 y All 80 suspected IBS patients had reported more (range = 20 to 76)] were analyzed. than 1 gastrointestinal symptom. At baseline, irrespective of whether they tested positive or negative with the Validation of Bowel Symptom Questionnaire fructose breath test, the prevalence of symptoms was not Twenty-five patients (m/f = 6/19, mean age = 39 y) statistically different, except for diarrhea. For example, completed the bowel symptom questionnaire on 2 the mean total symptom score for abdominal pain was 7.0 separate occasions to assess the test-retest reliability. Data obtained for each of the 9 individual symptoms are shown in Table 1. The weighed k statistic with 95% CI varied from 0.4 (0.13-0.68) to 0.82 (0.5-1.0). Overall reproducibility of the questionnaire was fairly good (Table 1).

Fructose Breath Test Among the 80 patients with suspected IBS, 31 (33%) patients had a positive breath test (fructose intolerant), and 49 (67%) had a negative breath test (fructose tolerant). Among the 31 fructose intolerant patients, 28 (90%) had elevated breath H2, 2 (7%) had elevated H2 and CH4, and 1 other patient (3%) had FIGURE 1. Reproducibility of symptoms during the fructose elevated CH4 only. breath test in patients with and without fructose intolerance. r 2008 Lippincott Williams & Wilkins 235 Choi et al J Clin Gastroenterol Volume 42, Number 3, March 2008 versus 6.42, bloating was 7.0 versus 6.33, and flatulence compliant group reported a temporal correlation between was 6.07 versus 6.83 in the fructose intolerant patients a trial of consuming fructose containing foods and relapse versus fructose tolerant patients (P>0.05). However, of symptoms. None of the noncompliant patients loose stools/diarrhea was reported by all patients who reported such a correlation. were fructose intolerant when compared with 35/49 (71%) patients who were fructose tolerant (P = 0.007). Effects on Lifestyle The effect of fructose-restricted diet on lifestyle in Effect of Fructose-restricted Diet on the dietary compliant group ranged from 1 to 3.5, with a Bowel Symptoms mean value of 2.93. This suggests a mild to moderate After 1 year, 26/31 fructose intolerant patients were effect on their lifestyle. In this group, the extra time spent available and agreed to participate in a follow-up by the patients per week to comply with the fructose- evaluation. Among these, 14/26 patients were designated restricted diet ranged from 1 to 3, with a mean value of as complaint, with a mean self-estimate of 71% (range 2.57. Despite these effects on lifestyle, all of the compliant 50% to 90%) compliance with a fructose-restricted diet. patients reported that they were planning to continue The mean duration of dietary restriction was 12.6 months with their dietary modification. The effect of fructose- (range 6 to 18 mo). restricted diet among the noncompliant group was In this group, there was significant improvement of reported as 1, suggesting that it did not alter their symptoms, notably abdominal pain, belching, bloating, lifestyle. fullness, indigestion, and diarrhea (Fig. 2A). In contrast, 12/26 patients were designated as noncompliant with a DISCUSSION mean self-estimate of 23.4% (range 0% to 30%) In this series of patients with suspected IBS, we compliance with the diet. In this group, there was no found that approximately one-third had a positive significant change in bowel symptoms, except for belching fructose breath test. In over 90% of these patients, the and nausea (Fig. 2B). Additionally, 12/16 patients in the breath test also reproduced their symptoms suggesting

FIGURE 2. A, Changes in symptom patterns in patients with fructose intolerance who complied with a fructose-restricted diet. B, Changes in symptom patterns in patients with fructose intolerance who did not comply with a fructose-restricted diet.

236 r 2008 Lippincott Williams & Wilkins J Clin Gastroenterol Volume 42, Number 3, March 2008 IBS, Diet, and Fructose Intolerance dietary fructose intolerance. Thus, it seems that in this ratio, most individuals who consume these products may selected group of patients presenting to a tertiary care not be symptomatic.9 However, many food products have center with symptoms suspicious of IBS, a significant excess fructose,20,21 and when these are ingested in proportion had fructose intolerance. significant amounts, fructose intolerance is likely to At baseline, patients with and without fructose ensue. In such individuals, our data show that dietary intolerance appeared to have similar symptom profiles. fructose restriction could be effective in ameliorating Thus, symptoms alone were not sufficiently reliable to symptoms. identify patients with fructose intolerance. However, one However, the adherence to dietary modification was interesting observation was that all patients who reported not easy and had some impact on the lifestyle of these loose stools/diarrhea at baseline had a positive fructose patients. We found that patients who were complaint with breath test. Also, the pretest incidence of loose stools/ the diet reported mild to moderate effects on their diarrhea was significantly higher in those with a positive lifestyle. Furthermore, they had to spend extra time, on breath test compared to those with a negative test. This average 2 to 3 hours per week, to maintain their dietary suggests that patients presenting with diarrhea-predomi- restriction. Despite these effects, when inquired, all of our nant IBS are more likely than others to have dietary compliant patients reported that they were willing to fructose intolerance. Many patients with a negative continue with dietary restriction, because of the overall fructose breath test also reported IBS symptoms such as benefit. bloating and abdominal pain. These patients may have We designated all individuals with a positive visceral hypersensitivity to physiologic stimuli.18,19 fructose breath test as having fructose intolerance and To our knowledge, there is no standard question- provided them with dietary advice. Only 9% of our naire for assessing symptoms in patients with suspected subjects did not develop symptoms during the breath test. carbohydrate intolerance or bacterial overgrowth. We Thus, a possible overestimation of fructose intolerance designed a simple questionnaire to assess the presence of in our patients may only apply to a small group of bowel symptoms related to carbohydrate malabsorption individuals. and its intensity and duration. Because this questionnaire Our study has several limitations that include the formed an integral part of our analysis, we also examined small sample size, the referral bias, the lack of blinding, a the test-retest reliability in a separate group of patients. possible recall bias for dietary restriction, the study of We found that the results were quite reproducible; hence, patients from a tertiary care center, and the retrospective this questionnaire may be useful for the routine assess- analysis of our data. Also, whether the noncompliant ment of symptoms at baseline and after therapeutic patients did not try or the diet was ineffective cannot be interventions. It also provides qualitative and semiquan- established. Nevertheless, these findings reveal an asso- titative information regarding the occurrence of symp- ciation between dietary fructose intolerance and IBS toms during the breath test. symptoms and that dietary intervention may be helpful in One potential explanation for the elevations in these patients. These observations merit further confirma- breath hydrogen and/or methane after ingestion of tion in a larger, prospective study. fructose could be the presence of small bowel bacterial In conclusion, our study shows that about one-third overgrowth. However, all patients included in this study of patients with suspected IBS may have fructose had a negative lactose and a negative glucose breath test intolerance. Fructose breath test may identify this subset making it less likely that they had proximal small bowel of treatable IBS patients. Without investigating this bacterial overgrowth. Whether some of our patients had possibility, many such patients, particularly those with distal small bowel bacterial overgrowth12 cannot be diarrhea-predominant illness may be mistakenly labeled excluded from this study. as having IBS. Fructose-restricted diet imposes some Although, we and others5–8 have reported dietary changes in lifestyle, but when adhered to may confer fructose intolerance as a potential cause of unexplained significant relief of symptoms. gastrointestinal symptoms, the efficacy of fructose-re- stricted diet in the management of these patients is not ACKNOWLEDGMENT known. In this study, we found that 54% of suspected The authors thank the secretarial assistance of IBS patients were mostly compliant with a fructose- Mrs Heidi Vekemans. restricted diet and showed significant improvement in their bowel symptoms. In contrast, 46% were not compliant with the diet and showed very little improve- REFERENCES ment. These observations establish a direct correlation 1. 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