Alimentary Pharmacology and Therapeutics

Fructose and intolerance and testing: the relationship with symptoms in functional gastrointestinal disorders

C. H. Wilder-Smith, A. Materna, C. Wermelinger & J. Schuler

Gastroenterology Group Practice, SUMMARY Brain-Gut Research Group, Bern, Switzerland. Background The association of and and malabsorption with the symp- Correspondence to: toms of different functional gastrointestinal disorders (FGID) remains unclear. Prof. C. H. Wilder-Smith, Brain-Gut Research Group, Aim Group Practice, Bubenbergplatz 11, CH-3011, Bern, Switzerland. To investigate the prevalence of fructose and lactose intolerance (symptom induc- E-mail: [email protected] tion) and malabsorption and their association with clinical gastrointestinal (GI) as well as non-GI symptoms in FGID and the outcome of dietary intervention.

Publication data Methods Submitted 18 December 2012 Fructose and lactose intolerance (defined by positive symptom index) and malab- First decision 22 January 2013 fi Resubmitted 19 March 2013 sorption (de ned by increased /) were determined in 1372 Accepted 20 March 2013 FGID patients in a single centre using breath testing. Results were correlated with EV Pub Online 9 April 2013 clinical symptoms in different FGID Rome III subgroups. The effectiveness of a targeted saccharide-reduced was assessed after 6–8 weeks.

Results Intolerance prevalence across all FGIDs was 60% to fructose, 51% to lactose and 33% to both. Malabsorption occurred in 45%, 32% and 16% respectively. There were no differences in intolerance or malabsorption prevalence between FGID subgroups. FGID symptoms correlated with symptoms evoked during testing (r = 0.35–0.61. P < 0.0001), but not with malabsorption. Non-GI symptoms occurred more com- monly in patients with intolerances. Methane breath levels were not associated with using several cut-off thresholds. Adequate symptom relief was achieved in >80% of intolerant patients, irrespective of malabsorption.

Conclusions Fructose and lactose intolerances are common in FGID and associated with increased non-GI symptoms, but not with specific FGID subtypes. Symptoms expe- rienced during breath testing, but not malabsorption, correlate with FGID symp- toms. Effective symptom relief with dietary adaptation is not associated with malabsorption. Mechanisms relating to the generation of GI and non-GI symptoms due to lactose and fructose in FGID need to be explored further.

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1074 ª 2013 Blackwell Publishing Ltd doi:10.1111/apt.12306 Sugar intolerances in functional GI disorders

INTRODUCTION inclusion in this prospective study, except those with evi- Adverse reactions to food are common in the population dence of organic disease, which was assessed by routine and are claimed by up to 67% of individuals with Func- haematology and blood testing and also tional Gastrointestinal Disorders (FGID).1 They form stool testing for calprotectin and deter- part of the Rome III definition of Functional Dyspepsia mined in two stool samples in all patients. Parasite and (FD), and are frequent in bacterial stool cultures were performed if clinically indi- (IBS).2 Food hypersensitivity is often difficult to confirm, cated. Upper and lower endoscopies with were but avoidance of specific foods often diminishes symp- required in patients older than 40 years or in patients toms. Possible underlying mechanisms include with diarrhoea or faecal blood.8 was maldigestion or malabsorption, chemical or mechanical excluded by antitranglutaminase antibodies or duodenal hypersensitivity, changes in gastrointestinal motility, the biopsies. One consultant gastroenterologist (CWS) per- enteric microbiome, and immune and psychological formed all the medical and dietary history taking and responses. Reliable tests are lacking for several of these physical examinations. The dietary history included two mechanisms and results may be ambiguous, for example, sections: an open question requesting a listing of avoided for tests of malabsorption and . However, there and poorly tolerated foods and then a specific list of the has been recent progress, both in more refined test main fructose, , galactosaccharide, methodology and in interventional studies.3, 4 Although lactose and -containing foods as well as the 10 intolerances, defined as symptoms associ- commonest food in Europe. In addition, skin ated with their ingestion, are probably not the cause of rashes, urticaria, rhinitis, headache, imperative defaecatory most FGID, the reduced consumption of fermentable urge, changes in stool consistency related to mealtimes saccharides in patients with malabsorption results in were documented. All patients completed a standardised symptom relief superior to most pharmaceutical treat- questionnaire, which included the specific questions for ments.5, 6 However, the significance of carbohydrate- classification of GI symptoms into FGID groups accord- related symptoms and of malabsorption in FGID ing to the Rome III criteria and additional questions remains unclear, as do the optimal diagnostic tech- regarding allergies, childhood and family history, central niques.7 Furthermore, the common association of GI in- nervous, musculoskeletal and cardiac system symptoms, tolerances with non-GI reactions in FGID remains and the use of polyol-containing sweets and chewing unexplained. gum. Patients were classified into FGID subgroups In this study, the following issues were examined in a according to the Rome III criteria.9 The most prominent large single-centre cohort of successive FGID patients: (i) FGID was chosen for classifying each patient. The study How common are lactose and fructose intolerance and was performed in accordance with the Helsinki Declara- malabsorption during breath testing in FGID and its tion of 1975 as revised in 1983. subgroups? (ii) What is the relationship between clinical symptoms and breath test results? (iii) Are non-GI Breath test protocol symptoms associated with intolerances? and (iv) What is Fructose and lactose breath tests were performed in all the symptomatic outcome of a standardised dietary FGID patients by one laboratory technician (AM). No intervention and is this related to malabsorption? Our , or laxatives were permitted hypotheses were that fructose and lactose intolerance within 14 days and a specific low-saccharide diet was would be equally common across all FGID, that symp- adhered to 1 day before the tests. Patients arrived for test- toms generated during breath testing would correlate ing in the morning after fasting overnight and without with the patients’ clinical symptoms and that intolerance having smoked, chewed gum or performed vigorous exer- would be more relevant than only malabsorption in the cise for at least 4 h. Chlorhexidine mouthwash was used diagnosis and dietary treatment outcome of fructose and and teeth were brushed before testing. The breath tests lactose intolerance. We expected a high incidence of were performed in randomised, patient-blinded sequence non-GI symptoms in patients with intolerances. on two separate occasions at least 4 days apart. Breath samples were collected in sealed glass tubes (Quintron MATERIALS AND METHODS Instruments, Milwaukee, WI, USA) before and hourly for All successive patients referred to our gastroenterology 5 h after ingestion of lactose 50 g or fructose 35 g dis- practice by general practitioners between January 2008 solved in 300 mL water. Hydrogen, methane and CO2 and May 2011 for evaluation of FGID were eligible for concentrations were measured within 72 h using the

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Quintron BreathTracker SC (Quintron Instruments). compliance was checked either by direct or telephonic Hourly testing was chosen based on our laboratory pilot interview by the dietician or the gastroenterologist 6– data, where identical qualitative results were obtained as 8 weeks after initiation of the dietary changes. Compli- with sampling every 15 min and concentrations were sta- ance was considered adequate if patients confirmed that ble in the tubes for 3 weeks. Malabsorption was defined as they adhered to the dietary guidelines during at least an increase of >20 ppm in hydrogen or >10 ppm in 50% of the meals consumed.19 methane levels over baseline twice in succession. The numbers of patients with early rises (in the first 60 min) Statistics above the 20 ppm threshold in breath hydrogen concen- Group differences in clinical GI and non-GI symptoms tration following fructose and lactose were calculated for and variables were compared by Kruskall–Wallis or ANO- 7, 10–16 comparison with other published data Intolerance VA tests, as appropriate. Categorical data were compared was defined as an increase of >2 over baseline using a by Chi-squared test or, if between multiple groups, by symptom score index, which was the sum of the intensi- logistical regression. Correlations were analysed using the ties (0 = none, 1 = mild, 2 = intense) of abdominal dis- Spearman–Rank test. A significance threshold of tension or , flatulence, fullness, , diarrhoea, P < 0.05 was adopted. Analysis was performed using abdominal , borborygmi and gastro-oesophageal Statistica 7.1 (StatSoft, Tulsa, OK, USA). reflux symptoms, which were scored hourly concurrently with the collection of the breath samples. Additional non- RESULTS GI symptoms rated, but not part of the symptom index, Patient characteristics are shown in Table 1. Seventy-six were tiredness, diminished concentration, headache, per cent of the 1372 patients were of Northern European myalgia, arthralgia, palpitations, oral aphthoid ulcers and and 19% of Mediterranean European Caucasian descent. skin rash. The choice of symptoms scored was based on Of these patients, the following subgroups were defined the literature and the most frequent atopic and co-morbid according to the Rome III criteria: Irritable Bowel Syn- functional disorders.6, 12, 17 drome (n = 212), comprised of IBS with constipation (IBS- Additional methane threshold definitions for malab- c, n = 37), IBS with diarrhoea (IBS-d, n = 67), IBS with sorption of >3 ppm at baseline and an increase of alternating constipation and diarrhoea (IBS-m, n = 94) >20 ppm over baseline at any time during the test were and IBS unclassified (IBS-u, n = 14), Functional Dyspepsia applied for correlations with stool patterns for compari- (n = 606), comprised of FD with postprandial distress son with previous publications.18 Diarrhoea was defined (FD-ppd, n = 368) and FD with epigastric pain syndrome as loose or watery stools during >25% of bowel motions (FD-eps, n = 238), and Functional Bloating (n = 109). or >3 motions daily in the last 3 months. Constipation was characterised by hard, lumpy stools and increased Prevalence of lactose and fructose intolerance during straining during >25% of bowel motions or <3 stools per testing and association with clinical symptoms week in the last 3 months. The prevalence of fructose, lactose and both intolerances in all FGID patients was 60.4%, 50.5% and 33.1% respec- Dietary protocol tively. In Northern European and Mediterranean Cauca- The 312 patients with positive intolerance tests after sians, 61.0% and 59.4% had fructose intolerance (not May 2010 were referred to an experienced dietician significant-N.S.), 47.8% and 53.6% had lactose intolerance (CW) for a standardised 4-week dietary adaptation, con- (P < 0.01), and 33.2% and 29.5% had both intolerances sisting of a diet low in saccharides and polyols for 1 (N.S.). Of males and females, 57.1% and 61.7% had fruc- week and subsequent weekly introduction of defined tose intolerance (N.S.), 43.6% and 53.3% had lactose intol- classes and amounts of fructose-, -, - and erance (P < 0.01), and 27.6% and 35.2% had both lactose-containing food to determine individual tolerabil- intolerances (P < 0.05). Fructose was more common than ity thresholds. Patients were maintained on the level of lactose intolerance in all FGID subgroups (P < 0.001)(Fig- saccharides and polyols below their threshold of symp- ure 1), with no differences between FGID groups, except toms. In general, four individual sessions were scheduled for more lactose and less fructose intolerance in consti- with patients and questionnaires regarding abdominal pated IBS (IBS-C) than in other subgroups (P < 0.05). symptoms, bowel and dietary habits were completed 14.1% of patients with lactose intolerance and 6.9% of before and after the dietary modification. Symptom scor- patients with fructose intolerance correctly suspected the ing was performed using 10-point Likert scales. Dietary target of their intolerance before breath testing.

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Table 1 | Patient All functional Irritable bowel Functional Functional † † † characteristics. There are no GI disorders syndrome dyspepsia bloating significant differences in the Number of patients 1372 212 606 109 main characteristics or Age (years)* 42 Æ 16 38 Æ 16 40 Æ 13 48 Æ 15 demographics between the Gender (% female) 73 77 73 62 groups of functional GI Symptom duration (years)* 5.9 Æ 57.2Æ 65.2Æ 5 5.6 Æ 6 disorders BMI (kg/m2)* 23.5 Æ 5 24.1 Æ 4 23.4 Æ 5 22.1 Æ 6 * Mean Æ s.d. † Subgroups of functional GI disorders as defined by the Rome III criteria.9

70

60

50 Fructose intolerance Lactose intolerance 40 Fructose and lactose intolerance Neither intolerance 30

20

10

0 IBS all IBS c IBS d IBS m IBS u FD all FD ppd FD eps FB total

Figure 1 | Prevalence of fructose and lactose intolerances in Rome III-defined Irritable Bowel Syndrome (IBS) (n = 212), Functional Dyspepsia (FD) (n = 606), Functional Bloating (FB) (n = 109) and their subgroups, IBS-c: IBS with constipation (n = 37), IBS-d: IBS with diarrhoea (n = 67), IBS-m: IBS with alternating constipation and diarrhoea (n = 94), IBS-u: unclassified IBS (n = 14), FD-ppd: Functional Dyspepsia with postprandial distress (n = 368), FD-eps: Functional Dyspepsia with epigastric pain syndrome (n = 238) and FB: Functional Bloating (n = 109).

The prevalence of non-GI and specific GI symptoms patients. Fifty-eight per cent of patients complained of at and related aspects of the medical history were compared least one central nervous system effect, with top- across intolerance groups (Table S1). Overall, patients with ping the list. Symptom incidences were similar between any intolerance had more symptoms than those without both intolerance tests. The time-to-maximum symptom (P < 0.001). Patients with both intolerances had signifi- score was 115.3 Æ 118 min with fructose and cantly more problems with concentration, joint and mus- 131.1 Æ 118 min with lactose (P < 0.001). Using a test cle pain, nausea, gastro-oesophageal reflux and allergic cut-off time of 3 h instead of 5 h, 16% of fructose and reactions than those with no intolerances and generally 23% of lactose intolerance results would have changed also than patients with only one intolerance (Table S1). from positive to negative. When comparing patients with either fructose or lactose The incidence of several of the most commonly evoked intolerance with patients with no intolerances, very simi- symptoms during breath testing, specifically bloating, lar, albeit less prominent, differences emerged (Table S1). diarrhoea, , gastro-oesophageal reflux, The incidence of symptoms during fructose and lactose tiredness, muscle pain and diminished concentration, breath tests is shown in Figure 2. , bloating correlated with patients’ FGID symptoms (r = 0.34–0.51, and abdominal fullness were predominant in >50% of all P < 0.005).

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70.00 Fructose intolerance 60.00 Lactose intolerance 50.00

40.00

30.00

20.00

10.00 Figure 2 | Percentages of 0.00 patients with Functional Gastrointestinal Disorders Reflux Rash Bloating FullnessCramps Nausea Myalgia (FGID) with symptoms Flatulence Diarrhoea Headache Tiredness Arthralgia Borborygmie Apthoid ulcers provoked during fructose or

Cardiac arrhythmia lactose breath testing (n = 1372). Diminished concentration

> fi Prevalence of lactose and symptoms. Peak concentrations of H2 20 ppm in the rst and the relationship with intolerance during testing 60 min, so-called early rises in breath hydrogen, were seen and clinical symptoms in 12.9% of patients following fructose and in 6.0% of Table 2 shows the prevalence and overlap of malabsorption patients following lactose ingestion. and intolerance in FGID and its subgroups. Malabsorption alone, i.e. with a negative intolerance test, occurred in 4.3% Breath gases and stool patterns of fructose, 3.4% of lactose and 3% of both tests. Intoler- In patients with fructose or lactose malabsorption, as fi ance alone, i.e. with a negative malabsorption test, was seen de ned by any of the H2 or CH4 thresholds, diarrhoea was in 20.0% of fructose, 22.4% of lactose and 20.2% of both more common than constipation (all P < 0.05) (Figure 3). tests, with no significant differences between the FGID sub- Conversely, patients with diarrhoea and constipation had groups. a similar prevalence of malabsorption demonstrated by fi Malabsorption was most frequently de ned by a com- isolated elevation of H2 (14.5% and 11.3%) and CH4 bination of supra-threshold H2 and CH4 concentrations (1.2% and 1.2%) concentrations following fructose and (Table 3). Isolated elevation of CH4 was seen in 4.1% of lactose ((7.7% and 6.5%) and (1.4% and 1.6%)) respec- patients following fructose and in 4.9% after lactose tively. Furthermore, a majority (69%) of IBS-C patients ingestion using the standard threshold of a CH4 increase did not have elevated CH4 levels after either sugar. of >10 ppm above baseline. Table 3 shows malabsorp- tion rates using alternative CH4 thresholds. Outcome of dietary advice H2 and CH4 peak concentrations correlated with the Complete outcomes were available in 237 of the 312 severity of bloating (r = 0.41, r = 0.43 respectively), patients (76%) with intolerances who received standar- abdominal pain (r = 0.35, r = 0.33 respectively) and diar- dised dietary counselling once it was initiated. Thirty-six rhoea (r = 0.5, r = 0.45 respectively)(all P < 0.001) during patients declined dietary counselling and 39 dropped out fructose and lactose (r = 0.53, r = 0.52; r = 0.48, r = 0.48; of the dietary programme and were lost to follow-up. and r = 0.61, r = 0.59, respectively, all P < 0.0001) test- Clinical characteristics did not differ between those hav- ing. The time-to-peak H2 and CH4 concentrations were ing discontinued or completed the programme. Adequate 107.7 Æ 71 min and 107.3 Æ 76 min with fructose, and symptomatic relief after 6–8 weeks was achieved in 84% 164.2 Æ 105 min and 168.5 Æ 106 min with lactose of all patients with fructose intolerance and in 86% when respectively (both P < 0.001 vs. fructose). Peak concentra- fructose malabsorption was present with intolerance. tions of H2 and CH4 were reached after 3 h in 10.1% and Respective results for lactose intolerance were 89% and 37.7% of fructose tests and in 9.8% and 33.8% of lactose 90%. Eight-five per cent of all patients reported adequate tests respectively. There were no significant correlations dietary compliance. Adequate relief rates were 85% and between H2 and CH4 peak concentrations and any FGID 96% in patients with diarrhoea and bloating, respectively,

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Table 2 | Percentages of Intolerance and patients with Irritable Bowel Intolerance Malabsorption malabsorption Syndrome, Functional Dyspepsia, (%) (%) (%) Functional Bloating, classified Fructose according to Rome III criteria9 Irritable Bowel Syndrome n = 212 59.9* 42.4 38.4 and of all Functional GI Disorder Functional dyspepsia 59.5* 41.6 37.2 (FGID) patients with intolerance n = 606 (increase in symptom scoring Functional bloating n = 109 54.4* 41.8 39.2 n = * >2), malabsorption (increases All FGID 1372 60.4 44.7 40.4 >20 ppm of H and/or >10 ppm Lactose 2 Irritable Bowel Syndrome n = 212 45.3* 29.1 25.0 of CH above baseline) or both 4 Functional dyspepsia 49.7* 30.8 27.8 intolerance and malabsorption n = 606 during fructose and lactose Functional bloating 43.0† 32.9 26.6 testing. There are no differences n = 109 in the prevalence of intolerance All FGID n = 1372 50.5* 31.5 28.1 or malabsorption between the Fructose and Lactose groups of functional disorders. Irritable Bowel 28.5* 14.0 11.0 Intolerance is significantly more Syndrome n = 212 common than malabsorption in Functional dyspepsia 31.0* 15.4 12.6 n = all groups 606 Functional bloating 27.8* 16.5 12.7 n = 109 All FGID n = 1372 33.1* 15.9 12.9 * P < 0.01 or † P < 0.05 intolerance vs. malabsorption and vs. intolerance & malabsorption.

lactose intolerant, and in 93% and 96% of those with Table 3 | The frequency (%) of positive hydrogen concurrent malabsorption, respectively. Average symp- > ( 20 ppm increase over baseline) or methane tom relief was between 6 and 7 on the 10-point scale for (>10 ppm increase over baseline) breath tests in all the above subgroups, except in constipated patients patients with Functional GI Disorders with malabsorption after ingestion of fructose 35 g or where the average was 3 (data not shown). lactose 50 g. Additional results for methane-only producers are shown using the thresholds of methane DISCUSSION >20 ppm over baseline at any time during the test, as Both fructose and lactose intolerance as shown by breath well as a baseline concentration >3 ppm. The testing were common in this large group of FGID patients, coincidence of increased hydrogen and methane is the one third of whom had an overlap of both intolerances. most common constellation for malabsorption. The The important question is whether intolerances are an definition of a methane producer is markedly underlying mechanism or an epiphenomenon in FGID. influenced by the threshold chosen The prevalence of intolerances was similar across all major Breath test results Fructose Lactose types of FGID, except IBS-C. As the different FGID phe- fi de ning malabsorption (%) (%) notypes were not related to distinct distributions of the in-

Thresholds of H2 > 20 ppm and n = 613 n = 432 tolerances, a causal relationship between FGID and the > CH4 10 increase intolerances would have to be explained by divergent host H + CH À 29.0 21.6 2 4 responses to the saccharide ingestion. Such potential host H2 + CH4 + 66.8 74.4 factors include the enteric microbiome, intestinal perme- H2ÀCH4 + 4.1 4.9 Alternative thresholds of CH4 ability, nervous system and immune responses, all of À + > H2 CH4 ( 20 ppm increase) 1.2 1.1 which are interrelated and differ between FGID and con- À + > – H2 CH4 (baseline 3 ppm) 18.0 21.3 trols.20 24 Hypersensitivity to distension and to ingested has been shown in different FGID, but we are compared to 51% in those patients with constipation not aware of comparisons between subgroups, except in (P < 0.01). Symptomatic relief >3 on the 10-point scale IBS-C, where processes may be influenced – was achieved in 90% of all fructose and 94% of all by a prolonged transit time.16, 25 31

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45 P < 0.05 P < 0.05 40

35 Fructose 30 Lactose 25 Figure 3 | Percentages of patients with Functional 20 Gastrointestinal Disorders (FGID) with fructose (n = 613) 15 or lactose (n = 432) malabsorption, i.e. an increase > 10 of H2 20 ppm or CH4>10 ppm over baseline, with diarrhoea or constipation. 5 *P < 0.05 constipation vs. diarrhoea for both fructose 0 + + + + and lactose. H2 : %diarrhoea CH4 : %diarrhoea H2 : %constipation CH4 : %constipation

The induction of symptoms (intolerance) following reflecting both intensity and symptom number was used sugar ingestion appears to be more relevant than malab- very similar to the 9-item validated score used by Choi sorption per se in FGID, as demonstrated by the follow- et al., with intolerance rates not greater than in other ing observations. Patients’ main clinical GI and non-GI large comparative studies in Caucasians for lactose – we symptoms were significantly reproduced during breath are not aware of any similar large studies for fructose testing, but there was no association with the markers of intolerance.6, 39 Only a small minority of these referred malabsorption. Malabsorption is similarly common after patients were able to correctly identify their food intoler- fructose or lactose loading in IBS and controls, but ance before the provocation testing, but this undoubtedly symptom induction is much higher in IBS.7, 12, 13, 32, 33 also partly reflects a referral bias to a GI practice. Furthermore, in patients with intolerance, effective Dietary modification based on fructose and lactose symptom relief with dietary adaptation was independent intolerance testing was clearly beneficial. Over 80% of all of the presence of malabsorption. The relationship FGID patients attained adequate global symptom relief between malabsorption and intolerance therefore appears and average relief was 7 on the 10-point symptom scale. to be indirect. Intolerance without evidence of malab- Adequate symptom relief was lower at about 50% in sorption occurred in approximately 20% of our patients patients with constipation. These data are consistent with and in 18–40% in earlier studies, whereas malabsorption an earlier study where 85% of 48 IBS patients compliant rarely existed without intolerance.6, 34 Potential explana- with a similar diet reported an improvement of >5 on the tions for this discrepancy are a microbiome not produc- 10-point scale for pooled symptoms after 14 months and ing measurable levels of hydrogen or methane in some also a reduced response rate in constipated patients.40 The individuals or an alternative mechanism for symptom impressive responses in this and smaller open trials in generation, such as increased chemosensitivity to fer- FGID are confirmed by a double-blinded, placebo-con- – – mentation products.35 37 Increased production of sul- trolled fructose and fructan challenge study.5, 6, 40 42 Psy- phide from carbohydrate fermentation has been shown chological and disease fluctuation components in our in IBS.38 It should be noted that the relationship between response rates could only be assessed in a blinded and pla- symptom induction, and therefore intolerance rates, and cebo-controlled dietary study, which was not feasible in a malabsorption is dependent on the choice of symptom study of this scale due to the inherent complexity. scoring, with a positive association between the number Non-GI co-morbidity was common in FGID, especially and intensity of induced symptoms and the percentage in the central nervous, musculoskeletal and atopic catego- of positive hydrogen breath tests following lactose having ries. An elevated prevalence of non-GI functional syn- been shown.38 In this study, a sensitive symptom index dromes, including fibromyalgia, migraine and chronic

1080 Aliment Pharmacol Ther 2013; 37: 1074-1083 ª 2013 Blackwell Publishing Ltd Sugar intolerances in functional GI disorders fatigue, is reported in FGID.43, 44 Over 50% of our patients confirm an earlier report and may be due to differences reported CNS symptoms, with fatigue being most fre- in the location of absorption/ or of bacterial quent. Tiredness has previously been associated with a metabolism.35 The definitions of the gas concentration high FODMAP diet in IBS patients.45 Non-GI symptoms thresholds for a positive breath test are the subject of in FGID patients progressively increased with the number debate, demonstrably affecting test interpretation.7, 13 of experienced intolerances. The mechanisms underlying We used the most widely reported dose of lactose (50 g) the association between GI and non-GI symptoms were and a fructose dose (35 g) in the range of daily con- not investigated, but they may be central (e.g. somatisa- sumption in Europe, inducing GI symptoms in <10% of tion, central sensory processing), peripheral (e.g. afferent controls, and allowing comparison with seminal FOD- sensory sensitisation) or both (e.g. neuro-immune activa- MAP studies.3, 5, 7, 14, 32, 35, 52 Both of these sugar doses tion, disseminated abnormality in transporter ). are higher than the average amounts of free saccharide The spectrum of non-GI symptoms was similar in fructose ingested during a single meal in normal life, but are used and lactose intolerances, except for more joint pain, pran- as provocation tests to identify patients likely to benefit dial rhinitis and reactions to cosmetics with fructose intol- from dietary manipulation. On the basis of the above, erance. Earlier, small studies demonstrated increased we recommend a 5-h test duration and, in case of dis- depression, lethargy, decreased plasma and crepancy between symptom and malabsorption data, to various trace elements in fructose intolerance and a range base the final test interpretation on the intolerance of non-GI symptoms in lactose intolerance, including car- results. This recommendation will result in effective diac arrhythmias, musculoskeletal, atopic and nervous sys- treatment of 20% more patients compared with current – tem symptoms.46 50 Intriguing potential links include practice in centres where clinical decisions are based toxic metabolites produced by anaerobic digestion, accu- exclusively on malabsorption. Furthermore, the correla- mulation of advanced glycation end-products, abnormali- tion between clinical symptoms and those experienced ties in fructose transporter proteins, increased intestinal during breath testing is an important confirmation for permeability, actions of the phlorizin hydrolase moiety of the patient. A breath collection duration longer than 3 h and homologies with inflammatory media- has been recommended in previous studies for improved tors, none of which have been confirmed. The short-chain diagnostics of lactose intolerance.17, 39 fatty acids derived from colonic fermentation of fructose This study provides no corroboration for an associa- and lactose are similar.51 Further evaluation with specific tion between exhaled methane and constipation using fi 18 tools is clearly warranted. any of the common CH4 threshold de nitions. Diar- The epidemiology of fructose intolerance is poorly char- rhoea was more common than constipation in patients acterised. In our FGID patients, fructose was more com- with elevated breath CH4. Conversely, increased CH4 mon than lactose intolerance and more frequent in was equally prevalent in constipation and diarrhoea. Fur- Northern than Southern Europeans, in contrast to lactose thermore, in IBS-C, breath tests were significantly more 16 intolerance. Intolerances were more prevalent in females, frequently CH4 negative than positive. This discrepancy significantly so for lactose, but confirmation is required in a with previous publications may be explained by varia- population-based study. Interestingly, the overall preva- tions in the definition of constipation (stool characteris- lence of intolerances was higher in all FGID patients than tics, transit, manometric changes, global evaluation), test in the more narrowly defined Rome III FGID subgroups. methodology (CH4 threshold defined by very low base- Consequently, studies employing Rome III criteria are line or peak concentrations, test duration, type of sugar) likely to underestimate the overall relevance of intolerances. or patient selection (IBS, functional constipation, propor- The optimal breath test methodology remains unclear tion with diarrhoea). Further study is required given this despite attempts at standardisation.10, 11 In this study, wide heterogeneity and the positive associations average maximum symptom scores were attained 15 min described mainly in smaller subgroups. earlier following fructose than lactose. Using the popular The relationship and overlap between small intestinal 3-h test duration, 16% of fructose and 23% of lactose bacterial overgrowth (SIBO) and sugar malabsorption is intolerance results would have changed from positive to extensive and it is acknowledged that currently a reliable 53 negative. H2 and CH4 concentrations peaked over distinction is not possible. Indeed, both conditions are 50 min earlier following fructose than lactose, and after intricately interrelated and the fermentation of sugars 3 h in approximately 10% and 35% of tests respectively. reaching in the colon (malabsorption) or in the The earlier exhaled gas and symptom peaks with fructose (SIBO) can register similarly in breath

Aliment Pharmacol Ther 2013; 37: 1074-1083 1081 ª 2013 Blackwell Publishing Ltd C. H. Wilder-Smith et al. tests, depending on the underlying rapidity of intestinal sorption, which consequently does not appear to be the transit and the composition of the microbiome, among main driver of symptoms. Mechanisms relating to carbo- other factors. Different constructs for a distinction have hydrate intolerance and accompanying non-GI symptoms been presented, such as early hydrogen peaks, gas are of special interest for future research. thresholds and different substrates, but a true distinction remains elusive and we have chosen not to attempt one AUTHORSHIP in our study. However, for a comparison with other Guarantor of the article: Clive H. Wilder-Smith. papers, we have included the rather low percentage of Author contributions: Clive Wilder-Smith designed the patients with early rises in breath hydrogen excretion. research. Andrea Materna and Corinne Wermelinger con- Study limitations are the absence of a blinded, placebo- ducted the research. Jonathan Schuler and Clive Wilder- controlled design with healthy controls. The choice of an Smith analysed the data or performed the statistical analysis. inert placebo in this group of sensitive patients is Clive Wilder-Smith wrote the paper and had primary challenging. Healthy controls were not included in this responsibility for the final content. All authors read and study aiming at comparisons within FGID. Comparisons approved the final version of the manuscript. with controls have been reported previously. An overlap between FGID subgroups is inevitable in all related ACKNOWLEDGEMENTS studies. We chose the most prominent FGID for Declaration of personal and funding interests: None. classifying each patient. Advantages of our single-centre study are the large number of successive patients with dif- SUPPORTING INFORMATION ferent FGID tested for both intolerance and malabsorp- Additional Supporting Information may be found in the tion and treated in standardised fashion. Meta-analyses in online version of this article: this field are problematic due to the inherent variability in Table S1. Prevalence (%) of clinical non-gastrointesti- patient selection and in testing and treatment procedures. nal and select gastrointestinal symptoms, and relevant In conclusion, fructose and lactose intolerance are com- aspects of the medical history according to fructose and mon and frequently overlap in FGID, with no differences lactose intolerance status. Intolerance is defined by an in prevalence between subgroups. Non-GI symptoms are increase of >2 in symptom scoring following administra- more common in FGID patients with intolerances. Effec- tion of the saccharide. Overall, the frequency of clinical tive symptom relief is achieved with standardised dietary symptoms and of a history of atopy was in the following adaptation. Clinical FGID symptoms correlate with the order of magnitude in patients: both fructose and lactose symptoms induced during testing and not with malab- intolerances > only one intolerance > no intolerances.

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