Dr J. S. Barrett, Department of Medicine, Monash University, Department of Gastroenterology, Box Hill Hospital, Level 8 Clive Ward Centre, 16 Arnold Street, Box Hill, Vic. 3128, Australia. E-mail: firstname.lastname@example.org
Background Fructose malabsorption, lactose malabsorption and an early rise in breath hydrogen after lactulose (ERBHAL) may play roles in induction of symptoms in gastrointestinal conditions.
Aim To compare prevalence and interactions of fructose malabsorption, lactose malabsorption and ERBHAL among healthy subjects and those with chronic intestinal disorders using consistent breath hydrogen testing methodologies.
Methods Consecutive series of Caucasian patients with Crohn’s disease (n = 91), ulcerative colitis (56), functional gastrointestinal disorders (FGID) (201), coeliac disease (136) and 71 healthy volunteers underwent breath hydrogen testing using lactulose, fructose and lactose.
Results Early rise in breath hydrogen after lactulose occurred more commonly in healthy controls (39%) than in Crohn’s disease (20%) and untreated coeliac disease (14%; P < 0.008), but not FGID (27%), ulcerative colitis (26%) or treated coeliac disease (29%). Fructose malabsorption was more frequent in Crohn’s disease (61%) than other groups (33–44%, P < 0.05). Lactose malabsorption was most common in Crohn’s disease (42%) and ulcerative colitis (40%) and uncommon (10%) in 79 patients with newly diagnosed coeliac disease. In Crohn’s disease, concurrent Fructose malabsorption and lactose malabsorption was most common (29%), and the association of fructose malabsorption with ERBHAL seen overall (62%) was not observed (36%, P < 0.0001).
Conclusions Carbohydrate malabsorption and ERBHAL are normal physiological phenomena. The abnormal patterns observed in Crohn’s disease may have pathogenic importance.
Functional gastrointestinal symptoms such as abdominal pain, bloating and distension and altered bowel habits commonly occur in patients with coeliac disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGID).1–4 Poorly absorbed short-chain carbohydrates (FODMAPs) have been identified as potential triggers for these symptoms5 and their dietary restriction appears to be efficacious.6–11 FODMAPs include oligosaccharides of fructose (fructans) and galactose (galactans), and polyols, such as sorbitol, which are known to have limited absorption in the human small intestine.12–15 In a proportion of the population, fructose and lactose are also poorly absorbed, the absorptive capacity of an individual determined by breath hydrogen testing after an oral load of fructose or lactose.
Breath hydrogen testing also provides information about fermentation patterns after ingestion of non-absorbable sugars, such as lactulose. An early rise in breath hydrogen after lactulose (ERBHAL) has been variably interpreted to indicate small intestinal bacterial overgrowth (SIBO) and/or rapid orocaecal transit.16 Evidence that ERBHAL represents SIBO in the majority of patients has been presented and benefits of its detection and subsequent use of antibiotics, probiotics or elemental diet have been reported to reduce gastrointestinal symptoms.17–21 It has also been suggested that SIBO may cause malabsorption of lactose and fructose with correction of SIBO by antibiotics normalizing the response to lactulose and demonstrating complete lactose and fructose absorption on hydrogen breath testing.22
There is a paucity of data regarding the prevalence of fructose malabsorption, ERBHAL and, to a lesser extent, lactose malabsorption in healthy individuals and across chronic intestinal disorders. Published data suffer from small sample size,22–24 ascertainment bias and heterogeneity of methodologies (including cut-off values for breath hydrogen and the dose of sugar used)25–27 rendering meta-analysis void. Whether fructose malabsorption and lactose malabsorption are more common in Crohn’s disease is of particular interest as their rapid delivery to colonic microbiota may play a role in the pathophysiology of the condition, i.e. the ‘FODMAP Hypothesis’.5
We hypothesized that fructose malabsorption, lactose malabsorption and ERBHAL are normal phenomena, but there is a higher prevalence of fructose malabsorption in Crohn’s disease in keeping with ‘The FODMAP Hypothesis’. The principal aims of this study were to determine and compare the prevalence and interactions of fructose malabsorption, lactose malabsorption and ERBHAL by applying consistent breath hydrogen test methodologies across large populations of patients with a variety of chronic intestinal diseases and in a large asymptomatic cohort.
Materials and methods
Four groups were studied.
(i)Healthy volunteers: In all, 83 healthy volunteers were recruited by word of mouth and newsletter advertisements. They had no known gastrointestinal disorders and considered themselves healthy. Each volunteer completed a questionnaire to report frequency of gastrointestinal symptoms and only those who experienced a maximum of one of these symptoms less frequently than once per week were invited into the study.
(ii)Coeliac disease: Two cohorts were studied: (a) Untreated coeliac disease: 85 patients newly-diagnosed according to ESPGAN criteria28 who were consecutively referred to a private/public dietetic practice were studied. Severity of the intestinal lesion was scored according to the Marsh grading29 and a gluten-free diet was consumed for less than 4 weeks prior to breath hydrogen testing. (b) Treated coeliac disease: 58 patients diagnosed at least 2 years prior to breath testing were recruited by advertising. Diet history confirmed adherence to the gluten-free diet and they all had normal coeliac serology (tissue transglutaminase).
(iii)Inflammatory bowel disease: 58 patients with ulcerative colitis (UC) and 100 with Crohn’s disease who were referred from 2002 to 2007 for breath hydrogen testing were studied as is standard clinical practice at Box Hill Hospital. Referral was made if gut symptoms were considered to have had a functional component without clinically significant disease activity. The source of patients was mainly from the IBD Clinic at Box Hill Hospital where 70% of patients are referred from family practitioners and 30% are tertiary referrals. Disease characteristics were obtained from medical histories or referring physicians. Patients with previous proctocolectomy and ileal pouch formation were excluded due to their known high prevalence of fructose malabsorption.30
(iv)Functional gastrointestinal disorders: 221 consecutive patients with functional gut symptoms referred as out-patients for breath hydrogen testing were studied. The vast majority was referred from family practitioners. Standard clinical practice at Box Hill Hospital and surrounding practices is to manage functional gut symptoms by dietary change upon breath test results.31 As part of the testing protocol used, patients are asked to fill out a simple questionnaire regarding the nature and frequency of their symptoms. Using their responses the patients were categorized according to Rome III criteria.32
Breath testing protocol
Patients were instructed to follow a low fibre, low FODMAP diet for 24 h prior to each test. Participants had not taken antibiotics in the previous 2 weeks or probiotics for at least 2 weeks in the past 6 months. Vigorous exercise and smoking were prohibited for 24 h prior to and during the tests. Participants fasted from 2200 h and presented the following morning to give a fasting breath sample using a Quintron Gastrolyser or Microlyzer (Quintron Instrument Co., Milwaukee, WI, USA). The test solution was given and repeat breath samples were taken every 15 min for 3 h (subjects could cease breath testing if two consecutive breath hydrogen levels 10 ppm or more above baseline were observed prior to 3 h). The duration necessary for lactulose testing was used as a guide for the test duration for subsequent fructose and lactose testing.33
Lactulose 15 g [15% weight/volume (w/v)] was tested on the first occasion to determine the timing of the first rise of breath hydrogen and the peak hydrogen response after ingestion of a poorly absorbed carbohydrate as recently described.33 Subjects who failed to increase breath hydrogen 10 ppm or more above baseline levels were designated as ‘non-hydrogen-producers’ and their results were excluded from the analysis. Fructose 35 g (17% w/v) and lactose 50 g (25% w/v) were then tested on separate days within 2 weeks of the lactulose test. As not all patients were tested for production of methane (Gastrolyser only measures hydrogen production), methane was not assessed. Doses were chosen to stress enzyme activity and to mimic levels potentially consumed in a normal diet for lactose and fructose respectively.33
Malabsorption of fructose or lactose was defined by breath hydrogen ≥10 ppm above baseline for at least two consecutive 15 min readings.33 ERBHAL was defined as a significant rise of ≥10 ppm in breath hydrogen after lactulose on at least two consecutive readings before 90 min.21 Additional data for ERBHAL were collected using two consecutive readings of at least 10 ppm above baseline before 75 min.33
All statistical tests were performed using graphpad prism (version 3.00 for Windows, GraphPad Software, San Diego, CA, USA). Fisher’s exact test was used to compare the prevalence of fructose malabsorption and lactose malabsorption between disease states with a Chi squared test examining trends across age groups. Spearman’s correlation was used to analyse relationships between peak hydrogen levels. A P value of ≤0.05 was considered significant and all tests were two-tailed.
Patients with coeliac disease, who were part of a nutritional study, and the healthy volunteers, gave written informed consent. The protocols for their participation were approved by the Eastern Health Research and Ethics Committee. Collection of clinical data for consecutive patients with IBD and FGID complied with the guidelines on clinical audit from the National Health & Medical Research Council of Australia and was also approved by the Eastern Health Research and Ethics Committee.
The demographics of the study population are detailed in Table 1. For reasons of their being a minority with uneven distribution across the groups and high risk of lactose malabsorption, subjects of Chinese/South East Asian decent (n = 10) were excluded from further analysis. There were 48 non-hydrogen producers (8%) and the results from these subjects were also excluded. Disease characteristics of the hydrogen-producers are shown in Table 2. All were tested with lactulose, 98% with fructose and 85% with lactose.
Table 1. Comparison of demographics across the subject groups
Functional gastrointestinal disorders
Treated coeliac disease
Untreated coeliac disease
* More male subjects compared with those for functional gastrointestinal disorders, treated and untreated coeliac disease (P < 0.008).
† More men than for functional gastrointestinal disorders (P = 0.01).
Male (% total)
Age, median (IQR) y
Chinese/South-East Asian descent
Table 2. Proportion of tested subjects with fructose malabsorption (FM), lactose malabsorption (LM) or early rise of breath hydrogen after lactulose (ERBHAL) according to subject group and specific features
† Significantly greater than for Crohn’s disease (P = 0.008) and treated coeliac disease (P = 0.002).
‡ P < 0.03 compared with all other subject groups.
§ P < 0.05 compared with all other subject groups.
¶ P = 0.058 compared with ileocolonic disease; P = 0.002 compared with colonic disease.
** P < 0.05 compared with all other subject groups except treated coeliac disease.
Coeliac disease – newly diagnosed
Coeliac disease – treated
Functional gastrointestinal disorders
Effect of age and sex
There were no significant differences in the prevalence of ERBHAL, fructose malabsorption or lactose malabsorption between men and women overall. Increasing age was associated with an increase in prevalence of lactose malabsorption and a trend towards increasing fructose malabsorption and a decrease in prevalence of ERBHAL (Figure 1).
Disease-related differences in fructose malabsorption
As shown in Table 2, fructose malabsorption was seen in significantly more subjects with Crohn’s disease compared with all other subject groups (P < 0.03). There were no statistically significant differences across disease characteristics for Crohn’s disease. Likewise, fructose malabsorption was observed with similar frequency across Marsh gradings in patients with newly diagnosed coeliac disease and Rome III subtypes in patients with FGID.
Disease-related differences in lactose malabsorption
Lactose malabsorption was most prevalent in patients with UC and Crohn’s disease, both significantly greater than all other groups (P < 0.05) except UC and treated coeliac disease (Table 2). While no relationship to disease distribution was observed in UC, lactose malabsorption was more frequent in patients with ileal Crohn’s disease than in those with ileocolonic (39%; P = 0.058) and colonic disease (18%; P = 0.002). Lactose malabsorption was observed in only 11% of patients with untreated coeliac disease, irrespective of severity of the intestinal lesion and this was similar to those with treated coeliac disease. No significant differences were found for the presence of lactose malabsorption across sub-groups of FGID.
Disease-related differences in time of breath hydrogen responses to lactulose
No disease-related differences in the time of first rise of breath hydrogen after lactulose (data not shown) or in the frequency of ERBHAL (Table 2) were observed. However, ERBHAL was significantly more common in healthy controls than in those with Crohn’s disease (P = 0.008) and treated coeliac disease (P = 0.002). If a stricter definition (two consecutive breath hydrogen readings above 10 ppm prior to 75 min) was applied, similar disease-related trends were present and ERBHAL in controls remained significantly more common than in patients with Crohn’s disease (P = 0.02; data not shown).
Concurrent malabsorption of fructose and lactose occurred in 29% of patients with Crohn’s disease, this being more common than in other groups (9% or less; all P < 0.01) except UC (17%). For ileal disease, 50% had concurrent fructose malabsorption and lactose malabsorption compared to 11% (P = 0.06) and 32% (P = 1.0) for ileocolonic and colonic disease respectively. In those with Crohn’s disease with previous surgery, concurrent fructose malabsorption and lactose malabsorption occurred in 40% of subjects compared to 23% of those without surgical resection (P = 0.3).
Relationship of ERBHAL to fructose malabsorption and lactose malabsorption
ERBHAL was not associated with lactose malabsorption overall (30% with vs. 24% without ERBHAL; P = 0.2) or in any subject group (data not shown). This is in contrast to fructose malabsorption, where the prevalence overall was 62% in those subjects demonstrating ERBHAL (n = 143) compared to 36% in those without ERBHAL (n = 401; P < 0.0001) (see Figure 2). This difference was also observed in patients with FGID (67% vs. 36%; P = 0.002), UC (64% vs. 34%; P = 0.06) and coeliac disease untreated (59% vs. 25%; P = 0.008) and treated (71% vs. 25%; P = 0.03). In healthy controls, almost twice as many with ERBHAL had fructose malabsorption (46% vs. 24%), but this failed to reach statistical significance (P = 0.07).
However, in patients with Crohn’s disease, ERBHAL was not specifically associated with fructose malabsorption (72% with vs. 59% without ERBHAL; P = 0.4), this also being evident in patients with ileal disease where three of four (75%) with ERBHAL vs. 18 of 24 (75%) without ERBHAL had fructose malabsorption. Likewise, fructose malabsorption in patients with Crohn’s disease having had surgical resection was not associated with ERBHAL (four of six (67%) with vs. 14 of 19 (74%) without ERBHAL).
This is the first study to provide comparable statistics on the prevalence of fructose malabsorption, lactose malabsorption and ERBHAL across patient groups with a variety of gastrointestinal disorders together with a large group of asymptomatic healthy subjects of similar age and gender distribution. The methodologies used were uniform across the groups – they all received the same dose of test sugars, were tested on the same equipment and followed the same diet prior to each test. The results clearly show that incomplete absorption of a load of fructose or lactose and ERBHAL are physiological phenomena carrying little disease specificity, except in patients with IBD.
Defining criteria for abnormal breath test results have little consensus in the published literature. Various cut-off values that represent a significant rise in breath hydrogen have been applied. Studies have suggested the appropriate cut-off to be 10 ppm.33–35 Nevertheless, if cut-off values of 15 or 20 ppm were applied to the current data, the same group differences were observed, although the prevalence figures were generally 7–13% lower (data not shown). The dose of test sugar used also sparks much debate. The aim of breath testing is to identify individuals who cannot completely absorb a load of fructose that might potentially be ingested in a normal diet. As discussed recently, a dose of 35 g might be considered a suitable loading dose of fructose.33 However, the prevalence data, particularly for fructose malabsorption, cannot necessarily be extrapolated to lower23, 24, 36–39 or higher23, 24, 40–42 doses as have been used in other studies. Of importance are that many of the observations made in this study were comparable to those from previous reports as discussed in the following paragraphs. In addition, all subjects in this study were exposed to the same dose of all test sugars and hence the prevalence rates across diseases and healthy controls can be validly compared.
Controversy also surrounds the interpretation of breath hydrogen patterns after ingestion of lactulose where, for instance, an early rise of hydrogen has been used to indicate SIBO, rapid transit or both. Differentiating these is problematic and generally not practical or practised. Therefore, the term, ERBHAL, has been adopted. The highest prevalence of ERBHAL in this study was in healthy volunteers. This was not because the diagnostic criteria used were too stringent; ERBHAL was also more common in healthy controls using a cut-off time of 75 min as opposed to the usual 90 min. Thus ERBHAL should be considered a normal phenomenon as confirmed in another recent study.43
Prevalence of lactose malabsorption increased with progressive age, consistent with previous reports, despite differences in methodologies.44, 45 A similar trend was noted for fructose malabsorption, where previous studies have demonstrated conflicting results with reduced frequency in those of younger age39 and no age effect.46 In the current cohort, ERBHAL demonstrated a reduction in prevalence with age, particularly in those greater than 30 years. Previous studies have reported SIBO to affect up to 90% of people over 75 years of age47, 48 and the prevalence to be increased with proton pump inhibitor use.49 Indeed, higher age groups and specific medication usage were not examined in the current study.
The issue of whether fructose malabsorption is a normal physiological phenomenon was addressed by examining a large healthy cohort, in which one in three demonstrated fructose malabsorption. Previous studies have reported fructose malabsorption in 0–80% of healthy volunteers, with variation depending on the breath testing protocol used and the number of subjects studied (nearly always small).8, 23, 41 Unlike lactose malabsorption, the physiological basis for fructose malabsorption is not well understood, but is likely to have two potential contributing factors. First, lower expression or activity of the GLUT5 transporter in the apical membrane of the small bowel epithelial cells might reduce the efficiency of fructose absorption.50 There are no data available pertinent to this and evaluation of polymorphisms in the GLUT5 gene has not identified associations.35 Secondly, because fructose absorption can be slow and probably occurs along the entire small intestinal tract,20 unlike the sugars released by hydrolysis of lactose, fructose might be exposed to bacteria prior to its absorption if small intestinal transit is rapid or there is a sufficient bacterial mass in the small intestine to ferment the fructose (that is, SIBO most commonly of the distal small intestine is present). The clear association of ERBHAL with fructose malabsorption in the present study strongly supports such mechanisms. Indeed, antibiotic treatment of patients believed to have SIBO in one study led to corrected absorption of fructose in the majority of patients.20 This association was not evident for lactose malabsorption in the present study confirming that neither SIBO nor rapid transit is a significant factor in the mechanism of lactose malabsorption, contrary to a previous report.22
Previous studies have suggested that untreated coeliac disease is associated with lactose malabsorption51–54 and that mucosal healing on the gluten-free diet leads to its correction.53 In contrast, the lowest prevalence of lactose malabsorption was observed in the current cohort with untreated coeliac disease and no association with the severity of the intestinal lesion was observed. What uniquely characterized the current study is that the population studied was relatively large, Caucasian and unselected. Previous cohorts have been small in size,53, 55, 56 have used subjects with known ethnic risk for hypolactasia,53 have not been compared with relevant controls51, 53, 57 and have been biased towards patients with gut symptoms.51, 55–58 Thus, the notion that coeliac disease is a risk factor for lactose malabsorption has been seriously challenged by the current findings.
Carbohydrate malabsorption was also found in similar proportions of patients with FGID as for healthy controls. This is similar to reports from small cohorts for fructose malabsorption but not for lactose malabsorption where some studies have suggested higher proportions of 27–53%.22, 59 It is unlikely that selection bias occurred in the present study; patients were consecutively referred for hydrogen breath testing by multiple practitioners routinely prior to dietary manipulation (low FODMAP diet) as is local practice.31 Referrals specifically for suspected lactose malabsorption are very uncommon, as shown by the extreme minority of patients who had testing with lactose but not with fructose. Furthermore, the spectrum of Rome III subtypes was broad. Thus, fructose malabsorption and lactose malabsorption cannot be considered an underlying cause of FGID. Rather, their presence offers opportunities for dietary therapy to reduce intestinal distension from the osmotic and fermentative effects of their malabsorption.6–10, 60
More controversial in FGID is the presence and clinical significance of ERBHAL and SIBO.16 In the present FGID group overall or in those classified with IBS, ERBHAL was found in 27%. This contrasts with reports where SIBO, defined by different breath hydrogen criteria, was present in 84% of patients with IBS.18 The apparent benefit of antibiotics in a subset of patients with IBS suggests that, like fructose malabsorption, ERBHAL should be considered a normal phenomenon, but one that provides a therapeutic opportunity.
An association of lactose malabsorption with UC has been previously reported,61 although there have also been negative studies.62 Such variance may relate to issues of patient selection in terms of, for example, ethnicity and presence of functional gut symptoms. The patients with UC were selected in the current study because of functional type symptoms such as bloating and diarrhoea without active colitis. This may have led to an increase in the proportion of those with carbohydrate malabsorption, but such enrichment did not occur for fructose malabsorption. In addition, if the presence of functional symptoms is thought to increase carbohydrate malabsorption, we would have expected similar results for the FGID population. It is, therefore, likely that lactose malabsorption is more common in patients with UC.
In the Crohn’s disease cohort, the patterns of breath testing differed from all other groups. The proportions of patients with fructose malabsorption and with concurrent fructose malabsorption and lactose malabsorption were significantly higher than for all other groups. This was especially evident in those with disease restricted to the ileum. Such an association with ileal disease has been previously reported for lactose malabsorption where 62% of patients with ileal disease had lactose malabsorption compared to 25% with colonic disease.62 Temporary reduction of lactase activity during acute flares has also been reported in Crohn’s disease,44 but patients in the current study were not referred if mucosal inflammation was not well controlled. Ready explanations for the increased frequency of fructose malabsorption include ascertainment bias (as discussed above); that the presence of small intestinal disease will impair fructose absorption; that many patients had intestinal resections with subsequent loss of absorptive surface and more rapid transit and that SIBO is more common in Crohn’s disease, particularly following resection of the ileocaecal valve.63–65 However, these possibilities are poorly supported by the data presented. Few of the patients had extensive small intestinal disease and fructose malabsorption is not more common in diffuse small intestinal inflammatory disease as demonstrated in those with untreated coeliac disease. Furthermore, previous intestinal resection was not specifically associated with fructose malabsorption or ERBHAL. In fact, the proportion of Crohn’s disease patients with ERBHAL was small (20%). Of more importance was the lack of association of ERBHAL with fructose malabsorption, unlike the significant relationship between the two in other groups, suggesting a different spectrum of mechanisms operating in the genesis of fructose malabsorption in patients with Crohn’s disease.
The higher prevalence of carbohydrate malabsorption in patients with Crohn’s disease and the difficulty supporting explanations for such observations raise the possibility that such malabsorption could be a primary phenomenon rather than secondary to the disease process itself. We have previously hypothesized that excessive delivery to the ileum and colon of poorly absorbed short-chain carbohydrates (FODMAPs) might be pathogenically linked to susceptibility to Crohn’s disease.5 The presence of such malabsorption in a high proportion of patients and the tendency for this to occur in the vast majority of those with ileal disease are consistent with the predictions made in that hypothesis. Evaluation of the ability to absorb fructose and lactose in an unselected cohort of patients with Crohn’s disease, preferably early in the course of the disease with assessment of their normal diet for intake of fructose and other FODMAPs using food composition data66, 67 is needed to explore further the potential significance of these observations.
In conclusion, from the results of the present study where breath testing was undertaken using consistent methodology across large populations, it can be readily postulated that both fructose malabsorption and ERBHAL are common features in healthy volunteers and have little disease-specific association. The only exception is that fructose malabsorption is more common in patients with Crohn’s disease. This does not appear to be related to disease processes, but rather may indicate that those who develop Crohn’s disease may inherently malabsorb fructose. Whether this finding represents selection bias or is a real phenomenon that increases susceptibility to Crohn’s disease needs to be further addressed. The results also indicate a high prevalence of lactose malabsorption in patients with IBD and question the notion that patients with untreated coeliac disease are more likely to have lactose malabsorption. The clinical value of breath hydrogen tests rests, therefore, with the clinical scenario in which they are being performed. The presence of fructose malabsorption and/or lactose malabsorption in patients with functional gut symptoms represents an opportunity for dietary manipulation to assist in the amelioration of such symptoms.
Declaration of personal interests: (i) SJS and PRG are owners of the trademark FODMAP. (ii) SJS has authored two food manufacturer’s shopping guides and three cookbooks concerning a FODMAP-reduced diet. Declaration of funding interests: (i) JSB was supported by a Menzies Foundation Allied Health scholarship. (ii) SJS was supported by a Dora Lush Scholarship from the National Health and Medical Research Foundation of Australia. (iii) PMI was supported by a Fellowship from Nycomed. (iv) JGM was supported by a grant from the Eva & Les Erdi Foundation.