Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Effect of Age on Fructose Malabsorption in Children Presenting With Gastrointestinal Symptoms
Jones, Hilary F*; Burt, Esther†; Dowling, Kate‡; Davidson, Geoff†; Brooks, Doug A*; Butler, Ross N*
*Cell Biology of Disease Research Group and PERI Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
†Gastroenterology Unit, Australia
‡Public Health Research Unit, Women's and Children's Hospital, Adelaide, Australia.
Received 21 July, 2010
Accepted 17 September, 2010
Address correspondence and reprint requests to Prof Doug Brooks, Sansom Institute for Health Sciences, University of South Australia, SA 5001, Australia (e-mail: Doug.Brooks@unisa.edu.au).
Hilary F. Jones was supported by an Australian Postgraduate Award, Ross N. Butler was directly funded for a professorial research position by Wyeth Australia.
The authors report no conflicts of interest.
Objectives: Fructose malabsorption can produce symptoms such as chronic diarrhoea and abdominal pain. Here, we retrospectively review breath hydrogen test (BHT) results to determine whether age has an effect on the clinical application of the fructose BHT and compare this with the lactose BHT.
Patients and Methods: Patients were referred to a gastroenterology breath-testing clinic (2003–2008) to investigate carbohydrate malabsorption as a cause of gastrointestinal symptoms. Patients received either 0.5 g/kg body weight of fructose (maximum of 10 g) or 2 g/kg of lactose (maximum of 20 g), in water, and were tested for 2.5 hours.
Results: Patient age showed a significant effect on the fructose BHT results (P < 0.001, 0.1–79 years old, n = 1093). The odds of testing positive for fructose malabsorption in paediatric patients (15 years old or younger, n = 760) decreased by a factor of 0.82/year (95% confidence interval 0.79–0.86, P < 0.001). There were 88.2% positive in younger than 1-year-olds, 66.6% in 1- to 5-year-olds, 40.4% in 6- to 10-year-olds, and 27.1% in 10- to 15-year-olds. In contrast, 39.3% of lactose BHTs were positive, with no significant relation between patient age and test result (P = 0.115, 0.1–89 years old, n = 3073).
Conclusions: The majority of infants with gastrointestinal symptoms exhibited fructose malabsorption, but the capacity to absorb fructose increased with patient age up to 10 years old. The low threshold for fructose absorption in younger children has significant implications for the performance and interpretation of the fructose BHT and for the dietary consumption of fructose in infants with gastrointestinal symptoms.
Fructose is a monosaccharide sugar, which is increasingly consumed in Western diets (1). It is present in food as a monosaccharide and as a constituent of the disaccharide sucrose. Fructose malabsorption involves a reduced capacity of the small intestine to absorb fructose. In patients who exhibit fructose malabsorption, the consumption of excess fructose, especially in apple and pear juices, can cause diarrhoea, flatulence, bloating, and abdominal pain (2–4). Higher intake of fructose-sweetened beverages, and especially fruit juice, by young children (5,6) is likely to exacerbate these gastrointestinal problems (7,8). Symptomatic patients who tested positive for fructose malabsorption by the breath hydrogen test (BHT), have shown a decrease in symptoms after the reduction or removal of fructose from their diet (2,9–11). In infants and children there may be a lower threshold for fructose absorption (3,12,13).
Malabsorption of fructose can be assessed by BHT (13), which uses the same principle established for the lactose BHT (14,15). Failure to fully absorb either sugar results in it reaching the large bowel, where it is metabolised by intestinal flora, which produces hydrogen. This rise in hydrogen is detectable in expired air. Here, a retrospective analysis was carried out on BHTs of symptomatic patients, who were investigated for carbohydrate malabsorption at the Department of Gastroenterology, Women's and Children's Hospital, Adelaide, Australia (a clinic where BHT has been extensively used for patient investigation) (14). There has been evidence for a possible link between fructose malabsorption and younger age in children, and here we have defined the number of patients with positive fructose and lactose BHTs in relation to age. In a clinical setting, we aimed to evaluate whether age had an effect on the diagnosis of fructose malabsorption.
PATIENTS AND METHODS
Patients and Pretest Conditions
Patients were referred to the gastroenterology breath-testing clinic by physicians, paediatricians, or gastroenterologists for testing of carbohydrate malabsorption. Some patients were referred for testing with a single carbohydrate, and many completed a panel of carbohydrate malabsorbtion tests, including fructose and lactose. Patients were asked to fast from solids and liquids for a minimum of 8 hours before the test and to have only small amounts of water; tests were generally conducted in the morning and patients fasted from midnight. For children younger than 6 months of age, the minimum fast was 6 hours. Patients were asked to eat a low-fibre evening meal, not to have smoked or exercised in the morning of or during the test, and not to have taken antibiotics within 4 weeks before the test.
For the fructose BHT, patients were given an oral dose of 10 g of fructose (Sigma, St Louis). Children received fructose at a dose of 0.5 g/kg body weight, up to a maximum dose of 10 g. The fructose was dissolved in 100 mL of water or in 80 mL of water for children younger than 6 months old. For the lactose BHT, the method was the same as above, except that the lactose dose was 2 g/kg body weight, up to a maximum dose of 20 g. Breath samples were collected at 30-minute intervals after sugar ingestion, for a total of 150 minutes. Breath samples were collected by blowing through a straw into a 30-mL syringe or duplicate 9-mL Exetainer tubes (Labco, High Wycombe, UK); alternatively, for children unable to blow through a straw, a nasal prong was used to collect air expired from the mouth or nose. Hydrogen, methane, and carbon dioxide levels were measured on a Quintron Microlyzer SC (Quintron, Milwaukee, WI), and corrected for CO2 level.
A positive BHT for fructose malabsorption was defined as a sustained increase in production of hydrogen ≥10 ppm for 2 consecutive time periods (14). Malabsorption was also indicated if the sample at the final timepoint was ≥10 ppm above the lowest value before the 60-minute time point.
Statistics were performed to analyse the effect of patient age on test result. Because the outcome variable was binary, the data were analysed by logistic regression, with post hoc least significant difference tests (GenStat version 11.1 VSN International, Hemel Hempstead, UK). Graphs were produced in GraphPad Prism 5 (GraphPad Software, La Jolla, CA). A P value of ≤ 0.05 was considered significant. The study was approved by the Women's and Children's Hospital research ethics committee.
There were 1093 test results investigated (Table 1), and 50.0% (546/1093) of the fructose tests were classified as positive. The number of referrals for fructose BHT per annum almost tripled between 2003 and 2008 (Table 1). Patient age had a significant effect (P < 0.001) on the fructose breath test results by logistic regression analysis. When the ages were grouped in 10-year brackets (Fig. 1A), those younger than 10 years had a significantly higher proportion of positive tests than those ages 10 to 79 years (P <0.001), with 64.5% of tests positive in patients younger than 10 years. Between all of the age groups 10 years and older, there was no significant difference in the percentage positive, and overall, 29.8% of tests were positive. The 80- to 89-year age group was excluded from the analysis because it only contained n = 3. There were 513 boys (54.8% positive) and 580 girls (45.7% positive) tested (Table 1). When age was taken into account, sex had no significant effect on the test result (P = 0.775).
Lactose BHT from the same period was used as a comparator with the fructose BHT results. The number of lactose BHT per annum doubled between 2003 and 2008 (Table 1). Five test results without a date of birth were excluded from the analysis. There were 3073 test results analysed, and of these 1290 were boys and 1783 were girls (Table 1). A total of 39.3% (1207/3073) of lactose BHT were classified as positive. Age did not have a significant effect on the test result for the lactose BHT by logistic regression (P = 0.115). Moreover, when grouped in 10-year age brackets (Fig. 1B), there was no significant difference between the age brackets (P = 0.095). The 90- to 99-year age group contained n = 1, and consequently this age group was excluded from the analysis.
In the paediatric patients tested with the fructose BHT (15 years old or younger, n = 760), there was a progressive decline in the percentage who tested positive (Fig. 2A): from 88.2% (95% CI 80.6%–95.9%, n = 68) in those younger than 1 year, to 66.6% in 1- to 5-year-old children (95% CI 62.2%–71.0%, n = 440), to 40.4% in 6- to 10-year-old children (95% CI 33.3%–48.7%, n = 156), and 27.1% in 10- to 15-year-old children (95% CI 18.2%–36.0%, n = 96). By 10 years of age the children had an equivalent level of positive tests to that observed in the adult population.
To determine the size of the age effect on test results in paediatric patients, with age as a continuous variable, we applied a logistic regression analysis. For the fructose BHT, age had a significant effect on the test result (P < 0.001), and the log odds for fructose malabsorption were −0.20. Therefore, for a 1-year increase in age, the odds of testing positive for fructose malabsorption decreased by a factor of 0.82 (95% CI 0.79–0.86), and the odds of testing negative increased by a factor of 1.22 (95% CI 1.17–1.27).
The percentage of paediatric patients (15 years old or younger, n = 1865) who tested positive on the lactose BHT was 40.1% (Fig. 2B). Age had a significant effect on the lactose BHT results in this patient group (P < 0.001), with a log odds of −0.049 for lactose malabsorption. Therefore, for a 1-year increase in age, the odds of testing positive for lactose malabsorption decreased by a factor of 0.95 (95% CI 0.93–0.97), and the odds of testing negative increased by a factor of 1.05 (95% CI 1.03–1.07).
In patients presenting with gastrointestinal symptoms, fructose malabsorption is being implicated increasingly as a contributing factor. Given the widespread adoption of BHTs for the diagnosis of fructose malabsorption, we have assessed the fructose BHT in a clinical setting for a large sample set and wide age spectrum.
In the present study, age had a significant effect on fructose malabsorption, with a higher proportion of young children testing positive. Previously, in healthy children, it was shown that significantly more children tested positive for fructose malabsorption from 1 to 3 years of age (16/23) than from 4 to 5 years of age (7/26) (12). Fructose malabsorption in young children has also been investigated with respect to fruit juice and infant diarrhoea, mainly comparing apple and pear juices with lower fructose-to-glucose-ratio for grape juice (2,16–18). Testing with these juices in healthy children showed that 1- and 3-year-olds had significantly higher breath hydrogen levels than 5-year-old children (3). The carbohydrates in juices with a higher proportion of fructose than glucose and higher levels of sorbitol were less well absorbed (4,19), but the efficiency of carbohydrate absorption from the juice increased with advancing age of the children. The significant effect of age on fructose malabsorption may represent the normal course of maturation of fructose transport in the developing intestine.
The proportion of malabsorption on the fructose BHT is also dependent on the dose of fructose given (9). This effect has been more extensively studied in adults than children; in healthy adults, 58% to 87% tested positive by BHT when given a 50-g dose of fructose (20–23), 10% to 53% tested positive with a 25-g dose (20,22–24), and 0% to 10% with a 15-g dose (22,24). Variation in the proportion of individuals testing positive may also reflect variance in factors such as the subject populations, the volume of water used to dilute the sugar, or differing diagnostic cutoffs (25) (cutoffs of 10 ppm (11,13) and 20 ppm (9,10,12) are used in children). In healthy children, the effect of fructose dose on malabsorption has been shown in 0.1- to 6-year-olds (n = 57); of whom 100% tested positive when challenged with a 2-g/kg dose, reducing to 44% positive with a 1-g/kg dose (12). In the present study, a lower dose of fructose was used, which was also relatively small when compared with potential dietary intake; children were given 0.5 g/kg to a maximum of 10 g, whereas 1 cup of apple juice would contain approximately 15.5 g of fructose (6.8 g of glucose and 3 g of sucrose) (17). The increasing proportion of incomplete absorption with higher fructose doses agrees with physiological research suggesting that the transport of fructose from the small intestine is a passive process (26). This may explain why, in children, the value of a dietary history has been emphasised in determining whether gastrointestinal symptoms are caused by fructose malabsorption (27); fructose consumption in excess of a normal threshold for absorption may have the same effect as a lower level of fructose consumption in excess of a lowered threshold for fructose absorption. To provide improved diagnosis of fructose malabsorption, it will be important to define the biological mechanism for the fructose-absorption defect.
Fructose is passively transported across the small intestinal epithelium by facilitative transporters GLUT5 and GLUT2 (28). The intestines of GLUT2 knockout mice had a 60% lower fructose uptake than wild-type mice (29). However, in a GLUT5 knockout mouse model, fructose absorption was decreased by 75% in the jejunum and the concentration of serum fructose decreased by 90%, relative to wild-type mice. When the GLUT5 knockout mice were fed a diet high in fructose, their intestine, especially the caecum and colon, became distended with fluid and gas, reminiscent of fructose malabsorption (30). GLUT5 also appears to be primarily responsible for the developmentally regulated component of fructose absorption (28). It has been shown that GLUT5 expression is delayed in rat pups until weaning, although it can be induced earlier by including fructose in the diet (31). A study of human foetal small intestine found lower levels of GLUT5 mRNA expression when compared with adults (32), suggesting that GLUT5 expression is also developmentally regulated in humans. It remains to be determined whether the developmental regulation of GLUT5 expression is responsible for the high proportion of infants testing positive for fructose malabsorption.
The observed effect of age on fructose malabsorption in the present study was in a symptomatic population, raising the possibility of referral bias. The patients were often referred for a panel of breath tests to address nonspecific symptoms. Where an indication was recorded, it was most commonly either diarrhoea or abdominal pain. Other indications included irritability and colic in infants, bloating, a distended belly, flatulence, wind, nausea, and vomiting. Although the lack of systematic recording of indications made it difficult to eliminate the possibility of referral bias influencing the strong relation between patient age and positivity on the fructose BHT, by comparison, the lactose BHT results carried out in the same clinic did not show this strong relation with age. The proportion that test positive for lactose malabsorption has been shown to rise in elderly adults (33), and in our study there was a trend for a higher proportion testing positive in the 70- to 89-year-old age brackets, but this did not reach statistical significance. The strong influence of age on fructose malabsorption may be mirrored in healthy populations of infants and children, but this needs to be definitively established.
This was a large retrospective analysis, which allowed us to examine the use of the fructose BHT in patients presenting with suspected carbohydrate malabsorption at a gastrointestinal breath-testing clinic. The data were consistent with a limited ability to absorb fructose in human infants, as suggested by previous studies on young children (3,12). The high proportion of positive fructose BHT in symptomatic infants younger than 1 year raises the question of the diagnostic value of the test in this age group. However, in patients presenting with gastrointestinal symptoms who are older than 1 year, the BHT will be of value in assessing whether patients have fructose malabsorption because at least 30% of patients tested positive. The observations here support the hypothesis of developmental regulation of physiological thresholds for fructose absorption and that in early life the ability to absorb fructose significantly improves with age. This also raises the possibility that some of the children diagnosed as being fructose malabsorbers in infancy may “grow out of” the problem, with the threshold for fructose absorption rising with age, which could be addressed in a longitudinal study. The present study indicates that it would be useful to establish guidelines for fructose intake in infants and young children, particularly in patients with gastrointestinal symptoms.
The authors thank Monica Metcalfe and Betty Zacharakis for collection and analysis of breath samples.
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