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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Keywords:Copyright 2011 by ESPGHAN and NASPGHAN
breath hydrogen test; fructose malabsorption; gastrointestinal disease