Triple sugar screen breath hydrogen test for sugar intolerance in children with functional abdominal symptoms

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1 Indian J Gastroenterol (2010) 29: DOI /s ORIGINAL ARTICLE Triple sugar screen breath hydrogen test for sugar intolerance in children with functional abdominal symptoms Jonathan E. Teitelbaum & Dolly Ubhrani Received: 20 February 2010 / Accepted: 6 October 2010 / Published online: 27 October 2010 # Indian Society of Gastroenterology 2010 Abstract Background Sugar intolerance and functional gastrointestinal disorders are both common in school age children. Both may present with similar complaints such as abdominal pain, diarrhea and bloating. Lactose, fructose and sucrose hydrogen breath tests are widely used to detect sugar malabsorption. Aim To determine the proportion of children with symptoms of functional gastrointestinal disorders (FGID) that have sugar intolerance as determined by using a breath hydrogen test. Methods We prospectively enrolled subjects with chronic abdominal pain, bloating and/or chronic diarrhea. All subjects underwent triple sugar screen hydrogen breath test (TSST) using the combined sugar solution. Breath hydrogen concentration 20 ppm above baseline was interpreted a positive test for sugar malabsorption. Results A positive hydrogen breath test consistent with sugar malabsorption was found in 5 out of 31 (16%) subjects. Three of these subjects were confirmed to have lactose malabsorption based on small bowel lactase enzyme J. E. Teitelbaum (*) Pediatric Gastroenterology and Nutrition, The Children s Hospital, Monmouth Medical Center, Long Branch, NJ 07750, USA jteitelbaum@sbhcs.com J. E. Teitelbaum Drexel University School of Medicine, Philadelphia, PA 19129, USA D. Ubhrani Department of Pediatrics, The Children s Hospital, Monmouth Medical Center, 300 Second Ave, Long Branch, NJ 07750, USA analysis or subsequent lactose hydrogen breath test. One subject with positive TSST was diagnosed with fructose malabsorption based on dietary history; he improved on a limited fructose diet, and one was diagnosed to have gastric Crohn s disease. Conclusion Approximately one in six children with symptoms of FGID had sugar intolerance as determined by the TSST. Keywords Fructose intolerance. Functional gastrointestinal disorders. Irritable bowel syndrome. Lactase. Sucrase isomaltase deficiency Introduction Hydrogen breath test is a valuable, non-invasive diagnostic strategy widely used in clinical practice to explore gastrointestinal disorders. It is useful in diagnosing carbohydrate malabsorption, small intestinal bacterial overgrowth (SIBO) and for measuring orocecal transit time [1]. Fructose, glucose and galactose are the three major dietary monosaccharides, while sucrose (glucose-fructose), lactose (glucose galactose), and maltose (glucose glucose) are disaccharides. Lactose is a unique carbohydrate present only in mammalian milk, 7.2 g/100 ml in mature human milk and 4.7 g/100 ml in cow s milk [2]. Sucrose on the other hand is present in table sugar and fruit juice. Fructose is present in fruits such as apples, peaches, melons, plums, cherries and oranges. In addition, high fructose corn syrup is a common sweetener used is sodas and juices. The presence of malabsorbed carbohydrate such as lactose, sucrose or fructose in the colonic lumen may cause gastrointestinal symptoms such as nausea, abdominal

2 Indian J Gastroenterol (2010) 29: distention, flatulence, diarrhea and abdominal pain. This clinical condition is known as carbohydrate intolerance and is named after the specific sugar that produces the symptoms. The diagnosis is assessed clinically by elimination of specific dietary sugars, quantification of disaccharidase enzyme activity in a biopsy sample, or by non-invasive hydrogen breath testing. The hydrogen breath test exploits the fact that normal colonic flora metabolize these sugars into hydrogen and short chain fatty acids. Hydrogen reaches the splanchnic venous circulation by diffusion through the intestinal wall and is transported from there through the portal system to the liver and systemic circulation and is eventually exhaled through the lungs [3]. Traditionally the hydrogen breath test is performed with only one sugar substrate administered per day. We describe the use of a triple sugar screen test (TSST) in which three sugars (sucrose, lactose and fructose) are administered simultaneously to determine if the patient has sugar intolerance. We feel that this is a more relevant clinical test as patients often consume multiple sugars in a given meal. It is also more practical than having patients do three independent tests, each of which takes three hours. Methods Study population Children with chronic abdominal pain, bloating and/or chronic diarrhea were recruited from an outpatient Pediatric Gastroenterology office. In patients with suspected sugar intolerance the dietary history was reviewed and a 1 2 week elimination diet of lactose and/or fructose was suggested. Those patients who refused a diagnostic trial of sugar elimination were offered the option of the TSST or three separate breath tests for each individual sugar. The study was approved by Institutional Review Board at Monmouth Medical Center. Written consent/permission to participate in the study was obtained from parents or legal guardian, and assent obtained from the patient, if appropriate. Patients who underwent triple sugar screen testing were prospectively enrolled between 2003 and Data collection included age, gender, clinical presentation, use of any medication, other co-morbidities, and follow up information. Based on the results of the triple sugar screen test, subjects received instructions for dietary modification or medication for a functional gastrointestinal disorder. Long term follow up, at subsequent outpatient visits or by telephone, assessed improvement in clinical symptoms after these specific recommendations were made. Protocol Breath hydrogen testing was scheduled at a time in which the patient had no antibiotics for at least two weeks prior to the study. Children presented for testing in the morning after an overnight fast and were asked to defer from using toothpaste or mouthwash. A fasting breath sample was analyzed prior to giving the combined sugar solution and designated as the baseline breath hydrogen concentration. The test substrate contained a mixture of lactose 1 g/kg body weight (max 25 g), fructose 2 g/kg body weight (max 50 g) and sucrose 1 g/kg body weight (max 25 g) placed into 5 oz of water. The test substrate was administered orally and end-alveolar breath samples were taken every 15 min for first half hour and later every 30 min for a total time of 3 h. The end alveolar breath sample was collected using a QuinTron AlveoSampler plastic bag. Approximately, 20 ml of alveolar air was analyzed immediately to ensure quality measurements. Samples were evaluated for hydrogen using a model 12i Microlyzer Gas Chromatograph (Quintron Instrument Company, Menomonee Falls, WI, USA). The analyzer did not measure methane or carbon dioxide. Results were expressed as hydrogen gas in parts per million (ppm). The measurements were then plotted and interpreted by the gastroenterologist (JET). Definition of abnormal testing The test results were interpreted as positive for sugar malabsorption if there was an elevation of breath hydrogen greater than or equal to 20 parts per million (ppm) over baseline at 1 to 3 h. Results During the five years of study enrolment, 1,250 children visited the Pediatric Gastroenterology office with symptoms consistent with symptoms of functional gastrointestinal disorder (non-ulcerative dyspepsia, functional abdominal pain, irritable bowel syndrome). A total of 31 subjects (12 female) were enrolled in the study. The mean age of the subjects was 11.4 years (range ). None of the patients who were eligible opted to have three separate breath hydrogen tests as opposed to the TSST. Clinical history of complaints at the time of consultation revealed 87% with abdominal pain, 54.8% with loose bowel movements, and 9.6% with bloating. TSST was positive, suggesting sugar malabsorption, in 5 out of 31 (16%) subjects (Table 1). The mean delta value

3 198 Indian J Gastroenterol (2010) 29: for 5 patients with a positive test was 46 ppm (range 29 75), while that for patients who had a negative test was 4.3 ppm (0 18). Subject 1: The stool guaiac test was positive; hemoglobin, serum albumin and erythrocyte sedimentation rate (ESR) were normal. Abdominal computerized tomography scan (CT scan) revealed possible thickening of the terminal ileum. In view of a positive family history of inflammatory bowel disease, she underwent gastroscopy and colonoscopy/ ileoscopy; biopsies from esophagus, stomach, duodenum, colon and ileum were normal. Disaccharide enzyme assay of duodenal biopsy specimen revealed a lactase level less than the 3rd percentile, consistent with the positive TSST. The patient s symptoms improved on a lactose free diet. Subject 2: She was advised to eliminate one sugar at a time, for 2 weeks each, as a diagnostic test to determine the causative sugar. However, she was unwilling to empirically eliminate the dietary sugars from her diet. She underwent a lactose hydrogen breath test, which was positive. Elimination of lactose from diet resulted in resolution of her symptoms. Subject 3: TSST demonstrated a double peak with early rise in breath hydrogen level, suggestive of SIBO, as well as a later rise indicating sugar malabsorption. Stool examination for ova and parasites, and giardia antigen were negative. This patient received metronidazole for two weeks with complete resolution of his symptoms. Subject 4: had a high baseline hydrogen on the TSST as well as a solitary late peak. The late peak appeared diagnostic for sugar malabsorption, while the high baseline hydrogen was suspicious for bacterial overgrowth. He was prescribed metronidazole which was not tolerated, and he continued to have abdominal pain. Gastroscopy showed retained gastric contents, and pyloric inflammation and narrowing. Histology of gastric biopsy revealed gastric inflammation. His intestinal biopsy revealed a lactase level less than the 3rd percentile. He was subsequently diagnosed with Crohn s disease. Subject 5: was diagnosed with fructose intolerance based on dietary history. He was doing well on a limited fructose containing diet. The remaining 26 subjects who had negative TSST were diagnosed with functional gastrointestinal disorders (irritable bowel syndrome or functional abdominal pain) based on Rome III criteria and were treated with antispasmodics or low dose tricyclic antidepressants (TCA). Medical treatment led to symptomatic improvement or resolution in 25 of these patients. One patient continued to have chronic abdominal pain in spite of increasing doses of antispasmodic medication and low doses of TCA. Three years after the negative TSST, this subject was found to have a mildly elevated C-reactive protein and ESR on laboratory analysis. His gastroscopy and colonoscopy were normal. Duodenal biopsy revealed a lactase enzyme activity less than the 3rd percentile. Despite a lactose free diet he continued to be symptomatic. Discussion Complaints of abdominal pain, diarrhea and bloating are common among school age children [4]. Distinguishing a Table 1 Subjects with positive triple sugar screen test suggesting a sugar malabsorption Subject No Age (y) Gender Symptoms Lactose intolerant Fructose intolerant Confirmatory test Treatment 1 11 F Pain + Intestinal biopsy with low lactase activity Lactose free diet 2 7 F Pain + Positive lactose hydrogen breath test Lactose free diet Bloating M Pain * * None Metronidazole 4 14 M Pain + Intestinal biopsy with low lactase activity ** Bloating 5 13 M Pain + None Fructose free diet *Subject with double peak, early rise suggesting possible small bowel bacterial overgrowth and late rise indicating sugar malabsorption, but since symptoms resolved with antibiotic treatment, the patient was not evaluated for specific sugar malabsorption ** Diagnosed with gastric Crohn s disease

4 Indian J Gastroenterol (2010) 29: diagnosis of sugar intolerance, from functional gastrointestinal disorders based on clinical history and physical exam alone can be challenging. Therefore, the hydrogen breath test provides a means for non-invasively helping to determine the correct diagnosis. To our knowledge, our study is the first to combine three sugars in a test substrate and perform a hydrogen breath test to diagnose carbohydrate malabsorption. Lactose hydrogen breath test has been used for more than 30 years to diagnose lactase deficiency in clinical practice. Studies have demonstrated that a standard lactose hydrogen breath test performed by administrating 18 g (12 oz of whole milk) of lactose orally and measuring breath hydrogen levels over 2 4 h with positive tests being defined as a greater than or equal to 20 ppm above baseline would provide 80% sensitivity and 100% specificity [5]. Accordingly, we used an oral lactose load of 1 gm/kg body weight (maximum 25 g) and measured breath hydrogen level for 3 h with greater than or equal to 20 ppm above baseline indicating sugar intolerance. We identified three individuals with positive TSST who were found to be lactase deficient, and confirmed by intestinal lactase quantification (2 patients), or lactose hydrogen breath test (1 patient). One individual tested negative on TSST but three years later had a biopsy sample diagnostic of lactase deficiency. An explanation for the false negative test could be absence of hydrogen producing bacteria in the colonic lumen. False negatives breath hydrogen tests have been reported in non-hydrogen producers (i.e., methane producers) in 9% of children in the absence of other causes such as recent antibiotic use [6]. Much higher rates of nonhydrogen producers (up to 20%) have been reported in adult studies [7]. Alternatively, the initial test may have been accurate, and this patient may have developed lactase deficiency in the three years following the negative TSST. Congenital sucrase isomaltase deficiency (CSID) is a rare autosomal recessive disease that typically causes chronic or intermittent watery diarrhea in affected children. Prevalence of CSID in the United States is less than or equal to 0.2% [8]. Diagnosis is usually made when low concentrations of these disaccharidases are found in mucosal samples from small bowel biopsy. Although there has been disagreement over the value of sucrose breath test in diagnosing this condition, studies have demonstrated complete identification of sucrase deficient children with close to 100% sensitivity [9, 10]. There has been some suggestion that individuals with CSID might be mislabelled with irritable bowel syndrome. For this reason sucrose was added to the TSST, however in our sample of 31 patients, no patients with CSID were identified. Fructose is absorbed in the small intestine through a process of facilitated diffusion and it is well known that glucose facilitates fructose absorption by solvent drag and passive diffusion. Some studies have shown that foods containing equimolar concentrations of glucose and fructose may result in better fructose absorption than foods in which fructose exceeds glucose [11]. One could thus speculate that the combined TSST may help to facilitate fructose absorption, and lead to a false negative test. However, in our study the test solution contained bound glucose as lactose. Secondly the amount of fructose in most instances exceeded the bound glucose concentration in the test solution indicating that fructose absorption should not be affected by the presence of any other sugar in the same test solution. Gomara et al. reported the first study measuring fructose malabsorption in children using fructose breath test with increasing doses of fructose, and reported the severity of resultant symptoms [12]. Dietary fructose restriction resulted in improvement in 88% of patients who tested positive by breath test using either 15 g or 45 g fructose. Although the appropriate dose and concentration of fructose for breath test is disputed, a 10% fructose concentration closely approximates dietary fructose concentrations (12% fructose in soft drinks). The estimated average intake of free fructose is between 25 g and50gdaily[13]. In our study we used a standard 10% fructose solution (2 g/kg body weight,maxof50g).using the TSST we identified one individual with fructose intolerance whose symptoms improved with dietary restriction. While traditionally clinicians have focused on eliminating a single dietary sugar, a newer approach to dietary change for patients with functional gastrointestinal disorders involves restricting all rapidly fermentable short chain carbohydrates (FODMAPs). Such an approach has been validated and recently reviewed by Gibson and Shepherd [14]. They describe the use of breath hydrogen testing to help individualize the diet, and guide the dietician as to the degree of dietary restriction necessary by defining who can completely absorb lactose and/or fructose. A combined sugar test may therefore be useful as a screening test to help guide the dietary intervention in patients with functional gastrointestinal disorders. Our study is limited by the fact that all patients did not undergo intestinal biopsy to quantitate lactase and sucrase, however such a test was deemed too invasive to be used on all subjects. Also, all patients did not undergo individual breath testing for each sugar in question, as multiple breath hydrogen tests were refused by the patient, likely because they are too time consuming. However, the improvement of symptoms during follow up supports the accuracy of the diagnoses. We found TSST to be useful in diagnosing sugar intolerance as a cause of abdominal pain, diarrhea, and/or bloating. The use of three simultaneous sugars was more

5 200 Indian J Gastroenterol (2010) 29: convenient for the patient, by allowing them to undergo a single test. This is particularly true for the majority of patients who have a negative TSST. Additionally, the TSST reflects real life sugar exposure as the typical American diet includes the simultaneous ingestion of multiple sugars. Conflict of interest References Nothing to declare. 1. Braden B. Methods and functions: Breath tests. Best Pract Res Clin Gastroenterol. 2009;23: Solomons NW. Fermentation, fermented foods and lactose intolerance. Eur J Clin Nutr. 2002;56 Suppl 4:S Beyerlein L, Pohl D, Delco F, Stutz B, Fried M, Tutuian R. Correlation between symptoms developed after the oral ingestion of 50 g lactose and results of hydrogen breath testing for lactose intolerance. Aliment Pharmacol Ther. 2008;27: Hyams JS, Burke G, Davis PM, Rzepski B, Andrulonis PA. Abdominal pain and irritable bowel syndrome in adolescents: a community-based study. J Pediatr. 1996;129: Rosado JL, Solomons NW. Sensitivity and specificity of the hydrogen breath-analysis test for detecting malabsorption of physiological doses of lactose. Clin Chem. 1983;29: Douwes AC, Schaap C, van der Klei-van Moorsel JM. Hydrogen breath test in schoolchildren. Arch Dis Child. 1985;60: Gilat T, Ben Hur H, Gelman-Malachi E, Terdiman R, Peled Y. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut. 1978;19: Rahhal RM, Bishop WP. Sacrosidase trial in chronic nonspecific diarrhea in children. Open Pediatr Med J. 2008;2: Perman JA, Barr RG, Watkins JB. Sucrose malabsorption in children: noninvasive diagnosis by interval breath hydrogen determination. J Pediatr. 1978;93: Ford RP, Barnes GL. Breath hydrogen test and sucrase isomaltase deficiency. Arch Dis Child. 1983;58: Skoog SM, Bharucha AE, Zinsmeister AR. Comparison of breath testing with fructose and high fructose corn syrups in health and IBS. Neurogastroenterol Motil. 2008;20: Gomara RE, Halata MS, Newman LJ, et al. Fructose intolerance in children presenting with abdominal pain. J Pediatr Gastroenterol Nutr. 2008;47: Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004;79: Gibson PR, Shepherd SJ. Evidence-based dietary management of functional symptoms: the FODMAP approach. J Gastroenterol Hepatol. 2010;25:252 8.