13C-Breath Tests for Sucrose Digestion in Congenital Sucrase Isomaltase–deficient and Sacrosidase-supplemented Patients : Journal of Pediatric Gastroenterology and Nutrition

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Original Articles: Gastroenterology

13C-Breath Tests for Sucrose Digestion in Congenital Sucrase Isomaltase–deficient and Sacrosidase-supplemented Patients

Robayo-Torres, Claudia C*; Opekun, Antone R; Quezada-Calvillo, Roberto; Villa, Xavier§; Smith, EO*; Navarrete, Marilyn*; Baker, Susan S; Nichols, Buford L*

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Journal of Pediatric Gastroenterology and Nutrition: April 2009 - Volume 48 - Issue 4 - p 412-418
doi: 10.1097/MPG.0b013e318180cd09
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Sucrose, also known as table sugar, is a disaccharide formed by glucose and fructose monosaccharide units. Sucrose is present in the human diet in fruits and is added to many prepared foods as refined beet or cane table sugar. Sucrase is the only brush border enzyme that digests sucrose. The membrane bound complex sucrase-isomaltase (SI) hydrolyzes disaccharide sucrose to free monosaccharides that are transported from the lumen by SGLT-1, GLUT-2, and GLUT-5 (1). A percentage of the absorbed glucose and fructose is quickly oxidized and exhaled as CO2 and the remainder is metabolized or stored. SI has 2 maltase activities, which together with the 2 maltase activities of the maltase-glucoamylase (MGAM) complex digest starch to free glucose. These 4 activities are better described as α-glucosidases. Approximately 60% to 80% of all mucosal α-glucosidase activity is accounted for by SI and the remainder of activity is due to MGAM (2). SI also has isomaltase and palatinase activities associated with the membrane bound isomaltase portion of the enzyme complex.

Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive intestinal disease caused by mutations of the SI gene (3–6). Duodenal mucosal histology is always normal. CSID patients have different phenotypes of enzymatic activities associated with SI, ranging from reductions of sucrase activity to total absence, as well as variable absence, of isomaltase activity (7–10). Low sucrase activity leads to malabsorption of sucrose, resulting in dyspeptic-like symptoms such as diet-related chronic osmotic diarrhea and abdominal pain. Only rarely does CSID lead to failure to thrive (11). The severity of symptoms is related to the amount of sucrase activity and quantity of sucrose fed (11,12). A reduced maltase activity is expected to occur in patients with CSID because both subunits in the SI complex contribute to the total mucosal maltase activity (2). The low maltase activity can lead to malabsorption of starch products, which may contribute to symptoms of dyspepsia and chronic abdominal pain (13). The prevalence of biopsy- and assay-proven CSID is 0.02% in individuals of European descent but is reported as high as 10% in indigenous Greenlanders (14). Frequency of heterozygous individuals carrying the CSID gene who have low but not deficient sucrase activity, and normal small intestinal histology is reported to be from 2% to 9% in Americans of European descent (7,11). We found a frequency of isolated sucrase deficiency of 1% in our recent study of unselected clinically indicated duodenal biopsy enzyme assays (2).

Specific diagnosis of CSID presently requires duodenal biopsies with low to absent sucrase activity detected by enzyme assay and presence of normal histology to rule out secondary deficiency (11,13,15). Multiple genotypes make it impossible to establish a single molecular test suitable for the diagnosis of all CSID (7). The technique for diagnosis of SI deficiency by intestinal biopsy and assay of mucosal hydrolysis of sucrose was first described 40 years ago by Anderson et al (16). Presently the principles for diagnosis of SI deficiencies remain the same, but the development of less invasive and less complex techniques is needed. The simplest treatment for CSID is dietary sucrose and occasionally starch restriction. Enzyme supplementation with liquid yeast sacrosidase (sucrase) enzyme derived from Saccharomyces cerevisiae relieves clinical symptoms and sucrose malabsorption in patients with CSID (17–19).

A hydrogen breath test (H2 BT) for detecting carbohydrate malabsorption was introduced in the early 1970s, creating the first clinical application for assessment of lactose malabsorption. The noninvasive nature of H2 BT makes it particularly useful for application in pediatric clinical practice as an indirect test of carbohydrate malabsorption, but it is not specific for the diagnosis of CSID (20). False-negative results may be obtained because of many factors affecting the H2 production. The test requires an absence of small bowel bacterial overgrowth and presence of colonic bacterial flora capable of fermenting proximally malabsorbed carbohydrates. There is great variability of fermentation by the colonic flora and no quantification of proximal carbohydrate malabsorption is possible. Failure to detect H2 occurs in 2% to 40% of subjects (21). A clinical problem arising from the H2 BT is the large load of sucrose given to the patient. In patients with CSID, this load often precipitates severe symptoms of sucrose intolerance.

An evolution of the H2 BT introduced in the early 1970s was the measurement of isotope-labeled CO2 in breath using 13C or 14C (22). These tests depend on measurement of changes in isotope-labeled breath CO2 concentration—delta over baseline (ΔOB)—detected by mass spectrometry or nuclear magnetic resonance (23,24).

Isotope ratio (13C/12C) enrichment measured by mass spectrometry is the traditional method for BT and has high accuracy for low levels of enrichment (0.001%–0.01%) (25–27). Most recently, infrared mass-dispersion spectrophotometry has been introduced for breath 13C/12C isotope measurements and is clinically useful due to its simplicity and short turnaround time (28–30). Since the introduction of mass spectrometers for the detection of the stable isotope of 13C in expired air, the BT technique has been adapted for the study of malabsorption in the pediatric population with collection systems that are well tolerated by infants and toddlers who cannot actively cooperate (31,32). The instruments required for measurement of 13C-labeled CO2 (13CO2) are less expensive now and naturally enriched and purified stable isotope-labeled substrates are currently available (33,34). The substrates most commonly used for 13C/12C BT include 13C-labeled carbohydrates, starch, fatty acids, bile acids, amino acids, and urea. Clinical applications include evaluation of the mucosal function, bacterial overgrowth, gastrointestinal motility, carbohydrate absorption, bile acid absorption, lipid absorption and lipase pancreatic activity, hepatic function, and protein absorption (35). However, the only test widely used in clinical practice is the 13C urea BT for the diagnosis of Helicobacter pylori infection.

Because presently there are no practical and noninvasive methods for specific confirmation of SI deficiency conditions, we developed and validated a sucrose breath test for screening and confirmation of CSID using a novel noninvasive 13C-sucrose labeled substrate. Our hypotheses were that primary sucrase deficiency can be confirmed using 13C-sucrose breath test and that the effectiveness of sucrase replacement therapy can be evaluated by the same noninvasive method. The objectives of our investigation were to determine whether CSID can be detected with the 13C-sucrose BT without duodenal biopsy sucrase assay and whether the 13C-sucrose BT can document restoration of sucrose digestion in patients with CSID after oral supplementation with yeast sucrase (Sucraid; QOL Medical, Mooresville, NC).



After we obtained institutional review board–approved informed consents under protocol H-10239, a total of 20 patients participated in this study. Ten CSID patients were diagnosed by intestinal enzyme activity determinations (5 female; ages = 1–15 years; Table 1). The patients with CSID were recruited in 3 different ways: referral by pediatric gastroenterologists, direct self-referral by CSID families who called our study coordinator after reading an information letter about the study inserted in the Sucraid package by QOL Medical, and families referred through the CSID Web site (www.csidinfo.com). A control group of subjects was recruited from the Nutrition and Gastroenterology Service at Texas Children's Hospital (TCH). Ten controls (6 female; ages = 1–15 years) were patients who underwent endoscopy and biopsy because of symptoms of dyspepsia or chronic diarrhea but with normal levels of mucosal enzymes measured according to the Dahlqvist method (36) and normal histology. The control group patients were participants in the institutional review board–approved protocol H-1320 for recruiting children of both sexes, 0 to 17 years old with dyspepsia (ROME II criteria) and chronic diarrhoea, pain, or discomfort centered in the upper abdomen (37).

Duodenal biopsy disaccharidase activities (U g/protein)

All CSID patients were biopsied and diagnosed by their primary gastrointestinal physician before coming to the General Clinical Research Center (GCRC) at TCH for the BT study. In the control group, the endoscopy procedures were performed for clinical indications by pediatric gastroenterologists at TCH. These biopsies were evaluated by the Pathology Department of TCH. Exclusion criteria for all subjects included villous atrophy on routine histology, fever, inability to cooperate with breath collections, failure to ingest the test 13C-solution, diabetes, and chronic lung disease.

Biopsy Enzyme Assay and Histology

The disaccharidase enzyme activity determinations for the control group and some of the CSID patients were done at the gastrointestinal lab of Buffalo Women and Children's Hospital in New York (2). The remainder of the CSID patient's biopsies were assayed in other reference labs with the histology interpreted locally.

Breath Tests

The 13CO2 breath tests were done on 2 separate days for the control group and on 3 separate days for the CSID group at the GCRC at the TCH under protocol G-695. After overnight fasting, a 2.5 L reference breath sample was collected for comparison with the timed breath samples. Then 20 mg uniformly labeled 13C-glucose (Isotec, Miamisburg, OH) was given using 10-gm unlabeled maltodextrins as a carrier dissolved in water to a total volume of 100 mL (Polycose; Ross Division of Abbot Laboratories, Columbus, OH). Starting 15 minutes after the 13C-glucose load, 0.25-L breath samples were collected every 15 minutes for 120 minutes. After finishing the BT, the subject was fed and released from the GCRC. On the second day, the procedure was the same, but 13C-sucrose was used. On the third day, CSID patients had a repeat 13C-sucrose load with the addition of 22 drops of Sucraid (8500 IU of sacrosidase) to the load solution.

Breath 13CO2 Enrichment Analysis

After 13C-labeled substrate loads were administered, breath collections and measurement of 13CO2 enrichments were performed every 15 minutes × 9 using a 13CO2 infrared spectrophotometer (POCone, Otsuka Electronics, Tokyo, Japan). At each time point, the total CO2 concentration exceeded 2% in the breath sample and was thus in the 13CO2 analytical range of the instrument. The BT results were recorded as total breath CO2 concentration expressed as glucose-ΔOB 13CO2 or sucrose-ΔOB 13CO2.


Because of the age-related variations of glucose oxidation to CO2 described below, glucose-ΔOB 13CO2 was used as denominator to overcome the effect of age on sucrose- ΔOB 13CO2.13C-sucrose digestion and oxidation was expressed as a percent coefficient of glucose oxidation (%CGO) as calculated from ΔOB 13CO2 breath enrichments as follows:

Because %CGO values were found to be relatively constant in the period of 30 to 90 minutes after the load, these values were averaged for each individual. The individual subject mean %CGO values were used to identify the lower reference limit of 13C-sucrose BT for controls and used to compare 13C-sucrose BT of CSID with duodenal sucrase activities (see below).

Statistical Procedures

Agreement between duodenal sucrase activity and 13C-sucrose BT mean %CGO was tested with receiver operating characteristic analysis using the statistics software SPSS. Additional subjects were recruited from the families of CSID patients for replicate 13C-glucose and 13C-sucrose BT to evaluate the within-subject variations (Table 2) and to test the effect of age on glucose-ΔOB 13CO2 (Fig. 1). General linear modeling techniques were used to assess possible effects of group age distribution differences on %CGO values and the ability of the breath test to discriminate between normal and CSID subjects. Two-tail t tests were used to compare groups; P < 0.05 was interpreted as significant.

Within individual 13C-glucose and 13C-sucrose BT mean 13CO2 ΔOB replicate variations (% CV) after 20-mg 13C-substrate oral loads
FIG. 1:
Effects of age in months on individual mean breath changes in 13CO2 concentration from baseline (ΔOB) enrichments after a 20-mg 13C-glucose load to controls, congenital sucrase-isomaltase deficiency patients, and their family members. Breath enrichments of 13CO2 ΔOB = 1/(age × 3.38 × 10−3 + 2.24 × 10−2); R 2 = 0.83, n = 44. Predicted mean 13CO2 ΔOB is shown as heavy black line ± 95% confidence interval thin lines.


Clinical Description of Patients With CSID

Patients from the CSID group were referred by pediatric gastroenterologists. Their duodenal biopsy enzyme assays are shown in Table 1. Clinical histories varied, but all CSID patients had duodenal biopsy sucrase activities below 6.5, all had maltase activities below 115, and 9 of 10 had palatinase activities below 5 U/g protein. None had villous atrophy.

Clinical Description of Control Subjects

Ten controls were children who received biopsy for clinical indications by the pediatric gastroenterology service at TCH because of the complaint of dyspepsia. All of the controls had levels of duodenal biopsy disaccharidase enzyme activities well above the reference levels (Table 1). None had mucosal histological abnormalities.

Glucose Oxidation With Age

The %CGO was used to normalize the sucrose-ΔOB 13CO2. The effect of age in months on glucose-ΔOB 13CO2 is shown in Figure 1. This analysis included 44 subjects owing to additional studies in CSID family members; 83% of the total variation of glucose-ΔOB 13CO2 was accounted for by the subject's age (Fig. 1) (R2 = 83%).

Replicate 13C-glucose and 13C-sucrose BT

On replicate BT testing of the same subject, separated by 1 to 12 months, a mean percent coefficient of variation of 14% for the 13C-glucose BT and 9% for 13C-sucrose BT were observed (Table 2).

13C-sucrose Oxidation in CSID and Controls

In the control group, an average of 146% ± 45.5% mean %CGO and for the CSID group an average of 25% ± 21% mean %CGO were observed (P < 0.001; Fig. 2). The lowest mean %CGO obtained was 0.7% and the highest was 56.5% in the CSID patients (Table 1). Analysis controlling for differences in group age distribution found no relation between %CGO and age or any effect of age on the above group averages. Therefore, age did not effect the assessment of the BT ability to discriminate.

FIG. 2:
Effects of congenital sucrase-isomaltase deficiency (CSID) on oral sucrose breath test mean percent coefficient of glucose oxidation (%CGO). Mean %CGO of individual subjects after a 20-mg 13C-sucrose BT load and group means of all control and CSID subjects are shown. The solid bar depicts the group average ± standard deviation (SD) of controls. Individual values are shown as filled circles. The open bar depicts the average ± SD of the patients with CSID. Individual values are shown as open circles. The dashed line is the 79% mean %CGO reference value for discriminating between control and CSID subjects (see text).

Clinical Utility of 13C-sucrose BT Mean %CGO

Receiver operating characteristic analysis of mucosal biopsy sucrase activity versus 13C-sucrose mean %CGO established a cutoff value for 13C-sucrose BT mean %CGO of 79%, which yielded 100% sensitivity and 100% specificity (95% confidence interval (CI) 74%–100% for both) for detection of low duodenal sucrase activity by 13C-sucrose BT mean %CGO (Figs. 2 and 3).

FIG. 3:
Effects of oral sacrosidase supplementation of congenital sucrase-isomaltase deficiency (CSID) patients on sucrose breath test mean percent coefficient of glucose oxidation (%CGO). Mean %CGO of individual patients with CSID (left) untreated and (right) treated with 22 drops of oral sacrosidase supplement added to the sucrose load (P = 0.001; n = 9). The dashed line is the 79% mean %CGO reference value for discriminating between normal and untreated CSID subjects (see text).

Response of CSID Patient's 13C-sucrose BT to Sucraid Supplement

All patients with CSID showed correction of sucrase deficiency with oral Sucraid supplementation, responding to levels greater than their baseline 13C-sucrose BT mean %CGO (P = 0.001; Fig. 3).


Duodenal Enzyme Activities

In this 13CO2 BT study, we included 10 patients with CSID with biopsy-proven sucrase deficiency and normal histology (Table 1). The 13CO2 BT's 9%–14% coefficient of variation for replicate BTs compares favorably with the 27% coefficient of variation of sucrase activity assayed reported in replicate duodenal biopsies (2). All CSID duodenal sucrase enzyme levels fell below the 10th percentile reference value (27 U/group) in a range from 0 to 6.5 U/group, and palatinase (isomaltase) levels were from 0 to 4.9 U/group. Patient 7 had normal isomaltase activity (6.7 U/group) (1). All patients with CSID had low maltase activities. Patient 1 and patient 8, the only 2 with glucoamylase enzyme determinations, were below the 10% reference value. For terminal starch digestion, mucosal enzymes in the brush border are armed with 4 complimentary maltase activities, 2 from the SI complex and 2 from MGAM. SI accounts for 60%–80% of the assayed maltase hydrolytic activity and the remainder is due to MGAM (2). From this, we deduce that the patients with CSID with mild reductions of maltase activities are retaining some hydrolytic activity from MGAM. In patient 7, in whom isomaltase was conserved, this also contributed to maintenance of maltase activity.

Glucose Oxidation With Age

Studies using combined gas chromatography-mass spectrometry (38) and neuroimaging techniques using positron emission tomography (39) have shown that fasting child endogenous glucose production and brain glucose oxidation are 2- to 4-fold greater than in the adult. In our study, we confirmed that glucose oxidation was 2 to 4 times higher in children than adults (Fig. 1). This may be due to the unique glucose needs for child brain development as reflected by our 13C-glucose BT results in children. Central nervous system glucose consumption represents 60%–80% of daily hepatic glucose output in the child, as it does in the adult (40), suggesting the importance of good carbohydrate digestion and absorption in early childhood neurodevelopment. Because of the age dependence of glucose oxidation, %CGO is a necessary normalization for the digestion, absorption, and oxidation of sucrose in children.

Gastric Emptying

Using the 13C-glucose BT, we addressed the uniformity of liquid phase of gastric emptying for our study. We used 10% maltodextrin (Polycose) instead of water because maltodextrin made from corn is poorly isotopically enriched (0.2%) and provides a standard osmotic and energy matrix for the uniformly enriched 13C-labeled tracer substrate. The same dose of maltodextrins was used for each loading test to increase the uniformity of gastric emptying and the small amount of 13C in the maltodextrin was thus blanked out in %CGO. The maltodextrin serves to standardize energy load to mimic a meal and provide a trigger for liquid gastric emptying (41).

Test of Hypothesis 1

One of our objectives was to compare the less invasive 13C-sucrose BT with duodenal biopsy sucrase assays obtained by endoscopy. A strong relation was observed and receiver operating characteristic analysis indicated that a reference value of 79% mean %CGO discriminated between CSID and control populations, as confirmed by duodenal sucrase activities, with 100% sensitivity and 100% specificity (95% CI 74%–100% for both). This supports our first hypothesis that CSID can be confirmed with the 13C-sucrose BT; however, secondary sucrase deficiency cannot be excluded without clinical evaluation and biopsy.

Test of Hypothesis 2

We tested the 13C-sucrose BT response to the enzyme supplement Sucraid documenting a rise in mean %CGO for each patient with CSID after the supplement to levels not different from controls (P = 0.293). The effectiveness of orally replacing sucrase was confirmed by the 13C-sucrose BT. This response supports our second hypothesis that 13C-sucrose BT quantitated the response of patients with CSID to Sucraid supplementation.

Noninvasive BT

One of the advantages of 13C-sucrose BT that we and parents observed was that many patients with CSID who had previous hydrogen BT experienced severe symptoms, passage of watery stools, bloating abdomen, and cramps from the 2 g/kg sucrose load. We did not observe this symptomatic response in any patient with CSID because the load of sucrose ingested was only 0.02 g for the 13C-sucrose BT. As previously noted, the H2 BT is not specific for sucrose malabsorption. With 13C-sucrose BT, we demonstrated a sensitivity and specificity of 100% (95% CI 74%–100% for both) in patients with CSID and suggest that this diagnostic tool can be used as a noninvasive method for the confirmation and management of CSID.


13C-sucrose BT was evaluated as a noninvasive method for the confirmation of CSID. The results of sucrose digestion and oxidation were expressed as percentage of glucose oxidation and averaged between 30 and 90 minutes after the 13C-substrate loads (mean %CGO). In controls and patients, 13C-sucrose BT mean %CGO agreed with duodenal sucrase enzyme activity determinations with 100% sensitivity and 100% specificity (95% CI = 74%–100% for both). All CSID patients tested had 13C-sucrose BT mean %CGO lower than 79%. Supplementation of patients with CSID with sacrosidase enzyme corrected 13C-sucrose BT mean %CGO to control levels.


The authors thank the pediatric gastroenterologists and Endoscopy Suite at Texas Children's Hospital for control subject referrals and Mary Slawson (www.csidinfo.com) and pediatric gastroenterologists around the United States for CSID referrals. This investigation was carried out at the National Institutes of Health–supported General Clinical Research Center at Texas Children's Hospital (M01-RR00188).


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13C-breath test; Congenital sucrase-isomaltase deficiency; Glucose oxidation; Sacrosidase supplementation; Sucrose digestion

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