Rovner, Alisha J.*; Schall, Joan I.*; Mondick, John T.‡; Zhuang, Hongming†; Mascarenhas, Maria R.*
Gastrointestinal (GI) disturbances are common in people with cystic fibrosis (CF) (1). The pancreas is one of the major organs affected by this disease and approximately 90% of people with CF have pancreatic insufficiency (PI) (2); however, the GI tract is not just affected in those with PI, but rather in all people with CF (1). Common GI manifestations of the disease include gastroesophageal reflux disease, distal intestinal obstruction syndrome (DIOS), and small bowel bacterial overgrowth (SBBO). These GI disturbances present clinically as abdominal pain, nausea, vomiting, diarrhea, bloating, and constipation (1).
GI motility in people with CF has been previously studied; however, results have been inconsistent (3). Some studies have reported delayed gastric emptying (GE) in people with CF (4–6), whereas others have reported normal (7–10) or accelerated GE (11,12). Additionally, delayed small bowel transit (SBT) has been reported in CF (10,13–15). Various protocols and methodologies have been used to assess motility among studies, which may partly explain the inconsistent results. Previous studies have used breath tests in children and adults, and wireless motility capsules and the magnetic-based motility tracking system in adults. Using breath tests in people with CF can be problematic because the results may be inaccurate in those with pulmonary disease or SBBO (16,17). Nuclear medicine scans are a preferred method to assess motility; however, this method has not been used in children with CF. Therefore, motility studies in children with CF using nuclear medicine scans are warranted.
This study examined GE and SBT time meal in children with CF and PI compared with a healthy adult reference group. We hypothesized that GI motility would be altered in subjects with CF compared with a healthy reference population.
Children with CF were recruited from The Children's Hospital of Philadelphia (CHOP). Inclusion criteria were ≥8 years of age, PI confirmed by a fecal elastase 1 of <200 μg/g stool, and no current pulmonary exacerbation. Exclusion criteria were forced expiratory volume in 1 second <40% of predicted, history of fibrosing colonopathy or bowel resection >10 cm, diabetes mellitus, major mucosal or structural GI disease, food allergy to any component of the liquid test meal, intolerance to Creon 20 (Abbott Laboratories, North Chicago, IL), and pregnancy. Study participants were enrolled in a larger study whose goal was to develop a blood test to quantify fat malabsorption.
Healthy adults were recruited to serve as a reference group. These participants were recruited from a sample of CHOP employees as well as from the surrounding community. Inclusion criteria were 18 years and older and general state of good health (eg, no fever, respiratory illness at the time of the study). Exclusion criteria included chronic illness known to affect food digestion or absorption, body mass index (BMI) <21 or >30 kg/m2, therapy with lipid-lowering drugs, diabetes mellitus, or disorders associated with GI motility, food allergy to any component of the liquid test meal, and pregnancy.
Clinical Information and Present Medication Use
For subjects with CF, information including medication use, respiratory treatments, and most recent pulmonary function test results was abstracted from medical charts. Present medication use for the healthy reference group was obtained by self-report.
Body weight was determined with an electronic scale (Scalatronix Inc, Wheaton, IL) accurate to 0.1 kg, and standing height with a stadiometer accurate to 0.1 cm (Holtain, Crymych, England) by standard research techniques (18). BMI was calculated by (weight [kg]/height [m]) (2). For children, weight and height were compared with the CDC 2000 growth charts, and age- and sex-specific z scores were calculated for subjects younger than 20 years (19).
GE and SBT Protocol
A standardized protocol was used to assess GE and SBT time (20–22). Study participants came to the General Clinical Research Center in the early morning after a 12-hour fast, having been instructed not to consume alcohol or dairy products during the previous 24 hours. Weight was measured on a digital scale (to 0.1 kg) and height was measured on a stadiometer (to 0.1 cm). Participants consumed an 8-ounce liquid test meal (approximately 550 calories, 32 g of fat) made of 64 g of chocolate Scandishake powder, 6 ounce of vanilla soymilk, 10 mL of microlipids, 5 g of pentadecanoic acid, and 5.5 g of triheptadecanoic acid and was labeled with 300 μCi 99m Technetium (Tc) sulfur colloid. The free fatty acids and triglycerides were included for another component of the protocol (malabsorption blood test). Participants ingested the liquid test meal within 5 minutes followed by 2 ounces of water. Subjects with CF received a standard dose of pancreatic enzymes (4 capsules of Creon 20, 80,000 lipase units) just before consuming the test meal. Subjects on a higher dinner dose of pancreatic enzymes received an equivalent dose of Creon 20.
GE and SBT studies were performed using a double-headed gamma camera (Philips Forte or the Philips Skylight, Milpitas, CA). Participants were supine while the camera monitored for the distribution of the tracer within the stomach and small intestine. Anterior and posterior images were obtained every 15 minutes for the first 2 hours to assess GE and subsequently every 60 minutes for 6 hours (or until the tracer reached the cecum) to assess SBT. The time was extended to 7 hours for a subset of subjects with CF. Participants could sit or stand between images.
The scans were analyzed with Philips Pegasys software. GE was calculated from regions of interest over the stomach selected from the first and last data frames in a computerized acquisition. Regions of interests were manually drawn at each time point (Fig. 1). GE was determined after correcting for 99mTc decay in both anterior and posterior images. Background subtraction and correction for radioactive decay were performed. The use of the geometric mean technique (square root [anterior counts times posterior counts]) results in more accurate measurements and accounts for the effects of attenuation (23,24). SBT was determined by following the movement of the tracer from the stomach to the cecum. The small bowel counts were calculated by subtracting any gastric counts and terminal ileum cecum/ascending colon counts from the counts of entire abdomen. The average total small bowel counts between 2 and 6 hours were used as the input value both for total counts available to fill the colon and for the percentage counts in the terminal ileum and cecum/ascending colon at 6 hours (25). The percentage arrival of total small bowel activity at the terminal ileum and cecum/ascending colon at 6 hours was used as an index of SBT. Two radiologists who were blinded to the study groups read the scans (level of agreement was 100%).
The protocol was approved by the institutional review board at CHOP. A parent/guardian provided consent for children younger than 18 years. Informed consent was obtained for participants older than 18 years and assent from children ages 8 and 17 years. Study participants were recruited between 2004 and 2006.
A sample size of 12 subjects in each group provides 80% power to detect a difference of 23% (ie, 50% vs 73% or 45% vs 68%) in the proportion of subjects with GE at 2 hours or SBT at 6 hours with a standard deviation of 20% for each group and an α <0.05. Descriptive analyses were conducted. Student t tests were used for comparison between groups in GE and SBT. A 1-way analysis of covariance was performed for comparisons between groups after adjustment for age, sex, and BMI. Group differences were also explored for subjects ages 18 to 30 years only. Statistical significance was defined as P < 0.05. Statistical analyses were performed using STATA 12 (StataCorp, College Station, TX).
A total of 16 subjects with CF and PI and 12 healthy subjects participated in the study (Table 1). Half of the subjects with CF were receiving a histamine-2 receptor antagonist, 13% were receiving a proton pump inhibitor, and 25% were routinely receiving a proton pump inhibitor and a laxative (lactulose n = 3, polyethylene glycol 3350 n = 1). Four subjects with CF had a history of DIOS and 1 had a history of bacterial overgrowth but not receiving any medications to treat it at the time of study. Four healthy participants were receiving oral contraceptives, 1 was receiving a selective serotonin reuptake inhibitor, 1 was receiving a β-blocker, and 1 was receiving a central nervous system stimulant. None of the healthy participants reported present GI medication use, and no subjects in either group were taking erythromycin.
There were no differences in GE between the 2 groups either by Student t test or by 1-way analysis of covariance adjusted for age, sex, and BMI. At 1 hour, GE was 25.2% ± 9.5% (95% CI 20.1–30.3) in subjects with CF and 21.2% ± 8.8% (95% CI 15.6–26.8) in the reference group. At 2 hours, GE was 47.4% ± 11.5% (95% CI 41.3–53.5) in subjects with CF and 46.9% ± 12.8% (95% CI 38.8–55.0) in the reference group.
Subjects with CF had significantly prolonged SBT time. At 6 hours, 37.2% ± 25.4% (95% CI 23.7–50.7) of the tracer reached the terminal ileum and colon compared with 68.6% ± 13.1% (95% CI 60.2–76.9) for the reference group (P < 0.001). After controlling for sex, age, and BMI, this difference remained statistically significant (F = 12.06, adjusted R2 = 0.45, P < 0.002). Eleven of the subjects with CF had SBT <50% at 6 hours and for 8 of those subjects, SBT was also estimated at 7 hours. In those 8 subjects, 49.2% ± 33.0% of the tracer had reached the cecum at 7 hours. The analysis for SBT at 6 hours was repeated in a subsample of subjects restricted to the age range 18 to 30 years and yielded similar results. SBT was significantly (P < 0.001) prolonged in subjects with CF (n = 6, 29.3% ± 19.4% [95% CI 9.0–49.7]) than in the reference group (n = 8, 71.1% ± 6.8% [95% CI 65.8–76.8]), and this remained significant after controlling for covariates (F = 28.9, adjusted R2 = 0.70, P < 0.001). There were no differences in SBT between the subjects with CF taking acid-modifying drugs, those with a history of DIOS, and those taking laxatives. Figure 1 shows the movement of the Tc through the stomach and intestine in a subject with CF.
This study is the first study to examine GI motility in children with CF and PI using nuclear medicine scan technology. Previous CF studies using varying methodologies have yielded mixed results (3–15). Our study found that children with CF and PI had unaltered GE but delayed SBT time compared with a healthy reference group when taking a standard dose of pancreatic enzymes and a high-fat, high-energy liquid meal.
Possible factors that may influence SBT in CF include SBBO, DIOS, dysmotility disorders (constipation), history of intestinal surgery, and the use of certain medications. DIOS is thought to be caused by inadequate fluid and electrolyte intake resulting in viscid stool that builds up primarily in the ileocecal area and colon. SBBO has been noted in patients with CF with a prevalence of up to 57% in 1 study (26). Constipation is also seen in CF and its frequency appears to increase in young adulthood. In our study, there were no differences in SBT between the subjects with a history of DIOS and those taking laxatives; however, the numbers were small. Larger studies are required to adequately address whether these factors contribute to delayed SBT in CF.
The major strength of this study was the methodology that was used to examine motility. Nuclear medicine scan technology has not been used in previous studies examining GI motility in children with CF. Although nuclear medicine scans are time intensive, this method may be more accurate compared with indirect methods, including breath tests, which may be more variable (16,17).
A major limitation of using breath tests in people with CF is that there is an assumption that pulmonary status is normal or near normal (16). The limitations of this study include a small sample size and a difference in age between the 2 groups. The subjects with CF were younger than the healthy reference group; however, there is no evidence to support that this age difference influenced SBT time. Although the CF sample had mildly reduced height-for-age and weight-for-age z scores scores, these growth deficits are common in children with CF and make the findings generalizable to the CF population.
Understanding GI motility in CF is important in determining the role of dysmotility in the common GI manifestations of the disease. Animal studies have demonstrated dramatically slower intestinal transit time in CF mice. In 1 study, when mice were treated with an osmotic laxative, the concomitant bacterial overgrowth was eradicated, inflammation was attenuated, and transit was normalized (27). This suggests a potential role between gut microbiome and transit in CF and is a potential future area for human research.
In conclusion, children with CF and PI had normal GE but delayed SBT while taking pancreatic enzymes and a high-fat, high-energy liquid meal. Future studies should focus on determining the factors that contribute to delayed SBT in CF and testing interventions to try to normalize SBT. A better understanding of GI motility in children with CF may lead to improvements in pancreatic enzyme replacement therapy, gut health, growth, and nutritional status.
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