What Is Known
- Patients with short bowel syndrome can have severe enteral malabsorption.
- Therapeutic interventions that improve enteral absorption in short bowel syndrome are limited.
What Is New
- This is the first study to assess changes in enteral absorption in patients with short bowel syndrome on pancreatic enzymes.
- Though the change in mean enteral fat and protein absorption in the whole cohort did not reach statistical significance, several subjects demonstrated improved fat and protein absorption with the use of pancreatic enzymes. There may be a role for pancreatic enzymes in this population but further studies are needed.
Morbidity and mortality in patients with short bowel syndrome (SBS) are largely related to complications from central venous access and parenteral nutrition (PN) (1–4). Though mortality rates have greatly improved over time (1,2,5), patients with SBS can still have significant morbidity (1–4). Morbidities in this population include central line-associated bloodstream infections, intestinal failure-associated liver disease, and mechanical complications of central venous catheters (1–4). The ultimate goal in clinical management of patients with SBS is enteral autonomy, which has been associated with improved long-term survival (1–3). Enteral autonomy while maintaining an acceptable nutritional state is often difficult to achieve if there is significant enteral malabsorption. Crenn et al (6) studied a cohort of 90 adult subjects with SBS and reported a mean CFA as low as 47% in PN-dependent subjects and 61% in PN-independent subjects. This study highlights the severe degree of fat malabsorption that can occur in SBS and illustrates the challenge that clinicians face in reducing PN dependency in this population.
There are few medical therapies to date that improve enteral absorption in SBS. Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is currently the only medication that has been shown to improve intestinal adaptation and allow PN to be weaned in both children and adults (7,8). Use of prescription pancreatic enzyme treatments have been successful in improving enteral absorption in other patient populations (9,10) and have anecdotally been described as useful in SBS (11). The effect of pancreatic enzyme therapy on enteral fat and nitrogen absorption in SBS has not been studied previously and was the primary aim of this study.
METHODS
Study Design and Participants
Pediatric subjects ≥4 to <18 years of age and adults 18 to ≤75 years of age were recruited from the Philadelphia and New York regions. All subjects were required to have a diagnosis of SBS, to be in a usual state of health, and to be on a stable medication regimen for at least 2 weeks prior to each study visit. SBS was defined differently based on the age of the subject at the time of bowel resection. Subjects <18 years of age with a history of a small bowel resection were required to have at least 3 months of PN dependence following resection. This criterion was selected to best capture those subjects with more significant malabsorption following bowel resection (3,12,13). Subjects ≥18 years of age with a history of small bowel resection were required to have 200 cm or less of residual bowel length (6,14) and greater than 3 bowel movements per day following resection. Subjects were required to take Creon orally in order to be eligible. Exclusion criteria included significant gastrointestinal disease other than SBS that would impact absorption or digestion, pancreatic insufficiency, motility disorders of the upper gastrointestinal tract, poorly controlled motility disorders of the lower gastrointestinal tract, the use of medications that alter fat absorption, cholestatic liver disease (serum conjugated bilirubin > 1.0 mg/dL), chronic renal failure requiring dialysis or eligibility for kidney transplant, or gout. Additional exclusion criteria included a status 1 listing for intestinal transplantation, history of fibrosing colonopathy, pregnancy, or lactation. Enrollment began in May 2017 and was completed in October 2018. The study was approved by the CHOP Institutional Review Board. All protocol visits were conducted at Children’s Hospital of Philadelphia (CHOP). Written consent was obtained prior to the first study visit from subjects ≥18 years and parents/legal guardians of subjects <18 years with verbal assent from subjects 7.0 to <18years.
Pancreatic Enzyme Medication
Creon (AbbVie Inc., Chicago, IL) was the pancreatic enzyme product used in this study and was provided to each subject with individualized dosing guidelines. Dosing was based on the consensus statement on pancreatic enzyme dosing in patients with cystic fibrosis (15). The goal was to administer 1500 to 2500 lipase units/kg body weight per meal or gastrostomy tube formula bolus and 750 to 1250 lipase units/kg body weight per snack. Several pediatric subjects had enteral nutrition regimens that included overnight continuous gastrostomy tube feeds. These subjects received 1500 to 2500 lipase units/kg body weight at the initiation and end of the feed. The total daily dose did not exceed 10,000 lipase units/kg/day.
Anthropometrics and Body Composition
Anthropometric measures were taken using standard methods (16). Baseline weight (0.1 kg) was measured using an electronic scale (Seca, Munich, Germany) and baseline height (0.1 cm) was measured using a stadiometer (Holtain, Crymych, UK), and BMI was calculated. Weight, height, and BMI z scores were generated for subjects between the ages of 4 and 17.9 years (17). Percent body fat, fat mass, and fat free mass were assessed by whole body dual energy x-ray absorptiometry (DXA) (Horizon A, Hologic, Inc., Bedford, MA). Triceps skinfold thickness was measured (0.1 mm) with a skinfold caliper and mid upper arm circumference was measured with a fiberglass tape (0.1 cm). Upper arm muscle area (UAMA) and upper arm muscle fat area (UAFA) were determined for each subject and UAMA and UAFA z scores were generated for subjects between the ages of 4 and 17.9 years (18).
Outcome Measures
The primary outcome measures for this study were coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA). Dietary fat and protein intake was assessed from 3-day dietary intake records that were completed at baseline and while on pancreatic enzyme medication. All subjects remained on their typical diet for the study. A 72-hour stool collection was performed at baseline and on pancreatic enzyme medication. Total fat content (in grams) in stool was assessed using nuclear magnetic resonance (NMR) spectroscopy (19) and total nitrogen content in stool was assessed using the Dumas combustion method (Mayo Medical Laboratories, Rochester, MN). CFA was calculated after determination of the mean daily grams of fat consumed and the mean daily grams of fat excreted. Similarly, CNA was calculated using the mean daily grams of nitrogen consumed and the mean daily grams of nitrogen excreted. Baseline serum 25-hydroxyvitamin D, retinol (vitamin A), α and γ tocopherol (vitamin E), serum zinc, and serum selenium were measured (CHOP Clinical Laboratory). A baseline plasma fatty acid profile was assessed by Mayo Medical Laboratories. To assess baseline exocrine pancreatic activity, fecal elastase-1 was measured using an enzyme-linked immunosorbent assay (ARUP Laboratory, Salt Lake City, UT) and was classified as normal if >200 μg/g (20,21).
Statistical Analysis
Descriptive statistics included means ± SD for continuous variables and frequency and percentages for categorical variable. Comparisons between the mean CFA and CNA before and after pancreatic enzyme use were made using paired student t tests. Statistical significance was set at P = 0.05.
RESULTS
A total of 16 subjects were enrolled, and 1 withdrew prior to the study intervention phase. A second subject withdrew after a baseline study visit prior to exposure to pancreatic enzyme medication. Three subjects were not included in the CFA and CNA analysis, as stool collections and dietary records were incomplete.
The mean age of pediatric (n = 8) and adult (n = 7) subjects was 9 years and 53.5 years, respectively (Table 1). Etiologies of SBS in the cohort included necrotizing enterocolitis, midgut volvulus, mesenteric ischemia, gastroschisis, long segment Hirschsprung’s disease, and a series of complications from diverticulitis (Fig. 1). At the time of the most recent small bowel resection, the mean pediatric small bowel length was 60 cm or 30% of the expected bowel length for age (22), whereas the mean adult small bowel length was 80 cm or 14% of the average adult small intestinal length (14,23). The mean time since the most recent small bowel resection was 6.6 years and the mean time length of PN dependence was 3.4 years. Two subjects were on PN at the time of the study. Anthropometric data for the cohort are listed in Table 1. One pediatric subject had a fecal elastase that met criteria for pancreatic insufficiency. This subject was PN-dependent with large volume watery stool per rectum. Fecal elastase is known to be low if stool samples are unformed with high water content (24). Several subjects had nutritional deficiencies (Table 1). Additional information on each subject is available in Table, Supplementary Digital Content, https://links.lww.com/MPG/C787.
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FIGURE 1.: Etiologies of short bowel syndrome in sample. Other (n=1): Previous surgery complicated by small bowel obstruction and enterocutaneous fistula formation resulting in short bowel syndrome
TABLE 1. -
Characteristics of subjects with short bowel syndrome
|
Children, n = 8 |
Adult, n = 7 |
All, n = 15 |
| Age, years |
9.0 ± 3.1 |
53.5 ± 18.9 |
29.8 ± 26.2 |
| Sex, % male |
63 |
29 |
47 |
| Race, % Caucasian |
63 |
71 |
67 |
| Small bowel length, cm*
|
60 ± 38 |
80 ± 42 |
70 ± 40 |
| Remaining % of expected bowel length for age, %*
|
30 ± 16 |
14 ± 7 |
22 ± 15 |
| Length of TPN dependence, years |
3.1 ± 3.3 |
3.7 ± 6.0 |
3.4 ± 4.5 |
| Current TPN dependence, n |
1 |
1 |
2 |
| Presence of IC valve, n |
0 |
1 |
1 |
| Presence of ostomy, n |
1 |
0 |
1 |
| Weight, kg |
27.1 ± 11.7 |
72.7 ± 15.4 |
48.4 ± 27.0 |
| Weight z score |
−0.8 ± 0.8 |
– |
– |
| Height, cm |
125.7 ± 20.6 |
161.6 ± 9.5 |
142.4 ± 24.4 |
| Height z score |
−1.2 ± 1.3 |
– |
– |
| BMI, kg/m2
|
16.5 ± 1.7 |
27.9 ± 5.7 |
21.8 ± 7.0 |
| BMI z score |
−0.1 ± 0.8 |
– |
– |
| UAMA, cm2
|
20 ± 6 |
48 ± 24 |
33 ± 22 |
| UAMA z score |
−0.2 ± 1.9 |
– |
– |
| UAFA, cm2
|
8 ± 4 |
34 ± 20 |
20 ± 19 |
| UAFA z score |
0.8 ± 1.6 |
– |
– |
| DXA, fat free mass, kg |
18.0 ± 7.2 |
42.7 ± 9.3 |
28.6 ± 14.9 |
| DXA, fat mass, kg |
8.0 ± 4.2 |
30.0 ± 8.2 |
17.5 ± 12.8 |
| DXA, fat, % |
29.3 ± 3.8 |
39.7 ± 5.8 |
33.8 ± 7.0 |
| Fecal elastase, μg/gb
|
342 ± 162 |
354 ± 86 |
349 ± 117 |
| Fecal elastase <200, n |
1 |
0 |
1 |
| Serum Vitamin D, ng/ml |
35.3 ± 9.2 |
31.9 ± 10.5 |
33.7 ± 9.7 |
| <20 (deficient), n |
0 |
1 |
1 |
| 20-29 (insufficient), n |
2 |
1 |
3 |
| Serum retinol, mg/L†
|
0.46 ± 0.17 |
0.49 ± 0.20 |
0.48 ± 0.18 |
| Vitamin A deficiency, n |
0 |
2 |
2 |
| Serum α-tocopherol, mg/L†
|
8.2 ± 3.1 |
7.5 ± 1.3 |
7.9 ± 2.4 |
| Vitamin E deficiency, n |
0 |
1 |
1 |
| Serum γ-tocopherol, mg/L†
|
0.9 ± 0.5 |
1.2 ± 1.1 |
1.0 ± 0.8 |
| Serum zinc, μg/dL *,†
|
77 ± 25 |
125 ± 89 |
98 ± 63 |
| Zinc deficiency, n |
2 |
0 |
2 |
| Serum selenium, μg/L†
|
119 ± 31 |
115 ± 22 |
117 ± 27 |
| Selenium deficiency, n |
0 |
0 |
0 |
| Essential fatty acid deficiency, n |
0 |
2 |
2 |
BMI = body mass index, DXA = dual energy x-ray absorptiometry, IC = ileocecal, TPN = total parenteral nutrition, UAFA = upper arm fat area, UAMA = upper arm muscle area.
*n = 14; b n = 9.
†Normal reference range: retinol 0.3 to 1.2 mg/L; α-tocopherol 5.5 to 18.0 mg/L; γ-tocopherol 0 to 6.0 mg/L; zinc 60 to 120 μg/dL; selenium 60 to 180 μg/L.
The mean CFA at baseline was 76% in the children and 41% in the adult subjects, consistent with enteral fat malabsorption in both groups (Table 2). Four of 11 subjects had a baseline CFA >80%. The mean CNA at baseline was 58% in the pediatric and 43% in the adult subjects, indicating enteral protein malabsorption in both groups.
TABLE 2. -
Coefficient of fat and nitrogen at pre- and postpancreatic enzyme medication
|
Pediatric, n = 6 |
Adult, n = 5 |
All, n = 11 |
|
Pre |
Post |
Pre |
Post |
Pre |
Post |
| Stool weight, total g/72 hours |
1360 ± 856 |
1315 ± 725 |
6428 ± 5686 |
4989 ± 5285 |
3275 ± 4046 |
2564 ± 3524 |
| Stool fat, g/24 hours |
30 ± 28 |
28 ± 33 |
147 ± 160 |
118 ± 126 |
74 ± 107 |
60 ± 86 |
| Stool nitrogen, g/24 hours |
4 ± 1 |
4 ± 2 |
16 ± 17 |
11 ± 13 |
8 ± 11 |
7 ± 9 |
| Fat intake, g/24 hours |
120 ± 35 |
109 ± 38 |
180 ± 113 |
149 ± 109 |
147 ± 82 |
127 ± 77 |
| Nitrogen intake, g/24 hours |
10 ± 3 |
10 ± 3 |
21 ± 15 |
19 ± 15 |
15 ± 11 |
14 ± 11 |
| Energy intake, kcal/day |
2525 ± 391 |
2453 ± 525 |
3565 ± 1509 |
3233 ± 1938 |
2998 ± 1132 |
2808 ± 1344 |
| CFA, % |
76 ± 18 |
75 ± 24 |
41 ± 25 |
47 ± 26 |
60 ± 27 |
63 ± 28*
|
| CFA <93%, n |
5 |
5 |
5 |
5 |
10 |
10 |
| CNA, % |
58 ± 17 |
61 ± 16 |
43 ± 19 |
55 ± 24 |
51 ± 19 |
58 ± 19†
|
| CNA, % <88%, n |
6 |
6 |
5 |
5 |
11 |
11 |
CFA = coefficient of fat absorption; CNA = coefficient of nitrogen absorption.
*P = 0.6.
†P = 0.2.
There was no statistically significant change in CFA and CNA in the whole cohort after pancreatic enzyme medication. Six of 11 subjects, however, demonstrated an improvement in CFA (Fig. 2A) and 8 of 11 subjects demonstrated an improvement in CNA (Fig. 2B) on pancreatic enzyme medication. Furthermore, of the subjects who had moderate-to-severe fat malabsorption at baseline (CFA < 80%), 5 of 7 subjects demonstrated an improvement in CFA on pancreatic enzyme medication. Of those subjects with a fat-soluble vitamin deficiency (vitamin D, E, or A), 4 out of 7 subjects demonstrated an improvement in CFA on therapy. In general, CFA and CNA had a similar response to pancreatic enzyme therapy in a given subject. Specifically, 6 subjects who demonstrated an improvement in CFA also demonstrated an improvement in CNA on pancreatic enzyme therapy and 3 subjects who had a decline in CFA on therapy, also demonstrated a decline in CNA. Two of the 4 subjects who received overnight gastrostomy tube feeds had no change in fat or protein absorption. Four of 11 subjects were on proton pump inhibitors (PPI) during the study. Of those subjects, 3 demonstrated an improvement in CFA and CNA on pancreatic enzyme medication.
FIGURE 2.: (A) Change in coefficient of fat absorption with pancreatic enzyme medication. (B) Change in coefficient of nitrogen absorption with pancreatic enzyme medication.
Minimal adverse events were reported in this study. One subject reported looser stools, and others reported constipation and a decrease in appetite. One subject complained of both abdominal pain and bloating. Side effects resolved with cessation of the medication. Fifty percentage of the subjects reported no adverse events.
DISCUSSION
Multiple studies demonstrate the ability of patients with SBS to achieve enteral autonomy over time, which highlights the capacity for the residual bowel to improve in function (1–3,25–28). Clinical predictors of enteral autonomy include a longer residual small bowel length, history of necrotizing enterocolitis, intact ileocecal valve, fewer bloodstream infections, and younger gestational age (2,26–28). Enteral nutrition itself plays a critical role in intestinal adaptation (29). Sophisticated enteral feeding regimens and a growing number of formula options have more anecdotally reduced parenteral nutrition dependence. There has, however, been a paucity of medications that clearly improve enteral absorption. More recently, teduglutide, a GLP-2 agonist, has been Food and Drug Administration (FDA)-approved in both children and adults. Teduglutide has been shown to improve intestinal adaptation and allow a reduction in both PN calories and fluid volume in both pediatric and adult subjects with SBS (7,8). There are, however, several concerns with drug administration, including loss of therapeutic response with medication withdrawal and possible increased risk of malignancy.
Pancreatic enzymes are considered a possible intervention for use in SBS but their use in this patient population has not previously been studied. Pancreatic enzymes provide an exogenous source of proteases and lipases that can aid digestion and allow absorption to occur more effectively in the setting of malabsorption related to both loss of surface area and rapid intestinal transit, as are seen in SBS.
In this study, we did not find a statistically significant increase in fat and protein absorption with pancreatic enzyme use. 55% of subjects (n = 6), however, demonstrated an improvement in CFA and 73% of subjects (n = 8) demonstrated an improvement in CNA on therapy. Given the overall small sample size of the study, this does support that larger studies are needed to further explore this topic. It is also worth noting that 4 of the 11 subjects had a CFA >80%. This is reflective of good intestinal adaptation and it may have been less likely for pancreatic enzymes to further improve enteral absorption in these subjects. When these subjects are excluded, 71% of subjects (n = 5 out of 7 total) demonstrated an improvement in CFA.
Four subjects in this study demonstrated a decrease in CFA following pancreatic enzymes and 3 subjects demonstrated a decrease in CNA following pancreatic enzyme therapy. This suggests that pancreatic enzymes may have worsened fat and nitrogen absorption in these subjects. It is possible that the medication worsened diarrhea by increasing the osmotic load of the gastrointestinal tract. Another potential explanation for small changes in CFA and CNA is a lack of sufficient precision because of the severity of malabsorption in SBS, lack of standardized diet used in this study, and any other clinical changes that may impact absorption between assessments. Data on the precision of CFA and CNA measurements does not exist for subjects with SBS. A previous study of the precision of CFA measurements has been performed in a small group of healthy subjects and subjects with CF (30). This study demonstrated decreased precision of CFA measurements in CF compared with healthy subjects.
CNA was lower than anticipated in this study. A previous study of healthy teenagers and adults demonstrated an average CNA of about 88% (30). All subjects in our study had a CNA less than 88% both before and after pancreatic enzymes. There are limited data on nitrogen absorption in patients with SBS. One study of 6 adults with SBS demonstrated an average CNA of 47% and a range of 38% to 80% (31). Another study of 9 adults with SBS demonstrated an average CNA of 47% (32). In contrast to our study, many of these subjects were on PN, suggesting significant malabsorption. The significant degree of nitrogen malabsorption noted in these studies matches our findings.
All subjects had at least a partial ileal resection. We were unable to draw conclusions about the impact of location of the bowel resection on likelihood of response to enzyme therapy.
There are several limitations to this study. It was a small sample size and the overall cohort was very heterogenous in underlying etiology of SBS and age. Additionally, some of the subjects received suboptimal pancreatic enzyme dosing as outlined below, which may have limited the ability to improve enteral absorption. Specifically, there were 4 subjects on overnight continuous tube feeds. These subjects received a dose of pancreatic enzymes at the start and end of the continuous feed about 8–12 hours apart. This is a suboptimal method of dosing pancreatic enzymes and was unlikely to have altered digestion and absorption of formula overnight. Fifty percentage of subjects on continuous overnight tube feeds did not demonstrate an improvement in fat or protein absorption. One of the subjects in this cohort had a unique enteral feeding regimen constituted of several meals, snacks, and GT boluses with very high calorie intake overall. In order not to exceed the recommended daily dose of pancreatic enzymes, this subject required small doses of pancreatic enzymes more frequently, which may have provided suboptimal coverage to improve digestion, and therefore, absorption. This subject did not demonstrate an improvement in CFA or CNA. Another limitation is that the intestinal transit of subjects with short bowel syndrome is highly variable. Ideally, dye markers would have been used at the start and end of the dietary records in order to inform the timing of the start and end of the stool collection (33). It is possible that data would have been more accurate if obtained in this manner.
Another limitation of this study was that Creon is an oral pancreatic enzyme preparation. As such, the medication may not have adequate time to take effect in patients who have rapid intestinal transit. We did not assess intestinal transit as part of the study. There are newer pancreatic enzyme preparations that utilize lipase to predigest formula before delivery to the gastrointestinal tract (34). These preparations are also of great interest as they eliminate rapid intestinal transit as a variable that may render the pancreatic enzymes less effective.
Use of pancreatic enzymes in this cohort of subjects with SBS was considered a low risk intervention. The assessment of side effects of pancreatic enzyme medication was limited by the short duration of the study and minimal adverse events.
CONCLUSION
In conclusion, this pilot study did not find statistically significant improvements in enteral fat or nitrogen absorption with the use of Creon in this heterogeneous cohort. Several subjects demonstrated an improvement in enteral fat and protein absorption, whereas a smaller number showed a decline in CFA and CNA. Further studies are needed to better understand the effect of pancreatic enzyme medication on enteral absorption in SBS and to help understand factors that are more likely to predict a meaningful clinical response.
Acknowledgments:
The authors thank the subjects and families for their study participation. The authors are grateful to Dr Joan Schall, Dr Natalie Terry, Dr Kishore Iyer, Dr Arieda Gjikopulli, Dr Maria Mascarenhas, Dr Jamie Merves, Dr Gayle Diamond, and Laura Grande for their contributions. This study was an investigator-initiated study funded by AbbVie, Inc. AbbVie had no role in the study design, study conduct, or data analysis. We would also like to acknowledge the support of the Center for Human Phenomic Science at CHOP (UL1RR024134, UL1TR000003), the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR001878), and Nutrition Center at CHOP.
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