Dana Boctor

Relationship between biopsy-proven parenteralnutrition-associated liver fibrosis and biochemical cholestasis in children with short bowel syndrome.

PURPOSE The aim of the study was to determine the frequency of biochemical cholestasis (direct bilirubin [DB] > or =2 mg/dL) in children with short bowel syndrome and biopsy-proven parenteral nutrition (PN)-associated liver disease and to define predictive factors for the occurrence and degree of hepatic fibrosis. METHODS After institutional review board approval, a retrospective review was conducted of patients followed by 2 multidisciplinary intestinal rehabilitation programs between January 1, 2000, and September 30, 2008. Inclusion criteria were exposure to PN (>30 days) and having undergone a liver biopsy. Liver biopsy specimens were graded from 0 to 3 based upon degree of fibrosis in the pathology report. The most recent DB within 10 days before biopsy was recorded. RESULTS A total of 66 children underwent 83 liver biopsy procedures. The most common diagnoses included necrotizing enterocolitis (NEC) (36.4%), gastroschisis (22.7%), and intestinal atresia (15.1%). Median age at biopsy was 6.1 months with a median duration of PN of 4.7 months. Of the patients, 70.3% had a history of exposure to parenteral omega-3 lipid emulsion. Of the liver biopsy specimens, 89% (74/83) demonstrated some degree of fibrosis (fibrosis scale 1-3), including 9.6% (8/83) with evidence of cirrhosis. 83% of biopsies without fibrosis and 55% of biopsies with fibrosis were obtained in patients without evidence of biochemical cholestasis (P = .20). Three (37%) of the 8 patients with cirrhosis on liver biopsy had no evidence of biochemical cholestasis. Univariate analysis identified only gestational age (GA) at birth as significantly associated with the degree of liver fibrosis (P = .03). A multivariate logistic regression model accounting for multiple biopsy procedures in patients revealed that GA was a predictor of fibrosis only in patients with a diagnosis other than NEC (P < .01). CONCLUSIONS In children with short bowel syndrome, biochemical cholestasis does not reflect the presence or degree of histologically confirmed PN-associated liver fibrosis. Careful follow-up, combined with further refinement of diagnostic and hepatoprotective strategies, may be warranted in this patient population.

Elements of successful intestinal rehabilitation

PURPOSE The optimal therapy for intestinal failure (IF) is unknown. The results of a systematic, protocol-driven management strategy by a multidisciplinary team are described. METHODS Intestinal failure was defined as bowel length of less than 40 cm or parenteral nutrition (PN) for more than 42 days. A multidisciplinary team and protocol to prevent PN-associated liver disease (PNALD) were instituted in 2006. Data were gathered prospectively with consent and ethics board approval. RESULTS From 1998 to 2006, 33 patients were treated (historical cohort) with an overall survival of 72%. Rotating prophylactic antibiotics for bacterial overgrowth were given to 27% of patients; 6% had lipid-sparing PN, and none received fish oil-based lipids. Median time to intestinal rehabilitation was 7 ± 3.1 months, and 27% of patients who developed PNALD died. From 2006 to 2009, 31 patients were treated. Seventy-seven percent received PAB; 60%, lipid-sparing PN; and 47%, parenteral fish oil emulsion. Eighty-seven percent weaned from PN at 3.9 ± 3.8 months, and no patients developed PNALD with 100% survival. Novel lipid therapies were associated with changes in essential fatty acid profile and one case of clinical essential fatty acid deficiency. CONCLUSION The institution of a multidisciplinary team and a protocol-driven strategy to prevent PNALD improves survival in IF. Further studies are recommended.

The assessment, and glucagon-like peptide-2 modulation, of intestinal absorption and function

The treatment of patients with short bowel syndrome is hampered by a lack of treatment and measurement methods. This article reviews our evolving understanding of the role of glucagon-like peptide 2 (GLP-2) in controlling the adaptive process. The ability of the remnant intestine to produce GLP-2 appears to be predictive of the adaptive process; exogenous GLP-2 may be a therapy to augment adaptation. Strategies for monitoring patients, including conventional means, such as anthropomorphic measurements, plasma levels of specific nutrients, and vitamins and radiological contrast studies are reviewed. Investigational methods, such as nutrient balance studies, plasma citrulline levels, and the absorption of inert sugars (3-0 methyl glucose, mannitol, and lactulose) are discussed with the evidence to support their use.

A Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure

Background and Aims: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. Methods: Native human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition–dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. Results: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral nutrition. GLP-2 treatment had no effect on vital signs (blood pressure, heart rate, and temperature) and caused no significant adverse events. Peak GLP-2 levels were 380 pM (day 3) and 295 pM (day 42), with no change in half-life or endogenous GLP-2 levels. Nutritional indices showed a numeric improvement in z scores and citrulline levels; the z score was maintained while citrulline levels returned to baseline once GLP-2 was discontinued. Conclusions: GLP-2 was well tolerated in children, with a pharmacokinetic profile similar to that of adults. There were no changes in endogenous GLP-2 release or metabolism. These results suggest that GLP-2 ligands may be safely used in pediatric patients; larger trials are suggested to investigate nutritional effects.

Energy and sports drinks in children and adolescents

Sports drinks and caffeinated energy drinks (CEDs) are commonly consumed by youth. Both sports drinks and CEDs pose potential risks for the health of children and adolescents and may contribute to obesity. Sports drinks are generally unnecessary for children engaged in routine or play-based physical activity. CEDs may affect children and adolescents more than adults because they weigh less and thus experience greater exposure to stimulant ingredients per kilogram of body weight. Paediatricians need to recognize and educate patients and families on the differences between sport drinks and CEDs. Screening for the consumption of CEDs, especially when mixed with alcohol, should be done routinely. The combination of CEDs and alcohol may be a marker for higher risk of substance use or abuse and for other health-compromising behaviours.

A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure

BACKGROUND & AIMS Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-μg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. RESULTS Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5μg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. CONCLUSIONS GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. LEVEL OF EVIDENCE 2b Prospective Interventional Study.

The glucagon like peptide-2 ‘axis’: Capacity for production and response following intestinal resection or repair of gastroschisis in infants

PURPOSE This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis. METHODS With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP-2 levels, and where possible, tissue sampling. RESULTS Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86±32) n=24 vs. controls: 45±20 n=10 and vs. patients on prolonged PN: 42±6 pM, n=10). This was maintained to one year: weaned patients: 72±49 vs. non-weaned: 35±15 pM (p<0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21±15 with first feeding vs. 102±60 at full feeds and 60±19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor. CONCLUSION GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested.

Su2093 Glucagon Like Peptide-2 Production and Sensitivity in Infants Post-Resection or Gastroschisis

G A A b st ra ct s enhanced microbial fermentation of dietary fiber and dysregulation of choline metabolism. The OPLS-DA model constructed based on samples collected post DI (R2X=30.7%, Q2Y= 0.37) showed higher concentrations of glutamate and 6-aminosalicylic acid in AA compared with AF. Microbial data acquired using HITChip was integrated with fecal profiles using OPLS. At the phylum level, 2 out of 22 identified phyla were significantly correlated with fecal profiles, which are Cyanobacteria and uncultured Mollicutes significantly correlating with fecal glutamate and valerate. By statistically integrating the fecal metabonome and the 130 microbial genus, Bacteroides vulgates et rel. and Bacteroides plebeius et rel. were observed to be correlated with choline, whereas Uncultured Clostridiales II was correlated with pyroglutamate. Uncultured Mollicutes, Eubacterium siraeum et rel and Aneurinibacillus demonstrated similar metabolic activity. Conclusions: These findings indicate that after only two-weeks of a dietary exchange diet, the fecal metabolic profile is significantly altered and that these metabolic changes are closely associated with alterations in the structure and function of the gut microbial network.