Impact of Pancreatic Enzymes on Enteral Fat and Nitrogen Absorption in Short Bowel Syndrome.

OBJECTIVES: Patients with short bowel syndrome (SBS) can have a high morbidity rate. To minimize morbidity, enteral autonomy is the primary goal in clinical management of patients with SBS. This is often difficult to achieve because of significant malabsorption. To date, there are limited therapies that improve absorption in patients with SBS. The impact of pancreatic enzyme replacement treatment on enteral absorption has not been studied in this population and was the primary aim of this study. SUBJECTS/METHODS: This was an interventional study in 11 subjects (6 pediatric subjects ages 4.0-17.9 years, 5 adult subjects 18-75 years) that compared enteral absorption in each subject before and after pancreatic enzyme medication (Creon). Coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA) were used as markers of enteral absorption of fat and protein, respectively. RESULTS: There was no statistically significant mean change in CFA and CNA before and after pancreatic enzyme medication therapy. Six subjects demonstrated an increase in CFA and 8 subjects demonstrated an increase in CNA after the use of pancreatic enzyme medication therapy. CONCLUSIONS: There was no statistically significant improvement in enteral fat and protein absorption in the cohort as a whole, though several subjects demonstrated an improvement. These results suggest that some patients with SBS may benefit from treatment with pancreatic enzymes. Further studies are needed to better evaluate the effect of pancreatic enzyme therapy on enteral absorption in subjects with SBS and to characterize factors that may predict a positive response.

Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea.

Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.

Italian and North American dietary intake after ivacaftor treatment for Cystic Fibrosis Gating Mutations.

BACKGROUND: In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored. METHODS: A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations. RESULTS: With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake. CONCLUSIONS: Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed.

Energy Balance and Mechanisms of Weight Gain with Ivacaftor Treatment of Cystic Fibrosis Gating Mutations.

OBJECTIVE: To determine if ivacaftor treatment results in weight gain and improved pulmonary function in people with cystic fibrosis transmembrane conductance regulator gating mutations. STUDY DESIGN: Children and adults with cystic fibrosis and at least 1 cystic fibrosis transmembrane conductance regulator gating mutation were evaluated in this observational study before and after 3 months of ivacaftor treatment. Body size and composition, total energy expenditure, resting energy expenditure (REE%) as percent predicted, coefficient of fat absorption (CFA%), fecal calprotectin, fecal elastase, and quality of life were assessed. Some outcomes were explored by pancreatic status. RESULTS: There were 23 patients (5-61 years of age) who completed the study; 70% had pancreatic insufficiency (PI). Patients gained 2.5 ± 2.2 kg (P < .001) with increased (P < .05) fat-free mass (0.9 ± 1.9 kg) and fat mass (1.6 ± 1.5 kg). REE% decreased by 5.5 ± 12.0% (P < .05), fecal calprotectin decreased by 30 ± 40 µg/g stool (P < .01), and total energy expenditure was unchanged. Improvements were greater for PI than patients who were pancreatic-sufficient. CFA% increased significantly only with PI. The change (Δ) in weight was positively correlated with the percent change in forced expiratory volume at 1 second (r = 0.46; P = .028) and ΔCFA% (r = 0.47; P = .032) and negatively with ΔREE% (r = -0.50; P = .017). Together, ΔREE%, ΔCFA%, and the percent change in forced expiratory volume at 1 second explained 58% of the variance in weight gain (adjusted R2 = 0.579; P = .0007). Growth status and muscle strength improved, as did quality of life in several domains. Fecal elastase increased in most patients with pancreatic sufficiency, with no change in those with PI. CONCLUSIONS: Mechanisms identified for ivacaftor-associated weight gain were decreased REE, gut inflammation, and fat malabsorption (CFA). TRIAL REGISTRATION: ClinicalTrials.gov: NCT02141464.

Bone density in post-pubertal adolescent survivors of childhood brain tumors.

BACKGROUND: Childhood cancer survivors are at high risk for reduced bone mineral density (BMD). Our objective was to determine whether post-pubertal adolescent survivors of brain tumors, whose tumor or treatments placed them at risk for pituitary hormone deficiencies, have low BMD near time of peak bone mass accrual, and to assess risk factors for decreased BMD. PROCEDURE: Chart review of 36 post-pubertal adolescents with history of tumor or radiation therapy (RT) of the hypothalamic-pituitary area who had undergone BMD screening via dual-energy X-ray absorptiometry (DXA). RESULTS: Age at DXA was 16.9 ± 1.9 years (mean ± SD). Time since diagnosis was 8.5 ± 3.6 years. Median BMD Z scores were -0.95 (range -2.7 to 1.7) at the femoral neck, -1.20 (-3.6 to 1.8) at the hip, and -0.90 (-3.7 to 1.8) at the spine. Bone mineral apparent density (BMAD) Z scores were -0.23 (-2.7 to 1.9) at the femoral neck and -0.45 (-3.0 to 2.3) at the spine. Those with history of ≥1 fracture had lower BMD Z scores of the femoral neck, total hip, and spine (P < 0.05). Those with treated GH deficiency (GHD) had a higher BMD Z-score at the femoral neck, total hip, and spine (P < 0.05) than those not treated. There was no difference in BMD with respect to treatment with chemotherapy, cranial or spinal RT, or hypogonadism. Spontaneous menarche and regular periods did not correlate with BMD. CONCLUSIONS: In post-pubertal adolescent survivors of childhood brain tumors, fracture history and untreated GHD are risk factors for decreased BMD.

Construction of a chimeric gene cluster for the biosynthesis of apoemulsan with altered molecular weight.

Acinetobacter venetianus RAG-1 produces an extracellular protein/high-molecular-weight (HMW) polysaccharide complex termed emulsan. As an emulsion stabilizer, emulsan has potential industrial applications. To control the molecular weight of the polymer, a stable chromosomal mutant was generated where RAG-1 wza, wzb, wzc genes were replaced by Escherichia coli homologs. The heterologous Wza, Wzb, Wzc proteins restored production of HMW polysaccharide. The polymer produced was of higher molecular weight than from the parent strain and with the cells exhibiting modified hydrophobicity.