Pancreatic Insufficient Cystic Fibrosis Research Articles

Insulin sensitivity, disposition index and insulin clearance in cystic fibrosis: a cross-sectional study

Aims/hypothesisThe aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency.MethodsIn a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity.ResultsAmong 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001).Conclusions/interpretationIn individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.Graphical

Changes in Sleep in Children and Adults with Cystic Fibrosis and Primary Ciliary Dyskinesia over Time and after CFTR Modulator Therapy.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are associated with sleep disturbances affecting quality of life (QOL) in both children and adults. However, little is known about the progression of these complaints over time, and the effect of CFTR modulator (CFTRm) therapies. Participants completed sleep quality (SDSC, PSQI) and quality of life questionnaires (PedQL, QOL-BE) as well as the Epworth sleepiness scale (ESS) at baseline and after 4 years. Medical records were reviewed for clinical data and correlations were sought between sleep, QOL, and clinical parameters. A total of 67 patients (33 pediatric), 37 pancreatic insufficient CF (CF-PI), 15 pancreatic sufficient CF (CF-PS), and 15 PCD patients, completed the study. In adults, global sleep quality decreased from 85.8% (76.2-90.5) to 80.9% (71.4-85.7); (p = 0.009). Analysis by disease cohort showed a significant deterioration only in the CF-PS group. In adults off CFTRm, sleep quality decreased from 85.7% (78.6-88.2) to 80.9% (71.4-87.3); (p = 0.021) and from 85.8% (76.2-92.9) to 76.2% (71.4-85.8); (p = 0.078) in people on CFTRm. Changes in sleep quality and changes in QOL over time were strongly associated with each other. In conclusion sleep quality deteriorates over time, correlates with QOL, and is driven primarily by adults and CF-PS patients. CFTRm has a possible effect on sleep initiation; however, results are mixed, and further long-term studies are required.

Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

1548-P: GLP-1 and GIP Reduce Insulin Clearance in Individuals with Pancreatic-Insufficient Cystic Fibrosis (PI-CF)

PI-CF is characterized by impaired insulin secretion with disruption of the enteroinsular axis and alterations in incretin secretion and action. We have reported augmented glucose-dependent insulin secretion to glucose-potentiated arginine (GPA) testing with GLP-1 infusion but not GIP, with these effects independent of glucose tolerance in PI-CF. We aimed to assess the effect of incretin infusion on insulin clearance during GPA testing and explore its relationship to second-phase insulin response in individuals with PI-CF in a retrospective analysis. Thirty-two individuals with PI-CF and abnormal glucose tolerance underwent GPA testing of islet function following intravenous infusion of incretin or placebo in a randomized cross-over study design. Sixteen individuals were randomized to incretin infusion with GLP-1 and sixteen with GIP. Insulin clearance was assessed by the molar ratio of acute C-peptide to insulin response over the 5-minutes following glucose-potentiation of arginine-induced insulin and C-peptide secretion (target glucose ~230 mg/dL). Insulin clearance was related to second-phase insulin secretion by hyperbolic function (y=P1/(P2 + x) with a reduction in insulin clearance for increasing second-phase insulin secretion (R2=0.20; p&amp;lt;0.001). A reduction in insulin clearance was observed with both GLP-1 vs. placebo (mean±SD 2.7±2.1 vs. 15.5±5.7; p&amp;lt;0.001) and GIP vs. placebo (2.4±0.8 vs. 18.0±10.8; p&amp;lt;0.001). GLP-1 and GIP appear to reduce insulin clearance in individuals with PI-CF presumably through effects at the liver. Reduced insulin clearance is most apparent following GIP infusion where there is no augmentation of second-phase insulin secretion, supporting that the effect of GIP occurs independently of an increase in pre-hepatic insulin secretion. Further work should explore underlying mechanisms of incretin-induced reduction in insulin clearance in PI-CF that could support therapeutic approaches to improve glucose homeostasis. Disclosure A.Flatt: None. A.Doliba: None. A.J.Peleckis: None. R.C.Rubenstein: None. A.Kelly: None. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. Funding National Institutes of Health (R01DK97830, UL1TR001878, P30DK19525, T32DK007314); Cystic Fibrosis Foundation (to M.R.R.)

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease

BackgroundThis study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). MethodsProspective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3–12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. Results722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. ConclusionsResearch US finding of HTG identifies children with CF with a 30–50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. Clinical Trial RegistrationProspective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist)

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine.

This review presents current updates of pancreatic enzyme replacement therapy in children with cystic fibrosis based on literature published in the last decade and some special considerations regarding pancreatic enzyme replacement therapy in the era of new therapies, such as cystic fibrosis transmembrane conductance regulator modulator therapies. Few articles evaluate the efficacy of pancreatic enzyme replacement therapy in the pediatric population, and most studies also included children and adults with cystic fibrosis. Approximately 85% of cystic fibrosis patients have exocrine pancreatic insufficiency and need pancreatic enzyme replacement therapy. Fecal elastase is the most commonly used diagnostic test for exocrine pancreatic insufficiency, although this value can fluctuate over time. While it is used as a diagnostic test, it cannot be used for monitoring the effectiveness of pancreatic enzyme replacement therapy and for adjusting doses. Pancreatic enzyme replacement therapy, the actual treatment for exocrine pancreatic insufficiency, is essential in children with cystic fibrosis to prevent malabsorption and malnutrition and needs to be urgently initiated. This therapy presents many considerations for physicians, patients, and their families, including types and timing of administration, dose monitoring, and therapy failures. Based on clinical trials, pancreatic enzyme replacement therapy is considered effective and well-tolerated in children with cystic fibrosis. An important key point in cystic fibrosis treatment is the recent hypothesis that cystic fibrosis transmembrane conductance regulator modulators could improve pancreatic function, further studies being essential. Pancreatic enzyme replacement therapy is addressed a complication of the disease (exocrine pancreatic insufficiency), while modulators target the defective cystic fibrosis transmembrane conductance regulator protein. Exocrine pancreatic insufficiency in cystic fibrosis remains an active area of research in this era of cystic fibrosis transmembrane conductance regulator modulator therapies. This new therapy could represent an example of personalized medicine in cystic fibrosis patients, with each class of modulators being addressed to patients with specific genetic mutations.

Comprehensive semen examination in patients with pancreatic-sufficient and pancreatic-insufficient cystic fibrosis.

We examined a cohort of 93 cystic fibrosis (CF) male patients who were pancreatic-sufficient (PS-CF; n=40) or pancreatic-insufficient (PI-CF; n = 53). Complex semen examination was performed, including standard semen analysis, quantitative karyological analysis (QKA) of immature germ cells (IGCs), transmission electronic microscopy (TEM), biochemical analysis, and sperm DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) assay. Azoospermia was diagnosed in 83 (89.2%) patients. The other 10 (10.8%) patients were found to be nonazoospermic and showed various spermatological diagnoses (asthenozoospermia, n = 2; asthenoteratozoospermia, n = 3; oligoasthenozoospermia, n = 1; oligoasthenoteratozoospermia, n = 3; and normozoospermia, n = 1) with no specific morphological abnormalities. Oligospermia was detected in 89.2% azoospermic and 30.0% nonazoospermic patients. Low seminal pH (<7.0) was found in 74 (89.2%) of 83 azoospermic patients. Moderate leukocytospermia (2.0 × 10 6 -2.2 × 10 6 ml -1 ) was revealed in 2.4% azoospermic and 40.0% nonazoospermic semen samples. The signs of partial meiotic arrest at prophase I were found in 4 of 6 nonazoospermic patients examined by QKA of IGCs. The content of fructose and citrate was low in oligospermic and normal in nonoligospermic semen samples. An increased percentage (>30%) of spermatozoa with noncondensed ("immature") chromatin was revealed in 2 of 6 nonazoospermic semen samples analyzed by TEM.

580 Preservation of beta-cell function in pancreatic insufficient cystic fibrosis with highly effective cystic fibrosis transmembrane conductance regulator modulator therapy

580 Preservation of beta-cell function in pancreatic insufficient cystic fibrosis with highly effective cystic fibrosis transmembrane conductance regulator modulator therapy

Bone metabolism and incretin hormones following glucose ingestion in young adults with pancreatic insufficient cystic fibrosis

BackgroundGut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone (“gut-bone axis”) has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF. MethodsWe performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14–30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I N-terminal propeptide [P1NP]) during OGTT were computed. ResultsCTX decreased by 32% by min 120 of OGTT (P < 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0–120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP. ConclusionsIntact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the “gut-bone axis” warrants further attention in CF during the years surrounding peak bone mass attainment.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

828-P: Preservation of ß-Cell Function in Pancreatic Insufficient Cystic Fibrosis (CF) with Highly Effective CFTR Modulator Therapy

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) . ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p&amp;lt;0.01) . No differences in lung function or HbA1c were observed; however, improvement in oral glucose tolerance test 2-hour glucose was observed in the ETI group (p&amp;lt;0.05) that was different by trend from the change seen in controls (p=0.09) . Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p&amp;lt;0.05) but not in the ETI group, while C-peptide changes differed between groups (p&amp;lt;0.05) . A trend towards lower acute proinsulin response was seen in the ETI group (p=0.07) with the change different between groups (p&amp;lt;0.05) . Deterioration in the proinsulin secretory ratio was observed in the control (p&amp;lt;0.05) but not the ETI group (between group change, p=0.01) . ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF. Disclosure A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None. Funding Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .

Bone accrual and structural changes over one year in youth with cystic fibrosis

BackgroundPediatric bone accrual governs peak bone mass and strength. Longitudinal studies of bone health in youth with cystic fibrosis (CF) may provide insight into CF-related bone disease (CFBD), a prevalent co-morbidity in adults with CF. MethodsThis one-year longitudinal study of youth with pancreatic insufficient CF, enrolled in a nutrition intervention study [n = 62 (36 M/26F)] 1) examined dual-energy x-ray absorptiometry (DXA)-defined lumbar spine (LS) and total body less head (TBLH) bone accrual and 2) compared their changes in peripheral quantitative computed tomography (pQCT) cortical and trabecular tibial bone density and geometry to those of a healthy reference group [n = 143 (68 M/75F)].Main outcome measures were 1) DXA: lumbar spine areal bone mineral density (LSaBMD) and total body less head bone mineral content (TBLH-BMC), sex- and pubertal status-specific, height velocity (HV)-adjusted or HV and lean body mass velocity (HV-LBMV)-adjusted annualized velocity-Z scores and 2) pQCT: age, sex, pubertal status and, when appropriate, tibial length adjusted Z-scores for bone architecture measures.DXA velocity-Z were compared to expected mean of 0 and correlations with clinical parameters (age, BMI-Z and FEV1%-predicted) tested. Within-subject comparisons of HV-adjusted and LBMV-HV-adjusted DXA velocity-Z were conducted in CF.pQCT Z-scores were compared between the two groups over one year using longitudinal models. Longitudinal relationships between measures of bone health and clinical parameters (age, BMI-Z and FEV1%-predicted) were examined in individuals with CF. ResultsDXA velocity-Z were higher than normal in females (p < 0.05) but not males with CF. HV-adjusted and LBMV-HV-adjusted velocity-Z did not differ for LSaBMD or TBLH-BMC.In males with CF, both HV-adjusted and LBMV-HV-adjusted LSaBMD velocity-Z scores correlated negatively with age (HV rho: −0.35; p = 0.045 and LBMV-HV rho: −0.47; p = 0.0046). In males with CF BMI-Z correlated positively with HV-adjusted LSaBMD velocity-Z (rho: 0.37; p = 0.034), but this relationship did not persist for LBMV-HV (rho: 0.14; p = 0.42). In females with CF, no correlations between LSaBMD velocity-Z scores and age or BMI-Z were found (all p > 0.05). No correlations between LSaBMD velocity-Z scores and FEV1%-predicted were seen in either sex (all p > 0.12). TBLH-BMC velocity Z-scores were not correlated with clinical parameters in either sex (all p > 0.1).At baseline, multiple pQCT parameters were lower in CF (p < 0.05). pQCT Z-scores did not differ between baseline and one-year in either CF or reference group. In a longitudinal model comparing pQCT-Z changes in CF and reference, multiple pQCT-Z outcomes remained lower in CF, but the changes in parameters did not differ in CF vs reference (all p > 0.26). Lower pQCT outcomes in CF were largely restricted to males (CF group*female sex interaction beta coefficients > 0). In this combined longitudinal model, of both CF and reference, BMI-Z was positively associated with pQCT-Z parameters(p < 0.001).Multiple pQCT-Z outcomes positively correlated with both BMI-Z and FEV1%-predicted in males with CF, and with FEV1%-predicted in females with CF (p < 0.05). Age was negatively associated with section modulus (p = 0.001) in males and with cortical density-Z in females (p < 0.001). ConclusionsWith improved longevity, bone health in CF is of increasing importance. On average, bone accrual was preserved in youth with CF, and while deficits in bone geometry and strength were found, these deficits did not worsen over the one-year study. Lower LS bone accrual with increasing age suggests emerging adulthood is a period of vulnerability in CF while the role of LBM in bone health is underscored by the lack of relationship between LBMV-adjusted accrual and BMI. These findings may be useful in targeting screening practices and interventions.

Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.

Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 09 September 2021. We also searched online trial registries. Date of last search: 12 October 2021. Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the certaintyof the evidence using GRADE criteria. We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias. Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05). We assessed the available data to be very low certainty. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the certaintya further level for precision. There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice. Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.

Fat-Soluble Vitamin Supplementation Using Liposomes, Cyclodextrins, or Medium-Chain Triglycerides in Cystic Fibrosis: A Randomized Controlled Trial.

Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-α-tocopherol, and 200 µg of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of β-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19–28), body mass index of 20.6 kg/m2 [18.4–22.0], and forced expiratory volume in 1 s of 65% (44–84%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng/mL (IQR −44.3–86.1) vs. −38.8 ng/mL (−71.2–6.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng/mL (1.0–17.0) vs. +3.0 ng/mL (−4.0–7.0), p = 0.012) and vitamin E (+4.34 µg/mL (0.33–6.52) vs. −0.34 µg/mL (−1.71–2.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).

Vitamin D Status in Pediatric and Young Adult Cystic Fibrosis Patients. Are the New Recommendations Effective?

Introduction: In recent years, guidelines for vitamin D supplementation have been updated and prophylactic recommended doses have been increased in patients with cystic fibrosis (CF). Objective: To evaluate safety and efficacy of these new recommendations. Results: Two cohorts of pancreatic insufficient CF patients were compared before (cohort 1: 179 patients) and after (cohort 2: 71 patients) American CF Foundation and European CF Society recommendations were published. Cohort 2 patients received higher Vitamin D doses: 1509 (1306–1711 95% CI) vs 1084 (983–1184 95% CI) IU/Day (p < 0.001), had higher 25 OH vitamin D levels: 30.6 (27.9–33.26 95% CI) vs. 27.4 (25.9–28.8 95% CI) ng/mL (p = 0.028), and had a lower prevalence of insufficient vitamin D levels (<30 ng/mL): 48% vs 65% (p = 0.011). Adjusted by confounding factors, patients in cohort 1 had a higher risk of vitamin D insufficiency: OR 2.23 (1.09–4.57 95% CI) (p = 0.028). Conclusion: After the implementation of new guidelines, CF patients received higher doses of vitamin D and a risk of vitamin D insufficiency decreased. Despite this, almost a third of CF patients still do not reach sufficient serum calcidiol levels.

CFTR modulators increase risk of acute pancreatitis in pancreatic insufficient patients with cystic fibrosis

Patients with pancreatic insufficient cystic fibrosis rarely develop acute pancreatitis due to insufficient acinar reserve. We describe a series of five patients under the age of 18 (range 8-16 years) with pancreatic insufficient cystic fibrosis who developed a phenotype in keeping with acute pancreatitis following initiation of CFTR modulator therapy. This occurred at a median of 30 months following CFTR modulator initiation. 3/5 of these patients also developed pancreatic sufficiency or at least an intermediary pancreas status, indicated by fecal elastases above 100 μg/g. This series highlights a mostly unrecognized potential side effect of this therapy as well as the potential of CFTR modulator therapies to improve exocrine pancreatic function, even in adolescent patients.

Persistent Nutritional Deficiency in Pancreatic-Insufficient Children and Adolescents with Cystic Fibrosis Despite Therapeutic Intervention

Abstract Background Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF Transmembrane Conductance Regulator (CFTR) protein, resulting in compromised pulmonary function, malabsorption, and pancreatic insufficiency. The sequelae of CF are heterogeneous, and contributing factors are multifactorial. Nutritional deficiencies, particularly in essential fatty acids (EFA) and vitamins, are known to alter the trajectory of CF unfavorably. The current treatment modalities focus on proactive management of the pulmonary, gastrointestinal, and pancreatic functions; however, information on the monitoring and treatment of nutritional deficiencies in CF patients is scant. The objective of our study was to evaluate the effects of pancreatic function and CFTR modulator therapy on pertinent nutritional deficiencies in children and adolescents diagnosed with CF. Methods The study was approved by our institutional IRB and included 77 non-fasted CF participants, 10.4 + 5.2 years of age (range: 4 months-18 years), and an equal ratio of both sexes. Participants were stratified as pancreatic sufficient (PS, n=6), and pancreatic insufficient with (PI, n=48) or without CFTR modulator treatment (PI-M, n=23). Twenty-two fatty acids were measured in plasma by GC-MS, including omega-6 linoleic acid (LA), and omega-3 α-linoleic acid (ALA). Medical records and 24-hour dietary recalls were reviewed to correlate biochemical and clinical findings. Vitamins A and E and zinc levels of the participants were also obtained. Data analyses were performed by one-way ANOVA and Tukey’s multiple comparisons using Prism software (LaJolla, CA). Results There were no significant differences in BMI and caloric intake among the groups. The concentrations of EFA, LA, and ALA were significantly higher in the PS group (3904±229 nmol/mL and 149±24 nmol/mL) compared to the PI (2387±89 nmol/mL and 53±4 nmol/mL, p&amp;lt;0.01) and PI-M (2335±159 nmol/mL and 58±7 nmol/mL, p&amp;lt;0.01) groups, respectively. Similarly, the biologically active omega-6 arachidonic acid and omega-3 docosahexaenoic acid were lower in the PI and PI-M groups compared to the PS group (p&amp;lt;0.05). Interestingly, EFA deficiency biomarkers, omega-9 mead acid, and the Triene:Tetraene ratio, were significantly higher in the PI group (17±2 nmol/mL and 0.033±0.003) vs PS group (13±3 nmol/mL and 0.019±0.002, p&amp;lt;0.05), respectively. Higher concentrations of vitamins A and E were observed in the PS group vs PI-M groups (p&amp;lt;0.05), and zinc concentrations were not different among the groups. There were no associations between the concentrations of EFA and BMI, age, total caloric intake, and % calories from fat in PS, PI, and PI-M patients. Conclusion While advances in CF therapeutics are remarkable, our data show the persistence of nutritional deficiencies in pancreatic insufficient CF patients regardless of CFTR modulator therapy and support the clinical utility of EFA and vitamins as potential adjuvant biomarkers to assess the severity and assist in the clinical monitoring of CF.

Acute Pancreatitis in a Previously Exocrine Pancreatic Insufficient Cystic Fibrosis Patient Who Had Improved Pancreatic Function After Being Treated With Lumacaftor/Ivacaftor

Exocrine pancreatic insufficiency (EPI) is a common complication of cystic fibrosis (CF). While previously considered to be irreversible, recent reported cases document improved pancreatic function in CF patients with mild mutations after ivacaftor treatment alone. We report a 12-year-old female with homozygous F508del CF and EPI who developed acute pancreatitis after 3 years on lumacaftor/ivacaftor and subsequently had improved pancreatic function. As CF therapies advance, some EPI CF patients with more severe CF transmembrane conductance regulator mutations may see improved pancreatic function and subsequently develop pancreatitis.

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Increased Fecal Calprotectin Is Associated with Worse Gastrointestinal Symptoms and Quality of Life Scores in Children with Cystic Fibrosis

In cystic fibrosis (CF), cystic fibrosis transmembrane regulator (CFTR) dysfunction leads to digestive disorders that promote intestinal inflammation and dysbiosis enhancing gastrointestinal symptoms. In pancreatic insufficiency CF patients, both intestinal inflammation and dysbiosis, are associated with an increase in the fecal calprotectin (FC) level. However, associations between the FC level, gastrointestinal symptoms, and quality of life (QoL) remain poorly studied. We aimed to assess such associations in pancreatic insufficiency CF children. The FC level was measured in pancreatic insufficiency CF children’s stool samples. Children and their parents completed two questionnaires: The Gastrointestinal Symptoms Scales 3.0-PedsQLTM and the Quality of Life Pediatric Inventory 4.0-PedsQLTM. Lower scores indicated worse symptomatology or QoL. Thirty-seven CF children were included. A FC level above 250 µg/g was associated with worse gastrointestinal symptoms and QoL scores. The FC level was inversely correlated with several gastrointestinal scores assessed by children (i.e., Total, “Heart Burn Reflux”, “Nausea and Vomiting”, and “Gas and Bloating”). Several QoL scores were correlated with gastrointestinal scores. The FC level was weakly associated with clinical parameters. Some gastrointestinal and QoL scores were related to disease severity associated parameters. In CF, the FC level, biomarker previously related to intestinal inflammation and dysbiosis, was associated with worse digestive symptoms and QoL scores.