Sarah Jane Schwarzenberg

Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 +/- 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD.

Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: A consensus conference report

Cystic fibrosis (CF) is the most common lifethreatening autosomal recessive disease of Caucasians in the USA, affecting 1/3000 live births [1]. Gene defects on the long arm of chromosome 7 lead to defective production of a protein called the cystic fibrosis transmembrane regulator (CFTR). CFTR is a cAMP-dependent chloride channel which influences the water and electrolyte composition of secretions from sweat glands, airways, pancreatic ducts, hepatobiliary ducts and intestinal glands. The common pathological finding in these organs is accumulation of thick, viscous secretions associated with progressive obstruction, scarring and destruction; 84% of CF patients die from respiratory disease [2]. Improvements in pulmonary and nutritional care over the last few decades have led to dramatic improvements in the mortality rate, and now many patients with CF live into their third, fourth or fifth decades. The median life expectancy for CF patients at present is 31.3 years [2]. As CF patients Abbre6iations: ADA, American Diabetes Association; CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes mellitus; CFTR, cystic fibrosis transmembrane regulator; DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; 2-h PG, 2-h plasma glucose during oral glucose tolerance test; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SMBG ,self-monitoring of blood glucose. * Corresponding author. Present address: Pediatric Department Box 404, University of Minnesota, 516 Delaware St. SE, Minneapolis, Minnesota 55455, USA. Tel.: +1-612-624-5409; fax: +1-612-624-2682. E-mail address: moran001@tc.umn.edu (A. Moran)

European Cystic Fibrosis Society Standards of Care: Best Practice guidelines.

Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously. To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. Our current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of our document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1. We hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres.

Quality of Life Improves for Pediatric Patients After Total Pancreatectomy and Islet Autotransplant for Chronic Pancreatitis

BACKGROUND & AIMS Total pancreatectomy (TP) and islet autotransplant (IAT) have been used to treat patients with painful chronic pancreatitis. Initial studies indicated that most patients experienced significant pain relief, but there were few validated measures of quality of life. We investigated whether health-related quality of life improved among pediatric patients undergoing TP/IAT. METHODS Nineteen consecutive children (aged 5-18 years) undergoing TP/IAT from December 2006 to December 2009 at the University of Minnesota completed the Medical Outcomes Study 36-item Short Form (SF-36) health questionnaire before and after surgery. Insulin requirements were recorded. RESULTS Before TP/IAT, patients had below average health-related quality of life, based on data from the Medical Outcomes Study SF-36; they had a mean physical component summary (PCS) score of 30 and mental component summary (MCS) score of 34 (2 and 1.5 standard deviations, respectively, below the mean for the US population). By 1 year after surgery, PCS and MCS scores improved to 50 and 46, respectively (global effect, PCS P < .001, MCS P = .06). Mean scores improved for all 8 component subscales. More than 60% of IAT recipients were insulin independent or required minimal insulin. Patients with prior surgical drainage procedures (Puestow) had lower yields of islets (P = .01) and greater incidence of insulin dependence (P = .04). CONCLUSIONS Quality of life (physical and emotional components) significantly improve after TP/IAT in subsets of pediatric patients with severe chronic pancreatitis. Minimal or no insulin was required for most patients, although islet yield was reduced in patients with previous surgical drainage operations.

Total pancreatectomy and islet autotransplantation in children for chronic pancreatitis: Indication, surgical techniques, postoperative management, and long-term outcomes

Objective:Describe the surgical technique, complications, and long-term outcomes of total pancreatectomy and islet autotransplantation (TP-IAT) in a large series of pediatric patients. Background:Surgical management of childhood pancreatitis is not clear; partial resection or drainage procedures often provide transient pain relief, but long-term recurrence is common due to the diffuse involvement of the pancreas. Total pancreatectomy (TP) removes the source of the pain, whereas islet autotransplantation (IAT) potentially can prevent or minimize TP-related diabetes. Methods:Retrospective review of 75 children undergoing TP-IAT for chronic pancreatitis who had failed medical, endoscopic, or surgical treatment between 1989 and 2012. Results:Pancreatitis pain and the severity of pain statistically improved in 90% of patients after TP-IAT (P < 0.001). The relief from narcotics was sustained. Of the 75 patients undergoing TP-IAT, 31 (41.3%) achieved insulin independence. Younger age (P = 0.032), lack of prior Puestow procedure (P = 0.018), lower body surface area (P = 0.048), higher islet equivalents (IEQ) per kilogram body weight (P = 0.001), and total IEQ (100,000) (P = 0.004) were associated with insulin independence. By multivariate analysis, 3 factors were associated with insulin independence after TP-IAT: (1) male sex, (2) lower body surface area, and (3) higher total IEQ per kilogram body weight. Total IEQ (100,000) was the single factor most strongly associated with insulin independence (odds ratio = 2.62; P < 0.001). Conclusions:Total pancreatectomy and islet autotransplantation provides sustained pain relief and improved quality of life. The &bgr;-cell function is dependent on islet yield. Total pancreatectomy and islet autotransplantation is an effective therapy for children with painful pancreatitis that failed medical and/or endoscopic management.

Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6‐month, randomized, open‐label, crossover, clinical trial consisting of two, 3‐month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase‐order (i.e., starting with control or drug therapy) then crossed‐over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3‐, and 6‐months. The mean change over each 3‐month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% confidence interval (CI) (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/l, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT‐derived insulin sensitivity (P = 0.02) and β‐cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well‐tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well‐controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Role of serology and routine laboratory tests in childhood inflammatory bowel disease

IntroductionSerology is reported to be helpful in evaluating children for inflammatory bowel disease (IBD), and distinguishing chronic ulcerative colitis (CUC) from Crohns disease (CD). The markers include perinuclear staining antineutrophil cytoplasmic antibody (pANCA) for CUC and anti-Saccharomyces cerevisiae antibody (ASCA) for CD. In the clinical setting, hemoglobin (Hgb) and erythrocyte sedimentation rate (ESR) are commonly performed for screening symptomatic children for IBD. We examined whether there was an additional benefit of serology in addition to specific symptoms and routine laboratory tests in screening for IBD. MethodMedical record data was reviewed on children investigated for IBD from February 1999 to April 2001. Children were included if they had blood analyzed for pANCA and ASCA, Hgb, ESR, and colonoscopy as part of their assessment. ResultsOf 177 cases reviewed, 51 were diagnosed with CUC, 39 with CD, and 26 other inflammatory conditions. Visible rectal bleeding was the most discriminating symptom (occurred in 60/90 cases of IBD and 5/61 without IBD). There was a significant difference between the proportion with CUC positive for pANCA (42/51) and those with abnormal Hgb and ESR (30/51) (p < 0.05), but not between children with CD who were ASCA positive (18/39) and those with abnormal Hgb and ESR (26/39) (p = 0.27). The sensitivity and specificity of combined pANCA and ASCA was 68% and 92%, respectively. For the combination of Hgb, ESR, and the presence of rectal bleeding the respective values were 86% and 67%. Serology combined with Hgb and ESR and rectal bleeding as independent factors significantly (p < 0.05) improved sensitivity (89%) but reduced specificity (60%). Screening with the combination of rectal bleeding, Hgb, and ESR identified 86% (77/90) patients with IBD prior to an endoscopic procedure. A further 3 of 90 (3.3%) screened positive with the addition of serology. ConclusionSerology tests have a high degree of specificity for IBD while routine laboratory test have a higher sensitivity. When serology is combined with rectal bleeding, Hgb, and ESR, the sensitivity of screening children for IBD is significantly improved. However the large majority of children with IBD can be identified with a clinical history and routine laboratory tests as needing an endoscopic procedure with little benefit of adding serology.

Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest.

DESCRIPTION Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure used to treat severe complications of chronic pancreatitis or very high risk of pancreatic cancer while reducing the risk of severe diabetes mellitus. However, clear guidance on indications, contraindications, evaluation, timing, and follow-up are lacking. METHODS A working group reviewed the medical, psychological, and surgical options and supporting literature related to TPIAT for a consensus meeting during PancreasFest. RESULTS Five major areas requiring clinical evaluation and management were addressed: These included: 1) indications for TPIAT; 2) contraindications for TPIAT; 3) optimal timing of the procedure; 4) need for a multi-disciplinary team and the roles of the members; 5) life-long management issues following TPIAP including diabetes monitoring and nutrition evaluation. CONCLUSIONS TPIAT is an effective method of managing the disabling complications of chronic pancreatitis and risk of pancreatic cancer in very high risk patients. Careful evaluation and long-term management of candidate patients by qualified multidisciplinary teams is required. Multiple recommendations for further research were also identified.

Circulating oxidized LDL and inflammation in extreme pediatric obesity.

Oxidative stress and inflammation have not been well‐characterized in extreme pediatric obesity. We compared levels of circulating oxidized low‐density lipoprotein (oxLDL), C‐reactive protein (CRP), and interleukin‐6 (IL‐6) in extremely obese (EO) children to normal weight (NW) and overweight/obese (OW/OB) children. OxLDL, CRP, IL‐6, BMI, blood pressure, and fasting glucose, insulin, and lipids were obtained in 225 children and adolescents (age 13.5 ± 2.5 years; boys 55%). Participants were classified into three groups based on gender‐ and age‐specific BMI percentile: NW (<85th, n = 127), OW/OB (85th– <1.2 times the 95th percentile, n = 64) and EO (≥1.2 times the 95th percentile or BMI ≥35 kg/m2, n = 34). Measures were compared across groups using analysis of covariance, adjusted for gender, age, and race. Blood pressure, insulin, and lipids worsened across BMI groups (all P < 0.0001). OxLDL (NW: 40.8 ± 9.0 U/l, OW/OB: 45.7 ± 12.1 U/l, EO: 63.5 ± 13.8 U/l) and CRP (NW: 0.5 ± 1.0 mg/l, OW/OB: 1.4 ± 2.9 mg/l, EO: 5.6 ± 4.9 mg/l) increased significantly across BMI groups (all groups differed with P < 0.01). IL‐6 was significantly higher in EO (2.0 ± 0.9 pg/ml) compared to OW/OB (1.3 ± 1.2 pg/ml, P < 0.001) and NW (1.1 ± 1.0 pg/ml, P < 0.0001) but was not different between NW and OW/OB. Extreme pediatric obesity, compared to milder forms of adiposity and NW, is associated with higher levels of oxidative stress and inflammation, suggesting that markers of early cardiovascular disease and type 2 diabetes mellitus are already present in this young population.

PEDIATRIC CHRONIC PANCREATITIS IS ASSOCIATED WITH GENETIC RISK FACTORS AND SUBSTANTIAL DISEASE BURDEN

OBJECTIVE To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. STUDY DESIGN We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. RESULTS Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). CONCLUSIONS Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.