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

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<0.01) and PI-M (2335±159 nmol/mL and 58±7 nmol/mL, p<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<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<0.05), respectively. Higher concentrations of vitamins A and E were observed in the PS group vs PI-M groups (p<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.

Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients—Effects of Lipid Emulsions

Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9–21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.

Impact of Treatment with RUTF on Plasma Lipid Profiles of Severely Malnourished Pakistani Children

(1) Background: Little is known on impacts of ready-to-use therapeutic food (RUTF) treatment on lipid metabolism in children with severe acute malnutrition (SAM). (2) Methods: We analyzed glycerophospholipid fatty acids (FA) and polar lipids in plasma of 41 Pakistani children with SAM before and after 3 months of RUTF treatment using gas chromatography and flow-injection analysis tandem mass spectrometry, respectively. Statistical analysis was performed using univariate, multivariate tests and evaluated for the impact of age, sex, breastfeeding status, hemoglobin, and anthropometry. (3) Results: Essential fatty acid (EFA) depletion at baseline was corrected by RUTF treatment which increased EFA. In addition, long-chain polyunsaturated fatty acids (LC-PUFA) and the ratio of arachidonic acid (AA)/linoleic acid increased reflecting greater EFA conversion to LC-PUFA, whereas Mead acid/AA decreased. Among phospholipids, lysophosphatidylcholines (lyso.PC) were most impacted by treatment; in particular, saturated lyso.PC decreased. Higher child age and breastfeeding were associated with great decrease in total saturated FA (ΣSFA) and lesser decrease in monounsaturated FA and total phosphatidylcholines (ΣPC). Conclusions: RUTF treatment improves EFA deficiency in SAM, appears to enhance EFA conversion to biologically active LC-PUFA, and reduces lipolysis reflected in decreased ΣSFA and saturated lyso.PC. Child age and breastfeeding modify treatment-induced changes in ΣSFA and ΣPC.

The Effects of Omega-3 Supplementation and Doxorubicin-Based Chemotherapy on the Murine Brain Lipidome

Objectives To determine how omega-3 (n3-FA) supplementation may confer protection against lipid modifications following doxorubicin-based chemotherapy (DOX). Methods Ovariectomized C57BL/6 mice consumed a diet with 0% or 2% kcal supplemental EPA + DHA for 4 weeks, followed by two injections of either DOX (9 mg/kg) + cyclophosphamide (90 mg/kg), or vehicle. In study 1, animals were sacrificed at 4, 7, and 14 days after the last injection (n = 120) and in study 2, at 10 days after the last injection (n = 40). Whole brain from study 1 were analyzed by targeted methods (UHPLC-MS/MS), to quantify specialized pro-resolving mediators resolvin D1 (RvD1), resolvin D2 (RvD2), resolvin D3 (RvD3), resolvin D5 (RvD5), resolvin E1 (RvE1), maresin (MaR1), and protectin (PD1). In study 2, lipidomics analyses were performed on hippocampus to determine changes in the lipidome after n3-FA supplementation and chemotherapy injection. Results Study 1 results: RvD1 was present in all samples, but no significant differences in concentration were observed regardless of treatment or dietary group. RvD3, PD1 and MaR1 were detected in a subset of samples. Study 2 results: EPA + DHA (2%) supplementation favorably altered lipids associated with cognitive function (i.e., PE (P-16:0/20:5), PE (P-18:0/22:6, with adjusted p-value equal to 0.003 and 0.04 respectively), which have been previously negatively correlated with Alzheimer's and Parkinson's disease. Chemotherapy treatment increases omega-9 fatty acids (i.e., nervonic, gadoleic and mead acid) previously positively correlated with diseases of cognitive decline (e.g., Alzheimer's, Parkinson's). No chemo*n3-FA interaction was observed (p-value > 0.05). Conclusions N3-FA supplementation favorably altered lipids associated with cognitive function. DOX increased lipids associated with diseases of cognitive decline. Future investigations will determine if the same biomarkers of n-3 FA consumption and chemotherapy are observed in human breast cancer patients. Funding Sources This research was supported by a Foods for Health Discovery Themes Initiative SEEDS grant, NIH R01CA189947, NIH Award Number Grant P30 CA016058, OSU, and OSUCCC.

The Impact of Glucose-Based or Lipid-Based Total Parenteral Nutrition on the Free Fatty Acids Profile in Critically Ill Patients

Introduction: Our study aim was to assess how the macronutrient intake during total parenteral nutrition (TPN) modulates plasma total free fatty acids (FFAs) levels and individual fatty acids in critically ill patients. Method: Adult patients aged 18–80, admitted to the intensive care unit (ICU), who were indicated for TPN, with an expected duration of more than three days, were included in the study. Isoenergetic and isonitrogenous TPN solutions were given with a major non-protein energy source, which was glucose (group G) or glucose and lipid emulsions (Smof lipid; group L). Blood samples were collected on days 0, 1, 3, 6, 9, 14, and 28. Results: A significant decrease (p < 0.001) in total FFAs occurred in both groups with a bigger decrease in group G (p < 0.001) from day 0 (0.41 ± 0.19 mmol∙L−1) to day 28 (0.10 ± 0.07 mmol∙L−1). Increased palmitooleic acid and decreased linoleic and docosahexaenoic acids, with a trend of increased mead acid to arachidonic acid ratio, on day 28 were observed in group G in comparison with group L. Group G had an insignificant increase in leptin with no differences in the concentrations of vitamin E, triacylglycerides, and plasminogen activator inhibitor-1. Conclusion: Decreased plasma FFA in critically ill patients who receive TPN may result from increased insulin sensitivity with a better effect in group G, owing to higher insulin and glucose dosing and no lipid emulsions. It is advisable to include a lipid emulsion at the latest from three weeks of TPN to prevent essential fatty acid deficiency.