Impact of intravenous fish oil on omega-3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) can lead to intestinal failure-associated liver disease (IFALD). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA-derived and DHA-derived oxylipins could contribute to this protective effect. METHODS: We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA-derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish-oil PN. RESULTS: EPA plus DHA in erythrocytes (the Omega-3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega-3-Index to 12.75%. EPA-derived and DHA-derived CYP-dependent and LOX-dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. CONCLUSIONS: This study shows that fish oil-containing PN leads to primarily CYP- and LOX-dependent n-3 PUFA-derived inflammation-dampening oxylipins arising from EPA and DHA. Within this short (16-week) study, there were no significant changes in inflammation and clinical readout parameters.

Oral intake and plasma citrulline predict quality of life in patients with intestinal failure.

OBJECTIVE: Chronic intestinal failure (cIF) is a rare medical condition usually treated by long-term parenteral nutrition (PN). Owing to disease-associated symptoms and treatment-specific complications, patients with cIF commonly present with reduced quality of life (QoL) compared with healthy controls. The aim of this study was to identify factors associated with QoL in patients with cIF. METHODS: Ninety adult patients with cIF receiving PN were included in an observational study between 2014 and 2017. QoL based on the novel Short Bowel Syndrome-Quality of Life (SBS-QoL) scale and the Short-Form 36 (SF-36) health survey and nutritional status, liver function, and standard blood chemistry were assessed in every study patient. Univariate and multivariable regressions were conducted to determine independent predictors of QoL. RESULTS: Oral food intake and plasma citrulline were the two independent variables associated with the SBS-QoL subscale 1 (R2 = 0.240) and subscale 2 (R2 = 0.235). Oral intake (ß = -43.909, P = 0.015) and citrulline (ß = -0.952, P = 0.003) were also significantly associated with the SBS-QoL sum scale (R2 = 0.209). The results of SF-36 health survey were significantly associated with both SBS-QoL subscale 1 (P <0.001) and subscale 2 (P <0.001) and the SBS-QoL sum scale (P <0.001). CONCLUSIONS: Citrulline and oral intake are predictors of QoL in patients with cIF. Although citrulline appears to be good screening tool, oral food ingestion should be considered as key goal in patients with cIF.

Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition-Results from the Prospective PNLiver Trial.

Abstract: Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB-4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests.

Determinants of Quality of Life in Patients With Intestinal Failure Receiving Long-Term Parenteral Nutrition Using the SF-36 Questionnaire: A German Single-Center Prospective Observational Study.

BACKGROUND: Parenteral nutrition (PN) is a life-sustaining therapy for patients with chronic intestinal failure (IF) but inevitably has an impact on patients' quality of life (QoL). The purpose of this study was to examine multiple aspects of QoL by utilizing the standardized Short Form 36 (SF-36) health survey. METHODS: Between 2014 and 2017, a total of 90 adult patients with IF who were receiving PN were prospectively enrolled in an observational study. All subjects underwent nutrition status assessment, liver assessment, blood tests, and QoL assessment based on the SF-36. Univariate and multivariable analyses were performed to identify determinants of 8 domains and 2 summary scales of the SF-36. RESULTS: Analysis of the SF-36 questionnaire data showed that QoL was significantly worse compared with the general German population across all categories. Multivariable analysis revealed that bioelectrical impedance analysis of phase angle (1/10 categories), stoma/fistula (4/10 categories), oral intake (4/10 categories), infusions per week (1/10 categories), duration of PN (1/10 categories), citrulline (4/10 categories), and hemoglobin levels (1/10 categories) are independent risk factors affecting QoL. CONCLUSION: This study uses the largest cohort of IF patients assessed by the standardized SF-36 questionnaire to comprehensively analyze QoL. Presence of oral intake, presence of ostomy, and citrulline levels were independently correlated with 4 of 10 categories of the SF-36. These results indicate that to improve QoL for IF patients, clinical care should focus on addressing the social and emotional value of oral intake, educational interventions, early stoma closure, and application of new targeted therapies.

Advanced liver function assessment in patients with intestinal failure on long-term parenteral nutrition.

BACKGROUND & AIMS: Intestinal failure associated liver disease (IFALD) is one of the leading complications and causes of deaths in adult patients receiving home parenteral nutrition for chronic intestinal failure (CIF). Early diagnosis of IFALD is key to alleviate the progression of hepatic dysfunction. The aim of this study was to evaluate the capability of noninvasive liver function tests. METHODS: 90 adult patients with CIF receiving long-term home parenteral nutrition were included in a prospective cross-sectional study at our department between 2014 and 2017. All participants underwent dynamic liver function assessment (maximum liver function capacity [LiMAx] test, indocyanine green [ICG] test), transient elastography (FibroScan), blood tests and comprehensive nutritional status assessment. Univariate and multivariable analysis were performed to identify predictors of liver function. RESULTS: LiMAx, ICG test, and FibroScan highly correlated with standard liver function tests. Multivariable analysis identified intact ileum (B = 520.895; p = 0.010), digestive anatomy type 3 (B = 75.612; p = 0.025), citrulline level (B = 3.428; p = 0.040), parenteral olive oil intake (B = -0.570; p = 0.043), and oral intake (B = 182.227; p = 0.040) as independent risk factors affecting liver function determined by LiMAx test. ICG test and FibroScan showed no correlation with gastrointestinal and nutrition-related parameters. CONCLUSION: The LiMAx test is significantly associated with widely accepted risk factors for IFALD by multivariable analysis, whereas ICG test and FibroScan failed to show significant correlations. Liver function assessment by LiMAx test may therefore have the potential to detect alterations in liver function and identify patients at risk for the development of IFALD. Longitudinal studies are needed to investigate the impact of liver function determined by LiMAx test on long-term outcome in patients with CIF.

Experience with teduglutide treatment for short bowel syndrome in clinical practice.

BACKGROUND & AIMS: Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is an approved medication specific for short bowel syndrome patients with chronic intestinal failure (SBS-IF). Due to its intestinotrophic properties, it improves intestinal absorption of fluids and nutrients, which was shown to reduce the need for parenteral support in clinical trials. The present report aims to describe the experience of teduglutide's effects in routine medical care with focus on clinical and nutritional effects. METHODS: Data of adult SBS-IF patients, treated with teduglutide between Sept. 2014 and May 2017 within a structured multidisciplinary program to enhance intestinal rehabilitation, were analyzed retrospectively from a single university medical center. RESULTS: In total, 27 patients were treated with teduglutide. Parenteral nutrition independency was achieved in 4/19 (21%) patients analyzed, with two remaining on intravenous fluids. A clinically significant reduction of parenteral volume was observed in 15/19 patients (79%) with onset between 1 and 45 weeks. Significant parenteral support reductions were observed, ranging from about -20% in patients treated for 3 months to about -45% in patients treated for 2 years. This was accompanied by an increase in parenteral nutrition-free days. We also report on a clinically relevant and significant effect of teduglutide-mediated improvement of stool frequency and consistency. Furthermore, nutritional status subgroup analysis revealed long-term stability in body weight, albumin levels and body composition albeit parenteral support reduction. Structural effects of teduglutide treatment were observed on small intestinal mucosa with significantly increased villus height, crypt depth and plasma citrulline levels. CONCLUSIONS: Teduglutide can be applied to anatomically and clinically heterogeneous SBS-IF patients and results in an adaptive response with variable time and effect range in routine medical care. Teduglutide-induced functional and structural changes bring on a gradual reduction of parenteral support at no cost to body composition and suggest an improved intestinal function with compensatory effect on nutritional status.

Chiral lipidomics of monoepoxy and monohydroxy metabolites derived from long-chain polyunsaturated fatty acids.

A chiral lipidomics approach was established for comprehensive profiling of regio- and stereoisomeric monoepoxy and monohydroxy metabolites of long-chain PUFAs as generated enzymatically by cytochromes P450 (CYPs), lipoxygenases (LOXs), and cyclooxygenases (COXs) and, in part, also unspecific oxidations. The method relies on reversed-phase chiral-LC coupled with ESI/MS/MS. Applications revealed partially opposing enantioselectivities of soluble and microsomal epoxide hydrolases (mEHs). Ablation of the soluble epoxide hydrolase (sEH) gene resulted in specific alterations in the enantiomeric composition of endogenous monoepoxy metabolites. For example, the (R,S)/(S,R)-ratio of circulating 14,15-EET changed from 2.1:1 in WT to 9.7:1 in the sEH-KO mice. Studies with liver microsomes suggested that CYP/mEH interactions play a primary role in determining the enantiomeric composition of monoepoxy metabolites during their generation and release from the ER. Analysis of human plasma showed significant enantiomeric excess with several monoepoxy metabolites. Monohydroxy metabolites were generally present as racemates; however, Ca2+-ionophore stimulation of whole blood samples resulted in enantioselective increases of LOX-derived metabolites (12S-HETE and 17S-hydroxydocosahexaenoic acid) and COX-derived metabolites (11R-HETE). Our chiral approach may provide novel opportunities for investigating the role of bioactive lipid mediators that generally exert their physiological functions in a highly regio- and stereospecific manner.

Possible Role of CYP450 Generated Omega-3/Omega-6 PUFA Metabolites in the Modulation of Blood Pressure and Vascular Function in Obese Children.

Obesity is often accompanied by metabolic and haemodynamic disorders such as hypertension, even during childhood. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), vasoactive and natriuretic metabolites that contribute to blood pressure (BP) regulation. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 polyunsaturated fatty acids may compete with AA for CYP450-dependent bioactive lipid mediator formation. We aimed at investigating the role of AA, EPA and DHA and their CYP450-dependent metabolites in BP control and vascular function in 66 overweight/obese children. Fatty acid profile moderately correlated with the corresponding CYP450-derived metabolites but their levels did not differ between children with normal BP (NBP) and high BP (HBP), except for higher EPA-derived epoxyeicosatetraenoic acids (EEQs) and their diols in HBP group, in which also the estimated CYP450-epoxygenase activity was higher. In the HBP group, EPA inversely correlated with BP, EEQs inversely correlated both with systolic BP and carotid Intima-Media Thickness (cIMT). The DHA-derived epoxydocosapentaenoic acids (EDPs) were inversely correlated with diastolic BP. Omega-3 derived epoxymetabolites appeared beneficially associated with BP and vascular structure/function only in obese children with HBP. Further investigations are needed to clarify the role of omega-3/omega-6 epoxymetabolites in children's hemodynamics.

Ketogenic diets attenuate cyclooxygenase and lipoxygenase gene expression in multiple sclerosis.

BACKGROUND: Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for inflammatory, hyperproliferative and neurodegenerative diseases. Pro-inflammatory eicosanoids have been implicated in the pathogenesis of multiple sclerosis since they augment vascular permeability and induce leukocyte migration into the brain. We explored the impact of ketogenic diets on gene expression of biosynthetic enzymes for pro- (ALOX5, COX1, COX2) and anti-inflammatory (ALOX15) eicosanoids in patients with relapsing-remitting multiple sclerosis. METHODS: 60 adults were prospectively recruited for this six months randomized controlled trial and the impact of dietary treatment on the Multiple Sclerosis Quality of Life-54 index (ClinicalTrials.gov (NCT01538355) has previously been published. Here we explored 24 patients (8 controls, 5 on CR and 11 on AKD). For statistical analysis we combined the two diet groups to a single pooled treatment group. FINDINGS: Inter-group comparison indicated that expression of the pro-inflammatory ALOX5 in the pooled treatment group was significantly (p < 0.05) reduced when compared with the control group. Moreover, intra-group comparison (same individuals before and after dietary treatment) suggested significantly impaired expression of other pro-inflammatory enzymes, such as COX1 (p < 0.001) and COX2 (p < 0.05). Finally, pretreatment cross-group analysis revealed a significant positive correlation between expression of pro-inflammatory ALOX5 and COX2 and an inverse correlation of ALOX5 and COX1 expression with the MSQoL-54 index. INTERPRETATION: Ketogenic diets can reduce the expression of enzymes involved in the biosynthesis of pro-inflammatory eicosanoids. Pharmacological interference with eicosanoid biosynthesis might constitute a strategy supplementing current therapeutic approaches for MS.