The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine.

The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 108 RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 108 RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.

Superior vena cava syndrome in chronic intestinal failure patients: When the going gets tough.

BACKGROUND & AIMS: Catheter-related venous thrombosis is a severe complication of home parenteral nutrition (HPN) with potentially devastating consequences such as superior vena cava syndrome (SVCS). Early recognition and awareness of factors leading to its development are of paramount importance. However, studies are lacking in HPN patients focusing on this topic. In this study, we aimed to determine the incidence of SVCS in HPN patients and describe SVCS-related outcomes. METHODS: This retrospective cohort study comprised all adult HPN patients who developed SVCS between 2000 and 2022 at our national HPN referral center. Primary outcome was the incidence of SVCS. Secondary outcomes include SVCS-related symptoms, tip location of central venous access device (CVAD) post-insertion and at time of SVCS, diagnostics and treatment. RESULTS: SVCS was diagnosed in 38 of 616 patients (6%), with an annual cumulative incidence rate ranging between 0 and 4.2%. Most common presenting symptoms were facial edema (82%) and arm edema (50%). Post-insertion, 17% (6/36) of patients had a correct position of the CVAD tip and 11% (4/36) during SVCS diagnosis. Computed tomography was the most used diagnostic imaging technique (66%). Sixty-three percent of patients started, 11% switched, and 21% continued anticoagulant treatment. CONCLUSIONS: The incidence of SVCS is relatively high in our vulnerable HPN population. It is key to recognize whenever such patients present with vascular obstruction-related symptoms and treat them in an early stage by a multidisciplinary team.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

The role of long-term parenteral support in patients with underlying benign conditions who do not have intestinal failure (IF) is contentious, not least since there are clear benefits in utilising the oral or enteral route for nutritional support. Furthermore, the risks of long-term home parenteral nutrition (HPN) are significant, with significant impacts on morbidity and mortality. There has, however, been a recent upsurge of the use of HPN in patients with conditions such as gastro-intestinal neuromuscular disorders, opioid bowel dysfunction, disorders of gut-brain interaction and possibly eating disorders, who do not have IF. As a result, the European Society of Clinical Nutrition and Metabolism (ESPEN), the European Society of Neuro-gastroenterology and Motility (ESNM) and the Rome Foundation for Disorders of Gut Brain Interaction felt that a position statement is required to clarify - and hopefully reduce the potential for harm associated with - the use of long-term parenteral support in patients without IF. Consensus opinion is that HPN should not be prescribed for patients without IF, where the oral and/or enteral route can be utilised. On the rare occasions that PN commencement is required to treat life-threatening malnutrition in conditions such as those listed above, it should only be prescribed for a time-limited period to achieve nutritional safety, while the wider multi-disciplinary team focus on more appropriate biopsychosocial holistic and rehabilitative approaches to manage the patient's primary underlying condition.

Quality-of-care standards in adult type 3 intestinal failure caused by benign disease: A European society of clinical nutrition and metabolism (ESPEN) position paper.

BACKGROUND: Outcomes related to chronic intestinal failure (CIF) vary significantly within and between countries. While there are extensive European Society of Clinical Nutrition and Metabolism (ESPEN) guidelines on the delivery of optimal care in CIF, there are no international consensus recommendations on the structure or resources required, nor on the process and appropriate outcome measures for delivering such quality care in CIF. AIM: The aim of this position paper is therefore to devise ESPEN-endorsed, internationally agreed quality of care standards, covering the resources, systems and standards that centres should aim for in order to deliver optimal CIF care. METHODS: Members of the Home Artificial Nutrition-CIF Special Interest Group of ESPEN proposed an initial set of quality-of-care standards which was submitted to voting amongst clinicians from international CIF centres using a modified Delphi process, with participants rating each proposed statement as 'essential', 'recommended' or 'not required'. Any statement receiving 80% of more 'not required' responses was excluded. RESULTS: All 30 proposed standards relating to the structure, 18 relating to the process and 16 to the outcome measures of CIF care were deemed to be essential or recommended in more than 80% of respondents. CONCLUSION: This is the first paper to determine and describe internationally-agreed quality of care standards in CIF, which are now aimed at forming the basis for all CIF teams to develop and monitor their service, while also informing policymakers and payers on the infrastructure required for the optimal approach to multi-disciplinary team CIF care delivery. The recording of standardised outcomes should also allow internal and external benchmarking of care delivery within and between CIF centres.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

The role of long-term parenteral support in patients with underlying benign conditions who do not have intestinal failure (IF) is contentious, not least since there are clear benefits in utilising the oral or enteral route for nutritional support. Furthermore, the risks of long-term home parenteral nutrition (HPN) are significant, with significant impacts on morbidity and mortality. There has, however, been a recent upsurge of the use of HPN in patients with conditions such as gastro-intestinal neuromuscular disorders, opioid bowel dysfunction, disorders of gut-brain interaction and possibly eating disorders, who do not have IF. As a result, the European Society of Clinical Nutrition and Metabolism (ESPEN), the European Society of Neuro-gastroenterology and Motility (ESNM) and the Rome Foundation for Disorders of Gut Brain Interaction felt that a position statement is required to clarify - and hopefully reduce the potential for harm associated with - the use of long-term parenteral support in patients without IF. Consensus opinion is that HPN should not be prescribed for patients without IF, where the oral and/or enteral route can be utilised. On the rare occasions that PN commencement is required to treat life-threatening malnutrition in conditions such as those listed above, it should only be prescribed for a time-limited period to achieve nutritional safety, while the wider multi-disciplinary team focus on more appropriate biopsychosocial holistic and rehabilitative approaches to manage the patient's primary underlying condition.

Taurolidine-related adverse events in patients on home parenteral nutrition frequently indicate catheter-related problems.

BACKGROUND & AIMS: A catheter-related bloodstream infection (CRBSI) is a serious complication of home parenteral nutrition (HPN) treatment. Despite taurolidine's frequent use as catheter lock solution (CLS) to prevent CRBSIs and its presumed favourable safety profile, data on taurolidine-related adverse events (AEs) and the clinical implications thereof remain merely anecdotal. Aim of this study was to explore taurolidine-related AEs in our large cohort of HPN patients and to develop an algorithm on how to deal with these AEs in clinical practice. METHODS: This retrospective cohort study comprised all adult HPN patients who used taurolidine as a CLS between 2006 and 2021 at our national HPN referral centre. Primary outcome was to identify taurolidine-related AEs. Secondary outcomes were median time to a taurolidine-related AEs and development of a clinical algorithm. A taurolidine-related AE was defined as an event that occurred directly after instillation of taurolidine in the CVAD or at start of fluid/PN infusion. RESULTS: In total, 470 patients used taurolidine during 700.232 catheter days. In 89 (19%) patients, 103 mild- to severe AEs related to taurolidine were observed. Six patients developed an allergic reaction. Reported AEs compromised vascular access device-related problems (group A) or taurolidine-related problems (group B) in 53 (51%) and 50 (49%), patients, respectively. In groups A and B, 51 (85%) and 21 (18%) patients presented with taurolidine infusion-related pain. Upon rechallenge, 45 (85%) and 16 (32%) patients, respectively, successfully resumed taurolidine locking without residual symptoms. CONCLUSION: In this study, use of taurolidine as CLS was generally safe. Most reported AEs were vascular access device-related, and the majority of symptoms concerned pain. Upon rechallenge, a substantial number of patients, especially those in whom pain was the main symptom, could resume CLS locking after addressing the underlying catheter-related problem. Based on these results, we present a clinical algorithm for patients with possible taurolidine-related symptoms.

A multi-national survey of experience and attitudes towards commencing home parenteral nutrition for patients with advanced cancer.

INTRODUCTION: Advanced cancer (AC) is increasingly an indication for home parenteral nutrition (HPN) but an area with possible variation in practice between geographical locations. The aims of this study are to explore the views and experiences of international multi-disciplinary teams to determine opinions and practices. METHODS: An online questionnaire was developed with members of the Home Artificial Nutrition and Chronic Intestinal Failure interest group of the European Society for Clinical Nutrition and Metabolism (ESPEN) and distributed to colleagues involved in managing patients with AC on HPN. RESULTS: A total of 220 responses were included from 5 continents including 36 countries, with 90% of all responses from Europe. Predicted survival was a key factor influencing the decision to commence HPN for most respondents 152/220 (75%), with the majority of participants reporting that patients should have a predicted survival of ≥3 months if considered for HPN (≥3 months: n = 124, 56% vs. <3 months: n = 47, 21%, p < 0.001). However, most respondents were not confident about predicting overall survival in more than 50% of cases (confident n = 40, 23% vs not confident n = 135, 77%, p < 0.001). Barriers to utilising HPN in AC included colleagues' objections (n = 91, 46%), lack of local expertise (n = 55, 28%) and funding restrictions (n = 34, 17%). CONCLUSIONS: Significant consensus was observed regarding AC as indication for HPN, while areas of variation exist. Survival prognostication is often used as an indication for commencing HPN in people with AC, although the majority of respondents were not confident in prognosticating, suggesting better clinical prognostication tools will be of assistance. Further studies are also required to better understand the obstacles faced by clinical teams to commencing HPN that may explain variations in clinical practice between countries, as well as adressing variation in funding.

[Severe malnutrition after gastric: the importance of lifelong follow-up]. / Ernstige malnutritie na gastric bypass.

Two cases are described of patients who present with severe malnutrition more than five years after undergoing a Roux-en-Y gastric bypass and who have deficiencies of both micronutrients (vitamins and minerals) and macronutrients (proteins). This problem appears to be caused by both iatrogenic malabsorption after gastric bypass as well as dysphagia due to a local anastomotic complication (stenosis and marginal ulcer). Although both the severity of the deficiencies and the timing are exceptional, we want to emphasize the importance of lifelong supplement use and follow-up after bariatric surgery. Given the important role of general practitioners in this, we argue for implementation of this topic in national guidelines to improve the quality of follow-up.

A critical appraisal of indications for endoscopic placement of nasojejunal feeding tubes.

BACKGROUND: Postpyloric feeding is indicated whenever nutritional intake is compromised because of impaired gastric emptying. Although guidelines concerning this feeding modality are available it remains unclear whether these are applied in clinical practice. We therefore evaluated the indications provided by applicants for endoscopic placement of nasojejunal feeding tubes at our centre. METHODS: A prospective study was conducted in patients who were referred for endoscopic nasojejunal-feeding tube placement in a 950-bed Dutch university hospital. State-of-the-art criteria for nasojejunal tube placement comprised severe gastro-oesophageal reflux, gastroparesis leading to aspiration, gastric stasis not responding to prokinetics, gastroduodenal obstruction or proximal enteric fistulae. The study endpoint was met if the feeding tube was no longer needed or had to be replaced, or if the patient was discharged from the hospital or died. RESULTS: During a four-month observation period, 131 patients were enrolled, of whom 57% came from intensive care units. Tube placement only met at least one of the mentioned criteria in the hospital protocol in 59% of all cases, while in intensive care patients a lower proportion was observed (50%, p. <0.05). In the latter group, in 35% of all cases no increased gastric residues had been measured at all. CONCLUSION: Although directives are at hand that provide clear indications for endoscopic placement of nasojejunal feeding tubes, our data show that these guidelines are frequently not followed in clinical practice. These findings suggest that supervised implementation of established guidelines might reduce the strain on both patients and the hospital's resources.

[Current options for percutaneous endoscopic access to the digestive tract]. / Huidige mogelijkheden voor percutane endoscopische toegang tot de tractus digestivus.

Four patients, aged 67, 52, 56 and 64 years, respectively, undergoing percutaneous colostomy or jejunostomy are presented to illustrate current options for percutaneous endoscopic access to the digestive tract. The first patient had Parkinson's disease and required percutaneous jejunostomy for continuous post-pyloric administration of medication. The second patient had impaired gastric emptying due to gastric graft-versus-host disease following bone marrow transplantation. He was successfully treated with percutaneous jejunostomy, which was removed 2 years later after full recovery. The third patient had severe constipation due to the use ofmorphinomimetic analgesics. She received percutaneous caecostomy for colonic lavage and desufflation. The fourth patient had combined constipation and sphincteric insufficiency. Although the percutaneous endoscopic colostomy was clinically successful, the catheter had to be removed due to local pain and abscess formation.

Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

[Treatment of intestinal failure in adults. II. Pharmacological treatment options]. / De behandeling van darmfalen bij volwassenen. II. Medicamenteuze opties.

For patients with severe intestinal failure caused by short-bowel syndrome, pharmacological treatment options are available that can reduce the period in which parenteral nutrition is required. Appropriate agents include acid inhibitors, bile-salt binders, inhibitors of motility and secretion, antibiotics and pre- and probiotics. A number of intestinotrophic factors have also been identified that are reported to enhance the functional adaptation of the intestine following surgery or illness. These include glutamine, growth hormone, and glucagon-like peptide 2 and its analogues. Absorption of certain agents is reduced when specific portions of the intestine are lacking. For example, fat-soluble cyclosporine is poorly resorbed in patients without an ileum.

[Treatment of intestinal failure in adults. I. Dietary measures]. / De behandeling van darmfalen bij volwassenen. I. Dieetmaatregelen.

Patients with intestinal failure, predominantly caused by short-bowel syndrome, have impaired quality of life due to the frequent development of complications. Dietary modifications have an established role in the treatment of short-bowel syndrome. Treatment of short-bowel syndrome includes optimising the balance of fluids and nutrients in the presence of reduced absorption. The population is heterogeneous due to differences in anatomical structure and the functional status of the remaining intestine. Diet must therefore be tailored to the individual patient. Determining the appropriate amount of carbohydrates is based on the presence of the colon, because carbohydrates are processed in the colon by bacterial fermentation. Patients with a jejunostomy rapidly become dehydrated because they lose more sodium and fluids than are taken up enterally. The jejunum rapidly absorbs solutions with high salt concentrations, such as the WHO-recommended oral rehydration solution. Replacement of long-chain fatty acids with water-soluble medium-chain fatty acids increases the energy intake in patients with short-bowel syndrome and a colon. Extra attention should be given to electrolytes, trace elements and vitamins. Patients with short-bowel syndrome and a colon are at risk for oxalate nephropathy. For these patients, a low oxalate diet is recommended. With these interventions, many patients with intestinal failure will ultimately become independent of total parenteral nutrition.

Risk factors for thiopurine-induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype.

BACKGROUND: Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases. AIM: To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections. METHODS: Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 109 /L and infections were classified according to the Common Terminology Criteria for Adverse Events. RESULTS: Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]). CONCLUSIONS: Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant.

Presentation of a nationwide multicenter registry of intestinal failure and intestinal transplantation.

BACKGROUND & AIMS: Exact data on Dutch patients with chronic intestinal failure (CIF) and after intestinal transplantation (ITx) have been lacking. To improve standard care of these patients, a nationwide collaboration has been established. Objectives of this study were obtaining an up-to-date prevalence of CIF and characterizing these patients using the specially developed multicenter web-based Dutch Registry of Intestinal Failure and Intestinal Transplantation (DRIFT). METHODS: Cross-sectional study. CIF was defined as type 3 intestinal failure in which >75% of nutritional requirements were given as home parenteral nutrition (HPN) for ≥ 4 weeks in children and >50% for ≥3 months in adults. All patients with CIF receiving HPN care by the three Dutch specialized centers on January 1, 2013 and all ITx patients were registered in DRIFT (https://drift.darmfalen.nl). RESULTS: In total, 195 patients with CIF (158 adults, 37 children) were identified, of whom 184 were registered in DRIFT. The Dutch point prevalence of CIF was 11.62 per million (12.24 for adults, 9.56 for children) on January 1, 2013. Fifty-seven patients (31%) had one or more indications for ITx, while 12 patients actually underwent ITx since its Dutch introduction. Four patients required transplantectomy of their intestinal graft and 3 intestinal transplant patients died. CONCLUSION: The multicenter registry DRIFT revealed an up-to-date prevalence of CIF and provided nationwide insight into the patients with CIF during HPN and after ITx in the Netherlands. DRIFT will facilitate the multicenter monitoring of individual patients, thereby supporting multidisciplinary care and decision-making.

Recurrent pancreatitis after trimethoprim-sulfamethoxazole rechallenge.

We report a female patient who repeatedly developed pancreatitis after trimethoprim-sulfamethoxazole (TMP/SMX) use. During childhood she had undergone an ureterosigmoidostomy after which she had been on TMP/SMX 480 mg daily as prophylaxis for pyelonephritis for many years. The patient presented with abdominal pain caused by acute pancreatitis. No other cause, except for TMP/SMX use, could be identified. A causal relationship was confirmed by relapse of the pancreatitis after rechallenge. Our case is unique in demonstrating that acute pancreatitis related to the use of TMP/SMX may occur even after long-term treatment. We advise that the medication is discontinued immediately if a causal relationship with pancreatitis is suspected.

Microbiocidal effects of various taurolidine containing catheter lock solutions.

BACKGROUND & AIMS: We have recently shown that a catheter lock solution containing taurolidine dramatically decreases catheter-related bloodstream infections (CRBSI) in patients on home parenteral nutrition (HPN) when compared to heparin. Since several taurolidine formulations are commercially available, some of which also contain citrate or heparin, we were interested in the effect of these different locks on growth and biofilm formation of fungal, Gram-negative and Gram-positive pathogens that are known to impede HPN treatment. METHODS: Clinical isolates obtained during CRBSI of HPN patients were grown in the presence of catheter locks (2% taurolidine, 1.34% taurolidine-citrate, 1.34% taurolidine-citrate-heparin, citrate and heparin) or phosphate buffered saline diluted in lysogeny broth medium for bacteria and sabouraud liquid medium for yeasts. Biofilm formation, assessed by crystal violet staining, and growth of clinical isolates were determined by optical density measurements. RESULTS: We found that 12.5× diluted solutions of all taurolidine containing formulations completely prevented growth of Escherichia coli, Staphylococcus aureus and Candida glabrata. Growth of these microbes was detected earlier in 1.34% taurolidine-citrate(-heparin) than in 2% taurolidine, while citrate and heparin did not inhibit growth of clinical isolates compared to PBS. No differences in biofilm formation were found between taurolidine containing solutions. CONCLUSION: Taurolidine containing lock solutions prevent growth of fungal, Gram-negative and Gram-positive pathogens. While 2% taurolidine appears to be the most potent in this respect in this in vitro setting, the relevance of the small differences in growth inhibition between the commercially available taurolidine containing lock solutions for clinical practice remains to be established.

Dysphagia, malnutrition and gastrointestinal problems in patients with mitochondrial disease caused by the m3243A>G mutation.

BACKGROUND: Previous research has shown that dysphagia and gastrointestinal problems occur frequently in carriers of the m.3243A>G mutation; however, the exact frequency and severity have not been determined. We hypothesise that adult carriers have an increased risk for malnutrition. METHODS: In this observational study we evaluated the presence of gastrointestinal problems and dysphagia in 92 carriers of the m.3243A>G mutation. The severity of the general disease involvement was classified using the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Gastrointestinal involvement, dysphagia and the risk for malnutrition were scored using the Gastrointestinal Symptoms Questionnaire and the Malnutrition Universal Screening Tool. Gastrointestinal symptoms and anthropometrics were compared with healthy controls. RESULTS: Our results show that the height, weight and body mass index (BMI) of these carriers were lower than the national average (p < 0.05). Seventy-nine carriers (86%) suffered from at least one gastrointestinal symptom, mainly flatulence or hard stools. Both frequency and severity of symptoms were significantly increased compared with reference data of healthy Dutch adults. Of the carriers, 45% reported (mostly mild) dysphagia. Solid foods cause more problems than liquids. A negative correlation between BMI and heteroplasmy levels in urinary epithelial cells (UEC) was present (Spearman correlation coefficient = - 0.319, p = 0.003). CONCLUSION: Dysphagia and gastrointestinal problems, especially constipation, are common symptoms in the total m.3243A>G carriers cohort and are not related to heteroplasmy levels in UEC or disease severity. The severity of gastrointestinal problems as well as overall disease severity is associated with an increased risk for malnutrition.

Tocopherol isoforms in parenteral lipid emulsions and neutrophil activation.

BACKGROUND AND AIMS: Tocopherol is a lipid-soluble anti-oxidant that exists in several isoforms. Patients on total parenteral nutrition depend on lipid emulsions for their tocopherol intake. In the present study, we analysed the content of tocopherol isoforms in various lipid emulsions. We also tested the hypothesis that immune-modulating effects of lipid emulsions could be attributed to different concentrations of alpha-tocopherol (alpha-toc) or peroxidation products. METHOD: alpha-, beta-, gamma- and delta-toc were measured in emulsions containing long-chain triglycerides (LCT), mixed long- and medium-chain triglycerides (LCT/MCT), structured lipids (SL), olive oil (OO) or fish oil (FO). As a measure for cellular activation, neutrophil membrane adhesion markers were assessed after exposure to two LCT/MCT emulsions that differ only in alpha-toc content. RESULTS: Various emulsions differed widely in tocopherol contents, especially with respect to the alpha- isoform. The latter isomer also was subject to considerable degradation despite adequate storage conditions. The previously observed activation of neutrophils by LCT/MCT was not influenced by the increased concentration of alpha-toc or the decreased concentration of lipid peroxidation products in a new LCT/MCT emulsion. CONCLUSIONS: Tocopherol supplementation by parenteral lipid emulsions strongly depends on the lipid source and the storage lifetime of the emulsion. The effects of LCT/MCT on the immune system are not modulated by alpha-toc or by lipid peroxidation products.

Effects of structurally different lipid emulsions on human neutrophil migration.

AIM: To test the hypothesis that structurally different lipid emulsions have distinct immunomodulatory properties, we analysed neutrophil migration in the presence of various lipid emulsions. METHOD: Neutrophils of 8 volunteers were pre-incubated in medium or physiological 2.5 mM emulsions containing long-chain (LCT), medium-chain (MCT), mixed LCT/MCT, alpha -tocopherol-enriched LCT/MCT (LCT/MCT-E) or structured triglycerides (SL). Thereafter, the cells were put on top of 3 microm-pore-sized cell culture filters and incubated for one hour in the presence or absence of a chemo-attractant. Neutrophil migration was measured as the percentage of cells that had passed the filter in the presence (chemotaxis) or absence (random migration) of a chemotactic factor. RESULTS: Compared to lipid-free incubation (19+/-1%) random neutrophil migration significantly decreased with LCT/MCT (11+/-2%), LCT/MCT-E (12+/-2) and MCT (5+/-2%), while LCT (18+/-3%) and SL (20+/-1%) had no effect. N-formyl-methionyl-leucyl-phenylalanine- (fMLP, 10(-8)M) or zymosan-activated-serum-induced (ZAS, 10%) filter passage under lipid-free conditions amounted to 61+/-14% and 70+/-13%, respectively. These values decreased with LCT/MCT to 11+/-9% and 15+/-7%; with LCT/MCT-E to 18+/-10% and 28+/-12%; with SL to 39+/-18% and 57+/-14%, and with MCT to 5+/-2% and 10+/-6%, (all P<0.01), while LCT had no effect. Compared to LCT/MCT, the alpha -tocopherol-enriched formulation significantly increased ZAS- and fMLP-induced chemotaxis. fMLP-induced chemotaxis decreased in direct proportion to LCT/MCT triglyceride concentration. CONCLUSIONS: Human neutrophil migration is distinctively inhibited by structurally different lipid emulsions, depending on triglyceride chain-length and concentration as well as alpha -tocopherol content.