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1 5 特集 3 短腸症候群, 腸管リハビリテーション, 腸管不全関連肝機能障害,ω 3 系脂肪乳剤, 治療効果 Ⅰ はじめに SBS short bowel syndrome PN parenteral nutrition USBS ultra short bowel syndrome, 40 cm PN PN PN IFALD intestinal failure associated liver disease CRBSI catheter related blood stream infection IF PN 6 IF IFALD 3 IF Intestinal Rehabilitation Program IRP SBS 3 Ⅱ ω 3 系脂肪乳剤について 3 表 1 Omegaven Fresenius Kabi SMOF lipid Fresenius Kabi SMOF Lipoplus B. Braun LA Linolenic acid EPA eicosapentaenoic acid, DHA docosahexaenoic acid 100% Omegaven SMOF Lipoplus Omegaven Omegaven g/kg/ day Omegaven 1 2 ml/kg/day IFALD 3 Intralipid Fresenius Kabi Omegaven 表 1 Omegaven

2 表 1 Intralipid Omegaven SMOF Lipid Lipoplus Fresenius Kabi Fresenius Kabi Fresenius Kabi B. Braun 100% 0 30% 40% MCT % 50% % % 15% 10% g/100g / mg/l NA mg/l Vanek VW et al. Nutr Clin Pract Jennifer C. Seida JPEN J Parenter Enteral Nutr published online 8 June 2012 SMOF Lipoplus 6/ 3 6/ Intralipid SMOF Lipoplus 6/ IFALD E 表 1 Ⅲ 短腸症候群の治療におけるω 3 系脂肪乳剤の役割 1 Intestinal Rehabilitation Program SBS PN 1990 PN Intestinal rehabilitation program IRP 10 IRP CRBSI IFALD PN EN enteral nutrition H 2 11 overgrowth D bacterial translocation IFALD 12,13 Bianchi 14 STEP serial transverse enteroplasty 15 2 IRP IFALD IRP 70 80% IFALD IFALD

3 7 EN cyclic PN 12,18,19 Omegaven 12,13,20 IRP IFALD 12,16,19,21 GH growth hormone GLP 2 glucagon like peptide 2 GH Somatropin Zorbtive GLP 2 Teduglutide Revestive, Gettex 22 PN IFALD CRBSI IRP 2 IFLAD 1960 PN PN 23 PN PNAC PN associated cholestasis PNALD PN associated liver disease IFALD intestinal failure associated liver disease American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review 24 PN PNAC PNALD PNAC PNALD Kelly IFALD 25 PNAC PNALD IFALD IFALD PN NASH nonalcoholic steatohepatitisnash 26 NASH NASH IFALD 図 1 CRBSI bacterial translocation PN IFALD 25 27,28 IFALD 24 3 g/kg/day 27 1g/kg/ day IFALD 29 6 IFALD 6 pro inflammatory mediator prostaglandin 2 PG2 leukotriene 4 LT4 IFALD IFALD 31

8 3 図 1 IFALD PN 32 33 T Bil 34 20 Intralipid 47.

4 8 3 図 1 IFALD PN T Bil Intralipid 47.7 IFALD 図 farnesoid X receptor FXR FXR 37 3 IFALD 3 Omegaven Omegaven 38 IFALD 2 Omegaven 39 Gura IFALD Omegaven Intralipid Omegaven Intralipid Puder IFALD Omegaven 42 Intralipid historical control 49 Omegaven Omegaven 4/42 vs Intralipid 17/49 D Bil ALT 41 Omegaven IFALD Diamond 12 IFALD D bil>100 mol/l 50 mol/l 1 Omegaven 11 Omegaven Intralipid Omegaven 3 42 Angsten IFALD Omegaven ClinOleic 20 Intralipid Omegaven g/kg/ day Omegaven 2014 IFALD systematic review IFALD RCT

5 9 44 systematic review Lam IFALD Double blind Randomized Controlled Trial DB RCT Omegaven 7 Intralipid 9 Intralipid D Bil Omegaven EN 10% D Bil ALT Omegaven 45 Omegaven Intralipid RCT ClinicalTrials. gov, U.S. National Institutes of Health. Minimization of Intralipid Versus Omegaven. November 23, Available at: show/nct Omegaven IFALD 44 D Bil<1ml/dl 21 PN DB RCT Omegaven 9Intralipid 10 IFALD 46 Omegaven RCT ClinicalTrials.gov, U.S. National Institutes of Health. Cholestasis Prevention Efficacy of IV Fish Oil. August 6, Available at clinicaltrials. gov/ct2/show/nct SMOF Omegaven RCT DB RCT RCT 51 Goulet HPN 5m 11y SMOF 15 Intralipid Intralipid SMOF T Bil ALT AST 3/ 6 tocopherol 47 Rayyan 34 SMOF 26 Intralipid 27 SMOF T Bil D Bil 3/ 6 48 Tomsits SMOF 30 Intralipid 30 SMOF GTP 3/ 6 49 Skouroliakou SMOF Oxidative stress 50 4 DB RCT AST ALT SMOF 51 IFALD SMOF lipid Omegaven g/kg/day 2 ClinicalTrials.gov, U.S. National Institutes of Health. Preventing Cholestasis Using SMOFLipid. April 16, Available at ClinicalTrials.gov, U.S. National Institutes of Health. Can SMOF lipid, a Composite Parenteral Nutrition Lipid Emulsion, Prevent Progression of Parenteral Nutrition Associated Liver Disease in Infants? November 18, Available at show/nct Omegaven SMOF IFLAD PN NASH NASH IFLAD NASH AST ALT

6 AST ALT NASH Soden IFALD 2 Omegaven 1g/kg/day Fibrosis 52 Matsumoto Omegaven 7 Omegaven 6 53 Omegaven F2 26 Omegaven NASH IFALD 4 IFALD 3 図 2 3 IFALD 2 Omegaven SMOF Intralipid 図 3 3 EPA COX LOX 図 2 3 図 3 PG F2/ E2/D PG2 3 de novo lipogenesis peroxisome proliferator activated receptor PPAR 55 3 IFALD DB RCT Intralipid Lipoplus TNF Sepsis TNF 56 PN RCT Lipoplus MCT T Bil LTB5/ LTB4 IL 6 TNFNF B 57 EPA DHA pro inflammatory mediator PG2 LT4

7 11 図 Pro-resolving lipid mediators anti inflammatory mediator PG3 LT5 3 PG LT pro resolving lipid mediator pro resolving lipid mediator EPA Resolvin E DHA Resolvin D Protectin 図 3 58 pro inflammatory mediator pro resolving lipid mediator Lipoxin 図 Gura Puder Omegaven TG INR T/T Triene/Tetraene ,43 de Meijer EN PN D Bil> 2.0 mg/dl 10 1 Omegaven 1g/kg/day 59 Ⅳ 国内の現状 1 IFALD Omegaven 表 2 3 Omegaven IFALD D Bil > 2 mg/dl IFALD IF PN ALT 40 IU/L 2 D Bil 0.5 mg/dl D Bil > 1.0mg/dl NASH ALT > 200 IU/L Omegaven

8 12 3 IF 表 2 Omegaven 0.5 g/kg/day 1.0 g/kg/day Omegaven g/kg/day g/kg/day IFALD ICV Intralipid IFALD Intralipid 1 M NASH 0.5 g/kg/day USBS 7 cm 8y8m PN>EN>PO ALT * D-Bil 2 NASH 0.4 g/kg/day 2 F MMIHS GIMD 41 cm 1y2m D-Bil 7 PN>PO>EN D-Bil ALT * 2y11m NASH D-Bil PN>PO>EN ALT 3 M 0.4 g/kg/day NASH 0.4 g/kg/day USBS 15 cm 2m PN>PO>EN D-Bil 1y5m PN>PO>EN 7 D-Bil 3 40 cm * NASH 4 F hypoganglionosis GIMD 1y3m PN>PO>EN ALT stoma D-Bil GIMD=gastro intestinal motility disorder 2 Omegaven 表 ALT 2 D Bil 3 Omegaven EPA DHA 1 2 ALT 1 ALT 1 EPA DHA 2 Omegaven Omegaven SMOF lipid Lipoplus pdf pdf Omegaven Omegaven Omegaven IFALD 35 Omegaven % Omegaven 2 ALT NASH ALT Ⅴ おわりに SBS IRP 3 IFALD

9 13 RCT 3 IRP 6 PN 3 IFALD 3 3 Nandivada Omegaven IFALD PN 60 3 IRP IF 3 IRP Omegaven IF IFALD 文献 , , , , , Omegaven , Fish oil , Vanek VW, Seidner DL, Allen P et al. A.S.P.E.N. Position Paper Clinical role for alternative intravenous fat emulsions. Nutr Clin Pract , Grimm H, Tibell A, Norrlind B et al. Immunoregulation by parenteral lipids impact of the n 3 to n 6 fatty acid ratio. J Parenter Enteral Nutr , Koehler AN, Yaworski JA, Gardner M et al. Coordinated interdisciplinary management of pediatric intestinal failure A 2 year review. J Pediatr Surg , Shatnawei A, Parekh NR, Rhoda KM et al. Intestinal failure management at the Cleveland Clinic. Arch Surg , Javid PJ, Malone FR, Reyes J et al. The experience of a regional pediatric intestinal failure program Successful outcomes from intestinal rehabilitation. Am J Surg , Sigalet D, Boctor D, Robertson M et al. Improved outcomes in paediatric intestinal failure with aggressive prevention of liver disease. Eur J Pediatr Surg , Bianchi A Intestinal loop lengthening for short gut syndrome. J Pediatr Surg , Kim HB, Fauza D, Garza J et al. Serial transverse enteroplasty STEP a novel bowel lengthening procedure. J Pediatr Surg , Nucci A, Burns RC, Armah T et al. Interdisciplinary management of pediatric intestinal failure a 10 year review of rehabilitation and transplantation. J Gastrointest Surg , Diamond IR, de Silve N, Pencharz PB et al. Neonatal short bowel syndrome outcomes after the establishment of the first Canadian multidisciplinary intestinal rehabilitation program preliminary experience. J Pediatr Surg , Torres C, Sudan D, Vanderhoof J Role of an intestinal rehabilitation program in the treatment of advanced intestinal failure. J Pediatr Gastroenterol Nutr

10 , Cowles RA, Ventura KA, Martinez M et al. Reversal of intestinal failure associated liver disease in infants and children on parenteral nutrition experience with 93 patients at a referral center for intestinal rehabilitation. J Pediatr Surg , Modi BP, Langer M, Ching YA et al. Improved survival in a multidisciplinary short bowel syndrome program. J Pediatr Surg , Sigalet D, Boctor D, Brindle M et al. Elements of successful intestinal rehabilitation. J Pediatr Surg , Jeppesen PB Pharmacologic options for intestinal rehabilitation in patients with short bowel syndrome. J Parenter Enteral Nutr Suppl 45S 52S, Peden VH, Witzleben CL, Skelton MA Total parenteral nutrition. J Pediatr , Rangel SJ, Calkins CM, Cowles RA et al. Parenteral nutrition associated cholestasis an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg , Kelly DA Intestinal failure associated liver disease What do we know today? Gastroenterology 130 S70 S77, , A.S.P.E.N. Board of Directors Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr. 26 1SA 138SA, Koletzko B, Goulet O, Hunt J et al. Guidelines on paediatric parenteral nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition ESPGHAN and the European Society for Clinical Nutrition and Metabolism ESPEN, Supported by the European Society of Paediatric Research ESPR, 5.Carbohydrates. J Pediatr Gastroenterol Nutr 41 S28 S32, Cavicchi M, Beau P, Crenn P et al. Prevalence of liver disease and permanent intestinal failure. Ann Intern Med , Diamond IR, Sterescu A, Pencharz PB et al. The rationale for the use of parenteral omega 3 lipids in children with short bowel syndrome and liver disease. Pediatr Surg Int , Clayton PT, Bowron A, Mills KA et al. Phytosterolemia in children with parenteral nutrition associated cholestatic liver disease. Gastroenterology , Pianese P, Salvia G, Campanozzi A et al. Pettoello Mantovani M, Corso G. Sterol profiling in red blood cell membranes and plasma of newborns receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr , Kurvinen A, Nissinen MJ, Andersson S et al. Parenteral plant sterols and intestinal failure associated liver disease in neonates. J Pediatr Gastroenterol Nutr , Llop JM, Virgili N, Moreno Villares JM et al. Phytosterolemia in parenteral nutrition patients implications for liver disease development. Nutrition , Clayton PT, Whitfield P, Iyer K The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition. Nutrition , Iyer KR, Spitz L, Clayton P New insight into mechanism of parenteral nutrition associated cholestasis role of plant sterols. J Pediatr Surg , Carter BA, Taylor OA, Prendergast DR Stigmasterol, a soy lipid derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res , Gura KM, Parsons SK, Bechard LJ et al. Use of a fish oil based lipid emulsion to treat essential fatty acid deficiency in a soy allergic patient receiving parenteral nutrition. Clin Nutr , Gura KM, Duggan CP, Collier SB et al. Reversal of parenteral nutrition associated liver disease in two infants with short bowel syndrome using parenteral fish oil implications for future management. Pediatrics 118 e , Gura KM, Lee S, Valim C et al. Safety and efficacy of a fish oil_based fat emulsion in the treatment of parenteral nutrition_associated liver disease. Pediatrics 121 e , Puder M, Valim C, Meisel JA et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition associated liver disease. Ann Surg , Diamond IR, Sterescu A, Pencharz PB et al. Changing the paradigm omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gas-

11 15 troenterol Nutr , Angsten G, Finkel Y, Lucas S et al. Improved outcome in neonatal short bowel syndrome using parenteral fish oil in combination with 6/9 lipid emulsions. J Parenter Enteral Nutr , Lauriti G, Zani A, Aufieri R et al. Incidence, prevention, and treatment of parenteral nutrition associated cholestasis and intestinal failure associated liver disease in infants and children A systematic review. J Parenter Enteral Nutr , Lam HS, Tam YH, Poon TCW et al. A double blind randomized controlled trial of fish oil based versus soy based lipid preparations in the treatment of infants with parenteral nutrition associated cholestasis. Neonatolory , Nehra D, Fallon EM, Potemkin AK et al. A comparison of 2 intravenous lipid emulsions interim analysis of a randomized controlled trial. J Parenter Enteral Nutr , Goulet O, Antébi H, Wolf C et al. A new intravenous fat emulsion containing soybean oil, medium chain triglycerides, olive oil, and fish oil A single center, double blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. J Parenter Enteral Nutr , Rayyan M, Devlieger H, Jochum F et al. Short term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium chain triglycerides, and fish oil A randomized double blind study in preterm infants. J Parenter Enteral Nutr S 94S, Tomsits E, Pataki M, Tolgyesi A et al. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium chain triglycerides, olive oil, and fish oil A randomized, double blind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr , Skouroliakou M, Konstantinou D, Koutri K et al. A double blind, randomized clinical trial of the effect of omega 3 fatty acids on the oxidative stress of preterm neonates fed through parenteral nutrition. Eur J Clin Nutr , Klek S, Chambrier C, Singer P et al. Four week parenteral nutrition using a third generation lipid emulsion SMOFlipid A double blind, randomised, multicentre study in adults. Clinical Nutrition , Soden JS, Lovell MA, Brown K et al. Failure of Resolution of Portal Fibrosis during Omega 3 Fatty Acid Lipid Emulsion Therapy in Two Patients with Irreversible Intestinal Failure. J Pediatr , Matsumoto CS, Kaufman SS, Island ER et al. Hepatic Explant Pathology of Pediatric Intestinal Transplant Recipients Previously Treated with Omega 3 Fatty Acid Lipid Emulsion. J Pediatr , Beckh K, Kneip S, Arnold R Direct regulation of bile secretion by prostaglandins in perfused rat liver. Hepatology. 19: , Burrin DG, Ng K, Stoll B et al. Impact of New Generation Lipid Emulsions on Cellular Mechanisms of Parenteral Nutrition Associated Liver Disease. Adv. Nutr , Larsen BMK, Goonewardene LA, Joffe AR et al. Pre treatment with an intravenous lipid emulsion containing fish oil eicosapentaenoic and docosahexaenoic acid decreases inflammatory markers after open heart surgery in infants A randomized, controlled trial. Clinical Nutrition , Wang J, Yu JC, Kang WM et al. Superiority of a fish oil enriched emulsion to medium chain triacylglycerols/ long chain triacylglycerols in gastrointestinal surgery patients A randomized clinical trial. Nutrition , Serhan CN, Ycoubian S, Yang R Anti inflammatory and pro resolving lipid mediators. Annu rev pathol , de Meijer VE, Le HD, Meisel JA et al. Pediatr Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition Dependent Patients. Gastroenterol Nutr , Nandivada P, Chang MI, Eng M et al. The Natural History of Cirrhosis From Parenteral Nutrition Associated Liver Disease After Resolution of Cholestasis With Parenteral Fish Oil Therapy. Ann Surg , 2013

外科と代謝・栄養_51巻2号.indb

外科と代謝・栄養_51巻2号.indb 51 2 2017 4 55 特集 Ⅰ はじめに intravenous fat emulsions IVFEs Ⅱ IVFEs の世代分類図 1 American Society for Parenteral and Enteral Nutrition AS- PEN 1 IVFEs 2 IVFEs soybean oil SO medium chain triglyceride MCT olive