日本外科代謝栄養学会

Omega ３ fatty acid

　脂肪酸の炭素原子は、カルボキシル基末端から番号が付けられており、二番、三番の炭素が各々α、βと、また、メチル基末端の炭素はω炭素と呼ばれる。不飽和結合の位置は、カルボキシル基末端から数えたときはΔｎ で、逆にω炭素から数えたときにはωｎ で表される。ω３ 脂肪酸とはCH3－CH2－CH=CH－CH2－R－COO－ で表示される脂肪酸を意味する。ω３ 脂肪酸は多価不飽和脂肪酸で、α－リノレン酸（C18:3）、イコサペンタエン酸（C20:6）、ドコサヘキサエン酸（C22:6）などが含まれる。

　ω３ 脂肪酸が注目されているのは、一つには、疫学的検討により魚油に含まれる長鎖不飽和ω ３脂肪酸の摂取が、乳癌をはじめ、ある種の癌化を抑制している可能性が示されたこと、実験的にVEGFα等の増殖因子を抑制することが示されたこと、更に、グルタミン、アルギニン、核酸などとともに高カロリー輸液に加え術前患者に投与すると、蛋白異化を抑制し、免疫機能を亢進、創傷治癒を促進させる効果が認められたこと等に起因している。アルギニン／ω ３脂肪酸／核酸（AON）の臨床的意義については、経腸栄養症例を対象とした十数個のrandomied studyと、これらをまとめた二つのメタ・アナリシスの報告がある。それらの結果では、免疫系が有意に低下した群で術後感染症の発症頻度を著明に低下させ、在院日数を短縮させる効果が示されているが、死亡率の低下には寄与していないとの報告であった。

参考文献抄録

１）Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer:a meta‐analysis of randomized controlled clinical trials.

　OBJECTIVE:To conduct a meta‐analysis of １１ randomized controlled trials comparing enteral nutritional support supplemented with key nutrients versus standard enteral nutritional support to determine effects on morbidity and mortality rates and hospital stay.BACKGROUND DATA:Recent studies have shown that malnutrition occurs in up to ３０％ of patients undergoing gastrointestinal surgery,resulting in an increased risk of postoperative complications and death.With the realization that key nutrients can modulate inflammatory,metabolic,and immune processes,enteral nutritional regimens（supplemented with large amounts of key nutrients）have been developed for clinical use.METHODS:Eleven prospective,randomized controlled trials evaluating １，００９ patients treated with combinations of key nutrients（Impact,Immun‐Aid）ware evaluated.Outcome measures examined were the incidences of pneumonia,infectious complications,and death,and length of hospital stay.Meta‐analyses were undertaken to obtain the odds ratio and ９５％ confidence interval for incidences of infectious complications,pneumonia,and death,and the weighted mean difference and ９５％ confidence interval for length of hospital stay.RESULTS:The provision of nutritional support supplemented with key nutrients to patients with critical illness resulted in a decrease in infectious complications when compared with patients receiving standard nutritional support and a significant reduction in overall hospital stay.Similar results were documented in patients with gastrointestinal cancer.However,there were no differences between patient groups for either pneumonia or death.CONCLUSIONS:This meta‐analysis has demonstrated that nutritional support supplemented with key nutrients results in a significant reduction in the risk of developing infectious complications and reduces the overall hospital stay in patients with critical illness and in patients with gastrointestinal cancer.However,there is no effect on death.These data have important implications for the management of such patients.

Heys SD,Walker LG,Smith I,Eremin O.Ann Surg 1999 Apr:229(4):467－77

２）Immunonutrition in the critically ill:a systematic review of clinical outcome.

　OBJECTIVE:To perform a mete‐analysis addressing whether enteral nutrition with immune‐enhancing feeds benefits critically patients after trauma,sepsis,or major surgey.DATA SOURCES:Studies were identified by MEDLINE search（１９６７ to January １９９８）for original articles in English using the search terms“human,”“enteral nutrition,”“arginine,”“nucleotides,”“omega－３ fatty acids,”“immunonutrition,”“IMPACT,”and“Immun‐Aid”Additionally,the authors of the studies and the manufacturers of the feeds were contacted for additional information.Access to original databases was obtained for the three largest studies.STUDY SELECTION:Fifteen randomized controlled trials comparing patients receiving standard enteral nutrition with patients receiving a commercially available immune‐enhancing feed with arginine with or without glutamine,nucleotides,and omega－３ fatty acids were identified by two independent reviewers（Dr.Beale and Dr.Bryg）.DATA EXTRACTION:Descriptive and outcome data were extracted independently from the papers by the same two reviewers,one of whom（Dr.Bryg）analyzed the original databases.Three studies were excluded from analysis,leaving １２ studies containing １，５５７ subjects,１，４８２ of whom were analyzed.Main outcome measures were mortality,infection,ventilator days,intensive care unit stay,hospital stay,diarrhea days,calorie intake,and nitrogen intake.The meta‐analysis was performed on an intent‐to‐treat basis.DATA SYNTHESIS:There was no effect of immunonutrition on mortality（relative risk＝１．０５,confidence interval ［CI］＝０．７８,１．４１;p＝．７６）.There were significant reductions in infection rate（relative risk＝０．６７,CI＝０．５０,０．８９;p＝．００６）,ventilator days（２．６ days,CI＝０．１,;p＝．０４）,and hospital length of stay（２．９ days,CI＝１．４,４．４;p＝．０００２）in the immunonutrition group.CONCLUSIONS:The benefits of enteral immunonutrition were most pronounced in surgical patients,although they were present in all groups.The reduction in hospital length of stay and infections has resource implications.

　

Beale RJ,Bryg DJ,Bihari DJ:Crit Care Med １９９９ Dec;27(12):2799－805

３）Omega－３ fatty acid supplementation reduces tumor growth and vascular endothelial growth factor expression in a model of progressive non‐metastasizing malignancy.

　BACKGROUND:Omega－３ fatty acids,the principal component of fish oil,have been demonstrated to have antiinflammatory properties.The role of eicosapentaenoic acid（EPA）supplementation for cancer patients is currently under investigation,however,the mechanisms of EPA activity have not been defined.The purpose of this study was to characterize tumor‐specific and treatment‐specific effects of supplemental dietary EPA in an animal model of progressive malignancy.METHODS:Fischer ３４４ rats（２００－２５０g）underwent flank implantation of the methylcholanthrene（MCA）－induced fibrosarcoma on day O.Rats were randomly divided into ３ treatment groups on daya １３:EPA（１mL,５．０g／kg per day）＋１０IU vitamin E,corn oil（１mL）＋１０IU vitamin E,and saline（１mL）＋１０IU vitamin E（vitamin E was used to prevent fatty acid oxidation）.On day １４,gavage feeding was started and was continued through day ２８.The animals were killed on day ２９,and the tumors were removed.The tumors were weighed and divided by the tumor‐free carcass weight to obtain percentage of tumor volume,and the livers were flash frozen.Vascular endothelial growth factor‐alpha（VEGF‐alpha）and cyclo‐oxygenase２（COX－２）mRNA were measured by reverse transcription‐polymerase chain reaction（RT‐PCR）.RESULTS:EPA rats had significant reductions in tumor volume compared with isocaloric corn oil and control saline animals（２５％,p＜．１ and ３３％,p＜．１,respectively）.Rats receiving EPA demonstrated decreased VEGF‐alpha mRNA levels（０．０２３±０．００１）compard with those receiving corn oil（０．１２９±０．０４７）or saline（０．１５０±０．０２６:p＜．０５）.

　CONCLUSIONS:These data demonstrate that EPA supplementation inhibits tumor growth,potentially through alterations in the expression of the pro‐angiogenic VEGF‐alpha.The mechanism（s）of EPA as an inhibitor of tumor‐related angiogenic growth factors may be associated with COX－２ enzyme fatty acid metabolism and merits further study.

Tevar R,Jho DH,Babcock T,Helton WS,Espat NJ:J Parenter Enteral Nutr 2002 Sep‐Oct;26(5):285－9

４）Effect of a fish oil‐enriched nutritional supplement on metabolic mediators in patients with a pancreatic cancer cachexia.

　Weight loss in advanced cancer patients is refractory to conventional nutritional support.This may be due to metabolic changes mediated by proinflammatory cytokines.hormones,and tumor‐derived products.We previously showed that a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia.The present study examines the effect of this supplement on a number of mediators thought to play a role in cancer cachexia.Twenty weight‐losing patients with pancreatic cancer were asked to consume a nutritional supplement providing ６００kcal and ２g of eicosapentaenoic acid per day.At baseline and after ３wk,patients were weighed and samples were collected to measure serum concentrations of interleukin（IL）－６ and its soluble receptor,tumor necrosis factor receptors1and2,cortisol,insulin,and leptin,peripheral blood mononuclear cell production of IL－１ beta,IL－６,and tumor necrosis factor,and urinary excretion of proteolysis inducing factor.After ３ wk of consumption of the fish oil‐enriched nutritional supplement,there was a significant fall in production of IL－６（from median １６．５ to １３．７ng／ml,P＝０．０１５）,a rise in serum insulin concentration（from ３．３ to ５．０mU／l,P＝０．００６４）,a fall in the cortisol‐to‐insulin ratio（P＝０．００８４）,and a fall in the proportion of patients excreting proteolysis inducing factor（from ８８％ to ４０％,P＝０．００８）.These changes occurred in association with weight gain（median１kg,P＝０．０２４）.Various mediators of catabolism in cachexia are modulated by administration of a fish oil‐enriched nutritional supplement in pancreatic cancer patients.This may account for the reversal of weight loss in patients consuming this supplement.

Barber MD,Fearon KC,Tisdale MJ,McMillan DC,Ross JA:Nutr Cancer 2001;40(2):118－24

５）Fish and omega－３ fatty acid intake and risk of coronary heart disease in women.

　CONTEXT:Higher consumption of fish and omega－３ fatty acids has been associated with a lower risk of coronary heart disease（CHD）in men,but limited data are available regarding women.OBJECTIVE:To examine the association between fish and long‐chain omega－３ fatty acid consumption and risk of CHD in women.DESIGN,SETTING,AND PARTICIPANTS:Dietary consumption and follow‐up data from ８４，６８８ female nurses enrolled in the Nurses’ Health Study,aged ３４ to ５９ years and free from cardiovascular disease and cancer at baseline in １９８０,were compared from validated questionnaires completed in １９８０,１９８４,１９８６,１９９０,and １９９４.MAIN OUTCOME MEASURES:Incident nonfatal myocardial infarction and CHD deaths.RESULTS:During １６ years of follow‐up,there were １，５１３ incident cases of CHD（４８４ CHD deaths and １，０２９ nonfatal myocardinal infarctions）.Compared with women who rarely ate fish（＜１per month）,those with a higher intake of fish had a lower risk of CHD.After adjustment for age,smoking,and other cardiovascular risk factors,the multivariable relative risks（RRs）of CHD were ０．７９（９５％ confidence interval［CI］,０．６４－０．９７）for fish consumption １ to ３ times per month,０．７１（９５％ CI,０．５８－０．８７）for once per week,０．６９ （９５％ CI,０．５５－０．８８） for ２ to ４ times per week,and ０．６６ （９５％ CI,０．５０－０．８９） for ５ or more times per week（P for trend＝．００１）.Similarly,women with a higher intake of omega－３ fatty acids had a lower risk of CHD,with multivariable RRs of １．０,０．９３,０．７８,０．６８,and ０．６７（P＜．００１ for trend）across quintiles of intake.For fish intake and omega－３ fatty acids,the inverse association appeared to be stronger for CHD deaths（multivariate RR for fish consumption ５ times per week,０．５５ ［９５％ CI,０．３３－０．９０］for CHD deaths vs ０．７３［０．５１－１．０４］）than for nonfatal myocardial infarction.CONCLUSION:Among women,higher consumption of fish and omega－３ fatty acids is associated with a lower risk of CHD,particulary CHD,deaths.

Hu FB,Bronner L,Willett WC,Stampfer MJ,Rexrode KM,Albert CM,Hunter D,Manson JE:JAMA 2002 Apr 10;287(14):1815－21

関　連　用　語

英文表記	略語	和文表記	定　義　・　備　考
Meta‐analysis		メタ・ アナリシス	いくつかの独立したデータセットを併合（combined pool）し、定量的に仮説検定する方法。１９７６年Glassが用語を初めて定義した。Mateとは、一段と高い理論性を有すとの意味。
Odds ratio	OR	オッズ比	オッズとはeventの数／non‐eventの数で表され（例：出産１００人中男児の数５１とすれば、出産が男児であるオッズは５１／４９（１.０４）。オッズ比とは（治療）群のオッズを（非治療）群のオッズで徐したもの。２因子間の関連性を示す値で、１に近いほど関連性がないとみなされる。
Relative risk	rr	相対危険率	例えば男児を出産する危険率（確率）；risk（probability）は５１／１００＝０.５１。危険率が２倍となればrr＝２、危険率が半減すればrr＝０.５となる。参考：ORとrr：eventが稀な場合には、危険率とオッズは近似する。治療群２９、０００の死亡数が２、２００の場合、危険率０.０７６（２２００／２９０００）、オッズ０.０８２（２２００／（２９０００－２２００）。同様のことが、rrとオッズ比との関係でも成立する。メタ・アナリシスでは、Peto法によりオッズ比を併合する。
Vascular endothelial growth factor α	VEGFα	血管内皮 増殖因子α	強力な血管新生作用を要するペプタイドで血液幹細胞の発育分化、細胞外マトリックスの再構築、炎症性サイトカインの産生等に関与する。
cyclooxygenase２	COX‐２		プロスタグランディン合成に関与する酵素で、種々の前癌、癌病変で過剰発現が認められている。COX－２は、免疫系、血管新生、アポトーシス等を介して、発癌と関わっていると考えられている。近年COX－２阻害剤が、消火器症状を起こさずNSAIDと同等の鎮痛効果を有するとして注目されている。
Proteolysis inducing factor	PIF	蛋白質分解 誘導因子	最近の研究で異化状態で、ユビキチン・プロテアソーム・システムを介して、蛋白分解が起こる事が判明した。敗血症では糖コルチコイドが、癌悪液質では腫瘍が産生する硫酸糖蛋白である蛋白質分解誘導因子がプロテアソームサブユニットとユビキチン輸送蛋白〔E２（１４K）〕を介し、骨格筋蛋白崩壊に関与する。
Proteasome		プロテアソーム	蛋白質分解酵素複合体で、分解される蛋白質はユビキチン鎖を付加されそれを目印にプロテアソームにより分解される。
Uniquitin‐proteasome system		ユビキチン・ プロテアソーム・ システム	細胞増殖を担う蛋白質の合成、分解は厳しく制御されており、ユビキチン・プロテアソーム・システムは不要となった蛋白質を速やかに分解する上で中心的役割を担っているとされる。