SMN SURGICAL METABOLISM AND NUTRITION Vol. 6, No. 1, June, 2015 ISSN 2233-5765 REVIEW ARTICLE 성인에서정맥영양요법을시행하는환자에서미량원소공급의임상적인고려사항 박준범 충남대학교의학전문대학원충남대학교병원외과학교실 Trace-Element: Clinical Consideration in Patients with Parental Nutritional Support Junbeom Park, M.D. Department of Surgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea Trace-elements play an important role in human metabolism. Often overlooked by clinicians, they are mandatory to supply for the patient with parenteral nutrition. When it is deficient or excessive, inadequate provision of trace elements can lead to serious complication. The nutrition provider should monitor deficiency and toxicity of each trace element carefully. In Korea, five trace elements (Zinc, Copper, Manganese, Chromium, and Selenium) are commercially available. However, according to the up to date recommendation, their dosages are not adequate for patients with long term parenteral nutrition. In this review, I considered the adequate dosage of each trace element under specific conditions, and provided a guideline for monitoring of trace elements. (Surg Metab Nutr 2015;6:1-6) Key Words: Trace Element, Parenteral Nutrition,, 서론 정맥영양요법 (PN, Parenteral Nutrition) 은위장관을통한영양공급을받지못하는환자에게정맥을통해필요한영양을공급하는방법이다. 이러한정맥영양요법을받는환자에서필요한영양소는칼로리공급에필요한주요영양소외에도여러대사작용에관련되어결핍이나과량투여에의한독성으로심각한합병증을초래할수있는미량원소의공급도또한매우중요하다.[1] 특히경구로섭취하는경우대부분용량의존적으로흡수를통한항상성기전을유지하게되어과량투여에대한독성이거의나타나지않는반면정맥으로투여하게되는 경우과량투여에의한독성이문제가될수있다.[2] 그러나이러한미량원소의적정공급량은정확히정립되지않은상태이고지금도권장공급량은지속적으로변화되고있는상태이다. 또한각개인의필요량또한개인별상태에따른다양성이존재하므로정확히평가하기힘들어미량원소의적정공급량을가늠하기힘든실정이다.[3] 따라서이종설에서는현재우리나라에서시판되어사용이가능한정맥영양용미량원소아연 (Zn, Zinc), 구리 (Cu, Copper), 망간 (Mn, Manganese), 크롬 (Cr, Chromium), 셀레늄 (Se, Selenium) 각각에따른적정용량과미량원소의공급에있어각임상적상황에따른고려사항, 그리고모니터링에대해고찰해보고자한다. Received November 16, 2014. Accepted January 29, 2015. Correspondence to: Junbeom Park, Department of Surgery, Chungnam National University Hospital, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 301-721, Korea Tel: +82-42-280-7175, Fax: +82-42-257-8024 E-mail: jbpark@cnuh.co.kr Copyrights c The Korean Society of Surgical Metabolism and Nutrition
2 Surgical Metabolism and Nutrition Vol. 6, No. 1, 2015 본론 1. 적정용량 1) 권장용량의변화미량원소는 1960년대정맥영양요법이도입된지얼마되지않아중요성이바로대두되었다. 1978년처음이주요미세원소에대한가이드라인이나오기시작했고 FDA 승인이후여러복합제형이등장하게되었다.[2,3] 처음 FDA 승인이후많은연구및학회에서적정용량에대한고찰을시작했고, 지속적인적정용량의변화에대한권고가있었으나, 아직 FDA의새로운승인은이루어지지않고있어, 시판되는복합제형들의함량은최신의권장용량과차이가있는실정이다 (Table 1).[3] 우리나라에서시판되는복합제형의경우역시최근의권장용량과차이가있고, 셀레늄의경우그중요성이지속적으로강조되어왔으나우리나라의경우보험인정을받지못하는제한점이있어새로운복합제형의개발및적절한적용, 또한새로운건강보험의적용이필요한상태이다 (Table 2).[4] 2) 미량원소의적정공급량에대한고려사항각미량원소는여러다양한경로를통해우리몸의대사작용에관여하는것으로알려져있다 (Table 3).[3] 이러한미량원소는환자의다양한상태에따라적정용량이차이가있는데, 우선 미량원소각각의경우에대해살펴보면, 1 아연아연은현재시판되는거의모든제품에포함되고있는데하루 3 4 mg의공급을권고하고있다.[5] 장피누공이나설사, 장관배액등, 위장관액의소실이심한경우에는소실되는용액 1 L당 12 17 mg 정도의추가적인공급을권고하고있다.[6,7] 또한심한화상환자의경우도화상부위를통한소실이커지므로많은양의추가적인공급이필요하다.[8] 2 셀레늄셀레늄공급의중요성은많은연구에서보고하고있으며, 미량원소의공급에서반드시고려해야되는요소이다.[9] 권고량은연구마다다양하게제시하고있는데, 최근 ASPEN position paper에서는그동안권장공급량을제공했던환자들도혈청농도가적게측정되는연구결과를근거로기존의권고용량에서 60 100 mcg/d로용량을증가하도록권고하고있다.[3] 특히중환자나패혈증환자그리고심한화상의경우단기간고용량의셀레늄이도움이된다는연구결과도있으나아직논란의여지는있는상태이다.[10-12] 그러나많은복합제제에서셀레늄이빠져있으며우리나라제품의경우보험인정이되는제품은셀레늄이빠져있고, 비보험복합제제나단독제제 ( 이또한비보험이다.) 로나와있다. Table 1. Historical changes in recommendations for parenteral trace elements for adults Published guidelines Zinc, mg Copper, mg Manganese, mcg Chromium, mcg Selenium, mcg 1979 NAG-AMA 2.5 4 0.5 1.5 150 800 10 15-1984 AMA; NY Ac Med 2.5 4 0.3 0.5 400 800 10 20 50 60 1994 9 th ed Mod Nutr H-D 2.5 4 0.3 0.5 60 100 10 15 40 80 1998 A.S.P.E.N and 2004 A.S.P.E.N 2.5 5 0.3 0.5 60 100 10 15 20 60 2012 A.S.P.E.N Position Paper 2.5 5 0.3 0.5 55 Omit or <1 60 100 AMA = American Medical Association; A.S.P.E.N. = American Society for Parenteral and Enteral Nutrition; Mod Nutr H-D = Modern Nutrition in Health & Disease; NAG-AMA = Nutrition Advisory Group of the American Medical Association; NY Ac Med = New York Academy of Medicine. Table 2. Commercial multi-trace element products in Korea Zinc, mg Copper, mg Chomium, mcg Manganese, mg Selenium, mcg Note Multi-trace elements product (supplemental dosage/ml) Furtman, Mineall, Trayman, Tracemin 5 1 10 0.5 - Within insurance coverage Multiblue5 1 0.4 4 0.1 20 Out of insurance coverage Single trace element products (supplemental dosage/ml) Zincure 1 - - - - Out of insurance coverage Selecure - - - - 40 Selenase - - - - 50 Reproduced from J Korean Soc Parenter Enter Nutr Vol. 5, No. 3, 2013.
Junbeom Park: Clinical Consideration in Patient with Parental Nutritional Support 3 Table 3. Brief function of trace element Trace element Selenium Zinc Copper Manganese Chromium Function Incorporated at the active site of glutathione peroxidase, an enzyme that catalyzes the breakdown of hydroperoxides and has metabolic interrelationships with vitamin E, an antioxidant Essential nutrient participating in multiple metalloenzyme involving zinc in most central metabolic pathway, including metabolism of protein, fat, and carbohydrate; DNA binding; gene regulation; transcription of DNA to RNA; synthesis of heme, long-chain fatty acid, and prostaglandins; cholesterol transport; stabilization of cell membrane lipid; sexual maturation and reproduction; and immune function Incorporated into metalloenzymes that are involved with connective tissue formation; metabolism of iron (ceruloplasmin), cholesterol, and glucose; myelin synthesis; conversion of dopamine to norepinephrine in the brain, serotonin synthesis, melanin pigment formation; and antioxidant participating in the immune system Incorporated into metalloenzymes involved with energy release, fatty acid and cholesterol synthesis, and release of lipids from the liver Enhance the ability of insulin to bind to insulin receptors on the cell surface and thereby participates in metabolism of carbohydrate, protein, and fat Reproduced from Appendix I of Vanek VW, Borum P, Buchman A, Fessler TA, Howard L, Jeejeebhoy K, et al. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nut Clin Pract 2012;27:440-91. 3 망간망간은정확히규명되지는않았으나신경학적독성이있을것으로추정되고있다. 한 MRI 연구에서는과망간혈증을보이는환자의기저핵 (basal ganglia) 에서고신호강도가보이는것을보고하고있고,[13] 한동물실험에서는 astrocyte에서망간에의해유도된미토콘드리아기능부전과 glutamine/glutamate cycling의변화가관찰되었다.[14] 또한소수이지만과망간혈증을보이는환자에서파킨슨증후군이나, 착란 (Confusion), 과민성 (Irritability), 발작 (Seuzure) 등도관찰되었으나직접적인연관성이규명되지는않았다.[13] 이망간의경우간부전이나신부전으로사망한환자에서시행한한부검연구에도간이나신장에서축적되는것또한관찰되므로답즙정체를보이는환자나신부전이있는환자에서는특별한주의를요하며공급을제한할필요가있을것으로보인다.[15] 4 구리구리의경우도앞서언급한한부검연구에서간부전으로사망한환자에서간과신장의조직에많이침착된것을보여주고있다.[15,16] 구리의독성은윌슨씨병을통해잘알려져있는데이경우각장기조직에축적된구리로인해여러신경학적증상을비롯해간독성신독성등이나타난다.[16] 현재우리나라에서시판되는복합제형의미량원소제제에서도 1 mg 정도공급하게되는데, 최근의 ASPEN position paper에의하면구리공급을 0.3 0.5 mg으로낮추도록권고하고있으며, 담즙정체나간부전이있는환자에서는구리를제한해야한다.[3] 통상하루구리의요구량은 0.3 mg 정도이며, 심한위장관액소실이있는경우는 0.4 0.5 mg 담즙정체가있는경우는 0.15 mg 정도로감량해야한다.[17] 또한장기간정맥영양을 시행하는경우도이로인한간부전으로구리의축적이일어날수있어유의해야한다.[15,17,18] 또위수술을시행한환자나화상환자의경우구리의결핍이보고되므로이러한경우에는구리의공급을고려해야한다.[8,19] 5 크롬크롬은인슐린이인슐린수용체에결합하는것을촉진시키는보조인자로작용하여이원소의결핍이발생하면포도당불내성 (Glucose intolerance) 이발생하는것으로알려져있다.[20] 현재상품으로나와있는복합제형에서도이크롬을포함하고있는데, 한연구에따르면성인이정상적인식사에서공급받는크롬의양이 0.4 0.9 mcg/d로복합제형에들어있는 10 15 mcg/d보다 10분의 1정도수준이다.[20] 또한미량원소의오염에관한한연구에의하면 2 L의 PN에오염에의해들어가는크롬의양이대략 15 mcg으로보고하고있어,[21] 오염에의해필요량이상이들어가는경우가많은것으로보인다. 따라서 ASPEN position paper에서는크롬의공급을제외하는것을권고하고있다. 그러나크롬의공급이제한되어크롬이부족한경우포도당불내성이발생하게되고, 화상이나외상환자, 그리고단장증후군환자에서는크롬의결핍이발생하는경우가많아이러한환자의경우각별한주의가필요하다.[20] 특히최근시판되어적용되는일체형총정맥영양 (TPN, Totally Parenteral Nutrition) 제제의경우오염도가매우낮아크롬공급이부족할수도있어이러한경우적절한모니터링이필요하다. 3) 특정상태에따른용량결정환자의상태에따른고려는매우중요하다. 특히이러한요소들의배설및대사에관련되는간질환환자들이나신장질환
4 Surgical Metabolism and Nutrition Vol. 6, No. 1, 2015 환자들의경우는특히더그러하다. 1 신부전환자에서의미량원소신부전환자의경우미량의원소의변화는 1) 신기능의이상에의한배설감소나과도한배설 2) 투석액이나수액의오염 3) 투석을통한과도한소실등으로유발되는것으로생각되나이외의다른인자들을비롯한여러원인에의해더욱예측이어렵다. 셀레늄의경우혈청의농도가투석환자에서감소되는것을보고하는연구가있고정상을보고하는연구의경우에도심장에서의셀레늄결핍을보인다는연구결과가있어투석환자에서의셀레늄공급은필요한것으로보인다.[22,23] 크롬은대부분의연구에서정상보다높은혈중농도를보이는데원인은주로앞에서언급한정상적인경우와마찬가지로수액의오염및투석환자들의경우투석액의오염에의해높은혈중농 도를보이는것으로생각되어크롬의공급은제한하는것이좋을것이다.[24] 아연의경우투석으로인해주로낮은혈중농도를보이며이로인한증상을보고하는연구도있어총정맥영양시첨가를고려해야할것이다.[25] 2 간부전환자에서의미량원소만성간질환환자와미량원소의관계가정확히정립되지는않았으나한연구에서만성간질환이있는환자의혈청내아연과셀레늄의농도가저하되어있는것이확인되고있어만성간질환환자에서아연과셀레늄의공급은고려되어야할것으로보인다.[26] 크롬, 망간, 구리의경우부검연구에의해장기간총정맥영양을시행한환자에서간조직및신장조직에침착되는것이확인되고간기능저하나담즙정체를보이는경우구리의침착이심해지는것이확인되므로만성간질환이있는경 Table 4. Detecting trace element deficiency and toxicity Element Pts of higher risk Physical signs & symptoms Clinical sign & symptoms Zn Severely malnourished, high GI losses, thiazide diuretic users Dermatitis, alopecia, stomatitis, glossitis, perioral ulcers, periungal lesions, poor wound healing, under-development, dysgeiusia, hypogeusia, poor night vision Anorexia delayed sexual maturation, poor immunity Nausea, dizziness Impaired neutrophil & lymphocyte function, copper deficiency, urinary tract infection Cu Mn Cr Se Short bowel syndrome, high GI losses, post-gastrectomy, small bowel resection or gastric bypass surgery, burns, on large doses of oral Zn, regular antacid use, Menkes disease Foot numbness, gait difficulty, hair hypopigmentation, kinky hair, general weakness Leukopenia, hypochromic and normocytic or microcytic anemia Cholestasis, hepatic hailure Metallic taste, jaundice Nausea, vomiting, epigastric pain, headache, dizziness, weakness, diarrhea, tarchycardia, elevated ALP, ALT, AST & Bil Weight loss, transient dermatitis Cholestasis, hepatic failure Parkinson s like signs and symptoms Iron deficiency anemia, halluciations, elevated ALP, AST, ALT and Bil Elderly, athletes, pregnant women, long term PN without Cr supplementation Poor renal function Long-term PN dependence, alcoholism, burns Neuropathy Whitened nail bed, hair and skin pigmentation loss, muscle tenderness, under-development Hair loss, brittle nails, skin changes, tooth decay, garlic greath odor, metallic taste Glucose intolerance, hyperlipidemia, neuropathy, rare encephlopathy Cardiomyopathy, skeletal muscle myopathy, macrocystic anemia, Keshan Disease Neurogenic abnormalities, mood changes Zn = Zinc; Cu = Copper; Mn = Manganese; Cr = Chromium; Se = Selenium; Pts = patients; Bil = bilirubin. Reproduced from Carol RP. Trace element supplementation and monitoring in the adult patient on parenteral nutrition. Pract Gastroenterol 2014;(129):27-38.
Junbeom Park: Clinical Consideration in Patient with Parental Nutritional Support 5 우이원소의공급은제한해야한다.[15] 2. 모니터링미량원소는투여하지않으면결핍증상을유발하게되며, 반대의경우의도치않은독성을야기할수도있다. 특히심한영양불균형이있는환자나장관에서의소실이심한경우, 그리고장기간가정에서총정맥영양을하는경우모니터링이매우중요하다. 모니터링은각원소의독성과결핍에대한임상증상 / 징후및실험실측정결과를이용해서시행된다. 1) 임상증상 / 징후 되고염증있을때감소하므로정확한지표가되지는못하며오히려투여후포도당불내성이호전되는양상으로알수있다 (Table 5).[20] 따라서임상의는실험실검사에의존하지말고환자의전반적인임상상 ( 실험실검사, 임상적징후, 아연보충이필요한질환요인들 ) 을함께파악해서치료계획을세워야한다. 3) 가이드라인환자의미량원소의상태를파악하기는사실어렵다. 따라서정기적으로계획된모니터링을하는것은중요하다. 다음은정맥영양을시행하는성인에서모니터링하는권고사항이다 (Table 6).[32] 미량원소의결핍이나독성의임상증상은다른임상상태와 혼재되어전형적으로보여지는경우는많지않다. 따라서고위험군환자에서주의를가지고세심한관찰을시행해야한다 (Table 4).[27] 결핍이나독성이의심되는경우는실험실검사를시행해야한다. 2) 실험실검사실험실검사는검체의수집에도상당한숙련이필요하며, 워낙미량이라오염에도취약하다. 또한비용적인부담도있어자주할수있는검사도아니다. 게다가정확한환자의조직에서의미량원소의농도를반영하기에도제한적이다. 구리의경우심한결핍상태에서는혈청의구리레벨이나 ceruloplasmin 같은경우좋은지표가된다. 그러나심하지않거나염증상태, 결론 미량원소의투여는영양공급을시행할때반드시고려해야하는주요영양요소이다. 그러나정맥으로만영양을공급하는환자의경우적절한모니터링이시행되지않으면결핍이나독성에의한심각한합병증이초래될수도있다. 또한각개인적인다양성이존재하므로환자의상태를고려해서각상황에맞춰유의해서투여해야하며, 세심한모니터링이중요하다. 이러한영양공급을담당하는외과의사 ( 특히집중영양지원팀 ) 의경우환자의각상태에대한정확한평가및각미량원소에대한최신지견을반드시습득해서나타날수있는결핍이나부작용 또는임신이나기타다른컨디션에서는영향을받을수있는제약이있다.[17] 망간은전혈망간이실제적으로많이쓰이며, erythrocyte 망간또한좋은지표가될수있으나임상에서쓰기에는비용등의제한점이있다.[28,29] 아연도혈청레벨은심한결핍이있기전까지는정상레벨로유지되기때문에사전에알기에는제약이있고,[30] 철도혈청 ferritin이좋은지표자가되지만, 급성염증기때증가하게된다. 이때는 transferrin이도움이될수있다.[31] 크롬의경우도너무극소량에오염도잘 Table 5. Trace element: laboratory test (inflammation effect on Lab value) Zinc Copper Manganese Chromium Selenium Iron Plasma Zn; negative acute phase reactant Serum Cu/ceruloplasmin; positive acute phase reactant Whole blood Mn (erythrocyte Mn); negative acute phase reactant Plasma Cr; negative acute phase reactant Plasma Se; negative acute phase reactant Serum Ferritin; positive acute phase reactant s-transferrin Zn = Zinc; Cu = Copper; Mn = Manganese; Cr = Chromium; Se = Selenium. Table 6. Suggestions for trace element monitoring for patients using PN Selenium Watch for signs of deficiency every 1 3 months. Check serum Se if deficiency suspected or symptoms are present. Zinc Watch for signs of deficiency every 1 3 months. Copper If PN does not contain Cu, watch for deficiency symptoms monthly. Check serum Cu every 6 month if standard multi-te products is used in patients with cholestasis or liver dysfunction or if deficiency is suspected. Manganese If standard multi-te products are used, watch for sign of Mn toxicity every 1 3 months. Check whole-blood Mn if symptoms of toxicity are present, or every 3 4 months, or monthly for patients with significant cholestasis. Chromium If providing standard multi-te products on the daily basis, consider checking serum Cr every 6 months in patients with renal insufficiency. Iron Monitor serum ferritin and iron studies every 3 months Se = Selenium; Zn = Zinc; Cu = Copper; Mn = Manganese; Cr = Chromium; PN = parenteral nutrition; TE = trace element. Reproduced from Fessler TA. Trace elements in parenteral nutrition: a practical guide for dosage and monitoring for adult patients. Nutr Clin Pract 2013;28:722-9.
6 Surgical Metabolism and Nutrition Vol. 6, No. 1, 2015 에대해예방및적절한대비가있어야환자에최적의영양치료를시행할수있다. 또한환자상태에대한파악에있어유용한생체지표에대한연구또한관심을가져야할것이다. REFERENCES 1. Sriram K, Lonchyna VA. Micronutrient supplementation in adult nutrition therapy: practical considerations. JPEN J Parenter Enteral Nutr 2009;33:548-62. 2. Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Compher CW, Tappenden KA. Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future. Gastroenterology 2009;137(5 Suppl):S1-6. 3. Vanek VW, Borum P, Buchman A, Fessler TA, Howard L, Jeejeebhoy K, et al; Novel Nutrient Task Force, Parenteral Multi-Vitamin and Multi Trace Element Working Group; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract 2012;27:440-91. 4. Choi S. 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