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1 Original Article J Clin Nutr 2017;9(1):21-29 pissn ㆍ eissn 신생아환자에서지방유제사용시어유함유여부에따른 Parenteral Nutrition-Associated Liver Disease 발생정도분석 박정아 1, 박지은 1,2, 정민재 1,2, 김재송 1, 손은선 1, 은호선 2,3 1 세브란스병원약무국, 2 세브란스병원소아영양집중지원팀, 3 연세대학교의과대학소아과학교실 Influence of Fish Oil-Containing Lipid Emulsions on Parenteral Nutrition-Associated Liver Disease in Neonates Jeong-A Park 1, Ji-Eun Park 1,2, Min-Jae Jeong 1,2, Jae-Song Kim 1, Eun-Sun Son 1, Ho-Seon Eun 2,3 1 Department of Pharmacy, Severance Hospital, 2 Pediatric Nutrition Support Team, Severance Hospital, 3 Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea Purpose: This study is a comparative evaluation of the incidence of parenteral nutrition-associated liver disease (PNALD) when administering intravenous fat emulsions containing fish oil. Methods: The medical records of patients who were in the neonatal intensive care unit at Severance Hospital from January, 2012 to December 2015, were reviewed retrospectively. Patients who were administered either soybean oil (SO) or SMOF (containing soybean oil, medium chain triglycerides, olive oil, and fish oil) more than 14 days were included. The patients were excluded if they were administered both agents or had underlying hepatic disease. An increase in bilirubin to 2 mg/dl was defined as PNALD. Results: PNALD occurred in only 8 out of a total of 77 patients: 6 out of 31 (19.4%) in the and 2 out of 46 (4.3%) in the (P=0.055). The number of patients, whose lab values, such as direct bilirubin, total bilirubin, asparate aminotransferase (AST), alanine amino-transferase, gamma-glutamyl transpeptidase, C-reactive protein, serum triglyceride, and alkaline phosphate, exceeded the normal range, were similar in both groups. The gestational age, birth body weight, and APGAR score at 1 min and 5 min were significantly higher in the and the PN duration was significantly long in the SMOF group. Considering only term infants, there were no significant differences in baseline characteristics and incidence of PNALD. The number of patients whose AST exceeded the normal range was significantly higher in the (P=0.034). Conclusion: The incidence of PNALD was similar in both groups. On the other hand, considering the tendency, there was a high correlation between the type of lipid emulsion and an increased direct bilirubin level in the. Key Words: Parenteral nutrition, Intravenous fat emulsions, Soybean oil, Fish oils Received Feb 8, 2017; Revised Feb 26, 2017; Accepted Feb 27, 2017 Correspondence to Jeong-A Park Department of Pharmacy, Severance Hospital, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: , Fax: , japark1216@yuhs.ac Conflict of interest: None. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론 위장관기능이원활하지않은소아환자에서의정맥영양 (parenteral nutrition, PN) 공급은질병치료와원활한성장에도움을주지만, 장기간공급할경우담즙정체와같은간질환이발생한다고알려져있다. 1 이와같은 PN에의한간담도계합병증을 parenteral nutrition-associated liver disease (PNALD) 2017, The Korean Society for Parenteral and Enteral Nutrition. All Rights Reserved.

2 Jeong-A Park, et al. 라고한다. PNALD는담즙울체에서부터간부전에이르기까지그증상이다양하며, 심할경우간이식이나사망에이르는경우도있으므로예방및치료가중요하다. 2 PNALD 발생은미숙아이거나저체중출생아일수록위험성이증가하고, 괴사성장염 (necrotic enterocolitis, NEC), 경장영양공급의부족, 동맥관개존증 (patent ductus arteriosus, PDA) 등에따른장기간의정맥영양공급, 패혈증 (sepsis) 등의요인도영향을미친다. 2,3 또한 PN 성분중지방유제의종류도 PNALD의발생정도에영향을미치는것으로알려져있으며, 지방유제중대두유 (soybean oil) 가주원인이되는것으로알려져있다. 2 대두유는필수지방산을공급하기때문에소아의원활한성장에필요하지만, 간손상을유발하는것으로알려진오메가-6와 phytosterol 등이높은비율로함유되어있다. 1,4,5 오메가-6는염증반응이나간효소의산화유발등여러가지기전으로간손상을일으키고, 6,7 식물성 steroid인 phytosterol은담즙분비와관련된신호물질에길항제로작용하여담즙배설을감소시킨다. 6,8 특히 phytosterol은위장관으로흡수가거의되지않아경구섭취시에는큰문제가되지않지만정맥투여시공급량에비례하여혈중농도가증가하고이것이간에축적되기때문에정맥투여될경우주로문제가된다. 6,9,10 반면어유 (fish oil) 의경우 docosahexaenoic acid, eicosapentanoic acid 등을포함하는오메가-3가주구성성분으로, 염증유발정도가적어 PNALD의예방과치료모두에효과가있다는이론이최근제시되고있다. 11,12 이에따라지방유제의조성에따른 PNALD에대한영향에대해많은연구가진행중이지만, 국내비교연구는미흡한실정이다. 신생아중환자실에서는 PNALD 발생의위험요인을가지고있으면서장기간의 PN 공급이필요한환자가많기때문에 PNALD 예방을위해적절한지방유제의선택이중요하다. 이에본연구에서는신생아환자에서대두유단일제제투여군과어유함유제제투여군간의임상적변화를비교하여지방유제의어유함유여부에따른 PNALD의발생정도를분석함으로써안전한지방유제선택에기여하고자하였다. 대상및방법 1. 자료수집 1) 대상자선정기준 2012년 1월 1일부터 2015년 12월 31일까지세브란스병원신생아중환자실에입원하여지방유제를투여한환자중대두유단일제제 (soybean oil, 100%) 혹은어유함유제제 (soybean oil 30%, middle chain triglyceride 30%, olive oil 25%, fish oil 15%) 를 14일이상투여한환자를연구대상으로선정하였다. 2) 대상자제외기준두제제모두투여한이력이있는환자, 간관련기저질환을가진환자와총정맥영양 (total parenteral nutrition, TPN) 투여기간에사망한환자는제외하였다. 3) 데이터수집항목환자의출생시특성과관련된항목으로재태기간 (gestational age), 출생시체중, 성별, APGAR score 1 min, APGAR score 5 min값을수집하였다. PNALD 발생의위험요인을파악하기위해패혈증, NEC, PDA 등의기저질환여부를확인하였고, PN 투여기간은연속해서투여한총투여기간을수집한후 PN을금식 (nothing per oral, NPO) 상태로투여한기간과경장영양 (enteral nutrition, EN) 을병용하여투여한기간으로분류하였다. Direct bilirubin이 2 mg/dl 이상으로측정된것을 PNALD 가발생했다고정의하여 6 이를 primary endpoint로보았고, 간기능관련수치인 direct bilirubin, total bilirubin, asparate aminotransferase (AST), alanine amino-transferase (ALT), alkaline phosphatase (ALP), -glutamyl transpeptidase ( - GT), C-reactive protein (CRP), serum triglyceride가원내기준에따라정상수치를초과한환자수와진단명을기준으로대사성산증이발생한환자수를 secondary endpoint로보았다. TPN 공급량이미치는영향을보기위해 glucose infusion rate (GIR, mg/kg/min), total protein intake (g/kg/d), total lipid intake (g/kg/d) 를수집하였다. 2. 통계분석연속형변수는 Student s t-test로비교하여결과값을평균 ± 표준편차로표시하고, 범주형변수는 chi-square test를시행하여결과값을빈도 (%) 로표시하였다, 통계분석은 IBM SPSS Statistics ver (IBM Co., Armonk, NY, USA) 을사용하여수행하였다. P가 0.05 미만인경우통계적으로유의한차이가있는것으로평가하였다. 3. 연구대상자보호본연구는연구대상자의안전및보호에관한사항등을포함한연구계획을세브란스병원연구심의위원회로부터승인 (IRB no ) 을받았으며, 전자의무기록에기록된내용만을수집하여분석하는후향적연구이기때문에연구대상자의 22 Journal of Clinical Nutrition

3 Influence of Fish Oil-Containing Lipid Emulsions on PNALD in Neonates 동의는생략하였다. 결 과 분류했을때초극소저체중출생아가대두유단일제제군 0%, 어유함유제제군 28.3% (P=0.001) 으로어유함유제제군에서유의하게많았다 (Fig. 3). 2012년 1월 1일부터 2015년 12월 31까지두지방유제중한종류만을 14일이상투여한환자는총 82명이었고, 이중 TPN 투여기간에사망한환자 5명을제외하여최종 77명을대상으로후향적전자의무기록검토를시행하였다 (Fig. 1). 대두유단일제제군 31명, 어유함유제제군 46명을대상으로하였으며, 생화학적검사결과는 TPN 종료후일주일이내가장최근결과까지, TPN 공급량은투여시작후 14일동안만을수집하여분석하였다. 1. PNALD 위험요인평가지방유제종류이외에 PNALD 발생에영향을줄수있는요인인출생시특성, TPN 투여기간및 PNALD와관련된질병등을비교하였다. 1) 출생시특성신생아의출생시건강상태가 PNALD 발생에미치는영향을파악하기위해두환자군의출생시특성을비교하였다. 성비는대두유단일제제군 ( 남, 51.6% vs. 여, 48.4%) 과어유함유제제군 ( 남, 50.0% vs. 여, 50.0%) 둘다비슷한비율이었고, 재태기간 ( 대두유단일제제군 vs. 어유함유제제군, 35.69주 vs 주, P=0.001) 과출생시체중 (2.35 kg vs kg, P= 0.003), 그리고 APGAR score 1 min (5.13 vs. 3.84, P=0.016) 및 5 min (6.77 vs. 5.63, P=0.010) 모두어유함유제제군에서유의하게낮은것을확인할수있었다 (Table 1). 그러나재태기간이 37주미만인미숙아가대두유단일제제군 (58.1%) 에비해어유함유제제군 (78.3%) 에서높은비율로나타났고 (Fig. 2), 출생시체중을저체중출생아분류기준 (Appendix 1) 에따라 2) TPN 투여기간 TPN을연속해서투여한총투여기간을비교하고, PN을 NPO 상태로투여한기간과 EN을병용하여투여한기간으로분류하여분석하였다 (Table 2). 총투여기간 ( 대두유단일제제군 vs. 어유함유제제군, 19.42일 vs 일, P=0.006) 및총투여기간에대한 EN 병용기간의비율 (59.24% vs %, P=0.014) 이어유함유제제군에서유의하게길었다. 3) PNALD 관련질병 PNALD 발생과연관성있는질병을진단명기준으로분석하 Table 1. Birth characteristics (n=77) Characteristic Sex Male 16 (51.6) 23 (50.0) Female 15 (48.4) 23 (50.0) GA (wk) 35.69± ± GA<28 1 (3.2) 10 (21.7) GA<37 17 (54.8) 26 (56.5) GA (41.9) 10 (21.7) Birth weight (kg) 2.35± ± APGAR score a 1 min 5.13± ± min 6.77± ± Values are presented as number (%) or mean±standard deviation. olive oil, fish oil; GA = gestational age. a APGAR score: Method to quickly summarize the health of neonate by scoring of breathing effort, heart rate, muscle tone, reflexes, skin color. Fig. 1. Flow chart of study population. IVFE = intravenous fat emulsion; NICU = neonatal intensive care unit; SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil; TPN = total parenteral nutrition. Volume 9, Number 1, June

4 Jeong-A Park, et al. Table 2. TPN duration (n=77) Duration TPN duration (d) 19.42± ± TPN duration depending on combination with EN a (n=49) NPO+PN (d) 6.96± ± EN+PN (d) 12.57± ± EN+PN/total TPN duration ratio (%) 59.24± ± Fig. 2. Distribution of gestational age. SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil. Values are presented as mean±standard deviation. TPN = total parenteral nutrition; SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil; NPO = nothing per oral; EN = enteral nutrition; PN = parenteral nutrition. a Evaluation of patients who only can be checked about feeding. Table 3. Underlying diseases related to parenteral nutrition-associated liver disease (n=77) Underlying diseases PDA 13 (41.9) 18 (39.1) NEC 0 (0) 1 (2.2) Sepsis 4 (12.9) 10 (21.7) Values are presented as number (%). olive oil, fish oil; PDA = patent ductus arteriosus; NEC = necrotic enterocolitis. Fig. 3. Distribution of birth weight. SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil; ELBW = extremely low body; VLBW = very low body weight; LBW = low body weight. 였을때, PDA ( 대두유단일제제군 vs. 어유함유제제군, 41.9% vs. 39.1%, P=0.894) 와 NEC (0% vs. 2.2%, P=0.401) 및패혈증 (12.9% vs. 21.7%, P=0.296) 모두두군간유의한차이가없었다 (Table 3). 2. PNALD 발생및간기능수치변화비교 Primary endpoint인 direct bilirubin이 2 mg/dl 이상으로측정된환자수는대두유단일제제군에서 6명 (19.4%), 어유함유제제군에서 2명 (4.3%) 이었다 (P=0.055). 한편간관련수치들이정상범위를초과한환자수는 direct bilirubin ( 대두유단일제제군 vs. 어유함유제제군, 77.4% vs. 84.8%, P=0.207), total bilirubin (90.3% vs. 89.1%, P= 1.000), AST (64.5% vs. 45.7%, P=0.104), ALT (12.9% vs. 4.3%, P=0.213), triglyceride (12.9% vs. 15.2%, P=1.000), ALP (74.2% vs. 84.8%, P=0.250), CRP (12.9% vs. 10.9%, Table 4. Laboratory test (n=77) Laboratory test The number of patients who 6 (19.4) 2 (4.3) observed on direct bilirubin 2 mg/dl Lab value exceeded normal range Direct bilirubin 24 (77.4) 39 (84.8) Total bilirubin 28 (90.3) 41 (89.1) AST 20 (64.5) 21 (45.7) ALT 4 (12.9) 2 (4.3) Triglyceride 4 (12.9) 7 (15.2) ALP 23 (74.2) 39 (84.8) CRP 4 (12.9) 5 (10.9) GT 4 (12.9) 5 (10.9) Diagnosed with metabolic acidosis 0 (0) 1 (2.2) Values are presented as number (%). olive oil, fish oil; AST = asparate aminotransferase; ALT = alanine amino-transferase; ALP = alkaline phosphatase; CRP = C-reactive protein; -GT = gamma-glutamyl transpeptidase. 24 Journal of Clinical Nutrition

5 Influence of Fish Oil-Containing Lipid Emulsions on PNALD in Neonates P=1.000), -GT (12.9% vs. 10.9%, P=1.000) 에서모두통계적으로유의한차이가없었다. 대사성산증발생빈도역시 (0% vs. 2.2%, P=0.409) 통계적으로유의한차이가없었다 (Table 4). 3. TPN 공급량 TPN 공급량은두군간유의한차이는있었지만두군모두 lipid ( 대두유단일제제군 vs. 어유함유제제군, 2.83 g/kg/d vs g/kg/d, P<0.05), amino acid (2.48 g/kg/d vs g/kg/d, P<0.05) 공급량및 GIR (10.17 mg/kg/min vs mg/kg/min, P<0.05) 의평균값이미국경장정맥영양학회 (American Society for Parenteral and Enteral Nutrition, ASPEN) 권장공급량 (Appendix 2) 범위내에포함되는것을확인할수 Table 5. TPN supply TPN supply Lipid (g/kg/d) 2.83± ±1.09 <0.05 GIR (mg/kg/min) 10.17± ±8.43 <0.05 Amino acid (g/kg/d) 2.48± ±0.90 <0.05 Values are presented as mean±standard deviation. TPN = total parenteral nutrition; SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil; GIR = glucose infusion rate. Table 6. Data of term infants (n=23) Term infants (n=13) (n=10) Sex Male 6 (46.2) 4 (40.0) Female 7 (53.8) 6 (60.0) Birth weight (kg) 2.92± ± APGAR score a 1 min 6.23± ± min 7.46± ± TPN duration (d) 24.64± ± TPN duration depending on combination with EN b (n=13) NPO+PN (d) 9.00± ± EN+PN (d) 16.13± ± PDA 8 (61.5) 4 (40.0) NEC 0 (0) 0 (0) - Sepsis 2 (15.4) 0 (0) Values are presented as number (%) or mean±standard deviation. olive oil, fish oil; TPN = total parenteral nutrition; NPO = nothing per oral; PN = parenteral nutrition; EN = enteral nutrition; PDA = patent ductus arteriosus; NEC = necrotic enterocolitis. a APGAR score: Method to quickly summarize the health of neonate by scoring of breathing effort, heart rate, muscle tone, reflexes, skin color. b Evaluation of patients who only can be checked about feeding. 있었다 (Table 5). 4. 미숙아를제외한비교분석 PNALD 영향요인을보정하기위해재태기간이 37주미만인미숙아를제외하여만삭아환자 23명 (Fig. 2의 37주이상에해당하는환자 ) 을대상으로추가분석을시행하였다. 출생시체중과 APGAR score, PN 투여기간및 PNALD 관련진단명에서모두두군간유의한차이가없었다 (Table 6). AST가대두유단일제제군 13명모두에게서정상범위를초과한것으로관찰되어 7명 (70%) 인어유함유제제군과유의한차이를보였다 (P=0.034). Direct bilirubin이 2 mg/dl 이상으 Table 7. Laboratory test_term infants (n=23) Laboratory test Table 8. Birth characteristics of patients diagnosed parenteral nutrition-associated liver disease (n=8) Characteristic (n=13) (n=6) (n=10) (n=2) Observed on direct bilirubin 2 mg/dl 4 (30.8) 1 (10.0) Lab value exceeded normal range Direct bilirubin 9 (69.2) 5 (50.0) Total bilirubin 11 (84.6) 7 (70.0) AST 13 (100.0) 7 (70.0) ALT 3 (23.1) 1 (10.0) Triglyceride 2 (15.4) 1 (10.0) ALP 9 (69.2) 7 (70.0) CRP 4 (30.8) 4 (40.0) GT 4 (30.8) 3 (30.0) Diagnosed with metabolic acidosis 0 (0) 1 (10.0) Values are presented as number (%). olive oil, fish oil; AST = asparate aminotransferase; ALT = alanine amino-transferase; ALP = alkaline phosphatase; CRP = C-reactive protein; -GT = gamma-glutamyl transpeptidase. Gestational age (wk) 37.1± ± Birth weight (kg) 2.63± ± APGAR score a 1 min 5.50± ± min 6.50± ± Values are presented as mean±standard deviation. olive oil, fish oil. a APGAR score: Method to quickly summarize the health of neonate by scoring of breathing effort, heart rate, muscle tone, reflexes, skin color. Volume 9, Number 1, June

6 Jeong-A Park, et al. 로관찰된환자수는대두유단일제제군 4명 (30.8%), 어유함유제제군 1명 (10.0%) 으로유의한차이가없었고, AST를제외한간관련수치가정상범위를초과한환자수역시통계적으로유 의한차이가없었다 (Table 7). Fig. 4. Correlation between the type of lipid emulsions and changes of direct bilirubin (D) in patients get parenteral nutrition associated-liver disease. Patients labeld as follows:, S1 S6;, F1 F2. SO = soybean oil; SMOF = soybean oil, medium-chain triglycerides, olive oil, fish oil; PN = parenteral nutrition. 26 Journal of Clinical Nutrition

7 Influence of Fish Oil-Containing Lipid Emulsions on PNALD in Neonates 고찰 본연구결과지방유제투여후 PNALD 발생에있어서통계적으로두군간유의한차이가없었다. 하지만 PNALD 위험요인과발생빈도사이의연관성을분석했을때두군간차이가있었다. 어유함유제제군은재태기간, 출생시체중및 APGAR score 가유의하게낮고미숙아와저체중출생아의비율이높은것을고려할때, 대두유단일제제군에비해유의한차이로더미숙한상태임을알수있으며이는 PNALD의위험성이더높은것을의미한다. 2,3 그럼에도불구하고 PNALD 발생환자수와비율이대두유단일제제군에비해적은것으로보아어유함유제제사용시 PANLD 예방에효과가있다는이론을뒷받침할수있을것이다. 11,12 반면에대두유단일제제군에서 PNALD가발생한환자들의기본특성과지방유제투여추이를분석해보았을때, 재태기간이평균 37.2주, 출생시체중이평균 2.63 kg으로정상이었고 6 명중 5명의환자에서지방유제투여가지속됨에따라 direct bilirubin이점차상승하였다 (Table 8, Fig. 4). 이를통해 direct bilirubin 상승의영향요인중지방유제투여가그원인으로서가능성이높은것으로판단할수있다. Vlaardingerbroek 등의전향적연구 17 에서도대두유단일제제군과어유함유제제군의담즙정체발생빈도와 total bilirubin 및 direct bilirubin의최대값은두군간유의한차이가없었다. 하지만담즙정체를일으키는성분인 phytosterol의혈중농도가대두유단일제제군에서유의하게높았고, 지방유제투여일수가증가함에따라혈중농도가유의한차이로높아지는것을확인하였다. 본연구는후향적으로진행되어혈중 phytosterol 농도를확인하지않았지만, 지방유제투여에따른 direct bilirubin의상승추이분석을통해해당연구결과와동일하게대두유단일제제의 PNALD 발생위험성을확인한것에의의가있다 (Table 8, Fig. 4). 대사성산증으로진단된환자수도두군간유의한차이가없었다. 대사성산증은정맥영양공급시발생할수있는합병증이나, 18 재태기간및패혈증등의기저질환에의해서도발생할수있다. 어유함유제제군에서대사성산증이발생한환자 1명의경우재태기간이 28.4주, 출생시체중이 1.66 kg인저체중미숙아였으며패혈증진단된것을고려할때이로인한영향을배제할수없었다. 본연구는두환자군을동일한기저상태에서비교할수없었던한계점이있었다. 세브란스병원에서어유함유제제도입시 PNALD 발생위험도가높은미숙아들을위주로투여하였기때 문에, 출생시특성에서두군간유의한차이가있었고 TPN 총투여기간이어유함유제제군에서유의하게길었다. 또한 EN 병용기간의비율이어유함유제제군에서유의하게길었던것으로보아 EN 투여가 PNALD 발생빈도를낮추는데에영향을미쳤을가능성도배제할수없고 (Table 2), EN 병용여부에대한정보를얻기어려운환자는제외하고 EN 병용기간의비율을비교한점이한계였다. 환자의특성차이를줄이기위하여재태기간보정후만삭아만을비교했을때대상환자수의부족으로인해 PNALD 발생빈도는통계적으로유의한차이를확인하기어려웠다. 하지만지방유제종류이외의요인에서유의한차이가없었으며 AST 가정상범위를초과한환자수가유의한차이로대두유단일제제군에서많았던결과를통해대두유단일제제와간기능변화와의연관성을확인할수있었다. 따라서본연구는신생아중환자를대상으로한대두유와어유의비교연구로서지방유제종류에따른간기능변화의차이를확인한연구라는점에서의의가있다. 결론 본연구는지방유제가투여된신생아를대상으로지방유제종류에따른 PNALD 발생정도및간기능관련수치의변화를분석하였다. 지방유제에따른 PNALD 발생빈도는유의한차이가없었지만대두유단일제제군에서발생경향이높았고, 만삭아만을대상으로추가분석하였을때 AST가정상범위를초과한환자수가대두유단일제제군에서유의하게더많았다. 이번연구는신생아지방유제선택시기초자료로활용할수있겠으나, 앞으로지방유제에따른 PNALD 발생빈도의유의한차이를확인하기위해서이번연구의한계점을보완한추가적연구가필요하겠다. REFERENCES 1. Nandivada P, Chang MI, Potemkin AK, Carlson SJ, Cowan E, Oʼloughlin AA, et al. The natural history of cirrhosis from parenteral nutrition-associated liver disease after resolution of cholestasis with parenteral fish oil therapy. Ann Surg 2015; 261(1): Wales PW, Allen N, Worthington P, George D, Compher C; American Society for Parenteral and Enteral Nutrition, Teitelbaum D. A.S.P.E.N. clinical guidelines: support of pediatric patients with intestinal failure at risk of parenteral nutrition-associated liver disease. JPEN J Parenter Enteral Nutr 2014;38(5): Volume 9, Number 1, June

8 Jeong-A Park, et al. 3. Rangel SJ, Calkins CM, Cowles RA, Barnhart DC, Huang EY, Abdullah F, et al. Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 2012; 47(1): Park HW, Lee NM, Kim JH, Kim KS, Kim SN. Parenteral fish oil-containing lipid emulsions may reverse parenteral nutritionassociated cholestasis in neonates: a systematic review and meta-analysis. J Nutr 2015;145(2): Deshpande G, Simmer K. Lipids for parenteral nutrition in neonates. Curr Opin Clin Nutr Metab Care 2011;14(2): Hojsak I, Colomb V, Braegger C, Bronsky J, Campoy C, Domellöf M, et al. ESPGHAN Committee on Nutrition Position Paper. Intravenous lipid emulsions and risk of hepatotoxicity in infants and children: a systematic review and meta-analysis. J Pediatr Gastroenterol Nutr 2016;62(5): Krohn K, Koletzko B. Parenteral lipid emulsions in paediatrics. Curr Opin Clin Nutr Metab Care 2006;9(3): Iyer KR, Spitz L, Clayton P. BAPS prize lecture: new insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons. J Pediatr Surg 1998;33(1): Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. Phytosterolemia in children with parenteral nutritionassociated cholestatic liver disease. Gastroenterology 1993; 105(6): Nikkilä K, Nissinen MJ, Gylling H, Isoniemi H, Miettinen TA. Serum sterols in patients with primary biliary cirrhosis and acute liver failure before and after liver transplantation. J Hepatol 2008;49(6): Puder M, Valim C, Meisel JA, Le HD, de Meijer VE, Robinson EM, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg 2009; 250(3): Yoon JH. Parenteral nutrition support in preterm infants. J Clin Nutr 2014;6(2): Skouroliakou M, Konstantinou D, Agakidis C, Delikou N, Koutri K, Antoniadi M, et al. Cholestasis, bronchopulmonary dysplasia, and lipid profile in preterm infants receiving MCT/ -3- PUFA-containing or soybean-based lipid emulsions. Nutr Clin Pract 2012;27(6): Savini S, D'Ascenzo R, Biagetti C, Serpentini G, Pompilio A, Bartoli A, et al. The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomized clinical trial. Am J Clin Nutr 2013; 98(2): Tomsits E, Pataki M, Tölgyesi A, Fekete G, Rischak K, Szollár L. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil: a randomised, double-blind clinical trial in premature infants requiring parenteral nutrition. J Pediatr Gastroenterol Nutr 2010;51(4): Beken S, Dilli D, Fettah ND, Kabataş EU, Zenciroğlu A, Okumuş N. The influence of fish-oil lipid emulsions on retinopathy of prematurity in very low birth weight infants: a randomized controlled trial. Early Hum Dev 2014;90(1): Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, van den Akker CH, van Goudoever JB. Growth and fatty acid profiles of VLBW infants receiving a multicomponent lipid emulsion from birth. J Pediatr Gastroenterol Nutr 2014;58(4): Dounousi E, Zikou X, Koulouras V, Katopodis K. Metabolic acidosis during parenteral nutrition: Pathophysiological mechanisms. Indian J Crit Care Med 2015;19(5): Journal of Clinical Nutrition

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar