간부전증의영양관리 Nutritional Management in Chronic Decompensated Liver Disease including Liver Cirrhosis 이주호 1,2 ㆍ최상운 1 차의과학대학교분당차병원 1 내과학교실, 2 소화기내과 Protein-energy malnutrition in the chronic decompensated liver disease, including liver cirrhosis (LC), develops as a result of multiple factors such as poor dietary intake, malabsorption, increased intestinal protein loss, decreased hepatic protein synthesis, abnormal substrate utilization, and hypermetabolism. Nutrition screening with the Subjective Global Assessment and anthropometric measurements are an important first step in the early identification of malnutrition in such patients. Evidence-based nutritional interventions are needed to minimize the nutritional decline associated with the decompensated liver disease and ultimately improve the prognosis of cirrhotic patients. Specific dietary recommendations to be implemented are so important to help prevent liver decompensation because malnutrition is an independent predictor of mortality. Protein restriction and prolonged fasting are discouraged in LC patients. Because hepatic encephalopathy can be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids, BCAA supplementation, probiotics, and fibers are generally recommended for cirrhotic patients. This review focuses on the nutritional assessment of cirrhotic patients and some general recommendations for nutritional supplementation in LC. Keywords: Liver cirrhosis; Malnutrition; Nutritional assessment; Nutritional supplementation; Branched-chain amino acids 서론 우리나라는만성간질환특히, 간경변증 (liver cirrhosis) 의유병률이높으며, 간경변증은주요사망원인의하나이다. 통계청에서발표한 2008년도와 2009년도의간질환에의한사망률은이전보다는감소했으나, 인구 10만명당 17.3명과 15.6명으로사망률 6, 7위를차지하고있다. 1 복수, 간성뇌증, 정맥류출혈등의합병증을동반한비대상성 (decompensated) 만성간질환또는간경변증의예후는매우불량하며, 간질환의정도가심할수록영양결핍의정도또한심한것으로보고되고있다. 한예로 Child Pugh A 및 B 등급간경변증환자의단백질칼로리영양불량 (malnutrition) 동반율은각각 21% 와 40% 인반면, Child Pugh 등급 C 환자는 70-90% 그리고간이식대기환자는거의모든환자가단백질칼로리영양불량을보여주었다. 2 www.kast.org 53
2015 대한간학회춘계 Single Topic Symposium Table 1. Causes of malnutrition in liver diseases* Decreased intake of nutrients - Abdominal distention (ascites, splenomegaly) - Nausea and vomiting - Anorexia (chronic esophagitis and portal gastropathy) - Encephalopathy-related decreased oral intake - Impaired gastric emptying - Iatrogenic causes (unnecessary restriction of protein for encephalopathy, repeated fasting due to diagnostic tests) - Impairment of taste (zinc deficiency) - Inhibition of gluconeogenesis due to alcohol abuse - Alcohol-related malabsorption of some nutrients (folate, vitamin B12, thiamine, magnesium) - Poor socioeconomic status - Recurrent uncontrolled infections in cirrhotic patients Metabolic derangements - Insulin resistance and its consequences - Increase in resting metabolic rate Malabsorption - Impairment of bile flow in chronic cholestasis - Bacterial overgrowth - Concomitant chronic pancreatitis (particularly in alcoholic steatohepatitis) - Concomitant chronic autoimmune liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis) Drug- or toxin-induced malnutrition - Use of cholestyramine and colestipol leading to lipid malabsorption - Metformin use for insulin resistance leading to vitamin B12 deficiency - Chronic steroid use leading to calcium and vitamin D malabsorption * Adapted from Best Pract Res Clin Gastroenterol 2013;27:619-629.3 이러한단백질과열량결핍 (protein-energy malnutrition) 은다양한요인에의해서발생하며식욕감소에의한경구섭취저하, 소화및흡수장애, 혈장단백질합성의감소그리고열량소모증가등이그원인으로추정된다 (Table 1). 3 이러한영양불량은간경변증의진행에따른합병증이면서, 동시에간경변증의비대상성합병증발생및이와관련된사망의독립적예후인자이다. 4 따라서, 인체계측 (anthropometric measurements) 및 Subjective Global Assessment (SGA) (Table 2) 3,5 등을통한영양평가가간경변증의진단당시에모든환자에서시행되는것이바람직하며이를바탕으로영양상태개선을위한적극적인영양관리가이루어져야할것이다. 6 복수와간성뇌증및정맥류출혈등의비대상성간질환의합병증발생을줄이고, 궁극적으로간경변증환자의생존율을향상시키기위한다양한근거중심의영양관리에대한관심이점차늘어나고있다. 만성간질환환자의영양소대사변화 간경변증환자는기초대사율증가로인하여섭취량을증가시키지않으면기아와비슷한대사상태에 54 대한간학회 The Korean Association for study of the Liver
이주호 간부전증의영양관리 Table 2. Subjective Global Assessment Questionnaire* History 1. Weight Change Loss in last six months Change in two weeks 2. Dietary changes: Search for the presence of starvation, full liquid diet, hypocaloric, and suboptimal liquid diet Physical examination 0 = normal, 1+ = mild, 2+ = moderate, 3+ = severe 1. Loss of subcutaneous fat in triceps and chest 2. Muscle wasting in deltoids and quadriceps 3. Ankle edema 4. Sacral edema 5. Ascites 3. Presence or absence of nausea, vomiting, and diarrhea persisting for last two weeks 4. Functional status 5. Evaluation of individual nutritional requirements Note the primary diagnosis and evaluate the presence of metabolic stress (no, low, moderate and high stress) * Adapted from Best Pract Res Clin Gastroenterol 2013;27:619-629. 3 SGA rating: A = well nourished B = moderately malnourished C = severely malnourished 놓이게된다. 7 이렇게간경변증환자에서대사가항진되어있는기전은유효혈류량감소로인하여교감신경계의활성이동반되어있으며, 이에따른 norepinephrine 및 epinephrine 의분비가증가하여대사적인측면에서는대사과다증을보이게되어쉽게영양결핍또는부족상태에빠지게된다고설명되고있다. 8 간경변증환자는간의당원합성능력의저하와당대사이상으로인해당신생을위한지방산화와단백질분해 (catabolism) 가증가하는데, 실제로간경변증환자가 12시간정도의금식을시행할경우건강인에서의 72 시간동안의기아상태와동일한지방산화및단백질분해가일어나게된다. 9 간기능저하시간에서요소합성이감소되어혈중암모니아농도는증가한다. 또한혈장단백질합성의감소로저단백혈증이나타나고근육량이감소된다. 간의단백질합성에사용되는아미노산은단백질섭취, 근육에서유래되거나일부는간에서직접생산되어공급되는데, 음식물로섭취된아미노산중분지쇄아미노산을제외한대부분은문맥을통하여간으로들어가요소로대사되나분지쇄아미노산 (leucine, isoleucine, valine) 은간에서분해되지않고근육, 신장, 지방조직및뇌와같은말초조직에서이용된다. 분지쇄아미노산은골격근의단백질분해에의해생성된다. 6 정상적으로분지쇄아미노산은 6-7% 의열량요구량을충당하나대사항진, 포도당저항성, 케톤합성의감소등이있을경우 30-40% 까지증가한다. 또한, 암모니아를골격근에서글루타민으로전환시켜해독하는데쓰이므로간경변증환자에서분지쇄아미노산의요구도는증가된다. 10 간기능장애시담즙산의합성과배설또한감소하므로지방의소화및흡수가저해되어지용성비타민의결핍이나타날수있다. 간경변증환자에서는무기질의흡수, 저장의문제로무기질농도가감소한다. 일반적으로아연과구리, 셀레니움은간질환시저장이감소되나알코올성간질환에서는간의철분저장량 www.kast.org 55
2015 대한간학회춘계 Single Topic Symposium 이증가하는양상을보인다. 6 만성간질환환자에서영양판정 간경변증환자에서영양상태를평가하기위하여여러가지방법이제시되고있다. 임상에서가장널리사용되는지표는체중의변화또는체질량지수 (Body mass index) 를기준으로평가하는방법이다. 7 이와 같이체중은영양판정시자주사용되는손쉬운평가방법이다. 지난 6 개월간 20-30% 의체중감소는중증 의영양불량, 30% 이상은심한영양불량을나타내며, 1 개월간 10% 이상의체중감소를보일경우도심한 영양불량으로정의한다. 6 체중은비교적간단하고객관적이긴하지만, 복수나부종이있는환자에서는체 중이영양판정의도구로사용될수없으며, 알부민, 트렌스페린, 프리알부민, 레티놀결합단백질과같은 혈중단백질수준또한간에서의합성능에따 라좌우되므로적절한영양상태의판정지표 로활용하기어렵다. 보다객관적인방법으로 캘리퍼를사용한삼두박근의피부두겹두께 (tricepsskinfold thickness, TSF) 와중완근위 (midarmmuscle circumference, MAMC) 의측정 은근육량과체지방수준을추정할수있는대 체지표로활용가능하다. 7 하지만, 이러한방법 은전신부종등에영향을받지않는다는장점 이있으나측정하는사람마다차이가발생할 수있다는단점이있다. 그외악력 (handgrip strength) 을이용하여평가하는방법이있으며, 최근연구에서 hand dynamometer 를이용해측 정한악력이단백질열량결핍 (protein-energy malnutrition) 을객관적으로반영하여간경변증 환자의비대상성합병증발생의독립적예후인자가될수있다고보고하였다. 3 인체계측및 Subjective Global Assessment (SGA) 는간경변증 환자에서가장실질적인영양결핍상태를반 영한다고볼수있다. 유럽영양학회 (European society of parenteral and enteral nutrition, Figure 1. Vectorial bioelectrical impedance. From the inner to the outer, those ellipses represent the 50%, 75%, and 95% tolerance ellipses, results falling outside the 75% tolerance ellipse indicate abnormality. The result can move across the more vertical axis of the plane shown, depending on the status of hydration, and across the more horizontal axis depending on the amount of soft tissue an individual has. The three cirrhotic patients shown tend to have few soft tissue as represented by their position at the right side of the center of the horizontal axis. As disease progresses, according to the Child-Pugh state, the patients move downward the vertical axis, representing hyperhydration (Adapted from Nutrition 2013;29:1279-1285.) 4 Xc, reactance; R, resistance; H, height;, Child A patient;, Child B patient;, Child C patient. 56 대한간학회 The Korean Association for study of the Liver
이주호 간부전증의영양관리 ESPN) 에서는신체계측과 SGA로일차적인평가를권고하고있다. SAG는최근의체중변화, 식사량, 소화기증상, 운동능력, 스트레스정도및간단한신체검사의 6개의항목을이용하여 3개의등급으로나누어영양상태를평가하는방법이다 (Table 2). 3 그외최근에체구성성분분석을할수있는기계가개발되어이를이용한연구가활발하게진행되고있다. 체구성성분분석을위해전기저항원리를이용한생체전기저항분석 (bioelectrical impedance analysis, BIA)(Fig. 1) 를 4 실시하거나, 복수가심할경우에는 dual-energy X-ray absorptiometry (DEXA) 로지방량, 골질량, 제지방량 (lean body mass) 의체구성성분을판정하는데사용될수있다. 간경변증환자에서혈청알부민농도의감소원인은부적절한단백질섭취, 간합성의감소와알부민이화율 (catabolism rate) 증가등이다. 11 혈청 prealbumin, retinol binding protein 과 transferrin 등도간세포에서합성되므로일반적인영양상태를반영하기는어려우나영양보충시이들농도의변화는주어진간세포기능에서단백질섭취를반영하는유용한지표이다. 총임파구수 (total lymphocyte count, TLC) 가 1000/μL 이하인경우면역기능저하와연관이있다. 간경변증환자의영양요법 1. 영양소요구량간경변증환자에서열량요구량의측정은 indirect calorimetry 를사용하는것이정확하고이외에도 Harris-Benedict 공식혹은다른공식을이용하여추정할수있으나부정확할수있다. 12 간경변증환자에서휴식기에너지소비가증가되어일반적으로하루에너지필요량을휴식기에너지소비의 150-175% 까지필요하다. 7 간경변증환자에서 1일필요열량은기초대사율의 1.2-1.4 배이며이는일반적으로체중 1 kg당 25-35 kcal에해당한다 (Table 3). 4 체중의손실을방지하고당신생을위한내인성단백의이화작용 (catabolism) 을늦추기위해, 360-480 kcal의열량은단백질을통해공급되어야한다. 복수가있을때열량 Table 3. Recommended daily values for cirrhotic patients* Encephalopathy No encephalopathy Glucose intolerance without encephalopathy Calories (kcal/kg/d) 25-35 25 Proteins (g/kg) Carbohydrates (%) Lipids (%) 1.2-1.5 72 28 Malnourished 30-40 Echephalopathy grades I II 35-40 0.5-1.2 75 25 Encephalopathy grades III IV 35-40 0.5-0.7 * Adapted from Nutrition 2013;29:1279-1285. According to estimated dry weight. Preferably of vegetable origin and rich in branched-chain amino acids. www.kast.org 57
2015 대한간학회춘계 Single Topic Symposium 과단백질함량은체중에서복수의무게를뺀값을기초로정한다. 간성뇌증이동반된경우총칼로리는 30-40 kcal/kg/day를섭취할것을권고하고있으며, 이는정상인의일일칼로리섭취량과비교하여다소높다. 7 단백질의경우 1.2-1.5 g/kg/day의섭취를권장하며, 하루총 100 g을넘지않도록한다. 당질은총열양의 57-80%, 지방은 25-30% 로구성하며 40% 를초과하지않는다. 4 공복상태인야간에체지방소모가늘어나고포도당의처리능력에장애가있다는것을고려하여한번에많은양의식사보다여러번적은양으로식사를나눠야간에도가벼운식사를섭취하는것이도움이된다. 7 최근일본의한연구에서는 Child Pugh 등급 A의간경변증환자를대상으로 200 kcal의단백질과탄수화물을포함한스낵을야간에매일섭취하게한후 6개월뒤추적검사에서, 그렇지않은대조군에비해더나은영양지표의개선과삶의질향상을보고하였다. 13 이와같이비대상성간질환에서당신생을위한지방과단백의소모를막고질소균형을유지하기위해서, 간경변증환자에서불필요한장기간의공복상태는피하는것이바람직하다. 2. 염분및수분섭취염분섭취는간질환시제한되어왔지만저염식사는식욕을감소시키고구토, 오심등을유발하므로간질환이진행된환자에서영양불량을초래할수있다. 따라서복수나부종이없는환자에서염분을심하게제한하지않는것이환자의영양상태를개선시킬수있다. 6 복수및부종이있을때에는체내수분축적을막기위해 1일염분섭취량은 5-6 g ( 나트륨으로 1-2 g) 이하로제한할것을권장한다. 1 하지만, 처음발생한복수에서저염식으로만복수가조절되는경우는 10-15% 정도에불과하므로, 저염식에순응하지못하는환자는적당량의염분을허용하면서이뇨제를증량하여복수를조절한다. 체내수분은신장의나트륨배설에의해수동적으로배출되기때문에대부분의복수환자에서수분섭취제한이절대적으로필요하지는않다. 혈중나트륨농도가 120-125 meq/l 이하일때수분섭취량을하루 1-1.5 리터로제한할수있으나, 효과가증명된연구가희박하다. 14 3. 간성뇌증의영양관리및분지쇄아미노산 (branched-chain amino acids) 간경변증환자는대사율증가및당원저장량감소로인하여섭취량을증가시키지않으면당신생 (gluconeogenesis) 의증가로인한단백질요구량이증가된다. 6 간경변증이많이진행된상태에서영양및간기능개선은이환율과사망률을감소시키기때문에, 영양불량환자는아미노산혹은단백질이풍부한영양보충이필요하다. 간경변증환자에서질소균형을달성하기위하여 1일체중 1 kg당 1.2-1.5 g 의단백질섭취가필요하다. 간성뇌증을유발하는독소는주로장에서기인하기때문에급성간성뇌증환자에서단백질섭취를제한하는것이가장기본적인치료로여겨져왔다. 그러나장기간의지나친단백질섭취제한은단백질의분해대사 (catabolism) 증가, 간기능저하및문맥- 전신단락증가뿐아니라체외암모니아 58 대한간학회 The Korean Association for study of the Liver
이주호 간부전증의영양관리 대사의주된장소인근육량을감소시킴으로써체내암모니아농도를더욱증가시킬수있다. 15 실제로간성뇌증을동반한간경변증환자에서단백질섭취제한은더이상권고되지않는실정이다. 16 따라서, 2단계이상의심한간성뇌증시에는초기일정기간동안만단백질섭취량을 1일 70 g 이하로제한하고, 이후회복기에는차츰환자가견딜수있는양으로점진적으로단백질섭취량을늘려서 1일최대 100 g 까지증량할수있다. 1,4 간경변증이많이진행된상태에서도대부분의환자들은간성뇌증의위험없이단백질섭취에잘순응한다. 이경우에는 standard formulas ( 표준처방 ) 보다는분지쇄아미노산이강화된처방사용시질소균형에유용하다. 간경변증환자에서분지쇄아미노산은근육에서열량공급원으로이용될수있어, 근육감소를최소화하며간의단백질합성을촉진한다. 6 영양불량환자에서분지쇄아미노산보충은단백질요구량을만족시킬것이고영양불량, 대사율증가, 단백질손실과관련된악순환을깰수있다. 만성간성뇌증환자에서분지쇄아미노산보충은정신상태를개선시키면서필요한질소를섭취할수있으나, 적절한단백질섭취가분지쇄아니노산보충전에이루어져야한다. 17 일반적으로표준아미노산처방은말기간질환환자에서도잘순응되어진다. 다른필수아미노산없이단지분지쇄아미노산을제공하는경우에는질소균형을보이지못하나다른필수아미노산과함께총아미노산의 16-53% 를분지쇄아미노산으로공급하는경우질소균형을개선시킨다. 6 대부분의간경변증환자에서표준아미노산처방은혈장 aminograms, 질소, 칼륨, 인의균형과 visceral protein 상태를개선시킨다. 분지쇄아미노산이강화된처방은간성뇌증개선과관련이있으나가격은표준아미노산처방보다 10배가량비싸다. 따라서일반적으로분지쇄아미노산이강화된처방은표준아미노산처방을사용한후간성뇌증이여전히주요임상문제로남는환자에만사용하는것을권장한다. 11 일반적으로임상에서는맛이뛰어난표준영양보충음료를일단사용하고, 소장 enteral feeding을받는환자에대해서만필수성분을포함한분지쇄아미노산처방을사용한다. 6 식물성단백질은간성뇌증을악화시키지않으면서질소평형 (nitrogen balance) 을호전시키며식물성단백질에풍부한식이섬유는위장관운동을빠르게하고장내세균에의한발효를유발하여장관내 ph를감소시킨다. 16 식물성단백질이동물성단백질에비해간성뇌증환자에서의식상태의호전, 혈중암모니아감소, 신경정신검사의호전에더효과적이라는연구보고가있지만, 장기적으로는영양학적으로우수한동물성단백질공급이간경변환자의장기예후에도움이될수있다. 1 필수미량원소중하나인아연 (zinc) 은단백질및질소대사조절에중요한역할을한다. 아연이결핍되면요소회로효소및글루타민합성효소의작용이저하되며아연을공급하면요소회로가활성화된다. 간성뇌증환자에서아연보충의효과는확실하지않으나간경변증환자에서아연결핍이간성뇌증의유발인자로작용할수있으므로, 18 아연이결핍되어있는경우경구로아연을보충해주는것이도움이될수있다. 아연의하루권장허용량은성인남성및여성에서각각 11 mg 및 8 mg이다. 아연을과량복용하였을때구역, 구토, 식욕부진, 복통, 설사및두통등의부작용이나타날수있다. 1 한편간성뇌증환자에서는장내미생물환경의변화가나타나며, www.kast.org 59
2015 대한간학회춘계 Single Topic Symposium Figure 2. One-carbon metabolism. (Adapted from Nutrients 2014;6:3303-3325. 21 ) SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; DNMT: DNA methyltransferase; HMT: histone methyltransferase; MAT: methionine adenosyltransferase; GNMT: glycine N-methyltransferase. 대개대장균과포도상구균총이더우세한양상을나타낸다. 보고에따르면락토바실러스등을포함한프로바이오틱스를이러한간성뇌증환자에게투여시혈중암모니아수치와내독소수치의감소를보였으며, Child-Pugh 등급의개선효과를나타냈다. 19 하지만이러한결과에대해서는아직더많은연구가필요한실정이다. 4. 비타민과기타영양성분부족하기쉬운아연, 비타민 B1, 엽산과종합비타민은간질환환자에게정기적으로공급하며, 간경변증말기의거의모든환자는대체적으로심한아연결핍을갖는다. 6 지용성비타민인비타민 A, D, E, K도만성간질환환자에서결핍이올수있어보충이필요하다. 엽산의일일권고량은성인에서 800-1000 μg 정도이며, 20 엽산부족이없는상태에서일일권고상한치인 1000 μg 을초과하는엽산의투여는오히려간내단일탄소대사 (one carbon metabolism)(fig. 2) 21 에부정적인영향을가져올수있다. 카니틴 (L-carnitine) 은간성뇌증을보이는간경변증환자에서식사보충으로유용한조효소이며, 탄소수가긴지방산의미토콘드리아내로의이동에관여하기때문에지질산화에중요한역할을한다. 알코올성간질환에서카니틴농도가증가되어있으나카니틴투여는임상연구에서간성뇌증을개선시키는것으로나타나므로필요할때카니틴은 1일 1g 경구투여할수있다. 6,22 카니틴은간내합성과정에서 S-adenosylmethionine (SAM) 에 60 대한간학회 The Korean Association for study of the Liver
이주호 간부전증의영양관리 의한메틸화과정을거치게된다. 이러한 SAM은엽산부족또는과다에의해불균형을초래하게되며, 대부분의만성간질환및간경변증에서간조직내 SAM의부족또는감소가나타난다. 21 특히, 알코올성또는비알콜성지방간이동반된간경변증환자에서이러한 SAM의보충이비대상성간부전및간암발생을예방하는효과가있음이알려져있으나 23 아직더많은연구가필요한실정이다. 글루타민은박테리아이동을막고면역기능을증가시키는장점막의정상구조를유지하는데중요한역할을하므로, 글루타민보충은박테리아로인한복막염의발생을감소시킬수있다. 그러나, 글루타민은잉여질소를갖고있기때문에간성뇌증을악화시킬수있으므로간질환말기환자에게는사용하지말아야한다. 6 결론 간경변증환자는대사율이증가되어있고질소균형유지를위해정상인보다충분한열량및단백질섭취가필요하다. 따라서신체계측또는 SGA 등을통하여정확한영양상태와근육량감소등의체구성성분을파악하고, 올바른영양관리를보다적극적으로지도해야할필요가있다. 4 경증의대상성간경변증환자는균형잡힌식단과영양소를골고루섭취할것을권유하며, 주기적으로영양지표를점검하여영양상태가개선되는지살펴보아야한다. 간경변증의진행정도에따라영양상태가불량한경우에는열량및단백질요구량을만족시키기위한보다적극적인대처가필요하며결핍된영양소를확인하여별도의보충 을권장하는것이바람직하다. 24 마지막으로, 간경변증환자의영양관리지침을위하여다음과같은일반 적인결론이받아들여진다. 1) 간경변증환자는질소균형을유지하기위해질병이없는정상인보다충분한열량섭취와더많은양의단백질섭취가필요하다. 2) 대부분의간경변증환자들은간성뇌증의위험없이증가된단백질섭취와잦은식사및야참에잘적응한다. 3) 비대상성간경변증에서영양불량은간관련사망의독립적예후인자이다. 4) 증가된단백질섭취에적응을못하는환자에서간성뇌증의위험없이필요한질소섭취를공급하기위해분지쇄아미노산보충을고려한다. 5) 프로바이오틱스및식이섬유는간성뇌증의예방에도움을줄수있다. Conflicts of Interest The authors have no conflicts to disclose. References 1. Suk KT, Baik SK, Yoon JH, Cheong JY, Paik YH, Lee CH, et al. Revision and update on clinical practice guideline for liver cirrhosis. Korean J Hepatol 2012;18:1-21. www.kast.org 61
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