대한내과학회지 : 제 70 권제 6 호 2006 간성뇌증과연관이있는생화학적단백질 - 칼로리영양평가지표 가톨릭대학교의과대학내과학교실 정지성 김진일 조세현 박수헌 한준열 김재광 이영석 정규원 선희식 =Abstract= Biochemical assessment of protein-calorie malnutrition in hepatic encephalopathy Ji Sung Chung, M.D., Jin Il Kim, M.D., Se Hyun Cho, M.D., Soo-Heon Park, M.D., Joon-Yeol Han, M.D., Jae Kwang Kim, M.D., Young Sok Lee, M.D., Kyu Won Chung, M.D. and Hee Sik Sun, M.D. Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea Background : Most patients with hepatic encephalopathy have their protein intake restricted. Therefore, protein-calorie malnutrition becomes more severe and may cause more serious problems, such as infection and poor prognosis. The aim of this study is to determine better biochemical parameters for the assessment of nutritional status in patients with hepatic encephalopathy. Methods : A total 109 patients (30 normal controls and 79 chronic hepatitis B) were enrolled. 79 patients were divided into three groups: chronic HBV infection (hepatitis group, n=28), liver cirrhosis without past history of hepatic encephalopathy (cirrhosis group, n=27), liver cirrhosis with present or past history of hepatic encephalopathy (encephalopathy group, n=24). Serum albumin, total lymphocyte count, IGF-1, growth hormone, retinol binding protein, leptin and fibronectin were measured. Results : Serum albumin level, total lymphocyte count, IGF-1, and growth hormone were significantly lower in encephalopathy group than other groups (p<0.001, p=0.003, p<0.001, and p<0.001, respectively). However, RBP, leptin, and fibronectin were not different among the groups. The level of serum albumin and IGF-1 were significantly lower in encephalopathy group than cirrhosis group (p=0.002, p<0.001, respectively), but growth hormone was not significantly different between cirrhosis group and encephalopathy group. Conclusions : The level of serum albumin and IGF-1 may be important parameter for nutritional support in chronic liver disease, especially in patients with hepatic encephalopathy, because the level of serum albumin and IGF-1 relate with hepatic encephalopathy as well as reflect the progression of chronic liver disease.(korean J Med 70:650-655, 2006) Key Words : Malnutrition, Hepatic encephalopathy, Insulin-like growth factor-1 접수 : 2006 년 2 월 23 일 통과 : 2006 년 5 월 11 일 교신저자 : 정규원, 서울시영등포구여의도동 62, 성모병원소화기내과 (150-713) E-mail : jyhan@catholic ac.kr * 본연구는보건복지부 2000 년도보건의료기술연구개발사업연구비 (HMP-00-CH-09-0008) 로이루어졌음 - 650 -
-Ji Sung Chung, et al : Biochemical assessment of protein-calorie malnutrition in hepatic encephalopathy - 서론만성간질환환자에서는단백질-칼로리영양실조가흔한것으로알려져있으며, 영양실조는간질환의증상인구역과식욕부진, 소화흡수장애, 간에서영양소의대사작용저하와관련이있다 1). 간질환환자에서불량한영양상태는예후에악영향을미치지만 2, 3) 적절한영양공급을하면간기능이호전되고생존율이향상되는것으로보고되어있다 3). 현증간성뇌증환자의치료에는단백질섭취제한이필요하지만, 회복기에는질소균형을유지하기위하여단백질공급이필요하다. 영국전역에걸쳐설문조사를한보고에의하면 1,046명의간성뇌증환자중 73% 의환자에서단백질섭취제한을하고있으며, 이들중대부분이장기간단백질제한을받고있는것으로보고하였다 4). 간성뇌증환자에서장기간단백질제한을함에따라간성뇌증의병력이없는간경변환자들보다단백질-칼로리영양실조가더심할수있다. 간성뇌증의치료에단백질공급여부와시기는아직도논란의대상이되고있다. 알코올성간질환환자에서위관삽입을통한영양공급으로간성뇌증이호전되고 5), 간성뇌증환자에서분지아미노산을정맥주입하여간성뇌증이호전된다는보고가있다 6). 그러나이와는반대로간성뇌증환자에서영양공급으로인한이득을확인할수없었다는보고들도있어 7, 8) 논란이있다. 영양상태의평가방법으로는병력청취및이학적검사, 음식섭취조사, 체질량지수, 인체계측법, bioelectrical impedence, 영상진단법등다양한방법들이이용되고있지만 9), 적절한영양공급을해야하는환자와미량영양소결핍이있는환자를알아내어치료하고, 영양공급의효과판정을위한기준을설정하기위하여는생화학적영양지표가필요하며, 생화학적영양지표들로는알부민, 총림프구수, insulin-like growth factor-1 (IGF-1), retinol binding protein (RBP), leptin, fibronectin 등다수가이용되고있다 10). 간성뇌증환자의치료로서단백질섭취제한의필요여부와단백질섭취의재개시기, 단백질섭취량, 치료효과등을판정하기위하여는단백질영양실조를평가할수있는지표가반드시필요할것으로생각되나, 간성뇌증과연관이있는단백질영양지표는아직잘알려져있지않다. 저자들은 B형간염에의한만성간질환환자를대상 으로알부민, 총림프구수, IGF-1, RBP, leptin, fibronectin 등생화학적영양지표들을측정하여간성뇌증환자에서적절한영양지표가무엇인지알아보았으며, 이결과는간성뇌증환자의경과관찰과예후판정및치료에도움이될수있을것으로생각한다. 대상및방법 1. 대상 1999년 5월부터 2003년 6월까지가톨릭의과대학부속성모병원에입원하여치료받은만성 B형간염과 B 형간염바이러스에의한간경변환자 79명을대상으로하였고, 건강검진을받은건강인 30명을정상대조군으로하였다. 대상환자는 HBsAg 양성이었으며, 간암의근거가없는환자로서임상경과와검사실소견및복부초음파검사등의방사선과적소견에의하여다음과같이분류하여비교분석하였다. 제 1군은정상대조군으로건강검진결과간염바이러스감염과알코올성간염의근거가없으면서간기능검사가정상인 30명이었다. 제2군은만성간염군으로서식도정맥류나복수또는간성뇌증등간경변의합병증의기왕력이없는환자 28 명이었고, 제3군은간경변군으로서식도정맥류나복수등간경변의합병증의기왕력이나현증이있지만간성뇌증의기왕력은없는환자 27명이었으며, 제4군은간성뇌증군으로서간성뇌증의기왕력이나현증이있는간경변환자 24명이었다. 대상환자 109명의성별은남자 69명, 여자 40명, 평균연령은 48세로네군간에차이가없었다. 만성간질환군인제2, 3, 4군간에 bilirubin, AST, creatinine은통계학적차이가없었고, ALT 만이제2군에서다른군보다높았다 ( 표 1). 2. 방법대상환자의혈청에서 ELISA Kit를이용하여생화학적영양지표인 IGF-1 (R&D Systems Inc., Minneapolis, MN, USA) 과, RBP (ALPCO diagnostics, Windham, NH, USA) 과, leptin (R&D Systems Inc., Minneapolis, MN, USA, USA), fibronectin (Takara Bio Inc., Marysville, WA, USA) 을측정하였고, IGF-1과되먹이관계인성장호르몬 (growth hormone, GH) (ICN pharmaceutics, Orangeburg, NY, USA) 을추가로측정하였으며, 건강검진또는입원당일시행한검사중영양지표로알려져 - 651 -
- 대한내과학회지 : 제 70 권제 6 호통권제 550 호 2006 - Table 1. Clinical characteristics of patients Group 1 (n=30) Group 2 (n=28) Group 3 (n=27) Group 4 (n=24) Sex (male/female) Age (years) Bilirubin (mg/dl) AST (IU/L) ALT (IU/L) Creatinine (mg/dl) 17 / 13 46.9±14.3 0.69±0.25 19±4 20±11 0.85±0.15 18 / 10 46.8±16.5 1.75±4.08 303±263 483±421 * 0.80±0.18 19 / 8 50.2±18.7 2.77±3.58 168±166 116±128 1.20±0.59 15 / 9 48.3±16.3 3.20±5.56 144±125 95±83 1.47±0.86 * p<0.01 between group 2 and group 3 or 4 Table 2. Comparison of nutritional parameters in patients with chronic liver disease Group 1 Group 2 Group 3 Group 4 p value Albumin (g/dl) TLC (x10 6 /L) IGF-1 (ng/ml) GH (ng/ml) RBP (mg/ml) Leptin (pg/ml) Fibronectin (ng/ml) 4.27±0.19 1816±492 161.2±42.5 0.85±1.26 43.1±6.1 8948±5757 50810±11716 3.61±0.58 1956±658 128.1±49.9 2.42±3.11 40.5±31.9 8693±8632 55722±6746 3.11±0.68 1800±797 70.9±37.8 5.77±7.20 41.4±65.6 5907±5137 43169±15164 2.63±0.53 * 1256±804 41.8±53.7 * 5.25±5.86 41.8±53.8 8063±11498 45346±18276 <0.001 0.003 <0.001 <0.001 0.183 0.48 0.018 TLC, total lymphocyte count; GH, Growth hormone; RBP, Retinol binding protein. * p<0.01 in the difference between group 3 and group 4 있는혈청알부민치와총림프구수를알아내어각군간의차이를비교하였다. 3. 통계자료의통계분석은 SPSS 통계프로그램 (version 10.0, SPSS Ins., Chicago, IL, USA) 을이용하였고, 모든측정치는평균 ± 표준편차로표시하였으며, 각군간의평균차이를보기위하여 one way ANOVA를사용하였고 p<0.01 일때를통계적으로유의한것으로하였다. 각측정치간의상관관계는 Pearson 상관계수를이용하였다. 결과 1. 만성간염, 간경변및간성뇌증환자에서영양지표의차이네군간에유의한차이를보였던영양지표들은혈청알부민 (p<0.001), 총림프구수 (p=0.003), IGF-1 (p<0.001), GH (p<0.001) 였으며, RBP, leptin, fibronectin은네군간에유의한차이가없었다 ( 표 2). 제3군인간경화군과제4군인간성혼수군간에유의한차이를보였던영양지표는혈청알부민 (p=0.002) 과 IGF-1 (p=0.001) 이었으며, IGF-1과되먹이관계인 GH 는 3군과 4군간에유의한차이가없었다 ( 표 2). 2. 영양지표간의상관관계네군간에의미있는차이를보였던혈청 IGF-1치는혈청알부민과상관계수 r=0.669로유의한상관관계를보였으며 (p<0.01) ( 그림 1), 총림프구수와의상관계수는 r=0.235 ( 그림 2) 로빌리루빈수치와의상관계수는 r=-0.197 ( 그림3) 로혈청알부민에비해상관관계가미약하였다 (p=0.05). 고찰만성간질환환자에서단백질-칼로리영양실조는 1 0~100% 까지다양하게보고되고있으며 11), 간이식이나수술후에사망률과예후에악영향을미치는것으로보고되어있다 12, 13). 본연구결과정상군과만성간질환의합병증유무에따라분류한대상군에서혈청알부민, 총 - 652 -
- 정지성외 8 인 : 간성뇌증과연관이있는생화학적단백질 - 칼로리영양평가지표 - Figure 1. Scatter plots of serum IGF-1 and albumin. The level of IGF-1 correlates with the level of serum albumin, significantly. Figure 2. Scatter plots of serum IGF-1 and total lymphocyte count. The level of IGF-1 does not correlate with total lymphocyte count. 림파구수, IGF-1, 성장호르몬수치가유의한차이를보였다. 이는만성간질환의진행에따라단백질-칼로리영양실조가심해지는것을반영하는것으로여겨진다. 현증간성뇌증환자의치료에서단백질을제한하여야하지만회복된후에는적절한단백질공급을하여야한다. 그러나간성뇌증환자에서장기간단백질을제한하는경우가많으며, 따라서현증의간성뇌증환자뿐아니라과거에간성뇌증의기왕력이있었던환자에서단백질-칼로리영양실조가심할것이라는것을예측할수있다. 본연구결과각군간에가장유의한차이를보인혈청영양지표는혈청알부민치와 IFG-1 이었으며, 현증또는기왕력의간성뇌증유무에따라분류한 3군과 4군간에도유의한차이를보였다. 알부민은간에서생성되는혈청단백질로서간경변의심한정도를평가하는가장유용한방법인 Child 분류의한요소이다. IGF-1은영양상태의급성변화에대한표지자로알려져있으며 14) 반감기가매우짧아영양결핍의예민한표지자로제시되어왔다 15). IGF-1은단백질분해를억제하여단백질동화작용을하고, 아미노산이공급되면단백질생산을촉진한다 16). 본연구결과혈청 IGF-1 치는간경변군에비해간성뇌증군에서낮았다. Arwert 등 17) 은메타분석을하여 IGF-1의감소와인지기능의저하와연관이있는것으로보고하였다. 인지기능의저하는간성뇌증의특징중하나이며, 간성뇌증군에서의 IGF-1 감소는인지기능이저하되어발생한간성뇌증과연관이 Figure 3. Scatter plots of serum IGF-1 and total bilirubin. The level of IGF-1 does not correlate with the level of serum total bilirubin. 있을가능성이있다. 본연구결과현증의간성뇌증이있거나기왕력이있는환자들에서는 IGF-1이감소되어있었지만간성뇌증이 IGF-1 감소의원인인지결과인지는확인할수없으며, IGF-1의반감기가짧은점은간성뇌증의경과에따라빠른변화를보일가능성이있다. 이런점들은향후 IGF-1의혈역학적연구를포함한보다많은연구들로규명되어야할것으로생각된다. 본연구결과에서간경변군과간성뇌증군간에 IGF-1 농도는유의한차이를보였지만, GH는유의한차이를 - 653 -
-The Korean Journal of Medicine : Vol. 70, No. 6, 2006 - 보이지않았다. GH는간에서 IGF-I을분비하게하는가장강력한물질이며, IGF-I은음성되먹이기를통하여뇌하수체에서의 GH 분비를억제한다. IGF-1의분비는 GH와밀접한연관성을가지고있지만, GH와무관하게영양상태에의해서조절되기도한다 18). 간경변환자에서는정상인보다 IGF-1이감소되어있으며 GH에대한음성되먹이기가소실되어 GH가증가되는데, IGF-1이감소한것은간질환환자의단백질영양실조와제지방체중의소실이원인일것으로생각되지만 19), IGF-1 이단백질영양실조의지표라기보다는간기능부전과더관련이있다는주장도있다 20, 21). 본연구에서는만성간질환의진행에따라 IGF-1은감소하고 GH은증가하여만성간질환환자에서후천적인 GH 저항상태를보인다는이전연구결과와일치하였다. 그러나간성뇌증환자에서는간성뇌증이없는환자보다 IGF-1이더감소한소견을보였으나, GH은양군간에차이가없었다. Gianotti 등 22) 은이화상태에서는단순간경변이나신경성식욕부진에서보이는것처럼 IGF-1이낮아져도 GH가증가하지않는다고보고하였는데, 이화상태에서는말초 GH 무감응과성장자극세포부전 (somatotrope insufficiency) 때문이라고하였다. 결론적으로 B형간염에의한만성간질환의진행을가장잘반영하고, 간성뇌증의발생과연관이있는생화학적영양지표는혈청알부민치와혈청 IGF-1 치였으며, 간성뇌증환자를위한단백질공급의지표로이용될수있을것으로생각된다. 알부민에비하여 IGF-1은반감기가현저히짧기때문에영양상태의변화에민감하게변화할가능성이높을것으로생각되며, 간성뇌증환자의영양공급판단에도움이되는보다좋은지표들을개발하고, 이를이용하여간성뇌증치료방침을개발하기위하여향후보다많은연구를통한노력이필요할것으로생각된다. 요약목적 : 간경변환자에서단백질-칼로리영양실조가흔하며, 영양실조의경우면역력이저하되어감염의위험성이높아지고예후도나쁜것으로알려져있다. 현증간성뇌증환자의경우, 단백질제한을하는경우가많으며, 장기간단백질제한을하는경우영양실조가악화될뿐아니라예후에도악영향을미칠수있다. 간성뇌증에서회복된이후에는단백질공급이필요할것으로생각 되나, 이를위한기준은미흡한실정이다. 이에간성뇌증과연관이있는영양평가지표들을알아보기위하여본연구를시행하였다. 방법 : 대상환자는 109명으로정상대조군 30명, B형간염에의한만성간질환환자 79 명이었다. 만성간질환환자 79명은세군으로세분하였다. 간경변의합병증이없는만성간질환환자 28명, 식도정맥류나복수등의기왕력이나현증이있지만간성뇌증의기왕력이없는환자 27명, 현증간성뇌증이나기왕력이있는환자 24명이었다. 영양지표로는혈청알부민치, 총림프구수, IGF-1, GH, retinol binding protein, fibronectin, leptin을동시에측정하여각군간의차이를비교분석하였다. 결과 : 혈청알부민과 IGF-1의농도는각군간에유의한차이를보였으며 (p<0.001), 간성뇌증환자군에서다른군에비하여유의하게감소하였다 (p<0.001). GH는만성간염군과간경변군에서는차이가있었지만 (p<0.05), 간경변군과간성뇌증군간에는유의한차이가관찰되지않았다. 결론 : 혈청알부민치와 IGF-1치는만성간질환의진행을가장잘반영하며, 간성뇌증과연관이있는영양지표인것으로생각되었다. 중심단어 : 영양실조, 간경변, 간성뇌증, 인슐린양성장인자 REFERENCES 1) Caregaro L, Alberino F, Amodio P, Merkel C, Bolognesi M, Angeli P, Gatta A. Malnutrition in alcoholic and virus-related cirrhosis. Am J Clin Nutr 63:602-609, 1996 2) Mendenhall CL, Tosch T, Weesner RE, Garcia-Pont P, Goldberg SJ, Kiernan T, Seeff LB, Sorell M, Tamburro C, Zetterman R. VA cooperative study on alcoholic hepatitis: II. prognostic significance of protein-calorie malnutrition. Am J Clin Nutr 43:213-218, 1986 3) Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 14:1090-1096, 1991 4) Soulsby CT, Morgan MY. Dietary management of hepatic encephalopathy in cirrhotic patients: survey - 654 -
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