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1 ORIGINAL ARTICLE Korean J Clin Lab Sci. 2018;50(2): pissn eissn Korean J Clin Lab Sci. Vol. 50, No. 2, June Association between the Components of Metabolic Syndrome and Total Bilirubin at the Health Care Check Up in Korean Men and Women: Based on Adults Except for Diabetes and Hypertension Kyung-A Shin Department of Clinical Laboratory Science, Shinsung University, Dangjin, Korea 당뇨와고혈압환자를제외한건강검진을실시한한국성인남녀의대사증후군구성요소와총빌리루빈간의관련성 신경아 신성대학교임상병리과 Bilirubin has an anti-inflammatory effect as an endogenous antioxidant and has been reported to be inversely correlated with hypertension, diabetes, metabolic syndrome, and insulin resistance. On the other hand, there is a lack of research evaluating the association between bilirubin and metabolic syndrome compared to liver-specific indicators. This study examined the association between the total bilirubin and metabolic syndrome prevalence in Korean adults who underwent health screening compared to ALT and GGT. This cross sectional study included 22,568 adult males and females aged 20 years or older who underwent a health examination at the General Hospital of Gyeonggi Province from March 2015 to February Metabolic syndrome was diagnosed based on the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) guidelines. In both genders, the metabolic syndrome diagnosed group had higher liver enzymes, and the total bilirubin and direct bilirubin were lower than those without the metabolic syndrome risk factors. The serum total bilirubin showed a weak inverse correlation with abdominal obesity (r= vs r= 0.055) and triglyceride (r= vs r= 0.136) in both males and females, which is weaker than ALT and GGT The data were statistically significant. In addition, total bilirubin as well as ALT and GGT in both men and women were not predictors of the likelihood of developing metabolic syndrome. Key words: ALT, GGT, Metabolic syndrome, Total bilirubin Corresponding author: Kyung-A Shin Department of Clinical Laboratory Science, Shinsung University, 1 Daehak-ro, Jeongmi-myeon, Dangjin 31801, Korea Tel: Fax: mobitz2@hanmail.net 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. Copyright 2018 The Korean Society for Clinical Laboratory Science. All rights reserved. Received: April 23, 2018 Revised 1 st : May 10, 2018 Revised 2 nd : May 17, 2018 Accepted: May 17, 2018 서론 대사증후군은복부비만, 인슐린저항성, 고혈압및이상지질혈증이함께동반되는질환으로심혈관계질환및제 2형당뇨 병의위험증가와관련이있다 [1]. 대사증후군의정확한병태생리학적특징은여전히불분명하다. 인슐린저항성, 아디포카인, 산화적스트레스, 만성염증및내피기능장애와같은복잡한병태생리학적기전이대사증후군을유발하는원인으로제시되

2 156 Kyung-A Shin, Metabolic Syndrome and Total Bilirubin 며, 이는산화스트레스와밀접하게관련되어있다 [1, 2]. 한편, 빌리루빈은헴이화작용의최종대사산물이며, 잠재적인항산화제, 항염증제및세포를보호하는역할을한다 [3]. 혈청빌리루빈이낮으면경동맥내막두께가증가하고혈관확장장애가나타나는반면, 혈청빌리루빈이높으면말초동맥질환및뇌졸중과같은동맥경화성폐색질환을낮추는것으로보고된다 [4-6]. 특히높은빌리루빈수치는아디포넥틴을증가시켜대사증후군발병핵심인자인인슐린저항성을개선시키는것으로알려져있다 [7]. 이를뒷받침하는몇몇의횡단면연구는빌리루빈과대사증후군간의역상관관계가있음을보고하였다 [8, 9]. 그러나혈청빌리루빈과대사증후군의연관성에대해서는논란의여지가있다. 일본코호트연구는총빌리루빈과대사증후군사이의유의한관련성을발견하지못하였으며, 빌리루빈은대사증후군위험인자가아니라고보고하였다 [10]. 더욱이대사증후군에서혈청빌리루빈의감소는대사증후군에의한것이아니라대사증후군과밀접한산화스트레스에의해유발된다고제시하였다 [10]. 이러한관점에서 Perera 등 [11] 은태국성인에서간특이적효소의상승이대사증후군위험과관련이있음을보고하였다. Shin [12] 의연구에서도대사적으로건강한비만남성을대상으로간효소인알라닌아미노전이효소 (alanine aminotransferase, ALT) 및감마글루타밀전이효소 (gamma-glutamyl transferase, GGT) 가대사적이상을예측할수있는지표임을제시하고있어간특이적효소와더불어혈청빌리루빈과대사증후군간의관련성을평가하는연구가필요하다. 이에본연구에서건강검진을실시한한국성인남녀를대상으로성별에따른간특이적지표인 ALT, GGT와비교하여총빌리루빈과대사증후군유병률사이의관련성을조사하고자하였다. 대상및방법 1. 연구대상연구대상자는 2015년 3월부터 2018년 2월까지경기도소재종합병원에서건강검진을실시한 20세이상성인남녀 23,356명이었다. 전체대상자중혈액검사상 B형간염표재성항원 (HBsAg) 양성자, C형간염항체 (anti-hcv) 양성자, 만성간질환의과거력이있는자, 고혈압, 당뇨병으로약물치료중인대상자, 해당연구자료에결측치가있는경우에해당하는 788 명을제외한최종연구대상자는 22,568명이었다. 대사증후군이동반된고혈압, 당뇨병환자를제외하고자고혈압과당뇨병으로약물치료중인대상자를제외하였다. 연구대상자의과거 병력이나약물치료에관한자료는건강검진공통문진표에의해조사하였으며, 이연구는경기도소재종합병원기관생명윤리위원회 (institutional review board, IRB) 의심의를거쳐승인후연구를진행하였다 (IRB No: SP ). 2. 연구방법 1) 신체계측및혈압측정연구대상자들의신체계측중신장및체중은 Inbody 720 (Biospace Co., Seoul, Korea) 체성분분석기로측정하였고, 체질량지수 (body mass index, BMI) 는체중 (kg) 을신장 (m) 의제곱 (kg/m 2 ) 으로나누어계산하였다. 허리둘레는늑골최하단부와장골능선사이의중간부위를줄자로측정하였다. 보정된아네로이드혈압계 (Medisave UK Ltd., Weymouth, UK) 를이용하여수축기혈압과이완기혈압을측정하였으며, 5분간안정상태에서 2회측정하여평균값을결과로제시하였다. 2) 대사증후군진단기준및혈액분석대사증후군의진단은 American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) 지침의 5가지기준중 3가지이상만족하는경우대사증후군으로판정하였으며, 복부비만기준은 World Health Organization (WHO) 의서태평양지부에서제시한아시아-태평양지역의기준으로 1 허리둘레 ; 남성 90 cm 이상, 여성 80 cm 이상 2 공복혈당 (fasting blood sugar); 100 mg/dl 이상 3중성지방 (triglyceride, TG); 150 mg/dl 이상 4 고밀도지단백콜레스테롤 (high density lipoprotein cholesterol, HDL-C); 남성 40 mg/dl 미만, 여성 50 mg/dl 미만 5 수축기혈압 ; 130 mmhg 이상이거나이완기혈압 ; 85 mmhg 이상인경우를적용하였다 [13, 14]. 혈액분석은검사당일오전에 8시간이상공복상태를확인한후상완정중주정맥 (median cubital vein) 에서채혈하여분석하였다. 생화학적분석항목중총콜레스테롤, 중성지방, HDL-콜레스테롤, 저밀도지단백콜레스테롤 (low density lipoprotein cholesterol, LDL-C), 공복혈당, 요산 (uric acid, U.A), 총빌리루빈 (total bilirubin, T-Bil), 직접빌리루빈 (direct bilirubin, D-Bil), 아스파테이트아미노전이효소 (aspartate aminotransferase, AST), 알라닌아미노전이효소 (alanine aminotransferase, ALT), 감마글루타밀기전이효소 (gamma-glutamyl transferase, GGT) 는 TBA-200FR NEO (Toshiba, Tokyo, Japan) 를이용하여측정하였다. 당화혈색소 (hemoglobin A1c, HbA1c) 는 EDTA (ethylene diamine tetra acetic acid, EDTA) 전혈검체로고속액체크로마토그래피법

3 Korean J Clin Lab Sci. Vol. 50, No. 2, June (high performance liquid chromatography, HPLC) 의원리에의해 Variant II (Bio Rad, CA, USA) 장비로분석하였다. 전기화학발광면역분석법 (electrochemiluminescence immunoassay) 의원리를이용한 Roche Modular Analytics E170 (Roche, Mannheim, Germany) 으로인슐린을검사하였다. 3. 통계분석이연구결과는평균 ± 표준편차또는 % 로제시하였다. 남녀모두에서대사증후군유무에따른연구대상자의인체측정및생화학적지표의차이는독립표본 t-test (independent sample t-test) 로비교하였다. 총빌리루빈, ALT, GGT 4분위수에따른대사증후군및대사증후군구성요소의발생빈도차이는카이제곱검정 (chi-square test) 으로확인하였다. 또한연령을보정한후총빌리루빈, ALT, GGT와대사증후군구성요소사이의상관관계 (correlation coefficient) 를분석하였다. 대사증후군구성요소의개수에따른총빌리루빈, ALT, GGT의차이는일원변량분석 (one way analysis of variance, one-way ANOVA) 으로확인하였으며, 사후검증은 Scheffe 방법을적용하였다. 총빌 리루빈, ALT, GGT 사분위수에따른대사증후군발생가능성을예측하기위해연령을보정한후이분형로지스틱회귀분석 (binominal logistic regression) 을적용하였다. 모든통계분석은 IBM SPSS Statistics 24.0 (IBM, NY, USA) 을이용하여처리하였으며, P<0.05 이면통계적으로유의한것으로평가하였다. 결과 1. 대사증후군유무에따른남녀대상자의임상적특성남녀대상자의대사증후군유무에따른임상적특징은 Table 1과같다. 남성은대사증후군유무에따라신장과 LDL-콜레스테롤을제외한모든변인에서집단간차이를보였다 ( 모두 P< 0.001). 특히 ALT, GGT는대사증후군진단군에서높았으나, 총빌리루빈과직접빌리루빈은대사증후군진단군에서낮게나타났다 ( 각각 P<0.001). 여성은대사증후군유무에따라모두측정변인에서차이를보였으며 ( 모두 P<0.001), ALT, GGT는대사증후군진단군에서높았으며 ( 각각 P<0.001), 총빌리루빈 (P=0.001) 과직접빌리루빈 (P<0.001) 은대사증후군진단군 Table 1. Clinical characteristics of men and women according to metabolic syndrome status Variables MetS (N=1,599) Men (N=13,773) Non-MetS (N=12,174) P-value MetS (N=601) Women (N=8,795) Non-MetS (N=8,194) P-value Age (years) 48.87± ±10.89 < ± ±11.10 <0.001 Height (cm) ± ± ± ±5.86 <0.001 Weight (kg) 81.42± ±9.60 < ± ±7.59 <0.001 BMI (kg/m 2 ) 27.63± ±2.75 < ± ±3.00 <0.001 WC (cm) 92.20± ±7.06 < ± ±7.37 <0.001 SBP (mmhg) ± ±12.08 < ± ±13.03 <0.001 DBP (mmhg) 80.46± ±9.36 < ± ±9.23 <0.001 TC (mg/dl) ± ±33.63 < ± ±33.04 <0.001 TG (mg/dl) ± ±83.41 < ± ±44.89 <0.001 HDL-C (mg/dl) 43.70± ±11.82 < ± ±13.05 <0.001 LDL-C (mg/dl) ± ± ± ±29.94 <0.001 Glucose (mg/dl) ± ±16.98 < ± ±11.48 <0.001 HbA1c (%) 6.24± ±1.15 < ± ±0.47 <0.001 Insulin ( U/mL) 7.77± ±2.94 < ± ±2.48 <0.001 Uric acid (mg/dl) 6.33± ±1.25 < ± ±0.92 <0.001 hs-crp (mg/dl) 0.21± ±0.46 < ± ±0.31 <0.001 AST (IU/L) 34.48± ±25.09 < ± ±12.66 <0.001 ALT (IU/L) 42.96± ±29.23 < ± ±13.38 <0.001 GGT (IU/L) 77.25± ±57.61 < ± ±18.89 <0.001 T-Bil (mg/dl) 1.03± ±0.46 < ± ± D-Bil (mg/dl) 0.18± ±0.08 < ± ±0.06 <0.001 Values are presented as means±standard deviations. Abbreviations: MetS, metabolic syndrome; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; HbA1c, hemoglobin A1c; hs-crp, high sensitivity C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; T-Bil, total bilirubin; D-Bil, direct bilirubin.

4 158 Kyung-A Shin, Metabolic Syndrome and Total Bilirubin 에서유의하게낮았다. 2. 총빌리루빈, ALT, GGT 사분위수에따른대사증후군및대사증후군구성요소의발생빈도남성의총빌리루빈, ALT, GGT 사분위수에따른대사증후군및대사증후군구성요소의발생빈도는 Table 2와같다. 남성은총빌리루빈, ALT, GGT 사분위수에따라대사증후군및 5가지대사증후군구성요소의발생빈도에차이가없었다. 여성의경우총빌리루빈, GGT 사분위수에따른대사증후군및대사증후군구성요소의발생빈도는차이가없었다. 그러나 ALT 사분위수에따른대사증후군 (P=0.005) 과높은혈압 (P=0.002) 의발생빈도는차이가있었으며, 2사분위수에서가장높은빈도를보였다 (Table 3). 3. 총빌리루빈, ALT, GGT와대사증후군구성요소간의상관관계연령을보정한후총빌리루빈, ALT, GGT와대사증후군구성요소간의상관성을확인한결과 Table 4와같다. 남성에서총빌리루빈은허리둘레 (r= 0.066), 총콜레스테롤 (r= 0.026), 중성지방 (r=-0.127), 공복혈당 (r= 0.045) 과유의한역상관관 계를보였으며, HDL-콜레스테롤 (r=0.087) 과는정적상관관계를나타냈다. ALT 는 HDL-콜레스테롤을제외한모든대사증후군구성요소와정적인상관관계를보였으며, HDL-콜레스테롤과는역상관관계를나타냈다. 또한 GGT는남성에서모든대사증후군구성요소와유의한정적상관관계를보였다. 여성의경우총빌리루빈은허리둘레 (r= 0.055), 중성지방 (r= 0.136) 과유의한역상관관계를보였으며, HDL- 콜레스테롤 (r=0.103) 과는정적상관관계를보였다. ALT 는총콜레스테롤, HDL-콜레스테롤과역상관관계를보였으며, 그외의대사증후군구성요소와는정적인상관관계를나타냈다. GGT는 HDL-콜레스테롤을제외한모든대사증후군구성요소와유의한정적상관성을보였다 (Table 4). 4. 대사증후군구성요소의개수에따른총빌리루빈, ALT, GGT의차이대사증후군구성요소의개수에따른총빌리루빈의차이를비교한결과남성에서는대사증후군구성요소가없는군보다대사증후군구성요소가 1개, 2개, 3개, 4개이상인군에서총빌리루빈치가낮았으며, 대사증후군구성요소가 1개인군보다대사증후군구성요소가 2개, 3개, 4개이상인군의총빌리루빈이 Table 2. Characteristics of study subjects based on serum bilirubin quartile categories men T-Bil (mg/dl) 1st quartile (<0.82) 2nd quartile ( ) 3rd quartile ( ) 4th quartile ( 1.30) P-value MetS (N=1,599) 382 (11.1) 408 (11.6) 414 (11.8) 395 (11.9) Abdominal obesity (N=2,868) 684 (19.9) 776 (22.1) 716 (20.3) 692 (20.9) High fasting glucose (N=2,458) 594 (17.3) 625 (17.8) 624 (17.7) 615 (18.6) Low HDL-C (N=1,819) 433 (12.6) 476 (13.6) 478 (13.6) 432 (13.1) High TG (N=4,890) 1,179 (34.4) 1,264 (36.0) 1,254 (35.6) 1,193 (36.1) High BP (N=2,350) 596 (17.4) 590 (16.8) 600 (17.0) 564 (17.0) ALT (IU/L) (<18) (18 24) (25 35) ( 36) P-value MetS (N=1,599) 365 (11.0) 427 (12.8) 410 (11.4) 397 (11.2) Abdominal obesity (N=2,868) 678 (20.5) 738 (22.1) 733 (20.5) 719 (20.3) High fasting glucose (N=2,458) 596 (18.0) 593 (17.8) 647 (18.1) 622 (17.5) Low HDL-C (N=1,819) 432 (13.1) 479 (14.4) 478 (13.3) 430 (12.1) High TG (N=4,890) 1,178 (35.6) 1,235 (37.1) 1,254 (35.0) 1,223 (34.5) High BP (N=2,350) 567 (17.1) 544 (16.3) 623 (17.4) 616 (17.4) GGT (IU/L) (<23) (23 34) (35 57) ( 58) P-value MetS (N=1,599) 343 (11.5) 465 (11.9) 406 (11.8) 385 (11.2) Abdominal obesity (N=2,868) 648 (21.7) 797 (20.4) 705 (20.5) 718 (20.8) High fasting glucose (N=2,458) 539 (18.1) 688 (17.6) 632 (18.4) 599 (17.4) Low HDL-C (N=1,819) 401 (13.4) 505 (12.9) 488 (14.2) 425 (12.3) High TG (N=4,890) 1,098 (36.8) 1,370 (35.0) 1,226 (35.7) 1,196 (34.7) High BP (N=2,350) 486 (16.3) 697 (17.8) 571 (16.6) 596 (17.3) Data are expressed as number of subjects (%). Abbreviations: T-Bil, total bilirubin; MetS, metabolic syndrome; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; BP, blood pressure; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase.

5 Korean J Clin Lab Sci. Vol. 50, No. 2, June Table 3. Characteristics of study subjects based on serum bilirubin quartile categories women T-Bil (mg/dl) 1 st quartile (<0.64) 2 nd quartile ( ) 3 rd quartile ( ) 4 th quartile ( 1.01) P-value MetS (N=601) 123 (6.3) 141 (6.6) 148 (6.4) 189 (7.9) Abdominal obesity (N=1,701) 355 (18.1) 430 (20.2) 424 (18.4) 492 (20.5) High fasting glucose (N=739) 165 (8.4) 172 (8.1) 181 (7.9) 221 (9.2) Low HDL-C (N=1,594) 352 (18.0) 389 (18.2) 386 (16.8) 467 (19.5) High TG (N=994) 213 (10.9) 231 (10.8) 243 (10.6) 307 (12.8) High BP (N=746) 183 (9.3) 162 (7.6) 175 (7.6) 226 (9.4) ALT (IU/L) (<11) (11 13) (14 19) ( 20) P-value MetS (N=601) 126 (6.3) 182 (8.5) 152 (6.6) 141 (6.0) Abdominal obesity (N=1,701) 379 (19.1) 452 (21.1) 450 (19.5) 420 (17.8) High fasting glucose (N=739) 159 (8.0) 207 (9.6) 188 (8.1) 185 (7.9) Low HDL-C (N=1,594) 359 (18.1) 402 (18.7) 429 (18.6) 4.4 (17.1) High TG (N=994) 205 (10.3) 252 (11.7) 280 (12.1) 257 (10.9) High BP (N=746) 178 (9.0) 216 (10.1) 162 (7.0) 190 (8.1) GGT (IU/L) (<12) (12 15) (16 21) ( 22) P-value MetS (N=601) 127 (7.2) 172 (6.8) 166 (7.5) 136 (5.9) Abdominal obesity (N=1,701) 341 (19.4) 503 (19.8) 420 (19.0) 437 (19.1) High fasting glucose (N=739) 157 (8.9) 216 (8.5) 181 (8.2) 185 (8.1) Low HDL-C (N=1,594) 305 (17.4) 457 (18.0) 431 (19.4) 401 (17.5) High TG (N=994) 194 (11.0) 301 (11.9) 258 (11.6) 241 (10.5) High BP (N=746) 159 (9.0) 237 (9.3) 173 (7.8) 177 (7.7) Data are expressed as number of subjects (%). Abbreviations: See Table 2. Table 4. Age adjusted correlations between bilirubin and metabolic components in men and women Parameters Men Women T-Bil ALT GGT T-Bil ALT GGT WC (cm) 0.066** 0.237** 0.174** 0.055** 0.183** 0.150** SBP (mmhg) ** 0.118** ** 0.073** DBP (mmhg) ** 0.119** ** 0.073** TC (mg/dl) 0.026* 0.110** 0.148** ** 0.101** TG (mg/dl) 0.127** 0.173** 0.267** 0.136** 0.105** 0.170** HDL-C (mg/dl) 0.087** 0.126** 0.042** 0.103** 0.079** LDL-C (mg/dl) ** 0.046** ** 0.068** Glucose (mg/dl) 0.045** 0.101** 0.185** ** 0.137** *P<0.05. **P< Abbreviations: See Table 1. 낮게나타났다 (P<0.001). 여성의경우대사증후군구성요소가없는군보다대사증후군구성요소가 1개, 2개, 3개인군에서총빌리루빈이낮았다 (P<0.001) (Figure 1). 대사증후군구성요소의개수에따른 ALT 와 GGT의차이를비교한결과남성의경우 ALT 와 GGT 모두대사증후군구성요소가없는군보다대사증후군구성요소가 1개, 2개, 3개, 4개이상인군의 ALT 와 GGT 가높았으며, 대사증후군구성요소가 1개인군보다대사증후군구성요소가 2개, 3개, 4개이상인군의 ALT 와 GGT가높았다. 또한대사증후군구성요소가 3개와 4개이상인군은대사증후 군구성요소가 2개인군보다 ALT 와 GGT가높게나타났다 (P< 0.001) (Figure 2, 3). 여성의경우대사증후군구성요소의개수가증가할수록비례하여 ALT 가상승하였다 (P<0.001) (Figure 2). 여성에서 GGT는대사증후군구성요소가없는군보다대사증후군구성요소가 1개, 2개, 3개, 4개이상인군에서높게나타났으며, 대사증후군구성요소가 1개인군보다대사증후군구성요소가 2개, 3개, 4개이상인군의 GGT가높았다. 또한대사증후군구성요소가 4개이상인군은대사증후군구성요소가 2개, 3개인군보다 GGT가높게나타났다 (P<0.001) (Figure 3).

6 160 Kyung-A Shin, Metabolic Syndrome and Total Bilirubin Figure 1. Differences in T-Bil according to the components of metabolic syndrome. a: significantly different from the without MetS components, b: significantly different from one components of the MetS, c: significantly different from two components of the MetS, d: significantly different from three components of the MetS. Abbreviations: See Table 2. Figure 3. Differences in GGT according to the components of metabolic syndrome. a: significantly different from the without MetS components, b: significantly different from one components of the MetS, c: significantly different from two components of the MetS, d: significantly different from three components of the MetS. Abbreviations: See Table 2. 다. 그러나 GGT 사분위수에따른대사증후군발생가능성은보정하지않은경우와연령을보정한경우모두에서의미있는차이가없었다 (Table 5). 고찰 Figure 2. Differences in ALT according to the components of metabolic syndrome. a: significantly different from the without MetS components, b: significantly different from one components of the MetS, c: significantly different from two components of the MetS, d: significantly different from three components of the MetS. Abbreviations: See Table 총빌리루빈, ALT, GGT 사분위수에따른대사증후군발생가능성 남성의경우총빌리루빈, ALT, GGT 사분위수에따른대사증후군발생가능성은보정하지않은경우와연령을보정한경우모두에서의미있는차이가없었다 (Table 5). 여성의경우총빌리루빈사분위수에따른대사증후군발생가능성은보정하지않은경우 1사분위수보다 2사분위수에서대사증후군발생가능성이 0.79배낮았으나, 연령을보정한경우의미있는차이가없었다. 또한 ALT 사분위수에따른대사증후군발생가능성은보정하지않은경우 1사분위수보다 3사분위수에서대사증후군발생가능성이 1.04배높았으며, 연령을보정한경우 1사분위수보다 3사분위수에서대사증후군발생가능성이 1.38배높았 건강검진을실시한한국성인남녀를대상으로한이횡단면연구는 ALT 와 GGT의간기능지표와비교하여총빌리루빈과대사증후군간의관련성을확인하였다. 성인남녀모두에서혈청총빌리루빈은대사증후군구성요소와약한역상관관계를보였으며, 이는 ALT 와 GGT보다약한관련성을나타냈다. 또한남녀모두에서 ALT 와 GGT뿐만아니라총빌리루빈은대사증후군발생가능성을예측하는지표는아닌것으로나타났다. 최근연구에따르면산화스트레스가인슐린저항성및대사증후군을특징짓는데중요한역할을한다고밝혀졌다 [1]. 빌리루빈은내인성항산화제로서항염작용이있으며, 지질및지질단백질의산화를억제하고활성산소를제거하며산화스트레스를방지하는것으로알려져있다 [3, 15]. 그러므로빌리루빈은대사증후군발병기전에영향을미칠수있다. 여러연구에서빌리루빈은고혈압, 당뇨병, 대사증후군및인슐린저항성과역상관관계가있음을보고하였다 [5, 6, 16]. Wu 등 [17] 은혈청총빌리루빈수치가남성과여성모두에서대사증후군위험과역상관관계에있다고보고하였다. 유사하게한국인 6,205명을대상으로한후향적코호트연구에서높은총빌리루빈은대사증후군과역상관관계가있음을보여주었다 [18]. 대조적으로, 일본코호트연구에따르면혈청총빌리루빈은남성에서는대사

7 Korean J Clin Lab Sci. Vol. 50, No. 2, June Table 5. Odds ratio for metabolic syndrome according to T-Bil, ALT and GGT quartile Men 1st quartile 2nd quartile 3rd quartile 4th quartile T-Bil (mg/dl) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) ALT (IU/L) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) GGT (IU/L) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) Women 1st quartile 2nd quartile 3rd quartile 4th quartile T-Bil (mg/dl) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) ALT (IU/L) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) GGT (IU/L) No adjusted ( ) ( ) ( ) Model ( ) ( ) ( ) Adjusted odds ratios for age. Model 1 was adjusted for age. Abbreviations: See Table 1. 증후군위험과역상관관계를보였지만, 여성에서는관련이없는것으로밝혀졌다 [19]. 또한다른일본코호트연구는총빌리루빈과대사증후군사이의유의한연관성을발견하지못하였다 [10]. 본연구에서총빌리루빈은남녀모두에서복부비만, 중성지방과역상관관계를보였으며, HDL-콜레스테롤과는정적상관성을나타냈다. 그러나이러한상관성은 ALT 및 GGT와같은간특이적효소보다약한상관성이었다. 또한남녀모두에서대사증후군위험요인이없는군보다대사증후군진단군에서간효소치가높았으며, 총빌리루빈과직접빌리루빈치는낮게나타났다. 그러나연구에따라이와같은불일치는총빌리루빈수준이그주요원인일수있다. 일본인코호트연구에서는총빌루리빈농도 1 mg/dl 미만인대상자가 75% 였으나, 한국인을대상으로한연구는 50% 이상에서총빌리루빈농도가 1 mg/dl보다높았다 [10, 18]. 본연구에서는 43% 의대상자가총빌리루빈농도 1 mg/dl 이상으로나타나대부분이기준범위에속해과소평가되었을가능성이있다고생각된다. 이러한관점에서다양한농도의빌리루빈치와대사증후군위험요인간의관련성에대한평가가필요하다. 빌리루빈은그자체뿐아니라대사과정에참여하는효소에의해대사증후군발병기작에영향을미칠수있다 [16]. 헴은속도제한효소 (rate-limiting enzyme) 인헴산화효소 (heme oxygenase, HO) 의이화작용에의해빌리버딘과일산화탄소 를형성하고, 빌리버딘은빌리버딘환원효소 (biliverdin reductase, BVR) 에의해빌리루빈으로전환된다 [3, 16]. 그러므로헴산화효소활성에의해빌리루빈은조절되며, 헴산화효소와빌리루빈은항염증및항산화작용에의해대사증후군활성을억제하는것으로보고된다 [3, 16, 20, 21]. 이와같은관점에서 Huang 등 [22] 은건강한중년비흡연남성에서빌리루빈이대사증후군을예측하는지표라고보고하였다. 그러나혈청빌리루빈과대사증후군의연관성에대해서는논란의여지가있다. Oda 등 [10] 은혈청빌리루빈이대사증후군과관련이없으므로혈청빌리루빈의감소가대사증후군의원인에의한것이아니라대사증후군과밀접한산화스트레스에의한것임을보고하였다. 본연구에서는흡연에대한조사가이루어지지않아단순비교는어려우나남녀모두에서 ALT 와 GGT뿐만아니라총빌리루빈은대사증후군발생가능성을예측할수있는지표는아닌것으로나타나 Oda 등 [10] 의결과를지지한다. 따라서높은빌리루빈수치는대사증후군의원인요인은아닐수있지만, 대사증후군발병위험이높은환자에서빌루리빈수치가낮게나타날수있음을확인하였다. 본연구는횡단면연구로서혈청총빌리루빈수치와대사증후군간의인과관계를확인할수없었다. 특히빌리루빈농도는헴산화효소의상승과더불어증가할가능성이있으므로헴산

8 162 Kyung-A Shin, Metabolic Syndrome and Total Bilirubin 화효소의유도와함께혈청빌리루빈치의상승이대사증후군의발병과진행을막는잠재적인요인이될수있는지전향적인연구가필요하다. 또한총빌리루빈수치는평가한반면, 직접및간접빌리루빈은평가에서제외되었으며, 향후간기능장애가있는환자를대상으로연구를진행할필요성이있겠다. 본연구는당뇨병, 고혈압에대한약물치료이외의고지혈증이나비만에의한약물치료및다른기본질병의영향을명확하게밝히지못하였으며, 음주, 흡연, 운동과같은생활습관에관한데이터를수집하였음에도불구하고정확성이떨어져분석에포함하지못한제한점이있다. 결론적으로, 한국성인남녀에서혈청총빌리루빈은대사증후군구성요소와약한역상관관계를보였으며, 총빌리루빈은대사증후군발생가능성을예측하는지표는아닌것으로나타났다. 요약빌리루빈은내인성항산화제로서항염작용이있으며, 고혈압, 당뇨병, 대사증후군및인슐린저항성과역상관관계에있다고보고된다. 그러나간특이적지표와비교하여빌리루빈과대사증후군간의관련성을평가한연구는부족하다. 본연구에서는건강검진을실시한한국성인남녀를대상으로 ALT, GGT와비교하여총빌리루빈과대사증후군유병률사이의관련성을조사하고자하였다. 이횡단면연구에는 2015년 3월부터 2018 년 2월까지경기도소재종합병원에서건강검진을실시한 20세이상성인남녀 22,568명이포함되었다. American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) 의지침에따라대사증후군을진단하였다. 남녀모두에서대사증후군위험요인이없는군보다대사증후군진단군에서간효소치가높았으며, 총빌리루빈과직접빌리루빈치는낮게나타났다. 남녀모두에서혈청총빌리루빈은복부비만 (r= vs r= 0.055), 중성지방 (r= vs r= 0.136) 과약한역상관관계를보였으며, 이는 ALT 와 GGT보다약한관련성이었다. 또한남녀모두에서 ALT 와 GGT뿐만아니라총빌리루빈은대사증후군발생가능성을예측하는지표는아닌것으로나타났다. Acknowledgements: None Conflict of interest: None REFERENCES 1. Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sci. 2009;84: Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112: Schwertner HA, Vítek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. 2008; 198: Erdogan D, Gullu H, Yildirim E, Tok D, Kirbas I, Ciftci O, et al. Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women. Atherosclerosis. 2006;184: Perlstein TS, Pande RL, Beckman JA, Creager MA. Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to Arterioscler Thromb Vasc Biol. 2008; 28: Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES Am J Med. 2008;121: Li M, Kim DH, Tsenovoy PL, Peterson SJ, Rezzani R, Rodella LF, et al. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes. 2008;57: Jo J, Yun JE, Lee H, Kim H, Jee SH. Total, direct, and indirect serum bilirubin concentrations and metabolic syndrome among the Korean population. Endocrine. 2011;39: Li XH, Lin HY, Guan LY, Peng H, Wen MM, Cao YQ, et al. Direct bilirubin levels and risk of metabolic syndrome in healthy Chinese men. Biomed Res Int. 2017;2017: Oda E, Aizawa Y. Total bilirubin is inversely associated with metabolic syndrome but not a risk factor for metabolic syndrome in Japanese men and women. Acta Diabetol. 2013;50: Perera S, Lohsoonthorn V, Jiamjarasrangsi W, Lertmaharit S, Williams MA. Association between elevated liver enzymes and metabolic syndrome among Thai adults. Diabetes Metab Syndr. 2008;2: Shin KA. The clinical implications of hepatic enzymes in metabolically healthy obese men. Korean J Clin Lab Sci. 2017; 49: Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112: World Health Organization. The Asia-Pacific Perspective: Redefining obesity and its treatment. Sydney, Australia: health communications Australia; p Wu TW, Fung KP, Wu J, Yang CC, Weisel RD. Antioxidation of

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DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%) aged over 30 years or older had diabetes in 2010. Based on fasting g

DIABETES FACT SHEET IN KOREA 2012 Korean Diabetes Association (KDA) / Korea Centers for Disease Control and Prevention (CDC) DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%)