하나가세포내 glutathione (GSH) 인데, GGT 효소는세포외막에존재하여세포내의 GSH 대사에중요한역할을한다 [16]. 따라서혈중 GGT 농도가인체내산화스트레스의정도를반영할수있는지표및만성퇴행성질환의발병위험에대한예측인자로서의가능성이제시되고있다 [17]. 특히혈중

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1 원저 Lab Med Online Vol. 3, No. 1: 15-22, January 2013 임상화학 성인에서참고구간내의혈중 Gamma-glutamyltransferase 농도에따른대사증후군및제 2 형당뇨병발병률과의관련성 Relationship between Serum Gamma-glutamyltransferase Levels within Reference Intervals and the Prevalence of Metabolic Syndrome and Diabetes Mellitus in Adults 최문석 1 배태원 1 이재현 1,2 조용곤 1,2,3 이혜수 1,2,3 최삼임 1,2 김달식 1,2 Moon Suk Choi, M.D. 1, Tae Won Bae, M.D. 1, Jae Hyeon Lee, M.D. 1,2, Yong Gon Cho, M.D. 1,2,3, Hye Soo Lee, M.D. 1,2,3, Sam Im Choi, M.D. 1,2, Dal Sik Kim, M.D. 1,2 전북대학교의학전문대학원진단검사의학교실 1, 전북대학교임상의학연구소 - 전북대학교병원의생명연구원 2, 전북대학교병원병원체자원은행 3 Department of Laboratory Medicine 1, Chonbuk National University Medical School; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital 2 ; Chonbuk National University Hospital Culture Collection for Pathogens 3, Jeonju, Korea Background: This study was conducted to establish reference intervals (RIs) for serum gamma-glutamyltransferase (GGT), and to evaluate the association between serum GGT levels within RIs and the prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (DM) in men and women. Methods: A total of 363 healthy adults (137 men and 226 women) were enrolled for establishing the RIs of serum GGT. A cross-sectional study was conducted with 919 individuals (519 men and 400 women) to evaluate the associations between gender-specific serum GGT RI quartiles and prevalence of MetS and DM. Results: The RIs for serum GGT levels (central 95th percentile ranges) were IU/L and IU/L in men and women, respectively. In men, the odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of MetS in 4 serum GGT quartiles (lowest to highest) were 1.0 (reference), 3.6 ( ), 8.8 ( ), and 17.4 ( ), respectively, while the ORs (95% CIs) for the prevalence of DM were 1.0 (reference), 1.0 ( ), 1.7 ( ), and 2.6 ( ), respectively. In women, the corresponding ORs (95% CIs) were 1.0 (reference), 3.3 ( ), 5.8 ( ), and 18.8 ( ) for MetS, respectively, and 1.0 (reference), 1.6 ( ), 1.6 ( ), and 8.0 ( ) for DM, respectively. These significant relationships persisted after adjusting for age, alcohol intake, body mass index, and smoking. Conclusions: Serum GGT levels, even within RIs, were proportionally associated with prevalence of metabolic syndrome and DM in both men and women. Serum GGT level may be an independent predictor for chronic degenerative diseases. Key Word: Gamma-glutamyltransferase, Metabolic syndrome, Type 2 diabetes mellitus, Reference interval 서론 혈중 gamma-glutamyltransferase (GGT) 의농도는주로간담도 Corresponding author: Dal Sik Kim, M.D. Department of Laboratory Medicine, Chonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju , Korea Tel: , FAX: , dskim@jbnu.ac.kr Received: August 21, 2012 Revision received: September 10, 2012 Accepted: September 10, 2012 This article is available from , Laboratory Medicine Online 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. 계질환이나과도한알코올섭취에대한임상적검사지표 (surrogate marker) 로널리사용되고있다. 그러나최근연구에따르면혈중 GGT 농도가알코올섭취나간담도계의질환등과관계없이심혈관계질환의위험요소, 대사증후군의구성요소, 당뇨병의발병위험, 뇌졸중, 심장관련치사율 (cardiac mortality) 및비치명적심근경색증 (nonfatal myocardial infarction) 등과뚜렷한용량-반응관계를나타내며 [1-7], 또한퇴행성인조질환 (degenerative and manmade diseases) 의발생위험을예측할수있다고보고하고있다 [8]. 인체에서는고혈압, 죽상경화증, 고지혈증, 당뇨병, 허혈-재관류, 암, 류마티스관절염, Behcet 질환, 신경손상성질환등만성퇴행성질환의발병기전및진행에산화스트레스 (oxidative stress) 와염증반응이중요한역할을하는것으로알려져있다 [9-15]. 이러한산화스트레스를조절하는체내의중요한대표적항산화작용물질중 eissn

2 하나가세포내 glutathione (GSH) 인데, GGT 효소는세포외막에존재하여세포내의 GSH 대사에중요한역할을한다 [16]. 따라서혈중 GGT 농도가인체내산화스트레스의정도를반영할수있는지표및만성퇴행성질환의발병위험에대한예측인자로서의가능성이제시되고있다 [17]. 특히혈중 GGT 농도가정상인의참고구간내에서도그농도가높을수록만성퇴행성질환에대한유병률과뚜렷한용량-반응관계를나타내며, 참고구간내에서도혈중 GGT 농도가낮은비만군에서는제2형당뇨병과비만과의관련성이매우낮다는보고는흥미롭다 [4, 18-20]. 최근연구에서는혈중 GGT 농도가인체내의다양한환경오염물질에대한노출의간접적지표로도제시되고있다. 일반인구집단에서도혈중잔류성유기오염물질 (persistent organic pollutants, POPs) 의농도가높을수록참고구간내의혈중 GGT 농도가높으며, 당뇨병의유병률과도강한용량-반응관계를보여준다 [21, 22]. 국내한연구에의하면일개철강회사의직원을대상으로실시한건강검진 (annual physical examination) 의분석결과혈중 GGT의평균농도가매년뚜렷하게증가하는경향을보였으며, 이는체질량지수 (body mass index, BMI), 알코올섭취, 흡연, 운동및혈중콜레스테롤농도등으로보정한후에도같은경향을나타냈다 [22]. 우리나라의질병양상은이미범유행감축시대 (The age of reducing pandemic) 에서퇴행성인조질환시대 (The age of degenerative and manmade diseases) 로의빠른역학적변천 (epidemiologic transition) 을보여주고있다 [23]. 현대인의감소된신체활동의생활양식, 서구화된식생활습관, 다양한환경오염물질에의노출증가그리고뚜렷한퇴행성인조질환의증가양상등을고려할때인체내산화스트레스의증가도예측되어혈중 GGT 농도가이를반영하는지에대한더많은연구가다양한집단및질환에서요구되며, 검사실에서도혈중 GGT 농도에대한참고구간의재설정및분석등의연구가필요하다고생각된다. 본연구에서는건강검진을받기위해일개대학교병원의건강증진센터를방문한건강한성인남녀를대상으로혈중 GGT 농도의참고구간을설정하고, 일정기간건강증진센터에방문한검진자를대상으로참고구간내의혈중 GGT 농도에따른대사증후군및당뇨병의유병률과의연관성을분석하고자하였다. 대상및방법 1. 연구대상 2011년 3월부터 10월까지전북대학교병원건강증진센터를방문하여연구에참여하기로동의하고설문지를작성한 1,084명 ( 남자 634명, 여자 450명 ) 을대상으로하였다. 혈중 GGT 농도의참고구간의설정은 CLSI guideline C28-A3에따랐으며 [24], 연구에동의 한전체대상자중다음의경우는배제하였다 : 1) 현재고혈압및당뇨병등의치료중인질병이있거나약물을복용하고있는경우, 2) 검진시수축기혈압이 140 mmhg 이상이거나이완기혈압이 90 mmhg 이상인경우, 3) 검진시공복혈당이 126 mg/dl 이상인경우, 4) 검진시낮은혈색소농도를갖는경우 ( 남자 ; <12 g/dl, 여자 ; <11 g/dl), 5) 검진시혈소판수가 130,000/μL 이하인경우, 6) 현재흡연자인경우, 7) 주 2회이상음주하는경우, 8) 검진시 HBsAg 또는 anti-hcv Ab 양성, 9) 과거주요장기의수술을받은병력이있는경우, 10) 검진시혈액또는임상화학검사에서이상소견을보인경우. 이에따라혈중 GGT 농도의참고구간을설정하기위한대상자는 363명 ( 남자 137명, 여자 226명 ) 였다. 2. 연구방법대상자의일반적특성, 질병및과거력, 가족력, 음주, 흡연, 수술및알레르기유무등은구조화된설문지를통해조사하였다. 음주는월 1회초과의경우음주자, 그이하는비음주자로분류하였다. 흡연은비흡연, 현재흡연및과거흡연으로분류하였으며과거흡연과현재흡연의경우구체적인흡연기간과흡연량을조사하였다. 신장과체중은속옷과검진복을입은상태에서 Inbody 3.0 (Biospace Co., Ltd., Seoul, Korea) 을이용하여측정하였고, 비만도의측정을위해신장 (m) 의제곱으로체중 (kg) 을나눠서체질량지수를계산하였다. 혈압은 10분이상편안하게앉은자세로안정을취한후자동혈압측정계로측정하였으며, 현재고혈압의진단을받아치료받고있거나, 검진시혈압이 140/90 mmhg 이상인경우를고혈압으로정의하였다. 제2형당뇨병의정의는검진시공복혈당치가 126 mg/dl 이상또는당뇨병의진단을받고현재치료중인사람으로하였다. 대사증후군의정의는 NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) 의기준중허리둘레대신체질량지수로대체하여체질량지수 ( 25 kg/ m 2 ), 혈중중성지방 ( 150 mg/dl), HDL-cholesterol (HDL-C) ( 남자 40 mg/dl, 여자 50 mg/dl), 혈압 ( 130/85 mmhg) 및공복혈당 ( 110 mg/dl) 의 5개항목중 3개이상일경우로하였다 [25, 26]. 8시간이상의공복상태유지후혈액채취를시행하였으며, complete blood count (CBC) 혈액검사 (Sysmex XE-2100; TOA Medical Electronics Co., Kobe, Japan), 임상화학및면역혈청검사 (ADVIA 2400 Chemistry system, ADVIA Centaur XP immunoassay system; Siemens Healthcare Diagnostics, Inc., Tarrytown, NY, USA) 를시행하였다. 3. 통계학적분석혈중 GGT농도의참고구간의설정은남자군과여자군으로층화하여시행하였으며, 혈청 GGT의측정값에서 1/3 법칙 [24] 에따라 16

3 이상치 (outlier) 를제거한후 Shapiro-Wilk test로정규분포를검정하였다. 혈중 GGT 농도는정규분포를나타내지않아 2.5 percentile에서 97.5 percentile까지의중앙 95백분위수 (central 95th percentile) 로참고구간을설정하였다. 또한새로설정한혈중 GGT 농도의참고구간내에해당되는최종분석대상자는 919명 ( 남자 519 명, 여자 400명 ) 였으며, 남녀두군사이의비교는독립표본 t-검정을시행하였고, 남자군과여자군의혈중 GGT 농도를 4분위수 (quartile) 로나누어 ANOVA 분석을시행하였다. 혈중 GGT 농도의사분위절단수치는남자군의경우 19, 27 및 42 IU/L였으며, 여자군의경우는 9, 13 및 18 IU/L였다. 대사증후군및당뇨병의대응위험도 (odds ratio) 는혈중 GGT 농도가제일낮은첫번째사분위군을참고집단 (reference group) 으로하여다변량로지스틱회귀분석 (multiple logistic regression analysis) 을시행하였고, 각각연령, 체질량지수, 흡연및음주량으로보정하였다. 모든통계분석은 SPSS version 18.0 software package (SPSS Inc., Chicago, IL, USA) 를이용하였으며, P <0.05인경우를통계적으로유의하다고판단하였다. 및 GGT의농도는모두남자에서유의하게높았다 (P <0.05). 혈중 HDL-C 농도는여자에서유의하게높았으며 (P <0.001), 총콜레스테롤농도는두군간에통계적차이가없었다 (P = 0.258). 대사증후군의유병률은남녀각각 9.2% 와 10.5% 를나타냈으며, 제2형당뇨병의유병률은각각 7.5% 와 5% 를보였다 (Table 2). 3. 참고구간내의혈청 GGT 농도의사분위수에따른남녀대상군의임상적특징여자군에서는연령의증가에따라혈중 GGT 농도의증가가관찰되었으나 (P = 0.007), 남자군에서는유의한차이를보이지않았다 (P = 0.956). 혈중 GGT 농도가증가함에따라혈중총콜레스테롤, LDL-C, 중성지방, 공복혈당, AST, ALT 및요산의농도그리고체질량지수와대사증후군의유병률은남녀군모두에서유의하게증가하였다 (P <0.05). 흡연과음주의경우는남자군에서혈중 GGT의증가와관련성을보였으며, HDL-C 농도그리고제2형당뇨병과고혈압의유병률은여자군에서혈중 GGT 농도의사분위수증가에따라유의한관련성을나타냈다 (Table 3). 결과 1. 혈중 GGT 농도의참고구간설정 참고구간설정은참여한전체대상자중제외기준에위배되지않는남자 137명과여자 226명이었다. 평균연령은남자 43.5±9.5 세와여자 43.3±10.8 세로유의한차이가없었으며 (P = 0.823), 수축기혈압, 이완기혈압, 신장, 몸무게, BMI 그리고혈청 LDL-cholesterol (LDL-C), 중성지방, 공복혈당, AST, ALT, 요산및 GGT의농도는모두남자에서유의하게높았다 (P <0.05). 혈중총콜레스테롤의농도는남녀사이에유의한차이가없었으며 (P = 0.659), HDL-C 의농도는여자에서유의하게높았다 (P <0.001). 혈중 GGT의평균농도 ( 평균 ±2SD) 는남자 28.3±16.0 IU/L와여자 13.2±6.0 IU/ L로통계적으로유의한차이를보였으며 (P <0.001), 남녀모두에서정규분포를하지않았으므로비모수적방법 ( 중앙 95백분위수 ) 으로설정한참고구간은남자 IU/L와여자 IU/L였다 (Table 1). 2. 설정된참고구간내의 GGT 농도를갖는전체대상군의임상적특징참여한전체대상자중설정된혈중 GGT의참고구간내농도를갖는대상은총 919명 ( 남자 519 명, 여자 400명 ) 였으며, 남자군과여자군의평균나이는각각 47±10.7 세및 47.1±12.2 세로유의한차이가없었다 (P = 0.940). 수축기혈압, 이완기혈압, 신장, 몸무게, 체질량지수그리고혈청 LDL-C, 중성지방, 공복혈당, AST, ALT, 요산 4. 참고구간내의혈중 GGT 농도에따른대사증후군및 제 2 형당뇨병유병률 혈중 GGT 농도의사분위수에따라 GGT 농도가가장낮은군 (Q1, GGT<19 IU/L) 의대사증후군및제 2 형당뇨병유병률을 1 로 했을때그에대한대응위험도를 Table 4 와 5 에정리하였다. 남녀 Table 1. Clinical and biochemical characteristics of the subjects selected for establishing the reference intervals for serum GGT levels Characteristics Men* Women* P value by t-test Number of subjects Age (yr) 43.5± ± Systolic BP (mmhg) 120.0± ±10.8 <0.001 Diastolic BP (mmhg) 76.0± ±8.8 <0.001 Height (cm) 170.3± ±5.5 <0.001 Weight (kg) 70.1± ±6.9 <0.001 BMI (kg/m 2 ) 24.1± ±2.6 <0.001 Total cholesterol (mg/dl) 183.4± ± HDL-cholesterol (mg/dl) 46.9± ±12.5 <0.001 LDL-cholesterol (mg/dl) 123.0± ± Triglyceride (mg/dl) 120.8± ±47.0 <0.001 Fasting glucose (mg/dl) 87.5± ± GGT (IU/L) 28.3± ±6.0 <0.001 AST (IU/L) 22.8± ±4.9 <0.001 ALT (IU/L) 24.0± ±6.2 <0.001 Uric acid (mg/dl) 6.0± ±0.8 <0.001 GGT (central 95th percentile, IU/L) *Data are expressed as mean±s.d. Abbreviations: GGT, gamma-glutamyltransferase; BP, blood pressure; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase. 17

4 Table 2. Clinical and biochemical characteristics of all subjects with serum GGT levels within the reference intervals Characteristics Men* Women* P value by t-test Number of subjects Age (yr) 47± ± Systolic BP (mmhg) 124.5± ±15.5 <0.001 Diastolic BP (mmhg) 77.8± ±10.3 <0.001 Height (cm) 170.3± ±5.8 <0.001 Weight (kg) 70.6± ±7.9 <0.001 BMI (kg/m 2 ) 24.3± ±3.0 <0.001 Total cholesterol (mg/dl) 183.6± ± HDL-cholesterol (mg/dl) 45.0± ±12.2 <0.001 LDL-cholesterol (mg/dl) 122.5± ±32.3 <0.001 Triglyceride (mg/dl) 137.2± ±64.4 <0.001 Fasting glucose (mg/dl) 92.7± ± GGT (IU/L) 30.5± ±6.0 <0.001 AST (IU/L) 23.6± ±6.0 <0.001 ALT (IU/L) 24.4± ±7.8 <0.001 Uric acid (mg/dl) 6.0± ±0.9 <0.001 Metabolic syndrome (%) Type 2 DM (%) *Data are expressed as mean±s.d, unless otherwise stated. Abbreviations: GGT, gamma-glutamyltransferase; BP, blood pressure; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; DM, diabetes mellitus. 군모두에서혈중 GGT 농도가증가함에따라대사증후군과제2 형당뇨병의유병률은뚜렷하게증가하는양상을나타냈다. 나이, BMI, 음주및흡연유무를보정한후사분위수군 Q2, Q3 및 Q4에서의대사증후군에대한대응위험도 (95% CI) 가남자군에서 3.3 ( ), 7.6 ( ) 및 12.6 ( ), 그리고여자군에서 2.2 ( ), 3.1 ( ) 및 8.5 ( ) 로모두뚜렷한용량-반응관계를나타냈다 (P for trend<0.05). 제2형당뇨병에대해서도남자군에서 1.2 ( ), 2.2 ( ) 및 3.5 ( ), 그리고여자군에서 1.6 ( ), 2.4 ( ) 및 6.1 ( ) 로모두유의한결과를나타냈다 (P for trend<0.05). 고찰 보통인체에서유래된가검물에서측청또는관측치는진단및치료의결정을위해또는생리학적상태를평가하기위해참고구간과비교하게된다. 그러므로신뢰성있는참고구간을확립하는것은검사실과시약의제조사에서는매우중요한업무이다. Clinical and Laboratory Standards Institute (CLSI) 에서는참고구간의설정을위한참고개체 (reference individual) 의선택을위해직접표본추출기법 (direct sampling techniques) 을이용할것을강력히 Table 3. Clinical and biochemical characteristics of male and female subgroups according to the quartiles of sex-specific serum GGT reference intervals Q1* (<19 IU/L) Q2* (20-26 IU/L) Men (N=519) Q3* (27-41 IU/L) Q4* (42-70 IU/L) Quartiles (Q) of serum GGT P value by ANOVA Q1* (<9 IU/L) Women (N=400) Q2* (10-12 IU/L) Q3* (13-17 IU/L) Q4* (18-31 IU/L) Number of subjects Age (yr) 47.4± ± ± ± ± ± ± ± BMI (kg/m 2 ) 23.0± ± ± ±2.9 < ± ± ± ±3.4 <0.001 Current smoker (%) Drinker (>1 time/month) (%) Hypertension (%) Metabolic syndrome (%) < <0.001 Type 2 DM (%) Total cholesterol (mg/dl) 172.7± ± ± ±31.8 < ± ± ± ± HDL-cholesterol (mg/dl) 45.9± ± ± ± ± ± ± ±10.2 <0.001 LDL-cholesterol (mg/dl) 113.2± ± ± ±31.2 < ± ± ± ±37.4 <0.001 Triglyceride (mg/dl) 106.1± ± ± ±91.6 < ± ± ± ±104.5 <0.001 Fasting glucose (mg/dl) 89.0± ± ± ± ± ± ± ±28.3 <0.001 GGT (IU/L) 14.7± ± ± ±8.1 < ± ± ± ±4.2 <0.001 AST (IU/L) 20.6± ± ± ±9.6 < ± ± ± ±8.4 <0.001 ALT (IU/L) 17.6± ± ± ±19.3 < ± ± ± ±11.9 <0.001 Uric acid (mg/dl) 5.58± ± ± ±1.12 < ± ± ± ± P value by ANOVA *Data are expressed as mean±s.d, unless otherwise stated. Abbreviations: GGT, gamma-glutamyltransferase; BP, blood pressure; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; DM, diabetes mellitus. 18

5 Table 4. Odds ratios and 95% confidence intervals for the prevalence of metabolic syndrome according to quartiles of sex-specific serum GGT RIs in men and women Quartiles (Q) of serum GGT Q1 Q2 Q3 Q4 Men (<19 IU/L) (20-26 IU/L) (27-41 IU/L) (42-70 IU/L) Number of subjects (N=519) GGT (IU/L) (mean±sd) 14.7± ± ± ±8.1 Odds ratio (95% CI) Model 1* ( ) 8.8 ( ) 17.4 ( ) <0.001 Model 2* ( ) 10 ( ) 20.6 ( ) <0.001 Model 3* ( ) 7.6 ( ) 12.6 ( ) <0.001 Women (<9 IU/L) (10-12 IU/L) (13-17 IU/L) (18-31 IU/L) Number of subjects (N=400) GGT (IU/L) (mean±sd) 7.41± ± ± ±4.2 Odds ratio (95% CI) Model 1* ( ) 5.8 ( ) 18.8 ( ) <0.001 Model 2* ( ) 5.5 ( ) 15.8 ( ) <0.001 Model 3* ( ) 3.1 ( ) 8.5 ( ) *Model 1, crude odds ratio; Model 2, model 1 plus adjustment for age; Model 3, model 2 plus adjustment for body mass index, alcohol intake, and smoking. Abbreviations: CI, confidence intervals; GGT, gamma-glutamyltransferase. P trend Table 5. Odds ratios and 95% confidence intervals for the prevalence of diabetes mellitus according to quartiles of sex-specific serum GGT reference intervals in men and women Quartiles (Q) of serum GGT Q1 Q2 Q3 Q4 Men (<19 IU/L) (20-26 IU/L) (27-41 IU/L) (42-70 IU/L) Number of subjects (N=519) GGT (IU/L) (mean±sd) 14.7± ± ± ±8.1 Odds ratio (95% CI) Model 1* ( ) 1.7 ( ) 2.6 ( ) Model 2* ( ) 2.2 ( ) 3.5 ( ) Model 3* ( ) 2.2 ( ) 3.5 ( ) Women (<9 IU/L) (10-12 IU/L) (13-17 IU/L) (18-31 IU/L) Number of subjects (N=400) GGT (IU/L) (mean±sd) 7.41± ± ± ±4.2 Odds ratio (95% CI) Model 1* ( ) 1.6 ( ) 8.0 ( ) Model 2* ( ) 1.4 ( ) 6.1 ( ) Model 3* ( ) 1.4 ( ) 6.1 ( ) *Model 1, crude odds ratio; Model 2, model 1 plus adjustment for age; Model 3, model 2 plus adjustment for body mass index, alcohol intake, and smoking. Abbreviations: CI, confidence intervals; GGT, gamma-glutamyltransferase. P trend 주장하고있다 [24]. 그러나이러한직접산정방법은현실적으로대상이되는참고모집단 (reference population) 을구하는것이어렵고경제적비용이발생하므로대다수의검사실은최소한의검증과정을거친참고구간을사용하게된다. 본연구에서는혈중 GGT 농도가인체내산화스트레스와밀접한연관성을보이는것으로보고되고있어서참고개체의선택을위한배제조건을엄격하게적용하였다. 비모수방법 ( 중앙 95백분위수 ) 에의한혈중 GGT 농도의참고구간은남자 IU/L와여자 IU/L로비교할 수있는다른국내연구는찾기가어려웠다. 다만본연구에서참고모집단의남자의평균나이및혈중 GGT 농도는각각 43.5세및 28.3 IU/L 그리고여자는 43.3세및 13.2 IU/L로, 단순하게비교하기는어렵지만 1977년 Kim 등의연구에서보여준결과보다는높았다 [27]. 본연구가한기관의건강검진센터에일정기간동안방문한사람을대상으로한단면연구였기때문에혈중 GGT 농도의변화에대한장기적추이를관찰할수는없었지만, 다양한연구에서보여주듯혈중 GGT 농도가인체내산화스트레스의정도를반영 19

6 한다면일반인구집단에서도혈중 GGT 농도의참고구간의장기적추이변화에대한지속적인관찰연구가필요하리라사료된다. 1996년부터 2003년까지국내한철강회사의남자직원을대상으로한건강검진의분석결과에서혈중 GGT 농도가 1996년의 10.5 IU/L에서 2003년 29.2 IU/L로 180% 의증가를보였으며이는 7년동안매년지속적으로증가하는뚜렷한장기추세 (secular trend) 를나타냈다. 본연구에서는참고구간내의혈중 GGT 농도를갖는전체남자대상자 519 명의평균혈중 GGT 농도가 30.5 IU/L로이등의연구에서보여준 2003년의혈중 GGT 농도와비슷했다. 이등의연구에서나타난혈중 GGT 농도의증가경향은환경적위험 (environmental hazard) 의요소에비교적노출되기쉬운현장근무자에서뿐만아니라사무직근로자에서도나타났다. 기존의보고에서와같이혈중 GGT 농도가만성퇴행성질환의발병등과매우밀접한연관성을보인다면본연구에서일반인구집단의건강검진대상자의혈중 GGT 농도는공중보건학적의미에서시사하는바가크다하겠다 [28]. 퇴행성인조질환시대로의빠른역학적변천을보여주고있는우리나라의질병양상은산화스트레스가그발병기전에서중요한역할을하는것으로알려져있고최근혈중 GGT 농도는산화스트레스에대한역학적표지자로써그관심이집중되고있다 [29, 30]. 본연구에서는정상참고구간내에서혈중 GGT 농도가증가할수록대사증후군과제2형당뇨병의발병률이남녀모두에서뚜렷한용량-반응관계를나타냈다. 혈중 GGT 농도가가장낮은사분위수군 (Q1, 남자 9-19 IU/L, 여자 4-9 IU/L) 을참고군으로했을때제일큰사분위수군 (Q4) 의대사증후군및제2형당뇨병에대한대응위험도가나이, BMI, 음주및흡연유무를보정한후남자에서는각각 12.6과 3.5였고, 여자에서는 8.5와 6.1로남녀모두에서강한관련성을보였다. 이러한결과는국내의다른단면조사연구에서와일치된소견이었으며, 대사증후군과제2형당뇨병에대한대응위험도가본연구에서더컸는데이는다른연구에서대상인구수가보다많았던점이영향을미친것으로사료된다 [31-33]. 본연구를비롯한여러연구에서와같이정상참고구간내의혈중 GGT 농도와대사증후군및제2형당뇨병의연관성은그기전을아직명확하게설명할수없으나제기되는가설로는첫째, 비알코올성지방간과관련한인슐린저항성의지표로정상참고구간내의높은혈중 GGT 농도는비만및내장지방침착의결과라는것이다 [34-36]. 본연구에서는내장지방과지방간의유무및정도에대한연구는이루어지지않았으나, 남녀두군모두에서 BMI가증가함에따라혈중 GGT 농도가유의하게증가하는소견을보임은이같은가설에부합된다. 또다른가설로는산화스트레스는당뇨병등의발생기전에중요한역할을하며혈중 GGT의농도가인체내산화스트레스의지표라는것이다 [22]. 세포내 GSH은 free radical에 대한세포내방어인자로세포내에높은농도로유지되고있는데, 과도한산화스트레스에대해요구되는세포내 GSH 농도를증가시키기위한대사과정에서혈중 GGT가증가하는것이다 [16, 17, 37]. 최근에는혈중 GGT 농도가여러가지다양한환경오염물질에의노출에대한지표로서다양한질환을예측할수있다는주장이제시되고있다. Lee 등의연구에의하면혈중 POPs의농도가높을수록혈중 GGT의농도, 비만및당뇨병과높은관련성이있음을보여주고있다 [38, 39]. 본연구의제한점은건강증진센터를방문한건강검진자를대상으로한단면조사연구로인과관계를명확하게규정하거나설명하기가어렵다는것이다. 특히건강검진자에서구조화된설문지로혈중 GGT 농도에영향을줄수있는상세한약물사용의병력, 식이습관, 환경적요소등에대한조사가쉽지않으며, 모든변수들의측정이한번에이뤄졌기때문에대사증후군및제2형당뇨병의유병률이과대평가될가능성을배제할수없다. 결론적으로본연구에서는일반인구집단의건강검진대상자에서혈중 GGT 농도가참고구간내에서도높을수록대사증후군및제2형당뇨병과뚜렷한용량-반응관계의연관성을나타냈다. 따라서혈중 GGT 검사는기존의간담도계질환이나과도한알코올섭취에대한임상적검사지표로서뿐만아니라많은만성퇴행성질환에서의임상적유용성이적지않을것으로판단된다. 또한최근혈중 GGT 농도가산화스트레스및역학적검사지표로서의유용성이제기되고있으며, 산화스트레스의유발요인이증가되고있는현대사회의공중보건학적측면에서생각할때검사실에서는혈중 GGT 농도에대한참고구간의설정, 분석및장기적추이관찰등에대해더욱심도있는연구와논의가필요할것으로사료된다. 요약 배경 : 본연구에서는건강한성인에서혈중 GGT 농도의참고구간을설정하고, 참고구간내의혈중 GGT 농도에따른대사증후군및제2형당뇨병발병률과의연관성을분석하고자하였다. 방법 : 혈중 GGT 농도의참고구간의설정을위해총 363명 ( 남자 137명, 여자 226명 ) 의건강한성인을대상으로하였다. 2011년 3월부터 10월까지한대학병원의건강증진센터를방문하여본연구에동의하고건강검진을실시한총 919명 ( 남자 519 명, 여자 400명 ) 을대상으로단면조사연구를시행하였다. 남자와여자의혈중 GGT 농도의참고구간을 4군으로나누어대사증후군과제2형당뇨병의발병률의관련성을분석하였다. 결과 : 중앙 95백분위수에의한혈중 GGT 농도의참고구간은남자에서 IU/L 그리고여자에서 IU/L였다. 참고구간내의혈중 GGT 농도의사분위수군에따른대사증후군유병률의대 20

7 응위험도 (95% CI) 는남자와여자에서각각 1.0, 3.6 ( ), 8.8 ( ), 17.4 ( ) 와 1.0, 3.3 ( ), 5.8 ( ), 18.8 ( ) 였고, 제2형당뇨병에대해서는각각 1.0, 1.0 ( ), 1.7 ( ), 2.6 ( ) 과 1.0, 1.6 ( ), 1.6 ( ), 8.0 ( ) 였다. 이러한연관성은나이, 알코올섭취, BMI 및흡연유무로보정한후에도유지되었다. 결론 : 혈중 GGT 농도는참고구간내의농도라할지라도대사증후군및제2형당뇨병의발병률과용량-반응관계의연관성을나타냈다. 따라서혈중 GGT 농도는만성퇴행성질환에대해하나의독립적예측인자가될수있을것이다. 참고문헌 1. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care 2004;27: Rantala AO, Lilja M, Kauma H, Savolainen MJ, Reunanen A, Kesäniemi YA. Gamma-glutamyl transpeptidase and the metabolic syndrome. J Intern Med 2000;248: Teschke R, Brand A, Strohmeyer G. Induction of hepatic microsomal gamma-glutamyltransferase activity following chronic alcohol consumption. Biochem Biophys Res Commun 1977;75: Lee DH, Ha MH, Kim JH, Christiani DC, Gross MD, Steffes M, et al. Gamma-glutamyltransferase and diabetes--a 4 year follow-up study. Diabetologia 2003;46: Perry IJ, Wannamethee SG, Shaper AG. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM. Diabetes Care 1998; 21: Miura K, Nakagawa H, Nakamura H, Tabata M, Nagase H, Yoshida M, et al. Serum gamma-glutamyl transferase level in predicting hypertension among male drinkers. J Hum Hypertens 1994;8: Jousilahti P, Rastenyte D, Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke 2000;31: Brenner H, Rothenbacher D, Arndt V, Schuberth S, Fraisse E, Fliedner TM. Distribution, determinants, and prognostic value of gamma-glutamyltransferase for all-cause mortality in a cohort of construction workers from southern Germany. Prev Med 1997;26: Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002;346: Witztum JL and Berliner JA. Oxidized phospholipids and isoprostanes in atherosclerosis. Curr Opin Lipidol 1998;9: Chisolm GM and Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 2000;28: Walter MF, Jacob RF, Jeffers B, Ghadanfar MM, Preston GM, Buch J, et al. Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: a longitudinal analysis of the PREVENT study. J Am Coll Cardiol 2004; 44: Taysi S, Polat F, Gul M, Sari RA, Bakan E. Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis. Rheumatol Int 2002;21: Niwa Y, Miyake S, Sakane T, Shingu M, Yokoyama M. Auto-oxidative damage in Behcet s disease--endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 1982;49: Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, et al. Parkinson s disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 1999;154: Carlisle ML, King MR, Karp DR. Gamma-glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis. Int Immunol 2003;15: Lee DH, Blomhoff R, Jacobs DR Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res 2004;38: Lee DH, Jacobs DR Jr, Gross M, Kiefe CI, Roseman J, Lewis CE, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem 2003;49: Lee DH, Silventoinen K, Jacobs DR Jr, Jousilahti P, Tuomileto J. Gamma- Glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. J Clin Endocrinol Metab 2004;89: Lim JS, Lee DH, Park JY, Jin SH, Jacobs DR Jr. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem 2007;53: Lee DH and Jacobs DR Jr. Association between serum concentrations of persistent organic pollutants and gamma glutamyltransferase: results from the National Health and Examination Survey Clin Chem 2006;52: Lee DH, Lee IK, Song K, Steffes M, Toscano W, Baker BA, et al. A strong dose-response relation between serum concentrations of per- 21

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