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1 Korean J Fam Pract. 2014;4:49-55 대사증후군과간기능, 폐기능, 백혈구, 페리틴의관련성 : 제 5 기국민건강영양조사자료 2010 Original Article 이채훈, 이가영 *, 박태진, 박다정, 이현주, 정용현, 김동현 1 인제대학교의과대학부산백병원과, 1 부산성모병원과 The Relationships between Metabolic Syndrome with Liver Function Test, Pulmonary Function Test, White Blood Cell Count, and Ferritin: The Fifth Korean National Health and Nutrition Examination Survey 2010 Chae-Hun Lee, Kayoung Lee*, Tae-Jin Park, Da-Jung Park, Hyun-Joo Lee, Yong-Hyun Jung, Dong-Hyun Kim 1 Department of Family Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine; 1 Department of Family Medicine, Busan St. Mary s Hospital, Busan, Korea Background: The aim of this study was to find the relationship between metabolic syndrome (MetS) and liver function test (LFT), pulmonary function test (PFT), white blood cell (WBC) count, and serum ferritin. Methods: The data of 6,740 individuals (2,958 men and 3,782 women) aged 19 years or older from the fifth Korea National Health and Nutrition Examination Survey in 2010 were used. The relationship of MetS which was defined using the ATP III criteria, with serum γ-glutamyltranspeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), WBC, and ferritin were analyzed using complex sample descriptive and logistic regression analyses, analysis of covariance (ANCOVA), and receiver operating characteristic curves (ROC). Results: The prevalence of MetS was 25.8% in men and 19.3% in women. When the model included age, education, alcohol consumption, cigarette smoking, physical activity, WBC, ferritin, AST, ALT, and GGT as independent variables, MetS was positively associated with WBC, ferritin, GGT, and ALT in men and with WBC and ALT in women. Although ANCOVA revealed an inverse relationship of MetS with FEV1 and FVC in men, these findings were not replicated in women. In the ROC analyses, the sensitivity and specificity of WBC, ferritin, LFT, and PFT for classifying MetS were respectively 36.2% to 69.2% and 46.5% to 72.3% in men and 59.8% to 75.7% and 50.7% to 67.1% in women. Conclusion: Higher WBC, ferritin, GGT and ALT in men and higher WBC and ALT in women may suggest the presence of MetS. Keywords: Metabolic Syndrome; Liver Function Tests; Leukocytes; Ferritins; Respiratory Function Tests 서론 Received: August 24, 2013, Accepted: January 23, 2014 *Corresponding Author: Kayoung Lee Tel: , Fax: fmlky@inje.ac.kr Korean Journal of Family Practice Copyright 2014 by The Korean Academy of Family Medicine 복부비만, 이상지질혈증, 고혈압, 공복혈당이상을진단적요소로포함하는대사증후군의유병률은세계적으로는성인에서 20 25% 로알려졌고국내유병률도진단기준에따른차이는있으나 2010년 18.8% 로보고되었다. 1,2) 대사증후군은심혈관질환의발생뿐아니라높은사망위험과관련이있어예방및관리가중요한질병이다. 1) 대사증후군의발병기전으로 Vol. 4, No. 1 Mar

2 Chae-Hun Lee, et al: Metabolic Syndrome, Liver Function, Pulmonary Function, WBC, and Ferritin 는인슐린저항성과만성적인염증상태에의한산화적스트레스외에도복부둘레의증가에따른흉벽탄력의감소및말초기도의저항증가와같은구조적요인과같은다양한가설이거론되고있다. 3-5) 이러한발병기전을지지하는근거로이전연구들에서염증상태를반영하는혈중백혈구수, 산화적스트레스를반영하는간효소치및혈청페리틴, 구조적요인을반영하는 1초당노력성호기량과노력성폐활량과대사증후군간에관련성을보고하였다. 6-9) 그러나대사증후군과각요인의개별적관련성에대한연구는있지만동일한대상자에서다른관련요인을고려한후에도각요인이대사증후군과독립적관련성이있는지에관한연구는미흡하다. 따라서본연구에서는 2010년에시행된국민건강영양조사자료를이용하여간효소치, 혈중백혈구수, 혈청페리틴, 폐기능검사와대사증후군과의관련성을알아보았다. 방법 1. 연구대상국민건강영양조사제5기 1차년도 (2010년) 에서만 19세이상의성인 6,740명 ( 남자 2,958명, 여자 3,782명 ) 을본연구대상에포함하였다. 이조사는동 읍 면, 주택유형, 연령대별인구구성비를기준으로층화후계통추출방법으로조사구를설정하여최종조사대상가구를추출하고조사구당 20개의최종조사대상가구를추출하여전국약 3,840가구, 만 1세이상가구원전체를조사대상으로 2010년 1월부터 12월까지시행되었다. 10) 폐기능검사는 40세이상에서만시행되었으므로페기능검사를포함한분석에는 40세이상의대상자 2,743명 ( 남자 1,241명, 여자 1,502명 ) 을연구대상자에포함하였다. 2. 대사증후군관련지표허리둘레측정은측정자가대상자측면 (mid-axillary line) 에서마지막늑골하단및장골능선상단두지점을촉지하여두지점중간에서대상자에게숨을내쉬게하고줄자를조인후소수점한자리까지측정하였다. 혈압은대상자가편안히의자에등을기대고앉게한후에측정매뉴얼에기술된방법으로측정되었고 3번측정치중 2회와 3회째측정치의평균치를사용하였다. 혈중 high density lipoprotein (HDL) 콜레스테롤, 중성지방, 공복혈당은 Hitachi Automatic Analyzer 7600 (Hitachi, Tokyo, Japan) 을이용한 enzymatic 검사방법으로, 백혈구수는 XE-2100D (Sysmex, Kobe, Japan) 을이용한 laser flow cytometry 검사방법으로, aspartate aminotransferase (AST), aspartate aminotransferase (ALT) 는 Hitachi Automatic Analyzer 7600 (Hitachi) 을이용한 UN method 검사방법으로, γ-glutamyltranspeptidase (GGT) 는 Hitachi Automatic Analyzer 7600 (Hitachi) 을이용한 enzymatic 검사방법으로, 페리틴은 1470 WIZARD gamma-counter (PerkinElmer, Turku, Finland) 를이용한 immunoradiometric assay 검사방법으로측정하였다. 10) 폐기능지표로 1초당노력성호기량 (forced expiratory volume in 1 second, FEV 1 ) 과노력성폐활량 (forced vital capacity, FVC) 를사용하였다, 폐기능검사는 rolling dry-seal spirometry (Vmax-2130; Sensor-Medics, Yorba Linda, CA, USA) 로표준화된방법을이용하여대상자당오류가없는적합한검사를 3회시행하도록하여최대 8회까지시행하였다. 11) 대사증후군의진단은수축기혈압 130 mm Hg 이상이거나이완기혈압 85 mm Hg 이상, 또는고혈압으로진단된경우, 허리둘레남 90 cm 이상, 여 85 cm 이상, HDL 콜레스테롤남 40 mg/dl 미만, 여 50 mg/dl 미만, 혈중중성지방 150 mg/dl 이상, 공복혈당 100 mg/dl 이상또는당뇨병으로진단된경우중 3 가지이상이있을경우로정의하였다. 12,13) 사회인구적특성및생활습관을평가하기위해성별, 나이, 교육수준 ( 재학연수 ), 신체활동, 1일흡연량, 1회음주량 ( 잔 ) 에관한자료를이용하였고 10) 신체활동의경우 1주일동안시행한신체활동의강도와신체활동시간을 International Physical Activity Questionnaire 의신체활동량계산법을사용하여주단위로계산하였다. 14) 3. 통계분석성별에따라복합표본설계분석을이용한기술적 / 빈도분석및로지스틱회귀분석과공변량분석, receiver operating characteristics (ROC) curve 분석을시행하였다. 기술적 / 빈도분석은평균 / 백분율과표준오차로결과를제시하였다. 대사증후군과간효소치, 백혈구수, 페리틴, 폐기능검사의관련성을로지스틱회귀분석및공변량분석으로분석하였고나이, 교육수준, 흡연량, 음주량, 신체활동량을보정하거나관련성을평가하기위한인자를추가적으로보정하여각인자와의독립적관련성을평가하였다. ROC 분석을이용하여각인자의대사증후군진단에대한민감도와특이도및 ROC 곡선하구간면적 (area under the ROC curve, AUC), 절단값을구하였다. 통계적유의성수준은 P-value<0.05로정의하였고, 자료분석은 IBM SPSS ver (IBM Co., Armonk, NY, USA) 및 MedCalc Software ver (MedCalc, Ostend, Belgium) 통계프로그램을사용하였다. 50 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

3 이채훈외 : 대사증후군과간기능, 폐기능, 백혈구, 페리틴의관련성 : 제 5 기국민건강영양조사자료 2010 결과 성별에따른대상자의일반적특성, 생활습관관련항목, 대사증후군구성요소및대사증후군유병상태와백혈구수, 혈청페리틴농도, 간기능수치및폐기능수치의분포를알기위해복합표본추출기술적분석을시행하였다. 대사증후군의유병률은남자에서 25.8%, 여자에서 19.3% 이었고대사증후군의구성요소중낮은 HDL 콜레스테롤의분율은남자에비해여자에서높았지만다른요소들의분율은남자에서높았다 (Table 1). 공변량분석을이용하여성별에따라대사증후군유무에따른백혈구수, 혈청페리틴농도, 간기능수치및폐기능수치를비교한결과를 Table 2에제시하였다. 일반적특성과생활습관항목을보정한후남녀모두에서대사증후군이없는군에비해있는군에서백혈구수, 혈청페리틴농도, 모든간기능수치가유의하게높았고, 폐기능수치는대사증후군이있 는남자군에서없는남자군에비해유의하게낮았다. 복합표본추출로지스틱회귀분석을시행한결과일반적특성과생활습관항목을보정한후백혈구수, 페리틴농도, 간기능수치가증가할수록남녀모두에서대사증후군에대한승산비가유의하게증가하였다 (Table 3에서모델 1). 독립변수로이들관련요인들을모두포함한로지스틱회귀분석모델 (Table 3에서모델 2) 에서남자에서는백혈구수, 페리틴농도, GGT, ALT가, 여자에서는백혈구수와 ALT가대사증후군유병과유의한관련이있었다. 반면폐기능지표는모든분석모델에서대사증후군의유병과유의한관련성이없었다. Table 4에서 ROC 분석을이용하여대사증후군을판별할때백혈구수, 페리틴농도, 간기능수치, 폐기능수치의민감도와특이도를분석한결과를제시하였다. 모든예측인자의 AUC는남녀모두에서유의하였으나판별값 (cutoff value) 은남녀간에달랐다. 남자에서이들예측인자의민감도는 %, 특이도는 % Table 1. Characteristics of study subjects by sex Characteristic Men (n=2,958) Women (n=3,782) Age (y) 44.2± ±0.35 Physical activity (MET-min/wk) 42,788±862 55,073±1008 Smoking (cigarette/d) 7.4± ±0.05 Alcohol consumption (glasses/time) 2.8± ±0.02 Education (y) 12.4± ±0.08 Metabolic syndrome component Waist circumference (men 90 cm, women 85 cm) 23.6%±1.1% 22.6%±0.9% Blood pressure ( 130/85 mm Hg) or hypertension 46.3%±1.3% 32.1%±1.0% Fasting blood glucose ( 100 mg/dl) or diabetes 29.6%±1.2% 20.9%±0.9% Triglyceride ( 150 mg/dl) 37.4%±1.3% 18.8%±0.9% High density lipoprotein cholesterol (men<40, women<50 mg/dl) 22.1%±1.1% 35.0%±1.0% Metabolic syndrome* 25.8%±1.1% 19.3%±0.8% White blood cell counts (1,000/μL) 6.6± ±0.37 Ferritin (ng/ml) 122.8± ±1.12 gamma-glutamyltranspeptidase (IU/L) 47.4± ±0.43 Aspartate aminotransaminase (IU/L) 24.6± ±0.16 Alanine aminotransferase (IU/L) 26.7± ±0.23 Forced expiratory volume 1 second (L) 3.27± ±0.02 Forced vital capacity (L) 4.26± ±0.02 Values are presented as mean (or %)±SE. Using complex sampling design analyses. MET-min/wk were calculated by using international physical activity questionnaire ) MET: metabolic equivalent. *Diagnosed when having 3 components of metabolic syndrome. n=1,241. n=1,502. Vol. 4, No. 1 Mar

4 Chae-Hun Lee, et al: Metabolic Syndrome, Liver Function, Pulmonary Function, WBC, and Ferritin Table 2. Analysis of covariance* for the comparison of liver function test, WBC, ferritin, and pulmonary function test for the MetS by sex Variable MetS Men Women N Mean±SE P-value N Mean±SE P-value WBC (1,000/μL) Yes ±0.06 < ±0.07 <0.001 No 1, ±0.04 2, ±0.03 Ferritin (ng/ml) Yes ±4.29 < ±1.85 <0.001 No 1, ±2.76 2, ±0.91 gamma-glutamyltranspeptidase (IU/L) Yes ±2.37 < ±0.94 <0.001 No 1, ±1.53 2, ±0.47 Aspartate aminotransaminase (IU/L) Yes ±0.51 < ±0.30 <0.001 No 1, ±0.32 2, ±0.15 Alanine aminotransferase (IU/L) Yes ±0.65 < ±0.48 <0.001 No 1, ±0.42 2, ±0.24 Forced expiratory volume 1 second (L) Yes ± ± No ±0.02 1, ±0.01 Forced vital capacity (L) Yes ± ± No ±0.02 1, ±0.01 MetS: metabolic syndrome, WBC: white blood cell. *After adjusting for age, education, daily alcohol consumption, number of cigarette smoking/d, and physical activity. Table 3. The odds ratios of liver function test, WBC, ferritin, and pulmonary function test for the metabolic syndrome by sex Variable Unit change Men Women Age-adjusted Model 1* Model 2 Age-adjusted Model 1* Model 2 WBC 1,000/μL 1.29 ( ) 1.29 ( ) 1.24 ( ) 1.37 ( ) 1.36 ( ) 1.32 ( ) Ferritin 10 ng/ml 1.05 ( ) 1.04 ( ) 1.02 ( ) 1.03 ( ) 1.03 ( ) 1.01 ( ) γgtp 10 IU/L 1.11 ( ) 1.10 ( ) 1.05 ( ) 1.21 ( ) 1.19 ( ) 1.06 ( ) AST 10 IU/L 1.36 ( ) 1.33 ( ) 0.85 ( ) 1.40 ( ) 1.38 ( ) 0.80 ( ) ALT 10 IU/L 1.38 ( ) 1.38 ( ) 1.33 ( ) 1.57 ( ) 1.56 ( ) 1.62 ( ) FEV 1 1 L 0.87 ( ) 0.85 ( ) 0.94 ( ) 0.85 ( ) 0.87 ( ) 0.97 ( ) FVC 1 L 0.86 ( ) 0.82 ( ) 0.89 ( ) 0.82 ( ) 0.84 ( ) 0.99 ( ) Values were odds ratio (95% confidence interval) using multiple logistic regression analysis with complex sampling design. WBC: white blood cell, γgtp: gamma-glutamyltranspeptidase, AST: aspartate aminotransaminase, ALT: alanine aminotransferase, FEV 1 : forced expiratory volume 1 second, FVC: forced vital capacity. *After adjusting for age, education, daily alcohol consumption, number of cigarette smoking/d, and physical activity. Including age, education, daily alcohol consumption, number of cigarette smoking/d, physical activity, WBC, ferritin, γgtp, AST, and ALT as independent variables. Including age, education, daily alcohol consumption, number of cigarette smoking/d, physical activity, WBC, ferritin, γgtp, AST, ALT, and FEV 1 (or FVC for corresponding analysis) as independent variables. 52 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

5 이채훈외 : 대사증후군과간기능, 폐기능, 백혈구, 페리틴의관련성 : 제 5 기국민건강영양조사자료 2010 Table 4. Cutoff value, sensitivity, specificity and AUC of liver function test, WBC, ferritin, and pulmonary function test for classifying the metabolic syndrome by sex Cutoff value AUC P-value Sensitivity (%) Specificity (%) WBC (1,000/µL) Men > < Women > < Ferritin (ng/ml) Men > < Women > < gamma-glutamyltranspeptidase (IU/L) Men > < Women > < Aspartate aminotransaminase (IU/L) Men > < Women > < Alanine aminotransferase (IU/L) Men > < Women > < Forced expiratory volume 1 second (L) Men Women < Forced vital capacity (L) Men Women < AUC: area under the receiver operating characteristic curve, WBC: white blood cell. 의범위에, 여자에서는각각 %, % 의범위에걸쳐있었다. 고찰 본연구에서는이전개별적연구에서대사증후군관련인자로보고된혈중백혈구수, 혈청간효소및페리틴, 폐기능이대표성있는동일한연구대상자에서대사증후군과유의한관련이있는지를알아보았다. 국민건강영양조사자료를이용하여 19세이상의성인에서일반적특성, 생활습관관련변수, 혈중백혈구수, 혈청페리틴농도, GGT, AST, ALT 를독립변수에포함하여대사증후군유병과관련성을분석한결과, 남자에서는백혈구수, 페리틴, GGT, ALT가증가할수록대사증후군이있을승산비가증가하였고, 여자에서는백혈구수와 ALT가대사증후군유병과유의한관련성을보였다. 대사증후군을판별할때이들지표들의민감도와특이도는남자에서 %, % 이었고여자에서는 %, % 이었다. 따라서본연구를통해이전에알려진대사증후군관련요인들을고려한후에도남녀모두에서혈중백혈구수와 ALT가일관성있게대사증후군과관련있음을알수있었고, 대사증후군관련요인들의대사증후군판별에있어민감도는남자보다여자에서높고, 항목간특이도의범위 가여자에서더좁은것을알수있었다. 대사증후군의병태생리는여러가지물질을분비하는일종의내분비기관으로인식되는복부지방축적과관련이있다. 3) 복부지방에서분비되는 tumor necrosis factor-α, interleukin-6를포함한염증성사이토카인에의해조직에서인슐린저항성이증가하여대사증후군을초래한다. 15) 뿐만아니라이들염증성사이토카인은백혈구분화를강력하게유도하고, 혈관내피세포에서의지속적염증반응및내피세포기능을변형시켜백혈구의유동성을방해하고, 유동성이감소한백혈구의내피세포부착경향을촉진하여말초혈액에서백혈구증다증을유도하게된다. 6) 이러한일련의염증성반응을반영하는지표는혈중백혈구수외에도 C-reactive protein와페리틴이있다. 16,17) 체내에서철의과도한축적은기관특이적인산화손상을유발하여간에서는인슐린추출저하및당신생합성억제저하가발생하며근육에서는유리지방산산화를증가시켜포도당의분포조절을방해하는것으로생각된다. 18) 반응성산화물 (reactive oxygen species) 로인한조직에서의산화스트레스 (oxidative stress) 는대사증후군의발병기전으로알려져있는데, 산화스트레스에반응하여상승하는세포내글루타치온 (glutathione) 농도가반영되는감마지티피는산화적스트레스의수준을반영한다. 3,19) 감소된폐기능은체지방증가에따른기계적부하에의해흉벽의탄력감소, 말초기도의 Vol. 4, No. 1 Mar

6 Chae-Hun Lee, et al: Metabolic Syndrome, Liver Function, Pulmonary Function, WBC, and Ferritin 저항증가의정도를반영할뿐아니라 10) 지속적인저산소증에의한인슐린조절및분비장애를유발하여대사증후군의발생에기여할수있다. 20) 따라서혈중백혈구수, 간효소, 페리틴, 폐기능은대사증후군의다양한발생기전을반영하는지표로생각된다. 그러나본연구에서폐기능이다른지표들보다대사증후군과의관련성이분석방법에따라유의성에차이를보인것은체지방증가에따르는호흡의기계적부하보다체지방에의한염증이나산화적스트레스가대사증후군발생에더큰영향을줄가능성을제시한다. 본연구에서관찰된대사증후군과혈중백혈구수, 페리틴, 간효소간의관련성은이전의연구와일치하며 6-8) 폐기능에관한공변량분석에서남자에서대사증후군과유의한관련성이있었던것은이전연구와일치하는결과를보였으나 21) 로지스틱회귀분석에서관련성이유의하지않았다. 혈액을이용한검사에비해폐기능검사는표준화된측정방법을사용하더라도정확도가낮을수있어연구에따라결과에차이를초래할수있을것이다. 본연구는단면적연구이므로관련성은제시하더라도인과관계를평가할수없는제한점이있다. 병원이아닌지역사회에서참여한연구대상자이긴하나검사치에영향을주는질병과약물복용과같은교란변수들을보정하지못하였으므로본연구에서관찰된결과에이들변수의효과가영향을주었을가능성이있다. 아울러연구자료에포함된검사항목이제한적이어서 C-reactive protein 등더욱다양한지표에대한분석을시행할수없는제한점도있다. 그렇지만이런제한점을고려하더라도본연구는한국성인의대표성있는집단을대상으로하였으므로본연구결과를한국성인에게일반화하는것은타당할것으로보인다. 결론적으로남자에서높은혈중백혈구수, 혈청페리틴, GGT, ALT 및여자에서높은혈중백혈구수와 ALT와대사증후군과의관련성을고려해서대사증후군의병태생리에대한추후연구가필요할것으로생각한다. 요약 연구배경 : 대사증후군과혈중백혈구수 (white blood cell, WBC), 혈청페리틴농도, 간효소치, 폐기능 (pulmonary function test, PFT) 과의관련성을평가하기위해본연구를시행하였다. 방법 : 2010년국민건강영양조사에참여한 19세이상성인 6,740명 ( 남자 2,958명, 여자 3,782명 ) 에서대사증후군과 WBC, 페리틴, γ-glutamyltranspeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 1초당노력성호기량, 노 력성폐활량과의관련성을공변량분석, 복합표본추출로지스틱회귀분석, receiver operating characteristic (ROC) 분석으로평가하였다. 결과 : 복합표본추출을고려한대사증후군의유병률은남자에서 25.8%, 여자에서 19.3% 이었다. 나이, 교육수준, 1일흡연량, 1회음주량, 신체활동량, WBC, 페리틴, AST, ALT, GGT 를독립변수로포함한로지스틱회귀분석을시행한결과남자에서는 WBC, 페리틴, ALT, GGT가증가할수록여자에서는 WBC, ALT가증가할수록대사증후군의승산비가증가하였다. PFT 는남자에서공변량분석에서만대사증후군과유의한역의관련성을보였다. ROC 분석결과이들지표들의민감도와특이도는남자에서 %, % 이었고여자에서는 %, % 이었다. 결론 : 남자에서혈중백혈구수, 페리틴, ALT, GGT의증가및여자에서혈중백혈구수와 ALT의증가는대사증후군을동반할가능성을시사한다. 중심단어 : 대사증후군 ; 혈중백혈구 ; 간효소 ; 폐기능 ; 페리틴 REFERENCES 1. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome: a new world-wide definition: a Consensus Statement from the International Diabetes Federation. Diabet Med 2006;23: Park E, Choi SJ, Lee HY. The prevalence of metabolic syndrome and related risk factors based on the KNHANES V J Agric Med Community Health 2013;38: Kim MK, Park JH. Metabolic syndrome. J Korean Med Assoc 2012;55: Collins LC, Hoberty PD, Walker JF, Fletcher EC, Peiris AN. The effect of body fat distribution on pulmonary function tests. Chest 1995;107: Sahebjami H, Gartside PS. Pulmonary function in obese subjects with a normal FEV1/FVC ratio. Chest 1996;110: Seo HS, Yun YW, Sohn SJ. Relationship between White blood cell counts and the metabolic syndrome. J Agric Med Community Health 2010;35: Kang YH, Min HK, Son SM, Kim IJ, Kim YK. The association of serum gamma glutamyltransferase with components of the metabolic syndrome in the Korean adults. Diabetes Res Clin Pract 2007;77: Kim HK, Lim JH, Kwon ER, Park YJ, Kim NE, Noh WY, et al. 54 Vol. 4, No. 1 Mar 2014 Korean J Fam Pract

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