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1 한국성인남성에서연령과전립선용적보정후 PSA 에영향을미치는인자 Factors Influencing the Prostate-specific Antigen Levels after Adjusting Age and Prostate Volume in Korean Men Jae I Koh, Won Jae Yang, Yun Seob Song, Young Ho Park From the Department of Urology, College of Medicine, Soonchunhyang University, Seoul, Korea Purpose: We investigated the influence of the anthropometric and serological parameters on the prostate-specific antigen (PSA) levels after adjusting for age and the prostate volume in Korean men who visited a health promotion center. Materials and Methods: From January 2004 to July 2007, among the 18,352 men (age range: 30 to 79) who visited our health promotion center for general check-ups, 1,230 (14.9%) men who wanted their prostate evaluated were included in this study. Thereafter, 151 men whose PSA level was over 4.0ng/ml, or their urinalysis revealed pyuria (>5 white blood cells (WBCs)/high power fields (HPF)) were excluded. The data of the remained 1,079 men was then analyzed. All the men underwent transrectal ultrasonography, detailed anthropometric measurements and serological tests. The correlation of the PSA level with the various anthropometric and serological parameters was investigated. Results: On the univariate analysis after adjusting for age and the prostate volume, the PSA level showed statistically significant positive correlation with the WBC, the red blood cell (RBC) and platelet (PLT) counts/μl, and the PSA level was negatively correlated with height, weight, the body surface area (BSA), the body mass index (BMI), γ-glutamyltransferase (GGT), and creatinine clearance (Ccr). On multivariate analysis, age, the prostate volume and the RBC/PLT counts/μl were positively correlated with the PSA level, and the BSA was negatively correlated with the PSA levels, whereas the BMI was not. Conclusions: Irrespective of age, the prostate volume and the BSA were the independent factor influencing the PSA level, that is, the larger the BSA, the lower the PSA. (Korean J Urol 2008;49: ) Key Words: Prostate-specific antigen, Body surface area, Body mass index 대한비뇨기과학회지제 49 권제 5 호 2008 순천향대학교의과대학비뇨기과학교실 고재이ㆍ양원재ㆍ송윤섭ㆍ박영호 접수일자 :2008년채택일자 :2008년 2월 15일 4월 14일 교신저자 : 양원재순천향대학교병원비뇨기과서울특별시용산구한남동대사관길 TEL: FAX: wonjya@hosp. sch.ac.kr 서론전립선특이항원 (prostate-specific antigen; PSA) 은전립선암선별검사에쓰이는종양표지자이다. 하지만 PSA는전립선암에특이적이지않아이상적인종양표지자라하기에는충분하지않으며, 전립선암진단에대한 PSA의민감도와특이도를높이기위해서는이에영향을미치는인자에 대한연구가필요하다. 현재까지정상성인에서 PSA에영향을미치는독립적인인자로연령, 전립선용적, 인종등이알려져있으며, 1-3 그밖에다른여러가지인체측정학적, 혈청학적인자들의관련성여부에대한연구들이산발적으로이루어졌으나대부분의연구들은이세가지중요한요소중특히전립선용적을보정하지않고도출한결과들로서그정확성에의문을가진다. 4-6 따라서, 본연구에서는건강검진을위해내원한한국남 411

2 412 대한비뇨기과학회지 : 제 49 권제 5 호 2008 성을대상으로연령과전립선용적을보정한후, 측정된인체측정학적지수와혈청학적인자들이 PSA와어떤상관성을보이는지알아보았다. 대상및방법 2004년 1월부터 2007년 7월까지본원건강증진센터를방문한 30세부터 79세까지의한국남성 18,352명중전립선에대한검사를원한 1,230명 (14.9%) 을대상으로하였으며, 이중 PSA가 4.0ng/ml 이상, 요검사고배율에서백혈구가 5개이상인 151명을제외하여총 1,079명을분석하였다. 대상자의연령을기록한후, PSA는동일한 monoclonal immunoradiometric assay(tandem-r PSA assay, Hybritech, Inc. San Diego, USA) 로, 전립선용적은경직장초음파 ( 메디슨초음파 SONOACE 6000C) 의 6.5 MHz의탐촉자를이용하여높이, 폭, 길이를측정한후타원체공식 (V=π/6xHxW xl) 에대입하여구하였다. 신장과체중은가벼운복장에서신발을신지않은상태에서측정하였으며혈압은최소 5분간의충분한휴식후전자식혈압계로수축기와이완기혈압을측정하였다. 체질량지수 (body mass index; BMI) 는신장 (height; H) 과체중 (weight; W) 을공식 (BMI=W/H 2 ) 에대입하여산출하였고, 체표면적 (body surface area; BSA) 은 Dubois 공식 (BSA=H xw x ) 에따라계산하였다. 7 방문자들의혈액샘플은전날자정부터최소 8시간이상금식하도록한후에채취하였으며, 이를이용하여 1μl 당백혈구 / 적혈구 / 혈소판수등을포함한일반혈액검사, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), creatinine 등을포함한일반화학검사, 지질검사, 전해질검사, 기타종양표지자검사등을시행하였다. 크레아티닌청소율 (creatinine clearance: Ccr) 의계산은 (140 연령)x체중 x60 (72xcreatinine) 의공식을이용하였고, 혈청삼투압의계산은 2xsodium+glucose/18+BUN/2.8의공식을이용하여계산하였다. 통계분석은 Window R 용 SPSS 14.0 KO을이용하여각각의측정값에대해 partial correlation analysis, 다중회귀분석, 로지스틱회귀분석을시행하였고, p값이 0.05 미만인경우통계학적으로유의한것으로간주하였다. 결과대상자의평균연령은 50.7세, PSA와전립선용적의평균값은각각 1.16ng/ml, 25.7ml이었다 (Table 1). 각측정치와 PSA의상관관계를알아보기위하여연령과전립선용적을보정한후시행한편상관분석에서 PSA는신장 (p=0.008), 체중 (p), BMI (p=0.005), BSA (p< 0.001) 와음의상관관계를나타냈으며각각의상관계수는 0.081, 0.114, 0.086, 0.116이었다. 또한일반혈액검사의 1μl 당백혈구수 (p=0.019)/ 적혈구수 (p=0.036)/ 혈소판수 (0.004) 와유의한양의상관관계를나타냈으며, 일반화학검사중 GGT (p=0.041) 와 Ccr (p=0.020) 과유의한음의상관관계를나타냈다 (Table 2). 이변량분석에서유의수준 0.25 미만을나타낸변수들중, 다중공선성현상을방지하기위하여상관성이높은신장, 체중 - BMI, BSA에서신장과체중을제거하고기존에 PSA와높은상관성을가진것으로알려진연령, 전립선용적을포함시켜단계선택방법으로다중회귀분석을시행한결과, PSA는연령 (p) 과전립선용적 (p) 이외에적혈구수 (p=0.019)/ 혈소판수 (p=0.014) 와의미있는양의상관관계를보였으며, BSA 와는음의상관관계를나타냈다 (p)(table 3). 50대의한국인에서일반적으로전립선이크다고여겨지는전립선용적 35ml를예측할수있는 PSA 절단치 1.2 ng/ml를종속변수로하여, 8 로지스틱선형회귀모형으로분석한결과연령 (>50세) 과전립선용적 (>25ml) 은 PSA 증가의위험인자였던반면, BSA (>1.8m 2 ) 는 PSA를감소시키는위험인자로나타났다 (Table 4). 고찰비만의지표로사용하는 BMI와 PSA와의연관성에대하여는여러보고가있다.9-14 Werny 등 9 과 Sohn 등 10 은 BMI가증가할수록 PSA가감소한다고하였으며반면에 Freedland 등 11 과 Thompson 등 12 은 BMI와 PSA는유의한관계가없다고하였다. 비만한사람은체내에지방조직이많아혈청에스트로겐이증가하는반면, 성호르몬결합글로불린과자유테스토스테론은감소하여남성호르몬에의해영향을받는 PSA는낮아질것이라는가설이있다. 11 반대로지방조직이적고근육량이많은사람은실제로비만하지않음에도 BMI가높게측정될수있는데, 이러한경우오히려남성호르몬이증가하며따라서 BMI가높은데도 PSA는높게측정될수있다. 15 본연구결과, 연령과전립선용적을보정한후시행한이변량분석에서신장, 체중, BMI와 BSA는 PSA와의상관계수가모두 0.1 정도로낮아경험적으로강한상관성이존재한다고할수없지만통계학적으로는의미있는음의상관성을나타냈다. 다변량분석에서는 BMI와 BSA 중

3 고재이외 : 한국성인남성에서연령과전립선용적후 PSA 에영향을미치는인자 413 Table 1. Distribution of the clinical parameters Parameters (Unit) Mean SD Median 25th, 75th percentiles IQR PSA (ng/ml) Age (years) Prostate volume (ml) Anthropometric measurements Height (cm) Weight (kg) BMI (kg/m 2 ) BSA (m 2 ) Systolic BP (mmhg) Diastolic BP (mmhg) Complete blood count WBC (x10 3 /μl) RBC (x10 6 /μl) Hb (g/dl) Hct (%) PLT (x10 3 /μl) Liver function tests AST (U/l) ALT (U/l) ALP (U/l) GGT (U/l) Albumin (g/dl) Bilirubin (mg/dl) Renal function tests BUN (mg/dl) Cr (mg/dl) Ccr (ml/min) Lipid profile Cholesterol (mg/dl) Triglyceride (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Other constitutes FBS (mg/dl) Total protein (g/dl) Sodium (mmol/l) Pottasium (mmol/l) Osmolarity (mol/kg) CA19-9 (ng/ml) AFP (ng/ml) CEA (ng/ml) TSH (μiu/ml) Amylase (U/l) Uric acid (mg/dl) Calcium (mg/dl) , , , , , , , , , , , , , , , , , , , , , 17.0, , , , , , , , , , , , , , , , , , th, 95th percentiles 0.40, , , , , , , , , , , , , , , , , , , , , 2 0.8, , , , , , , , , , , , , , , , , , 9.7 SD: standard deviation, IQR: interquartile range, PSA: prostate-specific antigen, BMI: body mass index, BSA: body surface area, BP: blood pressure, WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT:γ-glutamyltransferase, BUN: blood urea nitrogen, Cr: creatinine, Ccr: creatinine clearance, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, FBS: fasting blood glucose, CA19-9: carbohydrate antigen 19-9, AFP: α-fetoprotein, CEA: carcinoembryonic antigen, TSH: thyroid stimulating hormone

4 414 대한비뇨기과학회지 : 제 49 권제 5 호 2008 Table 2. The prostate volume and age-adjusted partial correlation between the PSA level and selected characteristics Variables Height (cm) Weight (kg) BMI (kg/m 2 ) BSA (m 2 ) Systolic BP (mmhg) Diastolic BP (mmhg) WBC (x10 3 /μl) RBC (x10 6 /μl) Hb (g/dl) Hct (%) PLT (x10 3 /μl) AST (U/l) ALT (U/l) ALP (U/l) GGT (U/l) Albumin (g/dl) Bilirubin (mg/dl) BUN (mg/dl) Cr (mg/dl) Ccr (ml/min) Cholesterol (mg/dl) Triglyceride (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) FBS (mg/dl) Total protein (g/dl) Sodium (mmol/l) Pottasium (mmol/l) Osmolarity (mol/kg) CA19-9 (ng/ml) AFP (ng/ml) CEA (ng/ml) TSH (μiu/ml) Amylase (U/l) Uric acid (mg/dl) Calcium (mg/dl) PSA r* p-value r*: partial correlation coefficient adjusted by prostate volume and age, PSA: prostate-specific antigen, BMI: body mass index, BSA: body surface area, BP: blood pressure, WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT:γ-glutamyltransferase, BUN: blood urea nitrogen, Cr: creatinine, Ccr: creatinine clearance, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, FBS: fasting blood glucose, CA19-9: carbohydrate antigen 19-9, AFP: α-fetoprotein, CEA: carcinoembryonic antigen, TSH: thyroid stimulating hormone Table 3. The multivariate linear regression model evaluating the factors correlated with the PSA level Variables Coefficient p-value VIF Age (years) Prostate volume (ml) BSA (m 2 ) RBC (x10 6 /μl) PLT (x10 3 /μl) Table 4. Results of the multivariates logistic regression analysis; the factors that affected the PSA level>1.2ng/ml Parameters (unit) Age (50 years >, ) Prostate volume (25ml >, ) BSA (1.8m 2 >, ) RBC (490x10 6 /μl >, ) PLT (240x10 3 /μl >, ) Odds ratio % Confidence interval for odds ratio 1.101, , , , , PSA: prostate-specific antigen, BSA: body surface area, RBC: red blood cell, PLT: platelet p-value PSA: prostate-specific antigen, BSA: body surface area, RBC: red blood cell, PLT: platelet BSA만이 PSA와의미있는음의상관성을보였는데이는신장이 PSA와음의상관성을보이기때문으로공식상신장에반비례하는 BMI와정비례하는 BSA를동시에분석하면다변량분석에서는 BSA만이상관성을나타내는것으로보인다. 즉, BMI가의미하는대상자의비만도보다는 BSA 에기초한체격의크기가 PSA와더높은상관성을가지며, 이는연령과전립선용적이같은경우체격이클수록 PSA 가상대적으로낮아진다는것을의미한다. 이러한현상과기전은아직잘알려져있지않지만, 최근 Banez 등 14 은전립선암으로근치적전립선적출술을시행받은 13,634명을대상으로한연구에서 BMI가클수록 PSA가낮게측정된다고하였는데, 이의기전을총혈장량증가에의한 PSA의상대적인희석으로추정하였다. 본연구와관련하여흥미로운것은총혈장량을 BSA를이용하여계산했다는점이다. 따라서이들연구에서도직접적인비교는안했지만본연구에서와같이 BSA와 PSA는음의상관성을가질것으로여겨진다. 물론이들의연구는전립선암환자를대상으로한것으로정상성인을대상으로한본연구와직접비교할수는없다. 50대의한국인에서일반적으로전립선이크다고여겨지

5 고재이외 : 한국성인남성에서연령과전립선용적후 PSA 에영향을미치는인자 415 는전립선용적 35ml를예측할수있는 PSA 절단치인 1.2ng/ml를기준으로 8 PSA 증가위험도에영향을미치는인자를알아보기위하여로지스틱회귀분석을시행한결과, 연령과전립선용적은 PSA 증가의위험인자였으나 BSA는 PSA를감소시키는위험인자인것으로나타났다. 즉, BSA 가 1.8m 2 이상인경우 PSA가 1.2ng/ml 이상이될위험도는 0.683으로 BSA가증가할경우 PSA는낮게측정될수있는결과를나타냈다. 로지스틱회기분석을하기위해서는 PSA 수치에따라대상자를이분해야하는데, 그절단치를본연구에서의평균값인 1.16ng/ml로하기보다는나름대로약간이라도임상적인의미가있는이분점으로나누는것이좋을것같아서 1.2ng/ml를기준으로나누었으나연령대에따라절단치가다르다는것을감안해야한다. 이와같이비만, 혹은체격이큰사람이상대적으로마르고체격이작은사람에비해같은조건에서 PSA 수치가더낮게측정된다는연구결과를고려하면, PSA 4.0ng/ml라는동일한절단치를가지고전립선생검을시행할경우비만, 혹은체격이큰사람에서의전립선암검출률이더높을것이라는가정을세울수있지만, 실제로그럴지의여부는알수없다. 왜냐하면비만이라는한가지인자가전립선암검출에미치는영향은복합적이기때문이다. 예를들어, 비만한사람이마른사람에비해 PSA가낮더라도전립선의용적은더큰것으로알려져있으며, 16,17 전립선용적은전립선생검의결과에영향을미친다. 18 따라서이에대해서는더많은연구가필요할것으로생각한다. 또한 PSA는다변량분석에서혈액학적요소인적혈구 / 혈소판수와양의상관관계를나타냈다. 이들은골수의조혈모세포에서기원하여분화되는세포들로서내분비계와호르몬변화의영향을적게받기때문에 PSA에영향을주는새로운요인으로서의미가있을것으로여겨지나역시그정확한기전은알려지지않았다. 간기능검사중 GGT는단변량분석에서 PSA와음의상관관계를나타냈다. PSA는 α 1-antichymotrypsin과 α 2-macroglobulin과같은 antiprotease와결합하여 19,20 대부분결합형 PSA로존재하며주로간에서배설된다. 21 간에서의 PSA의배설은 serine protease와 serine proteinase 억제인자를배설하는수용체에의하여 antiprotease가대사되면서함께배설된다는가설과 22,23 간의 Kupper cell은탄수화물특이수용체를통하여 glycoprotein의배설에관여하며 PSA는 glycoprotein의성분이므로 Kupper cell을통하여배설될수있다는가설이있다. 24 하지만간에서의대사기전은아직불명확하다. 정상성인과간경화또는만성간염환자에서 PSA 는차이가없다는보고가있으며 21 Jin 등 25 은간기능부전환자에서 PSA는정상성인보다낮으며간이식후정상화 된다고보고하였다. 간기능부전환자는성호르몬의대사에영향을받아여성호르몬이증가하고남성호르몬이감소하여 PSA는낮게측정될수있다는가정을할수있다. 15 간기능검사항목중에서간기능을직접적으로반영하는지표는아직밝혀지지않았다. AST, ALT는간질환의선별검사와질환의활성도평가에사용되며 ALP는간의배설기능을나타내며빌리루빈은간의합성기능을민감하게반영한다. 하지만 GGT의의미는아직정확히밝혀지지않은상태로본연구에서간기능검사항목중오직 GGT만이 PSA에영향을미치는인자로나타나간에서의 GGT의의미가명확히밝혀진다면 PSA의배설과관련하여 GGT와 PSA의상관관계는더욱명확해질것이다. 신기능검사중사구체여과율을의미하는 Ccr 역시 PSA 와음의상관관계를나타냈다. 하지만현재까지신장은 PSA의배설에크게관여하지않는것으로알려져있다. 26 Danisman 등 27 은만성신부전환자에서총 PSA와자유형 PSA는체내에축적되지않으며투석전, 후에도차이를보이지않는다고보고하였다. PSA의 95% 는 antiprotease와결합하며이러한결합형 PSA는분자량이크기때문에사구체에서여과되지못한다. 그러나분자량이작은자유형 PSA 와기존에알려지지않은새로운 antiprotease와결합된 PSA 는신장의사구체를통하여배설될수있다 이러한점에서사구체여과율을반영하는 Ccr은 PSA와음의상관관계를나타낼수있을거라여겨진다. 결 PSA에영향을미치는인자를살펴보기위하여시행한본연구결과, 다변량분석에서 PSA는비만의지표인 BMI와는상관관계를나타내지않았으며연령, 전립선용적, 1μl 당적혈구수 / 혈소판수와는양의상관관계를, BSA와는음의상관관계를나타냈다. 이는대상자의 BSA, 즉체격이클수록같은조건에서 PSA가낮게측정될수있다는것으로, PSA에의한전립선조직생검을결정할때연령, 전립선용적이외에도 BSA에기초한체격을고려해야할것으로여겨진다. 론 REFERENCES 1. Pinsky PF, Kramer BS, Crawford ED, Grubb RL, Urban DA, Andriole GL, et al. Prostate volume and prostate-specific antigen levels in men enrolled in a large screening trial. Urology 2006;68: Mochtar CA, Kiemeney LA, van Riemsdijk MM, Barnett GS, Laguna MP, Debruvne FM, et al. Prostate-specific antigen as

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전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II)

전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) 전립선암발생률추정과관련요인분석 : The Korean Cancer Prevention Study-II (KCPS-II) - i - - ii - - iii - - iv - - v - - vi - - vii - - viii - - ix - -