214 Jong Seong Lee, et al. LD and CRP in Patients of Coal Workers Pneumoconiosis ORIGINAL ARTICLE Korean J Clin Lab Sci. 2017;49(3):214-219 https://doi.org/10.15324/kjcls.2017.49.3.214 pissn 1738-3544 eissn 2288-1662 The Serum Levels of LD and CRP in Patients of Coal Workers Pneumoconiosis with Chronic Obstructive Pulmonary Disease Jong Seong Lee, Jae Hoon Shin, YouLim Lee, JinEe Baek, Byung-Soon Choi Occupational Lung Diseases Research Institute, Korea Workers Compensation & Welfare Service, Incheon, Korea 만성폐쇄성폐질환을동반한탄광부진폐증자의혈청중 LD 및 CRP 농도 이종성, 신재훈, 이유림, 백진이, 최병순 근로복지공단직업성폐질환연구소 Coal workers pneumoconiosis (CWP) and chronic obstructive pulmonary disease (COPD) are characterized as chronic inflammation of the lung in miners exposed to coal mine dust. The aim of the present study was to compare the levels of serum lactate dehydrogenase (LD) and C-reactive protein (CRP) as the inflammatory indices between subjects with CWP and those with CWP and COPD (CWP+COPD), among a total of 97 subjects (27 control, 40 CWP, and 30 CWP+COPD patients). The mean levels of serum LD (165.7 vs 184.6 U/L, p=0.016) and CRP (0.08 vs 0.15 mg/dl, p=0.002) in subjects with CWP were higher than those of in subjects without CWP. The mean level of serum CRP (0.10 vs 0.19 mg/dl, p=0.008) in subjects with COPD was higher than that in subjects without COPD. In an analysis of covariance adjusted by age, the mean level of serum CRP showed statistical significance among the study groups, control, CWP, and CWP+COPD (0.07 vs 0.13 vs 0.19 mg/dl, p=0.005); the mean level of serum CRP in the CWP+COPD group was significantly higher than that of the control group (p=0.001). The results suggest that a high level of CRP in the serum may be associated with CWP and COPD in retired coal miners. Key words: Coal workers pneumoconiosis, Chronic obstructive pulmonary disease, Lactate dehydrogenase, C-reactive protein Corresponding author: Jong Seong Lee Occupational Lung Diseases Research Institute, Korea Workers Compensation & Welfare Service, 478 Munemi-ro, Bupyeong-gu, Incheon 21417, Korea Tel: 82-32-540-4981 Fax: 82-32-540-4997 E-mail: ljs5075@kcomwel.or.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2017 The Korean Society for Clinical Laboratory Science. All rights reserved. Received: May 24, 2017 Revised 1 st : June 21, 2017 Revised 2 nd : June 30, 2017 Revised 3 rd : July 3, 2017 Revised 4 th : July 11, 2017 Accepted: July 11, 2017 서론석면, 결정형유리규산및석탄분진과같은분진의노출은탄광부진폐증 (coal workers pneumoconiosis, CWP), 진행성폐섬유화, 폐포염및기관지확장증등을유발한다 [1]. 특히결정형유리규산은국제암연구소 (International Agency for Research on Cancer, IARC) 에서 1급발암물질로규정하고있다 [2]. 만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 은지속적인폐환기장해를특징으로하는질병으로대개진행성이며독성분진또는가스흡입으로인한폐기도의만성염증성반응과관련이있다 [3]. 석탄분진노출근로자에서 CWP와 COPD는중요한직업성질환으로 [4], 우리나라
Korean J Clin Lab Sci. Vol. 49, No. 3, September 2017 215 에서도이러한광산근로자및이직근로자에대하여 진폐의예방및진폐근로자의보호등에관한법률 등의특별법으로진단, 치료, 요양및보상을관리하고있다 [5]. 석탄분진을흡입할경우, 폐세포의손상과섬유화로인해지속적인폐에흉터를남기는 CWP를일으킬수있다 [6]. 석탄에는결정형유리규산이포함되어있기때문에 CWP 역시결정형유리규산에의해발병되는규폐증 (silicosis) 과비슷한염증기전을가지며, 이로인해폐기능손실을유발한다 [1]. CWP는치료가불가능하기때문에증상의조기진단을위해전향적예측지표 (prospective markers) 로서생물학적반응의이용가능성을연구하는것이중요하다 [7]. CWP와 COPD를진단하기위하여흉부방사선학적소견에의한형태학적변화와폐기능검사와같은기능적변화에대한진단방법등에의존하고있으나, 이러한소견및변화는이미심각하게섬유화가진행되어야만진단이가능하다. 또한분진노출이중단된후에도흉부방사선학적진폐병형과폐기능손실이진행되는것으로볼때, 이러한분진에의한생물학적활성이지속된다고볼수있다 [8]. 유리규산은임계치를한번이라도초과할경우추가적인노출이없어도폐질환이진행되기때문에, 이러한유해인자에노출되었던이직근로자역시지속적인관리가중요하다 [9]. Lactate dehydrogenase (LD) 는세포손상지표로서이용될수있는데, 석탄광부에서혈청중 LD 농도가증가하며, 노출이중단되더라도그농도가오랫동안유지된다고하였고 [10], 질병의진행상태와관련성이있다고하였다 [7]. C-reactive protein (CRP) 은진폐증에서농도가증가하는염증성 cytokine 인 interleukin-6 (IL6) 과밀접한관련성이있으며 [11], COPD 환자에서도정상대조군에비해혈중 CRP 농도가증가하고, 이러한원인중에는일정부분 IL6와관련성이있다고하였다 [12]. 이와같이 CWP나 COPD 등과같은폐세포의손상으로인해세포막혹은세포내효소등의성분들이세포외액으로유리될수있기때문에, 이러한효소들은세포손상지표로이용될수있는데, 분진으로인한폐의염증여부를판단하기위해세포손상지표인 LD와 CRP 등의혈중농도가이용될수있다고하였다 [7]. 그러나 COPD와같은폐기능손실이동시에나타나는 CWP에서의혈중 LD 및 CRP 농도에대한연구는보고된바없다. 본연구는 CWP 및 COPD 수반한 CWP 집단을대상으로혈중 LD와 CRP 농도와의비교를통해이러한질병과생체지표간의특성을보고자하였다. 대상및방법 1. 연구대상진폐건강진단을위해내원한남자탄광부이직근로자 163명중간기능관련진단항목 (aspartate aminotransferase, alanine aminotransferase 또는 gamma-glutamyl transpeptidase) 의참고치이상을나타낸 66명을제외한 97명을최종연구대상자로하였다. 대조군 (non-cwp 및 non-copd) 은 27명이었고 CWP군은 70명이었는데, CWP 군은 I형 37명, II형 19명 III형 1명이었고, 진행성폐섬유화증 (progressive massive fibrosis, PMF) 13명이었다. 또한 CWP군중에서 CWP만있는대상자는 40명이었고 COPD를동반한집단 (CWP+COPD 군 ) 은 30명이었다. 2. CWP 및 COPD 진단 CWP의진단은국제노동기구 (International Labor Office, ILO) 에서정하고있는방법에따라연구대상자의흉부영상에대하여근로복지공단진폐심사위원회의영상의학전문의 2인에의한합의판정으로하였다 [13]. 폐기능검사는폐기능검사기 (Vmax22, SensorMedics, USA) 를이용하여미국흉부학회 (American Thoracic Society, ATS)/ 유럽호흡기학회 (European Respiratory Society, ERS) 에서권장하는방법으로시행하였는데 [14], 노력성폐활량 (forced vital capacity, FVC) 및노력성일초간호기량 (forced expiratory volume in one second, FEV 1) 을측정하였고, 각각의예측치는 Morris 방식으로계산하였다 [15]. COPD의진단은대한결핵및호흡기학회 (Korea Academy of Tuberculosis and Respiratory diseases, KATRD) 에서정하고있는일초율 (%FEV 1/FVC) 70% 미만이고, 속효성 2-기관지확장제를흡입한후 FEV 1 이 200 ml 및 12% 미만으로증가한경우로하였다 [16]. 혈청중 LD와 CRP는채혈즉시혈청분리한후자동생화학분석기 (7080, Hitachi Technology Co., Japan) 으로분석하였다. 연구대상자에대하여면접조사를통하여나이, 체질량지수 (body mass index, BMI), 분진노출기간, 흡연여부, 당뇨병및고혈압여부등의일반적특성을조사하였다. 연구대상자에대하여연구참여동의서에서명 (informed consent) 받았으며, 근로복지공단직업성폐질환연구소기관생명윤리위원회 (2011-30-02) 심의완료후연구를진행하였다. 3. 통계분석 모든통계분석은 SPSS 17.0 (SPSS, Chicago, IL, USA) 으로수행하였는데, 혈중 LD는정규분포하였고, CRP는 1/ 제곱근
216 Jong Seong Lee, et al. LD and CRP in Patients of Coal Workers Pneumoconiosis (square root) 으로변환후정규분포하였다. 비교군의일반적특성은 2 -test, t-test 및분산분석 (ANOVA) 으로비교분석하였고, 연구집단간의 LD 및 CRP의평균농도는혼란변수인연령을통제한후공분산분석 (analysis of covariance, ANCOVA) 으로검증하였다. 각분석의통계적유의수준은 p<0.05 로하였다. 결과 1. 일반적특성연구대상자의일반적특성은 Table 1과같다. 연구집단간 BMI, 분진노출기간, %FVC, 흡연여부, 당뇨병및고혈압의차이가없었으나나이, %FEV 1 및 %FEV 1 /FVC는통계적으로차이가있었다. 2. 혈중 LD 및 CRP 농도혈중 LD 및 CRP농도는연령, BMI, 분진노출기간, 흡연, 당뇨병및고혈압여부등일반적특성에따른차이가없었다. CWP 군의혈중 LD 평균농도 (165.7 U/L vs 184.6 U/L, p=0.016) 와 CRP 평균농도가 non-cwp군보다높았다 (0.08 mg/dl vs 0.15 mg/dl, p=0.002). COPD 군에서의혈중 CRP 평균농도는 non-copd군보다높았으나 (0.10 mg/dl vs 0.19 mg/dl, p=0.008) LD 평균농도는두집단간차이가없었다 (177.1 U/L vs 184.2 U/L, p=0.359) (Table 2). 연구집단간통계적유의성을보였던연령을통제한공분산 분석에서, 혈중 CRP 평균농도는대조군, CWP군및 CWP+COPD 군간에통계적으로유의하게증가하였는데 (0.07 vs 0.13 vs 0.19 mg/dl, p=0.005), 대조군과 CWP군은통계적으로유의한차이가없었지만 CWP+COPD 군은대조군에비해통계적으로유의하게높았다 (p=0.001). 혈중 LD의평균농도는대조군에비해 CWP군과 CWP+COPD군에서높은경향을보였지만통계적으로유의하지는않았다 (167.7 vs 184.6 vs 182.7 U/L, p=0.173) (Table 3). 고찰석탄분진과결정형유리규산에감수성이있는근로자가이러한분진에노출될경우여러가지폐질환으로진행될수있는데, 이러한질병에는고전적의미의진폐증을비롯한결절성간질성폐질환을비롯하여, 진행성폐섬유화, 폐부종및만성기관지염을포함한 COPD 등을일으킬수있다 [8,17]. 선행연구에따르면결정형유리규산또는석탄분진을흡입할경우결정형섬유성폐조직반응이나타난다고보고하고있다 [8]. CWP는폐포대식세포와상피세포의활성과관련이있는만성염증의특징을가진다 [18]. 결정형유리규산또는석탄분진의노출이중단된이직근로자에서도흉부방사선학적진폐병형과폐기능의손실이진행되는것으로볼때, 이러한분진에의한생물학적활성이지속된다고볼수있다 [8]. 그러나현재 CWP 와 COPD의진단과질병의정도는흉부방사선영상판독과 Table 1. General characteristics of the study subjects Parameters Control (N=27) CWP (N=40) CWP+COPD (N=30) p-values Age (yrs)* 59.1±6.4 65.1±7.5 68.5±5.8 <0.001 BMI (kg/m 2 )* 24.4±2.3 23.3±3.1 23.6±2.7 0.309 Exposure period (yrs)* 14.9±8.6 18.5±8.1 17.5±7.8 0.204 %FVC predicted 95.7±11.8 94.0±13.3 94.5±11.9 0.852 %FEV 1 predicted 103.8±15.7 104.0±15.9 85.2±13.3 <0.001 %FEV 1/FVC ratio 78.0±4.5 77.6±5.7 62.1±6.8 <0.001 Smoking, No. (%) No 19 (70.4) 24 (60.0) 20 (66.7) 0.664 Yes 8 (29.6) 16 (40.0) 10 (33.3) Diabetes, No. (%) No 23 (85.2) 36 (90.0) 26 (86.7) 0.662 Yes 4 (14.8) 4 (10.0) 4 (13.3) Hypertension, No. (%) No 18 (66.7) 26 (65.0) 24 (80.0) 0.359 Yes 9 (33.3) 14 (35.0) 6 (20.0) Arithmetic mean±arithmetic standard deviation. *Calculated by ANOVA. Calculated by 2 -test. Abbreviations: CWP, coal workers pneumoconiosis; COPD, chronic obstructive pulmonary diseases; BMI, body mass index; FVC, forced vital capacity; FEV 1, forced expiratory volume in 1 second.
Korean J Clin Lab Sci. Vol. 49, No. 3, September 2017 217 Table 2. Concentrations of serum LD and CRP according to general characteristics Characteristics N LD* CRP U/L p-values mg/dl p-values Age (yrs) 59 25 175.9 (29.0) 0.055 0.11 (0.62) 0.582 60 69 51 174.4 (32.4) 0.11 (0.38) 70 21 195.5 (43.7) 0.15 (0.76) BMI (kg/m 2 ) <25 66 178.3 (32.6) 0.680 0.13 (0.60) 0.354 25 31 181.5 (40.2) 0.10 (0.34) Exposure period (yrs) 9 14 168.1 (31.7) 0.355 0.14 (1.03) 0.758 10 19 45 183.5 (39.1) 0.12 (0.35) 20 38 178.5 (30.6) 0.11 (0.62) Smoking No 63 185.0 (37.0) 0.029 0.11 (0.43) 0.323 Yes 34 168.8 (28.6) 0.14 (0.61) Diabetes No 85 179.3 (32.7) 0.958 0.12 (0.48) 0.505 Yes 12 179.8 (50.5) 0.14 (0.49) Hypertension No 68 178.9 (34.4) 0.843 0.12 (0.42) 0.635 Yes 29 180.4 (37.0) 0.13 (0.72) CWP No 27 165.7 (27.1) 0.016 0.08 (0.33) 0.002 Yes 70 184.6 (36.4) 0.15 (0.68) COPD No 67 177.1 (32.3) 0.359 0.10 (0.48) 0.008 Yes 30 184.2 (40.6) 0.19 (0.59) *Arithmetic mean (Arithmetic standard deviation). Geometric mean (Geometric standard deviation). ILO category of chest radiographs: I, 37 subjects; II, 19 subjects; III, 1 subject; progressive massive fibrosis, 13 subjects. p-values were calculated by ANOVA or t-test. Abbreviations: CWP, coal workers pneumoconiosis COPD, chronic obstructive pulmonary diseases. Table 3. Serum LD and CRP among the study groups Age-adjustment Parameters Control (N=27) CWP (N=40) CWP+COPD (N=30) p-values Before* LD (U/L) 165.7 (5.22) 184.9 (5.30) 184.2 (7.41) 0.056 CRP (mg/dl) 0.08 (8.9) 0.12 (32.6) 0.19 (17.8) 0.002 After LD (U/L) 167.7 (7.21) 184.6 (5.45) 182.7 (6.63) 0.173 CRP (mg/dl) 0.07 (12.1) 0.13 (21.1) 0.19 (14.3) 0.005 *Calculated by ANOVA test. Calculated by analysis of covariance (ANCOVA) adjusted by age. Arithmetic mean (arithmetic standard error). Geometric mean (geometric standard error). In ANCOVA test adjusted by age, the p-value of serum CRP between control and CWP+COPD group was 0.001, but there was no statistical significance between control and CWP group. Abbreviations: CWP, coal workers pneumoconiosis (CWP); COPD, chronic obstructive pulmonary diseases. PFT에의존하고있는실정이다. 따라서흉부영상에서의비가역적변화와폐기능의손실이나타나기전에예후를판단할수있는유용한생체지표에대한연구가필요하다 [7]. 본연구에서는간기능손상에의한혈중 LD 및 CRP 농도의영향을배제하기위해간기능손상지표의참고치를초과한경우연구대상자에서제외하였다. 폐질환과혈중 LD의활성증가간의관련성에대한선행고찰연구 [19] 에서폐에서의염증, 세포손상, 개질및섬유화와같은간질성폐질환인진폐증과세포손상및사멸과관련이있는 COPD의경우에혈청중의 LD 농도가증가한다고하였다. 이번 연구에서혈중 LD 농도는연령을통제하지않았을경우 CWP군에서유의하게높았으나 (165.7 vs 184.6, p=0.016), 연령을통제한후대조군에비해 CWP군과 CWP+COPD군에서높은경향을보였으나통계적으로유의하지는않았다 (167.7 vs 184.6 vs 182.7 U/L, p=0.173). 이러한결과는탄광부에서혈청중 LD 농도가증가한다고보고한 Cobben 등 [10] 의연구결과와일치하였다. 이번연구에서혈청중 LD 농도는 COPD 여부에따른농도의차이는보이지않았다 (p=0.359). LD는 5가지의이성체의형태가존재하는데특히폐조직에는 LD3과관련이있는것으로알려져있다. Cobben 등 [10] 은석탄분진노출자에서
218 Jong Seong Lee, et al. LD and CRP in Patients of Coal Workers Pneumoconiosis FEV 1 이감소하고혈청중 LD 농도가증가하며특히 LD3 활성증가와관련성이있다고하였다. 따라서향후연구대상자를확대하고 CWP 및 COPD 등의합병증과 LD 이성체간의관련성에대한연구가필요하다. 혈중 CRP는생체내염증성변화를반영하는단백질로써대식세포와 T-cell 등의의한 IL6와연관되어간에서합성되는데 [20], CWP환자에대한기본적인건강진단검사항목으로도많이이용되고있다. Fernandez Rego 등 [21] 의선행연구에의하면진폐증및진행성진폐증의경우대조군에비해혈중 CRP 농도가증가하기때문에질병의정도에대한생체지표로써유용하다고하였고, Agusti 등 [22] 은 COPD환자의혈중 CRP 농도는흡연및비흡연대조군보다유의하게높았고, 흡연대조군역시비흡연대조군보다증가한다고하였다. 이번연구에서혈중 CRP 농도는분산분석에서 CWP군 (0.08 vs 0.15 mg/dl, p=0.002) 및 COPD군 (0.10 vs 0.19 mg/dl, p=0.008) 에서유의하게높았다. 연령을통제한후에도대조군, CWP군및 CWP+COPD 군간에통계적으로유의하게증가하였는데 (0.07 vs 0.13 vs 0.19 mg/dl, p=0.005), 대조군과 CWP군은통계적유의성이없었는데비해 CWP+COPD 군에서통계적으로유의하게증가하였다 (p=0.001). COPD를수반한 CWP 환자에대한혈중 LD 및 CRP에대한선행연구가없어직접적인비교는불가능하였지만, 이번연구결과혈중 LD 농도는통계적으로유의성은없지만 COPD 합병증과관계없이 CWP 집단에서농도가증가하는것으로보이는데, 통계적유의성이떨어지는원인으로는 CWP 군에속한연구대상자중에염증의진행이있는 PMF가 CWP군 70명중약 19% 인 13명인데비해나머지는폐섬유화흔적만있는단순진폐증 (simple pneumoconiosis) 이었기때문으로판단된다. 혈중 CRP 농도는 CWP 집단에서도농도가증가하지만 COPD 합병증이있을경우더욱증가하는것으로보인다. 비록 CRP가급성기염증변화에대한생체지표이지만만성적염증의특성을나타내는 COPD를동반한 CWP군에서도 CRP농도가증가하는것으로판단된다. 이번연구결과혈청중의 LD와 CRP 농도는 CWP 여부에대해민감도와특이도가높지는않지만진단지표로서유용하였고, 특히 CRP는 COPD를동반한 CWP환자에서더욱농도가증가한다는것을알수있었다. 요약탄광부진폐증 (CWP) 과만성폐쇄성폐질환 (COPD) 은석탄 분진에노출되는탄광부의폐에서나타나는만성적폐염증의특성을가진다. 이번연구의목적은대조군 27명, CWP 40명, COPD를동반한 CWP 30명등총97명을대상으로염증지표로서혈청중의 LD와 CRP 수준을비교하고자하였다. 혈청중의 LD 평균농도 (165.7 vs 184.6 U/L, p=0.016) 와 CRP 평균농도 (0.08 vs 0.15 mg/dl, p=0.002) 는 CWP군에서유의하게높았다. 혈청중의 CRP 평균농도 (0.10 vs 0.19 mg/dl, p=0.008) 는 COPD군에서높았다. 연령을통제한공분산분석에서, 혈청중 CRP 평균농도는대조군, CWP군및 CWP+COPD 군간에통계적으로유의한차이가있었으며 (0.07 vs 0.13 vs 0.19 mg/dl, p=0.005), CWP+COPD 군의혈청 CRP 평균농도가대조군보다유의하게높았다 (p=0.001). 이러한결과는높은수준의혈청중 CRP는탄광부이직근로자에서의 CWP 및 COPD와관련이있는것으로보인다. Acknowledgements: None Funding: None Conflict of interest: None REFERENCES 1. Schins RPF and Borm PJA. Mechanisms and mediators in coal dust induced toxicity: A review. Am Occup Hyg. 1999; 43(1): 7-33. 2. International Agency for Research on Cancer. IARC Monograph on the evaluation of the carcinogenic risk of chemicals to humans. In: Silica, some silicates, coal dust and para-aramid fibrils. Geneva, Switzerland. IARC Press; 1997. Vol. 68. 3. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4): 347-365. 4. Meijers JM, Swaen GM, Slangen JJ. Mortality of Dutch coal miners in relation to pneumoconiosis, chronic obstructive pulmonary disease, and lung function. Occup Environ Med. 1997; 54(10):708-713. 5. National Law Information Center. Act on the prevention of pneumoconiosis and protection, etc., of pneumoconiosis workers. Sejong: Korea Ministry of Government Legislation; 2016. No. 13911. 6. Castranova V. From coal mine dust to quartz: Mechanism of pulmonary pathology. Inhal Toxicol. 2000;12(Suppl 3):7-14. 7. Gulumian M, Borm PJA, Vallyathan, Castranova V, Donaldson K, Nelson G, et al. Mechanistically identified suitable biomarkers of exposure, effect, and susceptibility for silicosis and coal-worker's pneumoconiosis: a comprehensive review. J Toxicol Environ Health B Crit Rev. 2006;9(5):357-395.
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