대한내과학회지 : 제 84 권제 3 호 2013 http://dx.doi.org/10.3904/kjm.2013.84.3.372 한국인에서 D-Dimer 의위양성과관련된인자와검사의정확도향상을위한 Cut-Off Value 울산대학교의과대학강릉아산병원내과 홍만용 이창근 유상용 신대희 정상식 권장훈 장우성 유승진 오광훈 Cut-Off Value and Factors Associated with a False Positive D-Dimer Result for Venous Thromboembolism in Koreans Man Yong Hong, Changkun Lee, Sang-Yong Yoo, Dae-Hee Shin, Sang-Sig Cheong, Jang Hoon Kwon, Woo Sung Jang, Seung Jin Yoo, and Kwang Hoon Oh Division of Cardiology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea Background/Aims: The D-dimer value is a simple blood test used to evaluate venous thromboembolism (VTE). However, due to its low specificity, another test is needed for a definite diagnosis, such as a radiographic test. We evaluate the factors associated with a false positive D-dimer test and propose a new cut-off value for detecting VTE more effectively in Koreans. Methods: This was a retrospective, observational study. From January 2009 to December 2009, 2,047 patients (988 men, 63 ± 15 years) had the D-dimer value checked to evaluate VTE. The main outcome of interest was a positive D-dimer test. Odds ratio and 95% confidence intervals were determined using logistic regression analysis. The new D-dimer cut-off was evaluated using receiver operating characteristics (ROC) curves. Results: The result was positive in 1,093 patients (53%), for a false positive percentage for VTE of 95% and a false negative percentage for VTE of 1%. Significant false positive predictors for a positive D-dimer were increasing age, trauma, postoperative, acute infection, tuberculosis, stroke, malignancy, chronic renal failure, acute coronary syndrome, heart failure, and lung disease. The discriminative value of the D-dimer test was assessed using ROC curve analysis. A D-dimer value of 0.68 mg/l on admission was the best cut-off value for predicting the development of VTE with a sensitivity of 95% and specificity of 57%. Conclusions: Many factors affect the D-dimer value and we must consider these factors before using the D-dimer value to evaluate VTE. A D-dimer value of 0.68 mg/l appears to be a good cut-off value for evaluating VTE more effectively in Koreans. (Korean J Med 2013;84:372-378) Keywords: Venous thromboembolism; Fibrin fibrinogen degradation products; False positive reactions Received: 2012. 7. 30 Revised: 2012. 9. 3 Accepted: 2012. 10. 11 Correspondence to Changkun Lee, M.D. Division of Cardiology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, 415 Bangdong-ri, Sacheon-myeon, Gangneung 210-711, Korea Tel: +82-33-610-3947, Fax: +82-33-641-8130, E-mail: ckdreams@gmail.com Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 372 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- 홍만용외 8 인. D-dimer 의위양성과관련된인자와 cut-off value - 서론혈청 D-dimer 측정은일반적으로급성폐동맥색전증을진단하기위해일차적으로시행되는검사다. D-dimer 검사는비관혈적이고, 결과를빨리확인할수있어폐동맥색전증을확인하기위한매우유용한검사이다 [1]. 그러나 D-dimer 검사는특이도가 40% 에서 60% 정도로낮기때문에그유용성이제한된다 [2]. 폐동맥색전증과심부정맥혈전증을제외하고, 몇가지질환에서 D-dimer의양성소견을보이는데, 고령의나이, 악성종양그리고임신과같은경우에서폐동맥색전증과심부정맥혈전증이없음에도불구하고 D-dimer 가양성값을보이는것으로보고되었다 [3-11]. 특히, 환자의연령이높아질수록특이도가유의하게낮아지기때문에나이가많은환자에서 D-dimer의유용성은현저하게낮아진다 [3,4]. 현재까지한국인에서 D-dimer 의위양성에영향을미치는질환에대해서는명백하게알려진바가없고, 실제임상에서폐동맥색전증과심부정맥혈전증이발생한환자를대상으로 D-dimer 의결과치와그에따른민감도와특이도에대해서도명확히알려진바가없다. 따라서본연구는한국인에서 D-dimer 검사의폐동맥색전증과심부정맥혈전증진단의민감도와특이도를구하고, 좀더효과적으로이를진단할수있는새로운 cut-off value를제시하며, 또한 D-dimer 위양성을초래하는인자들을확인하고자시행하였다. 대상및방법대상 2009년 1월부터 12월까지본원에방문한환자중폐동맥색전증과심부정맥혈전증을진단하기위해 D-dimer 검사를시행받은 2,047명의환자를대상으로후향적분석을하였다. 평균나이는 63 ± 15세였으며남자가 988명, 여자가 1,059 명이었다. USA) 를이용하여혈청 D-dimer 를측정하였고, D-dimer 의농도가 0.5 mg/l 이상인경우를양성으로정의하였다. 폐동맥색전증과심부정맥혈전증은다검출기전산화단층촬영검사, 폐환기- 관류스캔, 압박정맥초음파검사, 고식적정맥조영술을통해진단하였다. 통계분석연속형변수는평균 ± 표준편차로나타냈고, 범주형변수는빈도및퍼센트로나타냈다. 통계분석은윈도우용 SPSS 14.0 (Statistical package for the social science, SPSS-PC Inc. Chicago, IL, USA) 을이용하였다. 오즈비 (odds ratio) 와 95% 신뢰구간 (confidence interval) 은로지스틱회귀분석을시행하였다. 통계분석결과 p 값이 0.05 미만에서통계학적으로유의한것으로간주하였다. D-dimer 의새로운 cut-off value는 ROC curve를이용하여분석하였다. 결과임상적특징총 2,047명의환자에서 D-dimer 검사가시행되었다. D-dimer가양성인 1,093명중, 폐동맥색전증과심부정맥혈전증으로진단된환자는 56명으로양성예측도는 5% 였으며, D-dimer가음성인 954명중, 폐동맥색전증과심부정맥혈전증이진단되지않은환자는 946명으로음성예측도는 99% 였다. D-dimer 검사의 cut-off value를현재사용되고있는 0.5 mg/l로했을때에민감도는 88%, 특이도는 48% 였고, 위양성률은 95%, 위음성률은 1% 로관찰되었다 (Fig. 1). D-dimer 검사가시행된전체환자의평균연령은 63 ± 15세였다. 연령이증가할수록 D-dimer 양성률이증가하는경향을 연구방법 2,047명의환자를대상으로환자의나이, 성별, 동반질환과최종진단명에대해전자의무기록을분석하여얻었다. 환자들은효소- 연결면역흡수측정검사 (enzyme-linked immunosorbent assay; VIDAS D-dimer exclusion, biomérieux, SA, Figure 1. The study population. VTE, venous thromboembolism. - 373 -
- 대한내과학회지 : 제 84 권제 3 호통권제 631 호 2013 - 보였으며, 60대이상에서는 50% 이상에서 D-dimer 양성결과를보였다. 각기저질환별로진양성에대한위양성의비율, 곧 D-dimer가양성으로나왔을때, 그양성결과가위양성일확률이높은질환으로는급성감염, 수술을받은기왕력, 외상등이었다 (Table 1). 특히, 급성감염의경우그수치가가장높았는데급성감염의종류로는신우신염, 간농양, 봉와직염등다양한감염병 (220명) 이확인되었고, 특히폐렴 (104명, 47.2%) 의빈도가가장높았다. 그리고수술의기왕력의경우정형외과적수술이가장많았고 (55명, 73.3%), 수술한뒤 D-dimer 검사는수술일에서부터수술후 44일까지시행되었으며, 중간값은 8일이었다. 외상의경우대부분의환자에서골절이동반된외상이었으며, 골절이확인되지않은 Table 1. Baseline characteristics Characteristic Total N = 2,047 (%) D-dimer Negative, N = 954 (%) - 374 - D-dimer Positive, N = 1,093 (%) Ratio of False- to-true positive D-dimer Women 1,059 (51.7) 489 (46) 570 (54) 14.0 Age (yr) <30 52 (2.5) 42 (81) 10 (19) - 30-39 113 (5.5) 88 (78) 25 (22) 11.5 40-49 188 (9.2) 127 (68) 61 (32) 29.5 50-59 422 (21) 287 (68) 135 (32) 66.5 60-69 451 (22.0) 226 (50) 225 (50) 17.8 70-79 533 (26.0) 156 (29) 377 (61) 17.9 80 288 (14.1) 28 (10) 260 (90) 14.3 CAD 144 (7.0) 57 (40) 87 (60) - Stroke 65 (3.2) 6 (9) 59 (91) 13.8 HF 34 (1.7) 6 (18) 28 (82) 13.0 Diabetes 21 (1.0) 8 (38) 13 (62) - CRF 28 (1.1) 2 (7) 26 (93) 12.0 Atrial Fibrillation 74 (3.6) 37 (50) 37 (50) - Lung disease 106 (5.2) 36 (34) 70 (66) - Asthma 25 (1.2) 10 (40) 15 (60) - COPD 53 (2.6) 14 (26) 39 (74) - Acute Infection 219 (10.6) 16 (7) 203 (93) 100.5 Bleeding 14 (0.7) 2 (14) 12 (86) - Malignancy 203 (9.9) 21 (10) 182 (90) 19.2 VTE Under treatment 32 (1.6) 17 (53) 15 (47) - Not under treatment 56 (2.7) 1 (2) 55 (98) 0 Pregnancy 2 (0.1) 1 (50) 1 (50) - Post-operation 65 (3.1) 0 (0) 65 (100) 64.0 Abdominal 12 (0.5) 0 (0) 12 (100) - Chest 2 (0.1) 0 (0) 2 (100) - Orthopedic 46 (2.2) 0 (0) 46 (100) 45.0 Neurosurgery 5 (0.2) 0 (0) 5 (100) - Trauma 80 (3.9) 2 (2) 78 (98) 77.0 CAD, coronary artery disease; HF, heart failure; CRF, chronic renal failure; COPD, chronic obstructive pulmonary disease; VTE, venous thromboembolism.
- 홍만용외 8 인. D-dimer 의위양성과관련된인자와 cut-off value - 환자의경우외상에의한지주막하출혈, 교통사고등에복합적인타박상등중증의외상에서 D-dimer 검사가시행되어 (80명) 대부분의환자에서 D-dimer 의양성소견이관찰되었다 (78명, 98%). D-dimer 검사의위양성결과와관련된질환들에대한로지스틱회귀분석 D-dimer 검사에서양성결과를보이는질환들에대한로지스틱회귀분석의결과, 연령의증가, 외상, 수술의기왕력, 급성감염, 결핵, 뇌혈관질환, 악성종양, 만성신부전, 급성 관동맥증후군, 심부전, 호흡기질환등이 D-dimer 위양성을유발하는인자로확인되었다 (Table 2). 이중가장관련성이높은질환은수술의기왕력이었고 (OR = 42.70 [95% CI = 5.55 to 328.80], p < 0.001), 폐결핵, 기관지결핵, 결핵성흉막염등, 결핵에의한감염도유의한유발인자로관찰되었다 (OR = 6.36 [95% CI = 2.73 to 14.77], p < 0.001). 그리고안정형협심증과변이형협심증을포함한심혈관질환의경우 D-dimer 검사의위양성결과와관련성이없었으나, 급성관동맥증후군만을분석하였을때는 D-dimer 검사의위양성을 Table 2. Multivariate analysis of the factors associated with a false positive D-dimer result Variables OR 95% CI p Age 1.10 1.06-1.14 < 0.001 Acute coronary syndrome 3.01 1.21-7.48 0.018 Stroke 5.34 2.43-11.74 < 0.001 Heart failure 3.47 1.46-8.22 0.005 Chronic renal failure 3.28 1.0-10.75 0.05 Lung disease 2.13 1.32-3.43 0.002 Tuberculosis 6.36 2.73-14.77 < 0.001 Infection 14.88 8.70-25.45 < 0.001 Malignancy 11.17 7.26-17.21 < 0.001 Trauma 36.98 10.35-132.07 < 0.001 Postoperative 42.70 5.55-328.80 < 0.001 Figure 2. The receiver operating characteristic (ROC) curve of D-dimer used to obtain the new cut-off value. A B Figure 3. The receiver operating characteristic (ROC) curve of D-dimer used to obtain the new cut-off value divided by the age of 65 years. - 375 -
- The Korean Journal of Medicine: Vol. 84, No. 3, 2013 - 유발하는인자로확인되었다 (OR = 3.01 [95% CI = 1.21 to 7.48], p = 0.018). 그리고연령을 65세기준으로나누었을때 65세이상의환자들이 65세미만의환자들에비해위양성을나타낼가능성이높았다 (OR = 1.93 [95% CI = 0.66 to 12.38], p = 0.008). Cut-off value 의평가폐동맥색전증과심부정맥혈전증의선별을위한최적의 D-dimer의값을알아보기위해 receiver-operating characteristic (ROC) curve를이용하여분석한결과 cut-off value는 0.68 mg/l로이때의민감도는 95%, 특이도는 57% 로나타났다 (Fig. 2). 그리고 65세를기준으로나누어분석해보았을때, 65세이하환자들에서의 cut-off value는 0.58 mg/l로민감도는 100%, 특이도는 71% 였으며, 65세초과환자들에서의 cut-off value는 0.77 mg/l로민감도는 89%, 특이도는 47% 였다 (Fig. 3). 고찰본연구는폐동맥색전증과심부정맥혈전증선별을위한 D-dimer 검사에서위양성을일으킬수있는인자들을확인하고, D-dimer 검사의민감도와특이도를향상시킬수있는새로운 cut-off value을알아보기위한연구였다. 본연구를통해연령의증가, 외상, 수술의기왕력, 급성감염, 결핵, 뇌혈관질환, 악성종양, 만성신부전, 급성관동맥증후군, 심부전, 호흡기질환등이 D-dimer 검사의위양성을유발할수있는예측인자로관찰되었다. 또한본연구에서 D-dimer 검사의 cut-off value를기존의 0.5 mg/l에서 0.68 mg/l로하였을때민감도를 88% 에서 95% 로, 특이도를 48% 에서 57% 로향상시킬수있었다. 이전연구를통해연령이증가함에따라 D-dimer 의특이도가유의하게감소하는것이알려져있고 [3,4], 본연구에서도이전의연구에서와같이연령이증가함에따라 D-dimer 양성률이증가하는결과를보였다. 50대까지는 D-dimer 양성률이 32% 로연령에따른영향이크지않았으나 60대 50%, 70대 61%, 80대이상에서는 90% 의환자에서 D-dimer 가양성으로나타나연령이증가할수록 D-dimer 의양성률이증가하는경향을보였다. 반면진양성에대한위양성의비율은연령이증가할수록 (50대; 66.5, 60대 ; 17.8, 70대 ; 17.9, 80대이 상 ; 14.3) 감소되는경향을보였는데, 이는연령이증가할수록폐동맥색전증과심부정맥혈전증의발생률도증가하기때문으로사료된다. 악성종양, 수술의기왕력, 만성폐질환, 울혈성심부전, 뇌혈관질환과혈관염등은폐동맥색전증을유발하는기저질환으로알려져있다 [5,6]. 그러나악성종양 [7,8,12], 감염 [12-14], 수술의기왕력 [15-17], 외상 [12,18], 뇌혈관질환 [12,19-21], 허혈성심질환 [12,22-24] 등은또한폐동맥색전증이나심부정맥혈전증이없이 D-dimer 의수치를상승시키는것으로보고되었다. 특히여러연구에서수술의기왕력이 D-dimer 의위양성결과와관련이깊은질환으로보고되고있는데, 본연구에서도수술의기왕력은 D-dimer 위양성과가장관련성이높은질환으로나타나기존의연구들과유사한결과를보여줬다. 또한급성감염병, 악성종양, 외상, 뇌혈관질환등의질환에대하여도이전보고된연구결과들과마찬가지로 D-dimer 검사에서위양성결과와관련이있는것으로확인되었다. 반면, 본연구에서는호흡기질환, 심부전이나만성신부전특히, 우리나라에서비교적흔한결핵균에의한감염도 D-dimer 검사에서위양성결과와관련이있는것으로확인되었다. 기존의연구에서는허혈성심질환이 D-dimer 의상승과관련이있는것으로보고하였으나 [22-24], 본연구에서는심혈관질환중에서병태생리학적으로혈전의생성이관련되어있다고알려져있는급성관동맥증후군만이 D-dimer 의위양성과관련되어있는것으로나타난것도흥미로운결과라고생각한다. 이처럼연령의증가, 외상, 수술의기왕력, 급성감염, 결핵, 뇌혈관질환, 악성종양, 만성신부전, 급성관동맥증후군, 심부전, 호흡기질환등의기저질환이있는경우 D-dimer 검사가위양성의결과를나타낼가능성을항상염두에두어야할것으로생각한다. 본원에서시행되고있는 D-dimer 검사는효소- 연결면역흡수측정검사 (enzyme-linked immunosorbent assay; VIDAS D-dimer exclusion) 를이용하여혈청 D-dimer 농도측정하고, 일반적으로 cut-off value 0.5 mg/l 이상일때를양성으로한다. VIDAS D-dimer assay의 cut-off value를 0.5 mg/l로하였을때, 이전의연구에서는 96-99% 의민감도와 38-40% 의특이도를보였다 [25,26]. 하지만현재까지국내에서는실제임상에서폐동맥색전증과심부정맥혈전증이발생한환자를대상으로 D-dimer 의결과치와그에따른민감도와특이도에대해보고된연구가없었다. 이에저자들은본연구를통하 - 376 -
- Man Yong Hong, et al. Cut-off value and false positive D-dimer - 여한국인에서 VIDAS D-dimer assay 법에의한민감도와특이도를구하였다. D-dimer 검사의 cut-off value를현재사용되는 0.5 mg/l로했을때의민감도는 88%, 특이도는 48% 였고, 위양성률은 95%, 위음성률은 1% 로관찰되었다. 또한, 민감도와특이도를향상시킬수있는 D-dimer의새로운 cut-off value을 ROC curve 을통하여 0.68 mg/l로정하였고이때민감도는 95%, 특이도는 57% 로향상시킬수있었다. 그리고 65세를기준으로나누어분석해보았을때, 65세이하환자들에서의 cut-off value는 0.58 mg/l로민감도는 100%, 특이도는 71% 였으며, 65세초과환자들에서의 cut-off value는 0.77 mg/l로민감도는 89%, 특이도는 47% 로확인되었다. 본연구는후향적연구로단일기관의결과이며, D-dimer 검사를시행한목적이폐동맥색전증과심부정맥혈전증을배제하기위한것이었음을추측할뿐그이유가정확히무엇이었는지확인할수는없었으며, 각환자들에서폐동맥색전증을임상적으로예측할수있는 Revised Geneva score나 Wells score 를확인하지못하였고, cut-off value를분석하기에는폐동맥색전증과심부정맥혈전증을진단받은환자들의수가적었다는제한점이있었다. 결론적으로폐동맥색전증과심부정맥혈전증을선별하기위하여시행되는 D-dimer 검사는연령의증가, 외상, 수술의기왕력, 급성감염, 결핵, 뇌혈관질환, 악성종양, 만성신부전, 급성관동맥증후군, 심부전, 호흡기질환등이있는환자에서검사의위양성이증가하게되어낮은특이도를나타내었다. 또한현재 VIDAS D-dimer assay법에사용되고있는 cut-off value인 0.5 mg/l를 0.68 mg/l로정하였을때, 민감도 88%, 특이도 48% 를민감도 95%, 특이도 57% 로향상시킬수있었다. 따라서임상에서 D-dimer 검사를시행하고적용할때는이러한인자들이결과치에영향을줄수있음을충분히고려하여야하겠다. 요약목적 : 폐동맥색전증과심부정맥혈전증이외에 D-dimer 검사의양성결과를나타내는여러질환들이보고되고있으나, 현재까지한국인에서위양성을유발하는인자에대해서는명백하게알려진바가없다. 따라서한국인에서위양성을초래하는인자들을확인하고, 정확도를향상시키기위한새로운 cut-off value를제시하고자한다. 방법 : 2009년 1월부터 12월까지본원에방문한환자중다양한이유로 D-dimer 검사를시행받은 2,047명의환자를대상으로분석하였고, 위양성을유발하는인자들을확인하기위해오즈비와 95% 신뢰구간을로지스틱회귀분석을이용하여분석하였다. 새로운 cut-off value는 ROC curve 를이용하여구하였다. 결과 : 연령의증가, 외상, 수술의기왕력, 급성감염, 결핵, 뇌혈관질환, 악성종양, 만성신부전, 급성관동맥증후군, 심부전, 호흡기질환등이 D-dimer 검사의위양성을유발하는인자로확인되었다. 또한민감도와특이도를향상시키기위해 ROC curve 를이용하여구한새로운 cut-off value는 0.68 mg/l였다 (65세이하에서는 0.58 mg/l, 65세이상에서는 0.77 mg/l). 결론 : 여러인자들이 D-dimer 위양성과관련이있었으며, 임상에서 D-dimer 검사를시행하고임상에적용할때에는이러한인자들이결과치에영향을줄수있음을충분히고려하여야겠다. 중심단어 : 정맥혈전색전증 ; 섬유소섬유소원분해산물 ; 위양성 REFERENCES 1. Kabrhel C, Matts C, McNamara M, Katz J, Ptak T. A highly sensitive ELISA D-dimer increases testing but not diagnosis of pulmonary embolism. Acad Emerg Med 2006;13: 519-524. 2. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004;140: 589-602. 3. Righini M, Nendaz M, Le Gal G, Bounameaux H, Perrier A. Influence of age on the cost-effectiveness of diagnostic strategies for suspected pulmonary embolism. J Thromb Haemost 2007;5:1869-1877. 4. Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med 2000;109:357-361. 5. Park YS, Ha JW, Kwon KH, et al. Clinical characteristics and predictors of in-hospital mortality for patients with acute major pulmonary embolism. Korean J Med 2000;3: 293-301. 6. Joo YS, Choi SW, Kim WS, et al. Incidence of pulmonary embolism in Korean patients undergoing hip or knee - 377 -
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