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1 54 Se-Young Kwon and Young-Ak Na. Validity for Use of Non HDL Cholesterol ORIGINAL ARTICLE Korean J Clin Lab Sci. 2013, 45(2):54-59 pissn eissn Validity for Use of Non-HDL Cholesterol Rather than LDL Cholesterol Se-Young Kwon and Young-Ak Na Department of Biomedical Laboratory Science, Daegu Health College, Daegu , Korea NonHDL cholesterol values have been suggested as a risk marker for cardiovascular disease. NonHDL cholesterol values were calculated, using a very simple measurement [nonhdl cholesterol =serum total cholesterol-hdl cholesterol]. This formula is very useful as a screening tool for identifying dyslipoproteinemias, risk assessment, and assessing the results of hypolipidemic therapy. The data from the 2009 Korean National Health and Nutrition Examination Survey were used. Analysis was done for 1,992 subjects with lipid panels (Cholesterol, HDL, LDLdirect and Triglycerides) results. We studied the relationship between nonhdl cholesterol and LDL cholesterol. As a result, nonhdl cholesterol values were plotted against the LDL direct and calculated values. The linear regression equation for nonhdl cholesterol and direct LDL cholesterol was nonhdlchol= LDLdirect (p<0.0001, r 2 =0.80) in all subjects. The subjects were classified into triglyceride values. When triglycerides are below 400 mg/dl, the linear fit to LDL direct is found to be [nonhdlchol= LDLdirect] (p<0.0001, r 2 =0.88) and to the Friedewald LDL calculation is [nonhdlchol= LDLcalc] (p<0.0001, r 2 =0.82). For triglycerides above 400 mg/dl, the linear fit equation is [nonhdlchol= LDLdirect] (p <0.0001, r 2 =0.50) and to the LDL calculated, it is [nonhdlchol= LDLcalc] (p <0.0001, r 2 =0.32). This study provides examples of the utility of nonhdl cholesterol concentrations in clinical medicine. Keywords: NonHDL cholesterol, Direct LDL cholesterol, Friedewald formula, Calculated LDL cholesterol Corresponding author: Se-Young Kwon Department of Biomedical Laboratory Science, Daegu Health College, Daegu , Korea. Tel: sykwon@dhc.ac.kr 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. Copyright 2013 The Korean Society of Clinical Laboratory Sciences. All rights reserved. Received: May 24, 2013 Revised: June 11, 2013 Accepted: June 19, 2013 서론콜레스테롤은혈액을비롯한여러조직에존재하며인체내필수요소의합성을담당하는기능적단위의스테로이드화합물이다. 콜레스테롤이인체기능에꼭필요한성분이지만상승된농도는죽상동맥경화와심혈관질환을초래한다고알려져있으며 (Vaccaro 와 Huffman, 2012), 특히여러연구결과를통해심혈관질환발병및허혈성질환의재발예방에중요한독립적인자로저밀도지단백콜레스테롤 (low-density lipoprotein cholesterol, LDL-C) 농도감소에대해그중요성이강조되고있다 (Stamler 등, 1986; Rossouw 등, 1990; Wilson 등, 1998; Hoenig, 2008). 저밀도지단백콜레스테롤은미국 NCEP-ATP III (National Cholesterol Education Program-Adult Treatment Panel III) 가이드라인에서도일차치료목표로설정되는중요한요소이며 (NCEP, 2001), 따라서정확한측정치를임상에적용하는것이무엇보다중요하다. LDL 콜레스테롤측정법은침전법, 베타정량법 (β-quantification), 면역법, 균질법 (homogenous assay), 전기영동법, 혼탁측정법, 고속액체크로마토그래피법 (high performance liquid chromatography, HPLC) 등이있으며, 각측정방법별로검사소요시간, 전처리유무, 검사비용등에서장단점이있다 (Miller 등, 2002; Nauck 등, 2002; Trembley 등, 2004). 또한국내뿐아니라미국에서도대규모집단검진이나일차의료기관에서는 Friedewald의공식에의한계산법을많이적용하고있는데, 이는직접측정법과좋은상관성을제시하고있긴하지만계산법은중성지방의농도가증가할수록정확도가떨어지고, 반드시공복상태에서채혈해야하는단점이있으며 (Friedewald, 1972), 여러연구에서 LDL 콜레스테롤계산치에의한고LDL 콜레스테롤혈증진단시직접측정치보다과소평가될수있음이보고되고있다 (Lindsey 등,

2 Korean J Clin Lab Sci. Vol. 45, No. 2, Jun ; Teerakanchana 등, 2007; Jun 등, 2008; Kamezaki 등, 2010; Kwon 과 Na, 2012). LDL 콜레스테롤계산치의오차발생의가장큰원인은공식에사용되는중성지방측정치와측정법에따른차이라고알려져있으며 (Ricos 등, 1999), 그로인해계산에사용되는세가지항목측정시생길수있는각각의오차가 LDL 콜레스테롤계산치에부정적인영향을미칠수있다고하였다 (Schectman 등, 1996). Non- 고밀도지단백콜레스테롤 (non-high density lipoprotein cholesterol, non-hdl-c) 은 NCEP-ATP III 가이드라인에서중성지방농도 2.26 mmol/l (200 mg/dl) 이상인환자군에서지질강하의이차치료목표로설정되는중요한요소이며 (NCEP, 2001), 총콜레스테롤농도와 HDL 콜레스테롤농도와의차이를통해계산된값으로서중성지방농도및측정오차에영향을받지않아오류발생을최소화시킬수있고, 반드시공복채혈을하지않아도되는장점이있다. 최근 non-hdl 콜레스테롤농도와 LDL 콜레스테롤농도를비교한연구가진행되면서 non-hdl 콜레스테롤농도가 LDL 콜레스테롤농도를대신할수있다는긍정적인결과가제시되고있다. 미국의한의료기관과 NIH에서 institutional review boards (IRB) 의승인을받아시행한연구결과에서이상지혈증환자군의심혈관질환위험등급의분류에 LDL 콜레스테롤측정치혹은계산치보다 non-hdl 콜레스테롤이더정확하다는보고가있었으며 (van Deventer 등, 2011), 심근경색환자군과정상인을대상으로한비교연구에서는 HDL 콜레스테롤농도와 non-hdl 콜레스테롤농도가 LDL 콜레스테롤농도보다심근경색을예측하는데더좋은결정적인자라고하여 LDL 콜레스테롤측정을위해공복채혈시간을기다리는것보다공복채혈이필요없는 non-hdl 콜레스테롤측정을시행하는것이더낫다고하였다 (Sigdel 등, 2012). 이에본연구에서는 non-hdl 콜레스테롤농도와 LDL 콜레스테롤직접측정치및계산치의관련성정도를살펴봄으로써집단검진이나선별검사에 LDL 콜레스테롤농도를대신하여계산된 non-hdl 콜레스테롤농도의적용여부를검토하고자하였다. 재료및방법 1. 연구대상 2009년 1월부터 12월까지시행된국민건강영양조사에서연구목적으로공개된데이터를사용하였다. 검진을시행한 20세이상의성인중지질검사항목결측치를제외하고총콜레스테롤, LDL 콜레스테롤 ( 직접법 ), HDL 콜레스테롤, 중성지방의동시측정치를가진 1,992명의결과를대상으로분석을시행하였다. 2. 연구방법혈액은대상자들을 8시간이상공복상태를유지한후정맥채혈을시행하였으며, 총콜레스테롤, LDL 콜레스테롤, HDL 콜레스테롤, 중성지방을측정하였다. 측정시약은총콜레스테롤은 Pureauto SCHO-N, HDL 콜레스테롤은 CHOLETEST N HDL, 중성지방은 Pureauto S TG-N, LDL 콜레스테롤은 CHOLETEST LDL (Daiichi Pure Chemicals Corporation, Tokyo, Japan) 을사용하여효소법으로측정하였다. 측정장비는 Hitachi 7600 (Hitachi high-technologies Co., Tokyo, Japan) 자동화학분석기를사용하였다. nonhdl 콜레스테롤과 calculated LDL 콜레스테롤은계산에의해산출되었으며, LDL 콜레스테롤의계산법은가장널리사용되고있는 Friedwald 공식을이용하였고, 계산식은다음과같다. NonHDL cholesterol = serum total cholesterol - HDL cholesterol Calculated LDL cholesterol = total cholesterol - HDL cholesterol - triglyceride/5 3. 통계분석 Friedwald 공식의적용기준과동일하게대상자를중성지방농도에따라 TG<400 mg/dl과 TG 400 mg/dl으로나누고 nonhdl 콜레스테롤과직접측정된 LDL 콜레스테롤및계산된 LDL 콜레스테롤의관계를살펴보기위해각각 linear regression analysis를시행하여, 회귀식을도출하고상관계수를구하였다. 이중에서이상지혈증판단에더적합한인자를분별하기위해고콜레스테롤혈증, 고중성지방혈증에해당하는환자를이상지혈증으로분류한후 receiver operating characteristics (ROC) curve를이용하여분석하고, area under the curve (AUC) 를비교하였다. 자료에대한통계분석은 SPSS 16.0 (SPSS, Inc., Chicago, IL, USA) 을사용하였으며, 결과해석시유의성검정은 p<0.05 로하였다. 결과 1. NonHDL 콜레스테롤과직접 LDL 콜레스테롤과의관련성중성지방농도 400 mg/dl 미만에서 nonhdl 콜레스테롤과직접측정된 LDL 콜레스테롤과의관계는 [nonhdlchol= LDLdirect] 이었으며 adjustment R 2 은 0.880으로설명력이높고통계적으로유의하였다 (p<0.0001) (Table 1, Fig. 1). 중성지방농도 400 mg/dl 이상에서 [nonhdlchol= LDLdirect] 이었으며 adjustment R 2 은 0.503으로통계적으로유의하였으나 (p<0.0001), 직접측정된 LDL 콜레스테롤에

56 Se-Young Kwon and Young-Ak Na. Validity for Use of Non HDL Cholesterol Table 1.

R 2 p NonHDLcholesterol (TG<400) NonHDLcholesterol (TG=400) Constant 17.341 1.048 16.545 0.938 0.880 0.000* Direct_LDLC 1.074 0.009 0.938 119.144 Constant 23.099 1.259 18.354 0.907 0.823 0.

564 5.328 HDLC, high density lipoprotein cholesterol; TG, Triglyceride; LDLC, low density lipoprotein cholesterol. p value is estimated by linear regression analysis. *p<0.05. Fig. 1.

3 56 Se-Young Kwon and Young-Ak Na. Validity for Use of Non HDL Cholesterol Table 1. Linear regression of nonhdl-cholesterol and LDL cholesterol according to triglyceride concentration Dependent variable Unstandardized coefficients Standardized coefficients B S.E β t R Adj. R 2 p NonHDLcholesterol (TG<400) NonHDLcholesterol (TG=400) Constant * Direct_LDLC Constant * Calc_LDLC Constant * Direct_LDLC Constant * Calc_LDLC HDLC, high density lipoprotein cholesterol; TG, Triglyceride; LDLC, low density lipoprotein cholesterol. p value is estimated by linear regression analysis. *p<0.05. Fig. 1. Correlation of non-hdl cholesterol with direct LDL cholesterol (TG<400 mg/dl). The linear fit to LDL direct is found to be [nonhdlchol= LDLdirect] (p<0.0001, r 2 =0.88). Fig. 3. Correlation of non-hdl cholesterol with calculated LDL cholesterol (TG<400 mg/dl). The linear fit to the Friedewald LDL calculation is found to be [nonhdlchol= LDLcalc] (p <0.0001, r 2 =0.823). Fig. 2. Correlation of non-hdl cholesterol with direct LDL cholesterol (TG 400 mg/dl). The linear fit equation is [nonhdlchol = LDLdirect] (p<0.0001, r 2 =0.503). Fig. 4. Correlation of non-hdl cholesterol with calculated LDL cholesterol (TG 400 mg/dl). The linear fit equation is [nonhdlchol = LDLcalc] (p<0.0001, r 2 =0.318).

Korean J Clin Lab Sci. Vol. 45, No. 2, Jun. 2013 57 Table 2.

4 Korean J Clin Lab Sci. Vol. 45, No. 2, Jun Table 2. Comparison of AUC between nonhdl cholesterol and LDL cholesterol (direct & calculated value) by receiver operating characteristics analysis Variable AUC S.E p Lower 95% C.I Upper NonHDL cholesterol Calculated_LDL cholesterol Direct_LDL cholesterol AUC, area under the curve; C.I, confidence interval. p value is estimated by receiver operating characteristics (ROC) analysis. 3. 이상지혈증분별을위한 nonhdl 콜레스테롤과 LDL 콜레스테롤의비교이상지혈증판단에더적합한인자를분별하기위해고콜레스테롤혈증, 고중성지방혈증을포함하는환자를이상지혈증으로분류한후 ROC curve 의 AUC 를비교한결과 nonhdl 콜레스테롤의경우 0.771, 계산된 LDL 콜레스테롤은 0.593, 직접측정된 LDL 콜레스테롤은 0.665로나타나더적합한분별인자는 nonhdl 콜레스테롤로나타났다 (Table 2, Fig. 5). 고찰 Fig. 5. Receiver operating characteristics curve for non-hdl cholesterol, direct LDL cholesterol and calculated LDL cholesterol in assessing dyslipidemia. When AUC was used, the data of each analysis result showed as follows: non-hdl cholesterol was 0.771, direct LDL cholesterol was 0.665, calculated LDL cholesterol was 비해설명력이낮았다 (Table 1, Fig. 2). 2. NonHDL 콜레스테롤과계산된 LDL 콜레스테롤과의관련성 중성지방농도 400 mg/dl 미만에서 nonhdl 콜레스테롤과 Friedewald 공식에의해계산된 LDL 콜레스테롤과의관계는 [nonhdlchol= LDLcalc] 이었으며 adjustment R 2 은 0.823으로설명력이높고통계적으로유의하였다 (p<0.0001) (Table 1, Fig. 3). 중성지방농도 400 mg/dl 이상에서 [nonhdlchol= LDLcalc] 이었으며 adjustment R 2 은 0.318로통계적으로유의하였으나 (p<0.0001) 설명력이낮게나타났다 (Table 1, Fig. 4). 계산된총 nonhdl 콜레스테롤농도와 LDL 콜레스테롤농도간의관계에대한근거를밝힌 Dinovo와 Howard (2010) 의연구에서중성지방농도 400 mg/dl 미만의경우 nonhdl 콜레스테롤과직접측정된 LDL 콜레스테롤과의관계는 [nonhdlchol= LDLdirect] 이었으며 adjustment R 2 은 0.90으로나타나본연구의설명력 (adjustment R 2 =0.88) 과비슷하였다. NonHDL 콜레스테롤과 Friedewald 공식에의해계산된 LDL 콜레스테롤과의관계도 nonhdlchol= LDLcalc (p<0.0001, r 2 =0.86) 으로나타나높은관련성을보이며이는계산된총 nonhdl 콜레스테롤농도가간단하고비용효과적인지질분석프로토콜로사용가능함을보여준다고하였다. 중성지방농도 400 mg/dl 이상에서 [nonhdlchol= LDLdirect] 이었으며 adjustment R 2 은 0.52로나타나본연구의 adjustment R 와비슷한관련성을보였으나, Friedewald 공식에의해계산된 LDL 콜레스테롤과의관계는 [nonhdlchol= LDLcalc] (p<0.0001, r 2 =0.53) 으로나타나본연구의 adjustment R 보다설명력이더높았다. 중성지방농도에따라구분하여살펴본관련성은본연구결과가선행연구와비슷하거나조금낮은경향을보였다. 그러나중성지방농도와상관없이전체대상자에서 nonhdl 콜레스테롤과직접측정된 LDL 콜레스테롤과의관계는본연구에서 nonhdlchol= LDLdirect (p<0.0001, r 2 =0.80) 으

5 58 Se-Young Kwon and Young-Ak Na. Validity for Use of Non HDL Cholesterol 로나타났으나 ( 결과미제시 ), 선행연구에서는 nonhdlchol= LDLdirect (p<0.0001, r 2 =0.47) 로나타나본연구의설명력이훨씬더높았다. 계산된총 nonhdl 콜레스테롤농도와 LDL 콜레스테롤농도간의관계는전체적으로상관성이높았으나, 그중에서도 Friedewald 공식에의해계산된 LDL 콜레스테롤보다직접측정된 LDL 콜레스테롤농도와의관계가조금더상관성이높음을알수있고, 중성지방농도 400 mg/dl 미만군이 400 mg/dl 이상군보다더높은상관성이있었다. 현재이용되는모든 LDL 콜레스테롤직접측정법과기준측정절차 (reference measurement procedures, RMP) 간의일치도및오차분석을실시한 van Deventer 등 (2011) 의연구에서도중성지방이 2.26 mmol/l (200 mg/dl) 미만인검체에서 dldl-c 방법과의비교에서나타난 rldl-c 의 R 2 은 , cldl-c 방법과의비교에서나타난 rldl-c의 R 2 은 로낮은오차와함께높은상관성을보였다. 또한이범위내에서는직접측정된 LDL 콜레스테롤농도가계산된 LDL 콜레스테롤농도보다더좋은결과가나타났다고하였다. 한편계산된 nonhdl 콜레스테롤농도는중성지방이 2.26 mmol/l (200 mg/dl) 미만인검체에서더강한상관관계 (R 2 >0.97) 를보였으며, 총 8개사의측정방법중 1개제품 (W 사 ) 을제외한모든방법에서계산된 nonhdl 콜레스테롤이직접측정된 LDL 콜레스테롤또는계산된 LDL 콜레스테롤방법보다오분류비율이더적었고, 이는중성지방이 2.26 mmol/l (200 mg/dl) 이상 4.52 mmol/l (400 mg/dl) 미만인환자군에서도더좋은일치도를보였다고하였다. 더불어중성지방농도와상관없이이상지혈증환자들을 NCEP 위험도분류로나누는경우에도 nonhdl 콜레스테롤이오분류율이더낮아 LDL 콜레스테롤을직접측정하거나계산하는경우보다더비용효과적이라고하였다. 본연구에서이상지혈증판단에더적합한인자를분별하기위해고콜레스테롤혈증, 고중성지방혈증을포함하는이상지혈증에대해 ROC curve 를이용하여분석하고, AUC 를비교한결과 nonhdl 콜레스테롤의경우 0.771로가장높게나타나계산된 LDL 콜레스테롤또는직접측정된 LDL 콜레스테롤보다 nonhdl 콜레스테롤이더좋은분별인자임을알수있었으며, 계산된 LDL 콜레스테롤이제일낮게나타났다. 심근경색환자군과정상인을대상으로한 Sigdel 등 (2012) 의비교연구에서는 ROC 분석결과 AUC가 nonhdl 콜레스테롤의경우 0.734, LDL 콜레스테롤의경우 로나타나 non-hdl 콜레스테롤농도가 LDL 콜레스테롤농도보다심근경색을예측하는데더좋은결정적인자라고하였다. Framingham heart study 를비롯한몇몇연구에서 nonhdl 콜레스테롤이 LDL 콜레스테롤보다더우월함이증명되었고 (Frost와 Havel, 1998; Liu, 2006; Miller, 2008), 직접측정된 LDL 콜레스테롤이계산된 LDL 콜레스테롤또는 nonhdl 콜레스테롤보다더유의하게낫다고볼수없으며중성지방정상농도또는고농도군모두에서 nonhdl 콜레스테롤이심혈관질환위험분류에더좋은인자임을제시하였다 (van Deventer 등, 2010; Boekholdt 등, 2012). 본연구에서는 non-hdl 콜레스테롤농도와 LDL 콜레스테롤직접측정치및계산치의관련성정도를살펴봄으로써계산된 non-hdl 콜레스테롤농도를 LDL 콜레스테롤농도에대신하여적용할수있을지여부를살펴보았다. 집단검진이나선별검사시 LDL-cholesterol 계산치로진단을하게되면 LDL-cholesterol 이과소추정될가능성이있으므로, 공복채혈이필요없는 non-hdl 콜레스테롤측정이 LDL-cholesterol 을대체할수있는여러결과들을검토하여추후임상에적용하면측정시발생할수있는오류를최소화하고비용효과면에서도효율적일것이다. 그러나, 이연구에는몇가지제한점이있다. 이상지혈증과관련된인자간의비교와분별이필요하였기에연구대상자에이상지혈증환자데이터를포함하고있어다른인구집단에적용하기에는추가연구가더필요하다. 특히본연구에서 Friedwald 공식에의해계산된 LDL 콜레스테롤과의비교를위해동일하게중성지방농도 400 mg/dl의기준을적용하여두그룹으로나누었는데, TG 400 mg/dl인그룹의대상자수가적었다. 국민건강영양조사의특성상나타날수있는분포이며, 따라서집단검진이나선별검사에적용하고자했던본연구의목적에는부합하나, 추후중성지방농도의간격을좀더세부적으로나누어검토하면임상에서이상지혈증환자에적용시좀더객관적인자료를제공할수있을것이다. 참고문헌 Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel JC, et al. Association of LDL cholesterol, non-hdl cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012, 307: Dinovo EC, Howard T, Dinovo E. Calculated nonhdl cholesterol - an alternative to LDL? Clin Chem. 2010, 56(6):Supplement A182. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972, 18: Frost PH, Havel RJ. Rationale for use of non high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol. 1998, 81(4) Supplement 1:26B 31B. Hoenig MR. Implication of the obesity epidemic for lipid-lowering therapy: non HDL Cholesterol should replace LDL cholesterol as

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대한진단검사의학회지 : 제 23 권제 2 호 2003 Korean J Lab Med 2003; 23: 임상화학 균질법에의한저밀도지단백콜레스테롤의측정및 Friedewald 계산법과의비교 허미나 김창수 박민정 곽인숙 1 이규만 한림대학교의과대학진단검사의학교실,

대한진단검사의학회지 : 제 23 권제 2 호 2003 Korean J Lab Med 2003; 23: 104-8 임상화학 균질법에의한저밀도지단백콜레스테롤의측정및 Friedewald 계산법과의비교 허미나 김창수 박민정 곽인숙 1 이규만 한림대학교의과대학진단검사의학교실, 마취통증의학교실 1 Analysis of Low-Density Lipoprotein Cholesterol