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1 대한내분비학회지 : 제 21 권제 6 호 2006 원저 무증상갑상선기능저하증환자와정상대조군사이의총경동맥내중막두께비교 포천중문의과대학내과학교실 박경선 류정임 김수경 김인재 임상욱 박석원 김유리 차동훈 조용욱 최영길 이상종 Comparison of Common Carotid Artery Intima-Media Thickness between Subclinical Hypothyroidism and Euthyroidism Kyung-Sun Park, Jung-Im Rue, Soo-Kyung Kim, In-Jae Kim, Sang-Wook Lim, Seok-Won Park, Yu-Lee Kim, Dong-Hoon Cha, Yong-Wook Cho, Young-Kil Choi, Sang-Jong Lee Department of Internal Medicine, College of Medicine, Pochon CHA University ABSTRACT Background: Common carotid artery intima-media thickness (IMT), which is increased in patients with overt hypothyroidism, is an independent risk factor of the atherosclerosis-related disease. This study was performed to compare serum lipid level and common carotid artery IMT among patients with overt hypothyroidism, subclinical hypothyroidism and euthyroidism. Methods: Patients with newly-diagnosed subclinical (n=32) and overt (n=32) hypothyroidism were selected for this study. All of the patients and an age- and sex-matched euthyroidism cohort were checked for clinical characteristics and serum lipid levels. Common carotid artery IMT was also measured using high resolution B-mode ultrasonography. Results: Statistically significant differences were observed between the total cholesterol levels of patients with subclinical hypothyroidism and those with euthyroidism. When common carotid artery IMT measured by ultrasonography, subclinical (0.67 ± 0.11 mm) and overt (0.71 ± 0.12 mm)) hypothyroidism showed significantly increased mean IMT compared to that of euthyroidism (0.58 ± 0.07 mm, P < 0.05, respectively), but no differences were found between subclinical and overt hypothyroidism. Conclusion: We concluded that subclinical hypothyroidism is related to increased common carotid artery IMT as well as dyslipidemia. Therefore, we recommend that treatment principle of subclinical hypothyroidism be established through large-scale, prospective studies performed to determine the effect of thyroid hormone replacement on the reduction of common carotid artery IMT. (J Kor Endocrinol Soc 21:490~496, 2006) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: Atherosclerosis, Intima-media thickness, Subclinical hypothyroidism 서론 1) 무증상또는불현성갑상선기능저하증이란특별한임상접수일자 : 2006년 9월 4일통과일자 : 2006년 10월 25일책임저자 : 김수경, 포천중문의과대학내과학교실 증상은없이총 T 3, 총 T 4 및유리 T 4 등의갑상선호르몬수치는정상이면서갑상선자극호르몬 (thyroid stimulating hormone, TSH) 만상승되어있는경우로, 전체빈도는 2~8% ( 남자 2.8%, 여자 7.5%), 특히 60세이상의여자에서는 16% 까지발견될수있는비교적흔한질환이다 [1]. 갑상선호르몬은저밀도지단백 (low-density lipoprotein, LDL) 콜레스테롤수용체의활성을증가시켜혈청콜레스테롤의제

2 - 박경선외 10인 : 무증상갑상선기능저하증환자와정상대조군사이의총경동맥내중막두께비교 - 거에관여하므로 [2], 갑상선기능저하증에서는 LDL 콜레스테롤의증가및고밀도지단백 (high-density lipoprotein, HDL) 콜레스테롤의감소로인해관상동맥질환의발생이증가한다는것은잘알려져있다 [3]. 반면무증상갑상선기능저하증의경우혈중지질에미치는영향은다양하게보고되고있다 [4~6]. 총경동맥내중막두께 (intima-media thickness, IMT) 는죽상동맥경화증의표지자로뇌졸중및관상동맥질환등의발생을예측할수있는독립적인위험인자이며 [7], 갑상선기능저하증에서그두께가증가될뿐아니라, 갑상선호르몬의투여로감소됨이보고된바있다 [8]. 본연구는무증상갑상선기능저하증에서이상지질혈증과총경동맥내중막두께를분석함으로써향후무증상갑상선기능저하증환자에서심혈관질환위험도에따른임상진료지침을마련하는데도움이되고자수행되었다. 대상및방법 1. 연구대상 2004년 5월부터 2005년 5월까지분당차병원내분비내과내원하여최초로진단받은갑상선기능저하증및무증상갑상선기능저하증환자와정상대조군을대상으로하였다. 갑상선기능저하증은 TSH > 5.5 μiu/ml ( 정상 : 0.35~5.5) 이면서유리 T 4 < 0.89 ng/dl (0.89~1.76) 인경우로정의하였고, 무증상갑상선기능저하증은 TSH > 5.5 μiu/ml이면서유리 T 4 가정상범위를보이는경우로정의하였다. 갑상선기능검사는약한달간격으로 2회반복하여, 2회모두동일한갑상선기능이상을보이는경우만대상군으로하였다. 항고혈압제나지질강하제등혈중지질대사에영향을줄수있는약물을복용하고있는경우, 갑상선질환이외의다른내분비질환을동반한경우, 중증의간및신질환이있는경우, 최근 3개월내에 3 kg 이상의심한체중변화가있었던경우는연구대상에서제외하였다. 정상대조군은 TSH와유리 T 4 가정상이고항갑상선과산화효소항체 (anti-thyroperoxidase antibody) 가음성이면서당뇨병, 고혈압및기타급, 만성질환이없으며환자군과연령과성비가비슷한 29명의건강한성인으로본연구에자발적으로참여하였다. 본연구는분당차병원의윤리위원회로부터승인을받았고, 모든연구대상자들로부터사전동의서를받아시행하였다. 2. 방법모든환자및정상대조군에서신장, 체중, 허리 / 엉덩이둘레및수축기 / 이완기혈압을측정하였고, 12시간이상금식후공복혈당, 총콜레스테롤, 트리글리세리드, HDL 콜레스테롤을검사하였다. 총경동맥내중막두께의측정은고해상도 B-mode 초음파기 (Sequoia C256, Acuson, Japan) 의 7.5 MHz 선상탐촉자 (axial resolution: 0.2 mm) 를이용하여 Pignoli 등 [9] 의방법으로시행하였으며, 검사자간의오차를없애기위하여대상자의속성을모르는동일한검사자가측정하였다. 좌우측경동맥의종단면을따라총경동맥이내경동맥과외경동맥으로분리되는분지점의근위부에위치하는총경동맥의원벽에서내중막두께가최고인지점을정하여이지점에서근위 10 mm, 원위 10 mm 위치사이에포함되는 99개부위의좌우평균치를평균내중막두께로정의하였다. 내중막두께는원벽의내막에해당되는첫번째반향적선과중막과외막의경계를나타내는두번째반향적선사이의거리로정의하였다 [10,11]. 얻어진영상은이미지파일로저장한후컴퓨터프로그램 (IntimaScope, MEDIA CROSS Co., LTD, Japan) 을이용하여측정하였다. 3. 통계분석자료의통계분석은 SPSS 소프트웨어 (version 11.0: SPSS Inc, Chicago, USA) 를이용하였고, 각변수의분포를평균 ± 표준편차로제시하였다. 대상군사이의임상양상, 갑상선기능검사결과, 혈중지질수치및총경동맥내중막두께의차이는 one-way ANOVA test를이용하였고사후검정은 Scheffe's test를이용하였다. 평균내중막두께에영향을미치는인자를찾고자단변량분석 (univariate analysis) 및다중회귀분석 (multiple regression analysis) 을시행하였다. 검정결과 P value가 0.05 미만인경우에통계적으로유의하다고판정하였다. 결과 1. 대상군의임상양상대상자총 93명중무증상갑상선기능저하증환자는 32 명, 갑상선기능저하증환자는 32명, 정상대조군은 29명이었다. 평균연령, 성별, 체질량지수, 허리둘레, 수축기 / 이완기혈압및공복혈당등은세군간에의미있는차이가없었다 (Table 1). 혈중지질수치측정에서총콜레스테롤은무증상갑상선기능저하증에서 ± 33.3 mg/dl로정상대조군에비해서는높았으며 (162.1 ± 29.0 mg/dl, P < 0.05), 갑상선기능저하증에비해서는낮았다 (231.6 ± 48.5 mg/dl, P < 0.05). 트리글리세리드의경우, 갑상선기능저하증을가진환자에서 ± 85.2 mg/dl로정상대조군이나무증상갑상선기능저하증군보다높았다 (92.0 ± 32.6 mg/dl, ± 41.8 mg/dl; P < 0.05, respectively). 그러나 HDL 콜레스테롤은세군사이에의미있는차이를발견할수없었다 (Table 1). 갑상선기능검사에서무증상갑상선기능저하증군은정상대조군에비해유리 T 4 의감소및 TSH의증가를보였다 (P < 0.05, respectively). 갑상선기능저하증군에서는총 T 3, 유

3 대한내분비학회지 : 제 21 권제 6 호 2006 Table 1. Baseline characteristics of the study population Euthyroidism (n = 29) Subclinical hypothyroidism (n = 32) Hypothyroidism (n = 32) P for trend Age (yr) 38.1 ± ± ± 10.7 NS Sex (female, %) NS BMI (kg/cm 2 ) 23.3 ± ± ± 3.1 NS Waist (cm) 80.9 ± ± ± 11.8 NS SBP (mmhg) ± ± ± 14.5 NS DBP (mmhg) 76.9 ± ± ± 12.1 NS Glucose (mg/dl) 94.7 ± ± ± 16.4 NS Total cholesterol (mg/dl) ± ± 33.3 * ± 48.5 * < LDL-C (mg/dl) ± ± ± 35.4 * < 0.05 HDL-C (mg/dl) 56.7 ± ± ± 15.5 NS Triglyceride (mg/dl) 92.0 ± ± ± 85.2 * < 0.05 T 3 (ng/ml) 1.45 ± ± ± 0.35 * < 0.05 free T 4 (mg/dl) 1.24 ± ± 0.18 * 0.63 ± 0.31 * < TSH (μiu/ml) 1.60 ± ± 5.90 * ± * < Positive Anti-TPO Ab (%) NS Values are expressed as mean ± SD. Anti-TPO Ab, anti-thyroperoxidase antibody; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TSH, thyroid stimulating hormone. * P < 0.05 vs. euthyroidism (one-way ANOVA followed by Scheffe's post hoc test). P < 0.05 vs. subclinical hypothyroidism (one-way ANOVA followed by Scheffe's post hoc test). Fig. 1. Common carotid artery intima-media thickness of the study population. * P < 0.05 (one-way ANOVA followed by Scheffe's post hoc test). IMTmean, mean intima-media thickness; IMTmax, maximal intima-media thickness. 리 T 4, TSH 모두정상군과유의한차이를보였으며, 무증상갑상선기능저하증군과비교한경우에는유리 T 4 와 TSH에서뚜렷한차이를보였다. 항갑상선과산화효소항체의양성률은무증상갑상선기능저하증군에서 81.3%, 갑상선기능저하증군에서 87.8% 로나타났다 (Table 1). 2. 총경동맥내중막두께초음파상최대내중막두께는갑상선기능저하증군에서 0.96 ± 0.27 mm로정상대조군의 0.75 ± 0.18 mm보다증가되어있었으나 (P < 0.05), 무증상갑상선기능저하증군에서는 0.90 ± 0.19 mm로다른두군과유의한차이는없었다. 평균내중막두께의경우무증상갑상선기능저하증군에서 0.67 ± 0.11 mm, 갑상선기능저하증군에서 0.71 ± 0.12 mm로정상대조군의 0.58 ± 0.07 mm에비해의미있게증가되었다 (P < 0.05, respectively)(fig. 1). 평균내중막두께에영향을주는인자를평가하기위해단

4 - 박경선외 10인 : 무증상갑상선기능저하증환자와정상대조군사이의총경동맥내중막두께비교 - Table 2. Multiple regression analysis on factors affecting mean intima-media thickness of common carotid artery Univariate analysis Multivariate analysis β P value β P value Age < < Sex NS BMI NS SBP DBP Glucose NS Total cholesterol NS HDL-cholesterol NS Triglyceride < < free T NS TSH NS Positive Anti-TPO Ab 0.04 NS Anti-TPO Ab, anti-thyroperoxidase antibody; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; TSH, thyroid stimulating hormone. R 2 = in multivariate analysis. 변량분석및다중회귀분석을시행하였다. 단변량분석에서는연령, 공복혈당, 총콜레스테롤및트리글리세리드가의미있는인자였고갑상선호르몬농도는의미가없었다. 다변량분석결과에서는연령과트리글리세리드만이평균내중막두께에독립적인인자였다 (Table 2). 고찰갑상선기능저하증에서는다양한혈청지질이상이동반된다. 그중총콜레스테롤의증가는주로 LDL 콜레스테롤의증가에의하며, 이는 LDL 수용체활성의저하에의한 LDL 분해감소가그주요한기전인것으로생각되고있다. 트리글리세리드역시증가됨이알려져있으며 [4,12,13], HDL 콜레스테롤의경우증가 [14~16], 감소 [17], 또는정상 [18] 으로다양하게보고되고있다. 이에반해무증상갑상선기능저하증에서이상지질혈증동반여부에대하여는논란이있는데, 이는무증상갑상선기능저하증의진단기준이각각의연구마다다소차이가있고, 또한연구대상으로선정된군의특성이다양했기때문으로생각된다. 즉나이, 성별, 비갑상선질환의동반유무, 한약이나기타약물등의복용유무나특히여성환자에서의폐경유무에대한구분이분명치않았기때문이다. 본연구에서는무증상갑상선기능저하증환자군과정상대조군사이에서상기한바와같은임상적특징들이통제되었을때혈중총콜레스테롤에의미있는차이가있음을확인하였고, 이는이전의 Shong 등 [19] 및 Kim 등 [20] 의연구결과와는상반된다. 총경동맥내중막두께는전신적죽상동맥경화증의표지자 이며 [7], 이의증가는혈청 C-반응성단백 (C-reactive protein, CRP) 등다른죽상동맥경화증표지자에독립적인위험인자로인정받고있다 [21]. 갑상선기능저하증에서총경동맥내중막두께가증가한다는보고가있었으며 [8], 이는고지혈증, 과다응고성, 동맥경직성증가, 비만등의여러기전에의한것으로생각된다. Monzani 등 [22] 은무증상갑상선기능저하증환자에서이상지질혈증을동반하였을때총경동맥내중막두께가증가함을보고한바있다. 본연구에서도무증상갑상선기능저하증환자에서정상군에비해콜레스테롤농도가증가되어있었으며, 다중회귀분석에서도평균내중막두께와트리글리세리드농도가관련이있음을보여주고있어, 갑상선기능저하증에서의내중막두께증가에이상지질혈증이중요한역할을할것으로추측할수있다. 최근까지본연구에참여한일부환자 (6명) 에서 12개월간추적관찰한결과갑상선호르몬투여후총콜레스테롤및트리글리세리드수치가유의하게감소하였고, 이와더불어평균및최대내중막두께가감소된것을확인할수있어갑상선기능저하증에서지질대사이상이동맥경화증발생의중요한기전이라생각할수있다 (data not shown). 갑상선기능저하증과더불어무증상갑상선기능저하증이심혈관질환및이와관련된사망률증가의위험인자임을밝히는연구결과가보고되고있으나 [23,24], 아직까지도무증상갑상선기능저하증환자에서적극적인갑상선호르몬투여를시행할것인지에대하여는논란이있다. 그이유는죽상동맥경화증관련질환의발병에이상지질혈증외에여러위험인자들이관련되어있을뿐아니라, 이전의연구들에서무증상갑상선기능저하증환자의이상지질혈증동반여부가

5 대한내분비학회지 : 제 21 권제 6 호 2006 분명치않았기때문이다. 또한갑상선호르몬투여로인해무증상갑상선기능항진증이생기는경우에는골밀도의감소및그에따를골절위험도가증가할수있고 [25], 심방세동이발생할위험성이증가된다는보고가있어 [26], 과치료로인한부작용의가능성이있다는것도하나의이유가될수있다. 그러나 Shong 등 [19] 과 Kim 등 [27] 의연구에따르면무증상갑상선기능저하증환자에서갑상선호르몬투여후총콜레스테롤과 LDL 콜레스테롤이유의하게감소하였으며, Monzani 등 [22] 은무증상갑상선기능저하증환자를대상으로갑상선호르몬투여후추적관찰한총경동맥내중막두께가의미있게감소함을보고한바있어, 갑상선기능검사를주기적으로시행하면서 TSH가억제되지않는용량으로갑상선호르몬을투여한다면무증상갑상선기능저하증환자에서죽상동맥경화증으로인한심혈관질환의발생을예방하는데도움이될것으로생각된다. 그러나본연구는몇가지의제한점을가지고있다. 첫째, 본연구는총 94명의갑상선기능저하증, 무증상갑상선기능저하증및정상대조군을대상으로한소규모의단면연구로, 갑상선기능저하증과동맥경화증의연관성과관련기전을연구하기위해좀더많은환자를참여시킨대규모연구가필요하다. 또한무증상갑상선기능저하증환자에서갑상선호르몬투여후장기추적관찰을통하여총경동맥내중막두께의변화및이에따른죽상동맥경화증관련질환의발생률과사망률등을관찰하는전향적연구가필요하다. 둘째, 본연구에서는지질수치만을관찰하였으나, 아포지단백 B, CRP 등과같은죽상동맥경화증및심혈관질환의위험인자들과갑상선기능과의연관관계를연구한다면, 갑상선기능저하증과동맥경화증관련질환과의연관성을자세히알아보는데좀더도움이될것으로생각된다. 결론적으로본연구를통하여무증상갑상선기능저하증에서혈중지질수치가정상대조군과비교하였을때의미있는차이를보이며, 총경동맥내중막두께역시유의하게증가함이확인되었다. 향후무증상갑상선기능저하증환자를대상으로대규모전향적연구를시행하여무증상갑상선기능저하증에서심혈관질환의위험도를감소시키는치료방침을확립하는임상적근거와자료가필요할것으로생각된다. 요약연구배경 : 현성갑상선기능저하증환자에서이상지질혈증이많이동반되는반면무증상갑상선기능저하증이혈중지질대사에미치는영향은다양하게보고되고있다. 총경동맥내중막두께는죽상동맥경화증관련질환에서이를예측하는독립적인위험인자로갑상선기능저하증에서증가된다. 본연구는한국인에서무증상갑상선기능저하증환자와정상대조군사이에혈중지질수치및총경동맥내중막두께 를비교하고자수행되었다. 대상및방법 : 2004년 5월부터 2005년 5월까지분당차병원내분비내과내원당시시행한갑상선기능검사상최초로진단된무증상갑상선기능저하증및현성갑상선기능저하증환자와정상대조군을대상으로임상적특징및혈중지질수치를확인하고, 고해상도초음파기로총경동맥내중막두께를측정하였다. 결과 : 갑상선기능저하증및무증상갑상선기능저하증환자군과정상대조군사이에통계적으로의미있는임상적특징의차이는보이지않았다. 혈중지질수치는무증상갑상선기능저하증환자군의총콜레스테롤이정상대조군에비해유의하게증가함이확인되었다. 총경동맥의평균내중막두께는갑상선기능저하증 (0.71 ± 0.12 mm) 및무증상갑상선기능저하증 (0.67 ± 0.11 mm) 모두에서정상대조군에비해유의한증가소견을보였다 (0.58 ± 0.07 mm, P < 0.05, respectively). 결론 : 본연구를통하여무증상갑상선기능저하증에서혈중지질수치및총경동맥내중막두께가정상대조군에비해의미있게증가함이확인되었다. 향후더많은무증상갑상선기능저하증환자를대상으로한전향적연구를통해무증상갑상선기능저하증의치료방침을확립하는것이필요하다. 참고문헌 1. Lee KW: Subclinical hypothyroidism. J Korean Soc Endocrinol 12:8-10, Thompson GR, Soutar AK, Spengel FA: Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Proc Natl Acad Sci U S A 78: , Vanhaelst L, Neve P, Chailly P, Basteine PA: Coronary artery disease in hypothyroidism. Lancet 2: , Kutty KM, Bryant DG, Farid NR: Serum lipids in hypothyroidism. J Clin Endocrinol Metab 46:55-60, Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Grimley EJ, Young E, Bird T, Smith PA: Lipid profiles and cardiovascular disease in the Wickham area with particular reference to thyroid failure. Clin Endocrinol (Oxf) 7: , Fowler PB, Swale J, Andrews H: Hypercholesterolemia in borderline hypothyroidism: Stage of premyxedema. Lancet 2: ,

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