Review Article J Korean Geriatr Soc 2014;18(3):111-121 http://dx.doi.org/10.4235/jkgs.2014.18.3.111 노인에서불현성 ( 무증상 ) 갑상선기능이상 가천의과학대학교길병원가정의학교실 고기동 Subclinical Thyroid Dysfunction in the Elderly Ki Dong Ko, MD Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Korea Subclinical thyroid dysfunction, including both subclinical hyperthyroidism and subclinical hypothyroidism is biochemically defined as an abnormal thyroid-stimulating hormone (TSH) level and thyroid hormone level within its reference range. The prevalence of this condition varies according to the reference range for TSH and geographic or demographic factors, but is common in the elderly and in women. Subclinical thyroid dysfunction has various causes. Thus, careful clinical assessment is needed. Subclinical thyroid dysfunction can be likely to progress to overt thyroid disease and be associated with various health outcomes. However, to date, supporting data are lacking and levels of evidence for the associations are different. Although the management of subclinical thyroid dysfunction is controversial, recommendations are based on the degree to which TSH levels have deviated from normal, age, symptoms, and underlying comorbidities. Further studies are needed to inform how to best care for the elderly with subclinical thyroid dysfunction. Key Words: Subclinical hypothyroidism, Subclinical hyperthyroidism, Elderly 서 외래진료과정이나건강검진결과에서불현성또는무증상갑상선기능이상 (subclinical thyroid dysfunction) 을자주접하게된다. 불현성또는무증상갑상선기능이상이란갑상선기능검사 (thyroid function test, TFT) 에서갑상선자극호르몬 (thyroid-stimulating hormone, TSH) 은증가 ( 불현성또는무 론 Received: July 29, 2014 Revised: August 24, 2014 Accepted: August 27, 2014 Address for correspondence: Ki Dong Ko, MD Department of Family Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774 Beon-gil, Namdong-gu, Incheon 405-760, Korea Tel: +82-32-460-3354, Fax: +82-32-460-3354 E-mail: highmove77@naver.com 증상갑상선기능저하증 ) 또는감소 ( 불현성또는무증상갑상선기능항진증 ) 되어있으나, 갑상선호르몬 (free T 4, T 3 ) 은정상인경우를말한다 1,2). 비록갑상선호르몬은정상이지만진단명을갑상선기능이상이라고한것은합당하다. 대부분의전문가들은증가또는감소되어있는 TSH가실제적으로경한수준의갑상선호르몬부족또는과잉의표지라고판단한다 3). 이에비해불현성또는무증상이라는표현은엄밀히따져잘못된지칭 (misnomer) 이다 4). 왜냐하면불현성또는무증상갑상선기능이상은갑상선기능검사결과에의한진단 (laboratory diagnosis) 이고, 증상은있을수도없을수도있기때문이다. 특히노인인구집단에서불현성갑상선기능이상이많다 1). 이번종설에서는노인불현성갑상선기능이상의역학, 원인및연관인자, 자연경과, 임상적의의, 치료방침에대해기술하고자한다. Copyright 2014 Korean Geriatric Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).
Ki Dong Ko: Subclinical Thyroid Dysfunction in the Elderly 노인에서의불현성갑상선기능이상 1. 역학 1) 불현성갑상선기능저하증불현성갑상선기능저하증의유병률은조사지역, 조사대상자연령, TSH 의정상상한등에따라차이가있다. 다른나라들의조사에따르면, 불현성갑상선기능저하증의유병률은 3-12% 정도였다 5). 최근에두개의코호트를대상으로우리나라불현성갑상선기능저하증의유병률이조사되었다. 40세에서 70세까지의성인을대상으로한안성코호트에서 11.7%, 65세이상의노인을대상으로한 KLoSHA (Korean Longitudinal Study on Health and Aging) 에서 17.3% 로보고되었다 6). 불현성갑상선기능저하증은노인에서그리고남성에비해여성에서특징적으로많이나타난다 5). 미국의국민건강영양조사에서불현성갑상선기능저하증의유병률은연령이높아질수록증가하였고, 여성이남성에비해약 2배높았다 7). 우리나라의안성코호트에서도비슷한결과를보였다 6). TSH 의정상범위에대해서는논란의여지가있는데, 특히노인에서그러하다. 연령의증가에따라 TSH 가증가하는경향은 100세가까이장수하는연령층에서도지속적으로나타난다 8). 따라서정상 TSH 범위를연령에따라차등적으로적용해야한다는주장이나오고있다 9). 2) 불현성갑상선기능항진증불현성갑상선기능항진증은불현성갑상선기능저하증보다는드물어서, 다른나라들의조사에따르면성인에서유병률은 1-6% 로추정되고있다 5). 우리나라불현성갑상선기능항진증의유병률은 1% 내외로보고되고있다 5). 불현성갑상선기능항진증은불현성갑상선기능저하증과반대의상태이지만, 그위험군은유사하다. 즉, 불현성갑상선기능항진증도노인, 그리고여성에서많이발생한다 7). 2. 원인및연관인자노인에서불현성갑상선기능이상의원인들은 Table 1에제시하였다. 1) 불현성갑상선기능저하증 지속적인불현성갑상선기능저하증의원인중가장흔한것은하시모토갑상선염 (Hashimoto s thyroiditis) 으로불리는자가면역성만성림프구성갑상선염 (autoimmune chronic lymphocytic thyroiditis) 이다 10). 하시모토갑상선염은갑상선자가항체 (anti-thyroid autoantibody) 가대체로증가 ( 항 thyroid peroxidase [TPO] 항체양성, 90%; 항 thyroglobulin 항체양성, 60%) 되어있으며, 갑상선종 (goiter) 을동반하기도한다 11). 이외에현성갑상선기능저하증 (overt or clinical hypothyroidism) 이불충분하게치료되는경우, 갑상선기능항진증 Table 1. Common causes of subclinical hypothyroidism and subclinical hyperthyroidism Subclinical hypothyroidism Causes of persistent subclinical hypothyroidism Chronic autoimmune thyroiditis (Hashimoto s thyroiditis) Inadequate replacement therapy for overt hypothyroidism Over-treatment of hyperthyroidism Infiltrative disorders of the thyroid gland (e.g., amyloidosis, sarcoidosis) Drugs impairing thyroid function (e.g., amiodarone, radiocontrast agent, lithium, interferon) External radiotherapy of the head and neck Causes of transient or physiologic subclinical hyperthyroidism Diurnal variation with a nocturnal surge and highest values early in the morning Cold weather Recovery phase from nonthyroidal illness Evolution of various forms of thyroiditis Subclinical hyperthyroidism Causes of persistent subclinical hyperthyroidism Exogenous Over-replacement therapy TSH suppressive therapy Endogenous Toxic multinodular nodule Solitary autonomous nodule Graves disease Causes of transient subclinical hyperthyroidism Transient episodes of thyroiditis or mild Graves disease Amiodarone-induced thyroiditis Delayed recovery of the pituitary after treatment for overt hyperthyroidism TSH, thyroid-stimulating hormone. 112 J Korean Geriatr Soc 18(3) September 2014
고기동 : 노인에서불현성갑상선기능이상 의치료경과, 갑상선의침윤성병변 ( 아밀로이드증, 사르코이드증등 ), 갑상선기능을떨어뜨리는약물 (amiodarone, radiographic contrast agent, lithium, interferon) 사용, 두경부에방사선치료등에서지속적인불현성갑상선기능저하증을나타낼수있다 10). 일시적또는생리적불현성갑상선기능저하증의원인으로자정이후부터이른새벽에걸쳐 TSH가상승하는일중변동 (diurnal variation), 추운계절, 비갑상선질환증후군 (nonthyroidal illness syndrome) 의회복기, 갑상선염의일시적경과등이있다 10,12). 또한불현성갑상선기능저하증은아니지만비만, 검사실분석문제, 노인에서연령을고려하지못한 TSH의정상상한등으로인해불현성갑상선기능저하증의검사소견을보일수있다. 미국의국민건강영양조사와영국의 Whickham survey 의결과는항 TPO 항체양성과불현성갑상선기능저하증은연관성이있음을보여주었다 7,13). 우리나라안성코호트와 KLoSHA 에서도항 TPO 항체양성률이불현성갑상선기능저하증환자군에서정상군보다높았다 6). 요오드섭취가또다른연관인자이다. 기존의여러유병률조사들의결과를통해, 요오도섭취가적은지역보다요오드섭취가많은지역에서불현성갑상선기능저하증의유병률이높은것으로알려져있다 5). 요오드섭취가많은아이슬란드와요오드섭취가적은덴마크지역의노인들을비교한연구 14) 와중국내 3개지역을비교한연구 15), 일본내 5개지역을비교한연구 16) 에서도요오드섭취과다와불현성갑상선기능저하증과의연관성을확인할수있었다. 2) 불현성갑상선기능항진증지속적인불현성갑상선기능항진증의원인은두개의범주 ( 외부요인, 내부요인 ) 로나눌수있다. 외부요인이더흔한데, 갑상선기능저하증의치료로서갑상선호르몬의과도한보충또는갑상선절제수술후에 TSH 억제요법이이에해당한다 10). 내부요인은현성갑상선기능항진증 (overt or clinical hyperthyroidism) 의원인과거의같다 10). 노인은주로중독성다결절성갑상선종 (toxic multinodular goiter) 과단일자율기능성결절 (solitary autonomous nodule) 의일부에서, 젊은사람에서는그레이브스병 (Graves disease) 의일부에서불현성갑상선기능항진증이있을수있다 17). 55세이상, TSH 0.40 μiu/ml 미만인사람들을대상으로한연구에서중독성다결절성갑상선종환자 의 57%, 그레이브스병환자의 10% 미만이불현성갑상선기능항진증이었다 18). 불현성갑상선기능저하증과마찬가지로불현성갑상선기능항진증도일시적인경우가많다 10). 특히노인에서일시적으로 TSH 가감소되었다가정상으로회복되는경우가많다 19). 이것은일시적인갑상선염, 또는그레이브스병때문으로생각된다. 아미오다론에의한갑상선염 (amiodarone-induced thyroiditis), 현성갑상선기능항진증의치료경과중에갑상선호르몬은정상이되었지만, TSH 는아직억제된시기에도일시적으로불현성갑상선기능항진증을보일수있다 10). 불현성갑상선기능항진증이아니지만검사에서불현성갑상선기능항진증처럼보이는경우들이있다. 흡연을하는경우, 중증의비갑상선질환에서그러하다 10). 이외에도연령의증가에따라 TSH 가증가한다는앞선내용과달리어떤노인들에서는정상적인노화에의해시상하부-뇌하수체 -갑상선축이변화함에따라 TSH 가감소될수있다 10). 불현성갑상선기능저하증과는반대로, 요오드섭취부족이불현성갑상선기능항진증과연관되어있다 5). 앞서나온중국내 3개지역을비교한연구에서도요오드섭취가상대적으로부족한두개지역의불현성갑상선기능항진증의유병률은 3.7%, 3.9% 였고, 섭취가상대적으로충분한지역의유병률은 1.1% 였다 15). 요오드섭취가충분한지역중의하나인우리나라의연구들에서불현성갑상선기능항진증유병률이 1% 내외로낮게나온것은이로써설명될수있다. 3. 자연경과 1) 불현성갑상선기능저하증불현성갑상선기능저하증은현성갑상선기능저하증으로진행할수있다. 특히 TSH 가 10 μiu/ml 이상, 갑상선자가항체양성, 여성인경우등이현성갑상선기능저하증으로진행할위험요인이다 10). TSH 가높고갑상선자가항체양성인여성에서매년약 4%, TSH만높은여성에서 2-4%, 갑상선자가항체만양성인여성에서 1-3% 가현성갑상선기능저하증으로발전한다 10). 60세이상의노인들을대상으로 4년간관찰한연구 20) 에서불현성갑상선기능저하증환자의 1/3 이현성갑상선기능저하증으로진행하였다. 초기 TSH 수치가 20 μiu/ml 보다높은경우모두에서, TSH 농도와독립적으로항 TPO 항체가높 J Korean Geriatr Soc 18(3) September 2014 113
Ki Dong Ko: Subclinical Thyroid Dysfunction in the Elderly 은환자의 80% 가현성갑상선기능항진증으로진행하였다. 2000 년대이후의여러전향적연구들을통해서도높은 TSH 수치와갑상선자가항체는불현성갑상선기능저하증의진행과관련한유의한예후인자임이입증되었다 21-24). 반대로 TSH 10 μiu/ml 미만, 갑상선자가항체음성은불현성갑상선기능저하증의자연적인정상화와유의한관련을보인다 22,25). 불현성갑상선기능저하증환자들을경과관찰했을때, 경한 TSH 증가군 (5.5-10 μiu/ml) 에서 TSH 가 10 μiu/ml 이상으로진행되는경우는 5년간오직 2.9% 에불과했다 26). 오히려, 경한 TSH 증가 (5.0-9.9 μiu/ml) 가있는환자들을약 2.5 년동안관찰한연구에서 52.1% 의환자가자연적으로갑상선기능이정상화되었다 22). 그밖에현성갑상선기능저하증으로진행할가능성을높이는유의한예후인자로, 갑상선자가항체가있는사람중에서도요오드섭취가많은경우, 갑상선초음파검사에서자가면역성질환을시사하는미 Table 2. Associated clinical conditions of subclinical hypothyroidism and subclinical hyperthyroidism Subclinical hypothyroidism Systemic nonspecific hypothyroid symptoms * (tiredness, dryskin, puffy eyes, feeling cold, etc.) Neuropsychiatric symptoms * (cognitive dysfunction, anxiety, depression, etc.) Elevations in serum total and LDL cholesterol Adverse cardiovascular events (incidence and mortality of coronary heart disease) Cardiac dysfunction (heart failure) Others (hypertension, obestiy, insulin resistance) * Subclinical hyperthyroidism Systemic hyperthyroid symptoms (palpitations, tremor, heat intolerance, sweating, etc.) Neuropsychiatric symptoms * (anxiety, nervousness, cognitive dysfunction, etc.) Atrial fibrillation Adverse cardiovascular events, (premature beat, cardiac dysfunction, increased left cular mass, atherosclerosis, cardiovascular mortality) Reduced bone mineral density, Fractures * LDL cholesterol, low-density lipoprotein cholesterol. Levels of evidence ( * limited; fair; good) were determined by number, quality, and consistency of the individual studies. Noted particularly in patients with serum thyroid-stimulating hormone (TSH)>10 miu/l than in those with serum TSH between 4.5 and 10 miu/l. Noted particularly in young and middle-aged patients than in those older than 65 years. Noted particularly in postmenopausal women. 만성갑상선염소견이최근보고되었다 23,27,28). 2) 불현성갑상선기능항진증현성갑상선기능항진증으로진행할확률은연구마다다르지만확실한위험요인은알려져있다. TSH가 0.1 μiu/ ml 미만, 원인질환이그레이브스병이아니라, 중독성다결절성갑상선종또는단일자율기능성결절일때, 현성갑상선기능항진증으로진행할위험이높다 10,29-33). TSH가 0.1-0.4 μiu/ml 인불현성갑상선기능항진증노인들을대상으로한연구에서현성갑상선기능항진증으로진행한경우는연간약 1% 에불과하였고 29), TSH가 0.1 μiu/ml 미만인중 노년환자들을대상으로한다른연구에서는연간 13.5 % 에서진행하였다 30). 그리고불현성갑상선기능항진증환자를대상으로한후향적분석연구에서중독성다결절성갑상선종또는단일자율기능성결절에의한불현성갑상선기능항진증이그레이브스병에서보다현성갑상선기능항진증으로진행하는경우가상대적으로흔했다 33). 4. 임상적의의노인에서불현성갑상선기능이상의임상적의의는 Table 2에제시하였다. 1) 불현성갑상선기능저하증 (1) 증상약 25,000명을대상으로한대규모단면연구인 Colorado thyroid disease prevalence study 는불현성갑상선기능저하증환자군이정상군에비해피부건조, 기억력저하, 사고지연, 근육위약 / 경련, 피곤, 추위민감, 푸석푸석한눈, 변비증상이작지만통계적으로유의하게많음을보였다 34). 일부환자에서위와같은비특이적인증상, 콜레스테롤상승, 심혈관증상등으로불현성갑상선기능저하증을발견하지만, 대부분의불현성갑상선기능저하증은특별한증상및징후가없이갑상선기능검사에서 TSH 는증가, 갑상선호르몬은정상인결과만으로확인된다 35). 특히노인들은무증상인경우가더욱많다 36,37). 갑상선기능이정상인군과불현성갑상선기능저하증환자군의증상을설문지를통해비교하였을때, 154 명의정상군과 TSH 가 3.5-114 J Korean Geriatr Soc 18(3) September 2014
고기동 : 노인에서불현성갑상선기능이상 10 μiu/ml 인 89명의불현성갑상선기능저하증환자군에서피곤을제외하고는차이가없었다 38). 또한대규모지역사회단면적연구들은불현성갑상선기능저하증노인에서정신신경학적증상 ( 인지기능저하, 불안, 우울 ) 에대해서도정상군과차이를찾지못했다 39,40). 오히려, 70대노인을대상으로 2년간관찰한연구에서불현성갑상선기능저하증이있는노인이갑상선기능이정상인노인보다보행속도등의신체기능에있어서좋았다 41). (2) 이상지혈증현성갑상선기능저하증이총콜레스테롤 (total cholesterol) 과저밀도지단백콜레스테롤 (low-density lipoprotein cholesterol) 을높게한다는사실은잘알려져있다 42). Colorado thyroid disease prevalence study 에서는불현성갑상선기능저하증환자도정상인에비하여유의하게총콜레스테롤과지단백콜레스테롤이높다고보고하였다 34). 하지만이후의연구들 43-46) 에서는이러한연관성을일관되게보이지못했다. 그렇더라도 TSH가 10 μiu/ml 이상인불현성갑상선기능저하증은높은콜레스테롤수준과유의한연관성을가질가능성이높다 1,47). (3) 심혈관질환영국의 Whickham survey 48), EPIC-Norfolk study 46) 내용에따르면, 각각 2,700 여명, 11,000 여명의성인을 10년이상추적관찰했을때, 불현성갑상선기능저하증과허혈성심장질환발생및이로인한사망률간에는연관성이없었다. 그러나로테르담연구 (Rotterdam study) 의일환으로, 폐경후여성을대상으로한단면연구에서불현성갑상선기능저하증과심근경색, 그리고대동맥동맥경화와의관련성을보였다 49). 그리고 Whickham 코호트를 20년간연장하여관찰했을때, 불현성갑상선기능저하증과허혈성심장질환발생및이로인한사망률간에유의한연관성이나타났다 50). 이외의여러연구들은대상환자세부군 (subgroup) 의성별, 연령, TSH 수치등에따라결과에차이를보였다. 구체적인예를들자면, 남성 51) 또는 10 μiu/ml 보다높은 TSH 52) 를가지는세부군에서만유의한심혈관질환증가를보였다. 최근의여러메타분석은 65세이하의연령군에서불현성갑상선기능저하증과관상동맥질환및심혈관사망률과의강한연관성을나타내었다 53,54). 이와는대조적으로 85세노인들을대상으로한 4년간의코호트연구 에서는불현성갑상선기능저하증환자에서심혈관사망률의감소가나타났다 36). 이에대한기전으로초고령군에서는갑상선기능저하에의한대사율감소가심혈관계에좋은영향을미칠가능성을제시하였다. 한종설에서는이런연구결과들을종합하여, 불현성갑상선기능저하증이 70세미만에서는심혈관위험을높이고, 70세에서 80세사이에서는중립효과, 그리고 80세이상에서는보호효과를보인다고하였다 55). (4) 심부전노인에서불현성갑상선기능저하증과심부전의관련성에대한연구는많지않다. 이중대표적인연구로서 Rodondi 등 56) 의 Cardiovascular Health Study에서 TSH가 10 μiu/ml 이상인경우에심부전의발생이증가하였다. Rodondi 등 57) 의다른연구에서도 TSH가 7-9.9 μiu/ml일때, 심부전이발생할상대위험도는 2.6 (95% 신뢰구간, 1.19-5.60) 였고, TSH가 10 μiu/ml 이상일때, 상대위험도는 3.26 (95% 신뢰구간, 1.37-7.77) 이었다. (5) 고혈압, 비만, 인슐린저항성불현성갑상선기능저하증과고혈압 58,59), 비만 60,61), 인슐린저항성 62) 의연관성을보고하는연구들이있다. 그러나아직확립된결론은없으며, 추가적인연구가필요하다. 2) 불현성갑상선기능항진증 (1) 증상불현성갑상선기능항진증은많은경우에심계항진, 더위에대한참을성의감소, 몸의떨림, 발한등의증상을보인다 4). 이것은불현성갑상선기능저하증에서대부분특별한증상및징후가없는것과대조적이다. 하지만노인만을대상으로연구를한다면다른결과가나올가능성이있다. 왜냐하면현성갑상선기능항진증이있을때에도노인에서는증상및징후가없을때가많기때문이다. 신체증상뿐만아니라, 불안, 초조, 인지기능저하같은정신신경학적증상도불현성갑상선기능항진증에서발생할수있다 63,64). 인지기능과관련하여로테르담연구의일환으로이루어진전향적연구 65) 에서불현성갑상선기능항진증이알츠하이머치매의위험을거의 3배이상높이는것은주목할만하다. 이와대조적으로최근에발표된단면적환자-대조군연구 66) 에서갑상선절제술후에 TSH 억제 J Korean Geriatr Soc 18(3) September 2014 115
Ki Dong Ko: Subclinical Thyroid Dysfunction in the Elderly 요법으로서갑상선호르몬을 5년이상받은노인환자군과대조군의인지기능에는차이가없었다. (2) 골대사갑상선호르몬은골흡수에직접적으로작용하므로, 현성갑상선기능항진증은골밀도감소와골절위험을초래할수있다 67,68). 불현성갑상선기능항진증의경우에도골밀도감소가일어날수있는데 ( 특히피질골이많은뼈 [ 예를들어원위요골 ] 에서 ), 이에대한기전으로상대적으로증가된갑상선호르몬뿐만아니라, TSH 감소가제시되고있다 69). 불현성갑상선기능항진증에의한골밀도감소는불현성갑상선기능항진증의정도와기간, 골밀도감소와관련된다른위험요소 ( 성별, 폐경여부 ) 에영향을받는다 70). 남성, 폐경전여성에서불현성갑상선기능항진증과골밀도감소의연관성을발견한연구는적고, 대부분의연구는폐경후여성에서유의한연관성을보였다 10,70). 하지만불현성갑상선기능항진증이폐경후여성에서골절의위험을높이는지는확실하지않다. 65세이상여성을대상으로한, 두개의전향적연구 71,72) 는상반된결론을보이고있다. 686명의노인여성을 4년간관찰한연구에서, TSH가 0.1μIU/mL 미만인불현성갑상선기능항진증환자군이정상군보다척추골절은 4배, 골반골절은 3배발생하였다 71). 다른연구에서는노인여성 3,800여명을중앙값 13년동안관찰했는데, 불현성갑상선기능항진증환자군에서골반골절의위험은증가하지않았다 72). (3) 심방세동약 24,000 명의노인을대상으로한단면연구에서정상대조군에비해불현성갑상선기능항진증이있는경우에심방세동의위험이 5.2배 (13% vs. 2%) 로보고된바있다 73). 이연구에서현성갑상선기능항진증의심방세동비율은 14% 로불현성갑상선기능항진증과차이가없었다. 이외에노인들을대상으로한여러연구들에서불현성갑상선기능항진증과심방세동과의연관성이주장되었다 74-76). 특히이러한연관성은 TSH 가억제된정도 (TSH<0.1 μiu/ml vs. TSH, 0.1-0.4 μiu/ml) 와상관없었다. (4) 심혈관질환갑상선호르몬 (T 3) 은여러경로를통해직 간접적으로심장의심박조절, 수축및이완에영향을끼친다 77). 불현성갑 상선기능항진증이있으면평균심박수는증가하고, 심방성 / 심실성조기수축의빈도를높일수있다 78,79). 그러나불현성갑상선기능항진증이수축기 / 이완기심장기능, 좌심실질량 (left ventricular mass) 에미치는영향에대해서는일치되지않는연구결과를보이고있다 78-82). 이러한불일치는연구대상자의나이, TSH가감소된정도, 불현성갑상선기능저하증의원인및기간등의차이에기인할것으로생각된다. 불현성갑상선기능항진증이혈액응고및혈전형성에관여할수있다 83). 실제로현성갑상선기능항진증에서혈전형성과관련한증례보고들은이에대한추가적인연구의필요성을제기한다 84). 또한불현성갑상선기능항진증이경동맥내막 - 중막두께 (carotid intima-media thickness) 를증가시키고경동맥플라크 (carotid plaque) 빈도를높인다는연구들이있다 85,86). 이러한동맥경화의지표들은결국협심증이나뇌졸중같은심혈관질환의이환및사망의가능성을높일수있다는점에서, 특히노인이나기존의심혈관질환이있는불현성갑상선기능항진증환자들에서주의가필요하겠다. 불현성갑상선기능항진증환자의심혈관또는총사망률 (all-cause mortality) 에대해서어떤연구들 36,87,88) 은불현성갑상선기능항진증이사망률을높인다고보고하였고, 다른연구들 39,46,75) 에서는사망률에차이가없다고보고하였다. 메타분석의결과들도마찬가지로일치하지않았다. 세개의메타분석 53,89,90) 에서는불현성갑상선기능항진증환자에서심혈관또는총사망률의증가가없었지만, 기존에포함되지않은몇개의연구를포함하여시행한메타분석 91) 에서는총사망률의증가가보였다. 수학적시뮬레이션으로추정해보았을때, 사망의위험은특히노인남성에서높았다 91). 5. 치료방침 1) 불현성갑상선기능저하증 ( 하시모토갑상선염 ) 불현성갑상선기능저하증을치료를해야할지경과를지켜볼지에대해서는아직논란이있다. 일반적으로치료를고려할수있는적응증으로는, TSH 가 10 miu/l 이상이며증상이있는경우, TPO 에대한자가항체가양성인경우, 심혈관위험 ( 고혈압, 당뇨, 이상지혈증 ) 이있는경우, 그리고갑상선종이있는경우이다 10,92). 하지만이적응증은주로 65세미만에해 116 J Korean Geriatr Soc 18(3) September 2014
고기동 : 노인에서불현성갑상선기능이상 당되는이야기이고, 노인들에서는좀더보수적으로적용해야한다. 왜냐하면연령의증가에따라 TSH가정상적으로증가하는경향이있고 8,9), 노인에서는불현성갑상선기능저하증과허혈성심질환의관련성이약하고 36,55), 코크란리뷰에의하면 levothyroxine 치료가불현성갑상선기능저하증노인의삶의질, 심혈관건강, 생존율을향상시키지못하기때문이다 93). 그럼에도불구하고 Cardiovascular Health Study 대상자중에서갑상선호르몬보충을받고있는 ( 갑상선절제수술후에 TSH 억제요법제외 ) 노인의 41% 에서용량과잉이있었다 94). 우리나라에서도이런연구가필요할것으로생각된다. 유럽갑상선학회에서 2013년에내놓은진료지침에서는환자의나이, TSH 수치, 증상, 개인의건강위험인자등을고려한치료알고리즘을제시하였다. Levothyroxine 치료의목표는 TSH를정상범위내에서도아래쪽 (0.4-2.5 μiu/ml) 에두는것이다. 노인에서는목표를좀더높게설정할수있다. 65세미만, 그리고심장질환이없는불현성갑상선기능저하증환자의 levothyroxine 초기용량은보통하루에 50-100 μg 이다. 그리고두달후에갑상선기능검사를다시확인하여용량을조절하게된다. 65세이상또는심장질환이있는불현성갑상선기능저하증환자는하루 25-50 μg으로시작하여, 2-3 주마다 25 μg씩증량할수있다. 2) 불현성갑상선기능항진증 ( 내부요인에의한지속적인불현성갑상선기능항진증 ) 불현성갑상선기능항진증의치료방침은더욱확실하지않다. 저자는 2004 년에나온전문가패널에의한진료지침 1) 그리고미국갑상선학회와미국임상내분비학회에서 2011 년에발표한진료지침 95) 을종합하여판단하였다. 일반적으로치료를고려할수있는적응증으로는 TSH 가 0.1 miu/l 미만으로 65세이상이며증상이있는경우, 심장질환또는폐경후골다공증이있거나, 그것들에대한위험인자를가진경우이다. 갑상선스캔과갑상선자가항체검사를통하여그레이브스병인지기능결절성갑상선질환 (functioning nodular thyroid disease; toxic multinodular goiter & solitary autonomous nodule) 인지파악할수있다. 기능결절성갑상선질환은갑상선스캔에서보이는그레이브스병의균일하게증가된섭취 (homogeneously increased uptake) 대신열결절 ( 들 )(hot nodule[s]) 소견이보이고, 갑상선자가항체가없다. 그레이브 스병은일차적으로항갑상선제를시작해야하고, 기능결절성갑상선질환은항갑상선제만으로는증상완화만이가능하고완치를이룰수없으므로방사성요오드치료나수술을고려해야한다. 결론 불현성갑상선기능이상은노인에서흔하게발견되지만, 임상결정을하거나환자에게설명을하는데어려움을겪는질병중의하나이다. 불현성갑상선기능이상환자를볼때우선적으로그원인을판단하여야하며, 질병의자연경과와관련하여어떠한양상으로진행할것인지와불현성기능이상과연관된현재의건강상태를고려하여치료방침을정하는것이중요하다. 지금까지의진료지침은충분한연구가뒷받침되지않아모호한면이많다. 따라서임상의들은지금까지의근거와환자요인등을기반으로스스로판단할수밖에없다. 향후에더많은대규모전향적연구들이필요한실정이다. 요약 불현성갑상선기능이상은갑상선기능검사에서 TSH 는증가 ( 불현성갑상선기능저하증 ) 또는감소 ( 불현성갑상선기능항진증 ) 되어있으나, 갑상선호르몬은정상인경우를말한다. 불현성갑상선기능이상은노인, 그리고여성에서상대적으로흔한질환이다. 불현성갑상선기능저하증의가장흔한원인은하시모토갑상선염이다. TSH가 10 μiu/ml 이상, 갑상선자가항체양성, 여성, 갑상선자가항체가있는사람중에서도요오드섭취가많은경우, 갑상선초음파검사에서자가면역성질환을시사하는미만성갑상선염소견이현성갑상선기능저하증으로진행할위험요인이다. 불현성갑상선기능항진증은갑상선기능저하증의치료로서갑상선호르몬의과도한보충또는갑상선절제수술후에 TSH 억제요법 ( 외부요인 ) 으로생길수있고, 내부요인으로는그레이브스병과기능결절성갑상선질환이있다. TSH 가 0.1 μiu/ml 미만, 원인질환이기능결절성갑상선질환일때, 현성갑상선기능항진증으로진행할위험이높다. 불현성갑상선기능이상은여러가지건강문제와관련성이있는것으로밝혀지고있다. 불현성갑상선기능저하증은콜레스테롤상승, 심혈관질환 ( 허혈성심질환, 심부 J Korean Geriatr Soc 18(3) September 2014 117
Ki Dong Ko: Subclinical Thyroid Dysfunction in the Elderly 전 ) 과불현성갑상선기능항진증은심방세동, 골밀도감소, 심혈관질환과의미있는연관성을보이고있다. 건강문제의종류에따라정도는다르지만, 아직까지는그근거의양과수준이부족한형편이다. 또한같은건강문제에서도 TSH가정상범위에서벗어난정도, 연령, 성별에따라연관성의강도가다를수있다. 불현성갑상선기능저하증 ( 하시모토갑상선염 ) 의치료적응증은 TSH가 10 miu/l 이상이며, 증상이있는경우, TPO 에대한자가항체가양성인경우, 심혈관위험 ( 고혈압, 당뇨, 이상지혈증 ) 이있는경우, 그리고갑상선종이있는경우이다. 노인들에서는좀더보수적인적용이필요하다. 치료는 levothyroxine 을증량하면서용량을조절하게된다. 불현성갑상선기능항진증의치료적응증은 TSH가 0.1 miu/l 미만으로 65세이상이며, 증상이있는경우, 심장질환또는폐경후골다공증이있거나, 그것들에대한위험인자를가진경우이다. 그레이브스병은일차적으로항갑상선제를시작해야하고, 기능결절성갑상선질환은항갑상선제만으로는증상완화만이가능하고완치를이룰수는없으므로, 방사성요오드치료나수술을고려해야한다. REFERENCES 1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291: 228-38. 2. Kim SJ. The evaluation of thyroid function test. J Korean Geriatr Soc 1999;3:19-27. 3. McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 2001;86:4585-90. 4. Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G. Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol 2005;152:1-9. 5. Kim YA, Park YJ. Prevalence and risk factors of subclinical thyroid disease. Endocrinol Metab (Seoul) 2014;29:20-9. 6. Choi HS, Park YJ, Kim HK, Choi SH, Lim S, Park DJ, et al. Prevalence of subclinical hypothyroidism in two population based-cohort: Ansung and KLoSHA cohort in Korea. J Korean Thyroid Assoc 2010;3:32-40. 7. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-99. 8. Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 2009;94:1251-4. 9. Boucai L, Surks MI. Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice. Clin Endocrinol (Oxf) 2009;70:788-93. 10. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379:1142-54. 11. Hahm JR. Autoimmune thyroid diseases. Hanyang Med Rev 2012;32:219-6. 12. Kim TH, Kim KW, Ahn HY, Choi HS, Won H, Choi Y, et al. Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status. J Clin Endocrinol Metab 2013;98:3420-9. 13. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7:481-93. 14. Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab 1998;83:765-9. 15. Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006;354:2783-93. 16. Konno N, Makita H, Yuri K, Iizuka N, Kawasaki K. Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab 1994;78:393-7. 17. Abraham-Nordling M, Torring O, Lantz M, Hallengren B, Ohrling H, Lundell G, et al. Incidence of hyperthyroidism in Stockholm, Sweden, 2003-2005. Eur J Endocrinol 2008; 158:823-7. 18. Diez JJ. Hyperthyroidism in patients older than 55 years: an analysis of the etiology and management. Gerontology 2003;49:316-23. 19. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77-83. 20. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987;258:209-13. 21. Huber G, Staub JJ, Meier C, Mitrache C, Guglielmetti M, Huber P, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002;87:3221-6. 22. Díez JJ, Iglesias P. Spontaneous subclinical hypothyroidism 118 J Korean Geriatr Soc 18(3) September 2014
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