Statement http://dx.doi.org/10.4093/jkd.2014.15.4.190 한양의대내분비내과박용수 Clinical Heterogeneity of Diabetes in Young Korean Patients Yongsoo Park Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea Abstract 190 Diabetes among young patients in Korea is caused by a complex set of factors. In addition to the typical T1aD and T2D patients, there is a variable incidence of cases of non-autoimmune types of T1D associated with insulin deficiency (T1b), such as fulminant T1D (FT1D). Although T1a is the major type of childhood diabetes, FT1D exists as a hyper-acute subtype of T1D that affects older children, without causing autoimmunity. They showed a complete loss of β-cell secretory capacity without evidence of recovery, necessitating long-term treatment with insulin. In addition, latent autoimmune diabetes in adults (LADA) is a form of autoimmune-mediated diabetes, usually diagnosed based on GAD autoantibody positivity. Although many epidemiological surveys of LADA have been conducted in Caucasian and Asian populations, their reported prevalence rates vary due to the use of different diagnostic criteria. In a recent study with a comparable design and valid methodology, the prevalence of LADA using GAD autoantibody positivity as the diagnostic criterion was higher (4.4%) than the previously reported prevalence of 1.7% in a population-based T2D survey. After 36 months of follow-up, only 3 of the 39 patients initially diagnosed with LADA had become insulin-dependent, and they were all positive for multiple autoantibodies (GAD, IA-2 and ZnT8 antibody). This demonstrates that true insulin dependency, which was initially indicated by multiple antibody positivity, has not increased in the Korean population. Therefore, despite etiological heterogeneity, in the clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds without measuring autoantibodies could be a possible method to minimize complications. (J Korean Diabetes 2014;15:190-195) Keywords: Genetic heterogeneity, Diabetes mellitus type 1, Latent autoimmune diabetes in adults, Autoantibodies 서 당뇨병은모두만성고혈당을나타내지만, 유전적으로또임상적으로다양한군의집합체이다. 크게당뇨병은원인및자연경과가다른, 제 1 형당뇨병및제 2 형당뇨병으로나누게되는데, 제 1 형당뇨병은인슐린분비의장애에서비롯하는데갑작스런당뇨병증세의발현, 인슐린의절대부족으로인한심한체중감소, 삶을영위하기위해인슐린주사의필요, 인슐린주사를시 론 행하지않을경우짧은기간내에급성합병증인케톤산증이나타나는소견을특징으로한다. 이를세분하여자가항체등췌도의면역성파괴의증거가나타나는자가면역성제 1 형당뇨병 (Type 1a) 및그원인을알수없는원발성제 1 형당뇨병으로분류하고있다 (Type 1b)[1]. 제 1 형당뇨병환자의전형적인형태는주로유년기에나타나는것으로알려지고있으나최근성인에서도인슐린요구형 (insulin-requiring) 당뇨병의증가가보고되고있다. 성인에서발생하는인슐린요구형 교신저자 : 박용수, 서울시성동구왕십리로 222-1 한양대학교병원내분비내과, E-mail : parkys@hanyang.ac.kr
당뇨병은제 2 형당뇨병과는임상적으로서로다르며, 다른질병경과를밟는비전형성당뇨병으로생각되어진다. 그발병원인은정확히모르지만감수성유전자가전형적인유년기발생제 1 형당뇨병과는차이가있고, 또최근원인이밝혀지고있는여러가지의유전질환과당뇨병의병발이알려지고있다. 비전형성당뇨병의존재 임상적으로전형적인제 1 형당뇨병, 제 2 형당뇨병이외에서로감별이어려운비전형성당뇨병이서구인의일부, 그리고아프리카유래미국인, Hispanics 등, 그리고최근에는아시아인에도널리존재함이보고되고있다 [2,3]. 서구인의경우발병당시에는제 2 형당뇨병으로진단받고식사요법또는경구혈당강하제를투여받고있던성인환자들중약 10% 는췌도세포항체를갖고있으며, 이환자들은결국인슐린투여가필요하게되어성인의제 2 형당뇨병환자중약 10% 의환자가소위지진성인슐린의존성당뇨병 (Slowly progressive type 1 diabetes, 제 1.5 형당뇨병 ) 환자임을시사하였다 [4]. 이처럼성인에서발병하는제 2 형당뇨병으로보이는환자중상당수가지진성인슐린의존성당뇨병의임상형태를보이고있음이알려진이래, 백인의경우는이러한유형의당뇨병의임상적특성, 면역학적특성및유전학적특성등이밝혀지고있다. 지금까지의연구결과는백인의경우이들이발병시는제 2 형당뇨병과임상적으로차이가없어보이지만궁극적으로인슐린의존성과케톤산증에쉽게이환되는제 1 형당뇨병의병태생리를가져제 1 형당뇨병의비전형적표현형으로생각된다. 이러한성인에서발생하는지진성자가면역성당뇨병을 LADA (Latent Autoimmune Diabetes in Adults) 라고통일하여부르고있다 [5]. 서구인에서는성인제 2 형당뇨병환자중약 10% 이상이 LADA 이며이들은소아연령의제 1 형당뇨병과비슷하게췌도세포항체가양성이며, 제 1 형당뇨병감수성유전자를갖는것으로알려지고있다 [6]. 즉자가면역기전에의해췌도세포가서서히파괴되어, 수개월내지수년의인슐린비의존성기간을거쳐결국인슐린투여가요구됨이알려지고있다. 이러한병태생리를바탕으로최근에는 LADA 를조기에발견하여조기인슐린투여및면역학적중재등으로당뇨병의유병상태및합병증의출현빈도를줄이고자조기진단방법에많은노력이경주되고있다. 같은맥락에서아프리카유래미국인, Hispanics, 그리고아시아인에서는다양한유형의, 제 1 형당뇨병및제 2 형당뇨병으로분류하기어려운비전형성당뇨병환자들이보고되어왔다 [2,3]. 특히아시아권에서는젊은연령에서발생하는당뇨병의원인이서구인에비해다양해서전격 성당뇨병, 제 1.5 형당뇨병및바이러스유발당뇨병등으로불리우고있는데, 이들은모두자가면역에기인하지않는, 미국당뇨병학회분류의 type 1b 에해당되는비전형성당뇨병으로생각되고있다. 또최근소아비만및인슐린저항성에기인되는소아연령의제 2 형당뇨병이폭발적으로증가되었는데이들에서급격한인슐린결핍을초래하는손상이있을경우인슐린저항성을극복하지못한다면비전형성당뇨병과유사한표현형으로발생하는경우가있으리라생각된다 [7]. 그렇지만우리나라를비롯한아시아권에서는비전형성당뇨병에대한연구가부족하여젊은연령에서발생하는당뇨병의분류및상대적인분포, 발생율등, 많은것이알려져있지않다. 이러한비전형성당뇨병의하나로이마가와등은일본인에서자가면역의활성화증거가관찰되지않으면서급격한인슐린분비능의감소를동반하는비전형성당뇨병을전격성당뇨병 (fulminant diabetes) 이라고정의하여그존재를보고하였고 [8], 이어이웃한아시아국가에서도그존재를확인한바있다. 그렇지만일본인급성당뇨병의중요한 (20% 이상유병률 ) 당뇨병으로보고된전격성당뇨병은우리나라등일부아시아권에서증례보고들은있었으나추시가많지않은상황이다. 최근일본에서도전국적으로등록관리중인전격성당뇨병환자코호트중상당수의환자에서췌도특이자가항체가양성으로나타나처음이마가와등이정의한진단기준에부합하지않은증례들이많이포함되어진단기준이모호해진상황이다. 우리나라의경우비교적나이든소아혹은청장년에서초급성 (hyper-acute) 발병을나타내며췌도특이자가항체가음성인환자들로전격성당뇨병정의에부합하는환자들을추적한자료에의하면이들은초기에소실된인슐린분비능이회복되지않아장기적인인슐린투여가필요하다고보고된바있다 [9]. 따라서소아및청장년연령에도전형적인자가면역성제 1 형당뇨병이외에도일부비전형성제 1 형당뇨병 (type 1b) 이존재하고발병후급, 만성합병증이환을최소화할조기진단, 분류및적절한치료방침이필요하다고하겠다. 한국인제 1 형당뇨병의특징 한국인에서는서구인에비해제 1 형당뇨병발병률이낮고, 제 1 형당뇨병에이환된환자들도케톤산증으로발현하는경우가드물며, 감수성유전자로전형적유전적감수성 (HLA DR3/DR4) 이외의다른감수성유전자를가지며, 발병시췌도세포항체유병률이서구인에비해낮아비교적비전형적제 1 형당뇨병환자가많은것으로추정되었다 [7,10]. 또제 2 형당뇨병에이환된환자들도서구인에비해마른체형을가진환자들이많으며경과중쉽게인슐린분비능의감소를동반한환자들이상대적으로많다. 191
Statement 192 제 1 형당뇨병환자의근친가족을성인연령까지추적한연구에서보면가족에서발병률이 25% 전후로당뇨병환자의가족이가장중요한발병고위험군으로알려지고, 제 1 형당뇨병발병에있어유전적감수성이매우중요하게작용한다. 제 1 형당뇨병발병과주요조직적합성복합체 (HLA) 와의상관성은잘알려져있는데, HLA 항원은 T 림프구가자가항원을감지할때 HLA 형에따라제한적으로감지되도록작용한다. 그렇지만제 1 형당뇨병은유전학적으로다양한질환이고질환의표현형의발현은 HLA 이외에여러가지감수성유전자와환경인자에영향을받는다. 한국인의경우 HLA DR3 는서구인과비슷한위험도를보이고 DR4 는증가된위험도를보이지않지만, DR3/4 는 12 배정도의증가된상대위험도를보인다. 또 HLA DR, DQ 유전자는독립적으로제 1 형당뇨병발병에상관을보이므로 DR-DQ 일배체형의제 1 형당뇨병발병에미치는효과가가장중요한유전학적표지자로알려졌다. 우리나라제 1 형당뇨병환자의경우 DR3, DRB1*0405 및 DR9 이감수성유전자이고, DR5, DR2 가방어유전자로일반적으로알려지고있는데, 특히 DRB1*0405-DQB1*0302, DRB1*0405-DQB1*0401, DRB1*03-DQB1*0201 및 DRB1*09-DQB1*0303 일배체형이감수성유전자로, DRB1*1201-DQB1*0301, DRB1*1501-DQB1*0602 와 DRB1*1502-DQB1*0601 일배체형이방어유전자로밝혀졌다 [7,11]. 일반인들에서주요유전자인 HLA 감수성유전자는발현빈도가서구인에비해낮고, 저항성유전자는빈도가높아제 1 형당뇨병발병률이적다 [10]. 실제발병은스칸디나비아인에서매년 10 만명당 29.5 명의제 1 형당뇨병이발생하지만아시아인의경우는 0.7 명의환자가발생한다. 이와마찬가지로아시아권에서성인연령에발생하는비전형성제 1 형당뇨병의경우도일반인의 HLA 감수성유전자의분포에따라적을것으로추정된다. 비전형성당뇨병의진단에있어자가항체와인슐린분비능추적의중요성 제 1 형당뇨병의발병은오랜기간동안서서히진행하는자가면역기전에의한췌장베타세포의선택적파괴의산물이다. 당뇨병이발병되기전소도염이시작되면다수의췌장소도특이, 혹은소도비특이자가항원에대한자가항체및 T 림프구가말초혈중에발견된다. 제 1 형당뇨병발병및경과를관찰하는데도움이되는자가항원은인슐린, GAD65, IA-2, Zinc transporter 등이다. 이러한자가항체들은모두췌도염이시작된뒤출현하여당뇨병발병시에도검출되지만곧역가가감소된다. 그렇지만 GAD65 자가항체는발병후에도오래지속되어지진성인슐린의존성당뇨병의표지자로사용되고있다 [12]. 그렇지만자가항체는사람에따라다양하게출현하고, 췌장베타세포의파괴가진행되어항원이고갈된경우항체의역가가매우감소되어나타난다. 이에따라상당수의환자가발병당시에자가항체를갖지않는경우도있다. 이러한자가항체들의발현빈도에있어서서구인과한국인이차이가있으며, 종족간의유전적인차이가자가항원에대한다양한자가면역현상에관여하리라추측하고있다. 또아시아권에서는자가면역기전에기인하지않은인슐린분비능의감소에따른 Type 1b ( 비전형성당뇨병 ) 환자들이상당수발견된다. 그렇지만소아에서발생하는전형적제 1 형당뇨병의경우는임상상, 자가항체유병률이서구인과비슷하다. 특히 GAD65, IA-2, Zinc transporter 자가항체가한국인제 1 형당뇨병의발병예측에중요하다 [7]. 이에따라대표성있는한국인일반인을대상으로자가항체를사용하여제 1 형당뇨병발병을예측하려는시도가가능해졌다 [13]. 제 1 형당뇨병의예측능은여러자가항체중특히 IA-2 자가항체가양성인경우증가하고, 또많은수의자가항체가출현하였을때증가한다. 실제젊은연령에서발생한당뇨병의경우다수의자가항체가양성인경우쉽게제 1 형당뇨병환자로분류할수있다. 면역학적표지자이외에대사적표지자로인슐린분비능의소실을알아보기위해정맥당부하검사후초기인슐린분비능소실을측정하는방법이있다. 이검사는재현성이떨어지고, 많은치험례를대상으로하는임상시험에사용하기에는번거로운점이있다. 최근대사적보상요구정도가과도할때증가하는혈장 proinsulin 농도가제 1 형당뇨병발병의중요표지자가됨이증명되었다. 그렇지만현재로선임상가에서흔히시행될수있는방법은공복 c- 펩타이드혹은글루카곤자극후 c- 펩타이드농도를측정하는것이다. 이와같은인슐린분비능표지자를이용하여자가항체는음성이더라도인슐린분비능이소실된환자들을추적할수있다. LADA 진단과인슐린투여의필요성 성인에서발생하는지진성자가면역성당뇨병을칭하는 LADA 의진단은 35 세이상의성인에서발병후 6 개월이상의인슐린비의존성기간이있으며자가항체가양성인경우진단할수있다 [12-14]. 주로는 GAD65 자가항체를이용하지만, 그외다른자가항체들이진단에도움이된다. 그렇지만자가항체양성인환자들중얼마나인슐린의존성을갖게되는지분명하지않아, 제 1 형당뇨병의유전적감수성이상대적으로낮은아시아권에서는 LADA 발병률및유병률에대해다양한자료들이보고되어왔다 (Table 1, Table 2)[15]. 그간진단
Table 1. Varying selection criteria for LADA Autoimmune evidence 30-70 yr Type 2 GAD antibody positivity Study name Age criteria Onset diagnosis (Agardh, 2005) Cuba (Cabrera-Rode, 2002) Japan (Kobayasahi, 1996) Japan (Maruyama, 2003) (Zhou, 2005) (Thunander, 2010) (Zhou, 2010) None given Type 2 GAD and ICA positive C-peptide Detectable C- peptide History of ketoacidosis Not specifically mentioned Comments Diagnosed within past 5 years and not requiring insulin - No ketoacidosis Divided into disease (in one month) treated durations of up to 3 years with insulin and and 3 + years sulfonylureas None given Type 2 ICA positive - No ketoacidosis or initial need for insulin None given Diabetes not treated with insulin Over 25 yr Diabetes GAD positive Fasting C-peptide of 0.3 mmol/l or more Over 30 yr Type 2 GAD or ICA positive GAD positive - No ketoacidosis Not treated with insulin for at least 6 months after diagnosis. Disease duration less than 10 years No ketoacidosis within 6 months of diagnosis - Not specifically mentioned 25-70 yr Diabetes GAD positive Fasting C-peptide No ketoacidosis within level of 0.2 nmol/l or more the first 6 months after diagnosis of diabetes LADA, latent autoimmune diabetes in adults; GAD, glutamic acid decarboxylase; ICA, islet cell antibody. Table 2. Comparison of different treatments for LADA Disease duration less than 5 years Not insulin requiring at onset Disease duration less than 3 yr. Fasting C-peptide of 0.2 mmol/l or more Study name Comparison of treatments No. HbA1c at Fasting c-peptide at 0 to 12 months a 0 to 12 months a Comments UK (Davis, 2005) sulfonylurea (FBG < 15 mmol/l) 235 (all patients type 2 and LADA) 0.4% - CI cannot be calculated Diamyd (GAD65) 47 0.08% - (Agardh, 2005) (20 ug or 100 ug or 500 ug) vs. Placebo/ 4 ug diamyd (0.4 to 0.7) Japan sulfonylurea 60-0.5 - (Maruyama, 2008) (-1.33 to 0.33) (Yang, 2009) insulin + rosiglitazone (GAD Ab > 175 U/mL and fasting c-peptide > 3 nmol/l) 24 2.01 (0.15 to 3.87) - (Zhou, 2005) (Li, 2009) (Thunander, 2010) (Zhou, 2010) insulin + rosiglitazone insulin + vitamin D diet +/- metformin and/or sulfonylurea insulin + sitagliptin 17 +1.2% -0.4 Estimates based on median values 35 - CI cannot 100 pmol/l be calculated 37 0.4 - Stimulated (-0.38 to 1.18) C-peptide only reported 30 No change 110 pmol/l a Difference in means between groups at study end. LADA, latent autoimmune diabetes in adults; FBG, fasting blood glucose; CI, confidence interval; GAD, glutamic acid decarboxylase. 193
Statement 194 기준, 자가항체측정법및대상집단의대표성등의차이로인해 LADA 발병률및유병률이왜곡되어왔으나한국지역사회의대표성있는표본에서새로진단된성인당뇨병중 LADA 의유병률은 1.7% 로나타나제 1 형당뇨병과비슷하게 LADA 유병률도낮을것으로생각되었다 [13]. 최근서구인과똑같은진단기준을이용하여 193 명의이태리 LADA 환자와 39 명의한국인 LADA 환자를검출해낸단면적연구결과한국인에서도증가된 4.4% 유병률결과를확인한바있으나이때 GAD 항체양성인환자모두 affinity 및역가가낮고, IA-2 항체및 Zinc transporter 항체모두음성이어서자가항체양성이인슐린사용을예측하는지표가될것인지는분명하지않았다. 이들을 36 개월동안추적한전향적연구에서 39 명중단지 3 명만이추후인슐린투여가필요하여한국인에서진정한의미의지진성인슐린의존성당뇨병발병률은매우낮다고할수있었다. 인슐린투여가필요했던 3 명모두 GAD 자가항체역가가높고 GAD 항체이외에 IA-2 항체및 Zinc transporter 항체모두양성이어서적어도한국인에서는 LADA 환자의진단에 GAD65 항체이외에도 IA-2 및 Zinc transporter 항체의측정이필요하리라생각되었다 [16]. 결론 일반적으로우리나라를위시한아시아권에서는당뇨병이처음발병하였을때, 당뇨병을제 1 형당뇨병과제 2 형당뇨병으로분류하는데어려움이있다. 특히인슐린을투여하고있는마른체구의제 2 형당뇨병환자는종종제 1 형당뇨병환자처럼보인다. 분류를위해모든환자들을대상으로췌도특이자가항체나인슐린분비정도를측정할필요는없다. 인슐린분비능검사로공복및자극후혈장 C- 펩타이드의측정이사용되지만유용한분류방법으로서증명되지는못하고있다. 자가항체의측정이당뇨병분류에있어서유용할수있겠지만모든병원에서가능하진않다. 현재로선우리나라에서유병기간이오래된환자나성인연령의환자들의진료를위해서는케톤산혈증의병력이나고혈당과동반된산혈증의존재하에혈장및요중케톤의검출이제 1 형당뇨병의진단에가장유용한지침이다. 실제젊은연령의당뇨병환자를만났을때유용한지침을 Fig. 1 에 Fig. 1. Approach to the treatment of the Asian adolescent with diabetes.
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