Focused Issue J Korean Diabetes 2017;18: Vol.18, No.3, 2017 ISSN 췌장질환과관련된당뇨병 김진화조선대학교병원내분비대

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1 J Korean Diabetes 2017;18: Vol.18, No.3, 2017 ISSN 췌장질환과관련된당뇨병 김진화조선대학교병원내분비대사내과 Pancreatogenic Diabetes Jin Hwa Kim Department of Endocrinology and Metabolism, Chosun University Hospital, Gwangju, Korea Abstract Diabetes can develop as a direct consequence of diseases of the exocrine pancreas. Diabetes due to diseases of the exocrine pancreas is described as pancreatogenic diabetes or type 3c diabetes. Pancreatogenic diabetes is not commonly recognized by clinicians and is frequently misclassified as type 1 diabetes or, more commonly, type 2 diabetes. The prevalence and clinical importance of pancreatogenic diabetes have been underestimated and underappreciated. Pancreatogenic diabetes has a unique pattern of hormonal and metabolic characteristics. The failure to correctly diagnose pancreatogenic diabetes leads to failure to implement an appropriate medical therapy in these patients. We will review the clinical implications and relevance of pancreatogenic diabetes. Keywords: Diabetes mellitus, Exocrine pancreas, Pancreas 서론 외분비췌장질환은당뇨병발생과연관될수있으며이를췌장성당뇨병 (pancreatogenic diabetes) 이라한다. 최근에는제3c형당뇨병 (type 3c diabetes) 으로분류되기 도하는데 [1], 전세계적인유병률은명확하지않다. 북아메리카당뇨병환자를대상으로한연구에서 0.5~1.15% [2], 그리고서구인을대상으로한연구에서 5~10% [3] 로그유병률은다양하다. 췌장성당뇨병의가장흔한원인은만성췌장염이다. 한단일기관의연구결과만성췌장염 Corresponding author: Jin Hwa Kim Department of Endocrinology and Metabolism, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 61453, Korea, endocrine@chosun.ac.kr Received: Aug. 5, 2017; Accepted: Aug. 7, 2017 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 c 2017 Korean Diabetes Association 150 The Journal of Korean Diabetes

2 김진화 (79%) 이췌장성당뇨병의가장흔한원인이었으며, 췌장관세포암 (pancreatic ductal adenocarcinoma, 8%), 혈색소증 (haemochromatosis, 7%), 그리고췌장의수술과거력 (2%) 순으로원인질환이분포되었다 [4]. 진료중제1형당뇨병과제2형당뇨병이비교적잘인지되고진단되는반면, 췌장성당뇨병은좀더간과되기쉽고인지하기가복잡하다. 정확한진단에따른개별화된맞춤치료는당뇨병관리의근간을이룬다. 이에본글에서는췌장성당뇨병의진단및임상적특성, 관리에관하여정리하고자한다. 본론 1. 췌장성당뇨병의진단췌장성당뇨병은개념상으로당뇨병의진단기준에합당한당뇨병이있고, 외분비췌장질환을동반하며, 당뇨병이외분비췌장질환에의하여이차적으로발생한상황에서진단할수있으나그기준은현재명확하지않다. Ewald와 Bretzel [5] 은다음과같은진단기준을제안하였다. 주요기준 ( 모두만족 ) 외분비췌장기능의이상 ( 대변소화효소검사 [monoclonal fecal elastase-1 test] 또는직접적기능검사 ) 췌장영상의이상 ( 내시경초음파, magnetic resonance imaging, computed tomography) 자가면역표지자와연관된제1형당뇨병배제그외기준 베타세포기능이상 ( 예 : homeostatic model assessment [HOMA]-B, C-peptide/glucose ratio) 과도한인슐린저항성배제 ( 예 : HOMA-insulin resistance) 인슐린분비저하 ( 예 : glucagon-like peptide [GLP-1], pancreatic polypeptide) 혈청지용성비타민수치저하 (A, D, E, and K) 그러나이기준을일반적으로적용하기에는몇가지한계점이있다. 오랜유병기간을가진제1형과제2형당뇨병환자에서도이러한특성이나타날수있으며, 베타세포기능과인슐린저항성을평가하는방법이표준화되어있지않다. 여러췌장성당뇨병환자들에서인슐린저항성이동반되며진단을위한표지자가명확하지않다. 당뇨병환자는급만성췌장염의발생위험도가높고, 췌장염환자들이외분비췌장질환과무관하게제1형이나제2형당뇨병이발생할수도있다. 췌장성당뇨병의포도당항상성에대한연구결과또한충분하지않아이에대한많은연구가요구된다. 2. 만성췌장염에의한당뇨병췌장실질의비가역적인손상의결과췌장의염증성, 섬유화성변화를특성으로하는만성췌장염은췌장성당뇨병의가장흔한원인이다. 인슐린생산부족이만성췌장염에의한당뇨병의주요기전이다. 단면적연구에서만성췌장염환자들은진행되는인슐린부족을보였고당뇨병발생전에도경미한인슐린부족을동반하였다. 이외에도사이토카인, 간의인슐린저항성, 말초인슐린저항성, 그리고인크레틴효과의저하등이관련될수있다 [6]. 만성췌장염의오랜유병기간은당뇨병발생의중요한위험요소로유전성췌장염환자에서당뇨병이발생하는나이의중앙값은 38세에서 53세사이였다 [3,7]. 당뇨병의만성합병증발생에관해서는명확하지않으나한전향적연구에서만성췌장염이있거나췌장전절제술을시행한 54명의환자에서당뇨병성망막병증의위험률은 31% 였고이는당뇨병의유병기간과연관되었다 [8]. 당뇨병과만성췌장염모두췌장관세포암의위험인자인점을고려해보면두질환이병발한경우췌장관세포암의증가를예상해볼수있는데, 타이완에서시행된한코호트연구 (hazard ratio, 33.5) 및여러연구들에서위험도증가가관찰되었다 [9-12]

3 췌장질환과당뇨병 1) 만성췌장염환자에서췌장성당뇨병의선별검사만성췌장염환자들은당뇨병발생에대한지속적인추적관찰이필요하다. 특히, 유병기간이오래되었거나부분췌장절제술을시행한경우, 그리고조기에석회화성병변이동반된경우더욱그러하다. 만성췌장염환자에서당뇨병에대한초기선별검사로공복혈당과당화혈색소를이용할수있으며, 이는적어도매년반복되어야한다. 이상소견이있을경우 75 g 경구당부하검사시행을추천한다. 인슐린과 C-peptide를동시에검사하는것이제2형당뇨병과의구분에도움이될수있다 [13]. 2) 만성췌장염환자에서췌장성당뇨병의치료만성췌장염에의한당뇨병은경미한혈당상승부터잦은저혈당을동반한심각한형태까지다양한경과를보인다 [14]. 저혈당에대한글루카곤반응저하로혈당패턴이불안정할수있으며, 특히환자가복부통증이나구역으로인하여식사가불규칙한경우, 만성알콜중독인경우, 이는더욱심각해진다. 대규모연구의부재로치료지침은명확하지않다. 제2형당뇨병환자의초치료로사용되는메트포르민을췌장성당뇨병환자에서도초치료로사용할수있는데, 특히, 고혈당상태가경미하고인슐린저항성이동반된경우도움이된다. 메트포르민의췌장암위험도감소효과를 [15] 고려해보면, 췌장암발생감소에이득이될수있다. 그러나만성췌장염으로인한구역, 복부불편감, 설사, 그리고췌중감소를동반한환자에서는메트포르민치료가제한된다. 인슐린또한초치료시투여될수있고, 실제로많은환자들이치료과정중인슐린치료가필요하게된다. 이러한모든치료들은다른형태의당뇨병과마찬가지로생활습관의개선이동반되어야한다. 다른경구혈당강하제투여에대해서는명확하지않다. 인크레틴에기반한치료제 (GLP-1 analoges, dipeptidyl peptidase -IV-inhibitors) 는제기되고있는췌장염발생위험도증가와의연관성을 [16] 고려하여사용을피하도록한다. 티아졸리디네디온은투여시골절위험도증가에대한고 려가요구된다. 3. 췌장암에의한당뇨병췌장암에의한당뇨병은만성췌장염에의한섬유화염증반응또는췌장절제술에의해발생된당뇨병과구분되는데, 암에서분비되는매개체에의한종양연관성반응과연관될수있다. 그기전은확실치않으나인슐린저항성, 베타세포기능이상, lipocalin 2 등아디포카인 (adipokine) 의영향, 그리고면역체계의병태생리학적연관가능성이제기되고있다. 췌장관세포암을제거한이후인슐린저항성및베타세포기능이상이호전되었고, adenomedullin이췌장관세포암모델에서베타세포의인슐린분비저하를매개함을보여주었다 [6]. 당뇨병이췌장암의위험도증가와연관되지만, 새로진단된당뇨병이기전된췌장암의여러표시중하나일수있다. 미국일반인구를대상으로한연구에서는 50세이상에서당뇨병이새로발생한대상자의최대 1% 가췌장암에의한당뇨병임을보고하였다 [17]. 또다른연구들은새로진단된당뇨병환자에서췌장관세포암의유병률을 5.2~13.6% 로보고하였다 [18,19]. 췌장관세포암이임상적으로진단되기전까지일반적으로 24~36개월이걸린다는점을고려해보면새로진단된당뇨병이췌장관세포암의조기진단에이용될수있는가능성을고려해볼수있겠다. 그러나췌장관세포암의유병률이비교적높지않다는점및비용-효과면을고려할때, 추가적위험요소를갖는고위험군의확인이필요하다. 제2 형당뇨병환자보다췌장관세포암에의한당뇨병환자에서당뇨병진단시체중감소가더흔하였다 (30% vs. 59%; P = 0.02) [20]. 제2형당뇨병환자에비하여췌장관세포암에의한당뇨병환자에서혼합식사자극에의한혈청췌장폴리펩타이드 (pancreatic polypeptide) 반응이감소됨을보여준또다른연구가있다 [21]. 그러나이러한이상반응이췌장의체부나미부에위치한종양을가진환자들에서는관찰되지않아서이결과를적용하기에는추가적연구들이요 152

4 김진화 구된다. 당뇨병은췌장관세포암환자의부정적예후와연관된다. 당뇨병은모든병기에서사망률증가의예측인자로확인되었다. 당뇨병은췌장관세포암수술후췌장액누수, 감염, 복강내농양, 그리고위배출속도지연등합병증의위험도와연관되었다 [9]. 췌장암에의한당뇨병에서고혈당의관리에대한직접적인연구는없으며다른형태의당뇨병과달리췌장암환자의여명이길지않다는점을고려할때당뇨병의장기간의예후가충분하지않다. 혈당상승에따른당뇨병의급성합병증이사망률증가및암관련치료를지연시킬수있다는점을고려할때췌장암에의한당뇨병환자에서일차적치료가급성합병증예방에맞추어지는것도타당하다하겠다. 결론 외분비췌장과당뇨병의상호영향을고려할때췌장성당뇨병환자의정확한진단및차별화된전략이필요하다. 그러나현재까지이러한환자들을대상으로한특성화된연구는부족한실정이다. 췌장성당뇨병환자들을대상으로한전향적대규모연구들이요구된다. 감사의글 이논문은 2013년도조선대학교병원선택진료학술연구비에의하여연구되었음. REFERENCES 1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S Vujasinovic M, Zaletel J, Tepes B, Popic B, Makuc J, Epsek Lenart M, Predikaka M, Rudolf S. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus. Pancreatology 2013;13: Howes N, Lerch MM, Greenhalf W, Stocken DD, Ellis I, Simon P, Truninger K, Ammann R, Cavallini G, Charnley RM, Uomo G, Delhaye M, Spicak J, Drumm B, Jansen J, Mountford R, Whitcomb DC, Neoptolemos JP; European Registry of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC). Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2: Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 2012;28: Ewald N, Bretzel RG. Diabetes mellitus secondary to pancreatic diseases (Type 3c)--are we neglecting an important disease? Eur J Intern Med 2013;24: Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz- Monserrate Z, Forsmark CE, Goodarzi MO, Habtezion A, Korc M, Kudva YC, Pandol SJ, Yadav D, Chari ST; Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer(CPDPC). Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol 2016;1: Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P. The natural history of hereditary pancreatitis: a national series. Gut 2009;58: Tiengo A, Segato T, Briani G, Setti A, Del Prato S, Devidé A, Padovan D, Virgili F, Crepaldi G. The presence of retinopathy in patients with secondary diabetes following pancreatectomy or chronic pancreatitis. Diabetes Care 1983;6:

5 췌장질환과당뇨병 9. Cui Y, Andersen DK. Diabetes and pancreatic cancer. Endocr Relat Cancer 2012;19:F Liao KF, Lai SW, Li CI, Chen WC. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol 2012;27: Munigala S, Singh A, Gelrud A, Agarwal B. Predictors pancreatic cancer diagnosis following new-onset diabetes mellitus. Clin Transl Gastroenterol 2015;6:e Brodovicz KG, Kou TD, Alexander CM, O'Neill EA, Engel SS, Girman CJ, Goldstein BJ. Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk. Diabetes Obes Metab 2012;14: Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis. World J Gastroenterol 2013;19: Alberti KGMM. Diabetes secondary to pancreatopathy: an example of brittle diabetes. In: Tiengo A, Alberti KGMM, Del Prato S, Vranic M, eds. Diabetes secondary to pancreatopathy: proceedings of the Post EASD International Symposium on Diabetes Secondary to Pancreatopathy, Padova, Italy, September Amsterdam: Excerpta Medica; p Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012;18: Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagonlike peptide-1-based therapies. Gastroenterology 2011;141: Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129: Damiano J, Bordier L, Le Berre JP, Margery J, Dupuy O, Mayaudon H, Bauduceau B. Should pancreas imaging be recommanded in patients over 50 years when diabetes is discovered because of acute symptoms? Diabetes Metab 2004;30: Illés D, Terzin V, Holzinger G, Kosár K, Róka R, Zsóri G, Ábrahám G, Czakó L. New-onset type 2 diabetes mellitus- -A high-risk group suitable for the screening of pancreatic cancer? Pancreatology 2016;16: Hart PA, Kamada P, Rabe KG, Srinivasan S, Basu A, Aggarwal G, Chari ST. Weight loss precedes cancerspecific symptoms in pancreatic cancer-associated diabetes mellitus. Pancreas 2011;40: Hart PA, Baichoo E, Bi Y, Hinton A, Kudva YC, Chari ST. Pancreatic polypeptide response to a mixed meal is blunted in pancreatic head cancer associated with diabetes mellitus. Pancreatology 2015;15:

한국성인에서초기황반변성질환과 연관된위험요인연구

한국성인에서초기황반변성질환과 연관된위험요인연구 한국성인에서초기황반변성질환과 연관된위험요인연구 - - i - - i - - ii - - iii - - iv - χ - v - - vi - - 1 - - 2 - - 3 - - 4 - 그림 1. 연구대상자선정도표 - 5 - - 6 - - 7 - - 8 - 그림 2. 연구의틀 χ - 9 - - 10 - - 11 -