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1 Case Report J Korean Diabetes 2016;17: Vol.17, No.4, 2016 ISSN Dapsone 사용후급성췌장염을동반한당뇨병성케톤산증 1 예 1, 2, 1, 1, 1, 1, 1, 3 경북대학교의과대학경북대학교병원내과학교실 1, 경북대학교약학대학약학연구소 2, 차의과학대학교구미차병원내분비내과 3 A Case of Diabetic Ketoacidosis Caused by Dapsone-Induced Acute Pancreatitis Jung Bum Seo 1, Kwang-Hee Shin 2, Min-Ji Kim 1, Ji-Eun Park 1, Keun-Kyu Park 1, Jung-Guk Kim 1, In-Kyu Lee 1, Sung Woo Kim 3 1 Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 3 Division of Endocrinology and Metabolism, Department of Internal Medicine, Cha Gumi Medical Center, CHA University, Gumi, Korea Abstract Drug-induced pancreatitis accounts for 0.1~2.0% of all pancreatitis cases. Generally, the mechanism of druginduced pancreatitis is an immune reaction, accumulation of toxic material, and/or ischemia. However, how dapsone causes pancreatitis remains unclear. A 61-year-old man presented with a 2-week history of epigastric discomfort. He had taken dapsone for 2 months to treat psoriasis. Laboratory findings showed high blood glucose levels and metabolic acidosis; however, hemoglobin A1c was low. Serum amylase and lipase levels were elevated to 125/4,479 U/L. Abdominal computed tomography was indicative of pancreatitis. There was no causative history of pancreatitis and no other medication history except dapsone. Thus, we reached a diagnosis of diabetic ketoacidosis (DKA) followed by dapsone-induced pancreatitis. The patient fasted and was treated with insulin administration and fluid hydration in accordance with treatment guidelines. After treatment, amylase and lipase decreased and symptoms subsided, but insulin injection was required to control blood glucose levels. Drug-induced pancreatitis is a very rare adverse effect of dapsone. Only four cases of pancreatitis related to dapsone could be found in a PubMed search. Moreover, diabetes caused by dapsone- Corresponding author: Sung Woo Kim Department of Internal Medicine, Cha Gumi Medical Center, CHA University, 12 Sinsi-ro 10-gil, Gumi 39295, Korea, sungwoocap@naver.com Received: Feb. 23, 2016; Revised: Mar. 11, 2016; Accepted: Apr. 14, 2016 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 2016 Korean Diabetes Association 282 The Journal of Korean Diabetes

2 서정범외 induced pancreatitis has not been reported previously. Here, we report a case of DKA caused by dapsoneinduced acute pancreatitis. Keywords: Dapsone, Diabetes, Pancreatitis 서론 Dapsone은전통적으로건선, 한센병, 포진성피부염등의질환에주로사용되고있으며, 수포성의전신홍반루푸스, 아프타성궤양, 피부혈관염등의피부질환및후천성면역결핍증후군환자의 Pneumocystis 폐렴, 말라리아, 톡소플라스마증등의감염성질환과같은다양한질환들에서도사용되고있다 [1]. Dapsone의부작용은다양하게보고되어있는데, 대표적으로는 dapsone syndrome 이라불리는과민성증후군이가장치명적인부작용이며 [2], 이외에도혈액학적부작용 ( 망상적혈구의증가, 용혈, 메트헤모글로빈혈증 ), 심혈관계부작용 ( 빈맥 ), 소화기질환 ( 간염 ) 등이있다 [3]. 약물유발췌장염은 dapsone의아주드문부작용으로알려져있으며, 몇몇증례들이보고되어있으나현재까지알려진증례의수는많지않다 [4]. 전세계적으로 dapsone에의한췌장염의발생증례에대한보고수는 2014년 12월까지단 4예만이보고되어있으며 (PubMed search using the key terms dapsone and pancreatitis) [4-7], 국내의증례보고는아직없는상태이다. 뿐만아니라 dapsone 치료중발생한췌장염환자에서새롭게당뇨병이발병한증례는세계적으로도보고된바가없다. 저자들은당뇨병병력이없던남성에서 dapsone 복용후발생한급성췌장염에의한당뇨병케톤산증환자를경험하였기에문헌고찰과함께보고하는바이다. 증례 61 세남자가 3 일간의구토로내원하였다. 환자는양측손 발의과각화성, 박탈성판소견으로개인의원에서건선으로진단받고 2개월간 dapsone (100 mg/day) 을복용하였으며내원 2주전부터는상복부불편감이있었다고한다. 병력청취상건선외에는다른특이병력이없었으며매년시행한직장건강검진상으로도특별한이상소견이없었다. 신체활력징후는혈압은 148/88 mm Hg, 맥박 111회 / 분, 호흡 20회 / 분, 체온 36.4 였으며, 키 170 cm, 몸무게 66.2 kg 이었다. 의식은명료하고복부진찰상압통은없었다. 일년에한두번, 소주한두잔정도의음주력, 40갑년의흡연력이있었으며최근다른약제를복용한과거력은없었다. 혈액및소변검사에서백혈구, 12,950/µL; 혈색소, 12.5 g/dl; 혈소판, 376,000/µL; 아스파르테이트아미노전이효소 / 알라닌아미노전이효소, 18/26 U/L; 혈청총단백 / 알부민, 6.1/4.0 g/dl; 혈청나트륨 / 포타슘, 130/5.5 mmol/ L; 칼슘 / 인 / 요산, 83.6/7.4/7.1 mg/dl; 혈액요소질소 / 크레아티닌, 27.8/1.41 mg/dl ( 사구체여과율, 51.2 ml/min per 1.73 m 2 ); 총콜레스테롤, 114 mg/dl; 초고밀도지질단백질, 32 mg/dl; 저밀도지질단백질, 68 mg/dl; 중성지방, 64 mg/dl였다. C 반응성단백은 9.64 mg/dl, 아밀라아제 / 리파아제는 125/4,479 U/L로증가되어있었다. 내원당시혈당은 527 mg/dl로상승되어있었으나당화혈색소는 4.0% 로정상이었다. 정맥혈액가스검사상 ph 7.155, HCO mmol/l로대사성산증을보였고, 혈장의케톤체 5.6 mmol/l, 소변의케톤은 3+ 로당뇨병성케톤산증에합당한소견을보였다. 소변단백은음성, 뇨당 3+ 였으며 C- 펩타이드 0.08 ng/ml로감소되어있었다. 반면혈청인슐린농도는 IU/mL로증가되어있었으나내원당시고혈당으로레귤러인슐린을정주한이후의결과로해석에제한성이있다. 소도항체검사는음성, 항인슐린항체검사는 283

1A, B). 환자는상복부불편감의증상과혈청아밀라아제와리파아제의상승그리고방사선학적소견으로급성췌장염으로진단되었다. 또한혈당의증가, 혈장및소변의케톤양성, 정맥혈검사상대사성산증등의소견으로당뇨병성케톤산증이진단되었다. 췌장염및당뇨병성케톤산증에대해금식및수액치료와함께지속적으로인슐린을정주하였으며 dapsone은중지하였다.

3 Case Report Dapsone 사용후급성췌장염을동반한당뇨병성케톤산증 1 예 5.3%, 항글루탐산탈카르복실효소항체검사는 0.2 U/mL 로정상소견이었다. 복부전산화단층촬영상담도및췌관의확장소견은없었고다른복부장기에는특이소견이없었으나, 췌장주위지방에침윤의소견이있으며불규칙한윤곽과불균질한감쇠를보여 Balthazar 전산화단층촬영점수 grade C에해당되었고급성췌장염에합당한방사선학적소견을보였다. 복부초음파촬영에서도간실의에코음영은정상이었으며국소적인병변은없었고, 담석소견없었으며담관내에도특이소견은없었다 (Fig. 1A, B). 환자는상복부불편감의증상과혈청아밀라아제와리파아제의상승그리고방사선학적소견으로급성췌장염으로진단되었다. 또한혈당의증가, 혈장및소변의케톤양성, 정맥혈검사상대사성산증등의소견으로당뇨병성케톤산증이진단되었다. 췌장염및당뇨병성케톤산증에대해금식및수액치료와함께지속적으로인슐린을정주하였으며 dapsone은중지하였다. 생체징후, 동맥혈의 ph, 혈당및전해질에대한모니터링을지속하며혈당조절및대사성산증의호전여부를관찰하였다. 입원 2일째환자는대사성 A B Fig. 1. (A) Abdominal and pelvic computed topography findings. Findings of indistinct pancreatic margins, heterogeneous pancreatic parenchymal tissue, and surrounding retroperitoneal fat stranding suggest acute pancreatitis. Obstruction of the biliary duct and pancreatic duct are not shown. (B) Abdominal ultrasonography findings. There are no focal lesions in the liver parenchyme. Also, there are no specific lesions in and the gallbladder (GB) or bile duct, nor any signs of GB stones. 5,000 4,000 Lipase (U/L) 3,000 2,000 1, Days Fig. 2. Flow chart of serum lipase levels. After cessation of dapsone, serum lipase levels improved

4 서정범외 Insulin (μiu/ml) C-peptide (ng/ml) Day 1 Day 71 Fig. 3. Flow chart of serum insulin and C-peptide levels. Despite improvement in acute pancreatitis, fasting insulin and C-peptide levels did not return to normal. 산증이교정되고, 입원 3일째복부불편감호전을보여경구식이를시작하였으며혈당조절을위해기저인슐린과매식전속효성인슐린을사용한후혼합형인슐린과메트포르민을병합하여퇴원하였다. 퇴원후외래에서시행한검사상혈청리파아제는점차감소하였으나 (Fig. 2), 혈청인슐린과혈청 C-펩타이드수치는회복되지않는결과를보여주었다 (Fig. 3). 혈당역시지속적으로조절이잘되지않아혼합형인슐린에서다시기저인슐린과식전인슐린용법으로변경하여조절하였고총인슐린사용량은 42단위였다. 의축적, 허혈, 췌장액의점도증가등이제시되고있으며, 기전에따라약물복용후췌장염의발생시기는수주에서수개월까지다양하게나타난다. 하지만 dapsone에의한췌장염의경우현재정확한발생기전은밝혀져있지않다. Dapsone에의한급성췌장염은매우드문경우로세계적으로몇몇증례만이보고되어있다. Jha 등 [4] 은 dapsone 을복용한 87세남자환자에서복부통증을동반한췌장염이발생하였고 dapsone 중단후복부증상이호전된 1예를보고하였다. 또다른증례에서 Das와 Jawed [6] 는음주력이 없는건강한 31 세남성에서 dapsone 을복용한후췌장염과 고찰 췌장염은대부분췌장관의결석, 알코올, 고지질혈증등에의해발생되는것으로알려져있으나 [8], 약물에의해서도이차적으로유발될수있으며약물에의한췌장염은전체췌장염의 0.1~2.0% 로보고되고있다 [9]. 고지혈증약제, angiotensin converting enzyme 차단제, 여성호르몬제, 이뇨제, 항바이러스제, valporic acid 등이대표적으로췌장염을일으킬수있는약제로알려져있고 [10], 매우드물지만 dapsone 역시췌장염을일으킬수있다고보고되고있다 [8]. 약물유발췌장염의발생기전은면역반응, 독성대사물 간염이발생한증례를보고하였다. 본환자는평소에일년에한두차례술을마실정도로거의음주력이없으며, 최근몇달간술을마신과거력이없었다. 병력상바이러스혹은세균성감염을의심할만한소견도없었으며, 복부전산화단층촬영과복부초음파상담도췌관내에폐쇄병변혹은담관석소견이없었고담낭내에담석또한관찰되지않았다. 또한고지질혈증소견역시보이지않아췌장염의원인이될만한다른요인들은명확히관찰되지않았다. 따라서본증례는 dapsone에의한약물유발성췌장염으로진단하는것이합당하다할수있겠다. 급성췌장염은당뇨병의원인중의하나이며, 췌성당뇨 285

5 Case Report Dapsone 사용후급성췌장염을동반한당뇨병성케톤산증 1 예 병은췌장염이후의췌장괴사로인한인슐린결핍으로인해주로발생한다 [11]. 나이, 성별, 췌장염의원인, 췌장염의정도등은당뇨병의발병에미미한영향만을끼치는것으로알려져있으며 [11], 급성질환에서일시적인고혈당은향후당뇨병발생의위험을증가시킬수있다 [12]. 한연구에서는췌장염이후췌성당뇨병의발생이 22.5% 까지보고되기도하였다 [13]. 하지만일반적으로급성췌장염이후의고혈당은일시적인증상으로췌장염의호전과함께대부분혈당이정상화되며, 1회의급성췌장염으로영구적인당뇨병이발생하는경우는흔하지않다. 그럼에도불구하고급성췌장염이후영구적인당뇨병의발생은꾸준히보고되어왔다 [11,13]. 급성췌장염발생후퇴원한환자를대상으로한연구에서당뇨병이발생한 50명의환자중 5명이퇴원후 12개월째에도지속적으로인슐린치료가필요하였으며, 또다른연구에서는 60개월까지추적관찰하였을때 108 명당뇨병환자들중 27명의환자가여전히인슐린치료가필요하였다는보고도있었다 [11]. 본환자의경우평소당뇨병과관련된다음, 다뇨등의증상은없었으며내원당시당화혈색소는 4.0% 로확인되었다. 비록당화혈색소수치가 ribavirin, 항레트로바이러스약제등과함께 dapsone을복용하는환자들에서실제보다낮게측정될수있기는하나 [14,15], 본소견은췌장염이후급성으로발생한췌성당뇨병에합당한소견이라할수있겠다. 본환자는 2개월전건선으로진단받고 dapsone의투약을지속하여왔다. 당뇨병환자에서몇몇피부질환들이동반될수있음이역시알려져왔는데, 특히환상육아종, 수포성유천포창등이당뇨병의발생과관련이있을가능성이제시되어왔다 [16-18]. 98명의수포성유천포창환자들중 15명의환자가당뇨병을동반하였다는보고가있으며, 통계적유의성은없으나환상육아종환자에서도 126명중 11명에게서당뇨병이동반되었음이보고되기도하였다 [16,17]. 본환자는건선에대한진단당시임상소견외특별히피부생검을시행하지않았고, 피부질환에대한정확한진단이이루어지지않아건선이아닌다른피부질환에의해당뇨병이동반되었을가능성도있다. 뿐만아니라, 최근드물지만 췌장세포에대한자가항체가음성이면서케톤산증을동반하며급격한진행양상을보이는전격성제1형당뇨병들이보고되고있다 [19]. 보고된증례들에따르면전격성제1형당뇨병의경우혈청췌장효소상승은있으나췌장염의소견은보이지않은것에반해 [20], 본환자는혈청리파아제수치의높은증가와복부전산화단층촬영에서중등도의췌장염소견을보였다는점에서차이가있으나전격성제1형당뇨병에대한가능성을완전히배제하기는어려울수있다. 저자들의문헌고찰에의하면본증례는 dapsone에의한약물유발췌장염에대한국내에서의첫보고일뿐만아니라이로인해당뇨병이발생한경우는세계적으로도첫번째증례보고이다. 현재까지 dapsone에의한췌장염에서병발한당뇨병에대한연구가거의없는상태로, 저자들은 dapsone에의한췌장염에서당뇨병이새롭게발생한증례를경험하였기에문헌고찰과함께보고하는바이다. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 1993;129: McKenna KE, Robinson J. The dapsone hypersensitivity syndrome occurring in a patient with dermatitis herpetiformis. Br J Dermatol 1997;137: Lawrence WA, Olsen HW, Nickles DJ. Dapsone hepatitis. Arch Intern Med 1987;147: Jha SH, Reddy JA, Dave JK. Dapsone-induced acute pancreatitis. Ann Pharmacother 2003;37: Navarro-Mingorance A, Castellanos-Alcarria AJ, Ibañez- Micó S, Cervantes-Pardo A, Sánchez-Pedreño P. Dapsone

6 서정범외 induced isolated acute pancreatitis in a child with linear IgA dermatitis. Indian J Pediatr 2014;81: Das AK, Jawed Q. Drug-induced acute pancreatitis: a rare manifestation of an incomplete "dapsone syndrome". Indian J Pharmacol 2014;46: Corp CC, Ghishan FK. The sulfone syndrome complicated by pancreatitis and pleural effusion in an adolescent receiving dapsone for treatment of acne vulgaris. J Pediatr Gastroenterol Nutr 1998;26: Kaurich T. Drug-induced acute pancreatitis. Proc (Bayl Univ Med Cent) 2008;21: Nitsche CJ, Jamieson N, Lerch MM, Mayerle JV. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol 2010;24: Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol 2005;39: Das SL, Singh PP, Phillips AR, Murphy R, Windsor JA, Petrov MS. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut 2014;63: Gornik I, Vujaklija A, Lukić E, Madzarac G, Gasparović V. Hyperglycemia in sepsis is a risk factor for development of type II diabetes. J Crit Care 2010;25: Shen HN, Yang CC, Chang YH, Lu CL, Li CY. Risk of diabetes mellitus after first-attack acute pancreatitis: a national population-based study. Am J Gastroenterol 2015;110: Shah AD, Fox RK, Rushakoff RJ. Falsely decreased HbA1c in a type 2 diabetic patient treated with dapsone. Endocr Pract 2014;20:e Unnikrishnan R, Anjana RM, Mohan V. Drugs affecting HbA1c levels. Indian J Endocrinol Metab 2012;16: Nebesio CL, Lewis C, Chuang TY. Lack of an association between granuloma annulare and type 2 diabetes mellitus. Br J Dermatol 2002;146: Kibsgaard L, Bay B, Deleuran M, Vestergaard C. A retrospective consecutive case-series study on the effect of systemic treatment, length of admission time, and comorbidities in 98 bullous pemphigoid patients admitted to a tertiary centre. Acta Derm Venereol 2015;95: Duff M, Demidova O, Blackburn S, Shubrook J. Cutaneous manifestations of diabetes mellitus. Clin Diabetes 2015;33: Imagawa A, Hanafusa T, Uchigata Y, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Toyoda T, Maruyama T, Makino H. Fulminant type 1 diabetes: a nationwide survey in Japan. Diabetes Care 2003;26: Hanafusa T, Imagawa A. Fulminant type 1 diabetes: a novel clinical entity requiring special attention by all medical practitioners. Nat Clin Pract Endocrinol Metab 2007;3:36-45; quiz 2p following

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract