Case Report J Korean Diabetes 2017;18: Vol.18, No.2, 2017 ISSN 불량한혈당조절을주소로내원한제 2 형당뇨병환자에서우연

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1 J Korean Diabetes 2017;18: Vol.18, No.2, 2017 ISSN 불량한혈당조절을주소로내원한제 2 형당뇨병환자에서우연히진단된제 1 형다발성내분비선종의 1 예,,,,, A Case of Multiple Endocrine Neoplasia Type 1 in Type 2 Diabetes Mellitus with Poor Glycemic Control Yong Hoon Lee, Yu Chang Lee, Jung Eun Lee, Sol Jae Lee, Su Jin Jeong, Chong Hwa Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea Abstract The primary causes of uncontrolled diabetes are poor life-style, infection, ischemic heart disease and inappropriate usage of oral anti-diabetic agents and insulin. Supplementary causes are stroke, acute pancreatitis and endocrine diseases. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant syndrome characterized by primary hyperparathyroidism, pituitary neoplasia, and foregut lineage neuroendocrine tumors, and is associated with increased glucose levels. We present a case of a 69-year-old woman who had polyuria, polydipsia, weight loss and hyperglycemia over 6 months. She had hypertrophy of the face, hand, and foot, and active bleeding and large folds were observed in the stomach and duodenum upon esophagogastroduodenoscopy. She also had high levels of IGF-1 and gastrin and got the failure of growth hormone suppression after an oral glucose load (75 g). These findings suggested a diagnosis of acromegaly and gastrinoma, which was clinically diagnosed along with MEN 1. The patient improved glycemic control and symptoms after being treated with somatostatin analogues and insulin therapy over a 5-month follow-up period. Here, we report a case of MEN 1 in type 2 diabetes mellitus with a poorly controlled blood glucose level. Clinicians should consider endocrine disease in patients with poor glycemic control in diabetes. Corresponding author: Chong Hwa Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, 28, Hohyeon-ro 489beon-gil, Bucheon 14754, Korea, drangelkr@hanmail.net Received: Oct. 10, 2016; Revised: Nov. 3, 2016; Accepted: Dec. 27, 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 2017 Korean Diabetes Association The Journal of Korean Diabetes 125

2 2 1 1 Keywords: Acromegaly, Gastrinoma, Multiple endocrine neoplasia type 1, Type 2 diabetes mellitus 서론 당뇨병은유전적또는환경적요인에의해인슐린의표적세포에대한인슐린의작용이감소되고이와함께인슐린의상대적또는절대적결핍이동반되어고혈당상태가초래되는질환이다. 당뇨병의한분류인제2형당뇨병을진단받고치료를받고있던환자들에게서불량한혈당조절이발생한경우, 흔하게생각해볼수있는 1차적원인으로는불량한생활습관, 감염, 심근허혈및심근경색, 부적절한약물요법-경구혈당강하제와인슐린치료등이며, 그외 2차적원인으로는뇌졸중, 급성췌장염, 임신및내당능장애를일으키는쿠싱증후군, 갑상선기능항진증, 말단비대증 (acromegaly), 갈색세포종, 원발성알도스테론증및다양한내분비질환이함께병발하는내분비질환등을생각해볼수있다. 본증례에서는 20년전제2형당뇨병을진단받고경구혈당강하제로치료를받고있던환자가 6개월전부터지속적으로발생한고혈당을주소로내원하여말단비대증과가스트린종 (gastrinoma) 으로제1형다발성내분비선종 (multiple endocrine neoplasia type 1, MEN 1) 을우연히진단받고이에대한치료를통해인슐린요구량및당화혈색소가감소한것을확인하였다. 본저자들은지속적인불량한혈당조절이발생한제2형당뇨병환자에서병발한 MEN 1의경험에대해보고하고자한다. 전부터다음, 다뇨, 체중감소와당화혈색소 12.0% 로혈당조절이잘되지않았고, 내원 2주전부터자가혈당측정시 500 mg/dl 이상지속되고복통을동반한수양성설사, 흑색변, 전신기력저하소견이있어개인의원에서고혈당으로전원되어외래통해입원하였다. 과거력 : 20년전제2형당뇨병및고혈압을진단받고개인의원에서경구혈당강하제약물투여중이었다. 가족력및사회력 : 2남 3녀중다섯째이며, 특이사항은없었다 (Fig. 1). 이학적소견 : 인체계측상키 151 cm, 몸무게 61.8 kg, 체질량지수 kg/m 2 였다. 혈압은 100/60 mm Hg, 맥박수 100회 /min, 호흡수 26회 /min, 체온은 36.5 였다. 의식은명료하였으나급성병색을보이고있었다. 두경부관찰시전두부돌출되어있었고, 코끝이돌출되어있었으며입술이두꺼워져있었다. 경부진찰상양쪽갑상선에촉진되는결절이있었다. 흉부청진상호흡음은깨끗하였고, 심음은정상이었다. 전반적인복부압통이있었으나반발통은없었다. 사지검사상수지말단비대가보였으며, 피부주름이증가되어있었다. 직장수지검사상흑색변이관찰되었고, 비위관삽입세척술결과상부위장관의출혈의심소견이보였다. 증례 환자 : 여자, 69세주소 : 6개월전부터지속된불량한혈당조절현병력 : 내원 20년전제2형당뇨병으로진단받고개인의원에서경구혈당강하제복용하던환자로, 내원 6개월 Fig. 1. A family pedigree of the patient (arrowhead). She refuses genetic test for MEN1 gene mutation

3 일반검사실검사 : 일반혈액검사에서혈색소백혈구 6,420/mm 2 ( 정상범위 4,000~10,000/mm 2 ), 혈색소 5.9 g/ dl ( 정상범위 12.0~14.9 g/dl), 혈소판 173,000/mm 2 ( 정상범위 150,000~400,000/mm 2 ), 망상적혈구비율 5.24% ( 정상범위 0.5~2.0%) 를보였다. 생화학검사에서혈청요소질소는 84 mg/dl ( 정상범위 8.0~23.0 mg/dl), 크레아티닌 0.91 mg/dl ( 정상범위 0.5~0.9 mg/dl), 혈중나트륨 132 mmol/l ( 정상범위 136~145 mmol/l), 혈중칼륨 5.1 mmol/l ( 정상범위 3.5~5.1 mmol/l), 혈중포도당 580 mg/dl ( 정상범위 70~100 mg/dl) 를보였다. 혈중칼슘 9.3 mg/dl ( 정상범위 8.6~10.0 mg/dl), 알부민 3.3 g/dl ( 정상범위 3.5~5.2 g/dl), 인 3.9 mg/dl ( 정상범위 2.5~4.5 mg/dl), 마그네슘 3.4 mg/dl ( 정상범위 1.6~2.4 mg/dl) 를보였으며, C 반응성단백은 < 0.3 mg/l ( 정상범위 < 0.5 mg/l) 를보였다. 요검사상포도당 4+ ( 정상수치음성 ), 케톤음성소견을보였다. 내분비학적검사 : 입원당시혈중당화혈색소 11.8% ( 정상범위 4.0~6.0%), 인슐린 8.7 μu/ml ( 정상범위 2.6~24.9 μg/ml), C-펩티드 (peptide) 6.14 ng/ml ( 정상범위 1.1~4.4 ng/ml) 를보였고, 부신피질자극호르몬은 28.5 pg/ml ( 정상범위 7.2~63.3 pg/ml), 혈청코르티솔 29.8 μg/dl ( 정상범위 7~28 μg/dl) 를보였다. 갑상선호르몬검사에서는 thyroid stimulating hormone, μiu/ ml ( 정상범위 0.35~5.0 μiu/ml); free T4, 1.4 ng/dl ( 정상범위 0.8~1.7 ng/dl) 를보였고, 부갑상선호르몬 25.0 pg/ml ( 정상범위 15~65 pg/ml), 칼시토닌 1.0 pg/ml ( 정상범위 0~10 pg/ml) 를보였다. 입원당시신체형태학적모습으로말단비대증의심소견을보여검사한인슐린양성장인자-1 (insulin-like growth factor-1, IGF-1) 은 ng/ml ( 정상범위 78~258 ng/ml) 로상승되어있었고, 공복시혈청가스트린 (gastrin) 은 pg/ml ( 정상범위 25~111 pg/ml), 프로락틴 ng/ml ( 정상범위 Table 1. Results of the GH response to the 75 g oral glucose loading test Time (minute) to 75 g OGTT 0 min 30 min 60 min 90 min 120 min GH (ng/ml) to 75 g OGTT GH, growth hormone; OGTT, oral glucose tolerance test. Table 2. Results of the combined pituitary stimulation test Time (minute) to 75 g combined pituitary stimulation test 0 min 30 min 60 min 90 min 120 min Glucose (mg/dl) to insulin induced hypoglycemia test GH (ng/ml) to insulin induced hypoglycemia > > test ACTH (pg/ml) to insulin induced hypoglycemia test Prolactin (ng/ml) to TRH stimulation test TSH (μiu/ml) to TRH stimulation test FSH (miu/ml) to GnRH stimulation test LH (miu/ml) to GnRH stimulation test GH, growth hormone; ACTH, adrenocorticotropic hormone; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone; FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; LH, luteinizing hormone

2 1 1 10~25 ng/ml), 황체형성호르몬 17.5 miu/ml ( 정상범위 16~66 miu/ml), 여포자극호르몬 51.

75 g 경구포도당부하에의한성장호르몬억제검사에서성장호르몬이억제되지않았으며, 복합뇌하수체자극검사에서뇌하수체기능저하는보이지않았다 (Table 1, 2).

1 1 cm 크기의뇌하수체거대선종이관찰되었고, 종양내부중앙에낭성부위가보였다.

. 갑상선초음파결과우엽에동일에코성결절 Fig. 2. Sella magnetic resonance imaging (MRI).

4 ~25 ng/ml), 황체형성호르몬 17.5 miu/ml ( 정상범위 16~66 miu/ml), 여포자극호르몬 51.7 miu/ml ( 정상범위 27.7~93.3 miu/ml), 에스트라디올 12.5 pg/ml ( 정상범위 15~50 pg/ml) 을보였다. 75 g 경구포도당부하에의한성장호르몬억제검사에서성장호르몬이억제되지않았으며, 복합뇌하수체자극검사에서뇌하수체기능저하는보이지않았다 (Table 1, 2). 방사선학적검사 : 단순흉부사진상특이소견은없었고, 두개골의단순 X선검사에서는터키안이확장되어있었다. 뇌하수체자기공명검사에서오른쪽안장부에 cm 크기의뇌하수체거대선종이관찰되었고, 종양내부중앙에낭성부위가보였다. 이선종은우측해면정맥동에부착되어있었고, 우측내경동맥은구경이좁아지게보였다 (Fig. 2). 갑상선초음파결과우엽에동일에코성결절 Fig. 2. Sella magnetic resonance imaging (MRI). T2 weighted coronal view of sella MRI shows poorly enhancing mass in right sella, cm. A B C D Fig. 3. Endoscopic findings show diffuse mucosal hypertrophy and enlarged gastric folds in the body of the stomach (A, B). There was a peptic ulcer with active bleeding in the 1st portion of the duodenum (C, D)

5 ( mm 2 ), 저에코성결절 ( mm 2 ), 좌엽에낭성 ( mm 2 ), 저에코성결절 ( mm 2 ) 이보였으며, 부갑상선에는특이적인소견은보이지않았다. 심장초음파에서는좌심실비대 (left ventricle mass = 158 g, 101 g/m 2 ), 좌심방확장 (left atrium dimension = 40 mm) 이보였으며, 심장박출률은 65% 였다. 유전자검사 : MEN 1 유전자부위염기서열분석을위해유전자검사를권유하였으나, 환자는비용문제로거부하였다. 상부위장관내시경소견및수술소견 : 흑색변을동반한혈색소감소및불안정한생체징후소견이있어위장관출혈감별을위해응급상부위장관내시경을시행하였다. 상부위장관내시경결과위, 십이지장점막주름이두꺼웠으며, 십이지장구부에서제2부로넘어가는부위에서혈괴가 관찰되고그밑으로십이지장궤양과활동성출혈관찰되었다 (Fig. 3). 출혈을동반한궤양부위에내시경적지혈술을시도하였으나시야확보가불가능한상태였으며, 환자는불안정한생체징후가지속되어외과적응급탐색적개복술을하였다. 개복시십이지장이간과유착되어있었으며, 십이지장후벽첫번째부위에 1.5 cm 크기의출혈성궤양이보였다. 이에대해봉합술을시행하였고, 지속되는출혈이없음을확인후수술을종료하였다. 수술은십이지장궤양에대한단순봉합술만시행하여조직검체는얻지못하였다. 수술 2 주후에재검사한위장관내시경결과십이지장구부에이전의절개부위가보였으며제2부로넘어가는십이지장각의전엽에치유기궤양이관찰되고출혈의증거는없었다. 환자는재시행한위장관내시경시비용의문제로조직생 Table 3. Results of the somatostatin induced growth hormone suppression test Time (minute) to somatostatin induced GH suppression test 0 min 60 min 120 min 240 min 360 min GH (ng/ml) to octreotide 0.1 mg GH, growth hormone. Fig. 4. Insulin-like growth factor-1 (IGF-1) and gastrin level during the treatment with long acting octretide (Sandostatin LAR R ; Sandoz Pharma Ltd., Basel, Switzerland) 20 mg for 0, 4th week, 30 mg for 8th, 12th week, 20 mg 16th, 20th week

6 2 1 1 A B C D Fig. 5. Before treatment, an enlarged nose, protruding lips and thicker fingers were observed (A, C). After treatment, the patient s appearance is better (B, D). Time (wk) Fig. 6. At 8 week, Patient wanted to switch insulin treatment to oral anti-diabetes drugs. During insulin treatment with long acting octretide, total insulin dose per day and HbA1c were decreased. IU, international unit

7 검을거부하였다. 치료및경과 : 75 g 경구포도당부하검사에서혈청성장호르몬은억제되지않고증가된소견을보였으며, 공복시검사한혈청가스트린은상승되어있어말단비대증과가스트린종을확인하였고, 뇌하수체종양과장췌장내분비종양의 MEN 1을임상적으로진단할수있었다. 말단비대증에대한치료로환자는십이지장의출혈로인한개복술의기왕력및전신기력저하를이유로외과적인수술을거부하여, 입원중 somatostatin induced growth hormone stimulation test 시행후양성소견을보여 long acting octretide (Sandostatin LAR R ; Sandoz Pharma Ltd., Basel, Switzerland) 20 mg 치료를시작하였다 (Table 3). 환자는퇴원후현재외래에서 5개월동안질병의활성도를볼수있는 IGF-1와공복시혈청가스트린농도를확인하고있으며, 점차감소하는양상을볼수있었고첫진단당시의손, 발의말단비대, 입술의비대, 피부주름증가, 이마돌출은호전된소견을볼수있었다 (Fig. 4, 5). 환자는 MEN 1에대한치료시작전하루인슐린요구량이 100 IU (international uint) 가넘는인슐린저항성을보였고당화혈색소는 11.5% 였으나, 입원중 MEN에대한치료시작후퇴원 8주에는인슐린하루요구량은 60 IU, 당화혈색소는 8.5% 로각각감소하였다 (Fig. 6). 이후환자에게지속적인인슐린치료를권고하였으나거부하여, 퇴원 8주이후부터경구혈당강하제로현재유지중이다. 고찰 대한당뇨병학회에서발생한 Diabetes Fact Sheet in Korea 2013에따르면 2011년우리나라 30세이상의성인을대상으로한연구에서조사대상의 12.4%, 약 800만여명이당뇨병환자였으며, 20% 인 61만명이당뇨병전단계인내당능장애를진단받은것으로나타났다. 연구에따르면당뇨병환자의 77% 가경구혈당강하제, 11% 가인슐린으로치료하고있었으나 11% 는당뇨병에대해어떠한치료도하지않고있었으며, 치료받는환자군중약 28% 만이치료 적목표혈당수치인당화혈색소 6.5% 이하를보여현재우리나라성인당뇨병환자들에게서적절한혈당조절이되지않고있음을알수있었다. 당뇨병환자에서불량한혈당조절을유발시키는데에는여러요인이있겠지만특히다양한내분비질환이함께병발된경우내당능장애및여러호르몬간의상호작용을일으켜지속적인불량한혈당조절을유발하며이는질환에의한사망률을증가시킨다고알려져있다 [1]. 본증례에서는 6개월전부터지속적으로발생한불량한혈당조절을주소로내원한환자에게서혈당상승의원인감별중이학적소견의심하에시행한 75 g 경구포도당검사와공복혈청가스트린검사를통해뇌하수체종양인말단비대증과장췌장내분비종양인가스트린종을확인하여 MEN 1을진단하였다. MEN은한환자에게다양한내분비종양들이발생하여복잡한임상양상을보이는드문질환이며, 진단이늦거나치료를소홀히할경우치명적인결과를초래하므로조기발견이매우중요하다. 임상양상에따라제1형과제2형으로구분한다 [2]. 이중본증례의 MEN 1은 MEN 중가장흔하며, 부갑상선종양 (> 80%), 장췌장내분비종양 (75%), 뇌하수체종양 (60%) 중 2개이상을동반한경우에진단할수있다 [3,4]. 본증례에서확인되는장췌장내분비종양인가스트린종은 MEN의 25% 에서진단되며, 발생부위는십이지장 (50~75%), 췌장 (20~40%) 이다. 가스트린종은상부소화관의궤양성질환과현저한위산분비의증가를보이며위산분비억제및궤양의치료에도움이되는양성자펌프억제제 (proton pump inhibitor) 제제를많이사용하고있으며, 궤양에대한합병증으로위절제술이필요한경우는반드시위전절제술을시행하도록한다 [5-7]. 본증례의환자는입원당시상부위장관내시경에서십이지장에활동성출혈을동반한궤양이있었고, 위, 십이지장의주름이비정상적으로두꺼워져가스트린종을의심할수있었으며공복시검사한혈청가스트린의상승소견으로진단할수있었다. 말단비대증은아주드문뇌하수체질환으로성장호르몬 131

8 2 1 1 의지속적인과다분비로인하여골격과결합조직및내부장기의과잉성장을특징으로하는질환이다. 말단비대증의원인으로는증례의경우처럼뇌하수체에서발생하는거대선종이대부분을차지하며 99% 이상에서성장호르몬의분비로인해발생한다 [8-10]. 말단비대증환자는전형적인말단비대의외형적인소견이외에두통및시력장애, 심비대, 대사성질환등이나타날수있으며, 이중 60~70% 에서내당능장애가동반되며이는고혈압과함께심근병을악화시켜사망률을증가시키는주요요인이된다 [11]. 일반적으로뇌하수체종양의치료는수술적인절제치료가치료원칙이며수술적인방법은성장호르몬수치를 1시간이내에, IGF-1은 3~4일이내에정상화될정도로치료효과가빠르다. 약물치료는수술적인치료에비해치료효과는낮다고평가되나, 40~50% 에서뇌하수체선종의크기감소, 75% 에서는 IGF-1 레벨의정상화가된다고알려져있다 [12,13]. 환자는입원중말단비대증과가스트린종에대해 Sandostatin LAR R 20 mg 투여를시작하였고, 4주단위로투약을유지하였다. 퇴원후 8주, 12주에는 Sandostatin LAR R 30 mg으로증량하여투약하였으며, 퇴원이후 20주현재 Sandostatin LAR R 20 mg으로투약을유지하고있다. 질병의활성도를나타내는 IGF-1과공복시혈청가스트린농도는지속적으로감소되고있으며, 외래에서관찰한손, 발및말단의비대도이전보다호전된모습을보이고있다. 아울러환자는입원당시하루인슐린요구량이 100 IU 가넘는인슐린저항성을보였으나 MEN에대한치료시작 4주, 8주후하루인슐린요구량및당화혈색소는감소되는소견을보였다. 환자에게지속적인인슐린치료를권고했으나환자는외래에서경구혈당강하제의복용만을원하여 8 주이후인슐린치료는중단하였으며경구혈당강하제로변경하였다. 본증례는환자의거부로 MEN 1에대한유전적검사와재시행내시경시조직생검을진행하지못하였으며, 수술시십이지장궤양에대한단순봉합술만시행하여조직검체를얻지못하였다는점을제한점으로가지고있다. 본저자들은조절되지않는혈당을주소로내원한제2형당뇨병환자에게서이에대한원인감별중우연히 MEN 1 을진단하였으며, 이는지속적고혈당의원인임을확인하였다. 이를바탕으로제2형당뇨병환자들에게서불량한혈당조절발생시생각해볼수있는원인으로내분비학적질환에대해서고려해보아야하겠다. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Kim DJ. The epidemiology of diabetes in Korea. Diabetes Metab J 2011;35: Marx SJ, Wells SA. Multiple endocrine neoplasia. In: Melmed S, Polonsky K, Larsen PR, Kronenberg H, eds. Williams textbook of endocrinology. 12th ed. Philadelphia: Elsevier; p Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E, Brandi ML. MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1. Eur J Endocrinol 2000;142: Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1(MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008,29: Stabile BE, Passaro E Jr. Recurrent peptic ulcer. Gastroenterology 1976;70: Hirschowitz BI. Zollinger-Ellison syndrome: pathogenesis, diagnosis, and management. Am J Gastroenterol 1997;92(4 Suppl):44S-48S; discussion 49S-50S. 7. Orloff SL, Debas HT. Advances in the management of patients with Zollinger-Ellison syndrome. Surg Clin 132

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DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%) aged over 30 years or older had diabetes in 2010. Based on fasting g

DIABETES FACT SHEET IN KOREA 2012 Korean Diabetes Association (KDA) / Korea Centers for Disease Control and Prevention (CDC) DIABETES FACT SHEET IN KOREA 2012 SUMMARY About 3.2 million Korean people (10.1%)