대한내과학회지 : 제 76 권제 5 호 2009 Alpha lipoic acid 와연관된인슐린자가면역증후군 1 예 1 가톨릭대학교의과대학내과학교실, 2 을지대학교의과대학내과학교실 장형진 1 최현숙 1 박미연 1 임성민 1 장이선 1 박강서 2 이종민 1 A case of insulin autoimmune syndrome related to alpha-lipoic acid Hyoung Jin Chang, M.D. 1, Hyun Sook Choi, M.D. 1, Mi Youn Park, M.D. 1, Sung Min Leem, M.D. 1, Yi Sun Jang, M.D. 1, Kang Seo Park, M.D. 2 and Jong Min Lee, M.D. 1 1 Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Daejeon, Korea; 2 Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea Insulin autoimmune syndrome is characterized by spontaneous hypoglycemia, high concentrations of serum immunoreactive insulin, and the presence of autoantibodies to insulin without previous insulin injection. A 71-year-old woman with diabetes, who had been treated with oral hypoglycemic agents, suffered from frequent hypoglycemia. High insulin levels and the presence of insulin autoantibodies were shown, so insulin autoimmune syndrome was diagnosed. Drugs containing sulfhydryl groups play an important role in the pathogenesis of insulin autoimmune syndrome. Alpha-lipoic acid, which contains a sulfhydryl group, was administered before the onset of hypoglycemia. The patient s human leukocyte antigen (HLA) type was HLA-Cw4 and DRB1*0406. There is a strong correlation between HLA-DRB1*0406 and insulin autoimmune syndrome. The patient was treated with prednisolone and has not had a hypoglycemic attack since. We report a case of insulin autoimmune syndrome, possibly associated with alpha-lipoic acid. (Korean J Med 76:600-604, 2009) Key Words: Insulin autoimmune syndrome; Alpha-lipoic acid; HLA-DRB1*0406 서론인슐린자가면역증후군은인슐린투여없이자발적으로발생하는공복저혈당, 혈중내높은인슐린수치, 인슐린자가항체의존재를특징으로하는드문질환으로 1970년 Hirata 등이처음발표 1) 한이래로우리나라에서도몇몇사례들이보고되었다 2-8). 질환의기전은잘모르지만, 인슐린자가항체에식후췌장에서분비된인슐린이결합하여상대적 인인슐린부족을유발하고활성인슐린을유리시키게되는데공복시낮은혈당수치에도계속유리되어공복저혈당을유발하는것으로알려져있다 4-6). Sulfhydryl 기를가지고있는약제에의해인슐린자가항체가생성된다는보고가있으며, 특정 HLA 및자가면역질환과의연관성이알려져있다. 저자들은인슐린자가면역증후군이진단된사람에서 sulfhydryl기가있는 alpha lipoic acid 유도체인치옥타시드복용력이있었던예를경험하였기에보고하는바이다. Received: 2007. 9. 6 Accepted: 2008. 6. 26 Correspondence to Yi Sun Jang, M.D., Department of Internal Medicine, St. Mary s Hospital of Daejeon Catholic University, Daeheung-dong, Jung-gu, Daejeon 301-723, Korea E-mail: jangyisun@hanmail.net - 600 -
- Hyoung Jin Chang, et al. Insulin autoimmune syndrome related to α-lipoic acid - Figure 1. Abdominal computed tomography shows no evidence of a tumor in the pancreas. Figure 2. Sellar magnetic resonance imaging shows a normal pituitary gland. 증례환자 : 김 순, 71세여자주소 : 두달간지속된손떨림및전신쇠약감현병력 : 환자는 5년전당뇨병진단받고설폰요소제로혈당조절중내원두달전부터손발이떨리고저리는증상과함께자주식은땀을흘리고피로감지속되어란투스로약 2~3일간치료하였으나호전보이지않아내원하였다. 과거력 : 2003년변이형협심증으로진단받고 diltiazem, molsiton 복용중이었고, 2005년맹장염으로절제술을시행받았다. 가족력 : 특이소견없음. 진찰소견 : 혈압 140/90 mmhg, 맥박 66회 / 분, 호흡수 20회 / 분, 체온 36.6 였고, 신장 150.5 cm, 체중 65.1 kg였다. 갑상선비대나피부색소침착은없었고, 다른이상소견은관찰되지않았다. 검사소견 : 혈액검사에서백혈구 6,300/mm 3, 혈색소 12.4 g/dl, 혈소판 185,000/mm 3, 공복혈당 41 mg/dl, BUN 11.6 mg/dl, Cr 0.77 mg/dl, 총단백 7.1 g/dl, 알부민 4.0 g/dl, 총빌리루빈 0.3 mg/dl, AST 22 IU/L, ALT 10 IU/L, ALP 80 IU/L, 총콜레스테롤 137 mg/dl, 중성지방 101 mg/dl, 고밀도지질단백 52.4 mg/dl, 칼슘 8.9 mg/dl, 인 3.9 mg/dl, 나트륨 148 meq/l, 칼륨 3.8 meq/l이었다. 소변검사에서요단백 (-), 포도당 (4+), 백혈구 0-1/HPF, 적혈구 0-1/HPF 이었다. 당화 혈색소 7.4%, 24시간미세알부민뇨 5.4 μg/min이었으며, 갑상선검사에서 T3 1.92 nmol/l ( 정상치 1.2~2.8 nmol/l), 유리 T4 1.21 ng/dl ( 정상치 0.89~1.78 ng/dl), TSH 0.69 μiu/l ( 정상치 0.3~6.05 μiu/l), 항미소체항체와항티로글로불린항체모두음성이었다. 저혈당증세가있었을당시시행한검사에서성장호르몬 2.7 ng/ml ( 정상치 0.66~3.68 ng/ml), ACTH 7.9 pg/ml, cortisol 9.06 μg/dl로나와 rapid ACTH 자극검사를시행하였으며 cortisol 수치가 0분 11.64 μg/dl, 30분 20.05 μg/dl, 60분 22.68 μg/dl로정상반응을보였다. 혈청인슐린은 37,300 μiu/ml 이상, C-peptide 86.9 ng/ml로증가되어있었고, percent 125 I-insulin binding은 90.9% ( 정상치 0~7%) 였다. 면역학적검사에서 IgG 1,372 mg/dl, IgA 152 mg/dl, IgM 184 mg/dl, C3 112.2 mg/dl, C4 24.2 mg/dl로정상이었고, 류마티스인자음성, 항핵항체음성이었다. 혈청및소변전기영동검사에서이상소견은보이지않았다. HLA 검사결과 class I에서 HLA-A24, A11, B35, B62, Cw3 및 Cw4, class II에서 HLA-DRB1*0406 및 HLA- DRB1*1201 를보였다. 방사선학적소견 : 복부초음파검사에서경한지방간외에는이상소견없었고, 복부전산화단층촬영에서췌장의이상소견은관찰되지않았다 ( 그림 1). 뇌하수체자기공명영상촬영에서도뇌하수체선종이나다른특이소견은없었다 ( 그림 2). - 601 -
- 대한내과학회지 : 제 76 권제 5 호통권제 585 호 2009 - Figure 3. The structure of alpha-lipoic acid. 치료및경과 : 빈번하게공복시저혈당이반복되어시행한호르몬검사에서특이소견없었고, 혈청인슐린수치증가및인슐린자가항체가증가되어있어인슐린자가면역증후군으로진단하였다. Sulfhydryl 기를가지고있는약제에의해발생한다는보고가많아환자에게투여되었던약제들을조사한결과저혈당발생약 4주전부터투여되었던 alpha lipoic acid 유도체인치옥타시드가 sulfhydryl기를포함하고있어투약을중지하였다 ( 그림 3). 하루 4번식사로저혈당이해결되어퇴원하였으나퇴원후에도저혈당을경험하여프레드니솔론 60 mg (1 mg/kg) 으로약 2주간사용후감량하여현재 7.5 mg으로유지하고있으며저혈당없이혈당조절은잘되고있다. 진단받고 6개월후에검사한 percent 125 I-insulin binding 80.8%, 인슐린 107.7 μiu/l로높은상태이나특별한자각증상없이경과관찰중이다. 고찰저혈당은여러가지원인에의해발생할수있으며특히공복저혈당은약물, 중증의간또는신장의질환, 인슐린종, 호르몬결핍등으로생기는경우가대부분이다. 이중에서고인슐린혈증을동반하는저혈당의원인으로는인슐린종과경구혈당강하제의무분별한사용, 자가면역성저혈당을들수있는데, 인슐린을투여받은적이없는환자에게서자발적인저혈당, 고인슐린혈증과인슐린결합자가항체를보이는질환이인슐린자가면역증후군이다 9). 인슐린자가항체의발생을촉진하는요인은잘모르지만인슐린을맞고있는제1형당뇨병, 다선증후군환자, 헌혈자의 2% 에서도발견되며이런경우대개인슐린자가항체수치가낮아서증세를발현시키지않고, 인슐린자가항체수치가높은인슐린자가면역증후군에서저혈당발생과관련이있다고한다 10). 이질환의호발연령은 60세에서 69세이며저혈당발현시기나나이및성별간의차이는없다고알려져있고 80% 에서그레이브스병, 류마티스관절염, 루푸스등의자가면역성질환과동반되어온다 9,12). 43% 는증세발현하기 4~6주전에약제복용력을가지고있다 9). 메티마졸, D-penicillamine, α- mercaptopropionyl glycine, glutathione, captopril 등이있으며공통적으로 sulfhydryl 기를가지고있는약제들이다 6,11). tolbutamide, diltiazem, loxoprofen sodium, interferon-α 등 sulfhydryl 기를가지고있지않은약제복용력도보고된바있다 10). 보통 sulfhydryl기가인슐린의 disulfide 결합과작용하여 hapten을형성하거나인슐린내의 disulfide 결합이분해되고분해된인슐린이면역반응을야기시킴으로써인슐린결합항체가생성되는것으로보고있다 12). 본증례의경우면역학적검사에서특이소견이없었고, 복용했던약제에대해조사한결과내원약 4주전부터복용했던 alpha lipoic acid 유도체인치옥타시드가 sulfhydryl 기를가지고있어복용을중지했으며 diltiazem은 sulfhydryl 기를가지고있지않으나인슐린자가면역증후군발생과관련된바가있어역시복용중단하였다. 문헌고찰결과 alpha lipoic acid와관련된사례가있음을확인할수있었다 13,14). 이질환은 HLA와연관이있으며, class I 항원보다는 class II 항원이좀더강한연관성을보이는것으로알려져있다. class I 항원중에서 Cw4, Bw62가인슐린자가면역증후군과연관이있음이보고되었고, class II 항원중에서는 HLA-DR4 와의연관성이보고되었다 15). 특히코카시아인들에비해일본등지에서의유병률이높은이유를 HLA-DR4 allele 의분포차이로설명할수있는데, 일본인인슐린자가면역증후군환자들에서보이는 3개의 DR4 alleles 즉, HLA-DRB1*0403, DRB1*0406, DRB1*0407의지리적분포와전세계적인인슐린자가면역증후군의유병률과의관계에대한문헌보고를보면, 질환의발생과강한연관성을보이는 DRB1*0406이한국인 5.4%, 일본인 3.5% 로동아시아인에게서높은빈도를보인반면코카시아인은낮은빈도를보여유전자와관련이있음을알수있다 16). 또한일본인인슐린자가면역증후군에서는 HLA-DR4 양성률이 96% 인반면코카시아인은 7예중에서 4예만이 DR4 양성으로나왔으며 DRB1*0407, DRB1* 0401, DRB1*0402, DRB1*0404 등일본인과는다른양상을보였다 17). 본증례에서도인슐린자가면역증후군과관련성이보고된 HLA-Cw4와 DRB1*0406이검출되어질환과합당한소견을보였다. 인슐린자가항체의특성도 HLA와연관이있다는보고가있다. 인슐린자가면역증후군환자 54명을대상으로한문헌보고에따르면 18) 이중 48명이다클론항체, 6명이단일클론항체를갖고있었으며, 단일클론항체가있었던환자중에서 1명을제외하고는모두코카시아인이었다. 또한다클론항체가있는환자는 HLA-DR4/DQ3, DR9/DQ3에양성인반면단 - 602 -
- 장형진외 6 인. α-lipoic acid 연관인슐린자가면역증후군 - 일클론항체환자는 3명만이 HLA-DR4 양성이었고, 나머지 3 명은 DR4 및 DR9 모두가지고있지않은것으로밝혀져다클론항체와단일클론항체는발생기전자체가다를것으로보았다. 인슐린자가면역증후군의자연경과는 1년이상증세가지속되기도하지만 9) 보통은특별한치료없이 1~3개월사이에 82% 에서저절로호전되며, 저혈당증세가지속될경우스테로이드, azathioprine, 6-mercaptopurine 등의약제를사용할수있고 10) 인슐린자가항체를제거하기위한혈장반출술을시행할수있다 11,19). 그외에도잦은음식섭취및 α-glucosidase 억제제가도움이된다고하였는데 9), 본증례의경우치옥타시드복용을중지한후하루 4번의식사로저혈당증세는호전되었으나, 퇴원후다시생긴저혈당으로인해스테로이드치료를시행하였으며 6개월이후에도인슐린자가항체는여전히높은상태이지만저혈당증세없이관찰중이다. 요 당뇨병으로경구혈당강하제복용중에발생한저혈당으로내원한 71세여자에서혈청인슐린수치와인슐린자가항체가높게측정되어인슐린자가면역증후군으로진단하였다. 약 4주전부터 sulfhydryl기가있는치옥타시드를복용하였고, HLA 분석결과인슐린자가면역증후군에서추출되는 Cw4, DRB1*0406이나와확진할수있었으며프레드니솔론투여로저혈당증세는호전되었다. 이미당뇨병으로치료중인환자에서는빈번한저혈당이온다고해도인슐린자가면역증후군을고려하기쉽지않지만전세계적으로동아시아지역에서유병률이높은것을감안하면이질환을염두해두어야할것이다. 중심단어 : 인슐린자가면역증후군 ; 알파리포익산 ; HLA- DRB1*0406 약 REFERENCES 1) Hirata Y, Ishizu H, Ouchi N, Motomura S, Abe M, Hara Y, Wakasugi H, Takahashi I, Takano M, Kawano H, Kanesaki T. Insulin autoimmunity in a case of spontaneous hypoglycemia. J Jpn Diabetes Soc 13:312-320, 1970 2) Cho BY, Lee HK, Koh CS, Min HK. Spontaneous hypoglycemia and insulin autoantibodies in a patient with Graves disease. Diabetes Res Clin Pract 3:119-124, 1987 3) Lim JK, Woo YA, Kang SJ, Yoo SS, Hong KY, Kim SH. Insulin autoimmune syndrome in a patient with methimazole-treated Graves disease: a case report. J Korean Soc Endocrinol 13: 612-616, 1998 4) Lee KS, Kim JH, Choi WH, Kim TH, Kim MH. A case report of insulin autoimmune syndrome in Graves disease. J Korean Soc Endocrinol 8:451-455, 1993 5) Kim MJ, Shim MS, Kim MK, Lee Y, Kim YU, Shin YG, Chung CH. A case of autoimmune hypoglycemia induced by insulin autoantibody and insulin receptor autoantibody. Korean Clin Diabetes 3:177-184, 2002 6) Kim DJ, Kim NH, Seo JA, Kim SG, Choi KM, Baik SH, Choi DS. A case of autoimmune insulin syndrome. Korean J Med 71: 683-687, 2006 7) Lee SJ, Kong JH, Nam JY, Park JS, Kim CS, Kim DM, Ahn CW, Cha BS, Lim SK, Kim KR, Lee HC. A case of primary insulin autoimmune syndrome in a patient suspected of having an insulinoma. J Korean Diabetes Assoc 28:45-50, 2004 8) Park SH, Lee SW, Jeong GH, Choi CH, Lee SH, Han JH, Kim JG, Ha SW, Kim BW. Two cases of autoimmune insulin syndrome with hypoglycemia. J Korean Soc Endocrinol 16:508-513, 2001 9) Virally ML, Guillausseau PJ. Hypoglycemia in adults. Diabetes Metab 25:477-490, 1999 10) Dozio N, Scavini M, Beretta A, Sarugeri E, Sartori S, Belloni C, Dosio F, Savi A, Fazio F, Sodoyez JC, Pozza G. Imaging of the buffering effect of insulin autoantibodies in the autoimmune hypoglycemia syndrome. J Clin Endocrinol Metab 83:643-648, 1998 11) Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y. Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract 22:89-94, 1994 12) Ichihara K, Shima K, Saito Y, Nonaka K, Tarui S. Mechanism of hypoglycemia observed in a patient with insulin autoimmune syndrome. Diabetes 26:500-506, 1977 13) Takeuchi Y, Miyamoto T, Kakizawa T, Shigematsu S, Hashizume K. Insulin autoimmune syndrome possibly caused by alpha lipoic acid. Intern Med 46:237-239, 2007 14) Furukawa N, Miyamura N, Nishida K, Motoshima H, Taketa K, Araki E. Possible relevance of alpha lipoic acid contained in a health supplement in a case of insulin autoimmune syndrome. Diabetes Res Clin Pract 75:366-367, 2007 15) Uchigata Y, Kuwata S, Tokunaga K, Equchi Y, Takayama- Hasumi S, Miyamoto M, Omori Y, Hirata Y. Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet 339:393-394, 1992 16) Uchigata Y, Hirata Y, Omori Y, Iwamoto Y, Tokunaga K. Worldwide differences in the incidence of insulin autoimmune syndrome (Hirata disease) with respect to the evolusion of HLA-DR4 alleles. Hum Immunol 61:154-157, 2000 17) Cavaco B, Uchigata Y, Porto T, Amparo-Santos M, Sobrinho L, Leite V. Hypoglycemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin - 603 -
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