J Korean Diabetes 2016;17:159-163 Vol.17, No.3, 2016 ISSN 2233-7431 김진화조선대학교병원내분비대사내과 Management of Diabetes in Liver Cirrhosis Jin Hwa Kim Department of Endocrinology and Metabolism, Chosun University Hospital, Gwangju, Korea Abstract Diabetes mellitus (DM) is common in patients with liver cirrhosis, indicating a bidirectional relationship between DM and liver cirrhosis. Type 2 DM is a risk factor for development and progression of chronic liver disease including liver cirrhosis, and DM may occur as a complication of liver cirrhosis. Hyperglycemia and hyperinsulinemia have profibrogenic properties on hepatic stellate cells, and contribute to liver damage by promoting inflammation and fibrosis through an increase in mitochodrial oxidative stress mediated by adipokines. The presence of DM in patients with liver cirrhosis is not only related to the poor survival rate but also associated with major complications of cirrhosis. This suggests that optimal management of DM could be beneficial in patients with liver cirrhosis. However, the management of DM in patients with liver cirrhosis is complex because of impaired liver function and of the potential hepatotoxicity of oral hypoglycemic agents. We review the clinical implications and the therapeutic management of DM in patients with liver cirrhosis. Keywords: Diabetes mellitus, Glucose control, Liver cirrhosis Corresponding author: Jin Hwa Kim Department of Endocrinology and Metabolism, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 61453, Korea, E-mail: endocrine@chosun.ac.kr Received: Jul. 30, 2016; Accepted: Aug. 5, 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) 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 The Journal of Korean Diabetes 159
서론 간은포도당항상성유지에중요한역할을담당하며, 간질환과포도당대사이상은서로밀접한연관성을지닌다. 간경화환자에서당뇨병의유병률은약 30% 로, 공복혈당이정상인경우에도경구당부하검사시환자들의 80% 에서내당능장애또는당뇨병이확인되었다 [1]. 당뇨병과간경화는서로상호간에영향을미칠수있다. 제2형당뇨병은만성간질환발생의위험도를증가시키며, 간경화합병증의하나로당뇨병 (hepatogenous diabetes) 을분류하기도한다 [2]. 간경화환자에서당뇨병은간경화와연관된여러합병증의위험도증가및사망률증가와관련된다. 비보상성간경화 (decompensated liver cirrhosis) 환자에서당뇨병은간성혼수, 간문맥고혈압, 그리고식도정맥류출혈과연관되었다 [3,4]. 간경화가있는당뇨병환자에서혈당관리는간기능의저하및경구약제들의간독성발생가능성등으로인하여간경화가없는당뇨병환자에비하여좀더복잡하고쉽지않다. 이에본글에서는당뇨병이간경화에미치는영향에대해서논의하고, 간경화가있는당뇨병환자의혈당관리에대하여정리하고자한다. 본론 1. 당뇨병과간경화간경화환자에서당뇨병이간경화와연관된여러합병증의발생위험도를증가시키고사망률증가와연관된다는후향적연구결과들이있다 [3,4]. 이는당뇨병과간경화사이에시너지효과가존재할수있음을시사한다. 당뇨병은지방세포에서분비된렙틴, 아디포넥틴, 인터루킨-6, 그리고 tumor necrosis factor- α (TNF-α) 의활성화를통하여미토콘드리아의산화스트레스를증가시킴으로써간의염증및섬유화를촉진하고간손상을유도한다. 이러한과정은인슐린저항성에의해자극되며, transforming growth factor- β1(tgf-β1) 과렙틴또한간성상세포 (stellate cells) 를활성화시켜콜라겐을생산함으로써섬유화를유도할수있다 [5]. 간경화환자는간용적감소등간의구성적변화에의하여인슐린대사가감소될수있고, 이는고인슐린혈증의결과를가져온다. 포도당과인슐린은간성상세포에서섬유화를유도하는특성을지닌다. 고농도의포도당또는인슐린에노출된간성상세포는섬유화과정의주요요소인결합조직성장인자 (connective tissue growth factor) 의유전자발현을증강시켰다 [6]. 고혈당과산화스트레스는최종당화산물 (advanced glycation end products) 의축적을야기시킨다. 최종당화산물의수용체가간성상세포에서확인되는데, 이는간성상세포에대한최종당화산물의영향을예측할수있다. 당뇨병의특징중하나인만성적염증상태또한간섬유화의발생및진행에영향을미친다 [7]. 당뇨병은간경화환자에서원발성세균성복막염등심각한감염의위험도를증가시키며, 이로인한사망률은당뇨병이없는간경화환자에비하여 4배정도높았다 [8]. 간성혼수의발생위험도또한당뇨병환자에서증가되는데, 소장의 K형글루타미나아제증강에의한암모니아생성증가및당뇨병성자율신경병증에의한장운동기능저하가발생에영향을미칠수있다 [9]. 2. 간경화가있는당뇨병환자에서혈당관리간경화가있는당뇨병환자의혈당관리는간경화가없는당뇨병환자와크게다르지는않으나간기능의저하및경구약제들의간독성발생가능성등으로인하여주의를요한다. 간경화가있는당뇨병환자만을대상으로시행된특성화된연구결과의부족으로현재이에대하여명확히제시하기는어려운현실이다. 대부분의경구약제가간에서대사된다는점을고려할때, 이에대한모니터링이요구된다. 1) 생활습관조절간이상을동반한당뇨병환자에서생활습관조절의효과 160
김진화 에대한명확한연구결과는없다. 그러나생활습관개선은혈당상태개선에긍정적영향을미칠수있을것으로기대된다. 간경화환자는영양결핍상태가흔히동반될수있어서극심한영양제한은피해야하며, 복수, 하지부종등이동반된진행된간경화환자의경우운동은제한해야한다 [10]. 2) 메트포르민메트포르민은인슐린저항성을완화시키고지질대사에긍정적효과를나타낸다. 또한간에서대사되지않으며, 주로신장을통해대사되지않은상태로배설된다. 따라서간경화를동반한당뇨병환자의초치료제로서메트포르민이추천될수있다. 그러나젖산증발생위험도를고려하여진행된간경화환자에서는그사용이추천되지않는다 [11]. 메트포르민투여가간세포암발생위험도감소와연관되었다는연구결과들이있다. 당뇨병과 C형감염에의한간경화를동반한환자들을대상으로평균 5.7년을관찰한결과메트포르민투여는간세포함발생률감소와유의하게연관되었다 [12]. 간경화를동반한당뇨병환자 250명을대상으로메트포르민의지속적치료효과를관찰한또다른코호트연구에서메트포르민을지속적으로복용한간경화를동반한당뇨병환자군이중단한환자군에비하여높은생존율증가를보였다 (11.8년 vs. 5.6년 ) [13]. 메트포르민이간성혼수의발생률저하와연관된다는코호트연구가있다. 간경화를동반한당뇨병환자 82명을대상으로시행된연구로, 메트포르민을복용하는환자군에서간성혼수의발생률이유의하게낮았다 (5% vs. 41%) [14]. 3) 알파글루코시데이즈억제제간경화를동반한당뇨병환자의경우공복혈당은정상이면서식후혈당만상승되는경우를흔히볼수있는데, 알파글루코시데이즈억제제는장에서탄수화물의흡수를억제하여간경화환자의식후고혈당감소에유용할수있다. 인슐린치료중인보상성 (compensated) 간경화를동반한당뇨병환자에서아카보스를 28주간투여한경우공복혈당및 식후혈당의유의한개선효과를보였다 [15]. 4) 티아졸리딘디온피오글리타존은 CYP2C81 및 CYP3A4에의하여대사되는데, 만성간질환을지닌환자에서의약물역동학적결과는없다. 간독성은낮지만, 간효소치가정상상한치보다 2.5 배상승한보상성간경화환자에서는사용에주의를요한다 [16]. 5) 인슐린분비촉진제간경화를동반한당뇨병환자에서설폰요소제투여시에는저혈당발생의위험도가증가될수있음을고려해야한다. 특히, 신기능저하를동반하거나고령의환자에서주의를요한다. 알코올성간경화환자의경우췌장의베타세포손상으로인하여그효과가제한될수있다. Glyburide, glibencrimide와같은반감기가짧은인슐린분비촉진제사용을추천하며, gliclazide 는간에서대사되므로심각한간기능장애를동반한환자에서는그사용을피해야한다 [17]. 메글리티나이드계약제인레파글리나이드와나테글리나이드는모두간에서대사된다. 레파글리나이드는답즙을통해서제거되는데, 만성간질환환자에서제거율의감소로인하여저혈당이유발될수있다. 따라서진행된간기능장애환자에서는그사용을피해야한다 [18]. 6) Glucagon-like peptidase-1 유사체및 dipeptidylpeptidase-4 (DPP-4) 억제제 Exenatide는일차적으로신장으로배설되며간기능저하에의해영향을받지않는다. Liraglutide는비알코올성지방간과당뇨병이동반된환자에서염증반응및간섬유화의감소를보여주었다 [19]. DPP-4 억제제계열의약제는소량만이간에서대사되고, 대부분대사되지않은상태로신장을통해배설된다 [20]. 따라서간경화를동반한당뇨병환자에서좀더안전하게사용할수있는있는가능성이존재한다. 그러나이러한약제의지속적투여에대한장기간의연구결과는현재없는 www.diabetes.or.kr 161
상태로, 진행된간기능장애환자에서는투여에주의를요한다. 구는부족한실정이다. 간경화를동반한당뇨병환자들을대상으로한전향적대규모연구들이요구된다. 7) Sodium glucose transporter 2 (SGLT2) 억제제 SGLT2에의한혈량저하발생가능성을고려하여순환성기능장애가동반된간경화환자에서는사용에주의를요한다. Dapagliflozin은글루크론산화 (glucuronidation) 를통해제거되는데, 약물역동학연구에서중등도이상의간기능장애를가진환자들은일반인에비하여약물에대한전신노출정도가더높았다. 임상적으로의미있는차이는아니었지만, 장기간의안전성및그효과에대한연구가현재는충분하지않아서간경화환자에게투여시개별화된접근및주의를요한다 [21]. Canagliflozin과 empagliflozin 또한간기능장애환자에서약제의전신노출정도가높았다. 경미한또는중등도의간기능장애를지닌환자에서간독성은낮았지만, 지속적투여에대한연구결과의부족으로투여에주의를요한다 [22,23]. 8) 인슐린간경화를동반한당뇨병환자의약 60% 에서인슐린투여가요구된다. 보상성간경화환자에서는인슐린요구량이증가될수있는반면, 비보상성간경화환자에서는간의포도당신생및인슐린제거률감소로인하여그요구량이낮을수있다. 따라서간경화정도에따라서인슐린투여량이다를수있으므로인슐린투여시개별화된접근및저혈당발생위험에대한지속적인감시가필요하다. 인슐린동족체들은간기능에의해영향을받지않아서속효성인슐린동족체들은간경화환자의식후고혈당조절에유용하게사용될수있다 [24]. 결론 당뇨병과간경화의상호영향을고려할때간경화를동반한당뇨병환자의혈당관리는차별화된전략이필요하다. 그러나현재까지이러한환자들을대상으로한특성화된연 REFERENCES 1. García-Compeán D, Jáquez-Quintana JO, Lavalle- González FJ, Reyes-Cabello E, González-González JA, Muñoz-Espinosa LE, Vázquez-Elizondo G, Villarreal- Pérez JZ, Maldonado-Garza HJ. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012;11:240-8. 2. García-Compean D, Jaquez-Quintana JO, Maldonado- Garza H. Hepatogenous diabetes. Current views of an ancient problem. Ann Hepatol 2009;8:13-20. 3. Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006;40:68-76. 4. Butt Z, Jadoon NA, Salaria ON, Mushtaq K, Riaz IB, Shahzad A, Hashmi AM, Sarwar S. Diabetes mellitus and decompensated cirrhosis: risk of hepatic encephalopathy in different age groups. J Diabetes 2013;5:449-55. 5. Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology 2008;15:91-101. 6. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738-44. 7. Fehrenbach H, Weiskirchen R, Kasper M, Gressner AM. Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. Hepatology 2001;34:943-52. 8. Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis 162
김진화 E, Pleguezuelo M, Burroughs AK. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:1246-56, 1256.e1-5. 9. Sigal SH, Stanca CM, Kontorinis N, Bodian C, Ryan E. Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis. Am J Gastroenterol 2006;101:1490-6. 10. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007;30:734-43. 11. Chan NN, Brain HP, Feher MD. Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 1999;16:273-81. 12. Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, Ganne-Carrie N, Grando-Lemaire V, Vicaut E, Trinchet JC, Beaugrand M. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011;96:2601-8. 13. Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinol Metab Clin North Am 1999;28:555-77. 14. Ampuero J, Ranchal I, Nuñez D, Díaz-Herrero Mdel M, Maraver M, del Campo JA, Rojas Á, Camacho I, Figueruela B, Bautista JD, Romero-Gómez M. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279. 15. Gentile S, Turco S, Guarino G, Oliviero B, Annunziata S, Cozzolino D, Sasso FC, Turco A, Salvatore T, Torella R. Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis. Diabetes Obes Metab 2001;3:33-40. 16. Jaakkola T, Laitila J, Neuvonen PJ, Backman JT. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol 2006;99:44-51. 17. Chitturi S, Le V, Kench J, Loh C, George J. Gliclazideinduced acute hepatitis with hypersensitivity features. Dig Dis Sci 2002;47:1107-10. 18. Hatorp V. Clinical pharmacokinetics and pharmacodynamics of repaglinide. Clin Pharmacokinet 2002;41:471-83. 19. Giorda CB, Nada E, Tartaglino B. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine 2014;46:406-19. 20. Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet 2012;51:501-14. 21. Kasichayanula S, Liu X, Zhang W, Pfister M, LaCreta FP, Boulton DW. Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study. Clin Ther 2011;33:1798-808. 22. Nigro SC, Riche DM, Pheng M, Baker WL. Canagliflozin, a novel SGLT2 inhibitor for treatment of type 2 diabetes. Ann Pharmacother 2013;47:1301-11. 23. Macha S, Rose P, Mattheus M, Cinca R, Pinnetti S, Broedl UC, Woerle HJ. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab 2014;16:118-23. 24. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005;60:469-76. www.diabetes.or.kr 163