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Hepatocellular carcinoma: Current trends in NAFLD 장병국계명대학교의과대학내과학교실 Byoung Kuk Jang Department of internal medicine, Keimyung University School of medicine, Daegu, Korea.

1 Hepatocellular carcinoma: Current trends in NAFLD 장병국계명대학교의과대학내과학교실 Byoung Kuk Jang Department of internal medicine, Keimyung University School of medicine, Daegu, Korea. Non alcoholic fatty liver disease (NAFLD) already has become the most common chronic liver disease in the world. NAFLD encompasses simple hepatic steatosis to non alcoholic steatohepatitis (NASH) with necroinflammation, ballooning and fibrosis which may progress to cirrhosis with accumulation of fibrosis. Several studies reported that the cumulative incidence of hepatocellular carcinoma (HCC) in NASH cirrhosis ranges between % over a years period. Recently, the development of HCC in non cirrhotic patients with NAFLD is increasingly reported. Therefore, the concept that HCC is a complication of NAFLD related cirrhosis has been changed. The major risk factors, obesity, diabetes and metabolic syndrome were closely related with development of HCC in NAFLD patients. The further understandings about the molecular mechanism of HCC development in NAFLD are needed in the future. Keywords: Non alcoholic fatty liver disease; Non alcoholic steatohepatitis; Cirrhosis; Hepatocellular carcinoma 서론 간세포암 (Hepatocellular carcinoma, HCC) 의주요원인으로는 B 형간염바이러스 (Hepatitis B virus, HBV), C 형간염바이러스 (Hepatitis C virus, HCV), 알코올및기타원인에의한간경변증 (liver cirrhosis, LC) 및 aflatoxin 등이잘알려져있다. 1 하지만상당수의 HCC 는이러한명확한원인없이 발생하는것으로알려져있으며, 2 최근연구에따르면원인이불명확한 HCC 의발생은비알코올 지방간질환 (Non alcoholic fatty liver disease, NAFLD) 과연관이많다고보고되고있다. 3,4 많은연구 결과를통해 NAFLD 는간경변증으로진행하고간세포암도발생할수있으며, 원인이불명확한 간경변증 (cryptogenic cirrhosis) 의가장주된원인으로밝혀졌다. 2-4 이에 NAFLD 와 HCC 와의연관성 에대해알아보고자한다. 18 대한간학회 The Korean Association for study of the Liver

2 장병국 Hepatocellular carcinoma: Current trends in NAFLD 본론 NAFLD는단순지방간 (Non alcoholic fatty liver, NAFL) 에서부터비알코올지방간염 (Non alcoholic steatohepatitis, NASH), 간경변증까지그스펙트럼이다양하다. NAFLD의유병률은미국성인에서는 30-40% 에이르며, 비만과당뇨병등과같은대사증후군의증가로향후더욱증가할것으로예상된다. 여러연구에따르면 NAFLD 환자중 23-44% NASH로진행하는것으로알려져있다. 5,6 최근시간간격을두고간조직검사를반복적으로시행한 11개의연구를메타분석한결과 NAFL과 NASH 환자들모두에서섬유화의진행이발생하였으며, 한등급의섬유화가진행하는데걸리는시간이 NAFL과 NASH 환자들에서 14.3년과 7.1년이었다. 7 최근미국에서 2004년부터 2013년까지간이식대기자자료에따르면보고에따르면간이식대기자의원인질환으로만성 C 형간염 (Chronic hepatitis C, CHC) 에이어 NASH가두번째많은원인이었으며, 증가율은가장높았다. 8 LC를동반한 510명의환자중 CHC가원인인 315명과 NASH가원인인경우인 195명의환자를추적관찰한결과연간 HCC 발생빈도가 CHC가원인인경우는 4%, NASH가원인인경우는 2.6% 로보고하였다. 9 이결과는 NASH에의한 L.C 환자에서 CHC가원인인 L.C 환자보다는약간낮은비율이지만상당한비율로 HCC가발생한다는것을보여주었다. 또다른연구에서는 61,868명의간이식을받은환자중 HCC를동반한 10,061명의환자를대상으로한연구결과에서도 NASH가두번째로많은 HCC의원인으로나타났으며가장빠른속도로증가되는원인이었다. 10 이결과는미국에서 HCC의발생률이 1975년 10만명당 1.6명에서 2000년에는 10만명당 4.9 명으로세배나증가한결과를부분적으로설명한다. 현재까지는 CHC가미국에서주된원인이기는하지만, 전체적인 NAFLD와 NASH의유병률과증가속도로볼때향후 NAFLD와 NASH가 HCC의주된원인이될것으로예측된다. 지금까지는 NAFLD로인한 LC가 HCC의주된위험인자로여겨졌으나최근에는 15-50% 의경우에서 LC를동반하지않은 NAFLD 환자에서 HCC가발생하였다고보고되고있다 그뿐만아니라 NASH나섬유화를동반하지않은 NAFL에서발생된 HCC의보고도있다. 14 이들중일부분은간선종 (Hepatic adenoma) 에서발생한 HCC가일부있을수도있지만대부분은대사성증후군, 비만, 당뇨병과같은 NAFLD의위험인자를동반하고있었다. 15 다양한연구에서이미 NAFLD의원인이되는비만과당뇨병이 HCC의위험인자로밝혀져있으며대규모코호트연구에따르면체질량지수 (body mass index, BMI) 가 kg/m2인비만환자는 HCC 발생의상대적위험이 1.13 배높고, BMI kg/m 2 인경우는 4.52배까지높았다. 16 당뇨병과 HCC의발생과의연관성을밝힌연구에따르면당뇨병환자에서도정상인에비해 HCC의발생이 4.1배까지높았다. 17 그이유로비만환자에서는 lepatin의분비가증가되어있으며 leptin은 Junus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphoinositide 3-kinase (PI3K)/AKT and extracellular sig- 19

3 2016 대한간학회추계 Single Topic Symposium nal-regulated kinase (ERK) signaling pathway 를통해염증및신생혈관생성을촉진한다. 18,19 이와는 반대로항염증, 항섬유화및종양의성장을억제하는작용을하는 adiponectin 은비만환자와 NAFPLD 환자에서감소되어있다. 20 Adiponectin 은 activated protein kinase (AMPK) 을활성화시키 며 AMPK는 mammalian target of rapamycin (mtor) pathway와 c-jun N-terminal kinase (JNK)/caspase 3 pathway를통해종양세포의성장을억제하고세포의자멸사를증가시킨다. 21 그외에도간세포에지방이침착되면 nuclear factor kappa B (NF-κB) 및 JNK/activator protein-1와같이종양발생과연관된유전자를활성화시킨다. 22,23 그외에도당뇨병과비만에의한인슐린저항성은 tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) 와같은염증및종양발생과관계가있는 cytokine과 oxidative stress 및 endoplasmic reticulum stress를유발시키는것으로알려져있다. 24 비만은장내미생물의변화를초래해서 NAFLD의진행과 HCC의발생에영향을미치는것으로밝혀지고있다. 25 Lipopolysaccharide (LPS) 는 Gram 음성세균의외막에존재하는내독소로염증을유발한다. 동물실 험에서장내세균을제거하여 LPS 를낮추었을때 HCC 의성장이억제되었다. 26 그외에도유전적 다형성이 NAFLD 에서 HCC 가발생하는데영향을준다는연구가있다. PNPLA3 re c444c>g minor allele는 NASH의발생과도연관성이있는것으로알려져있으며, 최근 HCC의발생과도연관성이있다고보고되었다. 27,28 결론 현재까지의여러증거들을종합해보면 NAFLD로인한 LC 환자들뿐만아니라 NASH와 NAFL 환자들에서도 HCC가발생할수있다는것을알수있다. 하지만바이러스성간염과같은다른원인과다르게환자들중아주낮은비율에서발생하고또발생에오랜시간이걸리는특성으로인해이에대한연구가어렵고그의미가과소평가가되고있다. 하지만최근 NAFLD 환자의유병률의증가를고려하면향후 NAFLD로인한 HCC 환자가증가할것으로생각된다. 하지만실제임상에서는 NAFLD 환자들을대상으로 HCC 발생에대한정기적인검사를하는것이필요한가에대해서도아직명확하지않다. 따라서향후이런해결되지않은의문점에대한연구가필요할것으로생각된다. REFERENCES 1. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology 2011;53: 대한간학회 The Korean Association for study of the Liver

4 장병국 Hepatocellular carcinoma: Current trends in NAFLD 2. White DL, Kanwal F, El-Serag HB. Association Between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10: Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29: Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002;3: Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010;59: McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015;62: Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015;13: Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148: Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51: Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014;59: Ertle J, Dechêne A, Sowa JP, Penndorf V, Herzer K, Kaiser G, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011;128: Guzman G1, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch Pathol Lab Med. 2008;132: Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009;49: Leung C, Yeoh SW, Patrick D, Ket S, Marion K, Gow P, et al. Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease. World J Gastroenterol 2015;21: Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9: Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348: Adami HO, Chow WH, Nyrén O, Berne C, Linet MS, Ekbom A, et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996;88: Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, et al. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology 2006;44: Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 2007;67: Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev 2012;33: Luo Z, Saha AK, Xiang X, Ruderman NB. AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 2005;26: Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 2006;281: Gómez-Lechón MJ, Donato MT, Martínez-Romero A, Jiménez N, Castell JV, O'Connor JE.. A human hepatocellular in vitro 21

5 2016 대한간학회추계 Single Topic Symposium model to investigate steatosis. Chem Biol Interact 2007;165: Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010;140: Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013;11: Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499: Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40: Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014;61: 대한간학회 The Korean Association for study of the Liver

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