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DOI: 10.1055/s-0037-1603572
Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis
Publication History
22 February 2017
25 April 2017
Publication Date:
01 June 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00032260/201702/lookinside/thumbnails/10-1055-s-0037-1603572_1700006-1.jpg)
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the United States. Approximately 10 to 20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis, which, in turn, can lead to hepatocellular carcinoma (HCC). However, evidence also supports that HCC can develop in patients with NASH who do not have cirrhosis or advanced fibrosis. Obesity, diabetes mellitus, hepatic iron deposition, and insulin resistance are potential risk factors for HCC in NASH. Mechanisms proposed include a role for tumor necrosis factor-α, interleukin-6, insulinlike growth factor, and nuclear factor κβ activation in progression of NASH to HCC. Polymorphisms in patatin-like phospholipase domain-containing 3 also support a genetic influence in NASH-related HCC. Surgical resection, liver directed therapy, and liver transplant remain the mainstay of therapy. Ultrasound has reduced sensitivity for surveillance of HCC in obese patients and alpha fetoprotein may have more value for HCC surveillance in the NASH patient as compared with the HCV patient. Although HCC can develop in noncirrhotic NASH, currently there are no guidelines to recommend surveillance in noncirrhotic NASH patients.
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References
- 1 World Health Organization. Mortality database. Available at www.who.int/whosis/en . Accessed February 2010
- 2 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61 (02) 69-90
- 3 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132 (07) 2557-2576
- 4 Altekruse SF, Henley SJ, Cucinelli JE, McGlynn KA. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol 2014; 109 (04) 542-553
- 5 Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology 2015; 61 (01) 191-199
- 6 Williams CD, Stengel J, Asike MI. , et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (01) 124-131
- 7 Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007; 11 (01) 1-16 , vii
- 8 Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 2007; 11 (01) 191-207 , x–xi
- 9 Kawada N, Imanaka K, Kawaguchi T. , et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (12) 1190-1194
- 10 Perumpail RB, Wong RJ, Ahmed A, Harrison SA. Hepatocellular carcinoma in the setting of non-cirrhotic nonalcoholic fatty liver disease and the metabolic syndrome: US experience. Dig Dis Sci 2015; 60 (10) 3142-3148
- 11 Browning JD, Szczepaniak LS, Dobbins R. , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (06) 1387-1395
- 12 Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98 (05) 960-967
- 13 Sass DA, Chang P, Chopra KB. Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci 2005; 50 (01) 171-180
- 14 Shen L, Fan JG, Shao Y. , et al. Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol 2003; 9 (05) 1106-1110
- 15 Omagari K, Kadokawa Y, Masuda J. , et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002; 17 (10) 1098-1105
- 16 Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med 1988; 27 (02) 142-149
- 17 Hilden M, Christoffersen P, Juhl E, Dalgaard JB. Liver histology in a ‘normal’ population--examinations of 503 consecutive fatal traffic casualties. Scand J Gastroenterol 1977; 12 (05) 593-597
- 18 Lai SW, Tan CK, Ng KC. Epidemiology of fatty liver in a hospital-based study in Taiwan. South Med J 2002; 95 (11) 1288-1292
- 19 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease - meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
- 20 Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999; 94 (10) 3010-3014
- 21 Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 2001; 35 (02) 195-199
- 22 Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 2009; 115 (24) 5651-5661
- 23 Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005; 42 (01) 132-138
- 24 Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003; 98 (09) 2042-2047
- 25 Pais R, Charlotte F, Fedchuk L. , et al; LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol 2013; 59 (03) 550-556
- 26 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (06) 1413-1419
- 27 Fassio E, Alvarez E, Domínguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 2004; 40 (04) 820-826
- 28 Kodali VP, Gordon SC, Silverman AL, McCray DG. Cryptogenic liver disease in the United States: further evidence for non-A, non-B, and non-C hepatitis. Am J Gastroenterol 1994; 89 (10) 1836-1839
- 29 Saunders JB, Walters JR, Davies AP, Paton A. A 20-year prospective study of cirrhosis. Br Med J (Clin Res Ed) 1981; 282 (6260): 263-266
- 30 Sakugawa H, Nakasone H, Nakayoshi T. , et al. Clinical characteristics of patients with cryptogenic liver cirrhosis in Okinawa, Japan. Hepatogastroenterology 2003; 50 (54) 2005-2008
- 31 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 (03) 664-669
- 32 Bugianesi E, Leone N, Vanni E. , et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123 (01) 134-140
- 33 Abdelmalek M, Ludwig J, Lindor KD. Two cases from the spectrum of nonalcoholic steatohepatitis. J Clin Gastroenterol 1995; 20 (02) 127-130
- 34 Ong J, Younossi ZM, Reddy V. , et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001; 7 (09) 797-801
- 35 Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin Gastroenterol Hepatol 2004; 2 (12) 1048-1058
- 36 Garcìa-Torres ML, Zaragoza A, Giner R. , et al. Incidencia y factores epidemiol Ûgicos del carcinoma hepatocelular en Valencia durante el año 2000. Rev Esp Enferm Dig 2003; 95: 381-384
- 37 Cotrim HP, Paraná R, Braga E, Lyra L. Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history?. Am J Gastroenterol 2000; 95 (10) 3018-3019
- 38 Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I, Nakanuma Y. Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathol Int 2001; 51 (02) 127-131
- 39 Orikasa H, Ohyama R, Tsuka N, Eyden BP, Yamazaki K. Lipid-rich clear-cell hepatocellular carcinoma arising in non-alcoholic steatohepatitis in a patient with diabetes mellitus. J Submicrosc Cytol Pathol 2001; 33 (1-2): 195-200
- 40 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; 36 (06) 1349-1354
- 41 Ratziu V, Bonyhay L, Di Martino V. , et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002; 35 (06) 1485-1493
- 42 Giannini EG, Marabotto E, Savarino V. , et al; Italian Liver Cancer (ITALICA) Group. Hepatocellular carcinoma in patients with cryptogenic cirrhosis. Clin Gastroenterol Hepatol 2009; 7 (05) 580-585
- 43 Lee SS, Jeong SH, Byoun YS. , et al. Clinical features and outcome of cryptogenic hepatocellular carcinoma compared to those of viral and alcoholic hepatocellular carcinoma. BMC Cancer 2013; 13: 335
- 44 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 (12) 1342-1359.e2
- 45 Yasui K, Hashimoto E, Komorizono Y. , et al; Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9 (05) 428-433 , quiz e50
- 46 Guzman G, 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 (11) 1761-1766
- 47 Leung C, Yeoh SW, Patrick D. , et al. Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease. World J Gastroenterol 2015; 21 (04) 1189-1196
- 48 Mittal S, El-Serag HB, Sada YH. , et al. Hepatocellular carcinoma in the absence of cirrhosis in United States Veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016; 14 (01) 124-31.e1
- 49 Alexander J, Torbenson M, Wu TT, Yeh MM. Non-alcoholic fatty liver disease contributes to hepatocarcinogenesis in non-cirrhotic liver: a clinical and pathological study. J Gastroenterol Hepatol 2013; 28 (05) 848-854
- 50 Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55 (07) 434-438
- 51 Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989; 20 (06) 594-598
- 52 Cortez-Pinto H, Camilo ME, Baptista A, De Oliveira AG, De Moura MC. Non-alcoholic fatty liver: another feature of the metabolic syndrome?. Clin Nutr 1999; 18 (06) 353-358
- 53 Nair S, Mason A, Eason J, Loss G, Perrillo RP. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?. Hepatology 2002; 36 (01) 150-155
- 54 Wolk A, Gridley G, Svensson M. , et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 2001; 12 (01) 13-21
- 55 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 (17) 1625-1638
- 56 Møller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A (03) 344-350
- 57 Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 2005; 23 (21) 4742-4754
- 58 Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 2007; 97 (07) 1005-1008
- 59 Chen CL, Yang HI, Yang WS. , et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008; 135 (01) 111-121
- 60 Stefan N, Häring HU. The metabolically benign and malignant fatty liver. Diabetes 2011; 60 (08) 2011-2017
- 61 Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005; 54 (04) 533-539
- 62 La Vecchia C, Negri E, D'Avanzo B, Boyle P, Franceschi S. Medical history and primary liver cancer. Cancer Res 1990; 50 (19) 6274-6277
- 63 Adami HO, McLaughlin J, Ekbom A. , et al. Cancer risk in patients with diabetes mellitus. Cancer Causes Control 1991; 2 (05) 307-314
- 64 Yu MC, Tong MJ, Govindarajan S, Henderson BE. Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 1991; 83 (24) 1820-1826
- 65 Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000; 92 (13) 1096-1099
- 66 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126 (02) 460-468
- 67 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4 (03) 369-380
- 68 Mendler MH, Turlin B, Moirand R. , et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117 (05) 1155-1163
- 69 Bozzini C, Girelli D, Olivieri O. , et al. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care 2005; 28 (08) 2061-2063
- 70 Felipe A, Guadalupe E, Druso P. , et al. Serum ferritin is associated with metabolic syndrome and red meat consumption. Oxid Med Cell Longev 2015; 2015: 769-735
- 71 George DK, Goldwurm S, MacDonald GA. , et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114 (02) 311-318
- 72 Bugianesi E, Manzini P, D'Antico S. , et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39 (01) 179-187
- 73 Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009; 50 (02) 351-357
- 74 Svegliati-Baroni G, Bugianesi E, Bouserhal T. , et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut 2007; 56 (09) 1296-1301
- 75 De Minicis S, Agostinelli L, Rychlicki C. , et al. HCC development is associated to peripheral insulin resistance in a mouse model of NASH. PLoS One 2014; 9 (05) e97136
- 76 Levene AP, Goldin RD. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology 2012; 61 (02) 141-152
- 77 Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int J Mol Sci 2013; 14 (10) 20704-20728
- 78 Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: growing evidence of an epidemic?. Hepatol Res 2012; 42 (01) 1-14
- 79 Castell JV, Gómez-Lechón MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990; 12 (05) 1179-1186
- 80 Park EJ, Lee JH, Yu GY. , et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140 (02) 197-208
- 81 Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 2009; 124 (03) 540-546
- 82 Bettermann K, Vucur M, Haybaeck J. , et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 2010; 17 (05) 481-496
- 83 Solinas G, Naugler W, Galimi F, Lee MS, Karin M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A 2006; 103 (44) 16454-16459
- 84 Wang XJ, Yuan SL, Lu Q. , et al. Potential involvement of leptin in carcinogenesis of hepatocellular carcinoma. World J Gastroenterol 2004; 10 (17) 2478-2481
- 85 Watanabe N, Takai K, Imai K. , et al. Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment. J Clin Biochem Nutr 2011; 49 (03) 153-158
- 86 Kamada Y, Matsumoto H, Tamura S. , et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 2007; 47 (04) 556-564
- 87 Saxena NK, Fu PP, Nagalingam A. , et al. Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 2010; 139 (05) 1762-1773 , 1773.e1–1773.e5
- 88 Price JA, Kovach SJ, Johnson T. , et al. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology 2002; 36 (05) 1089-1097
- 89 Aleem E, Nehrbass D, Klimek F, Mayer D, Bannasch P. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol 2011; 39 (03) 524-543
- 90 Longato L, de la Monte S, Kuzushita N. , et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology 2009; 49 (06) 1935-1943
- 91 Chiang SH, Bazuine M, Lumeng CN. , et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009; 138 (05) 961-975
- 92 Feldstein AE, Werneburg NW, Canbay A. , et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40 (01) 185-194
- 93 Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8 (02) 108-118
- 94 Sass G, Klinger N, Sirma H. , et al. Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. Int J Oncol 2011; 39 (02) 433-442
- 95 Maeda S. NF-κB, JNK, and TLR signaling pathways in hepatocarcinogenesis. Gastroenterol Res Pract 2010; 2010: 367694
- 96 Chang Q, Zhang Y, Beezhold KJ. , et al. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol 2009; 50 (02) 323-333
- 97 Eferl R, Ricci R, Kenner L. , et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 2003; 112 (02) 181-192
- 98 Petta S, Muratore C, Craxì A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis 2009; 41 (09) 615-625
- 99 Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001; 96 (10) 2957-2961
- 100 Makkonen J, Pietiläinen KH, Rissanen A, Kaprio J, Yki-Järvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 2009; 50 (05) 1035-1042
- 101 Bathum L, Petersen HC, Rosholm JU, Hyltoft Petersen P, Vaupel J, Christensen K. Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem 2001; 47 (01) 81-87
- 102 Dixon JB, Bhathal PS, Jonsson JR, Dixon AF, Powell EE, O'Brien PE. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J Hepatol 2003; 39 (06) 967-971
- 103 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
- 104 Valenti L, Al-Serri A, Daly AK. , et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51 (04) 1209-1217
- 105 Hassan MM, Kaseb A, Etzel CJ. , et al. Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction. Mol Carcinog 2013; 52 (Suppl. 01) E139-E147
- 106 Speliotes EK, Yerges-Armstrong LM, Wu J. , et al; NASH CRN; GIANT Consortium; MAGIC Investigators; GOLD Consortium. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011; 7 (03) e1001324
- 107 Yoneda M, Hotta K, Nozaki Y. , et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009; 29 (07) 1078-1085
- 108 Sreenivasa Baba C, Alexander G, Kalyani B. , et al. Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis. J Gastroenterol Hepatol 2006; 21 (1 Pt 1): 191-198
- 109 Hickman IJ, Jonsson JR, Prins JB. , et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004; 53 (03) 413-419
- 110 Lazo M, Solga SF, Horska A. , et al; Fatty Liver Subgroup of the Look AHEAD Research Group. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care 2010; 33 (10) 2156-2163
- 111 Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009; 136 (05) 1552-1560
- 112 Wang RT, Koretz RL, Yee Jr HF. Is weight reduction an effective therapy for nonalcoholic fatty liver? A systematic review. Am J Med 2003; 115 (07) 554-559
- 113 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001; 358 (9285): 893-894
- 114 Uygun A, Kadayifci A, Isik AT. , et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004; 19 (05) 537-544
- 115 Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34 (03) 274-285
- 116 Aithal GP, Thomas JA, Kaye PV. , et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135 (04) 1176-1184
- 117 Sanyal AJ, Chalasani N, Kowdley KV. , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
- 118 Laurin J, Lindor KD, Crippin JS. , et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23 (06) 1464-1467
- 119 Leuschner UF, Lindenthal B, Herrmann G. , et al; NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 2010; 52 (02) 472-479
- 120 Horlander JC, Kwo PY, Cummings OW. , et al. Atorvastatin for the treatment of NASH. Gastroenterology 2001; 120 (Suppl): 2767
- 121 Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006; 23 (11) 1643-1647
- 122 Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016; 352: i1541
- 123 Riche DM, King ST. Bone loss and fracture risk associated with thiazolidinedione therapy. Pharmacotherapy 2010; 30 (07) 716-727
- 124 Klein EA, Thompson Jr IM, Tangen CM. , et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306 (14) 1549-1556
- 125 Chen HP, Shieh JJ, Chang CC. , et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013; 62 (04) 606-615
- 126 Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008; 6 (12) 1396-1402
- 127 Malik SM, Gupte PA, de Vera ME, Ahmad J. Liver transplantation in patients with nonalcoholic steatohepatitis-related hepatocellular carcinoma. Clin Gastroenterol Hepatol 2009; 7 (07) 800-806
- 128 Reddy SK, Steel JL, Chen HW. , et al. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012; 55 (06) 1809-1819
- 129 Wong RJ, Chou C, Bonham CA, Concepcion W, Esquivel CO, Ahmed A. Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data. Clin Transplant 2014; 28 (06) 713-721
- 130 Bruix J, Sherman M. ; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53 (03) 1020-1022
- 131 Del Poggio P, Olmi S, Ciccarese F. , et al; Italian Liver Cancer (ITA.LI.CA) Group. Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2014; 12 (11) 1927-33.e2
- 132 Gopal P, Yopp AC, Waljee AK. , et al. Factors that affect accuracy of α-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2014; 12 (05) 870-877