The Natural Course of Non-Alcoholic Fatty Liver Disease
Abstract
:1. Introduction
2. Histological Course of Non-Alcoholic Fatty Liver Disease (NAFLD)
3. Predictors of Progressive Fibrosis in Non-Alcoholic Steatohepatitis (NASH)
3.1. Sex
3.2. Race and Ethnicity
3.3. Genetic Polymorphisms
3.4. Age
3.5. Metabolic Features
3.6. Histological Factors
4. Clinical Course of NAFLD
4.1. Liver Cirrhosis, Decompensation, and Liver Related Mortality
4.2. Non-Liver Related Death
5. Evolving Concepts
5.1. NAFL vs. NASH
5.2. Prognostic Significance of NASH vs. Fibrosis
6. Hepatocellular Carcinoma (HCC)
6.1. HCC in NAFLD
6.2. HCC in NAFLD Cirrhosis
6.3. HCC in NAFLD without Cirrhosis
7. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
NAFLD | Nonalcoholic fatty liver disease |
T2DM | Type 2 Diabetes mellitus |
NASH | Nonalcoholic steatohepatitis |
HCC | Hepatocellular carcinoma |
MetS | Metabolic syndrome |
NAFL | Nonalcoholic fatty liver |
SNP’s | Single nucleotide polymorphisms |
CVD | Cardiovascular disease |
NAS | NAFLD activity score |
TGF-β1 | Transforming growth factor-beta1 |
References
- NCD-RisC. Trends in adult body mass index in 200 countries from 1975 to 2014. Lancet 2016, 387, 1377–1396. [Google Scholar]
- Ray, K. NAFLD–The next global epidemic. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 621. [Google Scholar] [CrossRef] [PubMed]
- Powell, E.E.; Cooksley, W.G.E.; Hanson, R.; Searle, J.; Halliday, J.W.; Powell, W. The natural history of nonalcoholic steatohepatitis: A follow-up study of forty-two patients for up to 21 years. Hepatology 1990, 11, 74–80. [Google Scholar] [CrossRef] [PubMed]
- Caldwell, S.H.; Oelsner, D.H.; Iezzoni, J.C.; Hespenheide, E.E.; Battle, E.H.; Driscoll, C.J. Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease. Hepatology 1999, 29, 664–669. [Google Scholar] [CrossRef] [PubMed]
- Poonawala, A.; Nair, S.P.; Thuluvath, P.J. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: A case-control study. Hepatology 2000, 32, 689–692. [Google Scholar] [CrossRef] [PubMed]
- Teli, M.R.; James, O.F.; Burt, A.D.; Bennett, M.K.; Day, C.P. The natural history of nonalcoholic fatty liver: A follow-up study. Hepatology 1995, 22, 1714–1719. [Google Scholar] [CrossRef] [PubMed]
- Wong, V.W.-S.; Wong, G.L.-H.; Choi, P.C.-L.; Chan, A.W.-H.; Li, M.K.-P.; Chan, H.-Y.; Chim, A.M.; Yu, J.; Sung, J.J.; Chan, H.L. Disease progression of non-alcoholic fatty liver disease: A prospective study with paired liver biopsies at 3 years. Gut 2010, 59, 969–974. [Google Scholar] [CrossRef] [PubMed]
- Pais, R.; Charlotte, F.; Fedchuk, L.; Bedossa, P.; Lebray, P.; Poynard, T.; Ratziu, V.; LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J. Hepatol. 2013, 59, 550–556. [Google Scholar] [CrossRef] [PubMed]
- McPherson, S.; Hardy, T.; Henderson, E.; Burt, A.D.; Day, C.P.; Anstee, Q.M. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J. Hepatol. 2015, 62, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
- Angulo, P.; Hui, J.M.; Marchesini, G.; Bugianesi, E.; George, J.; Farrell, G.C.; Enders, F.; Saksena, S.; Burt, A.D.; Bida, J.P.; et al. The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007, 45, 846–854. [Google Scholar] [CrossRef] [PubMed]
- Ekstedt, M.; Franzén, L.E.; Mathiesen, U.L.; Thorelius, L.; Holmqvist, M.; Bodemar, G.; Kechagias, S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44, 865–873. [Google Scholar] [CrossRef] [PubMed]
- Adams, L.A.; Sanderson, S.; Lindor, K.D.; Angulo, P. The histological course of nonalcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 2005, 42, 132–138. [Google Scholar] [CrossRef] [PubMed]
- Angulo, P.; Keach, J.C.; Batts, K.P.; Lindor, K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999, 30, 1356–1362. [Google Scholar] [CrossRef] [PubMed]
- Bacon, B.R.; Farahvash, M.J.; Janney, C.G.; Neuschwander-Tetri, B.A. Nonalcoholic steatohepatitis: An expanded clinical entity. Gastroenterol.-Orlando 1994, 107, 1103–1109. [Google Scholar]
- Evans, C.; Oien, K.; MacSween, R.; Mills, P. Non-alcoholic steatohepatitis: A common cause of progressive chronic liver injury? J. Clin. Pathol. 2002, 55, 689–692. [Google Scholar] [CrossRef] [PubMed]
- Fassio, E.; Álvarez, E.; Domínguez, N.; Landeira, G.; Longo, C. Natural history of nonalcoholic steathepatitis: A longitudinal study of repeat liver biopsies. Hepatology 2004, 40, 820–826. [Google Scholar] [CrossRef] [PubMed]
- Harrison, S.A.; Torgerson, S.; Hayashi, P.H. The natural history of nonalcoholic fatty liver disease: A clinical histopathological study. Am. J. Gastroenterol. 2003, 98, 2042–2047. [Google Scholar] [CrossRef] [PubMed]
- Hui, A.; Wong, V.S.; Chan, H.Y.; Liew, C.T.; Chan, J.Y.; Chan, F.L.; Sung, J.Y. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment. Pharmacol. Ther. 2005, 21, 407–413. [Google Scholar] [CrossRef] [PubMed]
- Lee, R.G. Nonalcoholic steatohepatitis: A study of 49 patients. Hum. Pathol. 1989, 20, 594–598. [Google Scholar] [CrossRef]
- Ratziu, V.; Giral, P.; Charlotte, F.; Bruckert, E.; Thibault, V.; Theodorou, I.; Khalil, L.; Turpin, G.; Opolon, P.; Poynard, T. Liver fibrosis in overweight patients. Gastroenterology 2000, 118, 1117–1123. [Google Scholar] [CrossRef]
- Duan, X.F.; Tang, P.; Li, Q.; Yu, Z.T. Obesity, adipokines and hepatocellular carcinoma. Int. J. Cancer 2013, 133, 1776–1783. [Google Scholar] [CrossRef] [PubMed]
- Henao-Mejia, J.; Elinav, E.; Jin, C.; Hao, L.; Mehal, W.Z.; Strowig, T.; Thaiss, C.A.; Kau, A.L.; Eisenbarth, S.C.; Jurczak, M.J.; et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482, 179–185. [Google Scholar] [CrossRef] [PubMed]
- Oliveira, C.P.; Stefano, J.T. Genetic polymorphisms and oxidative stress in non-alcoholic steatohepatitis (NASH): A mini review. Clin. Res. Hepatol. Gastroenterol. 2015, 39, S35–S40. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Allen, A.M.; Wang, Z.; Prokop, L.J.; Murad, M.H.; 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, 643–654. [Google Scholar] [CrossRef] [PubMed]
- McPherson, S.; Stewart, S.F.; Henderson, E.; Burt, A.D.; Day, C.P. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010, 59, 1265–1269. [Google Scholar] [CrossRef] [PubMed]
- Hossain, N.; Afendy, A.; Stepanova, M.; Nader, F.; Srishord, M.; Rafiq, N.; Goodman, Z.; Younossi, Z. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2009, 7, 1224–1229. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.D.; Abdelmalek, M.F.; Pang, H.; Guy, C.D.; Smith, A.D.; Diehl, A.M.; Suzuki, A. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014, 59, 1406–1414. [Google Scholar] [CrossRef] [PubMed]
- Klair, J.S.; Yang, J.D.; Abdelmalek, M.F.; Guy, C.D.; Gill, R.M.; Yates, K.; Unalp-Adrida, A.; Lavine, J.; Clark, J.; Diehl, A.M.; et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology 2016. [Google Scholar] [CrossRef] [PubMed]
- Lomonaco, R.; Ortiz-Lopez, C.; Orsak, B.; Finch, J.; Webb, A.; Bril, F.; Louden, C.; Tio, F.; Cusi, K. Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis. Hepatology 2011, 54, 837–845. [Google Scholar] [CrossRef] [PubMed]
- Bambha, K.; Belt, P.; Abraham, M.; Wilson, L.A.; Pabst, M.; Ferrell, L.; Unalp-Arida, A.; Bass, N. Ethnicity and nonalcoholic fatty liver disease. Hepatology 2012, 55, 769–780. [Google Scholar] [CrossRef] [PubMed]
- Mohanty, S.R.; Troy, T.N.; Huo, D.; O’Brien, B.L.; Jensen, D.M.; Hart, J. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 2009, 50, 797–804. [Google Scholar] [CrossRef] [PubMed]
- Solga, S.F.; Clark, J.M.; Alkhuraishi, A.R.; Torbenson, M.; Tabesh, A.; Schweitzer, M.; Diehl, A.M.; Magnuson, T.H. Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients. Surg. Obes. Relat. Dis. 2005, 1, 6–11. [Google Scholar] [CrossRef] [PubMed]
- Kallwitz, E.R.; Guzman, G.; TenCate, V.; Vitello, J.; Layden-Almer, J.; Berkes, J.; Patel, R.; Layden, T.J.; Cotler, S.J. The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients. Am. J. Gastroenterol. 2009, 104, 64–69. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.L.; Reeves, H.L.; Burt, A.D.; Tiniakos, D.; McPherson, S.; Leathart, J.B.; Allison, M.E.; Alexander, G.J.; Piguet, A.C.; Anty, R.; et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 2014, 5, 4309. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Al-Serri, A.; Daly, A.K.; Galmozzi, E.; Rametta, R.; Dongiovanni, P.; Nobili, V.; Mozzi, E.; Roviaro, G.; Vanni, E.; 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, 1209–1217. [Google Scholar] [CrossRef] [PubMed]
- Eslam, M.; Hashem, A.M.; Romero-Gomez, M.; Berg, T.; Dore, G.J.; Mangia, A.; Chan, H.L.; Irving, W.L.; Sheridan, D.; Abate, M.L.; et al. FibroGENE: A gene-based model for staging liver fibrosis. J. Hepatol. 2016, 64, 390–398. [Google Scholar] [CrossRef] [PubMed]
- Yki-Järvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014, 2, 901–910. [Google Scholar] [CrossRef]
- Neuschwander-Tetri, B.A.; Clark, J.M.; Bass, N.M.; van Natta, M.L.; Unalp-Arida, A.; Tonascia, J.; Zein, C.O.; Brunt, E.M.; Kleiner, D.E.; McCullough, A.J.; et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010, 52, 913–924. [Google Scholar] [CrossRef] [PubMed]
- Tarantino, G.; Conca, P.; Riccio, A.; Tarantino, M.; di Minno, M.N.; Chianese, D.; Pasanisi, F.; Contaldo, F.; Scopacasa, F.; Capone, D. Enhanced serum concentrations of transforming growth factor-β1 in simple fatty liver: Is it really benign? J. Transl. Med. 2008, 6, 72. [Google Scholar] [CrossRef] [PubMed]
- Adams, L.A.; Lymp, J.F.; Sauver, J.S.; Sanderson, S.O.; Lindor, K.D.; Feldstein, A.; Angulo, P. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005, 129, 113–121. [Google Scholar] [CrossRef] [PubMed]
- Williams, C.D.; Stengel, J.; Asike, M.I.; Torres, D.M.; Shaw, J.; Contreras, M.; Landt, C.L.; Harrison, S.A. 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, 124–131. [Google Scholar] [CrossRef] [PubMed]
- Dam-Larsen, S.; Becker, U.; Franzmann, M.B.; Larsen, K.; Christoffersen, P.; Bendtsen, F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand. J. Gastroenterol. 2009, 44, 1236–1243. [Google Scholar] [CrossRef] [PubMed]
- Matteoni, C.A.; Younossi, Z.M.; Gramlich, T.; Boparai, N.; Liu, Y.C.; McCullough, A.J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999, 116, 1413–1419. [Google Scholar] [CrossRef]
- El-serag, H.B.; Tran, T.; Everhart, J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004, 126, 460–468. [Google Scholar] [CrossRef] [PubMed]
- Loomba, R.; Abraham, M.; Unalp, A.; Wilson, L.; Lavine, J.; Doo, E.; Bass, N.M. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012, 56, 943–951. [Google Scholar] [CrossRef] [PubMed]
- Hui, J.M.; Kench, J.G.; Chitturi, S.; Sud, A.; Farrell, G.C.; Byth, K.; Hall, P.; Khan, M.; George, J. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003, 38, 420–427. [Google Scholar] [CrossRef] [PubMed]
- Sanyal, A.J.; Banas, C.; Sargeant, C.; Luketic, V.A.; Sterling, R.K.; Stravitz, R.T.; Shiffman, M.L.; Heuman, D.; Coterrell, A.; Fisher, R.A.; et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006, 43, 682–689. [Google Scholar] [CrossRef] [PubMed]
- Singal, A.K.; Guturu, P.; Hmoud, B.; Kuo, Y.-F.; Salameh, H.; Wiesner, R.H. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013, 95, 755–760. [Google Scholar] [CrossRef] [PubMed]
- Agopian, V.G.; Kaldas, F.M.; Hong, J.C.; Whittaker, M.; Holt, C.; Rana, A.; Zarrinpar, A.; Petrowsky, H.; Farmer, D.; Yersiz, H.; et al. Liver transplantation for nonalcoholic steatohepatitis: The new epidemic. Ann. Surg. 2012, 256, 624–633. [Google Scholar] [CrossRef] [PubMed]
- Charlton, M.R.; Burns, J.M.; Pedersen, R.A.; Watt, K.D.; Heimbach, J.K.; Dierkhising, R.A. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011, 141, 1249–1253. [Google Scholar] [CrossRef] [PubMed]
- Wong, R.J.; Aguilar, M.; Cheung, R.; Perumpail, R.B.; Harrison, S.A.; Younossi, Z.M.; Ahmed, A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015, 148, 547–555. [Google Scholar] [CrossRef] [PubMed]
- Caldwell, S.H.; Crespo, D.M. The spectrum expanded: Cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J. Hepatol. 2004, 40, 578–584. [Google Scholar] [CrossRef] [PubMed]
- Long, M.T.; Wang, N.; Larson, M.G.; Mitchell, G.F.; Palmisano, J.; Vasan, R.S.; Hoffmann, U.; Speliotes, E.K.; Vita, J.A.; Benjamin, E.J.; et al. Nonalcoholic fatty liver disease and vascular function: Cross-sectional analysis in the Framingham heart study. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1284–1291. [Google Scholar] [CrossRef] [PubMed]
- Huang, R.C.; Beilin, L.J.; Ayonrinde, O.; Mori, T.A.; Olynyk, J.K.; Burrows, S.; Hands, B.; Adams, L.A. Importance of cardiometabolic risk factors in the association between nonalcoholic fatty liver disease and arterial stiffness in adolescents. Hepatology 2013, 58, 1306–1314. [Google Scholar] [CrossRef] [PubMed]
- VanWagner, L.B.; Wilcox, J.E.; Colangelo, L.A.; Lloyd-Jones, D.M.; Carr, J.J.; Lima, J.A.; Lewis, C.E.; Rinella, M.E.; Shah, S.J. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. Hepatology 2015, 62, 773–783. [Google Scholar] [CrossRef] [PubMed]
- Oni, E.T.; Agatston, A.S.; Blaha, M.J.; Fialkow, J.; Cury, R.; Sposito, A.; Erbel, R.; Blankstein, R.; Feldman, T.; Al-Mallah, M.H.; et al. A systematic review: Burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013, 230, 258–267. [Google Scholar] [CrossRef] [PubMed]
- Anstee, Q.M.; Targher, G.; Day, C.P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 330–344. [Google Scholar] [CrossRef] [PubMed]
- Vanni, E.; Marengo, A.; Mezzabotta, L.; Bugianesi, E. Systemic complications of nonalcoholic fatty liver disease: When the liver is not an innocent bystander. Semin. Liver Dis. 2015, 35, 236–249. [Google Scholar] [CrossRef] [PubMed]
- Kim, D.; Kim, W.R.; Kim, H.J.; Therneau, T.M. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 2013, 57, 1357–1365. [Google Scholar] [CrossRef] [PubMed]
- Haring, R.; Wallaschofski, H.; Nauck, M.; Dorr, M.; Baumeister, S.E.; Volzke, H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009, 50, 1403–1411. [Google Scholar] [CrossRef] [PubMed]
- Ekstedt, M.; Hagström, H.; Nasr, P.; Fredrikson, M.; Stål, P.; Kechagias, S.; Hultcrantz, R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015, 61, 1547–1554. [Google Scholar] [CrossRef] [PubMed]
- Adams, L.A.; Ratziu, V. Non-alcoholic fatty liver—Perhaps not so benign. J. Hepatol. 2015, 62, 1002–1004. [Google Scholar] [CrossRef] [PubMed]
- Younossi, Z.M.; Stepanova, M.; Rafiq, N.; Makhlouf, H.; Younoszai, Z.; Agrawal, R.; Goodman, Z. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011, 53, 1874–1882. [Google Scholar] [CrossRef] [PubMed]
- Angulo, P.; Kleiner, D.E.; Dam-Larsen, S.; Adams, L.A.; Bjornsson, E.S.; Charatcharoenwitthaya, P.; Mills, P.R.; Keach, J.C.; Lafferty, H.D.; Stahler, A.; et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015, 149, 389–397. [Google Scholar] [CrossRef] [PubMed]
- Bruix, J.; Gores, G.J.; Mazzaferro, V. Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut 2014, 63, 844–855. [Google Scholar] [CrossRef] [PubMed]
- Dyson, J.; Jaques, B.; Chattopadyhay, D.; Lochan, R.; Graham, J.; Das, D.; Aslam, T.; Patanwala, I.; Gaggar, S.; Cole, M.; et al. Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol. 2014, 60, 110–117. [Google Scholar] [CrossRef] [PubMed]
- Baffy, G.; Brunt, E.M.; Caldwell, S.H. Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace. J. Hepatol. 2012, 56, 1384–1391. [Google Scholar] [CrossRef] [PubMed]
- Park, E.J.; Lee, J.H.; Yu, G.-Y.; He, G.; Ali, S.R.; Holzer, R.G.; Österreicher, C.H.; Takahashi, H.; Karin, M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010, 140, 197–208. [Google Scholar] [CrossRef] [PubMed]
- Zámbó, V.; Simon-Szabó, L.; Szelényi, P.; Kereszturi, E.; Bánhegyi, G.; Csala, M. Lipotoxicity in the liver. World J. Hepatol. 2013, 5, 550–557. [Google Scholar] [PubMed]
- Mittal, S.; Sada, Y.H.; El-Serag, H.B.; Kanwal, F.; Duan, Z.; Temple, S.; May, S.B.; Kramer, J.R.; Richardson, P.A.; Davila, J.A. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin. Gastroenterol. Hepatol. 2015, 13, 594–601. [Google Scholar] [CrossRef] [PubMed]
- Kawamura, Y.; Arase, Y.; Ikeda, K.; Seko, Y.; Imai, N.; Hosaka, T.; Kobayashi, M.; Saitoh, S.; Sezaki, H.; Akuta, N.; et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am. J. Gastroenterol. 2012, 107, 253–261. [Google Scholar] [CrossRef] [PubMed]
- Ertle, J.; Dechene, A.; Sowa, J.P.; Penndorf, V.; Herzer, K.; Kaiser, G.; Schlaak, J.F.; Gerken, G.; Syn, W.K.; Canbay, A. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 2011, 128, 2436–2443. [Google Scholar] [CrossRef] [PubMed]
- White, D.L.; Kanwal, F.; El-Serag, H.B. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin. Gastroenterol. Hepatol. 2012, 10, 1342–1359. [Google Scholar] [CrossRef] [PubMed]
- Ascha, M.S.; Hanouneh, I.A.; Lopez, R.; Tamimi, T.A.; Feldstein, A.F.; Zein, N.N. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010, 51, 1972–1978. [Google Scholar] [CrossRef] [PubMed]
- Yatsuji, S.; Hashimoto, E.; Tobari, M.; Taniai, M.; Tokushige, K.; Shiratori, K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J. Gastroenterol. Hepatol. 2009, 24, 248–254. [Google Scholar] [CrossRef] [PubMed]
- 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, 351–357. [Google Scholar] [CrossRef] [PubMed]
- Singh, S.; Singh, P.P.; Singh, A.G.; Murad, M.H.; Sanchez, W. Anti-diabetic medications and the risk of hepatocellular cancer: A systematic review and meta-analysis. Am. J. Gastroenterol. 2013, 108, 881–891. [Google Scholar] [CrossRef] [PubMed]
- Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S.; Bolondi, L.; Zoli, M.; Malagotti, D.; et al. Clinical patterns of hepatocellular carcinoma (HCC) in non alcoholic fatty liver disease (NAFLD): A multicenter prospective study. Hepatology 2015, 47, e36–e37. [Google Scholar]
- Marrero, J.A.; Fontana, R.J.; Su, G.L.; Conjeevaram, H.S.; Emick, D.M.; Lok, A.S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002, 36, 1349–1354. [Google Scholar] [CrossRef] [PubMed]
- Guzman, G.; Brunt, E.M.; Petrovic, L.M.; Chejfec, G.; Layden, T.J.; Cotler, S.J. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis? Arch. Pathol. Lab. Med. 2008, 132, 1761–1766. [Google Scholar] [PubMed]
- Reddy, S.K.; Steel, J.L.; Chen, H.W.; DeMateo, D.J.; Cardinal, J.; Behari, J.; Humar, A.; Marsh, J.W.; Geller, D.A.; Tsung, A. Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease. Hepatology 2012, 55, 1809–1819. [Google Scholar] [CrossRef] [PubMed]
- Leung, C.; Yeoh, S.W.; Patrick, D.; Ket, S.; Marion, K.; Gow, P.; Angus, P.W. Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease. World J. Gastroenterol. 2015, 21, 1189–1196. [Google Scholar] [CrossRef] [PubMed]
- Calle, E.E.; Rodriguez, C.; Walker-Thurmond, K.; Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003, 348, 1625–1638. [Google Scholar] [CrossRef] [PubMed]
- Paradis, V.; Zalinski, S.; Chelbi, E.; Guedj, N.; Degos, F.; Vilgrain, V.; Bedossa, P.; Belghiti, J. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysis. Hepatology 2009, 49, 851–859. [Google Scholar] [CrossRef] [PubMed]
- Liu, T.C.; Vachharajani, N.; Chapman, W.C.; Brunt, E.M. Noncirrhotic hepatocellular carcinoma: Derivation from hepatocellular adenoma? Clinicopathologic analysis. Mod. Pathol. 2014, 27, 420–432. [Google Scholar] [CrossRef] [PubMed]
- Yasui, K.; Hashimoto, E.; Komorizono, Y.; Koike, K.; Arii, S.; Imai, Y.; Shima, T.; Kanbara, Y.; Saibara, T.; Mori, T.; et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 2011, 9, 428–433. [Google Scholar] [CrossRef] [PubMed]
Study Author, Year | n | Mean/Median (Standard Deviation or Range) Follow up in Years | Predictors of Fibrosis Progression | Odds Ratio (95% CI) |
---|---|---|---|---|
Adams (2005) | 103 | 3.2 (±3.0) | Diabetes | 1.48 |
Fibrosis stage | 0.80 | |||
BMI (per kg/m2) | 1.04 | |||
Fassio (2004) | 22 | 4.3 (3.0–14.3) | Obesity | NR |
Argo (2009) * | 221 | 5.3 (1.0–21.3) | Age | 0.98 (0.96–0.99) |
Any inflammation at initial biopsy | 2.5 (1.4–4.3) | |||
Wong (2010) | 52 | 3, NR | High LDL | 2.7 (1.2 to 6.1) |
High waist circumference | 1.3 (1.1 to 1.5) | |||
Sorrentino (2010) | 149 | 6.4 | Fibronectin immunohistochemistry | 14.1 (6.9–32.3) |
Hypertension | 4.8 (2.7–18.2) | |||
HOMA-IR > 10 | 1.9 (1.6–12.1) | |||
Pais (2013) | 70 | 3.7 (±2.1) | ^ steatosis grade | NR |
Chan (2014) | 35 | 6.4 (±0.8) | nil | - |
McPherson (2014) | 108 | 6.6 (1.3–22.6) | At baseline biopsy FIB 4 score | 2.1 (1.1–3.9) |
At follow up biopsy FIB 4 score | 3.1 (1.4–6.8) | |||
Diabetes | 6.25 (1.88–20) | |||
Singh (2015) ** | 411 | NR | Hypertension | 1.94 (1.00–3.74) |
Low AST:ALT ratio at baseline biopsy | −0.08 (−0.16–0.00) |
Study Author, Year | NAFLD Patients (n) | Mean Follow up (Years) | Histological Subgroup (N) | Cirrhosis and Liver Related Complications HR | Liver Related Mortality HR | Overall Mortality HR |
---|---|---|---|---|---|---|
Ekstedt et al., 2015 | 229 | 26.4 | NAS 0–8 | 10.8 | 3.3 | 3.28 |
Fibrosis stage 3–4 | ||||||
n = 16 | ||||||
Younossi et al., 2011 | 257 | 12.1 | Fibrosis stage 3–4 | - | 5.68 | - |
n = NR | ||||||
Angulo et al., 2015 | 619 | 12.6 | Fibrosis stage | |||
F1 n = 141 | * 2.38 | - | 1.88 | |||
F2 n = 85 | * 7.51 | 11.2 | 2.89 | |||
F3 n = 53 | * 13.78 | 85.79 | 3.76 | |||
F4 n = 18 | * 47.46 | - | 10.9 |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Calzadilla Bertot, L.; Adams, L.A. The Natural Course of Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2016, 17, 774. https://doi.org/10.3390/ijms17050774
Calzadilla Bertot L, Adams LA. The Natural Course of Non-Alcoholic Fatty Liver Disease. International Journal of Molecular Sciences. 2016; 17(5):774. https://doi.org/10.3390/ijms17050774
Chicago/Turabian StyleCalzadilla Bertot, Luis, and Leon Anton Adams. 2016. "The Natural Course of Non-Alcoholic Fatty Liver Disease" International Journal of Molecular Sciences 17, no. 5: 774. https://doi.org/10.3390/ijms17050774