Abstract
The spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from asymptomatic steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Hepatic steatosis occurs when free fatty acids, released in the setting of insulin resistance and the metabolic syndrome, are taken up by the liver. Additional biochemical insults, including oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, can result in inflammation (producing NASH) and fibrosis. Noninvasive methods (e.g., abdominal ultrasonography) are safe ways to support a diagnosis of hepatic steatosis, but advanced liver histopathologic findings including NASH and fibrosis cannot be identified without pursuing liver biopsy. Recent advances in serologic and imaging methods aim to determine severity of inflammation and fibrosis noninvasively. Currently, therapeutic options for NAFLD are limited to medications that reduce risk factors, but the future holds promise for therapies that might slow the progression of this increasingly prevalent disorder.
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References
Maxwell JD, Sanderson I, Butler WH, Gazet JC, Pilkington TR. Hepatic structure and function after modified jejunoileal bypass surgery for obesity. Br Med J. 1977;2:726–729.
Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231.
Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. 2007;11:75–104. ix.
Roberts EA. Pediatric nonalcoholic fatty liver disease (NAFLD): a “growing” problem? J Hepatol. 2007;46:1133–1142.
Arun J, Clements RH, Lazenby AJ, Leeth RR, Abrams GA. The prevalence of nonalcoholic steatohepatitis is greater in morbidly obese men compared to women. Obes Surg. 2006;16:1351–1358.
Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41:372–379.
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;40:1387–1395.
Caldwell SH, Harris DM, Patrie JT, Hespenheide EE. Is NASH underdiagnosed among African Americans? Am J Gastroenterol. 2002;97:1496–1500.
Stepanova M, Elariny H, Rafiq N, Afendy A, Srishord M, Younossi ZM, Baranova A, Srishord M, Chandhoke V. Differences in hepatic gene expression of caucasians and african american patients with non-alcoholic fatty liver disease (NAFLD) The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD. Non-alcoholic fatty liver disease in the Asia-pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol. 2007;22:778–787.
Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A. What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific? J Gastroenterol Hepatol. 2007;22:794–800.
Wang Z, Xia B, Ma C, Hu Z, Chen X, Cao P. Prevalence and risk factors of fatty liver disease in the Shuiguohu district of Wuhan city, Central China. Postgrad Med J. 2007;83:192–195.
Lee JY, Kim KM, Lee SG, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol. 2007;47:239–244.
Hsieh SD, Yoshinaga H, Muto T, Sakurai Y, Kosaka K. Health risks among Japanese men with moderate body mass index. Int J Obes Relat Metab Disord. 2000;24:358–362.
Deurenberg P, Deurenberg-Yap M, Guricci S. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev. 2002;3:141–146.
Suzuki A, Abdelmalek MF, Diehl A, Guy CD. Gender-specific associations between regional anthropometric measures and hepatic fibrosis in patients with NAFLD: The 59th Annual Meeting of the American Associations for the Study of Liver Diseases. San Francisco, CA, 2008.
Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.
Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100.
Colicchio P, Tarantino G, del Genio F, et al. Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in south Italy. Ann Nutr Metab. 2005;49:289–295.
Treeprasertsuk S, Angulo P, Romero-Corral A, Lopez-Jimenez F, Somers VK. Association of adiposity, measures of metabolic dysregulation, and nonalcoholic fatty liver disease in subjects with normal body mass index: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Angulo P. Nafld, obesity, and bariatric surgery. Gastroenterology. 2006;130:1848–1852.
Stranges S, Dorn JM, Muti P, et al. Body fat distribution, relative weight, and liver enzyme levels: a population-based study. Hepatology. 2004;39:754–763.
Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367–372.
Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45:1929–1934.
Furuta K, Sato S, Ishine J, Okamoto E, Tobita H, Miyake T, Ishihara S, Amano Y, Adachi K, Maruyama R, Kinoshita Y. Predictive factors for severity of liver histology in patients with non-alcoholic steatohepatitis: Usefulness of measurement of arteriosclerosis indicators: Digestive Disease Week 2008. San Diego, CA, 2008.
Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005;25:1045–1050.
Kim DH, Choi SY, Park EH, Yang JI, Kim W, Kim YJ, Yoon JH, Lee HS, Shin CS, Cho SH, Oh BH. Non-alcoholic fatty liver disease (NAFLD) as a risk factor of coronary heart disease; relation of NAFLD to coronary artery calcification score by multi- detector computed tomography: The 43rd Annual Meeting of the European Association for the Study of the Liver Milan, Italy, 2008.
Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.
Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121.
Dam-Larsen S, Franzmann M, andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755.
Teli MR, James OF, Burt AD, Bennett MK, Bennett CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719.
Chalasani N. It remains unclear whether simple steatosis is truly benign. AGA Perspectives 2008; February/March 2008.
Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–378.
Tarantino G, Conca P, Riccio A, et al. Enhanced serum concentrations of transforming growth factor-beta1 in simple fatty liver: is it really benign? J Transl Med. 2008;6:72.
Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.
Yatsuji S, Hashimoto E, Noto H, Akahide A, Tobari M, Taniai M, Tokushige K, Shiratori K. Characteristic features and outcomes of patients with hepatocellular carcinoma in nonalcoholic steatohepatitis The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med. 2008;359:2045–2047.
Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.
Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–379.
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152.
Ikejima K, Honda H, Yoshikawa M, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001;34:288–297.
Honda H, Ikejima K, Hirose M, et al. Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 2002;36:12–21.
Poniachik J, Santibañez C, Haim D, Tapia G, Araya J, Rodrigo R, Araya V, Csendes A, Burdiles P, Castillo J, Diaz J, Maluenda F, Korn O, Gutierrez L, Rojas J, Rencoret G, Ibarra J, Videla L. Enhancement in liver nuclear factor-kb (nf-kb) and activator protein 1 (ap-1) DNA binding in obese patients with non-alcoholic fatty liver disease The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–1295.
Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2006;64:679–683.
Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112:91–100.
Pessayre D, Fromenty B, Mansouri A. Mitochondrial injury in steatohepatitis. Eur J Gastroenterol Hepatol. 2004;16:1095–1105.
Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158–1163.
Old LJ. Tumor necrosis factor (TNF). Science. 1985;230:630–632.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–2415.
Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol. 2009;51(1):212–233.
Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2006;18:21–29.
Vendemiale G, Grattagliano I, Caraceni P, et al. Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status. Hepatology. 2001;33:808–815.
Nelson JE, Kowdley KV, Nelson JE, Kowdley KV, Yeh MM, Belt P, Wilson L. Serum ferritin is associated with the presence of NASH, increased alt, ast and histologic severity among patients with NAFLD.: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
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;39:179–187.
Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–2563.
Grozovski M, Shatil T, Beniashvili Z, Korem S, Assy N. Retinol binding protein-4 expression is up regulated in rats with fatty liver during quiescent and regenerative state and improves with insulin sensitizing agents: The 43rh Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Wu H, Jia W, Bao Y, et al. Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;79:185–190.
Petta S, Camma C, Di Marco V, et al. Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis C virus genotype 1. Hepatology. 2008;48:28–37.
Bluher M, Tonjes A, Stumvoll M. Does retinol-binding protein 4 cause or reflect fatty liver disease? Hepatology. 2008;48:4–6.
Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–1271.
Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology. 2008;134:1682–1698.
Pantsari MW, Harrison SA. Nonalcoholic fatty liver disease presenting with an isolated elevated alkaline phosphatase. J Clin Gastroenterol. 2006;40:633–635.
Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 2006;26:151–156.
Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (steatotest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10.
Ratziu V, Massard J, Charlotte F, et al. Diagnostic value of biochemical markers (fibrotest-fibrosure) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:6.
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854.
Adams LA, MacQuillan GC, Jeffrey GP, George J, van der Poorten D, Kench JG, Rossi E, DeBoer B. Non-invasive prediction of liver fibrosis in nonalcoholic fatty liver disease: The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447.
Horoz M, Bolukbas C, Bolukbas FF, et al. Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis. BMC Gastroenterol. 2005;5:35.
Bonnefont-Rousselot D, Ratziu V, Giral P, Charlotte F, Beucler I, Poynard T. Blood oxidative stress markers are unreliable markers of hepatic steatosis. Aliment Pharmacol Ther. 2006;23:91–98.
Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54.
Chalasani N, Crabb DW, Cummings OW, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol. 2003;98:2771–2776.
Uygun A, Kadayifci A, Yesilova Z, et al. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2000;95:3584–3589.
Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002;36:403–409.
Abiru S, Migita K, Maeda Y, et al. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006;26:39–45.
Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. 2006;44:1167–1174.
Suzuki A, Angulo P, Lymp J, Li D, Satomura S, Lindor K. Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease. Liver Int. 2005;25:779–786.
Pares A, Deulofeu R, Gimenez A, et al. Serum hyaluronate reflects hepatic fibrogenesis in alcoholic liver disease and is useful as a marker of fibrosis. Hepatology. 1996;24:1399–1403.
Kolesnikova O, Nemtsova V, Filippovsky O. Serum hyaluronic acid, 7s domain of type iv collagen and ast/alt ratio as markers of hepatic fibrosis in patients with non-alcoholic fatty liver disease: The 43rd Annual Meeting of rhte European Association for the Study of the Liver. Milan, Italy, 2008.
Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10:429–434.
Schmilovitz-Weiss H, Chitty Chen C, Contreras R, Pappo C, Halpern M, Sulkes J, Braun M, Cohen M, Barak N, Tur-Kaspa R, Ben-Ari Z. The innovative serum protein n-glycans analysis predicts the extent of hepatic fibrosis in patients with nonalcoholic fatty liver disease The 58th Annual Meeting of the American Association for the Study of the Liver. Boston, MA, 2007.
Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to fas mediated liver injury in mice. J Hepatol. 2003;39:978–983.
Wieckowska A, Feldstein AE. Nonalcoholic fatty liver disease in the pediatric population: a review. Curr Opin Pediatr. 2005;17:636–641.
Tarantino G, Conca P, Coppola A, Vecchione R, Di Minno G. Serum concentrations of the tissue polypeptide specific antigen in patients suffering from non-alcoholic steatohepatitis. Eur J Clin Invest. 2007;37:48–53.
Malik R, Lai M, Bhaskar K, Nasser I, Curry M, Schuppan D, Afdhal N. Identification of biomarkers that measure disease activity in patients with nonalcoholic fatty liver disease: The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Yilmaz Y, Dolar E, Ulukaya E, et al. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol. 2007;13:837–844.
Tabesh A, Duan Z, Wright EC, Loomba R, Liang T, Hoofnagle JH, Ghany MG, Kleiner DE. Serum caspase-3 generated cytokeratin 18 fragments (ck-18) as a marker for non-alcoholic steatohepatitis (NASH) and response to therapy: The 59th Annual Meeting of the American Association for Study of Liver Diseases. San Francisco, CA, 2008.
Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745–750.
Mottin CC, Moretto M, Padoin AV, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–637.
Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38:485–489.
Zelber-Sagi S, Webb M, Ratziu V, Poynard T, Halpern Z, Oren R. A comparison between the hepatorenal ultrasound index and steatotest for the non-invasive quantification of liver steatosis: The 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–1725.
Osawa H, Mori Y. Sonographic diagnosis of fatty liver using a histogram technique that compares liver and renal cortical echo amplitudes. J Clin Ultrasound. 1996;24:25–29.
Webb M, Hanny Yeshua H, Zelber-Sagie S, Santo M, Barazovski E, Katz R, Halpern Z, Oren R. A practical index for ultrasonographic quantification of liver steatosis The 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, 2007.
Iijima H, Moriyasu F, Tsuchiya K, et al. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res. 2007;37:722–730.
Iijima H, Moriyasu F, Miyahara T, Yanagisawa K. Ultrasound contrast agent, levovist microbubbles are phagocytosed by kupffer cells-in vitro and in vivo studies. Hepatol Res. 2006;35:235–237.
Piekarski J, Goldberg HI, Royal SA, Axel L, Axel L, Moss AA. Difference between liver and spleen CT numbers in the normal adult: its usefulness in predicting the presence of diffuse liver disease. Radiology. 1980;137:727–729.
Park SH, Kim PN, Kim KW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006;239:105–112.
Lee SW, Park SH, Kim KW, et al. Unenhanced CT for assessment of macrovesicular hepatic steatosis in living liver donors: comparison of visual grading with liver attenuation index. Radiology. 2007;244:479–485.
Jacobs JE, Birnbaum BA, Shapiro MA, et al. Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. AJR Am J Roentgenol. 1998;171:659–664.
Fishbein M, Castro F, Cheruku S, et al. Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol. 2005;39:619–625.
Longo RPP, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1994;5:281–285.
Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–E468.
Castera L, Pawlotsky JM. Noninvasive diagnosis of liver fibrosis in patients with chronic hepatitis C. MedGenMed. 2005;7:39.
Takeda T, Yasuda T, Kimura M, Nakaya M, Fujii H, Nakayama Y, Sakaguchi H, Seki S. Noninvasive diagnosis of nonalcoholic steatohepatitis using elastometry The 58th Annual Meeting of the American Association for the Study of the Liver. Boston, MA, 2007.
Fukuzawa Y, Kizawa S, Ohashi T, Matsumoto E, Sato K, Ayada M, Hotta N, Okumura A, Ishikawa T, Kakumu S. Efficacy of non-invasive hepatic fibrosis quantificated- evaluation by liver elasticity measurement in nonalcoholic steatohepatitis (NASH)- comparison of ultrasonic transient elastography and histopathological diagnosis: The 58th Annual Meeting of the Association for the Study of Liver Diseases. Boston, MA, 2007.
Salameh N, Larrat B, Abarca-Quinones J, Leclercq I, Sinkus R, Van Beers BE. Mr elastopgraphy of dietary steatohepatitis in the rat: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Manduca A, Oliphant TE, Dresner MA, et al. Magnetic resonance elastography: non-invasive mapping of tissue elasticity. Med Image Anal. 2001;5:237–254.
Yin M, Talwalkar JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5:1207–1213. e1202.
Leen E, Goldberg JA, Angerson WJ, McArdle CS. Potential role of Doppler perfusion index in selection of patients with colorectal cancer for adjuvant chemotherapy. Lancet. 2000;355:34–37.
Bellentani S, Dugoni M, Miglioli L, anderlini R, Mariano M, Borelli L, Battistini NC. Doppler perfusion index (dpi) is highly predictive of the grade of fatty liver in overweight patients with NAFLD: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Dugoni M, Miglioli L, Borelli L, et al. Doppler perfusion index (DPI) and homa are highly predictive of fatty liver in patients with NAFLD. Dig Liver Dis. 2007;40:A39.
Kakkos SK, Yarmenitis SD, Tsamandas AC, Gogos CA, Kalfarentzos F. Fatty liver in obesity: relation to Doppler perfusion index measurement of the liver. Scand J Gastroenterol. 2000;35:976–980.
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474.
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.
Campbell MS, Reddy KR. Review article: the evolving role of liver biopsy. Aliment Pharmacol Ther. 2004;20:249–259.
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236.
Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906.
Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–1413.
Park HS, Kim MW, Shin ES. Effect of weight control on hepatic abnormalities in obese patients with fatty liver. J Korean Med Sci. 1995;10:414–421.
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;53:413–419.
Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–107.
Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100:1072–1081.
Sato F, Tamura Y, Watada H, et al. Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects. J Clin Endocrinol Metab. 2007;92:3326–3329.
Bonekamp S. The effect of an exercise training intervention on hepatic steatosis The 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation. 2002;105:804–809.
Ryan MC, Abbasi F, Lamendola C, Carter S, McLaughlin TL. Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults. Diabetes Care. 2007;30:1075–1080.
Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–999.
Le KA, Tappy L, D’Alessio DA. Mitochondrial dysfunction and insulin resistance: a matter of lifestyle? Curr Opin Clin Nutr Metab Care. 2007;10:494–497.
Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology. 2009;49:306–317.
Krempf M, Louvet JP, Allanic H, Miloradovich T, Joubert JM, Attali JR. Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity. Int J Obes Relat Metab Disord. 2003;27:591–597.
Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281:235–242.
Harrison SA, Ramrakhiani S, Brunt EM, Anbari MA, Cortese C, Bacon BR. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol. 2003;98:926–930.
Hatzitolios A, Savopoulos C, Lazaraki G, et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol. 2004;23:131–134.
Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol. 2003;12:189–192.
Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63:PL113–PL117.
Gary-Bobo M, Elachouri G, Gallas JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007;46:122–129.
Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121–2134.
Verdich C, Toubro S, Buemann B, Lysgard Madsen J, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001;25:1206–1214.
Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (glp-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173–181.
Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006;26:1015–1017.
Kral JG, Thung SN, Biron S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135:48–58.
Klein S, Mittendorfer B, Eagon JC, et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology. 2006;130:1564–1572.
Mathurin P, Gonzalez F, Kerdraon O, et al. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology. 2006;130:1617–1624.
Antal SC. Prevention and reversal of liver damage following biliopancreatic diversion for obesity. Obes Surg. 1994;4:285–290.
anderson T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese patients. J Hepatol. 1991;12:224–229.
Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519–525.
Neuschwander-Tetri BA, Isley WL, Oki JC, et al. Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med. 1998;129:38–41.
Bailey CJ. The rise and fall of troglitazone. Diabet Med. 2000;17:414–415.
Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.
Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.
Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184.
Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017.
Balas B, Belfort R, Harrison SA, et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol. 2007;47:565–570.
Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology. 2008;135:100–110.
Ratziu FC, Bernhardt C, Moussalli J, Benhamou Y, Poynard T. Long-term efficacy of rosiglitazone in NASH: Results of the extension phase of the flirt-2 trial. The 59th Annual Meeting of the American Association for the Study of Liver Disease, 2008.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471.
Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578–581.
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188.
McNear S, Harrison S. Current status of therapy in nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2009;2:29–43.
Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30:88–96.
Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000;6:998–1003.
Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–894.
Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–28.
Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19:537–544.
Nobili V, Manco M, Ciampalini P, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther. 2008;30:1168–1176.
Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338:265–266.
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;23:1464–1467.
Santos VN, Lanzoni VP, Szejnfeld J, Shigueoka D, Parise ER. A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Braz J Med Biol Res. 2003;36:723–729.
Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537–1543.
Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778.
Detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III), 2004.
Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther. 2006;23:1643–1647.
Kiyici M, Gulten M, Gurel S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol. 2003;17:713–718.
Ekstedt M, Franzen LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: A histopathological follow-up study. J Hepatol. 2007;47:135–141.
Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis. 2006;184:233–234.
Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999;31:384.
Daughtery K. Pravastatin-induced hepatotoxicity in a patients with fatty liver disease: a case presentation with literature review. J Pharm Pract. 2007;20:192–197.
McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the national lipid association statin safety assessment task force. Am J Cardiol. 2006;97:89C–94C.
Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.
Chang CY, Argo CK, Al-Osaimi AM, Caldwell SH. Therapy of NAFLD: antioxidants and cytoprotective agents. J Clin Gastroenterol. 2006;40(Suppl 1):S51–S60.
Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38:413–419.
Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15:1667–1672.
Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–1115.
Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.
Shimada M, Yoshida S, Kitamura Y, Yoshino M. The efficacy of the long-term vitamins E and C treatment for NASH: the 59th Annual Meeting of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Madan K, Batra Y, Gupta DS, et al. Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease. Indian J Gastroenterol. 2005;24:251–255.
Song Z, Deaciuc I, Zhou Z, et al. Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2007;293:G894–G902.
Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol. 2001;96:2711–2717.
Miglio F, Rovati LC, Santoro A, Setnikar I. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung. 2000;50:722–727.
Abdelmalek MF, Lindor KD, Cave MC, Falkner KC, Khan R, McClain CJ. High-dose betaine treatment does not positively influence second hit mechanisms in NASH: The 59th Annual Meetinf of the American Association for the Study of Liver Diseases. San Francisco, CA, 2008.
Bendich A, Machlin LJ. Safety of oral intake of vitamin E. Am J Clin Nutr. 1988;48:612–619.
Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.
Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–750.
Georgescu EF, Ionescu R, Georgescu M, Florescu G, Dobrinescu A, Vancica L, Niculescu M. Are angiotensin-receptor blockers candidates for the first choice treatment in non-alcoholic steatohepatitis with mild-to moderate hypertension: 43rd Annual Meeting of the European Association for the Study of the Liver. Milan, Italy, 2008.
Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225.
Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005;172:899–905.
Molloy R, Komorowski R, Varma R. Recurrent nonalcoholic steatohepatitis and cirrhosis after liver transplantation. Liver Transplant. 2003;3:177–178.
Clinicaltrials.Gov, 2008, 2008.
Trophos: BioPortfolio, 2008, 2008.
Bordet T, Buisson B, Michaud M, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322:709–720.
Phase 1 pharmacokinetic study of cp-945598 in patients with NASH, 2008.
Recombinant leptin therapy for treatment of nonalcoholic steatohepatitis (NASH). 2008.
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Lewis JR: None; Mohanty SR: None
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J. R. Lewis and S. R. Mohanty contributed equally to this work.
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Lewis, J.R., Mohanty, S.R. Nonalcoholic Fatty Liver Disease: A Review and Update. Dig Dis Sci 55, 560–578 (2010). https://doi.org/10.1007/s10620-009-1081-0
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DOI: https://doi.org/10.1007/s10620-009-1081-0