Non-alcoholic fatty liver disease is increasingly being diagnosed worldwide and considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis (fatty liver) through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and, ultimately, cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH can lead to cirrhosis, liver failure and hepatocellular carcinoma. Therapeutic strategies can be divided into those directed at components of the metabolic syndrome with potential beneficial liver effects and those directed specifically at the liver. Recent data suggest that diet and exercise improve NASH, particular in those achieving >7% weight loss. Obesity surgery has been shown to improve steatosis in all studies and inflammation and fibrosis in some. With respect to anti-diabetic drugs, results for metformin have not been convincing and concerns over the safety of glitazones have reduced the initial enthusiasm for their use. ACE inhibitors and angiotensin II receptor blockers hold the most promise as anti-hypertensive agents for patients with NASH and hypertension. With respect to more specific liver-directed therapies, there have been promising studies of antioxidants, including betaine and probucol, and vitamin E may improve NASH in adults and children. The TNF-α-lowering agent pentoxifylline may have beneficial effects on NASH. Liver transplantation is successful, but the disease recurrence rate is high in the absence of treatment of the underlying metabolic syndrome.

1.
Machado M, Marques-Vidal P, Cortez-Pinto H: Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 2006;45:600–606.
2.
Targher G, Bertolini L, Padovani R, et al: Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212–1218.
3.
Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH: Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009;51:371–379.
4.
Sanyal AJ, Banas C, Sargeant C, et al: Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006;43:682–689.
5.
Ekstedt M, Franzen LE, Mathiesen UL, et al: Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865–873.
6.
Younossi ZM, Stepanova M, Rafiq N, et al: Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53:1874–1882.
7.
Targher G, Day CP, Bonora E: Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010;363:1341–1350.
8.
Newton JL, Jones DEJ, Henderson E, et al: Fatigue in non-alcoholic fatty liver disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance. Gut 2008;57:807–813.
9.
Browning JS, Dobbins LS, Nuremberg R, et al: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–1395.
10.
Cerda C, Perez-Ayuso RM, Riquelme A, et al: Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol 2007;47:412–417.
11.
Javor E, Ghany M, Cochran E, et al: Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005;41:753–760.
12.
Yoneda M, Yoneda M, Mawatari H, et al: Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Gut 2008;56:1330–1331.
13.
Nobili V, Vizzutti F, Arena U, et al: Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008;48:442–448.
14.
Saadeh S, Younossi ZM, Remer ME, et al: The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–750.
15.
Ratziu V, Bellentani S, Cortez-Pinto H, Day CP, Marchesini G: A position statement on NAFLD/NASH based on the EASL 2009 Special Conference. J Hepatol 2010;53:372–384.
16.
McPherson S, Stewart SF, Henderson E, Burt AD, Day CP: Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265–1269.
17.
Day CP: From fat to inflammation. Gastroenterology 2006;130:207–210.
18.
Promrat K, Kleiner DE, Niemeier HM, et al: Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121–129.
19.
Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor RW, Day CP, Trenell MI: Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 2011;60:1278–1283.
20.
Lavine JE, Schwimmer JB, Van Natta M, et al: Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents. The TONIC randomized controlled trial. JAMA 2011;305:1659–1668.
21.
Sanyal AJ, Chalasani N, Kowdley KV, et al: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–1685.
22.
Loke YK, Kwok CS, Singh S: Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. Br Med J 2011;342:d1309.
23.
Browning J: Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006;44:466–471.
24.
Parker HM, Johnson NA, Burdon CA, et al: Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012;56:944–951.
25.
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.
26.
De Alwis NM, Day CP: Current and future therapeutic strategies in NAFLD. Curr Pharm Des 2010;16:1958–1962.
27.
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.
28.
Klein EA, Thompson IM, Tangen CM, et al: Vitamin E and the risk of prostate cancer. The selenium and vitamin E cancer prevention trial (SELECT). JAMA 2011;306:1549–1556.
29.
Zein CO, Yerian LM, Gogate P, et al: Pentoxifylline improves nonalcoholic steatohepatitis: a randomized, placebo-controlled trial. Hepatology 2011;54:1610–1619.
30.
Ratziu V, Sheikh MY, Sanyal AJ, et al: A phase 2, randomized, double-blind placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 2012;55:419–428.
31.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith R, Gorgun C, et al: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137–1140.
32.
Beraza N, Malato Y, Vander Borght S, Liedtke C, Wasmuth HE, Dreano M, de Vos R, Roskams T, Trautwein C: Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 2008;57:655–663.
33.
Zhang S, Wang J, Liu Q, Harnish DC: Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009;51:380–388.
34.
Lee JM, Lee YK, Mamrosh JL, et al: A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 2011;474:506–512.
35.
Contos MJ, Cales W, Sterling RK, et al: Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl 2001;7:363–373.
36.
Ong J, Younossi ZM, Reddy V, et al: Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001;7:797–801.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.