Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-wq484 Total loading time: 0 Render date: 2024-04-27T05:03:57.788Z Has data issue: false hasContentIssue false

5 - Nonalcoholic Fatty Liver Disease

Published online by Cambridge University Press:  08 August 2009

By
Poonam Mishra ,
Nila Rafiq  and
Zobair M. Younossi
Edited by
Zobair M. Younossi
Zobair M. Younossi
Affiliation:
Inova Fairfax Hospital, Annandale, VA
Get access

Summary

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease but it occurs in individuals who do not have a history of significant alcohol consumption. The term nonalcoholic steatohepatitis (NASH) was coined by Ludwig and colleagues in 1980 to describe the biopsy findings of steatohepatitis occurring in obese, diabetic, women who did not consume excessive amounts of alcohol.

NAFLD is now recognized as one of the most common causes of chronic liver disease in the United States and many other parts of the world. It is recognized as the hepatic manifestation of metabolic syndrome, a cluster of metabolic abnormalities that include central obesity, hypertriglyceridemia, hypertension, and type II diabetes mellitus.

NAFLD is an umbrella term that encompasses a wide spectrum of clinical and pathologic entities ranging from simple steatosis, which typically follows a benign course, to NASH, which can potentially progress to cirrhosis, liver failure, and hepatocellular carcinoma. “Burned-out NASH” is a leading cause of cryptogenic cirrhosis. In the United States, cryptogenic cirrhosis accounts for about 10% of all liver transplants and can recur after transplantation. A population-based study showed that subjects with NAFLD have a higher risk for all cause mortality than the general population. Needless to say, NAFLD has major health and health care utilization implications worldwide.

NAFLD Epidemiology

Investigations of the epidemiology of NAFLD and NASH are hampered by the lack of accurate, sensitive, and noninvasive disease markers.

Type
Chapter
Information
Practical Management of Liver Diseases , pp. 77 - 97
Publisher: Cambridge University Press
Print publication year: 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ludwig, J, Viggiano, TR, McGill, DB, et al. Nonalcoholic steatohepatitis: mayo Clinic experience with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434–438.Google Scholar
Chitturi, S, Farrell, G, George, J. Non-alcoholic steatohepatitis in the Asia-Pacific Region: Future Shock?J Gastroenter Hepatol 2004;19:368–374.CrossRefGoogle ScholarPubMed
Chitturi, C, George, J. NAFLD/NASH is not just a “Western” problem: Some perspectives on NAFLD/NASH from the east. In: ,Fatty Liver Disease: NASH and related disorders. Eds. Farell, GC, George, J, Hall, P, McCullough, AJ. Blackwell Publishing, Oxford; 2005, pp. 219–228.Google Scholar
Marchesini, G, Forlani, G. NASH: from liver diseases to metabolic disorders and back to clinical hepatology. Hepatology 2002;35:497–9.CrossRefGoogle ScholarPubMed
Marchesini, G, Brizi, M, Bianchi, G, Tomassetti, S, Bugianesi, E, Lenzi, M, McCullough, AJ, Natale, S, Forlani, G, Melchionda, N. Nonalcoholic fatty liver liver disease. A feature of the metabolic syndrome. Diabetes 2001;50:1844–50.CrossRefGoogle ScholarPubMed
Caldwell, SH, Hespenheide, EE. Subacute liver failure in obese women. Am J Gastroenterol 2002;97:2058–67CrossRefGoogle ScholarPubMed
Bugianesi, E, Leone, A, Vanni, E, Marchesini, G, Brunello, F, Carucci, P, Musso, A, DePaolis, P, Carussoti, L, Salizzoni, M, Rizzeto, M. Expanding the natural history of nonalcoholic steatohepatitis: From cryptogenic cirrhosis to hepatocellular cancer. Gastroenterology 2002;123:134–40.CrossRefGoogle Scholar
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(3):664–9.CrossRefGoogle Scholar
Nair, S, Mason, A, Eason, J, Loss, G, Perrillo, RP. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?Hepatology 2002;36:150–5.CrossRefGoogle ScholarPubMed
Ong, J, Younossi, ZM, Reddy, V, Price, LL, Gramlich, T, Mayes, J, Boparai, N. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl 2001;7:797–801.CrossRefGoogle ScholarPubMed
Adams, , Lymp, J, St Sauver, J, et al. The natural history of nonalcoholic fatty liver disease: a population based cohort study. Gastroenterology 2005;129;113–21.CrossRefGoogle ScholarPubMed
,Prevalence of Overweight and Obesity Among Adults: United States, 1999–2002. National Center for Health Statistics Web site: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/obese/obse99.htm. Accessed and Modified August 9, 2007.
,Prevalence of Diabetes and NAFLD, United States 1980–2005. Data & Trends, National Diabetes Surveillance System. Center for Disease Control and Prevention Web site: http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Accessed and modified August 9, 2007.
Tarantino, G, Saldalamacchia, G, Conca, P, Arena, A. Non-alcoholic Fatty Liver Disease: Further Expression of the Metabolic Syndrome. J Gastroenterol Hepatol. 2007;22(3): 293–303.CrossRefGoogle Scholar
Browning, JD, Szczepaniak, LS, Dobbins, R, Nuremberg, P, Horton, JD, Cohen, JC, Grundy, SM, Hobbs, HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefGoogle Scholar
Clark, JM, Brancati, FL, Diehl, AM. The prevalence and etiology of elevated aminotransferase levels in the united states. Am J gastroenterol 2003:98(5):960–67.CrossRefGoogle Scholar
Ruhl, CE, Everhart, JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the united states. Gastoenterology 2003;124(1):71–9.CrossRefGoogle Scholar
Ioannou, GN, Boyko, EJ, Lee, SP. The prevalence and predictors of elevated serum aminotransferase activity in the united states in 1999–2002. Am J Gastroenterol 2006;101(1):76–82.CrossRefGoogle Scholar
Mccullough, AJ. The epidemiology and risk factors of NASH. In: Fatty Liver Disease: NASH and related Disorders. Eds. Farrell, GC, George, J, Hall, P and Cullough, AJ Mc. Blackwell Publishing, Oxford. 2005, pp. 23–37.Google Scholar
Weston, SR, Leyden, W, Murphy, R, Bass, NM, Bell, BP, Manos, MM, Terrault, NA. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology 2005;41(2):372–79.CrossRefGoogle Scholar
Caldwell, SH, Harris, DM, Patrie, JT, Hespenheide, EE. Is NASH underdiagnosed among African Americans?Am J Gastroenterol 2002;97(6):1496–1500.CrossRefGoogle Scholar
Lobstein, T, Baur, L, Uauy, R. Obesity in children and young people: a crisis in public health. Obes Rev. 2004; Suppl 1): 4–104.CrossRefGoogle Scholar
Ogden, CL, Carroll, MD, Curtin, LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295(13):1549–55.CrossRefGoogle Scholar
Kinugasa, A, Tsunamoto, K, Furukawa, N, et al. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutrit 1984;3(3): 408–14.CrossRefGoogle Scholar
Schwimmer, JB, Deutsch, R, Rauch, JB, et al. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143(4):500–5.CrossRefGoogle Scholar
Talvensaari, KK, Lanning, M, Tapanainen, P, et al. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab. 1996;81(8):3051–5.Google Scholar
Adams, , Feldstein, A, Lindor, KD, et al. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39(4):909–14.CrossRefGoogle Scholar
Srinivasan, S, Ogle, GD, Garnett, SP, et al. Features of the metabolic syndrome after childhood craniopharyngioma. J Clin Endocrinol Metab. 2004;89(1) 81–6.CrossRefGoogle Scholar
Yigit, S, Estrada, E, Bucci, K et al. Diabetic Ketoacidosis secondary to growth hormone treatment in a boy with Prader-Willi syndrome and steatohepatitis. J Pediatr Endocrinol Metab. 2004;17(3):361–4.Google Scholar
Setji, TL, Holland, ND, Sanders, LL, et al. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006.CrossRefGoogle ScholarPubMed
Powell, EE, Searle, J, Mortimer, R. Steatohepatitis associated with limb lipodystrophy. Gastroenterology. 1989;97(4):1022–4.CrossRefGoogle Scholar
Cauble, MS, Gilroy, R, Sorrell, MF, et al. Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantration. Transplantation. 2001;71(7):892–5.CrossRefGoogle Scholar
Willner, IR, Waters, B, Patil, SR, et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroentero. 2001;96(10):2957–61.CrossRefGoogle Scholar
Matteoni, CA, Younossi, ZM, Gramlich, T, Bopari, N, Liu, YC, McCullough, AJ. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999;116: 1413–19.CrossRefGoogle ScholarPubMed
Teli, MR, James, OFW, Burt, AD, Bennett, MK, Day, CP. The natural history of nonalcoholic fatty liver. A follow-up study. Hepatology 1995;22:1714–19.CrossRefGoogle ScholarPubMed
Dam-larsen, S, Franzmann, M, Anderson, IB, Christoffersen, P, Jensen, LB, Surensen, TIA, Becker, U, Bendsten, F. Long term prognosis of fatty liver disease and death. GUT 2004;53:750–5.CrossRefGoogle ScholarPubMed
Powell, EE, Cooksley, WG, Hanson, R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74–80.CrossRefGoogle ScholarPubMed
Ratziu, V, Bonyhay, L, Di Martino, V, Charlotte, F, Cavallaro, L, Sayegh-Tainturier, MH, Giral, P, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002;35(6):1485–93.CrossRefGoogle Scholar
Hui, JM, Kench, JG, Chitturi, S, Sud, A, Farrell, GC, Byth, K, Hall, P, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38(2):420–7.CrossRefGoogle Scholar
Cotrim, HP, Parana, R, Braga, E, Lyra, L. Nonalcoholic steatohepatitis and hepatocellular carcinoma: Natural history?Am j Gastroenterol 2000;95.10):3018–19.CrossRefGoogle Scholar
Zen, Y, Katayanagi, K, Tsuneyama, K, Harada, K, Araki, I, Nakanuma, Y. Hepatocellular carcinoma arising in non-alcoholic steatohepatitis. Pathol Int 2001;51(2):127–31.CrossRefGoogle Scholar
Shimada, M, Hashimoto, E, Taniai, M, Hasegawa, K, Okuda, H, Hayashi, N, Takasaki, K, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2002;37(1):154–60.CrossRefGoogle Scholar
Ong, JP, Younossi, ZM. Is Hepatocellular carcinoma part of the natural history of nonalcoholic steatohepatitis?Gastroenterology 2002;123.1):375–78.CrossRefGoogle Scholar
Angulo, P, Keach, JC, Batts, KP, Lindor, KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–1366.CrossRefGoogle ScholarPubMed
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;118:1117–23.CrossRefGoogle ScholarPubMed
Lonardo, A, Adinolfi, , Loria, P, et al. Steatosis and Hepatitis c virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126(2):586–97.CrossRefGoogle Scholar
Czaja, AJ, Carpenter, HA, Santrach, PJ, et al. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J hepatol. 1998;29(2):198–206.CrossRefGoogle Scholar
Hourigan, LF, Macdonald, GA, Purdie, D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29(4):1215–19.CrossRefGoogle Scholar
Jonsson, JR, Edwards-Smith, CJ, Purdie, D et al. Body composition and hepatic steatosis as precursors of fibrosis in chronic hepatitis C patients. Hepatology. 1999;30:1531–2.Google Scholar
Guidi, M, Muratori, P, Granito, A, et al. Hepatic steatosis in chronic hepatitis C: impact on response to anti-viral treatment with peg-interferon and ribavirin. Aliment Pharmacol Ther. 2005;22(10):943–9.CrossRefGoogle Scholar
Bressler, BL, Guindi, M, Tomlinson, G, et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38(3):639–44.CrossRefGoogle Scholar
Powell, EE, Jonsson, JR, Clouston, AD. Steatosis: co-factor in other liver diseases. Hepatology. 2005;42(1):5–13.CrossRefGoogle Scholar
Powell, EE, Ali, A, Clouston, AD, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005;129(6):1937–43.CrossRefGoogle Scholar
Falck-Ytter, Y, Younossi, ZM, Marchesini, G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Seminars in Liver Disease. 2001;21(1):17–26.CrossRefGoogle Scholar
Yousseff, WI, McCullough, AJ. Steatohepatitis in obese individuals. Best Pract Res Clin Gastoenterol 2002;16:733–47.CrossRefGoogle Scholar
Lee, RG, Nonalcoholis, Steatohepatitis: a study of 49 patients. Hum pathol 1989;20: 594–8.CrossRefGoogle ScholarPubMed
Hamaguchi, M, Kojima, T, Takeda, N, Nakagawa, T, Taniguchi, H, Fujii, K, Omatsu, T, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143(10);722–8.CrossRefGoogle Scholar
Suzuki, A, Angulo, P, Lymp, J, St Sauver, J, Muto, A, Okada, T, Lindor, K. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 2005;41(1):64–71.CrossRefGoogle Scholar
Adams, , Angulo, P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J 2006;82:315–22.CrossRefGoogle ScholarPubMed
Fong, DG, Nehra, V, Lindor, K, Buchman, AL. Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology 2000;32:3–10.CrossRefGoogle ScholarPubMed
Younossi, ZM. Nonalcoholic fatty liver disease. Current Gastroenterology Reports. 1999;1(1):57–62.CrossRefGoogle Scholar
Sheth, SG, Gordan, FD, Chopra, S. Nonalcoholic steatohepatitis. Ann Intern Med 1997;126: 136–45.CrossRefGoogle ScholarPubMed
Leevy, CM. Fatty Liver: a study of 270 patients with biopsy proven fatty liver and a review of the literature. Medicine. 1962;4:249–58.CrossRefGoogle Scholar
Mathieson, NL, Franzen, , Fryden, A, Fuberg, U, Bodenar, G. The clinical significances of slightly to moderately increased liver transaminase values in asymptomatic patients. Scand J Gastroenterol 1999;34:55–91.Google Scholar
Mofrad, P, Contos, M, Haque, M, Sargeant, C, Fisher, RA, Luketic, VA. Clinical and histologic spectrum of nonalcoholic fatty liver disease with normal ALT values. Hepatology 2003;37:1286–92.CrossRefGoogle ScholarPubMed
Sorrentino, P, Tarantino, G, Conca, P, et al. Silent nonalcoholic fatty liver disease-a clinical-histological study. J Hepatol 2004;41:751–57.CrossRefGoogle ScholarPubMed
Prati, D, Taioli, E, Zanella, A, Torre, ED, Butelli, S, DelVecchio, E, et al. Updated definitions of health ranges for serum amino transferase levels. Ann Intern Med 2002;137:1–9.CrossRefGoogle Scholar
Bacon, BR, farahvash, MJ, Jannay, CG, Neuschwander-Tetri, BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–9.CrossRefGoogle ScholarPubMed
Kumar, KS, Malet, PF. Nonalcoholic steatohepatitis. Mayo Clin Proc 2000;75:733–9.CrossRefGoogle ScholarPubMed
Sadeeh, S, Younossi, ZM, Remer, EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123(3):745–50.CrossRefGoogle Scholar
Mottin, CC, Moretto, M, Padoin, AV, et al. The role of ultrasound in the diagnosis of hepatic staetosis in morbidly obese patients. Obes surg 2004;14:635–7.CrossRefGoogle Scholar
Siegelman, ES, Rosen, MA. Imaging of hepatic steatosis. Seminars Liver Disease. 2001;21:71–80.CrossRefGoogle ScholarPubMed
Fishbein, MH, Mogren, C, Gleason, T, Stevens, WR. Relationship of hepatic steatosis to adipose tissue distribution in paediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2006;42:83–8.Google Scholar
Foucher, J, Chanteloup, E, Vergniol, J, et al. Diagnosis of cirrhosis by transient elastography (Fibroscan): a prospective study. Gut. 2006;55: 403–8.CrossRefGoogle ScholarPubMed
Ziol, M, Handra-Luca, A, Kettaneh, A, Christidis, C, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41: 48–54.CrossRefGoogle ScholarPubMed
Promrat, K, Lutchman, G, Uwaifo, GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–96.CrossRefGoogle ScholarPubMed
Cairns, SR, Peters, T. Biochemical analysis of hepatic lipid in alcoholic and diadetic and control subjects. Clin Sci.Lond) 1983;65:645–2.CrossRefGoogle Scholar
Wanless, IR, Lentz, JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106–10.CrossRefGoogle ScholarPubMed
Adams, , 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(1):132–38.CrossRefGoogle Scholar
Kleiner, , Brunt, EM, Nonalcoholic Steatohepatitis Clinical Research Network et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41: 1313–21CrossRefGoogle ScholarPubMed
Bugianesi, E, Gastaldelli, A, Vanni, E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005;48(4):634–42.CrossRefGoogle Scholar
Anderson, T, Gluud, C, Franzmann, MB, Christoffersen, P. hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol 1991;12(2):224–9.CrossRefGoogle Scholar
Ota, T, Takamura, T, et al. Insulin Resistance Accelerates a Dietary Rat Model of Nonalcoholic Steatohepatitis. Gastroenterology 2007;132(1): 282–93.CrossRefGoogle Scholar
Kim, JK, Fillmore, JJ, Chen, Y, Yu, C, Moore, IK, Pypaert, M, Lutz, EP, Kako, Y, Velez-Carrasco, W, Goldberg, IJ, Breslow, JL, Shulman, GI. Tissue specific overexpression of lipoprotein lipase cause tissue specific insulin resistance. PNAS 2001;98:7522–27.CrossRefGoogle Scholar
Pessayre, D, Mansouri, A, Hauzi, D, et al. Hepatotoxicity due to mitochondrial dysfunction. Cell Biology and Toxicology. 1999;15(6):367–73.CrossRefGoogle Scholar
Leclercq, IA, Farrell, GC, Field, J, et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. Journal of Clinical Investigation. 200;10598):1067–75.
Chitturi, S, Farell, GC. Etiopathogenesis of nonalcoholic steatohepatitis. Seminars in Liver Disease. 2001;21(1):27–41.5.CrossRefGoogle Scholar
Tilg, H, Diehl, AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000;343(20):1467–76.CrossRefGoogle Scholar
Edmison, J, McCullough, AJ. Pathogenesis of Non-alcoholic Steatohepatitis: Human Data; Clinics in Liver Disease. 2007;11(1):75–104.CrossRefGoogle Scholar
Warne, JP. Tumour necrosis factor alpha: A key regulator of adipose tissue mass. J Endocrinol 2003;177: 351–5.CrossRefGoogle ScholarPubMed
Satapathy, SK, Garg, S, Chauhan, R, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastrenterol 2004;99:1946–52.CrossRefGoogle ScholarPubMed
Adams, , Zien, CO, Angulo, P, et al. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365–8.CrossRefGoogle ScholarPubMed
Wigg, AJ, Roberts-Thomson, IC, Dymock, RB, McCarthy, PJ, Grose, Rh, Cummins, AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non alcoholic steatohepatitis. Gut 2001;48(2):206–11.CrossRefGoogle Scholar
Saxena, NK, Ikeda, K, Rockey, DC, Freidman, SL, Anania, FA. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 2002;35:762–71.CrossRefGoogle ScholarPubMed
Honda, H, Ikejima, K, Hirose, M, Yoshikawa, M, Lang, T, Enomoto, N, Kitamura, T et al. leptin is required for fibrogenic responses induced by thiocacetamide in the murine liver. Hepatology 2002;36:12–21.CrossRefGoogle ScholarPubMed
Leclercq, IA, Farrell, GC, Schriemer, R, et al. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol 2002;37:206–13.CrossRefGoogle ScholarPubMed
Angulo, P, Alba, LM, Petrovic, LM, et al. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J hepatol 2004;41:943–9.CrossRefGoogle ScholarPubMed
Piccino, F, Sangnelli, E, Pasquale, G, et al. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol !986;2:165–73.CrossRefGoogle Scholar
Dixon, JB, Bhathal, PS, O'Brien, PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severly obese. Gastroenterology 2001;121: 91–100.CrossRefGoogle Scholar
Younossi, ZM, Gramlich, T, Matteoni, CA, Boparai, N, McCullough, AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin gastroenterol Hepatol 2004;2:262–5.CrossRefGoogle ScholarPubMed
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: 151–6.CrossRefGoogle ScholarPubMed
Kadayifci, A, Merriman, R, Bass, N. Medical treatment of non-alcoholic steatohepatitis;Clinics in Liver Disease. 2007;11(1):119–40.CrossRefGoogle Scholar
Menshikova, EV, Ritov, VB, Toledo, FG, Ferrell, RE, Goodpaster, BH, Kelly, . Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity. Am J Physiol Endocrinol Metab 2005;288(4):818–25.CrossRefGoogle Scholar
Saris, WH, Blair, SN, Baak, MA, et al. How much physical activity is enough to prevent unhealthy weight gain? Outcome of the IASO 1st stock conference and consensus statement. Obes Rev 2003;4(2):101–14.CrossRefGoogle Scholar
Palmer, M, Schaffer, F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990;99(5):1408–13.CrossRefGoogle Scholar
Vajro, P, Fontanella, A, Perna, C, Orso, G, Tedesco, M, VincenZo, A. Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr 1994;125(2):239–41.CrossRefGoogle Scholar
Ueno, T, Sugawara, H, Sujaka, K, Hashimoto, O, Tsuji, R, Tamaki, S et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol 1997;27(1):103–7.CrossRefGoogle Scholar
Kugelmas, M, hill, DB, Vivian, B, et al. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003;38:413–19.CrossRefGoogle ScholarPubMed
Hickman, IJ, Jonsson, JR, Prins, JB, Ash, S, Purdie, DM, Clouston, AD, 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(3):413–9.CrossRefGoogle Scholar
Huang, MA, Greenson, JK, Chao, C, Anderson, L, Peterman, D, Jacobson, J, et al. One-year intense nutritional counseling results in histological improvements in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005;100(5):1072–81.CrossRefGoogle Scholar
Harrison, SA, Ramrakhiani, S, Brunt, EM, et al. Orlistat in the treatment of NASH: a case series. American journal of Gastroenterology. 2003;98(4):926–30.CrossRefGoogle Scholar
Sabuncu, T, Nazligul, Y, Karaoglanoglu, M, et al. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Romanian Journal of Gastroenterology. 2003;98(4):926–30.Google Scholar
Brolin, RE. Bariatric surgery and long-term control of morbid obesity. Jama 2002;288:2793–6.CrossRefGoogle ScholarPubMed
Sjostrom, L, Lindroos, AK, Peltonen, M, Torgerson, J, Bouchard, C, Carlsson, B, Dahlgren, S, Larsson, B, Narbro, K, Sjostrom, CD, Sullivan, M, Wedel, H, ,Group SOSSS. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–93.CrossRefGoogle ScholarPubMed
Dixon, JB, Bhathal, PS, Hughes, NR, O'Brien, PE. Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647–54.CrossRefGoogle ScholarPubMed
Yki-Jarvinen, H. Thiazolidinediones. N Engl J Med 2004;351(11) 1106–18.CrossRefGoogle Scholar
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;38:1008–17.CrossRefGoogle ScholarPubMed
Promrat, K, Lutchman, G, Uwaifo, GI, Freedman, RJ, Soza, A, Heller, T, Doo, E, Ghany, M, Premkumar, A, Park, Y, Liang, Tj, Yanovski, JA, Kleiner, , Hoofnagle, JH. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004;39:188–96.CrossRefGoogle ScholarPubMed
Minassian, C, Tarpin, S, Mithieux, G. Role of glucose-6 phosphatase, glucokinase, and glucose-6-phosphatase in liver insulin resistance and its correction by metformin. Biochem Pharmacol 1998;55(8):1213–9.CrossRefGoogle Scholar
Arslanian, SA, Lewy, V, Danadian, K, Saad, R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002;87(4):1555–9.CrossRefGoogle Scholar
Solomon, SS, Mishra, SK, Cwik, C, Rajanna, B, Postlethwaite, AE, Pioglitazone and metformin reverse in sulin resistance induced by tumor necrosis factor-alpha in liver cells. Horm Metab Res 1997;29(8):379–82.CrossRefGoogle Scholar
Marchesini, G, Brii, M, Bianchi, G, et al. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358;893–4.CrossRefGoogle ScholarPubMed
Schwimmer, JB, Middleton, MS, Deutsch, R, et al. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005;21:871–9.CrossRefGoogle ScholarPubMed
Magalotti, D, Marchesini, G, Ramilli, s, et al. splanchnic haemodynamics in non-alcoholic fatty liver disease: effect of a dietary/pharmacological treatment. A pilot study. Dig Liver Dis 2004;36;406–11.Google ScholarPubMed
Nair, S, Diehl, Am, Wiseman, M, et al. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004;20:23–8.CrossRefGoogle ScholarPubMed
Bugianesi, E, Gentilcore, E, Manini, R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082–90.CrossRefGoogle ScholarPubMed
Basaranoglu, M, Acbay, O, Sonsuz, A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999;31(2):384.CrossRefGoogle Scholar
Laurin, J, Lindor, KD, Crippin, JS, Gossard, A, Gores, GJ, Ludwig, J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23(6):1464–7.CrossRefGoogle Scholar
Kiyici, M, Gulten, M, Gurel, S, Nak, SG, Dolar, E, Savci, G, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 2003;17(12):713–8.CrossRefGoogle Scholar
Hatzitolios, A, Savopoulos, C, Lazaraki, G, et al. Efficacy of omega-3 fatty acids, atarvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastrenterol 2004;23: 131–4.Google Scholar
Rallidis, LS, Drakoulis, CK, Parasi, AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193–6.CrossRefGoogle ScholarPubMed
Dominguez, E.G., Gisbert, J.P., et al. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Alimentary Pharmacology &Therapeutics. 2006;23(11):1643–7.CrossRefGoogle Scholar
Chalasani, N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41:690–5.CrossRefGoogle ScholarPubMed
Hasegawa, T, Yoneda, m, Nakamura, K, et al. Plasma transforming growth factor-beta 1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001;15:1667–72.CrossRefGoogle ScholarPubMed
Lavine, JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. Journal of Peadiatrics. 2000;136(6):734–8.CrossRefGoogle Scholar
Vajro, P, Mandato, C, Franzese, A, et al. Vitamin treatment in paediatric obesity-related liver disease: a randomized study. J Pediatr Gastroenterol Nutr 2004;38:48–55.CrossRefGoogle ScholarPubMed
Harrison, SA, Torgerson, S, Hayashi, P, et al. Vitamin E and Vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. American journal of Gastroenterology. 2003;98(11):2485–90.CrossRefGoogle Scholar
Guallar, E, Hanley, DF, Miller, ER3rd. n editorial update: Annus horribilis for vitamin E. Ann Intern Med 2005;143: 143–5.CrossRefGoogle Scholar
Abdelmalek, MF, Angulo, P, Jorgensen, RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. American journal of Gastroenterology.2001;96(9):2711–7.CrossRefGoogle Scholar
Gulbahar, O, Karasu, ZA, Ersoz, G, et al. Treatment of nonalcoholic steatohepatitis with N-acetylcysteine.Abstract Gastroenterology. 2000;118:A1444.CrossRefGoogle Scholar
Lirussi, F, Azzalini, L, Orlando, S et al. Antioxidant supplements for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev. 2007 Jan 24(1).Google Scholar
Kiyici, M, Gulten, M, Gurel, S, et al. Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 2003;17:713–8.CrossRefGoogle ScholarPubMed
Lindor, KD, Kowdley, KV, Heathcote, EJ et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770–8.CrossRefGoogle ScholarPubMed
Scheen, AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A metaanalysis of randomized clinical trials. Diabetes Metab 2004;30(6):487–96.CrossRefGoogle Scholar
Vitale, C, Mercuro, G, Castiglioni, C, Cornoldi, A, TulliA, Fini M et al. Metabolic effects oftelmisartan and losartan in hypertensive patients with metabolic syndrome. Cardiovasc Diabetol 2005:4:6–14.CrossRefGoogle Scholar
Sloniger, JA, Saengsirisuwan, V, Diehl, CJ, Kim, JS, Henriksen, EJ. Selective angiotensin II receptor antagonism enhances whole-body insulin sensitivity and muscle glucose transport in hypertensive TG(mREN2)27 rats. Metabolism 2005;54(12):1659–68.CrossRefGoogle Scholar
Yokohama, S, Yoneda, M, Haneda, M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with non alcoholic steatohepatitis. Hepatology 2004;40: 1222–5.CrossRefGoogle Scholar
Charatcharoenwitthaya, P, Levy, C, Angulo, P, et al. Open-label pilot study of folic acid in patients with nonalcoholic steatohepatitis. Liver Int. 2007;27(2):220–6.CrossRefGoogle Scholar
Solga, SF, Diehl, AM. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol 2003;38(5):681–7.CrossRefGoogle Scholar
Loguercio, C, Federico, A, Tuccillo, C, Terracciano, F, D'Auria, MV, Simone, C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005;39(6):540–3.CrossRefGoogle Scholar
Daubioul, CA, Horsmans, Y, Lambert, P, Danse, E, Delzenne, NM. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 2005;59(5):723–6.CrossRefGoogle Scholar
Morito, Y, Ueno, T, Sasaki, N, Tateishi, Y, Nagata, E, Kage, M, et al. Nateglinide is useful for. (NASH) patients with type 2 diabetes. Hepatogastroenterology 2005;52(65):1338–43.Google Scholar
Despres, JP, Golay, A, Sjostrom, L; ,Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353(20):2121–34.CrossRefGoogle Scholar
Pershadsingh, HA. Dual Peroxisome Proliferator-Activated Receptor-alpha/gamma Agonists: In the Treatment of Type 2 Diabetes Mellitus and the metabolic Syndrome. Treat Endocrinol 2006;5(2):89–99.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×