Digestive Diseases and Sciences

, Volume 52, Issue 10, pp 2512–2519 | Cite as

Orlistat Reverse Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH)

  • Osamah Hussein
  • Masha Grosovski
  • Sorina Schlesinger
  • Sergio Szvalb
  • Nimer Assy
Original Article

Abstract

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0–3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAıc remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.

Keywords

Orlistat Fatty liver Nonalcoholic steatohepatitis (NASH) Liver biopsy Metabolic syndrome Insulin resistance Lipid peroxidation Obesity 

References

  1. 1.
    Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA (2001) Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 96:2957–2961PubMedCrossRefGoogle Scholar
  2. 2.
    Bugianesi E, Leone N, Vanni E, et al. (2002) Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123:134–140PubMedCrossRefGoogle Scholar
  3. 3.
    Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231PubMedCrossRefGoogle Scholar
  4. 4.
    Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G (2000) Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 45:1929–1934PubMedCrossRefGoogle Scholar
  5. 5.
    Bellentani S, Saccoccio G, Masutti F, et al. (2000) Prevalence and risk factors for hepatic steatosis in northern Italy. Ann Intern Med 132:112–117PubMedGoogle Scholar
  6. 6.
    Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S (1998) The metabolically obese, normal-weight individual revisited. Diabetes 47:699–713PubMedCrossRefGoogle Scholar
  7. 7.
    Vessby B (2003) Dietary fat, fatty acid composition in plasma and the metabolic syndrome. Curr Opin Lipidol 14:15–19PubMedCrossRefGoogle Scholar
  8. 8.
    Rivellese AA, De Natale C, Lilli S (2002) Type of dietary fat and insulin resistance. Ann NY Acad Sci 967:329–335PubMedCrossRefGoogle Scholar
  9. 9.
    Grundy SM, Abate N, Chandalia M (2002) Diet composition and the metabolic syndrome: what is the optimal fat intake? Am J Med 113(Suppl 9B):25S–29SGoogle Scholar
  10. 10.
    Yanovski SZ, Yanovski JA (2002) Obesity. N Engl J Med 346:591–602PubMedCrossRefGoogle Scholar
  11. 11.
    Lee RG (1989) Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 20:594–598PubMedCrossRefGoogle Scholar
  12. 12.
    Capron JP, Delamarre J, Dupas JL, Braillon A, Degott C, Quenum C (1982) Fasting in obesity: Another cause of liver injury with alcoholic hyaline? Dig Dis Sci 27:265–268PubMedCrossRefGoogle Scholar
  13. 13.
    Lindor KD, Kowdley, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P (2004) Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39:770–778PubMedCrossRefGoogle Scholar
  14. 14.
    Basaranoglu M, Acbay O, Sonsuz A (1999) A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 31:384PubMedCrossRefGoogle Scholar
  15. 15.
    Lavine JE (2000) Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 136:734–738PubMedCrossRefGoogle Scholar
  16. 16.
    Marchesini G, Brizi M, Morselli Labate AM, et al. (1999) Association of non alcoholic fatty liver disease to insulin resistance. Am J Med 107:450–455PubMedCrossRefGoogle Scholar
  17. 17.
    Mehta K, Van Thiel DH, Shah N, Mobarhan S (2002) Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev 60:289–293PubMedCrossRefGoogle Scholar
  18. 18.
    Kushner RF (2002) Medical management of obesity. Semin Gastrointest Dis 13:123–132PubMedGoogle Scholar
  19. 19.
    Davidson MH, Hauptman J, DiGirolamo M, et al. (1999) Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 281:235–242PubMedCrossRefGoogle Scholar
  20. 20.
    Zavoral JH (1998) Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertens 16:2013–2017PubMedCrossRefGoogle Scholar
  21. 21.
    Dixon JB, Bhathal PS, O’Brien PE (2001) Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91–100PubMedCrossRefGoogle Scholar
  22. 22.
    Haffner SM, Kennedy E, Gonzalez C, Stern MP, Miettinen H (1996) A prospective analysis of the HOMA model. The Mexico City Diabetes Study. Diabetes Care 19:1138–1141PubMedCrossRefGoogle Scholar
  23. 23.
    Aviram M (1983) Plasma lipoprotein separation by discontinuous density gradient ultracentrifugation in hyperlipoproteinemic patients. Biochem Med 30:111–118PubMedCrossRefGoogle Scholar
  24. 24.
    Esterbauer H, Striegl G, Puhl H, et al. (1989) Continuous monitoring of in vitro oxidation of human low-density lipoprotein. Free Radic Res Commun 6:67–75PubMedGoogle Scholar
  25. 25.
    Brunt EM (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474PubMedCrossRefGoogle Scholar
  26. 26.
    Drenick EJ (1970) Effect on hepatic morphology of treatment of obesity by fasting, reducing diets and small-bowel bypass. N Engl J Med 282:829–834PubMedCrossRefGoogle Scholar
  27. 27.
    Friedman SL (1993) The cellular basis of hepatic fibrosis: mechanisms and treatment strategies. N Engl J Med 328:1828–1835PubMedCrossRefGoogle Scholar
  28. 28.
    Poupon RE, Balkau B, Eschwège E, Poupon R, UDCA-PBC Study Group (1991) A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 324:1548–1554PubMedCrossRefGoogle Scholar
  29. 29.
    Kaplan MM, DeLellis RA, Wolfe HJ (1997) Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 126:682–688PubMedGoogle Scholar
  30. 30.
    Sobesky R, Mathurin P, Charlotte F, et al. (1999) Modeling the impact of interferon alpha treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. Gastroenterology 116:378–386PubMedCrossRefGoogle Scholar
  31. 31.
    MacDonald GA, Bridle KR, Ward PJ, et al. (2001) Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3. J Gastroenterol Hepatol 16:953CrossRefGoogle Scholar
  32. 32.
    Jonkers IJ, Mohrschladt MF, Westendorp RG, Van Der Laarse A, Smelt AH (2002) Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 112:275–280PubMedCrossRefGoogle Scholar
  33. 33.
    Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL (2001) A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 96:519–525PubMedCrossRefGoogle Scholar
  34. 34.
    Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD (2001) Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 96:2711–2717PubMedCrossRefGoogle Scholar
  35. 35.
    Tong PC, Lee ZS, Sea MM, et al. (2002) The effect of Orlistat-induced weight loss, without concomitant hypo caloric diet, on cardiovascular risk factors and insulin sensitivity in young obese Chinese subjects with or without type 2 diabetes. Arch Intern Med 162:2428–2435PubMedCrossRefGoogle Scholar
  36. 36.
    Albano E, Clot P, Morimoto M, Tomasi A, Ingelman-Sundberg M, French S (1996) Role of cytochrome p450 2E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 23:155–163PubMedCrossRefGoogle Scholar
  37. 37.
    Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A (1995) Antioxidants, vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 142:1269–1278Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Osamah Hussein
    • 1
  • Masha Grosovski
    • 3
  • Sorina Schlesinger
    • 1
  • Sergio Szvalb
    • 2
  • Nimer Assy
    • 1
    • 3
    • 4
    • 5
  1. 1.Department of Internal Medicine ASieff Government HospitalSafedIsrael
  2. 2.Department of PathologySieff Government HospitalSafedIsrael
  3. 3.Liver UnitSieff Government HospitalHaifaIsrael
  4. 4.Technion Institute of TechnologyFaculty of MedicineHaifaIsrael
  5. 5.Liver Clinic and Internal Medicine ASieff Government Hospital, P.O.H 1008HaifaIsrael

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