Digestive Diseases and Sciences

, Volume 52, Issue 9, pp 2387–2395 | Cite as

The Effect of a Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study

  • Carmela Loguercio
  • Alessandro Federico
  • Marco Trappoliere
  • Concetta Tuccillo
  • Ilario de Sio
  • Agnese Di Leva
  • Marco Niosi
  • Mauro Valeriano D’Auria
  • Rita Capasso
  • Camillo Del Vecchio Blanco
  • Real Sud Group
Original Paper


Oxidative stress leads to chronic liver damage. Silybin has been conjugated with vitamin E and phospholipids to improve its antioxidant activity. Eighty-five patients were divided into 2 groups: those affected by nonalcoholic fatty liver disease (group A) and those with HCV-related chronic hepatitis associated with nonalcoholic fatty liver disease (group B), nonresponders to treatment. The treatment consisted of silybin/vitamin E/phospholipids. After treatment, group A showed a significant reduction in ultrasonographic scores for liver steatosis. Liver enzyme levels, hyperinsulinemia, and indexes of liver fibrosis showed an improvement in treated individuals. A significant correlation among indexes of fibrosis, body mass index, insulinemia, plasma levels of transforming growth factor-β, tumor necrosis factor-α, degree of steatosis, and γ-glutamyl transpeptidase was observed. Our data suggest that silybin conjugated with vitamin E and phospholipids could be used as a complementary approach to the treatment of patients with chronic liver damage.


Silybin Nonalcoholic fatty liver disease Oxidative stress Hepatitis C virus 


  1. 1.
    Patrick L (1999) Hepatitis C: epidemiology and review of complementary/alternative medicine treatments. Altern Med Rev 4:220–238PubMedGoogle Scholar
  2. 2.
    Bean P (2002) The use of alternative medicine in the treatment of hepatitis C. Am Clin Lab 21:19–21Google Scholar
  3. 3.
    Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37:1202–1219PubMedCrossRefGoogle Scholar
  4. 4.
    Loguercio C, De Simone T, D’Auria MV, de Sio I, Federico A, Tuccillo C, Abbatecola AM, Del Vecchio Blanco C, Italian AISF Clinical Group (2004) Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver. Dig Liver Dis 36:398–405PubMedGoogle Scholar
  5. 5.
    Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP (2004) Steatosis and hepatitis C virus: mechanism and significant for hepatic and extrahepatic disease. Gastroenterology 126:586–597PubMedCrossRefGoogle Scholar
  6. 6.
    Ramesh S, Sanyal AJ (2004) Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis 24:399–413PubMedCrossRefGoogle Scholar
  7. 7.
    Younossi ZM, McCullough AJ, Ong JP, Barnes DS, Post A, Tavill A, Bringman D, Martin LM, Assmann J, Gramlich T, Mullen KD, O’Shea R, Carey WD, Ferguson R (2004) Obesity and non-alcoholic fatty liver disease in chronic hepatitis C. J Clin Gastroenterol 38:705–709PubMedCrossRefGoogle Scholar
  8. 8.
    Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM (2000) Metformin reverts fatty liver disease in obese, leptin-deficient mice. Nat Med 6:998–1003PubMedCrossRefGoogle Scholar
  9. 9.
    Cadranel JF, Jouannaud V, Loison S (2004) Improving insulin resistance: certain progress in the management of patients with non-alcoholic steatohepatitis … but the story continues. Gastroenterol Clin Biol 28:265–267PubMedCrossRefGoogle Scholar
  10. 10.
    Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB (1996) Ursodeoxycolic acid or clofibrate in the treatment of non alcohol induced steatohepatitis; a pilot study. Hepatology 23:1464–1467PubMedCrossRefGoogle Scholar
  11. 11.
    Lazaridis KN, Gores GJ, Lindor KD (2001) Ursodeoxycolic acid “mechanism of action and clinical use in hepatobilary disorders.” J Hepatol 35:134–146PubMedCrossRefGoogle Scholar
  12. 12.
    Wellington K, Jarvis B (2001) Silymarin: a review of its clinical properties in the management of hepatic disorders. Bio Drugs 15:465–489Google Scholar
  13. 13.
    Lang I, Nekam K, Gonzalez-Cabello R, Muzes G, Gergely P, Feher J (1990) Hepatoprotective and immunological effects of antioxidant drugs. Tokai J Exp Clin Med 15:123–127PubMedGoogle Scholar
  14. 14.
    Feher J, Lang I, Nekam K, Muzes G, Deak G (1988) Effect of free radical scavengers on superoxide dismutase (SOD) enzyme in patients with alcoholic cirrhosis. Acta Med Hung 45:265–276PubMedGoogle Scholar
  15. 15.
    Lucena MI, Andrade RJ, de la Cruz JP, Rodriguez-Mendizabal M, Blanco E, Sanchez de la Cuesta F (2002) Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther 40:2–8PubMedGoogle Scholar
  16. 16.
    Liu J, Manheimer E, Tsutani K, Gluud C (2003) Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol 98:538–544PubMedCrossRefGoogle Scholar
  17. 17.
    Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C, Zilli M (1997) Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 26:871–879PubMedCrossRefGoogle Scholar
  18. 18.
    Fuchs EC, Weyhenmeyer R, Weiner OH (1997) Effects of silybin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Arzneimittelforschung 47:1883–1887Google Scholar
  19. 19.
    Dehmlow C, Murawski N, de Groot H (1996) Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sci 58:1591–1600PubMedCrossRefGoogle Scholar
  20. 20.
    Buzzelli G, Moscarella S, Giusti A, Duchini A, Marena C, Lampertico M (1993) A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol 31:456–460PubMedGoogle Scholar
  21. 21.
    Zhao J, Agarwal R (1999) Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20:2101–2108PubMedCrossRefGoogle Scholar
  22. 22.
    Di Sario A, Bendie E, Taffetani S (2003) Realsil, a new sylibin-phospatidylcoline complex, reduces dimethylnitrosamine-induced hepatic fibrosis in the rat. J Hepatol 38:P76CrossRefGoogle Scholar
  23. 23.
    Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, Del Vecchio Blanco C, Loguercio C (2006) A new silybin–vitamin E–phospholipid complex improves insulin resistance and liver damage in patients with non alcoholic fatty liver disease: preliminary observations. Gut (in press)Google Scholar
  24. 24.
    Joseph AE, Saverymuttu SH, al-Sam S, Cook MG, Maxwell JD (1991) Comparison of liver histology with ultrasonography in assessing diffuse parenchimal liver disease. Clin Radiol 9:91–94Google Scholar
  25. 25.
    Liu CJ, Jeng YM, Chen PJ, Lai MY, Yang HC, Huang WL, Kao JH, Chen DS (2005) Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C. Antivir Ther 10:405–415PubMedGoogle Scholar
  26. 26.
    Reid AE (2001) Nonalcoholic steatohepatitis. Gastroenterology 121:710–723PubMedCrossRefGoogle Scholar
  27. 27.
    Adam JM, Tarigan NP (2004) Comparison of the World Health Organization (WHO) two-step strategy and OGTT for diabetes mellitus screening. Acta Med Indones 36:3–7PubMedGoogle Scholar
  28. 28.
    Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231PubMedCrossRefGoogle Scholar
  29. 29.
    Marchesini G, Bugianesi E, Forlani G, et al. (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923PubMedCrossRefGoogle Scholar
  30. 30.
    Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, Arthur MJ, European Liver Fibrosis Group (2004) Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 127:1704–1713PubMedCrossRefGoogle Scholar
  31. 31.
    Guglielmi FW, Panella C, Buda A, Budillon G, Caregaro L, Clerici C, Conte D, Federico A, Gasbarrini G, Guglielmi A, Loguercio C, Losco A, Martines D, Mazzuoli S, Merli M, Mingrone G, Morelli A, Nardone G, Zoli G, Francavilla A (2005) Nutritional state and energy balance in cirrhotic patients with or without hypermetabolism. Dig Liver Dis 37:681–688PubMedCrossRefGoogle Scholar
  32. 32.
    Melchionda N, Forlani G, Marchesini G, Baraldi L, Natale S (2002) WHO and ADA criteria for the diagnosis of diabetes mellitus in relation to body mass index. Insulin sensitivity and secretion in resulting subcategories of glucose tolerance. Int J Obes Relat Metab Disord 26:90–96PubMedCrossRefGoogle Scholar
  33. 33.
    Armitage P, Berry G (1994) Statistical methods in medical research. Blackwell Science, OxfordGoogle Scholar
  34. 34.
    Loguercio C, Federico A (2003) Oxidative stress in viral and alcoholic hepatitis. Free Rad Biol Med 34:1–10PubMedCrossRefGoogle Scholar
  35. 35.
    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
  36. 36.
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ (2003) Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413–419PubMedCrossRefGoogle Scholar
  37. 37.
    Dixon JB, Bhathal PS, Hughes NR, O’Brien PE (2004) Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 39:1647–1654PubMedCrossRefGoogle Scholar
  38. 38.
    Loguercio C, De Girolamo V, de Sio I, Tuccillo C, Ascione A, Baldi F, Budillon G, Cimino L, Di Carlo A, Di Marino MP, Morisco F, Picciotto F, Terracciano L, Vecchione R, Verde V, Del Vecchio Blanco C (2001) Nonalcoholic fatty liver disease in an area of southern Italy: main clinical, histological and pathophysiological aspects. J Hepatol 35:568–574PubMedCrossRefGoogle Scholar
  39. 39.
    Harrison SA, Fincke C, Helinski D, Torgerson S, Hayashi P (2004) A pílot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther 20:623–628PubMedCrossRefGoogle Scholar
  40. 40.
    Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, Faga E, Silli B, Pagano G (2003) Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37:909–916PubMedCrossRefGoogle Scholar
  41. 41.
    Huang MA, Greenson JK, Chao C, Anderson L, Peterman D, Jacobson J, Emick D, Lok AS, Conjeevaram HS (2005) One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 100:1072–1081PubMedCrossRefGoogle Scholar
  42. 42.
    Solga S, Alkhuraishe AR, Clark JM, Torbenson M, Greenwald A, Diehl AM, Magnuson T (2004) Dietary composition and nonalcoholic fatty liver disease. Dig Dis Sci 49:1578–1583PubMedCrossRefGoogle Scholar
  43. 43.
    Gupte P, Amarapurkar D, Agal S, Baijal R, Kulshrestha P, Pramanik S, Patel N, Madan A, Amarapurkar A, Hafeezunnisa (2004) Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 19:854–858PubMedCrossRefGoogle Scholar
  44. 44.
    Friis-Liby I, Aldenborg F, Jerlstad P, Rundstrom K, Bjornsson E (2004) High prevalence of metabolic complications in patients with non-alcoholic fatty liver disease. Scand J Gastroenterol 39:864–869PubMedCrossRefGoogle Scholar
  45. 45.
    Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP (2004) Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 20:23–28PubMedCrossRefGoogle Scholar
  46. 46.
    Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, Yesilova Z, Gulsen M, Dagalp K (2004) Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 19:537–544PubMedCrossRefGoogle Scholar
  47. 47.
    Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G (2005) A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 100:1082–1090PubMedCrossRefGoogle Scholar
  48. 48.
    Schwimmer JB, Middleton MS, Deutsch R, Lavine JE (2005) A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 21:871–879PubMedCrossRefGoogle Scholar
  49. 49.
    Kawaguchi K, Sakaida I, Tsuchiya M, Omori K, Takami T, Okita K (2004) Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme–altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun 315:187–195PubMedCrossRefGoogle Scholar
  50. 50.
    Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, Shiffman ML, Clore J, Mills AS (2004) A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2:1107–1115PubMedCrossRefGoogle Scholar
  51. 51.
    Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR (2003) Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38:1008–1017PubMedGoogle Scholar
  52. 52.
    Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM (2003) Protection against post-ischemic mitochondrial injury in rat liver by silymarin or TUDC. Hepatol Res 26:217–224PubMedCrossRefGoogle Scholar
  53. 53.
    Lirussi F, Beccarello A, Zanette G, De Monte A, Donadon V, Velussi M, Crepaldi G (2002) Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Diabetes Nutr Metab 15:222–231PubMedGoogle Scholar
  54. 54.
    McCarty MF (2005) Potential utility of natural polyphenols for reversing fat-induced insulin resistance. Med Hypotheses 64:628–635PubMedCrossRefGoogle Scholar
  55. 55.
    Bataller R, Brenner DA (2001) Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis 21:437–451PubMedCrossRefGoogle Scholar
  56. 56.
    Di Sario A, Bendia E, Macarri G, Candelaresi C, Taffetani S, Marzioni M, Omenetti A, De Minicis S, Trozzi L, Benedetti A (2004) The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1(I), TIMP-1 and MMP-2. Dig Liver Dis 36:744–751PubMedCrossRefGoogle Scholar
  57. 57.
    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
  58. 58.
    Oliveira CP, Gayotto LC, Tatai C, Della Nina BI, Lima ES, Abdalla DS, Lopasso FP, Laurindo FR, Carrilho FJ (2003) Vitamin C and vitamin E in Prevention of nonalcoholic fatty liver disease (NAFLD) in choline deficient diet fed rats. Nutr J 2:9PubMedCrossRefGoogle Scholar
  59. 59.
    Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S (2003) Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 98:2485–2490PubMedCrossRefGoogle Scholar
  60. 60.
    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A (2001) Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 15:1667–1672PubMedCrossRefGoogle Scholar
  61. 61.
    Kravchenko LV, Morozov SV, Tutel’yan VA (2003) Effects of flavonoids on the resistance of microsomes to lipid peroxidation in vitro and ex vivo. J Hepatol 39:333–340CrossRefGoogle Scholar
  62. 62.
    Valenzuela A, Lagos C, Schmidt K, Videla LA (1985) Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochem Pharmacol 34:2209–2212PubMedCrossRefGoogle Scholar
  63. 63.
    Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G (2003) Silibinin protects mice from T cell-dependent liver injury. J Hepatol 39:333–340PubMedCrossRefGoogle Scholar
  64. 64.
    Jia JD, Bauer M, Cho JJ, Ruehl M, Milani S, Boigk G, Riecken EO, Schuppan D (2001) Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol 35:392–398PubMedCrossRefGoogle Scholar
  65. 65.
    Ma X, Zhao J, Lieber CS (1996) Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression. J Hepatol 24:604–613PubMedCrossRefGoogle Scholar
  66. 66.
    Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB (1999) Silymarin suppresses activation of NFkB, c–Jun–N–Terminal kinase and apoptosis. J Immunol 163:6800–6809PubMedGoogle Scholar
  67. 67.
    Yoo HG, Jung SN, Hwang YS, Park JS, Kim MH, Jeong M, Ahn SJ, Ahn BW, Shin BA, Park RK, Jung YD (2004) Involvement of NFkB and caspases in silibinin-induced apoptosis of endothelial cells. Int J Mol Med 13:81–86PubMedGoogle Scholar
  68. 68.
    Wright TL, Rocky DC (2004) Liver disease: from bench to bedside. Postgraduate course. American Association for the Study of Liver Diseases, Boston (abstr book)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Carmela Loguercio
    • 1
  • Alessandro Federico
    • 1
    • 2
  • Marco Trappoliere
    • 1
  • Concetta Tuccillo
    • 1
  • Ilario de Sio
    • 1
  • Agnese Di Leva
    • 1
  • Marco Niosi
    • 1
  • Mauro Valeriano D’Auria
    • 1
  • Rita Capasso
    • 1
  • Camillo Del Vecchio Blanco
    • 1
  • Real Sud Group
    • 1
  1. 1.Interuniversity Research Center on Foods, Nutrition and Gastrointestinal Tract (CIRANAD), Unit of GastroenterologySecond University of NaplesNaplesItaly
  2. 2.Via Alcide De Gasperi 80Scafati (SA)Italy

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