Digestive Diseases and Sciences

, Volume 53, Issue 4, pp 1114–1121 | Cite as

l-Carnitine Treatment Reduces Steatosis in Patients with Chronic Hepatitis C Treated with α-Interferon and Ribavirin

  • Marcello Romano
  • Marco Vacante
  • Erika Cristaldi
  • Valentina Colonna
  • Maria Pia Gargante
  • Lisa Cammalleri
  • Mariano Malaguarnera
Original Paper

Abstract

Background Hepatic steatosis is a common presentation in patients with chronic hepatitis C. Interferon α exerts both antiviral and immunomodulating actions, and influences on lipid metabolism. The aim of our study was to test whether l-carnitine reduces steatosis in patients treated with interferon and ribavirin. Patients and methods A total of 70 patients were randomly assigned to receive either leucocyte IFN alpha at a dose of 3 MIU thrice a week plus 1,000 mg ribavirin per day for 12 months (group A) or IFN alpha and ribavirin at the same dose plus 2 g carnitine per day (group B). Results Comparison of the two treatments showed significant differences between the mean values of the following parameters at the end of the treatment: ALT −68 vs −95 IU/ml (P < 0.05), total cholesterol 0.08 vs −0.91 mmol/l (P <  0.05) and triglycerides +0.25 vs −20 mmol/l (P < 0.05); and at the follow-up: AST −35 vs −65 IU/ml (P < 0.05) and ALT −55 vs −84 IU/ml (P < 0.05). All values were lower in group B (IFN + Ribavirin + Carnitine) than in group A (IFN plus Ribavirin). When comparing those patients treated with IFN + ribavirin with those treated with IFN plus ribavirin plus carnitine, the response at the end of the treatment was 48% vs 56%, and the sustained response 39% vs 46%, respectively. Conclusions Combined treatment with l-carnitine, ribavirin and IFN alpha resulted in greater antihyperlipidaemic effects and than with ribavirin and IFN alpha alone. The results of this study suggest that l-carnitine may have a role among the reduction of steatosis strategies in patients with hepatitis C treated with IFN alpha and ribavirin.

Keywords

Hepatic steatosis Antihyperlipidaemic effects HCV Interferon alpha Ribavirin 

References

  1. 1.
    Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G, Schaff Z, Chapman MJ, Miyamura T, Brechot C (1997) Hepatitis C Virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci U S A 94:1200–1205PubMedCrossRefGoogle Scholar
  2. 2.
    Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, Miyamura T, Koike K (1997) Hepatitis C Virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78:1527–1531PubMedGoogle Scholar
  3. 3.
    Garcia-Monzon C, Martin-Perez E, Iacono OL, Fernandez-Bermejo M, Majano Pl, Apolinario A, Larranaga E, Moreno-Otero R (2000) Characterization of pathogenetic and prognostic factors of non-alcoholic steatohepatitis associated with obesity. J Hepatol 33:716–724PubMedCrossRefGoogle Scholar
  4. 4.
    Czaya AJ, Carpenter HA, Santrach PJ, Moore SB (1998) Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol 29:198–206CrossRefGoogle Scholar
  5. 5.
    Bach N, Thung SN, Shaffner F (1992) The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology 15:572–577PubMedCrossRefGoogle Scholar
  6. 6.
    Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T (2000) Liver fibrosis in overweight patients. Gastroenterology 118:1117–1123PubMedCrossRefGoogle Scholar
  7. 7.
    Angulo P, Keach JC, Batts KP, Lindor KD (1999) Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis. Hepatology 30:1356–1362PubMedCrossRefGoogle Scholar
  8. 8.
    Alter MJ, Kruszon-Moran D, Nainan OV, Mcquillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS (1999) The prevalence of hepatitis C virus infection in the United States 1988 through 1994. N Engl J Med 341:556–562PubMedCrossRefGoogle Scholar
  9. 9.
    Lauer GM, Waker BD (2001) Hepatitis C Virus infection. N Engl J Med 345:41–52PubMedCrossRefGoogle Scholar
  10. 10.
    Malaguarnera M, Giugno I, Trovato BA, Panebianco MP, Siciliano R, Ruello P (1995) Lipoprotein (A) concentration in patients with chronic active C before and after interferon treatment. Clin Ther 17:721–728PubMedCrossRefGoogle Scholar
  11. 11.
    Malaguarnera M, Giugno I, Ruello P, Pistone G, Restuccia S, Trovato BA (1996) Effects of interferon on blood lipids. Clin Drug Invest 11:43–48CrossRefGoogle Scholar
  12. 12.
    Naeem M, Bacon BR, Mistry B, Britton RS, Di Bisceglie AM (2001) Changes in serum lipoprotein profile during interferon therapy in chronic hepatitis C. Am J Gastroenterol 96:2468–2472PubMedCrossRefGoogle Scholar
  13. 13.
    Rebouche CJ, Seim H (1998) Carnitine metabolism and its regulation in microorganisms and mammals. Ann Rev Nut 18:39–61CrossRefGoogle Scholar
  14. 14.
    Romano M, Malaguarnera M, Vinci M, Batticani S, Consoli G, Navarria G (1996) Incidence and ultrasonographic patterns of hepatic steatosis in the elderly. Arch Gerontol Geriatr 5:313–316CrossRefGoogle Scholar
  15. 15.
    Malaguarnera M, Restuccia N, Di Fazio I, Panebianco MP, Gulizia G, Giugno I (1999) Fish oil treatment of interferon-alpha-induced dyslipidemia: study in patients with chronic hepatitis C. Biodrugs 11:285–291PubMedCrossRefGoogle Scholar
  16. 16.
    Malaguarnera M, Maugeri D, Saraceno B, Romano M, Neri S, Rapisarda R, Pistone G (2002) Effects of carnitine on biochemical responses in patients with chronic hepatitis C treated with interferon-Α. Clin Drug Invest 22:443–448CrossRefGoogle Scholar
  17. 17.
    Malaguarnera I, Di Fazio S, Restuccia G, Pistone N, Restuccia BA (1998) Trovato efficacy of different schedules in the management of chronic hepatitis C with interferon-α. Ann Med 30:213–217PubMedCrossRefGoogle Scholar
  18. 18.
    Alberti A, Benvegnu L (2003) Management of hepatitis C. J Hepatol 38:S104–118PubMedCrossRefGoogle Scholar
  19. 19.
    Stuyver L, Wyseur A, Van Arnhem W, Hernandez F, Maertens G (1996) Second-generation line probe assay for hepatitis C virus genotyping. J Clin Microbiol 34:2259–2266PubMedGoogle Scholar
  20. 20.
    Simmonds P, Alberti P, Halter HJ, Bonino F, Bradley DW, Brechot C, Brouwer JT (1994) A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 19:1321–1324PubMedCrossRefGoogle Scholar
  21. 21.
    Knodell R, Ishack K, Black W (1981) Formulation and application of numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1:431–435PubMedCrossRefGoogle Scholar
  22. 22.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR (1999) Non-alcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474PubMedCrossRefGoogle Scholar
  23. 23.
    Deufel T (1990) Determination of l-carnitine in biological fluids and tissues. J Clin Chem Clin Biochem 28:307–311PubMedGoogle Scholar
  24. 24.
    Malaguarnera L, Rosa MD, Zambito AM, Dell’ombra N, Marco RD, Malaguarnera M (2006) Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. Am J Gastroenterol 101(9):2060–2069 Epub 2006 Jul 18PubMedCrossRefGoogle Scholar
  25. 25.
    Malaguarnera L, Di Rosa M, Zambito Am, Dell’ombra N, Nicoletti F, Malaguarnera M (2006) Chitotriosidase gene expression in Kupffer cells from patients with non-alcoholic fatty liver disease. Gut 55(9):1313–1320 Epub 2006 Jul 6PubMedCrossRefGoogle Scholar
  26. 26.
    Thomssen R, Bonk S, Propfee C, Heerman KH, Kochel HG, Uy A (1992) Association of hepatitis C virus in human sera with beta lipoprotein. Med Microbiol Immunol 181:293–300PubMedCrossRefGoogle Scholar
  27. 27.
    Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A, Negro F (2000) Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype. J Hepatol 33:106–115PubMedCrossRefGoogle Scholar
  28. 28.
    Kumar D, Farrell GC, Fung C, George J (2002) Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology. 36:1266–1272PubMedCrossRefGoogle Scholar
  29. 29.
    Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis c patients and correlates with specific hcv genotype and visceral obesity. Hepatology 33:1358–1364PubMedCrossRefGoogle Scholar
  30. 30.
    Shinohara E, Yamashita S, Kihara S, Hirano K, Ishigami M, Arai T, Nozaki S, Kameda-Takemura K, Kawata S, Matsuzawa Y (1997) Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Hepatology 25:1502–1506PubMedCrossRefGoogle Scholar
  31. 31.
    Dixon RM, Borden EC, Keim NL, Anderson S, Spennetta TL, Tormey DC, Shrago E (1984) Decreases in serum high-density lipoprotein cholesterol and total cholesterol resulting from naturally produced and recombinant DNA-derived leukocyte interferons. Metabolism 33:400–404PubMedCrossRefGoogle Scholar
  32. 32.
    Massaro ER, Borden EC, Hawkins MJ, Wiebe DA, Shrago E (1986) Effects of recombinant interferon-alpha 2 treatment upon lipid concentrations and lipoprotein composition. J Interferon Res 6:655–665PubMedGoogle Scholar
  33. 33.
    Maebashi M, Kawamura N, Sato M, Imamura A, Yoshinaga K (1978) Lipid-lowering effect of carnitine in patients with type-IV hyperlipoproteinaemia. Lancet 2:805–807PubMedCrossRefGoogle Scholar
  34. 34.
    Khan L, Bamji MS (1979) Tissue carnitine deficiency due to dietary lysine deficiency: triglyceride accumulation and concomitant impairment in fatty acid oxidation. J Nutr 109:24–31PubMedGoogle Scholar
  35. 35.
    Richter V, Rassoul F, Schulz G, Sittner WD, Seim H, Loster H, Rotzsch W (1987) Carnitine and experimental carbohydrate-induced hyperlipoproteinemia. Arch Int Pharmacodyn Ther 290(1):138–144PubMedGoogle Scholar
  36. 36.
    Feng Y, Guo C, Wei J, Yang J, Ge Y, Gao L (2001) Necessity of carnitine supplementation in semistarved rats fed a high-fat diet. Nutrition 17(7–8):628–631PubMedCrossRefGoogle Scholar
  37. 37.
    Malaguarnera M, Pistone G, Neri S, Romano M, Brogna A, Musumeci S (2004) Interleukin-2 plus ribavirin versus interferon-alpha-2b plus ribavirin in patients with chronic hepatitis C who did not respond to previous interferon-alpha-2b treatment. Biodrugs 18:407–413PubMedCrossRefGoogle Scholar
  38. 38.
    Famularo G, De Simone C (1995) A new era for carnitine? Immunol Today 16:211–213PubMedCrossRefGoogle Scholar
  39. 39.
    Sougero C, Joo M, Chianese-Bulock KA, Nguyen DT, Tung K, Hahn V (2002) Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol 76:9345–9354CrossRefGoogle Scholar
  40. 40.
    Lederblad G (1976) Plasma carnitine and body composition. Clin Chim Acta 67:207–212CrossRefGoogle Scholar
  41. 41.
    Lysiak W, Lilly K, Dilisa F, Toth PP, Bieber LL (1988) Quantitation of the effect of l-carnitine on levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria. J Biol Chem 263:1151–1155PubMedGoogle Scholar
  42. 42.
    Feng V, Suo CJ, Wei JV et al (2000) The impact of fat rich feeding on carnitine and lipid metabolism in half-starved rats. Chin J Clin Nutr 8:96–101Google Scholar
  43. 43.
    Lewis JA, Huq A, Najarro P (1996) Inhibition of mitochondrial function by interferon. J Biol Chem 271:13184–13190PubMedCrossRefGoogle Scholar
  44. 44.
    Kraemer WJ, Volek JS, French DN, Rubin MR, Sharman MJ, Gomez AL, Ratamess NA, Newton RU, Jemiolo B, Craig BW, Hakkinen K (2003) The effects of l-carnitine l-tartrate supplementation on hormonal responses to resistance exercise and recovery. J Strength Cond Res 17(3):455–462. Pmid: 12930169PubMedCrossRefGoogle Scholar
  45. 45.
    Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A, Miranda M, Mari M, Ardite E, Morales A (1997) Gsh transport in mitochondria: defense against tnf-induced oxidative stress and alcohol-induced defect. Am J Physiol 273(1 Pt 1):G7–17. Review. Pmid: 9252504PubMedGoogle Scholar
  46. 46.
    Quillet-Mary A, Jaffrezou JP, Mansat V, Bordier C, Naval J, Laurent G (1997) Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 272(34):21388–21395. Pmid: 9261153PubMedCrossRefGoogle Scholar
  47. 47.
    Perez-Carreras M, Del Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, Colina F, Arenas J, Solis-Herruzo JA (2003) Defective hepatic mitochondrial respiratory chain in patients with non-alcoholic steatohepatitis. Hepatology 38:999–1007PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Marcello Romano
    • 1
  • Marco Vacante
    • 1
  • Erika Cristaldi
    • 1
  • Valentina Colonna
    • 1
  • Maria Pia Gargante
    • 1
  • Lisa Cammalleri
    • 1
  • Mariano Malaguarnera
    • 1
  1. 1.Department Of SenescenceUrological And Neurological Sciences Ospedale CannizzaroViale MessinaItaly

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