Gastroenterology
Volume 138, Issue 5 , Pages 1755-1762.e2 , May 2010

Pentoxifylline Does Not Decrease Short-term Mortality but Does Reduce Complications in Patients With Advanced Cirrhosis

  • Didier Lebrec

      Affiliations

    • INSERM, Unité 773, Centre de Recherche Biomédicle Bichat-Beaujon CRB3, Paris, France and Service d'Hépatologie, Hôpital Beaujon, Clichy, France
    • Corresponding Author InformationReprint requests Address requests for reprints to: Dr Didier Lebrec, INSERM, Hôpital Beaujon, 92100 Clichy, France
    • ,
  • Dominique Thabut

      Affiliations

    • Service d'Hépato-Gastroentérologie, Groupe Pitié Salpêtrière, APHP-UPMC Liver Center, Paris, France
    • ,
  • Frederic Oberti

      Affiliations

    • Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire, Angers, France
    • ,
  • Jean–Marc Perarnau

      Affiliations

    • Service d'Hépato-Gastroentérologie, Hôpital Trousseau, Tours, France
    • ,
  • Bertrand Condat

      Affiliations

    • Service d'Hépato-Gastroentérologie, Hôpital Saint Camille, Bry-sur-Marne, France
    • ,
  • Helene Barraud

      Affiliations

    • Service d'Hépato-Gastroentérologie, Hôpitaux de Brabois, Vandoeuvre, France
    • ,
  • Faouzi Saliba

      Affiliations

    • Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
    • ,
  • Nicolas Carbonell

      Affiliations

    • Service d'Hépatologie, Hôpital Saint Antoine, Paris, France
    • ,
  • Philippe Renard

      Affiliations

    • Service d'Hépato-Gastroentérologie, Hôpital Victor Dupouy, Argenteuil, France
    • ,
  • Marie–Jose Ramond

      Affiliations

    • INSERM, Unité 773, Centre de Recherche Biomédicle Bichat-Beaujon CRB3, Paris, France and Service d'Hépatologie, Hôpital Beaujon, Clichy, France
    • ,
  • Richard Moreau

      Affiliations

    • INSERM, Unité 773, Centre de Recherche Biomédicle Bichat-Beaujon CRB3, Paris, France and Service d'Hépatologie, Hôpital Beaujon, Clichy, France
    • ,
  • Thierry Poynard

      Affiliations

    • Service d'Hépato-Gastroentérologie, Groupe Pitié Salpêtrière, APHP-UPMC Liver Center, Paris, France
    • ,
  • Pentocir Group

      Affiliations

    • Investigators of the Pentocir Group are listed in the Appendix

Received 10 July 2009 ,Accepted 14 January 2010.

References 

  1. Simpson KJ, Luckacs NW, Colletti L, et al. Cytokines and the liver. J Hepatol. 1997;27:1120–1132
  2. Maher JJ. Cytokines: overview. Semin Liver Dis. 1999;19:109–115
  3. Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology. 1992;103:264–274
  4. Bird GLA, Sheron N, Goka AKJ, et al. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med. 1990;112:917–920
  5. Navasa M, Follo A, Filella X, et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology. 1998;27:1227–1232
  6. Goulis J, Patch D, Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet. 1999;353:139–142
  7. Tilg H, Diehl AM. Cytokines in alcoholic and non-alcoholic steatohepatitis. N Engl J Med. 2000;343:1467–1476
  8. Byl B, Roucloux I, Crusiaux A, et al. Tumor necrosis factor alpha and interleukin-6 plasma levels in infected cirrhotic patients. Gastroenterology. 1993;104:1492–1497
  9. Tazi KA, Quioc JJ, Saada V, et al. Upregulation of TNF-alpha production signalling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J Hepatol. 2006;45:280–289
  10. McClain C, Cohen D. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology. 1989;9:349–351
  11. Bradham CA, Plumpe JR, Manns MP, et al. Mechanism of hepatic toxicity (I. TNF-induced liver injury). Am J Physiol. 1998;275:G387–G392
  12. McClain C, Barve S, Deaciuc I, et al. Cytokines in alcoholic liver disease. Semin Liver Dis. 1999;19:205–220
  13. Nathan C. Points of control in inflammation. Nature. 2002;420:19–26
  14. Soupison T, Yang S, Bernard C, et al. Acute haemodynamic responses and inhibition of tumor necrosis factor-alpha by pentoxifylline in rats with cirrhosis. Clin Sci. 1979;91:29–33
  15. Tazi KA, Bièche I, Paradis V, et al. In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J Hepatol. 2007;46:1075–1088
  16. Satapathy SK, Sakhuja P, Malhotra V, et al. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:634–638
  17. Yalniz M, Bahcecioglu IH, Kuzu N, et al. Amelioration of steatohepatitis with pentoxifylline in a novel nonalcholic steatohepatitis model induced by high-fat diet. Dig Dis Sci. 2007;52:2380–2386
  18. Akriviadis E, Botla R, Briggs W, et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:1637–1648
  19. Sztrymf B, Rabiller A, Nunes H, et al. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J. 2004;23:752–758
  20. Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol. 2005;42(Suppl 1):S100–S107
  21. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709
  22. Peterson T, Isbrucker R, Hooper M. In vitro effect of platelet-derived growth factor on fibroproliferation and effect on cytokine antagonists. Immunopharmacology. 1994;28:259–270
  23. Krakauer T. Pentoxifylline inhibits ICAM-1 expression and chemokine production induced by proinflammatory cytokines in human pulmonary epithelial cells. Immunopharmacology. 2000;46:253–261
  24. Zabel P, Schade F, Schlaak M. Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology. 1993;187:1230–1236
  25. Neuner P, Klosner G, Pourmojib M, et al. Pentoxifylline in vivo down-regulates the expression of the intercellular adhesion molecule-1 in monocytes. Immunology. 1997;90:435–439
  26. SidhuS , Singla M, Bhatia KL, et al. Pentoxifylline reduces disease severity and prevent renal impairment in severe acute alcoholic hepatitis: a double blind, placebo controlled trial. Hepatology. 2006;44(Suppl 1):373A
  27. Tazi KA, Moreau R, Herve P, et al. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signalling. Gastroenterology. 2005;129:303–314
  28. Perez-Paramo M, Munoz J, Albillos A, et al. Effect of propranolol on the factor promoting bacterial translocation in cirrhotic rats with ascites. Hepatology. 2000;31:43–48
  29. Ogawa S, Lozach J, Benner C, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 2005;122:707–721
  30. Wehler M, Kokoska J, Reulbach U, et al. Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology. 2001;34:255–261
  31. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464–470
  32. Felver M, Mezey E, McGuire M, et al. Plasma tumor necrosis factor predicts decreased long-termsurvival in severe alcoholic hepatitis. Alcohol Clin Res. 1990;14:255–259
  33. Spahr L, Giostra E, Frossard JL, et al. Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J Hepatol. 2004;41:229–234
  34. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004;39:1390–1397
  35. Boetticher NC, Peine CJ, Kwo P, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology. 2008;135:1953–1960
  36. Corradi F, Fernandez J, Navasa M, et al. Pentoxifylline prevents small intestinal bacterial overgrowth, bacterial translocation, and spontaneous bacterial peritonitis in experimental cirrhosis. J Hepatol. 2004;40(Suppl 1):14
  37. Odeh M, Sabo E, Srugo I, et al. Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure. Liver Intern. 2004;24:110–116

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by a grant from the French Ministry of Health. The sponsor was the Département de la Recherche Clinique et du Développement, Assistance Publique-Hôpitaux de Paris (PHRC AOM03120).

PII: S0016-5085(10)00109-5

doi: 10.1053/j.gastro.2010.01.040

Gastroenterology
Volume 138, Issue 5 , Pages 1755-1762.e2 , May 2010

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