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Órgano Oficial de la Asociación Mexicana de Hepatología

2014, Number 3

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Ann Hepatol 2014; 13 (3)

Treatment with Metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis

Higuera-de la Tijera F, Servín-Caamaño AI, Cruz-Herrera J, Serralde-Zúñiga AE, Abdo-Francis JM, Gutiérrez-Reyes G, Pérez-Hernández JL

Language: English
References: 38
Page: 343-352
PDF size: 122.82 Kb.


ABSTRACT

Background & Aim. Despite treatment with glucocorticoids, mortality remains high in patients with severe alcoholic hepatitis. Oxidative stress and depletion of mitochondrial glutathione are implicated factors in liver injury. The aim of this study was to evaluate the impact of the addition of metadoxine, a drug which possesses a multifactorial mechanism of action, including antioxidant properties, to standard treatment with glucocorticoids in patients with severe alcoholic hepatitis. Material and methods. This randomized open label clinical trial was performed in Mexico’s General Hospital (Registry Key DIC/10/107/03/043). We randomized 70 patients with severe alcoholic hepatitis. The first group received prednisone (40 mg/day), and the second group received prednisone (40 mg/day) plus metadoxine tablets (500 mg three times daily). The duration of treatment in both groups was 30 days. Survival at 30 and 90 days, development of complications, adverse events and response to treatment (Lille model) were assessed. Results. In the group receiving metadoxine, significant improvements were observed, as follows: survival at 30 days (74.3 vs. 45.7%, P = 0.02); survival at 90 days (68.6 vs. 20.0%, P = 0.0001). There was less development or progression of encephalopathy (28.6 vs. 60.0%, P = 0.008) and hepatorenal syndrome (31.4 vs. 54.3%, P = 0.05), and the response to treatment (Lille model) was higher in the metadoxine group (0.38 vs. 0.63, P = 0.001; 95% CI 0.11 to 0.40). There were no differences between groups regarding the development or progression of variceal hemorrhage or infection. The incidence of adverse events, mainly gastrointestinal, was similar in both groups. Conclusions. Addition of metadoxine to glucocorticoid treatment improves the short-term survival of patients with severe alcoholic hepatitis and diminishes the development or progression of encephalopathy and hepatorenal syndrome.


REFERENCES

  1. Haber PS, Warner R, Seth D, Gorrell MD, McCaughan GW. Pathogenesis and management of alcoholic hepatitis. J Gastroenterol Hepatol 2003; 18: 1332-44.

  2. Mathurin P, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, Valla D, et al. Early change in bilirubin levels is an important prognostic factor in Severe Alcoholic Hepatitis treated with Prednisolone. Hepatology 2003; 38: 1363-69.

  3. McCullough AJ, O’Connor JF. Alcoholic Liver Disease: Proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol 1998; 93: 2022-36.

  4. Punukollu R, Gopalswamy N. The hepatorenal syndrome. Med Clin North Am 1990; 74: 933-44.

  5. Carithers RL Jr, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med 1989; 110: 685-90.

  6. Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 1996; 110: 1847-53.

  7. Mathurin P, Mendenhall CL, Carithers RL Jr, Ramond MJ, Maddrey WC, Garstide P, Rueff B, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double-blind trials of corticosteroids in severe AH. J Hepatol 2002; 36: 480-7.

  8. Di Mambro AJ, Parker R, McCune A, Gordon F, Dayan CM, Collins P. In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis. Hepatology 2011; 53: 1316-22.

  9. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Díaz E, Fartoux L, Dharancy S, et al. The Lille model: A new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007; 45: 1348-54.

  10. Ruíz-Zavala A, Gil-Rojas N, Higuera-de la Tijera MF. Response to prednisone in Mexican patients with alcoholic hepatitis in a period of four years in the Hospital General de México. Ann Hepatol 2012; 11: 602.

  11. Altamirano J, Higuera-de la Tijera F, Duarte-Rojo A, Martínez- Vázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, et al. The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis. Am J Gastroenterol 2011; 106: 1472-80.

  12. Sass DA, Shaikh OS. Alcoholic hepatitis. Clin Liver Dis 2006; 10: 219-37.

  13. Voican CS, Perlemuter G, Naveau S. Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update. Clin Res Hepatol Gastroenterol 2011; 35: 465-74.

  14. Colell A, García-Ruiz C, Miranda M, Ardite E, Marí M, Morales A, Corrales F, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 1998; 115: 1541-51.

  15. Cederbaum AI, Yongke L, Defeng W. Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol 2009; 83: 519-48.

  16. Gutiérrez-Ruíz MC, Bucio L, Correa A, Souza V, Hernández E, Gómez-Quiroz LE, Kershenobich D. Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stellate cells in culture. Pharmacol Res 2001; 44: 431-6.

  17. Muriel P, Deheza R. Fibrosis and glycogen stores depletion induced by prolonged biliary obstruction in the rat are ameliorated by metadoxine. Liver Int 2003; 23: 262-8.

  18. Shpilenya LS, Muzychenko AP, Gasbarrini G, Addolorato G. Metadoxine in acute alcohol intoxication: a double-blind, randomized, placebo-controlled study. Alcohol Clin Exp Res 2002; 26: 340-6.

  19. Díaz-Martínez MC, Díaz-Martínez A, Villamil-Salcedo V, Cruz-Fuentes C. Efficacy of metadoxine in the management of acute alcohol intoxication. J Int Med Res 2002; 30: 44-51.

  20. Caballería J, Parés A, Brú C, Mercader J, Garcia Plaza A, Caballería L, Clemente G, et al. Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo control trial. Spanish group for the study of alcoholic fatty liver. J Hepatol 1998; 28: 54-60.

  21. Leggio L, Kenna GA, Ferrulli A, Zywiak WH, Caputo F, Swift RM, Addolorato G. Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease. Hum Psychopharmacol Clin Exp 2011; 26: 554-59.

  22. Fehér J, Lengyel G. A New Approach to Drug Therapy in Non-alcoholic Steatohepatitis (NASH). J Int Med Res 2003; 31: 537-51.

  23. Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut 1982; 23: 75-9.

  24. Lucey MR, Mathurin P, Morgan TR. Alcoholic Hepatitis. N Engl J Med 2009; 360: 2758-69.

  25. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.

  26. García-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48: 2064-77.

  27. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310-8.

  28. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010; 53: 397-417.

  29. Córdoba J. New assessment of hepatic encephalopathy. J Hepatol 2011; 54: 1030-40.

  30. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-38.

  31. Ramond MJ, Poynard T, Rueff B, Mathurin P, Théodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326: 507-12.

  32. Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011; 60: 255-60.

  33. Garrido-García JR, Sánchez-Hernández G, Melchor-López A, Elizalde-Barrera CI, Sánchez-Vargas L. Pentoxifilina versus esteroide en la sobrevivencia a corto plazo en hepatitis aguda alcohólica severa. Med Int Mex 2012; 28: 227-33.

  34. Dominguez M, Rincón D, Abraldes JG, Miquel R, Colmenero J, Bellot P, García-Pagán JC, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol 2008; 103: 2747-56.

  35. Stewart S, Prince M, Bassendine M, Hudson M, James O, Jones D, Record C, et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 2007; 47: 277-83.

  36. Nguyen.Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011; 365: 1781-9.

  37. Higuera-de la Tijera MF, Pérez-Hernández JL, Servín-Caamaño AI, Serralde-Zúñiga AE, Cruz-Palacios A. Cantidad de alcohol, hemorragia de tubo digestivo alto, insuficiencia renal aguda y encefalopatía hepática como factores de riesgo implicados en el incremento de la mortalidad en pacientes con hepatitis por alcohol. Rev Gastroenterol Mex 2009; 74: 306-13.

  38. Calabrese V, De Bernardis E, Rizza V. Metadoxine in the control of oxidative stress caused by acute and chronic ethanol poisoning. Boll Soc Ital Biol Sper 1986; 62: 1357-63.




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