Effect of Omega 5 Fatty Acid as an Adyuvant Treatment to Prednisone in Patients With Severe Alcoholic Hepatitis
Study Details
Study Description
Brief Summary
In Mexico, alcoholic liver disease is the fourth cause of mortality (INEGI). Patients with severe alcoholic hepatitis have a high mortality at 28 days and 6 months, patients receiving standard therapy with prednisone that are non responders (Lille> 0.45) have a survival of 53.3 ± 5.1 % to 28 days. At present, there is not a completely effective treatment for non responders patients, with a high mortality, so it is necessary to look for other therapeutic strategies.
The omega-5 fatty acid (punicic acid) has been considered a powerful antioxidant, it is an agonist of PPAR gamma, has been shown to reduce lipid peroxidation, and restore levels of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. It has also been shown to inhibit the expression of proinflammatory cytokines (such as IL6, IL8, IL23, IL12 and TNFalpha) through PPAR and modulation delta.
The objective of this study is to evaluate the effect of Omega 5 fatty acid on inflammatory markers and antioxidant-oxidant balance markers in patients with severe alcoholic hepatitis treated with prednisone. HYPOTHESIS. Omega 5 fatty acid being a PPARgamma agonist reduces lipid peroxidation and protein damage, restoring reduced glutathione levels, as well as decreasing proinflammatory cytokines, in patients with Severe Alcoholic Hepatitis treated with prednisone and supplementation with fatty acid Omega 5.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
Detailed Description
Double-blind clinical trial.
Two groups:
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GROUP A (standard treatment): Prednisone 40 mg a day + Placebo (manufactured by the same laboratory with the same presentation and physical appearance as the nanoemulsifyied pomegranate seed oil rich in Omega 5 fatty acid)
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GROUP B (combined treatment): Prednisone 40 mg per day + nanoemulsifiyied pomegranate seed oil rich in Omega 5 fatty acid (2 capsules of 0.64g each / day).
STUDY UNIVERSE: Patients> 18 years old, indistinct gender, with a diagnosis of severe alcoholic hepatitis.
STUDY POPULATION: Patients with clinical and laboratory diagnosis of alcoholic hepatitis Severe Maddrey score ≥32.
SAMPLE SIZE: Double-blind clinical trial, which will include 20 patients for standard treatment and 20 patients for combined treatment, patients who meet the inclusion criteria will be invited to participate. If they agree to participate (after signing the informed consent), the AUDIT C and CAGE questionnaires will be applied, as well as the measurement of anthropometric values and the taking of 3 blood tubes (2 purple and 1 yellow) for the measurement of cytokines, markers of oxidative stress, lipid peroxidation and protein carbonyls.
The initial evaluation will include liver ultrasound, heart rate, blood pressure, temperature, anthropometric evaluation (weight (kilograms), height (meters), BMI (kg/m2), evaluation of ascites (abdominal circumference), hepatic encephalopathy (West Haven Scale). Alcohol abuse will be assessed using the AUDIT and CAGE score. Start-up laboratories will be carried out: TP, INR, Complete liver function tests (BT, BD, FA, AST, ALT, GGT, Albumin), Seric electrolytes (Na, K, Phosphorus, Magnesium), Creatinine, Blood cytometry (Leukocytes (PMN) ), hemoglobin, VCM, platelets), lipid profile (ColT, HDL, LDL, TGs), ferritin and transferrin saturation, Anti-nuclear antibodies, Anti mithochondrial antibodies, AgHBs, AcHBc, anti HCV, anti HIV. The scrutiny of bacterial infections will be carried out through urine culture, blood cultures and in case of suspicion of SBP (paracenthesis). Child-Pugh score (A5-6, B7-9, C10-12), Maddrey score, MELD, ABIC score, Glasgow score. Chest x-Ray, General Urine Test.
Patients who meet the inclusion criteria, previously described, will be proposed to participate in the study, explaining in detail the procedures as well as the studiesthat will be performed. If they agree to participate, they will proceed to the signature of the informed consent by the patient and their responsible family member. Samples (2 yellow tubes and 2 purple tubes) will be taken for the measurement of cytokines, markers of oxidative stress, lipid peroxidation and protein carbonyls prior to the supply of the supplement vs placebo as well as the start of standard treatment. It will be explained to the patient that these samples will be done in 4 times (at diagnosis, on day 7, 14 and 28), which will be carried out during their hospitalization and follow-up.
Both treatments will be taken for 28 days.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Omega 5 fatty acid supplement 20 patients will be assigned to traditional treatment with prednisone 40 mg per day plus dietary supplement with omega 5 fatty acid |
Dietary Supplement: Omega 5 fatty acid supplement
Patients will be randomized to receive traditional treatment (prednisone 40 mg per day) plus omega 5 fatty acid ( 2 capsules of 0.64g per day) for 28 days.
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Placebo Comparator: PLACEBO 20 patients will be assigned to traditional treatment (prednisone 40 mg per day) plus placebo |
Other: PLACEBO
Patients will be randomized to receive the traditional treatment (prednisone 40 mg per day) plus placebo (2 capsules of placebo with identical appereance and size like omega 5 supplement) for 28 days.
Other Names:
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Outcome Measures
Primary Outcome Measures
- 30 Day Survival [day 30]
Better survival in patients with omega 5 supplement associated to prednisone
Secondary Outcome Measures
- Rate of reponse to steroids at day 7 [day 7]
To describe the response to steroids (Lille score) at 7 days of treatment in patients with severe alcoholic hepatitis with combined treatment (Omega 5 and steroids) compared to standard treatment. (Lille response describe a below of 0.45)
- Malondialdehyde serum levels [basal, day 7, day 14 and day 28]
To determine the serum concentrations of lipid peroxidation molecules (malondialdehyde (MDA expressed in mM) in patients with severe alcoholic hepatitis treated with prednisone compare to those treated with prednisona and omega5.
- Oxidative Stress molecules serum levels [basal, day 7, day 14 and day 28]
To assess changes in oxidative stress markers (Oxidative glutation and reduced glutation expressed in mM) in patients with severe alcoholic hepatitis treated with prednisone compared to those treated with prednisone and omega 5.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with clinical and biochemical criteria for severe alcoholic hepatitis (Total bilirubin greater than 5 mg/dl in absence of biliary tract obstruction evidenced by ultrasound)
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history of chronic alcohol intake (greater than 50 g / day for at least 3 months),
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leukocytosis (neutrophilia)
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elevation of transaminases with an aspartate aminotransferase / alanine aminotransferase ratio equal or greater than 2)
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discriminant function greater than 32.
Exclusion Criteria:
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Hepatorenal syndrome (serum creatinine >2.5mg/dl)
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Hepatocellular carcinoma.
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Hepatitis C virus, hepatitis B virus or human immunodeficiency virus infection.
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Cancer, heart disease, neurological or severe neurological.
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Patients taking pentoxifylline, steroids, S-adenosyl L- methionine or N-Acetylcysteine.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Laboratorio de Higado, Pancreas y Motilidad Intestinal. UNIVERSIDAD AUTONOMA DE MEXICO | Mexico City | Cuauhtemoc | Mexico | 06720 |
2 | Hospital General Dr. Manuel Gea Gonzalez | Mexico City | Tlalpan | Mexico | 14080 |
Sponsors and Collaborators
- Hospital General Dr. Manuel Gea González
- Universidad Nacional Autonoma de Mexico
Investigators
- Principal Investigator: Jacqueline Cordova-Gallardo, MD, Hospital General Dr. Manuel Gea Gonzalez
- Principal Investigator: Gabriela Gutierrez-Reyes, DSc, Universidad Autonoma de México
Study Documents (Full-Text)
None provided.More Information
Publications
- Altamirano J, Higuera-de laTijera F, Duarte-Rojo A, Martínez-Vázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Perez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginès P, Caballería J, Bataller R. The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis. Am J Gastroenterol. 2011 Aug;106(8):1472-80. doi: 10.1038/ajg.2011.141. Epub 2011 May 10.
- Ambade A, Mandrekar P. Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int J Hepatol. 2012;2012:853175. doi: 10.1155/2012/853175. Epub 2012 Mar 1.
- Amini M, Runyon BA. Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy. World J Gastroenterol. 2010 Oct 21;16(39):4905-12. Review.
- Basra G, Basra S, Parupudi S. Symptoms and signs of acute alcoholic hepatitis. World J Hepatol. 2011 May 27;3(5):118-20. doi: 10.4254/wjh.v3.i5.118.
- Cohen SM, Ahn J. Review article: the diagnosis and management of alcoholic hepatitis. Aliment Pharmacol Ther. 2009 Jul;30(1):3-13. doi: 10.1111/j.1365-2036.2009.04002.x. Epub 2009 Mar 26. Review.
- Dominguez M, Rincón D, Abraldes JG, Miquel R, Colmenero J, Bellot P, García-Pagán JC, Fernández R, Moreno M, Bañares R, Arroyo V, Caballería J, Ginès P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008 Nov;103(11):2747-56. doi: 10.1111/j.1572-0241.2008.02104.x. Epub 2008 Aug 21.
- Dugum MF, McCullough AJ. Acute Alcoholic Hepatitis, the Clinical Aspects. Clin Liver Dis. 2016 Aug;20(3):499-508. doi: 10.1016/j.cld.2016.02.008. Epub 2016 May 14. Review.
- European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012 Aug;57(2):399-420. doi: 10.1016/j.jhep.2012.04.004. Epub 2012 May 26.
- Gholam PM. Prognosis and Prognostic Scoring Models for Alcoholic Liver Disease and Acute Alcoholic Hepatitis. Clin Liver Dis. 2016 Aug;20(3):491-7. doi: 10.1016/j.cld.2016.02.007. Epub 2016 May 14. Review.
- Higuera-de la Tijera F, Servín-Caamaño AI, Serralde-Zúñiga AE, Cruz-Herrera J, Pérez-Torres E, Abdo-Francis JM, Salas-Gordillo F, Pérez-Hernández JL. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis. World J Gastroenterol. 2015 Apr 28;21(16):4975-85. doi: 10.3748/wjg.v21.i16.4975.
- Higuera-de la Tijera MF, Pérez-Hernández JL, Serralde-Zúñiga AE, Servín-Caamaño AI, Cruz-Palacios A, Bernal-Sahagún F, Salas-Gordillo F. [Three prognostic utility scales to determine early mortality in patients with alcoholic hepatitis in the General Hospital of Mexico]. Rev Gastroenterol Mex. 2010;75(3):281-6. Spanish.
- Higuera-de la Tijera MF, Pérez-Hernández JL, Servín-Caamaño AL, Serralde-Zúñiga AE, Cruz-Palacios A. [The amount of alcohol intake, upper gastrointestinal bleeding, acute renal failure and hepatic encephalopathy as the risk factors implied in the increase of patients with alcoholic hepatitis]. Rev Gastroenterol Mex. 2009 Oct-Dec;74(4):306-13. Spanish.
- Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liver Dis. 2005 Feb;9(1):37-53. Review.
- Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007 Jun;45(6):1348-54.
- Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009 Aug;137(2):541-8. doi: 10.1053/j.gastro.2009.04.062. Epub 2009 May 13.
- Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. doi: 10.1056/NEJMra0805786. Review.
- Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011 Feb;60(2):255-60. doi: 10.1136/gut.2010.224097. Epub 2010 Oct 12.
- Méndez-Sánchez N, Villa AR, Chávez-Tapia NC, Ponciano-Rodriguez G, Almeda-Valdés P, González D, Uribe M. Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality data. Ann Hepatol. 2005 Jan-Mar;4(1):52-5.
- Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL; AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011 Nov 10;365(19):1781-9. doi: 10.1056/NEJMoa1101214.
- Phillips PK, Lucey MR. Acute Alcoholic Hepatitis: Therapy. Clin Liver Dis. 2016 Aug;20(3):509-19. doi: 10.1016/j.cld.2016.02.015. Epub 2016 May 31. Review.
- Sass DA, Shaikh OS. Alcoholic hepatitis. Clin Liver Dis. 2006 May;10(2):219-37, vii. Review.
- Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. BMC Gastroenterol. 2002;2:2. Epub 2002 Jan 22.
- Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O'Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278.
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