Evaluation of the Effectiveness of Ellagic Acid on Liver Steatosis in Overweight/Obese Non-Alcoholic Fatty Liver Disease Patients: Study Protocol for a Randomized Controlled Trial

Document Type : Protocol Study

Authors

1 Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Department of Nutrition, Varastegan Institute for Medical Sciences, Mashhad, Iran.

3 Department of Radiology, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran.

4 Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

5 Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

6 Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

7 Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.

8 Neurogenic Inflammation Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.

Abstract

Introduction: Non-alcoholic fatty liver (NAFLD) is a condition that can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. There is no definite treatment for NAFLD. Ellagic acid (EA) is natural polyphenol with proven pharmacological properties, but its effectiveness on NAFLD in patients is not clear. The aim of this study is to evaluate the effect of ellagic acid on liver fibrosis in NAFLD patients. Method: This randomized, double-blind, controlled, and parallel clinical trial will be conducted on 60 patients with NAFLD (grade 2 or above) who will be allocated in intervention or placebo groups with 1:1 ratio. The intervention group will receive capsules containing 200 mg EA while the placebo group will receive avicel as placebo for 8 weeks. Body composition and anthropometric indices will be measured at baseline, end of 4th and 8th week. Transient elastography, 3-day food record, International Physical Activity Questionnaire (IPAQ), and laboratory tests (CBC/diff, uric acid, creatinine, lipid profile (total cholesterol, triglyceride [TG], low-density lipoprotein cholesterol [LDL-c], and high-density lipoprotein cholesterol [HDL-c]), aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], and gamma-glutamyl transpeptidase [GGT], albumin, high sensitive C-reactive protein [hs-CRP] and insulin) will be performed for both groups at baseline and end of the study. Conclusion: We expect that 200 mg EA ellagic acid administration for 8 weeks will improve liver steatosis, clinical and paraclinical outcomes in NAFLD patients.

Keywords

Main Subjects

References

  1. Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. The Lancet. 2021;397(10290):2212-24.
  2. Zhang C, Yang M. Current options and future directions for NAFLD and NASH treatment. International Journal of Molecular Sciences. 2021;22(14):7571.
  3. Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Translational gastroenterology and hepatology. 2020;5.
  4. Karimi-Sari H, Mousavi-Naeini SM, Khonche A. Comments on prevalence of non-alcoholic fatty liver disease and its related factors in Iran. International Journal of Organ Transplantation Medicine. 2017;8(1):52.
  5. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017 Jun 1;66(6):1138-53.
  6. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. Jama. 2020 Mar 24;323(12):1175-83.
  7. Myers RP, Fong A, Shaheen AA. Utilization rates, complications and costs of percutaneous liver biopsy: a population‐based study including 4275 biopsies. Liver International. 2008;28(5):705-12.
  8. Kose S, Ersan G, Tatar B, Adar P, Sengel BE. Evaluation of percutaneous liver biopsy complications in patients with chronic viral hepatitis. The Eurasian journal of medicine. 2015;47(3):161.
  9. Fallatah HI. Noninvasive biomarkers of liver fibrosis: an overview. Advances in Hepatology. 2014;2014(1):357287.
  10. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. Journal of hepatology. 2013;58(5):1007-19.
  11. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. Journal of hepatology. 2010;53(2):372-84.
  12. Podrug K, Sporea I, Lupusoru R, Pastrovic F, Mustapic S, Bâldea V, Bozin T, Bokun T, Salkic N, Șirli R, Popescu A. Diagnostic performance of 2-D shear-wave elastography with propagation maps and attenuation imaging in patients with non-alcoholic fatty liver disease. Ultrasound in medicine & biology. 2021 Aug 1;47(8):2128-37.
  13. Berzigotti A, Seijo S, Arena U, Abraldes JG, Vizzutti F, García–Pagán JC, Pinzani M, Bosch J. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology. 2013 Jan 1;144(1):102-11.
  14. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(S1):S99-112.
  15. Black PH. The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II. Medical hypotheses. 2006;67(4):879-91.
  16. Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. Journal of Hepatology. 2009;50(5):1029-34.
  17. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nature medicine. 2018 Jul;24(7):908-22.
  18. Marina A, Von Frankenberg AD, Suvag S, Callahan HS, Kratz M, Richards TL, Utzschneider KM. Effects of dietary fat and saturated fat content on liver fat and markers of oxidative stress in overweight/obese men and women under weight-stable conditions. Nutrients. 2014 Oct 28;6(11):4678-90.
  19. Periasamy S, Chien SP, Chang PC, Hsu DZ, Liu MY. Sesame oil mitigates nutritional steatohepatitis via attenuation of oxidative stress and inflammation: a tale of two-hit hypothesis. The Journal of nutritional biochemistry. 2014 Feb 1;25(2):232-40.
  20. George ES, Forsyth A, Itsiopoulos C, Nicoll AJ, Ryan M, Sood S, Roberts SK, Tierney AC. Practical dietary recommendations for the prevention and management of nonalcoholic fatty liver disease in adults. Advances in nutrition. 2018 Jan 1;9(1):30-40.
  21. Nseir W, Hellou E, Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World journal of gastroenterology: WJG. 2014 Jul 7;20(28):9338.
  22. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. The Journal of clinical investigation. 2005 May 2;115(5):1343-51.
  23. Tasaki M, Umemura T, Maeda M, Ishii Y, Okamura T, Inoue T, Kuroiwa Y, Hirose M, Nishikawa A. Safety assessment of ellagic acid, a food additive, in a subchronic toxicity study using F344 rats. Food and Chemical Toxicology. 2008 Mar 1;46(3):1119-24.
  24. Bobinaitė R, Viškelis P, Venskutonis PR. Variation of total phenolics, anthocyanins, ellagic acid and radical scavenging capacity in various raspberry (Rubus spp.) cultivars. Food chemistry. 2012 Jun 1;132(3):1495-501.
  25. de Andrade Neves N, Stringheta PC, Gómez-Alonso S, Hermosín-Gutiérrez I. Flavonols and ellagic acid derivatives in peels of different species of jabuticaba (Plinia spp.) identified by HPLC-DAD-ESI/MSn. Food chemistry. 2018 Jun 30;252:61-71.
  26. Raudone L, Bobinaite R, Janulis V, Viskelis P, Trumbeckaite S. Effects of raspberry fruit extracts and ellagic acid on respiratory burst in murine macrophages. Food & function. 2014;5(6):1167-74.
  27. Bate-Smith EC. Detection and determination of ellagitannins. Phytochemistry. 1972;11(3):1153-6.
  28. Maas JL, Galletta GJ, Stoner GD. Ellagic acid, an anticarcinogen in fruits, especially in strawberries: a review. HortScience. 1991;26(1):10-4.
  29. Tiwari MK, Mishra PC. Scavenging of hydroxyl, methoxy, and nitrogen dioxide free radicals by some methylated isoflavones. Journal of Molecular Modeling. 2018;24:1-7.
  30. Kang I, Buckner T, Shay NF, Gu L, Chung S. Improvements in metabolic health with consumption of ellagic acid and subsequent conversion into urolithins: evidence and mechanisms. Advances in nutrition. 2016 Sep 1;7(5):961-72.
  31. Kang I, Kim Y, Tomás‐Barberán FA, Espín JC, Chung S. Urolithin A, C, and D, but not iso‐urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes. Molecular nutrition & food research. 2016;60(5):1129-38.
  32. Aishwarya V, Solaipriya S, Sivaramakrishnan V. Role of ellagic acid for the prevention and treatment of liver diseases. Phytotherapy Research. 2021;35(6):2925-44.
  33. Soleimani D, Rezaie M, Rajabzadeh F, Gholizadeh Navashenaq J, Abbaspour M, Miryan M, Razmpour F, Ranjbar G, Rezvani R, Jarahi L, Hashemy SI. Protective effects of propolis on hepatic steatosis and fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) evaluated by real‐time two‐dimensional shear wave elastography: A randomized clinical trial. Phytotherapy Research. 2021;35(3):1669-79.
  34. Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, Carty C, Chaput JP, Chastin S, Chou R, Dempsey PC. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. British journal of sports medicine. 2020 Dec 1;54(24):1451-62.
  35. Kazemi M, Lalooha F, Nooshabadi MR, Dashti F, Kavianpour M, Haghighian HK. Randomized double blind clinical trial evaluating the Ellagic acid effects on insulin resistance, oxidative stress and sex hormones levels in women with polycystic ovarian syndrome. Journal of ovarian research. 2021;14:1-2.
  36. Vancells Lujan P, Vinas Esmel E, Sacanella Meseguer E. Overview of non-alcoholic fatty liver disease (NAFLD) and the role of sugary food consumption and other dietary components in its development. Nutrients. 2021;13(5):1442.
  37. Panchal SK, Ward L, Brown L. Ellagic acid attenuates high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. European journal of nutrition. 2013;52:559-68.
  38. Mişe Yonar S, Yonar ME, Yöntürk Y, Pala A. Effect of ellagic acid on some haematological, immunological and antioxidant parameters of rainbow trout (O ncorhynchus mykiss). Journal of animal physiology and animal nutrition. 2014;98(5):936-41.
  39. Polce SA, Burke C, França LM, Kramer B, Paes AM, Carrillo-Sepulveda MA. Ellagic acid alleviates hepatic oxidative stress and insulin resistance in diabetic female rats. Nutrients. 2018;10(5):531.
  40. Zhang C, Hu J, Sheng L, Yuan M, Wu Y, Chen L, Wang G, Qiu Z. Ellagic acid ameliorates AKT-driven hepatic steatosis in mice by suppressing de novo lipogenesis via the AKT/SREBP-1/FASN pathway. Food & Function. 2019;10(6):3410-20.
  41. Venkatasubramanian A, Thiyagaraj A, Subbiah V, Solairaja S, Arumugam S, Ramalingam S, Venkatabalasubramanian S. Ameliorative role of ellagic acid against acute liver steatosis in adult zebrafish experimental model. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2021;247:109061.
  42. Bidanchi RM, Lalrindika L, Khushboo M, Bhanushree B, Dinata R, Das M, Nisa N, Lalrinzuali S, Manikandan B, Saeed-Ahmed L, Sanjeev S. Antioxidative, anti-inflammatory and anti-apoptotic action of ellagic acid against lead acetate induced testicular and hepato-renal oxidative damages and pathophysiological changes in male Long Evans rats. Environmental Pollution. 2022;302:119048.
  43. Elseweidy MM, Elesawy AE, Sobh MS, Elnagar GM. Ellagic acid ameliorates high fructose-induced hyperuricemia and non-alcoholic fatty liver in Wistar rats: Focusing on the role of C1q/tumor necrosis factor-related protein-3 and ATP citrate lyase. Life Sciences. 2022;305:120751.
  44. ALTamimi JZ, Alshammari GM, AlFaris NA, Alagal RI, Aljabryn DH, Albekairi NA, Alkhateeb MA, Yahya MA. Ellagic acid protects against non-alcoholic fatty liver disease in streptozotocin-diabetic rats by activating AMPK. Pharmaceutical biology. 2022;60(1):25-37.
  45. Kábelová A, Malínská H, Marková I, Oliyarnyk O, Chylíková B, Šeda O. Ellagic acid affects metabolic and transcriptomic profiles and attenuates features of metabolic syndrome in adult male rats. Nutrients. 2021;13(3):804.
  46. Kasai K, Yoshimura M, Koga T, Arii M, Kawasaki S. Effects of oral administration of ellagic acid-rich pomegranate extract on ultraviolet-induced pigmentation in the human skin. Journal of nutritional science and vitaminology. 2006;52(5):383-8.
  47. Ertam I, Mutlu B, Unal I, Alper S, Kivcak B, Ozer O. Efficiency of ellagic acid and arbutin in melasma: A randomized, prospective, open‐label study. The Journal of dermatology. 2008;35(9):570-4.
  48. Ghadimi M, Foroughi F, Hashemipour S, Rashidi Nooshabadi M, Ahmadi MH, Ahadi Nezhad B, Khadem Haghighian H. Randomized double‐blind clinical trial examining the Ellagic acid effects on glycemic status, insulin resistance, antioxidant, and inflammatory factors in patients with type 2 diabetes. Phytotherapy Research. 2021;35(2):1023-32.
  49. Mirzaie Z, Bastani A, Hesami S, Pouryousefi E, Kavianpour M, Haghighian HK. Improving effect of ellagic acid on sleep quality and gastrointestinal symptoms in patient with irritable bowel syndrome: randomized double-blind clinical trial. The Turkish Journal of Gastroenterology. 2021;32(11):937.
  50. Liu Y, Yu S, Wang F, Yu H, Li X, Dong W, Lin R, Liu Q. Chronic administration of ellagic acid improved the cognition in middle-aged overweight men. Applied Physiology, Nutrition, and Metabolism. 2018;43(3):266-73.
  51. Barr RG, Ferraioli G, Palmeri ML, Goodman ZD, Garcia-Tsao G, Rubin J, Garra B, Myers RP, Wilson SR, Rubens D, Levine D. Elastography assessment of liver fibrosis: society of radiologists in ultrasound consensus conference statement. Radiology. 2015;276(3):845-61.
Journal of Nutrition,Fasting and Health
Volume 13, Issue 2
June 2025
Pages 77-85

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History

  • Receive Date: 30 December 2023
  • Revise Date: 02 January 2024
  • Accept Date: 03 January 2024

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