Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review

References

• Asrani SK, Hall L, Hagan M, et al. Trends in chronic liver disease-related hospitalizations: a population-based study. Am J Gastroenterol. 2019;114(1):1548–106.
   Web of Science ®Google Scholar
• Lee BP, Terrault NA. Liver-related mortality in the United States: hepatitis C declines, non-alcoholic fatty liver and alcohol rise. Transl Gastroenterol Hepatol. 2019;4:19.
   PubMed Web of Science ®Google Scholar
• Seto WK, Mandell MS. Chronic liver disease: global perspectives and future challenges to delivering quality health care. PLoS One. 2021;16(1):e0243607.
   PubMed Web of Science ®Google Scholar
• Kim D, Li AA, Gadiparthi C, et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154–1163.e3.
   PubMed Web of Science ®Google Scholar
• Lazebnik LB, Radchenko VG, Golovanova EV, et al. Non-alcoholic fatty liver disease: clinic, diagnostics, treatment. Exp Clin Gastroenterol. 2017;138:2.
   Google Scholar
• Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73(1):202–209.
   PubMed Web of Science ®Google Scholar
• Younossi ZM. Non-alcoholic fatty liver disease - a global public health perspective. J Hepatol. 2019;70(3):531–544.
   PubMed Web of Science ®Google Scholar
• Lazebnik LB, Golovanova EV, Tarasova LV, et al. Adult alcoholic liver disease (ALD). Jour. 2020a;174(2):4–28.
   Google Scholar
• Lazebnik LB, Golovanova EV, Hlynova OV, et al. Adults drug-induced liver injury (DILI). Exp. Clin. Gastroenterol. 2020;174(2):29–54.
   Google Scholar
• Crabb DW, Im GY, Szabo G, et al. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the American association for the study of liver diseases. Hepatology. 2020;71(1):306–333.
   PubMed Web of Science ®Google Scholar
• Eslam M, Sarin SK, Wong VW-S, et al. The Asian pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int. 2020;14(6):889–919.
   PubMed Web of Science ®Google Scholar
• EASL clinical practice guidelines: management of alcohol-related liver disease. J Hepatol. 2018;69(1):154–181.
   PubMed Web of Science ®Google Scholar
• Leoni S, Tovoli F, Napoli L, et al. Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis. World J Gastroenterol. 2018;24(30):3361–3373.
   PubMed Web of Science ®Google Scholar
• Bakulin BI, Abatsieva AMP, Skalinskaya SM, et al. Clinical and medico-social significance of NAFLD through the prism of comorbidity. Therapy. 2019;6:76–86.
   Google Scholar
• Hirode G, Saab S, Wong RJ. Trends in the burden of chronic liver disease among hospitalized US adults. JAMA Netw Open. 2020;3(4):e201997.
   PubMed Web of Science ®Google Scholar
• Yang J, Fernández-Galilea M, Martínez-Fernández L, et al. Oxidative stress and non-alcoholic fatty liver disease: effects of omega-3 fatty acid supplementation. Nutrients. 2019;11(4):872.
   PubMed Web of Science ®Google Scholar
• Wu D, Cederbaum AI. Oxidative stress and alcoholic liver disease. Semin Liver Dis. 2009;29(2):141–154.
   PubMed Web of Science ®Google Scholar
• Villanueva-Paz M, Morán L, López-Alcántara N, et al. Oxidative stress in drug-induced liver injury (DILI): from mechanisms to biomarkers for use in clinical practice. Antioxidants (Basel). 2021;10(3):390.
   PubMedGoogle Scholar
• Li S, Tan HY, Wang N, et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci. 2015;16(11):26087–26124.
   PubMed Web of Science ®Google Scholar
• Kitade H, Chen G, Ni Y, et al. Nonalcoholic fatty liver disease and insulin resistance: NEW insights and potential new treatments. Nutrients. 2017;9(4):387.
   PubMed Web of Science ®Google Scholar
• Gillessen A, Schmidt HH. Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther. 2020;37(4):1279–1301.
   PubMed Web of Science ®Google Scholar
• Hashem A, Shastri Y, Al Otaibi M, et al. Expert opinion on the management of Non-alcoholic fatty liver disease (NAFLD) in the Middle east with a focus on the use of silymarin. Gastroenterol Insights. 2021;12(2):155–165.
   Web of Science ®Google Scholar
• Osna NA, Donohue TM, Jr., Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res. 2017;38(2):147–161.
   PubMed Web of Science ®Google Scholar
• Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol. 2020;31(2):49–55.
   PubMed Web of Science ®Google Scholar
• Baratta F, Pastori D, Tozzi G, et al. Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non-alcoholic fatty liver disease. Liver Int. 2019;39(12):2301–2308.
   PubMed Web of Science ®Google Scholar
• European association for the study of the Liver, European association for the study of Diabetes, European association for the study of Obesity. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology. 2018;67(1):328–357.
   PubMed Web of Science ®Google Scholar
• Xian YX, Weng JP, Xu F. MAFLD vs. NAFLD: shared features and potential changes in epidemiology, pathophysiology, diagnosis, and pharmacotherapy. Chin Med J (Engl). 2020;134(1):8–19.
   PubMed Web of Science ®Google Scholar
• Injury ECPGD-IL. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222–1261.
   PubMed Web of Science ®Google Scholar
• Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2020;2(6):100192.
   PubMedGoogle Scholar
• Saithanyamurthi H, Faust AJ. Drug-induced liver disease: clinical course. Clin Liver Dis. 2017;21(1):21–34.
   PubMed Web of Science ®Google Scholar
• Andrade RJ, Chalasani N, Björnsson ES, et al. Drug-induced liver injury. Nat Rev Dis Primers. 2019;5(1):58.
   PubMed Web of Science ®Google Scholar
• Mathurin P, Lucey MR. Liver transplantation in patients with alcohol-related liver disease: current status and future directions. Lancet Gastroenterol Hepatol. 2020;5(5):507–514.
   PubMed Web of Science ®Google Scholar
• Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic steatohepatitis. Gastroenterol Hepatol (N Y). 2018;14(10):582–589.
   PubMedGoogle Scholar
• Baratta F, Pastori D, Bartimoccia S, et al. Poor adherence to Mediterranean diet and serum lipopolysaccharide are associated with oxidative stress in patients with non-alcoholic fatty liver disease. Nutrients. 2020;12(6):1732.
   PubMed Web of Science ®Google Scholar
• Ferro D, Baratta F, Pastori D, et al. New insights into the pathogenesis of non-alcoholic fatty liver disease: gut-derived lipopolysaccharides and oxidative stress. Nutrients. 2020;12(9):2762.
   PubMed Web of Science ®Google Scholar
• Ambade A, Mandrekar P. Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int J Hepatol. 2012;2012:853175.
   PubMedGoogle Scholar
• Tan HK, Yates E, Lilly K, et al. Oxidative stress in alcohol-related liver disease. World J Hepatol. 2020;12(7):332–349.
   PubMed Web of Science ®Google Scholar
• Galicia-Moreno M, Gutiérrez-Reyes G. The role of oxidative stress in the development of alcoholic liver disease. Revista de Gastroenterología de México (English Edition). 2014;79(2):135–144.
   Google Scholar
• Masarone M, Rosato V, Dallio M, et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2018;2018:1–14.
   Web of Science ®Google Scholar
• Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1):S47–S64.
   PubMed Web of Science ®Google Scholar
• Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: an update. Metabolism. 2016;65(8):1109–1123.
   PubMed Web of Science ®Google Scholar
• Arroyave-Ospina JC, Wu Z, Geng Y, et al. Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy. Antioxidants (Basel). 2021;10(2):174.
   PubMedGoogle Scholar
• Mansouri A, Gattolliat CH, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology. 2018;155(3):629–647.
   PubMed Web of Science ®Google Scholar
• Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10(11):656–665.
   PubMed Web of Science ®Google Scholar
• Ye H, Nelson LJ, Gómez Del Moral M, et al. Dissecting the molecular pathophysiology of drug-induced liver injury. World J Gastroenterol. 2018;24(13):1373–1385.
   PubMed Web of Science ®Google Scholar
• Garcia-Cortes M, Robles-Diaz M, Stephens C, et al. Drug induced liver injury: an update. Arch Toxicol. 2020;94(10):3381–3407.
   PubMed Web of Science ®Google Scholar
• Will Y, Dykens J. Mitochondrial toxicity assessment in industry-a decade of technology development and insight. Expert Opin Drug Metab Toxicol. 2014;10(8):1061–1067.
   PubMed Web of Science ®Google Scholar
• Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284(20):13291–13295.
   PubMed Web of Science ®Google Scholar
• Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol. 2001;35(3):392–398.
   PubMed Web of Science ®Google Scholar
• Yao J, Zhi M, Gao X, et al. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver. Braz J Med Biol Res. 2013;46(3):270–277.
   PubMed Web of Science ®Google Scholar
• Kim M, Yang SG, Kim JM, et al. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. Int J Mol Med. 2012;30(3):473–479.
   PubMed Web of Science ®Google Scholar
• Li CC, Hsiang CY, Wu SL, et al. Identification of novel mechanisms of silymarin on the carbon tetrachloride-induced liver fibrosis in mice by nuclear factor-κB bioluminescent imaging-guided transcriptomic analysis. Food Chem Toxicol. 2012;50(5):1568–1575.
   PubMed Web of Science ®Google Scholar
• Singh RP, Tyagi AK, Zhao J, et al. Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis. 2002;23(3):499–510.
   PubMed Web of Science ®Google Scholar
• Wah Kheong C, Nik Mustapha NR, Mahadeva S. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2017;15(12):1940–1949.e8.
   PubMedGoogle Scholar
• de Avelar CR, Pereira EM, de Farias Costa PR, et al. Effect of silymarin on biochemical indicators in patients with liver disease: systematic review with meta-analysis. WJG. 2017;23(27):5004–5017.
   PubMed Web of Science ®Google Scholar
• Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035–2063.
   PubMed Web of Science ®Google Scholar
• Tao L, Qu X, Zhang Y, et al. Prophylactic therapy of silymarin (milk thistle) on antituberculosis Drug-Induced liver injury: a meta-analysis of randomized controlled trials. Can J Gastroenterol Hepatol. 2019;2019:1–11.
   Web of Science ®Google Scholar
• Zhong S, Fan Y, Yan Q, et al. The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: a meta-analysis (PRISMA) of randomized control trials. Medicine (Baltimore). 2017;96(49):e9061.
   PubMed Web of Science ®Google Scholar
• Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol. 1989;9(1):105–113.
   PubMed Web of Science ®Google Scholar
• Trinchet JC, Coste T, Lévy VG[, et al. Treatment of alcoholic hepatitis with silymarin. A double-blind comparative study in 116 patients. Gastroenterol Clin Biol. 1989;13(2):120–124.
   PubMed Web of Science ®Google Scholar
• Bunout D, Hirsch S, Petermann M[, et al. Controlled study of the effect of silymarin on alcoholic liver disease. Rev Med Chil. 1992;120(12):1370–1375.
   PubMed Web of Science ®Google Scholar
• Parés A, Planas R, Torres M, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28(4):615–621.
   PubMed Web of Science ®Google Scholar
• Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559–567.
   PubMed Web of Science ®Google Scholar
• Gillessen A, Herrmann WA, Kemper M[, et al. Effect of silymarin on liver health and quality of life. Results of a non-interventional study. ]. MMW Fortschr Med. 2014;156(S21):120–126.
   PubMedGoogle Scholar
• Hajiaghamohammadi AA, Ziaee A, Oveisi S, et al. Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic fatty liver disease: a randomized controlled pilot study. Hepat Mon. 2012;12(8):e6099.
   PubMed Web of Science ®Google Scholar
• Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol. 1982;17(4):517–521.
   PubMed Web of Science ®Google Scholar
• Lucena MI, Andrade RJ, de la Cruz JP, et al. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. CP. 2002;40(01):2–8.
   Google Scholar
• Velussi M, Cernigoi AM, De Monte A, et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol. 1997;26(4):871–879.
   PubMed Web of Science ®Google Scholar
• Solhi H, Ghahremani R, Kazemifar AM, et al. Silymarin in treatment of non-alcoholic steatohepatitis: a randomized clinical trial. Caspian J Intern Med. 2014;5(1):9–12.
   PubMedGoogle Scholar
• Loguercio C, Federico A, Trappoliere M, et al. The effect of a silybin-vitamin E-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007;52(9):2387–2395.
   PubMed Web of Science ®Google Scholar
• Sorrentino G, Crispino P, Coppola D, et al. Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. Drugs R D. 2015;15(1):21–25.
   PubMedGoogle Scholar
• Asgarshirazi M, Shariat M, Sheikh M. Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury: a randomized clinical trial. Hepatobiliary Pancreat Dis Int. 2017;16(3):296–302.
   PubMed Web of Science ®Google Scholar
• Luangchosiri C, Thakkinstian A, Chitphuk S, et al. A double-blinded randomized controlled trial of silymarin for the prevention of antituberculosis drug-induced liver injury. BMC Complement Altern Med. 2015;15:334.
   PubMed Web of Science ®Google Scholar
• Anushiravani A, Haddadi N, Pourfarmanbar M, et al. Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial. Eur J Gastroenterol Hepatol. 2019;31(5):613–617.
   PubMed Web of Science ®Google Scholar
• Federico A, Dallio M, Masarone M, et al. Evaluation of the effect derived from silybin with vitamin D and vitamin E administration on clinical, metabolic, endothelial dysfunction, oxidative stress parameters, and serological worsening markers in nonalcoholic fatty liver disease patients. Oxid Med Cell Longev. 2019;2019:1–12.
   Web of Science ®Google Scholar
• Aller R, Izaola O, Gómez S, et al. Effect of silymarin plus vitamin E in patients with non-alcoholic fatty liver disease. A randomized clinical pilot study. Eur Rev Med Pharmacol Sci. 2015;19(16):3118–3124.
   PubMed Web of Science ®Google Scholar
• Abenavoli L, Greco M, Nazionale I, et al. Effects of mediterranean diet supplemented with silybin-vitamin E-phospholipid complex in overweight patients with non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2015;9(4):519–527.
   PubMed Web of Science ®Google Scholar
• Müzes G, Deák G, Láng I, et al. [Effect of silimarin (legalon) therapy on the antioxidant defense mechanism and lipid peroxidation in alcoholic liver disease (double blind protocol)]. Orv Hetil. 1990;131(16):863–866.
   PubMedGoogle Scholar
• Navarro VJ, Belle SH, D'Amato M, et al. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: a randomized, double-blind, placebo controlled trial. PLoS One. 2019;14(9):e0221683.
   PubMed Web of Science ®Google Scholar
• Iakimchuk GN, Gendrikson LN. Study of clinical efficiency of essential phospholipids and silymarin combination in nonalcoholic and alcoholic steatohepatitis. Eksp Klin Gastroenterol. 2011;7:64–69.
   Google Scholar
• El-Kamary SS, Shardell MD, Abdel-Hamid M, et al. A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis. Phytomedicine. 2009;16(5):391–400.
   PubMed Web of Science ®Google Scholar
• Brezgin AG. BIG. Severe alcoholic hepatitis in patients with alcoholic liver cirrhosis. Eff Pharmacother Gastroenterol Spec Iss. 2014;2:43.
   Google Scholar
• Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. 2016;65(8):1080–1086.
   PubMed Web of Science ®Google Scholar
• Targher G, Byrne CD. From nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease: is it time for a change of terminology? HR. 2020;2020:64.
   Google Scholar
• Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999–2014.e1.
   PubMed Web of Science ®Google Scholar
• Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017;66(6):1154–1164.
   PubMed Web of Science ®Google Scholar
• O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51(1):307–328.
   PubMed Web of Science ®Google Scholar
• Sandhu N, Navarro V. Drug-induced liver injury in GI practice. Hepatol Commun. 2020;4(5):631–645.
   PubMed Web of Science ®Google Scholar
• Devarbhavi H, Aithal G, Treeprasertsuk S, et al. Drug-induced liver injury: Asia pacific association of study of liver consensus guidelines. Hepatol Int. 2021;15(2):258–282.
   PubMed Web of Science ®Google Scholar