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

Alessio Aghemo, Olga P Alekseeva, Francesco Angelico, Igor G Bakulin, Natalia V Bakulina, Dmitry Bordin, Alexey O Bueverov, Oxana M Drapkina, Anton Gillessen, Elvira M Kagarmanova, Natalia V Korochanskaya, U A Kucheryavii, Leonid B Lazebnik, Maria A Livzan, Igor V Maev, Anatolii I Martynov, Marina F Osipenko, Evgenii I Sas, Antonina Starodubova, Yurii P Uspensky, Elena V Vinnitskaya, Emilia P Yakovenko, Alexey A Yakovlev, Alessio Aghemo, Olga P Alekseeva, Francesco Angelico, Igor G Bakulin, Natalia V Bakulina, Dmitry Bordin, Alexey O Bueverov, Oxana M Drapkina, Anton Gillessen, Elvira M Kagarmanova, Natalia V Korochanskaya, U A Kucheryavii, Leonid B Lazebnik, Maria A Livzan, Igor V Maev, Anatolii I Martynov, Marina F Osipenko, Evgenii I Sas, Antonina Starodubova, Yurii P Uspensky, Elena V Vinnitskaya, Emilia P Yakovenko, Alexey A Yakovlev

Abstract

Chronic liver disease (CLD), manifested as hepatic injury, is a major cause of global morbidity and mortality. CLD progresses to fibrosis, cirrhosis, and-ultimately-hepatocellular carcinoma (HCC) if left untreated. The different phenotypes of CLD based on their respective clinical features and causative agents include alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and drug-induced liver injury (DILI). The preferred treatment modality for CLD includes lifestyle modification and diet, along with limited pharmacological agents for symptomatic treatment. Moreover, oxidative stress (OS) is an important pathological mechanism underlying all CLD phenotypes; hence, the use of antioxidants to manage the disease is justified. Based on available clinical evidence, silymarin can be utilized as a hepatoprotective agent, given its potent antioxidant, antifibrotic, and anti-inflammatory properties. The role of silymarin in suppressing OS has been well established, and therefore silymarin is recommended for use in ALD and NAFLD in the guidelines approved by the Russian Medical Scientific Society of Therapists and the Gastroenterology Scientific Society of Russia. However, to discuss the positioning of the original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies, an expert panel of international and Russian medical professionals was convened on 11 November 2020. The panel reviewed approaches for the prevention and treatment of OS, existing guidelines for patient management for CLD, and available evidence on the effectiveness of silymarin in reducing OS, fibrosis, and hepatic inflammation and presented in the form of a narrative review. Key messagesAn expert panel of international and Russian medical professionals reviewed existing guidelines for ALD, NAFLD, MAFLD, and DILI to establish consensus recommendations that oxidative stress is the common pathophysiological mechanism underlying these conditions.The panel also discussed the positioning of original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies.The panel reviewed the effectiveness of 140 mg original silymarin three times a day in reducing oxidative stress in chronic liver diseases such as ALD, NAFLD, MAFLD, and DILI.

Keywords: Chronic liver disease; alcoholic fatty liver disease; drug-induced liver injury; hepatoprotective and hepatotropic effects; metabolic-associated fatty liver disease; non-alcoholic fatty liver disease; oxidative stress; silymarin.

Conflict of interest statement

No potential competing interests were reported by the authors.

References

    1. 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.
    1. 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.
    1. Seto WK, Mandell MS.. Chronic liver disease: global perspectives and future challenges to delivering quality health care. PLoS One. 2021;16(1):e0243607.
    1. 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.
    1. Lazebnik LB, Radchenko VG, Golovanova EV, et al. . Non-alcoholic fatty liver disease: clinic, diagnostics, treatment. Exp Clin Gastroenterol. 2017;138:2.
    1. 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.
    1. Younossi ZM. Non-alcoholic fatty liver disease - a global public health perspective. J Hepatol. 2019;70(3):531–544.
    1. Lazebnik LB, Golovanova EV, Tarasova LV, et al. . Adult alcoholic liver disease (ALD). Jour. 2020a;174(2):4–28.
    1. Lazebnik LB, Golovanova EV, Hlynova OV, et al. . Adults drug-induced liver injury (DILI). Exp. Clin. Gastroenterol. 2020;174(2):29–54.
    1. 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.
    1. 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.
    1. EASL clinical practice guidelines: management of alcohol-related liver disease. J Hepatol. 2018;69(1):154–181.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Wu D, Cederbaum AI.. Oxidative stress and alcoholic liver disease. Semin Liver Dis. 2009;29(2):141–154.
    1. 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.
    1. 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.
    1. 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.
    1. Gillessen A, Schmidt HH.. Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther. 2020;37(4):1279–1301.
    1. 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.
    1. Osna NA, Donohue TM, Jr., Kharbanda KK.. Alcoholic liver disease: pathogenesis and current management. Alcohol Res. 2017;38(2):147–161.
    1. Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol. 2020;31(2):49–55.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Injury ECPGD-IL. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222–1261.
    1. Burra P, Becchetti C, Germani G.. NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2020;2(6):100192.
    1. Saithanyamurthi H, Faust AJ.. Drug-induced liver disease: clinical course. Clin Liver Dis. 2017;21(1):21–34.
    1. Andrade RJ, Chalasani N, Björnsson ES, et al. . Drug-induced liver injury. Nat Rev Dis Primers. 2019;5(1):58.
    1. 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.
    1. Buzzetti E, Pinzani M, Tsochatzis EA.. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048.
    1. Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic steatohepatitis. Gastroenterol Hepatol (N Y). 2018;14(10):582–589.
    1. 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.
    1. 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.
    1. Ambade A, Mandrekar P.. Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int J Hepatol. 2012;2012:853175.
    1. Tan HK, Yates E, Lilly K, et al. . Oxidative stress in alcohol-related liver disease. World J Hepatol. 2020;12(7):332–349.
    1. 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.
    1. 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.
    1. Byrne CD, Targher G.. NAFLD: a multisystem disease. J Hepatol. 2015;62(1):S47–S64.
    1. Katsiki N, Mikhailidis DP, Mantzoros CS.. Non-alcoholic fatty liver disease and dyslipidemia: an update. Metabolism. 2016;65(8):1109–1123.
    1. 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.
    1. Mansouri A, Gattolliat CH, Asselah T.. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology. 2018;155(3):629–647.
    1. Michelotti GA, Machado MV, Diehl AM.. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10(11):656–665.
    1. 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.
    1. Garcia-Cortes M, Robles-Diaz M, Stephens C, et al. . Drug induced liver injury: an update. Arch Toxicol. 2020;94(10):3381–3407.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Saller R, Meier R, Brignoli R.. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035–2063.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Mayer KE, Myers RP, Lee SS.. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559–567.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Brezgin AG. BIG. Severe alcoholic hepatitis in patients with alcoholic liver cirrhosis. Eff Pharmacother Gastroenterol Spec Iss. 2014;2:43.
    1. Brown GT, Kleiner DE.. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. 2016;65(8):1080–1086.
    1. 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.
    1. 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.
    1. 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.
    1. O'Shea RS, Dasarathy S, McCullough AJ.. Alcoholic liver disease. Hepatology. 2010;51(1):307–328.
    1. Sandhu N, Navarro V.. Drug-induced liver injury in GI practice. Hepatol Commun. 2020;4(5):631–645.
    1. 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.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera