Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases

Milk thistle (MT; Silybum marianum), a member of the Asteraceae family, is a therapeutic herb with a 2,000‐year history of use. MT fruits contain a mixture of flavonolignans collectively known as silymarin, being silybin (also named silibinin) the main component. This article reviews the chemistry of MT, the pharmacokinetics and bioavailability, the pharmacologically relevant actions for liver diseases (e.g., anti‐inflammatory, immunomodulating, antifibrotic, antioxidant, and liver‐regenerating properties) as well as the clinical potential in patients with alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, drug‐induced liver injury, and mushroom poisoning. Overall, literature data suggest that, despite encouraging preclinical data, further well‐designed randomized clinical trials are needed to fully substantiate the real value of MT preparations in liver diseases.

[1]  A. Alipour,et al.  Iron‐chelating effect of silymarin in patients with β‐thalassemia major: A crossover randomised control trial , 2018, Phytotherapy research : PTR.

[2]  G. Bedogni,et al.  Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future , 2018, Liver international : official journal of the International Association for the Study of the Liver.

[3]  Huimao Zhang,et al.  The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease , 2017, Medicine.

[4]  Jian Chen,et al.  Spatial organization of silybin biosynthesis in milk thistle [Silybum marianum (L.) Gaertn] , 2017, The Plant journal : for cell and molecular biology.

[5]  Nik Raihan Nik Mustapha,et al.  A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis , 2017, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[6]  U. Udomsubpayakul,et al.  Clinical characteristics and outcome of toxicity from Amanita mushroom poisoning , 2017, International journal of general medicine.

[7]  M. Bijak Silybin, a Major Bioactive Component of Milk Thistle (Silybum marianum L. Gaernt.)—Chemistry, Bioavailability, and Metabolism , 2017, Molecules.

[8]  M. El Raziky,et al.  High Dose of Silymarin in Patients with Decompensated Liver Disease: A Randomized Controlled Trial. , 2017, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[9]  N. Alaca,et al.  Treatment with milk thistle extract (Silybum marianum), ursodeoxycholic acid, or their combination attenuates cholestatic liver injury in rats: Role of the hepatic stem cells. , 2017, The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology.

[10]  V. Křen,et al.  The silymarin composition… and why does it matter??? , 2017, Food research international.

[11]  N. Braidy,et al.  A Mini Review on the Chemistry and Neuroprotective Effects of Silymarin. , 2017, Current drug targets.

[12]  Guangji Wang,et al.  Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  M. Gharagozloo,et al.  Silymarin impacts on immune system as an immunomodulator: One key for many locks , 2017, International immunopharmacology.

[14]  C. Avellini,et al.  Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis , 2017, Nutrients.

[15]  G. Kouraklis,et al.  From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world , 2017, World journal of gastroenterology.

[16]  N. Milić,et al.  Effect of Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study , 2017, Nutrients.

[17]  L. P. M. de Oliveira,et al.  Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis , 2017, World journal of gastroenterology.

[18]  J. Bosch-Barrera,et al.  Targeting STAT3 with silibinin to improve cancer therapeutics. , 2017, Cancer treatment reviews.

[19]  R. Andrew,et al.  Principles of pharmacological research of nutraceuticals , 2017, British journal of pharmacology.

[20]  J. Markowitz,et al.  The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes. , 2017, Chemico-biological interactions.

[21]  J. Rowe,et al.  Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis , 2017, Journal of carcinogenesis.

[22]  S. Sokar,et al.  Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[23]  B. Oh,et al.  Traditional Oriental Herbal Medicine and Natural Killer Cells for Cancer Patients: A Systematic Review and Meta‐analysis , 2017, Phytotherapy research : PTR.

[24]  A. Acco,et al.  Effects of Silymarin on Diabetes Mellitus Complications: A Review , 2017, Phytotherapy research : PTR.

[25]  R. Ullah,et al.  A systematic review on ethnomedicines of anti‐cancer plants , 2017, Phytotherapy research : PTR.

[26]  Changxiao Liu,et al.  Modulatory effects of silibinin in various cell signaling pathways against liver disorders and cancer - A comprehensive review. , 2016, European journal of medicinal chemistry.

[27]  M. Petersen,et al.  Variation in the flavonolignan composition of fruits from different Silybum marianum chemotypes and suspension cultures derived therefrom. , 2016, Phytochemistry.

[28]  Stephen Safe,et al.  Natural Products as Mechanism‐based Anticancer Agents: Sp Transcription Factors as Targets , 2016, Phytotherapy research : PTR.

[29]  Reza Assadi,et al.  The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 , 2016, The Lancet.

[30]  S. Karthikeyan,et al.  Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin. , 2016, Environmental toxicology and pharmacology.

[31]  A. Federico,et al.  Epidemiology and Natural History of Alcoholic Liver Disease. , 2016, Reviews on recent clinical trials.

[32]  A. Federico,et al.  Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment. , 2016, Reviews on recent clinical trials.

[33]  N. Milić,et al.  Metabolic aspects of adult patients with nonalcoholic fatty liver disease. , 2016, World journal of gastroenterology.

[34]  A. Hekmatdoost,et al.  Dietary supplementation in patients with alcoholic liver disease: a review on current evidence. , 2016, Hepatobiliary & pancreatic diseases international : HBPD INT.

[35]  P. Mircea,et al.  Beneficial Effects of Silymarin After the Discontinuation of CCl4-Induced Liver Fibrosis. , 2016, Journal of medicinal food.

[36]  Justin Shields,et al.  Highly bioavailable silibinin nanoparticles inhibit HCV infection , 2016, Gut.

[37]  Qiang He,et al.  Silibinin: a potential old drug for cancer therapy , 2016, Expert review of clinical pharmacology.

[38]  William M. Lee,et al.  Acute liver injury and acute liver failure from mushroom poisoning in North America , 2016, Liver international : official journal of the International Association for the Study of the Liver.

[39]  Marwa H. Abdallah,et al.  Silymarin-loaded Eudragit(®) RS100 nanoparticles improved the ability of silymarin to resolve hepatic fibrosis in bile duct ligated rats. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[40]  Shao-Ru Chen,et al.  Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma , 2016, Phytotherapy research : PTR.

[41]  Cheng-bao Wang,et al.  Silybin nanoparticles for liver cancer: development, optimization and in vitro - in vivo evaluation. , 2016, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[42]  D. Oh,et al.  Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response , 2016, Molecules.

[43]  H. Pan,et al.  Preventive use of a hepatoprotectant against anti‐tuberculosis drug‐induced liver injury: A randomized controlled trial , 2016, Journal of gastroenterology and hepatology.

[44]  J. Godos,et al.  Natural antioxidants for non‐alcoholic fatty liver disease: molecular targets and clinical perspectives , 2016, Liver international : official journal of the International Association for the Study of the Liver.

[45]  Yaping Zhao,et al.  Enhanced oral bioavailability of silymarin using liposomes containing a bile salt: preparation by supercritical fluid technology and evaluation in vitro and in vivo , 2015, International journal of nanomedicine.

[46]  A. Thakkinstian,et al.  A double-blinded randomized controlled trial of silymarin for the prevention of antituberculosis drug-induced liver injury , 2015, BMC Complementary and Alternative Medicine.

[47]  A. Bishayee,et al.  Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review , 2015, Anti-cancer drugs.

[48]  Min Young Lee,et al.  Silymarin Inhibits Morphological Changes in LPS-Stimulated Macrophages by Blocking NF-κB Pathway , 2015, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[49]  N. Milić,et al.  Effects of Mediterranean diet supplemented with silybin–vitamin E–phospholipid complex in overweight patients with non-alcoholic fatty liver disease , 2015, Expert review of gastroenterology & hepatology.

[50]  N. Reisi,et al.  Evaluating the Safety and Efficacy of Silymarin in β-Thalassemia Patients: A Review , 2015, Hemoglobin.

[51]  P. Mircea,et al.  Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl₄-treated rats. , 2015, Journal of medicinal food.

[52]  Peter F Surai Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives , 2015, Antioxidants.

[53]  Jae-Hoon Jeong,et al.  Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells , 2015, Clinical and molecular hepatology.

[54]  E. Yurtçu,et al.  Effects of silymarin and silymarin-doxorubicin applications on telomerase activity of human hepatocellular carcinoma cell line HepG2. , 2015, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[55]  R. Schwabe,et al.  Hepatic inflammation and fibrosis: Functional links and key pathways , 2015, Hepatology.

[56]  N. Milošević,et al.  Phytotherapy and NAFLD--from goals and challenges to clinical practice. , 2015, Reviews on recent clinical trials.

[57]  A. Federico,et al.  Non alcoholic fatty liver: epidemiology and natural history. , 2015, Reviews on recent clinical trials.

[58]  R. Attam,et al.  Effect of Liverubin™ on hepatic biochemical profile in patients of alcoholic liver disease: a retrospective study. , 2014, Minerva medica.

[59]  M. D'Amato,et al.  In Vivo Efficacy Study of Milk Thistle Extract (ETHIS-094™) in STAM™ Model of Nonalcoholic Steatohepatitis , 2014, Drugs in R&D.

[60]  B. Ledergerber,et al.  Efficacy of lead‐in silibinin and subsequent triple therapy in difficult‐to‐treat HIV/hepatitis C virus‐coinfected patients , 2014, HIV medicine.

[61]  J. Markowitz,et al.  The Effects of Milk Thistle (Silybum marianum) on Human Cytochrome P450 Activity , 2014, Drug Metabolism and Disposition.

[62]  Qingnian Xu,et al.  Effects and Tolerance of Silymarin (Milk Thistle) in Chronic Hepatitis C Virus Infection Patients: A Meta-Analysis of Randomized Controlled Trials , 2014, BioMed research international.

[63]  V. Křen,et al.  Chemistry of silybin. , 2014, Natural product reports.

[64]  F. Bellanti,et al.  Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis. , 2014, Free radical biology & medicine.

[65]  P. Ferranti,et al.  Serum Oxidative Stress Markers and Lipidomic Profile to Detect NASH Patients Responsive to an Antioxidant Treatment: A Pilot Study , 2014, Oxidative medicine and cellular longevity.

[66]  S. Polyak,et al.  Inhibition of HIV by Legalon-SIL is independent of its effect on cellular metabolism. , 2014, Virology.

[67]  H. Solhi,et al.  Silymarin in treatment of non-alcoholic steatohepatitis: A randomized clinical trial. , 2014, Caspian journal of internal medicine.

[68]  T. Flaig,et al.  A Phase I Dose-Finding Study of Silybin Phosphatidylcholine (Milk Thistle) in Patients With Advanced Hepatocellular Carcinoma , 2014, Integrative cancer therapies.

[69]  Lin Zhao,et al.  Traditional Chinese medicine and related active compounds: a review of their role on hepatitis B virus infection. , 2013, Drug discoveries & therapeutics.

[70]  N. Milošević,et al.  New Therapeutic Potentials of Milk Thistle (Silybum marianum) , 2013, Natural product communications.

[71]  S. Polyak,et al.  Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin‐dependent trafficking , 2013, Cellular microbiology.

[72]  S. Bellentani,et al.  Milk thistle to treat non-alcoholic fatty liver disease: dream or reality? , 2013, Expert review of gastroenterology & hepatology.

[73]  J. Markowitz,et al.  An Assessment of Pharmacokinetics and Antioxidant Activity of Free Silymarin Flavonolignans in Healthy Volunteers: A Dose Escalation Study , 2013, Drug Metabolism and Disposition.

[74]  J. Stebbing,et al.  Milk thistle: early seeds of potential. , 2013, The Lancet. Oncology.

[75]  M. Gharagozloo,et al.  Immunosuppressive Effect of Silymarin on Mitogen‐Activated Protein Kinase Signalling Pathway: the Impact on T Cell Proliferation and Cytokine Production , 2013, Basic & clinical pharmacology & toxicology.

[76]  H.-Y. Zhang,et al.  Meta-analysis: silymarin and its combination therapy for the treatment of chronic hepatitis B , 2013, European Journal of Clinical Microbiology & Infectious Diseases.

[77]  F. Cacciapuoti,et al.  Silymarin in non alcoholic fatty liver disease. , 2013, World journal of hepatology.

[78]  L. Calani,et al.  Absorption and metabolism of milk thistle flavanolignans in humans. , 2012, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[79]  Ralf-Torsten Pohl,et al.  Legalon® SIL: The Antidote of Choice in Patients with Acute Hepatotoxicity from Amatoxin Poisoning , 2012, Current pharmaceutical biotechnology.

[80]  K. Reddy,et al.  Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. , 2012, JAMA.

[81]  P. Caraceni,et al.  Acute Liver Failure Caused by Amanita phalloides Poisoning , 2012, International journal of hepatology.

[82]  J. Marescaux,et al.  Silibinin inhibits tumor growth in a murine orthotopic hepatocarcinoma model and activates the TRAIL apoptotic signaling pathway. , 2012, Anticancer research.

[83]  Mina Kim,et al.  Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells , 2012, International journal of molecular medicine.

[84]  I. de Sio,et al.  Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. , 2012, Free radical biology & medicine.

[85]  Chia-Cheng Li,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. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[86]  A. Izzo Interactions between Herbs and Conventional Drugs: Overview of the Clinical Data , 2012, Medical Principles and Practice.

[87]  S. J. Schrieber,et al.  Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C , 2011, Drug Metabolism and Disposition.

[88]  R. Yazdanparast,et al.  Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. , 2011, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[89]  Mushir M. Ali,et al.  Reassessing bioavailability of silymarin. , 2011, Alternative medicine review : a journal of clinical therapeutic.

[90]  V. Křen,et al.  Evidence for differences in regioselective and stereoselective glucuronidation of silybin diastereomers from milk thistle (Silybum marianum) by human UDP-glucuronosyltransferases , 2011, Xenobiotica; the fate of foreign compounds in biological systems.

[91]  R. Capasso,et al.  Milk thistle in liver diseases: past, present, future , 2010, Phytotherapy research : PTR.

[92]  S. J. Schrieber,et al.  Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C , 2010, Journal of clinical pharmacology.

[93]  B. Perissutti,et al.  Solid state mechanochemical activation of Silybum marianum dry extract with betacyclodextrins: Characterization and bioavailability of the coground systems. , 2009, Journal of pharmaceutical sciences.

[94]  P. Kidd Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts. , 2009, Alternative medicine review : a journal of clinical therapeutic.

[95]  Lie-Chwen Lin,et al.  Drug-drug interactions of silymarin on the perspective of pharmacokinetics. , 2009, Journal of ethnopharmacology.

[96]  S. J. Schrieber,et al.  The Pharmacokinetics of Silymarin Is Altered in Patients with Hepatitis C Virus and Nonalcoholic Fatty Liver Disease and Correlates with Plasma Caspase-3/7 Activity , 2008, Drug Metabolism and Disposition.

[97]  Z. Amir,et al.  The Efficacy of Silymarin in Decreasing Transaminase Activities in Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial , 2008 .

[98]  R. Saller,et al.  An Updated Systematic Review with Meta-Analysis for the Clinical Evidence of Silymarin , 2008, Complementary Medicine Research.

[99]  S. J. Schrieber,et al.  Pharmacokinetics and Metabolic Profile of Free, Conjugated, and Total Silymarin Flavonolignans in Human Plasma after Oral Administration of Milk Thistle Extract , 2008, Drug Metabolism and Disposition.

[100]  A. Federico,et al.  The Effect of a Silybin-Vitamin E-Phospholipid Complex on Nonalcoholic Fatty Liver Disease: A Pilot Study , 2007, Digestive Diseases and Sciences.

[101]  C. Girish,et al.  Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. , 2006, The Indian journal of medical research.

[102]  Bill Gurley,et al.  Assessing the Clinical Significance of Botanical Supplementation on Human Cytochrome P450 3A Activity: Comparison of a Milk Thistle and Black Cohosh Product to Rifampin and Clarithromycin , 2006, Journal of clinical pharmacology.

[103]  J. Nortier,et al.  Effect of Milk Thistle (Silybum marianum) on the Pharmacokinetics of Irinotecan , 2005, Clinical Cancer Research.

[104]  T. Goosen,et al.  Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[105]  Song-Kyu Park,et al.  Silymarin inhibits TNF‐α‐induced expression of adhesion molecules in human umbilical vein endothelial cells , 2003, FEBS letters.

[106]  R. Ševčík,et al.  Analysis of the active components of silymarin. , 2003, Journal of chromatography. A.

[107]  S. Strom,et al.  Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[108]  A. Chan,et al.  First enantioselective syntheses of (2 R ,3 R )- and (2 S ,3 S )-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6-carbaldehyde , 2000 .

[109]  P. Brissot,et al.  Aminotransferase Levels and Silymarin in de novo Tacrine-Treated Patients with Alzheimer’s Disease , 1999, Dementia and Geriatric Cognitive Disorders.

[110]  J. Panés,et al.  Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. , 1998, Journal of hepatology.

[111]  H. Rosen,et al.  Milk Thistle (Silybum marianum) for the Therapy of Liver Disease , 1998, American Journal of Gastroenterology.

[112]  E. Perucca,et al.  Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers. , 1994, International journal of clinical pharmacology and therapeutics.

[113]  H. Mascher,et al.  Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. , 1992, International journal of clinical pharmacology, therapy, and toxicology.

[114]  E. Perucca,et al.  Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects , 1990, European Journal of Drug Metabolism and Pharmacokinetics.

[115]  B. Schneider,et al.  Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. , 1989, Journal of hepatology.

[116]  J. Sonnenbichler,et al.  Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines. , 1986, Biochemical pharmacology.

[117]  D. Lorenz,et al.  Pharmacokinetic studies with silymarin in human serum and bile. , 1984, Methods and findings in experimental and clinical pharmacology.

[118]  S. Sarna,et al.  Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. , 1982, Scandinavian journal of gastroenterology.

[119]  H. Schadewaldt [The history of Silymarin. Contribution to the history of liver therapy]. , 1969, Die Medizinische Welt.

[120]  J. Markowitz,et al.  Relative Bioavailability of Silybin A and Silybin B From 2 Multiconstituent Dietary Supplement Formulations Containing Milk Thistle Extract: A Single-dose Study. , 2018, Clinical therapeutics.

[121]  H. Yıldız,et al.  The comparison of the effects of hepatic regeneration after partial hepatectomy, silybum marinaum, propofol, N-acetylcysteine and vitamin E on liver. , 2012, Bratislavske lekarske listy.

[122]  Tagreed S. Altaei,et al.  Protective effect of silymarin during coronary artery bypass grafting surgery. , 2012, Experimental and clinical cardiology.

[123]  R. Capasso,et al.  Milk thistle for treatment of nonalcoholic fatty liver disease , 2011 .

[124]  E. Hajiani,et al.  A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease. , 2009 .

[125]  J P de la Cruz,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. , 2002, International journal of clinical pharmacology and therapeutics.

[126]  E. Ascari,et al.  Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis , 1993 .

[127]  J. Trinchet,et al.  [Treatment of alcoholic hepatitis with silymarin. A double-blind comparative study in 116 patients]. , 1989, Gastroenterologie clinique et biologique.