Efficiency and safety of silymarine in patients with chronic liver diseases – multicenter, prospective, open clinical trial IMHOTEP

Czech version

Authors: J. Holomáň ¹; P. Borecký ²; J. Lietava ³
Authors‘ workplace: Národné referenčné centrum pre liečbu chronických hepatitíd, SZU v Bratislave ¹; ŠGN Podunajské Biskupice, UN Bratislava ²; II. interná klinika LFUK a UN Bratislava ³
Published in: Gastroent Hepatol 2014; 68(4): 346-355
Category: Hepatology: Original Article

Overview

Silymarine is the most commonly prescribed hepatoprotective medicine in real clinical practice. The evidence from the last decades has confirmed a relationship between its efficiency and dosing. The prescribing practice is actually not always fast enough to reflect the latest findings and changes in rational pharmacotherapy.

Design:
A multicenter, prospective, open clinical study IMHOTEP in patients with chronic hepatopathy of different etiology, indicated for chronic treatment with therapeutic dosing of silymarine as chosen by the doctor during a 36-week observation. Selected markers of hepatic injury (AST, ALT, GMT, ALP, total and conjugated bilirubin) as well as the objective symptoms and patients’ subjective complaints were monitored at defined time intervals.

Population size and results:
A total of 1,069 patients were included, of which 594 (55.6%) were men with an average BMI of 29.4 kg/m² and 475 (44.4%) were women with an average BMI of 29.1 kg/m². The average age of males was significantly higher than that of women (57 ± 12 vs 50 ± 13 years) (p < 0.001). Etiologies of chronic liver disease were dominated by non-alcoholic fatty liver disease (41.3%), followed by alcohol (17.2%) and drug-induced (9.2%) etiology. Alcohol etiology was significantly more common among men (24.1 vs 8.6%; p < 0.001). Smoking was more common among men (26.7 vs 14%; p < 0.001). The average dose of silymarine in the entire population was 472 ± 131 mg/day in the initial phase of the study and 470 ± 162 mg/day at the end of the study, while in men the daily therapeutic dose (DTD) of silymarine was 20 mg higher on average. During treatment with silymarine (V0 vs V4) we recorded a statistically significant decrease in the markers of hepatic damage in ALT: 2.2 ± 1.47 µkat/L vs 0.75 ± 0.50 µkat/L (p < 0.001); AST: 1.07 ± 1.24 µkat/L vs 0.62 ± 0.37 µkat/L (p < 0.001); GMT: 2.82 ± 3.39 µkat/L vs 1.97 ± 1.52 µkat/L (p < 0.001); ALP: 1.66 ± 1.18 µkat/L vs 1.41 ± 0.68 µkat/L (p < 0.001). The total amount of bilirubin in the entire study group decreased non-significantly 15.7 ± 12.6 vs 15.3 ± 13.13 (p < 0.599), while the decline in conjugated bilirubin was statistically significant 5.7 ± 8.2 µmol/L ± 4.3 vs 3.3 µmol/L (p < 0.001). Although we did not find any statistically significant differences in the entry values or in the ALT, AST, or ALP activities changes between men and women, in men we recorded a more significant decrease of GMT, both types of bilirubin and ALP. In parallel with the decrease in laboratory markers, a statistically significant decrease in the perception of symptoms associated with chronic hepatopathy and an increase in the number of asymptomatic patients was recorded.

Conclusions:
Treatment with silymarine has confirmed its hepatoprotective effects; we noticed a significant improvement in laboratory markers, as well as in the subjective and objective manifestations of chronic hepatic injury symptoms. The average dosing of silymarine over the entire course of the study was higher in comparison with the “traditional” dosing. We confirmed the relationship between the efficiency and the dosage of the medicine. Intersexual differences in efficiency were probably due to the higher values of the hepatic injury markers and higher prevalence of alcoholic etiology of chronic hepatopathy in men. In the course of the study no serious adverse effects related to the silymarine treatment were recorded.

Key words:
chronic liver disease – hepatoprotective drugs – silymarine – intersexual differences – rational pharmacotherapy – adverse effects

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
20. 1. 2014

Accepted:
18. 5. 2014

Sources

1. Rambaldi A, Jacobs BP, Iaquinto G et al. Milk thistle for alcoholic and/or hepatitis B or C liver diseases – a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials. Am J Gastroenterol 2005; 100(11): 2583–2591.

2. Saller R, Brignoli R, Melzer J et al. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplementmed 2008; 15(1): 9–20. doi: 10.1159/000113648.

3. Berger J, Kowdley KV. Is silymarin hepatoprotective in alcoholic liver disease? J Clin Gastroenterol 2003; 37(4): 278–279.

4. Trappoliere M, Tuccillo C, Federico A et al. The treatment of NAFLD. Eur Rev Med Pharmacol Sci 2005; 9(5): 299–304.

5. Navarro VJ. Medical management of NASH and the SyNCH NASH TRIAL. 46th Annual Meeting of EASL, Satellite symposium. Berlin, Germany 2011.

6. Holomáň J, Kristián P. Štandardný diagnostický a terapeutický postup. 52. Metodický list racionálnej farmakoterapie. Manažment liečby chronickej hepatitídy C trojkombináciou 3K-TVR: Telaprevir – pegylovaný interferón α – ribavirín. Zdravotnícke vydavateľstvo HERBA, spol. s r. o. 2012.

7. Holomáň J, Glasa J. EASL clinical practice guidelines. Letters to the Editor. J Hepatol 2009; 51: 821–828.

8. Holomáň J, Glasa J, Galbavý Š et al. Serum markers of liver fibrogenesis and liver histology findings in patients with chronic liver diseases. Bratisl Lek Listy 2002; 103(2): 70–75.

9. Holomáň J, Glasa J, Kazár J et al. Serum markers of liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). Correlation to liver morphology and effect of therapy. J Hepatol 2000; 32: 210. doi: 10.1016/S0168-8278(00)81130-7.

10. Holomáň J, Glasa J, Galbavý Š et al. Non-alcoholic steatohepatitis: treatment with ursodeoxycholic acid. Liver & Drugs 2000; 5 (Suppl 1): 73.

11. Laboratórna príručka. Bratislava: Medirex 2013.

12. Flora K, Hahn M, Rosen H et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998; 93(2): 139–143.

13. Yang KY, Hwang du H, Yousaf AM et al. Silymarin-loaded solid nanoparticles provide excellent hepatic protection: physicochemical characterization and in vivo evaluation. Int J Nanomedicine 2013; 8: 3333–3343. doi: 10.2147/IJN.S50683.

14. Hawke RL, Schrieber SJ, Soule TA et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol 2010; 50(4): 434–449. doi: 10.1177/0091270009347475.

15. Schrieber SJ, Wen Z, Vourvahis M 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. Drug Metab Dispos 2008; 36(9): 1909–1916. doi: 10.1124/dmd.107.019604.

16. Ferenci P, Scherzer TM, Kerschner H et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135(5): 1561–1567. doi: 10.1053/j.gastro.2008.07.072.

17. Mariño Z, Crespo G, D'Amato M et al. Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period. J Hepatol 2013; 58(3): 415–420. doi: 10.1016/j.jhep.2012.09.034.

18. Neumann UP, Biermer M, Eurich D et al. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol 2010; 52(6): 951–952. doi: 10.1016/j.jhep.2010.02.002.

19. Beinhardt S, Rasoul-Rockenschaub S, Scherzer TM et al. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol 2011; 54(3): 591–592. doi: 10.1016/j.jhep.2010.09.009.

20. Bárcena R, Moreno A, Rodríguez-Gandía MA et al. Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. J Hepatol 2013; 58(3): 421–426. doi: 10.1016/j.jhep.2012.10.009.

21. Fried MW, Navarro VJ, Afdhal N 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. JAMA 2012; 308(3): 274–282. doi: 10.1001/jama.2012.8265.

22. Freedman ND, Curto TM, Morishima C et al. Silymarin use and liver disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Aliment Pharmacol Ther 2011; 33(1): 127–137. doi: 10.1111/j.1365-2036.2010.04503.x.

23. Polyak SJ, Morishima C, Lohmann V et al. Identification of hepatoprotective flavonolignans from silymarin. Proc Natl Acad U S A 2010; 107(13): 5995–5999. doi: 10.1073/pnas.0914009107.

24. Yilmaz Y. Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions? Aliment Pharmacol Ther 2012; 36(9): 815–823.

25. Holomáň J, Glasa J, Kazár J et al. Liver fibrosis in patients with non-alcoholic steatohepatitis. Hepatology 2000; 32: P210.

26. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55(6): 2005–2023. doi: 10.1002/hep.25762.

27. Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2011; 4(4): 249–263. doi: 10.1177/1756283X11403809.

28. Dukát A, Lietava J, Krahulec B et al. Prevalencia abdominálnej obezity na Slovensku. Štúdia. Idea Slovakia. Vnitř Lék 2007; 53(4): 326–330.

29. Lietava J, Kosmálová V, Turek P. New metabolic syndrome in Slovakia: NEMESIS. Bratislava: Fami 2010.

30. 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.

31. Huseini HF, Larijani B, Heshmat R et al. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res 2006; 20(12): 1036–1039.

32. 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.

33. Hajaghamohammadi AA, Ziaee A, Rafiei R. The efficacy of silymarin in decreasing transaminase activities in non-alcoholic fatty liver disease: a randomized controlled clinical trial. Hepat Mon 2008; 8(3): 191–195.

34. Hashemi SJ, Hajiani E, Sardabi EH. A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease. Hepat Mon 2009; 9(4): 265–270.

35. Cacciapuoti F, Scognamiglio A, Palumbo R et al. Silymarin in non alcoholic fatty liver disease. World J Hepatol 2013; 5(3): 109–113. doi: 10.4254/wjh.v5.i3.109.

36. Holomáň J. Hepatológia – medicínsky špecializačný odbor. Zdravotnícke noviny, Lekárske listy 1998; 15: 1–15.

37. Williams R, Horton R. Liver disease in the UK: a Lancet Commission. Lancet 2013; 382(9904): 1537–1538. doi: 10.1016/S0140-6736(13)62152-2.

38. Seeff LB, Curto TM, Szabo G et al. Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology 2008; 47(2): 605–612.

39. Hsing AW, McLaughlin JK, Hrubec Z et al. Cigarette smoking and liver cancer among US veterans. Cancer Causes Control 1990; 1(3): 217–221.

40. Wang LY, Chen CJ, Zhang YJ et al. 4-aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls. Am J Epidemiol 1998; 147(3): 315–323.

41. Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 2004; 127 (5 Suppl 1): S72–S78.

42. Pessione F, Ramond MJ, Njapoum C et al. Cigarette smoking and hepatic lesions in patients with chronic hepatitis C. Hepatology 2001; 34(1): 121–125.

43. Felippe MJ, Meira DA. Comparison of risk factors among blood donors, volunteers and replacement individuals, infected or not by hepatitis C virus. J Venom Anim Toxins Incl Trop Dis 2009; 15(1).

44. Súhrn charakteristických vlastností lieku – LAGOSA. Príloha č. 1 k rozhodnutiu o predĺžení registrácie, ev. č. 2133/2005. Dostupné z: http://www.adcc.sk/web/humanne-lieky/spc/lagosa-spc-12989.html.