Evidence Based Medicine: Herbal Medicines in Liver Diseases

1. Evidence Based Medicine: Herbal Medicines in Liver Diseases Radha K. Dhiman,MD, DM, MNAMS, FACGDepartment of Hepatology,PGIMER, Chandigarh

2. Phyllanthus amarus Milk thistle (Silymarin) Glycyrrhizin (lecorice root extract) Liv 52 (mixture of herbs) Picroliv Ursodeoxy cholic acid SAMe Lecithin/Phosphatidyl Choline L-Carnitine Selenium Vitamin E Hepatoprotective Drugs

3. Herbal Medicine • China - 2100 BC • India - Vedic period • First written reports • India - 600 BC with Charaka Samhita • China - 400 BC • Popular but not acceptable treatment modalities

4. Herbal Medicine • Lack of standardization and lack of identification of active ingredient(s) • Lack of randomized controlled clinical trials (RCTs) • Lack of toxicological evaluation

5. Quality of Evidence • Grade I: Randomized controlled trials, systematic reviews • Grade II-1: Controlled trials without randomization • Grade II-2: Cohort or case-control analytic studies • Grade II-3: Multiple time series, dramatic uncontrolled experiments, retrospective studies • Grade III: Opinions of respected authorities; descriptive epidemiology

6. Phyllanthus • Tropical and subtropical countries • P. amarus, P. niruri, P. myrtifolius, P urinaria • Inhibit DNA polymerase activity, mRNA transcription and replication

7. Phyllanthus: Clinical Trials • N=213 (7 clinical trials from India) • Patients with • Mean HBsAg clearance 25.6% • Mean HBeAg seroconversion rate 55.3% • Only 3 trials are controlled trials (n=78,22,16) (Thyagarajan, IJG 1999)

8. Phyllanthus:Metanalysis • 22 RCTs • N=1947 with chronic HBV infection • Quality of trials • High (Jadad score  3) 5 • Low (Jadad score < 3) 17 • Follow-up • >6 mo 6 • None 16 • Mortality, QOL, cirrhosis/HCC X Liu, J Viral Hepatitis 2001

9. Phyllanthus:Metanalysis • 22 RCTs • Phyllanthus v • Controls 6 • No Rx 1 • Nonspecific Rx 3 • Interferon 2 • Thymosin 2 • Other herbs 6 • Phyllanthus + IFN v • Interferon 2 Liu, J Viral Hepatitis 2001

10. Loss of HBsAg Loss of HBeAg Phyllanthus v Placebo 1.7 (.7-4.1), p=NS 5.6 (1.9-17.2), p=.002 .01 .1 1 10 100 .01 .1 1 10 100 Favors Controls Favors Phyllanthus Favors Controls Favors Phyllanthus

11. Loss of HBsAg Loss of HBeAg Phyllanthus v Other Medicines 3.1 (2.2-4.4), p=.00001 2.3 (1.3-4.3),p-.008 .01 .1 1 10 100 .01 .1 1 10 100 Favors Controls Favors Phyllanthus Favors Phyllanthus Favors Controls Favors Phyllanthus

12. Loss of HBsAg Loss of HBeAg Phyllanthus + IFN v IFN 0.8 (.13-5.5), p=NS 1.6 (1.1-2.3), p=.03 .01 .1 1 10 100 .01 .1 1 10 100 Favors Controls Favors Phyllanthus + IFN Favors Controls Favors Phyllanthus + IFN

13. Loss of HBsAg Loss of HBeAg Phyllanthus + Thymosin v Thymosin 2.0 (1.1-3.4), p=.02 2.1 (.7-6.4), p=NS .01 .1 1 10 100 .01 .1 1 10 100 Favors Controls Favors Phyllanthus Favors Controls Favors Phyllanthus

14. Phyllanthus v other med. Phyllanthus +IFN v IFN Phyllanthus: Loss of HBV DNA 1.5 (1.1-2.2), p=.03 2.9 (2.0-4.3), p=.0001 .01 .1 1 10 100 .01 .1 1 10 100 Favors Controls Favors Phyllanthus Favors Controls Favors Phyllanthus

15. Phyllanthus:Conclusions • Phyllanthus has positive effect on clearance of HBV markers (Grade 1) • No major adverse effects (Grade 1)

16. Phyllanthus:Conclusions • Poor methodological quality (17/22 RCTs) • Mostly from China • No data on clinically relevant outcomes • Not recommended for clinical use • Further large trials are needed.

17. Silymarin (Milk Thistle) • Silybum marianum (Milk thistle) - daisy family • Pliny the El-der (A.D. 77), a noted naturalist, “excellent for carrying off bile.” • Silymarin: silybin, silychristin and silydianin

18. Silymarin (Milk Thistle) • Antioxidant:  free radical production and lipid peroxidation • Antifibrotic:  procollagen type III • Toxin blockade agent: inhibit toxin binding to hepatocyte membrane receptors

19. Silymarin : Animal Studies • Acetaminophen • Carbon tetra chloride • Radiation • Iron overload • Phenylhydrazine • Alcohol • Cold ischemia • Amanita phalloides

20. Silymarin : Human Studies • Alcoholic liver disease • Acute viral hepatitis • Chronic viral hepatitis • Toxin-induced hepatitis

21. Silymarin: Metanalysis • 14 RCTs • N=1209 • Alcohol 7, viral 3, mixed 3,drug 1 • Sample size 20-200 • Quality of trials • High (Jadad score  3) 14 • Low (Jadad score < 3) 3 Jacobs, Am J Med 2002

22. Silymarin: Effect on Mortality . RR = 0.8 (.5-1.5), p=NS .01 .1 .3 1 3 10 100 Favors Silymarin Favors control

23. Silymarin: Effect on ALT . Duration <90 days Duration >90 days -9 IU/L (-18 to -1), p=.05 -90 -75 -60 -45 -30 -15 0 15 30 45 60 75 90 Favors Silymarin Favors control

24. Silymarin: Effect on AST . -5 IU/L (-15 to 5), p+NS -90 -75 -60 -45 -30 -15 0 15 30 45 60 75 90 Favors Silymarin Favors control

25. Silymarin: Effect on Prothrombin Time . -2 s (-6 to 2), p=NS -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30 Favors Silymarin Favors control

26. Silymarin: Side effects • 18/7000 • Seroius side effects 3 patients • Gastroenteritis  Collapse • Anaphylactic reactions • Minor 2-10% • GI symptoms, headaches, dermatological reactions

27. Silymarin:Conclusions • Milk thistle (Silymarin) appears to be safe and well tolerated (Grade 1) • It does not reduce mortality among patients with chronic liver disease (Grade 1) • It does not improve histology at biopsy among patients with chronic liver disease (Grade 1) • It does not improve biochemical markers among patients with chronic liver disease (Grade 1) • At present “Silymarin” can not be recommended for treatment of liver disease

28. Glycyrrhizin • Extract of the licorice root, Glycyrrhizin glabra • Major constituents – glycyrrhizic acid, multiple flavonoids, isoflavonoids, hydroxy-coumarins and sterols • Stronger Neominophagen C (SNMC) - 0.2% glycyrrhizin, 0.1% cysteine and 2% glyceine

29. Glycyrrhizin: Mechanisms of Action • Anti-inflammatory:  PGE2 and arachodonic acid metabolism • Antioxidant:  glutathione-S-transferase and catalase activity • Stimulate endogenous interferon production • Inhibits TNF mediated cytotoxicity

30. SNMC: Uses • Subacute hepatic failure (SAHF) • Chronic hepatitis • Cirrhosis with activity • Renal allograft recipients with CHC • ATT induced hepatitis • Severe acute sporadic hepatitis E

31. SNMC: SAHF(Acharya, ICMR 1992-1997) • N=56 • Open trial • Dose 100 mL/day for 30 days, then EOD for 8 weeks • Survival rate 73% v 33% (98 historical control) (p <0.001) • Clinical and biochemical improvement + + • Liver failure related complications  • Viral clearance  • Chronic sequalae 

32. SNMC: Chronic Hepatitis(Acharya, ICMR 1992-1997) • Open labeled (n=21), RCT (n=26) • HBV 25, HCV 9, Both 5, None 9) • Dose 60 mL/day for 1 mo, then EOD for 5 mo • Biochemical improvement + + • Histological improvement 25% • Viral clearance • HCV None • HBV (seroconversion) 3/25 (12%)

33. SNMC: Cirrhosis with Activity(Acharya, ICMR 1992-1997) • RCT (n=43, SNMC 21, Placebo 22) • HBV 25, HCV 8, Both 2, None 8) • Dose 60 mL/day for 1 mo, then EOD for 5 mo • Mortality and complications  • Biochemical improvement + + • 36% relapse • Viral clearance No effect

34. SNMC: Long-Term Results Retrospective, nonrandomized, varying doses

35. Renal Allograft Recipients with Ch Hepatitis C N=12 Anand, IJG,2004 N=6

36. SNMC: Conclusions • SNMC has no antiviral effect (Grade I) • Improves mortality in patients with SAHF (Grade II-3) • Improve liver functions in patients with SAHF (Grade II-3) and in CH and cirrhosis with activity (Grade I) • SNMC does not reduce mortality among patients with cirrhosis with activity (Grade I)

37. SNMC: Conclusion • Prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C (Grade II-3) • Ribavirin + SNMC is more effective than ribavirin monotherapy in renal allograft recipients with ch hepatitis C (Grade II-1) • Small number of patients

38. Liv. 52: Ingredients • Capparins spinosa (Himsara), • Cichorium intybus (Kasani), • Tamarix gallica (Jhavaka) • Solanum nigrum (Kalcamachi), • Terminalia arjuna (Arjuna), • Cassia accidentalis (Kasamarda), • Achillea millefolium (Biranjasipha) • Tamarix gallica (Jhavaka) • Mandur bhasma,

39. Liv. 52: Indications • In the prevention and treatment of: • Viral hepatitis • Alcoholic liver disease • Pre-cirrhotic conditions and early cirrhosis • Protein energy malnutrition • Loss of appetite • Radiation and chemotherapy-induced liver damage • As an adjuvant with hepatotoxic drugs • A valuable adjuvant during convalescence and prolonged illness www.himalayahealthcare.com/products/liv_drops.htm

40. Liv. 52: Animal Studies • In market for over 50 years • Medline search (1966 to date) 49 papers, 22 animal studies • Experimental data: • Inhibits lipid peroxidation • Protective effect on alcohol induced fetotoxicity • Inhibit TNF activity

41. Liv. 52: Human Studies European Multicenter Study Group (Fleig, J Hepatol, 1997) • N=188, alcohol related cirrhosis • Child A & B 127 • Child C 59 • Prospective, randomized, placebo-controlled trial, 2 yr • Mortality Liv. 52 Placebo • Child A & B NS • Child C 81% S 40% • Liver related 22/23 (96%) S 3/11 (27%)

42. Liv. 52: Human Studies de Silva, J Ethnopharmacol 2003 • N=80, alcohol liver disease • Prospective, randomized, double-blind, placebo-controlled trial, 2 yr • Groups • Liv. 52 40 patients • Placebo 40 patients • No significant difference in clinical outcome and liver chemistry

43. Liv. 52: Conclusion No evidence to suggest that Liv. 52 is useful in the treatment of any of the liver conditions that have been claimed

44. Picroliv • Alcoholic extract from the root of Picrorhiza kurroa • Iridoid alkaloids: kutkoside and picroside • Antioxidant similar to superoxide dismutase, metal-ion chelators, xanthine oxidase inhibitors

45. Picroliv: Animal Studies Ameliorates toxic effects of carbon tetrachloride, thioacetamide, galactosamine, paracetamol, aflatoxin B1 in a concentration-dependant manner

46. Picroliv: Human Studies

47. Conclusion When things are investigated, then true knowledge is achieved. -Confucius

48. Conclusion • Methodological quality of clinical trials • Larger randomized, double blind, placebo-controlled trials • Outcome measures should include molecular methods, such as, HBV DNA, HCV RNA estimation etc, liver histology, and end-point events.