Evidence Based Medicine: Herbal Medicines in Liver Diseases

Radha K. Dhiman, MD, DM, MNAMS, FACG Department of Hepatology, PGIMER, Chandigarh 1

Hepatoprotective Drugs

    

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 2

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 3

Herbal Medicine

 Lack of standardization and lack of identification of active ingredient(s)  Lack of randomized controlled clinical trials (RCTs)  Lack of toxicological evaluation 4



Grade I:

Quality of Evidence



Grade II-1:



Grade II-2:



Grade II-3:



Grade III:

Randomized controlled trials, systematic reviews Controlled trials without randomization Cohort or case-control analytic studies Multiple time series, dramatic uncontrolled experiments, retrospective studies Opinions of respected authorities; descriptive epidemiology 5

Phyllanthus

 Tropical and subtropical countries 

P. amarus, P. niruri, P. myrtifolius, P urinaria

 Inhibit DNA polymerase activity, mRNA transcription and replication 6

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)

7

Phyllanthus:

Metanalysis

 22 RCTs  N=1947 with chronic HBV infection  Quality of trials  High (Jadad score  3)  Low (Jadad score < 3) 5 17   Follow-up  >6 mo 6  None 16 Mortality, QOL, cirrhosis/HCC

X

Liu, J Viral Hepatitis 2001

8

Phyllanthus:

Metanalysis

   22 RCTs

Phyllanthus v

 Controls      No Rx Nonspecific Rx Interferon Thymosin Other herbs

Phyllanthus + IFN v

 Interferon 6 1 3 2 2 6 2

Liu, J Viral Hepatitis 2001

9

Phyllanthus v

Placebo

Loss of HBsAg Loss of HBeAg 1.7 (.7-4.1), p=NS 5.6 (1.9-17.2), p=.002

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus

10

Phyllanthus v

Other Medicines

Loss of HBsAg Loss of HBeAg 2.3 (1.3-4.3),p-.008

.01

.1

Favors Controls

1 10

3.1 (2.2-4.4), p=.00001

100 .01

.1

Favors Controls

1 10 100

Favors Phyllanthus

11

Phyllanthus +

IFN

v

IFN

Loss of HBsAg Loss of HBeAg 0.8 (.13-5.5), p=NS 1.6 (1.1-2.3), p=.03

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus + IFN

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus + IFN

12

Phyllanthus +

Thymosin v Thymosin

Loss of HBsAg Loss of HBeAg 2.1 (.7-6.4), p=NS

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus 2.0 (1.1-3.4), p=.02

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus

13

Phyllanthus:

Loss of HBV DNA

Phyllanthus v other med.

Phyllanthus +IFN v IFN

2.9 (2.0-4.3), p=.0001

1.5 (1.1-2.2), p=.03

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus

.01

.1

Favors Controls

1 10 100

Favors Phyllanthus

14

Phyllanthus:

Conclusions

 Phyllanthus has positive effect on clearance of HBV markers (Grade 1)  No major adverse effects (Grade 1) 15

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.

16

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 17

Silymarin (Milk Thistle)

  Antioxidant:  free radical production and lipid peroxidation Antifibrotic:  procollagen type III  Toxin blockade agent: inhibit toxin binding to hepatocyte membrane receptors 18

Silymarin : Animal Studies

 Acetaminophen  Carbon tetra chloride  Radiation  Iron overload  Phenylhydrazine  Alcohol  Cold ischemia  Amanita phalloides 19

Silymarin : Human Studies

 Alcoholic liver disease  Acute viral hepatitis  Chronic viral hepatitis  Toxin-induced hepatitis 20

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)  Low (Jadad score < 3) 14 3

Jacobs, Am J Med 2002

21

.

Silymarin: Effect on Mortality

RR = 0.8 (.5-1.5), p=NS

.01

.1

.3

Favors Silymarin

1 3 10

Favors control

100 22

.

Silymarin: Effect on ALT

Duration <90 days Duration >90 days

-9 IU/L (-18 to -1), p=.05

-90 -75 -60 -45 -30

Favors Silymarin

-15 0 15 30 45 60

Favors control

75 90 23

.

Silymarin: Effect on AST

-90

-5 IU/L (-15 to 5), p+NS

-75 -60 -45 -30

Favors Silymarin

-15 0 15 30 45 60

Favors control

75 90 24

.

Silymarin: Effect on Prothrombin Time

-30

-2 s (-6 to 2), p=NS

-25 -20 -15 -10

Favors Silymarin

-5 0 5 10 15 20

Favors control

25 30 25

Silymarin: Side effects

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

Silymarin: Conclusions

1.

2.

3.

4.

5.

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 27

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 28

Glycyrrhizin:

Mechanisms of Action

  Anti-inflammatory:  and catalase activity PGE2 and arachodonic acid metabolism Antioxidant:  glutathione-S-transferase  Stimulate endogenous interferon production  Inhibits TNF mediated cytotoxicity 29

SNMC: Uses

 Subacute hepatic failure (SAHF)  Chronic hepatitis  Cirrhosis with activity  Renal allograft recipients with CHC  ATT induced hepatitis  Severe acute sporadic hepatitis E 30

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

+ +

   31

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  HBV (seroconversion) None 3/25 (12%) 32

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 33

SNMC: Long-Term Results

Arase Cancer 1997 Kumada, Oncology 2002

SNMC Controls SNMC Controls N (CHC) Cirrhosis 84 109 178

28%

100

40%

HCC - 15 yr

12% 25% 13% 25%

Retrospective, nonrandomized, varying doses 34

Renal Allograft Recipients with Ch Hepatitis C

70 60 50 40 30 20 10 0 SNMC+Ribavirin

N=6

Ribavirin

N=12

ALT HCV RNA

Anand, IJG,2004 35

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) 36

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 37

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, 38

Liv. 52: Indications

1.

2.

3.

a.

b.

c.

d.

e.

f.

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

39

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 40

Liv. 52: Human Studies

European Multicenter Study Group

(Fleig, J Hepatol, 1997)

 N=188, alcohol related cirrhosis   Child A & B Child C 127 59   Prospective, randomized, placebo-controlled trial, 2 yr Mortality    Child A & B Child C Liver related

Liv. 52

81% 22/23 (96%)

NS S S

Placebo

40% 3/11 (27%) 41

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 N o significant difference in clinical outcome and liver chemistry 42

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 43

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 44

Picroliv: Animal Studies

Ameliorates toxic effects of carbon tetrachloride, thioacetamide, galactosamine, paracetamol, aflatoxin B1 in a concentration-dependant manner 45

Picroliv: Human Studies

AVH (HBsAg –ve) Picroliv 375 mg tds 15 Time in days required for total bilirubin to drop to 2.5 mg% 27 days Bilirubin, SGOT and SGPT  Placebo 18 80 days  46

Conclusion

When things are investigated, then true knowledge is achieved.

-Confucius

47

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.

48