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 Ursodeoxy cholic acid
Milk thistle (Silymarin) SAMe
Glycyrrhizin (lecorice Lecithin/Phosphatidyl
root extract) Choline
Liv 52 (mixture of L-Carnitine
herbs) Selenium
Picroliv 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
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
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) 5
Low (Jadad score 6 mo 6
None 16
Mortality, QOL, cirrhosis/HCC X
Liu, J Viral Hepatitis 2001 8
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
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 1 10 100 .01 .1 1 10 100
Favors Controls Favors Phyllanthus Favors Controls Favors Phyllanthus
10
Phyllanthus v Other Medicines
Loss of HBsAg Loss of HBeAg
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 Controls 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 1 10 100 .01 .1 1 10 100
Favors Controls Favors Phyllanthus + IFN Favors Controls Favors Phyllanthus + IFN
12
Phyllanthus + Thymosin v
Thymosin
Loss of HBsAg Loss of HBeAg
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
13
Phyllanthus: Loss of HBV DNA
Phyllanthus v other med. Phyllanthus +IFN v IFN
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
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) 14
Low (Jadad score 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
23
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
24
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
25
Silymarin: Side effects
18/7000
Seroius side effects 3 patients
Gastroenteritis Collapse
Anaphylactic reactions
Minor 2-10%
GI symptoms, headaches, dermatological
reactions
26
Silymarin: Conclusions
1. Milk thistle (Silymarin) appears to be safe and
well tolerated (Grade 1)
2. It does not reduce mortality among patients with
chronic liver disease (Grade 1)
3. It does not improve histology at biopsy among
patients with chronic liver disease (Grade 1)
4. It does not improve biochemical markers among
patients with chronic liver disease (Grade 1)
5. 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: PGE2 and
arachodonic acid metabolism
Antioxidant: glutathione-S-transferase
and catalase activity
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 None
HBV (seroconversion) 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 Kumada,
Cancer 1997 Oncology 2002
SNMC Controls SNMC Controls
N (CHC) 84 109 178 100
Cirrhosis 28% 40%
HCC - 15 yr 12% 25% 13% 25%
Retrospective, nonrandomized, varying doses
34
Renal Allograft Recipients
with Ch Hepatitis C
70
60
50
40
ALT
30 HCV RNA
20
10
0
SNMC+Ribavirin Ribavirin
N=12 Anand, IJG,2004
N=6 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. In the prevention and treatment of:
a. Viral hepatitis
b. Alcoholic liver disease
c. Pre-cirrhotic conditions and early cirrhosis
d. Protein energy malnutrition
e. Loss of appetite
f. Radiation and chemotherapy-induced liver damage
2. As an adjuvant with hepatotoxic drugs
3. 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 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%)
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
No 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
Picroliv Placebo
375 mg tds
AVH (HBsAg –ve) 15 18
Time in days required 27 days 80 days
for total bilirubin to drop
to 2.5 mg%
Bilirubin, SGOT and
SGPT
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