Herbal products for liver diseases: A therapeutic challenge for the new millennium

Full text

Clinical Challenge
Herbal Products for Liver Diseases: A Therapeutic Challenge for
the New Millennium
DETLEF SCHUPPAN,1JI-DONG JIA,1,2 BENNO BRINKHAUS,1AND ECKHART G. HAHN1
Use of herbal drugs in the treatment of liver diseases has a
long tradition, especially in Eastern medicine. Standardiza-
tion has been a problem, and randomized, placebo-controlled
clinical trials to support efficacy are lacking. Some herbal
extracts promoted for gastrointestinal or biliary disorders
contain potent hepatotoxic alkaloids and are harmful. How-
ever, some of these extracts have yielded molecules, often
related to flavonoids, with proven antioxidative, antifibrotic,
antiviral, or anticarcinogenic properties, including glycyrrhi-
zin, phyllanthin, silibinin, picroside, and baicalein, which
derive from licorice root, Phyllanthus amarus, milk thistle,
Picrorhiza kurroa, and sho-saiko-to, respectively, that can
serve as primary compounds for the development of specific
hepatotropic drugs.
BACKGROUND
Natural remedies represent a $1.8 billion market in the
United States, and a single herbal preparation, silymarin,
which is used almost exclusively for liver diseases, amounts
to $180 million in Germany alone.1Marketing of herbals
tripled between 1992 and 1996,1and nearly a third of
outpatients attending liver clinics use these products.2This is
reflected in the internet home pages of hepatitis foundations.
Herbal products have been classified as food supplements and
thus are exempt from regulations on quality control and proof
of efficacy that govern standard pharmaceuticals. This is
contentious in view of the biological activity of many herbals
and, more worrisome, their occasionally severe toxicity.
Use of herbal medicines can be traced back as far as 2100
B.C. in ancient China (Xia dynasty) and India (Vedic period).
The first written reports date back to 600 B.C. with the
Caraka Samhita of India and the early notes of the Eastern
Zhou dynasty of China that became systematized around 400
B.C. The recipes, once formulated, were usually expanded
rather than abandoned during subsequent centuries. Expan-
sion was stimulated by a growing understanding of the
natural evolution of frequently encountered diseases and by
emerging hypotheses regarding their causes. Hepatitis was
and continues to be prominent. Biliary stasis in patients with
jaundice, often associated with ascites and encephalopathy,
led to the discovery that the liver is responsible for bile
production and excretion. However, contrary to the Aristote-
lian Western world, which preferred the analytical approach
to medicine, even when based on unfounded assumptions,
the Eastern hemisphere always considered disease a manifes-
tation of a more general imbalance of the dichotomous
energies that govern life as a whole and human life in
particular. In China these energies are represented by the
complementary Yin (representing earth and moon, moist-
ness, darkness and passivity the female aspect) and Yang
(representing sun, dryness, light, and activity the male
aspect), the balance and timely sequence of which is neces-
sary to maintain health. In the Ayurveda (sanskrit: ayur, life;
veda, knowledge) of India, similar forces are agni (strength,
health, and innovation) and ama (weakness, disease, and
intoxication).
With the revolution of the natural sciences and evidence-
based medicine, the divide between Western and Eastern
medicines appeared to widen. However, given the limitations
of conventional treatment for chronic diseases and tumors,
both patients and scientifically trained physicians are giving
increased attention to the more holistic approach of Eastern
medicine. Although this may represent in part a trend
towards mysticism in our modern world, the effectiveness of
Eastern medicine is amenable to Western analysis. One
explanation is the placebo effect, part of which can be
explained by modulation of neurotransmitters or the immune
system in the brain, and another is the fact that some herbal
drugs contain ingredients that specifically treat disease.
EFFICACY AND SAFETY OF HERBAL PRODUCTS
Any evaluation of herbal products faces major problems.
The first is the use of mixed extracts (concoctions) and
variations in methods of harvesting, preparing, and extract-
ing the herb, which can result in dramatically different levels
of certain alkaloids. The biologically active substances have
been structurally defined and standardized for only a few of
the herbs. Even then, it may not be known if this molecule is
the sole active principle or if efficacy depends on the mixture
of compounds.
The second problem is a lack of randomized, placebo-
controlled clinical studies. Traditional Eastern medicine relies
on empiricism and a holistic philosophy, and controlled studies
are considered unnecessary. This is a view shared by many
Western supporters of alternative medicine. Also, trials may not
use end points, such as death from liver disease, histological
fibrosis or inflammation, cancer, and transplantation.
Abbreviation: HBsAg, hepatitis B surface antigen.
From the 1Department of Medicine I, University of Erlangen-Nuernberg, and the
2Department of Gastroenterology and Hepatology, Klinikum B. Franklin, Free Univer-
sity of Berlin, Berlin, Germany.
Received February 25, 1999; accepted August 4, 1999.
Supported in part by grant IZKF B18 from the Federal Ministry of Research and by the
Balsen and Schoeller Foundations for Research into Natural Medicine.
Address reprint requests to: Detlef Schuppan, M.D., Ph.D., Department of Medicine I,
Division of Gastroenterology, Hepatology and Infectiology, University of Erlangen-
Nuernberg, Krankenhausstr. 12, 91054 Erlangen, Germany. E-mail: detlef.schuppan@
med1.med.uni-erlangen.de; fax: (49) 9131-85-36003.
Copyright r1999 by the American Association for the Study of Liver Diseases.
0270-9139/99/3004-0037$3.00/0
1099

Related to these issues is concern about the safety of herbal
remedies. Numerous reports of toxic effects contradict the
popular view that herbals are natural and therefore harmless.
A survey of the National Poison Information Service for the
years 1991-1995 documented 785 cases of possible or con-
firmed adverse reactions to herbal drugs, among which
hepatotoxicity was the most frequent.3The real number is
probably much higher because of underreporting. Although
abnormal liver function tests mostly return to normal once
the offending drug is withdrawn, cases of chronic disease and
acute liver failure requiring transplantation have been re-
ported.4There are groups of plant alkaloids with well
established hepatotoxicity (Table 1).4-6 The pyrrolizidine
alkaloids found in herbal teas or enemas containing Crota-
laria, Senecio, Heliotropium, or Symphytum damage the
hepatic central vein endothelia, causing veno-occlusive dis-
ease that may be lethal or require transplantation. Germander
(Teucrium chamaedrys L.), broadly used in France as an
antipyretic for treatment of abdominal discomfort and for
weight reduction, contains hepatotoxic alkaloids identified as
furano-diterpenoids that, after activation by the hepatic
cytochrome P450 3A, deplete glutathione and precipitate
hepatocyte necrosis, apoptosis, and cytoskeletal disorganiza-
tion.7,8 Greater celandine (Chelidonium majus) has resulted in
acute hepatitis; extracts of this herb are broadly used in
Europe to treat gallstone disease and dyspepsia.9Hepatotoxic-
ity can result also from misidentification or mislabeling of a
plant, contamination by chemicals such as heavy metals, and
incorrect storage that leads to microbial or fungal growth and
toxin production. Safety testing is needed. Before this can be
implemented, however, preparations must be standardized
and must replace in the market the uncontrolled and individu-
alized concoctions currently being offered. Safety concerns
notwithstanding, sufficient scientifically useful data have
accumulated during the last few years to allow an overview of
herbal compounds, some of which appear to be beneficial and
may serve as a basis for future drug development.
STUDIES OF DEFINED FORMULATIONS OF HERBAL
MEDICINES
Some herbal preparations exist as standardized extracts
with major known ingredients or even pure compounds, for
which pharmacodynamic and pharmacokinetic data are usu-
ally available. These resemble the medications of traditional
Western medicine. In only a few cases, however, have studies
documented their efficacy using accepted parameters of
disease progression.
Glycyrrhizin. This group of related, sulfated saponins and
lectins from the licorice root has been used for over 20 years
to treat chronic viral hepatitis in Japan. It has a well-
documented transaminase-lowering effect. The standardized
aqueous extract (Stronger Neo-Minophagen C) has to be
administered parenterally. A daily dose of 80 mg given for 2
weeks can normalize aspartate transaminase and alanine
transaminase in over 60% of patients.10 The preparation has
immunosuppressive and anti-inflammatory effects in cell
culture, where glycyrrhizin inhibits CD4⫹-T cell- and tumor
necrosis factor-mediated cytotoxicity.11 Furthermore, the ex-
tract modifies glycosylation and blocks sialylation of hepatitis
B surface antigen (HBsAg), which leads to its retention in the
trans-Golgi apparatus.12 In an uncontrolled trial of 17 hepati-
tis Be antigen–positive patients with chronic hepatitis B, a
4-week course of glycyrrhizin followed by 4 weeks of
interferon-alfa produced loss of hepatitis B e antigen in 10 of
17 patients after 6 months.13 However, only 3 of the 10
patients underwent seroconversion to antibodies to e antigen,
and virus titers were not reported. In a small randomized
study of 28 patients with chronic hepatitis C who were
nonresponders to interferon monotherapy, 13.3% became
hepatitis C virus–RNA negative after interferon alone com-
pared with 33.3% after a glycyrrhizin/interferon combination
therapy over 3 months.14 However, this was not statistically
significant. In a retrospective analysis of 84 patients with
chronic hepatitis C virus infection who were treated with
intravenous glycyrrhizin 2 to 7 times weekly for a median of
10.1 years, comparison with a matched group of 109 patients
who remained untreated over 9.2 years revealed a 2.5-fold
reduction of the relative risk of hepatocellular carcinoma.15
This could be due to an anti-inflammatory effect of the
preparation rather than to its weak antiviral effect. Because of
its aldosterone-like activities,16 use of the drug requires
caution and monitoring for hypertension, hyperkalemia, and
worsening ascites.
Phyllanthus amarus. This herb and related species are Indian
plants that contain phyllantins, hypophyllantins, and polyphe-
noles with antiviral properties. An aqueous extract inhibited
TABLE 1. Selection of Herbal Preparations With Proven Hepatotoxicity
Causative Plants Toxic Agents Symptoms Mechanism/Pathology
Crotalaria
Senecio
Heliotropium
Symphytum officinale (Comfrey)
Pyrrolizidine alkaloids Veno-occlusive disease Endothelial cell glutathione depletion,
central vein necrosis, thrombosis,
and fibrosis
Atractylis gummifera Atractylate, gummiferin Hepatitis Inhibition of oxidative phosphoryla-
tion, hepatic necrosis
Callilepsis laureola Atractylate Hepatitis Hepatocyte necrosis
Chelidonum majus (greater celandine) Chelidonine, sanguinarine, berberine,
coptisine?
Hepatitis (cholestatic) Lymphocyte infiltration
Larrea tridentata (chaparral) Guaiaretic acid derivatives Hepatitis ?
Teucrium chamaedrys (germander) Furano-diterpenoids Hepatitis Hepatocyte glutathione depletion and
apoptosis
Chinese herbal mixtures (artemisia,
hare’s ear, chrysanthemum, plantago
seed, gardinia, red peony root, etc.)
Largely undefined Hepatitis ?
NOTE. Data are selected from Larrey and Pageaux,5Kaplowitz,6Benninger et al.,9and Yoshida et al.4
1100 SCHUPPAN ET AL. HEPATOLOGY October 1999

woodchuck hepatitis virus DNA polymerase and surface
antigen expression17,18 and several protein kinases such as
cAMP-dependent protein kinase, protein kinase C, and
myosin light-chain kinase in rat liver.19 A nonrandomized
clinical study showed a remarkable 59% (22 of 37 patients)
clearance of HBsAg in chronic carriers who were treated for
30 days compared with only 4% (1 of 23 patients) given
placebo.20 However, these results await confirmation. There
was no effect of P. amarus on duck hepatitis B virus.21
Daphnoretin. This dicoumarin drug extracted from the
Chinese herb Wilkstroemia indica was shown to suppress
HBsAg in Hep3B cells, an effect mediated by activation of
protein kinase C.22 The same investigators reported a power-
ful suppression of HBsAg by costunlite and dehydrocostus
lactone, two alkaloids from Saussurea lappa Clarks root.23
However, no clinical studies with these compounds have
been reported.
Silymarin. A standardized extract from the milk thistle
Silybum marianum contains as its main constituents the
flavonoids silybinin, silydianin, and silychristin.24 Milk thistle
extracts were used as early as the 4th century B.C., became a
favored medicine for hepatobiliary diseases in the 16th
century, and experienced a revival in central Europe in the
late 1960s (Table 2). The flavonoid silibinin, which consti-
tutes 60% to 70% of silymarin, has been identified as the
major active ingredient.25,26 Its pharmacological profile is
well defined, and studies in cell culture and animal models
clearly show its hepatoprotective action with little or no
toxicity.26,27,33-41 Silymarin enhances the activity of hepatocyte
RNA-polymerase I,26 complexes toxic free iron,33 protects the
cell membrane from radical-induced damage,34 and blocks
the uptake of toxins such as Amanita phalloides toxin.32,35 A
potent scavenger, it prevents lipid peroxidation and normal-
izes the lipid profile of hepatocyte membranes.36 Silymarin
provided liver protection in rat models of liver damage
induced by carbon tetrachloride and paracetamol.37,38 Four of
12 dogs fed lyophilized Amanita toxin and given supportive
care died from hepatic failure and coma within 35 to 54
hours, whereas all 11 dogs receiving high-dose silymarin
survived.39 In a retrospective analysis of 205 patients with
Amanita intoxication, of whom 30 received treatment, the
death rate of those given intravenous silymarin was reduced
significantly (12.8% vs. 22.4%).40
In recent in vitro studies, silymarin down-regulated the
proinflammatory leukotriene B4 in Kupffer cells.41 In random-
ized clinical trials for acute viral hepatitis A or B, oral
silymarin either exerted no benefit29 or accelerated clinical
recovery, causing a significantly more rapid normalization of
bilirubin and aspartate transaminase than did the control.30
Similarly, in alcohol-related hepatitis treated with silymarin,
transaminase levels dropped more rapidly than in the un-
treated disease.42 A 4-month course of silymarin in patients
with moderately active alcohol-related liver disease led to a
41% reduction of alanine transaminase, compared with no
change in controls.43 In a randomized trial, 170 biopsy-
proven cirrhotic patients, 92 with alcohol-related and 78 with
nonalcohol-related liver disease, were treated with silymarin
or placebo for a mean of 41 months.44 Although serum
biochemistry values did not differ between the 2 groups, the
number of surviving cirrhotic patients with alcohol-related
liver disease was significantly higher in the silymarin group,
especially in those with Child-Pugh class A cirrhosis. Most of
the latter patients continued to drink, which may have
influenced the results. Also, the dropout rate was high,
although dropouts were counted as therapy failures. A
subsequent randomized, placebo-controlled study of 200
patients with alcohol-related cirrhosis, 75 of whom dropped
out, could not confirm a survival benefit.45
These data point up the difficulty of studying a heteroge-
neous group of patients and of using death as the endpoint for
a condition that progresses over many years. An intermediate
endpoint is progression of fibrosis to cirrhosis, which is the
primary determinant of morbidity and mortality in patients
with chronic liver diseases. In vitro, silymarin blocks prolifera-
tion of hepatic stellate cells, the main source of excess
collagen in fibrosis. This is accompanied by down-regulation
of the profibrogenic transforming growth factor ␤.46 In liver
injury induced by complete occlusion of the biliary system in
the rat, oral silymarin reduced collagen accumulation in a
dose-dependent fashion.47 It was similarly antifibrotic when
administered from weeks 4 to 6, i.e., starting at a time when
liver collagen is already increased 4-fold, a situation encoun-
tered in most patients with chronic liver disease. The
antifibrotic effect was accompanied by reduced numbers
TABLE 2. History of the Milk Thistle as a Liver Remedy
Century/Year Use/Indication Source
4th Century B.C. General medicinal herb Theophrastus
1st Century A.D. Emetic, general
medicinal herb
Dioskurides
11th Century A.D. Ulcers, shingles Hildegard von Bingen,
Causae et curae
1564 Stitch in the side,
astringent
A. Lonicerus, Kreuter-
buch, Frankfurt
1626 Stitch in the side, pesti-
lence, renal calculi
P.A. Matthiolus, Neues
Kreuterbuch, Prague
1755 Liver disease, liver pain A. von Haller, Medici-
nisches Lexikon,
Frankfurt
1846/1951 Liver disease, icterus,
biliary colic
J.G. Rademacher,
Erfahrungsheillehre,
Berlin
1938 Hepato-cholangiopa-
thies, chronic leg
ulcers
G. Madaus, Lehrbuch
der biologischen
Heilmittel, Leipzig
Year
Characterization/First
Clinical Studies Source (reference)
1968-1974 Characterization of
active compounds
Wagner et al.25 and
Sonnenbichler et
al.26
1971 First animal experi-
mental studies on
liver protection
Platt et al.27
Antidote for Amanita
phalloides intoxica-
tion in the rat
Schriewer et al.28
1976-1988 Elucidation of
molecular actions of
silibinin
Sonnenbichler et al.26
1977/1978 First controlled clinical
studies in acute viral
hepatitis
Bode et al.29 and
Magliulo et al.30
1980 First controlled study
in alcoholic cirrhosis
Benda et al.31
1980-1981 Amanita phalloides
antidote in clinical
studies
Hruby et al.32
HEPATOLOGY Vol. 30, No. 4, 1999 SCHUPPAN ET AL. 1101

of activated stellate cells48 and a greater than 50% reduction
of both procollagen I and tissue inhibitor of metalloprotein-
ase messenger RNA, both being major effectors of fibrogen-
esis.49 These data have spawned randomized, placebo-
controlled studies of silymarin in patients with chronic viral
hepatitis that include follow-up biopsies and a panel of serum
markers of liver fibrosis.50
Picroliv. Picroliv is an alcoholic extract from the root of
Picrorhiza kurroa that contains the iridoid glycosides kutko-
side and picroside. In the rat these glycosides act as antioxi-
dants51 and ameliorate the hepatotoxic effects of carbon
tetrachloride,52 thioacetamide, galactosamine,53 and
paracetamol.54 Despite their wide oral usage in India, no
reliable data for human liver disease exist.
TJ-9. TJ-9, commonly prescribed in China as xiao-chai-hu-
tang and in Japan as sho-saiko-to, is an aqueous extract from
the roots of scutellaria, glycyrrhiza, bupleurum, and ginseng;
the pinella tuber; the jujube fruit; and the thew ginger
rhizome. Two major alkaloids from scutellaria, baicalin and
baicalein, are strong inhibitors of lipid peroxidation.55 The
extract prevented hepatocellular membrane damage and
restored mitochondrial function in endotoxin-treated rats,
increasing hepatic levels of superoxide dismutase and gluta-
thione.56,57 Other in vitro effects that are related to the
observed antitumour activity of sho-saiko-to include up-
regulation of the inducible nitric oxide synthase in hepato-
cytes cultured in the presence of interferon ␥58 and inhibition
of proliferation and induction of apoptosis in hepatoma
cells.59,60 The extract modulated the in vitro cytokine produc-
tion in peripheral blood mononuclear cells, stimulated re-
lease of tumor necrosis factor-␣and granulocyte–colony-
stimulating factor in patients with hepatocellular carcinoma
and down-regulated synthesis of interleukin-4 and -5 in favor
of interleukin-10 in patients with chronic hepatitis C.61,62
Other in vitro effects include stimulation of inducible nitric
oxide synthase and down-regulation of interleukin-4 and -5
in favor of interleukin-10 in patients with chronic hepatitis
C.61,62 In the rat model of dimethylnitrosamine-induced liver
injury, the extract sho-saiko-to protected liver synthetic
function63 and restored hepatic retinoid levels.64 Sho-saiko-to
reduced hepatic collagen content in the rat models of fibrosis
due to choline-deficiency,65 dimethylnitrosamine, and pig
serum.66 The latter work identified baicalin and baicalein,
which are structurally similar to silibinin,67 as major active
compounds, leading to the hypothesis that these agents may
have an antifibrotic activity separable from their effect as
inhibitors of lipid peroxidation. Whereas information on the
antiviral efficacy of sho-saiko-to is at best rudimentary,68 a
prospective randomized 5-year study of 260 patients with
cirrhosis showed a near-significant (P⬍.053) survival
benefit for the treated patients; this reached significance in
those patients without HBs-Ag.69
FORMULAS CONTAINING MIXTURES OF HERBS WITH
PARTIALLY KNOWN OR LARGELY UNKNOWN
INGREDIENTS
The literature is replete with experimental studies using
herbs of largely unknown composition. The following are
those preparations for which human studies or mechanistic
data exist.
Compound 861. Known as cpd 861, this is an aqueous
extract of 10 defined herbs based on traditional Chinese
medicine. The aim of traditional Chinese medicine is resolu-
tion of blood stasis and liver stagnation, two conditions that
form the basis of liver pathology and patient discomfort.70
The chief herbs used in cpd 861 are Salvia miltiorrhiza,
Astragalus membranaceous, and Spatholobus suberectus.71 Rats
with experimental liver fibrosis showed a 50% reduction of
the 5-fold increased hepatic collagen level when cpd 861 was
administered daily by gavage.72 This was accompanied by a
comparable down-regulation of hepatic messenger RNA for
transforming growth factor ␤1 and for procollagens I, III, and
IV, as well as by increased hepatic collagenase activity.
Because procollagen messenger RNAs, major effectors of liver
fibrogenesis, were also down-regulated in cultures of hepatic
stellate cells, a direct antifibrotic effect was proposed.73 From
1993 to 1995, 60 patients with chronic hepatitis B were
treated in an open trial with cpd 861.71 After 2 years,
subjective improvement was reported by 50 patients (83%),
and this was accompanied by a reduction in spleen size in
41% and a decrease in liver enzyme levels and serum fibrosis
markers such as PIIINP and laminin. In a nonrandomized
controlled trial, 22 patients with chronic hepatitis B were
treated with cpd 861 for 6 months and compared with 12
matched patients receiving a control herbal medicine.74
Follow-up liver biopsy results showed a statistically signifi-
cant improvement in both histological inflammation and
fibrosis in the cpd 861 group but no change in the control
subjects.
LIV.52. An extract of several plants prepared for ayurvedic
medicine has been marketed in the West as LIV.52. Standard-
ization, chemical characterization, functional, and pharmaco-
logical studies are not well documented. The extract was
reported to improve serum biochemistry values in rats with
toxic liver damage,75 and uncontrolled observations in pa-
tients with liver disease seemingly gave similar results.76
Furthermore, it lowered circulating levels of acetaldehyde in
healthy adults consuming alcohol.77 Therefore, Fleig et al.78
performed a randomized, placebo-controlled, 2-year clinical
trial in 188 patients with alcohol-related cirrhosis. LIV.52 did
not affect the survival rate of Child class A and B patients but
increased mortality among the 59 Child class C patients (81%
in the treated group, compared with 40% in the placebo
group). Twenty-two of 23 deaths in the LIV.52 group were
related to bleeding or liver disease compared with only 3 of
11 deaths in the placebo group. This result led to immediate
withdrawal of the drug. It highlights the danger of ill-defined
herbal preparations and the necessity for in-depth preclinical
testing.
FUTURE DIRECTIONS
There is no doubt that certain herbal products contain
chemically defined components that can protect the liver
from oxidative injury, promote virus elimination, block
fibrogenesis, or inhibit tumor growth. Although additive
effects may be lost, the active molecules must be isolated and
tested in suitable culture and animal experiments and finally
in randomized, placebo-controlled studies to enable rational
clinical use of the agents. Biologically active molecules
derived from herbal extracts can serve as suitable primary
compounds for effective and targeted hepatotropic drugs.
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