Hepatitis C: Epidemiology and Review of Complementary/Alternative Medicine Treatments

[Guest guest]

Hepatitis C: Epidemiology and Review of

Complementary/Alternative Medicine Treatments

by Lyn , ND

--------------------------------------------------------------------------------

Abstract

Hepatitis C is emerging as a serious worldwide

problem. In the United States the current mortality

figures may triple in the next ten years, rivaling

HIV. The disease has a latency of 10-30 years and

symptoms or signs may not appear until cirrhosis is

evident. Adequate diagnosis, including liver biopsy,

is essential in assessing the current stage of the

viral infection and the need for treatment. Hepatitis

C may manifest as hepatic fibrosis, cirrhosis,

hepatocellular carcinoma, lichen planus,

glomerulonephritis, mixed cryoglobulinemia, or

porphyria. The hepatic damage is due both to the

cytopathic effect of the virus and the inflammatory

changes secondary to immune activation. The use of the

botanical components glycyrrhizin, catechin, silymarin

and phytosterols, and the antioxidants

N-acetylcysteine and vitamin E are reviewed for their

efficacy in treating chronic hepatitis and affecting

liver damage. (Altern Med Rev 1999;4(4):220-238.)

--------------------------------------------------------------------------------

Introduction

The World Health Organization has estimated 170

million people worldwide are infected with hepatitis

C.1 The prevalence in the United States is estimated

at 3.9 million, approximately four times the current

number of those infected with the HIV virus. Due to

the latent nature of the disease (infection may

precede symptoms by an average of 25 years) only one

million of these individuals have actually been

diagnosed.2 An estimated 8-10 thousand deaths occur

annually in the United States as a result of hepatitis

C-related liver disease, compared to 16,685 AIDS

deaths in 1997.3 Hepatitis C mortality figures are

expected to triple by the year 2010, giving hepatitis

C a resultant mortality that may rival HIV. Ninety

percent of those infected internationally cannot

afford treatment and due to the specific

characteristics of the virus, a vaccine is not

expected.4 Hepatitis C has been estimated to be the

most common cause of chronic liver disease, cirrhosis,

and liver cancer in the Western Hemisphere.5

Attempts to treat the virus have been disappointing.

Interferon alfa is an FDA approved treatment for

chronic hepatitis C. In six-month treatment regimens,

studies have shown an immediate (20-25%) failure rate

determined by lack of clearance of the virus.6

Those who exhibit viral clearance experience a 30-70

percent relapse rate within the first few months of

discontinuing therapy. A sustained response lasting at

least six months is seen in only 10-15 percent of

patients.7 The side-effect profile of interferon

alfa2b is high: nausea, headache, fever, myalgias,

fatigue, leukopenia, thrombocytopenia, alopecia,

irritability, depression, infrequent thyroid

abnormalities, pulmonary complications, and retinal

damage. Patients with autoimmune disorders, thyroid

dysfunction, decompensated cirrhosis and

thrombocytopenia, and post-transplant patients are

usually not eligible for treatment with interferon due

to the risk of serious side-effects.7 Although

evidence from multiple studies shows interferon does

decrease risk for progression to hepatocellular

carcinoma, the risk/benefit ratio and cost of

treatment may render it prohibitive.8

The anti-viral drug ribavirin has been used in

combination with interferon and has resulted in

significantly improved responses: current studies show

a 28-66 percent sustained response after 48 weeks of

treatment.9 The side-effects of the combination

therapy are, however, " universal, significant, and

possibly serious. " Ribavirin frequently causes

hemolytic anemia leading to necessary dose reductions

and is a known teratogen.10

As a result of the worldwide need for treatment

options, the National Institutes of Health (NIH) will

sponsor an international conference on " Complementary

and Alternative Medicine in Chronic Liver Disease "

August 22-24, 1999 at NIH in Bethesda, land.

--------------------------------------------------------------------------------

History of Hepatitis C

In 1975, when the hepatitis A and B antibody tests

became available, it was determined the majority of

transfusion-related hepatitis was neither hepatitis A

nor B.11 Hepatitis C was isolated in 1989 with viral

genome sequencing that led to the first screening

antibody assay in 1990. At that point, incidences in

multiple-transfusion recipients were high: 80 percent

in more than 1,000 transfusion-dependent

thalassemics,12 and 75 percent of multi-transfused

patients in remission from leukemia.13 In 1992, a more

sensitive second-generation EIA was introduced, which

led to a significant reduction in contamination of the

blood supply. Today, with more sensitive screening, it

is estimated the risk of receiving blood from a donor

who is infectious but has not yet seroconverted is

1/100,000.14

Current diagnostic antibody assays include the

recombinant immunoblot assay (RIBA) which is more

effective at excluding false-positive results than

previous EIA antibody screening assays. Detection of

viral load can be accomplished within days of

infection via RT-PCR assays. Viral load assessment is

necessary in immuno-compromised individuals who may

not produce sufficient antibodies or for those

symptomatic individuals who may have false-negative

antibody results. It is also necessary as a monitoring

tool in antiviral therapy.15

--------------------------------------------------------------------------------

The Virus

As a result of host selectivity and hepatitis C viral

mutations, the virus now occurs in six different types

or genotypes. They appear to vary in virulence and

certain genotypes (genotype 1b) may carry a poorer

prognosis and be less susceptible to treatment with

interferon alfa.16,17

Like other RNA viruses, the hepatitis C virus (HCV)

genome is " fluid, " meaning it changes substantially,

even within the same infected individual. Because,

like other RNA viruses, HCV has an absence of repair

mechanisms that operate during DNA replication, it

mutates freely. These mutations lead to production of

different viral isolates called " quasi-species " that

can occur within any given genotype.18 A person

infected with the 1b genotype (the most difficult to

treat) could therefore have many different

quasi-species of that genotype in their body. These

mutations have the ability to sidestep the host's

immune surveillance mechanisms because the immune

system develops antibodies to only a minority of the

quasi-species. This is believed to be the reason 85

percent of infected individuals do not develop

immunity to HCV and go on to develop chronic

infections.

Attempts to develop vaccines have been unsuccessful

for the same reason: neutralizing antibodies produced

against HCV are specific for certain quasi-species and

not for others. It would be very difficult to develop

a vaccine that would recognize the genetic variants of

this diverse virus.12

--------------------------------------------------------------------------------

Transmission

Case-control studies of non-A, non-B hepatitis

(hepatitis strains labeled A-G have been identified)

have found significant associations between viral

infection and a history of blood transfusions at least

six months previously, direct patient care or

laboratory work, intravenous (IV) drug use, multiple

sexual partners, or sexual or household contact with

an infected person. The highest prevalence is among

hemophiliacs who received factor concentrate

transfusions before 1992.19 Persons with a history of

IV drug use account for possibly 50 percent of chronic

infections.19 Approximately 20 percent of hemodialysis

patients worldwide are reported to show anti-HCV

antibodies, independent of receiving blood

transfusions and positively associated with increasing

years on dialysis.14 Geographical variations of all

sources of HCV exist, however, and hemodialysis is not

an exception to this rule. In the United States, 35

percent of hemodialysis patients in one study were HCV

infected. Sexual transmission and household exposure

transmission is a route of infection, but appears to

occur infrequently and accounts for possibly 10-15

percent of all cases.19 In a Japanese study of 154

infected couples, 18 percent of monogamous HCV spouses

were co-infected, the risk increasing for each decade

of marriage.20 Alter19 estimates the likelihood of

sexual transmission is approximately five percent, and

neither the U.S. Public Health Service nor the NIH

recommend barrier precautions in monogamous

relationships. Perinatal spread is uncommon and, when

it occurs, rarely leads to chronic infection of the

child unless the mother is co-infected with HIV.21

Current risks for acquiring or having acquired

hepatitis C include: illegal intravenous drug use

(including short-term use in the previous 20 years),

being an organ or transfusion recipient prior to 1992,

intranasal cocaine use with shared equipment, tattoo

or body piercing with nonsterile instruments, using an

infected person's razor or toothbrush, and engaging in

high-risk sexual behavior (having multiple partners or

failing to use a condom).22

Prior hospitalization is a risk factor (prevalence in

hospitalized patients is 2-20 percent).23

Patient-to-patient transmission has been implicated in

outbreaks of HCV in a hematology ward, and

surgeon-to-patient transmission has been identified as

a cause in a pediatric oncology unit.24,25

--------------------------------------------------------------------------------

Clinical Course

The current incubation time of HCV is between 2-26

weeks, although 80-90 percent of cases occur within

5-12 weeks post-transfusion.26 Most patients with

acute hepatitis C do not have demonstrable signs or

symptoms at the onset of infection. Twelve percent of

a cohort of 50 HCV patients had a remembered past

history of symptomatic hepatitis; however, due to the

high incidence of coinfection hepatitis, the

symptomatic episode may have been simultaneous

infection with acute hepatitis A.27 Only 25 percent of

acute non-A, non-B hepatitis patients are jaundiced

and only 33 percent have significantly elevated

alanine aminotransferase (ALT) levels (>800 I.U.).28

As mentioned previously, the ability of the virus to

mutate appears to prevent effective immune

eradication, even in the case of a healthy cellular

immune response. This is reflected by the high

percentage of cases that become chronically infected:

studies range from 90 percent for those with genotype

1b, to 75 percent with genotype 2a or 2b.29 In the

United States, it is generally accepted that at least

85 percent of anti-HCV antibody positive patients will

progress to chronic hepatitis (Figure 1).30

Chronic hepatitis C is usually characterized by serum

ALT levels that have been elevated for 6-12 months

after acute onset. ALT levels may normalize within one

year, but may again rise and become chronically

elevated (Figure 2).31 Fluctuating transaminases in

the absence of alcoholism are accepted to be

diagnostic of hepatitis C.2 However, HCV can and does

progress in the absence of signs and symptoms;

approximately one-third of those chronically infected

with HCV exhibit consistently normal serum ALT

levels.35

Even in the face of normal liver enzymes and an

asymptomatic course, there is a high prevalence of

liver disease. In a study of 98 healthy, anti-HCV

antibody positive blood donors, 95 percent had

histological abnormalities evidenced by liver biopsy

and 75 percent were diagnosed with histological

evidence of chronic hepatitis.32 The progression of

HCV appears to vary geographically and possibly with

genomic type. In Japan, where the predominant genotype

is 1b, only two percent of HCV patients appear to

recover from acute infections, while the remainder

will most commonly progress to chronic hepatitis

(30%), cirrhosis (20%), and hepatocellular carcinoma

(15%) a mere eight years later.2 In the United States,

progression is slower, with the development of

cirrhosis in 20-30 percent of patients in 10-20 years

of follow-up.35

The most common symptom of HCV is fatigue. In one

study of 102 patients referred to a liver unit,

fatigue occurred in 35 percent of subjects.33 The

onset of cirrhosis may be relatively asymptomatic with

only subtle physical changes: palmar erythema, spider

angiomas (blanching with pressure), hypertrophy of the

parotids, gynecomastia in men (due to decreased

clearance of estrogen in the liver), and fibrosis of

the palmar tendons of the hand. Once cirrhosis occurs,

other symptoms such as muscle weakness, fluid

retention, jaundice, bilirubin in the urine, purpura,

upper intestinal hemorrhage, and pruritis may follow.

HCV can also manifest as arthritis, lichen planus,

glomerulonephrosis, and essential mixed

cryoglobulinemia (arthritis, purpura, hives,

vasculitis, glomerulonephritis, and neuropathy).

Although cryoglobulins are evident in approximately 33

percent of patients, the clinical syndrome occurs only

in 1-2 percent.34 Another potential complication of

HCV is porphyria cutanea tarda. It is associated with

alcohol abuse, iron overload, and estrogen use, and

appears as cutaneous vesicles in sun-exposed areas.

The condition, if progressive, leads to skin

fragility, bruising, and hyperpigmentation.35

--------------------------------------------------------------------------------

Co-Infection with HIV

Among HIV-infected persons, HCV appears to progress

more rapidly and lead to increased risk for liver

disease. In a population of HCV-infected male

hemophiliacs in the United Kingdom, liver-related

death rates were approximately 20 times higher than

the general population, and 94 times higher in men

co-infected with HIV and HCV.36 Other studies have

noted increased replication rates of HCV in

HIV-positive individuals with a more rapid progression

to cirrhosis.37

--------------------------------------------------------------------------------

Hepatocellular Carcinoma

One of the most concerning aspects of HCV is the risk

for hepatocellular carcinoma (HCC). In a cohort of

hemophiliacs, an HCV infection of 25 years duration

(as compared to those who are HCV-negative) resulted

in a 17-fold increase in risk of death from liver

disease and a six-fold increased risk of death from

liver cancer.38 In Europe and Japan, 50-75 percent of

all patients with HCC have evidence of HCV

infection.39,40 The incidence of HCC varies with

different population studies. In general, 20 percent

of patients with chronic HCV develop cirrhosis over a

ten-year period.41 In patients with established

cirrhosis due to HCV infection, surveillance studies

show 3-4 percent may develop HCC in the first 4-5

years.42 Progression from cirrhosis to HCC usually

takes approximately ten years.43 Liver Biopsy and the

Pathology of HCV Progression of HCV is determined by

liver biopsy and measurement of serum ALT. When serum

ALT is consistently above 200 IU/L it is predictive of

chronic active hepatitis.44 The current histological

classification system for liver biopsies in HCV

consists of a grading scale based on necrosis and

inflammation, and staging based on fibrosis.45 This

system differentiates mild hepatitis (grade 1-stage 1)

from more progressive states of hepatitis (grades

2-4). A biopsy without evidence of fibrosis

infrequently progresses to cirrhosis.46

--------------------------------------------------------------------------------

Evidence for Oxidative Stress and Cytokine-Induced

Inflammation in HCV

Results of 317 liver biopsy samples from patients with

HCV showed evidence of HCV-induced liver damage:

lymphoid follicles, large droplet fat, bile duct

damage, and Mallory body-like material. " 47 Scheur and

Sherlock sampled 45 HCV patients, 44 percent of whom

exhibited developing or established cirrhosis. They

concluded the evidence of lymphoid aggregates

(lymphocyte clusters) or follicles in the portal

tracts and fatty changes, along with lobular activity,

are the characteristic changes in hepatitis C.48 Bach

and Thung examined 50 biopsy samples from patients

with HCV compared to 21 patients with autoimmune

chronic hepatitis, and found similar pathologic traits

that distinguished the HCV samples: bile duct damage,

bile duct loss, steatosis, lymphoid cell aggregation

(follicles), and lobular and piecemeal necrosis.49

The mechanisms involved with liver damage in chronic

hepatitis C are not completely understood. HCV is

thought to be directly cytopathic to hepatic cells,

and there is evidence immune mechanisms involved in

viricidal activity are responsible for the

inflammatory infiltrates (lymphoid follicles) that can

progress to necrosis.50 Tumor necrosis factor alpha

(TNF-a) is a cytokine secreted by HCV-specific

cytotoxic lymphocytes; TNF-a levels are elevated in

chronic hepatitis C. Elevated levels of TNF-a have

also been correlated with elevated markers of liver

damage (serum ALT levels and

alpha-glutathione-S-transferase levels) independent of

levels of hepatitis C virus in the blood.51 TNF-a is

one of the cytokines secreted by the specific TH2

humoral defense arm of the T lymphocyte cell-mediated

immune system. TH2 cells also secrete the

proinflammatory lymphokines interleukin 6 (IL-6),

interleukin 4 (IL-4), interleukin 10 (IL-10), and

interleukin 1 (IL-1).52 The other arm of the T

lymphocyte system is comprised of TH1 cells, which

promote cell-mediated defense, and secrete interleukin

2 (IL-2), interleukin 12 (IL-12), and gamma-interferon

(IFN-g).

The TH1 and TH2 systems are mutually inhibitory,

serving as a regulatory system in balancing humoral

and cell-mediated responses. In the well-studied

immune activation of HIV infection, the TH2 system

becomes dominant, destroying immune equilibrium and

resulting in a progressive reduction of IL-2 and

IL-12.53 In HCV infections, the same dominance of the

TH2 system appears to exist: IL-4, IL-6, and IL-10

stimulate humoral immunity and lead to the

overproduction of TNF-a, resulting in inflammation and

suppressing the production of IL-2 and IFN-g54 In a

healthy immune system, TH1 cells also support the

transformation of CD+8 suppressor cells into active

natural killer/cytotoxic cells that directly

inactivate virus. Lirussi55 evaluated natural killer

cytotoxic response of NK cells in 15 chronic HCV

patients and compared them with 23 controls. The NK

cell activity in the chronic HCV patients was

approximately 50 percent that of the healthy group in

three different concentrations of NK cells. The

authors suggest an impaired immune response appears to

favor chronicity of the disease in chronic HCV.

Whether impaired activity of the NK cells in chronic

HCV infections is due to a dominance of TH2

lymphocytes remains to be seen.

--------------------------------------------------------------------------------

Ribavirin: Mechanisms of Action

Ribavirin is a guanosine analogue with antiviral

activity against RNA and DNA viruses. In combination

trials with interferon, sustained virological

responses have been as high as 47 percent after 24

weeks of treatment.56 Although repeated studies have

shown significant reduction of ALT levels after six

months of treatment with ribavirin alone,57 multiple

studies have failed to detect any significant

antiviral activity.58,59 The benefit of ribavirin in

post-liver transplant patients with hepatitis C is a

result of decreased lobular inflammation and

normalization of ALT levels, and not a reduction of

viral load.60

There is evidence ribavirin specifically inhibits

cytokine production by macrophages. Ning61 assessed

the effect of ribavirin in an experimental model of

fulminant murine hepatitis (MHV-3). Even though

ribavirin had minimal antiviral activity, it

significantly reduced macrophage activation and

decreased production of IL-4, but did not effect the

production of IL-2 or IFN-g. The authors concluded the

beneficial effect of ribavirin in this situation was

the specific preservation of TH1 cytokines and the

inhibition of TH2 cytokines.

--------------------------------------------------------------------------------

Phytosterols

Phytosterols are a family of plant lipids that have

structural similarity to cholesterol but with a

fraction of the absorption: a rate 800-1000 times

lower than the absorption rate for cholesterol. In

humans, less than five percent of phytosterol

compounds are absorbed;62 however, the amount

necessary to be physiologically active is small.

Beta-sitosterol and its glycoside have been found to

exert lymphoproliferative action in picogram to

femtogram amounts Ñ at the same concentrations that

endogenous hormones are found.63 Approximately 80

percent of plant phytosterol content is b-sitosterol

with about one percent in the glycoside form

b-sitosterol glycoside.64

Plant sterols and sterolins have anti-inflammatory,65

hypocholesterolemic,63 and insulin regulating

activity.66 They have been used in the treatment of

benign prostatic hypertrophy.67 Sterols and sterolins

are thought to be responsible for the activity of

Serenoa repens, Silybum marianum, Harpagophytum

procumbens, Ginkgo biloba, Eleutherococcus senticosus,

and Pygeum africanus.68

Phytosterols, particularly b-sitosterol and its

glycoside b-sitosterolin, have been shown to have

immunomodulating properties, preserving TH1

cell-mediated immunity while lowering elevated TH2

production of inflammatory cytokines.69

--------------------------------------------------------------------------------

Clinical Trials

Bouic64 evaluated the immune-stimulating effect of a

combination of b-sitosterol and b-sitosterol glycoside

on human lymphocytes, both in vitro and in vivo. Blood

was obtained from eight healthy volunteers on 60 mg

b-sitosterol and 0.6 mg b-sitosterol glycoside after

two and four weeks. Figure 3 illustrates the T-cell

proliferation in six healthy subjects after four weeks

of b-sitosterol. Individual increases in T-cell

proliferation ranged from 20-920 percent. The

sitosterol compound also enhanced in vitro production

of IFN-g, IL-2, and NK cell activity.

An open trial of b-sitosterol and b-sitosterol

glycoside in HIV+ patients for 36 months resulted in a

stabilization of CD4+ counts for 24 months, and a

significant decrease in IL-6, the cytokine implicated

in the induction of HIV replication in infected

cells.70 As a result of preliminary trials, current

trials in treating HCV are currently in progress in

South Africa.71

--------------------------------------------------------------------------------

Antioxidants in the Treatment of Hepatitis C

Recent evidence has shown oxidative stress and lipid

peroxidation play a major role in the fatty liver

accumulation (steatosis) that leads to

necroinflammation and necrosis of hepatic cells.72,73

Necrosis, both the piecemeal and bridging types, are

associated with a poor prognosis in chronic

hepatitis.74 Fatty tissue accumulation in the liver

increases the potential for oxidative stress to

trigger lipid peroxidation, leading to cytotoxic

intermediates that induce inflammation and fibrosis

via immunological pathways.75 Both in alcoholic and

nonalcoholic hepatitis, steatosis (fatty tissue

accumulation) and the lipid peroxidation that follows

can lead to activation of stellate cells, the

principal cells in the liver responsible for

fibrogenesis and, ultimately, cirrhosis.76

Understanding the role of lipid peroxidation in liver

disease has lead to studies using antioxidant therapy

in a variety of hepatic disease states.

Alcohol-induced hepatitis has a free radical related

pathogenesis. Wenzel studied a group of 56 patients

with acute alcohol-induced toxic hepatitis. Half of

them (n=31) were given 600 mg d-alpha tocopherol, 200

mcg selenium, and 12 mg zinc. This protocol lowered

the levels of bilirubin, ammonia, and malondialdehyde

(a marker of hepatic free radical production)

significantly when compared to the control group. The

hospital stay of the supplemented group was reduced by

six days and the mortality was reduced to 6.5 percent

(2 of 31 patients) compared to 40 percent (10 of 25

patients) in the control group.77

Antioxidants have also been used in combination with

interferon alfa2 in children with acute hepatitis B.

One study looked at 73 children with acute hepatitis B

given tocopherol and interferon alfa2 simultaneously,

and found significantly shorter recovery times, higher

levels of endogenous alpha-interferon, and a

significant increase in the elimination of Hbe antigen

with the addition of vitamin E.78

Studies using antioxidants in hepatitis C have focused

on the effect of a variety of antioxidants, both

nutrients and botanicals.79 Beloqui treated 24

patients with chronic hepatitis C, 14 who had shown no

response to interferon after four months. The group

was given 600 mg N-acetylcysteine three times daily

for 5-6 months in addition to interferon. Serum ALT

values steadily declined in all 14 subjects over the

5-6 month period and normalized in 41 percent of the

group on combination therapy. The group previously

receiving no treatment had no effect from the

N-acetylcysteine after one month.

Hoglum80 treated six patients who had failed

interferon therapy and had evidence of fibrosis on

liver biopsy. Stellate cell activation in the liver

was subsequently measured by the presence of

malondialdehyde protein adducts in the biopsy.

Treatment with d-alpha tocopherol at the dosage of

1200 I.U. daily for eight weeks was found to stop the

fibrogenesis initiated by stellate cell activation.

The treatment did not, however, decrease ALT levels,

viral titers, or the degree of hepatocellular

inflammation.

--------------------------------------------------------------------------------

Glycyrrhizin

Phytopharmacology

In Japan, glycyrrhizin has been an accepted treatment

of chronic hepatitis for over 20 years.81 Glycyrrhizin

is a conjugate of glycyrrhetinic acid and glucuronic

acid. Orally administered glycyrrhizin is metabolized

in the intestine to glycyrrhetinic acid, while

intravenous glycyrrhizin cannot be metabolized to

glycyrrhetinic acid until it is excreted through the

bile into the intestines (Figure 4).82 Both

glycyrrhizin and glycyrrhetinic acid have been found

to possess antiviral activity. In in vitro studies

Nose83 found smaller doses of glycyrrhetinic acid (5

micrograms/mL) were as effective as larger doses of

glycyrrhizin (1000 micrograms/mL) in lowering

transaminase levels. On the other hand, in other

studies, using murine IFN-g production as a measure of

immune modulation, glycyrrhizin was more effective

than glycyrrhetinic acid.84

The first evidence of glycyrrhizin's antiviral effect

was found in 1977 in culture studies with herpes

simplex virus type 1.85 In 1990, Crance86 found

complete inhibition of hepatitis A virus antigen

expression at concentrations of 1000 and 2000 mcg/mL.

The mechanism of glycyrrhizin's antiviral effect was

later discovered not to be direct viral inhibition, as

previously thought, but inhibition of the virus's

ability to penetrate the human hepatocyte. The

hepatitis A virus enters cells by the process of

endocytosis, a process that glycyrrhizin interrupts by

altering cell membrane penetrability.87 Glycyrrhizin

also appears to work as a free radical scavenger:

studies with ischemia-reperfusion damage in rat liver

(using pre-treatment with subcutaneous glycyrrhizin)

significantly decreased lipid peroxides and

transaminase levels.93 As mentioned earlier,

glycyrrhizin also acts via immune modulation:

intravenous injections in mice induced IFN-g peaks and

subcutaneous glycyrrhizin activated murine hepatic

T-cells.88,89

Clinical Trials

The first randomized trial using intravenous

glycyrrhizin was run in 1977 when Suzuki looked at its

effect in 133 cases of chronic hepatitis B.90 The

glycyrrhizin was given as Stronger Neo Minophagen C

(SNMC) Ñ a solution of 2 mg glycyrrhizin, 1 mg

cysteine, and 20 mg glycine per mL. Glycine was added

to prevent pseudoaldosteronism, and cysteine was added

to assist cysteine-related conjugation reactions in

liver detoxification pathways. SNMC(40 mL) was

administered intravenously daily for four weeks.

Significant improvements were found in transaminase

values and no side-effects were observed.

Later studies found improvements in liver histology:

39 of 45 hospitalized patients had histologically

significant improvements in liver biopsy after eight

weeks of SNMC at 100 mL daily.91 Withdrawal of the

SNMC caused a rebound of the transaminases which could

be reduced with a step-wise withdrawal of the daily

eight-week dose of 100 mL.92 A similar phenomenon of

transaminase rebound is found after elimination of

long-term therapy with ribavirin.93

A long-term trial with SNMC in patients with chronic

hepatitis C included 84 patients who were given the

medication between January 1979 and April 1984.94

These patients were given 100 mL of SNMC intravenously

daily for eight weeks and 2-7 times weekly for 2-16

years (median 10.1 years). They were compared to a

control group of 109 patients who, due to a lack of

home health-care services, received only oral

botanical and nutritional supplements. On follow-up

the serum ALT levels fell to normal in 30 (35.7%) of

the group receiving SNMC and in seven (6.4%) of the

control group. The 15-year incidence of cirrhosis was

21 percent in the SNMC group and 37 percent in the

control group. The incidence of HCC after 15 years of

treatment was 12 percent in the SNMC group and 25

percent in the control group. In this study, patients

treated with SNMC for 10 years had incidences of HCC

comparable to Japanese interferon-treated patients.

The incidence of HCC in lymphoblastoid

interferon-treated hepatitis C patients in the same

Japanese hospital was 0.1%, 0.6% and 1.5% per year

(for the histologic stages I, II, and III,

respectively). The incidence in the SNMC patients was

0.3% for Stage I and II, and 1.3% for stage III.104

Side-effects related to hypokalemia (10.7%) and

hypertension (3.6%) necessitated the use of

spironolactone. No one in the study discontinued

medication as a result of side-effects. Several

questions arise as a result of the data on SNMC; for

example, it is not clear to what extent the cysteine

and glycine contributed to the positive effects of the

glycyrrhizin.

While the metabolism of oral glycyrrhizin is mediated

by intestinal bacteria and results in enzymatic

conversion to glycyrrhetinic acid (Figure 4), both

oral and intravenous routes of administration appear

to have hepatoprotective properties. Eighty subjects

with acute or chronic hepatitis B were given either

oral doses of 7.5 g crude glycyrrhiza root,

concentrated to contain 750 mg glycyrrhizin, (30 days

for the acute group and 90 days for the chronic group;

n=20 in each group), and compared to identical groups

receiving conventional treatment of inosine plus Poly

I:C.95 Results showed significantly more marked

improvement in indices of liver function and negative

conversion of HbsAG and HbeAg in the glycyrrhizin

group than in the control group (Table 1). In fact,

none of the patients in either control group

seroconverted. In the glycyrrhizin groups, indicators

of liver function returned to normal in 85 percent of

subjects with acute hepatitis and 75 percent of those

with chronic hepatitis, compared to 35 percent and 10

percent, respectively, in the control groups.

--------------------------------------------------------------------------------

Catechins

Catechins are a class of flavonoids with

hepatoprotective activity. Early research in animals

has shown their ability to decrease the hepatotoxicity

of ethanol, carbon tetrachloride, phalloidin, and

other toxic compounds in rat hepatic tissue.96

Numerous animal studies have also demonstrated

catechins' antioxidant effects (including the

inhibition of lipid peroxidation) and ability to

stimulate cell-mediated immunity.97

(+)-Cyanidanol-3 is pure catechin (trade names ­

Catergen, Kanebo, Zyma) derived from Uncaria gambir

(Figure 5). In the early 1980s it was the subject of

extensive study in the United Kingdom and other parts

of Europe as a potential treatment for alcoholic

hepatitis.98 Results were disappointing; evidence for

alteration in the course of alcohol-related liver

disease was not evident, even at dosages of 2-3 grams

daily for six months.99 The research on its use in

viral hepatitis has been more promising. A

double-blind trial compared 3 gm catechin daily (n=58)

with placebo (n=66) for 50 days in 124 patients with

acute viral hepatitis of various types. Serum AST,

ALT, and serum bilirubin were tested every five days.

There was a significant difference in effectiveness

depending on the type of hepatitis being treated. For

patients with hepatitis C the serum AST and ALT levels

were significantly lower in the catechin group than

the placebo group from the fortieth day on. There were

moderate but significant differences in the hepatitis

B group in favor of catechin, and no significant

difference in the hepatitis A group.100

In other clinical trials of acute hepatitis B,

catechin was shown to lower serum bilirubin and

transaminase levels, and accelerate the disappearance

of HbsAg.101,102 Trials using catechin in chronic

hepatitis showed improvements in liver histologies103

and inhibition of liver lipid peroxidation.104 In a

study with 338 chronic hepatitis B patients, Suzuki105

showed catechin increased the rates of disappearance

of HbeAg in chronic hepatitis. In this trial, 174

patients received catechin at a dose of 1.5 grams

daily for two weeks, followed by 2.25 grams daily for

14 weeks. The HbeAg titer decreased by at least 50

percent in 44/144 patients, and the HbeAg disappeared

in 16/144 catechin patients compared to 4/140 placebo

patients. The nutrient was well tolerated with the

only appreciable side-effect being a transient febrile

reaction in 13 patients.

There have been reports of six patients with

catechin-related hemolytic anemia, all with

demonstrable red blood cell (RBC) antibodies.106 The

hemolysis resolved after discontinuation of the drug

and did not return even though autoantibodies to RBCs

were still detectable in the blood. Other researchers

have reported incidents of hemolysis in patients on

catechin but the symptoms remit when the drug is

withdrawn and no sequelae or fatalities have been

documented.107 This data, however, was collected from

patients who were taking a highly purified

pharmaceutical form of catechin (AKA cyanidanol) at a

dose of 1-2 grams per day, duplicating the average

dose used in treating hepatitis. In the United States,

whole botanical sources of catechins, from Uncaria

gambir for example, are typically used. Catechin

content of gambir ranges from 2-10 percent. While

these doses are unlikely to result in side-effects, it

remains to be seen whether lower concentrations of

catechin will afford the same effectiveness as the

purified form.

--------------------------------------------------------------------------------

Silymarin

The pharmacokinetics of the flavonolignans in Silybum

marianum have been thoroughly reviewed previously in

this journal.108 Due to the antioxidant, antilipid

peroxidation, and antifibrotic actions of the

silymarin complex, the main component, silybin, has

been evaluated for its potential in treating both

acute and chronic hepatitis. Multiple trials have

shown silymarin, in doses of 70 mg three times daily,

can accelerate recovery from acute, symptomatic states

in chronic hepatitis, and result in an accelerated

return to normal of liver enzyme levels.109 In a trial

assessing the effect of a silybin/phosphatidylcholine

complex in chronic hepatitis, eight patients with

chronic hepatitis B and/or C were given a

silybin/phosphatidylcholine complex equivalent to 120

mg silybin twice daily for 60 days.110 At the end of

the 60-day period, levels of AST, ALT, GGT, total

bilirubin, and serum malondialdehyde (a marker of

lipid peroxidation in hepatic tissue) were all

significantly reduced. The levels of GEC (galactose

elimination capacity, a marker for hepatic metabolic

activity) were significantly elevated. The therapeutic

action in this study was believed to be a result of

the botanical complex's ability to stabilize cell

membranes by decreasing the phospholipid turnover

rate.

The silybin/phosphatidylcholine complex has also been

evaluated for a dose-response relationship in a

phase-II randomized, open trial in patients with

either alcoholic or non-alcoholic chronic

hepatitis.111 Differing doses of either 80 mg twice

daily, 120 mg twice daily, or 120 mg three times daily

were given to groups of 20 patients for two weeks.

Four patients had to discontinue treatment due to

gastrointestinal complaints. A statistically

significant drop (P<.01-.001) in ALT and GGT occurred

at doses of 240 mg or 360 mg daily, but not 160 mg.

--------------------------------------------------------------------------------

Other Potential Botanicals

Several other botanicals hold promise as potential

treatments for hepatitis C, although the research to

this point has been primarily on hepatitis B. In vitro

studies have found Picrorhiza kurroa, Phyllanthus

niruri,112 and Phyllanthus amarus113 have anti-HBsAg

activity. Phyllanthus amarus appears to exert its

antiviral effect, at least in part, by down-regulating

HBV mRNA transcription.114 One of three species of

Phyllanthus Ñ niruri, (n=42), amarus (n=11), and

urinaria (n=35) Ñ were tested on 123 patients with

chronic hepatitis B. Thirty-five control patients

received no herbal therapy. Patients receiving

Phyllanthus urinaria were more likely to become HBeAg

negative than those taking the other species.115 Other

studies have found minimal or no effect of Phyllanthus

amarus on eradication of HBsAg in hepatitis B

carriers.116,117

--------------------------------------------------------------------------------

Conclusion

Hepatitis C is a chronic viral infection that is

currently treated with pharmaceuticals that have a

high side-effect profile. Complementary/alternative

therapies include antioxidants, and immunomodulatory

and antiviral botanicals and plant extracts. A number

of human studies point to their efficacy in treating

hepatitis.

Although some of the botanicals discussed in this

review have only been evaluated in hepatitis B, there

is reason to think that they may have applicability in

hepatitis C. Even though the two viruses belong to

separate families (hepatitis B is a member of the

genus, Hepadnaviridae, and hepatitis C, the

Flaviviridae genus), they are both RNA viruses, and

similarities exist in the pathology of chronic

hepatitis B and C. Similar to hepatitis C,

pathological effects of acute and chronic hepatitis B

are not as much the result of the cytotoxicity of the

virus, but due more to the host defense mechanisms

against the virus.118 This hypothesis is supported by

the evidence in patients with high viral loads who

have minimal liver disease and in patients with

undetectable viral loads and strong T-cell responses

who have severe liver disease.119 Treatment for both

types of chronic hepatitis includes interferon alfa,

although it is more effective in chronic hepatitis B,

where it appears to be successful in 30-40 percent of

chronic infections of adult acquisition.118 Interferon

alfa is both directly antiviral and immunomodulating,

increasing both natural killer cell populations and

major histocompatability complex class I.120 The

similarity here is one of pathogenesis Ñ substances

that are both antiviral and immunomodulatory, and

which have an anti-inflammatory effect on hepatocytes,

may be effective in both types of chronic hepatitis.

However, only long-term randomized trials of specific

botanicals in chronic HCV using hepatocellular damage

and serum markers as end-points will provide

conclusive evidence of efficacy.

__________________________________________________