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

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  • claudine intexas
    Hepatitis C: Epidemiology and Review of Complementary/Alternative Medicine Treatments by Lyn Patrick, ND ... Abstract Hepatitis C is emerging as a serious
    Message 1 of 1 , Jan 1, 2001
      Hepatitis C: Epidemiology and Review of
      Complementary/Alternative Medicine Treatments

      by Lyn Patrick, ND



      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.)



      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, Maryland.


      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

      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

      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



      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

      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

      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 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 � 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




      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

      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) � 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

      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 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.



      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

      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 � niruri, (n=42), amarus (n=11), and
      urinaria (n=35) � 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



      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

      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 � 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.

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