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Use of herbal supplements for chronic liver disease

2004; Elsevier BV; Volume: 2; Issue: 11 Linguagem: Inglês

10.1016/s1542-3565(04)00455-0

1542-7714

Cynthia Levy, L. B. Seeff, Keith D. Lindor,

Phytochemistry and Bioactivity Studies

Background & Aims: Complementary and alternative medicine (CAM) is becoming popular among patients with liver disease. Although there is a growing body of evidence regarding potential mechanisms of action of these and other herbs, caution must be used to interpret the results of the few clinical trials available. Our goal was to discuss the biologic rationale for the use of specific herbs (silymarin, glycyrrhizin, sho-saiko-to, Phyllanthus amarus, Picrorrhiza kurroa, Compound 861, CH-100, and LIV.52) in the treatment of chronic liver diseases, as well as the evidence for their efficacy and adverse effects according to clinical trials. Methods: Because of the relative paucity of clinical studies using herbs, every trial published in English was reviewed. Results: Although many trials suggest that these herbs can decrease serum transaminase levels, the effects on hepatic histopathology and long-term survival are either poorly studied or conflicting. LIV.52 has been withdrawn from the market because of deleterious effects in patients with liver disease. Conclusions: Based on current evidence, we cannot recommend the use of herbal supplements for the routine treatment of any chronic liver disease and further well-designed clinical trials are necessary. Background & Aims: Complementary and alternative medicine (CAM) is becoming popular among patients with liver disease. Although there is a growing body of evidence regarding potential mechanisms of action of these and other herbs, caution must be used to interpret the results of the few clinical trials available. Our goal was to discuss the biologic rationale for the use of specific herbs (silymarin, glycyrrhizin, sho-saiko-to, Phyllanthus amarus, Picrorrhiza kurroa, Compound 861, CH-100, and LIV.52) in the treatment of chronic liver diseases, as well as the evidence for their efficacy and adverse effects according to clinical trials. Methods: Because of the relative paucity of clinical studies using herbs, every trial published in English was reviewed. Results: Although many trials suggest that these herbs can decrease serum transaminase levels, the effects on hepatic histopathology and long-term survival are either poorly studied or conflicting. LIV.52 has been withdrawn from the market because of deleterious effects in patients with liver disease. Conclusions: Based on current evidence, we cannot recommend the use of herbal supplements for the routine treatment of any chronic liver disease and further well-designed clinical trials are necessary. Complementary and alternative medicine (CAM) has gained significant popularity in the United States, especially during the past decade. Defined by Eisenberg et al1Eisenberg D.M. Kessler R.C. Foster C. Norlock F.E. Calkins D.R. Delbanco T.L. Unconventional medicine in the United States. Prevalence, costs, and patterns of use.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (3603) Google Scholar as "medical interventions not taught widely at US medical schools or generally available at US hospitals," CAM encompasses over 16 modalities of therapy. Acupuncture, chiropractic, homeopathy, megavitamin therapy, and the use of herbal medicine are among them, and each modality has a specific aim, whether it is balancing the body's energy or building the physical body.2Cohen M.R. Herbal and complementary and alternative medicine therapies for liver disease. A focus on Chinese traditional medicine in hepatitis C virus.Clin Liver Dis. 2001; 5 (vii.): 461-478Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The proportion of the US population using CAM is impressive. In a national telephone survey involving 1539 adults in 1990, 34% of respondents admitted to having used CAM during the past year, and this percentage increased to 42% of 2055 people surveyed in 1997.1Eisenberg D.M. Kessler R.C. Foster C. Norlock F.E. Calkins D.R. Delbanco T.L. Unconventional medicine in the United States. Prevalence, costs, and patterns of use.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (3603) Google Scholar, 3Eisenberg D.M. Davis R.B. Ettner S.L. Appel S. Wilkey S. Van Rompay M. Kessler R.C. Trends in alternative medicine use in the United States, 1990–1997 results of a follow-up national survey.JAMA. 1998; 280: 1569-1575Crossref PubMed Scopus (5916) Google Scholar The use of herbal supplements increased from 2.5% to 12% during that time period and it was estimated that total out-of-pocket expenditures related to CAM approached $27 billion. A new administrative body within the National Institutes of Health specially designed to assess safety and efficacy of such therapies was created in 1998 and called the National Center for Complementary and Alternative Medicine, which provides granting mechanisms for research in this area. In 1999, the National Institutes of Health held a workshop on CAM for liver disease with the main goals of informing the community about the pertinent literature, discussing issues of quality-control related to non-Food and Drug Administration–approved substances, and encouraging laboratory and clinical research on the use of botanicals and herbal preparations.4Seeff L.B. Lindsay K.L. Bacon B.R. Kresina T.F. Hoofnagle J.H. Complementary and alternative medicine in chronic liver disease.Hepatology. 2001; 34: 595-603Crossref PubMed Scopus (229) Google Scholar A questionnaire survey directed at the use of unconventional medicine for liver disease involving almost 1000 participants revealed that 40% of patients had used CAM at least once in the preceding month, and, among these, a median of 21% had used herbals.5Strader D.B. Bacon B.R. Lindsay K.L. La Brecque D.R. Morgan T. Wright E.C. Allen J. Khokar M.F. Hoofnagle J.H. Seeff L.B. Use of complementary and alternative medicine in patients with liver disease.Am J Gastroenterol. 2002; 97: 2391-2397Crossref PubMed Google Scholar Historically, herbals have been used for a number of liver conditions, particularly chronic hepatitis C and alcohol-induced liver disease. Silymarin, glycyrrhizin, Chinese traditional medicine, herbal medicine 861, CH-100, TJ-9, TJ-108, and Phyllanthus amarus are the herbs or blends most commonly used for hepatic disorders around the world.2Cohen M.R. Herbal and complementary and alternative medicine therapies for liver disease. A focus on Chinese traditional medicine in hepatitis C virus.Clin Liver Dis. 2001; 5 (vii.): 461-478Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In the US survey, 21% admitted to using herbal preparations and 13% used these herbs to treat their liver disease. Silymarin was the most reported herb used (12%), followed by garlic (8%), ginseng (6%), green tea (5%), gingko (5%), echinacea (5%), and St. John's wort (4%). Other than silymarin, the only herb used specifically for liver diseases was licorice root (1%).5Strader D.B. Bacon B.R. Lindsay K.L. La Brecque D.R. Morgan T. Wright E.C. Allen J. Khokar M.F. Hoofnagle J.H. Seeff L.B. Use of complementary and alternative medicine in patients with liver disease.Am J Gastroenterol. 2002; 97: 2391-2397Crossref PubMed Google Scholar Clinical trials to evaluate the efficacy of herbs are difficult to conduct, mostly because of heterogeneous formulations and dosages, because these products are not regulated by the Food and Drug Administration and their production is not standardized. In addition, the use of concoctions (mixed extractions) permits other active ingredients to be present in the mixture as contaminants. We must also understand the limitations imposed by medical progress. One disadvantage of early studies is that the methodology used to diagnose liver diseases was either not available or became obsolete. Despite these obstacles, a few clinical studies have been accomplished. In this article we review the herbs that are used most frequently among patients with liver disease. We performed a search through Medline library (1966–2002). Search headings and key words used were combinations of complementary and alternative medicine, herbals, blends, silymarin, glycyrrhizin, licorice root, Chinese traditional medicine, herbal medicine 861, CH-100, TJ-9, sho-saiko-to, TJ-108, P. amarus, Picrorrhiza kurroa, picroliv, hepatitis, cirrhosis, and liver disease. The retrieved publications were supplemented further with relevant articles found in their respective reference lists. Clinical trials published in English were included. Because of the relative paucity of clinical trials to evaluate the use of herbals, we did not exclude any study merely on the basis of its methodology. Studies presented in this article used standardized preparations of herbs unless otherwise noted. Basic science information related to mechanism of action of these herbals was included if abstracts were published in English. Milk thistle is an extract of Silybum marianum, a western herb that recently has been added to the Chinese pharmacopoeia. Its active ingredient is silymarin, which consists of a mixture of 3 flavonoids (silybinin, silydianin, and silychristin) present in the seeds, leaves, and fruits of the milk thistle plant. The standardized preparation usually contains 70%–80% of silymarin.6Pepping J. Milk thistle Silybum marianum.Am J Health Syst Pharm. 1999; 56: 1195-1197PubMed Google Scholar The postulated mechanisms of action of silymarin are multiple. It has been shown to protect against glutathione depletion7Mira L. Silva M. Manso C.F. Scavenging of reactive oxygen species by silibinin dihemisuccinate.Biochem Pharmacol. 1994; 48: 753-759Crossref PubMed Scopus (181) Google Scholar and iron overload8Pietrangelo A. Borella F. Casalgrandi G. Montosi G. Ceccarelli D. Gallesi D. Giovannini F. Gasparetto A. Masini A. Antioxidant activity of silybin in vivo during long-term iron overload in rats.Gastroenterology. 1995; 109: 1941-1949Abstract Full Text PDF PubMed Scopus (162) Google Scholar in rats, and against lipid peroxidation (antioxidant activity)9Carini R. Comoglio A. Albano E. Poli G. Lipid peroxidation and irreversible damage in the rat hepatocyte model. Protection by the silybin-phospholipid complex IdB 1016.Biochem Pharmacol. 1992; 43: 2111-2115Crossref PubMed Scopus (116) Google Scholar in rat hepatocytes. Silymarin also has been shown to increase protein synthesis through stimulation of ribosomal RNA polymerase in hepatocytes,10Sonnenbichler J. Zetl I. Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers.Prog Clin Biol Res. 1986; 213: 319-331PubMed Google Scholar and decrease formation of leukotrienes,11Fiebrich F. Koch H. Silymarin, an inhibitor of lipoxygenase.Experientia. 1979; 35: 1548-1560Crossref PubMed Scopus (61) Google Scholar prostaglandins, and tumor necrosis factor-alpha by Kupffer cells.12Dehmlow C. Erhard J. de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.Hepatology. 1996; 23: 749-754Crossref PubMed Google Scholar In rats previously subjected to complete bile duct obstruction, it blocked proliferation of stellate cells and production of procollagen type III (antifibrotic properties).13Boigk G. Stroedter L. Herbst H. Waldschmidt J. Riecken E.O. Schuppan D. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats.Hepatology. 1997; 26: 643-649Crossref PubMed Scopus (254) Google Scholar In addition, silymarin has been shown to decrease the activity of tumor promoters in human prostate and breast cancer cells,14Zi X. Grasso A.W. Kung H.J. Agarwal R. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells.Cancer Res. 1998; 58: 1920-1929PubMed Google Scholar, 15Zi X. Feyes D.K. Agarwal R. Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468 induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins.Clin Cancer Res. 1998; 4: 1055-1064PubMed Google Scholar and to protect against radiation injury.16Hakov'a H. Misurova E. The effect of silymarin and gamma radiation on nucleic acids in rat organs.J Pharm Pharmacol. 1993; 45: 910-912Crossref PubMed Scopus (16) Google Scholar Finally, silymarin may inhibit the activity of both CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocytes, thereby inhibiting the metabolism of certain drugs.17Venkataramanan R. Ramachandran V. Komoroski B.J. Zhang S. Schiff P.L. Strom S.C. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures.Drug Metab Dispos. 2000; 28: 1270-1273PubMed Google Scholar Theoretically, silymarin may increase the clearance of estrogen by inhibiting β-glucuronidase, and decrease the clearance of drugs that undergo glucuronidation, such as lorazepam. Since the characterization of its active compounds in the early 1970s,18Wagner H. Diesel P. Seitz M. The chemistry and analysis of silymarin from Silybum marianum Gaertn.Arzneimittelforschung. 1974; 24: 466-471PubMed Google Scholar silymarin has been used for alcohol-induced liver disease, acute and chronic viral hepatitis, and drug-induced hepatitis, as well as several other nonhepatic indications. The early articles emphasized the hepatoprotective effect of silymarin in view of intoxication with Amanita phalloides (also known as the death-cap mushroom), which has been confirmed in animal and human studies.19Hruby K. Csomos G. Fuhrmann M. Thaler H. Chemotherapy of Amanita phalloides poisoning with intravenous silibinin.Hum Toxicol. 1983; 2: 183-195Crossref PubMed Scopus (107) Google Scholar Accidental Amanita mushroom poisoning has a mortality rate as high as 30% and data from an uncontrolled study suggests that the use of silymarin up to 48 hours after the ingestion is effective in preventing severe hepatotoxicity. In alcohol-induced liver disease, acute viral hepatitis, and chronic hepatitis, silymarin is thought to accelerate normalization of serum transaminase levels and improve subjective symptoms. One study with 170 cirrhotic patients showed improved survival in those treated with silymarin compared with placebo at the end of 2–6 years of therapy (4-year survival rates: 58% ± 9% vs. 39% ± 9%, respectively, P = .036).20Ferenci P. Dragosics B. Dittrich H. Frank H. Benda L. Lochs H. Meryn S. Base W. Schneider B. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.J Hepatol. 1989; 9: 105-113Abstract Full Text PDF PubMed Scopus (424) Google Scholar A subgroup analysis revealed that patients with alcohol-induced cirrhosis and those initially rated as Child A were more likely to benefit from the active treatment. However, such survival benefit was not confirmed in a larger trial involving 200 patients with alcohol-induced cirrhosis.21Pares A. Planas R. Torres M. Caballeria J. Viver J.M. Acero D. Panes J. Rigau J. Santos J. Rodes J. Effects of silymarin in alcoholic patients with cirrhosis of the liver results of a controlled, double-blind, randomized and multicenter trial.J Hepatol. 1998; 28: 615-621Abstract Full Text PDF PubMed Scopus (273) Google Scholar Of these 200 patients, only 125 completed 2 years of therapy, and survival was similar in both placebo- and silymarin-treated arms. Table 1 summarizes all placebo-controlled trials published in the English literature. Results are difficult to interpret and/or compare owing to different methodologies, small sample sizes, and ill-defined end points. To date, results are controversial and we cannot state that silymarin adds any reliable clinical benefit, except perhaps in Amanita intoxication.Table 1Controlled Studies (Silymarin vs Placebo) in the English LiteratureStudyStudy characteristicsStudy population and preparationOutcome measureResultsNotesSalmi and Sarna79Salmi H.A. Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study.Scand J Gastroenterol. 1982; 17: 517-521Crossref PubMed Scopus (156) Google ScholarRCT, DB, 4 weeks, 106 patientsAny patient with abnormal serum transaminase levels for at least 1 month despite abstinenceSerum liver biochemistriesAST ↓ by 30% in silymarin-treated and ↑ by 5% in controls (P < .001)Great variability of individual values before and after treatmentALT ↓ by 40% in silymarin-treated and ↑ by 3% in controls (P < .001)Patients were mostly alcoholics, abstinence was not closely monitoredSilymarin 420 mg/day or placeboNo difference in ALP, bilirubin, albumin, or gamma-globulin levelsPatients with various liver diseasesShort follow-up periodFerenci et al,20Ferenci P. Dragosics B. Dittrich H. Frank H. Benda L. Lochs H. Meryn S. Base W. Schneider B. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.J Hepatol. 1989; 9: 105-113Abstract Full Text PDF PubMed Scopus (424) Google Scholar 1989RCT, DB, Mean duration of 41 months, 170 patientsCirrhotic patients (92 alcohol-induced cirrhosis and 78 not related to alcohol)Survival4-year survival 58% ± 9% in silymarin-treated patients, compared with 39% ± 9% in the placebo group, P = .03670% of study patients had biopsy examination–proven cirrhosisPatients in the placebo group were slightly sicker (greater number of Child C patients)Silymarin 420 mg/day or placeboSubgroup analysis showed benefit for patients with alcohol-induced cirrhosis and those initially rated as Child AAbstinence was not closely monitoredHigh drop-out rateNo side effectsPares et al,21Pares A. Planas R. Torres M. Caballeria J. Viver J.M. Acero D. Panes J. Rigau J. Santos J. Rodes J. Effects of silymarin in alcoholic patients with cirrhosis of the liver results of a controlled, double-blind, randomized and multicenter trial.J Hepatol. 1998; 28: 615-621Abstract Full Text PDF PubMed Scopus (273) Google Scholar 1998RCT, DB, MC 2-year duration, 200 patientsAlcohol-induced cirrhosisSurvivalNo difference between groupsBetter patient selectionNo side effectsMulticentricSilymarin 450 mg/day or placeboAbstinence was closely monitoredHigh drop-out rateLucena et al,80Lucena M.I. Andrade R.J. de la Cruz J.P. Rodriguez-Mendizabal M. Blanco E. Sanchez de la Cuesta F. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study.Int J Clin Pharmacol Ther. 2002; 40: 2-8Crossref PubMed Scopus (91) Google Scholar 2002RCT, DB, 6 months, 60 patientsAlcohol-induced cirrhosisEffects on oxidative stress↑ glutathione and ↓ lipid peroxidation and PIIINP in the treated groupDespite apparent decrease in the oxidative stress level, serum liver biochemistry tests did not differ between groupsSilymarin 450 mg/day or placebo11 patients dropped outRCT, randomized controlled trial; DB, double blind; AST, aspartate transaminase; ↓, decreased; ↑, increased; ALT, alanine transaminase; ALP, alkaline phosphatase; MC, multicenter; PIIINP, amino-terminal propeptide of procollagen type III. Open table in a new tab RCT, randomized controlled trial; DB, double blind; AST, aspartate transaminase; ↓, decreased; ↑, increased; ALT, alanine transaminase; ALP, alkaline phosphatase; MC, multicenter; PIIINP, amino-terminal propeptide of procollagen type III. Silymarin (420 mg/day) was evaluated in an open-label pilot study in patients with primary biliary cirrhosis who had had incomplete response to ursodeoxycholic acid.22Angulo P. Patel T. Jorgensen R.A. Therneau T.M. Lindor K.D. Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.Hepatology. 2000; 32: 897-900Crossref PubMed Scopus (78) Google Scholar Despite promising results seen in animal studies, no additional benefits could be shown after 1 year of therapy regarding serum liver biochemistries or the Mayo risk score in these patients. Silymarin usually is well tolerated, but a severe adverse reaction consisting of intermittent episodes of abdominal pain, nausea, vomiting, diarrhea, weakness, and collapse have been described in association with its use in a patient who also had been taking amitriptyline and ethinylestradiol.23Adverse Drug Reactions Advisory CommitteeAn adverse reaction to the herbal medication milk thistle (Silybum marianum).Med J Aust. 1999; 170: 218-219PubMed Google Scholar Glycyrrhiza glabra (licorice root) originates from the Mediterranean and Middle East and has been cultivated in Europe since the 16th century. The roots, collected in the fall, are used to prepare an aqueous extract known for its antiallergic, antiviral, and detoxifying effects. It is said to be effective in the treatment of bronchitis, pharyngitis, malaria, peptic ulcers, abdominal pain, hepatitis, and other infections. The active constituent of Glycyrrhiza is glycyrrhizin, which is a conjugate of glucuronic acid and glycyrrhetinic acid. Other components include flavonoids, isoflavonoids, coumarins, triterpenoids, and phytosterols. Glycyrrhizin is metabolized in the liver into 3-mono-glucuronide-glycyrrhetinic acid, which is excreted in bile and further metabolized by intestinal bacteria into glycyrrhetinic acid. This metabolite can be reabsorbed. The pharmacokinetic characteristics of intravenous administration of glycyrrhizin has been studied in Japan and Europe in patients with liver disease, and comparable results have been found.24van Rossum T.G. Vulto A.G. Hop W.C. Schalm S.W. Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection.Clin Ther. 1999; 21: 2080-2090Abstract Full Text PDF PubMed Scopus (48) Google Scholar The drug has linear pharmacokinetics up to 200 mg, and steady state is achieved after 2 weeks of 200-mg doses administered 6 times per week. The hepatoprotective effect of glycyrrhizin has been attributed to its anti–lipid peroxidation, antioxidant, anti-inflammatory, and immunosuppressive properties.25Yoshikawa M. Matsui Y. Kawamoto H. Umemoto N. Oku K. Koizumi M. Yamao J. Kuriyama S. Nakano H. Hozumi N. Ishizaka S. Fukui H. Effects of glycyrrhizin on immune-mediated cytotoxicity.J Gastroenterol Hepatol. 1997; 12: 243-248Crossref PubMed Scopus (59) Google Scholar, 26Shiki Y. Ishikawa Y. Shirai K. Saito Y. Yoshida S. Effect of glycyrrhizin on lysosomes labilization by phospholipase A2.Am J Chin Med. 1986; 14: 131-137Crossref PubMed Google Scholar, 27Shiki Y. Shirai K. Saito Y. Yoshida S. Mori Y. Wakashin M. Effect of glycyrrhizin on lysis of hepatocyte membranes induced by anti-liver cell membrane antibody.J Gastroenterol Hepatol. 1992; 7: 12-16Crossref PubMed Scopus (48) Google Scholar Animal studies have shown that it enhances hepatic glucuronidation and activates P450 phase I detoxification reactions, although perhaps requiring doses high enough that they would not be tolerated by humans without significant side effects. Through in vitro studies with human hepatoma cells, Crance et al28Crance J.M. Leveque F. Biziagos E. van Cuyck-Gandre H. Jouan A. Deloince R. Studies on mechanism of action of glycyrrhizin against hepatitis A virus replication in vitro.Antiviral Res. 1994; 23: 63-76Crossref PubMed Scopus (70) Google Scholar showed that glycyrrhizin inhibited penetration of hepatitis A virus likely by altering cell membrane fluidity. In addition, glycyrrhizin has been shown to decrease the release of aspartate transaminase by hepatocytes, possibly by inhibiting the activation of phospholipase A2, as well as by preventing changes in the hepatocyte membrane permeability. In that setting of prevention of release of transaminases, it has been suggested that glycyrrhetinic acid is a better hepatoprotective agent than glycyrrhizin.29van Rossum T.G. Vulto A.G. de Man R.A. Brouwer J.T. Schalm S.W. Review article glycyrrhizin as a potential treatment for chronic hepatitis C.Aliment Pharmacol Ther. 1998; 12: 199-205Crossref PubMed Scopus (250) Google Scholar In mice, glycyrrhizin can induce production of endogenous interferon.30Abe N. Ebina T. Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice.Microbiol Immunol. 1982; 26: 535-539PubMed Google Scholar Glycyrrhizin may inhibit tumor necrosis factor-α–mediated cytotoxicity,25Yoshikawa M. Matsui Y. Kawamoto H. Umemoto N. Oku K. Koizumi M. Yamao J. Kuriyama S. Nakano H. Hozumi N. Ishizaka S. Fukui H. Effects of glycyrrhizin on immune-mediated cytotoxicity.J Gastroenterol Hepatol. 1997; 12: 243-248Crossref PubMed Scopus (59) Google Scholar and it is well known that serum levels of tumor necrosis factor-α and its intrahepatic receptors are increased in patients with chronic hepatitis.31Yoshioka K. Kakumu S. Arao M. Tsutsumi Y. Inoue M. Tumor necrosis factor alpha production by peripheral blood mononuclear cells of patients with chronic liver disease.Hepatology. 1989; 10: 769-773Crossref PubMed Scopus (121) Google Scholar, 32Marinos G. Naoumov N.V. Rossol S. Torre F. Wong P.Y. Gallati H. Portmann B. Williams R. Tumor necrosis factor receptors in patients with chronic hepatitis B virus infection.Gastroenterology. 1995; 108: 1453-1463Abstract Full Text PDF PubMed Scopus (116) Google Scholar Also, adding to its immunomodulating properties, glycyrrhizin was found to suppress hepatitis B surface antigen production without increasing cytotoxicity.33Takahara T. Watanabe A. Shiraki K. Effects of glycyrrhizin on hepatitis B surface antigen a biochemical and morphological study.J Hepatol. 1994; 21: 601-609Abstract Full Text PDF PubMed Scopus (80) Google Scholar The active metabolite glycyrrhetinic acid inhibits 11-β hydroxysteroid dehydrogenase, which probably accounts for its pseudoaldosterone effect,34Stewart P.M. Wallace A.M. Valentino R. Burt D. Shackleton C.H. Edwards C.R. Mineralocorticoid activity of liquorice 11-beta-hydroxysteroid dehydrogenase deficiency comes of age.Lancet. 1987; 2: 821-824Abstract PubMed Scopus (689) Google Scholar as is discussed later in this review. Clinical trials using glycyrrhizin for hepatitis C published in the English literature are summarized in Table 2. Overall, glycyrrhizin has been shown to decrease the serum transaminase levels in patients with chronic hepatitis. This, coupled with the information that patients with decreased levels of transaminases have less chance of developing hepatocellular carcinoma, has led to the hope that glycyrrhizin could be a reasonable therapy for patients refractory to, or intolerant to, interferon treatment.35Arase Y. Ikeda K. Murashima N. Chayama K. Tsubota A. Koida I. Suzuki Y. Saitoh S. Kobayashi M. Kumada H. The long term efficacy of glycyrrhizin in chronic hepatitis C patients.Cancer. 1997; 79: 1494-1500Crossref PubMed Scopus (385) Google Scholar, 36Tarao K. Rino Y. Ohkawa S. Shimizu A. Tamai S. Miyakawa K. Aoki H. Imada T. Shindo K. Okamoto N. Totsuka S. Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis.Cancer. 1999; 86: 589-595Crossref PubMed Scopus (151) Google ScholarTable 2Clinical Trials on Hepatitis C Using GlycyrrhizinStudyStudy characteristicsStudy population and preparationOutcome measuredResultsNotesSuzuki et al,81Suzuki H. Ohta Y. Takino T. Fujisawa K. Hirayama C. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis.Asian Med J. 1983; 26: 423-438Google Scholar 1983RCT, DB, MCChronic active hepatitis, diagnosed histologicallyBiochemical responseAST ↓ by 44% in GL group vs. 2% in placebo group (P < .001)Trial did not assess long term effects1-month duration133 patientsIt is not clear that patients enrolled had hepatitis CALT ↓ by 42% in GL group vs. 2% in placebo group (P < .001)Daily intravenous injections of 80 mg SNMCALT ↓ by 42% in GL group vs. 2% in placebo group (P < .001)Short follow-up periodGGT only improved by 4th wkNo significant side effectsArase et al,35Arase Y. Ikeda K. Murashima N. Chayama K. Tsubota A. Koida I. Suzuki Y. Saitoh S. Kobayashi M. Kumada H. The long term efficacy of glycyrrhizin in chronic hepatitis C patients.Cancer. 1997; 79: 1494-1500Crossref PubMed Scopus (385) Google Scholar 1997RetrospectiveChronic hepatitis CRate of development of HCC10th year rates of HCC: 7% for GL-treated and 12% for untreated patientsRetrospective, limited information on duration of disease, demographics, viral loads, and follow-up results of liver biopsy examination; highly variable doses of GL, unknown standardization of preparation2–16 years of follow-up evaluation200-mg dose, 2–7 days/wk84 treated with GL and 109 untreated15th year rates of HCC: 12% for GL-treated and 25% for untreated patientsOverall rate of HCC was significantly lower in treated patients (P = .032)Lower incidence of HCC in patients with histologic stages 2 or 3 who received SNMC and among those who normalized their ALT levelsALT level normalized in 36% of treated and 6.4% of untreated patients (P < .0001)Tsubota et al,82Tsubota A. Kumada H. Arase Y. Chayama K. Saitoh S. Ikeda K. Kobayashi M. Suzuki Y. Murashima N. Combined ursodeoxycholic acid and glycyrrhizin therapy for chronic hepatitis C virus infection a randomized controlled trial in 170 patients.Eur J Gastroenterol Hepatol. 1999; 11: 1077-1083Crossref PubMed Scopus (53) Google Scholar 1999RCT, DBChronic hepatitis C (must not have had interferon therapy in the previous year)Biochemical responseMean percentage decrease in AST: 23.4% (UDCA + GL) and 8.8% (GL) (P = .025)No placebo arm. This study did not assess efficacy of glycyrrhizin Clinical relevance unclear24-weeks duration170 patientsMean percentage decrease