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Complementary and Alternative Medicine in Hepatology: Review of the Evidence of Efficacy

2007; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês

10.1016/j.cgh.2006.10.014

1542-7714

Sumita Verma, Paul J. Thuluvath,

Pharmacological Effects of Natural Compounds

There is an increase in the use of complementary and alternative medicine (CAM), especially herbal therapy, among patients with liver disease. The most commonly used herbal agent is silymarin. In animal models, many of the commonly used agents have shown anti-inflammatory and antifibrotic effects. Although many human studies have shown improvements in subjective symptoms (well being) and liver biochemistry, there are no convincing data to suggest a definite histologic and/or virologic improvement with most of these agents. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature. Hepatotoxicity and drug interactions are common with many herbal medications, and therefore physicians need to be cognizant of known or occult use of CAM by their patients. Only well-designed, randomized, controlled trials will be able to ascertain whether CAM has any role in the management of patients with acute or chronic liver diseases. Until such time, the use of CAM cannot be recommended as a therapy for patients with liver disease. There is an increase in the use of complementary and alternative medicine (CAM), especially herbal therapy, among patients with liver disease. The most commonly used herbal agent is silymarin. In animal models, many of the commonly used agents have shown anti-inflammatory and antifibrotic effects. Although many human studies have shown improvements in subjective symptoms (well being) and liver biochemistry, there are no convincing data to suggest a definite histologic and/or virologic improvement with most of these agents. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature. Hepatotoxicity and drug interactions are common with many herbal medications, and therefore physicians need to be cognizant of known or occult use of CAM by their patients. Only well-designed, randomized, controlled trials will be able to ascertain whether CAM has any role in the management of patients with acute or chronic liver diseases. Until such time, the use of CAM cannot be recommended as a therapy for patients with liver disease. Chronic liver disease is an important cause of morbidity and mortality throughout the world. Conventional medical therapies for many common liver disorders, including nonalcoholic fatty liver disease and viral hepatitis, have limited efficacy and potentially life-threatening side effects. This has lead to increased dependence on complementary and alternative medicine (CAM), especially herbal therapy. In fact, the use of herbal medicine can be traced back as far as 2100 BC in ancient China (Xia dynasty) and India (Vedic period).1Schuppan D. Jia J.D. Brinkhaus B. et al.Herbal products for liver disease: a therapeutic challenge for the new millennium.Hepatology. 1999; 30: 1099-1103Crossref PubMed Scopus (235) Google Scholar Despite their unproven therapeutic potential, natural remedies represent a $180 billion market in the United States. Americans spend more than $6 billion annually on nutritional supplements, and $1 billion on herbs and teas alone. A single herb preparation, silymarin (used almost exclusively for liver disorders), accounts for $180 million in Europe (predominantly in Germany).2Breevort P. The U.S. botanical market—an overview.Herbalgramm. 1996; 36: 49-57Google Scholar The increasing use of CAM by the American public has been documented by many surveys (Table 1).3Eisenberg D.M. Kessler R.C. Foster C. Unconventional medicine in the United States.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (3603) Google Scholar, 4Eisenberg D.M. Davis R.B. Ettner S.L. et al.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, 5Flora K.D. Rosen H.R. Benner K.G. The use of naturopathic remedies for chronic liver disease (letter).Am J Gastroenterol. 1996; 91: 2654-2655PubMed Google Scholar, 6Berk B.S. Chaya C. Benner K.G. et al.Comparison of herbal remedies for liver disease: 1996 versus 1999 (abstr).Hepatology. 1999; : A478Google Scholar, 7Peyton B.G. Spears T.L. Lindsey A. et al.A survey of the use of herbal medicine in patients with hepatitis C (abstr).Hepatology. 1999; 30: A123Google Scholar, 8Strader D.B. Bacon B.R. Lindsay K.L. et al.Use of complementary and alternative medicine in patients with liver disease.Am J Gastroenterol. 2002; 97: 2391-2397Crossref PubMed Google Scholar, 9Detkova Z. Lefebvre A. Bastide C. et al.Herbal medicines consumption for chronic liver disease and functional intestinal disorders (abstr).Gastroenterology. 2001; 120: A228Google Scholar, 10Russo M.W. Esposito S. Brown Jr, R.S. et al.Complementary-alternative medicine (CAM) use amongst patients with chronic hepatitis C infection (HCV) (abstr).Gastroenterology. 2001; 120: A409Google Scholar These surveys further illustrate that the use of CAM is independent of the cause or severity of liver disease, is more common in women, and in those with higher incomes or a college education.8Strader D.B. Bacon B.R. Lindsay K.L. et al.Use of complementary and alternative medicine in patients with liver disease.Am J Gastroenterol. 2002; 97: 2391-2397Crossref PubMed Google Scholar, 9Detkova Z. Lefebvre A. Bastide C. et al.Herbal medicines consumption for chronic liver disease and functional intestinal disorders (abstr).Gastroenterology. 2001; 120: A228Google Scholar Furthermore, 31%–40% of the respondents admitted that they do not disclose the use of CAM to their physicians.3Eisenberg D.M. Kessler R.C. Foster C. Unconventional medicine in the United States.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (3603) Google Scholar, 4Eisenberg D.M. Davis R.B. Ettner S.L. et al.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, 7Peyton B.G. Spears T.L. Lindsey A. et al.A survey of the use of herbal medicine in patients with hepatitis C (abstr).Hepatology. 1999; 30: A123Google Scholar The National Center for Complementary and Alternative Medicine was therefore established by Congress in 1998. It is part of the National Institutes of Health and receives its funding from Congress. Its aim is to provide the public with a reliable assessment of safety and efficacy of CAM and to help integrate proven CAM into conventional medical care.11Marwick C. Medical news and perspectives: alterations are ahead at the OAM.JAMA. 1998; 280: 1553-1554Crossref PubMed Scopus (30) Google Scholar An additional goal of the National Center for Complementary and Alternative Medicine is to provide research grants specifically directed toward CAM. Ongoing studies include assessing the efficacy of broccoli sprout tea in preventing liver cancer. Other National Institutes of Health–funded studies include the use of silymarin in those with human immunodeficiency virus and hepatitis C virus (HCV) co-infection.Table 1Surveys Assessing the Prevalence of CAM Use by Patients With Liver DiseaseSurveyYearNo.Patients using CAMEisenberg et al3Eisenberg D.M. Kessler R.C. Foster C. Unconventional medicine in the United States.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (3603) Google Scholar1990153934%Eisenberg et al4Eisenberg D.M. Davis R.B. Ettner S.L. et al.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 Scholar19972055 (general patients)Increased to 42%; use of herbal supplements increased from 2.5% to 12%Flora et al5Flora K.D. Rosen H.R. Benner K.G. The use of naturopathic remedies for chronic liver disease (letter).Am J Gastroenterol. 1996; 91: 2654-2655PubMed Google Scholar1996103 with liver disease31%, most common being silymarin; median expense per month per patient $10–$30Flora et al6Berk B.S. Chaya C. Benner K.G. et al.Comparison of herbal remedies for liver disease: 1996 versus 1999 (abstr).Hepatology. 1999; : A478Google Scholar1999175 with liver diseaseIncrease to 42%, silymarin still most commonPeyton et al7Peyton B.G. Spears T.L. Lindsey A. et al.A survey of the use of herbal medicine in patients with hepatitis C (abstr).Hepatology. 1999; 30: A123Google Scholar1999117 with HCV36%, silymarin most commonStrader et al8Strader D.B. Bacon B.R. Lindsay K.L. et al.Use of complementary and alternative medicine in patients with liver disease.Am J Gastroenterol. 2002; 97: 2391-2397Crossref PubMed Google Scholar1999809 with liver disease41% in preceding month, most common silymarin in 12%Detkova et al9Detkova Z. Lefebvre A. Bastide C. et al.Herbal medicines consumption for chronic liver disease and functional intestinal disorders (abstr).Gastroenterology. 2001; 120: A228Google Scholar2001365 with liver disease30% using herbal medication, of whom majority (60%) were womenRusso et al10Russo M.W. Esposito S. Brown Jr, R.S. et al.Complementary-alternative medicine (CAM) use amongst patients with chronic hepatitis C infection (HCV) (abstr).Gastroenterology. 2001; 120: A409Google Scholar2001207 with HCV62%, of whom 50% were taking silymarin, 20% green tea Open table in a new tab There are many reasons for the increasing dependence on CAM throughout the world including the relative failure or limitations of conventional therapies for conditions such as HCV, hepatitis B (HBV), nonalcoholic fatty liver disease, and hepatocellular cancer (HCC); the perception that CAM is natural and therefore a safer form of therapy; and the relative cost factor. A critical review of herbal products is always a challenge for those practicing conventional medicine because randomized controlled trials (RCTs) using structurally defined and standardized preparations with well-defined end points are the basis for safe and effective prescribing. In contrast, CAM, especially herbal preparations, often are concoctions of various extracts, many of which are unidentified. In addition, the efficacy of most of these remedies has not been tested by RCTs, but rather by uncontrolled studies using subjective (eg, a feeling of well being) symptoms instead of objective (liver histology, sustained viral clearance, or survival) end points. Despite these limitations, in this review we attempt to provide a critical overview of CAM in patients with liver disease (Figure 1). Because numerous forms of CAM are available, this review focuses on the most commonly used therapies or those associated with hepatotoxicity. Milk thistle, an extract of Silybum marianum, is a member of the aster family.12Greive M. A modern herbal. Volume 2. Dover Publications, New York1981Google Scholar The active component of silymarin includes 4 flavonoids, the major one being silibinin (also known as silybin). The latter constitutes 80%–90% of the herb, but the remainder is chemically undefined.13Simanek V. Kren V. Ulrichova J. Silymarin: what is in the name … ? An appeal for change in editorial policy (letter).Hepatology. 2000; 32: 442-443Crossref PubMed Scopus (14) Google Scholar, 14Monograph Silybum marianum (milk thistle).Altern Med Rev. 1999; 4: 272-274PubMed Google Scholar, 15Flora K. Hahn M. Rosen H. et al.Milk thistle for the therapy of liver disease.Am J Gastroenterol. 1998; 93: 139-143Crossref PubMed Scopus (648) Google Scholar Pharmacokinetic studies have shown that there is rapid absorption of silibinin after an oral dose, with a half-life of 6 hours.16Lorenz D. Lucker P.W. Mennicke W.H. et al.Meth find exp.Clin Pharmacol. 1984; 6: 655Google Scholar, 17Barzaghi N. Crema F. Gatti G. et al.Pharmokinetic studies in IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects.Eur J Drug Metab Pharmacokinet. 1990; 15: 333-338Crossref PubMed Scopus (184) Google Scholar, 18Flory P.J. Krug G. Lorenz D. et al.Studies on elimination of silymarin in cholecystectomized patients. I. Biliary and renal elimination after a single oral dose.Planta Med. 1980; 38: 227Crossref PubMed Scopus (27) Google Scholar Experimental evidence in animal models has suggested that silymarin has antioxidant properties, and prevents glutathione depletion19Rauen U. Reuters I. Fuchs A. et al.Oxygen-free radical-mediated injury to cultured rat hepatocytes during cold incubation in preservation solutions.Hepatology. 1997; 26: 351-357Crossref PubMed Scopus (52) Google Scholar, 20Campos R. Gurrido A. Guerra R. et al.Silibinin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen in rat liver.Planta Med. 1989; 55: 417-419Crossref PubMed Scopus (152) Google Scholar, 21Pietrangelo A. Borella F. Casalgrandi G. et al.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 and liver injury induced by Amanita phalloides,22Hruby K. Csomos G. Fuhrmann M. et al.Chemotherapy of Amanita phalloides poisoning with intravenous silibinin.Hum Toxicol. 1983; 2: 138-195Crossref Scopus (107) Google Scholar, 23Reichert R. Phytotherapeutic alternatives for chronic active hepatitis.Q Rev Nat Med. 1997; summer: 103-108Google Scholar carbon tetrachloride, and paracetamol.24Mira 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 Silymarin also is thought to be antifibrotic.25Fuchs E.C. Weyhenmeyer R. Meiner O.H. Effects of silybinin and a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts.Arzneimittelforschung. 1997; 47: 1383-1387PubMed Google Scholar, 26Boigk G. Stroedter L. Herbst H. et al.Silymarin retards collagen accumulation in early and advanced bilary fibrosis secondary to complete bile duct obliteration in rats.Hepatology. 1987; 26: 643-649Crossref Scopus (254) Google Scholar, 27Jia J.D. Boigk G. Bauer M. et al.Silymarin downregulates TIMP-I and collagen I mRNA in rats with secondary biliary cirrhosis (abstr).Hepatology. 1998; 28: A546Google Scholar In vitro, silymarin blocks the proliferation of stellate cells and down-regulates transforming growth factor β.25Fuchs E.C. Weyhenmeyer R. Meiner O.H. Effects of silybinin and a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts.Arzneimittelforschung. 1997; 47: 1383-1387PubMed Google Scholar In rat models, oral silymarin reduced collagen accumulation in a dose-dependent fashion.26Boigk G. Stroedter L. Herbst H. et al.Silymarin retards collagen accumulation in early and advanced bilary fibrosis secondary to complete bile duct obliteration in rats.Hepatology. 1987; 26: 643-649Crossref Scopus (254) Google Scholar In addition, recent in vitro studies have suggested that silymarin may have anti-inflammatory properties by down-regulating the proinflammatory leukotriene B4 in Kupffer cells.28Dehmlow 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 Despite the experimental evidence, the efficacy of silymarin remains largely unproven because of the paucity of well-conducted clinical trials. Moreover, many studies are conducted in acute viral hepatitis in which spontaneous resolution is very common. In addition, the results of many trials are published in non-English journals that often are not indexed by Pubmed or Medline. Finally, pharmacokinetic studies using different preparations of silymarin have shown great variations in peak drug levels.29Seeff L.B. Lindsay K.L. Bacon B.R. et al.Complementary and alternative medicine in chronic liver disease.Hepatology. 2001; 34: 595-603Crossref PubMed Scopus (229) Google Scholar Despite these limitations, we have reviewed the use of silymarin in various liver disorders in detail because it is a commonly used preparation in the United States. In an early trial of silymarin in acute viral hepatitis, Cavalieri30Cavalieri S. Kontrollierte klinische Pruefung von Legalon.Gaz Med Ital. 1974; 133: 628Google Scholar reported a significantly shorter hospitalization (23 vs 30 days) and time to development of immunity to HBV in patients treated with silymarin compared with those with supportive care. Magliulo et al31Magliulo E. Gagliardi B. Fiori G.P. Zur wirkung von Silymarin bei der Behandlung der akuten Virushepatitis.Med Klin. 1978; 73: 1060-1065PubMed Google Scholar randomized 57 patients with acute viral hepatitis A or B to silymarin 70 mg 3 times daily for at least 3 weeks or placebo.32Bode J.C. Schmidt U. Durr H.K. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial.Med Klin. 1977; 72: 513-518PubMed Google Scholar Serum bilirubin and enzyme levels (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) were lower in the silymarin group compared with the placebo group at day 5 and at 3 weeks, with a significantly higher percentage of patients with normal bilirubin (40 vs 11) and enzyme levels (82 vs 52) in the treated group. However, the seroconversion rate in HBV-positive patients was not influenced by silymarin.31Magliulo E. Gagliardi B. Fiori G.P. Zur wirkung von Silymarin bei der Behandlung der akuten Virushepatitis.Med Klin. 1978; 73: 1060-1065PubMed Google Scholar In a subsequent controlled study (n = 151) in patients with acute viral hepatitis (cause not mentioned), Bode et al32Bode J.C. Schmidt U. Durr H.K. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial.Med Klin. 1977; 72: 513-518PubMed Google Scholar found no significant differences in liver tests or coagulation profile in the silymarin group compared with the placebo group. There are currently no available data on the use of silymarin for acute hepatitis C. Based on the current evidence, the use of silymarin for the treatment of acute viral hepatitis (A, B, or C) cannot be recommended. There have been no RCTs of silymarin in patients with chronic HBV. In chronic hepatitis C (CHC) infection there is anecdotal evidence to suggest that silymarin may decrease transaminase levels without any impact on HCV RNA levels.29Seeff L.B. Lindsay K.L. Bacon B.R. et al.Complementary and alternative medicine in chronic liver disease.Hepatology. 2001; 34: 595-603Crossref PubMed Scopus (229) Google Scholar, 33Berkson B.M. A conservative triple antioxidant approach to the treatment of hepatitis C Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories.Med Klin. 1999; 15: 84-89Crossref Google Scholar In a recent RCT from Egypt, 117 patients with chronic HCV infection were randomized to either silymarin or multivitamins. After 1 year of treatment, no differences in quality-of-life scores, serum transaminase levels, viral clearance rates, or noninvasive markers of hepatic fibrosis (hyaluronic acid and YKL-40) were observed.34Tanamly M.D. Tadros F. Labeeb S. et al.Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results.Dig Liver Dis. 2004; 36: 752-759Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Huber et al35Huber R. Futter I. Ludtke R. Oral silymarin for chronic hepatitis C—a retrospective analysis comparing three dose regimens.Eur J Med Res. 2005; 10: 68-70PubMed Google Scholar reported similar results. Despite the popularity of silymarin among lay public, based on published evidence, the routine use of silymarin cannot be justified in chronic HCV or HBV. A number of placebo-controlled trials have been conducted in alcoholic liver disease (ALD) (Table 2), but many of these studies are difficult to interpret because of patient heterogeneity and nonstratification by disease severity. In addition, most studies did not provide histologic follow-up data36Salmi H.A. Sarna S. Effect of silymarin on chemical functional and morphological alterations of the liver.Scand J Gastroenterol. 1982; 17: 517-521Crossref PubMed Scopus (156) Google Scholar, 37Ferenci P. Dragosics B. Dittrich H. et al.Randomised 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, 38Feher J. Deak G. Muzes G. et al.Liver-protective action of silymarin therapy in chronic alcoholic liver diseases.Orv Hetil. 1989; 130: 2723-2727PubMed Google Scholar, 39Pares A. Planas R. Torres M. et al.Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double blind randomised and multicentre trial.J Hepatol. 1998; 28: 615-621Abstract Full Text PDF PubMed Scopus (273) Google Scholar, 40Lucena M.I. Andrade R.J. de la Cruz J.P. et al.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 and alcohol abstinence rates using objective criteria.Table 2Clinical Trials With Silymarin in Alcohol-Related Liver DiseaseStudyNature of trialNo.Outcome measuresDosageResults in silymarin group vs controlsSalmi et al,36Salmi H.A. Sarna S. Effect of silymarin on chemical functional and morphological alterations of the liver.Scand J Gastroenterol. 1982; 17: 517-521Crossref PubMed Scopus (156) Google Scholar 1982; fatty liver/hepatitis (biopsy examination–proven)RCT, DB106Transaminase levels; BSP test; histologySilymarin 420 mg/day or placebo 4 wkAST 30% vs increased 5%; ALT level decreased 40% vs increased 3%No differences in bilirubin or albumin; % decrease of bromosulphophthalein higher in treated group; normalization of histology more often in silymarin groupFerenci et al,37Ferenci P. Dragosics B. Dittrich H. et al.Randomised 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 1989; 70% had biopsy examination–proven cirrhosisRCT, DB170Transaminase levels; survival420 mg/day 41 mo (median)2- and 4-year survival benefit in silymarin groupFeher et al,38Feher J. Deak G. Muzes G. et al.Liver-protective action of silymarin therapy in chronic alcoholic liver diseases.Orv Hetil. 1989; 130: 2723-2727PubMed Google Scholar 1989; chronic ALD (biopsy N/A)DB36Liver enzyme levels; procollagenN/ADecreased procollagen 111 and histologic improvement in silymarin groupPares et al,39Pares A. Planas R. Torres M. et al.Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double blind randomised and multicentre trial.J Hepatol. 1998; 28: 615-621Abstract Full Text PDF PubMed Scopus (273) Google Scholar 1998; cirrhosis (biopsy/laproscopy proven)RCT, DB200Survival; progression of liver failure450 mg/day or placebo 2 yNo survival benefit in silymarin groupLucena et al,40Lucena M.I. Andrade R.J. de la Cruz J.P. et al.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 2002; cirrhosisRCT, DB60Oxidative stress450 mg/day or placebo 6 moIncreased glutathione; decreased lipid peroxidation and procollagen III in silymarin groupDB, double blind. Open table in a new tab DB, double blind. In the largest trial,38Feher J. Deak G. Muzes G. et al.Liver-protective action of silymarin therapy in chronic alcoholic liver diseases.Orv Hetil. 1989; 130: 2723-2727PubMed Google Scholar 170 patients with cirrhosis (biopsy examination proven in 70%; 92 with ALD and 78 with other causes) were randomized to silymarin (420 mg/day; n = 87) or placebo (n = 83) for a period of 2–6 years (mean, 41 mo). Although the biochemical parameters did not change significantly, survival improved in the treated group (77% vs 67% at 2 y; 58% vs 39% at 4 y), especially in Child A patients. In contrast, Pares et al39Pares A. Planas R. Torres M. et al.Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double blind randomised and multicentre trial.J Hepatol. 1998; 28: 615-621Abstract Full Text PDF PubMed Scopus (273) Google Scholar reported a similar survival rate in the silymarin and placebo groups (17% vs 12% at 2 y; 19% vs 16% at 5 y), with about 75% of the deaths directly related to liver disease. Therefore, at present, there are no data to support the use of silymarin in ALD despite the safety of the drug. There has been only 1 study (n = 27) that addressed the impact of silymarin (420 mg) in patients with primary biliary cirrhosis with no biochemical response to ursodeoxycholic acid. After 1 year of follow-up evaluation no significant improvement was observed in the liver panel or the Mayo risk score.41Angulo P. Patel T. Jorgensen R.A. et al.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 However, this study was flawed by poor design, small sample size, and a short follow-up period. Silymarin has been shown to be hepatoprotective against a variety of drugs and toxins, both in animal and human studies.22Hruby K. Csomos G. Fuhrmann M. et al.Chemotherapy of Amanita phalloides poisoning with intravenous silibinin.Hum Toxicol. 1983; 2: 138-195Crossref Scopus (107) Google Scholar, 42Vogel G. Tuchweber B. Trost W. et al.Protection by silybinin against Amanita phalloides intoxication in beagles.Toxicol Appl Pharmacol. 1984; 73: 355-362Crossref PubMed Scopus (145) Google Scholar In a retrospective analysis of 205 patients with Amanita intoxication, a subgroup of 30 patients who had received intravenous silymarin were found to have lower mortality (12.8% vs 22.4%).43Floersheim G.L. Weber O. Tschumi P. et al.Poisoning by the death cap fungus (Amanita phalloides): prognostic factors and therapeutic measures.Schweiz Med Wochenschr. 1982; 112: 1164-1177PubMed Google Scholar In another uncontrolled study (n = 60), patients were treated with intravenous silymarin (20 mg/kg/day) within 24–36 hours after Amanita ingestion and all of them survived.44Hruby C. Silybinin in the treatment of deathcap fungus poisoning.Forum (Genova). 1984; 6: 23-26Google Scholar Other trials assessing the efficacy of silymarin against other toxins and drugs have involved a very small number of patients and the results were inconsistent.45Boari C. Baldi E. Rizzoli O. et al.Silymarin in the protection against exogenous noxae.Drugs Exp Clin Res. 1981; 7: 115-120Google Scholar, 46Szilard S. Szentgyorgyi D. Demeter I. Protective effect of Legalon in workers exposed to organic solvents.Acta Med Hung. 1988; 45: 249-256PubMed Google Scholar, 47Palasciano G. Portinacasa P. Palmieri V. et al.The effects of silymarin on plasma levels of malondialdehyde in patients receiving long-term treatment with psychotropic drugs.Curr Ther Res. 1994; 55: 537-545Abstract Full Text PDF Scopus (32) Google Scholar, 48Saba P. Galeone F. Salvadorini F. et al.Effetti terapeutici della silimarina nelle epatopatie croniche indotte da psicofarmaci.Gaz Med Ital. 1976; 135: 236-251Google Scholar There is compelling experimental evidence to recommend further studies with silymarin in chronic liver diseases including nonalcoholic fatty liver disease. However, these studies need to be well-designed RCTs, as was recommended by Rambaldi et al49Rambaldi A. Jacobs B.P. Iaquinto G. et al.Milk thistle for alcoholic and/or hepatitis B or C liver diseases—a systematic Cochrane hepato-biliary group review with meta-analyses of randomized clinical trials.Am J Gastroenterol. 2005; 100: 2583-2591Crossref PubMed Scopus (83) Google Scholar in a recent meta-analysis. Currently, there is insufficient evidence to justify the use of silymarin in acute or chronic liver diseases of any cause.