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      Subject: NATAP: Alternative Medicine-Efficacy Lacking & Hepatotoxicity


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

      Clinical Gastroenterology & Hepatology
      Sumita VermaâZ, Paul J. ThuluvathâZ
      published online 13 January 2007.
      Article in PressCorrected Proof

      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).1

      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).2 The increasing use of CAM by the American public has been documented by many surveys (Table 1).3, 4, 5, 6, 7, 8, 9, 10 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.8, 9 Furthermore, 31%-40% of the respondents admitted that they do not disclose the use of CAM to their physicians.3, 4, 7 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.11 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.

      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.

      Herbal Products With Well-Defined Chemical Formulations

      Milk Thistle (Silymarin)

      Milk thistle, an extract of Silybum marianum, is a member of the aster family.12 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.13, 14, 15 Pharmacokinetic studies have shown that there is rapid absorption of silibinin after an oral dose, with a half-life of 6 hours.16, 17, 18

      Experimental evidence in animal models has suggested that silymarin has antioxidant properties, and prevents glutathione depletion19, 20, 21 and liver injury induced by Amanita phalloides,22, 23 carbon tetrachloride, and paracetamol.24 Silymarin also is thought to be antifibrotic.25, 26, 27 In vitro, silymarin blocks the proliferation of stellate cells and down-regulates transforming growth factor _.25 In rat models, oral silymarin reduced collagen accumulation in a dose-dependent fashion.26 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.28

      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.29 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.

      Acute viral hepatitis
      In an early trial of silymarin in acute viral hepatitis, Cavalieri30 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 al31 randomized 57 patients with acute viral hepatitis A or B to silymarin 70 mg 3 times daily for at least 3 weeks or placebo.32 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.31 In a subsequent controlled study (n = 151) in patients with acute viral hepatitis (cause not mentioned), Bode et al32 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.

      Chronic viral hepatitis
      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.29, 33 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.34 Huber et al35 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.

      Alcoholic liver disease
      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 data36, 37, 38, 39, 40 and alcohol abstinence rates using objective criteria.

      In the largest trial,38 170 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 al39 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.

      Primary biliary cirrhosis
      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.41 However, this study was flawed by poor design, small sample size, and a short follow-up period.

      Toxic and drug-induced hepatitis
      Silymarin has been shown to be hepatoprotective against a variety of drugs and toxins, both in animal and human studies.22, 42 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%).43 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.44 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.45, 46, 47, 48

      Conclusions
      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 al49 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.

      Glycyrrhizin

      Glycyrrhizin is an aqueous extract of the licorice root Glycyrrhiza glabra that originated from the Mediterranean and Middle East and has been used for more than 20 years to treat a variety of disorders including cough, gastritis, and liver inflammation.50 The active component of G glabra is glycyrrhizin, which is a conjugate of glucoronic acid and glycyrrhetinic acid. Other components include flavonoids, isoflavonoids, coumarins, triterpenoids, and phytosterols.29, 50 In patients with liver disease, the drug has linear pharmacokinetics up to 200 mg.51 The active metabolite glycyrrhetinic acid inhibits 11-_ hydroxysteroid dehydrogenase, which probably accounts for its pseudoaldosterone effect.52 Glycyrrhizin is also a component of other herbal preparations including Kampo, TJ-9, and Herbal Medicine 861 (HM861).29 In Japan, a product referred to as Stronger Neo-Minophagen C (SNMC), containing glycyrrhizin, cysteine, and glycine, is used to treat a variety of liver diseases.29, 53

      In animal models glycyrrhizin has been shown to have antioxidant properties,54 and it has been shown to improve liver enzyme levels and attenuate liver fibrosis. The proposed mechanisms include its action on nuclear factor _ B,55 inhibition of tumor necrosis factor (TNF),56 induction of endogenous interferon production,57 and suppression of hepatitis B surface antigen (HBsAg) secretion.58

      Glycyrrhizin has been used to treat patients with chronic viral hepatitis.59, 60, 61, 62 Two studies59, 60 (n = 182) reported improvement in liver enzyme levels and histology, although the exact nature of the liver disease was not specified. In a recent study in chronic HBV patients, SNMC at 2 doses (40 and 100 mL for 4 weeks followed by oral glycyrrhizin for 4 more weeks) resulted in normalization of ALT levels in more than 50% in both groups, although details on HBV DNA levels were lacking.62

      SNMC also is being used increasingly in patients with CHC.63, 64, 65, 66, 67 Two studies with glycyrrhizin in 226 patients with CHC, although well designed, were disappointing because viral clearance was not achieved in any of the patients.64, 65 In the study by Tsubota et al65 (n = 170), the patients received either ursodeoxycholic acid plus intravenous glycyrrhizin (200 mg 3 times/wk) or glycyrrhizin alone, and those on combination therapy showed a better improvement (AST, 23% vs 9%; ALT, 33% vs 10%) and normalization (AST, 54% vs 22%; ALT, 32% vs 18%) of liver enzyme levels. In another large, retrospective, nonrandomized Japanese study with a 15-year follow-up period, Arase et al66 observed significantly lower (P = .03) prevalence of cirrhosis (21% vs 35%) and HCC (12% vs 25%) in those treated with SNMC. However, 10% developed hypokalemia and 3% developed hypertension. Furthermore, limited information was provided on viral loads and follow-up biopsy results, and variable doses of glycyrrhizin were used (200 mg 2-7 days/wk).

      These clinical trials showed that the beneficial effects of glycyrrhizin were largely biochemical (improvement in liver enzyme levels). Side effects (fluid retention, hypokalemia) were seen in up to 20%.50 Based on current evidence, the use of this drug cannot be recommended to patients with liver disease.

      TJ-9 (Xiao-Chai-Hutang/Sho-Saiko-To)

      TJ-9 is a Chinese herbal medicine that is used widely in Japan for the treatment of liver disorders and is part of the Japanese Kampo medical system. It is a dried decoction of 7 herbs (roots of scutellaria, glycyrrhiza, bupleurum, ginseng, pinella tuber, jujube fruit, and the thew ginger rhizome). Two major alkaloids from scutellaria, biacalin and biacalein, are strong inhibitors of lipid peroxidation.68, 69 Other in vitro actions include the inhibition of proliferation and induction of apoptosis in hepatoma cells.70 In animal models and stellate cell cultures, TJ-9 has been shown to inhibit stellate cell activation and decrease hepatic collagen levels, expression of _-smooth muscle actin, and type-1 collagen.69

      There have been only few human clinical trials using TJ-9.71, 72, 73, 74 Hirayama et al73 treated 116 patients with chronic hepatitis with active drug (5.4 g for 12 wk), and 106 with placebo (which also had 0.5 g of TJ-9) for 12 weeks, followed by a cross-over to TJ-9 for a further 12 weeks. The patients' liver functions improved significantly after administration of TJ-9, and in patients with chronic HBV infection a tendency toward a decrease of hepatitis B e antigen (HBeAg) and an increase of HBe antibodies was observed. More importantly, no adverse effects related to the herb were noted. Oka et al74 studied the chemoprotective effects and impact on survival of TJ-9 in a 5-year prospective randomized study involving 260 patients with cirrhosis (37 HBsAg-positive, 76 HCV-positive), of whom half received TJ-9 (7.5 g/day) plus conventional drugs and the remainder received conventional therapy only. The overall incidence of HCC was 25%, of which there were 23 (23%) in the treatment group and 33 (34%) in the control group (P = .07). However, the incidence of HCC in patients without HBsAg was significantly lower in the TJ-9 group vs the control group (22% vs 39%, P = .02). The 5-year survival rate also was higher for the TJ-9 group (P = .05), and again the difference was significant only in HBsAg-negative patients (P = .04).

      Side effects from TJ-9 are uncommon but include interstitial pneumonitis (especially when it is used in conjunction with interferon for treatment of chronic hepatitis),75, 76 and hepatotoxicity.77, 78, 79 The component of TJ-9 that causes hepatotoxicity is not identified to date. Until further data are available, it is better to avoid TJ-9 in patients with liver disease.

      Phyllanthus amarus

      P amarus is a herb that is a component of Indian ayurvedic medicine. P amarus has been used to treat diabetes, kidney and urinary problems, diarrhea, and viral hepatitis. In India this herb also is known as bahupatra. It contains phyllantins, hypophyllantins, and polyphenoles, which are known to have antiviral properties. In animal models it inhibits HBV DNA polymerase and suppresses viral release by inhibiting HBV enhancer 1 activity.80 In human hepatoma cells, P amarus suppressed HBsAg gene expression and HBsAg production, but did not inhibit HBeAg production.81 A nonrandomized clinical study showed HBsAg clearance in 59% of chronic carriers who were treated for 30 days compared with only 4% (1 of 23) given placebo.82 However, in a subsequent study, Leelarasamee et al83 were unable to reproduce the findings. Liu et al84 reviewed 22 randomized clinical trials that included more than 1900 patients. The analysis of pooled data suggested a beneficial effect of P amarus in clearing HBsAg when compared with no intervention or other herbal compounds. However, of the 22 trials, only 582, 83, 85, 86, 87 were considered to be of good quality and except for the original Indian study by Thyagajaran et al,82 the other 4 did not show a beneficial effect on HBV clearance. This was confirmed further by Chan et al88 who randomized patients with chronic hepatitis B (HBeAg positive) to receive P. urinaris (1, 2, 3 gms three times a day for 6 months) or placebo. On an intention-to-treat analysis there were no differences in end-of-treatment HBV DNA reduction, HBeAg seroconversion (0%, 9.1%, 8.3%, and 16.7%) and, or ALT normalization (0%, 0%, 8.3%, and 33.3%) among the placebo and Phyllanthus groups. Further studies are necessary before this herb is recommended for use in patients with viral hepatitis or chronic liver diseases.

      St. John's Wort

      Extracts of the herb Hypericum perforatum (St. John's wort) have been used for a long time for a range of indications including depressive disorders.89 It contains at least 10 pharmacologically active ingredients, the main one being the pholoroglucinol-derivative hyperforin. This derivative inhibits the synaptosomal uptake of 5-hydroxytryptamine, noradrenaline, dopamine, glutamate, and _-aminobutyric acid.90 In a recent survey by Russo et al10 of 207 consecutive HCV patients, 10% reported using St. John's wort, most probably because of its mood-elevating effect. There have been no RCTs of St. John's wort in patients with liver disease. However, a phase 1 study (n = 19) assessed the effects of hypericin (a natural derivative of H perforatum) in HCV infection. At the end of the 8-week treatment period, no subject had a change of plasma HCV RNA level of more than 1.0 log1091 and 11 developed phototoxic reactions.90 Other side effects included fatigue, serotonin syndrome,92 and inhibition of cytochrome P450 enzyme.93 The latter has resulted in serious drug interactions (including acute rejection) after solid organ transplantation.94, 95, 96 Because of the potential side effects and the absence of efficacy data, liver patients should be discouraged from using St. John's wort.


      Herbal Products With a Mixture of Herbs or Partially Known Ingredients

      This group includes a number of drugs that are used commonly with only partially known ingredients.

      Chinese Traditional Medicine
      Chinese traditional medicine has been practiced for approximately 2 millennia and is based on the homeostatic concept of the balance of yin and yang, 2 aspects that are in opposition and in unity, and their imbalance results in disease. It includes herbal therapy (HM861, CH-100), acupuncture, and moxibustion (dermal counter irritation therapy). Chinese herbal therapy comprises more than 100,000 recorded treatments, with roughly 80% being combination or herbal mixtures. Most mixtures contain 4-5 herbs with 1-2 major active compounds (king herbs).29 The following herbal mixtures have been used in chronic liver diseases.

      Plantago asiatic
      The seeds of this herb contain the active component aucubin, which inhibits HBV replication in animal models.97 In human trials it led to a 10%-40% decrease in HBV DNA, but levels returned to pretreatment levels after stopping therapy.98

      Herbal Medicine 861
      The Chinese compound HM861 is an aqueous extract of 10 herbs, the chief ones being Saliva miltiorrhiza, Astragalus membranaceous, and Spatholobus suberectus.99 In animal models, HM861 down-regulates the messenger RNA for transforming growth factor _1 and types I, III, and IV collagen.100 It also inhibits proliferation and induces apoptosis of stellate cells both in vitro and in vivo in patients with chronic hepatitis.101 Two clinical trials with HM861 in patients with chronic HBV infection indicated that it decreased hepatic inflammation and fibrosis.29 These trials were originally published in Chinese but a recent review has been published in English by the principal investigator.102 Minimal information was provided on HBV DNA levels, hepatic inflammatory scores, or the use of alcohol. Despite the claims of antifibrotic effects, better-designed clinical trials are necessary before its use in patients with chronic liver disease.

      CH-100
      CH-100 is a Chinese herb formulation consisting of 19 different herbs and it has been used for the treatment of CHC.103, 104, 105, 106 Its production is now standardized and the quality and quantity of each ingredient is known.50 In animal models of alcohol-induced hepatitis, CH-100 decreases TNF-_ production by CD4+ T cells.103 Two double-blind RCTs in patients with CHC infection have reported improvements in serum transaminase levels, although viral clearance was not achieved.104, 105 The National Center for Complementary and Alternative Medicine is currently supporting a study of a 10-herb combination (3AR) in patients with chronic HCV who do not qualify for interferon-based therapy. The aim will be to assess symptoms such as fatigue, quality of life, and HCV RNA levels.29

      Liv 52
      Liv 52 is an Indian ayurvedic drug that has been marketed specifically for the treatment of liver diseases. It is a herbal formulation that comprises Capparis spinosa (capers), Cichorium intybus (wild chicory), Terminalia arjuna (arjuna), Solanum nigrum (black nightshade), Achillea millefolium (yarrow), and Tamarix gallica (tatarisk).27 It has been shown to protect rats from carbon tetrachloride- and alcohol-induced toxic damage,106, 107, 108 and improve liver functions of patients with acute viral hepatitis.109 In an RCT (n = 188) in biopsy-proven alcoholic hepatitis, patients received either 1200 mg of Liv 52 or placebo. The cumulative survival was 74% in the treated group vs 86% in the placebo group (P = .06), with survival being the worst in those with Child C disease (53% vs 81%). Twenty-two of the 23 deaths in the treated group vs 3 of 11 in the control group were related to liver failure or bleeding complications.110 The results of this study resulted in the immediate withdrawal of the drug from the US market.

      Antioxidants, Immune Modulators, and Dietary Supplements
      Immune dysfunction is a characteristic feature of many forms of chronic liver disease. In ALD there is overproduction of proinflammatory cytokines such as TNF by peripheral blood monocytes and hepatic Kupffer cells.111 Antioxidants such as vitamin E and glutathione prodrugs (N-acetyl cysteine and procysteine) inhibit this cytokine production. Intravenous procysteine administered to patients with stable cirrhosis resulted in increased blood glutathione levels and decreased monocyte production of TNF, interleukin 8, and interleukin 6.112 Polyphenols derived from green tea also may have an immune-modulating role.113 Finally, dietary supplements such as S-adenosyl-methionine (SAMe) have been shown to protect against TNF hepatotoxicity in vitro and in animal models of liver injury. Patients with ALD may have decreased SAMe levels, which may predispose to mitochondrial glutathione depletion and dysfunction.29 In a double-blind RCT of SAMe (1.2 g/day orally for 2 years) in 123 patients with alcoholic cirrhosis, the overall mortality liver transplantation was 30% in the placebo group and 16% in the SAMe group (P = .08). When patients with more advanced cirrhosis (Child class C) were excluded from the analysis, the overall mortality liver transplantation was significantly greater in the placebo group (29% vs 12%; P = .02).114 However, a subsequent Cochrane database systematic review, including the earlier-described study, found no significant benefits with SAMe on all-cause or liver-related mortality.115 This underscores the need for more, high-quality RCTs of SAMe in ALD.

      Homeopathy
      The other main form of CAM besides herbal therapy is homeopathic medicine, which dates back to approximately 200 years ago and was discovered by the German doctor Samuel Hahnemann. In the past decade US sales of homeopathic remedies has exploded, increasing from $170 million in 1995 to $400 million in 1999.116 A recent survey of hepatitis C patients in the United States revealed that 4% were using homeopathic drugs.10 No RCTs using homeopathic drugs in liver disease have been performed to date.

      Acupuncture
      Acupuncture is a treatment based on Chinese traditional medicine. A recent survey by Russo et al10 of 207 patients with HCV infection revealed that 9% were using acupuncture as an alternative form of therapy. Chen et al117 studied the effects of acupuncture on 60 patients with chronic HBV infection and commented on the negative turnover rates of HBsAg and HBeAg, and the positive turnover rates of anti-HBe. Li et al118 found acupuncture a useful adjunctive therapy for relieving postoperative pain in patients with liver cancer. However, currently this form of therapy cannot be recommended. Additional concerns include the increased risk of hepatitis B and C transmission.119, 120

      Hepatotoxicity of Herbal Products

      A survey of the National Poison Information Service for the years 1991-1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs, among which hepatotoxicity was the most frequent.121 In another study, 1500 consecutive patients taking Chinese herbal drugs were evaluated for a greater than 2-fold ALT increase, and the incidence was found to be 1%.122

      Hepatotoxicity from herbal products is difficult to diagnose and is underreported because many patients do not inform their physicians about their use. It is therefore mandatory that all physicians question their patients about the use of CAM in a nonthreatening and nonbiased manner. Table 3 highlights the various forms of liver injury induced by herbal agents. Veno-occlusive disease is a well-known side effect of pyrrolizidine alkaloids such as senecio, heliotropium, crotalaria, and symphytum (comfrey).126 Germander also causes severe hepatotoxicity and has been banned in some European countries.127 Many Chinese herbs are hepatotoxic and have been known to cause acute liver failure.128 Along with hepatotoxicity, clinicians also need to be aware of potential interactions between herbal products and conventional drugs.94, 95, 96, 129

      Because of the Dietary Supplement Health and Education Act, passed in 1994, herbal products are not well regulated by the Food and Drug Administration (FDA). There is also no equivalent to postmarketing surveys for herbs. MEDwatch is an FDA-sponsored program available for physicians to report adverse events associated with FDA-monitored products including special nutritional supplements (telephone: 1-800-FDA-1088). Patients can make similar reports through the FDA office of Consumer Affairs (1-800-532-4400). Finally, although the Centers for Disease Control investigates hepatotoxicity attributed to CAM, many such cases remain unreported.29 In 1999, the National Institutes of Health held a workshop on CAM for liver diseases to increase awareness among the public and the medical profession, and also to improve quality control and research in this area.29
      Conclusions

      There is an increase in the reported use of CAM by patients with liver disease, with a similar proportion failing to disclose this to their physicians. Physicians who manage liver disease need to have a better understanding of CAM, its potential benefits, its side effects, and various drug interactions. There is experimental evidence to suggest that many of the commonly used CAM products have anti-inflammatory, antifibrotic, anti-oxidant, and immune-modulatory effects. However, there have been only a few RCTs using herbal products and these trials have reported little or no impact on important outcome measures (viral clearance, histology, and survival) despite some improvements in liver enzyme levels and subjective measures. The lack of standardized formulations and uncertainty about active ingredient(s) are additional problems that make it difficult to interpret the published studies. In addition, hepatotoxicity remains a serious side effect of some of the herbal therapies. Therefore, despite the increasing use of CAM, spurred by a totally unregulated industry, until further evidence is available from well-designed RCTs, it would be inappropriate to advocate CAM as a therapy for patients with liver diseases.



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