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Acute hepatitis associated with the use of green tea infusions
Journal of Hepatology 44 (2006) 616–619 www.elsevier.com/locate/jhep
Letters to the Editor
Acute hepatitis associated with the use of green tea infusions To the Editor: We have read with interest the recent review by Stickel et al. [1], who analyse the emerging problem of herbal hepatotoxicity. Really, nowadays, use of complementary and alternative medicine (CAM) is a debatable situation, with very important economic and health implications, in which conventional medicine (CM) has to accept the challenge of CAM, but CAM, in turn, should be regulated according to the legal and scientific rules for CM. However, legislation in this field is not uniform, even lacking in some countries. In USA, for instance, herbal products are labelled as dietary supplements, whereas the European Parliament has recently voted a directive on traditional herbal medicinal products, which stipulates that they must undergo a registration procedure before they can be legally marketed [2]. However, this directive does not include a provision of efficacy and safety data on the candidate product, as required for conventional drugs, but provides a simplified registration procedure for certain traditional medicinal products. According to that, ‘pre-clinical tests do not seem necessary, where the medicinal product on the basis of the information on its traditional use proves not to be harmful in specified conditions of use’. Certainly, herbal medicines have been used for more than 1000 years in some countries, but, as mentioned by Stickel et al. for unknown reasons, ‘herbals as a cause of adverse hepatic reactions, have only recently been recognized, as their use has become more widespread’. Consequently, a long list of herbals has been incriminated, with a variable degree of evidence, as potential hepatotoxic agents. In our opinion, if we consider the most recent reports, this list should be even longer than reported in the above mentioned review. In this respect, in the last 2 years, 14 cases of severe toxic hepatitis have been reported in Europe in patients taking an ethanolic extract of green tea, leading to a suspension of the marketing authorization of this product [3]. Two additional cases have been published in patients treated with micronized powder of Camellia sinensis leaflets [4]. Furthermore, we treated a 45-year-old man who presented with astenia and jaundice of 10-days duration. He had been consuming six cups/day of a marketed green tea infusion over the previous 4 months, but no other medication. Laboratory evaluation revealed a normal hemogram. Prothrombin time was 21 s (11–13)
serum AST 1033 U/l (!37), ALT 1613 U/l (!40), lactate dehydrogenase 602 U/l (!425), alkaline phosphatase 310 U/l (!110), GGT 394 U/l (!30), total bilirubin 119 mg/dl (!17) and direct bilirubin 102 mg/dl. Serum ceruloplasmin, ferritin and copper levels were normal. Serum antiHA–IgM, HbsAg, antiHBc–IgM, antiHCV and non organ-specific autoantibodies (ANA, ASMA, AMA and antiKLM1) were negative. An abdominal ultrasonography and a magnetic resonance cholangiography were normal. A diagnosis of acute hepatitis of unknown origin was made, the patient abandoned tea intake during the follow-up and liver function tests normalized in 2 months. Six weeks later the patient reassumed green tea consumption and a significant increase of liver enzymes levels was shown 1 month later (AST 764 U/l, ALT 1460 U/l, lactate dehydrogenase 616 U/l, GGT 368 U/l, total bilirubin 25 mg/dl). Green tea was withdrawn and liver functions tests normalized in 2 months and remained so during the next year. These findings are surprising, since tea beverages have been consumed for almost 50 centuries, and in vitro and in vivo studies in rats suggest that green tea has hepatoprotective properties [5,6]. Otherwise, the mechanism of hepatotoxicity is unknown, though the low human bioavailability of the green tea metabolites suggests that a metabolic-based idiosyncratic, or a immune-allergic mechanism, would be involved in these exceptional cases. In fact, high concentrations of green tea extract induce acute toxicity in rat liver cells, whereas high doses of epigallocatechin gallate has been associated with extensive liver necrosis in animals [7,8]. In our patient, the CIOMS score (C9), but specially the inadvertent reexposure to the potential hepatotoxin, confirm that green tea, even conventional infusions, may induce severe acute mixed liver injury in predisposed individuals and it should be included between the potential hepatotoxic botanicals. Thus, we agree with Stickel et al. in the critical role of post-marketing surveillance, also in CAM, especially when adverse effects have a low incidence. As stated by these authors, long-standing experience in traditional remedies does not always guarantee safety. On the contrary, diagnosis of herbal hepatotoxicity requires an increasing index of suspicion in order to prevent a delayed diagnosis and long-term consume of ‘natural’ remedies, often considered as food supplements, but potentially harmful for the liver.
Letters to the Editor / Journal of Hepatology 44 (2006) 616–619
Manuel Jimenez-Saenz, Maria del Carmen Martinez-Sanchez Department of Gastroenterology, Hospital Universitario Virgen Macarena, 41070 Seville, Spain E-mail address: [email protected] References [1] Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005;43:901–910. [2] Cox P, Roche D. Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official J Eur Union 2004;136:85–90. [3] Gloro R, Hourmand-Ollivier I, Mosquet B, Mosquet L, Rousselot P, Salame E, et al. Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea. Eur J Gastroenterol Hepatol 2005; 17:1135–1137.
617
[4] Garcia-Moran S, Saez-Royuela F, Gento E, Lopez Morante A, Arias L. Acute hepatitis associated with Camellia thea and Orthosiphon stamineus ingestion. Gastroenterol Hepatol 2004;27:559–560. [5] Jimenez-Lo´pez JM, Cederbaum AI. Green tea polyphenol epigallocatechin-3-gallate protects HepG2 cells against CYPE21-dependent toxicity. Free Radic Biol Med 2004;36:359–370. [6] Zhong Z, Connor HD, Froh M, Lind H, Bunzedahl H, Mason RP, et al. Polyphenols from Camellia sinenesis prevent primary graft failure after transplantation of ethanol-induced fatty livers from rats. Free Radic Biol Med 2004;36:1248–1258. [7] Schmidt M, Schmitz HJ, Baumgart A, Gue´don D, Netsch MI, Kreuter MH, et al. Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture. Food Chem Toxicol 2005;43: 307–314. [8] Goodin MG, Rosengren RJ. Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss–Webster mouse. Toxicol Sci 2003;76:262–270. doi:10.1016/j.jhep.2005.11.041
Occult hepatitis B virus infection and transfusion To the Editor: Since 1972 when blood screening for hepatitis B surface antigen (HBsAg) was first implemented, the viral safety of blood transfusion has continuously improved. Antibody screening for HIV and HCV was implemented in 1985 and 1990, respectively. The tests performance regularly improved and was considered adequate until nucleic acid testing (NAT) was introduced successively for HCV and HIV RNA, reducing the risk of transmission in low prevalence developed countries below 1:M. HBV NAT was not readily introduced for several reasons. (1) The low viral load during the window period and at the tail end of chronic carriage limited the efficacy of testing in pools of donation plasmas ranging between 16 and 96 as routinely utilized for HIV and HCV NAT in order to reduce cost. Full efficacy of HBV DNA screening would require single donation screening often considered not economically justified and feasible only with full automation to cope with the increasing size of blood testing operations. (2) Several developed countries had used anti-HBc screening, initially as surrogate for non-A, non-B hepatitis and subsequently for improving HBV safety in removing most chronic infections escaping HBsAg detection generally called ‘occult’ HBV infections. In this debate, the position of most of the world where HBV infection is endemic and the prevalence of anti-HBc too high to implement anti-HBc screening without jeopardizing the blood supply was hardly considered. The recent availability of high throughput, fully automated, HBV DNA detection as a single assay or, more conveniently, associated with HCV and HIV NAT in triplex assays allowing single unit screening, modified the situation for both developed and developing countries. The former had to decide whether anti-HBc was sufficiently protective, the latter having the technical opportunity, but often not the resources, to improve HBV blood safety. Decision-making on HBV safety strategy requires evidence on two critical issues. First, on the yield of HBV
DNA-carrying blood donations in a wide range of epidemiological backgrounds; second on the infectivity of units containing no detectable HBsAg but HBV DNA with or without anti-HBc or anti-HBs. Predictably, preliminary data from high prevalence areas identified a considerable number of ‘occult’ HBV. In Taiwan for instance where 95% of the adult population carries HBV markers, up to 7% of HBsAg negative blood donors appear to carry HBV DNA [1]. In Ghana where the prevalence of HBV markers in adult is similar, 1.4% HBsAg seronegative blood donors carry occult HBV [2]. The article published in the present issue of the journal by Liu et al. from Taiwan addresses the issue of the frequency of transfusion-transmitted occult HBV. Infectivity could not be properly studied since no donation samples paired to the tested recipients were available. In addition, the end points of the study were the detection of HBV DNA 1 week posttransfusion and anti-HBc and anti-HBs levels up to 6 months post-transfusion, limiting the possibilities of interpreting the data. The main finding of circulating HBV DNA in the 10E4–10E5 copies/ml range 1 week posttransfusion was not confirmed by testing subsequent samples. Assuming that the infection was related to a breakthrough strain bypassing the protection provided by vaccine-induced anti-HBs, the secondary response observed in two pediatric patients suggested some degree of antigenic cross-reactivity. The delayed anti-HBs response of the third patient is more compatible with the assumption. Contact with viral antigens was evidenced by the development of anti-HBc. These three patients apparently received chemotherapy to treat their underlying diseases that may well have helped permitting relatively high levels of replication of occult breakthrough HBV strains so soon after infection. In reported HBV window periods, the eclipse phase during which viral DNA is generally undetectable usually lasts 10 days and the viral load when detected is consistently very low [3,4]. This apparent early period of replication might
Letters to the Editor
Acute hepatitis associated with the use of green tea infusions To the Editor: We have read with interest the recent review by Stickel et al. [1], who analyse the emerging problem of herbal hepatotoxicity. Really, nowadays, use of complementary and alternative medicine (CAM) is a debatable situation, with very important economic and health implications, in which conventional medicine (CM) has to accept the challenge of CAM, but CAM, in turn, should be regulated according to the legal and scientific rules for CM. However, legislation in this field is not uniform, even lacking in some countries. In USA, for instance, herbal products are labelled as dietary supplements, whereas the European Parliament has recently voted a directive on traditional herbal medicinal products, which stipulates that they must undergo a registration procedure before they can be legally marketed [2]. However, this directive does not include a provision of efficacy and safety data on the candidate product, as required for conventional drugs, but provides a simplified registration procedure for certain traditional medicinal products. According to that, ‘pre-clinical tests do not seem necessary, where the medicinal product on the basis of the information on its traditional use proves not to be harmful in specified conditions of use’. Certainly, herbal medicines have been used for more than 1000 years in some countries, but, as mentioned by Stickel et al. for unknown reasons, ‘herbals as a cause of adverse hepatic reactions, have only recently been recognized, as their use has become more widespread’. Consequently, a long list of herbals has been incriminated, with a variable degree of evidence, as potential hepatotoxic agents. In our opinion, if we consider the most recent reports, this list should be even longer than reported in the above mentioned review. In this respect, in the last 2 years, 14 cases of severe toxic hepatitis have been reported in Europe in patients taking an ethanolic extract of green tea, leading to a suspension of the marketing authorization of this product [3]. Two additional cases have been published in patients treated with micronized powder of Camellia sinensis leaflets [4]. Furthermore, we treated a 45-year-old man who presented with astenia and jaundice of 10-days duration. He had been consuming six cups/day of a marketed green tea infusion over the previous 4 months, but no other medication. Laboratory evaluation revealed a normal hemogram. Prothrombin time was 21 s (11–13)
serum AST 1033 U/l (!37), ALT 1613 U/l (!40), lactate dehydrogenase 602 U/l (!425), alkaline phosphatase 310 U/l (!110), GGT 394 U/l (!30), total bilirubin 119 mg/dl (!17) and direct bilirubin 102 mg/dl. Serum ceruloplasmin, ferritin and copper levels were normal. Serum antiHA–IgM, HbsAg, antiHBc–IgM, antiHCV and non organ-specific autoantibodies (ANA, ASMA, AMA and antiKLM1) were negative. An abdominal ultrasonography and a magnetic resonance cholangiography were normal. A diagnosis of acute hepatitis of unknown origin was made, the patient abandoned tea intake during the follow-up and liver function tests normalized in 2 months. Six weeks later the patient reassumed green tea consumption and a significant increase of liver enzymes levels was shown 1 month later (AST 764 U/l, ALT 1460 U/l, lactate dehydrogenase 616 U/l, GGT 368 U/l, total bilirubin 25 mg/dl). Green tea was withdrawn and liver functions tests normalized in 2 months and remained so during the next year. These findings are surprising, since tea beverages have been consumed for almost 50 centuries, and in vitro and in vivo studies in rats suggest that green tea has hepatoprotective properties [5,6]. Otherwise, the mechanism of hepatotoxicity is unknown, though the low human bioavailability of the green tea metabolites suggests that a metabolic-based idiosyncratic, or a immune-allergic mechanism, would be involved in these exceptional cases. In fact, high concentrations of green tea extract induce acute toxicity in rat liver cells, whereas high doses of epigallocatechin gallate has been associated with extensive liver necrosis in animals [7,8]. In our patient, the CIOMS score (C9), but specially the inadvertent reexposure to the potential hepatotoxin, confirm that green tea, even conventional infusions, may induce severe acute mixed liver injury in predisposed individuals and it should be included between the potential hepatotoxic botanicals. Thus, we agree with Stickel et al. in the critical role of post-marketing surveillance, also in CAM, especially when adverse effects have a low incidence. As stated by these authors, long-standing experience in traditional remedies does not always guarantee safety. On the contrary, diagnosis of herbal hepatotoxicity requires an increasing index of suspicion in order to prevent a delayed diagnosis and long-term consume of ‘natural’ remedies, often considered as food supplements, but potentially harmful for the liver.
Letters to the Editor / Journal of Hepatology 44 (2006) 616–619
Manuel Jimenez-Saenz, Maria del Carmen Martinez-Sanchez Department of Gastroenterology, Hospital Universitario Virgen Macarena, 41070 Seville, Spain E-mail address: [email protected] References [1] Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005;43:901–910. [2] Cox P, Roche D. Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official J Eur Union 2004;136:85–90. [3] Gloro R, Hourmand-Ollivier I, Mosquet B, Mosquet L, Rousselot P, Salame E, et al. Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea. Eur J Gastroenterol Hepatol 2005; 17:1135–1137.
617
[4] Garcia-Moran S, Saez-Royuela F, Gento E, Lopez Morante A, Arias L. Acute hepatitis associated with Camellia thea and Orthosiphon stamineus ingestion. Gastroenterol Hepatol 2004;27:559–560. [5] Jimenez-Lo´pez JM, Cederbaum AI. Green tea polyphenol epigallocatechin-3-gallate protects HepG2 cells against CYPE21-dependent toxicity. Free Radic Biol Med 2004;36:359–370. [6] Zhong Z, Connor HD, Froh M, Lind H, Bunzedahl H, Mason RP, et al. Polyphenols from Camellia sinenesis prevent primary graft failure after transplantation of ethanol-induced fatty livers from rats. Free Radic Biol Med 2004;36:1248–1258. [7] Schmidt M, Schmitz HJ, Baumgart A, Gue´don D, Netsch MI, Kreuter MH, et al. Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture. Food Chem Toxicol 2005;43: 307–314. [8] Goodin MG, Rosengren RJ. Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss–Webster mouse. Toxicol Sci 2003;76:262–270. doi:10.1016/j.jhep.2005.11.041
Occult hepatitis B virus infection and transfusion To the Editor: Since 1972 when blood screening for hepatitis B surface antigen (HBsAg) was first implemented, the viral safety of blood transfusion has continuously improved. Antibody screening for HIV and HCV was implemented in 1985 and 1990, respectively. The tests performance regularly improved and was considered adequate until nucleic acid testing (NAT) was introduced successively for HCV and HIV RNA, reducing the risk of transmission in low prevalence developed countries below 1:M. HBV NAT was not readily introduced for several reasons. (1) The low viral load during the window period and at the tail end of chronic carriage limited the efficacy of testing in pools of donation plasmas ranging between 16 and 96 as routinely utilized for HIV and HCV NAT in order to reduce cost. Full efficacy of HBV DNA screening would require single donation screening often considered not economically justified and feasible only with full automation to cope with the increasing size of blood testing operations. (2) Several developed countries had used anti-HBc screening, initially as surrogate for non-A, non-B hepatitis and subsequently for improving HBV safety in removing most chronic infections escaping HBsAg detection generally called ‘occult’ HBV infections. In this debate, the position of most of the world where HBV infection is endemic and the prevalence of anti-HBc too high to implement anti-HBc screening without jeopardizing the blood supply was hardly considered. The recent availability of high throughput, fully automated, HBV DNA detection as a single assay or, more conveniently, associated with HCV and HIV NAT in triplex assays allowing single unit screening, modified the situation for both developed and developing countries. The former had to decide whether anti-HBc was sufficiently protective, the latter having the technical opportunity, but often not the resources, to improve HBV blood safety. Decision-making on HBV safety strategy requires evidence on two critical issues. First, on the yield of HBV
DNA-carrying blood donations in a wide range of epidemiological backgrounds; second on the infectivity of units containing no detectable HBsAg but HBV DNA with or without anti-HBc or anti-HBs. Predictably, preliminary data from high prevalence areas identified a considerable number of ‘occult’ HBV. In Taiwan for instance where 95% of the adult population carries HBV markers, up to 7% of HBsAg negative blood donors appear to carry HBV DNA [1]. In Ghana where the prevalence of HBV markers in adult is similar, 1.4% HBsAg seronegative blood donors carry occult HBV [2]. The article published in the present issue of the journal by Liu et al. from Taiwan addresses the issue of the frequency of transfusion-transmitted occult HBV. Infectivity could not be properly studied since no donation samples paired to the tested recipients were available. In addition, the end points of the study were the detection of HBV DNA 1 week posttransfusion and anti-HBc and anti-HBs levels up to 6 months post-transfusion, limiting the possibilities of interpreting the data. The main finding of circulating HBV DNA in the 10E4–10E5 copies/ml range 1 week posttransfusion was not confirmed by testing subsequent samples. Assuming that the infection was related to a breakthrough strain bypassing the protection provided by vaccine-induced anti-HBs, the secondary response observed in two pediatric patients suggested some degree of antigenic cross-reactivity. The delayed anti-HBs response of the third patient is more compatible with the assumption. Contact with viral antigens was evidenced by the development of anti-HBc. These three patients apparently received chemotherapy to treat their underlying diseases that may well have helped permitting relatively high levels of replication of occult breakthrough HBV strains so soon after infection. In reported HBV window periods, the eclipse phase during which viral DNA is generally undetectable usually lasts 10 days and the viral load when detected is consistently very low [3,4]. This apparent early period of replication might