Green tea is among the most frequently consumed drinks in the USA and often used as a DS. The first report on liver injury following the ingestion of green tea extracts and preparations thereof was published in 1999 (31), and since then, numerous consecutive cases were reported to regulatory agencies worldwide. With effect of April 2003, the manufacturer of Exolise® (Arkopharma, Carros, France), a hydro-alcoholic extract of C. sinensis, has revocated all of their products after altogether 13 cases of acute liver damage following its intake were reported to the French pharmacovigilance authorities (Agence Francaise de Securité Sanitaire de Produits de Sanité; http://www.afssaps.sante.fr). As a reaction to these accumulating reports, the US Pharmacopeia performed a systematic review of all cases accessible from PubMed, EMBASE and pharmacovigilance data bases in the USA, Canada, UK and Australia reporting on 34 single cases of liver injury following the ingestion of numerous different green tea preparations (32). Herein, case reports were retrospectively evaluated according to the Naranjo causality algorithm scale (33), and 27 reports pertaining to liver damage were labelled as ‘possibly’ and the remaining seven cases as ‘probably’ linked to green tea. Another Medline search review of cases on green tea liver injury from the same year also retrieved 34 published reports and described two further yet unpublished cases (34). On histological examination, livers of patients revealed inflammatory reactions, cholestasis, occasionally steatosis and necrosis. Although there was some overlap of single reports between these two review articles, collected case reports were not identical and jointly provided details on 58 cases of hepatotoxicity along with the intake of green tea extracts, powdered leaves, green tea infusions and hydro-alcoholic and aqueous extracts. In Mazzanti's summary, no causality re-evaluation was performed, but information on de- and rechallenge is provided for every case indicating a positive rechallenge response with accelerated recurrence of liver injury in seven of 36 incidents, which strongly suggests a causal relationship between the observed liver injury and green tea consumption. Of concern is that there was one reported death. However, a note of caution is warranted in many of the cases regarding an exclusive assignment of causality to green tea, because many patients who experienced adverse hepatic reactions also took numerous other products with a published record of hepatotoxicity, such as Cassia angustifolia, Hydroxycut and Ephedra sinica (for all three, please see below). Since these two review articles, additional cases have been published from Belgium reporting on a 42-year-old female patient who developed cholestatic hepatitis 6 months after starting Densitive® (Kerastase Nutritients, L'Oréal, Paris), which contains C. sinensis (35). Upon dechallenge, a full recovery was recorded. Other causes of liver injury were carefully excluded, but formal causality assessment using an established score was not performed. In the second case, jaundice, weight loss and subacute hepatitis developed in a 76-year-old man who regularly drank green tea infusions (36). Histology showed marked necro-inflammation, and transiently elevated antismooth muscle auto-antibodies were suggestive of autoimmunity induced by green tea constituents.
The mode of toxicity derived from green tea still remains incompletely understood but could be because of (−)-epigallocatechin gallate or its metabolite (−)-epicatechin gallate, which, under certain conditions such as fasting, can induce oxidative stress-related liver damage (37). Interestingly, in vitro and in vivo experimental studies have demonstrated both hepatoprotective as well as hepatotoxic properties (37–40). Along this line, support for potentially hepatoprotective activity from green tea extracts comes from clinical studies studying its therapeutic effects in humans with liver diseases including liver cancer, cirrhosis and steatosis. Four randomized-controlled clinical trials, two cohort, one case–control and three cross-sectional studies from China, Japan and the USA were recently subjected to a systematic review and found overall favourable effects from green tea as reflected by reduced mortality, attenuated steatosis and reduced incidence of primary liver cancer (41).
Whether the risks from green tea consumption outweigh their benefits remains open, but current evidence as outlined above suggests a causal relationship between intake of green tea-containing products and hepatotoxicity. Consequently, in their systematic review, the US Pharmacopeia included a cautionary statement on green tea indicating this possibility (32).