Green Tea Extract Hepatotoxicity

Green tea is one of the most frequently consumed beverages in the world and is used daily by hundreds of millions of people. Green tea extract (GTE), derived from leaves of the Camellia sinensis plant, is considered to have beneficial medicinal properties. Recently, there are claims that GTEs have weight loss properties, enhancing fat metabolism (“fat burning). The bases for these claims are in vitro studies using concentrated GTEs that demonstrate antioxidant activity, inhibition of lipogenesis, and increase in several metabolic pathways.(16) Studies of green tea in humans have not demonstrated an effect on weight loss, although small studies have suggested a trend. (17) Nevertheless, a large number of commercial products have been developed containing GTE which are advertised as weight loss agents. While prospective clinical trials have not shown clear effects on weight, they also had not shown appreciable adverse events.

With this background, it came as a surprise when GTE was first linked to rare instances of acute hepatitis. (18) Since 2006, there have been more than 50 reports in the medical literature of clinically apparent acute liver injury with jaundice attributed to green tea extracts. (19, 20) In 2008, the United States Pharmacopeia (USP) assessed 34 reports of liver injury linked to GTE. (21) It concluded that a warning label in the quality monograph for GTE was not warranted at the time for several reasons, including a lack of additional adverse reports over time, missing epidemiological data, and paucity of information on the quality of the preparations specifically linked to liver injury. Among cases of HDS-related liver injury in the DILIN Prospective Trial, 97 implicated products were available for testing; 49 contained catechins indicative of GTE, 29 of which were from products that were not labelled as containing GTE. (22) The patients with liver injury attributed to GTE presented with a characteristic acute-hepatitis like illness occurring within 1 to 3 months of starting use of the product. The illness was generally self-limited, but fatal instances have been reported in up to 10% of cases, typically those who presented with acute hepatocellular injury and jaundice.

The cause of the liver injury due to GTE is not known. High doses of the types of catechins present in GTE are hepatotoxic in mice, particularly epigallocatechin gallate [EGCG] which represents 30-50% of the dry weight of GTE. (23) In most reports of GTE hepatotoxicity, however, the human dose of EGCG (generally less than 12 mg/kg daily) did not appear to be excessive or in the range that might have direct toxicity (estimated for humans to be 30-90 mg/kg). These findings suggest that the liver injury from GTE is an idiosyncratic reaction, typical of conventional DILI.

Other popular herbal products have been linked to cases of clinically apparent liver injury, but in many instances, there have been alternative explanations for the liver injury. One important potential contributor is contamination of the HDS product, not just with toxic elements but also with other unknown herbs or the illicit addition of actual conventional Western medications (such as 5-phosphodiesterase inhibitors [sildenafil], nonsteroidal anti-inflammatory agents, statins and corticosteroids). Other implicated herbal products in the DILIN database included black cohosh (Actaea racemosa), kratom (Mitragyna speciosa), valerian (Valeriana officinalis), Eurycoma longfolia, wormwood (Artemisia herba-alba), cat’s claw (Uncaria tomentosa), Ganoderma applantum (artist’s conk), Fo-Ti (Fallopia multiflora), Red Yeast rice (Monascus purpureus), and Garcinia cambogia. However, the role of these specific herbal products in causing the liver injury was often difficult to assign with any assurance, because of the lack of documentation of their chemical presence and purity, the possibility of contamination with other herbal products or mislabeling of the ingredients.