By Hellen Oketch-Rabah, PhD, & Kristi Muldoon Jacobs, PhD, US Pharmacopeia09.08.20
Green tea has a long history of use as a traditional beverage in many countries. In contrast, green tea extracts (GTEs) are a fairly recent addition to the marketplace. GTEs have become popular as an ingredient in dietary supplements and are often marketed as a weight loss aid. The main components in green tea extracts are polyphenolic compounds in a class known as catechins. One specific catechin, epigallocatechin gallate (EGCG), is an important constituent of GTEs.
Some research studies have found a link between green tea extract consumption and hepatotoxicity (liver toxicity), also referred to as liver damage or injury. Cases of severe, potentially irreversible liver damage have been reported in individuals taking GTE. Concerns about GTE were raised in the early 2000s when a popular weight-loss product sold in France and Spain was banned after reports that it caused liver injury.
Background
In the U.S., dietary supplements are regulated under the umbrella of foods rather than drugs. Although dietary supplement suppliers and manufacturers are responsible for ensuring the safety of the products they sell, many of these products have not been evaluated by the FDA. The Dietary Supplement Health and Education Act (DSHEA), which is the law regulating dietary supplements, took effect in 1994, and dietary supplements that were on the market before that date are exempt from FDA review.
The US Pharmacopeia (USP), a non-profit, scientific, standard-setting organization, convenes volunteers from industry and academia to collaborate in Expert Committees and Expert Panels to develop quality standards for drugs, dietary supplements, and foods. One of the USP expert committees—USP Dietary Supplements Admission Evaluations Joint Standard-Setting Subcommittee (USP DSAE JS3)—determines the admissibility of dietary ingredients into USP’s monograph development process based on an assessment of available safety data to exclude (or label) ingredients associated with serious risk to health or other public health concerns. In 2008, USP published a systematic safety review of cases of liver injury associated with green tea extract. Based on the safety research available at that time, USP determined that consumers should be informed about the potential risk of liver toxicity from taking GTE supplements.
To provide consumers with this information, USP proposed in 2008 that certain GTE products should carry a cautionary label statement. The cautionary statement was tentatively added to the monograph for Powdered Decaffeinated Green Tea Extract (PDGTE). Manufacturers of PDGTE would have been required to put the cautionary statement on their product labels for any product that claimed to be compliant with USP standards for PDGTE. However, before moving ahead, USP published its proposal with a public comment period during which stakeholders could voice their opinions.
USP received a variety of public comments, some of which questioned whether the evidence was sufficient to justify the cautionary label statement. After considering the public comments, USP placed a temporary hold on the cautionary statement in 2008 and decided to gather more scientific evidence regarding the potential risk of liver damage from GTE. Scientists and expert volunteers at USP continued to monitor the safety data about GTE for approximately 10 more years, and then they performed a large, comprehensive search to gather all the latest GTE research literature.
The search identified 550 relevant publications, including experimental trials in animals, human clinical trials, case reports, research reviews, and studies of chemistry, manufacturing, and controls. A total of 75 individual cases of liver injury associated with GTE consumption were identified and analyzed. Experts at the Drug-Induced Liver Injury Network examined the case reports to determine the most likely cause of the liver toxicity in each patient. In addition to these 75 cases, USP reviewed many other research studies of various types.
Comprehensive Review
Once this comprehensive review of all the relevant data was complete, the USP DSAE JS3 concluded that GTE consumption has indeed been linked to hepatotoxicity. “Based on our assessment, it is reasonable to conclude that risks of hepatotoxicity due to GTE intake are real, and exposure may lead to liver injury, including serious liver injury,” wrote Dr. Hellen Oketch-Rabah and co-authors (Toxicology Reports 2020;7(386-402)).
Meanwhile, USP decided to go forward with the cautionary labeling statement and added it to the monograph for PDGTE. The revised PDGTE monograph, which became official on March 1, 2019, now states: “Dosage forms prepared with this article should bear the following statement: ‘Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes).’” This cautionary label statement is only required under DSHEA for products that claim to comply with USP quality standards for green tea extract, such as PDGTE.
Mechanism Search
Once the decision about the cautionary label statement was now settled, an important question remained unanswered. The research had not revealed whether GTE itself is the direct cause of liver toxicity, or some other factor in the manufacturing process could be the cause. For example, contaminants could enter the GTE raw material before or during manufacturing. Unwanted substances might include solvent residues, pesticide residues, or toxic elemental impurities such as pyrrolizidine alkaloids, any of which could be potential causes of liver damage.
Conversely, if manufacturing factors are not the cause, the problem could be the green tea extract itself. One mechanistic theory involves saturation of drug-metabolizing enzymes. In this scenario, high doses of GTE containing large amounts of catechins such as EGCG could be the culprit. This would be plausible because in the human body metabolism of drugs is based on the amount of the drug over a specific time frame (the catechins would function like drugs). For instance, if large amounts of catechins are consumed and absorbed quickly from the digestive tract, these quantities could overwhelm the body’s ability to process them, and liver toxicity might occur.
To gather more evidence and better inform the industry, as well as consumers, USP decided to investigate further. It formed the Green Tea Extract Hepatotoxicity Expert Panel to search for the specific mechanism behind the hepatotoxicity linked to GTE consumption.
Discovery
The Expert Panel looked at 28 new clinical studies and found that one large study, the Minnesota Green Tea Trial, provided the strongest evidence that the catechin EGCG in green tea extract is toxic to the liver. More than 1,000 postmenopausal women took either a placebo or GTE containing 800 mg EGCG every day for 1 year. After a year, the GTE group had 7 times the rate of liver function abnormalities compared to the placebo group, a highly significant difference.
In the course of its research, the Expert Panel also discovered that most consumers who developed liver toxicity were taking a wide range of GTE doses, from 500 to 3,000 mg/day, which is equivalent to 250 to 1,800 mg/day of EGCG. In the case reports, liver damage occurred in patients taking anywhere from 140 to 1,000 mg/day of EGCG. These dosages are representative of green tea extract dietary supplement products on the market.
The Expert Panel also considered the length of time that a patient took green tea extract. Most patients who developed acute liver injury had taken the GTE daily for 2 weeks or longer. Numerous reports on hepatotoxicity from GTE suggest that the risk of liver damage rises with higher doses (more than 800 mg of GTE) taken for longer periods of time.
Informing the Public
Many of the people studied were taking GTE to help with weight loss, and they were taking the supplement with little or no food. Interestingly, when GTE is taken on an empty stomach, the bioavailability of EGCG is much higher (in some studies, 4 to 5 times higher) than when it is taken with food. This means that the EGCG is absorbed into the body much more rapidly from an empty stomach, and the body might become overloaded when trying to absorb and metabolize it. This is important because EGCG is thought to be the main constituent in GTE that is linked to liver damage. Product labels should state the amount of EGCG in the product, Oketch-Rabah and co-authors said.
“The public should be informed about the potential risk of liver injury from consuming a high, sustained dose of GTE as a dietary supplement, especially for those who are obese or have preexisting liver disease,” the authors wrote. Obese individuals who take GTE supplements are at especially high risk for liver toxicity because obesity itself is linked to liver disease. Independent of GTE use, obesity raises the risk for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). People with these conditions have a liver disorder already, and if they take GTE, their risk for liver damage could be higher.
A Blurry Picture of Safety
Another question is whether there is a “safe” level of GTE intake that is not associated with liver injury. To date, no safe level has been established, if such a level exists. In general, the answers to certain questions remain elusive because useful information is often missing from the case reports. It would be very helpful to know how much EGCG or GTE each patient took, and for what length of time, but the patient may not have known, or the healthcare provider may not have asked. Also pertinent is what other supplements and medications they were taking, as well as their medical history. These facts are often missing as well. Even genetic variability could play a role by making some individuals more susceptible to liver damage than others. For all of these reasons, it is not possible to know whether there is a GTE intake level that is safe for everyone.
Outside the U.S., health authorities in Norway and Canada, as well as the European Food Safety Authority (EFSA), have reached similar conclusions about GTE and the risk of harm to the liver. EFSA concluded that it was not possible to identify a safe dose of EGCG because at least one patient who took a low dose developed liver damage. EFSA also stated that taking GTE containing 800 mg EGCG or more per day was linked to liver injury. Health Canada had already placed cautionary risk statements in its GTE monographs in 2017 when it decided to strengthen those statements based on new research.
In conclusion, USP’s comprehensive review of the evidence clearly shows that severe hepatotoxicity can result from consuming green tea extract. Research also suggests that EGCG is the most likely component in GTE to be the cause of the liver toxicity. Interestingly, no evidence was found in USP’s reviews that linked manufacturing issues or contaminants (solvent or pesticide residues, pyrrolizidine alkaloids, or elemental impurities) to the risk for liver damage. Finally, USP’s decision to require the cautionary label statement on certain GTE products was based on a thorough review of the evidence. The statement informs consumers that green tea extract has potential damaging effects on the liver, particularly if taken on an empty stomach or by a person with an underlying liver disorder.
Dr. Hellen A. Oketch-Rabah is a harmacognosist and practicing senior toxicologist. Currently, she is the senior manager & senior scientific liaison at the US Pharmacopeia (USP) in the Department of Dietary Supplements and Herbal Medicines, where she has been for over 9 years. She leads the front end of USP-NF monograph development activities that determine the nomenclature and admission of dietary supplements ingredients slated for monograph development. Dr. Kristi Muldoon Jacobs is a regulatory toxicologist with over 15 years of experience in the pre-clinical assessment of FDA regulated products including drugs, dietary supplements, and foods. She has extensive knowledge in use of standards to support regulatory systems globally to ensure quality and safety of products. Jacobs joined USP in 2017 after working more than eight years at the US Food and Drug Administration (FDA). Christina Chase, MS, and Claudia Costabile, MA, of USP, contributed to this article. For more information: www.usp.org
Some research studies have found a link between green tea extract consumption and hepatotoxicity (liver toxicity), also referred to as liver damage or injury. Cases of severe, potentially irreversible liver damage have been reported in individuals taking GTE. Concerns about GTE were raised in the early 2000s when a popular weight-loss product sold in France and Spain was banned after reports that it caused liver injury.
Background
In the U.S., dietary supplements are regulated under the umbrella of foods rather than drugs. Although dietary supplement suppliers and manufacturers are responsible for ensuring the safety of the products they sell, many of these products have not been evaluated by the FDA. The Dietary Supplement Health and Education Act (DSHEA), which is the law regulating dietary supplements, took effect in 1994, and dietary supplements that were on the market before that date are exempt from FDA review.
The US Pharmacopeia (USP), a non-profit, scientific, standard-setting organization, convenes volunteers from industry and academia to collaborate in Expert Committees and Expert Panels to develop quality standards for drugs, dietary supplements, and foods. One of the USP expert committees—USP Dietary Supplements Admission Evaluations Joint Standard-Setting Subcommittee (USP DSAE JS3)—determines the admissibility of dietary ingredients into USP’s monograph development process based on an assessment of available safety data to exclude (or label) ingredients associated with serious risk to health or other public health concerns. In 2008, USP published a systematic safety review of cases of liver injury associated with green tea extract. Based on the safety research available at that time, USP determined that consumers should be informed about the potential risk of liver toxicity from taking GTE supplements.
To provide consumers with this information, USP proposed in 2008 that certain GTE products should carry a cautionary label statement. The cautionary statement was tentatively added to the monograph for Powdered Decaffeinated Green Tea Extract (PDGTE). Manufacturers of PDGTE would have been required to put the cautionary statement on their product labels for any product that claimed to be compliant with USP standards for PDGTE. However, before moving ahead, USP published its proposal with a public comment period during which stakeholders could voice their opinions.
USP received a variety of public comments, some of which questioned whether the evidence was sufficient to justify the cautionary label statement. After considering the public comments, USP placed a temporary hold on the cautionary statement in 2008 and decided to gather more scientific evidence regarding the potential risk of liver damage from GTE. Scientists and expert volunteers at USP continued to monitor the safety data about GTE for approximately 10 more years, and then they performed a large, comprehensive search to gather all the latest GTE research literature.
The search identified 550 relevant publications, including experimental trials in animals, human clinical trials, case reports, research reviews, and studies of chemistry, manufacturing, and controls. A total of 75 individual cases of liver injury associated with GTE consumption were identified and analyzed. Experts at the Drug-Induced Liver Injury Network examined the case reports to determine the most likely cause of the liver toxicity in each patient. In addition to these 75 cases, USP reviewed many other research studies of various types.
Comprehensive Review
Once this comprehensive review of all the relevant data was complete, the USP DSAE JS3 concluded that GTE consumption has indeed been linked to hepatotoxicity. “Based on our assessment, it is reasonable to conclude that risks of hepatotoxicity due to GTE intake are real, and exposure may lead to liver injury, including serious liver injury,” wrote Dr. Hellen Oketch-Rabah and co-authors (Toxicology Reports 2020;7(386-402)).
Meanwhile, USP decided to go forward with the cautionary labeling statement and added it to the monograph for PDGTE. The revised PDGTE monograph, which became official on March 1, 2019, now states: “Dosage forms prepared with this article should bear the following statement: ‘Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes).’” This cautionary label statement is only required under DSHEA for products that claim to comply with USP quality standards for green tea extract, such as PDGTE.
Mechanism Search
Once the decision about the cautionary label statement was now settled, an important question remained unanswered. The research had not revealed whether GTE itself is the direct cause of liver toxicity, or some other factor in the manufacturing process could be the cause. For example, contaminants could enter the GTE raw material before or during manufacturing. Unwanted substances might include solvent residues, pesticide residues, or toxic elemental impurities such as pyrrolizidine alkaloids, any of which could be potential causes of liver damage.
Conversely, if manufacturing factors are not the cause, the problem could be the green tea extract itself. One mechanistic theory involves saturation of drug-metabolizing enzymes. In this scenario, high doses of GTE containing large amounts of catechins such as EGCG could be the culprit. This would be plausible because in the human body metabolism of drugs is based on the amount of the drug over a specific time frame (the catechins would function like drugs). For instance, if large amounts of catechins are consumed and absorbed quickly from the digestive tract, these quantities could overwhelm the body’s ability to process them, and liver toxicity might occur.
To gather more evidence and better inform the industry, as well as consumers, USP decided to investigate further. It formed the Green Tea Extract Hepatotoxicity Expert Panel to search for the specific mechanism behind the hepatotoxicity linked to GTE consumption.
Discovery
The Expert Panel looked at 28 new clinical studies and found that one large study, the Minnesota Green Tea Trial, provided the strongest evidence that the catechin EGCG in green tea extract is toxic to the liver. More than 1,000 postmenopausal women took either a placebo or GTE containing 800 mg EGCG every day for 1 year. After a year, the GTE group had 7 times the rate of liver function abnormalities compared to the placebo group, a highly significant difference.
In the course of its research, the Expert Panel also discovered that most consumers who developed liver toxicity were taking a wide range of GTE doses, from 500 to 3,000 mg/day, which is equivalent to 250 to 1,800 mg/day of EGCG. In the case reports, liver damage occurred in patients taking anywhere from 140 to 1,000 mg/day of EGCG. These dosages are representative of green tea extract dietary supplement products on the market.
The Expert Panel also considered the length of time that a patient took green tea extract. Most patients who developed acute liver injury had taken the GTE daily for 2 weeks or longer. Numerous reports on hepatotoxicity from GTE suggest that the risk of liver damage rises with higher doses (more than 800 mg of GTE) taken for longer periods of time.
Informing the Public
Many of the people studied were taking GTE to help with weight loss, and they were taking the supplement with little or no food. Interestingly, when GTE is taken on an empty stomach, the bioavailability of EGCG is much higher (in some studies, 4 to 5 times higher) than when it is taken with food. This means that the EGCG is absorbed into the body much more rapidly from an empty stomach, and the body might become overloaded when trying to absorb and metabolize it. This is important because EGCG is thought to be the main constituent in GTE that is linked to liver damage. Product labels should state the amount of EGCG in the product, Oketch-Rabah and co-authors said.
“The public should be informed about the potential risk of liver injury from consuming a high, sustained dose of GTE as a dietary supplement, especially for those who are obese or have preexisting liver disease,” the authors wrote. Obese individuals who take GTE supplements are at especially high risk for liver toxicity because obesity itself is linked to liver disease. Independent of GTE use, obesity raises the risk for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). People with these conditions have a liver disorder already, and if they take GTE, their risk for liver damage could be higher.
A Blurry Picture of Safety
Another question is whether there is a “safe” level of GTE intake that is not associated with liver injury. To date, no safe level has been established, if such a level exists. In general, the answers to certain questions remain elusive because useful information is often missing from the case reports. It would be very helpful to know how much EGCG or GTE each patient took, and for what length of time, but the patient may not have known, or the healthcare provider may not have asked. Also pertinent is what other supplements and medications they were taking, as well as their medical history. These facts are often missing as well. Even genetic variability could play a role by making some individuals more susceptible to liver damage than others. For all of these reasons, it is not possible to know whether there is a GTE intake level that is safe for everyone.
Outside the U.S., health authorities in Norway and Canada, as well as the European Food Safety Authority (EFSA), have reached similar conclusions about GTE and the risk of harm to the liver. EFSA concluded that it was not possible to identify a safe dose of EGCG because at least one patient who took a low dose developed liver damage. EFSA also stated that taking GTE containing 800 mg EGCG or more per day was linked to liver injury. Health Canada had already placed cautionary risk statements in its GTE monographs in 2017 when it decided to strengthen those statements based on new research.
In conclusion, USP’s comprehensive review of the evidence clearly shows that severe hepatotoxicity can result from consuming green tea extract. Research also suggests that EGCG is the most likely component in GTE to be the cause of the liver toxicity. Interestingly, no evidence was found in USP’s reviews that linked manufacturing issues or contaminants (solvent or pesticide residues, pyrrolizidine alkaloids, or elemental impurities) to the risk for liver damage. Finally, USP’s decision to require the cautionary label statement on certain GTE products was based on a thorough review of the evidence. The statement informs consumers that green tea extract has potential damaging effects on the liver, particularly if taken on an empty stomach or by a person with an underlying liver disorder.
Dr. Hellen A. Oketch-Rabah is a harmacognosist and practicing senior toxicologist. Currently, she is the senior manager & senior scientific liaison at the US Pharmacopeia (USP) in the Department of Dietary Supplements and Herbal Medicines, where she has been for over 9 years. She leads the front end of USP-NF monograph development activities that determine the nomenclature and admission of dietary supplements ingredients slated for monograph development. Dr. Kristi Muldoon Jacobs is a regulatory toxicologist with over 15 years of experience in the pre-clinical assessment of FDA regulated products including drugs, dietary supplements, and foods. She has extensive knowledge in use of standards to support regulatory systems globally to ensure quality and safety of products. Jacobs joined USP in 2017 after working more than eight years at the US Food and Drug Administration (FDA). Christina Chase, MS, and Claudia Costabile, MA, of USP, contributed to this article. For more information: www.usp.org
