Introduction
9144001143000CLINICAL TRIAL OF HIGH-DOSE GREEN TEA EXTRACT ON HEPATOCELLULAR INJURY IN POSTMENOPAUSAL WOMEN IN THE UNITED STATES byZheming YuBMed, Nanjing Medical University, China 2009MMed, Fudan University, China, 2012Submitted to the Graduate Faculty ofGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public HealthUniversity of Pittsburgh201600CLINICAL TRIAL OF HIGH-DOSE GREEN TEA EXTRACT ON HEPATOCELLULAR INJURY IN POSTMENOPAUSAL WOMEN IN THE UNITED STATES byZheming YuBMed, Nanjing Medical University, China 2009MMed, Fudan University, China, 2012Submitted to the Graduate Faculty ofGraduate School of Public Health in partial fulfillment of the requirements for the degree ofMaster of Public HealthUniversity of Pittsburgh2016center301625UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyZheming YuonApril 27, 2016Essay Advisor: Jian-Min Yuan, MD PhD ______________________________________Professor of EpidemiologyGraduate School of Public HealthUniversity of Pittsburgh Essay Readers:Lesley Butler, PhD ______________________________________ Associate Professor of EpidemiologyGraduation School of Public HealthUniversity of Pittsburgh Thomas W. Kensler, PhD ______________________________________Professor of Pharmacology and Chemical BiologySchool of MedicineUniversity of Pittsburgh00UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyZheming YuonApril 27, 2016Essay Advisor: Jian-Min Yuan, MD PhD ______________________________________Professor of EpidemiologyGraduate School of Public HealthUniversity of Pittsburgh Essay Readers:Lesley Butler, PhD ______________________________________ Associate Professor of EpidemiologyGraduation School of Public HealthUniversity of Pittsburgh Thomas W. Kensler, PhD ______________________________________Professor of Pharmacology and Chemical BiologySchool of MedicineUniversity of Pittsburghcenter4648200Copyright ? by Zheming Yu201600Copyright ? by Zheming Yu20160-323850Jian-Min Yuan, MD PhD CLINICAL TRIAL OF HIGH-DOSE GREEN TEA EXTRACT ON HEPATOCELLULAR INJURY IN POSTMENOPAUSAL WOMEN IN THE UNITED STATES Zheming Yu, MPHUniversity of Pittsburgh, 201600Jian-Min Yuan, MD PhD CLINICAL TRIAL OF HIGH-DOSE GREEN TEA EXTRACT ON HEPATOCELLULAR INJURY IN POSTMENOPAUSAL WOMEN IN THE UNITED STATES Zheming Yu, MPHUniversity of Pittsburgh, 2016ABSTRACTObjective: To evaluate the liver toxicity effect of oral supplementation of a concentrated green tea extract (GTE) in postmenopausal women in the United States. Methods: In a clinical trial, 999 postmenopausal women were randomly assigned to either placebo arm or treatment arm receiving a daily dose of 1315 mg total tea catechins (including 843 mg epigallocatechin gallate) for 12 months. Baseline information on demographic characteristics, dietary intake and medication use were collected. Alanine transaminase (ALT) and aspartate transaminase (AST) as liver function tests were quantified in plasma collected from study participants at baseline, monthly for the first 6 months, and every 3 months for the last 6 months. A linear mixed-effect model was used to evaluate the effect of GTE intake on plasma ALT and AST levels, respectively. An unconditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of developing abnormal liver function test (ALT > 60 U/L or AST >35 U/L) during the 12-month study period.Results: Overall, GTE supplements significantly increased ALT by 4.9 U/L (95% CI =3.8-6.0 U/L, P < 0.0001) and AST by 3.6 U/L (95% CI=2.7-4.5 U/L, P < 0.0001) during 12-month study period. After randomization, 48 participants taking GTE and 11 participants taking placebo capsules had at least once ALT greater 60 U/L. Among these 59 participants, GTE group had 383.4% increase of ALT over baseline compared to 76.7% increase of ALT in placebo group at the third month. Women in the GTE arm had a statistically significant increased odds of having abnormal ALT (OR =4.1, 95% CI= 2.1-8.2) and abnormal AST (OR=2.8, 95% CI = 1.8-4.3). Increased body mass index, alcohol consumption, and current use of antibiotics and non-steroidal anti-inflammatory drugs significantly aggravated the effect of GTE on ALT and/or AST elevations.Conclusion: High dose of GTE intake significantly induced elevation of liver transaminases. With increasing global consumption of green tea, the potential liver toxicity effect of high-dose GTE as a dietary supplement has public health significance. Future studies are warranted to elucidate the potential biological mechanism of GTE in inducing liver injury. TABLE OF CONTENTS TOC \o "2-4" \h \z \t "Heading 1,1,Appendix,1,Heading,1" 1.0Introduction PAGEREF _Toc448316491 \h 12.0Subjects and METHODS PAGEREF _Toc448316492 \h 32.1study sUBJECTS and recruitment PAGEREF _Toc448316493 \h 32.2Questionnaire Data, BIospecimens and Biomarker data collection PAGEREF _Toc448316494 \h 42.3study Interventions PAGEREF _Toc448316495 \h 62.4HEPATIC Laboratory measurements PAGEREF _Toc448316496 \h 72.5Statistical analysis PAGEREF _Toc448316497 \h 83.0Results PAGEREF _Toc448316498 \h 104.0discussion PAGEREF _Toc448316499 \h 135.0CONCLUSION PAGEREF _Toc448316500 \h 19Acknowledgement PAGEREF _Toc448316501 \h 20bibliography PAGEREF _Toc448316502 \h 21appendix: SUPPLEMENTAL TABLES PAGEREF _Toc448316503 \h 36List of tables TOC \h \z \c "Table" Table 1 Distributions of characteristics at baseline among study participants in the green tea extract and placebo group, The Minnesota Green Tea Trial, 2009-2015 PAGEREF _Toc447988153 \h 25Table 2 Change of plasma alanine transaminase (ALT) and aspartate transaminase (AST) during the intervention period from baseline in all subjects as well as in subgroups stratified by selected baseline characteristics, the Minnesota Green Tea Trial, 2009-2015 PAGEREF _Toc447988154 \h 27Table 3 Odds ratio of developing abnormal liver enzyme (ALT or AST) for women assigned in the GTE versus placebo group during the 12-month treatment period, the Minnesota Green Tea Trial, 2009-2015 PAGEREF _Toc447988155 \h 30List of figures TOC \h \z \c "Figure" Figure 1 Flow diagram of participant screening, enrollment, randomization, and eligible for the present sub-study, the Minnesota Green Trial, 2009-2015 PAGEREF _Toc449451418 \h 33Figure 2 Joint lines of percentage of ALT increases over the baseline (a) and average ALT level (b) at each visit.. PAGEREF _Toc449451419 \h 34Figure 3 Joint lines of percentage of AST increases over the baseline (a) and average AST level (b) at each visit... PAGEREF _Toc449451420 \h 35 TOC \h \z \c "Figure" IntroductionTea, obtained from the plant Camellia Sinensis, is the second most popular beverage in the world. Several types of tea are produced by different postharvest processing methods. Green tea comes from fresh tea leaves steamed immediately after harvest with minimal enzymatic oxidation. Water-extractable components from green tea contain about 30-40% tea catechins by tea leaf dry weight, with epigallocatechin gallate (EGCG) comprising on average two-thirds of total tea catechins ADDIN EN.CITE <EndNote><Cite><Author>Graham</Author><Year>1992</Year><RecNum>451</RecNum><DisplayText>(1)</DisplayText><record><rec-number>451</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1453148378">451</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Graham, H. N.</author></authors></contributors><titles><title>Green tea composition, consumption, and polyphenol chemistry</title><secondary-title>Prev Med</secondary-title><alt-title>Preventive medicine</alt-title></titles><periodical><full-title>Prev Med</full-title><abbr-1>Preventive medicine</abbr-1></periodical><alt-periodical><full-title>Prev Med</full-title><abbr-1>Preventive medicine</abbr-1></alt-periodical><pages>334-50</pages><volume>21</volume><number>3</number><edition>1992/05/01</edition><keywords><keyword>Agriculture</keyword><keyword>*Flavonoids</keyword><keyword>Food Preservation/methods</keyword><keyword>Humans</keyword><keyword>Phenols/analysis/*chemistry</keyword><keyword>Polymers/analysis/*chemistry</keyword><keyword>Polyphenols</keyword><keyword>Statistics as Topic</keyword><keyword>Tea/*chemistry</keyword></keywords><dates><year>1992</year><pub-dates><date>May</date></pub-dates></dates><isbn>0091-7435 (Print)
0091-7435</isbn><accession-num>1614995</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(1). A large body of evidence across the world has shown potential benefits of tea catechins, especially EGCG, across the world. The anti-oxidative characteristics of tea catechins were observed to have a beneficial influence on body weight reduction among obese individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxpYnVyc2thPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh
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ADDIN EN.CITE.DATA (5). With an increasing public awareness of tea’s abundant health benefits, US adults - with equal number of males and females - have begun to consume larger amounts of tea catechins by using dietary tea supplements PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (6). Nevertheless, the safety of these tea supplements has gained wide attention due to the increasing number of reports on associated adverse hepatic reactions.There were 53 reported hepatic adverse events associated with consuming dietary tea supplements during the past 15 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXp6YW50aTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA (7-9). Among these 53 cases, 44 cases were women, the types of liver damage for 50 subjects were hepatocellular injury (i.e., increased liver enzymes), and 28 subjects had consumed other medications, including both synthetic and herbal drugs. These reviews and reports suggested a potential causal relationship between green tea supplements and liver damage, which also suggested that the interaction between use of green tea extracts and other medications at the same time was a major concern. Catechol-O-methyltransferase (COMT) is involved in the metabolic pathway of tea catechins’ degeneration. In particular, genetic variability of COMT may have an impact on catechins’ degeneration. A COMT polymorphism at condon 108/158 (rs4680), resulting in a guanine (G) to adenine (A) transition, further decreases the enzymatic activity among individuals with homozygous low-activity (A/A) genotype PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXdsaW5nPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48
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ADDIN EN.CITE.DATA (10, 11). These individuals metabolize tea catechins more slowly than individuals with high-activity (G/G) genotype, which may lead to longer and greater exposure to catechins. High urinary levels of epigallocatechin (EGC), used as a biomarker of green tea intake, were found to be associated with increased risk of developing hepatocellular carcinoma in individuals with positive serology for hepatitis B surface antigen PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXRsZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (12). Despite case reports and observational epidemiological studies, there has been no well controlled clinical trial investigating the relationship between green tea supplements and liver injury. Utilizing the resources of the Minnesota Green Tea Trial (MGTT), a randomized, placebo-controlled, double-blinded phase II clinical trial with a primary aim to investigate the effect of concentrated green tea extract (GTE) supplementation for 12 months on biomarkers of breast cancer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hdmF0PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA (13), we conducted a comprehensive analysis for the effect of oral daily dose of 1315 mg total tea catechin on hepatocellular injury. In addition, we evaluate the potential modifying effect of COMT genotypes, lifestyles factors and medication use on the association between GTE consumption and hepatocellular injury.Subjects and METHODSstudy sUBJECTS and recruitmentThe design of the MGTT has been described in detail previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hdmF0PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA (13). In brief, MGTT was a randomized, double-blinded, placebo-controlled phase II clinical trial that was designed to investigate the modifying effects of oral intake of GTE on mammographic density, circulating reproductive hormones and circulating insulin-like growth factor axis proteins in postmenopausal women. This clinical trial was approved by the Institutional Review Boards of the University of Minnesota, each of the participating clinical centers, and the University of Pittsburgh. All participants provided written informed consents.The inclusion and exclusion criteria were described previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hdmF0PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA (13). Briefly, postmenopausal women 50-70 years old with heterogeneously or extremely dense breasts otherwise in good health were eligible for the clinical trial. Women with any of the following characteristics at baseline were ineligible for MGTT: 1) tested positive for serological status of hepatitis B surface antigen or antibodies to hepatitis C virus; 2) baseline alanine aminotransferase (ALT) higher than 1.5 times the upper limit of normal (ULN) (defined in this study as 60 U/L); 3) any history of cancer, proliferative breast disease, breast augmentation; 4) body mass index (BMI) below 18.5 or above 40 kg/m2 or weight change more than 10 pounds during the previous 12 months; 5) current or recent (within 6 months) use of hormone replacement therapy or anti-inflammatory agents such as methotrexate and Enbrel; 6) current smoker or regular consumption of 7 or more alcoholic beverages per week; and 7) regular consumption of 1 or more cups of green tea per week. A total of 1075 eligible subjects were recruited from 2009 to 2013 at 8 clinical centers in the Minneapolis-St. Paul metropolitan area; 538 were randomly assigned to the GTE intervention group and 537 to the placebo group (Figure 1). Participants were eligible for the present analysis of GTE on liver toxicity if their baseline blood ALT was less than or equal to 60 U/L and aspartate transaminase (AST) less than or equal to 35 U/L and they had at least one follow-up liver function test of ALT and AST after the baseline test. Among the 1075 women randomized, 3 participants (all in GTE group) were excluded due to missing baseline hepatic tests, 51 participants (22 in the GTE and 29 in the placebo group) without hepatic tests at any follow-up visit were also excluded, and other 22 participants (8 in the GTE and 12 in the placebo group) were excluded for the present analysis due to their elevated ALT (> 60 U/L) or AST (> 35 U/L) tests at the baseline because we defined ALT greater than 60 U/L or AST greater than 35 U/L as being abnormal. The present analysis included 999 women (505 in the GTE and 494 in the placebo group). Questionnaire Data, BIospecimens and Biomarker data collectionAt the baseline visit, each participant completed an in-depth health history questionnaire for demographics, lifestyle factors, medical history, medication use, and reproductive history. The status of alcohol use were collected at the baseline by asking whether the patients consumed alcohol chronically. If the answer was positive, the subject was defined as a current drinker and the amounts of drinks per week were recorded. One alcoholic drink was quantified as 12 fluid ounces (355 ml) of regular beer, 5 fluid ounces (148 ml) of wine, or 1.5 fluid ounces (44 ml) of liquor. Similarly, the current user of a specific medication, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, antibiotics, anti-viral drugs and statin, were recorded as using the specific drug during the past 6 months.We used the Diet History Questionnaire I (DHQI), developed and validated by the National Cancer Institute (NCI), for our study. The DHQI included 124 food items and inquiries about the food intake during the past 12 months with portion size, dietary supplements. Average daily food and nutrient intake were estimated using NCI DietCalc software. Anthropometric measurements including weight, height, and waist and hip circumferences were taken for all participants by trained clinic staff. Weight was measured to the nearest 0.1 kg using a digital scale at screening, baseline and every three months. Standing height was determined to the nearest 0.1 cm at baseline and month 12 with a wall-mounted stadiometer. BMI was calculated as weight in kilograms divided by squared height in meters (kg/m2). Whole blood samples were collected by a trained nurse or phlebotomist via venipuncture at the Human Nutrition Research Clinic at the University of Minnesota St. Paul Campus. Serum and plasma were separated from whole blood by centrifugation at 3000 rpm for 10 minutes, measured into 1.5 mL aliquots and stored at -70 degrees Celsius until analysis. Frozen samples were sent in batches to Quest Diagnostics for measurement of a standard lipid panel. Batches were prepared by arranging participants into GTE-placebo pairs, and all samples from a given study participant were bundled together with a counterpart and analyzed in the same lab batch. Total cholesterol and triglycerides were measured in serum using the Beckman Olympus AU5400 chemistry analyzer at baseline, month 6 and month 12.Buffy coat was collected by removing plasma from whole blood and adding 0.5 ml of 0.9% sodium chloride to each 0.5 ml aliquot, and then stored at -70 degrees Celsius until analysis. DNA was extracted from buffy coat samples by the Qiagen DNAeasy Blood and Tissue Kit method (Qiagen Inc., Gaithersburg, MD, US). COMT genotype analysis was completed at the University of Minnesota Genomics Center. A TaqMan assay was developed for defining the COMT G/A polymorphism by using a TaqMan PCR Core Reagent kit (Applied Biosystems, Foster City, CA). Cell lines with known COMT genotype were used as quality controls with each PCR run.study InterventionsGreen Tea Extract Catechin Complex (Corban complex GTB, referred to as GTE) and placebo capsules were provided by Corban Laboratories (Eniva Nutraceutics, Plymouth, MN). All capsules were stored at ambient temperature and moisture conditions. Eight batches of GTE were produced for the clinical trial. The catechin contents for each batch was quantified using the high-performance liquid chromatography technology at the laboratory in Rutgers University (Chung S. Yang). Mean (± standard deviation, SD) total catechins of each GTE capsule was 328.8±28.9 mg, including 210.7±11.0 mg EGCG, 50.6±18.5 mg epicatechin gallate (ECG), 26.7±29.7 mg EGC, and 26.8±5.9 mg epicatechin (EC). Placebo capsules, identical to the GTE capsules in appearance, contained 816 mg maltodextrin (50%), 808 mg cellulose (49.5%), and 8 mg magnesium stearate (0.5%), but no tea catechins. Both capsules contained 3.9 mg caffeine. Participants were instructed to take two GTE or placebo capsules, twice daily with breakfast and dinner for 12 months. That was four capsules a day, which contained an average (± SD) of 1315 ±115.4 mg total catechins (including 843±44.1 mg EGCG, 202±74.0 mg ECG, 106±118.8 mg EGC, 107±23.4 mg EC), and 15.8 mg caffeine. The daily dose of total catechins or EGCG was equivalent to approximately five cups (8-ounce or 240 ml per cup) of brewed green tea ADDIN EN.CITE <EndNote><Cite><Author>Bhagwat</Author><Year>2014</Year><RecNum>496</RecNum><DisplayText>(14)</DisplayText><record><rec-number>496</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1458335520">496</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Bhagwat, S</author><author>Haytowitz, DB</author><author>Holden, JM</author></authors></contributors><titles><title>USDA database for the flavonoid content of selected foods. Release 3.1. 15 May 2015</title></titles><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>(14). HEPATIC Laboratory measurementsDuring the first 2 years of the study, participants came to the clinic monthly for ALT monitoring. Because very few women developed elevated ALT, especially after month 6 of entry into the study, we did not require study subjects, who were recruited in the trial in the last 3 years, to have clinical visits at months 7, 8, 10, and 11. As a result, only 24% of total study participants who completed the study had hepatic panel results at months 7, 8, 10, and 11 clinic visits.Blood was draw into serum separator tubes with clot activator and gel for serum at the HNRC. Samples were centrifuged as described above and then sent to Quest Diagnostics for hepatic panel measurement. Hepatic panel results were available within 2 business days after the laboratory analysis. For the present analysis, a study participant with at least once ALT greater than 60 U/L or AST greater than 35 U/L at any clinic visits after randomization was defined as having a hepatocellular injury event. A participant found to have ALT levels at 1.5-5 times ULN (90-300 U/L) elevation was asked to refrain from taking study product for 14 days and a hepatic panel re-test was conducted. If the re-test ALT value was within acceptable range (below 1.5 times ULN or < 90 U/L), the participant was put back on study product. If the re-test ALT remained above 1.5 but below 5 times ULN, the participant was asked to complete another liver function re-test after additional 14 days. The participant was tested every two weeks until ALT levels returned to below 1.5 times ULN, at which time she was asked to resume taking study capsules. After retaking GTE or placebo capsules, the participant would be permanently withdrawal from the study if her ALT level was above 1.5 time ULN again. Any ALT elevation above 5.0 times ULN (> 300 U/L) was considered a severe adverse event. In such an event, the participant was permanently taken off from the study product but asked to continue in the study. Participants were re-tested for hepatic panels at 14-day intervals until their ALT level returned to within normal range. Statistical analysisThe distributions of demographic characteristics (age, race, level of education, BMI, smoking and alcohol status), dietary intake (vitamin C, vitamin E and et al.), and use of medication (antibiotics, antiviral drugs, NSAIDs, acetaminophen, statin and et al.) were compared between the GTE and placebo groups. Independent Student’s t-tests or Wilcoxon rank sum test were employed for comparisons between the two groups of continuous variables in normal or non-normal distributions, respectively. Pearson χ2test was used for comparing the frequencies of categorical or nominal variables between the two groups. Differences in the plasma concentrations of liver enzymes (ALT and AST) between the GTE and placebo groups from the baseline to each of the follow-up liver function tests after randomization were assessed using the generalized linear mixed effect model with controlling for age, level of education, BMI, and smoking status (never versus. former smokers) at baseline. The changes of liver enzymes over time were estimated by least squares means and their 95% confidence interval (CI). We also investigated a potential modifying effect of dietary nutrients (e.g. vitamin C, vitamin E), levels of BMI (normal, overweight, and obese), alcohol consumption, plasma lipid levels (cholesterol and triglyceride), use of medications and COMT genotypes (HH, HL and LL) on the relationship between GTE consumption and hepatocellular injury. The same generalized linear mixed effect model was employed with an additional interaction term between a modifying factor of interest and the treatment assignment (GTE or placebo). Analyses were also performed to evaluate the effect of GTE supplementation on the risk of developing hepatocellular injury defined as above the ULN of ALT and AST, respectively. The unconditional logistic regression method was employed to estimate the odds ratios (ORs) and their 95% CIs of developing hepatocellular injury due to the supplementation of GTE, controlling for age, level of education, BMI, and smoking status at the baseline. The same modifiers described in the above mixed effected models were also tested in the logistic regression models.Statistical computing was conducted using SAS version 9.4 (SAS Inc., Cary, NC). All P values were two-sided. P values <0.05 were considered being statistically significant.ResultsThe distributions of baseline characteristics among study participants in the GTE and placebo groups are shown in Table 1. The mean ages (SD) of women in the GTE and placebo groups were 59.9 (5.0) and 59.6 (5.1) years, respectively. More than 97% of study participants were Caucasians. No difference was found in the distributions of BMI, level of education, smoking status, alcohol consumption status, current use of medications, dietary intake of vitamin C and other nutrients, plasma levels of total cholesterol, and COMT genotypes. Total triglyceride concentration was about 9-10 mg/dl lower in the GTE group than triglyceride in the placebo group (P=0.005). The mean levels of ALT at baseline were comparable between women in GTE (17.9 U/L) and placebo groups (17.3 U/L) whereas women in the placebo had a slightly higher AST (20.2 U/L) than those in the GTE group (19.6 U/L) (P = 0.023) (Supplemental Table 1). Use of statin was associated with significantly higher baseline levels of ALT and AST in both GTE and placebo groups (both P < 0.001). In the placebo group, women with BMI ≥ 30 kg/m2 or serum triglyceride ≥ 150 mg/dl had significantly elevated ALT whereas those of current use of non-aspirin NSAIDs showed a lower ALT at baseline (all P < 0.05). We did not observe similar differences in ALT at the baseline among women in the GTE group. The difference in baseline ALT levels between the GTE and placebo groups reached statistical significance for women with BMI ≥30 kg/m2, non-drinking of alcohol, non-users of non-aspirin NSAIDs or acetaminophen. Baseline level of AST was slightly reduced in obese women or current drinkers of alcohol (Ps < 0.05) in placebo group. A reduced baseline level of AST was observed in the GTE for women with normal weight (BMI < 25 kg/m2), current drinkers of alcohol, lower intake of dietary vitamin C (below median), lower serum triglyceride (<150 mg/dl), non-users of acetaminophen or statin (Supplemental Table 1). The supplementation of GTE significantly increased plasma ALT and AST levels, where ALT increased by 4.9 U/L (28.5% over baseline level) and AST increased by 3.6 U/L (18.2% over baseline level) (both Ps < 0.0001). The largest increase in ALT was observed between months 2 and 3 after the initial supplementation of GTE. At month 3, the mean ALT was 90.3 U/L among women (n = 47) in GTE group who had at least one abnormal ALT test (>60 U/L) during the entire study period (Figure 2b), which was 383.4% over their mean baseline ALT (Figure 2a). Among women in the placebo group, the corresponding ALT was 46.1 U/L, which was 76.7% over their mean baseline ALT level. The decrease in ALT after month 3 in the GTE group was the result of the temporarily stopping taking GTE by women with ALT >1.5 - <5 times ULN and permanent withdrawals of women whose ALT was greater than 5 times ULN. A similar pattern of AST enzyme changes was over the course of GTE supplementation. At month 3, subjects with at least once AST greater than 35 U/L (ULN) had a 120.9% increase of AST over their baseline level and an average 45.9 U/L of AST, as compared to women in the placebo group who had 29.7% increase over their baseline AST and an average 30.2 U/L of AST (Figure 3). After randomization, 19 participants stopped taking study products (GTE or placebo capsules) because of persistent ALT elevation or ALT greater than 5.0 times ULN (300 U/L), and 11 of them dropped off the study before month 6 (Supplemental table 3). The hepatic transaminases levels of the rest participants were steady without obvious fluctuation. The effects of GTE supplementation on increasing ALT and AST were different among women with different characteristics at baseline (Table 2). The effect of GTE supplementation on the elevation of liver enzymes (both ALT and AST) was stronger in obese women (BMI ≥30 kg/m2) or current use of antibiotics (both Ps for interaction < 0.05). In contrast, the GTE supplementation had a smaller effect on ALT elevation for current drinkers of alcoholic beverages or current users of non-aspirin NSAIDs. Participants with different COMT activity did not show significant differences in hepatic transaminase changes after intake of GTE (Supplemental table 2). There was no statistically significant modifying effect of dietary intake of vitamin C, plasma total cholesterol and triglyceride, or use of aspirin, acetaminophen, statin or antiviral drugs on the GTE’s effect on elevation of ALT or AST (Table 2). The effects of GTE supplementation on the risk of developing hepatocellular injury (defined as ALT or AST > ULN) are shown in Table 3. Overall, the supplementation of GTE resulted in 4.1-fold increased risk of developing abnormal ALT (95% CI = 2.1-8.1) and 2.8-fold increased risk of developing abnormal AST (95% CI = 1.8-4.3) compared with the placebo group. The ORs of having abnormal ALT were even greater among non-drinkers of alcohol (OR = 9.3, 95% CI = 1.2-75.4), current non-users of NSAIDs (OR = 7.4, 95% CI = 1.6-33.7), or current users of antibiotics (OR = 9.3, 95% CI = 1.1-77.7) for GTE supplementation compared with their counterparts in the placebo group. The ORs of having abnormal AST were greater among current non-users of NSAIDs (OR = 5.7, 95% CI = 2.3-14.3), but less among non-drinkers of alcohol (OR = 1.8, 95% CI = 0.8-4.2), and current users of antibiotics (OR = 2.2, 95% CI = 0.8- 5.9) for GTE supplementation compared with placebo group counterparts.discussionThe present analysis has demonstrated the daily oral intake of 4 GTE capsules containing 1315 mg total catechins including 843 mg EGCG for approximately 90 days resulted in significant increase in ALT by 46.9% and AST by 26% among all participants. Women in the GTE group experienced a significant 4.1 times higher likelihood for developing abnormal ALT elevation and 2.8 times for abnormal AST elevation during the 12-month intervention period compared with those in the placebo group. To my knowledge, this is the first randomized clinical trial showing GTE supplementations-associated hepatic injury. Overall, our data support previous case reports on hepatic adverse events after taking commercial GTE, and also show that the duration of GTE supplements intake may also contribute to occurrence of liver toxicity. The onset of hepatic adverse reaction was within 3 months in 70% of the reported cases. Among subjects who consumed the green tea supplement, the mean (± SE) latent time was 179.1± 58.9 days corresponding to the amount of polyphenols varying between 186 and 1395 mg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXp6YW50aTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (7, 8). In the present study, 8 subjects began to have ALT greater than 90 U/L (1.5ULN) and stopped taking study capsules because of adverse hepatic events after taking 1315 mg catechins daily for three months. At the third month, the GTE subjects with at least one ALT greater than 60 U/L had an average 90.3 U/L ALT, which was 383.4% increase over the baseline. The drop of ALT and AST levels in the two figures after month 3 was partially due to temporary stoppage from taking GTE by participants with ALT at 1.5-5.0 ULN or those who were permanently withdrawal from the study by ALT greater than 5.0 times ULN. On the contrary, twenty healthy female and male subjects aged greater than 30 years old recruited in a phase I pharmacokinetic study consuming a single dose of 800mg EGCG or polyphenon E did not show any adverse hepatic event PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG93PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (15). The same subjects consumed 800mg EGCG or polyphenon E once daily for 4 weeks. No liver toxicity cases were reported after the 4-week catechin intervention PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG93PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (16). A longer intervention period might be required to detect liver toxicity events among high dose consumers of green tea or green tea-based supplements. Abundant evidence supported anti-oxidative healthy benefits from catechins, however catechins as pro-oxidants may contribute to collapse the mitochondrial membrane potential, generate reactive oxygen species (ROS) and deplete glutathione (GSH) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxhdGk8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (18). GSH-depleted cells were susceptible to DNA oxidation and further cell damage PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdXJ1a2F3YTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+
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ADDIN EN.CITE.DATA (19). In the rat model, EGCG related ROS formation was biphasic, indicating that low dose EGCG decreased ROS production, while high dose EGCG increased ROS generation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdWNlcmE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (25-27). However, high dose of tea catechins (e.g. ≈800mg EGCG) as pro-oxidative agents may enhance liver injury in obese subjects by exacerbating ROS production, accumulation and succeeding damages PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG93PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (28). Alcohol is one of the most common causes of chronic liver disease in the US ADDIN EN.CITE <EndNote><Cite><Author>Scaglione</Author><Year>2015</Year><RecNum>520</RecNum><DisplayText>(29)</DisplayText><record><rec-number>520</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1459103614">520</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scaglione, S.</author><author>Kliethermes, S.</author><author>Cao, G.</author><author>Shoham, D.</author><author>Durazo, R.</author><author>Luke, A.</author><author>Volk, M. L.</author></authors></contributors><auth-address>*Department of Internal Medicine, Division of Hepatology, Loyola University Medical Center daggerDepartment of Preventive Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL double daggerDivision of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI.</auth-address><titles><title>The Epidemiology of Cirrhosis in the United States: A Population-based Study</title><secondary-title>J Clin Gastroenterol</secondary-title><alt-title>Journal of clinical gastroenterology</alt-title></titles><periodical><full-title>J Clin Gastroenterol</full-title><abbr-1>Journal of clinical gastroenterology</abbr-1></periodical><alt-periodical><full-title>J Clin Gastroenterol</full-title><abbr-1>Journal of clinical gastroenterology</abbr-1></alt-periodical><pages>690-6</pages><volume>49</volume><number>8</number><edition>2014/10/08</edition><dates><year>2015</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0192-0790</isbn><accession-num>25291348</accession-num><urls><related-urls><url>;(29). The production of ROS from ethanol metabolic process is involved in mitochondrial damage and further liver toxicity ADDIN EN.CITE <EndNote><Cite><Author>Han</Author><Year>2016</Year><RecNum>431</RecNum><DisplayText>(30)</DisplayText><record><rec-number>431</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1452872447">431</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Han, K. H.</author><author>Hashimoto, N.</author><author>Fukushima, M.</author></authors></contributors><auth-address>Kyu-Ho Han, Michihiro Fukushima, Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine, Inada, Obihiro, Hokkaido 080-8555, Japan.</auth-address><titles><title>Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes</title><secondary-title>World J Gastroenterol</secondary-title><alt-title>World journal of gastroenterology</alt-title></titles><periodical><full-title>World J Gastroenterol</full-title><abbr-1>World journal of gastroenterology : WJG</abbr-1></periodical><pages>37-49</pages><volume>22</volume><number>1</number><edition>2016/01/13</edition><keywords><keyword>Electrophile</keyword><keyword>Mitogen-activating protein kinase</keyword><keyword>Plant antioxidants</keyword><keyword>Preconditioning</keyword><keyword>Reactive oxygen species</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>1007-9327</isbn><accession-num>26755859</accession-num><urls><related-urls><url>;(30). Diverse anti-oxidants can protect against hepatocellular injury from ROS damage, such as vitamins E and CPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmhpbGFzaDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA (31, 32), ademetionine, and silymarin ADDIN EN.CITE <EndNote><Cite><Author>Testino</Author><Year>2013</Year><RecNum>439</RecNum><DisplayText>(33)</DisplayText><record><rec-number>439</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1452887092">439</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Testino, G.</author><author>Leone, S.</author><author>Ansaldi, F.</author><author>Borro, P.</author></authors></contributors><auth-address>Centro Alcologico Regionale - Regione Liguria Unita Operativa di Alcologia e Patologie Correlate, Department of General Internal and Specialistic Medicine Irccs AOU San Martino -National Institute for CancerResearch, Genoa, Italy - gianni.testino@hsanmartino.it.</auth-address><titles><title>Silymarin and S-adenosyl-L-methionine (SAMe): two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view</title><secondary-title>Minerva Gastroenterol Dietol</secondary-title><alt-title>Minerva gastroenterologica e dietologica</alt-title></titles><periodical><full-title>Minerva Gastroenterol Dietol</full-title><abbr-1>Minerva gastroenterologica e dietologica</abbr-1></periodical><alt-periodical><full-title>Minerva Gastroenterol Dietol</full-title><abbr-1>Minerva gastroenterologica e dietologica</abbr-1></alt-periodical><pages>341-56</pages><volume>59</volume><number>4</number><edition>2013/11/12</edition><keywords><keyword>Antioxidants/therapeutic use</keyword><keyword>Chronic Disease</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Hepatitis, Alcoholic/*drug therapy/physiopathology</keyword><keyword>Humans</keyword><keyword>S-Adenosylmethionine/*therapeutic use</keyword><keyword>Silymarin/*therapeutic use</keyword></keywords><dates><year>2013</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1121-421X (Print)
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ADDIN EN.CITE.DATA (34-38). Catechins, agents with both anti-oxidative and pro-oxidative effects, are involved with the 63 kDa laminin receptor stimulation, which further down-regulate the Toll-like receptor 2 and 4 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5kaW1lZGE8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy
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ADDIN EN.CITE.DATA (34-36). Toll-like receptor 4 signaling pathway is associated with lipopolysaccharide-induced stimulation of inflammatory cytokines and Kupffer cell, which further induced alcoholic liver disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXVuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXVuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (34). Thus, catechins may protect from alcoholic liver disease via the reduction of lipopolysaccharide and inflammatory cytokines. Statins, antimicrobial agents and NSAIDs are most critical causes of drug-induced liver injury PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ybnNzb248L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy
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ADDIN EN.CITE.DATA (40). A systemic review concluded that use of statin increased the risk of liver enzyme elevation (OR = 1.5, 95% CI = 1.5-1.6), though the definition of raised liver enzymes was heterogeneous among different studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNlZG88L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (41).Our present study observed that the supplementation of GTE significantly decreased ALT for current users of non-aspirin NSAIDs. One possible hypothesis is that increased concentration of these drugs may increase susceptibility to hepatocellular toxicity. EGCG is a competitive inhibitor against human hepatic CYP2B6, CYP2C8, and CYP3A, which may increase the concentration of drugs metabolized by the same hepatic metabolic enzymes and induce drug interactions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNha2E8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (43). NSAIDs thus contribute to oxidative stress, increase susceptibility of mitochondrial damages and liver cell apoptosis ADDIN EN.CITE <EndNote><Cite><Author>Boelsterli</Author><Year>2002</Year><RecNum>532</RecNum><DisplayText>(44)</DisplayText><record><rec-number>532</rec-number><foreign-keys><key app="EN" db-id="2vxwws2pftftdgez52spx2z5re050zw5ser9" timestamp="1459120672">532</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boelsterli, U. A.</author></authors></contributors><auth-address>HepaTox Consulting, Pfeffingen, and Institute of Clinical Pharmacy, University of Basel, Basel, Switzerland. boelterli@hepatox.ch</auth-address><titles><title>Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide</title><secondary-title>Drug Saf</secondary-title><alt-title>Drug safety</alt-title></titles><periodical><full-title>Drug Saf</full-title><abbr-1>Drug safety</abbr-1></periodical><alt-periodical><full-title>Drug Saf</full-title><abbr-1>Drug safety</abbr-1></alt-periodical><pages>633-48</pages><volume>25</volume><number>9</number><edition>2002/07/26</edition><keywords><keyword>Anti-Inflammatory Agents, Non-Steroidal/*adverse effects/metabolism</keyword><keyword>Cholestasis/*chemically induced</keyword><keyword>Cyclooxygenase 2</keyword><keyword>Drug-Induced Liver Injury/*enzymology/metabolism</keyword><keyword>Humans</keyword><keyword>Isoenzymes/antagonists & inhibitors</keyword><keyword>Liver/*drug effects</keyword><keyword>Membrane Proteins</keyword><keyword>Oxidative Stress</keyword><keyword>Prostaglandin-Endoperoxide Synthases</keyword><keyword>Risk Factors</keyword><keyword>Sulfonamides/*adverse effects/metabolism</keyword></keywords><dates><year>2002</year></dates><isbn>0114-5916 (Print)
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ADDIN EN.CITE.DATA (13). Additionally, we used levels of both plasma aminotransferases, ALT and AST, to identify GTE-induced liver injury in the current study. Both ALT and AST had significant increases after the administration of GTE supplements, which reflected hepatotoxicity. However, since AST does not only exist in liver cells, its increase may also reflect damage in other organs. The ORs of abnormal ALT and AST elevation did not have similar change directions between non-users and users of vitamin C, aspirin and antibiotics, as well as non-drinkers and drinkers of alcohol (Table 3).A limitation of the study is that all subjects were predominant women and 97.69% were Caucasian. Lack of diversity in sex and race/ethnicity may limit the generalization of these results to the whole population. DHQI collects food intake information about the previous 12 months, and then average daily nutrient intakes at the baseline are estimated by NCI DietCalc software. This self-reported data collected at the baseline visit in the current study provided steady estimation of nutrient intakes for our trial duration. In contrast, current medication use was collected by an in-depth health survey only at the baseline visit. The duration of co-administration of these medications and GTE were unknown. The 3-5 U/L change of aminotransferase levels after 12-month GTE intervention were statistically significant, but perhaps not clinically significant. In clinical practices, a small aminotransferase elevation cannot determine hepatotoxicity, and the magnitude of elevation is not associated with the severity of liver damage. Mild hepatic aminotransferase elevation (< 5 times ULN) is a common phenomenon in the daily clinical practice. Repeated hepatic enzyme tests along with clinical guided screen tests should be firstly implemented for excluding top-ranked conditions, such as hepatitis B and C infection, and chronic alcohol consumption PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWFubmluaTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA (47). However, it is still meaningful that our findings of strong association between aminotransferase elevation and long-term high dose tea catechins could contribute to attention on tea supplements use among subjects with complicated conditions. Subjects with risk factors, such as alcohol consumption and other medication intakes, may be susceptible to moderate or marked aminotransferase elevations.CONCLUSIONThere remains uncertainty regarding the safety of long-term green tea supplementation use. This study emphasizes the importance of research evaluating the association between GTE supplementation and liver injury. Our current study demonstrates that elevations of plasma liver enzymes are associated with the use of GTE, and are aggravated by co-administrated medications. To the best of our knowledge, no prior study has used multiple measurements of plasma liver enzymes to examine their relationship with GTE use over a 12-month. Since the consumption of dietary green tea supplementation is increasingly globally, it has clinical and public health implications to monitor liver enzyme levels for high-dose long-term green tea or tea supplement users in the future. AcknowledgementI would like to thank my academic advisor Dr. Jian-Min Yuan, for his mentorship I have received during my graduate years. I sincerely appreciate for the learning and practicing opportunities provided by Dr. Yuan. Without his guidance and persistent help this master project would not have been possible. I am also thankful for valuable comments from my committee members Dr. Lesley Butler and Dr. Thomas Kensler.I would also like to thank the principal investigator of the Green Tea Study, Dr. Mindy Kurzer, Professor and Director of Healthy Foods, Healthy Lives Institute, University of Minnesota, who offered me the opportunity to be involved in such a great study. I acknowledge Dr. Hamed Samavat, Dr. Allison Dostal, and all staffs in the Department of Food Science and Nutrition, University of Minnesota, for their great work in the Green Tea Study. I appreciate their detailed explanations and supports when I had misunderstandings about the data.My sincere thanks also goes to Renwei Wang who gave me supports in analysis and interpretation of data. Finally, I would especially like to express my very profound gratitude to my parents for their continuous supports and encouragements throughout my years of study. bibliography ADDIN EN.REFLIST 1.Graham HN. Green tea composition, consumption, and polyphenol chemistry. Preventive medicine. 1992;21:334-50.2.Suliburska J, Bogdanski P, Szulinska M, Stepien M, Pupek-Musialik D, Jablecka A. Effects of green tea supplementation on elements, total antioxidants, lipids, and glucose values in the serum of obese patients. Biological trace element research. 2012;149:315-22.3.Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, et al. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. Jama. 2006;296:1255-65.4.Sun CL, Yuan JM, Lee MJ, Yang CS, Gao YT, Ross RK, et al. Urinary tea polyphenols in relation to gastric and esophageal cancers: a prospective study of men in Shanghai, China. Carcinogenesis. 2002;23:1497-503.5.Yuan JM, Gao YT, Yang CS, Yu MC. Urinary biomarkers of tea polyphenols and risk of colorectal cancer in the Shanghai Cohort Study. International journal of cancer Journal international du cancer. 2007;120:1344-50.6.Kim K, Vance TM, Chun OK. Estimated intake and major food sources of flavonoids among US adults: changes between 1999-2002 and 2007-2010 in NHANES. European journal of nutrition. 2016;55:833-43.7.Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F, Raschetti R, Santuccio C, et al. 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Clinical chemistry. 2000;46:2050-68.Table SEQ Table \* ARABIC 1 Distributions of characteristics at baseline among study participants in the green tea extract and placebo group, The Minnesota Green Tea Trial, 2009-2015Characteristics aPlaceboGTEPbNo. of total subjects, n (%)494 (100)c505 (100)cAge at baseline (year), mean (SD)59.6(5.1)59.9(5.0)0.444Caucasian race, N (%)b477(97.2)494(98.2)0.266Level of education, N (%)High school or below37(7.5)30(6.0)0.181Some College84(17.1)108(21.5)College Graduate212(43.2)224(44.5)Postgraduate/Professional Degree158(32.2)141(28.0)Body Mass Index (kg/m2), mean (SD)25.1(3.8)25.2(3.7)0.843<25, n (%)271 (54.9)277 (54.8)0.27425- <30, n (%)175 (35.4)164 (32.5)≥30, n (%)48 (9.7)64 (12.7)Former smokers, n (%)156(31.6)157(31.1)0.777No. years of quitting smoking, mean (SD) 25.8(11.4)25.3(10.4)0.488Current use of alcohol, n (%)414(84.2)402(79.6)0.063No. of drinks per week, mean (SD) 3.4(3.0)3.3(2.9)0.929Current use of antibiotics, n (%)68 (13.8)71 (14.1)0.893Current use of antiviral drugs, n (%)15 (3.0)17 (3.4)0.767Current use of aspirin, n (%)137 (27.8)135 (26.8)0.722Current use of non-aspirin NSAIDs, n (%)328 (66.5)348 (69.1)0.395Current use of acetaminophen, n (%)133 (27.0)149 (29.6)0.365Current use of statin, n (%)105 (21.3)112 (22.2)0.724Dietary intake of vitamin C (mg/Kcal), mean (SD)78.1 (35.7)77.0 (37.4)0.661Less than median (≤71.57), n (%)224(48.7)232(51.3)0.427Greater than median (>71.57), n (%)236(51.3)220(48.7)Total cholesterol (mg/dl), mean (SD)209.2 (31.7)206.8 (30.6)0.234<200, n (%)185 (40.3)194 (42.9)0.671200-240, n (%)203 (44.2)195 (43.2)>240, n (%)71 (15.5)63 (13.9)Total triglyceride (mg/dl), mean (SD)102.1 (48.9)93.6 (43.3)0.005<150, n (%)395 (86.1)407 (90.0)0.064≥150, n (%)64 (13.9)45 (10.0)COMT Genotypes, n (%)LL (low activity)150(30.4)171(33.9)0.388HL (Intermediate activity)213(43.1)198(39.2)HH (High activity)131(26.5)136(26.9)?a GTE, green tea extract; SD, standard deviation; COMT, catecheol-O-methyltransferase; NSAIDs, non-steroidal anti-inflammatory drugsb 2-sided P values were derived from t-test (for continuous variables) or chi-squared test (for categorical or nominal variables).c The sum of some variables may be less than the total due to missing values.Table SEQ Table \* ARABIC 2 Average changes of plasma alanine transaminase (ALT) and aspartate transaminase (AST) during the intervention period from baseline in all subjects as well as in subgroups stratified by selected baseline characteristics, the Minnesota Green Tea Trial, 2009-2015?ALT (U/L), mean (95% CI)Pint bAST (U/L), mean (95% CI)Pint bPlaceboGTEPaPlaceboGTEPaMean enzyme level at baseline17.9 (17.3, 18.5)17.3 (16.7, 17.9)0.13920.2 (19.8, 20.7)19.6 (19.1, 20.0)0.023Mean changes of enzyme from baselineAll subjects0.1 (-1.0, 1.2)4.9(3.8, 6.1)<.00010.2(-0.7, 1.1)3.6(2.7, 4.5)<.0001Subgroups stratified byBMI (kg/m2)0.03080962513335000295275333375000.036<25-0.1 (-1.3, 1.2)4.8 (3.5, 6.0)<.00010.3 (-0.6, 1.3)3.6 (2.6, 4.6)<.000125- <300.4 (-0.9, 1.7)4.3 (2.9, 5.7)<.00010.2 (-0.9, 1.2)2.8 (1.8, 3.9)0.000≥30-0.3 (-2.3, 1.8)7.3 (5.5, 9.1)<.0001-0.01 (-1.5, 1.5)5.3 (3.9, 6.6)<.0001Pc0.6990.0050.8780.002Current Alcohol Drinker0.004295275152400000.004No-1.3 (-3.0, 0.4)6.0 (4.5, 7.5)<.0001-0.5 (-1.8, 0.8)4.5 (3.4, 5.7)<.0001Yes0.3 (-0.8, 1.5)4.6 (3.5, 5.8)<.00010.4 (-0.5, 1.3)3.3 (2.4, 4.2)<.0001Pc0.0380.0470.1080.012Dietary vitamin C 0.0770.269Low (≤71.57 mg/Kcal)-0.1 (-1.3, 1.1)4.7 (3.5, 5.9)<.00010.3 (-0.5, 1.2)3.4 (2.6, 4.2))<.0001High (>71.57 mg/Kcal)0.02 (-1.2, 1.2)3.4 (2.2, 4.6)<.00010.02 (-0.8, 0.8)2.5 (1.6, 3.3)<.0001Pc0.8220.0240.4410.021Total cholesterol level (mg/dl)0.3380.576<200-0.8 (-2.1, 0.4)4.0 (2.8, 5.3)<.00014286258572500-0.06 (-0.9, 0.8)2.9 (2.1, 3.8)<.0001200-2400.3 (-0.9, 1.6)4.0 (2.7, 5.2)<.0001161925133350000.2 (-0.6, 1.1)3.0 (2.2, 3.9)<.0001>2401.2 (-0.5, 2.8)4.8 (3.1, 6.6)0.0020.7 (-0.4, 1.9)2.8 (1.6, 4.0)0.014Pc0.0320.5840.4080.926Total triglyceride level (mg/dl)0.8150.829<150-0.3 (-1.4, 0.8)3.9 (2.8, 5.0)<.0001-0.04 (-0.8, 0.7)2.8 (2.1, 3.5)<.0001≥1501.5 (-0.3, 3.2)5.9 (4.0, 7.9)0.0011.3 (0.1, 2.5)3.9 (2.6, 5.3)0.004Pc0.0300.0280.0220.086Table 2 continuedALT (U/L), mean (95% CI)Pint bAST (U/L), mean (95% CI)Pint bPlaceboGTEPaPlaceboGTEPaCurrent Use of Aspirin0.1010.331No0.2 (-0.9, 1.4)5.2 (4.1, 6.4)<.00010.4 (-0.6, 1.3)3.9 (2.9, 4.8)<.0001Yes-0.2 (-1.6, 1.2)4.2 (2.7, 5.6)<.0001-0.01 (-1.1, 1.1)2.9 (1.8, 4.0)0.000Pc0.5080.0950.4390.035Current Use of Non-aspirin NSAIDs0.0020.081No-0.9 (-2.3, 0.4)5.7 (4.3, 7.1)<.0001-0.07 (-1.1, 1.0)4.0 (2.9, 5.1)<.0001Yes0.6 (-0.6, 1.8)4.6 (3.4, 5.8)<.00010.4 (-0.5, 1.3)3.4 (2.5, 4.3)<.0001Pc0.0120.0710.2880.165Current Use of Acetaminophen0.0870.390No-0.2 (-1.4, 0.9)5.0 (3.9, 6.2)<.00010.1 (-0.8, 1.0)3.6 (2.6, 4.5)<.0001Yes1.0 (-0.5, 2.4)4.8 (3.4,6.1)<.0010.7 (-0.5, 1.8)3.6 (2.5, 4.7)<.001Pc0.0560.6340.2280.984Current Use of Statin0.5720.707No0.3 (-0.9, 1.4)5.0 (3.8, 6.2)<.00010.3 (-0.6, 1.3)3.6 (2.7, 4.6)<.0001Yes-0.5 (-2.1, 1.0)4.8 (3.2, 6.3)<.0001-0.1 (-1.3, 1.1)3.5 (2.3, 4.6)<.0001Pc0.2570.7100.3990.735Current Use of Antivirus medications0.4520.134No0.1 (-1.0, 1.2)4.9 (3.8, 6.1)<.00010.3 (-0.6, 1.2)3.5 (2.6, 4.4)<.0001Yes-1.1 (-4.3, 2.1)5.3 (2.3, 8.4)0.004-0.7 (-3.0, 1.7)5.0 (2.7, 7.2)0.001Pc0.4410.7820.4260.179Current Use of Antibiotics0.0380.005No0.3(-0.8, 1.5)4.8 (3.7, 6.0)<.0001 0.4 (-0.5, 1.3)3.4 (2.5, 4.3)<.0001Yes-1.3 (-3.1, 0.5)5.6 (3.9, 7.3)<.0001-0.6 (-1.9, 0.8)4.7 (3.4, 6.0)<.0001Pc0.0530.3330.1140.017GTE, green tea extract; BMI, body mass index; CI, confidence interval; NASID, Nonsteroidal anti-inflammatory drug; All means are from Least Squares Means.a 2-sided P values were derived from generalized linear mixed models comparing the changes of liver enzyme (ALT or AST) during the intervention period from baseline of women in the GTE group to the corresponding changes in the placebo group after adjustments for age, BMI, smoking status and level of education.b 2-sided P values were derived from the same model assessing the interaction between the intervention (GTE or placebo) and the stratifying variables on the liver enzyme (ALT or AST) with the same adjustments. c 2-sided P values were derived from the same model comparing the differences in changes of liver enzyme (ALT or AST) from baseline among different levels of stratifying variables within the GTE or placebo group.Table SEQ Table \* ARABIC 3 Odds ratio of developing abnormal liver enzyme (ALT or AST) for women assigned in the GTE versus placebo group during the 12-month treatment period, the Minnesota Green Tea Trial, 2009-2015Treatment status by stratifying variable aAlanine transaminase (ALT)Aspartate transaminase (AST)NormalAbnormal bOR (95% CI) c?NormalAbnormal bOR (95% CI) cAll SubjectsPlacebo483111.00458361.00GTE457484.1 (2.1, 8.2)412932.8 (1.8, 4.3)BMINormal BMI (< 25 kg/m2)Placebo26741.00252191.00GTE251266.1 (2.1, 18.1)219583.3 (1.9, 5.8)Overweight (25- <30 kg/m2)Placebo16871.00161141.00GTE150141.8 (0.7, 4.9)141231.6 (0.7, 3.3)Obesity (≥30 kg/m2)Placebo480N/A4531.00GTE568N/A52124.9 (1.0, 24.4)Alcohol ConsumptionNon-drinkers of alcohol Placebo7711.0068101.00GTE89149.3 (1.2, 75.4)79241.8 (0.8, 4.2)Current drinkers of alcoholPlacebo404101.00388261.00GTE368343.5 (1.7, 7.3)333693.1 (1.9, 5.1)Use of AntibioticsNon-users of antibioticsPlacebo415101.00396291.00GTE395383.7 (1.8, 7.6)356773.0 (1.8, 4.8)Current users of antibioticsPlacebo6711.006171.00GTE61109.3 (1.1, 77.7)55162.2 (0.8, 5.9)Use of Anti-viral drugsNon-users of anti-viral drugsPlacebo467111.00442361.00GTE443443.9 (2.0, 7.7)399882.7 (1.7, 4.1)Table 3 continuedTreatment status by stratifying variable aAlanine transaminase (ALT)Aspartate transaminase (AST)NormalAbnormal bOR (95% CI) cNormalAbnormal bOR (95% CI) cUse of Anti-viral drugsCurrent users of anti-viral drugsPlacebo150N/A150N/AGTE134N/A125N/AUse of AspirinNon-users of aspirinPlacebo34791.00327291.00GTE332374.2 (2.0, 8.8)295742.9 (1.8, 4.8)Current users of aspirinPlacebo13521.0013071.00GTE124115.1 (1.0, 27.2)116192.2 (0.8, 5.6)Use of Non-aspirin NSAIDsNon-users of Non-aspirin NSAIDsPlacebo16321.0015781.00GTE142147.4 (1.6, 33.7)127295.7 (2.3, 14.3)Current users of Non-aspirin NSAIDsPlacebo31991.00300281.00GTE314343.4 (1.6, 7.4)284642.2 (1.3, 3.6)Use of AcetaminophenNon-users of AcetaminophenPlacebo35461.00336241.00GTE321345.4 (2.2, 13.3)290652.9 (1.7, 4.8)Current users of AcetaminophenPlacebo12851.00121121.00GTE135142.7 (0.9, 7.7)121282.6 (1.2, 5.6)Use of StatinNon-users of StatinPlacebo38171.00362261.00GTE358344.8 (2.1, 11.0)322703.1 (1.9, 5.2)Current users of StatinPlacebo10141.0095101.00GTE98143.5 (1.0, 11.9)89232.2 (0.9, 5.1)Table 3 continuedTreatment status by stratifying variable aAlanine transaminase (ALT)Aspartate transaminase (AST)NormalAbnormal bOR (95% CI) cNormalAbnormal bOR (95% CI) cVitamin C intakeLow vitamin C intakePlacebo22041.00206181.00GTE213194.7 (1.6, 14.2)191412.5 (1.4, 4.7)High vitamin C intakes Placebo23061.00220161.00GTE206142.3 (0.8, 6.5)185353.0 (1.5, 5.9)Cholesterol LevelsNormal cholesterol level (<200mg/dl)Placebo18231.00168171.00GTE177175.6 (1.6, 20.1)162322.0 (1.0, 3.8)Mildly high cholesterol level (200-240mg/dl)Placebo19761.00191121.00GTE183122.0 (0.7, 5.4)162333.3 (1.6, 7.0)High cholesterol level (>240mg/dl)Placebo7011.006651.00GTE5942.4 (0.2,26.5)52112.2 (0.7, 7.4)Triglyceride LevelsNormal triglyceride level (<150mg/dl)Placebo38871.00368271.00GTE378293.9 (1.7, 9.3)341662.8 (1.7, 4.5)High triglyceride level (≥150mg/dl)Placebo6131.005771.00GTE4141.5 (0.3, 8.1)?35101.6 (0.5, 5.0)a GTE, green tea extract; CI, confidence interval; BMI, body mass index; OR, odds ratio; NSAIDs, non-steroidal anti-inflammatory drugsb Abnormal ALT > 60 U/L; abnormal AST>35 U/L, at least in one of the monthly liver function test after randomization.c Odds ratios were derived from unconditional logistic regression models that also included age, smoking status and level of education. 19050190500106,758 women’s mammograms screened?24,416 invitations mailed to eligible women?82,342 women ineligible due to not meeting age and breast density criteria?76 ineligible for the present study3 missing baseline liver tests51 none liver tests at any follow-up visit22 had baseline ALT greater than 60 U/L or baseline AST greater than 35 U/L?999 participants in the present study?505 women in GTE group?494 women in Placebo group?5,473 women further assessed for eligibility via phone screening?1,081 consented1,075 randomized?516 non-respondents?516 ineligible?00106,758 women’s mammograms screened?24,416 invitations mailed to eligible women?82,342 women ineligible due to not meeting age and breast density criteria?76 ineligible for the present study3 missing baseline liver tests51 none liver tests at any follow-up visit22 had baseline ALT greater than 60 U/L or baseline AST greater than 35 U/L?999 participants in the present study?505 women in GTE group?494 women in Placebo group?5,473 women further assessed for eligibility via phone screening?1,081 consented1,075 randomized?516 non-respondents?516 ineligible?190505876925Figure SEQ Figure \* ARABIC 1 Flow diagram of participant screening, enrollment, randomization, and eligible for the present sub-study, the Minnesota Green Trial, 2009-2015. ALT Alanine transaminase; AST Aspartate transaminaseFigure 1 Flow diagram of participant screening, enrollment, randomization, and eligible for the present sub-study, the Minnesota Green Trial, 2009-2015. ALT Alanine transaminase; AST Aspartate transaminase7597111475860U/L0060U/LFigure SEQ Figure \* ARABIC 2 Joint lines of percentage of ALT increases over the baseline (a) and average ALT level (b) at each visit. Each line in the figure shows the outcomes among all subjects or subjects with at least once ALT greater than 60 U/L during 12-month intervention period in GTE or placebo group. For subjects with at least once ALT abnormal elevation, figure 1(a) also shows the number of subjects at each visit, the number of subjects without taking GTE or placebo capsules, and the number of accumulated drop-offs at the same time point. ALT alanine transaminase; GTE green tea extract.82552292350Figure SEQ Figure \* ARABIC 3 Joint lines of percentage of AST increases over the baseline (a) and average AST level (b) at each visit. Each line in the figure shows the outcomes among all subjects or subjects with at least once AST greater than 35 U/L during 12-month intervention period in GTE or placebo group. AST aspartate transaminase; GTE green tea extract.Figure 3 Joint lines of percentage of AST increases over the baseline (a) and average AST level (b) at each visit. Each line in the figure shows the outcomes among all subjects or subjects with at least once AST greater than 35 U/L during 12-month intervention period in GTE or placebo group. AST aspartate transaminase; GTE green tea extract.825515973835U/L0035U/Lappendix: SUPPLEMENTAL TABLESSupplemental Table SEQ Supplemental_Table \* ARABIC 1 Baseline mean concentrations of alanine transaminase (ALT) and aspartate transaminase (AST) in all subjects as well as in subgroups stratified by selected characteristics of study participants by treatment status (GTE or placebo) , the Minnesota Green Trial, 2009-2015?ALT (U/L), mean (95% CI)?AST (U/L), mean (95% CI)PlaceboGTEP*PlaceboGTEP*Mean enzyme levels at baseline 17.9 (17.3, 18.5)17.3 (16.7, 17.9)0.13920.2 (19.8, 20.7)19.6 (19.1, 20.0)0.023Mean enzyme levels within stratified categories BMI (kg/m2)<2517.3 (16.5, 18.1)17.0 (16.2, 17.8)0.62120.7 (20.2, 21.3)20.0 (19.4, 20.5)0.04325- <3018.2 (17.3, 19.2)17.9 (16.9, 18.9)0.58019.7 (19.0, 20.4)19.4 (18.7, 20.1)0.540≥3020.4 (18.6, 22.2)17.5 (15.9, 19.1)0.01619.6 (18.3, 20.9)18.5 (17.4, 19.6)0.214P*0.0060.39955245085725000.0300.056Current Alcohol DrinkerNo19.2 (17.8, 20.6)17.2 (16.0, 18.4)0.03121.9 (20.9, 22.9)19.6 (18.8, 20.4)<0.01Yes17.7 (17.1, 18.4)17.4 (16.7, 18.1)0.44119.9 (19.4, 20.4)19.6 (19.1, 20.1)0.283P*0.05680.768<0.0010.948Dietary vitamin C intake (mg/Kcal)Less than median intake level (≤71.57)18.0 (17.1, 18.9)16.9 (16.1, 17.8)0.06820.3 (19.6, 20.9)19.3 (18.7, 20.0)0.026Greater than median intake level (>71.57)17.8 (16.9, 18.7)18.0 (17.1, 18.9)0.79020.3 (19.6, 20.9)19.8 (19.1, 20.4)0.272P*0.7720.0770.9870.289Baseline blood cholesterol level (mg/dl)<20018.6 (17.7, 19.6)17.7 (16.8, 18.7)0.15820.5 (19.8, 21.2)19.8 (19.1, 20.5)0.142200-24017.3 (16.4, 18.2)17.7 (16.7, 18.6)0.53720.1 (19.5, 20.8)19.5 (18.8, 20.2)0.145>24017.7 (16.2, 19.1)15.6 (14.1, 17.2)0.06220.0 (19.0, 21.1)19.0 (17.9, 20.1)0.181P*0.1060.0510.6660.431Baseline blood triglycerides level (mg/dl)<15017.6 (16.9, 18.3)17.2 (16.5, 17.9)0.42920.3 (19.8, 20.8)19.4 (18.9, 19.9)0.007≥15019.5 (18.0, 21.1)18.6 (16.8, 20.4)0.44120.0 (18.8, 21.1)20.3 (19.0, 21.6)0.678P*0.0230.1640.5810.215Supplemental Table 1 continuedALT (U/L), mean (95% CI)AST (U/L), mean (95% CI)PlaceboGTEP*PlaceboGTEP*Current Use of AspirinNo17.8 (17.0, 18.5)17.1 (16.4, 17.9)0.18420.2 (19.7, 20.7)19.6 (19.1, 20.1)0.051Yes18.2 (17.2, 19.3)17.9 (16.8, 18.9)0.62720.3 (19.5, 21.1)19.7 (18.9, 20.5)0.250P*0.4450.6270.8590.809Current Use of Non-aspirin NSAIDsNo18.8 (17.8, 19.8)16.5 (15.5, 17.5)0.00120.4 (19.7, 21.1)19.7 (19.0, 20.5)0.165Yes17.4 (16.7, 18.2)17.7 (17.0, 18.5)0.51920.2 (19.6, 20.7)19.5 (19.0, 20.1)0.075P*0.0230.5190.5660.684Current Use of AcetaminophenNo18.2 (17.5, 18.9)17.3 (16.5, 18.0)0.04720.3 (19.8, 20.8)19.6 (19.0, 20.1)0.023Yes17.1 (16.0, 18.2)17.5 (16.5, 18.5)0.54620.0 (19.0, 20.1)19.7 (19.0, 20.4)0.539P*0.0770.6750.5080.754Current Use of StatinNo17.4 (16.7, 18.0)16.8 (16.1, 17.5)0.16720.0 (19.5, 20.5)19.2 (18.6, 19.7)0.011Yes19.6 (18.3, 20.8)19.1 (18.0, 20.3)0.59521.1 (20.2, 22.0)21.0 (20.1, 21.8)0.835P*0.0010.0000.021<0.01Current Use of Antivirus No18.0 (17.3, 18.6)17.4 (16.8, 18.0)0.17420.2 (19.8, 20.7)19.7 (19.2, 20.1)0.051Yes16.3 (13.2, 19.3)15.7 (12.8, 18.6)0.78620.7 (18.5, 22.9)17.8 (15.8, 19.9)0.062P*0.2860.2460.6750.087Current Use of AntibioticsNo17.8 (17.1, 18.4)17.2 (16.5, 17.8)0.15620.1 (19.7, 20.6)19.6 (19.1, 20.1)0.081Yes18.6 (17.1, 20.2)18.2 (16.8, 19.7)0.70520.9 (19.8, 22.0)19.5 (18.5, 20.6)0.071P*0.3130.178??0.2100.876?GTE, green tea extract; CI, confidence interval; BMI, body mass index; NSAIDs, non-steroidal anti-inflammatory drugs*2-sided P values were derived from generalized linear models comparing the baseline liver enzymes (ALT or AST) between treatment groups, or between different categories of stratifying variable within placebo/GTE group after adjustments for age, smoking status and level of education.Supplemental Table SEQ Supplemental_Table \* ARABIC 2 The changes of alanine transaminase (ALT) and aspartate transaminase (AST) during the GTE treatment by COMT genotype, the Minnesota Green Tea Trial, 2009-2015Mean changes from baseline (95% CI)ALT (U/L), mean (95% CI)Pint*AST (U/L), mean (95% CI)Pint *PlaceboGTEP*PlaceboGTEP*All subjects0.1 (-1.0, 1.2)4.9(3.8, 6.1)<.00010.2(-0.7, 1.1)3.6(2.7, 4.5)<.0001Stratifying VariablesCOMT Genotypes0.9140.683LL (low activity)0.2 (-1.2, 1.6)5.2 (3.8, 6.5)<.00010.6 (-0.5, 1.7)3.6 (2.5, 4.6)<.0001HL (Intermediate activity)-0.3 (-1.6, 1.0)4.3 (3.1, 5.7)<.0001-0.02 (-1.0, 1.0)3.5 (2.4, 4.5)<.0001HH (High activity)0.5 (-0.9, 1.9)5.4 (4.1, 7.0)<.00010.2 (-0.9, 1.3)3.7 (2.6, 4.8)<.0001P*0.4780.202??47625104775000.4190.897??GTE, green tea extract; COMT catecheol-O-methyltransferase; CI, confidence interval; BMI, body mass index; All means are from Least Squares Means.*All 2-sided P values were derived from generalized linear mixed models comparing the changes of liver enzyme (ALT or AST) during the intervention period from baseline between treatment groups, or among different categories of COMT genotype, as well as interactions after adjustments for age, BMI, smoking status and level of education.Supplemental Table SEQ Supplemental_Table \* ARABIC 3 Demographic details and alanine transaminase (ALT) examinations of subjects who had at least once ALT greater than 60 U/L and stopped taking GTE or placebo during the 12-month study period, the Minnesota Green Trial, 2009-2015IDAge at baselineTreatment Assignment COMT genotypeBaselineDate of RandomizationFirst Abnormal ElevationHighest ALT TestLast ALT TestDate of Stopping taking GTEStatusNoteDateALT (U/L)DateALT (U/L)DateValue (U/L)DateValue (U/L)2054.3GTELL11/16/20091412/2/20096/14/2010686/14/2010688/23/2010336/14/2010WithdrawalShe was off the study for 2 months before her ALT got back6351GTEHH3/4/2010174/16/20108/3/2010658/3/20106511/2/2010418/3/2010WithdrawalHer ALT was high again when retaking the GTE.7254.3GTELL3/24/2010174/23/20107/2/20101187/2/20101188/12/2010227/2/2010WithdrawalShe was terminated from the study immediately when her ALT was 118U/L.9255.3PlaceboHL4/7/2010215/24/20109/28/2010679/28/20106710/25/2010539/28/2010WithdrawalShe was terminated from the study immediately when her AST was 90U/L.11662.1GTEHH4/22/2010177/1/20109/16/20101179/16/201011711/24/2010589/16/2010WithdrawalHer ALT was high again when retaking the GTE.13261.6GTEHL5/26/2010177/18/201011/29/201026811/29/201026812/20/20108211/29/2010WithdrawalShe was terminated from the study immediately when her ALT was 268U/L.14553.4GTEHL5/27/2010287/28/20109/3/2010809/3/2010803/28/2011299/3/2010WithdrawalHer ALT was high again when retaking the GTE. She asked to withdraw from the study.19751.7GTEHH7/16/2010169/28/20102/4/20113832/23/20113993/8/2011312/4/2011WithdrawalShe was terminated from the study immediately when her ALT was 383U/L.21854.5GTELL9/1/20101210/14/20101/18/20114831/18/20114834/5/2011381/18/2011WithdrawalShe was terminated from the study immediately when her ALT was 483U/L.Supplemental Table 3 continuedIDAge at baselineTreatment Assignment COMT genotypeBaselineDate of RandomizationFirst Abnormal ElevationHighest ALT TestLast ALT TestDate of Stopping taking GTEStatusNotesDateALT (U/L)DateALT (U/L)DateValue (U/L)DateValue (U/L)24064.1GTEHL10/14/20101411/9/20102/17/20111282/17/20111284/15/2011472/17/2011WithdrawalShe was terminated from the study immediately when her ALT was 128U/L.46165.4GTEHL12/20/2011181/19/20125/10/20121028/6/20121438/22/2012835/10/2012WithdrawalHer ALT was high again when retaking the GTE.47562.8GTEHL12/23/2011301/26/20123/15/2012813/15/2012818/13/2012273/15/2012WithdrawalShe asked to withdraw from the study.47752.8GTELL12/9/2011162/1/20128/9/20127011/2/2012205511/6/2012176211/2/2012WithdrawalShe was terminated from the study immediately when her ALT was 2055U/L.55857.1GTEHL2/8/2012133/6/20126/19/20124976/19/20124978/8/2012596/19/2012Completed - ITTShe was terminated from the study immediately when her ALT was 497U/L.60856.4GTEHL2/20/2012274/2/20127/11/20121927/11/20121928/7/2012797/11/2012WithdrawalShe was terminated from the study immediately when her ALT was 192U/L.83363.8GTEHH6/12/2012207/20/201211/1/20121141/2/20133032/25/20135911/1/2012Completed - ITTHer ALT was high again when retaking the GTE. She was terminated from the study immediately when her ALT was 303U/L.86465.9GTELL6/22/2012148/9/201211/20/201289611/20/20128961/10/20138011/20/2012Completed - ITTShe was terminated from the study immediately when her ALT was 896U/L.99268.5GTELL10/9/20121712/13/20122/21/2013933/21/20131205/24/52013542/21/2013WithdrawalHer ALT was high again when retaking the GTE. Supplemental Table 3 continuedIDAge at baselineTreatment Assignment COMT genotypeBaselineDate of RandomizationFirst Abnormal ElevationHighest ALT TestLast ALT TestDate of Stopping taking GTEStatusNotesDateALT (U/L)DateALT (U/L)DateValue (U/L)DateValue (U/L)99667.6GTEHH11/15/20122612/27/20123/7/20132433/7/20132433/21/2013413/7/2013WithdrawalShe was terminated from the study immediately when her ALT was 243U/L.GTE, green tea extract; COMT catecheol-O-methyltransferase; LL low activity; HL intermediate activity; HH high activity; AST aspartate transaminase; ITT intention-to-treat ................
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