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Abstract
The medical disorders of alcoholism rank among the leading public health problems worldwide and the need for predictive and prognostic risk markers for assessing alcohol use disorders (AUD) has been widely acknowledged. Early-phase detection of problem drinking and associated tissue toxicity are important prerequisites for timely initiations of appropriate treatments and improving patient's committing to the objective of reducing drinking. Recent advances in clinical chemistry have provided novel approaches for a specific detection of heavy drinking through assays of unique ethanol metabolites, phosphatidylethanol (PEth) or ethyl glucuronide (EtG). Carbohydrate-deficient transferrin (CDT) measurements can be used to indicate severe alcohol problems. Hazardous drinking frequently manifests as heavy episodic drinking or in combinations with other unfavorable lifestyle factors, such as smoking, physical inactivity, poor diet or adiposity, which aggravate the metabolic consequences of alcohol intake in a supra-additive manner. Such interactions are also reflected in multiple disease outcomes and distinct abnormalities in biomarkers of liver function, inflammation and oxidative stress. Use of predictive biomarkers either alone or as part of specifically designed biological algorithms helps to predict both hepatic and extrahepatic morbidity in individuals with such risk factors. Novel approaches for assessing progression of fibrosis, a major determinant of prognosis in AUD, have also been made available. Predictive algorithms based on the combined use of biomarkers and clinical observations may prove to have a major impact on clinical decisions to detect AUD in early pre-symptomatic stages, stratify patients according to their substantially different disease risks and predict individual responses to treatment.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and Tampere University, Seinäjoki, Finland.
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2
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Eguchi A, Franz N, Kobayashi Y, Iwasa M, Wagner N, Hildebrand F, Takei Y, Marzi I, Relja B. Circulating Extracellular Vesicles and Their miR "Barcode" Differentiate Alcohol Drinkers With Liver Injury and Those Without Liver Injury in Severe Trauma Patients. Front Med (Lausanne) 2019; 6:30. [PMID: 30859103 PMCID: PMC6397866 DOI: 10.3389/fmed.2019.00030] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 02/01/2019] [Indexed: 12/16/2022] Open
Abstract
Short Summary: Extracellular vesicles (EVs), released during tissue/cell injury, contain a “barcode” indicating specific microRNAs (miRs) that can uncover their origin. We examined whether systemic EVs possessing hepatic miR-signatures would indicate ongoing liver injury and clinical complications in trauma patients (TP). We grouped the patients of alcoholic drinkers into “alcohol-drinkers with liver injury (LI)” (EtOH with LI) or “alcohol-drinkers without LI” (EtOH w/o LI) and we compared these groups to “non-drinkers” (no EtOH). When we examined patient blood from the EtOH with LI group we found the total number of EVs to be increased, along with an increase in miR-122 and let7f—two EV-associated miRNAs—and several inflammation-associating cytokines, such as interleukin (IL)-6 and IL-33. In contrast, all of the aforementioned readouts were found to be decreased in the EtOH w/o LI group. These novel data demonstrate that hepatocyte damage in alcohol-intoxicated trauma patients presenting with liver injury can be reflected by an increase in circulating serum EVs, their specific miR-“barcode” and the concomitant increase of systemic inflammatory markers IL-6 and IL-33. Anti-inflammatory effect of alcohol-drinking in EtOH w/o LI can be presented by a reduced number of hepato-derived EVs, no upregulation of IL-6 and IL-33, and a miR “barcode” different from patients presenting with liver injury. Background: Alcohol abuse is associated with (neuro)protective effects related to (head) injuries, and with negative effects regarding infection rates and survival in severely injured trauma patients (TP). Extracellular vesicles (EVs), which are released during tissue and/or cell injury, can contain a “barcode” including specific microRNAs (miRs) that uncover their origin. We examined whether EVs with a hepatic miR signature can be systemically measured, and whether they can indicate ongoing liver injury in alcohol-intoxicated TP and foretell clinical complications. Patients/Methods: We enrolled 35 TP and measured blood EVs, IL-6, TNF-alpha, IL-1beta, IL-10 and IL-33, alcohol (ethanol, EtOH) concentration (BAC), GLDH, GGT, AST, ALT, leukocytes, platelets, and bilirubin. Within circulating EVs we measured the expression levels of miR-122, let7f, miR21, miR29a, miR-155, and miR-146a. Patients of alcohol-drinkers were grouped into “alcohol drinkers with liver injury (LI)” (EtOH with LI) or “alcohol drinkers without LI” (EtOH w/o LI) and compared to “non-drinkers” (no EtOH). We assessed systemic injury characteristics and the outcome of hospitalization with regard to sepsis, septic shock, pneumonia, or mortality. Results: EtOH with LI patients had significantly increased rates of pneumonia vs. the EtOH w/o LI group. EVs, IL-6, and IL-33 levels were significantly increased in EtOH with LI vs. EtOH w/o LI group (p < 0.05). EV number correlated positively with ALT and IL-6 (p < 0.0001). Two miRs, miR-122 and let7f, were increased only in the blood EVs from the EtOH with LI group (p < 0.05). Five miRs, miR-122, let7f, miR-21, miR-29a, and miR-146a, were reduced in the blood EVs from the EtOH w/o LI group, vs. no EtOH (p < 0.05). Notably miR-122 correlated significantly with increased bilirubin levels in the EtOH with LI group (p < 0.05). Conclusions: Liver injury in alcohol-intoxicated TP is reflected by increased EV numbers, their specific miR barcode, and the correlated increase of systemic inflammatory markers IL-6 and IL-33. Interestingly, severely injured TP without liver injury were found to have a reduced number of liver-derived EVs, no observed inflammatory infiltration and reduced specific miR “barcode.”
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Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan.,JST, PRESTO, Saitama, Japan
| | - Niklas Franz
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Yoshinao Kobayashi
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Nils Wagner
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Frank Hildebrand
- Department of Orthopaedic Trauma, RWTH Aachen University, Aachen, Germany
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
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Hulsegge G, Herber-Gast GCM, Spijkerman AMW, Susan H, Picavet J, van der Schouw YT, Bakker SJL, Gansevoort RT, Dollé MET, Smit HA, Monique Verschuren WM. Obesity and Age-Related Changes in Markers of Oxidative Stress and Inflammation Across Four Generations. Obesity (Silver Spring) 2016; 24:1389-96. [PMID: 27145150 DOI: 10.1002/oby.21515] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 02/24/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The prevalence of obesity increases with age and is higher in each younger generation (unfavorable generation shift). This may influence patterns of oxidative stress and inflammation. Age-related changes and generation shifts in markers of oxidative stress and inflammation were investigated, specifically addressing the role of body mass index (BMI). METHODS Four generations (aged 26-35, 36-45, 46-55, and 56-65 at baseline) (N = 5,155) were examined every 5 years for 15 years between 1993 and 2012. Random coefficient analyses were used to study age-related changes and generation shifts in BMI, γ-glutamyltransferase (GGT), uric acid (UA), and C-reactive protein (CRP). RESULTS Levels of BMI, UA, and CRP increased in all generations up to age 75, whereas GGT increased up to age 55. No consistent generation shifts were observed for GGT, UA, and CRP (P ≥ 0.05). Participants with a stable BMI (change ≤1 kg/m(2) /15 years) had either no or small increases with age in GGT, UA, and CRP, whereas participants with increasing BMI (increase >1 kg/m(2) /15 years) had much larger increases (P < 0.01). CONCLUSIONS The unfavorable age-related changes in obesity-related biochemical markers, particularly among individuals with increasing BMI, show the importance of maintaining a healthy weight to improve population levels of oxidative stress and inflammation.
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Affiliation(s)
- Gerben Hulsegge
- Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerrie-Cor M Herber-Gast
- Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
- Department of Internal Medicine and Cardiovascular Research Institute, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Annemieke M W Spijkerman
- Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
| | | | - J Picavet
- Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
| | - Yvonne T van der Schouw
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
| | - Ron T Gansevoort
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
| | - Martijn E T Dollé
- Laboratory of Health Protection Research, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
| | - Henriette A Smit
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - W M Monique Verschuren
- Centre for Nutrition, Prevention and Health Services, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
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Niemelä O. Biomarker-Based Approaches for Assessing Alcohol Use Disorders. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:166. [PMID: 26828506 PMCID: PMC4772186 DOI: 10.3390/ijerph13020166] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/14/2016] [Accepted: 01/20/2016] [Indexed: 12/11/2022]
Abstract
Although alcohol use disorders rank among the leading public health problems worldwide, hazardous drinking practices and associated morbidity continue to remain underdiagnosed. It is postulated here that a more systematic use of biomarkers improves the detection of the specific role of alcohol abuse behind poor health. Interventions should be initiated by obtaining information on the actual amounts of recent alcohol consumption through questionnaires and measurements of ethanol and its specific metabolites, such as ethyl glucuronide. Carbohydrate-deficient transferrin is a valuable tool for assessing chronic heavy drinking. Activities of common liver enzymes can be used for screening ethanol-induced liver dysfunction and to provide information on the risk of co-morbidities including insulin resistance, metabolic syndrome and vascular diseases. Conventional biomarkers supplemented with indices of immune activation and fibrogenesis can help to assess the severity and prognosis of ethanol-induced tissue damage. Many ethanol-sensitive biomarkers respond to the status of oxidative stress, and their levels are modulated by factors of life style, including weight gain, physical exercise or coffee consumption in an age- and gender-dependent manner. Therefore, further attention should be paid to defining safe limits of ethanol intake in various demographic categories and establishing common reference intervals for biomarkers of alcohol use disorders.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki 60220, Finland.
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Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk. DISEASE MARKERS 2015; 2015:818570. [PMID: 26543300 PMCID: PMC4620378 DOI: 10.1155/2015/818570] [Citation(s) in RCA: 211] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/20/2015] [Indexed: 01/09/2023]
Abstract
Gamma-glutamyltransferase (GGT) is a well-established serum marker for alcohol-related liver disease. However, GGT's predictive utility applies well beyond liver disease: elevated GGT is linked to increased risk to a multitude of diseases and conditions, including cardiovascular disease, diabetes, metabolic syndrome (MetS), and all-cause mortality. The literature from multiple population groups worldwide consistently shows strong predictive power for GGT, even across different gender and ethnic categories. Here, we examine the relationship of GGT to other serum markers such as serum ferritin (SF) levels, and we suggest a link to exposure to environmental and endogenous toxins, resulting in oxidative and nitrosative stress. We observe a general upward trend in population levels of GGT over time, particularly in the US and Korea. Since the late 1970s, both GGT and incident MetS and its related disorders have risen in virtual lockstep. GGT is an early predictive marker for atherosclerosis, heart failure, arterial stiffness and plaque, gestational diabetes, and various liver diseases, including viral hepatitis, other infectious diseases, and several life-threatening cancers. We review literature both from the medical sciences and from life insurance industries demonstrating that serum GGT is a superior marker for future disease risk, when compared against multiple other known mortality risk factors.
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Bizoń A, Kepinska M, Snacki K, Milnerowicz H. The impact of environmental and biological factors on paraoxonase 1 and γ-glutamyltranspeptydase activities in the blood of smelters. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2015; 26:222-238. [PMID: 26418915 DOI: 10.1080/09603123.2015.1089533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Disorders of paraoxonase and γ-glutamyltranspeptydase activities can induce development of the atherosclerotic process. The aim of the study was to examine the effect of occupational exposure to heavy metals, tobacco smoke and alcohol consumption on the activities of paraoxonase and γ-glutamyltranspeptydase as well as glutathione concentration. We have observed reduced paraoxonase activity and higher γ-glutamyltranspeptydase activity in serum of smelters when compared to control groups. In the blood of smoking smelters was demonstrated a negative correlation between paraoxonase activity and BMI value as well as between paraoxonase activity and tobacco smoke and consumption of 40% alcohol. Also, negative correlation was found for the activity of paraoxonase and glutathione concentration as well as γ-glutamyltranspeptydase activity. Higher γ-glutamyltranspeptydase activity and lower paraoxonase activity in the serum of smelters exposed to heavy metals and tobacco smoke can cause disorders in functioning of the body.
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Affiliation(s)
- Anna Bizoń
- a Faculty of Pharmacy, Department of Biomedical and Environmental Analysis , Wroclaw Medical University , Wrocław , Poland
| | - Marta Kepinska
- a Faculty of Pharmacy, Department of Biomedical and Environmental Analysis , Wroclaw Medical University , Wrocław , Poland
| | - Krzysztof Snacki
- b Faculty of Pharmacy, Students Scientific Society at the Department of Biomedical Environmental Analysis , Wroclaw Medical University , Wrocław , Poland
| | - Halina Milnerowicz
- a Faculty of Pharmacy, Department of Biomedical and Environmental Analysis , Wroclaw Medical University , Wrocław , Poland
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Danielsson J, Kangastupa P, Laatikainen T, Aalto M, Niemelä O. Impacts of common factors of life style on serum liver enzymes. World J Gastroenterol 2014; 20:11743-11752. [PMID: 25206278 PMCID: PMC4155364 DOI: 10.3748/wjg.v20.i33.11743] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impacts of gender, age and factors of life style (alcohol, overweight, coffee and smoking) on serum liver enzymes.
METHODS: Serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were measured from 6269 apparently healthy individuals (2851 men, 3418 women, mean age 45 ± 12 years, range 25-74 years) in a national cross-sectional health survey. All subjects underwent detailed clinical examinations and interviews including the amount and pattern of alcohol use, coffee consumption and smoking habits.
RESULTS: In this population with a mean ± SD alcohol consumption of 65 ± 105 g/wk and body mass index (BMI) of 26.1 ± 4.3 kg/m2, both ALT and GGT were significantly influenced by alcohol use (P < 0.001) and BMI (P < 0.001), whereas smoking increased only GGT (P < 0.001). A significant effect of age on ALT was seen in men (P < 0.001) whereas not in women. Significant two-factor interactions of alcohol use in men were observed with age (ALT: P < 0.01; GGT: P < 0.001) and BMI (GGT: P < 0.05). For ALT, a significant interaction also occurred between BMI and age (P < 0.005). In contrast, women showed significant interactions of alcohol use with BMI (GGT: P < 0.05), smoking (GGT: P < 0.001), and coffee consumption (GGT: P < 0.001).
CONCLUSION: Life-style associated changes in liver enzymes may reflect health risks, which should be considered in the definition of normal limits for liver enzymes.
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Long Y, Zeng F, Shi J, Tian H, Chen T. Gamma-glutamyltransferase predicts increased risk of mortality: a systematic review and meta-analysis of prospective observational studies. Free Radic Res 2014; 48:716-28. [PMID: 24684379 DOI: 10.3109/10715762.2014.902055] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of this study was to evaluate the association between gamma-glutamyltransferase (GGT) and mortality through a comprehensive analysis of existing evidence. PubMed, Embase, Chinese Biomedical Literature, and Science Citation Index databases were electronically searched. Studies were included if the study design was prospective and included reference and at-risk levels of GGT at baseline and mortality as a separate outcome. The quality of the studies included was assessed on the basis of Newcastle-Ottawa scale. Data from selected qualified studies were systematically reviewed, pooled, and analyzed according to the MOOSE guidelines and PRISMA statement. The results included the following: 1. 35 studies including 571,511 participants and 72,196 cases of mortality; 2. GGT, even at physiologic levels, was associated with increased all-cause mortality and cardiovascular mortality, and might also be associated with cancer-related mortality in the general population; and 3. GGT was very likely to be associated with all-cause mortality and cardiovascular mortality in patients with coronary artery disease and type 2 diabetes mellitus. Many of the studies included did not specifically exclude subjects with hepatic diseases or alcohol abuse, which may have obscured the results. Moderate heterogeneity was observed in the meta-analysis of GGT and all-cause mortality. Different compositions of cause-specific mortality might be the reason. However, subgroup analysis could only be performed on cardiovascular death because of insufficient information. GGT, even at physiologic high levels, predicted mortality, especially cardiovascular mortality and cancer mortality. The underlining mechanism and potential effects of GGT-targeted intervention on health warrant further investigation.
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Affiliation(s)
- Y Long
- Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University , Chengdu, Sichuan , P. R. China
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Individual and joint impacts of ethanol use, BMI, age and gender on serum gamma-glutamyltransferase levels in healthy volunteers. Int J Mol Sci 2013; 14:11929-41. [PMID: 23736697 PMCID: PMC3709764 DOI: 10.3390/ijms140611929] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 05/20/2013] [Accepted: 05/22/2013] [Indexed: 12/16/2022] Open
Abstract
Excessive ethanol consumption, obesity and increasing age may all lead to increased serum levels of gamma-glutamyltransferase (GGT) enzyme, which plays a key role in the metabolism of extracellular reduced glutathione. However, as yet, the interactions between the various modulators of GGT activities have remained poorly defined. We analyzed data from 15,617 apparently healthy individuals (7254 men and 8363 women, mean age 46 ± 13 years, range 25–74 years) who participated in a national cross-sectional health survey in Finland between 1997 and 2007. All subjects underwent detailed clinical examinations and interviews, including the amount of ethanol use and smoking habits. GGT levels were measured from all participants, and the individual and joint impacts of the different study variables on GGT levels were assessed. Significant individual effects were noted for ethanol use (p < 0.001), body mass index (BMI) (p < 0.001), age (p < 0.001) and smoking (p < 0.001). In men, significant two-factor interactions occurred between ethanol use and age (p < 0.020). Among those over 40 years of age, ethanol consumption was found to be a stronger determinant of increased GGT levels than in men below 40 years, whereas in the latter age group, BMI was found to predominate. In women, a significant two-factor interaction occurred between ethanol and BMI (p = 0.010), whereas it did not with ethanol use and age. The data underscores the role of ethanol consumption and age as major determinants of increased GGT levels in men, whereas in women, a relatively stronger impact was noted for ethanol intake and BMI. In light of the ability of GGT enzyme to modulate crucial redox-sensitive functions, the present findings also support the use of GGT as a biomarker of oxidative stress.
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Danielsson J, Kangastupa P, Laatikainen T, Aalto M, Niemelä O. Dose- and gender-dependent interactions between coffee consumption and serum GGT activity in alcohol consumers. Alcohol Alcohol 2013; 48:303-7. [PMID: 23492307 DOI: 10.1093/alcalc/agt017] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIMS Coffee consumption has been recently linked with decreased blood gamma-glutamyltransferase (GGT) activities and protection from alcoholic liver disease. To explore the relationship and dose response, we assessed the impacts of coffee and alcohol intake on serum GGT activity in apparently healthy men and women with varying levels of coffee and alcohol consumption. METHODS Data on coffee, alcohol consumption and serum GGT activities were collected from 18,899 individuals (8807 men and 10,092 women), mean age 48 years, range 25-74 years, who participated in a large national cross-sectional health survey. Body mass index, smoking index and age were used as covariates in all analyses. RESULTS Among the study population, 89.8% reported varying levels of coffee consumption; 6.9% were abstainers from alcohol, 86.1% moderate drinkers, 3.7% heavy drinkers and 3.3% former drinkers. In men, the elevation of GGT induced by heavy drinking (>280 g/week) was found to be significantly reduced by coffee consumption exceeding 4 cups per day. A similar trend was also observed among women, which however, did not reach statistical significance. CONCLUSION Coffee modulates the effect of ethanol on serum GGT activities in a dose- and gender-dependent manner. These observations should be implicated in studies on the possible hepatoprotective effects of coffee in alcohol consumers.
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Affiliation(s)
- Joanna Danielsson
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Hanneksenrinne 7, 60220 Seinäjoki, Finland
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Karahalios A, Baglietto L, Carlin JB, English DR, Simpson JA. A review of the reporting and handling of missing data in cohort studies with repeated assessment of exposure measures. BMC Med Res Methodol 2012; 12:96. [PMID: 22784200 PMCID: PMC3464662 DOI: 10.1186/1471-2288-12-96] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 07/11/2012] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Retaining participants in cohort studies with multiple follow-up waves is difficult. Commonly, researchers are faced with the problem of missing data, which may introduce biased results as well as a loss of statistical power and precision. The STROBE guidelines von Elm et al. (Lancet, 370:1453-1457, 2007); Vandenbroucke et al. (PLoS Med, 4:e297, 2007) and the guidelines proposed by Sterne et al. (BMJ, 338:b2393, 2009) recommend that cohort studies report on the amount of missing data, the reasons for non-participation and non-response, and the method used to handle missing data in the analyses. We have conducted a review of publications from cohort studies in order to document the reporting of missing data for exposure measures and to describe the statistical methods used to account for the missing data. METHODS A systematic search of English language papers published from January 2000 to December 2009 was carried out in PubMed. Prospective cohort studies with a sample size greater than 1,000 that analysed data using repeated measures of exposure were included. RESULTS Among the 82 papers meeting the inclusion criteria, only 35 (43%) reported the amount of missing data according to the suggested guidelines. Sixty-eight papers (83%) described how they dealt with missing data in the analysis. Most of the papers excluded participants with missing data and performed a complete-case analysis (n=54, 66%). Other papers used more sophisticated methods including multiple imputation (n=5) or fully Bayesian modeling (n=1). Methods known to produce biased results were also used, for example, Last Observation Carried Forward (n=7), the missing indicator method (n=1), and mean value substitution (n=3). For the remaining 14 papers, the method used to handle missing data in the analysis was not stated. CONCLUSIONS This review highlights the inconsistent reporting of missing data in cohort studies and the continuing use of inappropriate methods to handle missing data in the analysis. Epidemiological journals should invoke the STROBE guidelines as a framework for authors so that the amount of missing data and how this was accounted for in the analysis is transparent in the reporting of cohort studies.
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Affiliation(s)
- Amalia Karahalios
- Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, VIC, Australia
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Tynjälä J, Kangastupa P, Laatikainen T, Aalto M, Niemelä O. Effect of age and gender on the relationship between alcohol consumption and serum GGT: time to recalibrate goals for normal ranges. Alcohol Alcohol 2012; 47:558-62. [PMID: 22753786 DOI: 10.1093/alcalc/ags072] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
AIMS While serum gamma-glutamyltransferase (GGT) enzyme activity is a well established biomarker of excessive alcohol consumption and liver dysfunction, recent studies have also implicated it as a predictor of morbidity due to extrahepatic causes. Therefore, further information on the associations between ethanol intake and GGT activities in apparently healthy individuals appears warranted. METHODS Data on alcohol consumption and serum GGT activities were collected from 18,899 individuals (8807 men, 10,092 women), mean age 48 years and range 25-74 years, who participated in a national cross-sectional health survey. Alcohol use was assessed by detailed questionnaires and the study population was subsequently divided into subgroups according to age and gender. Body mass index and smoking were used as covariates in all analyses. RESULTS In men over 40 years, a reported regular consumption of 8 standard ethanol doses ('dose' = 12 g ethanol) or more per week was found to lead to a significant elevation in serum GGT activities, whereas those below 40 showed first significant changes not until the reported ethanol intake exceeded 14 doses per week. For women, the corresponding threshold levels were four and seven standard ethanol doses, respectively. CONCLUSION The data pertaining to the present population sample indicate that rather low levels of reported regular ethanol consumption lead to elevated levels of GGT and that age over 40 markedly enhances the impact of alcohol consumption on GGT activity. The present findings should form the basis for defining safe levels of ethanol consumption and in recalibrating goals for normal limits in the clinical use of GGT measurements.
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Affiliation(s)
- Joanna Tynjälä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, University of Tampere, Seinäjoki FIN-60220, Finland
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Tsuboya T, Kuriyama S, Nagai M, Hozawa A, Sugawara Y, Tomata Y, Kakizaki M, Nishino Y, Tsuji I. Gamma-glutamyltransferase and cancer incidence: the Ohsaki cohort study. J Epidemiol 2012; 22:144-50. [PMID: 22277791 PMCID: PMC3798593 DOI: 10.2188/jea.je20110071] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background Although experimental studies have shown that gamma-glutamyltransferase (GGT) has a role in tumor progression, epidemiologic evidence for a relationship between GGT and cancer incidence is limited. The present study investigated the association between GGT and cancer incidence and assessed the role of alcohol consumption in this association. Methods We examined a cohort of 15 031 Japanese adults aged 40 to 79 years who attended a health checkup in 1995 and were free of cancer at that time. GGT was measured using the Szasz method. The participants were then followed from 1 January 1996 until 31 December 2005, and cancer incidence was recorded by using the Miyagi Regional Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for each quartile of GGT and compared. The lowest quartile (GGT <13.0 IU/ml) was used as the reference category. Results We documented 1505 cancers. Among participants in the highest quartile (GGT ≥31.0 IU/ml), the multivariate HR for any cancer was 1.28 (95% CI, 1.08–1.53; P for trend, <0.001), the HR for colorectal cancer was significantly greater than unity, and the HRs for esophageal, pancreatic, and breast cancers were greater than unity but not significantly so. This positive trend was observed only in current drinkers. Conclusions Our findings suggest that there is a positive relationship between GGT and cancer incidence only for alcohol-related cancers in current drinkers and that the positive association of GGT with cancer incidence largely reflects alcohol consumption.
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Affiliation(s)
- Toru Tsuboya
- Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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14
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Völzke H, Alte D, Ittermann T, Schmidt CO, Rettig R, Mayerle J, Lowenfels AB, Lerch MM, Nauck M. Subjects with sonographical hepatic steatosis should be excluded from studies to establish upper reference levels of serum transaminases. Liver Int 2011; 31:985-93. [PMID: 21078068 DOI: 10.1111/j.1478-3231.2010.02371.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS Correct upper reference limits (URL) of serum liver enzyme activities are used to select individuals in whom further diagnostic procedures for suspected liver disorders are warranted and to compare the prevalence and incidence of increased serum liver enzyme levels within and among populations. We sought to establish URL in a general adult population by not only generating a disease-free population but also further excluding subjects with ultrasonographical diagnosis of hepatic steatosis. METHODS We used data from 4,242 subjects (2,154 women) aged 20-79 years recruited for the population-based Study of Health in Pomerania. A reference population was selected comprising 1,953 subjects (1,129 women). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (GGT) were measured photometrically. RESULTS The exclusion of 630 subjects with hepatic steatosis and 20 subjects with equivocal data on liver ultrasound from the reference population predominantly affected the URL for serum ALT and GGT levels in younger age groups. URL for serum ALT, AST and GGT levels were 1.00 μmol/L/s (60 U/L), 0.55 μmol/L/s (33 U/L) and 1.11 μmol/L/s (67 U/L), respectively, in men as well as 0.57 μmol/L/s (34 U/L), μmol/L/s (25 U/L) and μmol/L/s (39 U/L), respectively, in women. CONCLUSIONS URL for serum liver enzyme activities are higher than recommended previously. Creating a reference population for establishing URL for serum liver enzyme activities should include liver ultrasound in order to exclude subjects with subclinical hepatic steatosis.
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Affiliation(s)
- Henry Völzke
- Institute for Community Medicine, Unit Study of Health in Pomerania - Clinical Epidemiological Research, Ernst Moritz Arndt University, Greifswald, Germany.
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Associations of serum uric acid and gamma-glutamyltransferase with cancer in the Vorarlberg Health Monitoring and Promotion Programme (VHM&PP) – a short review. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2011. [DOI: 10.1007/s12254-011-0249-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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16
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Niemelä O, Alatalo P. Biomarkers of alcohol consumption and related liver disease. Scandinavian Journal of Clinical and Laboratory Investigation 2010; 70:305-12. [PMID: 20470213 DOI: 10.3109/00365513.2010.486442] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abstract Alcohol abuse is a major cause of abnormal liver function throughout the world. While measurements of liver enzyme activities (GGT, ALT, AST) are important screening tools for detecting liver disease, due to lack of ethanol-specificity and inconsistencies regarding the definitions of significant alcohol consumption, several other blood tests are usually needed to exclude competing and co-existing causes of abnormal liver function. Information on the specific role of ethanol consumption behind hepatotoxicity may be obtained through measurements of blood ethanol and its specific metabolites (ethyl glucuronide, phosphatidylethanol, protein-acetaldehyde condensates and associated autoimmune responses). Recent studies have indicated that being overweight is another increasingly common cause of abnormal liver enzyme levels and adiposity may also increase the impact of ethanol consumption on liver pathology. Interestingly, increased liver enzyme activities in circulation may reflect not only hepatic function but can also serve as indicators of general health and the status of oxidative stress in vivo. ALT and GGT activities predict insulin resistance, metabolic syndrome, mortality from coronary heart diseases and even mortality from all causes. If the upper reference limits for liver enzyme activities were defined based on the data obtained from normal weight abstainers, the clinical value of liver enzyme measurements as screening tools and in patient follow-up could be significantly improved.
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Affiliation(s)
- Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland.
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17
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Skakkebaek NE. Normal reference ranges for semen quality and their relations to fecundity. Asian J Androl 2010; 12:95-8. [PMID: 20111088 DOI: 10.1038/aja.2008.43] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Several recent studies have shown that the fecundity of a man decreases progressively with sperm concentrations below 40 million spermatozoa per mL. Therefore, it is unfortunate that the new World Health Organization guidelines for semen analysis recommend lowering the lower cutoff value for normal sperm concentration from 20 to 15 million spermatozoa per mL. As a result large groups of subfertile men across the world may not receive appropriate andrological help in the future.
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Affiliation(s)
- Niels E Skakkebaek
- University Department of Growth and Reproduction, Rigshospitalet, Copenhagen DK, Denmark.
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18
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Alanine aminotransferase and γ-glutamyltransferase as markers for elevated insulin resistance-associated metabolic abnormalities in obese Japanese men younger than 30 years of age. Obes Res Clin Pract 2010; 4:e1-e82. [DOI: 10.1016/j.orcp.2009.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2009] [Revised: 08/30/2009] [Accepted: 09/23/2009] [Indexed: 01/14/2023]
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Lee DH, Jacobs DR. Is serum gamma-glutamyltransferase a marker of exposure to various environmental pollutants? Free Radic Res 2009; 43:533-7. [PMID: 19370474 DOI: 10.1080/10715760902893324] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
It was previously hypothesized that serum gamma-glutamyltransferase (GGT) within its reference range predicts various clinical outcomes as a sensitive marker of oxidative stress in humans. This study further hypothesizes that serum GGT can mark exposure to various environmental pollutants, based both on recent epidemiological findings and on well-established biochemical features of cellular GGT. Cellular GGT is a prerequisite for metabolism of GSH conjugates that detoxify xenobiotics to mercapturic acid. Under this concept, serum GGT may increase with increasing exposure to environmental pollutants which need to be conjugated to GSH. Supporting this concept, it was recently reported that serum GGT within its reference range was linearly associated with important environmental pollutants, including lead, cadmium, dioxin and organochlorine pesticides. As a marker of the amount of conjugated xenobiotics, recent epidemiological findings about serum GGT imply the possibility of harmful effects of various environmental pollutants at background levels currently regarded as safe.
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Affiliation(s)
- Duk-Hee Lee
- Department of Preventive Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
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20
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Jo SK, Lee WY, Rhee EJ, Won JC, Jung CH, Park CY, Oh KW, Park SW, Kim SW. Serum gamma-glutamyl transferase activity predicts future development of metabolic syndrome defined by 2 different criteria. Clin Chim Acta 2009; 403:234-40. [PMID: 19332046 DOI: 10.1016/j.cca.2009.03.035] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2008] [Revised: 03/19/2009] [Accepted: 03/24/2009] [Indexed: 01/11/2023]
Abstract
BACKGROUND Recent studies suggest the role of liver enzymes, such as serum gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT) as the predictor for future development of metabolic syndrome (MetS), diabetes and cardiovascular disease in epidemiologic studies. We hypothesized that serum concentrations of GGT and ALT are associated with the development of MetS, according to newly recommended criteria from International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) definition in Koreans. METHODS A total of 15,250 males (mean 38 y) and 6280 females (mean 41 y) who visited the Health Promotion Center at Kangbuk Samsung Hospital for medical check-up in 2002, were followed-up after 4 y. We analyzed the development of MetS in their follow-up data in 2006. RESULTS When the subjects were divided into quartiles by the baseline GGT levels, the odds ratio for the MetS defined by both criteria across the quartile groups increased as the quartile groups increased in both gender groups. This association remained significant even after adjustment for confounding factors, such as, age, alcohol intake, smoking status, physical activity, ALT, fasting insulin and HOMA-IR. Serum ALT concentration also showed significantly positive correlation with development of MetS defined by the two criteria even after adjustment for age and GGT in both gender groups. In addition, risk for the individual MetS components increased as the baseline GGT concentrations increased, except low high-density lipoprotein cholesterol (HDL-C) in female group. In receiver operating characteristic (ROC) curves, the area under the curves (AUC) of GGT and ALT to predict future MetS by both criteria was larger than the AUCs of blood pressure, fasting glucose and HDL-C. CONCLUSIONS In this large prospective study in Koreans, high baseline GGT and ALT concentrations predicted future development of MetS defined by IDF and AHA/NHLBI criteria after 4 y of follow-up.
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Affiliation(s)
- Sook-Kyoung Jo
- Department of Endocrinology and Rheumatology, SAM Anyang Hospital, Anyang, Republic of Korea
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Alatalo P, Koivisto H, Puukka K, Hietala J, Anttila P, Bloigu R, Niemelä O. Biomarkers of liver status in heavy drinkers, moderate drinkers and abstainers. Alcohol Alcohol 2008; 44:199-203. [PMID: 19054785 DOI: 10.1093/alcalc/agn099] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIMS Although a wide variety of biomarkers reflecting liver status are known to be influenced by excessive ethanol consumption, the dose-response relationships between ethanol intake and marker changes have remained less understood. METHODS Serum gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, and ferritin and albumin protein concentrations were compared in a large population of heavy drinkers (105 men, 28 women), moderate drinkers (781 men, 723 women) and abstainers (252 men, 433 women), who were devoid of apparent liver disease. RESULTS In heavy drinkers, serum GGT, AST, ALT, ferritin and albumin were all significantly higher than in moderate drinkers or abstainers (P < 0.001 for all comparisons). The highest incidences of elevated values were found for GGT (62%) followed by AST (53%), ALT (39%), ferritin (34%) and albumin (20%). Serum GGT (P < 0.001), ALT (P < 0.01) and ferritin (P < 0.05) in moderate drinkers were also higher than the levels observed in abstainers. When the study population was further divided into subgroups according to gender, significant differences between moderate drinkers and abstainers in GGT and ALT were noted in men whereas not in women. CONCLUSIONS The data demonstrate that biomarkers of alcohol abuse and liver function may respond to even rather low levels of ethanol intake in a gender-dependent manner, which should be implicated in studies on the early-phase interactions of ethanol and the liver and in the definition of normal ranges for such biomarkers.
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Affiliation(s)
- Päivikki Alatalo
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland
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22
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Alatalo PI, Koivisto HM, Hietala JP, Puukka KS, Bloigu R, Niemelä OJ. Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index. Am J Clin Nutr 2008; 88:1097-103. [PMID: 18842799 DOI: 10.1093/ajcn/88.4.1097] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although both ethanol consumption and overweight alter the activities of hepatic enzymes in circulation, the differentiation of an alcohol or nonalcohol basis for such changes remains problematic. The magnitude of alterations occurring among moderate drinkers has remained obscure. OBJECTIVE We examined the links between moderate ethanol consumption, body mass index (BMI; in kg/m(2)), and liver enzymes. DESIGN Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were recorded from 2,164 apparently healthy participants (1,028 men, 1,136 women) reporting either no alcohol (abstainers) or <40 g ethanol consumption per day (moderate drinkers). The study population was further classified according to BMI as follows: <19 (underweight), > or =19 and <25 (normal weight), > or =25 and <30 (overweight), and > or =30 (obese). RESULTS Serum ALT (P < 0.05) and GGT (P < 0.001) but not AST (P = 0.805) activities in moderate drinkers were higher than those in abstainers. For all enzymes, a significant main effect was observed of increasing BMI, which was more striking in moderate drinkers than in abstainers. Tests of between-subjects effects indicated significant interactions with sex and drinking status, although not with sex and BMI. CONCLUSIONS The effect of moderate alcohol consumption on liver enzymes increases with increasing BMI. These findings should be considered in the clinical assessment of overweight alcohol consumers and in the definition of normal ranges for liver enzymes. These results may also help to develop new approaches for examining patients with fatty liver induced by either ethanol or adiposity.
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Affiliation(s)
- Päivikki I Alatalo
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Seinäjoki, Finland
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Strasak AM, Kelleher CC, Klenk J, Brant LJ, Ruttmann E, Rapp K, Concin H, Diem G, Pfeiffer KP, Ulmer H, the VHM&PP Study Group. Longitudinal change in serum gamma-glutamyltransferase and cardiovascular disease mortality: a prospective population-based study in 76,113 Austrian adults. Arterioscler Thromb Vasc Biol 2008; 28:1857-65. [PMID: 18617645 PMCID: PMC2643843 DOI: 10.1161/atvbaha.108.170597] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate the association of longitudinal change in serum gamma-glutamyltransferase (GGT) with mortality from cardiovascular disease (CVD). METHODS AND RESULTS A population-based cohort of 76,113 Austrian men and women with 455,331 serial GGT measurements was prospectively followed-up for a median of 10.2 years after assessment of longitudinal GGT change during an average period of 6.9 years. Cox proportional hazards regression with time-varying covariates was used to evaluate GGT change as an independent predictor for CVD death. Independently of baseline GGT and other classical CVD risk factors, a pronounced increase in GGT (7-year change >9.2 U/L) was significantly associated with increased total CVD mortality in men (P=0.005); the adjusted hazard ratio (95% confidence interval) in comparison to stable GGT (7-year change -0.7 to 1.3 U/L) was 1.40 (1.09 to 1.81). Similarly, total CVD risk was elevated for increasing GGT in women, although effects were less pronounced and statistically significant only in subanalyses regarding coronary heart disease. Age of participants significantly modified the relation between GGT change and CVD mortality, with markedly stronger associations to be observable for younger individuals. CONCLUSIONS Our study is the first to demonstrate that a longitudinal increase in GGT, independently of baseline GGT and even within its normal range, significantly increases risk of fatal CVD.
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Affiliation(s)
- Alexander M Strasak
- Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria
| | - Cecily C Kelleher
- School of Public Health and Population Sciences, University College Dublin, Ireland
| | - Jochen Klenk
- Institute of Epidemiology, Ulm University, Germany
| | - Larry J Brant
- Gerontology Research Center, National Institute on Aging, Baltimore, U.S.A
| | - Elfriede Ruttmann
- Department of Cardiac Surgery, Innsbruck Medical University, Austria
| | - Kilian Rapp
- Institute of Epidemiology, Ulm University, Germany
| | - Hans Concin
- Agency for Preventive and Social Medicine, Bregenz, Austria
| | - Günter Diem
- Agency for Preventive and Social Medicine, Bregenz, Austria
| | - Karl P Pfeiffer
- Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria
| | - Hanno Ulmer
- Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria
- Agency for Preventive and Social Medicine, Bregenz, Austria
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Lee DH, Steffes MW, Jacobs DR. Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? Diabetologia 2008; 51:402-7. [PMID: 18071669 DOI: 10.1007/s00125-007-0896-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Accepted: 11/12/2007] [Indexed: 10/22/2022]
Abstract
The results of several epidemiological studies of serum gamma-glutamyltransferase (GGT) led us to hypothesise that associations of GGT within its normal range with type 2 diabetes may reflect detrimental effects of xenobiotics found in the environment, such as persistent organic pollutants (POPs). Epidemiological observations showed that serum GGT activity within its normal range strongly predicted future type 2 diabetes; the predictability of diabetes from obesity was low with GGT at the low end of the normal range; and GGT showed a positive association with known markers of oxidative stress or inflammation. Experimental findings on cellular GGT suggest that serum GGT levels within the normal range may reflect oxidative stress related to the re-synthesis of intracellular glutathione; however, this interpretation is not completely satisfying because, in its role of regenerating intracellular glutathione, GGT activity should be antioxidative. Alternatively, serum GGT activity may reflect amounts of glutathione conjugates formed during the metabolism of xenobiotics. Accordingly, we postulate a two-part hypothesis: that the association of serum GGT with type 2 diabetes reflects exposure to POPs, as these substances, which have a very long half-life, may influence diabetes risk by residing in adipose tissue as endocrine disruptors; and that POPs or similar substances may interact with obesity to cause type 2 diabetes. Supporting this hypothesis, cross-sectional investigation of background exposure to POPs in the National Health and Nutrition Examination Survey showed relationships similar to those observed for GGT, including a powerful association with prevalent diabetes and no association between obesity and diabetes for very low POP concentrations. Our hypothesis can be tested in both prospective studies and toxicological studies.
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Affiliation(s)
- D-H Lee
- Department of Preventive Medicine and Health Promotion Research Center, School of Medicine, Kyungpook National University, Daegu, South Korea.
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Puukka K, Hietala J, Koivisto H, Anttila P, Bloigu R, Niemelä O. Obesity and the clinical use of serum GGT activity as a marker of heavy drinking. Scandinavian Journal of Clinical and Laboratory Investigation 2007; 67:480-8. [PMID: 17763184 DOI: 10.1080/00365510601146035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Gamma-glutamyl transferase (GGT) is a widely used clinical marker of alcohol abuse. However, although obesity may also elevate serum GGT activities, the effects of overweight on the interpretation of GGT testing have remained poorly defined. MATERIAL AND METHODS GGT activities from 1147 moderate drinkers and 449 abstainers who were classified according to body mass index (BMI) were compared with those of 208 heavy drinkers admitted for detoxification. RESULTS GGT upper normal limits, defined based on normal weight abstainers (men 53 U/L; women 45 U/L) were lower than those based on moderate drinkers (men 68 U/L; women 50 U/L). The relative increases in GGT activities in male moderate drinkers with overweight (54%) or obesity (125%) exceeded the corresponding changes found in women (25% and 75%, respectively). The BMI-dependent variation on the sensitivity of GGT for correctly classifying heavy drinkers ranged from 29% to 67%. The rates of false-positive values in the subgroups from low to high BMI varied from 0% to 27%, respectively. CONCLUSIONS The data indicate that the diagnostic value of serum GGT testing could be improved by using reference data derived from databases of abstainers with normal weight or BMI-based categorization of reference ranges.
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Affiliation(s)
- K Puukka
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland
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André P, Balkau B, Vol S, Charles MA, Eschwège E. Gamma-glutamyltransferase activity and development of the metabolic syndrome (International Diabetes Federation Definition) in middle-aged men and women: Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort. Diabetes Care 2007; 30:2355-61. [PMID: 17586745 DOI: 10.2337/dc07-0440] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Among hepatic enzymes, gamma-glutamyltransferase (GGT) is the main predictor of type 2 diabetes incidence, although it has not been shown that GGT predicts pre-diabetes states. Our aim was to study the association of GGT with the development of the metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS We analyzed the 3-year data from the Data from Epidemiological Study on the Insulin Resistance Syndrome prospective cohort of 1,656 men and 1,889 women without MetS at baseline, according to the International Diabetes Federation definition. RESULTS Over 3 years, 309 participants developed the MetS. After adjustment for age, alcohol intake, physical activity, smoking habits, and alanine aminotransferase (ALT), the odds ratios for incident MetS increased across baseline GGT quartiles (1, 1.96, 2.25, and 3.81 in men, P < 0.03; and 1, 1.23, 1.80, and 1.58 in women, P < 0.05). After additional adjustment for insulin resistance markers (fasting insulin or homeostasis model assessment of insulin resistance index), the association was attenuated and the linear relation no longer significant in both sexes (P = 0.08, P = 0.16). However, men in the highest in comparison to the lowest quartile of GGT retained a significant risk for incident MetS. In women, there was no longer a significant risk. GGT was significantly associated with the 3-year incidence of individual components of the MetS. The incidence of the MetS also increased with ALT, but after adjustment on GGT this association remained significant only in women. CONCLUSIONS GGT, a predictor of type 2 diabetes, was associated with a risk of incident MetS. This association was mainly related with insulin resistance but was independent of other confounding factors.
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Affiliation(s)
- Philippe André
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 780-IFR69, Epidemiological and Biostatistical Research, Villejuif, France.
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Kazemi-Shirazi L, Endler G, Winkler S, Schickbauer T, Wagner O, Marsik C. Gamma glutamyltransferase and long-term survival: is it just the liver? Clin Chem 2007; 53:940-6. [PMID: 17384006 DOI: 10.1373/clinchem.2006.081620] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Increased gamma glutamyltransferase (GGT) is associated with cardiovascular disease. To date, however, few studies with sufficient sample size and follow-up have investigated the association of GGT with all-cause mortality. METHODS The relation of GGT to the risk of death was examined in a cohort of 283 438 first attendants (inpatients or outpatients) of the Vienna General Hospital with request for GGT analysis as part of a routine screening panel and was monitored for up to 13 years. To evaluate GGT as a predictor, Cox proportional hazards models were calculated, which were adjusted for age and sex. RESULTS In both men and women, GGT above the reference category (GGT > or = 9 U/L in women, > or = 14 U/L in men) was significantly (P <0.001) associated with all-cause, cancer, hepatobiliary, and vascular mortalities. Hazard ratios (HRs) for men and women were similar in all categories. Among patients who presented with GGT above the reference category, those younger than 30 years had higher all-cause mortality rates than did older individuals (HR 1.5-3.3 vs HR 1-1.3 >80 years, respectively). CONCLUSIONS GGT is associated with mortality in both men and women, especially in patients younger than 30 years, and even high-normal GGT is a risk factor for all-cause mortality.
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Affiliation(s)
- Lili Kazemi-Shirazi
- Institute of Medical and Chemical Laboratory Diagnostics, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Lee DH, Jacobs DR. Association between Serum Concentrations of Persistent Organic Pollutants and γ Glutamyltransferase: Results from the National Health and Examination Survey 1999–2002. Clin Chem 2006; 52:1825-7. [PMID: 16940464 DOI: 10.1373/clinchem.2006.071563] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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