Serum liver enzymes are associated with all‐cause mortality in an elderly population

Koehler, Edith M.; Sanna, Donatella; Hansen, Bettina E.; Rooij, Frank J. van; Heeringa, Jan; Hofman, Albert; Tiemeier, Henning; Stricker, Bruno H.; Schouten, Jeoffrey N.L.; Janssen, Harry L A

doi:10.1111/liv.12311

Cited by 91 publications

(106 citation statements)

References 36 publications

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“…To propose possible factors contributing to the association between lower ALT and mortality is challenging given that, similar to our findings (Table 2), increasing ALT has been directly linked to components of the metabolic syndrome and to markers of insulin resistance and systemic inflammation [1,3,6,9]. The most widely accepted theory in current literature behind the association, is that low ALT is correlated with both frailty and sarcopenia, each associated with mortality in their own right [6,7].…”

Section: Discussionsupporting

confidence: 67%

“…The finding of a positive association between GGT and mortality would be consistent with its known function as a sensitive but non-specific marker of liver injury, alcohol intake, oxidative stress, vascular disease and other co-morbidities, through primary pathology and also through enzyme induction from medications [1,2,4,[9][10][11]48]. Indeed, this fact is supported by our finding that GGT >70 U/L associated with mortality in all three categories (cardiovascular, cancer and non-cardiovascular/non-cancer; Table 3).…”

Section: Accepted M Manuscriptsupporting

confidence: 63%

“…Several recent publications report an inverse association between ALT and mortality [5,6]. While this would seem counterintuitive if lower ALT is to be considered a marker of liver health, this observation has been repeatedly noted in different populations, including in the elderly, the middle-aged and those with HIV infection [5][6][7][8][9]. Intriguingly, the relationship is opposite to that for GGT, which has a positive association with mortality [4,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Alternative causes for the relationship between low ALT and mortality could include associations of low ALT with pyridoxine deficiency [9,42], low levels of sex hormones [32,43], higher Nterminal pro-Brain natriuretic peptide (BNP, secreted by ventricular myocytes in response to…”

mentioning

confidence: 99%

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Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: Analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

et al. 2016

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Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the fenofibrate intervention and event lowering in diabetes (FIELD) study Kathryn H. Williams, David R. Sullivan, Geoffrey C. Nicholson, Jacob George, Alicia J. Jenkins, Andrzej S. Januszewski, Val J. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (2) 9562 5304; E-mail: fieldtrial@ctc.usyd.edu.au. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 Abstract AimsReported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. MethodsData from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. ResultsOver 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p<0.001.Conversely, GGT >70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p<0.001.For cause-specific mortality, lower ALT was associated with a higher risk of cardiovascular death only, whereas GGT >70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. ConclusionsAs in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes.

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Section: Discussionsupporting

confidence: 67%

Section: Accepted M Manuscriptsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: Analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

et al. 2016

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“…The authors concluded that in subjects with increased GGT levels, ultrasound examination of liver should be performed for diagnostic and risk stratification reasons (30). Other studies have demonstrated an association of GGT with mortality in elderly subjects (31,32).…”

Section: Ggt Cvd and Mortalitymentioning

confidence: 99%

Gamma-glutamyl transferase and cardiovascular disease

Ndrepepa¹,

Kastrati²

2016

Ann. Transl. Med.

103

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Gamma-glutamyl transferase (GGT) is an enzyme located on the external surface of cellular membranes. GGT contributes in maintaining the physiological concentrations of cytoplasmic glutathione and cellular defense against oxidative stress via cleavage of extracellular glutathione and increased availability of amino acids for its intracellular synthesis. Increased GGT activity is a marker of antioxidant inadequacy and increased oxidative stress. Ample evidence suggests that elevated GGT activity is associated with increased risk of cardiovascular disease (CVD) such as coronary heart disease (CHD), stroke, arterial hypertension, heart failure, cardiac arrhythmias and all-cause and CVD-related mortality. The evidence is weaker for an association between elevated GGT activity and acute ischemic events and myocardial infarction. The risk for CVD or CVD-related mortality mediated by GGT may be explained by the close correlation of GGT with conventional CVD risk factors and various comorbidities, particularly non-alcoholic fatty liver disease, alcohol consumption, oxidative stress, metabolic syndrome, insulin resistance and systemic inflammation. The finding of GGT activity in atherosclerotic plaques and correlation of intra-plaque GGT activity with histological indexes of plaque instability may suggest a participation of GGT in the pathophysiology of CVD, particularly atherosclerosis. However, whether GGT has a direct role in the pathophysiology of CVD or it is an epiphenomenon of coexisting CVD risk factors or comorbidities remains unknown and Hill's criteria of causality relationship between GGT and CVD are not fulfilled. The exploration whether GGT provides prognostic information on top of the information provided by known cardiovascular risk factors regarding the CVD or CVD-related outcome and exploration of molecular mechanisms of GGT involvement in the pathophysiology of CVD and eventual use of interventions to reduce circulating GGT activity remain a duty of future studies.

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Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: Systematic review and meta‐analysis

Kunutsor

Apekey

Hemelrijck

et al. 2014

Intl Journal of Cancer

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The prospective evidence for the associations of gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) with risk of cancer in the general population is uncertain. We conducted a systematic review and meta-analysis of published prospective observational studies evaluating the associations of baseline levels of GGT and ALT with risk of overall (incidence and/or mortality) and site-specific cancers. Relevant studies were identified in a literature search of MEDLINE, EMBASE, Web of Science, reference lists of relevant studies to April 2014 and email contact with investigators. Study specific relative risks (RRs) were meta-analyzed using random effects models. Fourteen cohort studies with data on 1.79 million participants and 57,534 cancer outcomes were included. Comparing top versus bottom thirds of baseline circulating GGT levels, pooled RRs (95% confidence intervals) were 1.32 (1.15-1.52) for overall cancer, 1.09 (0.95-1.24) for cancers of the breast and female genital organs, 1.09 (1.02-1.16) for cancers of male genital organs, 1.94 (1.35-2.79) for cancers of digestive organs and 1.33 (0.94-1.89) for cancers of respiratory and intrathoracic organs. For ALT, corresponding RRs for overall cancer were 0.96 (0.94-0.99) and 1.65 (1.52-1.79) in European and Asian populations, respectively. There was an increased risk of cancers of the digestive organs 2.44 (1.23-4.84). The pooled RR for overall cancer per 5 U/L increment in GGT levels was 1.04 (1.03-1.05). Available observational data indicate a positive log-linear association of GGT levels with overall cancer risk. The positive association was generally evident for site-specific cancers. There are geographical variations in the association of ALT and overall cancer.

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Serum liver enzymes are associated with all‐cause mortality in an elderly population

Abstract: All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated.

Cited by 91 publications

References 36 publications

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: Analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: Analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Gamma-glutamyl transferase and cardiovascular disease

Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: Systematic review and meta‐analysis

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