title: 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.
abstract: OBJECTIVE
  Reported 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.
  
  
  METHODS
  Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analyzed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5years.
  
  
  RESULTS
  Over 5years, 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 >70U/L, compared with GGT ≤70U/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 >70U/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.
  
  
  CONCLUSIONS
  As 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 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.
authors.affiliation: Sydney Medical School, University of Sydney, Sydney NSW, Australia; Royal Prince Alfred Hospital, Sydney NSW, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Williams
authors.affiliation: Royal Prince Alfred Hospital, Sydney NSW, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Sullivan
authors.affiliation: Rural Clinical School, University of Queensland, Brisbane QLD, Australia.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Nicholson
authors.affiliation: Sydney Medical School, University of Sydney, Sydney NSW, Australia; Storr Liver Unit, Westmead Millennium Institute, Westmead Hospital, Sydney NSW, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Januszewski
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Val J
authors.initials: VJ
authors.lastname: Gebski
authors.affiliation: Department of Medical and Surgical Sciences, Dunedin School of Medicine, Dunedin, New Zealand.
authors.forename: Patrick
authors.initials: P
authors.lastname: Manning
authors.affiliation: Townsville Diabetes and Endocrine Unit, Townsville Hospital, Townsville QLD, Australia.
authors.forename: Yong Mong
authors.initials: YM
authors.lastname: Tan
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Donoghoe
authors.affiliation: Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.affiliation: Diabetes Clinic, Northshore Hospital, Auckland, New Zealand.
authors.forename: Simon
authors.initials: S
authors.lastname: Young
authors.affiliation: Austin hospital, Melbourne VIC, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: O'Brien
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Buizen
authors.affiliation: Sydney Medical School, University of Sydney, Sydney NSW, Australia; Royal Prince Alfred Hospital, Sydney NSW, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Twigg
authors.affiliation: Royal Prince Alfred Hospital, Sydney NSW, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney NSW, Australia. Electronic address: fieldtrial@ctc.usyd.edu.au.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Keech
mesh_terms: D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D001315:Australia / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000401:mortality / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D058065:Diabetic Cardiomyopathies / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control; D004311:Double-Blind Method; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D005387:Finland / Q000453:epidemiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009520:New Zealand / Q000453:epidemiology; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control*; D015995:Prevalence; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D015415:Biomarkers; D000960:Hypolipidemic Agents; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human; D000410:Alanine Transaminase; D011345:Fenofibrate
keywords: Alanine aminotransferase; Diabetes mellitus; Mortality; Non-alcoholic fatty liver disease; γ-Glutamyl transferase