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We greatly appreciate the opportunity to respond to the letter by Wang and Kao titled “From Liver Markers to Life Expectancy”, which is pertinent to our recently published article on the association of elevated gamma-glutamyl transpeptidase (GGT) levels and hepatic steatosis with mortality.1

Indeed, there is growing evidence suggesting that serum alanine aminotransferase (ALT) levels are predictive of adverse cardiovascular disease (CVD) events and mortality.2, 3 To assess that association in our study population, we divided ALT levels by age-specific (in decades) and sex-specific quintiles and used Cox proportional hazards regression models as previously described.1 In doing so, we detected no evidence for an association between ALT levels and mortality in neither crude, nor age-adjusted, and multiple-adjusted Cox models for men and women. Although lacking statistical significance, further analyses stratified by ultrasonographic finding of hepatic steatosis revealed that elevated ALT levels (highest versus lowest quintile) were associated with an increased risk of mortality in men with hepatic steatosis (hazard ratio [HR] = 2.24; 95% confidence interval [CI] = 0.68-7.38) but not in women (HR = 0.91; 95% CI = 0.13-2.12). Additionally, we compared Harrell's C from multiple-adjusted Cox models with (0.848) and without (0.846) continuous ALT levels, suggesting no improved predictive power of combined GGT and ALT levels in the association with mortality. Therefore, our additional results were not able to affirm previous studies suggesting that GGT and ALT have similar or even synergistic associations with CVD and mortality risk.4, 5

Furthermore, we fully agree with Wang and Kao that the issue of alcohol intake is relevant. There is no doubt that the participants from our study region are known to be exposed to high-normal levels of alcohol intake,6 explaining that the mean alcohol consumption in men was near the levels of risk (>20 g/day). Therefore, we carefully addressed that issue by performing multiple sensitivity analyses with the exclusion of heavy drinkers (>60 g/day for men and >30 g/day for women), exclusion of nondrinkers (<10 g/day for men and women), and stratification by riskful alcohol consumption (<10/>10 g/day in women and <20/>20 g/day in men), without revealing any major impact on our main results.1

Finally, Wang and Kao addressed recent findings that identified metabolic syndrome (MS) as a strong predictor of nonalcoholic fatty liver disease (NAFLD)7 and suspected that due to the chronological sequence of the development, NAFLD may be an earlier manifestation of MS compared to CVD. We sought to address this very interesting comment by the inclusion of the single MS components as potential mediators of the revealed GGT-NAFLD-mortality association. Yet, sex-stratified Cox models adjusted for age and the single MS components revealed only minor mediating effects on the association of GGT and hepatic steatosis with mortality.

In conclusion, the issues raised by Wang and Kao extrapolate our recently reported association of elevated GGT levels and hepatic steatosis with mortality,1 broadening the picture to alternative or complementary pathophysiological mechanisms associated with NAFLD. However, we advocate further large-scale studies in longitudinal population-based cohorts similar to ours, to elucidate the further potential of liver-associated biomarkers in the risk prediction of CVD and mortality.

References

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  • 1
    Haring R, Wallaschofski H, Nauck M, Dorr M, Baumeister SE, Volzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. HEPATOLOGY 2009; 50: 14031411.
  • 2
    Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007; 191: 391396.
  • 3
    Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink T, Heine RJ. Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes/metabolism research and reviews 2006; 22: 437443.
  • 4
    Lee DH, Lim JS, Yang JH, Ha MH, Jacobs DR Jr. Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: a four year follow-up study. Free Radical Res 2005; 39: 589593.
  • 5
    Yamada J, Tomiyama H, Yambe M, Koji Y, Motobe K, Shiina K, et al. Elevated serum levels of alanine aminotransferase and gamma glutamyltransferase are markers of inflammation and oxidative stress independent of the metabolic syndrome. Atherosclerosis 2006; 189: 198205.
  • 6
    Baumeister SE, Alte D, Meyer C, John U. Health risk drinking and problematic consumption of alcohol in Pomerania: comparative analysis of the Study of Health in Pomerania (SHIP) compared with the Federal German Health and Examination Survey in 1998 [in German]. Gesundheitswesen 2005; 67: 3947.
  • 7
    Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143: 722728.

Robin Haring* †, Henri Wallaschofski†, Matthias Nauck†, Marcus Dörr‡, Sebastian E. Baumeister†, Henry Völzke†, * Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany, † Institute of Clinical Chemistry and Laboratory Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany, ‡ Department of Cardiology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.