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To the Editor:

We read with great interest the article by Haring et al.1 In this population-based study, they found that elevated gamma-glutamyl transpeptidase (GGT) level was associated with an increased risk of all-cause and cardiovascular disease (CVD) mortality in men, and these associations were even stronger in men with hepatic steatosis. Their results indeed provide important data to improve our understanding about the interactions among GGT, CVD risk, and mortality; however, several issues deserve further discussion.

First, GGT level is found to be strongly associated with all-cause mortality, largely due to CVD in the top quintile of the GGT distribution. This is the first study to document a direct association of elevated GGT level and hepatic steatosis with all-cause and CVD mortality in men, suggesting ultrasonographic hepatic steatosis may increase the prediction value of elevated GGT level in mortality risk. Of interest is that serum alanine aminotransferase (ALT), a marker of liver inflammation or injury, can also predict CVD events in a 10-year follow-up study.2 Additionally, increased overall mortality and risk of CVD were reported in patients with nonalcoholic fatty liver disease (NAFLD).3 Taking these lines of evidence together, serum liver enzymes including GGT and ALT as well as hepatic steatosis seem to have similar and even synergistic association with the risks of CVD and all-cause mortality. Our previous study also demonstrated that serum ALT level was positively associated with carotid atherosclerosis in patients with NAFLD, suggesting serum ALT level may predict CVD risk in patients with NAFLD.4 Therefore, it will help us understand more about the relationship among these parameters with CVD risk and mortality if the authors could perform further analyses stratified by different serum ALT levels.

Second, the present study didn't exclude participants with the habit of alcohol consumption, and the mean alcohol consumption in men was near the level of risk (20 g/day). In our clinical practice, elevated GGT level is usually observed in patients with biliary or alcoholic liver diseases that could be the major component of the top quintile GGT group. In addition, heavy alcohol consumption has been reported to increase mortality risk.5 To solve this issue, the authors should provide data about the percentage of alcohol consumption in the top quintile group and the association of GGT with all-cause mortality in men without alcohol consumption to prevent the confounding effect of alcohol on serum GGT level and all-cause mortality.

Finally, finding an ideal marker to predict mortality or life expectancy is a dream of practicing physicians. All of the reported candidate markers seem to be associated with the existence of NAFLD. It is generally believed that NAFLD is a hepatic manifestation of metabolic syndrome, which contributes to the risk of CVD. According to the chronological sequence of development, NAFLD may be an earlier manifestation of metabolic syndrome compared to CVD. Therefore, NAFLD-related markers including serum GGT, ALT, and hepatic steatosis may predict CVD risk or even mortality. However, whether liver itself could serve as an alarm bell for mortality or life expectancy deserves further investigations.

References

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  • 1
    Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke 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, 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
    Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007; 191: 235240.
  • 4
    Wang CC, Lin SK, Tseng YF, Hsu CS, Tseng TC, Lin HH, et al. Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2009; 24: 14111416.
  • 5
    Mukamal KJ, Rimm EB. Alcohol consumption: risks and benefits. Curr Atheroscler Rep 2008; 10: 536543.

Chia-Chi Wang M.D.*, Jia-Horng Kao Ph.D.†, * Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University, Hualien, Taiwan, † Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.