To the Editor:

We read with great interest the excellent article by Ghouri and coworkers,1 who reviewed the current literature on the levels of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) as potential predictors of incident cardiovascular disease. The authors elegantly demonstrate that there may be a statistically significant association between higher GGT levels and incident cardiovascular disease events, although this association may be clinically questionable because it is confounded by age. In contrast, ALT levels are not significantly associated with cardiovascular risk. Based on these findings, the authors question the potential usefulness of cardiovascular risk screening based on the presence of nonalcoholic fatty liver disease (NAFLD). The authors are to be congratulated for their straightforward, clear, and concise presentation of the available material on this highly debated topic. One important issue raised by Ghouri et al.1 is the observation that even when statistical adjustments have been made in previous studies, they have frequently been limited by weak variables such as the metabolic syndrome. Despite the overwhelming attention given to the metabolic syndrome in recent years, evidence is finally emerging that the diagnosis of this entity is an artificial construct that is less informative than the sum of its parts.2, 3 Of much interest and importance, no common pathophysiology has been elucidated as basis for the risk factors included in the definition of the metabolic syndrome.4, 5 We therefore endorse the authors' conclusion that an important point for future research in the field of liver enzymes as predictors of cardiovascular outcomes should consider all traditional vascular risk factors as potential confounders.1 In light of the limited evidence of an association between liver enzymes and cardiac outcomes, further research is needed to shed more light on this issue. To fully achieve this goal, we should pay attention to the following issues in future research:

  • 1
    Even after adjustment for known risk factors, associations of GGT with cardiovascular events appear stronger in males than in females.6 Therefore, sex-based subgroup analysis is necessary to clarify whether there are sex-related effects or relative risks.
  • 2
    It is necessary to clarify whether the association with cardiovascular events of elevated GGT differs between initially healthy individuals compared with patients with ultrasound-diagnosed NAFLD. This would help to disentangle the impact of the NAFLD diagnosis per se on cardiac outcomes. Indeed, NAFLD with normal liver enzymes is currently a widely accepted entity.7
  • 3
    Besides classical liver enzymes (GGT and ALT), it will be helpful to assess more sensitive biochemical markers of NAFLD, such as cytokeratin-18 fragments,8 in relation to cardiovascular outcomes. This is an important issue inasmuch as ALT is not only a marker of NAFLD but also of ectopic fat in general.9


  1. Top of page
  • 1
    Ghouri N, Preiss D, Sattar N. Liver enzymes, NAFLD and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. HEPATOLOGY 2010; doi:10.1002/hep.23789.
  • 2
    Reaven G. The metabolic syndrome: is this diagnosis necessary? Am J Clin Nutr 2006; 83: 1248-1251.
  • 3
    Kahn R. Metabolic syndrome: is it a syndrome? Does it matter? Circulation 2007; 115: 1806-1810.
  • 4
    Gale EA. The myth of the metabolic syndrome. Diabetologia 2005; 48: 1679-1683.
  • 5
    Solbu MD, Kronborg J, Jenssen TG, Njølstad I, Løchen ML, Mathiesen EB, et al. Albuminuria, metabolic syndrome and the risk of mortality and cardiovascular events. Atherosclerosis 2009; 204: 503-508.
  • 6
    Yilmaz Y. Liver function tests: association with cardiovascular outcomes. World J Hepatol 2010; 2: 143-145.
  • 7
    Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni E. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. HEPATOLOGY 2008; 48: 792-798.
  • 8
    Yilmaz Y. Systematic review: caspase-cleaved fragments of cytokeratin 18 - the promises and challenges of a biomarker for chronic liver disease. Aliment Pharmacol Ther 2009; 30: 1103-1109.
  • 9
    Ioannou GN. Implications of elevated serum alanine aminotransferase levels: think outside the liver. Gastroenterology 2008; 135: 1851-1854.

Yusuf Yilmaz M.D.*, Ramazan Kurt M.D.*, Cem Kalayci M.D.*, * Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey.