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World J Hepatol. Apr 27, 2010; 2(4): 143-145
Published online Apr 27, 2010. doi: 10.4254/wjh.v2.i4.143
Liver function tests: Association with cardiovascular outcomes
Yusuf Yilmaz, Department of Gastroenterology, Marmara University, School of Medicine, Altunizade 34662, Istanbul, Turkey
Author contributions: Yilmaz Y contributed solely to this paper.
Correspondence to: Yusuf Yilmaz, MD, Department of Gastroenterology, Marmara University, School of Medicine, Altunizade 34662, Istanbul, Turkey.
Telephone: +90-533-4403995 Fax: +90-216-6886681
Received: November 11, 2009
Revised: March 26, 2010
Accepted: April 2, 2010
Published online: April 27, 2010


An association between nonalcoholic fatty liver disease and cardiovascular disease has been repeatedly reported. Several studies have focused on levels of gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT) in relation to cardiovascular outcomes. Evidence indicates that GGT may have a potential role for cardiovascular risk stratification while the role of ALT for cardiac prognosis remains controversial. A conceptual framework that includes not only GGT and ALT but also markers of hepatocyte apoptosis such as cytokeratin-18 fragments should be developed.

Key Words: Nonalcoholic fatty liver disease, Liver function tests, Cardiovascular disease, Outcomes


The evidence in favour of an association between nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease is now considerable[1]. For example, NAFLD patients diagnosed on ultrasonographic findings have an increased risk of incident cardiac events[2]. The nature of the association between NAFLD and cardiovascular events has generated a great deal of interest in the scientific community and levels of common biomarkers of NAFLD, including gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT), have been repeatedly studied in relation to cardiovascular outcomes. The objective of this editorial is to give an overview of the current evidence linking levels of GGT and ALT to cardiac prognosis. The overview provided in this paper is not intended to be exhaustive; rather, a brief summary of some key findings is provided.


In a previous meta-analysis of 10 population-based cohort studies, it was reported that an increase in 1 unit of log-transformed GGT was associated with an adjusted hazard ratio of 1.34 (95% CI: 1.22-1.48) for incident vascular events[3]. Besides being an early subclinical marker of fatty liver, GGT may act as a marker of oxidative stress and exposure to environmental chemicals[4]. It has thus been suggested that increased GGT levels may be linked to cardiovascular disease via different biological processes such as oxidative stress or lifestyle behaviours[3].

In contrast, the association of serum ALT, an enzyme more specific to the liver than GGT, with cardiac outcomes appears more controversial. There are at least six published studies that have addressed the association between serum ALT and incident cardiovascular events[3,5-9]. Figure 1 shows that the results have been quite divergent, casting doubts on an independent association between ALT and incident cardiac events. There are several possible explanations for this lack of association. Firstly, significant heterogeneity between studies could have resulted in null findings. Secondly, ALT is not only a marker of NAFLD but also of ectopic fat in general[10]. Finally, the association between ALT and cardiac risk may be confounded by other cardiovascular risk-equivalent such as diabetes[11].

Figure 1
Figure 1 Fully-adjusted hazard ratios and 95% confidence intervals for incident cardiovascular disease for an increase in 1 unit of log-transformed ALT in six published prospective studies. OR indicates odds ratio and CI confidence interval.

In summary, GGT may have a potential role for cardiovascular risk stratification but its predictive power appears modest overall. Evidence suggests that a doubling of GGT is associated with a 34 percent increase in the risk of incident cardiovascular events[3]. In contrast, there is not enough evidence that ALT may predict future cardiovascular events. As scientific evidence is insufficient, more research is needed into the prognostic significance of liver function tests for incident cardiovascular events. In particular, there are a number of issues that should be systematically addressed in the future. For example, it will be necessary to clarify the association with cardiovascular events of elevated GGT or ALT for initially healthy individuals compared with patients with NAFLD diagnosed by ultrasound. Future detailed analysis of the current studies will provide better discrimination on who is at increased risk and who is not. Another open issue is whether there are sex-related effects or relative risks. Even after adjustment for known risk factors, associations of GGT/ALT with cardiovascular events appear stronger in males than in females. A conceptual framework that includes not only classical markers of NAFLD but also markers of hepatocyte apoptosis such as cytokeratin-18 fragments[12,13] or other non-invasive liver tests such as Fibroscan[14] should form the basis for this research agenda.


Peer reviewers: Frank Tacke, MD, PhD, Department of Medicine III, University Hospital Aachen, Pauwelsstr. 30, Aachen 52074, Germany; Kezhong Zhang, PhD, Assistant Professor, Center for Molecular Medicine & Genetics, Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 E Canfield Avenue, Detroit, MI 48201, United States

S- Editor Zhang HN L- Editor Roemmele A E- Editor Liu N

1.  Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007;191:235-240.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Hamaguchi M, Kojima T, Takeda N, Nagata C, Takeda J, Sarui H, Kawahito Y, Yoshida N, Suetsugu A, Kato T. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13:1579-1584.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Gamma-glutamyltransferase is associated with incident vascular events independently of alcohol intake: analysis of the British Women’s Heart and Health Study and Meta-Analysis. Arterioscler Thromb Vasc Biol. 2007;27:2729-2735.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Lee DH, Jacobs DR Jr. Serum gamma-glutamyltransferase: new insights about an old enzyme. J Epidemiol Community Health. 2009;63:884-886.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis. 2007;191:391-396.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Monami M, Bardini G, Lamanna C, Pala L, Cresci B, Francesconi P, Buiatti E, Rotella CM, Mannucci E. Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism. 2008;57:387-392.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Goessling W, Massaro JM, Vasan RS, D’Agostino RB Sr, Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology. 2008;135:1935-1944, 1944.e1.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136:477-485.e11.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Ioannou GN. Implications of elevated serum alanine aminotransferase levels: think outside the liver. Gastroenterology. 2008;135:1851-1854.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  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 Metab Res Rev. 2006;22:437-443.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  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.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatit-is: a multicenter validation study. Hepatology. 2009;50:1072-1078.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48:835-847.  [PubMed]  [DOI]  [Cited in This Article: ]