Liver Enzymes and Risk of All-Cause Mortality in General Populations: A Systematic Review and Meta-analysis

Setor K Kunutsor; Tanefa A Apekey; Dorothy Seddoh; John Walley


Int J Epidemiol. 2014;43(1):187-201. 

In This Article

Abstract and Introduction


Background Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), commonly used as markers of liver dysfunction, have been implicated with risk of all-cause mortality. The prospective evidence on the associations in general populations has not been reliably quantified.

Methods We conducted a systematic review and meta-analysis of published prospective cohort studies evaluating the associations of baseline levels of these enzymes with all-cause mortality in general populations. Relevant studies were identified in a literature search of MEDLINE, EMBASE and Web of Science up to March 2013. Authors of unpublished studies provided data on request.

Results Nineteen unique cohort studies with aggregate data on over 9.24 million participants and 242 953 all-cause mortality outcomes were included. In a comparison of extreme thirds of baseline GGT and ALP levels, relative risks (RRs) (95% confidence intervals) for all-cause mortality were 1.60 (1.42–1.80) and 1.38 (1.17–1.63), respectively. The corresponding RRs for ALT were 0.82 (0.78–0.86) and 1.43 (1.08–1.90) in North American and Asian populations, respectively. There was no strong evidence of an association of AST with all-cause mortality: RR 1.23 (0.80–1.88). The pooled RRs per 5 U/l increment in GGT and ALP levels were 1.07 (1.04–1.10) and 1.03 (1.01–1.06), respectively.

Conclusions Available data indicate positive independent associations of baseline levels of GGT and ALP with all-cause mortality, consistent with linear dose-response relationships. There were geographical variations in the association of ALT with all-cause mortality which require further investigation. The potential incremental prognostic values of GGT and ALP in mortality risk assessment need evaluation.


Assays for gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) are the most common laboratory tests used for the detection of liver diseases. Circulating GGT is present on the external surfaces of most cells, particularly hepatocytes, and in serum, and is used as a biological marker of excessive alcohol intake.[1] The liver aminotransferases (ALT and AST) are found abundantly within hepatocytes and they catalyze the transfer of amino groups to generate products in gluconeogenesis and amino acid metabolism.[2,3] Alkaline phosphatase is a hydrolase enzyme that catalyzes the hydrolysis of inorganic pyrophosphate, which is a vascular calcification inhibitor. Serum levels of ALP are commonly used in clinical practice as a marker of liver or bone disease.[4]

There have been important advances in the understanding of the physiological functions of these liver enzymes and several epidemiological associations have been reported. Several prospective epidemiological associations have been demonstrated between these markers of liver dysfunction and risk of type 2 diabetes mellitus,[5–7] cardiovascular disease (CVD)[8–11] or mortality from vascular and nonvascular causes,[4,12,13] after accounting for important risk factors. Furthermore, baseline circulating levels of GGT, ALT, AST and ALP have been reported to be associated with future risk of all-cause mortality (which is a more ultimate indicator of health than cause-specific outcomes[14]).[11,13,15–22] However, the majority of these studies were conducted in selected populations such as in the elderly, participants at high vascular risk or those with pre-existing disease.[17–20,22] Therefore the nature of the individual associations of these enzymes with risk of all-cause mortality among general populations is not very clear. A number of prospective studies have been published reporting on the associations between baseline levels of these enzymes and risk of all-cause mortality in general populations, but their results have been inconsistent.[9,11,13,15,17,20,21] Although they generally have low specificities for the liver, assays for these liver enzymes are sensitive, well standardized, simple, inexpensive and commonly used laboratory tests. These enzymes may be useful for the prediction of all-cause mortality[23] and the identification of individuals at high risk of dying from all-causes. Although, among the liver enzymes, GGT is a less specific indicator of liver dysfunction, research has largely focused on GGT and the evidence suggests that it may be a strong risk indicator for all-cause mortality. The aminotransferases and ALP (which are often measured simultaneously with GGT) have received less attention and their significance for all-cause mortality is less certain. We therefore, for the very first time, aimed to quantify precisely the nature and magnitude of the associations between baseline levels of GGT, ALT, AST and ALP with the risk of all-cause mortality in general populations using a meta-analytic approach.