The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53–2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45–5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging
THERE are several reasons why blood tests of liver function and injury might be associated with age and mortality in older people. First, nonalcoholic fatty liver disease (NAFLD) secondary to obesity is associated with increased mortality and morbidity (1), and in modern societies, overweight and obesity tend to become more prevalent in older people (2). In fact, NAFLD is now one of the most common liver diseases in the Western world, directly as a consequence of the obesity epidemic. One of the key clinical markers of fatty liver is raised blood activity of alanine transaminase (ALT), which is an enzyme released from damaged hepatocytes (1). Yet, there has been at least one report suggesting that ALT decreases with old age (3). The relationship between ALT and obesity in older people and the implication for survival in older people remain unclear.
Furthermore, many studies have reported that the metabolic and detoxification functions of the liver are decreased in old age, although this is controversial (4–6). Because of the role of the liver in regulating systemic metabolism and protecting the body from circulating endogenous and exogenous toxins, any age-related change in liver function has implications for age-related conditions and diseases. Despite the potential significance of liver function in aging, the impact of old age on blood markers of liver injury and liver disease including ALT, gamma-glutamyl transferase (GGT), and bilirubin have not been established in old age, particularly in very elderly people. On the other hand, albumin, which is synthesized by the liver, has been investigated widely. Low albumin is associated with aging, frailty, and reduced survival (7–10), although this might reflect systemic inflammation rather than impaired hepatic function (7,10).
For these reasons, we hypothesized that blood liver function tests will be associated with age and subsequent mortality in older people. In particular, we focused on ALT as a marker of general liver injury and more specifically as a marker of fatty liver, which is associated with obesity. As part of this process, we also describe the changes in liver function tests and body composition in elderly men.
In conclusion, low circulating ALT activity was found to be associated with aging and frailty in old men and to be a predictor of their subsequent survival. The effect of ALT on mortality was mediated via its association with frailty and aging. ALT may be a useful biomarker for aging and frailty and should be considered for future studies, especially because the decrease in ALT with age and frailty was greater than that seen with albumin. However, it must be acknowledged that the mechanisms for the associations that we have reported here remain unclear.
This work was supported by the Australian National Health and Medical Research Council (NHMRC Project Grant No. 301916 and 512364), the Ageing and Alzheimer’s Research Foundation, and the Medical Foundation of the University of Sydney.
Wednesday
Alanine Aminotransferase, Metabolic Syndrome, and Cardiovascular Disease: A Missing Link?
Chia-Chi Wang MD1 and Jia-Horng Kao MD, PhD2
1Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University, Hualien, Taiwan
2Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
published to the editor:
We read with great interest the article by Olynyk et al. (1). In this population-based cohort study, whether elevated alanine aminotransferase (ALT) concentration could predict metabolic syndrome (MS) or cardiovascular disease (CVD) was investigated. Olynyk et al. found a strong association between baseline ALT concentration and MS, independent of insulin resistance. However, serum ALT levels did not seem to contribute to the risk of CVD. Although their results provided additional data to this area of active investigation, several issues deserve further discussion.
First, previous studies have shown similar findings regarding the relationship between serum ALT activity and MS. However, the lack of association of serum ALT levels with the risk of CVD was contradictory to recent reports. In the Hoorn study on an elderly population, a positive association between serum ALT and coronary heart disease events was observed even after adjustment for the components of MS and traditional risk factors (2). In another 20-year follow-up study, higher ALT levels were significantly associated with incident CVD in age-/gender-adjusted models, but this association was attenuated on multivariable adjustment (3). These discrepant findings may be attributed to the more stringent definition of incident CVD, younger participants, or to shorter follow-up period. In this study by Olynyk et al., incident CVD events were ascertained only from hospital admission or death records. However, CVD such as angina pectoris could possibly have been diagnosed and treated by primary care physicians without admission. Therefore, incident CVD events might be underestimated in this study.
Second, nonalcoholic fatty liver disease has been recognized as the hepatic manifestation of MS, by which the risk of CVD could be predicted. On the basis of time to development, CVD may be a later manifestation of MS compared with nonalcoholic fatty liver disease. Therefore, it is possible to show positive results among these parameters in case larger or elderly populations, longer follow-up periods, or more sensitive tests to define the risk of CVD could be adopted in future studies. In a cross-sectional analysis using the Framingham risk score to estimate the 10-year risk of coronary heart disease (4), elevated serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption was found to be associated with increased calculated risk of coronary heart disease.
In summary, serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption serves not only as a marker of nonalcoholic fatty liver disease but also as a possible predictor of MS and CVD (5).
1.Olynyk JK, Knuiman MW, Divitini ML et al. Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population. Am J Gastroenterol 2009;104:1715–1722. | Article | PubMed | ChemPort |
2.Schindhelm RK, Dekker JM, Nijpels G et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007;191:391–396. | Article | PubMed | ChemPort |
3.Goessling W, Massaro JM, Vasan RS et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008;135:1935–1944. | Article | PubMed | ChemPort |
4.Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006;43:1145–1151. | Article | PubMed | ChemPort |
5.Wang CC, Lin SK, Tseng YF et al. Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2009;24:1411–1416. | Article | PubMed | ChemPort |
1Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University, Hualien, Taiwan
2Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
published to the editor:
We read with great interest the article by Olynyk et al. (1). In this population-based cohort study, whether elevated alanine aminotransferase (ALT) concentration could predict metabolic syndrome (MS) or cardiovascular disease (CVD) was investigated. Olynyk et al. found a strong association between baseline ALT concentration and MS, independent of insulin resistance. However, serum ALT levels did not seem to contribute to the risk of CVD. Although their results provided additional data to this area of active investigation, several issues deserve further discussion.
First, previous studies have shown similar findings regarding the relationship between serum ALT activity and MS. However, the lack of association of serum ALT levels with the risk of CVD was contradictory to recent reports. In the Hoorn study on an elderly population, a positive association between serum ALT and coronary heart disease events was observed even after adjustment for the components of MS and traditional risk factors (2). In another 20-year follow-up study, higher ALT levels were significantly associated with incident CVD in age-/gender-adjusted models, but this association was attenuated on multivariable adjustment (3). These discrepant findings may be attributed to the more stringent definition of incident CVD, younger participants, or to shorter follow-up period. In this study by Olynyk et al., incident CVD events were ascertained only from hospital admission or death records. However, CVD such as angina pectoris could possibly have been diagnosed and treated by primary care physicians without admission. Therefore, incident CVD events might be underestimated in this study.
Second, nonalcoholic fatty liver disease has been recognized as the hepatic manifestation of MS, by which the risk of CVD could be predicted. On the basis of time to development, CVD may be a later manifestation of MS compared with nonalcoholic fatty liver disease. Therefore, it is possible to show positive results among these parameters in case larger or elderly populations, longer follow-up periods, or more sensitive tests to define the risk of CVD could be adopted in future studies. In a cross-sectional analysis using the Framingham risk score to estimate the 10-year risk of coronary heart disease (4), elevated serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption was found to be associated with increased calculated risk of coronary heart disease.
In summary, serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption serves not only as a marker of nonalcoholic fatty liver disease but also as a possible predictor of MS and CVD (5).
1.Olynyk JK, Knuiman MW, Divitini ML et al. Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population. Am J Gastroenterol 2009;104:1715–1722. | Article | PubMed | ChemPort |
2.Schindhelm RK, Dekker JM, Nijpels G et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007;191:391–396. | Article | PubMed | ChemPort |
3.Goessling W, Massaro JM, Vasan RS et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008;135:1935–1944. | Article | PubMed | ChemPort |
4.Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006;43:1145–1151. | Article | PubMed | ChemPort |
5.Wang CC, Lin SK, Tseng YF et al. Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2009;24:1411–1416. | Article | PubMed | ChemPort |
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