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Liver and heart: A new link? - ALT Predicts Heart Disease
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Journal of Hepatology
May 22, 2008
Articles in Press
Stefano Bellentani1, Giorgio Bedogni12, Claudio Tiribelli2
published online 22 May 2008.
Uncorrected Proof
Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study.
"Strongly suggests that elevation of ALT and NAFLD are associated with increased risk of cardiovascular disease, and are independent predictors of cardiovascular mortality. Further studies are needed to confirm these findings and to evaluate the possibility that NAFLD may or may not be an early marker (or mediator) of atherosclerosis, and possibly unravel what is the trigger for lipotoxicity in the liver or in the heart. In the meantime, there is a clear take-home message for the practising physician: perform an evaluation of common cardiovascular risk factors in patients with elevated ALT or NALFD"
Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M.
Alanine aminotransferase (ALT) is a marker of non-alcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50-75 years, at baseline. The 10-year risk of all-cause mortality, fatal and non-fatal CVD and CHD events in relation to ALT was assessed in 1439 subjects participating in the Hoorn Study, using Cox survival analysis. Subjects with prevalent CVD/CHD and missing data were excluded. As compared with the first tertile, the age- and sex-adjusted hazard ratios (95% confidence intervals) for all-cause mortality, CVD events and CHD events were 1.30 (0.92-1.83), 1.40 (1.09-1.81) and 2.04 (1.35-3.10), respectively, for subjects in the upper tertile of ALT. After adjustment for components of the metabolic syndrome and traditional risk factors, the association of ALT and CHD events remained significant for subjects in the third relative to those in the first tertile, with a hazard ratio of 1.88 (1.21-2.92) and 1.75 (1.12-2.73), respectively. In conclusion, the predictive value of ALT for coronary events, seems independent of traditional risk factors and the features of the metabolic syndrome in a population-based cohort. Further studies should confirm these findings and elucidate the pathophysiological mechanisms.
[Abstract reproduced by permission of Atherosclerosis 2007;191:391-396]
Article Outline
The relationship between liver and heart diseases has been historically a matter of debate. Cardiac hyperdynamic abnormalities, characterized by increased baseline cardiac output and mean arterial pressure, were first reported in 1953 by Kowalski & Abelmann in patients with cirrhosis [1]. Today, the complex hemodynamic alterations present in cirrhotic patients are classified as "cirrhotic cardiomyopathy", and are recognized to play a role in the pathogenesis of the hepatorenal syndrome and in the mortality associated with TIPS insertion or liver transplantation. However, both old and modern clinicians would certainly agree that when the liver is damaged as in cirrhosis, the principal clinical problem is the liver and not the heart.
With the appearance on the clinical scenario of non-alcoholic fatty liver disease (NAFLD), and with the rapid recognition that NAFLD is the commonest hepatic disorder in the developed world affecting up to a third of individuals and the increasing number of heart disease, the relationship between liver and the heart has been revisited. It is becoming increasingly evident that the so-called "metabolic syndrome" (MS) represents the main link between liver and heart diseases [2]. Subjects with MS are in fact considered at risk of cardiovascular and coronary heart disease, although the clinical usefulness of this syndrome is still debated [3], [4].
Recent studies have stressed the importance of fatty liver as an independent predictor of some cardiovascular outcomes [2], [5]. Other studies have shown that subjects with abnormal liver enzymes, mainly ALT, are at risk of developing hypertension and diabetes. In addition, NAFLD has been associated with surrogate cardiovascular outcomes such as endothelial dysfunction, abnormal vascular reactivity, increased carotid intimal thickness and a number of carotid plaques [5], [6]. Recently, in a prospective study, Ekstedt and colleagues have shown that the 14-year risk of cardiovascular mortality is doubled in tertiary care patients with biopsy-proven NAFLD as compared to a reference population [7].
Cardiac lipotoxicity is a well-described phenomenon associated with insulin resistance, and is generally attributed to an excess production of free fatty acids [8]. Perseghin and colleagues have recently shown that individuals with an increased amount of fat in the liver have also an increased amount of epicardial fat [9]. Despite alterations in cardiac metabolism detected by phosphorous magnetic resonance spectroscopy, these subjects had a normal morphology and function of the heart.
In the general population of the Hoorn Study, Schindhelm and colleagues reported that elevated serum ALT activity significantly increased the 10-year risk of coronary hearth disease, even after adjustment for alcohol intake and for the component of MS. They concluded that in the general population, ALT is a predictor of 10-year cardiovascular mortality independently of traditional cardiovascular risk factors, such as systolic blood pressure, HbA1c, LDL-cholesterol and BMI [10]. As acknowledged by the Authors, the study has several limitations: (1) a highly selected population (Caucasians aged 50-75 years); (2) the lack of information on non-fatal disease; (3) the use of ALT as a surrogate marker of NAFLD in place of more reliable imaging or histological procedures; and (4) the lack of exclusion of ALT elevations due to hepatotropic viruses and drugs. Despite these shortcomings the message of the study is clearly important. An additional problem to be considered is that not all the patients with fatty liver do show increased ALT level as recently demonstrated in the general population of the Dionysos Study where 50% of subjects with steatosis detected by ultrasonography had normal levels of ALT [11]. Taking ALT as the only surrogate marker of NAFLD, instead of performing hepatic ultrasound to find out if steatosis was present, probably underestimates the predictive value of ALT, questioning the validity of the message.
Collectively, the paper by Schindhelm and colleagues [10] challenges the assumption that ALT is only a marker of liver disease, and strongly suggests that elevation of ALT and NAFLD are associated with increased risk of cardiovascular disease, and are independent predictors of cardiovascular mortality. Further studies are needed to confirm these findings and to evaluate the possibility that NAFLD may or may not be an early marker (or mediator) of atherosclerosis, and possibly unravel what is the trigger for lipotoxicity in the liver or in the heart. In the meantime, there is a clear take-home message for the practising physician: perform an evaluation of common cardiovascular risk factors in patients with elevated ALT or NALFD [6].
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