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increased intima-media thickness and of impaired flow-mediated vasodilatation; the presence of carotid
atherosclerotic plaques; an increased coronary artery calcium score on cardiac computed tomography;
and abnormal coronary flow reserve as a marker for impaired coronary microcirculation.
In addition, clinical CHD data are emerging from large cohorts of patients, both cross-sectional and
longitudinal studies as well community-based cohorts and more selected patient groups (e.g. patients
with T2DM, type 1 diabetes, patients undergoing coronary angiography or patients with documented
NAFLD). These data, reviewed elsewhere [2, 3], reveal that NAFLD is an independent predictor
for clinical CHD, measured as the severity of the atherosclerotic lesions on coronarography or the
occurrence of fatal and non-fatal CHD events. Only a few studies did not confirm the independent
relationship of NAFLD with incident CHD or showed it to be confined to patients with NAFLD
who concomitantly met the diagnosis of the MetS. Overall the data strongly support the independent
contribution of NAFLD to an increased risk of clinically relevant CHD, even after correction for an
extended set of well-established risk factors for CHD.
Several studies also showed a link between NAFLD and alterations in cardiac metabolism, structure
and hemodynamic function, such as myocardial insulin resistance and mitochondrial ATP production,
cardiac steatosis, myocardial hypertrophy and left ventricular diastolic dysfunction, not attributable
to concomitant diabetes, obesity or arterial hypertension. The severity of these cardiac abnormalities
correlated with the severity of the NAFLD. Finally, NAFLD has been associated with an increased risk
of autonomic dysfunction and cardiac arrhythmias (mainly atrial fibrillation). Interestingly, recent data
have shown that NAFLD is also independently linked with QTc interval prolongation, a major risk
factor for ventricular arrhythmias and sudden cardiac death, which might explain in part the increased
CV mortality associated with NAFLD. Finally, congestive heart failure and aortic valve sclerosis have
also been linked with NAFLD independently of known risk factors.
Not all of these data are methodologically robust and most of the studies lack a liver biopsy diagnosis.
However, the concept of NAFLD as being an independent contributor to the development of
atherosclerosis and other functional and structural CV alterations, which subsequently lead to clinical
CVD, appear to be sufficiently substantiated to integrate into the clinical approach for both the NAFLD
patient and the CVD patient.
NAFLD and CVD: pathophysiological considerations
The mechanisms by which NAFLD influences the development of atherosclerosis and CVD are
incompletely understood. NAFLD, T2DM, MetS and CVD share many metabolic features and risk
factors, leading to the concept that they belong to a complex multi-system disease with several organ
manifestations and a complex interplay between the different entities, with multiple bidirectional cause-
effect relationships. The specific contribution of one entity to the others is therefore difficult to discern,
and there might be substantial inter-individual variability.
The contribution of NAFLD to CVD, seen as a unidirectional cause-effect relationship, can be either
indirect or direct and the potential mechanisms are summarized in Fig. 1.
First, as the liver is a key organ in both glucose and lipid homeostasis, it is not surprising that evidence
is accumulating that NAFLD plays a role in the development of T2DM and the MetS, which are by
themselves risk factors for CVD. This links NAFLD only indirectly to CVD. NAFLD has indeed been
shown to contribute to the development of T2DM. Several studies, mostly diagnosing NAFLD by
ultrasound or liver enzymes, have shown that NAFLD precedes and predicts the future development of
T2DM independent of obesity and other factors of the MetS [4].
Secondly, the liver might also contribute directly to the development of CVD. It is clear that NAFLD is
associated with an atherogenic lipid profile. In NAFLD, production of triglyceride-rich VLDL particles
is increased. Insulin normally inhibits adipose tissue lipolysis (the main source of FFA flux to the liver
60 Postgraduate Course Syllabus • Metabolic Liver Disease
atherosclerotic plaques; an increased coronary artery calcium score on cardiac computed tomography;
and abnormal coronary flow reserve as a marker for impaired coronary microcirculation.
In addition, clinical CHD data are emerging from large cohorts of patients, both cross-sectional and
longitudinal studies as well community-based cohorts and more selected patient groups (e.g. patients
with T2DM, type 1 diabetes, patients undergoing coronary angiography or patients with documented
NAFLD). These data, reviewed elsewhere [2, 3], reveal that NAFLD is an independent predictor
for clinical CHD, measured as the severity of the atherosclerotic lesions on coronarography or the
occurrence of fatal and non-fatal CHD events. Only a few studies did not confirm the independent
relationship of NAFLD with incident CHD or showed it to be confined to patients with NAFLD
who concomitantly met the diagnosis of the MetS. Overall the data strongly support the independent
contribution of NAFLD to an increased risk of clinically relevant CHD, even after correction for an
extended set of well-established risk factors for CHD.
Several studies also showed a link between NAFLD and alterations in cardiac metabolism, structure
and hemodynamic function, such as myocardial insulin resistance and mitochondrial ATP production,
cardiac steatosis, myocardial hypertrophy and left ventricular diastolic dysfunction, not attributable
to concomitant diabetes, obesity or arterial hypertension. The severity of these cardiac abnormalities
correlated with the severity of the NAFLD. Finally, NAFLD has been associated with an increased risk
of autonomic dysfunction and cardiac arrhythmias (mainly atrial fibrillation). Interestingly, recent data
have shown that NAFLD is also independently linked with QTc interval prolongation, a major risk
factor for ventricular arrhythmias and sudden cardiac death, which might explain in part the increased
CV mortality associated with NAFLD. Finally, congestive heart failure and aortic valve sclerosis have
also been linked with NAFLD independently of known risk factors.
Not all of these data are methodologically robust and most of the studies lack a liver biopsy diagnosis.
However, the concept of NAFLD as being an independent contributor to the development of
atherosclerosis and other functional and structural CV alterations, which subsequently lead to clinical
CVD, appear to be sufficiently substantiated to integrate into the clinical approach for both the NAFLD
patient and the CVD patient.
NAFLD and CVD: pathophysiological considerations
The mechanisms by which NAFLD influences the development of atherosclerosis and CVD are
incompletely understood. NAFLD, T2DM, MetS and CVD share many metabolic features and risk
factors, leading to the concept that they belong to a complex multi-system disease with several organ
manifestations and a complex interplay between the different entities, with multiple bidirectional cause-
effect relationships. The specific contribution of one entity to the others is therefore difficult to discern,
and there might be substantial inter-individual variability.
The contribution of NAFLD to CVD, seen as a unidirectional cause-effect relationship, can be either
indirect or direct and the potential mechanisms are summarized in Fig. 1.
First, as the liver is a key organ in both glucose and lipid homeostasis, it is not surprising that evidence
is accumulating that NAFLD plays a role in the development of T2DM and the MetS, which are by
themselves risk factors for CVD. This links NAFLD only indirectly to CVD. NAFLD has indeed been
shown to contribute to the development of T2DM. Several studies, mostly diagnosing NAFLD by
ultrasound or liver enzymes, have shown that NAFLD precedes and predicts the future development of
T2DM independent of obesity and other factors of the MetS [4].
Secondly, the liver might also contribute directly to the development of CVD. It is clear that NAFLD is
associated with an atherogenic lipid profile. In NAFLD, production of triglyceride-rich VLDL particles
is increased. Insulin normally inhibits adipose tissue lipolysis (the main source of FFA flux to the liver
60 Postgraduate Course Syllabus • Metabolic Liver Disease
