Non-alcoholic fatty liver disease (NAFLD) is not an innocent bystander but is rather a "driving force" behind coronary artery disease (CAD), French researchers said.
In a large cohort study, steatosis predicted carotid intima-media thickness (C-IMT) and Framingham Risk Score independently of established risk factors such as diabetes and dyslipidemia, a research team led by Raluca Pais, MD, of the Pierre and Marie Curie University in Paris, reported in the Journal of Hepatology.
The study also found that steatosis at baseline predicted carotid plaque development over 8 years of follow-up, independently of risk factors including age, sex, diabetes, smoking, and hypertension (odds ratio 1.63; 95% CI 1.10-2.41; P=0.014), Pais and colleagues said.
"The clinical implications are of critical importance, since patients at cardiovascular risk presenting with one or more metabolic syndrome characteristics are at even greater risk if they have steatosis," Pais said in a press release. "It follows that the diagnosis of steatosis is extremely important and, therefore, a thorough cardiovascular and metabolic work-up and strict monitoring of cardiovascular disease or metabolic complications are needed in the clinical management of NAFLD.
"Since these data are derived from an at-risk primary prevention cohort rather than a highly selected population that had already experienced cardiovascular events, the conclusions of this study apply to the large majority of patients with steatosis from the general population," the investigators noted.
The study included 5,671 patients without a history of cardiovascular disease but with at least two risk factors. The mean age was 52, and roughly half were women. Half the patients had more than two cardiovascular risk factors, and a third had steatosis as defined by a validated surrogate marker, the fatty liver index (FLI).
Carotid ultrasound was performed on all patients at baseline as part of a primary prevention program. In addition, 1,872 patients had a follow-up carotid ultrasound at least 2 years after the initial evaluation. The investigators examined the impact of steatosis on the presence and progression of C-IMT and carotid plaques over a mean follow-up of 8±4 years.
The investigators found that C-IMT increased along FLI quartiles:
- First quartile: 0.58±0.12mm;
- Second quartile: 0.61±0.14mm;
- Third quartile: 0.63±0.14mm; and
- Fourth quartile: 0.64±0.14mm.
Framingham risk score also increased along FLI quartiles:
- First quartile: 5±5%;
- Second quartile: 9±7%;
- Third quartile: 12±8%; and
- Fourth quartile: 15±9%.
Steatosis predicted C-IMT better than diabetes or dyslipidemia, and steatosis independently predicted C-IMT (P=0.002) and FRS (P <0.001) after adjustment for the metabolic syndrome and cardiovascular risk factors, Pais and colleagues reported.
In the 1,872 patients with a follow-up ultrasound, C-IMT increased in patients with steatosis, from 0.60 ± 0.13 mm to 0.66 ± 0.14 mm (P=0.001), but C-IMT did not change in patients who remained free of steatosis.
A chief limitation of the study, the authors noted, was that steatosis was assessed by FLI and not histologically. "Unfortunately, because histological data were not available, this study cannot provide evidence as to whether steatohepatitis, which combines steatosis, hepatic inflammation, and liver cell injury, has a stronger association with early atherosclerosis than steatosis alone," they said.
Clinical Implications and Potential Mechanisms
"The study by Pais et al provides further support for the view that NAFLD is an independent risk factor for atherosclerosis and therefore cardiovascular disease," said Leon Adams, PhD, of the University of Western Australia, Nedlands, and Quentin Anstee, PhD, of Newcastle University in the U.K., in an accompanying editorial.
"Clinicians should be aware of the increased cardiovascular risk in patients with NAFLD and consequently screen for conventional cardiovascular risk factors and use accepted risk calculators to make decisions regarding preventative pharmacotherapy, including statins. Additional prospective studies will be needed to determine what other factors modify the association between NAFLD and cardiovascular disease," Adams and Anstee said.
"It should not be surprising that NAFLD plays a likely role in the genesis of cardiovascular disease. The normal glucose and lipid homeostasis within the liver becomes disturbed with the accumulation of hepatic fat, resulting in hepatic insulin resistance, increased fasting glucose levels and an atherogenic lipid profile.
"The fatty liver is also a producer of a number of inflammatory pro-atherogenic cytokines, hyper-coagulable factors, and adhesion molecules, which have been implicated in the pathogenesis of myocardial dysfunction and atherosclerosis," they added.
The study was funded by the European Community's Seventh Framework Programme and the Romanian Ministry of Education.
No researchers reported financial relationships with industry.
Adams and Anstee reported no financial relationships with industry.
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