Resarch Article
Fatty liver is an independent predictor of early carotid atherosclerosis

https://doi.org/10.1016/j.jhep.2016.02.023Get rights and content

Background & Aims

Whether steatosis is incidentally or causally associated with carotid atherosclerosis is debated, and long-term follow-up data are missing. This study aims to examine the impact of steatosis on the presence and progression of carotid intima-media thickness (C-IMT) and carotid plaques (CP) in a large cohort with longitudinal follow-up.

Methods

A retrospective single-center study between 1995 and 2012. Transversal cohort: patients with ⩾2 cardiovascular risk factors without previous cardiovascular events. Longitudinal cohort: patients with two consecutive C-IMT measurements more than 2 years apart. Steatosis was defined by a surrogate marker, the fatty liver index (FLI). CP and C-IMT were assessed by carotid ultrasound.

Results

In the transversal cohort (n = 5671) both C-IMT and the Framingham risk score (FRS) increased across FLI quartiles (0.58 ± 0.12, 0.61 ± 0.14, 0.63 ± 0.14, 0.64 ± 0.14 mm, and 5 ± 5%, 9 ± 7%, 12 ± 8%, 15 ± 9%, p <0.001 for both). Steatosis predicted C-IMT better than diabetes or dyslipidemia. Steatosis independently predicted C-IMT (p = 0.002) and FRS (p <0.001) after adjustment for metabolic syndrome and cardiovascular risk factors.

In the longitudinal cohort (n = 1872, mean follow-up 8 ± 4 years), steatosis occurred in 12% and CP in 23% of patients. C-IMT increased in patients with steatosis occurrence (from 0.60 ± 0.13 mm to 0.66 ± 0.14 mm, p = 0.001) whereas it did not change in those that stayed free of steatosis. Steatosis at baseline predicted CP occurrence (OR = 1.63, 95% CI 1.10–2.41, p = 0.014), independent of age, sex, type-2 diabetes, tobacco use, hsCRP, hypertension and C-IMT.

Conclusions

In patients with metabolic syndrome at risk for cardiovascular events, steatosis contributes to early atherosclerosis and progression thereof, independent of traditional cardiovascular risk factors.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition seen in patients with obesity, type 2 diabetes, atherogenic dyslipidemia and arterial hypertension. The leading cause of death in patients with NAFLD is cardiovascular mortality, which is not surprising given the high prevalence of the above-mentioned cardiometabolic risk factors [1], [2]. However, a large body of data indicates that the fatty and inflamed liver expresses several pro-inflammatory and procoagulant factors, as well as genes involved in accelerated atherogenesis [3], [4]. This raises the possibility that the link between NAFLD and cardiovascular mortality might not simply be mediated by shared, underlying, common risk factors but rather that NAFLD independently contributes to increasing this risk.

While an increased prevalence of cardiovascular disease in NAFLD is largely accepted, existing data also show an increased incidence [5], [6], [7]. This suggests that steatosis predates clinical cardiovascular disease, and that it may trigger or accelerate its occurrence. Providing support for this causal hypothesis, some reports have demonstrated an increased proportion of subclinical atherosclerosis or pre-atherosclerotic lesions in patients with NAFLD. For instance, ultrasound-diagnosed steatosis was associated with increased coronary calcium scores [8] and with increased intima-media thickness (C-IMT) [9], independent of conventional cardiovascular risk factors and insulin resistance. C-IMT is a marker of early atherosclerosis that predicts coronary and cerebrovascular events: a 0.1 mm increase in C-IMT increases the risk of myocardial infarction by 10–15% and the risk of stroke by 13–18% [10]. Taken together, these data suggest that steatosis actively contributes to atherogenesis. However, there are few, if any, longitudinal, long-term studies assessing the impact of steatosis on the progression of pre-atherosclerotic lesions. In this study we hypothesized that steatosis is an independent predictor of C-IMT progression. Our objectives were: (1) to determine the relationship between steatosis, C-IMT and the 10-year Framingham risk score (FRS) in a population at risk for cardiovascular events; and (2) to determine in a longitudinal follow-up study if the occurrence or reversal of steatosis independently predicts the occurrence of carotid plaques (CP).

Section snippets

Study population

This is a retrospective analysis of consecutive patients between 20 and 75 years of age referred to a Primary Cardiovascular Prévention Center at Pitié-Salpêtrière Hospital, Paris, France, between 1995 and 2012. Inclusion criteria were: (1) at least two cardiovascular risk factors among the following: age >60 years in women and >50 years in men; systolic blood pressure ⩾130 or diastolic blood pressure ⩾85 mmHg or treatment of previously diagnosed hypertension; fasting plasma glucose ⩾5.6 mmol/L or

Relationship between steatosis, carotid atherosclerosis and 10-year FRS (transversal study)

5671 patients had available carotid ultrasound and met the inclusion and exclusion criteria (transversal cohort) (Fig. 1). Patient characteristics are shown in Table 1. 50% of patients had more than 2 cardiovascular risk factors and 37% had the metabolic syndrome. Half of the entire cohort had a family history of cardiovascular disease. Mean alcohol consumption was low, only 5% of patients consumed more than 30 g/day. Forty-six percent of patients were active or former smokers with a mean

Discussion

Patients with NAFLD die primarily of cardiovascular disease, and the extent to which the liver disease rather than associated comorbidities is responsible for excess cardiovascular death is still under debate [17]. Most studies have detailed the relationship between steatosis, associated cardiometabolic risk factors and cardiovascular events [18], [19]. However, clinical events are by definition a late step in the atherogenic process, which makes it difficult to ascertain the contribution of

Financial support

The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2009-241762 for the project FLIP; PN-II-ID-PCE-2011-3-0917, no. 297/2011 of the Romanian Ministry of Education represented by UEFISDCI. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contributions

Study design: Raluca Pais, Philippe Giral, Vlad Ratziu; Acquisition of data: Philippe Giral, Jean Francois Khan and David Rosenbaum; Carotid Ultrasound: Jean Francois Khan and David Rosenbaum; Statistical analysis: Raluca Pais; Analysis and interpretation of data: Raluca Pais, Philippe Giral, Vlad Ratziu; Drafting of the manuscript: Raluca Pais, Philippe Giral, Vlad Ratziu; Critical revision of the manuscript for important intellectual content: Vlad Ratziu, Philippe Giral. Obtained funding:

Acknowledgements

Members of the LIDO (Liver Injury in Diabetes and Obesity) Study Group: André Grimaldi, Philippe Giral, Eric Bruckert, Arnaud Basdevant, Karine Clement, Agnès Hartemann-Heurtier, Fabrizio Andreelli, Sophie Gombert, Sophie Jacqueminet, Dominique Simon, Joseph Moussalli, Pascal Lebray, Dominique Bonnefont-Rousselot, Yves Benhamou, Cecilia D’Arrondel, Philippe Podevin, Carole Bernhardt, Sophie Delignat (prélevements), Hôpital Pitié-Salpêtrière; Christian Boitard, Etienne Larger, Agnès Sola,

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