Prescription of Statins in Suspected Non-alcoholic Fatty Liver Disease and High Cardiovascular Risk, a Population-based Study

Eline H. van den Berg; Alba A. B. Wolters; Robin P. F. Dullaart; Han Moshage; David Zurakowski; Vincent E. de Meijer; Hans Blokzijl


Liver International. 2019;39(7):1343-1354. 

In This Article

Abstract and Introduction


Background & Aims: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, with concomitant high incidence of lipoprotein abnormalities. Cardiovascular disease (CVD) is the main cause of death in subjects with NAFLD and management of dyslipidaemia is pivotal for prevention. We aimed to determine cardiovascular risk and indication for statin therapy in subjects with NAFLD.

Methods: A cross-sectional analysis of the population-based Lifelines Cohort Study of 34 240 adult individuals. Subjects with reported use of lipid-lowering drugs were excluded. Suspected NAFLD was defined as Fatty Liver Index (FLI) ≥60 and advanced hepatic fibrosis as NAFLD fibrosis score (NFS) >0.676. Cardiovascular risk and indication for statin therapy were defined according to the European Society of Cardiology and European Atherosclerosis Society Guideline for the Management of Dyslipidaemias.

Results: FLI ≥ 60 was present in 7067 (20.6%) participants and coincided with increased prevalence of type 2 diabetes mellitus, metabolic syndrome, CVD and impaired renal function (all P < 0.001). 10-year predicted cardiovascular risk was significantly increased in subjects with elevated FLI and NFS (both P < 0.001). Indication for statin use was significantly increased in subjects with FLI ≥ 60 (31.0% vs 15.6%, P < 0.001) and NFS > 0.676 (73.2% vs 30.6%, P < 0.001). In multivariable analyses, FLI ≥ 60 (OR 1.26, 95%CI: 1.13-1.41, P < 0.001) and NFS > 0.676 (OR 5.03, 95%CI: 2.76-9.17, P < 0.001) were independent predictors for indication regarding statin therapy.

Conclusions: Because of increased cardiovascular risk, substantial proportions of subjects with suspected NAFLD and/or fibrosis have an indication for lipid-lowering treatment and could benefit from statin therapy.


Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of excessive alcohol use, and is emerging as the most common cause of chronic liver disease as a result of the global obesity epidemic. The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and eventually cirrhosis.[1] NAFLD is the hepatic manifestation of the metabolic syndrome (MetS) and coincides with an increased risk for development of type 2 diabetes mellitus (T2D).[1,2]

NAFLD coincides with plasma lipoprotein abnormalities, including elevations in apolipoprotein (Apo)B-containing lipoproteins, an increase in the ratio of ApoB to ApoA-I, decreased levels of high-density lipoprotein (HDL) cholesterol and increased levels of low-density lipoprotein (LDL) cholesterol.[3–5] Enhanced delivery of adipose tissue-derived fatty acids to the liver provides a central mechanism responsible for hepatic fat accumulation. In turn, increased liver fat content is regarded as the driving force of enhanced production of very low-density lipoproteins (VLDL) by the liver, resulting in an increased plasma concentration of large VLDL particles and consequently in higher triglycerides.[6,7] Such plasma lipoprotein abnormalities predispose to atherosclerotic cardiovascular disease (CVD)[8,9] with increased intima-media thickness and carotid plaques indicating higher risk of atherosclerotic CVD in NAFLD.[10]

Although most patients with NAFLD are not at risk of dying from liver disease, they have increased risk of early morbidity and mortality because of CVD, which is the main cause of death in NAFLD.[1,9] Furthermore, cardiovascular and all-cause morbidity and mortality increases exponentially with increasing fibrosis stage in NAFLD.[11,12] Consequently, prevention and treatment of dyslipidaemia are especially important in subjects with NAFLD. The main therapeutic aim in the treatment of dyslipidaemias is LDL cholesterol-lowering treatment with 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitors (statins).[13] However, restraint has been shown in the prescription of statins because of concerns about increased risk of hepatotoxicity.[14,15] Nevertheless, statin treatment appears to be safe in NAFLD patients with elevated liver enzymes.[16–19] In addition, experimental animal models with chronic liver injury have shown that statins have an anti-inflammatory and anti-fibrotic effect and decrease complications in NAFLD.[20–23] Also in humans, statin use may improve disease progression, reduce cardiovascular morbidity[14,16,17] and decrease complications of chronic liver disease.[24]

There are only a few small studies, which assess the utilization of statin therapy in patients with NAFLD and dyslipidaemia. Three small studies described appropriate prescription of statin therapy in only 44%-71% of NAFLD patients with dyslipidaemias and these patients were less likely than patients without NAFLD to receive appropriate statin care.[25–27] Furthermore, NAFLD was an independent factor in the lack of statin prescription in subjects with indication for lipid-lowering treatment.[27]

Given the pivotal role of lipoprotein abnormalities in the development of NAFLD and consequent CVD, with high morbidity and mortality, the importance of dyslipidaemia treatment in subjects with NAFLD is evident. Therefore, we sought to determine the cardiovascular risk as well as the proportion of subjects with indication for statin therapy in subjects with suspected NAFLD in a large population-based cohort study.