Scripties UMCG - Rijksuniversiteit Groningen
English | Nederlands

Statin treatment is not associated with protection against development of fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD): a population-based cohort study and in vitro study

(2018) Doornebosch, V.L.E.

Background: Because of the increasing incidence of people with obesity, type 2 diabetes and the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) is a rising health problem. Although, there is still no specific drugs to cure patients with NAFLD, statins are suggested as a promising treatment. The aims of this study were to investigate the frequency of statin treatment and its possible protective effect against development of advanced fibrosis among participants at risk for NAFLD and fibrosis, in a large population-based cohort. Secondly, in an in vitro model the possible cytoprotective effects of statins were explored.
Material & methods: From the Lifelines Cohort study, a population-based cohort in the North of the Netherlands, participants were identified who were at high risk of NAFLD, specified with a fatty liver index (FLI)≥60. Among groups, biochemical characteristics, type 2 diabetes mellitus and statin treatment were determined. The presence of advanced fibrosis was defined by the non-alcoholic fatty liver fibrosis score (NFS)>0.676. In an experimental study, the effect of two different statins (atorvastatin and fluvastatin) was investigated in primary cultures of rat hepatocytes and human HepG2-cells treated with different concentrations of palmitic acid. The cell lines were tested for intracellular fat accumulation by using Oil red O staining, necrosis by using Sytox Green staining, and apoptosis which was quantified by Caspase-3-activity.
Results: 37,496 Lifelines participants were included with a median age of 44 years (62.1% female). 8259 participants (22%) had a FLI ≥60, of which 124 participants (0.33%) had an NFS>0.676, indicating a high risk of NALFD and severe liver fibrosis. Multivariate logistic regression analyses showed that female gender (OR: 1.552, 95% CI: 1.080-2.229, P=0.018) and current statin treatment increased the odds on having NAFLD with advanced fibrosis (OR: 1.568, 95% CI: 2.111-4.804). Remarkably, within the group of participants with an FLI60, 6476 (93%) did not use a statin while they had a strong indication for statin treatment to reduce the risk of cardiovascular diseases. In vitro experiments showed that statins did not have a cytoprotective effect in palmitic acid-induced apoptosis in primary hepatocytes and HepG2-cells. In contrast, it seems that treatment with lipophilic statins can possible cause hepatotoxic damage.
Conclusion: Our study demonstrated that the majority of participants (93%), who were at high risk of NAFLD, did not report current use of statin treatment while statin treatment was indicated. Statin use was overrepresented in those participants at increased risk for advanced fibrosis. This could indicate that participants at high risk for advanced fibrosis simply have more statins prescribed (due to other comorbidities) or that statin use could be associated with development instead of protection against advanced fibrosis. In vitro experiments revealed that lipophilic statins did not protect against palmitic acid-induced apoptosis in cultured hepatocytes. This would provide a rationale to investigate the effects of hydrophilic statins in future in vitro experiments.

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