Dissecting the multifaceted impact of statin use on fatty liver disease: A multidimensional studyResearch in context
Ibrahim Ayada,
Laurens A. van Kleef,
Huai Zhang,
Kuan Liu,
Pengfei Li,
Yasir J. Abozaid,
Marla Lavrijsen,
Harry L.A. Janssen,
Luc J.W. van der Laan,
Mohsen Ghanbari,
Maikel P. Peppelenbosch,
Ming-Hua Zheng,
Robert J. de Knegt,
Qiuwei Pan
Affiliations
Ibrahim Ayada
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Laurens A. van Kleef
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Huai Zhang
Department of Biostatistics and Records Room, Medical Quality Management Office, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Kuan Liu
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Pengfei Li
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Yasir J. Abozaid
Department of Epidemiology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Marla Lavrijsen
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Harry L.A. Janssen
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Toronto Center for Liver Disease, Toronto General Hospital, University of Toronto, Canada
Luc J.W. van der Laan
Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Mohsen Ghanbari
Department of Epidemiology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Maikel P. Peppelenbosch
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Ming-Hua Zheng
NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China; Corresponding author.
Robert J. de Knegt
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Corresponding author.
Qiuwei Pan
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Corresponding author.
Summary: Background: Statin use could benefit patients with non-alcoholic fatty liver disease (NAFLD), but the evidence is segmented and inconclusive. This multidimensional study comprehensively investigated the potential benefits and mechanism-of-action of statins in NAFLD. Methods: A cross-sectional investigation was performed within the Rotterdam Study (general population; n = 4.576) and the PERSONS cohort (biopsy-proven NAFLD patients; n = 569). Exclusion criteria were secondary causes for steatosis and insufficient data on alcohol, dyslipidemia or statin use. Associations of statin use with NAFLD (among entire general population), fibrosis and NASH (among NAFLD individuals and patients) were quantified. These results were pooled with available literature in meta-analysis. Last, we assessed statins’ anti-lipid and anti-inflammatory effects in 3D cultured human liver organoids and THP-1 macrophages, respectively. Findings: Statin use was inversely associated with NAFLD in the Rotterdam study compared to participants with untreated dyslipidemia. In the PERSONS cohort, statin use was inversely associated with NASH, but not with fibrosis. The meta-analysis included 7 studies and indicated a not significant inverse association for statin use with NAFLD (pooled-Odds Ratio: 0.69, 95% Confidence Interval: 0.46–1.01) and significant inverse associations with NASH (pooled-OR: 0.59, 95% CI: 0.44–0.79) and fibrosis (pooled-OR: 0.48, 95% CI: 0.33–0.70). In vitro, statins significantly reduced lipid droplet accumulation in human liver organoids and downregulated expression of pro-inflammatory cytokines in macrophages. Interpretation: Pooled results demonstrated that statin use was associated with a lower prevalence of NASH and fibrosis and might prevent NAFLD. This may be partially attributed to the anti-lipid and anti-inflammatory characteristics of statins. Given their under-prescription, adequate prescription of statins may limit the disease burden of NAFLD. Funding: ZonMw, KWF, NWO, SLO, DGXII, RIDE, National and regional government, Erasmus MC and Erasmus University.
