Reply to: “Coagulation and fibrosis: A potential non-negligible target of statins in chronic hepatitis”
Authors: Tracey G. Simon, Lindsay Y. King, Raymond T. Chung
Journal: Journal of Hepatology (2015)

Coagulation and fibrosis: A potential non-negligible target of statins in chronic hepatitisJournal of HepatologyVol. 63Issue 1PreviewWe read with interest the paper by Simon and colleagues demonstrating a reduced rate of fibrosis progression in HCV positive patients receiving a chronic treatment with statins [1]. This observation could be clinically relevant in a scenario where we have not effective antifibrotic drugs. It emerges alongside the growing agreement on the safety of statins in patients with liver disease, including cirrhosis [2]. Statins inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and interfere with the “mevalonate pathway”. Full-Text PDF Open AccessStatin use is associated with a reduced risk of fibrosis progression in chronic hepatitis CJournal of HepatologyVol. 62Issue 1PreviewHepatitis C virus (HCV) is one of the most common causes of chronic liver disease and the leading indication for liver transplantation worldwide [1,2]. Chronic hepatitis C (CHC) leads to cirrhosis and hepatocellular carcinoma (HCC). Estimates suggest that over a period of twenty to thirty years, cirrhosis will develop in 10% to 25% of patients with CHC, and HCC will develop in 1% to 5% [2]. Although the success of HCV therapy now improved with the introduction of direct-acting antiviral medications, there are still many patients with advanced fibrosis in whom disease progression may nevertheless occur, despite successful viral clearance. Full-Text PDF We appreciate the comments of Bitto and colleagues, who highlight the potential impact of statins on hepatic endothelial function in patients with chronic liver disease. Indeed, multiple recent reports support these observations. In an in vivo animal model of cirrhosis, simvastatin was shown to upregulate Kruppel-Like Factor 2 (KLF2) signaling pathways, resulting in deactivation of hepatic stellate cells (HSC), reduced circulating levels of von Willebrand Factor (vWF), and improvement in hepatic fibrosis [1Ray K. Liver: Sussing out statins in cirrhosis-KLF2 is the key.Nat Rev Gastroenterol Hepatol. 2015; 12: 64Crossref PubMed Scopus (6) Google Scholar, 2Marrone G. Maeso-Diaz R. Garcia-Cardena G. Abraldes J.G. Garcia-Pagan J.C. Bosch J. et al.KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins.Gut. 2014; ([Epub ahead of print])https://doi.org/10.1136/gutjnl-2014-308338Crossref PubMed Scopus (130) Google Scholar]. Statins also have been shown to reduce expression of tissue factor and thrombin, while increasing the activity of protein C [[3]Undas A. Brummel-Ziedins K.E. Mann K.G. Anticoagulant effects of statins and their clinical implications.Thromb Haemost. 2014; 111: 392-400Crossref PubMed Scopus (90) Google Scholar]. It is thought that the antithrombotic and vasoprotective effects of statins are related to increased nitric oxide (NO) availability and enhanced fibrinolysis, reduced platelet activity and modulation of the coagulation cascade [4Colli S. Eligini S. Lalli M. Camera M. Paoletti R. Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.Arterioscler Thromb Vasc Biol. 1997; 17: 265-272Crossref PubMed Scopus (365) Google Scholar, 5Takemoto M. Liao J.K. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.Arterioscler Thromb Vasc Biol. 2001; 21: 1712-1719Crossref PubMed Scopus (1234) Google Scholar, 6Violi F. Calvieri C. Ferro D. Pignatelli P. Statins as antithrombotic drugs.Circulation. 2013; 127: 251-257Crossref PubMed Scopus (141) Google Scholar]. In a recent prospective cohort study of 51 patients who received statin therapy, thrombin generation was significantly reduced among statin users, a finding which supports the hypothesis that the antithrombotic effects of statins may be mediated in part by their ability to directly modify the coagulation cascade [[7]Tripodi A. Pellegatta F. Chantarangkul V. Grigore L. Garlaschelli K. Baragetti A. et al.Statins decrease thrombin generation in patients with hypercholesterolemia.Eur J Int Med. 2014; 25: 449-451Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. As Bitto and colleagues suggest, it stands to reason that the vasoprotective effects of statins may be especially pronounced in patients with non-alcoholic fatty liver disease (NAFLD) and a metabolic syndrome. Accumulating evidence shows that patients with NAFLD suffer from hemostatic dysregulation resulting in a significant procoagulant imbalance, compared to healthy controls [[8]Tripodi A. Fracanzani A.L. Primignani M. Chantarangkul V. Clerici M. Mannucci P.M. et al.Procoagulant imbalance in patients with non-alcoholic fatty liver disease.J Hepatol. 2014; 61: 148-154Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. This includes increased thrombin generation and tissue factor levels, as well as simultaneously increased factor VIII levels and reduction in the expression of protein C [7Tripodi A. Pellegatta F. Chantarangkul V. Grigore L. Garlaschelli K. Baragetti A. et al.Statins decrease thrombin generation in patients with hypercholesterolemia.Eur J Int Med. 2014; 25: 449-451Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 8Tripodi A. Fracanzani A.L. Primignani M. Chantarangkul V. Clerici M. Mannucci P.M. et al.Procoagulant imbalance in patients with non-alcoholic fatty liver disease.J Hepatol. 2014; 61: 148-154Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. In addition, the chronic inflammatory state associated with NAFLD is marked by increased circulating free fatty acids, and subsequently increased levels of E-selectin, myeloperoxidase, and total plasminogen activator inhibitor-1 (PAI-1), which in turn serve to perpetuate vascular dysfunction and enhance the procoagulant state [[9]Lomonaco R. Chen J. Cusi K. An endocrine perspective of Nonalcoholic Fatty Liver Disease (NAFLD).Ther Adv Endocrinol Metab. 2011; 2: 211-225Crossref PubMed Scopus (30) Google Scholar]. Although a significant proportion of patients within the cohort that we examined from the HALT-C trial demonstrated baseline steatosis and dyslipidemia, we did not have specific markers of endothelial dysfunction or coagulation assays available for analysis. As such, we look forward with great interest to future prospective studies designed to address this question. Currently, the precise mechanisms by which statins may exert vasoprotective, anti-inflammatory and anti-fibrotic effects have yet to be fully characterized. Large prospective studies with histological endpoints, using well-defined markers of endothelial dysfunction, are needed in order to define how and to what degree statins exert vasoprotective, anti-inflammatory and antithrombotic effects, for the modulation of hepatic fibrosis. The authors who have taken part in this letter to the editor declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.