Should We Lower Lipids in Nonalcoholic Fatty Liver Disease?
2013; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês
10.1016/j.cgh.2013.07.041
ISSN1542-7714
Autores Tópico(s)Diet, Metabolism, and Disease
ResumoNonalcoholic fatty liver disease (NAFLD) is causally linked to overnutrition, central obesity, and insulin resistance.1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar, 2Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.Gastroenterology. 2012; 142: 711-725Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar The pathologic spectrum embraces both simple steatosis and nonalcoholic steatohepatitis (NASH). NASH causes liver fibrosis that can progress to cirrhosis and hepatocellular carcinoma. NASH is more strongly related to metabolic risk factors than simple steatosis.1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar Thus, whereas NAFLD is a risk factor for developing diabetes during 3- to 5-year follow-up (hazard ratio, 3–4), 70% of cases with NASH are known to have type 2 diabetes (T2D), or this is revealed by oral glucose tolerance testing.3Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia–as common and important as in the West.Nat Rev Gastro Hep. 2013; 10: 307-318Crossref PubMed Scopus (318) Google Scholar Glucose intolerance, T2D, and a family history of T2D are also risk factors for fibrotic progression of NASH.3Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia–as common and important as in the West.Nat Rev Gastro Hep. 2013; 10: 307-318Crossref PubMed Scopus (318) Google Scholar, 4Loomba R. Abraham M. Unalp A. et al.Association between diabetes, family history of diabetes and risk of non-alcoholic steatohepatitis and fibrosis.Hepatology. 2012; 56: 943-951Crossref PubMed Scopus (318) Google Scholar Along the same lines, the prevalence of NAFLD is proportional to the number of components of metabolic syndrome, but with NASH pathology, 85% of patients have established metabolic syndrome,1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar, 2Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.Gastroenterology. 2012; 142: 711-725Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 3Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia–as common and important as in the West.Nat Rev Gastro Hep. 2013; 10: 307-318Crossref PubMed Scopus (318) Google Scholar defined by the International Diabetes Federation as central obesity plus 2 or more of glucose intolerance, high blood pressure, and atherogenic dyslipidemia.Statins Combat the Increased Cardiovascular Risk of Nonalcoholic Fatty Liver DiseaseThe link to atherogenic dyslipidemia, particularly low serum levels of high-density lipoprotein (HDL) cholesterol and raised levels of low-density lipoprotein (LDL) cholesterol,5Corey K.E. Lai M. Gelrud L.G. et al.Non-high-density lipoprotein cholesterol as a biomarker for non-alcoholic steatohepatitis.Clin Gastroenterol Hepatol. 2012; 10: 651-656Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar but also hypertriglyceridemia, introduces the importance to lipid-lowering therapy in patients with NAFLD. Should we lower lipids in all patients with NAFLD? The answer is yes! The 1.7-fold increase in standardized mortality of people with NAFLD is largely from increased cardiovascular mortality, followed by common cancers; liver disease is third.3Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia–as common and important as in the West.Nat Rev Gastro Hep. 2013; 10: 307-318Crossref PubMed Scopus (318) Google Scholar, 6Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2235) Google Scholar Furthermore, NAFLD (both simple steatosis and NASH cases) is an independent risk factor for cardiovascular disease whether or not LDL is raised; as recently reviewed, some reasons for this include postprandial lipoprotein abnormalities and inflammation.7Musso G. Cassader M. Rosina F. et al.Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD).Diabetologia. 2012; 55: 885-904Crossref PubMed Scopus (450) Google Scholar In this context, the most attractive group of lipid-lowering agents for cardiovascular protection is the statins. In addition to a major effect in lowering LDL, they have modest effects at increasing HDL and lowering serum triglyceride, as well as non–cholesterol-lowering effects on vascular endothelium by inducing endothelial nitric oxide synthase. Ezetimibe is less effective as a single agent to lower serum cholesterol and does not have the same vascular protective effects as statins. However, it is often forgotten that for cases where the cholesterol-lowering effect of statins does not reach “target,” adding ezetimibe synergizes with statin to produce a more satisfactory response. In the author’s opinion, this strategy should be considered more often in preference to very large doses of statin, and it is very useful when patients experience partially dose-dependent statin adverse effects such as myopathy.Evidence that cholesterol lowering with statin reduces cardiovascular risk comes from the Greek Artorvastatin and Coronary Heart Disease Evaluation (GREACE) study, in which artorvastatin reduced the incidence of new cardiovascular events to a greater extent in patients with NAFLD (assumed by raised liver enzymes) than among those with normal liver enzymes.8Athyros V.G. Tziomalos K. Gossios T.D. et al.Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Artorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.Lancet. 2010; 376: 1916-1922Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar Patients without serum cholesterol elevation benefited as well, and there was ∼40% reduction in serum triglyceride. It is also abundantly clear that patients with raised serum alanine aminotransferase (ALT) level are not at increased risk of statin-induced liver injury (which is extremely rare) than those with normal ALT level.8Athyros V.G. Tziomalos K. Gossios T.D. et al.Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Artorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.Lancet. 2010; 376: 1916-1922Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, 9Cohen D.E. Anania F.A. Chalasani N. National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists.Am J Cardiol. 2006; 97: 77C-81CAbstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar Outstanding issues with use of statins and/or ezetimibe in NAFLD include whether all agents are equally efficacious and whether there are any detriments in diabetic control (as suggested by some data).7Musso G. Cassader M. Rosina F. et al.Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD).Diabetologia. 2012; 55: 885-904Crossref PubMed Scopus (450) Google Scholar On the other hand, there actually appears to be an “off target” beneficial effect of protection against chronic kidney disease, which is increasingly associated with NAFLD.Triglyceride elevations are also a risk factor for cardiovascular disease, albeit less so than cholesterol. In addition to use of a statin, approaches to lowering triglyceride should focus on weight reduction and improving insulin resistance and diabetes control (particularly by improving levels of physical activity and adherence to a diabetic diet). Use of N-3 polyunsaturated fatty acids such as fish oil preparations are the first-line pharmacologic approach. Probucol and fibrates have been studied to a limited extent in NASH without clear evidence of safety and efficacy.The Lipotoxicity Concept of Nonalcoholic Steatohepatitis PathogenesisShould we lower lipids to improve liver disease and liver outcomes? The evolving concept of NASH pathogenesis is that the closely linked metabolic disorders favor hepatic accumulation of lipid species, one or more of which injures liver cells and promotes inflammation and fibrosis.1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar, 2Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.Gastroenterology. 2012; 142: 711-725Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar The 20-year old idea that ectopic (non-adipose) distribution of lipids injures tissues is termed lipotoxicity. It is the likely mechanism for injury to pancreatic beta cells in T2D, atheroma (intimal inflammation in response to cholesterol-mediated macrophage activation), and cardiac/skeletal muscle in metabolic syndrome. With NAFLD, an earlier concept was that excess lipid (steatosis) was the setting for NASH (a “first hit”), and a second injurious/proinflammatory factor (“second hit”) was required to transform steatosis to steatohepatitis. However, such second-hit processes, such as oxidative stress and cytokines, are integrally linked to consequences of lipotoxicity. It is now important to ask which lipids are important (the amount of triglyceride is not10Neuschwander-Tetri B.A. Hepatic lipotoxicity and pathogenesis of nonalcoholic steato-hepatitis: the central role of nontriglyceride fatty acid metabolites.Hepatology. 2010; 52: 774-788Crossref PubMed Scopus (714) Google Scholar), how do they cause injury, and how does that lead to inflammation and fibrosis? These are not rhetorical questions; lifestyle (diet and exercise) and pharmacologic means to lower hepatic levels of some lipids are in current use and could potentially be used as part of strategies to treat NASH and prevent its adverse liver outcomes, as well as to combat high cardiovascular risk.Free Cholesterol Is a Prime Candidate Lipotoxin in Nonalcoholic SteatohepatitisCandidate liver lipotoxins in NASH include saturated free fatty acids, diacylglycerides, free cholesterol (FC), and toxic phospholipids such as lysophosphatidylcholine.1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar, 2Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.Gastroenterology. 2012; 142: 711-725Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 10Neuschwander-Tetri B.A. Hepatic lipotoxicity and pathogenesis of nonalcoholic steato-hepatitis: the central role of nontriglyceride fatty acid metabolites.Hepatology. 2010; 52: 774-788Crossref PubMed Scopus (714) Google Scholar, 11Malhi H. Gores G. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis. 2008; 28: 360-369Crossref PubMed Scopus (415) Google Scholar, 12Puri P. Baillie R.A. Wiest M.M. et al.A lipidomic analysis of nonalcoholic fatty liver disease.Hepatology. 2007; 46: 1081-1090Crossref PubMed Scopus (881) Google Scholar, 13Caballero F. Fernández A. De Lacy A.M. et al.Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.J Hepatol. 2009; 50: 789-796Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 14Wouters K. van Gorp P.J. Bieghs V. et al.Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis.Hepatology. 2008; 48: 474-486Crossref PubMed Scopus (372) Google Scholar, 15Farrell G.C. van Rooyen D. Liver cholesterol: is it playing possum in NASH?.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G9-G11Crossref PubMed Scopus (29) Google Scholar, 16Arteel G.E. Beyond reasonable doubt: who is the culprit in lipotoxicity in NAFLD/NASH?.Hepatology. 2012; 55: 2030-2032Crossref PubMed Scopus (13) Google Scholar, 17Van Rooyen D.M. Larter C.Z. Haigh W.G. et al.Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.Gastroenterology. 2011; 141: 1393-1403Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 19Van Rooyen D.M. Gan L.T. Yeh M.M. et al.Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice.J Hepatol. 2013; 59: 144-152Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar At present, the weight of evidence from the few available human lipidomic studies and animal models of metabolic syndrome–related NASH favors FC as a lipotoxic mediator of NASH.15Farrell G.C. van Rooyen D. Liver cholesterol: is it playing possum in NASH?.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G9-G11Crossref PubMed Scopus (29) Google Scholar, 16Arteel G.E. Beyond reasonable doubt: who is the culprit in lipotoxicity in NAFLD/NASH?.Hepatology. 2012; 55: 2030-2032Crossref PubMed Scopus (13) Google Scholar Likewise, in small animal models in which 1%–2% cholesterol is added to a high fat and high carbohydrate diet,20Matsuzawa N. Takamura T. Kurita S. et al.Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet.Hepatology. 2007; 46: 1392-1403Crossref PubMed Scopus (400) Google Scholar, 21Ogawa T. Fujii H. Yoshizato K. et al.A human-type non-alcoholic steatohepatitis model with advanced fibrosis in rabbits.Am J Pathol. 2010; 177: 153-165Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 22Charlton M. Krishnan A. Viker K. et al.Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition.Am J Physiol Gastrointest Liver Physiol. 2011; 301: G825-G834Crossref PubMed Scopus (261) Google Scholar increases in hepatic FC are associated with NASH that resemble the human condition by showing abundant ballooned hepatocytes and macrophage accumulation, but this is less clear in other dietary models.23Neuschwander-Tetri B.A. Ford D.A. Acharya S. et al.Dietary trans-fatty acid induced NASH is normalized following loss of trans-fatty acids from hepatic lipid pools.Lipids. 2012; 47: 941-950Crossref PubMed Scopus (40) Google Scholar, 24Kohli R. Kirby M. Xanthakos S.A. et al.High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma co-enzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis.Hepatology. 2010; 52: 934-944Crossref PubMed Scopus (254) Google Scholar In addition to dietary cholesterol content, pathophysiologic pathways leading to hepatic FC accumulation have been revealed in our murine obese, diabetic model17Van Rooyen D.M. Larter C.Z. Haigh W.G. et al.Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.Gastroenterology. 2011; 141: 1393-1403Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and partially replicated in a later human study.18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar We showed that insulin mediates up-regulation of sterol regulatory element binding protein 2, which in turn up-regulates cholesterol uptake pathways such as CD36 and LDL receptor as a likely primary mechanism, whereas the activity of the 3-hydroxy-3-methylglutaryl–coenzyme A (HMGCoA) reductase, the rate-limiting step for cholesterol biosynthesis, was actually decreased.17Van Rooyen D.M. Larter C.Z. Haigh W.G. et al.Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.Gastroenterology. 2011; 141: 1393-1403Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar In human studies, sterol regulatory element binding protein 2 expression was enhanced in NASH (2 studies),13Caballero F. Fernández A. De Lacy A.M. et al.Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.J Hepatol. 2009; 50: 789-796Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar but there was no evident up-regulation of LDL receptor (one study18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar); the 2 other uptake pathways, CD36 and the HDL receptor, scavenger receptor (SR)B1, were not studied, whereas indirect estimates of HMGCoA reductase (circulating metabolites, HMGCoA reductase phosphorylation) were interpreted as indicating increased cholesterol biosynthesis.18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar There may be species differences, or the human data may be incomplete.What is clear is that in both the author’s murine model and the human study, striking additional features were increased expression of cholesterol ester hydrolase, decreased expression of key pathways of cholesterol biotransformation to form bile acids (CYPs7A and 27A), and decreased expression of canalicular transporters of cholesterol (ABCG5 and G8) and bile acids (BSEP, MRP-2, MDR3).17Van Rooyen D.M. Larter C.Z. Haigh W.G. et al.Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.Gastroenterology. 2011; 141: 1393-1403Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 18Min H.K. Kapoor A. Fuchs M. et al.Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.Cell Metab. 2012; 15: 665-674Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Both FC (unpublished data) and saturated free fatty acids11Malhi H. Gores G. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis. 2008; 28: 360-369Crossref PubMed Scopus (415) Google Scholar cause apoptosis and necrosis in hepatocytes by a Jun N-terminal kinase–dependent pathway via mitochondrial injury, whereas inflammatory recruitment involves innate immunity by activation of Toll-like receptors and downstream nuclear factor kappa B.Does Lowering Hepatic Free Cholesterol Alter Nonalcoholic Steatohepatitis?If these concepts of a lipotoxic pathogenesis of NASH are correct, lowering hepatic FC (or other relevant lipids) should reverse steatohepatitis. In a rabbit atherogenic diet model, ezetimibe attenuated NASH severity and decreased fibrogenesis.21Ogawa T. Fujii H. Yoshizato K. et al.A human-type non-alcoholic steatohepatitis model with advanced fibrosis in rabbits.Am J Pathol. 2010; 177: 153-165Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Likewise, in our obese, diabetic mouse model with metabolic syndrome (the mice also have arterial hypertension and hypercholesterolemia), both atorvastatin and ezetimibe lowered hepatic FC levels, with reductions in serum ALT, improved liver histology (decreased in NAFLD activity score), reduction of apoptosis and numbers of both macrophages and polymorphs.19Van Rooyen D.M. Gan L.T. Yeh M.M. et al.Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice.J Hepatol. 2013; 59: 144-152Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Ezetimibe inhibits cholesterol transport via NPC1L1, which is abundantly expressed on biliary epithelium in humans and rabbits25Hawas B.E. O’Neill K.A. Yao X. et al.In vivo responsiveness to ezetimibe correlates with Niemann-Pick C1-like-1 (NPC1L1) binding affinity: comparison of multiple species NPC1L1 orthologs.Mol Pharm. 2007; 71: 19-29Crossref Scopus (58) Google Scholar as well as intestine, and its effects on lowering liver cholesterol may be to interrupt recycling of FC secreted into bile and taken up from bile duct epithelium. In our experiments, the most striking effects on hepatic FC content were obtained by combination of ezetimibe and statin, and this lowering of tissue cholesterol translated into even more striking improvements in liver injury, inflammation, and particularly liver fibrosis.19Van Rooyen D.M. Gan L.T. Yeh M.M. et al.Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice.J Hepatol. 2013; 59: 144-152Abstract Full Text Full Text PDF PubMed Scopus (87) Google ScholarHuman Data on Efficacy of Statins and EzetimibeIn humans, data on beneficial effects of statins or ezetimibe on NAFLD/NASH progression are relatively few and currently insufficient on which to base firm conclusions.7Musso G. Cassader M. Rosina F. et al.Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD).Diabetologia. 2012; 55: 885-904Crossref PubMed Scopus (450) Google Scholar, 26Musso G. Molinaro F. Paschetta E. et al.Lipid modifiers and NASH: statins, ezetimibe, fibrates, and other agents.in: Farrell G.C. McCullough A.J. Day C.P. Non-alcoholic fatty liver disease: a practical guide. Wiley-Blackwell, Oxford2013: 293-307Crossref Scopus (5) Google Scholar In one uncontrolled study of changes in liver pathology among subjects with NAFLD, fibrotic progression was less among those treated with statin.27Ekstedt M. Franzen L.E. Mathiesen U.L. et al.Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873Crossref PubMed Scopus (1753) Google Scholar As reviewed recently,7Musso G. Cassader M. Rosina F. et al.Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD).Diabetologia. 2012; 55: 885-904Crossref PubMed Scopus (450) Google Scholar, 26Musso G. Molinaro F. Paschetta E. et al.Lipid modifiers and NASH: statins, ezetimibe, fibrates, and other agents.in: Farrell G.C. McCullough A.J. Day C.P. Non-alcoholic fatty liver disease: a practical guide. Wiley-Blackwell, Oxford2013: 293-307Crossref Scopus (5) Google Scholar there are very few controlled trials of statins in patients with NASH, and the results are inconclusive, particularly for histologic reversal of NASH and reduction of fibrosis. With ezetimibe, there are now at least 4 studies, 2 open and 2 randomized, of a total of ∼250 patients.26Musso G. Molinaro F. Paschetta E. et al.Lipid modifiers and NASH: statins, ezetimibe, fibrates, and other agents.in: Farrell G.C. McCullough A.J. Day C.P. Non-alcoholic fatty liver disease: a practical guide. Wiley-Blackwell, Oxford2013: 293-307Crossref Scopus (5) Google Scholar, 28Park H. Shima T. Yamaguchi K. et al.Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease.J Gastroenterol. 2011; 46: 101-107Crossref PubMed Scopus (153) Google Scholar Ezetimibe improved metabolic indices, serum ALT level, and liver histology; in one study, histologic improvement included beneficial effects on necroinflammatory change as well as liver fibrosis.28Park H. Shima T. Yamaguchi K. et al.Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease.J Gastroenterol. 2011; 46: 101-107Crossref PubMed Scopus (153) Google Scholar Future studies with ezetimibe/statin combination, which we have shown is highly efficacious in obese, diabetic mice with NASH (and others in rabbits with NASH21Ogawa T. Fujii H. Yoshizato K. et al.A human-type non-alcoholic steatohepatitis model with advanced fibrosis in rabbits.Am J Pathol. 2010; 177: 153-165Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar), reversing steatohepatitis and liver fibrosis, would be of interest.19Van Rooyen D.M. Gan L.T. Yeh M.M. et al.Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice.J Hepatol. 2013; 59: 144-152Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar FXR agonists may also have beneficial effects, but the increase in serum LDL associated with obeticholic acid administration may be a concern.29Mudaliar S. Henry R.R. Sanyal A.J. et al.Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and non-alcoholic fatty liver disease.Gastroenterology. 2013; 145: 574-582Abstract Full Text Full Text PDF PubMed Scopus (638) Google ScholarConclusionsThe take home messages are summarized in Table 1. There is no doubt we must lower serum LDL (and possibly triglyceride) at least to normal values in all patients with NAFLD to prevent cardiovascular events and reduce mortality. Whether the targets used for cardiovascular protection and T2D are informative (or too liberal) for NAFLD requires future studies, because the GREACE study suggested benefits beyond those for patients without NAFLD. Present approaches to treat NASH are inadequate to halt the inexorable progression of this common liver disease. Some individuals do reverse insulin resistance by lifestyle measures (weight reduction, increased exercise, dietary composition). In them, it is important to establish the need for additional measures to lower accumulated hepatic lipids as a measure to resolve liver fibrosis and reduce risk of cirrhosis and hepatocellular carcinoma. The conceptual basis for tissue (liver) lowering of FC is at least as strong as earlier ideas about correcting hepatic lipid partitioning, insulin resistance, and oxidative stress. Whether one conventional agent (statin or ezetimibe) will be sufficient to remove hepatic FC and reverse NASH fibrosis or whether combination lipid-lowering or novel agents will be necessary requires rigorous study.Table 1Take Home Messages•NAFLD (irrespective of liver pathology) is a risk factor for cardiovascular disease, irrespective of whether serum LDL cholesterol is raised.•Because of the attendant high risk of cardiovascular disease, serum lipid abnormalities should be corrected in all patients with NAFLD.•The most attractive group of lipid-lowering agents for cardiovascular protection is the statins.•Statins lower LDL and have modest effects in raising HDL and lowering serum triglyceride levels, whereas non–cholesterol-lowering effects on endothelial cells (by inducing endothelial nitric oxide synthase) may also be part of their therapeutic efficacy.•Evidence that statins reduce cardiovascular risk comes from the GREACE study in which artorvastatin lowered the incidence of new cardiovascular events to a greater extent in those with NAFLD than in those without fatty liver.•Patients with raised ALT are not at increased risk of statin-related hepatotoxicity.•Attempts to reduce raised serum triglyceride levels center around weight reduction, improving insulin resistance (physical activity) and diabetic control, with use of polyunsaturated fatty acids (fish oil) as the first-line pharmacologic approach.•The presently most favored concept of NASH pathogenesis is that liver cell injury, inflammatory recruitment, and fibrogenesis are consequences of lipotoxicity.•FC is a possible mediator of hepatic lipotoxicity in NASH and has been associated with oxidative stress, cytokine release, and macrophage recruitment.•Although one study shows apparently delayed rate of fibrotic progression in NAFLD patients treated with a statin, controlled and prospective data are too few to make recommendations about use of statins to combat disease progression in NASH.•There is now strong experimental evidence that ezetimibe alone or with statin may reverse NASH pathology and prevent liver fibrosis. Data in humans are encouraging but insufficient to make recommendations about use of ezetimibe in NASH.•FXR agonist (obeticholic acid) may improve insulin sensitivity and liver disease in NASH, but early data suggest an increase in serum LDL may be a concern. Open table in a new tab Nonalcoholic fatty liver disease (NAFLD) is causally linked to overnutrition, central obesity, and insulin resistance.1Larter C.Z. Chitturi S. Farrell G.C. A fresh look at NASH pathogenesis. Part 1: the metabolic movers.J Gastroenterol Hepatol. 2010; 25: 672-690Crossref PubMed Scopus (144) Google Scholar, 2Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.Gastroenterology. 2012; 142: 711-725Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar The pathologic spectrum
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