Future of pharmacological treatment of non-alcoholic steatohepatitis in terms of key pathophysiological mechanisms

Česká verzia

Authors: Marek Rác ^1,2; Ľubomír Skladaný ³
Authors place of work: Hepatologická ambulancia Internej kliniky FN Nitra, Slovenská republika ¹; Vysoká škola zdravotníctva a sociálnej práce sv. Alžbety, Bratislava, Slovenská republika ²; Hepatologické, gastroenterologické a transplantačné oddelenie II. internej kliniky SZU a FNsP F. D. Roosevelta Banské Bystrica, Slovenská republika ³
Published in the journal: Vnitř Lék 2018; 64(7-8): 735-741
Category: Reviews

Summary

Obesity reaches the dimensions of the global epidemic. It directly contributes to an increase in the prevalence of systemic diseases associated with obesity. Obesity and overweight globally cause 3.5 million deaths annually [1]. Non-alcoholic fatty liver disease has become the most common chronic liver disease in developed countries and is considered to be a liver manifestation of metabolic syndrome. The extent and burden of the disease are increasing and reaching epidemic proportions because of its close association with the epidemic of obesity and diabetes mellitus type [2]. It affects 30 % of the adult population [2]. There is an alarming increase in prevalence among children and adolescents. However, in the group of patients with high cardiometabolic risk, we can see a significantly higher prevalence of NAFLD. Prevalence in obese patients is 75 -92 %, in diabetic patients prevalence is between 60 -70 % [3]. A significant proportion of patients with NAFLD will suffer from a progressive form of the disease – non-alcoholic steatohepatitis (NASH), which is associated with the development of advanced liver fibrosis, cirrhosis, and its complications. The growing prevalence of NASH in the near future will bring the advanced cohort of our patients to the stage of an advanced liver disease. If the adverse epidemiological trend is not reversed, in the next decade the most common cause of liver transplantation will be NASH. A steadily rising trend can be seen in an increase in the number of cases of hepatocellular carcinoma causally related to NASH [4]. Treatment based on the influence of key pathogenetic mechanisms could alter the individual‘s future as well as the global burden arising with NASH. New molecules with anti-inflammatory and antifibrotic effects will play a key role in the future.

Key words:

cirrhosis – insulin resistance – metabolic syndrome – NASH

Zdroje

Ng M, Fleming T, Robinson M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384(9945): 766–781. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(14)60460–8>.

Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15(1):11–20. Dostupné z DOI: <http://dx.doi.org/10.1038/nrgastro.2017.109>.

Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10(6): 330–344. Dostupné z DOI: <http://dx.doi.org/10.1038/nrgastro.2013.41>.

Rác M, Koller T, Klepanec A et al. Nealkoholová tuková choroba pečene a hepatocelulárny karcinóm: prehľad a analýza nitrianskeho súboru. Interná Med 2017; 17(4): 167–174.

Angulo P. Nonalcoholic Fatty Liver Disease. N Engl J Med 2002; 346(16): 1221–1231. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMra011775>.

Harrison SA, Fecht W, Brunt EM et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology 2009; 49(1): 80–86. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.22575>.

Hannah WN, Harrison SA. Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2016; 20(2): 339–350. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cld.2015.10.008>.

McPherson S, Hardy T, Henderson E et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J Hepatol 2015; 62(5): 1148–1155. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jhep.2014.11.034>.

Ekstedt M, Hagström H, Nasr P et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61(5): 1547–1554. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.27368>.

Bedossa P. [FLIP Pathology Consortium]. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology 2014; 60(2): 565–575. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.27173>.

Adams LA, Lymp JF, St. Sauver J et al. The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study. Gastroenterology 2005; 129(1): 113–121.

Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites. Hepatology 2010; 52(2): 774–788. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.23719>.

Peverill W, Powell L, Skoien R. Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation. Int J Mol Sci 2014; 15(5): 8591–8638. Dostupné z DOI: <http://dx.doi.org/10.3390/ijms15058591>.

Ratziu V, Bellentani S, Cortez-Pinto H et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53(2): 372–384. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jhep.2010.04.008>.

Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17(17–18): 988–997. Dostupné z DOI: <http://dx.doi.org/10.1016/j.drudis.2012.05.012>.

Jiao Y, Lu Y, Li X. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015; 36(1): 44–50. Dostupné z DOI: <http://dx.doi.org/10.1038/aps.2014.116>.

Verbeke L, Mannaerts I, Schierwagen R et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 2016; 6: 33453. Dostupné z DOI: <http://dx.doi.org/10.1038/srep33453>.

Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385(9972): 956–965. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(14)61933–4>. Erratum in Lancet 2015; 385(9972): 946.

Verbeke L, Farre R, Verbinnen B et al. The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats. Am J Pathol 2015; 185(2): 409–419. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ajpath.2014.10.009>.

Verbeke L, Farre R, Trebicka J et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59(6): 2286–2298. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.26939>.

Qin X, Xie X, Fan Y et al. Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 2008; 48(2): 432–441. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.22334>.

Barish GD, Narkar VA, Evans RM. PPAR: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006; 116(3): 590–597. Dostupné z DOI: <http://dx.doi.org/10.1172/JCI27955>.

Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62(3): 720–733. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jhep.2014.10.039>.

Staels B, Rubenstrunk A, Noel B et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013; 58(6): 1941–1952. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.26461>.

Cariou B, Hanf R, Lambert-Porcheron S et al. Dual Peroxisome Proliferator-Activated Receptor/Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects. Diabetes Care 2013; 36(10): 2923–2930. Dostupné z DOI: <http://dx.doi.org/10.2337/dc12–2012>.

Ratziu V, Harrison SA, Francque S et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016; 150(5): 1147–1159.e5. Dostupné z DOI: <http://dx.doi.org/10.1053/j.gastro.2016.01.038>.

Ratziu V, Francque S, Harrison SH et al. Improvement in NASH histological activity highly correlates with fibrosis regression. Hepatology 2016; 64(Suppl 1).

Yu JG, Javorschi S, Hevener AL et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51(10): 2968–2974.

Sanyal AJ, Chalasani N, Kowdley KV et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med 2010; 362(18): 1675–1685. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa0907929>.

Lavine JE, Schwimmer JB, Natta ML Van et al. Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents. JAMA 2011; 305(16): 1659. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2011.520>.

Zhang P, Li H, Tan X et al. Association of metformin use with cancer incidence and mortality: A meta-analysis. Cancer Epidemiol 2013; 37(3): 207–218. Dostupné z DOI: <http://dx.doi.org/10.1016/j.canep.2012.12.009>.

Berres ML, Koenen RR, Rueland A et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest 2010; 120(11): 4129–4140. Dostupné z DOI: <http://dx.doi.org/10.1172/JCI41732>.

Zimmermann HW, Tacke F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets 2011; 10(6): 509–536.

Friedman S, Sanyal A, Goodman Z et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials 2016; 47: 356–365. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cct.2016.02.012>.

Gilat T, Somjen GJ, Mazur Y et al. Fatty acid bile acid conjugates (FABACs) – new molecules for the prevention of cholesterol crystallisation in bile. Gut 2001; 48(1): 75–79.

Leikin-Frenkel A, Gonen A, Shaish A et al. Fatty Acid Bile Acid Conjugate Inhibits Hepatic Stearoyl Coenzyme A Desaturase and Is Non-atherogenic. Arch Med Res 2010; 41(6): 397–404. Dostupné z DOI: <http://dx.doi.org/10.1016/j.arcmed.2010.09.001>.

Goldiner I, van der Velde AE, Vandenberghe KE et al. ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid–bile acid conjugates (FABACs). Biochem J 2006; 396(3): 529–536. Dostupné z DOI: <http://dx.doi.org/10.1042/BJ20051694>.

Powell DA. An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors (2009–2013). Expert Opin Ther Pat 2014; 24(2): 155–175. Dostupné z DOI: <http://dx.doi.org/10.1517/13543776.2014.851669>.

Safadi R, Konikoff FM, Mahamid M et al. The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2014; 12(12): 2085–2091. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cgh.2014.04.038>.

Villanova N, Moscatiello S, Ramilli S et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005; 42(2): 473–480. Dostupné z DOI: <http://dx.doi.org/10.1002/hep.20781>.

Mells J, Anania F. The Role of Gastrointestinal Hormones in Hepatic Lipid Metabolism. Semin Liver Dis 2013; 33(4): 343–357. Dostupné z DOI: <http://dx.doi.org/10.1055/s-0033–1358527>.

Mells JE, Fu PP, Sharma S et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. AJP Gastrointest. Liver Physiol 2012; 302(2): G225-G235. Dostupné z DOI: <http://d.doi.org/10.1152/ajpgi.00274.2011>.

Armstrong MJ, Hull D, Guo K et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol 2016; 64(2): 399–408. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jhep.2015.08.038>.

Armstrong MJ, Houlihan DD, Rowe IA et al. Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes: individual patient data meta-analysis of the LEAD programme. Aliment Pharmacol Ther 2013; 37(2): 234–242. Dostupné z DOI: <http://doi: 10.1111/apt.12149>.

Armstrong MJ, Gaunt P, Aithal GP et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387(10019): 679–690. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(15)00803-X>.

Kagan HM. Lysyl Oxidase: Mechanism, Regulation and Relationship to Liver Fibrosis. Pathol Res Pract 1994; 190(9–10): 910–919. Dostupné z DOI: <http://dx.doi.org/10.1016/S0344–0338(11)80995–7>.

Barry-Hamilton V, Spangler R, Marshall D et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16(9): 1009–1017. Dostupné z DOI: <http://dx.doi.org/10.1038/nm.2208>.

Sanyal A, Abdelmalek MF, Diehl AM et al. Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J Hepatol 2017; 66(1 Suppl): S54. Dostupné z DOI: <https://doi.org/10.1016/S0168–8278(17)30370–7>.

Henderson NC, Mackinnon AC, Farnworth SL et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci 2006; 103(13): 5060–5065. Dostupné z DOI: <http://dx.doi.org/10.1073/pnas.0511167103>.

Traber PG, Chou H, Zomer E et al. Regression of Fibrosis and Reversal of Cirrhosis in Rats by Galectin Inhibitors in Thioacetamide-Induced Liver Disease. PLoS One 2013; 8(10): e75361. Dostupné z DOI: <http://dx.doi.org/10.1371/journal.pone.0075361>.

Harrison SA, Marri SR, Chalasani N et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther 2016; 44(11–12): 1183–1198. Dostupné z DOI: <http://dx.doi.org/10.1111/apt.13816>.