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Pharmacologic therapy for nonalcoholic steatohepatitis focusing on pathophysiology

  • Yoon, In Cheol (Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine) ;
  • Eun, Jong Ryeol (Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine)
  • Received : 2019.03.20
  • Accepted : 2019.04.04
  • Published : 2019.05.31

Abstract

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.

Keywords

References

  1. Oh H, Jun DW, Saeed WK, Nguyen MH. Non-alcoholic fatty liver diseases: update on the challenge of diagnosis and treatment. Clin Mol Hepatol 2016;22:327-35. https://doi.org/10.3350/cmh.2016.0049
  2. Alkhouri N, Dixon LJ, Feldstein AE. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev Gastroenterol Hepatol 2009;3:445-51. https://doi.org/10.1586/egh.09.32
  3. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008;134:1641-54. https://doi.org/10.1053/j.gastro.2008.03.002
  4. Yang L, Roh YS, Song J, Zhang B, Liu C, Loomba R, et al. Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology 2014;59:483-95. https://doi.org/10.1002/hep.26698
  5. Okazaki I. [Non-alcoholic steatohepatitis]. Cho YK, Eun JR, translators. Paju: Koonja Publishing Inc.; 2018.
  6. Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol 2012;302:G1310-21. https://doi.org/10.1152/ajpgi.00365.2011
  7. Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin Investig Drugs 2018;27:301-11. https://doi.org/10.1080/13543784.2018.1442436
  8. Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, 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;47:356-65. https://doi.org/10.1016/j.cct.2016.02.012
  9. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738-44. https://doi.org/10.1053/jhep.2001.28055
  10. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51:1820-32. https://doi.org/10.1002/hep.23594
  11. Derosa G. Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus: comparison with other oral antihyperglycaemic agents. Drugs 2010;70:1945-61. https://doi.org/10.2165/11538100-000000000-00000
  12. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85. https://doi.org/10.1056/NEJMoa0907929
  13. Schuster S, Feldstein AE. NASH: novel therapeutic strategies targeting ASK1 in NASH. Nat Rev Gastroenterol Hepatol 2017;14:329-30. https://doi.org/10.1038/nrgastro.2017.42
  14. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2018;67:549-59. https://doi.org/10.1002/hep.29514
  15. Ikenaga N, Peng ZW, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 2017;66:1697-708. https://doi.org/10.1136/gutjnl-2016-312473
  16. Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018;155:1140-53. https://doi.org/10.1053/j.gastro.2018.07.006
  17. Keely SJ, Walters JR. The farnesoid X receptor: good for BAD. Cell Mol Gastroenterol Hepatol 2016;2:725-32. https://doi.org/10.1016/j.jcmgh.2016.08.004
  18. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-82. https://doi.org/10.1053/j.gastro.2013.05.042
  19. Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J 2014;13:17. https://doi.org/10.1186/1475-2891-13-17
  20. Miyahara T, Schrum L, Rippe R, Xiong S, Yee HF Jr, Motomura K, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 2000;275:35715-22. https://doi.org/10.1074/jbc.M006577200
  21. van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2011;4:249-63. https://doi.org/10.1177/1756283X11403809
  22. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082-90. https://doi.org/10.1111/j.1572-0241.2005.41583.x
  23. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 2012;107:811-26. https://doi.org/10.1038/ajg.2012.128
  24. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, 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;387:679-90. https://doi.org/10.1016/S0140-6736(15)00803-X
  25. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443-51. https://doi.org/10.1038/ijo.2013.120
  26. Milder TY, Stocker SL, Abdel Shaheed C, McGrath-Cadell L, Samocha-Bonet D, Greenfield JR, et al. Combination therapy with an SGLT2 inhibitor as initial treatment for type 2 diabetes: a systematic review and meta-analysis. J Clin Med 2019;8:pii: E45. https://doi.org/10.3390/jcm8010045
  27. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018;53:362-76. https://doi.org/10.1007/s00535-017-1415-1
  28. Shibuya T, Fushimi N, Kawai M, Yoshida Y, Hachiya H, Ito S, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab 2018;20:438-42. https://doi.org/10.1111/dom.13061
  29. Ito D, Shimizu S, Inoue K, Saito D, Yanagisawa M, Inukai K, et al. Comparison of ipragliflozin and pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care 2017;40:1364-72. https://doi.org/10.2337/dc17-0518
  30. Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 2014;59:154-69. https://doi.org/10.1002/hep.26604
  31. Muir K, Hazim A, He Y, Peyressatre M, Kim DY, Song X, et al. Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma. Cancer Res 2013;73:4722-31. https://doi.org/10.1158/0008-5472.CAN-12-3797
  32. Filozof C, Goldstein BJ, Williams RN, Sanyal A. Non-alcoholic steatohepatitis: limited available treatment options but promising drugs in development and recent progress towards a regulatory approval pathway. Drugs 2015;75:1373-92. https://doi.org/10.1007/s40265-015-0437-3
  33. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M; EPE-A Study Group. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 2014;147:377-84. https://doi.org/10.1053/j.gastro.2014.04.046
  34. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology 2014;60:1211-21. https://doi.org/10.1002/hep.27289
  35. Wang X, Ren Q, Wu T, Guo Y, Liang Y, Liu S. Ezetimibe prevents the development of non alcoholic fatty liver disease induced by high fat diet in C57BL/6J mice. Mol Med Rep 2014;10:2917-23. https://doi.org/10.3892/mmr.2014.2623
  36. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015;61:1239-50. https://doi.org/10.1002/hep.27647
  37. Hirose A, Ono M, Saibara T, Nozaki Y, Masuda K, Yoshioka A, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007;45:1375-81. https://doi.org/10.1002/hep.21638
  38. Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol 2009;15:942-54. https://doi.org/10.3748/wjg.15.942
  39. McPherson S, Wilkinson N, Tiniakos D, Wilkinson J, Burt AD, McColl E, et al. A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis. PLoS One 2017;12:e0175717. https://doi.org/10.1371/journal.pone.0175717
  40. Connolly JJ, Ooka K, Lim JK. Future pharmacotherapy for non-alcoholic steatohepatitis (NASH): review of phase 2 and 3 trials. J Clin Transl Hepatol 2018;6:264-75.
  41. Abenavoli L, Falalyeyeva T, Boccuto L, Tsyryuk O, Kobyliak N. Obeticholic acid: a new era in the treatment of nonalcoholic fatty liver disease. Pharmaceuticals (Basel) 2018;11:pii: E104. https://doi.org/10.3390/ph11040104
  42. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-65. https://doi.org/10.1016/S0140-6736(14)61933-4
  43. Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, et al. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. Diabetes 2006;55:1197-204. https://doi.org/10.2337/db05-1187
  44. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-${\alpha}$ and -${\delta}$, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150:1147-59. https://doi.org/10.1053/j.gastro.2016.01.038
  45. Shiffman M, Freilich B, Vuppalanchi R, Watt K, Chan JL, Spada A, et al. Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase 3/7 activation in subjects with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2019;49:64-73. https://doi.org/10.1111/apt.15030
  46. Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, et al. Emricasan (IDN-6556) Lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology 2019;69:717-28. https://doi.org/10.1002/hep.30199
  47. Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014;12:2085-91. https://doi.org/10.1016/j.cgh.2014.04.038
  48. Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018;391:1174-85. https://doi.org/10.1016/S0140-6736(18)30474-4
  49. Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2019;392:2705-17. https://doi.org/10.1016/s0140-6736(18)31785-9

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