Skip to main content
SpringerLink
Log in

Reversal of NASH fibrosis with pharmacotherapy

Hepatology International volume 13, pages 534–545 (2019)Cite this article

Abstract

NAFLD is a spectrum of liver disease starting with fatty liver at one end of the spectrum and cirrhosis or liver cancer at the other end. Worldwide, NAFLD has become one of the most common liver diseases and it has also become one of the leading indications for liver transplantation. Our understanding of the NAFLD epidemiology, pathogenesis and its progression to cirrhosis has improved over the last 2 decades. Currently, however, there are no FDA-approved treatment options for fibrosis resulting from NAFLD. A number of compounds targeting multiple pathways involved in the progression of NAFLD are currently in phase 2–3 trials. In this review, we will briefly discuss the epidemiology, the pathogenesis and the current status of treatment of NAFLD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1):73–84

    Article  Google Scholar 

  2. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 2017;377(21):2063–2072

    Article  CAS  PubMed  Google Scholar 

  3. Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic fatty liver disease: mechanisms and clinical implications. Semin Liver Dis 2015;35(2):132–145

    Article  CAS  PubMed  Google Scholar 

  4. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009;51(2):371–379

    Article  CAS  Google Scholar 

  5. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53(6):1874–1882

    Article  PubMed  Google Scholar 

  6. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi ZR. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017;65(5):1557–1565

  7. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547–1554

    Article  CAS  Google Scholar 

  8. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. 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

    Article  Google Scholar 

  9. Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010;59:969–74

    Article  PubMed  Google Scholar 

  10. Roskilly A, Hicks A, Taylor E, Jones R, Parker R, Rowe I. Slow fibrosis progression rates in placebo-treated randomized controlled trial participants with non-alcoholic steatohepatitis predict low rates of cirrhosis development. Hepatology 2018;68:21A–22A

    Article  Google Scholar 

  11. Estes C, Anstee QM, Arias-Loste MT, Bantel H, Bellentani S, Caballeria J, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol 2018;69(4):896–904

    Article  PubMed  Google Scholar 

  12. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 2017;377(21):2063–2072

    Article  CAS  PubMed  Google Scholar 

  13. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016;65(8):1038–1048

    Article  CAS  PubMed  Google Scholar 

  14. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(4):1100

    Article  CAS  PubMed Central  Google Scholar 

  15. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88(1):125–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol 2018;68(2):238–250

    Article  CAS  PubMed  Google Scholar 

  17. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol 2010;2(4):237–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications. Semin Liver Dis 2015;35(2):132–145

    Article  CAS  PubMed  Google Scholar 

  19. Choi SS, Omenetti A, Witek RP, Moylan CA, Syn WK, Jung Y, et al. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2009;297(6):G1093–G1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Omenetti A, Diehl AM. Hedgehog signaling in cholangiocytes. Curr Opin Gastroenterol 2011;27(3):268–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA. Identification of bipotential progenitor cells in human liver development. Hepatology 1996;23(3):476–481

    Article  CAS  PubMed  Google Scholar 

  22. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 2015;61:1740–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xie G, Choi SS, Syn WK, Michelotti GA, Swiderska M, Karaca G, et al. Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation. Gut. 2012;62(2):299–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practic eguidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357

    Article  PubMed  Google Scholar 

  25. 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(18):1675–1685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med 2015;3(1):5

    PubMed  PubMed Central  Google Scholar 

  27. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008;48(5):1632–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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(3):574–582

    Article  CAS  PubMed  Google Scholar 

  29. 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 multicenter, randomized, placebo-controlled trial. Lancet 2015;385(9972):956–965

    Article  CAS  PubMed  Google Scholar 

  30. Younossi Z, Ratziu V, Loomba R, Rinella M, Anstee Q, Goodman Z, et al. GS-06-positive results from REGENERATE: a phase 3 international, randomized, placebo-controlled study. J Hepatol. 2019;70(1):e5

    Article  Google Scholar 

  31. http://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-positive-topline-results-pivotal-phase-3

  32. Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D. Reduction of liver steatosis and fibrosis with an Ask1 inhibitor in a murine model of NASH is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64:S170

    Article  Google Scholar 

  33. 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 2017

  34. https://www.gilead.com/news-and-press/press-room/press-releases/2019/2/gilead-announces-topline-data-from-phase-3-stellar4-study-of-selonsertib-in-compensated-cirrhosis-f4-due-to-nonalcoholic-steatohepatitis-nash

  35. https://www.gilead.com/news-and-press/press-room/press-releases/2019/4/gilead-announces-topline-data-from-phase-3-stellar3-study-of-selonsertib-in-bridging-fibrosis-f3-due-to-nonalcoholic-steatohepatitis-nash

  36. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2011;2(4):236–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zingarelli B, Piraino G, Hake PW, O’Connor M, Denenberg A, Fan H, et al. Peroxisome proliferator-activated receptor delta regulates inflammation via NF-{kappa}B signaling in polymicrobial sepsis. Am J Pathol 2010;177(4):1834–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-a and -d, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150:1147–1159

  39. Roh YS, Seki E. Chemokines and chemokine receptors in the development of NAFLD. Adv Exp Med Biol 2018;1061:45–53

    Article  CAS  PubMed  Google Scholar 

  40. Tamura Y, Sugimoto M, Murayama T, Minami M, Nishikaze Y, Ariyasu H, et al. C–C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J Atheroscler Thromb 2010;17:219–228

    Article  CAS  PubMed  Google Scholar 

  41. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR43/CCR43 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One 2016;11(6):e0158156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–1767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol 2011;5(2):201–212

    Article  PubMed  PubMed Central  Google Scholar 

  44. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, et al. The pan-caspase inhibitor Emricasan(IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 2015;35(3):953–966

    Article  CAS  PubMed  Google Scholar 

  45. Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol 2019;17(4):774.e4–783.e4

    Article  CAS  Google Scholar 

  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(2):717–728

    Article  CAS  PubMed  Google Scholar 

  47. 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 multicenter, double-blind, randomized, placebo-controlled phase 2 study. Lancet 2016;387(10019):679–690

  48. Uto Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chem Phys Lipids 2016;197:3–12

    Article  CAS  PubMed  Google Scholar 

  49. 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(12):2085–2091

  50. Ratziu V, Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a steroyl CoA desaturase inhibitor, in patients with NASH. AASLD Liver Meeting, abstract LB-5, 2018

  51. Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther 2014;351(2):336–343

    Article  CAS  PubMed  Google Scholar 

  52. Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chalasani N, Garcia-Tsao G, Goodman Z, Lawitz E, Abdelmalek M, Rinella M, et al. A multicenter, randomized, double-blind, PLB-controlled trial of Galectin-3 inhibitor (GR-MD-02) in patients with NASH cirrhosis and portal hypertension. J Hepatol 2018;68(Supplement 1):S100–S101

    Article  Google Scholar 

  54. http://investor.galectintherapeutics.com/news-releases/news-release-details/galectin-therapeutics-proceeds-phase-3-development-gr-md-02-nash

  55. Ishida Y, Nagata K. Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol 2011;499:167–182

    Article  CAS  PubMed  Google Scholar 

  56. Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol. 2008;26(4):431–442

    Article  CAS  PubMed  Google Scholar 

  57. Soule B, Tirucherai G, Kavita U, Kundu S, Christian R. Safety, tolerability, and pharmacokinetics of BMS-986263/ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 siRNA, in healthy participants: a randomized, placebo-controlled, double-blind, phase 1 study. J Hepatol 2018;68:S112

    Article  Google Scholar 

  58. Colca JR, McDonald WG, McCommis KS, Finck BN. Treating fatty liver disease by modulating mitochondrial pyruvate metabolism. Hepatol Commun 2017;1(3):193–197

    Article  PubMed  PubMed Central  Google Scholar 

  59. McCommis KS, Hodges WT, Brunt EM, Nalbantoglu I, McDonald WG, Holley et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 2017;65(5):1543–1556

  60. Liu H, Pang G, Ren J, Zhao Y, Wang J. A novel class of apical sodium–dependent bile salt transporter inhibitors: 1-(2,4-bifluorophenyl)-7-dialkylamino-1,8-naphthyridine-3-carboxamides. Acta Pharm Sin B 2016;7(2):223–229

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rao A, Kosters A, Mells JE, Zhang W, Setchell KD, Amanso AM, et al. Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 2016;8(357):357ra122

  62. Newsome P, Palmer M, Freilich B, Sheikh M, Sheikh A, Sarles H, et al. Safety, tolerability and efficacy of volixibat, an apical sodium-dependent bile acid transporter inhibitor, in adults with non-alcoholic steatohepatitis: 24-week interim analysis results from a phase 2 study. J Hepatol. 2019;70:e141–e382

    Article  Google Scholar 

  63. 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 2018;392(10165):2705–2717

    Article  CAS  PubMed  Google Scholar 

  64. Harrison SA, Moussa S, Bashir M, Alkhouri N, Frias J, Baum S, et al. MGL-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study. J Hepatol. 2018;68:S38

    Article  Google Scholar 

  65. Ikenaga N, Liu SB, Peng ZW, Greenstein AE, French D, Smith V, et al. Dual combination therapy directed against lysyl oxidase‐like 2 (LOXL2) and apoptosis signal-regulating kinase 1 (ASK1) potently inhibits fibrosis and portal hypertension in a new mouse model of PSC‐like liver disease. Hepatology 2015;62(Suppl.):881A

  66. Lawitz E, Gane E, Ruane P, Herring R Younes ZP. A combination of the ACC inhibitor GS-0976 and the nonsteroidal FXR agonist GS-9674 improves hepatic steatosis, biochemistry, and stiffness in patients with non-alcoholic steatohepatitis. J Hepatol 70(Issue 1):e794

  67. Belanger C, Foucart C, Legry V, Brozek J, Noel B. Elafibranor and nitazoxanide synergize to reduce fibrosis in a NASH model. J Hepatol 68:S352–S353

  68. Legry V, Descamps E, Noel B, Foucart C, Degallaix N, Belanger C, et al. Elafibranor, a drug candidate for first line NASH monotherapy and a universal backbone for drug combination treatment. J Hepatol 70(Issue 1):e551

  69. Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2019;16(6):377–386

    Article  PubMed  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, MD, 21202, USA

    Joseph J. Alukal & Paul J. Thuluvath

  2. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Paul J. Thuluvath

Authors
  1. Joseph J. Alukal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul J. Thuluvath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JJA and PJT contributed to the drafting of the article or critical revision of important intellectual content.

Corresponding author

Correspondence to Paul J. Thuluvath.

Ethics declarations

Conflict of interest

Joseph J. Alukal and Paul J. Thuluvath declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alukal, J.J., Thuluvath, P.J. Reversal of NASH fibrosis with pharmacotherapy. Hepatol Int 13, 534–545 (2019). https://doi.org/10.1007/s12072-019-09970-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-019-09970-3

Keywords

search

Navigation