Nonalcoholic steatohepatitis: Emerging targeted therapies to optimize treatment options

Drug Design, Development and Therapy

Volumn 9, Issue , 2015, Pages 4835-4845

  Milic, Sandra ^a   Mikolasevic, Ivana ^a   Krznaric Zrnic, Irena ^a   Stanic, Marija ^a   Poropat, Goran ^a   Stimac, Davor ^a   Vlahovic Palcevski, Vera ^b   Orlic, Lidija ^a  

^a KBC RIJEKA   (Croatia)

^b UNIVERSITY OF RIJEKA   (Croatia)

Author keywords

Insulin resistance; Metabolic syndrome; Nonalcoholic fatty liver disease; Therapy

Indexed keywords

ALPHA TOCOPHEROL; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIINFECTIVE AGENT; ANTILIPEMIC AGENT; ASCORBIC ACID; BICYCLOL; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; EZETIMIBE; METFORMIN; OBETICHOLIC ACID; PHOSPHATIDYLCHOLINE; PIOGLITAZONE; PLACEBO; PPC; ROSIGLITAZONE; ROSUVASTATIN; SILYMARIN; SIMVASTATIN; UNCLASSIFIED DRUG; URSODEOXYCHOLIC ACID; VITAMIN D; 2,4 THIAZOLIDINEDIONE DERIVATIVE; ANGIOTENSIN 1 RECEPTOR ANTAGONIST;

AEROBIC EXERCISE; ALGORITHM; ANTIPROLIFERATIVE ACTIVITY; BARIATRIC SURGERY; BLADDER CANCER; BODY WEIGHT DISORDER; BONE DENSITY; BONE DISEASE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CLINICAL PRACTICE; DRUG CONTRAINDICATION; DRUG MECHANISM; DRUG TREATMENT FAILURE; DYSLIPIDEMIA; EDEMA; HEART FAILURE; HIGH RISK PATIENT; HUMAN; IMPAIRED GLUCOSE TOLERANCE; LIFESTYLE MODIFICATION; LIVER CIRRHOSIS; LONG TERM CARE; MORBIDITY; MULTICENTER STUDY (TOPIC); NONALCOHOLIC FATTY LIVER; PHLEBOTOMY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK REDUCTION; SILYBUM MARIANUM; WEIGHT GAIN; WEIGHT REDUCTION; ANIMAL; CLINICAL PATHWAY; DECISION SUPPORT SYSTEM; DRUG EFFECTS; INCIDENCE; LIFESTYLE; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOPHYSIOLOGY; PREVALENCE; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RISK FACTOR; TREATMENT OUTCOME;

ALGORITHMS; ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; ANIMALS; CRITICAL PATHWAYS; DECISION SUPPORT TECHNIQUES; HUMANS; INCIDENCE; LIFE STYLE; NON-ALCOHOLIC FATTY LIVER DISEASE; PREVALENCE; RENIN-ANGIOTENSIN SYSTEM; RISK FACTORS; RISK REDUCTION BEHAVIOR; THIAZOLIDINEDIONES; TREATMENT OUTCOME; VITAMIN D;

EID: 84939781578     PISSN: None     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S64877     Document Type: Review

References (88)

1. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47–S64.
2. Koplay M, Sivri M, Erdogan H, Nayman A. Importance of imaging and recent developments in diagnosis of nonalcoholic fatty liver disease. World J Hepatol. 2015;7:769–776.
3. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.
4. Lee JJ, Lambert JE, Hovhannisyan Y, et al. Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis. Am J Clin Nutr. 2015;101:34–43.
5. Mazo DF, de Oliveira MG, Pereira IV, et al. S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis. Drug Des Devel Ther. 2013;7:553–563.
6. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014;11:e1001680
7. Watanabe S, Hashimoto E, Ikejima K, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol. 2015;50:364–377.
8. Chaldakov GN, Stankulov IS, Hristova M, Ghenev PA. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Curr Pharm Des. 2003;9:1023–1031.
9. Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21:3777–3785.
10. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–1846.
11. Abenavoli L, Scarpellini E, Rouabhia S, Balsano C, Luzza F. Probiotics in non-alcoholic fatty liver disease: which and when. Ann Hepatol. 2013;12:357–363.
12. Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:7381–7391.
13. Chalasani N, Younossi Z, Lavine JE, 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. Hepatology. 2012;55:2005–2023.
14. Le TA, Loomba R. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis. J Clin Exp Hepatol. 2012;2:156–173.
15. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.
16. Ross AB, Godin JP, Minehira K, Kirwan JP. Increasing whole grain intake as part of prevention and treatment of nonalcoholic Fatty liver disease. Int J Endocrinol. 2013;2013:585876.
17. Abenavoli L, Milic N, Peta V, Alfieri F, De Lorenzo A, Bellentani S. Alimentary regimen in non-alcoholic fatty liver disease: Mediterranean diet. World J Gastroenterol. 2014;20:16831–16840.
18. Ryan MC, Itsiopoulos C, Thodis T, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013;59:138–143.
19. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol. 2011;57:1299–1313.
20. Jin R, Welsh JA, Le NA, et al. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients. 2014;6:3187–3201.
21. Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–1971.
22. Vos MB, Colvin R, Belt P, et al. Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. JPediatr Gastroenterol Nutr. 2012;54:90–96.
23. Askari F, Rashidkhani B, Hekmatdoost A. Cinnamon may have therapeutic benefits on lipid profile, liver enzymes, insulin resistance, and high-sensitivity C-reactive protein in nonalcoholic fatty liver disease patients. Nutr Res. 2014;34:143–148.
24. Janczyk W, Socha P, Lebensztejn D, et al. Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial. BMC Pediatr. 2013;13:85.
25. Malaguarnera M, Vacante M, Antic T, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2012;57:545–553.
26. Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease. World J Hepatol. 2015;7:559–565.
27. Baran B, Akyüz F. Non-alcoholic fatty liver disease: what has changed in the treatment since beginning? World J Gastroenterol. 2014;20:14219–14229.
28. Wong VW, Chan RS, Wong GL, et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2013;59:536–542.
29. Yoshimura E, Kumahara H, Tobina T, et al. Lifestyle intervention involving calorie restriction with or without aerobic exercise training improves liver fat in adults with visceral adiposity. J Obes. 2014;2014:197216.
30. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–1668.
31. Bell LN, Wang J, Muralidharan S, et al. Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. Hepatology. 2012;56:1311–1318.
32. Gastaldelli A, Harrison S, Belfort-Aguiar R, et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment Pharmacol Ther. 2010;32:769–775.
33. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916–922.
34. Stone JC, Furuya-Kanamori L, Barendregt JJ, Doi SA. Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes? Pharmacoepidemiol Drug Saf. 2015;24:223–227.
35. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371–379.
36. Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135:100–110.
37. Ratziu V, Charlotte F, Bernhardt C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51:445–453.
38. Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open-label trial. Hepatology. 2011;54:1631–1639.
39. Arab JP, Candia R, Zapata R, et al. Management of nonalcoholic fatty liver disease: an evidence-based clinical practice review. World J Gastroenterol. 2014;20:12182–12201.
40. Hoofnagle JH, Van Natta ML, Kleiner DE, et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013;38:134–143.
41. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.
42. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.
43. Watanabe S, Hashimoto E, Ikejima K, et al. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatol Res. 2015;45:363–377.
44. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313:2263–2273.
45. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464–1467.
46. Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. JHepatol. 2011;54:1011–1019.
47. Leuschner UF, Lindenthal B, Herrmann G, et al. NASH Study Group. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–479.
48. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicenter, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.
49. Liu GT. Bicyclol: a novel drug for treating chronic viral hepatitis B and C. Med Chem. 2009;5:29–43.
50. Han Y, Shi JP, Ma AL, Xu Y, Ding XD, Fan JG. Randomized, vitamin E-controlled trial of bicyclol plus metformin in non-alcoholic fatty liver disease patients with impaired fasting glucose. Clin Drug Investig. 2014;34:1–7.
51. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–994.
52. Kargiotis K, Katsiki N, Athyros VG, et al. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol. 2014;12:505–511.
53. Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomized controlled trial. Diabetologia. 2014;57:878–890.
54. Loomba R, Sirlin CB, Ang B, 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;61:1239–1250.
55. Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623.
56. Mansourian PG, Yoneda M, Krishna Rao M, Martinez FJ, Thomas E, Schiff ER. Effects of statins on the risk of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2014;10:417–426.
57. Paschos P, Tziomalos K. Nonalcoholic fatty liver disease and the rennin-angiotensin system: implications for treatment. World J Hepatol. 2012;4:327–331.
58. Abbas G, Silveira MG, Lindor KD. Hepatic fibrosis and the rennin-angiotensin system. Am J Ther. 2011;18:e202–e208.
59. Tobli JE, Muñoz MC, Cao G, Mella J, Pereyra L, Mastai R. ACE inhibition and AT1 blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring). 2008;16:770–776.
60. Orlic L, Mikolasevic I, Lukenda V, Anic K, Jelic I, Racki S. Nonalcoholic fatty liver disease and the renin-angiotensin system blockers in the patients with chronic kidney disease. Wien Klin Wochenschr. 2015;127:355–362.
61. Orlić L, Mikolasevic I, Bagic Z, Racki S, Stimac D, Milic S. Chronic kidney disease and nonalcoholic Fatty liver disease-is there a link? Gastroenterol Res Pract. 2014;2014:847539.
62. Grace JA, Herath CB, Mak KY, Burrell LM, Angus PW. Update on new aspects of the rennin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin Sci (Lond). 2012;123:225–239.
63. Pereira RM, dos Santos RAS, da Costa Dias FL, Teixeira MM, Simões e Silva AC. Renin-angiotensin system in the pathogenesis of liver fibrosis. World J Gastroenterol. 2009;15:2579–2586.
64. Hirata T, Tomita K, Kawai T, et al. Effect of telmisartan for treatment of nonalcoholic fatty liver disease: Fatty Liver Protection Trial by telmisartan or losartan study (FANTASY). Int J Endocrinol. 2013;2013:587140.
65. Goh GB, Pagadala MR, Dasarathy J, et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int. 2015;35:979–985.
66. 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;15:942–954.
67. Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol. 2012;57:897–909.
68. Küçükazman M, Ata N, Dal K, et al. The association of vitamin D deficiency with nonalcoholic fatty liver disease. Clinics (Sao Paulo). 2014;69:542–546.
69. Han YP, Kong M, Zheng S, et al. Vitamin D in liver disease: from mechanisms to clinical trials. J Gastroenterol Hepatol. 2013;28 Suppl 1:49–55.
70. Strange RC, Shipman KE, Ramachandran S. Metabolic syndrome: A review of the role of vitamin D in mediating susceptibility and outcome. World J Diabetes. 2015;6:896–911.
71. Targher G, Bertolini L, Scala L, et al. Association between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007;17:517–524.
72. Dasarathy J, Periyalwar P, Allampati S et al. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Liver Int. 2014;34:e118–127.
73. Manco M, Ciampalini P, Nobili V. Low levels of 25-hydroxycitamin D(3) in children with biopsy-proven nonalcoholic fatty liver disease. Hepatology. 2010;51:2229.
74. Nobili V, Giorgio V, Liccardo D, et al. Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease. Eur J Endocrinol. 2014;170:547–553.
75. Potter JJ, Liu X, Koteish A, Mezey E. 1,25-dihydroxyvitamin D3 and its nuclear receptor repress human α1 (I) collagen expression and type I collagen formation. Liver Int. 2013;33:677–686.
76. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24:1423–1432.
77. Del Ben M, Polimeni L, Baratta F, Pastori D, Loffredo L, Angelico F. Modern approach to the clinical management of non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:8341–8350.
78. Loguercio C, Andreone P, Brisc C, et al. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012;52:1658–1665.
79. Horejsová M, Urban J. [The effect of polyene phosphatidylcholine (Essentiale forte) in the treatment of liver steatosis and ultrasound findings– preliminary study]. Cas Lek Cesk. 1994;133:366–369. Czech.
80. Li J, Kim CI, Leo MA, Mak KM, Rojkind M, Lieber CS. Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. Hepatology. 1992;15:373–381.
81. Caiazzo R, Lassailly G, Leteurtre E, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260:893–898; discussion 898–899.
82. Hafeez S, Ahmed MH. Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: a future treatment by choice or by chance? J Obes. 2013;2013:839275.
83. Milić S, Lulić D, Štimac D D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World JGastroenterol. 2014;20:9330–9337.
84. Milić S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis. 2012;30:158–162.
85. Valenti L, Fracanzani AL, Dongiovanni P, et al. A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia. World J Gastroenterol. 2014;20:3002–3010.
86. Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. JHepatol. 2011;55:920–932.
87. Adams LA, Crawford DH, Stuart K, et al. The impact of phlebotomy in nonalcoholic fatty liver disease: a prospective, randomized, controlled trial. Hepatology. 2015;61:1555–1564.
88. Review Team, LaBrecque DR, Abbas Z, et al. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48:467–473.