Non-Alcoholic Steatohepatitis: Limited Available Treatment Options but Promising Drugs in Development and Recent Progress Towards a Regulatory Approval Pathway

Drugs

Volumn 75, Issue 12, 2015, Pages 1373-1392

  Filozof, Claudia ^a   Goldstein, Barry J ^b   Williams, Richard N ^c   Sanyal, Arun ^d  

^a Osprey House ^*  (United Kingdom)

^b 206 Carnegie Center   (United States)

^c 2056 Carnegie Center ^*  (United States)

^d VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOBESITY AGENT; ANTIOXIDANT; CENICRIVIROC; DIGESTIVE TRACT AGENT; ELAFIBRANOR; EMRICASAN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INSULIN SENSITIZING AGENT; LIRAGLUTIDE; MERCAPTAMINE; OBETICHOLIC ACID; OMEGA 3 FATTY ACID; SIMTUZUMAB; GASTROINTESTINAL AGENT; NEW DRUG;

ALCOHOL CONSUMPTION; ARTICLE; BARIATRIC SURGERY; COMPUTER ASSISTED TOMOGRAPHY; DISEASE ACTIVITY; DISEASE COURSE; DRUG APPROVAL; DRUG INDICATION; DRUG MECHANISM; ETHNIC DIFFERENCE; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; NONALCOHOLIC FATTY LIVER; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OBESITY; OUTCOME ASSESSMENT; OXIDATIVE STRESS; PATHOGENESIS; PREVALENCE; TREATMENT RESPONSE; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECTS; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; RISK FACTOR; TREATMENT OUTCOME; TRENDS;

ANIMALS; DRUG APPROVAL; DRUG DISCOVERY; DRUGS, INVESTIGATIONAL; GASTROINTESTINAL AGENTS; HUMANS; LIVER; NON-ALCOHOLIC FATTY LIVER DISEASE; PREVALENCE; RISK FACTORS; TREATMENT OUTCOME;

EID: 84939266502     PISSN: 00126667     EISSN: 11791950     Source Type: Journal    
DOI: 10.1007/s40265-015-0437-3     Document Type: Article

References (129)

1. Sanyal AJ. NASH: a global health problem. Hepatol Res. 2011;41(7):670-4.
2. Misra VL, Khashab M, Chalasani N. Nonalcoholic fatty liver disease and cardiovascular risk. Curr Gastroenterol Rep. 2009;11(1):50-5.
3. Lomonaco R, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(5):1389-97.
4. Marchesini G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50(8):1844-50.
5. Wattacheril J, Chalasani N. Nonalcoholic fatty liver disease (NAFLD): is it really a serious condition? Hepatology. 2012;56(4):1580-4.
6. Wieckowska A, Feldstein AE. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Semin Liver Dis. 2008;28(4):386-95.
7. Lominadze Z, et al. Survey of diagnostic and treatment patterns of NAFLD and NASH in the United States: real life practices differ from published guidelines. Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) 2014; November 7-11, 2014; Boston, Massachusetts. Abstract 838.
8. Chalasani N, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592-609.
9. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274-85.
10. Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387-95.
11. Williams CD, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124-31.
12. Boza C, et al. Predictors of nonalcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg. 2005;15(8):1148-53.
13. Cusi K. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2009;16(2):141-9.
14. Lomonaco R, et al. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs. 2013;73(1):1-14.
15. Assy N, et al. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45(10):1929-34.
16. Smits MM, et al. Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups. J Gastroenterol Hepatol. 2013;28(4):664-70.
17. Kallwitz ER, et al. The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients. Am J Gastroenterol. 2009;104(1):64-9.
18. Lomonaco R, et al. Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis. Hepatology. 2011;54(3):837-45.
19. Fraser A, Longnecker MP, Lawlor DA. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999-2004. Gastroenterology. 2007;133(6):1814-20.
20. Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance? Hepatology. 2010;51(2):373-5.
21. Eksted M, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44(4):865-73.
22. Ertle J, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 2011;128(10):2436-43.
23. Rafiq N, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234-8.
24. Ekstedt M, 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):1547-54.
25. Wong VW, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59(7):969-74.
26. Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):545-63.
27. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142(4):711-725 e6.
28. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998;114(4):842-5.
29. Wolfs MG, et al. Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity. Nutr Diabetes. 2015;5:e146.
30. Hubscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathology. 2006;49(5):450-65.
31. Toshikuni N, Tsutsumi M, Arisawa A. Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(26):8393-406.
32. Allen JP, et al. Assessing the drinking status of liver transplant patients with alcoholic liver disease. Liver Transpl. 2013;19(4):369-76.
33. Matteoni CA, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-9.
34. Marcos A, et al. Selection and outcome of living donors for adult to adult right lobe transplantation. Transplantation. 2000;69(11):2410-5.
35. Sanyal AJ, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344-53.
36. Brunt EM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467-74.
37. Kleiner DE, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-21.
38. Brunt EM, et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810-20.
39. Juluri R, et al. Generalizability of the nonalcoholic steatohepatitis Clinical Research Network histologic scoring system for nonalcoholic fatty liver disease. J Clin Gastroenterol. 2011;45(1):55-8.
40. Park HN, et al. Upper normal threshold of serum alanine aminotransferase in identifying individuals at risk for chronic liver disease. Liver Int. 2012;32(6):937-44.
41. Chalasani N, 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(6):2005-23.
42. Alkhouri N, McCullough AJ. Noninvasive diagnosis of NASH and liver fibrosis within the spectrum of NAFLD. Gastroenterol Hepatol (N Y). 2012;8(10):661-8.
43. Pearce SG, Thosani NC, Pan JJ. Noninvasive biomarkers for the diagnosis of steatohepatitis and advanced fibrosis in NAFLD. Biomark Res. 2013;1(1):7.
44. Aida Y, et al. Serum cytokeratin 18 fragment level as a noninvasive biomarker for non-alcoholic fatty liver disease. Int J Clin Exp Med. 2014;7(11):4191-8.
45. Kwok R, et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease-the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther. 2014;39(3):254-69.
46. Tamim TI, et al. An apoptosis panel for nonalcoholic steatohepatitis diagnosis. J Hepatol. 2011;54(6):1224-9.
47. Younossi ZM, et al. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg. 2011;21(4):431-9.
48. Ratziu V, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898-906.
49. Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-54.
50. Ratziu V, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118(6):1117-23.
51. Guha IN, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47(2):455-60.
52. Szczepaniak LS, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288(2):E462-8.
53. Noureddin M, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology. 2013;58(6):1930-40.
54. Huwart L, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135(1):32-40.
55. Yoneda M, et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 2007;56(9):1330-1.
56. Friedrich-Rust M, et al. Transient elastography with a new probe for obese patients for non-invasive staging of non-alcoholic steatohepatitis. Eur Radiol. 2010;20(10):2390-6.
57. Ripoll C, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-8.
58. Thalheimer U, et al. Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients. Dig Liver Dis. 2005;37(8):601-8.
59. Abraldes JG, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37(4):902-8.
60. D'Amico G, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131(5):1611-24.
61. Sanyal AJ, et al. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases (AASLD) - food and drug administration (FDA) joint workshop. Hepatology. 2015;61(4):1392-405.
62. Andersen T, et al. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12(2):224-9.
63. Ueno T, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27(1):103-7.
64. Larson-Meyer DE, et al. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care. 2006;29(6):1337-44.
65. Westerbacka J, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab. 2005;90(5):2804-9.
66. Lazo M, et al. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care. 2010;33(10):2156-63.
67. Thamer C, et al. High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention. Obesity (Silver Spring). 2007;15(2):531-8.
68. Musso G, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52(1):79-104.
69. Harrison SA, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49(1):80-6.
70. Clark JM. Weight loss as a treatment for nonalcoholic fatty liver disease. J Clin Gastroenterol. 2006;40:S39-43.
71. Wierzbicki AS, et al. Rimonabant improves cholesterol, insulin resistance and markers of non-alcoholic fatty liver in morbidly obese patients: a retrospective cohort study. Int J Clin Pract. 2011;65(6):713-5.
72. Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoid signaling and liver therapeutics. J Hepatol. 2013;59(4):891-6.
73. Sasaki A, et al. Bariatric surgery and non-alcoholic Fatty liver disease: current and potential future treatments. Front Endocrinol (Lausanne). 2014;5(164):1-6.
74. Mathurin P, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137(2):532-40.
75. Chavez-Tapia NC, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010; (1):(CD007340) 1-30.
76. Belfort R, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297-307.
77. Promrat K, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39(1):188-96.
78. Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-85.
79. Ratziu V, 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(1):100-10.
80. Chalasani N, 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(6):811-26.
81. Samson SL, et al. Gene therapy for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. Mol Ther. 2008;16(11):1805-12.
82. Ding X, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43(1):173-81.
83. Klonoff DC, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275-86.
84. Vilsboll T, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.
85. Sathyanarayana P, et al. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring). 2011;19(12):2310-5.
86. Shirakawa J, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes. 2011;60(4):1246-57.
87. Iwasaki T, et al. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology. 2011;58(112):2103-5.
88. Cholesterol Treatment Trialists' (CTT) collaborators. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376(9753):1670-81.
89. Eslami L, et al. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623.
90. Athyros VG, 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 Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376(9756):1916-22.
91. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids - a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;31(7):679-92.
92. Sanyal AJ, et al. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147(2):377-84 e1.
93. Harrison SA, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98(11):2485-90.
94. Kugelmas M, et al. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38(2):413-9.
95. Miller ER, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46.
96. Lavine JE, 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(16):1659-68.
97. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today. 2012;17(17-18):988-97.
98. Neuschwander-Tetri BA, 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.
99. Raptor Pharmaceutical announces phase 2a NASH study meets primary endpoints: results released at Digestive Disease Week conference. PR. http://ir.raptorpharma.com/releasedetail.cfm?releaseid=633914. Accessed 9 Apr 2015.
100. New proof of efficacy of GFT505 in NASH and positive expert opinion. PR. http://www.genfit.com/wp-content/uploads/2015/04/2015.04.24-PR-GENFIT-EASL-Minutes.pdf. Accessed 19 June 2015.
101. Talal AH, et al. Simtuzumab, an antifibrotic monoclonal antibody against lysyl oxidase-like 2 (loxl2) enzyme, appears safe and well tolerated in patients with liver disease of diverse etiology. J Hepatol. 2013;58(Suppl 1):S532.
102. Safadi R, 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):2085-91 e1.
103. Armstrong MJ, et al. Glucagon like peptide 1 analogue, Liraglutide, reduces adipose insulin resistance and hepatic de novo lipogenesis in Nonalcoholic Steatohepatitis: sub-study results of a phase II randomised-control clinical trial. In: 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC 2013. November 1-5: Abstract 562.
104. Armstrong MJ, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37(2):234-42.
105. Shiffman M, et al. A placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J Hepatol. 2015;62:S282.
106. Thomson M, et al. Improvements in APRI and FIB-4 fibrosis scores correlate with decreases in sCD14 in HIV-1 infected adults receiving cenicriviroc over 48 weeks. Hepatology. 2014;60(S1):424A.
107. Wilkison W, Cheatham B, Walker S. Remogliflozin etabonate reduces insulin resistance and liver function enzymes: role for treatment of NASH. J Hepatol. 2015;62:S211.
108. Guidance for Industry. Expedited Programs for Serious Conditions - Drugs and Biologics. Food and Drug Administration; 2014.
109. Eichler HG, et al. From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients. Clin Pharmacol Ther. 2015;97(3):234-46.
110. Baird LG, et al. Accelerated access to innovative medicines for patients in need. Clin Pharmacol Ther. 2014;96(5):559-71.
111. Intercept receives breakthrough therapy designation from FDA for obeticholic acid for nonalcoholic steatohepatitis (NASH) with liver fibrosis. http://ir.interceptpharma.com/releasedetail.cfm?releaseid=893699. Accessed 20 Apr 2015.
112. Guidance for Industry. Adaptive design clinical trials for drugs and biologics. Food and Drug Administration; 2010.
113. Enrichment strategies for clinical trials to support approval of human drugs and biological products. Guidance for Industry; 2012.
114. Parekh A, et al. Catalyzing the critical path initiative: FDA's progress in drug development activities. Clin Pharmacol Ther. 2015;97(3):221-33.
115. NASH drugs soon may have a registrational pathway, finally. The Pink Sheet, 30 Mar 2015.
116. Sanyal AJ, et al. Trial designs and endpoints for liver disease secondary to nonalcoholic fatty liver disease (NAFLD). In: AASLD/FDA Workshop 2013. September 5-6. FDA White Oak Campus. Silver Spring.
117. Alaaeddine N, et al. TNF-alpha messenger ribonucleic acid (mRNA) in patients with nonalcoholic steatohepatitis. Eur Cytokine Netw. 2012;23(3):107-11.
118. Tarantino G, et al. Could inflammatory markers help diagnose nonalcoholic steatohepatitis? Eur J Gastroenterol Hepatol. 2009;21(5):504-11.
119. Fierbinteanu-Braticevici C, et al. Predictive factors for nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). J Gastrointestin Liver Dis. 2011;20(2):153-9.
120. Manousou P, et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int. 2011;31(5):730-9.
121. Shimada M, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol. 2007;102(9):1931-8.
122. Wieckowska A, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44(1):27-33.
123. Sakugawa H, et al. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World J Gastroenterol. 2005;11(2):255-9.
124. Lydatakis H, et al. Non-invasive markers to predict the liver fibrosis in non-alcoholic fatty liver disease. Liver Int. 2006;26(7):864-71.
125. Shah AG, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-12.
126. Obika M, Noguchi H. Diagnosis and evaluation of nonalcoholic fatty liver disease. Exp Diabetes Res. 2012;2012:145754.
127. Ratziu V, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:6.
128. Intercept pharmaceuticals announces pivotal phase 3 clinical trial of obeticholic acid in NASH. http://files.shareholder.com/downloads/AMDA-1AUOV7/200272109x0x830355/0913035A-93C6-4748-9F9C-D3A4879C09A4/ICPT-News-2015-5-19-General-Releases.pdf. Accessed 25 May 2015.
129. Topline PhIIb results: conference call and webcast transcript. http://www.genfit.com/wp-content/uploads/2015/03/Topline-Phase-2b-results-TC-Transcript.pdf. Accessed 9 Apr 2015.