Non-alcoholic fatty liver disease: time for changes

Main Article Content

T.I. Yefimenko
M.R. Mykytyuk

Abstract

The review contains updated information on the epidemiology, etiology, pathogenesis, diagnosis, treatment and prevention of non-alcoholic fatty liver disease (NAFLD). We searched for terms including NAFLD, non-alcoholic steatohepatitis (NASH), metabolic syndrome and type 2 diabetes mellitus in literature published over the past 5 years using the Scopus, Web of Science, CyberLeninka, PubMed databases. The concept of NAFLD includes two morphological forms of the disease with different prognosis: non-alcoholic fatty hepatosis and NASH. The severity of NASH is quite variable, including fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD, a spectrum of fatty liver disorders of viral, autoimmune, drug-induced, and genetic origin, which are not caused by alcohol abuse, has recently been renamed as metabolic (dysfunction) associated fatty liver disease (MAFLD). The average prevalence of NAFLD is approximately 25 % among the adult population worldwide, and in some regions exceeds 30 %. An increase in the prevalence of this pathology is in parallel with the global epidemic of obesity and type 2 diabetes mellitus in the world. It is time to reach a general consensus in the scientific community on changing the nomenclature and moving from a negative to a positive definition of NAFLD/NASH. The new nomenclature points to the “positive” determinants of the disease, namely the close relationship with metabolic disorders, instead of defining it as what it is not (ie. non-alcoholic). The MAFLD abbreviation more accurately discloses existing knowledge about fatty liver diseases associated with metabolic dysfunction and should replace NAFLD/NASH, as this will stimulate the research community’s efforts to update the disease nomenclature and subphenotype and accelerate the transition to new treatments. It is important that primary care physicians, endocrinologists, and other specialists are aware of the extent and long-term consequences of NAFLD. Early identification of patients with NASH can help improve treatment outcomes, avoid liver transplantation in patients with decompensated cirrhosis. There are currently no effective treatments for NAFLD, so it is important to follow a multidisciplinary approach, which means using measures to improve prognosis, reduce the risk of death associated with NAFLD, the development of cirrhosis or hepatocellular carcinoma. Epidemiological data suggest a close relationship between unhealthy lifestyles and NAFLD, so lifestyle adjustments are needed to all patients. Insulin sensitizers, statins, ezetimibe, a cholesterol absorption inhibitor, hepatoprotectors, antioxidants, incretin analogues, dipeptidyl peptidase 4 inhibitors, pentoxifylline, probiotics, angiotensin-converting enzyme inhibitors, and endocannabinoid antagonists are used in the treatment of NAFLD.

Article Details

How to Cite
Yefimenko, T., and M. Mykytyuk. “Non-Alcoholic Fatty Liver Disease: Time for Changes”. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), vol. 17, no. 4, Sept. 2021, pp. 334-45, doi:10.22141/2224-0721.17.4.2021.237350.
Section
Literature Review

References

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. Obes Facts. 2016;9(2):65-90. doi:10.1159/000443344.

Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver Int. 2017 Jan;37 Suppl 1:85-89. doi:10.1111/liv.13301.

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018 Jul;24(7):908-922. doi:10.1038/s41591-018-0104-9.

Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020 May;158(7):1999-2014.e1. doi:10.1053/j.gastro.2019.11.312.

Choi HSJ, Brouwer WP, Zanjir WMR, et al. Nonalcoholic Steatohepatitis Is Associated With Liver-Related Outcomes and All-Cause Mortality in Chronic Hepatitis B. Hepatology. 2020 Feb;71(2):539-548. doi:10.1002/hep.30857.

Brunt EM, Ramrakhiani S, Cordes BG, et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol. 2003 Jan;16(1):49-56. doi:10.1097/01.MP.0000042420.21088.C7.

Bellentani S, Tiribelli C. Is it time to change NAFLD and NASH nomenclature? Lancet Gastroenterol Hepatol. 2017 Aug;2(8):547-548. doi:10.1016/S2468-1253(17)30146-2.

Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019 Apr;156(5):1264-1281.e4. doi:10.1053/j.gastro.2018.12.036.

Younossi Z, Tacke F, Arrese M, et al. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology. 2019 Jun;69(6):2672-2682. doi:10.1002/hep.30251.

Fiorucci S, Biagioli M, Distrutti E. Future trends in the treatment of non-alcoholic steatohepatitis. Pharmacol Res. 2018 Aug;134:289-298. doi:10.1016/j.phrs.2018.07.014.

Pankiv VI, Yuzvenko TYu, Pashkovska NV, Pankiv IV. Effect of vitamin D on insulin resistance and anthropometric parameters in patients with type 2 diabetes mellitus. Clinical Endocrinology and Endocrine Surgery. 2019;1(65):53-58. doi:10.30978/CEES-2019-1-53.

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 Aug;34(3):274-85. doi:10.1111/j.1365-2036.2011.04724.x.

Younossi ZM, Stepanova M, Negro F, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore). 2012 Nov;91(6):319-327. doi:10.1097/MD.0b013e3182779d49.

Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006 Oct;118(4):1388-93. doi:10.1542/peds.2006-1212.

Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015 Jun 9;313(22):2263-73. doi:10.1001/jama.2015.5370.

Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020 May;158(7):1851-1864. doi:10.1053/j.gastro.2020.01.052.

Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019 Oct;71(4):793-801. doi:10.1016/j.jhep.2019.06.021.

Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980 Jul;55(7):434-8.

Lazo M, Clark JM. Nonalcoholic fatty liver disease and type 2 diabetes: a burgeoning problem with unclear solutions. Hepatobiliary Surg Nutr. 2020 Aug;9(4):514-517. doi:10.21037/hbsn.2019.11.28.

Frerichs FT. A Clinical Treatise on Diseases of the Liver, Part 2. London: New Syden Soc; 1861. 584p.

Pankiv VI. Diabetes Mellitus Type 2 and Non-alcoholic Fatty Liver Disease, The Effects of Metformin. Mìžnarodnij endokrinologìčnij žurnal. 2013;5:55-63. doi:10.22141/2224-0721.5.53.2013.84493. (in Russian).

Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006 Oct;44(4):865-73. doi:10.1002/hep.21327.

White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012 Dec;10(12):1342-1359.e2. doi:10.1016/j.cgh.2012.10.001.

Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi:10.1002/hep.29367.

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 May;61(5):1547-54. doi:10.1002/hep.27368.

Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015 Aug;149(2):389-97.e10. doi:10.1053/j.gastro.2015.04.043.

Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017 May;65(5):1557-1565. doi:10.1002/hep.29085.

Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015 Apr;13(4):643-54.e1-9; quiz e39-40. doi:10.1016/j.cgh.2014.04.014.

Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007 Apr;45(4):846-54. doi:10.1002/hep.21496.

Sørensen HT, Mellemkjaer L, Jepsen P, et al. Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study. J Clin Gastroenterol. 2003 Apr;36(4):356-9. doi:10.1097/00004836-200304000-00015.

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 May;62(5):1148-55. doi:10.1016/j.jhep.2014.11.034.

Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010 May;51(5):1820-32. doi:10.1002/hep.23594.

Yasui K, Hashimoto E, Komorizono Y, et al; Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011 May;9(5):428-33; quiz e50. doi:10.1016/j.cgh.2011.01.023.

White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012 Dec;10(12):1342-1359.e2. doi:10.1016/j.cgh.2012.10.001.

Milić S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis. 2012;30(2):158-62. doi:10.1159/000336669.

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 Jun;55(6):2005-23. doi:10.1002/hep.25762.

Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ. 2010 Aug 10;182(11):E526-31. doi:10.1503/cmaj.092144.

Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000 Jul;106(2):171-6. doi:10.1172/JCI10583.

Ciupińska-Kajor M, Hartleb M, Kajor M, et al. Hepatic angiogenesis and fibrosis are common features in morbidly obese patients. Hepatol Int. 2013 Mar;7(1):233-40. doi:10.1007/s12072-011-9320-9.

National Guideline Centre (UK). Non-Alcoholic Fatty Liver Disease: Assessment and Management. London: National Institute for Health and Care Excellence (UK); 2016 Jul.

World Gastroenterology Organisation Global Guidelines. Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. 2012 Jun.

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51. doi:10.1172/JCI23621.

Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clin Med (Lond). 2018 Jun;18(3):245-250. doi:10.7861/clinmedicine.18-3-245.

Jelenik T, Kaul K, Séquaris G, et al. Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver. Diabetes. 2017 Aug;66(8):2241-2253. doi:10.2337/db16-1147.

Finck BN. Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis. Diabetes. 2018 Dec;67(12):2485-2493. doi:10.2337/dbi18-0024.

Kobyliak NM, Abenavoli L, Pavlenko GP, Komisarenko YuI. Gut microbiota composition changes associated with obesity: new lights from metagenomic analysis. Mìžnarodnij endokrinologìčnij žurnal. 2020;16(8):78-85. doi:10.22141/2224-0721.16.8.2020.222886.

Greco D, Kotronen A, Westerbacka J, et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1281-7. doi:10.1152/ajpgi.00074.2008.

Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15430-5. doi:10.1073/pnas.0904944106.

Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008 Nov;28(4):370-9. doi:10.1055/s-0028-1091981.

Jiang W, Wu N, Wang X, et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep. 2015 Feb 3;5:8096. doi:10.1038/srep08096.

Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev. 2008 Sep;60(3):311-57. doi:10.1124/pr.108.00001.

Ramadori G, Armbrust T. Cytokines in the liver. Eur J Gastroenterol Hepatol. 2001 Jul;13(7):777-84. doi:10.1097/00042737-200107000-00004.

Torisu T, Sato N, Yoshiga D, et al. The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells. 2007 Feb;12(2):143-54. doi:10.1111/j.1365-2443.2007.01044.x.

Shao RX, Zhang L, Peng LF, et al, Hyppolite G, Chung RT. Suppressor of cytokine signaling 3 suppresses hepatitis C virus replication in an mTOR-dependent manner. J Virol. 2010 Jun;84(12):6060-9. doi:10.1128/JVI.02484-09.

Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018 Feb;14(2):99-114. doi:10.1038/nrendo.2017.173.

Tarantino G, Finelli C. What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? World J Gastroenterol. 2013 Jun 14;19(22):3375-84. doi:10.3748/wjg.v19.i22.3375.

Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. ScientificWorldJournal. 2013;2013:481893. doi:10.1155/2013/481893.

Targher G, Bertolini L, Rodella S, et al. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring). 2008 Jun;16(6):1394-9. doi:10.1038/oby.2008.64.

Milner KL, van der Poorten D, Xu A, et al. Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease. Hepatology. 2009 Jun;49(6):1926-34. doi:10.1002/hep.22896.

Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003 Jun;37(6):1286-92. doi:10.1053/jhep.2003.50229.

Musso G, Gambino R, Cassader M. Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev. 2010 Jun;11(6):430-45. doi:10.1111/j.1467-789X.2009.00657.x.

Milić S, Lulić D, Štimac D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World J Gastroenterol. 2014 Jul 28;20(28):9330-7. doi:10.3748/wjg.v20.i28.9330.

Monsour HP Jr, Frenette CT, Wyne K. Fatty liver: a link to cardiovascular disease--its natural history, pathogenesis, and treatment. Methodist Debakey Cardiovasc J. 2012 Jul-Sep;8(3):21-5. doi:10.14797/mdcj-8-3-21.

Abiru S, Migita K, Maeda Y, et al. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int. 2006 Feb;26(1):39-45. doi:10.1111/j.1478-3231.2005.01191.x.

Italian Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig Liver Dis. 2017 May;49(5):471-483. doi:10.1016/j.dld.2017.01.147.

Glen J, Floros L, Day C, Pryke R; Guideline Development Group. Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance. BMJ. 2016 Sep 7;354:i4428. doi:10.1136/bmj.i4428.

Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357. doi:10.1002/hep.29367.

Portillo-Sanchez P, Bril F, Maximos M, et al. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015 Jun;100(6):2231-8. doi:10.1210/jc.2015-1966.

National Guideline Centre (UK). Non-Alcoholic Fatty Liver Disease: Assessment and Management. London: National Institute for Health and Care Excellence (UK); 2016 Jul.

Kleiner DE, Brunt EM, Van Natta M, et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. doi:10.1002/hep.20701.

Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012 Nov;56(5):1751-9. doi:10.1002/hep.25889.

Kleiner DE, Makhlouf HR. Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children. Clin Liver Dis. 2016 May;20(2):293-312. doi:10.1016/j.cld.2015.10.011.

Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003 Dec;29(12):1705-13. doi:10.1016/j.ultrasmedbio.2003.07.001.

Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. ScientificWorldJournal. 2013;2013:481893. doi:10.1155/2013/481893.

Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010 Mar;51(3):828-35. doi:10.1002/hep.23425.

Wong GL, Wong VW, Chim AM, et al. Factors associated with unreliable liver stiffness measurement and its failure with transient elastography in the Chinese population. J Gastroenterol Hepatol. 2011 Feb;26(2):300-5. doi:10.1111/j.1440-1746.2010.06510.x.

Bonder A, Tapper EB, Afdhal NH. Contemporary assessment of hepatic fibrosis. Clin Liver Dis. 2015 Feb;19(1):123-34. doi:10.1016/j.cld.2014.09.007.

Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E462-8. doi:10.1152/ajpendo.00064.2004.

Bonekamp S, Tang A, Mashhood A, et al. Spatial distribution of MRI-Determined hepatic proton density fat fraction in adults with nonalcoholic fatty liver disease. J Magn Reson Imaging. 2014 Jun;39(6):1525-32. doi:10.1002/jmri.24321.

Caussy C, Reeder SB, Sirlin CB, Loomba R. Noninvasive, Quantitative Assessment of Liver Fat by MRI-PDFF as an Endpoint in NASH Trials. Hepatology. 2018 Aug;68(2):763-772. doi:10.1002/hep.29797.

Gu J, Liu S, Du S, et al. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur Radiol. 2019 Jul;29(7):3564-3573. doi:10.1007/s00330-019-06072-4.

Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006 Nov 2;6:33. doi:10.1186/1471-230X-6-33.

Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009 Sep;137(3):865-72. doi:10.1053/j.gastro.2009.06.005.

Lee JH, Kim D, Kim HJ, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010 Jul;42(7):503-8. doi:10.1016/j.dld.2009.08.002.

Amato MC, Giordano C, Galia M, et al; AlkaMeSy Study Group. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010 Apr;33(4):920-2. doi:10.2337/dc09-1825.

Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V; LIDO Study Group. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2014 Nov;40(10):1209-22. doi:10.1111/apt.12963.

Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001 Jul;121(1):91-100. doi:10.1053/gast.2001.25540.

Byrne CD, Patel J, Scorletti E, Targher G. Tests for diagnosing and monitoring non-alcoholic fatty liver disease in adults. BMJ. 2018 Jul 12;362:k2734. doi:10.1136/bmj.k2734.

Lichtinghagen R, Pietsch D, Bantel H, Manns MP, Brand K, Bahr MJ. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013 Aug;59(2):236-42. doi:10.1016/j.jhep.2013.03.016.

NAFLD fibrosis score. Online calculator. Available from: https://nafldscore.com .

Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011 Dec;43(8):617-49. doi:10.3109/07853890.2010.518623.

Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007 Aug;46(2):582-9. doi:10.1002/hep.21768.

Zelber-Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol. 2011 Aug 7;17(29):3377-89. doi:10.3748/wjg.v17.i29.3377.

Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005 Mar;54(3):603-8. doi:10.2337/diabetes.54.3.603.

Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015 Aug;149(2):367-78.e5; quiz e14-5. doi:10.1053/j.gastro.2015.04.005.

Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005 Jan;42(1):132-8. doi:10.1016/j.jhep.2004.09.012.

Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L; American Association for the Study of Liver Diseases; United States Food and Drug Administration. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology. 2015 Apr;61(4):1392-405. doi:10.1002/hep.27678.

Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017 Sep 28;23(36):6549-6570. doi:10.3748/wjg.v23.i36.6549.

Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009 Jan;29(2):172-82. doi:10.1111/j.1365-2036.2008.03869.x.

Haukeland JW, Konopski Z, Eggesbø HB, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853-60. doi:10.1080/00365520902845268.

Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004 Sep 9;351(11):1106-18. doi:10.1056/NEJMra041001.

Bajaj M, Suraamornkul S, Piper P, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab. 2004 Jan;89(1):200-6. doi:10.1210/jc.2003-031315.

Agarwal B, Lamba BMS, Sharma N, Tanwar M. Prevalence of non-alcoholic fatty liver disease in patients with prediabetes. Mìžnarodnij endokrinologìčnij žurnal. 2021;17(1):35-40. doi:10.22141/2224-0721.17.1.2021.226427.

Ratziu V, Giral P, Jacqueminet S, et al; LIDO Study Group. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008 Jul;135(1):100-10. doi:10.1053/j.gastro.2008.03.078.

Sanyal AJ, Chalasani N, Kowdley KV, et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675-85. doi:10.1056/NEJMoa0907929.

Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. doi:10.7326/0003-4819-142-1-200501040-00110.

Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006 Oct;26(8):1015-7. doi:10.1111/j.1478-3231.2006.01315.x.

Balaban YH, Korkusuz P, Simsek H, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007 Oct-Dec;6(4):242-50.

Firneisz G, Varga T, Lengyel G, et al. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One. 2010 Aug 18;5(8):e12226. doi:10.1371/journal.pone.0012226.

Baumeier C, Saussenthaler S, Kammel A, et al. Hepatic DPP4 DNA Methylation Associates With Fatty Liver. Diabetes. 2017 Jan;66(1):25-35. doi:10.2337/db15-1716.

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 Jun;23(6):1464-7. doi:10.1002/hep.510230624.

Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999 Aug;31(2):384. doi:10.1016/s0168-8278(99)80243-8.

Duman DG, Ozdemir F, Birben E, et al. Effects of pentoxifylline on TNF-alpha production by peripheral blood mononuclear cells in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2007 Oct;52(10):2520-4. doi:10.1007/s10620-006-9723-y.

Van Wagner LB, Koppe SW, Brunt EM, et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011 Jul-Sep;10(3):277-86.

Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015 Nov;62(5):1417-32. doi:10.1002/hep.27999.

Shiffman M, Freilich B, Vuppalanchi R, 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 Jan;49(1):64-73. doi:10.1111/apt.15030.

Ratziu V, Harrison SA, Francque S, et al; GOLDEN-505 Investigator Study Group. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.e5. doi:10.1053/j.gastro.2016.01.038.

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 Mar;47:356-65. doi:10.1016/j.cct.2016.02.012.

Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Mar 14;385(9972):956-65. doi:10.1016/S0140-6736(14)61933-4.

Inagaki T. Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD. Front Endocrinol (Lausanne). 2015 Sep 23;6:147. doi:10.3389/fendo.2015.00147.

Safadi R, Konikoff FM, Mahamid M, et al; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014 Dec;12(12):2085-91.e1. doi:10.1016/j.cgh.2014.04.038.

Safety and Efficacy of Simtuzumab (SIM, GS-6624) in Adults With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH). ClinicalTrials.gov Identifier: NCT01672866. March 27, 2019.

Colak Y, Ozturk O, Senates E, et al. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit. 2011 May;17(5):HY5-9. doi:10.12659/msm.881749.

Stephen S, Baranova A, Younossi ZM. Nonalcoholic fatty liver disease and bariatric surgery. Expert Rev Gastroenterol Hepatol. 2012 Apr;6(2):163-71. doi:10.1586/egh.11.97.

Charlton M, Kasparova P, Weston S, et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001 Jul;7(7):608-14. doi:10.1053/jlts.2001.25453.