Generic placeholder image

Current Hypertension Reviews

Editor-in-Chief

ISSN (Print): 1573-4021
ISSN (Online): 1875-6506

Review Article

Nonalcoholic Fatty Liver Disease (NAFLD) for Primary Care Providers: Beyond the Liver

Author(s): Eddison Godinez-Leiva and Fernando Bril*

Volume 17, Issue 2, 2021

Published on: 09 December, 2020

Page: [94 - 111] Pages: 18

DOI: 10.2174/1573402116999201209203534

Price: $65

Abstract

Nonalcoholic fatty liver disease (NAFLD) has consolidated as a major public health problem, affecting ~25% of the global population. This percentage is significantly higher in the setting of obesity and/or type 2 diabetes. The presence of NAFLD is associated with severe liver complications, such as nonalcoholic steatohepatitis (NASH; i.e., presence of inflammation and necrosis), cirrhosis and hepatocellular carcinoma. However, the majority of these patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team, where primary care providers are at center stage. However, important misconceptions remain among primary care providers, preventing them from appropriately approach these patients. Nonalcoholic fatty liver disease should be understood as part of a systemic disease characterized for abnormal accumulation of fat in tissues other than the adipose tissue. This, in turn, produces dysfunction of those organs or tissues (process sometimes referred to as lipotoxicity). Therefore, due to the systemic nature of this condition, it should not surprise that NAFLD is closely related to other metabolic conditions. This review will focus on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications. We believe these are the most important issues primary care providers should understand in order to effectively manage these complicated patients. In addition, we have provided a simple and straightforward approach to the diagnosis and treatment of patients with NAFLD and/or NASH. We hope this review will serve as a guide for primary care providers to approach their patients with NAFLD.

Keywords: NAFLD, steatohepatitis, NASH, T2DM, insulin resistance, liver.

Graphical Abstract
[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.
[http://dx.doi.org/10.1002/hep.28431] [PMID: 26707365]
[2]
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; 71(4): 793-801.
[http://dx.doi.org/10.1016/j.jhep.2019.06.021] [PMID: 31279902]
[3]
Rinella ME, Lominadze Z, Loomba R, et al. Practice patterns in NAFLD and NASH: real life differs from published guidelines. Therap Adv Gastroenterol 2016; 9(1): 4-12.
[http://dx.doi.org/10.1177/1756283X15611581] [PMID: 26770262]
[4]
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. Diabetologia 2016; 59(6): 1121-40.
[http://dx.doi.org/10.1007/s00125-016-3902-y] [PMID: 27053230]
[5]
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; 67(1): 328-57.
[http://dx.doi.org/10.1002/hep.29367] [PMID: 28714183]
[6]
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018; 67(1): 123-33.
[http://dx.doi.org/10.1002/hep.29466] [PMID: 28802062]
[7]
Wang C, Wang X, Gong G, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer 2012; 130(7): 1639-48.
[http://dx.doi.org/10.1002/ijc.26165] [PMID: 21544812]
[8]
Mittal S, Sada YH, El-Serag HB, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015; 13: 601-591.
[http://dx.doi.org/10.1016/j.cgh.2014.08.013]
[9]
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014; 59(6): 2188-95.
[http://dx.doi.org/10.1002/hep.26986] [PMID: 24375711]
[10]
Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148(3): 547-55.
[http://dx.doi.org/10.1053/j.gastro.2014.11.039] [PMID: 25461851]
[11]
Setiawan VW, Stram DO, Porcel J, Lu SC, Le Marchand L, Noureddin M. Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: The multiethnic cohort. Hepatology 2016; 64(6): 1969-77.
[http://dx.doi.org/10.1002/hep.28677] [PMID: 27301913]
[12]
Bril F, Barb D, Portillo-Sanchez P, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology 2017; 65(4): 1132-44.
[http://dx.doi.org/10.1002/hep.28985] [PMID: 27981615]
[13]
Park SK, Seo MH, Shin HC, Ryoo JH. Clinical availability of nonalcoholic fatty liver disease as an early predictor of type 2 diabetes mellitus in Korean men: 5-year prospective cohort study. Hepatology 2013; 57(4): 1378-83.
[http://dx.doi.org/10.1002/hep.26183] [PMID: 23213066]
[14]
Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 2009; 104(4): 861-7.
[http://dx.doi.org/10.1038/ajg.2009.67] [PMID: 19293782]
[15]
Bae JC, Rhee EJ, Lee WY, et al. Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes: a 4-year retrospective longitudinal study. Diabetes Care 2011; 34(3): 727-9.
[http://dx.doi.org/10.2337/dc10-1991] [PMID: 21278140]
[16]
Bril F, Sninsky JJ, Baca AM, et al. Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin Endocrinol Metab 2016; 101(2): 644-52.
[http://dx.doi.org/10.1210/jc.2015-3111] [PMID: 26672634]
[17]
Siddiqui MS, Fuchs M, Idowu MO, et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol 2015; 13: 1000-8.
[http://dx.doi.org/10.1016/j.cgh.2014.10.008]
[18]
Zhao YC, Zhao GJ, Chen Z, She ZG, Cai J, Li H. Nonalcoholic fatty liver disease: An emerging driver of hypertension. Hypertension 2020; 75(2): 275-84.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13419] [PMID: 31865799]
[19]
Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: A call to action. Diabetes Care 2017; 40(3): 419-30.
[http://dx.doi.org/10.2337/dc16-1787] [PMID: 28223446]
[20]
Bril F, Cusi K. Nonalcoholic fatty liver disease: The new complication of type 2 diabetes mellitus. Endocrinol Metab Clin North Am 2016; 45(4): 765-81.
[http://dx.doi.org/10.1016/j.ecl.2016.06.005] [PMID: 27823604]
[21]
Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30(5): 1212-8.
[http://dx.doi.org/10.2337/dc06-2247] [PMID: 17277038]
[22]
Chang Y, Jung HS, Yun KE, Cho J, Cho YK, Ryu S. Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol 2013; 108(12): 1861-8.
[http://dx.doi.org/10.1038/ajg.2013.349] [PMID: 24100261]
[23]
Sung KC, Seo DC, Lee SJ, Lee MY, Wild SH, Byrne CD. Non alcoholic fatty liver disease and risk of incident diabetes in subjects who are not obese. Nutr Metab Cardiovasc Dis 2019; 29(5): 489-95.
[http://dx.doi.org/10.1016/j.numecd.2019.01.016] [PMID: 30940491]
[24]
Alexander M, Loomis AK, van der Lei J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med 2019; 17(1): 95.
[http://dx.doi.org/10.1186/s12916-019-1321-x] [PMID: 31104631]
[25]
Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 2008; 51(11): 1947-53.
[http://dx.doi.org/10.1007/s00125-008-1135-4] [PMID: 18762907]
[26]
Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007; 30(8): 2119-21.
[http://dx.doi.org/10.2337/dc07-0349] [PMID: 17519430]
[27]
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016; 65(3): 589-600.
[http://dx.doi.org/10.1016/j.jhep.2016.05.013] [PMID: 27212244]
[28]
Khan RS, Bril F, Cusi K, Newsome PN. Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology 2019; 70(2): 711-24.
[http://dx.doi.org/10.1002/hep.30429] [PMID: 30556145]
[29]
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010; 52(2): 774-88.
[http://dx.doi.org/10.1002/hep.23719] [PMID: 20683968]
[30]
Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012; 142: 711-25.
[http://dx.doi.org/10.1053/j.gastro.2012.02.003]
[31]
Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016; 65(8): 1049-61.
[http://dx.doi.org/10.1016/j.metabol.2016.02.014] [PMID: 26997538]
[32]
Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]
[33]
Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377(7): 644-57.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]
[34]
Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375(4): 311-22.
[http://dx.doi.org/10.1056/NEJMoa1603827] [PMID: 27295427]
[35]
Marso SP, Bain SC, Consoli A, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375(19): 1834-44.
[http://dx.doi.org/10.1056/NEJMoa1607141] [PMID: 27633186]
[36]
Adams LA. Mortality in nonalcoholic fatty liver disease: clues from the Cremona study. Hepatology 2011; 54(1): 6-8.
[http://dx.doi.org/10.1002/hep.24445] [PMID: 21618568]
[37]
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; 65(5): 1557-65.
[http://dx.doi.org/10.1002/hep.29085] [PMID: 28130788]
[38]
Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol 2008; 103(9): 2263-71.
[http://dx.doi.org/10.1111/j.1572-0241.2008.02034.x] [PMID: 18684196]
[39]
Lazo M, Hernaez R, Bonekamp S, et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343: d6891.
[http://dx.doi.org/10.1136/bmj.d6891] [PMID: 22102439]
[40]
Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 2008; 49(4): 608-12.
[http://dx.doi.org/10.1016/j.jhep.2008.06.018] [PMID: 18682312]
[41]
Stepanova M, Rafiq N, Makhlouf H, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci 2013; 58(10): 3017-23.
[http://dx.doi.org/10.1007/s10620-013-2743-5] [PMID: 23775317]
[42]
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; 288(2): E462-8.
[http://dx.doi.org/10.1152/ajpendo.00064.2004] [PMID: 15339742]
[43]
Yang S, Kwak S, Lee JH, Kang S, Lee SP. Nonalcoholic fatty liver disease is an early predictor of metabolic diseases in a metabolically healthy population. PLoS One 2019; 14(11): e0224626.
[http://dx.doi.org/10.1371/journal.pone.0224626] [PMID: 31682638]
[44]
Bril F, Lomonaco R, Cusi K. The challenge of managing dyslipidemia in patients with nonalcoholic fatty liver disease. Clin Lipidol 2012; 7: 471-81.
[http://dx.doi.org/10.2217/clp.12.47]
[45]
Koehler EM, Plompen EP, Schouten JN, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study. Hepatology 2016; 63(1): 138-47.
[http://dx.doi.org/10.1002/hep.27981] [PMID: 26171685]
[46]
Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016; 65(8): 1096-108.
[http://dx.doi.org/10.1016/j.metabol.2016.01.001] [PMID: 26856933]
[47]
Doycheva I, Cui J, Nguyen P, et al. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther 2016; 43(1): 83-95.
[http://dx.doi.org/10.1111/apt.13405] [PMID: 26369383]
[48]
Lomonaco R, Bril F, Portillo-Sanchez P, et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 2016; 39(4): 632-8.
[http://dx.doi.org/10.2337/dc15-1876] [PMID: 26861926]
[49]
Bril F, Lomonaco R, Orsak B, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology 2014; 59(6): 2178-87.
[http://dx.doi.org/10.1002/hep.26988] [PMID: 24777953]
[50]
Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Järvinen H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 2008; 135(1): 122-30.
[http://dx.doi.org/10.1053/j.gastro.2008.03.021] [PMID: 18474251]
[51]
Kotronen A, Vehkavaara S, Seppälä-Lindroos A, Bergholm R, Yki-Järvinen H. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab 2007; 293(6): E1709-15.
[http://dx.doi.org/10.1152/ajpendo.00444.2007] [PMID: 17895288]
[52]
Najjar SM, Perdomo G. Hepatic insulin clearance: Mechanism and physiology. Physiology (Bethesda) 2019; 34(3): 198-215.
[http://dx.doi.org/10.1152/physiol.00048.2018] [PMID: 30968756]
[53]
Bril F, Cusi K. Hepatic insulin extraction in nafld is related to insulin resistance rather than liver fat content. J Clin Endocrinol Metab 2019; 104: 5249-50.
[http://dx.doi.org/10.1210/jc.2018-01808] [PMID: 30566676]
[54]
Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 2008; 31(Suppl. 2): S262-8.
[http://dx.doi.org/10.2337/dc08-s264] [PMID: 18227495]
[55]
Sung KC, Wild SH, Byrne CD. Development of new fatty liver, or resolution of existing fatty liver, over five years of follow-up, and risk of incident hypertension. J Hepatol 2014; 60(5): 1040-5.
[http://dx.doi.org/10.1016/j.jhep.2014.01.009] [PMID: 24445219]
[56]
Ryoo JH, Suh YJ, Shin HC, Cho YK, Choi JM, Park SK. Clinical association between non-alcoholic fatty liver disease and the development of hypertension. J Gastroenterol Hepatol 2014; 29(11): 1926-31.
[http://dx.doi.org/10.1111/jgh.12643] [PMID: 24910023]
[57]
Ma J, Hwang SJ, Pedley A, et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol 2017; 66(2): 390-7.
[http://dx.doi.org/10.1016/j.jhep.2016.09.022] [PMID: 27729222]
[58]
Lonardo A, Mantovani A, Lugari S, Targher G. NAFLD in some common endocrine diseases: Prevalence, pathophysiology, and principles of diagnosis and management. Int J Mol Sci 2019; 20(11): 20.
[http://dx.doi.org/10.3390/ijms20112841] [PMID: 31212642]
[59]
Mantovani A, Nascimbeni F, Lonardo A, et al. Association between primary hypothyroidism and nonalcoholic fatty liver disease: A systematic review and meta-analysis. Thyroid 2018; 28(10): 1270-84.
[http://dx.doi.org/10.1089/thy.2018.0257] [PMID: 30084737]
[60]
Chung GE, Kim D, Kim W, et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol 2012; 57(1): 150-6.
[http://dx.doi.org/10.1016/j.jhep.2012.02.027] [PMID: 22425701]
[61]
Tao Y, Gu H, Wu J, Sui J. Thyroid function is associated with non-alcoholic fatty liver disease in euthyroid subjects. Endocr Res 2015; 40(2): 74-8.
[PMID: 25330278]
[62]
Xu C, Xu L, Yu C, Miao M, Li Y. Association between thyroid function and nonalcoholic fatty liver disease in euthyroid elderly Chinese. Clin Endocrinol (Oxf) 2011; 75(2): 240-6.
[http://dx.doi.org/10.1111/j.1365-2265.2011.04016.x] [PMID: 21521285]
[63]
Bril F, Kadiyala S, Portillo Sanchez P, et al. Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes. J Investig Med 2016; 64(1): 63-8.
[http://dx.doi.org/10.1136/jim-2015-000019] [PMID: 26755815]
[64]
Kim D, Kim W, Joo SK, Bae JM, Kim JH, Ahmed A. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin Gastroenterol Hepatol 2018; 16: 123-31.
[http://dx.doi.org/10.1016/j.cgh.2017.08.014]
[65]
Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019; 394(10213): 2012-24.
[http://dx.doi.org/10.1016/S0140-6736(19)32517-6] [PMID: 31727409]
[66]
Barchetta I, Angelico F, Del Ben M, et al. Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes. BMC Med 2011; 9: 85.
[http://dx.doi.org/10.1186/1741-7015-9-85] [PMID: 21749681]
[67]
Jablonski KL, Jovanovich A, Holmen J, et al. Low 25-hydroxyvitamin D level is independently associated with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2013; 23(8): 792-8.
[http://dx.doi.org/10.1016/j.numecd.2012.12.006] [PMID: 23415456]
[68]
Seo JA, Eun CR, Cho H, et al. Low vitamin D status is associated with nonalcoholic Fatty liver disease independent of visceral obesity in Korean adults. PLoS One 2013; 8(10): e75197.
[http://dx.doi.org/10.1371/journal.pone.0075197] [PMID: 24130687]
[69]
Bril F, Maximos M, Portillo-Sanchez P, et al. Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. J Hepatol 2015; 62(2): 405-11.
[http://dx.doi.org/10.1016/j.jhep.2014.08.040] [PMID: 25195551]
[70]
Pannu PK, Zhao Y, Soares MJ. Reductions in body weight and percent fat mass increase the vitamin D status of obese subjects: a systematic review and metaregression analysis. Nutr Res 2016; 36(3): 201-13.
[http://dx.doi.org/10.1016/j.nutres.2015.11.013] [PMID: 26923506]
[71]
Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, sex hormone-binding globulin and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ann Hepatol 2017; 16(3): 382-94.
[http://dx.doi.org/10.5604/01.3001.0009.8593] [PMID: 28425408]
[72]
Sarkar M, VanWagner LB, Terry JG, et al. Coronary Artery Risk Development in Young Adults (CARDIA) Cohort. Sex hormone-binding globulin levels in young men are associated with nonalcoholic fatty liver disease in midlife. Am J Gastroenterol 2019; 114(5): 758-63.
[http://dx.doi.org/10.14309/ajg.0000000000000138] [PMID: 30730350]
[73]
Sarkar M, Yates K, Suzuki A, et al. Low testosterone is associated with Nonalcoholic Steatohepatitis (NASH) and severity of NASH fibrosis in men with NAFLD. Clin Gastroenterol Hepatol 2021; 19(2): 400-402.e2.
[http://dx.doi.org/10.1016/j.cgh.2019.11.053] [PMID: 31812658]
[74]
Dhindsa S, Ghanim H, Batra M, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 2016; 39(1): 82-91.
[http://dx.doi.org/10.2337/dc15-1518] [PMID: 26622051]
[75]
Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014; 59(4): 1406-14.
[http://dx.doi.org/10.1002/hep.26761] [PMID: 24123276]
[76]
Dayton K, Bril F, Barb D, Lai J, Kalavalapalli S, Cusi K. Severity of non-alcoholic steatohepatitis is not linked to testosterone concentration in patients with type 2 diabetes. PLoS One 2021; 16(6): e0251449.
[http://dx.doi.org/10.1371/journal.pone.0251449]
[77]
Long MT, Wang N, Larson MG, et al. Nonalcoholic fatty liver disease and vascular function: cross-sectional analysis in the Framingham heart study. Arterioscler Thromb Vasc Biol 2015; 35(5): 1284-91.
[http://dx.doi.org/10.1161/ATVBAHA.114.305200] [PMID: 25745056]
[78]
Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study. Hepatology 2018; 67(5): 1726-36.
[http://dx.doi.org/10.1002/hep.29546] [PMID: 28941364]
[79]
Söderberg C, Stål P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51(2): 595-602.
[http://dx.doi.org/10.1002/hep.23314] [PMID: 20014114]
[80]
Henson JB, Simon TG, Kaplan A, Osganian S, Masia R, Corey KE. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2020; 51(7): 728-36.
[http://dx.doi.org/10.1111/apt.15660] [PMID: 32043602]
[81]
Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 2018; 155: 443-57.
[http://dx.doi.org/10.1053/j.gastro.2018.04.034]
[82]
Rijzewijk LJ, van der Meer RW, Smit JW, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 2008; 52(22): 1793-9.
[http://dx.doi.org/10.1016/j.jacc.2008.07.062] [PMID: 19022158]
[83]
Utz W, Engeli S, Haufe S, et al. Myocardial steatosis, cardiac remodelling and fitness in insulin-sensitive and insulin-resistant obese women. Heart 2011; 97(19): 1585-9.
[http://dx.doi.org/10.1136/hrt.2011.224451] [PMID: 21775510]
[84]
McGavock JM, Lingvay I, Zib I, et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 2007; 116(10): 1170-5.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.645614] [PMID: 17698735]
[85]
Granér M, Nyman K, Siren R, et al. Ectopic fat depots and left ventricular function in nondiabetic men with nonalcoholic fatty liver disease. Circ Cardiovasc Imaging 2014; 8(1): 8.
[PMID: 25550397]
[86]
Hallsworth K, Hollingsworth KG, Thoma C, et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol 2013; 58(4): 757-62.
[http://dx.doi.org/10.1016/j.jhep.2012.11.015] [PMID: 23178979]
[87]
Ouni A, Jacobs C, Lomonaco R, et al. Role of intercellular adhesion molecules in the severity of liver disease in nonalcoholic fatty liver disease (NAFLD). DDW meeting 2020. Gastroenterology 2020; 158(6): S1-3.
[88]
Ajmera V, Perito ER, Bass NM, et al. NASH Clinical Research Network. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology 2017; 65(1): 65-77.
[http://dx.doi.org/10.1002/hep.28776] [PMID: 27532276]
[89]
Verma S, Jensen D, Hart J, Mohanty SR. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int 2013; 33(9): 1398-405.
[http://dx.doi.org/10.1111/liv.12226] [PMID: 23763360]
[90]
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; 100(6): 2231-8.
[http://dx.doi.org/10.1210/jc.2015-1966] [PMID: 25885947]
[91]
Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 2008; 48(3): 792-8.
[http://dx.doi.org/10.1002/hep.22429] [PMID: 18752331]
[92]
Bril F, McPhaul MJ, Caulfield MP, et al. Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with Type 2 diabetes. Diabetes Care 2020; 43(2): 290-7.
[http://dx.doi.org/10.2337/dc19-1071] [PMID: 31604692]
[93]
Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005; 42(3): 650-6.
[http://dx.doi.org/10.1002/hep.20818] [PMID: 16037946]
[94]
Tahan V, Canbakan B, Balci H, et al. Serum gamma-glutamyltranspeptidase distinguishes non-alcoholic fatty liver disease at high risk. Hepatogastroenterology 2008; 55(85): 1433-8.
[PMID: 18795706]
[95]
Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50(4): 1072-8.
[http://dx.doi.org/10.1002/hep.23050] [PMID: 19585618]
[96]
Cusi K, Chang Z, Harrison S, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 60(1): 167-74.
[http://dx.doi.org/10.1016/j.jhep.2013.07.042] [PMID: 23973932]
[97]
Barb D, Bril F, Kalavalapalli S, Cusi K. Plasma fibroblast growth factor 21 Is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetes. J Clin Endocrinol Metab 2019; 104(8): 3327-36.
[http://dx.doi.org/10.1210/jc.2018-02414] [PMID: 30848827]
[98]
Bril F, Lomonaco R, Orsak B, et al. Predictors of response after extended pioglitazone treatment in patients with prediabetes or T2DM and nonalcoholic steatohepatitis (NASH). Hepatology 2013; 58: 513a-4a.
[99]
Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002; 36(2): 403-9.
[http://dx.doi.org/10.1053/jhep.2002.34738] [PMID: 12143049]
[100]
Nobili V, Alkhouri N, Alisi A, et al. Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009; 7(5): 575-9.
[http://dx.doi.org/10.1016/j.cgh.2008.12.031] [PMID: 19268270]
[101]
Daniels SJ, Leeming DJ, Eslam M, et al. ADAPT: An algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 2019; 69(3): 1075-86.
[PMID: 30014517]
[102]
Bril F, Leeming DJ, Karsdal MA, et al. Use of plasma fragments of propeptides of type III, V, and VI procollagen for the detection of liver fibrosis in type 2 diabetes. Diabetes Care 2019; 42(7): 1348-51.
[http://dx.doi.org/10.2337/dc18-2578] [PMID: 31221701]
[103]
Pearce SG, Thosani NC, Pan JJ. Noninvasive biomarkers for the diagnosis of steatohepatitis and advanced fibrosis in NAFLD. Biomark Res 2013; 1(1): 7.
[http://dx.doi.org/10.1186/2050-7771-1-7] [PMID: 24252302]
[104]
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; 45(4): 846-54.
[http://dx.doi.org/10.1002/hep.21496] [PMID: 17393509]
[105]
Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008; 57(10): 1441-7.
[http://dx.doi.org/10.1136/gut.2007.146019] [PMID: 18390575]
[106]
Ratziu V, Massard J, Charlotte F, et al. LIDO Study Group; CYTOL study group. 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.
[http://dx.doi.org/10.1186/1471-230X-6-6] [PMID: 16503961]
[107]
Bertot LC, Jeffrey GP, de Boer B, et al. Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease. Liver Int 2018; 38(10): 1793-802.
[http://dx.doi.org/10.1111/liv.13739] [PMID: 29575516]
[108]
Bril F, Ortiz-Lopez C, Lomonaco R, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int 2015; 35(9): 2139-46.
[http://dx.doi.org/10.1111/liv.12840] [PMID: 25847730]
[109]
Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011; 54(3): 1082-90.
[http://dx.doi.org/10.1002/hep.24452] [PMID: 21618575]
[110]
Liang RJ, Wang HH, Lee WJ, Liew PL, Lin JT, Wu MS. Diagnostic value of ultrasonographic examination for nonalcoholic steatohepatitis in morbidly obese patients undergoing laparoscopic bariatric surgery. Obes Surg 2007; 17(1): 45-56.
[http://dx.doi.org/10.1007/s11695-007-9005-6] [PMID: 17355768]
[111]
Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016; 63(6): 1817-27.
[http://dx.doi.org/10.1002/hep.28394] [PMID: 26659452]
[112]
Kwok R, Tse YK, Wong GL, 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.
[http://dx.doi.org/10.1111/apt.12569] [PMID: 24308774]
[113]
Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017; 66(5): 1022-30.
[http://dx.doi.org/10.1016/j.jhep.2016.12.022] [PMID: 28039099]
[114]
Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis. Hepatology 2017; 66(5): 1486-501.
[http://dx.doi.org/10.1002/hep.29302] [PMID: 28586172]
[115]
de Lédinghen V, Hiriart JB, Vergniol J, Merrouche W, Bedossa P, Paradis V. Controlled Attenuation Parameter (CAP) with the XL Probe of the Fibroscan®: A comparative study with the M probe and liver biopsy. Dig Dis Sci 2017; 62(9): 2569-77.
[http://dx.doi.org/10.1007/s10620-017-4638-3] [PMID: 28577247]
[116]
Tapper EB, Challies T, Nasser I, Afdhal NH, Lai M. The performance of vibration controlled transient elastography in a US cohort of patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2016; 111(5): 677-84.
[http://dx.doi.org/10.1038/ajg.2016.49] [PMID: 26977758]
[117]
Noureddin M, Lam J, Peterson MR, 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.
[http://dx.doi.org/10.1002/hep.26455] [PMID: 23696515]
[118]
Park CC, Nguyen P, Hernandez C, et al. Magnetic resonance elastography vs. transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology 2017; 152: 598-607.
[119]
Younossi ZM, Loomba R, Rinella ME, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018; 68(1): 361-71.
[http://dx.doi.org/10.1002/hep.29724] [PMID: 29222911]
[120]
Sanyal AJ, Chalasani N, Kowdley KV, et al. NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362(18): 1675-85.
[http://dx.doi.org/10.1056/NEJMoa0907929] [PMID: 20427778]
[121]
Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: A randomized trial. Ann Intern Med 2016; 165(5): 305-15.
[http://dx.doi.org/10.7326/M15-1774] [PMID: 27322798]
[122]
Bril F, Biernacki DM, Kalavalapalli S, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: A randomized controlled trial. Diabetes Care 2019; 42(8): 1481-8.
[http://dx.doi.org/10.2337/dc19-0167] [PMID: 31332029]
[123]
Younossi ZM, Ratziu V, Loomba R, et al. REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019; 394(10215): 2184-96.
[http://dx.doi.org/10.1016/S0140-6736(19)33041-7] [PMID: 31813633]
[124]
Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54(1): 344-53.
[http://dx.doi.org/10.1002/hep.24376] [PMID: 21520200]
[125]
Ratziu V, Charlotte F, Heurtier A, et al. LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128(7): 1898-906.
[http://dx.doi.org/10.1053/j.gastro.2005.03.084] [PMID: 15940625]
[126]
Bril F, Barb D, Lomonaco R, Lai J, Cusi K. Change in hepatic fat content measured by MRI does not predict treatment-induced histological improvement of steatohepatitis. J Hepatol 2020; 72(3): 401-10.
[http://dx.doi.org/10.1016/j.jhep.2019.09.018] [PMID: 31589891]
[127]
Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010; 51(1): 121-9.
[http://dx.doi.org/10.1002/hep.23276] [PMID: 19827166]
[128]
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149: 367-78.
[http://dx.doi.org/10.1053/j.gastro.2015.04.005]
[129]
Estruch R, Ros E, Salas-Salvadó J, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368(14): 1279-90.
[http://dx.doi.org/10.1056/NEJMoa1200303] [PMID: 23432189]
[130]
Parry SA, Hodson L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J Investig Med 2017; 65(8): 1102-15.
[http://dx.doi.org/10.1136/jim-2017-000524] [PMID: 28947639]
[131]
Wing RR, Bolin P, Brancati FL, et al. Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369(2): 145-54.
[http://dx.doi.org/10.1056/NEJMoa1212914] [PMID: 23796131]
[132]
Hallsworth K, Adams LA. Lifestyle modification in NAFLD/NASH: Facts and figures. JHEP Rep 2019; 1(6): 468-79.
[http://dx.doi.org/10.1016/j.jhepr.2019.10.008] [PMID: 32039399]
[133]
Lee Y, Doumouras AG, Yu J, et al. Complete resolution of nonalcoholic fatty liver Disease after bariatric surgery: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2019; 17: 1040-60.
[http://dx.doi.org/10.1016/j.cgh.2018.10.017]
[134]
Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015; 149(2): 379-88.
[http://dx.doi.org/10.1053/j.gastro.2015.04.014] [PMID: 25917783]
[135]
Sjöström L, Narbro K, Sjöström CD, et al. Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357(8): 741-52.
[http://dx.doi.org/10.1056/NEJMoa066254] [PMID: 17715408]
[136]
Adams TD, Davidson LE, Litwin SE, et al. Weight and metabolic outcomes 12 years after gastric bypass. N Engl J Med 2017; 377(12): 1143-55.
[http://dx.doi.org/10.1056/NEJMoa1700459] [PMID: 28930514]
[137]
McCarty TR, Echouffo-Tcheugui JB, Lange A, Haque L, Njei B. Impact of bariatric surgery on outcomes of patients with nonalcoholic fatty liver disease: a nationwide inpatient sample analysis, 2004-2012. Surg Obes Relat Dis 2018; 14(1): 74-80.
[http://dx.doi.org/10.1016/j.soard.2017.09.511] [PMID: 29055669]
[138]
Ratziu V, Charlotte F, Bernhardt C, et al. LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51(2): 445-53.
[http://dx.doi.org/10.1002/hep.23270] [PMID: 19877169]
[139]
Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355(22): 2297-307.
[http://dx.doi.org/10.1056/NEJMoa060326] [PMID: 17135584]
[140]
Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366(9493): 1279-89.
[http://dx.doi.org/10.1016/S0140-6736(05)67528-9] [PMID: 16214598]
[141]
Nissen SE, Nicholls SJ, Wolski K, et al. PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299(13): 1561-73.
[http://dx.doi.org/10.1001/jama.299.13.1561] [PMID: 18378631]
[142]
Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006; 296(21): 2572-81.
[http://dx.doi.org/10.1001/jama.296.21.joc60158] [PMID: 17101640]
[143]
Kernan WN, Viscoli CM, Furie KL, et al. IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374(14): 1321-31.
[http://dx.doi.org/10.1056/NEJMoa1506930] [PMID: 26886418]
[144]
DeFronzo RA, Tripathy D, Schwenke DC, et al. ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011; 364(12): 1104-15.
[http://dx.doi.org/10.1056/NEJMoa1010949] [PMID: 21428766]
[145]
Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr Diab Rep 2013; 13(3): 329-41.
[http://dx.doi.org/10.1007/s11892-013-0378-8] [PMID: 23625197]
[146]
Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S, Loke YK. Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis. Br J Clin Pharmacol 2014; 78(2): 258-73.
[PMID: 24325197]
[147]
Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med 2018; 7(4): 1070-80.
[http://dx.doi.org/10.1002/cam4.1354] [PMID: 29476615]
[148]
Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017; 177(5): 633-40.
[http://dx.doi.org/10.1001/jamainternmed.2016.9607] [PMID: 28241279]
[149]
Petit JM, Cercueil JP, Loffroy R, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: The Lira-NAFLD Study. J Clin Endocrinol Metab 2017; 102(2): 407-15.
[PMID: 27732328]
[150]
Armstrong MJ, Gaunt P, Aithal GP, et al. LEAN trial team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387(10019): 679-90.
[http://dx.doi.org/10.1016/S0140-6736(15)00803-X] [PMID: 26608256]
[151]
Pi-Sunyer X, Astrup A, Fujioka K, et al. SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of Liraglutide in weight management. N Engl J Med 2015; 373(1): 11-22.
[http://dx.doi.org/10.1056/NEJMoa1411892] [PMID: 26132939]
[152]
Mann JFE, Ørsted DD, Brown-Frandsen K, et al. LEADER Steering Committee and Investigators. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377(9): 839-48.
[http://dx.doi.org/10.1056/NEJMoa1616011] [PMID: 28854085]
[153]
Kalavalapalli S, Bril F, Guingab J, et al. Impact of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic steatohepatitis. J Endocrinol 2019; 241(3): 293-305.
[http://dx.doi.org/10.1530/JOE-19-0007] [PMID: 31082799]
[154]
Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 7(10): 776-85.
[http://dx.doi.org/10.1016/S2213-8587(19)30249-9] [PMID: 31422062]
[155]
Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: A randomized controlled trial (E-LIFT Trial). Diabetes Care 2018; 41(8): 1801-8.
[http://dx.doi.org/10.2337/dc18-0165] [PMID: 29895557]
[156]
Kahl S, Gancheva S, Straßburger K, et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: A randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care 2020; 43(2): 298-305.
[http://dx.doi.org/10.2337/dc19-0641] [PMID: 31540903]
[157]
Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab 2019; 21(4): 812-21.
[PMID: 30447037]
[158]
McMurray JJV, Solomon SD, Inzucchi SE, et al. DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21): 1995-2008.
[http://dx.doi.org/10.1056/NEJMoa1911303] [PMID: 31535829]
[159]
Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016; 101(1): 157-66.
[http://dx.doi.org/10.1210/jc.2015-3167] [PMID: 26580237]
[160]
Tang A, Rabasa-Lhoret R, Castel H, et al. Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: A randomized trial. Diabetes Care 2015; 38(7): 1339-46.
[http://dx.doi.org/10.2337/dc14-2548] [PMID: 25813773]
[161]
Blatt DH, Pryor WA. High-dosage vitamin E supplementation and all-cause mortality. Ann Intern Med 2005; 143(2): 150-1.
[http://dx.doi.org/10.7326/0003-4819-143-2-200507190-00018] [PMID: 16027460]
[162]
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; 385(9972): 956-65.
[http://dx.doi.org/10.1016/S0140-6736(14)61933-4] [PMID: 25468160]
[163]
Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150: 1147-59.
[164]
Ratziu V, Sanyal A, Harrison SA, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: Final analysis of the phase 2b CENTAUR study. Hepatology 2020; 72(3): 892-905.
[http://dx.doi.org/10.1002/hep.31108] [PMID: 31943293]
[165]
Safadi R, Konikoff FM, Mahamid M, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12: 2085-91.
[http://dx.doi.org/10.1016/j.cgh.2014.04.038]
[166]
Loomba R, Lawitz E, Mantry PS, et al. GS-US-384-1497 Investigators. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018; 67(2): 549-59.
[http://dx.doi.org/10.1002/hep.29514] [PMID: 28892558]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy