Fatty liver index is a predictor of incident diabetes in patients with prediabetes: The PREDAPS study

PLoS ONE

Volumn 13, Issue 6, 2018, Pages

  Franch Nadal, Josep ^a,b,c,d   Caballeria, Llorenç ^b,d,e   Mata Cases, Manel ^a,b,c   Mauricio, Didac ^a,b,c,f   Giraldez García, Carolina ^a,g,h   Mancera, José ^a,i   Goday, Albert ^a,j   Mundet Tuduri, Xavier ^a,b,k   Regidor, Enrique ^a,h,l,m  

^a RedGDPS   (Spain)

^b Research Institute University Primary Care IDIAP Jordi Gol   (Spain)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

^d UNIVERSITY OF BARCELONA   (Spain)

^e INSTITUTO DE SALUD CARLOS III   (Spain)

^f HOSPITAL UNIVERSITARI GERMANS TRIAS I PUJOL   (Spain)

^g HOSPITAL INFANTA ELENA   (Spain)

^h UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

ⁱ Ciudad Jardín Health Center   (Spain)

^j HOSPITAL DEL MAR   (Spain)

^k UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^l CIBER EPIDEMIOLOGÍA Y SALUD PÚBLICA CIBERESP   (Spain)

^m HOSPITAL CLÍNICO SAN CARLOS   (Spain)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; AGED; ARTICLE; DIGESTIVE TRACT PARAMETERS; FATTY LIVER; FATTY LIVER INDEX; FEMALE; HUMAN; IMPAIRED GLUCOSE TOLERANCE; INCIDENCE; INSULIN RESISTANCE; MAJOR CLINICAL STUDY; MALE; METABOLIC SYNDROME X; MIDDLE AGED; NON INSULIN DEPENDENT DIABETES MELLITUS; PREDICTION; PRIMARY MEDICAL CARE; SPANIARD; COHORT ANALYSIS; COMPLICATION; DISEASE EXACERBATION; NONALCOHOLIC FATTY LIVER; PATHOLOGY; PROGNOSIS; RISK FACTOR; SEVERITY OF ILLNESS INDEX; VERY ELDERLY;

BIOLOGICAL MARKER;

ADULT; AGED; AGED, 80 AND OVER; BIOMARKERS; COHORT STUDIES; DIABETES MELLITUS, TYPE 2; DISEASE PROGRESSION; FEMALE; HUMANS; INCIDENCE; MALE; MIDDLE AGED; NON-ALCOHOLIC FATTY LIVER DISEASE; PREDIABETIC STATE; PROGNOSIS; RISK FACTORS; SEVERITY OF ILLNESS INDEX;

EID: 85048031882     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0198327     Document Type: Article

References (74)

1. Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol. 2009; 8 Suppl 1: S4–8. PMID: 19381118
2. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010; 51(2): 679–89. https://doi.org/10.1002/hep.23280 PMID: 20041406
3. 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. https://doi.org/10.1002/hep.28431 PMID: 26707365
4. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013; 10(11): 645–55. https://doi.org/10.1038/nrgastro.2013.182 PMID: 24061205
5. Caballeria L, Pera G, Auladell MA, Toran P, Munoz L, Miranda D, et al. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain. Eur J Gastroenterol Hepatol. 2010; 22(1): 24–32. https://doi.org/10.1097/MEG.0b013e32832fcdf0 PMID: 19730384
6. Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism. 2016; 65(8): 1096–108. https://doi.org/10.1016/j.metabol.2016.01.001 PMID: 26856933
7. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016; 31(5): 936–44. https://doi.org/10.1111/jgh.13264 PMID: 26667191
8. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013; 10(6): 330–44. https://doi.org/10.1038/nrgastro.2013. 41 PMID: 23507799
9. 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. https://doi.org/10.2337/dc16-1787 PMID: 28223446
10. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014; 20 (2): 475–85. https://doi.org/10.3748/wjg.v20.i2.475 PMID: 24574716
11. Papagianni M, Sofogianni A, Tziomalos K. Non-invasive methods for the diagnosis of nonalcoholic fatty liver disease. World J Hepatol. 2015; 7(4): 638–48. https://doi.org/10.4254/wjh.v7.i4.638 PMID: 25866601
12. Kahl S, Strassburger K, Nowotny B, Livingstone R, Kluppelholz B, Kessel K, et al. Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance. PLoS ONE. 2014; 9(4): e94059. https://doi.org/10.1371/journal.pone.0094059 PMID: 24732091
13. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006; 6: 33. https://doi.org/10.1186/1471-230X-6-33 PMID: 17081293
14. Yang BL, Wu WC, Fang KC, Wang YC, Huo TI, Huang YH, et al. External validation of fatty liver index for identifying ultrasonographic fatty liver in a large-scale cross-sectional study in Taiwan. PLoS ONE. 2015; 10(3): e0120443. https://doi.org/10.1371/journal.pone.0120443 PMID: 25781622
15. Koehler EM, Schouten JN, Hansen BE, Hofman A, Stricker BH, Janssen HL. External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study. Clin Gastroenterol Hepatol. 2013; 11(9): 1201–4. https://doi.org/10.1016/j.cgh.2012.12.031 PMID: 23353640
16. Rogulj D, Konjevoda P, Milic M, Mladinic M, Domijan AM. Fatty liver index as an indicator of metabolic syndrome. Clin Biochem. 2012; 45(1–2): 68–71. https://doi.org/10.1016/j.clinbiochem.2011.10.014PMID: 22056738
17. Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, Mitrakou A, et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009; 49(5): 1537–44. https://doi.org/10.1002/hep.22845 PMID: 19291789
18. Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, et al. Fatty liver index and mortality: the Cremona study in the 15th year of follow-up. Hepatology. 2011; 54(1): 145–52. https://doi.org/10.1002/hep.24356 PMID: 21488080
19. Leutner M, Gobl C, Schlager O, Charwat-Resl S, Wielandner A, Howorka E, et al. The Fatty Liver Index (FLI) Relates to Diabetes-Specific Parameters and an Adverse Lipid Profile in a Cohort of Nondiabetic, Dyslipidemic Patients. J Am Coll Nutr. 2017; 36(4): 287–94. https://doi.org/10.1080/07315724.2016. 1262802 PMID: 28506114
20. Bonnet F, Gastaldelli A, Pihan-Le Bars F, Natali A, Roussel R, Petrie J, et al. Gamma-glutamyltransferase, fatty liver index and hepatic insulin resistance are associated with incident hypertension in two longitudinal studies. J Hypertens. 2017; 35(3): 493–500. https://doi.org/10.1097/HJH.0000000000001204PMID: 27984413
21. Bozkurt L, Gobl CS, Tura A, Chmelik M, Prikoszovich T, Kosi L, et al. Fatty liver index predicts further metabolic deteriorations in women with previous gestational diabetes. PLoS ONE. 2012; 7(2): e32710. https://doi.org/10.1371/journal.pone.0032710 PMID: 22393439
22. 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; 43(8): 617–49. https://doi.org/10.3109/07853890.2010.518623 PMID: 21039302
23. Balkau B, Lange C, Vol S, Fumeron F, Bonnet F, Group Study DESIR. Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol. 2010; 10: 56. https://doi.org/10.1186/1471-230X-10-56 PMID: 20529259
24. Jung CH, Lee WJ, Hwang JY, Yu JH, Shin MS, Lee MJ, et al. Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population. Diabet Med. 2013; 30(4): 428–35. https://doi.org/10.1111/dme.12104 PMID: 23278318
25. Jager S, Jacobs S, Kroger J, Stefan N, Fritsche A, Weikert C, et al. Association between the Fatty Liver Index and Risk of Type 2 Diabetes in the EPIC-Potsdam Study. PLoS ONE. 2015; 10(4): e0124749. https://doi.org/10.1371/journal.pone.0124749 PMID: 25902304
26. Yadav D, Choi E, Ahn SV, Koh SB, Sung KC, Kim JY, et al. Fatty liver index as a simple predictor of incident diabetes from the KoGES-ARIRANG study. Medicine (Baltimore). 2016; 95(31): e4447. https://doi.org/10.1097/MD.0000000000004447 PMID: 27495073
27. Fan JG, Li F, Cai XB, Peng YD, Ao QH, Gao Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol. 2007; 22(7): 1086–91. https://doi.org/10.1111/j.1440-1746.2006.04781.x PMID: 17608855
28. Arase Y, Suzuki F, Ikeda K, Kumada H, Tsuji H, Kobayashi T. Multivariate analysis of risk factors for the development of type 2 diabetes in nonalcoholic fatty liver disease. J Gastroenterol. 2009; 44(10): 1064–70. https://doi.org/10.1007/s00535-009-0091-1 PMID: 19533014
29. Yamada T, Fukatsu M, Suzuki S, Wada T, Yoshida T, Joh T. Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health checkup. J Gastroenterol Hepatol. 2010; 25(2): 352–6. https://doi.org/10.1111/j.1440-1746.2009.05998.x PMID: 19817963
30. Bae JC, Rhee EJ, Lee WY, Park SE, Park CY, Oh KW, 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. https://doi.org/10.2337/dc10-1991 PMID: 21278140
31. Zelber-Sagi S, Lotan R, Shibolet O, Webb M, Buch A, Nitzan-Kaluski D, et al. Non-alcoholic fatty liver disease independently predicts prediabetes during a 7-year prospective follow-up. Liver Int. 2013; 33 (9): 1406–12. https://doi.org/10.1111/liv.12200 PMID: 23656177
32. Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol. 2010; 105 (11): 2389–95. https://doi.org/10.1038/ajg.2010.275 PMID: 20628364
33. Nishi T, Babazono A, Maeda T, Imatoh T, Une H. Evaluation of the fatty liver index as a predictor for the development of diabetes among insurance beneficiaries with prediabetes. J Diabetes Investig. 2015; 6 (3): 309–16. https://doi.org/10.1111/jdi.12290 PMID: 25969716
34. ADA. American Diabetes Association. 2. Classification and Diagnosis of Diabetes. Diabetes Care.
35. 2016; 39(Supplement 1): S13–S22. https://doi.org/10.2337/dc16-S005 PMID: 26696675
36. Serrano R, Garcia-Soidan FJ, Diaz-Redondo A, Artola S, Franch J, Diez J, et al. [Cohort Study in Primary Health Care on the Evolution of Patients with Prediabetes (PREDAPS): basis and methodology]. Rev Esp Salud Publica. 2013; 87(2): 121–35. https://doi.org/10.4321/S1135-57272013000200003PMID: 23775102
37. ADA. American Diabetes Association. Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care. 2017; 40(Suppl 1): S4–S5. https://doi.org/10.2337/dc17-S003 PMID: 27979887
38. Kahn R, Buse J, Ferrannini E, Stern M, American Diabetes A, European Association for the Study of D. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005; 28(9): 2289–304. PMID: 16123508
39. Simental-Mendia LE, Rodriguez-Moran M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metabolic syndrome and related disorders. 2008; 6(4): 299–304. Epub 2008/12/11. https://doi.org/10.1089/met.2008. 0034 PMID: 19067533
40. Guerrero-Romero F, Simental-Mendia LE, Gonzalez-Ortiz M, Martinez-Abundis E, Ramos-Zavala MG, Hernandez-Gonzalez SO, et al. The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab. 2010; 95 (7): 3347–51. Epub 2010/05/21. https://doi.org/10.1210/jc.2010-0288 PMID: 20484475
41. Giannini C, Santoro N, Caprio S, Kim G, Lartaud D, Shaw M, et al. The triglyceride-to-HDL cholesterol ratio: association with insulin resistance in obese youths of different ethnic backgrounds. Diabetes Care. 2011; 34(8): 1869–74. Epub 2011/07/07. https://doi.org/10.2337/dc10-2234 PMID: 21730284
42. Mostafa SA, Davies MJ, Morris DH, Yates T, Srinivasan BT, Webb D, et al. The association of the triglyceride-to-HDL cholesterol ratio with insulin resistance in White European and South Asian men and women. PLoS ONE. 2012; 7(12): e50931. Epub 2012/12/20. https://doi.org/10.1371/journal.pone. 0050931 PMID: 23251403
43. Du T, Yuan G, Zhang M, Zhou X, Sun X, Yu X. Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance. Cardiovasc Diabe-tol. 2014; 13: 146. Epub 2014/10/20. https://doi.org/10.1186/s12933-014-0146-3 PMID: 25326814
44. Zhang L, Chen S, Deng A, Liu X, Liang Y, Shao X, et al. Association between lipid ratios and insulin resistance in a Chinese population. PLoS ONE. 2015; 10(1): e0116110. Epub 2015/01/31. https://doi.org/10.1371/journal.pone.0116110 PMID: 25635876
45. Er LK, Wu S, Chou HH, Hsu LA, Teng MS, Sun YC, et al. Triglyceride Glucose-Body Mass Index Is a Simple and Clinically Useful Surrogate Marker for Insulin Resistance in Nondiabetic Individuals. PLoS ONE. 2016; 11(3): e0149731. Epub 2016/03/02. https://doi.org/10.1371/journal.pone.0149731 PMID: 26930652
46. Lee DY, Lee ES, Kim JH, Park SE, Park CY, Oh KW, et al. Predictive Value of Triglyceride Glucose Index for the Risk of Incident Diabetes: A 4-Year Retrospective Longitudinal Study. PLoS ONE. 2016; 11(9): e0163465. Epub 2016/09/30. https://doi.org/10.1371/journal.pone.0163465 PMID: 27682598
47. Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005; 22(9): 1141–5. https://doi.org/10.1111/j.1464-5491.2005.01582.x PMID: 16108839
48. Wong VW, Hui AY, Tsang SW, Chan JL, Wong GL, Chan AW, et al. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Aliment Phar-macol Ther. 2006; 24(8): 1215–22. https://doi.org/10.1111/j.1365-2036.2006.03112.x PMID: 17014580
49. Singh SP, Singh A, Pati GK, Misr B, Misra D, Kar SK, et al. A Study of Prevalence of Diabetes and Prediabetes in Patients of Non-Alcoholic Fatty Liver Disease and the Impact of Diabetes on Liver Histology in Coastal Eastern India. Journal of Diabetes Mellitus. 2014; 4(4): 290–6.
50. Bansal A, Mourya S, Verma A, Khanam B, Bansal R. A Study of Prevalence of Diabetes and Prediabetes in Patients with Non Alcoholic Fatty Liver Disease and Impact of Diabetes on Liver Histology. Journal of Clinical and Experimental Hepatology. 2016; 6: S23. https://doi.org/10.1016/j.jceh.2016.06.043
51. Ortiz-Lopez C, Lomonaco R, Orsak B, Finch J, Chang Z, Kochunov VG, et al. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care. 2012; 35(4): 873–8. https://doi.org/10.2337/dc11-1849 PMID: 22374640
52. Forlani G, Giorda C, Manti R, Mazzella N, De Cosmo S, Rossi MC, et al. The Burden of NAFLD and Its Characteristics in a Nationwide Population with Type 2 Diabetes. J Diabetes Res. 2016; 2016: 2931985. https://doi.org/10.1155/2016/2931985 PMID: 27123461
53. Lonardo A, Ballestri S, Marchesini G, Angulo P, Loria P. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis. 2015; 47(3): 181–90. https://doi.org/10.1016/j.dld.2014.09.020PMID: 25739820
54. Saponaro C, Gaggini M, Gastaldelli A. Nonalcoholic fatty liver disease and type 2 diabetes: common pathophysiologic mechanisms. Curr Diab Rep. 2015; 15(6): 607. https://doi.org/10.1007/s11892-015-0607-4 PMID: 25894944
55. Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002; 137(1): 1–10. PMID: 12093239
56. Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni 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. https://doi.org/10.1002/hep.22429 PMID: 18752331
57. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, 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. https://doi.org/10.1210/jc.2015-1966 PMID: 25885947
58. Lee DH, Ha MH, Kim JH, Christiani DC, Gross MD, Steffes M, et al. Gamma-glutamyltransferase and diabetes—a 4 year follow-up study. Diabetologia. 2003; 46(3): 359–64. https://doi.org/10.1007/s00125-003-1036-5 PMID: 12687334
59. Goessling W, Massaro JM, Vasan RS, D’Agostino RB Sr., Ellison RC, Fox CS. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology. 2008; 135(6): 1935–44, 44 e1. https://doi.org/10.1053/j.gastro.2008.09.018 PMID: 19010326
60. Ryu S, Chang Y, Woo HY, Yoo SH, Choi NK, Lee WY, et al. Longitudinal increase in gamma-glutamyl-transferase within the reference interval predicts metabolic syndrome in middle-aged Korean men. Metabolism. 2010; 59(5): 683–9. https://doi.org/10.1016/j.metabol.2009.08.024 PMID: 19922966
61. Mata-Cases M, Artola S, Escalada J, Ezkurra-Loyola P, Ferrer-Garcia JC, Fornos JA, et al. Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society. Rev Clin Esp. 2015; 215(2): 117–29. https://doi.org/10.1016/j.rce.2014.10.012 PMID: 25553948
62. Sato F, Tamura Y, Watada H, Kumashiro N, Igarashi Y, Uchino H, et al. Effects of diet-induced moderate weight reduction on intrahepatic and intramyocellular triglycerides and glucose metabolism in obese subjects. J Clin Endocrinol Metab. 2007; 92(8): 3326–9. https://doi.org/10.1210/jc.2006-2384 PMID: 17519317
63. Viljanen AP, Iozzo P, Borra R, Kankaanpaa M, Karmi A, Lautamaki R, et al. Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. J Clin Endocrinol Metab. 2009; 94(1): 50–5. https://doi.org/10.1210/jc.2008-1689 PMID: 18957499
64. Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab. 2013; 98(9): 3637–43. https://doi.org/10.1210/jc.2013-1519 PMID: 23873989
65. Yamazaki H, Tsuboya T, Tsuji K, Dohke M, Maguchi H. Independent Association Between Improvement of Nonalcoholic Fatty Liver Disease and Reduced Incidence of Type 2 Diabetes. Diabetes Care. 2015; 38(9): 1673–9. https://doi.org/10.2337/dc15-0140 PMID: 26156527
66. Berkowitz SA, Krumme AA, Avorn J, Brennan T, Matlin OS, Spettell CM, et al. Initial choice of oral glucose-lowering medication for diabetes mellitus: a patient-centered comparative effectiveness study. JAMA Intern Med. 2014; 174(12): 1955–62. https://doi.org/10.1001/jamainternmed.2014.5294 PMID: 25347323
67. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015; 62(5): 1148–55. https://doi.org/10.1016/j.jhep.2014.11.034 PMID: 25477264
68. 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. https://doi.org/10.1016/j.ecl.2016.06.005 PMID: 27823604
69. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, 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. https://doi.org/10.7326/M15-1774 PMID: 27322798
70. Targher G, Bertolini L, Chonchol M, Rodella S, Zoppini G, Lippi G, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia. 2010; 53(7): 1341–8. https://doi.org/10.1007/s00125-010-1720-1PMID: 20369224
71. 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. https://doi.org/10.1016/j.jhep.2016.05.013 PMID: 27212244
72. Athyros VG, Alexandrides TK, Bilianou H, Cholongitas E, Doumas M, Ganotakis ES, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism—Clinical and Experimental. 71: 17–32. https://doi.org/10.1016/j.metabol.2017.02. 014 PMID: 28521870
73. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term followup of patients with NAFLD and elevated liver enzymes. Hepatology. 2006; 44(4): 865–73. https://doi.org/10.1002/hep.21327 PMID: 17006923
74. Sinn DH, Gwak GY, Park HN, Kim JE, Min YW, Kim KM, et al. Ultrasonographically detected non-alcoholic fatty liver disease is an independent predictor for identifying patients with insulin resistance in non-obese, non-diabetic middle-aged Asian adults. Am J Gastroenterol. 2012; 107(4): 561–7. https://doi.org/10.1038/ajg.2011.400 PMID: 22108448