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Journal of Endocrinological Investigation

, Volume 41, Issue 5, pp 509–521 | Cite as

NAFLD/NASH in patients with type 2 diabetes and related treatment options

  • M. G. Radaelli
  • F. Martucci
  • S. Perra
  • S. Accornero
  • G. Castoldi
  • G. Lattuada
  • G. Manzoni
  • G. Perseghin
Review

Abstract

Type 2 diabetes may reduce life expectancy and patients’ quality of life due to its micro- and macro-vascular complications and to the higher risk of several types of cancer. An emerging important factor is represented by the hepatic involvement; it is recognized that excessive hepatic fat accumulation represents a typical feature of diabetic patients and that it also plays an important pathogenic role. It is now evident that non-alcoholic fatty liver disease (NAFLD), generally perceived as a benign condition, may have on the contrary an important deleterious impact for diabetic patients increasing the risk to develop cardiovascular complications but also serious hepatic diseases, in particular non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Lifestyle intervention, bariatric surgery and several drug therapies have now accumulated evidence of efficacy in treating NASH. On the other hand, their durability and safety in the long-term is yet to be proven and their use may be sometimes associated with side effects or higher risk of adverse events limiting the regular administration or contraindicating it. Professional health care providers, building awareness about the importance of these hepatic complications, should put more efforts in primary prevention using a behavioral therapy needing a multidisciplinary approach, in secondary prevention applying on a regular basis in the clinical setting available predictive algorithms to identify the patients at higher cardiovascular and hepatologic risk, and in tertiary prevention treating, when not contraindicated, the diabetic patients preferentially with drugs with proven benefit on NAFLD/NASH.

Keywords

Hepatocellular ballooning Fibrosis Cirrhosis Hepatocellular carcinoma NAFLD score Fatty liver index (FLI) 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest related to the manuscript.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

None.

References

  1. 1.
    Trombetta M, Spiazzi G, Zoppini G et al (2005) Type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther 22(Suppl 2):24–27PubMedCrossRefGoogle Scholar
  2. 2.
    De Marco R, Locatelli F, Zoppini G et al (1999) Cause-specific mortality in type 2 diabetes. The Verona diabetes study. Diabetes Care 22:756–761PubMedCrossRefGoogle Scholar
  3. 3.
    Der Diabetes Mellitus (1906) In: Naunyn B (ed) Nothnagels Handbuch. Wien: A. HolderGoogle Scholar
  4. 4.
    Perseghin G, Mazzaferro V, Sereni LP et al (2000) Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 31:694–703PubMedCrossRefGoogle Scholar
  5. 5.
    Megyesi C, Samols E, Marks V (1967) Glucose tolerance and diabetes in chronic liver disease. Lancet 2:1051–1056PubMedCrossRefGoogle Scholar
  6. 6.
    Conn HO, Schreiber W, Elkington SG et al (1969) Cirrhosis and diabetes. Increased incidence of diabetes in patients with Laennec’s cirrhosis. I. Am J Dig Dis 14:837–852PubMedCrossRefGoogle Scholar
  7. 7.
    Conn HO, Schreiber W, Elkington SG (1971) Cirrhosis and diabetes. Association of impaired glucose tolerance with portal-systemic shunting in Laennec’s cirrhosis. Am J Dig Dis 16:227–239PubMedCrossRefGoogle Scholar
  8. 8.
    Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM et al (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 107:811–826PubMedCrossRefGoogle Scholar
  9. 9.
    EASL-EASD-EASO (2016) Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia 59:1121–1240CrossRefGoogle Scholar
  10. 10.
    Marchesini G, Brizi M, Bianchi G et al (2001) Nonalcoholic fatty liver disease; a feature of the metabolic syndrome. Diabetes 50:1844–1850PubMedCrossRefGoogle Scholar
  11. 11.
    Pietilainen KH, Rissanen A, Kaprio J et al (2005) Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins. Am J Physiol Endocrinol Metab 288:E768–E774PubMedCrossRefGoogle Scholar
  12. 12.
    Rocha ALL, Faria LC, Guimarães TCM, Moreira GV, Cândido AL et al (2017) Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Investig.  https://doi.org/10.1007/s40618-017-0708-9 CrossRefGoogle Scholar
  13. 13.
    Lee SH, Yun JM, Kim SH, Seo YG, Min H et al (2016) Association between bone mineral density and nonalcoholic fatty liver disease in Korean adults. J Endocrinol Investig 39:1329–1336CrossRefGoogle Scholar
  14. 14.
    Petersen KF, Dufour S, Befroy D et al (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54:603–608PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ryysy L, Häkkinen A-M, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758PubMedCrossRefGoogle Scholar
  16. 16.
    Hwang J-H, Stein DT, Barzilai N et al (2007) Increased intrahepatic is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy. Am J Physiol Endocrinol Metab 293:E1663–E1669PubMedCrossRefGoogle Scholar
  17. 17.
    Marchesini G, Brizi M, Morselli-Labate AM et al (1999) Association of non-alcoholic fatty liver disease with insulin resistance. Am J Med 107:450–455PubMedCrossRefGoogle Scholar
  18. 18.
    Gastaldelli A, Cusi K, Pettiti M et al (2007) Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133:496–506PubMedCrossRefGoogle Scholar
  19. 19.
    Stefan N, Kantartzis K, Machann J et al (2008) Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 68:1609–1616CrossRefGoogle Scholar
  20. 20.
    Perseghin G, Bonfanti R, Magni S et al (2006) Insulin resistance and whole body energy homeostasis in obese adolescents with fatty liver disease. Am J Physiol Endocrinol Metab 291:E697–E703PubMedCrossRefGoogle Scholar
  21. 21.
    Petersen KF, Arioglu Oral E, Dufour S et al (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Investig 109:1345–1350PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Perseghin G, Caumo A, Lattuada G et al (2009) Elevated fasting plasma C-peptide occurs in non-diabetic individuals with fatty liver irrespectively of insulin resistance. Diabet Med 26:847–854PubMedCrossRefGoogle Scholar
  23. 23.
    Bedogni G, Gastaldelli A, Tiribelli C, Agosti F, De Col A et al (2014) Relationship between glucose metabolism and non-alcoholic fatty liver disease severity in morbidly obese women. J Endocrinol Investig 37:739–744CrossRefGoogle Scholar
  24. 24.
    Kotronen A, Vehkavaara S, Seppälä-Lindroos A et al (2007) Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab 293:E1709–E1715PubMedCrossRefGoogle Scholar
  25. 25.
    Kotronen A, Juurinen L, Tiikkainen M et al (2008) Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135:122–130PubMedCrossRefGoogle Scholar
  26. 26.
    Battezzati A, Terruzzi I, Perseghin G et al (1995) Defective insulin action on protein and glucose metabolism during chronic hyperinsulinemia in subjects with benign insulinoma. Diabetes 44:837–844PubMedCrossRefGoogle Scholar
  27. 27.
    Petrides AS, Stanley T, Matthews DE et al (1998) Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology 28:141–149PubMedCrossRefGoogle Scholar
  28. 28.
    Westerbacka J, Kolak M, Kiviluoto T et al (2007) Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 56:2759–2765PubMedCrossRefGoogle Scholar
  29. 29.
    Tripathy D, Mohanty P, Dhindsa S et al (2003) Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52:2882–2887PubMedCrossRefGoogle Scholar
  30. 30.
    Perseghin G, Petersen KF, Shulman GI (2003) Cellular mechanisms of insulin resistance; potential links with inflammation. Int J Obes 27:S6–S11CrossRefGoogle Scholar
  31. 31.
    André P, Balkau B, Born C et al (2005) Hepatic markers and development of type 2 diabetes in middle aged men and women: a three-year follow-up study. The D.E.S.I.R. Study. [Data from an Epidemiological Study on the Insulin Resistance syndrome). Diabetes Metab 31:542–550PubMedCrossRefGoogle Scholar
  32. 32.
    Fraser A, Thinggaard M, Christensen K, Lawlor DA (2009) Alanine aminotransferase, gamma-glutamyltransferase (GGT) and all cause mortality: results from a population-based Danish twins study alanine aminotransferase, GGT and mortality in elderly twins. Liver Int 29:1494–1499PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Sattar N, Scherbakova O, Ford I et al (2004) Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes 53:2855–2860PubMedCrossRefGoogle Scholar
  34. 34.
    Shlomai A, Kariv R, Leshno M et al (2010) Large-scale population analysis reveals an extremely low threshold for “non-healthy” alanine aminotransferase that predicts diabetes mellitus. J Gastroenterol Hepatol 25:1687–1691PubMedCrossRefGoogle Scholar
  35. 35.
    Kim CH, Park JY, Lee KU et al (2008) Fatty liver is an independent risk factor for the development of type 2 diabetes in Korean adults. Diabet Med 25:476–781PubMedCrossRefGoogle Scholar
  36. 36.
    Fan JG, Li F, Cai XB et al (2007) Effects of non alcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol 22:1086–1091PubMedCrossRefGoogle Scholar
  37. 37.
    Shibata M, Kihara Y, Taguchi M et al (2007) Non-alcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 30:2940–2944PubMedCrossRefGoogle Scholar
  38. 38.
    Bedogni G, Bellentani S, Miglioli L et al (2006) The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 6:33PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Balkau B, Lange C, Vol S, Fumeron F, Bonnet F, For Group Study D.E.S.I.R. (2010) Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol 10:56PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Targher G, Chonchol MB, Byrne CD (2014) CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 64:638–652PubMedCrossRefGoogle Scholar
  41. 41.
    Musso G, Gambino R, Tabibian JH et al (2014) Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 11:e1001680PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Mantovani A, Rigolon R, Mingolla L et al (2017) Nonalcoholic fatty liver disease is associated with an increased prevalence of distal symmetric polyneuropathy in adult patients with type 1 diabetes. J Diabetes Complicat 31:1021–1026PubMedCrossRefGoogle Scholar
  43. 43.
    Liccardo D, Mosca A, Petroni S et al (2015) The association between retinal microvascular changes, metabolic risk factors, and liver histology in pediatric patients with non-alcoholic fatty liver disease (NAFLD). J Gastroenterol 50:903–912PubMedCrossRefGoogle Scholar
  44. 44.
    Perseghin G (2010) The role of non-alcoholic fatty liver disease in cardiovascular disease. Dig Dis 28:210–213PubMedCrossRefGoogle Scholar
  45. 45.
    Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363:1341–1350PubMedCrossRefGoogle Scholar
  46. 46.
    Villanova N, Moscatiello S, Ramilli S et al (2005) Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 42:473–480PubMedCrossRefGoogle Scholar
  47. 47.
    Lautamaki R, Borra R, Iozzo P et al (2006) Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 291:E282–E290PubMedCrossRefGoogle Scholar
  48. 48.
    Assy N, Djibre A, Farah R et al (2010) Presence of coronary plaques in patients with non-alcoholic fatty liver disease. Radiology 254:393–400PubMedCrossRefGoogle Scholar
  49. 49.
    Perseghin G, Lattuada G, De Cobelli F et al (2008) Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47:51–58PubMedCrossRefGoogle Scholar
  50. 50.
    Bonapace S, Perseghin G, Molon G et al (2012) Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35:389–395PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Mantovani A, Pernigo M, Bergamini C et al (2015) nonalcoholic fatty liver disease is independently associated with early left ventricular diastolic dysfunction in patients with type 2 diabetes. PLoS One 10:e0135329PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Alonso A, Misialek JR, Amiin MA et al (2014) Circulating levels of liver enzymes and incidence of atrial fibrillation: the atherosclerosis risk in communities cohort. Heart 100:1511–1516PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Markus MR, Meffert PJ, Baumeister SE, Lieb W, Siewert U et al (2016) Association between hepatic steatosis and serum liver enzyme levels with atrial fibrillation in the general population: the Study of Health in Pomerania (SHIP). Atherosclerosis 245:123–131PubMedCrossRefGoogle Scholar
  54. 54.
    Targher G, Valbusa F, Bonapace S et al (2013) Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. PLoS One 8:e57183PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Targher G, Mantovani A, Pichiri I et al (2013) Nonalcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. Clin Sci (Lond) 125:301–309CrossRefGoogle Scholar
  56. 56.
    Mantovani A, Rigolon R, Pichiri I et al (2017) Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus. PLoS One 12:e0185459PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Mantovani A, Pernigo M, Bergamini C et al (2015) Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease. Metabolism 64:879–887PubMedCrossRefGoogle Scholar
  58. 58.
    Wannamethee SG, Lennon L, Shaper AG (2008) The value of gamma-glutamyltransferase in cardiovascular risk prediction in men without diagnosed cardiovascular disease or diabetes. Atherosclerosis 201:168–175PubMedCrossRefGoogle Scholar
  59. 59.
    Hamaguchi M, Kojima T, Takeda N et al (2007) Non-alcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 13:1579–1584PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Targher G, Bertolini L, Poli F et al (2005) Non-alcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54:3541–3546PubMedCrossRefGoogle Scholar
  61. 61.
    Targher G, Bertolini L, Rodella S et al (2007) Non-alcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 30:2119–2121PubMedCrossRefGoogle Scholar
  62. 62.
    Haring R, Wallaschofski H, Nauck M et al (2009) Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl-transpeptidase levels. Hepatology 50:1403–1411PubMedCrossRefGoogle Scholar
  63. 63.
    Calori G, Lattuada G, Ragogna F et al (2011) Fatty liver index (FLI) and mortality: the Cremona Study in the 15th year of follow up. Hepatology 54:145–152PubMedCrossRefGoogle Scholar
  64. 64.
    McKimmie RL, Daniel KR, Carr J et al (2008) Hepatic steatosis and subclinical cardiovascular disease in a cohort enriched for type 2 diabetes: the diabetes heart study. Am J Gastroenterol 103:3029–3035PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Petit JM, Guiu B, Terriat B et al (2009) Non-alcoholic fatty liver is not associated with carotid intima-media thickness in type 2 diabetic patients. J Clin Endocrinol Metab 94:4103–4106PubMedCrossRefGoogle Scholar
  66. 66.
    Targher G, Bertolini L, Padovani R, Poli F, Scala L et al (2006) Non-alcoholic fatty liver disease is associated with carotid artery wall thickness in diet-controlled type 2 diabetic patients. J Endocrinol Investig 29:55–60CrossRefGoogle Scholar
  67. 67.
    Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845PubMedCrossRefGoogle Scholar
  68. 68.
    Tilg H, Moschen AR (2010) Evolution of inflammation in non-alcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846PubMedCrossRefGoogle Scholar
  69. 69.
    Labruna G, Pasanisi F, Nardelli C, Tarantino G, Vitale DF et al (2009) UCP1-3826 AG + GG genotypes, adiponectin, and leptin/adiponectin ratio in severe obesity. J Endocrinol Investig 32:525–529CrossRefGoogle Scholar
  70. 70.
    Loria P, Lonardo A, Anania F (2013) Liver and diabetes. A vicious circle. Hepatol Res 43:51–64PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Starley BQ, Calcagno CJ, Harrison SA (2010) Non-alcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51:1820–1832PubMedCrossRefGoogle Scholar
  72. 72.
    Peyrou M, Bourgoin L, Foti M (2010) PTEN in liver diseases and cancer. World J Gastroenterol 16:4627–4633PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Nkontchou G, Cosson E, Aout M et al (2011) Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 96:2601–2608PubMedCrossRefGoogle Scholar
  74. 74.
    Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA (2012) Association of Thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus. Hepatology 55:1462–1472PubMedCrossRefGoogle Scholar
  75. 75.
    Wanless IR, Lentz JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12:1106–1110PubMedCrossRefGoogle Scholar
  76. 76.
    Adams LA, Lymp JF, St Sauver J et al (2005) The natural history of nonalcoholic fatty liver disease: a population based cohort study. Gastroenterology 129:113–121PubMedCrossRefGoogle Scholar
  77. 77.
    Adams LA, Harmsen S, St Sauver JL et al (2010) Non-alcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 105:1567–1573PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    The US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: OPTN/SRTR annual report: table 9.4a: transplant recipient characteristics, 1995 to 2004: recipients of deceased donor livers [Internet), Ann Arbor, MI. Available from http://www.optn.org/AR2005/904a_rec-dgn_li.htm. Accessed 2 May 2005
  79. 79.
    Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 364:829–841CrossRefGoogle Scholar
  80. 80.
    El-Serag HB, Tran T, Everhart JE et al (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468PubMedCrossRefGoogle Scholar
  81. 81.
    Welzel TM, Graubard BI, Zeuzem S et al (2011) Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEERMedicare database. Hepatology 54:463–471PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Paradis V, Zalinski S, Chelbi E et al (2009) Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49:851–859PubMedCrossRefGoogle Scholar
  83. 83.
    Ertle J, Dechêne A, Sowa JP et al (2011) Non-alcoholic fatty liver disease progresses to HCC in the absence of apparent cirrhosis. Int J Cancer 128:2436–2443PubMedCrossRefGoogle Scholar
  84. 84.
    Simo R, Hernandez C, Genesca J, Jardi R, Mesa J (1996) High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care 19:998–1000PubMedCrossRefGoogle Scholar
  85. 85.
    Ozyilkan E, Arslan M (1996) Increased prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. Am J Gastroenterol 91:1480–1481PubMedGoogle Scholar
  86. 86.
    Kawaguchi T, Yoshida T, Harada M et al (2004) Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through upregulation of suppressor of cytokine signalling 3. Am J Pathol 165:1499–1508PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Rubbia-Brandt L, Leandro G, Spahr L et al (2001) Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 39:119–124PubMedCrossRefGoogle Scholar
  88. 88.
    El-Serag HB, Everhart JE (2002) Diabetes increases the risk of acute hepatic failure. Gastroenterology 122:1822–1828PubMedCrossRefGoogle Scholar
  89. 89.
    Chan KA, Truman A, Gurwitz JH et al (2003) A cohort study of the incidence of serious acute liver injury in diabetic patients treated with hypoglycaemic agents. Arch Intern Med 163:728–734PubMedCrossRefGoogle Scholar
  90. 90.
    Zimmerman HJ (1991) Drug-induced liver disease. In: Zimmerman HJ (ed) Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver, 2nd edn. Lippincott Williams and Williams, Philadelphia, pp 427–456Google Scholar
  91. 91.
    Byrne CD, Targher G (2016) EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease: is universal screening appropriate? Diabetologia 59:1141–1144PubMedCrossRefGoogle Scholar
  92. 92.
    Sanyal AJ, Brunt EM, Kleiner DE, Kowdley K, Chalasani N, Lavine J, Ratziu V, McCullough A (2011) Endpoints and clinical trial design for non-alcoholic steatohepatitis. Hepatology 54(1):344–353PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L (2015) 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-US Food and Drug Administration Joint Workshop. Hepatology 61(4):1392–1405PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ et al (2005) Non-alcoholic steatohepatitis clinical research network. Design and validation of a histological scoring system for non-alcoholic fatty liver disease. Hepatology 41(6):1313–1321PubMedCrossRefGoogle Scholar
  95. 95.
    Thoma C, Day CP, Trenell MI (2012) Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol 56:255–266PubMedCrossRefGoogle Scholar
  96. 96.
    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B et al (2015) Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149:367–378PubMedCrossRefGoogle Scholar
  97. 97.
    Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A et al (2016) Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology 63:1875–1887PubMedCrossRefGoogle Scholar
  98. 98.
    Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB (2011) The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 57:1299–1313PubMedCrossRefGoogle Scholar
  99. 99.
    Boden G (2009) High- or low-carbohydrate diets: which is better for weight loss, insulin resistance, and fatty livers? Gastroenterology 136:1490–1492PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Perseghin G, Lattuada G, De Cobelli F et al (2007) Habitual physical activity is associated with the intra-hepatic fat content in humans. Diabetes Care 30:683–688PubMedCrossRefGoogle Scholar
  101. 101.
    Keating SE, Hackett DA, Parker HM, O’Connor HT, Gerofi JA et al (2015) Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol 63:174–182PubMedCrossRefGoogle Scholar
  102. 102.
    Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H et al (2017) Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review. J Hepatol 66:142–152PubMedCrossRefGoogle Scholar
  103. 103.
    Belfort R, Harrison SA, Brown K et al (2006) A placebo-controlled trial of Pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355:2297–2307PubMedCrossRefGoogle Scholar
  104. 104.
    Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J et al (2016) Long-term Pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 165:305–315PubMedCrossRefGoogle Scholar
  105. 105.
    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD et al (2008) Randomized, placebo-controlled trial of Pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135:1176–1184PubMedCrossRefGoogle Scholar
  106. 106.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM et al (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M et al (2010) LIDO Study Group. Long-term efficacy of rosiglitazone in non-alcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51:445–453PubMedCrossRefGoogle Scholar
  108. 108.
    Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M (2010) Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 28:220–224PubMedCrossRefGoogle Scholar
  109. 109.
    Karpen SJ (2013) Do therapeutic bile acids hit the sweet spot of glucose metabolism in NAFLD? Gastroenterology 145:508–510PubMedCrossRefGoogle Scholar
  110. 110.
    Cipriani S, Mencarelli A, Palladino G, Fiorucci S (2010) FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 51:771–784PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF et al (2015) Farnesoid X nuclear receptor ligand Obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965PubMedCrossRefGoogle Scholar
  112. 112.
    Gupta NA, Mells J, Dunham RM et al (2010) Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51:1584–1592PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ben-Shlomo S, Zvibel I, Shnell M et al (2011) Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 54:1214–1223PubMedCrossRefGoogle Scholar
  114. 114.
    Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D et al (2016) Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387:679–690PubMedCrossRefGoogle Scholar
  115. 115.
    Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K et al (2012) Bariatric surgery and long-term cardiovascular events. JAMA 307:56–65PubMedCrossRefGoogle Scholar
  116. 116.
    Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H et al (2015) Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 149:379–388PubMedCrossRefGoogle Scholar
  117. 117.
    Staels B, Rubenstrunk A, Noel B et al (2013) Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58:1941–1952PubMedCrossRefGoogle Scholar
  118. 118.
    Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P et al (2016) GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of non-alcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:1147–1159PubMedCrossRefGoogle Scholar
  119. 119.
    Ito D, Shimizu S, Inoue K, Saito D, Yanagisawa M et al (2017) Comparison of Ipragliflozin and Pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a randomized, 24-week, open-label, active-controlled trial. Diabetes Care.  https://doi.org/10.2337/dc17-0518 (Epub ahead of print) CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Shibuya T, Fushimi N, Kawai M, Yoshida Y, Hachiya H et al (2017) Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab.  https://doi.org/10.1111/dom.13061 PubMedCrossRefGoogle Scholar
  121. 121.
    Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D et al (2015) High prevalence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 100:2231–2238PubMedCrossRefGoogle Scholar
  122. 122.
    Bellentani S, Dalle Grave R, Suppini A, Marchesini G, The Fatty Liver Italian Network [FLIN] (2008) Behavior therapy for nonalcoholic fatty liver disease: the need for a multidisciplinary approach. Hepatology 47:746–754PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • M. G. Radaelli
    • 1
  • F. Martucci
    • 1
  • S. Perra
    • 1
  • S. Accornero
    • 1
  • G. Castoldi
    • 2
  • G. Lattuada
    • 1
  • G. Manzoni
    • 1
  • G. Perseghin
    • 1
    • 2
  1. 1.Dipartimento di Medicina e RiabilitazionePoliclinico di MonzaMonzaItaly
  2. 2.Dipartimento di Medicina e ChirurgiaUniversità degli Studi di Milano BicoccaMilanItaly

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