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Diabetes and Liver Disease

  • Robert HirtenEmail author
  • Henry C. BodenheimerJr.
  • David Bernstein
Reference work entry

Abstract

The prevalence of diabetes is rising in the United States, with a similar increase in associated complications. Diabetes has significant deleterious effects on many organ systems including the liver. Hepatic complications include the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatocellular carcinoma, liver failure, and the onset of diabetes following liver transplantation. There is significant morbidity and mortality associated with these conditions. Understanding the clinical characteristics and pathophysiology of diabetes related liver disease affords care providers an opportunity to prevent, monitor, and treat these complications. In order to successfully impact clinical outcomes the specific treatment of hepatic disorders must be coordinated with the management of underlying diabetes. While limited treatments currently exist, new therapeutic modalities are being developed that target insulin resistance, cytokine induced injury, and fatty acid metabolism.

Keywords

Nonalcoholic fatty liver disease Cirrhosis Cryptogenic Cirrhosis Nonalcoholic steatohepatitis Hepatocellular carcinoma Hepatic steatosis Vitamin E Liver Transplantation Acute Liver Failure Hepatitis C 

References

  1. 1.
    Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. J Am Med Assoc. 2001;286:1195–200.CrossRefGoogle Scholar
  2. 2.
    Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefPubMedGoogle Scholar
  4. 4.
    Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44(4):865–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Ratziu V, Bonyhay L, DiMartino V, et al. Survival, liver failure and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Marchesini G, Brizi M, Bainchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Li Z, Clark J, Diehl AM. The liver in obesity and type 2 diabetes mellitus. Clin Liver Dis. 2002;6(4):867–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Vikram NK, Pandey RM, Misra A, et al. Non-obese (body mass index < 25 kg/m2) Asian Indians with normal waist circumference have high cardiovascular risk. Nutrition. 2003;19:503–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Ikai E, Ishizaki M, Suzuki Y, et al. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens. 1995;9(2):101–5.PubMedGoogle Scholar
  10. 10.
    Assy N, Kaita K, Mymin D, et al. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45(10):1929–34.CrossRefPubMedGoogle Scholar
  11. 11.
    Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124–31.CrossRefPubMedGoogle Scholar
  12. 12.
    Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology. 2005;41:372–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Jimba S, Nakagami S, Takahashi M, et al. Prevalence of nonalcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese Adults. Diabet Med. 2005;22:1141–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Machado M, Marques-Vidal P, Cortez-Pinto H, et al. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006;45:600–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systemic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Teli MR, James OF, Burt AD, et al. The natural history of nonalcoholic fatty liver disease. A follow-up study. Hepatology. 1995;22:1714–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389–97.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.CrossRefPubMedGoogle Scholar
  21. 21.
    Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121(1):91–100.CrossRefPubMedGoogle Scholar
  23. 23.
    Argo CK, Northup PG, Al-Osaimi A, et al. Systemic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):371–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42(1):132–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Soderberg C, Stal 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Adams LA, Lymp JF, St. Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Caldwell SH, Oelsner DH, Lezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Bhala N, Angulo P, van der Poorten D, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54(4):1208–16.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bugianesi E. Non alcoholic steatohepatitis (NASH) and cancer. Clin Liver Dis. 2007;11:191–207.CrossRefPubMedGoogle Scholar
  32. 32.
    Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–62.CrossRefPubMedGoogle Scholar
  33. 33.
    Roesch-Dietlen F, Dorantes-Cuellar A, Carrillo-Toledo MG, et al. Frequency of NAFLD in a group of patients with metabolic syndrome in Veracruz. Mexico Rev Gastroenterol Mex. 2006;71(4):446–52.PubMedGoogle Scholar
  34. 34.
    Leite NC, Salles GF, Araujo AL, et al. Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int. 2009;29(1):113–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Younossi ZM, Gramlich T, Matteoni CA, et al. Nonalcoholic fatty liver disease and type 2 diabetes. Clin Gastroenterol Hepatol. 2004;2:262–5.CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    de Marco R, Locatelli F, Zoppini G, et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diab Care. 1999;22(5):756–61.CrossRefGoogle Scholar
  38. 38.
    Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab. 2013;98(9):3637–43.CrossRefPubMedGoogle Scholar
  39. 39.
    Yamazaki H, Tsuboya T, Tsuji K, et al. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes mellitus. Diabetes Care. 2015;38(9):1673–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999;84(5):1513–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Taitano AA, Markow M, Finan JE, et al. Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis. J Gastrointest Surg. 2015;19(3):429–36.CrossRefPubMedGoogle Scholar
  42. 42.
    Silverman JF, Pories WJ, Caro J. Liver pathology in diabetes mellitus and morbid obesity. Clinical, pathological, and biochemical considerations. Pathol Annu. 1989;24(Pt 1):275–302.PubMedGoogle Scholar
  43. 43.
    Marchesini G, Avagnina S, Barantani G, et al. Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. J Endocrinol Invest. 2005;28(4):333–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Papadia FS, Marinari GM, Camerini G, et al. Liver damage in severely obese patients: a clinical-biochemical-morphologic study on 1,000 liver biopsies. Obes Surg. 2004;14(7):952–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Marchesini G, Bugianesi E, Forlani G, et al. Non-alcoholic steatohepatitis in patients cared in metabolic units. Diabetes Res Clin Pract. 2004;63(2):143–51.CrossRefPubMedGoogle Scholar
  46. 46.
    Day CP, James UF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114(4):842–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Chitturi S, Farrell G. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis. 2001;21(1):27–41.CrossRefPubMedGoogle Scholar
  48. 48.
    Yang SQ, Lin HZ, Lane MD, et al. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A. 1997;94(6):2557–62.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Dong W, Simeonova PP, Galluci R, et al. Cytokine expression in hepatocytes: role of oxidant stress. J Interferon Cytokine Res. 1998;18(8):629–38.CrossRefPubMedGoogle Scholar
  50. 50.
    Palmer MA, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990;99:1408–13.CrossRefPubMedGoogle Scholar
  51. 51.
    Ueno T, Sugawara H, Sujaku K. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27:103–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Dixon JB, Bhathal PS, Hughs NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–54.CrossRefPubMedGoogle Scholar
  53. 53.
    Rajala MW, Scherer PE. The adipocyte at the crossroads of energy, homeostasis, inflammation and atherosclerosis. Endocrinology. 2003;144:3765–73.CrossRefPubMedGoogle Scholar
  54. 54.
    Uygun A, Kadayifci A, Yesilova Z, et al. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2000;95:3584–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Pajvani UB, Scherer PE. Adiponectin: systemic contributor to insulin sensitivity. Curr Diab Rep. 2003;3:207–13.CrossRefPubMedGoogle Scholar
  56. 56.
    Ailhaud G, Teboul M, Massiera F. Angiotensinogen, alihaud differentiation and fatty mass enlargement. Curr Opin Clin Nutr Metab Care. 2002;5:385–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Boden G, Cheung P, Stein TP, et al. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab. 2002;283:E12–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Katsuki A, Sumida Y, Murashima S, et al. Serum levels of tumor necrosis factor-α are increased in obese patients with non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab. 1998;83:859–62.PubMedGoogle Scholar
  59. 59.
    Giby VG, Ajith TA. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease. World J Hepatol. 2014;6(8):570–9.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Hui JM, Hodge A, Farrell GC, et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40(1):46–54.CrossRefPubMedGoogle Scholar
  61. 61.
    Ueki K, Kondo T, Tseng YH, et al. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance and the metabolic syndrome of the mouse. Proc Natl Acad Sci U S A. 2004;101:10422–7.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hotamisligil GS, Peraldi A, Budavari A, et al. IRS-1 mediated kinase activity in TNF-α and obesity induced insulin resistance. Science. 1996;271:665–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Wei Y, Rector RS, Thyfault JP, et al. Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol. 2008;14(2):193–9.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sudheesh NP, Ajith TA, Mathew J, et al. Ganoderma lucidum protects liver mitochondrial oxidative stress and improves the activity of electron transport chain in carbon tetrachloride intoxicated rats. Hepatol Res. 2012;42(2):181–91.CrossRefPubMedGoogle Scholar
  65. 65.
    Haukeland JW, Damås JK, Konopski Z, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. 2006;44(6):1167–74.CrossRefPubMedGoogle Scholar
  66. 66.
    Mas E, Danjoux M, Garcia V, et al. IL-6 deficiency attenuates murine diet-induced non-alcoholic steatohepatitis. PLoS One. 2009;4(11), e7929.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology. 2005;146(8):3417–27.CrossRefPubMedGoogle Scholar
  68. 68.
    Friedman JM, Leibel R, Siegel DS, et al. Molecular mapping of the mouse ob mutation. Genomics. 1991;11(4):1054–62.CrossRefPubMedGoogle Scholar
  69. 69.
    Cohen P, Zhao C, Cai X, et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest. 2001;108(8):1113–21.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Fuentes T, Ara I, Guadalupe-Grau A, et al. Leptin receptor 170 kDa (OB-R170) protein expression is reduced in obese human skeletal muscle: a potential mechanism of leptin resistance. Exp Physiol. 2010;95(1):160–71.CrossRefPubMedGoogle Scholar
  71. 71.
    Kern PA, Saghizadeh M, Ong JM, et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95(5):2111–9.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Spranger J, Kruke A, Mohlig M, et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet. 2003;361:226–8.CrossRefPubMedGoogle Scholar
  73. 73.
    Savvidou S, Hytiroglou P, Orfanou-Koumerkeridou H, et al. Low serum adiponectin levels are predictive of advanced hepatic fibrosis in patients with NAFLD. J Clin Gastroenterol. 2009;43(8):765–72.CrossRefPubMedGoogle Scholar
  74. 74.
    Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–95.CrossRefPubMedGoogle Scholar
  75. 75.
    Ding X, Saxena NK, Lin S, et al. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166(6):1655–69.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Arner P. Not all fat is alike. Lancet. 1998;351:1301–2.CrossRefPubMedGoogle Scholar
  77. 77.
    Nielsen S, Guo Z, Johnson CM, et al. Splanchnic lipolysis in human obesity. J Clin Invest. 2004;113:1582–8.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in the liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–50.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Otgonsuren M, Stepanova M, Gerber L, et al. Antropometric and clinical factors associated with mortality in subjects with nonalcoholic fatty liver disease. Dig Dis Sci. 2013;58(4):1132–40.CrossRefPubMedGoogle Scholar
  80. 80.
    Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab. 2003;29(5):478–85.CrossRefPubMedGoogle Scholar
  81. 81.
    Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634–42.CrossRefPubMedGoogle Scholar
  82. 82.
    Washington K, Wright K, Shyr Y, et al. Hepatic stellate cell activation in nonalcoholic steatohepatitis and fatty liver. Hum Pathol. 2000;31(7):822–8.CrossRefPubMedGoogle Scholar
  83. 83.
    Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48(2):206–11.Google Scholar
  84. 84.
    Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–87.CrossRefPubMedGoogle Scholar
  85. 85.
    Solga SF, Diehl AM. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol. 2003;38(5):681–7.CrossRefPubMedGoogle Scholar
  86. 86.
    Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343–50.CrossRefPubMedGoogle Scholar
  87. 87.
    Drenick EJ, Fisler J, Johnson D, et al. Hepatic steatosis after intestinal bypass-prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenteorlogy. 1982;82(3):535–48.Google Scholar
  88. 88.
    Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62(12):1787–94.CrossRefPubMedGoogle Scholar
  89. 89.
    Sanyal AJ, Campbell-Sargent C, Mirashahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183–92.CrossRefPubMedGoogle Scholar
  90. 90.
    Koruk M, Taysi S, Savas MC. Oxidative stress and enzymatic antioxidant status in patients with nonalcoholic steatohepatitis. Ann Clin Lab Sci. 2004;34(1):57–62.PubMedGoogle Scholar
  91. 91.
    Mavrelis PG, Ammon HV, Gleysteen JJ, et al. Hepatic free fatty acids in alcoholic liver disease and morbid obesity. Hepatology. 1983;3(2):226–31.CrossRefPubMedGoogle Scholar
  92. 92.
    Chalasani N, Gorski JC, Asghar MS, et al. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology. 2003;37(3):544–50.CrossRefPubMedGoogle Scholar
  93. 93.
    Sreekumar R, Rosado B, Rasmussen D, et al. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology. 2003;38(1):244–51.CrossRefPubMedGoogle Scholar
  94. 94.
    Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31(3):430–4.CrossRefPubMedGoogle Scholar
  95. 95.
    Perez-Carreras M, Del Hoyo P, Martin MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38(4):999–1007.CrossRefPubMedGoogle Scholar
  96. 96.
    Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000;21(3):49–98.CrossRefPubMedGoogle Scholar
  97. 97.
    Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34(6):1158–63.CrossRefPubMedGoogle Scholar
  98. 98.
    Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40(1):185–94.CrossRefPubMedGoogle Scholar
  99. 99.
    Paradies G, Paradies V, Ruggiero FM, et al. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(39):14205–18.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    LeMasters JJ. Rusty notions of cell injury. J Hepatol. 2004;40(4):696–8.CrossRefPubMedGoogle Scholar
  101. 101.
    Woods Jr JR, Plessinger MA, Fantel A. An introduction to reactive oxygen species and their possible roles in substance abuse. Obstet Gynecol Clin North Am. 1998;25(1):219–36.CrossRefPubMedGoogle Scholar
  102. 102.
    George DK, Goldwurm S, MacDonald G, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114(2):311–8.CrossRefPubMedGoogle Scholar
  103. 103.
    Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol. 1999;31(3):421–9.CrossRefPubMedGoogle Scholar
  104. 104.
    Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53(2):448–57.CrossRefPubMedGoogle Scholar
  105. 105.
    Valenti L, Facanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2010;138(3):905–12.CrossRefPubMedGoogle Scholar
  106. 106.
    MacDonald GA, Powell LW. More clues to the relationship between hepatic iron and steatosis: an association with insulin resistance? Gastroenterology. 1999;117(5):1241–4.CrossRefPubMedGoogle Scholar
  107. 107.
    Vendemiale G, Grattagliano I, Caraceni P, et al. Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status. Hepatology. 2001;33(4):808–15.CrossRefPubMedGoogle Scholar
  108. 108.
    Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. 2007;11(1):75–104.CrossRefPubMedGoogle Scholar
  109. 109.
    McClain CJ, Hill DB, Song Z, et al. S-adenosylmethionine, cytokines, and alcoholic liver disease. Alcohol. 2002;27(3):185–92.CrossRefPubMedGoogle Scholar
  110. 110.
    Mato JM, Alvarez L, Ortiz P, et al. S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol Ther. 1997;73(3):265–80.CrossRefPubMedGoogle Scholar
  111. 111.
    Lavine JE. Vitamin E, treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136(6):734–8.CrossRefPubMedGoogle Scholar
  112. 112.
    Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98(11):2485–90.CrossRefPubMedGoogle Scholar
  113. 113.
    Mia X, Hua J, Mohamood AR, et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007;46(5):1519–29.CrossRefGoogle Scholar
  114. 114.
    Younossi ZM, Baranova A, Ziegler K, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology. 2005;42(3):665–74.CrossRefPubMedGoogle Scholar
  115. 115.
    Speliotes EK, Butler JL, Palmer CD, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. 2010;52(3):904–12.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Loomba R, Schork N, Chen CH, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149(7):1784–93. pii:S0016-5085(15)01179-8.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Falck-Ytter Y, Younossi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndrome. Semin Liver Dis. 2001;21:17–26.CrossRefPubMedGoogle Scholar
  118. 118.
    Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001;35(2):195–9.CrossRefPubMedGoogle Scholar
  119. 119.
    Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–92.CrossRefPubMedGoogle Scholar
  120. 120.
    Nugent C, Younossi ZM. Evaluation and management of obesity-related nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:432–41.CrossRefPubMedGoogle Scholar
  121. 121.
    Chalasani N, Younossi Z, Lavine J, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–609.CrossRefPubMedGoogle Scholar
  122. 122.
    Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in non-alcoholic fatty liver disease. Gastroenterology. 2002;123:745–50.CrossRefPubMedGoogle Scholar
  123. 123.
    Limanond P, Raman SS, Lassman C, et al. Macrovesicular hepatic steatosis in living related donors: correlation between CT and histological findings. Radiology. 2004;230:276–80.Google Scholar
  124. 124.
    Fishbein M, Castro F, Cheruku S, et al. Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis and ultrasound. J Clin Gastroenterol. 2005;39:619–25.CrossRefPubMedGoogle Scholar
  125. 125.
    Schiano TD, Azeem S, Bodian CA, et al. Importance of specimen size in accurate needle liver biopsy evaluation of patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3(9):930–5.CrossRefPubMedGoogle Scholar
  126. 126.
    Ratzui V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.CrossRefGoogle Scholar
  127. 127.
    Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2:165–73.CrossRefPubMedGoogle Scholar
  128. 128.
    Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMedGoogle Scholar
  129. 129.
    Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(27):9026–37.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Tapper E, Sengupta N, Hunink M, et al. Cost-effectiveness evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastrography. Am J Gastroenterol. 2015;110(9):1298–304.CrossRefPubMedGoogle Scholar
  131. 131.
    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.CrossRefPubMedGoogle Scholar
  132. 132.
    Andersen T, Gluud C, Franzmann NB, et al. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12(2):224–9.CrossRefPubMedGoogle Scholar
  133. 133.
    Chavez-Tapai NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010;(1):CD007340.Google Scholar
  134. 134.
    Dixon JB. Surgical treatment for obesity and its impact on non-alcoholic steatohepatitis. Clin Liver Dis. 2007;11(1):141–54.CrossRefPubMedGoogle Scholar
  135. 135.
    Silverman EM, Sapala JA, Appelman HD. Regression of hepatic steatosis in morbidly obese persons after gastric bypass. Am J Clin Pathol. 1995;104(1):23–31.Google Scholar
  136. 136.
    Friis R, Vazin ND, Akbarpour F, et al. Effect of rapid weight loss with supplemented fasting on liver tests. J Clin Gastroenterol. 1987;9(2):204–7.CrossRefPubMedGoogle Scholar
  137. 137.
    Harrison SA, Fincke C, Helinski D, et al. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther. 2004;20(6):623–8.CrossRefPubMedGoogle Scholar
  138. 138.
    Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96(2):519–25.CrossRefPubMedGoogle Scholar
  139. 139.
    Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38(4):1008–17.CrossRefPubMedGoogle Scholar
  140. 140.
    Promrat K, Lutchman G, Uwaif GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39(1):188–96.Google Scholar
  141. 141.
    Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358(9285):893–4.CrossRefPubMedGoogle Scholar
  142. 142.
    Nair S, Diehl AM, Wiseman M, et al. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20(1):23–8.CrossRefPubMedGoogle Scholar
  143. 143.
    Harrison SA, Fecht W, Brunt EM, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49(1):80–6.CrossRefPubMedGoogle Scholar
  144. 144.
    Zelber-Sagi S, Kessler A, Brazowsky E, et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4(5):639–44.CrossRefPubMedGoogle Scholar
  145. 145.
    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.CrossRefPubMedGoogle Scholar
  146. 146.
    Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2(12):1107–15.CrossRefPubMedGoogle Scholar
  147. 147.
    Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004;19(5):537–44.Google Scholar
  148. 148.
    Duseja A, Murlidharan R, Bhansali A, et al. Assessment of insulin resistance and effect of metformin in nonalcoholic steatohepatitis – a preliminary report. Indian J Gastroenterol. 2004;23(1):12–5.PubMedGoogle Scholar
  149. 149.
    Hasegawa T, Yoneda M, Nakamura K, et al. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther. 2001;15(10):1667–72.CrossRefPubMedGoogle Scholar
  150. 150.
    Ersoz G, Gunsar F, Karazu Z, et al. Management of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatment. Turk J Gastroenterol. 2005;16(3):124–8.PubMedGoogle Scholar
  151. 151.
    Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66–75.CrossRefPubMedGoogle Scholar
  152. 152.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.CrossRefPubMedGoogle Scholar
  153. 153.
    Musso G, Gambino R, Cassader M, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52(1):79–104.CrossRefPubMedGoogle Scholar
  154. 154.
    Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Hoofnagle JH, Van Natta ML, Kleiner DE, et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013;38(2):134–43.CrossRefPubMedGoogle Scholar
  156. 156.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomized, placebo-controlled trial. Lancet. 2015;385(9972):956–65.CrossRefPubMedGoogle Scholar
  157. 157.
    Bower G, Toma T, Harling L, et al. Bariatric surgery and non-alcoholic fatty liver disease: a systemic review of liver biochemistry and histology. Obes Surg. 2015;25(12):2280–9. Accessed http://www.ncbi.nlm.nih.gov/pubmed/25917981 ahead of print.CrossRefPubMedGoogle Scholar
  158. 158.
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMedGoogle Scholar
  159. 159.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50.CrossRefPubMedGoogle Scholar
  160. 160.
    Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer worldwide incidence and trends. Gastroenterology. 2004;127:5–16.CrossRefGoogle Scholar
  161. 161.
    Liang Y, Yang A, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology. 2012;56(4):1409–17.CrossRefPubMedGoogle Scholar
  162. 162.
    Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–40.CrossRefPubMedGoogle Scholar
  163. 163.
    El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004;126(2):460–8.CrossRefPubMedGoogle Scholar
  164. 164.
    Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54(4):533–9.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Welzel TM, Graubard BI, Zeuzem S, et al. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011;54(2):463–71.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Coughlin SS, Calle EE, Teras LR, et al. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159(12):1160–7.CrossRefPubMedGoogle Scholar
  167. 167.
    El-Serag HB, Richardson PA, Everhart JE, et al. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol. 2001;96(8):2462–7.CrossRefPubMedGoogle Scholar
  168. 168.
    Pocha C, Kolly P, Dufour JF. Nonalcoholic fatty liver disease related hepatocellular carcinoma: a problem of growing magnitude. Semin Liver Dis. 2015;35(3):304–17.CrossRefPubMedGoogle Scholar
  169. 169.
    Fu SC, Huang YW, Wang TC, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with new onset diabetes: a nationwide cohort study. Aliment Pharmacol Ther. 2015;41(11):1200–9.CrossRefPubMedGoogle Scholar
  170. 170.
    Huang YW, Wang TC, Yang SS, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis C patients with new onset diabetes: a nation-wide cohort study. Aliment Pharmacol Ther. 2015;42(7):902–11.CrossRefPubMedGoogle Scholar
  171. 171.
    Moore MA, Park CB, Tsuda H. Implications of the hyperinsulinemia-diabetes-cancer link for preventive efforts. Eur J Cancer Prev. 1998;7:89–107.CrossRefPubMedGoogle Scholar
  172. 172.
    Kim SO, Park JG, Lee YI. Increased expression of the insulin-like growth factor 1 (IGF-1) receptor gene in hepatocellular carcinoma cell lines: implications of IGF-1 receptor gene activation by hepatitis B virus X gene products. Cancer Res. 1996;56:3831–6.PubMedGoogle Scholar
  173. 173.
    Tanaka S, Wands JR. Insulin receptor substrate -1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta 1-induced apoptosis. Cancer Res. 1996;56(15):3391–4.PubMedGoogle Scholar
  174. 174.
    Hu W, Feng Z, Eveleigh J, et al. The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis. 2002;23:1781–9.CrossRefPubMedGoogle Scholar
  175. 175.
    Pikarsky E, Porat RM, Stein I, et al. NF-kappa B functions as a tumor promoter in inflammation-associated cancer. Nature. 2004;431:461–6.CrossRefPubMedGoogle Scholar
  176. 176.
    Farrell G. Insulin resistance, obesity, and liver cancer. Clin Gastroenterol Hepatol. 2014;12(1):117–9.CrossRefPubMedGoogle Scholar
  177. 177.
    Ikeda Y, Shimada Y, Hasegawa H, et al. Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection. Hepatology. 1998;27(6):1567–71.CrossRefPubMedGoogle Scholar
  178. 178.
    Huo TI, Lui WY, Huang YH, et al. Diabetes mellitus is a risk factor for hepatic decompensation in patients with hepatocellular carcinoma undergoing resection: a longitudinal study. Am J Gastroenterol. 2003;98(10):2293–8.CrossRefPubMedGoogle Scholar
  179. 179.
    Komura T, Mizukoshi E, Kita Y, et al. Impact of diabetes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis. Am J Gastroenterol. 2007;102(9):1939–46.CrossRefPubMedGoogle Scholar
  180. 180.
    Ting CT, Chen RC, Chen CC, et al. Diabetes worsens the surgical outcomes in cirrhotic patients with hepatocellular carcinoma. Tohoku J Exp Med. 2012;227(1):73–81.CrossRefPubMedGoogle Scholar
  181. 181.
    Huo TI, Wu JC, Lui WY, et al. Differential mechanism and prognostic impact of diabetes mellitus on patients with hepatocellular carcinoma undergoing surgical and nonsurgical treatment. Am J Gastroenterol. 2004;99(8):1479–87.CrossRefPubMedGoogle Scholar
  182. 182.
    Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C infection. Hepatology. 1999;29(2):328–33.CrossRefPubMedGoogle Scholar
  183. 183.
    Lecube A, Hernandez C, Genesca J, et al. Glucose abnormalities in patients with hepatitis C virus infection: epidemiology and pathogenesis. Diabetes Care. 2006;29(5):1140–9.CrossRefPubMedGoogle Scholar
  184. 184.
    Yoo HY, Thulvath PJ. The effect of insulin-dependent diabetes mellitus on outcome of liver transplantation. Transplantation. 2002;74:1007–12.CrossRefPubMedGoogle Scholar
  185. 185.
    Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation. 2001;72(6):1066–72.CrossRefPubMedGoogle Scholar
  186. 186.
    Zein NN, Abdulkarim AS, Weisner RH, et al. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol. 2000;32(2):209–17.CrossRefPubMedGoogle Scholar
  187. 187.
    Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, et al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol. 2009;15(3):280–8.CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Petrides AS, DeFronzo RA. Glucose metabolism in cirrhosis: a review with some perspectives for the future. Diabetes Metab Rev. 1989;5(8):691–709.CrossRefPubMedGoogle Scholar
  189. 189.
    Navasa M, Bustamante J, Marroni C, et al. Diabetes mellitus after liver transplantation: prevalence and predictive factors. J Hepatol. 1996;25:64–71.CrossRefPubMedGoogle Scholar
  190. 190.
    Trail KC, Strata RJ, Larsen JL, et al. Results of liver transplantation in diabetic recipients. Surgery. 1993;114:650–8.PubMedGoogle Scholar
  191. 191.
    Younossi ZM, Stepanova M, Saab S, et al. The impact of type 2 diabetes and obesity on the long-term outcomes of more than 85,000 liver transplant recipients in the US. Aliment Pharmacol Ther. 2014;40(6):686–94.CrossRefPubMedGoogle Scholar
  192. 192.
    Hoehn RS, Singhal A, Wima K, et al. Effect of pretransplant diabetes on short-term outcomes after liver transplantation: a national cohort study. Liver Int. 2015;35(7):1902–9.CrossRefPubMedGoogle Scholar
  193. 193.
    Moon JI, Barbeito R, Faradji RN, et al. Negative impact of new-onset diabetes mellitus on patient and graft survival after liver transplantation: long-term follow up. Transplantation. 2006;82(12):1625–8.CrossRefPubMedGoogle Scholar
  194. 194.
    John PR, Thulvath PJ. Outcomes of patients with new-onset diabetes mellitus after liver transplantation compared with those without diabetes mellitus. Liver Transpl. 2002;8:708–13.CrossRefPubMedGoogle Scholar
  195. 195.
    Krentz AJ, Dmitrewski J, Mayer D, et al. Postoperative glucose metabolism in liver transplant recipients: a two-year prospective randomized study of cyclosporine versus FK 506. Transplantation. 1994;57(11):1666–9.CrossRefPubMedGoogle Scholar
  196. 196.
    AlDosary AA, Ramji AS, Elliot TG, et al. Post-liver transplantation diabetes mellitus: an association with hepatitis C. Liver Transpl. 2002;8(4):356–61.CrossRefPubMedGoogle Scholar
  197. 197.
    Saab S, Shpaner A, Zhao Y, et al. Prevalence and risk factors for diabetes mellitus in moderate term survivors of liver transplantation. Am J Transplant. 2006;6(8):1890–5.CrossRefPubMedGoogle Scholar
  198. 198.
    Knobler H, Stagnaro-Green A, Wallenstein S, et al. Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol. 1998;26:30–3.CrossRefPubMedGoogle Scholar
  199. 199.
    Scantlebury V, Shapiro R, Fung J, et al. New onset diabetes in FK506 vs cyclosporine-treated kidney transplant recipients. Transplant Proc. 1991;23:3169–70.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Li DW, Lu TF, Hua XW, et al. Risk factors for new onset diabetes mellitus after liver transplantation: a meta-analysis. World J Gastroenterol. 2015;21(20):6329–40.CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Stegall MD, Everson G, Schroter G, et al. Metabolic complications after liver transplantation, diabetes, hypercholesterolemia, hypertension, and obesity. Transplantation. 1995;60(9):1057–60.PubMedGoogle Scholar
  202. 202.
    Soule JL, Olyaei AJ, Boslaugh TA, et al. Hepatitis C infection increases the risk of new onset diabetes after transplantation in liver allograft recipients. Am J Surg. 2005;189(5):552–7.CrossRefPubMedGoogle Scholar
  203. 203.
    Foxton MR, Quaglia A, Muiesan P, et al. The impact of diabetes mellitus on fibrosis progression in patients transplanted for hepatitis C. Am J Transplant. 2006;6(8):1922–9.CrossRefPubMedGoogle Scholar
  204. 204.
    Ericzon B, Groth C, Bismuth H, et al. Glucose metabolism in liver transplant recipients treated with FK506 or cyclosporine in the European multicentre study. Transpl Int. 1994;7 Suppl 1:S11–4.CrossRefPubMedGoogle Scholar
  205. 205.
    Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation. 1999;68(3):396–402.CrossRefPubMedGoogle Scholar
  206. 206.
    Dumortier J, Bernard S, Bouffard Y, et al. Conversion from tacrolimus to cyclosporine in liver transplanted patients with diabetes mellitus. Liver Transpl. 2006;12(4):659–64.CrossRefPubMedGoogle Scholar
  207. 207.
    Reuben A. Long-term management of the liver transplant patient: diabetes, hyperlipidemia, and obesity. Liver Transpl. 2001;7(11 Suppl 1):S13–21.CrossRefPubMedGoogle Scholar
  208. 208.
    Regelmann MO, Goldis M, Arnon R, et al. New-onset diabetes mellitus after pediatric liver transplantation. Pediatr Transplant. 2015;19(5):452–9.CrossRefPubMedGoogle Scholar
  209. 209.
    Davidson J, Wilkinson A, Dantal J, et al. New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation. 2003;75(10 Suppl):S3–s24.Google Scholar
  210. 210.
    Liu LU, Schiano TD. Long-term care of the liver transplant recipient. Clin Liver Dis. 2007;11(2):397–416.CrossRefPubMedGoogle Scholar
  211. 211.
    Charlton MC, Kasparova P, Weston S, et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001;7(7):608–14.CrossRefPubMedGoogle Scholar
  212. 212.
    Kim WR, Poterucha JJ, Porayko MK, et al. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation. 1996;62:1802–5.CrossRefPubMedGoogle Scholar
  213. 213.
    Bhagat V, Mindikoglu AL, Nudo CG, et al. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transpl. 2009;15(12):1814–20.CrossRefPubMedGoogle Scholar
  214. 214.
    Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. Am J Transplant. 2004;4(5):686–93.CrossRefPubMedGoogle Scholar
  215. 215.
    Yalamanchili K, Saadeh S, Klintmalm GB, et al. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transpl. 2010;16(4):431–9.PubMedGoogle Scholar
  216. 216.
    Poonawala A, Nair SP, Thuluvath PJ, et al. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case control study. Hepatology. 2000;32:689–93.CrossRefPubMedGoogle Scholar
  217. 217.
    Cantos MJ, Cales W, Sterling RK, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2001;7:363–73.CrossRefGoogle Scholar
  218. 218.
    El-Serag HB, Everhart JE. Diabetes increases the risk of acute liver failure. Gastroenterology. 2002;122:1822–8.CrossRefPubMedGoogle Scholar
  219. 219.
    Chan KA, Truman A, Gurwitz JH, et al. A cohort study of the incidence of serious acute injury in diabetic patients treated with hypoglycemic agents. Arch Intern Med. 2003;163:728–34.CrossRefPubMedGoogle Scholar
  220. 220.
    Edlin BR, Eckhardt BJ, Shu MA, et al. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353–63.CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Ferri C, Monti M, LaCivita L, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood. 1993;82(12):3701–4.PubMedGoogle Scholar
  222. 222.
    Blackard JT, Kemmer N, Sherman KE. Extrahepatic replication of HCV: insights into clinical manifestations and biological consequences. Hepatology. 2006;44(1):15–22.CrossRefPubMedGoogle Scholar
  223. 223.
    Mehta SH, Brancati FL, Sulkowski MS, et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–9.CrossRefPubMedGoogle Scholar
  224. 224.
    Knobler H, Schihmanter R, Ziforni A, et al. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc. 2000;75(4):355–9.CrossRefPubMedGoogle Scholar
  225. 225.
    Bahtiyar G, Shin JJ, Aytaman A, et al. Association of diabetes and hepatitis C infection: epidemiologic evidence and pathophysiologic insights. Curr Diab Rep. 2004;4(3):194–8.CrossRefPubMedGoogle Scholar
  226. 226.
    White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systemic review and meta-analysis. J Hepatol. 2008;49(5):831–44.CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Lecube A, Hernandez C, Genesca J, et al. High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care. 2004;27(5):1171–5.CrossRefPubMedGoogle Scholar
  228. 228.
    Thuluvath PJ, John PR. Association between hepatitis C, diabetes mellitus, and race. A case-control study. Am J Gastroenterol. 2003;98(2):438–41.PubMedGoogle Scholar
  229. 229.
    Taura N, Ichikawa T, Hamasaki K, et al. Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients. Am J Gastroenterol. 2006;101(12):2752–9.CrossRefPubMedGoogle Scholar
  230. 230.
    Petit JM, Bour JB, Galland-Jos C, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35(2):279–83.CrossRefPubMedGoogle Scholar
  231. 231.
    Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology. 2003;125(6):1695–704.CrossRefPubMedGoogle Scholar
  232. 232.
    Moriya K, Yotsuyangi H, Shintani Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol. 1997;78(Pt 7):1527–31.CrossRefPubMedGoogle Scholar
  233. 233.
    Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126(3):840–8.CrossRefPubMedGoogle Scholar
  234. 234.
    Miyamoto H, Moriishi K, Moriya K, et al. Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol. 2007;81(4):1727–35.CrossRefPubMedGoogle Scholar
  235. 235.
    Walsh MJ, Jonsson JR, Richardson MM, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55(4):529–35.CrossRefPubMedPubMedCentralGoogle Scholar
  236. 236.
    Castera L, Chouteau P, Hezode C, et al. Hepatitis C virus-induced hepatocellular steatosis. Am J Gastroenterol. 2005;100(3):711–5.CrossRefPubMedGoogle Scholar
  237. 237.
    Lecube A, Hernandez C, Genesca J, et al. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: a case-control study. Diabetes Care. 2006;29(5):1096–101.CrossRefPubMedGoogle Scholar
  238. 238.
    Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38(6):1384–92.CrossRefPubMedGoogle Scholar
  239. 239.
    Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102(3):570–6.CrossRefPubMedGoogle Scholar
  240. 240.
    Conjeevaram HS, Wahed AS, Afdhal N, et al. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology. 2011;140(2):469–77.CrossRefPubMedGoogle Scholar
  241. 241.
    Kawaguchi Y, Mizuta T, Oza N, et al. Eradication of hepatitis C virus by interferon improves whole-body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C. Liver Int. 2009;29(6):871–7.CrossRefPubMedGoogle Scholar
  242. 242.
    Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50–6.CrossRefPubMedGoogle Scholar
  243. 243.
    Romero-Gomez M, Fernandez-Rodriguez CM, Andrade RJ, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721–7.CrossRefPubMedGoogle Scholar
  244. 244.
    Giordanino C, Bugianesi E, Smedile A, et al. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol. 2008;103:2481–7.CrossRefPubMedGoogle Scholar
  245. 245.
    Recommendations for testing, managing, and treating hepatitis C. AASLD/IDSA/IAS–USA; Updated Aug 2015; Accessed Oct 2015. Available from: http://www.hcvguidelines.org
  246. 246.
    Asselah T, Rubbia-Brandt L, Marcellin P, et al. Steatosis in chronic hepatitis C: why does it really matter? Gut. 2006;55(1):123–30.CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Hwang SJ, Lee SD. Hepatic steatosis and hepatitis C: still unhappy bedfellows? J Gastroenterol Hepatol. 2011;26 Suppl 1:96–101.CrossRefPubMedGoogle Scholar
  248. 248.
    Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130(6):1636–42.CrossRefPubMedGoogle Scholar
  249. 249.
    Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16(2):185–94.CrossRefPubMedGoogle Scholar
  250. 250.
    Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128(2):334–42.CrossRefPubMedGoogle Scholar
  251. 251.
    Adinolfi L, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33(6):1358–64.CrossRefPubMedGoogle Scholar
  252. 252.
    Jackel-Cram C, Babiuk L, Liu Q, et al. Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core. J Hepatol. 2007;46(6):999–1008.CrossRefPubMedGoogle Scholar
  253. 253.
    Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130(6):1661–9.CrossRefPubMedGoogle Scholar
  254. 254.
    Kumar D, Farrell GC, Fung C, et al. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology. 2002;36(5):1266–72.CrossRefPubMedGoogle Scholar
  255. 255.
    Ratziu V, Munteanu M, Charlotte F, et al. Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol. 2003;39(6):1049–55.CrossRefPubMedGoogle Scholar
  256. 256.
    D‘Souza R, Sabin C, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005;100(7):1509–15.CrossRefPubMedGoogle Scholar
  257. 257.
    Castera L, Hezode C, Roudot-Thoraval F, et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut. 2003;52(2):288–92.CrossRefPubMedPubMedCentralGoogle Scholar
  258. 258.
    Westin J, Nordlinder H, Lagging M, et al. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol. 2002;37(6):837–42.CrossRefPubMedGoogle Scholar
  259. 259.
    Harrison SA, Brunt EM, Qazi RA, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3(6):604–9.CrossRefPubMedGoogle Scholar
  260. 260.
    Romero-Gomez M, Del Mar VM, Andrade R, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128(3):636–41.CrossRefPubMedGoogle Scholar
  261. 261.
    Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38(1):75–85.CrossRefPubMedGoogle Scholar
  262. 262.
    Westin J, Lagging M, Dhillon AP, et al. Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection. J Viral Hepat. 2007;14(1):29–35.CrossRefPubMedGoogle Scholar
  263. 263.
    Monazahian M, Bohme I, Bonk S, et al. Low density lipoprotein receptor as a candidate receptor for hepatitis C virus. J Med Virol. 1999;57(3):223–9.CrossRefPubMedGoogle Scholar
  264. 264.
    Ikeda M, Abe K, Yamada M, et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology. 2006;44(1):117–25.CrossRefPubMedGoogle Scholar
  265. 265.
    O‘Leary JG, Chan JL, McMahon CM CM, et al. Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology. 2007;45(4):895–8.CrossRefPubMedGoogle Scholar
  266. 266.
    Eibl N, Gschwantler M, Ferenci P, et al. Development of insulin-dependent diabetes mellitus in a patient with chronic hepatitis C during therapy with interferon-alpha. Eur J Gastroenterol Hepatol. 2001;13(3):295–8.CrossRefPubMedGoogle Scholar
  267. 267.
    Ellervik C, Mandrup-Poulsen T, Nordestgaard BG, et al. Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study. Lancet. 2001;358(9291):1405–9.CrossRefPubMedGoogle Scholar
  268. 268.
    Utzschneider KM, Kowdley KV. Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. Nat Rev Endocrinol. 2010;6(1):26–33.CrossRefPubMedGoogle Scholar
  269. 269.
    Fida S, Myers MA, Whittingham S, et al. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. J Autoimmun. 2002;19(4):251–7.CrossRefPubMedGoogle Scholar
  270. 270.
    Nakasone H, Kinjo K, Yamashiro M, et al. A patient with primary biliary cirrhosis complicated with slowly progressive insulin-dependent diabetes mellitus. Intern Med. 2003;42(6):496–9.CrossRefPubMedGoogle Scholar
  271. 271.
    Oki K, Yamane K, Koide J, et al. A case of polyglandular autoimmune syndrome type III complicated with autoimmune hepatitis. Endocr J. 2006;53(5):705–9.CrossRefPubMedGoogle Scholar
  272. 272.
    Al-Hussaini AA, Alzahrani MD, Alenizi AS, et al. Autoimmune hepatitis related autoantibodies in children with type 1 diabetes. Diabetol Metab Syndr. 2014;6(1):38.CrossRefPubMedPubMedCentralGoogle Scholar
  273. 273.
    Kim WR, Flamm SL, Di Bisceglie AM, et al. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. 2008;47(4):1363–70.CrossRefPubMedGoogle Scholar
  274. 274.
    West J, Brousil J, Gazis A, et al. Elevated serum alanine transaminase in patients with type 1 or type 2 diabetes mellitus. QJM. 2006;99(12):871–6.CrossRefPubMedGoogle Scholar
  275. 275.
    Leeds JS, Forman EM, Morley S, et al. Abnormal liver function tests in patients with Type 1 diabetes mellitus: prevalence, clinical correlations and underlying pathologies. Diabet Med. 2009;26(12):1235–41.CrossRefPubMedGoogle Scholar
  276. 276.
    Sayuk GS, Elwing JE, Lisker-Melman M. Hepatic glycogenosis: an underrecognized source of abnormal liver function tests? Dig Dis Sci. 2007;52(4):936–8.CrossRefPubMedGoogle Scholar
  277. 277.
    Abaci A, Bekem O, Unuvar T, et al. Hepatic glycogenosis: a rare cause of hepatomegaly in Type 1 diabetes mellitus. J Diabetes Complications. 2008;22(5):325–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Robert Hirten
    • 1
    Email author
  • Henry C. BodenheimerJr.
    • 2
  • David Bernstein
    • 1
  1. 1.Division of HepatologyNorthwell Health System, Hofstra Northwell School of MedicineManhassetUSA
  2. 2.Division of Hepatology, Hofstra Northwell School of Medicine, Northwell HealthManhassetUSA

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