2009, Number 1
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Ann Hepatol 2009; 8 (1)
Hepatogenous diabetes.Current views of an ancient problem
García-Compean D, Jaquez-Quintana JO, Maldonado-Garza H
Language: Spanish
References: 72
Page: 13-20
PDF size: 135.89 Kb.
Text Extraction
Diabetes developed as a complication of cirrhosis is known as «hepatogenous diabetes» (HD). Around 30% to 60% of cirrhotic patients suffer from this metabolic disorder. Insulin resistance in muscular, hepatic and adipose tissues as well as hyperinsulinemia, seem to be pathophysiologic bases for HD. An impaired response of the islet β-cells of the pancreas and the hepatic insulin resistance are also contributing factors. Diabetes develops when defective oxidative and nonoxidative muscle glucose metabolism develops. Non-alcoholic fatty liver disease (NAFLD), alcoholic cirrhosis, chronic hepatitis C (CHC), and hemochromatosis are more frequently associated with HD. HD in early cirrhosis stages may be sub clinical. Only insulin resistance and glucose intolerance may be observed. As liver disease advances, diabetes becomes clinically manifest, therefore HD may be considered as a marker for liver function deterioration. HD is clinically different from that of type 2 DM since it is less frequently associated with microangiopathy and patients suffer complications of cirrhosis more frequently as well as increased mortality. Insulin resistance and HD associate to a decrease in the sustained response to antiviral therapy and an increased progression of fibrosis in patients with CHC. Diabetes treatment is complex due to liver damage and hepatotoxicity of oral hypoglycemic drugs that are frequently prescribed to these patients. This paper will review current concepts in relation to the pathopysiology, the impact on the clinical outcome of cirrhosis, and the therapy of HD. Finally, the role of HD as a risk factor for the occurrence and exacerbation of hepatocellular carcinoma (HCC) will also be reviewed.
REFERENCES
Hickman IJ, Macdonald GA. Impact of diabetes on the severity of liver disease. Is J Med 2007; 120: 829-34? Review. PMID: 17904449
Holstein A, Hinze S, Thiessen E, Plaschke A, Egberts EH. Clinical implications of hepatogenous diabetes in liver cirrhosis. J Gastroenterol Hepatol 2002; 17: 677-81. PMID: 12100613
Picardi A, D’Avola D, Gentilucci UV, Galati G, Fiori E, Spataro S, Afeltra A. Diabetes in chronic liver disease: from old concepts to new evidence. Diabetes Metab Res Rev 2006; 22: 274-83. PMID: 16506276
Custro N, Carroccio A, Ganci A, Scafidi V, Campagna P, Di Prima L, Montalto G. Glicemic homeostasis in chronic viral hepatitis and liver cirrhosis. Diabetes Metab 2001: 27, 476-81. PMID: 11547221
Postic C, Dentin R, Girad J. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 2004; 30: 398-408. PMID: 15671906
Barthel A, Schmoll D. Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2003; 285: 685-92. PMID: 12959935
Cotrozzi G, Casini Raggi V, Relli P, Buzzelli G. Role of the liver in the regulation of glucose metabolism in diabetes and chronic liver disease. Ann Ital Med Int 1997; 12: 84-91. PMID: 9333317
Tappy L, Minehira K. New data and new concepts on the role of the liver in glucose homeostasis. Curr Opin Clin Nutr Metab Care 2001; 4: 273-7. PMID: 11458020
Nielsen MF, Caumo A, Agar NK, Chandramouli V, Schumann WC, Landau BR, Schmitz O, Vilstrup H. Contribution of defects in glucose uptake to carbohydrate intolerance in liver cirrhosis: assessment during physiological glucose and insulin concentrations. Am J Physiol Gastrointest Liver Physiol 2005; 288: 1135-43. PMID: 15637182
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307-12. PMID: 11201732
El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126: 460-8. PMID: 14762783
Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007; 30: 734 - 43. PMID: 17327353
Lecube A, Hernández C, Genescà J, Esteban JI, Jardí R, Simó R. High prevalence of glucose abnormalities in patients with hepatitis C virus infection: a multivariate analysis considering the liver injury. Diabetes Care 2004; 27: 1171-5. PMID: 15111540
Nishida T, Tsuji S, Tsujii M, Arimitsu S, Haruna Y, Imano E, Suzuki M, Kanda T, Kawano S, Hiramatsu N, Hayashi N, Hori M. Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 2006; 101: 70-5. PMID: 16405536
El-Serag HB, Everhart JE. Diabetes increases the risk of acute hepatic failure. Gastroenterology 2002; 122: 1822-8. PMID: 12055590
Di Bisceglie AM. What every hepatologist should know about endocrinology: obesity, diabetes and liver disease. Gastroenterology 2004; 126: 604-5. Editorial. PMID: 14762798
Buzzelli G, Chiarantini E, Cotrozzi G, Relli P, Matassi L, Romanelli RG, Gentilini P. Estimate of prevalence of glucose intolerance in chronic liver disease. Degree of agreement among some diagnostic criteria. Liver 1988; 8: 354-9. PMID: 3265171
Niederau C, Fischer R, Pürschel A, Stremmel W, Häussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107-19. PMID: 8613000
Del Vecchio Blanco C, Gentile S, Marmo R, Carbone L, Coltorti M. Alterations of glucose metabolism in chronic liver disease. Diabetes Res Clin Pract 1990; 8: 29-36. PMID: 2153513
Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006; 40: 68-76. Review. PMID: 16340637
Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30: 1356-62. PMID: 10573511
Romero-Gómez M. Insulin resistance and hepatitis C. World J Gastroenterol 2006; 12: 7075-80. PMID: 17131467
Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2007; 13: 3540-53. Review. PMID: 17659704
Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592-9. PMID: 11033586
Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc 2000; 75: 355-9. PMID: 10761489
Anty R, Gelsi E, Giudicelli J, Mariné-Barjoan E, Gual P, Benzaken S, Saint-Paul MC, Sadoul JL, Huet PM, Tran A. Glucose intolerance and hypoadiponectinemia are already present in lean patients with chronic hepatitis C infected with genotype non-3 viruses. Eur J Gastroenterol Hepatol 2007; 19: 671-7. PMID: 17625437
Lecube A, Hernández C, Genescà J, Simó R. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care 2006; 29: 1096-101. PMID: 16644643
Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH, Paradis V, Vidaud M, Valla D, Bedossa P, Marcellin P. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134: 416-23. PMID: 18164296
Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology 2003; 125: 1695-704. PMID: 14724822
Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, Corpas R, Cruz M, Grande L, Vazquez L, Munoz-De-Rueda P, Lopez-Serrano P, Gila A, Gutierrez ML, Perez C, Ruiz-Extremera A, Suarez E, Castillo J. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128: 636-641. PMID: 15765399
Sanyal A J, Chand N, Comar K, Mirshahi F. Hyperinsulinemia blocks the inhibition of hepatitis C virus (HCV) replication by interferon: a potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic liver disease. Hepatology 2004; 40(4 Suppl. 1): 179A.
Simó R, Lecube A, Genescà J, Esteban JI, Hernández C. Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care 2006; 29: 2462-6. PMID: 17065685
Giordanino C, Bugianesi E, Smedile A, Ciancio A, Abate ML, Olivero A, Pellicano R, Cassader M, Gambino R, Bo S, Ciccone G, Rizzetto M, Saracco G. 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 Aug 8. PMID: 18702647
Zein NN, Abdulkarim AS, Wiesner RH, Egan KS, Persing DH. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol 2000; 32: 209-17. PMID: 10707860
Wei M, Gibbons LW, Mitchell TL, Kampert JB, Blair SN. Alcohol intake and incidence of type 2 diabetes in men. Diabetes Care 2000; 23: 18-22. PMID: 10857962
Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991; 90: 445-9. PMID: 2012084
37.Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994; 19: 616-27. PMID: 8119686
Petrides AS, Stanley T, Matthews DE, Vogt C, Bush AJ, Lambeth H. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology 1998; 28: 141-9. PMID: 9657106
Merli M, Leonetti F, Riggio O, Valeriano V, Ribaudo MC, Strati F, Tisone G, Casciani CU, Capocaccia L. Glucose intolerance and insulin resistance in cirrhosis are normalized alter liver transplantation. Hepatology 1999; 30: 649-54. PMID: 10462370
Petrides AS, Groop LC, Riely CA, DeFronzo RA. Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis. J Clin Invest 1991; 88: 561-70. PMID: 1864966
Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Mechanisms of hyperinsulinaemia in Child’s disease grade B liver cirrhosis investigated in free living conditions. Gut 2002; 51: 870-5. PMID: 12427792
Kim MG, Choi WC. Differential diagnosis of diabetes mellitus caused by liver cirrhosis and other type 2 diabetes mellitus. Korean J Hepatol 2006; 12: 524-9. PMID: 17237630
Flores-Rendón AR, González-González JA, García-Compean D, Maldonado-Garza HJ, Garza-Galindo AA. Model for end stage of liver disease (MELD) is better than the Child-Pugh score for predicting in-hospital mortality related to esophageal variceal bleeding. Ann Hepatol 2008; 7: 230-4. PMID: 18753990
Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh vs MELD. J Hepatol 2005; 42: 100-7. PMID: 15777564
Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic significance of diabetes in patients with cirrhosis. Hepatology 1994; 20: 119-25. PMID: 8020880
Moreau R, Delègue P, Pessione F, Hillaire S, Durand F, Lebrec D, Valla DC. Clinical characteristics and outcome of patients with cirrhosis and refractory ascites. Liver Int 2004; 24: 457-64. PMID: 15482343.
Kalaitzakis E, Olsson R, Henfridsson P, Hugosson I, Bengtsson M, Jalan R, Björnsson E. Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis. Liver Int 2007; 27: 1194-201. PMID: 17919230
Donadon V, Balbi M, Casarin P, Vario A, Alberti A. Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: Potential role of insulin. World J Gastroenterol 2008; 14: 5695-700. PMID: 18837086
Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 2008; 47: 1856-62. PMID: 18506898
Amarapurkar DN, Patel ND, Kamani PM. Impact of diabetes mellitus on outcome of HCC. Ann Hepatol 2008; 7: 148-51. PMID: 18626433
Garcia-Tsao G. Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 2005; 42: 85-92. PMID: 15777576
Cheruvattath R, Balan V. Infections in patients with end-stage liver disease. J Clin Gastroenterol 2007; 41: 403-11. PMID: 17413611
Roden M. Mechanisms of disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006; 2: 335-48. PMID: 16932311
Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006; 8: 264-80. Review. PMID: 16634986
Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology 2008; 15(2): 91-101. PMID: 18602801
Jonsson JR, Moschen AR, Hickman IJ, Richardson MM, Kaser S, Clouston AD, Powell EE, Tilg H. Adiponectin and its receptors in patients with chronic hepatitis C. J Hepatol 2005; 43: 929-36. PMID: 16139921
Svegliati-Baroni G, Ridolfi F, Di Sario A, Casini A, Marucci L, Gaggiotti G, Orlandoni P, Macarri G, Perego L, Benedetti A, Folli F. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology 1999; 29: 1743-51. PMID: 10347117
Tietge UJ, Böker KH, Manns MP, Bahr MJ. Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics. Am J Physiol Endocrinol Metab 2004; 287: 82-9. PMID: 15010338
Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, Lee SD. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004; 39: 746-53. PMID: 14999693
Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinol Metab Clin North Am 1999; 28: 555-77. Review. PMID: 10500931
Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004; 20: 23-8. PMID: 15225167
Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, Bhansali A. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol 2007; 6: 222-6. PMID: 18007551
Choudhury S, Hirschberg Y, Filipek R, Lasseter K, McLeod JF. Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis. J Clin Pharmacol 2000; 40: 634-40. PMID: 10868314
Gentile S, Turco S, Guarino G, Oliviero B, Annunziata S, Cozzolino D, Sasso FC, Turco A, Salvatore T, Torella R. Effect of treatment with acarbose and insulin in patients with non-insulin-dependent diabetes mellitus associated with non-alcoholic liver cirrhosis. Diabetes Obes Metab 2001; 3: 33-40. PMID: 11213597
Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, Magliano PL, Gravina AG, Torella R. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3: 184-91. PMID: 15704053
Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002; 25: 815-21. PMID: 11978674
Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, Coban S, Erden E, Soykan I, Emral R, Uysal AR, Ozden A. Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2008; 28: 200-8. PMID: 18445142
Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2008 Sep 2. PMID: 19065650
Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev 1994; 2: 2-18.
Blanco JJ, Herrero JI, Quiroga J, Sangro B, Gómez-Manero N, Pardo F, Cienfuegos JA, Prieto J. Liver transplantation in cirrhotic patients with diabetes mellitus: midterm results, survival, and adverse events. Liver Transpl 2001; 7: 226-33. PMID: 11244164
Perseghin G, Mazzaferro V, Sereni LP, Regalia E, Benedini S, Bazzigaluppi E, Pulvirenti A, Leão AA, Calori G, Romito R, Baratti D, Luzi L. Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 2000; 31: 694-703. PMID: 10706560
Portincasa P, Grattagliano I, Palmieri VO, Palasciano G. Current pharmacological treatment of nonalcoholic fatty liver. Curr Med Chem 2006; 13: 2889-900. PMID: 17073635