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Prof. and Consultant gastroenterology and diabetes Military Medical Academy

Insulin Resistance And Liver Fibrosis. Prof. and Consultant gastroenterology and diabetes Military Medical Academy. Prof. Dr. Abd-Elkhalek Hamed. MD. Insulin resistance (IR) and liver fibrosis. IR acts as major player in liver fibrosis (in addition to conventional host and viral factors )

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Prof. and Consultant gastroenterology and diabetes Military Medical Academy

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  1. Insulin Resistance And Liver Fibrosis Prof. and Consultant gastroenterology and diabetes Military Medical Academy Prof. Dr. Abd-Elkhalek Hamed. MD

  2. Insulin resistance (IR) and liver fibrosis IR acts as major player in liver fibrosis (in addition to conventional host and viral factors ) *This occurs specifically in NAFLD, *Common in western patients with chronic hepatitis C *And seems also associated with chronic hepatitis B.

  3. NASH IR and fibrosis Inflammation acts as a potential link between NAFLD and IR Besides the genetic susceptibility to develop NAFLD 1, the possible promoting factors include: 1) lipid intermediates accumulation. 2) Altered expression of pro inflammatory cytokines, 3) Mitochondrial dysfunction . 2

  4. lipid accumulation denovo lipogenesis. diacylglycerols & ceramides WAT hepatic and whole organism IR

  5. SOCs-3 Increased hepatic free cholesterol in NASH mTOR

  6. collagen synthesis LP Dysregulated iron overload might be a contributing factor for NAFLD advanced liver disease. Serum ferritin can be related to advanced fibrosis. (28)

  7. HCV and liver fibrosis Morbidity and mortality associated with HCV(accelerated progression of liver fibrosis, resistance to antiviral therapy &development of HCC) Co-factors associated with HCV infection. HCV induced liver disease. Metabolic disorders ( EHM): IR and steatosis (MS)

  8. CB2-63 QQ variant: more severe necroinflammation NS3, NS4, NS5: human KCs TNFa&IL-1B IL6,8 HCV core, NS3, &NS5 TLR NF-κB-microRNA-155 &TNF-α LPS (IBO) TNFa EHM EHM HCV Macrophages &HSCs inflammasomeIL-1β Factors associated with HCV chronicinflammation and its involvement in hepatic & EHM (IR/Steatosis) Rosa Zampino; Et al :World J Hepatol 2013 October 27; 5(10)

  9. Mechanism of HCV IR HCV core-induced SOCS3may promote proteosomal degradation of IRS1 and IRS2 through ubiquitination. HCV core TNFa SOCS-3 Takumi Kawaguchi;etal:A J of Pathology.2004;165 Romero-Gomez M; World J Gastroenterol. 2006 28;12(44) An infected liver secretes cytokines or soluble factors. peripheral IR in HCV infection . Musso G,et al Obes Rev. 2010;11 tyrosin kinase activity Hyperglycemia Modified from A. El-Zayadi &M. Anis; World J Gastroenterol 2012 January 21; 18(3)

  10. Ch hc: IR , steatosis &liver fibrosis MS Non G 3 HOMA IR+ ~50% OXS & proinflammatory cytokines * * HCC Goossen N& Negro F :Clin liver dis 2014 Feb.18(1) Modified from Alessandra Mangia & Maria Ripoli: Hepatol Int (2013) 7 (Suppl 2)

  11. Obesity and HBV fibrosis Promote immunosuppressive/pro-fibrogenic macrophage .3 In CHB fibrosis was associated with higher waist circumference , higher HBV-DNA copies/ml, and elevated ALT >40 IU/l. 2 Generally, viral infections and the MS/T2DM may coexist (large prevalence). BMI and HOMA-IR showed independent predictors to metabolic syndrome in patients with CHB.1

  12. Statements 1- Insulin resistance act as major liver disease modifier (NAFLD,G1CHC, CHB). B 2a 2- Liver fat was associated not only with hepatic IR but also with systemic IR . B 2b 3-In NASH steatosis induces ROS which trigger lipid peroxidation ,TNF-a and TGF-b which activate stellate cells with ensuing fibrogenesis. B 2a

  13. 4-Steatosis is confirmed as significantly and independently associated with fibrosis in CHC. A 1a 5-Most accredited evidence suggests that HCV induces IR development and that steatosis is a consequence of IT. Diabetes is also a consequence of IR leading to a more severe liver disease. B 2a 6-Post-load insulin resistance (by the oral glucose insulin sensitivity index ) is associated with severe hepatic fibrosis independently of steatosis in both NAFLD and CHC patients (more specific test than HOMA-IR). A 1b

  14. 7-BMI and HOMA-IR showed independent predictors to metabolic syndrome in patients with CHB. Fibrosis was associated with higher waist circumference. A 1b 8-In patients with CLD (NAFLD, G1CHC, CHB) , IR is independently linked to liver fibrosis only in patients with abnormal g-GT values. A 1b

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