Nonalcoholic Fatty Liver Disease

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Nonalcoholic Fatty Liver Disease. a growing worldwide problem. may be the most common disease encountered in general medical practice and in health check up. . Nonalcoholic Fatty Liver Disease. affects 10 to 24% of the general population in various countries 57% to 74% in obese persons 2.6% of

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Nonalcoholic Fatty Liver Disease

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1. Nonalcoholic Fatty Liver Disease Clinical Implication and Related Biochemical Studies

2. Nonalcoholic Fatty Liver Disease a growing worldwide problem. may be the most common disease encountered in general medical practice and in health check up.

3. Nonalcoholic Fatty Liver Disease affects 10 to 24% of the general population in various countries 57% to 74% in obese persons 2.6% of children 22.5% to 52% of obese children

4. Nonalcoholic Fatty Liver Disease mistaken as “non-progressive” or “of nothing” previously

5. Nonalcoholic Fatty Liver Disease simple steatosis, steatohepatitis, fibrosis, cirrhosis

6. Progression of Disease Progression of fibrosis : histologically in 32% to 37% of NASH. Risk of developing liver complications within 7 years NASH/advanced stage fibrosis Mortality, liver related 12 to 25% within 7 to 10 years in cirrhotic N

7. Progression of Disease Cirrhosis: Age Activity of NASH Mortality, liver related 12 to 25% within 7 to 10 years in cirrhotic N

8. Progression of Disease Cryptogenic cirrhosis Many cryptogenic cirrhosis are probably NAFLD Liver transplant Account for 4 to 10 % of liver transplant in America : End Stage of NAFLD

9. Clinical Condition Related to NAFLD Obesity T2DM Hyperlipidemia Insulin Resistant Impaired glucose tolerance Cardiovascular Disease Celebrovascular Disease Endocrine Disease

11. Nonalcoholic Fatty Liver Disease Lugwig coined the term nonalcoholic steatohepatitis (NASH) in 1980 Angulo P. nonalcoholic fatty liver disese in New England Journal of Medicine 2002

12. Pathogenic Relationships Metabolic studies in human and animals Inextricable relationships between vieral adiposity (central obesity), steatosis and insulin resistance

13. Insulin Resistance In peripheral tissues, muscle and adipose, decreased uptake of glucose In liver, failure of insulin to stimulate glycogen synthesis and suppress gluconeogenesis? failure of insulin to downregulate hepatic glucose production

14. Steatosis before hepatic IR Sequence of steatosis before hepatic IR By several studies in animals. Samuel VT. J Biol Chem 2004, Kraegen EW. Diabetes 1991 Correction of steatosis reverses hepatic IR in leptin-deficient ob/ob mice. Friedman J. Nature 2002; 415:268

15. Steatosis (in human, current focus) Mitochondrial defects as primary cause of steatosis Impaired B-oxidation of fatty acid Possibly have a genetic basis, worsened by aging and environmental factors Lowell BB. Science 2005; 307. Browning JD. J Clin Invest 2004; 114.

16. Steatosis cause hepatic IR

17. Peripheral IR a role with NASH Nearly universal association of NASH, usually with two of more features of metabolic syndrome Recurrent of NASH after liver transplant? metabolic milieu rather then primary hepatic defect

18. Key Issue in NASH Whether hepatic IR ?cellular injury and hepatic inflammation Or inflammation and steatosis? hepatic IR Recent studies: latter by block hepatic insulin receptor signaling

19. Hepatic and peripheral insulin receptor signaling IR? intracellular accumulation of fatty acids and their metabolites? activate protein kinase C isoforms Protein kinase C catalyzes serin/threonine phosphorylation of the insulin receptor substrate IRS-1 and IRS-2? impair the tyrosine phophorylation required for signaling IRS-2 are critical in liver

20. Other serine/threonine kinases Inhibitor of kappaB kinase IKKB-ß C-Jun N-terminal kinase Both can be activated by oxidative stress or indirectly by engagement of the TNFa type 1 receptor Cytokines induce suppressors of cytokine signaling (SOCS)?another family protein? mediate hepatic IR

21. Hepatic Expression of Cytochrome P450 (CYP)2E1 Creates Oxidative Stress Associate with impaired insulin receptor signaling in both NASH and some forms of experimental steatohepatitis

22. TNFa Activation of IKK-B or c-Jun N-terminal kinase, induction IL-6 which induce SOCS3? womorsening hepatic insulin resistance A candidate molecule in the transition of steatosis to steatohepatitis

23. Peripheral Insulin Resistance and failure of humoral mediator Resulting in steatosis and NASH Increased fatty acid uptake and synthesis (lipogenesis), suppression of mitochondrial B-oxidation, and impaired TG seretion as VLDL Alternatively, steatosis and NASH coud be attributable to the combined effect of severe peripheral IR and relative failure of humoral (adipokine) mediators that combat the effects of high insulin levels and fasting hyperglycemia on hepatic lipid turnover.

24. Adiponectin Adiponectin + transport of fatty acids into mitrochondria for B-oxidation and – hepatic fatty acid synthesis? countering the effect of high insulin Low serum adiponectin distinguishes NASH from simple steatosis Decreased adiponectin before T2DM and cardiovasular disease

25. Adiponectin Adiponectin + transport of fatty acids into mitrochondria for B-oxidation and – hepatic fatty acid synthesis? countering the effect of high insulin Low serum adiponectin distinguishes NASH from simple steatosis Decreased adiponectin before T2DM and cardiovasular disease

26. Adiponectin Administer adiponectin reverse steatohepatitis by combating release of TNF-a Masaki T. Hepatology 2004; 40:19 A potential therapeutic targets in NASH Larter C. J Hepatol 2006; 44:253

27. Transition of Steatosis to Steatohepatitis

28. Lipotoxicity Capacity of hepatocytes to safely store fat is overwhelmed by Continued uptake Impaired egress of fatty acids Fatty acid become toxic?lipotoxicity

29. Lipotoxicity Cause cell death by Direct effects of lipid mediators on apoptosis Alternatively, liberation of oxidized lipids and their peroxidation products ?recruiting and perpetuating the inflammatory response

30. The First Hit Steatosis Fatty liver: predisposed to forms of injury that involve oxidant stress

31. The Second Hit TNFa Oxidative Stress Cytokines Chemokines

32. The Second Hit Exaggerated release of TNFa in rodent models of steatosis Over-express CYP2E1 in animal model and in NASH human Increased CCL2/MCP-1 (CC-chemokine ligand/ Monocyte chemoattractant protein) in NASH Haukeland JW. J of Hepatol 2006; 44:1167

33. The Second Hit Recent data: TNFa may not be essential Oxidative stress may recruit inflammation via activcation of nuclear factor-kappa B

35. Grading for steatohepatitis Grade 1, mild Grade 2, moderate Grade 3, severe

36. Staging for fibrosis Stage 1: zone 3 perivenular, perisinusoidal, or pericellular fibrosis; focal or extensive Stage 2: as above, with focal or extensive periportal fibrosis Stage 3: bridging fibrosis, focal or extensive Stage 4: cirrhosis

41. Possible Topics Prospective observation of NAFLD with different biochemical marker  Cohort studies of NAFLD with different biochemical marker Controversy in leptin in NAFLD Inflammatory mediators in NAFLD other than TNF  

42. IR in NAFLD and its relation with clinical parameter  Prevalence of NAFLD in type II DM  Impaired glucose tolerance vs NAFLD (normal ALT/ abnormal ALT?)   Differences between Metabolic syndrome or type II DM with or without NAFLD***

43. The influence of steatosis in the treatment with chronic hepatitis C Predictor of type II DM Predictor of fibrosis Treatment with Metformin or other insulin sensitizer**********

44. Health Control Normal BMI Normal fasting blood sugar, TG, cholesterol, normal OGGT Normal AST/ALT/Bilirubin/rGT No evidence of hepatitis including HBV, HCV, autoimmune disease Alcohol consumption <20g/day

45. Essential Recording Age, Gender Body weight, body height, waist circumference, hip circumference, BMI Alcohol consumption (amount/frequency, at least g/day) History of liver disease, including HBV, HCV, autoimmune disease, DM, hyperlipidema Family History of above mentioned (at least first degree)

46. NAFLD and Related Biochemical Studies Including OGTT and, IR Arthrometry: BMI, Wait/hip ratio AST/ALT, rGT, Bilirubin, ALP Cholesterol, HDL, TG, UA SBP/DBP OGTT Insulin Resistance ANA, Ferritin

47. Ultrasound Increased echogenicity, increased L/K contrast Attenuation Lost of detail Sandford, NL. Walsh, P. Matis, C, et al.Gastroenterology 1985: 89: 186-91. Is Ultrasonography useful in the assessment of diffuse parenchyma liver disease. Yang PM. Huang, GT. Lin, JT, et al. J Formosan Med Asoc 1988; 87: 966- 77 Riley TR, Mendoza A, Bruno MA. Bedside ultrasound can predict nonalcoholic fatty liver disease in the hands of clinicians using a prototype image. Dig Dis Sci 2006; 51(5): 982- 985 Needleman L, Kurtz AB, Rifkin MD, et al. Sonography of diffuse benign liver disease: Accuracy of pattern recognition and grading. AJR 1986; 146:1011- 1015 Riley TR, Kahn A. Risk factors and ultrasound can predict chronic hepatitis caused by nonalcoholic fatty liver disease. Dig Dis Sci 2006; 51(1): 41- 44

48. HOMA Homa index: insulin concentration (µU/ml)x fasting glucose concentration (mmol/l)/22.5 Cutoff level: 2.5 for adult Cutoff level: 3.16 for aldolescent Keskin M, et al. Padiactric 2005 March

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