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Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem

From NAFLD to NASH. Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem. An Illustration: a real case. 1978 : D.Z. a 26 year old medical student, ALT 56 iu , hepatomegaly - etiology? 1985: DM type 2, Hypertension, heperlipidemia

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Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem

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  1. From NAFLD to NASH Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem

  2. An Illustration: a real case 1978: D.Z. a 26 year old medical student, ALT 56 iu, hepatomegaly- etiology? 1985: DM type 2, Hypertension, heperlipidemia 1996: 44 year old, MI/CABG 2000: Chronic Liver Disease

  3. The one million $ question Had we known in 1978 everything we know today about NAFLD, could we change the natural history? Could we prevent the metabolic syndrome? Heart disease? Liver disease?

  4. Could Netanyahu have normal liver enzymes? Normal serum glucose?Could Obama have NAFLD?

  5. Who has normal liver? NAFLD? NASH?

  6. 0-1999 DON’T WORRY IT IS JUST FATTY LIVER 1999- DO WORRY- FATTY LIVER DISEASE 2004- MOREOVER- THE METABOLIC SYNDROME 2006- CARDIO- VASCULAR DISEASE

  7. Primary NAFLD prevalence (US) Men Women NAFLD NAFLD 21% 38% Normal Normal 95%CI 31-45% 95% CI 14-28%

  8. Fatty Liver vs. Metabolic Syndrome P<0.001 71 % Prevalence of fatty liver among the metabolic syndrome Prevalence of metabolic syndrome among fatty liver

  9. Liver Biopsy, the Gold Standard is neither Gold nor Standard

  10. Liver Biopsy for patients with NAFLD • Is it the gold standard for the diagnosis? • Who should undergo biopsy? • When should we biopsy? • Can we biopsy everybody? Liver International 2007

  11. Sampling Variability of Liver Biopsy in Nonalcoholic Fatty Liver Disease Sampling Variability of Liver Biopsy in Nonalcoholic Fatty Liver Disease

  12. Non-invasive markers of liver injury • Fibroscan- elastometry • MRI • BioMarkers • FibroTest-ActiTes-FibroMax • Other markers published • Hyaluronicacid • SpectroTest: HA, A2M, TIMP1 • GlycoCirrhotest • APRI: AST, platelets • Forns: Age,GGT, Platelets • Rosenberg: HA, PIIIP, TIMP1 • Leroy: TIMP1, MMP2 • FPI: Age, CT, AST, Insulin, OH • Laine: HA, CarbohydrateDeficT, Transferrin • AP: Age-platelets

  13. So why is NAFLD so dangerous?

  14. From Champs-Elysées to ICCU ICCU The Metbolic Syndrome 40-60 years old NAFLD <40 year old

  15. Why Paris and not Rome? Please calculate BMI !!!

  16. ICCU

  17. A RISK FACTOR OR A MARKER OF CVD? NAFLD CARDIO- VASCULAR THE METABOLIC SYNDROME

  18. NASH: PATHOGENESIS

  19. Who are the players in the Pathogenesis of NASH? Adipose Tissue DietaryFactors Kupffer cells FFA Inflammation Fibrogenesis PNPLA3 Mutation Adipokins & Soluble Mediators Insulin Signalling Immune pathway Heritability Microbiota

  20. Endocrine, paracrine, autocrine, intracrine Insulin, TNF, adiponectin, resistin etc Diet Lifestyle Genetics Adipocyte mass Transcriptional regulators LXR, FXR, SREBP,PPARs Synthesis Utilization LIPIDS Import Export DISEASE PHENOTYPE Hepatic Steatosis: a complex system Greenfield and Sanyal, Current opinion in Gastroenterol, 2008

  21. Update on Therapy for NASH Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem Paris Nov 2013

  22. 1st hit Steatosis (vulnerable) Normal Oxidative Stress 2nd hit Steatohepatitis

  23. Free Fatty Acids Flux Dietary TG- Chylomicrons Peripheral adipocytes Endogenous fatty acid synthesis Mitochondrial B oxidation VLDL

  24. Free Fatty Acids Flux Dietary TG- Chylomicrons Peripheral adipocytes Endogenous fatty acid synthesis HSL apoB-100 Mitochondrial B oxidation VLDL

  25. NASH Pathogenesis

  26. Role of FFA

  27. The Immune Pathways Implicated in the Pathogenesis of NASH Blue-stimulation Red-inhibition

  28. The 1148M PNPLA3 Mutation & Progressive Liver Disease

  29. The inflammasome is a multiproteinoligomer consisting of caspase 1, PYCARD, NALP and sometimes caspase 5 The inflammasome is responsible for activation of inflammatory processes

  30. A microbiome is the ecological community of comenssal, symbiotic, and pathogenic microorganisms that literally share our body space

  31. The intestinal microbiome modulates insulin resistance and metabolism Gravitz, Nature 2012, 485, S12-13

  32. So, in summary, who are the players in the Pathogenesis of NASH? Adipose Tissue DietaryFactors Kupffer cells FFA Inflammation Fibrogenesis PNPLA3 Mutation Adipokins & Soluble Mediators Insulin Signalling Immune pathway Heritability Microbiota

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