gastroenterology 3rd year

1. ALCOHOLIC FATTY LIVER DISEASE Diana Alcantara-Payawal, MD

2. Histologic Spectrum Fatty Liver FAT Fat + Inflam +/- Fibrosis Scar + Nodules +/- Fat Alcoholic Hepatitis ? 40% Cirrhosis 10- 35 % 8-20% NORMAL 90-100 %

7. Enzymatic pathways of ethanol metabolism Ethanol Acetaldehyde Acetate NAD+ NADH NAD+ NADH Acetaminophen CCl4 Toxic metabolites, reactive oxygen species CYP2E1 ADH ALDH

8. New mechanism for control of lipid metabolism FFA Induction of FFA oxidation, transport and export genes PPAR/RXR Sterol SREBP Induction of sterol/fat synthesizing genes + + + - Ethanol - +

9. FFA HOOC(CH 2 ) N CH 3 L-FABP FFA Triglycerides PL,CE Peroxismal B Oxidation AOX Microsomal B Oxidation CYP4A1 Mitochondrial B Oxidation CPT-1 HOOC(CH 2 ) N CH 3 Hepatic Fatty Acid Metabolism

10. HC ROS TNFa TGFb IL-6 IL-1 TXA2 HSC Inflammation; Hypoxia KC Ethanol and acetaldehyde EC Injury Death (necrosis, apoptosis) Fibrogenesis Adhesion Molecule cytokines ROS TNFa Activating factors

11. Activated HSC Irreversible activation maybe mediated by HSC products, retinoid depletion, and changes in the matrix ECM protein collagen I, fibronectin Activation of HSC TGF B

12. Interactions of ethanol and endotoxin Endotoxin Scavenger receptor Ethanol Activation of Kupffer cell LBP Endotoxin CD14 Ethanol induces LBP and CD14 Kupffer cell FIRST HIT Second Hit

13. Activation of Hepatic Stellate Cells The very earliest event in HSC activation is unknown Receptors present TNFa, IL-1 Matrix changes ? Activation of NF kB Via degradation of IkB Induction of PDGF-R, TGFB-Rs, ICAM-1

14. Consequences of Kupffer cell activation by ethanol Cytokines TNFa IL-1, IL-6 PDGF Eicosanoids ROS MIP2, IL-8 Activated Kupffer Cell

15. CHRONIC ETHANOL INGESTION Acetaldehyde Lipid peroxidation Aldehydes Protein adducts MAA adducts Autoantibodies Autoimmune response Collagen Fibrotic response Intestine + Endotoxin Kuppfer cells Hepatocyte PPARg/RXR Stellate cell TNF-a TGF-B IL-1 IL-6 Inflammatory Response

17. Maddrey’s discriminatory function 4.6(protime- control in seconds) + bilirubin (umol/L)/17 >32 assess severity of AH Alcoholic hepatitis has poor prognosis Presence of ascites, variceal hemmorrhage, deep encephalopathy or hepatorenal syndrome has dismal prognosis

18. Lifestyle modification EtOH intake Obesity Smoking