Alcoholic liver 2005 ust


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Alcoholic liver 2005 ust

  1. 1. ALCOHOLIC FATTY LIVER DISEASE Diana Alcantara-Payawal, MD
  2. 2. Histologic Spectrum Fatty Liver FAT Fat + Inflam +/- Fibrosis Scar + Nodules +/- Fat Alcoholic Hepatitis ? 40% Cirrhosis 10- 35 % 8-20% NORMAL 90-100 %
  3. 3. Risk factors for alcoholic liver disease: <ul><li>Quantity </li></ul><ul><li>Gender </li></ul><ul><li>Hepatitis C: Accelerated disease progression, more advanced histology and decreased survival rates </li></ul><ul><li>Genetics: alcohol dehydrogenase, acetaldehyde dehydrogenase </li></ul><ul><li>Malnutrition: </li></ul>
  4. 4. Major forms of alcoholic liver disease: <ul><li>Fatty liver </li></ul><ul><li>Alcoholic hepatitis </li></ul><ul><li>Cirrhosis </li></ul>Time to develop liver disease = to amount of alcohol consumed One beer, 4 ounces of wine, one ounce of 80% spirits = 12 grams of alcohol Men:60-80 gm/day for 10 years Women 20-40 gm/day for 10 years
  5. 5. Women’s Risk of ALD <ul><li>Women alcoholics begin drinking later, and drink less alcohol per day than men </li></ul><ul><li>Women drink for fewer years than men and have a lower cumulative alcohol exposure at the time of diagnosis of cirrhosis </li></ul><ul><li>Women die of ALD at a 10 year earlier age than men. </li></ul>
  6. 6. Susceptibility of females to hepatotoxicity of ethanol <ul><li>More pronounced fatty liver </li></ul><ul><li>Less induction of fatty acid binding protein (higher FFA) </li></ul><ul><li>Increased plasma endotoxin levels </li></ul><ul><li>Increased CD 13 and LBP </li></ul><ul><li>More severe pericentral hypoxia </li></ul><ul><li>More marked activation of NfkB </li></ul>
  7. 7. Enzymatic pathways of ethanol metabolism Ethanol Acetaldehyde Acetate NAD+ NADH NAD+ NADH Acetaminophen CCl4 Toxic metabolites, reactive oxygen species CYP2E1 ADH ALDH
  8. 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. 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. 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. 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. 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. 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. 14. Consequences of Kupffer cell activation by ethanol Cytokines TNFa IL-1, IL-6 PDGF Eicosanoids ROS MIP2, IL-8 Activated Kupffer Cell
  15. 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
  16. 16. Laboratory findings <ul><li>Increased GGT :Not specific to alcohol, easily inducible, elevated in all forms of fatty liver </li></ul><ul><li>Macrocytosis (Increased PMN). If >5500/uL predictws asevere alcoholic hepatitis when discriminatory index is >32 </li></ul><ul><li>AST>ALT by 2 fold </li></ul><ul><li>High CDT </li></ul><ul><li>High gamma globulin (IgA) </li></ul><ul><li>High uric acid </li></ul><ul><li>High serum lactate </li></ul><ul><li>Low albumin </li></ul><ul><li>Low protime </li></ul><ul><li>High triglycerides </li></ul>
  17. 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. 18. Lifestyle modification EtOH intake Obesity Smoking
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