Drug and toxin Induced liver Disease hepatotoxicity from chemicals Drug Induced liver Disease Liver is the mayor detoxifying organ in the body. Liver is subjet to potential damage from pharamceutical and environmental chemicals. Injury may result from: Direct toxicity Hepatic conversion of chemical. Immune mechanisms. Drug Induced liver Disease Liver damage from chemicals may be immediate or take months. Forms of liver injury: Hepatocyte necrosis Cholestasis Insidious onset of dysfunction. Drug induced chronic hepatitis is indistinguishable from chrinc viral hepatitis Drug Induced liver Disease Hepatocelular damage Chemicals Microvesicular fatty change Tetracycline, salicylates. Macrovesicular fatty change Ethanol, methrotexate. Massive necrosis Acetaminophen, insoniazid. Hepatitis, acute and chronic Methyldopa, phenytoin. Cholestasis Anabolic steroids, oral contraceptives. Drug Induced liver Disease Reye syndrome Mitochonrdial dysfuntion in liver and some other organs. Predminantly in children given acetylsalicylic acid cause of fever. Produces microvesicular steatosis with severe liver dysfuntion. Alcholic liver disease (Ethanol Metabolism) Epidemiology It develop only after a "threshold" dose 600 kg for men and 150 to 300 kg for women. one must consume eight 6-oz beers, 1 L of wine, daily for a period of 20 years Almost all people who exceed this threshold dose of ethanol exhibit some biochemical or histologic abnormality suggestive of liver injury Epidemiology fewer than 50% of people who ingest the calculated threshold dose of ethanol eventually develop serious alcoholic liver disease (e.g., alcoholic hepatitis or fibrosis). This suggest that the pathogenesis involves hereditary and enviromental disorders. Metabolism Liver. 3 enzyme systems: ADH MEOS Catalase. There exist several isoforms of the ADH enzyme (alfa, beta and gamma) and its variation changes the metabolic rate of ethanol. Asians (beta2) 20% faster. ADH acts alone when tissue levels do not exceed 10 mmol/L MEOS Cytochrome P-450 2E1 (CYP2E1) also the metabolism of other drugs such as acetaminophen, haloalkanes, and nitrosamines Chronic ethanol consumption up-regulates CYP2E1 CYP2E1-mediated ethanol oxidation yields reactive oxygen intermediates These are capable of provoking hepatocellular damage Acetaldehyde is a highly reactive and potentially toxic compound. It is metabolized by the ALDH . Half of Chinese people are deficient of this enzyme. Gastric metabolism Gastric ADH is implicated in first-pass metabolism of ethanol This limit the ethanol delivery to the portal circulation This enzyme is lower in Women. Eventos mórbidos Oxidant Stress DNA is sensitive to oxidant stress. Mitochondrial DNA is more susceptible than nuclear DNA to oxidative damage because of reduced protection by histone and nonhistone proteins and because of a decreased capacity for repair This causes deletion and mutations in DNA Alcoholic hepatitis Hepatocyte necrosis Infiltrate of neutrophils +/- fatty change +/- Mallory bodies +/- bile stasis Alcoholic liver disease Traditional spectrum of injury * Fatty change * Alcoholic hepatitis * Alcoholic cirrhosis MECHANISMS OF TISSUE DAMAGE 2 ways of damage: Indirect Ingestion of Ethanol Increases the release of endotoxins, from the gram negative bacteria in the natural flora of the intestinal tract Kupffer cells release toxic mediators:Reactive Oxygen Intermediates (ROIs) and Tumor Necrosis Factor (TNF) Synergize to cause oxidative damage to hepatocytes. the inflammatory response. Injury on structures of the liver A. Mitochondria Know as “megamitochondria” 25% of the patient with AAH. B. citokines. C. Kupfer Cells Secretes high levels of: TNF-alpha. This is a strong factor for adherence and activation of the leucocytes. IL-8- main mediator for neutrophils atraction D. Alterations of the hepatocelular protein Aldehide and ethanol change conformation of the surface proteins. In such way the immune system recognizes them as “Neoantigens E. Fibrosis Irreversible Occurs at only 10 – 15% of the alcoholics Due to activation of the Ito Cells (Fat store cells or perisinusoids cells) that are at Disse Spece. Function: normally stores vitamyn A, But en presence of Ethanol miofibrobñastic cells and Hipersecretes collagen fibrosis This liver is slightly enlarged and has a pale yellow appearance, seen both on the capsule and cut surface. This uniform change is consistent with fatty metamorphosis (fatty change). Massive hepatomegaly in an elderly alcoholic; the liver weighed 2010 grams. Note the tinge of yellow. Micro ballooning degeneration of hepatocytes, inflammation with neutrophils near mallory bodies Mallory bodies (abnormal perinuclear aggregations of cellular intermediate filament proteins “citokeratin”). Mallory's hyaline is seen here, but there are also neutrophils, necrosis of hepatocytes, collagen deposition, and fatty change. These findings are typical for acute alcoholic hepatitis. Such inflammation can occur in a person with a history of alcoholism who goes on a drinking "binge" and consumes large quantities of alcohol over a short time. Hyaline Mallory´s Bodies In globoid hepatocyte. There Is an interstitial infiltrate of Neutrophils. Mallory´s bodies are positive For CK immunoperoxidase. Clinical manifestations Vomiting Diarrhea Jaundice Psychological disturbances. Hepatic encephalopathy Ascites Bleeding esophageal Varices (varicose veins in the esophagus), abnormal blood clotting and coma. Main Reason for consulting: Pathologically, it results in an enlarged liver Painful to palpation. Enlargement is due to the accumulation of fat and the swelling of liver cells, and to the accumulation of proteins that are normally secreted. Lab AST to ALT ratio = 2:1 Alkaline Phosphatase elevated Gamma glutamyl transferase (GGT) Hypoalbuminemia Management Alcohol Cessation Increased caloric and protein intake Vitamin supplementation (Thiamine) Corticosteroids Prognosis Mortality 10-15% from acute hepatitis Cirrhosis develops in 50% of alcoholic hepatitis Alcoholic liver disease Immediate causes of death: * massive gastrointestinal * variceal haemorrhage * hepatic coma * infection * hepatorenal syndrome Alcoholic Liver Disease. The End.