TOXIC RESPONSES TO THE LIVER

Liver Anatomy and Physiology

Liver- main organ where exogenous compounds are metabolized and eventually secreted. - Has multiple cell types and numerous functions which can respond in many different ways to acute and chronic insults.

Major functions of liver and consequences of impaired hepatic function

Type of function Examples Nutrient homeostasis Glucose storage and synthesis Cholesterol uptake Filtration of particulates Consequences of impaired function Hypoglycemia and confusion Hypercholesterolemia

Products of intestinal Endotoxemia bacteria (e.g. Endotoxin)

Protein Synthesis

Clotting factors Albumin Transport proteins (e.g. VLDL)

Excess bleeding Hypoalbuminemia Fatty liver

Type of Examples function Bioactivation Bilirubin and and ammonia detoxification Steroid hormones Xenobiotics

Formation of bile and biliary seretion

Bile acid-dependent uptake of dietary lipid and vitamins Bilirubin and cholesterol Metals (e.g. Cu and Mn) Xenobiotics

Consequences of Impaired functions Jaundice, hyperammonemia-related coma Loss of sec. Male sex characteritics Diminished drug metabolism Inadequate detoxification Fatty diarrhea, malnutrition, Vitamin E deficiency jaundice, gallstones,hypercholester olemia, Mn-induced neurotoxicity Delayed drug clearance

Types of hepatobiliary injury

Types of injury with damage Fatty liver,- build up of lipids in the hepatocyte Hepatotocyte death/necrosis Immune-mediated response Canalicular cholestasis-decrease in the volume of the bile formed or an impaired secretion of solutes into bile Representative Toxin Amiodarone, CCl4, ethanol, fialurudine, tamoxifen, valproic acid Acetaminophen, allyl alcohol, Cu, dimethylformamide, ethanol Diclofenal, ethanol, halothane, tieniilic acid Cyclosporin A, 1,1dichloroethylene, estrogens, Mn, phalloidin

Bile duct damage

Alpha-napthylisothiocyanate, amoxicillin, methylene dianiline, sporidesmin

Sinusoidal disorders

Anabolic steroids, cyclophosphamide, microcystin, pyrrolizidine alkaloids Fibrosis and cirrhosis CCl4, ethanol, thioacetamide, vitamin A, vinyl chloride

Tumors

Aflatoxin, androgens, arsenic, thorium dioxide, vinyl chloride

Fatty liver
Steatosis,- build up of lipids in the hepatocyte. -brought about by alcohol -others include ethionine, puromycin, cycloheximide

Cell Death can be due to 2 modes: a. Necrosis- is characterized by swelling leakage, nuclear disintegration and an influx of inflammatory cells (can be detected through ALT and AST levels) b. Apoptosis- is characterized by cell shrinkage, nuclear fragmentation, formation of apoptotic bodies and lack of inflammation and a single cell event with the main purpose of removing cells no longer needed during development or eliminating aging cells.

Mechanisms of toxin induced injury to liver cells include lipid peroxidation, binding to cell macromolecules, mitochondrial damage, disruption of the cytoskeleton and massive calcium influx.

Canicular Cholestasis
Decrease in the volume of bile formed or an impaired secretion of specific solutes into bile Characterized by elevated serum levels of compounds normally concentrated in bile, particularly bile salts and bilirubin

Bile Duct damage

Cholandiodestructive cholestasis- damage into the intrahepatic bile ducts which carry bile from the liver to the GI tract -indicator is increase levels of serum alkaline phosphatase, bile slats and bilirubin

Sinusoidal disorders
sinusoids- are the channels between cords of hepatocytes where blood percolates on its way to the terminal hepatic vein. The sinusoids are made up of tissues namely endothelial cells, Kupffer cells and stellate. Sinusoidal disorders due to Xenobiotic may be manifested as: a. Blockade of its lumen b. Dilation of lumen c. Progressive destruction of its endothelial lining

Factors in the site-specific injury of representative hepatotoxicants

Site Zone 1 hepatocytes Zone 3 hepatocytes Representative Toxicants Fe CCl4 Potential Explanation for Site Specificity Preferential uptake and high oxygen levels More P450 isozyme for bioactivation and less GSH for detoxification More P450 isozyme for bioactivation and less GSH for detoxification More hypoxic and grester imbalance in bioactivation/detoxification reaction

Acetaminophen

Alcohol

Bile duct cells

Sinusoidal endothelium

Kupflerr cells

Methylene dianiline, Exposure to the high sporidesmin concentration of reactive metabolites in bile Cyclophosphamide, Greater vulnerability to monocrotaline toxic metabolites and less ability to maintain glutathione levels. Endotoxins Preferential site for storage and then engorgement Vitamin A Preferential site

Stellate cells

Examples of drugs with known idiosyncratic hepatotoxicity

A. Immune mediated (allergic) idiosyncratic hepatotoxicity Diclofenac (analgesic) Halothane (anesthetic) Nitrofurantoin (antibiotic) Phenytoin ( anticonvulsant) Tienilic acid (diuretic)

B. Non-immune mediated (non-allergic) idiosyncratic toxicity Amiodarone (antiarrythmic) Bromfenac (analgesic)-withdrawn from market Diclofenac- (analgesic) Disulfiram (alcoholism) Isoniazid (antituberculosis) Ketoconazole(antifungal) Rifampicin( antimicrobial) Troglitazone( antidiabetic) Valproate(anticonvulsant)