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    Toxic Responses of Liver

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    Syeda Eshaal Javaid
    This document summarizes mechanisms of liver injury and drug-induced liver disease. It outlines the major hepatic functions including nutrient homeostasis, filtration, protein synthesis, and detoxification. Mechanisms of injury include disruption of the cytoskeleton, cholestasis affecting bile transport, and mitochondrial damage from miscoding drugs. Drug-induced liver injury can result from direct toxicity, hepatic metabolism of chemicals, or immune-mediated responses. Specific chemicals are associated with different types of injury such as fatty liver, cell death, cholestasis, or bile duct damage. Reye syndrome predominantly affects children and causes microvesicular steatosis and liver dysfunction.

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    Toxic Responses of Liver

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    Syeda Eshaal Javaid
    22 views16 pages
    This document summarizes mechanisms of liver injury and drug-induced liver disease. It outlines the major hepatic functions including nutrient homeostasis, filtration, protein synthesis, and detoxification. Mechanisms of injury include disruption of the cytoskeleton, cholestasis affecting bile transport, and mitochondrial damage from miscoding drugs. Drug-induced liver injury can result from direct toxicity, hepatic metabolism of chemicals, or immune-mediated responses. Specific chemicals are associated with different types of injury such as fatty liver, cell death, cholestasis, or bile duct damage. Reye syndrome predominantly affects children and causes microvesicular steatosis and liver dysfunction.

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    This document summarizes mechanisms of liver injury and drug-induced liver disease. It outlines the major hepatic functions including nutrient homeostasis, filtration, protein synthesis, and detoxification. Mechanisms of injury include disruption of the cytoskeleton, cholestasis affecting bile transport, and mitochondrial damage from miscoding drugs. Drug-induced liver injury can result from direct toxicity, hepatic metabolism of chemicals, or immune-mediated responses. Specific chemicals are associated with different types of injury such as fatty liver, cell death, cholestasis, or bile duct damage. Reye syndrome predominantly affects children and causes microvesicular steatosis and liver dysfunction.

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    22 views16 pages

    Toxic Responses of Liver

    Uploaded by

    Syeda Eshaal Javaid
    This document summarizes mechanisms of liver injury and drug-induced liver disease. It outlines the major hepatic functions including nutrient homeostasis, filtration, protein synthesis, and detoxification. Mechanisms of injury include disruption of the cytoskeleton, cholestasis affecting bile transport, and mitochondrial damage from miscoding drugs. Drug-induced liver injury can result from direct toxicity, hepatic metabolism of chemicals, or immune-mediated responses. Specific chemicals are associated with different types of injury such as fatty liver, cell death, cholestasis, or bile duct damage. Reye syndrome predominantly affects children and causes microvesicular steatosis and liver dysfunction.

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    Toxic Responses of Liver

    Chapter 13
    Major hepatic functions (table13-1)

    • Nutrient homeostasis
    • Filtration of particulates
    • Protein synthesis
    • Bioactivation and detoxification
    • Formation of bile and biliary secretion
    Mechanisms of liver injury
    •Disruption of the cytoskeleton ;
    Phalloidin; Hexapeptide poison from mushroom causes asthenia,
    vomitting, diaarhea, convulsions and death. It blocks actin filaments and
    leads to hepatocyte necrosis. It crosses sinusoidal plasma membranes of
    hepatocytes by a carrier mediated process. Microcystin; class of toxins
    produced by freshwater cyanobacteria hepatotoxins. Large amount leads
    to marked deformation of hepatocytes by blocking actin filaments.

    •Cholestasis ; Sinusoids and Canaliculi


    Effect bile acid uptake and canalicular contractility for eg., estrogens
    diminish the transport of glutathions and reduce bile salt transporters.

    • (page # 205-206)
    Cont.,
    •Mitochondrial damage ; damage because of miscoding
    DNA codes for several proteins . Nucleoside analog drugs for therapy for
    hepatitis B and AIDS causes direct mitochondrial damage because miscoding
    targets polymerase that is responsible for mitochondrial DNA synthesis rather
    than polymerase for nuclear DNA synthesis.
    Alcohol abuse also cause damage due to accumulation of its reactive
    metabolite i.e. acetaldehyde.
    Drug Induced liver Disease

    • Injury results from chemicals may cause;

    • Direct toxicity
    • Hepatic conversion of chemical.
    • Immune mechanisms; migration of neutrophils,
    lymphocytes and other inflammatory cells into regions of
    damaged liver is a well recognised feature of
    hepatotoxicity by chemicals.
    Drug Induced liver Disease
    • Liver damage from chemicals may be immediate or
    take months.
    • Forms of liver injury:
    • Hepatocyte necrosis;inc. Aminotransferase levels leads to jaundice and
    hepatic failure.
    • Cholestasis;subs. Normally excreted into bile are retained. Disruption in bile
    production or flow.
    • Insidious onset of dysfunction;enzyme elevation bilirubin, alkaline
    phosphatse and GTT. Risk factors includes; sepsis, prentral nutrition, hyperglycemia
    and super added drug induced cholestatsis.
    • Drug induced chronic hepatitis is indistinguishable from
    chronic viral hepatitis
    Drug Induced liver Disease
    Hepatocellular
    Chemicals
    damage
    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.
    Types of Injury & Toxic chemicals(table 13-2)
    • Fatty liver( CCl4, ethanol, valproic acid)
    • Cell death( acetaminophen, Cu, ethanol,
    dimethylformamide, ecstasy)
    • Immune mediated response (Diclofenac, ethanol, halothane)
    • Canalicular cholestasis (Chlorpromazine, cyclosporin A,
    estrogens, Mn, )
    • Bile duct damage (amoxicillin, methylene dianiline, α-
    naphthyliso-thiocyanate)
    Cont..,

    • Sinusoidal disorder (anabolic steroids, cyclophosphamide,


    microcystin, pyrrolidine alkaloids.
    • Fibrosis & Cirrhosis ( Arsenic, ethanol, Vit A, vinyl Cl,)
    • Tumors (Aflatoxin, androgens, thorium dioxide, vinyl
    chloride)
    Drug Induced liver Disease

    • Reye syndrome
    • Mitochonrdial dysfuntion in liver and some other organs
    causes swelling in liver and brain.

    • Predominantly in children given acetylsalicylic acid cause


    of fever.

    • Produces microvesicular steatosis with severe liver


    dysfuntion.
    REFERENCE:

    • Reference:, Essentials of Toxicology, Casarett & Doull’s chapter 13

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