Toxic Responses to the Liver

7/30/2019 Toxic Responses to the Liver

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TOXIC RESPONSES TO THE LIVER


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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.


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Major functions of liver and consequences

of impaired hepatic function

Type of function Examples Consequences of

impaired function

Nutrient homeostasis Glucose storage and

synthesis

Cholesterol uptake

Hypoglycemia and

confusion

Hypercholesterolemia

Filtration of

particulates

Products of intestinal

bacteria (e.g.

Endotoxin)

Endotoxemia

Protein Synthesis Clotting factors

Albumin

Transport proteins

(e.g. VLDL)

Excess bleeding

Hypoalbuminemia

Fatty liver


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Type of

function

Examples Consequences of

Impaired functions

Bioactivation

anddetoxification

Bilirubin and

ammonia

Steroid hormones

Xenobiotics

Jaundice,

hyperammonemia-relatedcoma

Loss of sec. Male sex

characteritics

Diminished drug

metabolism

Inadequate detoxification

Formation of

bile and

biliaryseretion

Bile acid-dependent

uptake of dietary

lipid and vitaminsBilirubin and

cholesterol

Metals (e.g. Cu and

Mn) Xenobiotics

Fatty diarrhea,

malnutrition, Vitamin E

deficiency jaundice,gallstones,hypercholester

olemia,

Mn-induced neurotoxicity

Delayed drug clearance


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Types of hepatobiliary injury

Types of injury with damage Representative Toxin

Fatty liver,- build up of lipids in

the hepatocyte

Amiodarone, CCl4, ethanol,

fialurudine, tamoxifen, valproic

acid

Hepatotocyte death/necrosis Acetaminophen, allyl alcohol, Cu,

dimethylformamide, ethanol

Immune-mediated response Diclofenal, ethanol, halothane,

tieniilic acidCanalicular cholestasis-decrease

in the volume of the bile formed

or an impaired secretion of

solutes into bile

Cyclosporin A, 1,1-

dichloroethylene, estrogens, Mn,

phalloidin


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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


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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.


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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


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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


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Sinusoidal disorders

sinusoids- are the channels between cords ofhepatocytes where blood percolates on its way tothe terminal hepatic vein. The sinusoids are madeup 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


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Factors in the site-specific injury of

representative hepatotoxicantsSite Representative Toxicants Potential Explanation for Site

Specificity

Zone 1 hepatocytes Fe Preferential uptake and high

oxygen levels

Zone 3 hepatocytes CCl4 More P450 isozyme for

bioactivation and less GSH for

detoxification

Acetaminophen More P450 isozyme for

bioactivation and less GSH for

detoxification

Alcohol More hypoxic and gresterimbalance in

bioactivation/detoxification

reaction


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Bile duct cells Methylene dianiline,

sporidesmin

Exposure to the high

concentration of

reactive metabolites inbile

Sinusoidal

endothelium

Cyclophosphamide,

monocrotaline

Greater vulnerability to

toxic metabolites and

less ability to maintainglutathione levels.

Kupflerr cells Endotoxins Preferential site for

storage and then

engorgementStellate cells Vitamin A Preferential site


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Examples of drugs with known

idiosyncratic hepatotoxicity

A. Immune mediated (allergic) idiosyncratic

hepatotoxicity

Diclofenac (analgesic)

Halothane (anesthetic)

Nitrofurantoin (antibiotic)

Phenytoin ( anticonvulsant) Tienilic acid (diuretic)


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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)

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Toxic Responses to the Liver