HEPATOTOXICITY: TOXIC

EFFECTS ON THE LIVER

By Prandeep Borah

FUNCTIONS

(1) Filtration

(2) carbohydrate storage and metabolism;

(3) metabolism of hormones, endogenous wastes, and

foreign chemicals;

(4) synthesis of blood proteins;

(5) urea formation;

(6) metabolism of fats; and

(7) bile formation

TYPES OF TOXIN INDUCED LIVER INJURY:

Hepatocellular Degeneration and Death-

1. Mitochondria. These organelles are important for

energy metabolism and synthesis of ATP.

-> Release calcium/ maintain homeostasis

->lose the ability to regulate solute and water balance,

and undergo swelling.

-> chemicals- carbon tetrachloride, cocaine,

dichloroethylene etc.

2. Plasma Membrane- Important in maintaining the ion

balance between the cytoplasm and the external

environment.

-> Loss of ionic control can cause a net movement of water

into the cell, resulting in cell swelling.

->chemicals- acetaminophen, ethanol etc.

3. Endoplasmic Reticulum- Responsible for synthesis of

proteins and phospholipids in the hepatocyte.

->Principal site of biotransformation of foreign

chemicals;maintain Ca homeostasis.

->chemicals- acetaminophen, bromobenzene, carbon

tetrachloride, and cocaine.

4. Nucleus-

->Some chemicals or their metabolites can bind to DNA,

producing mutations > leading to cell death.

->Some chemicals appear to cause activation of

endonucleases, enzymes located in the nucleus that

digest chromatin material >leads to uncontrolled

digestion of the cell’s DNA.

->chemicals- aflatoxin B, beryllium, Ethionine etc.

5. Lysosomes- These subcellular structures contain

digestive enzymes (e.g., proteases) and are important in

degrading damaged or aging cellular constituents

-> In hepatocytes injured by chemical toxicants, their

numbers and size are often increased.

FIBROSIS & CIRRHOSIS

Hepatic fibrosis (scaring) occurs by the accumulation of

excessive amounts of fibrous tissue, specifically fibril

forming collagens type I and III.

> central veins, portal tracts, disse

>With continuing collagen deposition,

>fibrous scars.

> nodular regeneration of hepatocytes leads fibrosis to

progress to cirrhosis

* Blood flow through the liver becomes obstructed,

leading to portal hypertension, internal hemorrhage.

* Chemicals involves ethanol, carbon tetrachloride,

trinitrotoluene.

LIVER TUMORS

Chemicals can induce neoplasia which leads

to tumors . Etiology :-

• Hepatitis B

• Hepatitis C

• Cirrhosis

- 70% of HCC arise on top of cirrhosis

• Toxins -Alcohol -Tobacco - Aflatoxins

• Autoimmune hepatitis

• States of insulin resistance- Overweight in males

Diabetes mellitus

CLASSIFICATION

Malignant

>hepatocellular

carcinomas:-derived

from hepatocytes,

>cholangiocarcinomas:

-from bile duct cells,

>hemangiosarcoma:-

arising from liver cells.

Benign

>adenomas:-epithelial

origin with gland.

>fibromas-fibrotic cell

origin.

>cholangiofibromas:-

Arise from bile ducts

TUMORS

CHOLESTASIS

>Refers to decreased or arrested bile flow.

>elevated serum levels-bile salts and bilirubin.

>Impairment of yellowish bilirubin pigment reflects

jaundice.

>Structural changes I

>dilation of the bile canaliculus

>presence of bile plugs in bile ducts and canaliculi.

* Chemical involves- Chlorpromazine, cyclosporin A,

ethanol, ampicillin,estrogens etc.

CHOLESTASIS

SINUSOIDAL DAMAGE

Its a specialized capillary with numerous fenestrae for

high permeability.

>damages occurs two pathways-

1.Dilation of the sinusoid- whenever efflux of hepatic

blood is impeded. Known as peliosis hepatis.

*Chemials- anabolic steroids ,danazol.

2.blockade of its lumen- occurs due to enlargement

of fenestrae & red blood cells become caught.

*Chemicals- acetaminophen

PELIOSIS HEPATIS

Fatty liver :- Caused by chemicals produce an accumulation of lipids in the liver, called fatty liver or steatosis.

> hepatocellular necrosis occurs in specific acinarzones.

> zone 1 –lipid accumulation from white phosphorus.

>zone 3 -lipid accumulation with tetracycline and ethanol.

The lipid accumulates in vacuoles within the cytoplasm.

> macrovesicular steatosis

> microvesicular steatosis

> This vesicular steatosis has been associated with tetracycline, valproic acid, salicylates, aflatoxin etc.

POTENTIAL CHEMICAL EFFECTS GIVE RISE TO

ACCUMULATION OF LIPID

1. Inhibition of Lipoprotein Synthesis.- Eg. carbon

tetrachloride, ethionine.

2. Decreased Conjugation of Triglycerides with

Lipoproteins . Eg.Carbon tetrachloride

3. Interference with Very-Low-Density Lipoprotein

(VLDL) Transfer: Eg. Tetracycline

4. Impaired Oxidation of Lipids by Mitochondria: Eg.

Carbon tetrachloride, ethionine.

5. Increased Synthesis of Fatty Acids: Eg. Ethanol.

FATTY LIVER

THANK YOU !