ORGAN DIRECTED TOXICITY (LIVER)

Lobule

Contains several types of liver cells, including hepatocytes (the main functional cells of the liver), Kupffer cells (specialized macrophages), and stellate cells (cells involved in liver regeneration and fibrosis).

Hepatocytes
Kupffer Cells
Stellate Cells

What types of several liver cells does lobule contains?

Hepatocytes

The main functional cells of the liver.

Kupffer Cells

Specialized Macrophages
For examples:
If the lifespan of red blood cells (RBCs) is 120 days and they exceed this, they are responsible for removing or cleaning them.

Stellate Cells

Cells involved in liver regeneration and fibrosis.

Acinus

Involved in the metabolism of nutrients and the detoxification of harmful substances.

Zone 1 (Closest to the Entry of Blood)
Zone 3 (Abuts the Terminal Hepatic Vein)
Zone 2 (Intermediate)

ACINUS
Has Three Zones

Direct Hepatotoxicity
Mitochondrial Injury
Oxidative Stress
Inflammation
Immune- Mediated Injury

Mechanism of Toxicant-Induced Liver Injury

Direct Hepatoxicity

Mechanism of Toxicant-Induced Liver Injury
Toxicants can directly damage hepatocytes (liver cells), leading to hepatocellular injury. This can occur through various mechanisms, including inhibition of protein synthesis, disruption of cellular membranes, and interference with mitochondrial function.

Inhibition of Protein Synthesis
Disruption of Cellular Membranes
Interference with Mitochondrial Function

Direct Hepatoxicity can occur through various mechanisms including:

Valproic Acid
Amiodarone
Tetracycline

What are certain drugs that could induce mitochondrial injury?
- Can lead to fatty liver disease because it causes damage to the mitochondria and it cannot metabolize the intakes correctly such as fatty diet. If not converted to energy and not enough the liver cannot do its function to metabolize.

Valproic Acid

Can cause mitochondrial injury by inhibiting mitochondrial beta oxidation, leading to fat accumulation in the liver.
- Accumulation of fat can lead to cirrhosis if not managed and then lead to hepatoxicity which reduces the function of the liver.

Amiodarone

Used to treat heart arrhythmias, can also cause mitochondrial injury and fatty liver disease.

Tetracycline

An antibiotic, can cause fatty liver disease by interfering with mitochondrial protein synthesis.

Oxidative Stress

Mechanism of Toxicant-Induced Liver Injury
Occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify them. This can lead to liver injury through cholestasis, which is the impaired flow of bile from the liver to the intestines

Cholestasis

What liver injury can occur due to oxidative stress, where there is impaired bile flow from the liver to the intestines?

Inflammation

Mechanism of Toxicant-Induced Liver Injury
Occurs when the immune system responds to injury or infection.

Chronic Inflammation

INFLAMMATION
Can lead to hepatic fibrosis, which is the formation of scar tissue in the liver.

Alcohol

INFLAMMATION
Is a well known example of a toxicant that can cause liver inflammation and fibrosis through chronic use.

Immune-Mediated Injury

Mechanism of Toxicant-Induced Liver Injury
The immune system can also cause liver injury through an autoimmune response or by attacking liver cells infected with viruses.

Hepatitis Viruses (B, C, and D)

IMMUNE MEDIATED INJURY
Can cause liver inflammation (chronic) and cirrhosis.

Autoimmune Hepatitis

IMMUNE MEDIATED INJURY
Is a condition in which the immune system mistakenly attacks liver cells, leading to chronic liver inflammation and fibrosis.

Wilson's Disease
Alpha-1 Antitrypsin Deficiency

IMMUNE MEDIATED INJURY
Are genetic disorders that can also cause immune-mediated liver injury.

Steatosis (Fatty Liver Disease)

Mechanism of Toxicant-Induced Liver Injury
Occurs when there is an accumulation of fat in the liver. Alcohol is a well-known example of a toxicant that can cause this disease through chronic use.

Necrosis

Mechanism of Toxicant-Induced Liver Injury
Is a type of cell death that occurs when cells are exposed to extreme stress or toxins.

Aflatoxin B1

A toxin produced by certain strains of Aspergillus fungus, can cause necrosis and liver cancer (found in peanut not properly dried)

Nutrient Homeostasis
Filtration of Particulates
Protein Synthesis
Bioactivation and Detoxification
Formation of Bile and Biliary Secretion

Major Functions of Liver

Hypoglycemia, confusion
Hypercholesterolemia

Ex:
Glucose storage and synthesis
Cholesterol Uptake

FUNCTIONS OF LIVER AND CONSEQUENCES OF IMPAIREDHEPATIC FX
Nutrient Homeostasis

Endotoxemia

Ex:
Products of Intestinal Bacteria

FUNCTIONS OF LIVER AND CONSEQUENCES OF IMPAIREDHEPATIC FX
Filtration of Particulates

Excess Bleeding
Hypoalbuminemia, Ascites, Fatty Liver

Ex:
Clotting Factors, Albumin, Transport Proteins (VLDL)

FUNCTIONS OF LIVER AND CONSEQUENCES OF IMPAIREDHEPATIC FX
Protein Synthesis

Jaundice, hyperammonemia- related coma
Loss of secondary male sex characteristics
Diminished drug metabolism
Inadequate Detoxification

Ex:
Bilirubin, Ammonia, Steroid Hormones, Xenobiotics

FUNCTIONS OF LIVER AND CONSEQUENCES OF IMPAIREDHEPATIC FX
Bioactivation and Detoxification

Fatty Diarrhea, Malnutrition, Vitamin E Deficiency
Jaundice, Gallstone, Hypercholesterolemia
Mn- induced neurotoxicity
Delayed Drug Clearance

Ex:
Bile Acid Dependent uptake of Dietary Lipids and Vitamins
Bilirubin and Cholesterol
Metals (Cu and Mn)
Xenobiotics

FUNCTIONS OF LIVER AND CONSEQUENCES OF IMPAIREDHEPATIC FX
Formation of Bile and Biliary Secretion

Immune-Mediated (allergic) Idiosyncratic Hepatotoxicity
Nonimmune- Mediated (Nonallergic) Idiosyncratic Hepatoxicity

Examples of Drugs with Known Idiosyncratic Hepatoxicity

Diclofenac (analgesic)
Halothane (anesthetic)
Nitrofurantoin (antibiotic)
Phenytoin (anticonvulsant)
Tienilic acid (diuretic)

Immune-Mediated (allergic) Idiosyncratic Hepatotoxicity

Amiodarone (antiarrhythmic)
Bromfenac (analgesic)-withdrawn from market
Diclofenac (analgesic)
Disulfiram (alcoholism)
Isoniazid (antituberculosis)
Ketoconazole (antifungal)
Rifampicin (antimicrobial)
Troglitazone (antidiabetes)-withdrawn from market
Valproate (anticonvulsant)

Nonimmune- Mediated (Nonallergic) Idiosyncratic Hepatoxicity