Toxin and Drug Induced Hepatitis (HBT - GI)

Summary

In this video, Dr. Aditi discusses drug-induced liver injury (DILI), a leading cause of acute liver failure. The video covers the mechanisms through which drugs damage the liver, including direct hepatocyte toxicity, activation of nuclear transporters, immune system activation, and interference with bile excretion. Dr. Aditi also explains the phases of drug metabolism, highlighting how toxic metabolites contribute to liver damage. The difference between predictable direct hepatotoxicity and unpredictable idiosyncratic reactions is explored, with examples of drugs causing both types of injury. The video also emphasizes the role of chronic liver disease in worsening drug-induced liver injury.

Takeaways

• 😀 Drug-induced liver injury (DILI) is the most common cause of acute liver failure and requires thorough understanding.
• 😀 DILI can occur through four primary mechanisms: direct hepatocyte toxicity, nuclear transporter activation, immune activation, and bile excretion pathway disruption.
• 😀 Direct hepatocyte toxicity results from reactive oxygen species and metabolites formed during drug metabolism, leading to lipid peroxidation and liver cell damage.
• 😀 Nuclear transporters such as pregnane X receptor and constitutive androstane receptor can be activated by certain drugs, resulting in hepatocyte damage.
• 😀 Some drugs act as haptens, triggering immune activation and leading to apoptosis, cytotoxic lymphocyte activation, and antibody-mediated damage to the liver.
• 😀 Disruption of bile excretion pathways by certain drugs causes bile acid stasis, leading to hepatocyte necrosis and microvesicular steatosis.
• 😀 Drugs are metabolized in the liver, where phase 1 (oxidation and methylation) and phase 2 (glucuronidation, sulfation, glutathione inactivation) reactions occur.
• 😀 Phase 1 reactions may produce toxic intermediates that contribute to liver injury, while phase 2 reactions help detoxify metabolites.
• 😀 Glutathione depletion, a key antioxidant in the liver, can exacerbate liver toxicity by allowing reactive oxygen species to accumulate.
• 😀 Direct toxicity reactions are dose-dependent, predictable, and lead to similar liver injury patterns each time the drug is administered.
• 😀 Idiosyncratic reactions are unpredictable, non-dose-dependent, and may produce variable liver injury patterns that differ with each drug exposure.
• 😀 Drugs causing idiosyncratic reactions include statins, valproate, phenytone, and anti-tuberculous drugs like isoniazid.
• 😀 The severity of DILI is higher in patients with chronic liver disease, and a thorough drug history is essential in identifying possible causes of acute hepatitis.

Q & A

What is drug-induced liver injury (DILI)?

Drug-induced liver injury (DILI) is the liver damage caused by certain drugs and toxins, and it is the most common cause of acute liver failure. The injury can result from direct hepatocyte toxicity, immune activation, or disruption of bile excretion pathways.

What are the four major mechanisms through which drugs cause liver injury?

The four major mechanisms of drug-induced liver injury include: 1) Direct hepatocyte toxicity, 2) Activation of nuclear transporters, 3) Immune activation, and 4) Disruption of bile excretion pathways.

How do drugs lead to direct hepatocyte toxicity?

Direct hepatocyte toxicity occurs when drugs generate reactive oxygen species (ROS) and toxic metabolites during metabolism, leading to lipid peroxidation of cellular membranes and hepatocyte damage. These metabolites can also sensitize the liver cells to toxic cytokines.

What role do nuclear transporters like PXR and CAR play in drug-induced liver injury?

Activation of nuclear transporters like the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) has been found to result in hepatocyte damage, contributing to liver injury.

What is the significance of immune activation in drug-induced liver injury?

Some drugs act as haptens, which activate the immune system, leading to the induction of apoptotic pathways, activation of cytotoxic lymphocytes, and antibody-mediated cellular cytotoxicity. This immune response can cause liver injury.

How do drugs affect the bile excretory pathway in the liver?

Certain drugs interfere with the function of bile canalicular pumps, causing bile acid stasis. This leads to hepatocyte necrosis and microvesicular steatosis, contributing to liver injury.

What happens during phase 1 and phase 2 drug metabolism in the liver?

In phase 1, drugs undergo oxidation and methylation, often by cytochrome P450 enzymes. This produces intermediate metabolites that can sometimes be toxic. In phase 2, these metabolites undergo further reactions like glucuronidation, sulfation, or inactivation by glutathione to make them water-soluble and easier to excrete.

How does glutathione depletion contribute to drug toxicity in the liver?

When glutathione is depleted, the liver loses its antioxidant defenses, leading to the accumulation of reactive oxygen species. This accelerates oxidative stress and liver damage.

How do drugs cause direct toxicity in a predictable manner?

Drugs causing direct toxicity result in predictable and reproducible liver injury patterns. The injury typically happens within a short latency period, with severity increasing with dose. Examples include acetaminophen and Amanita phalloides mushroom toxicity.

What are the key characteristics of idiosyncratic drug-induced liver injury?

Idiosyncratic reactions are unpredictable and may vary in severity and morphological patterns across patients. Unlike direct toxicity, the liver injury may not occur consistently upon repeated exposure to the drug, and the injury can take up to 90 days to manifest.

Which drugs are known to cause idiosyncratic drug-induced liver injury?

Drugs known to cause idiosyncratic drug-induced liver injury include statins, certain antibiotics like valproate and phenytoin, and anti-tuberculosis drugs like isoniazid.