Podcast
Questions and Answers
What is a factor that can contribute to the susceptibility of a patient to IDILI?
What is a factor that can contribute to the susceptibility of a patient to IDILI?
What is a common feature of idiosyncratic, drug-induced liver injury (IDILI)?
What is a common feature of idiosyncratic, drug-induced liver injury (IDILI)?
Which of the following is NOT a type of liver injury associated with IDILI?
Which of the following is NOT a type of liver injury associated with IDILI?
What is the most common type of drug associated with IDILI in Western countries?
What is the most common type of drug associated with IDILI in Western countries?
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What is the term for the phenomenon where the probability of an IDILI reaction is related to the product of individual probabilities of susceptibility factors?
What is the term for the phenomenon where the probability of an IDILI reaction is related to the product of individual probabilities of susceptibility factors?
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Which of the following is a dietary nutrient that can exacerbate hepatotoxicity when consumed in excess?
Which of the following is a dietary nutrient that can exacerbate hepatotoxicity when consumed in excess?
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What is the most common type of liver injury associated with IDILI?
What is the most common type of liver injury associated with IDILI?
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What is the outcome for many patients who recover from IDILI?
What is the outcome for many patients who recover from IDILI?
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What is the primary mechanism by which some drugs contribute to IDILI responses?
What is the primary mechanism by which some drugs contribute to IDILI responses?
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What is the primary function of Gamma-glutamyl transferase (GGT) in the diagnosis of liver injury?
What is the primary function of Gamma-glutamyl transferase (GGT) in the diagnosis of liver injury?
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What percentage of patients taking isoniazid experience life-threatening liver injury?
What percentage of patients taking isoniazid experience life-threatening liver injury?
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Which of the following enzymes is localized to the canalicular and sinusoidal membranes of HPCs?
Which of the following enzymes is localized to the canalicular and sinusoidal membranes of HPCs?
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According to the inflammatory stress hypothesis, what triggers liver damage?
According to the inflammatory stress hypothesis, what triggers liver damage?
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What is the characteristic of idiosyncratic drug-induced liver injury (IDILI)?
What is the characteristic of idiosyncratic drug-induced liver injury (IDILI)?
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What is the primary difference between intrinsic and idiosyncratic reactions?
What is the primary difference between intrinsic and idiosyncratic reactions?
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What is a pleiotropic effect of cytokines in the context of IDILI responses?
What is a pleiotropic effect of cytokines in the context of IDILI responses?
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What is the primary target organ of idiosyncratic drug reactions?
What is the primary target organ of idiosyncratic drug reactions?
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What is a potential consequence of some drugs interfering with the liver's ability to adapt to modest injury?
What is a potential consequence of some drugs interfering with the liver's ability to adapt to modest injury?
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What is the result of the failure-to-adapt hypothesis in some patients?
What is the result of the failure-to-adapt hypothesis in some patients?
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What is the characteristic of intrinsic toxic responses in liver injury?
What is the characteristic of intrinsic toxic responses in liver injury?
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What is a common characteristic of idiosyncratic drug-induced liver injury (IDILI)?
What is a common characteristic of idiosyncratic drug-induced liver injury (IDILI)?
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What is the term for adverse responses that occur in a minority of patients taking therapeutic doses of a drug?
What is the term for adverse responses that occur in a minority of patients taking therapeutic doses of a drug?
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What is a potential trigger for liver injury in patients on maintenance drug therapy?
What is a potential trigger for liver injury in patients on maintenance drug therapy?
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What is the characteristic of liver pathology in idiosyncratic drug-induced liver injury (IDILI)?
What is the characteristic of liver pathology in idiosyncratic drug-induced liver injury (IDILI)?
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Study Notes
Liver Functions and Anatomy
- The liver performs critical life functions, including processing of foods and substances absorbed from the intestinal tract and delivering processed nutrients to other organs.
- The liver contributes to immunity, protecting mammals from harmful pathogens.
- It is the main organ where exogenous chemicals are metabolized for eventual excretion into bile and urine.
Hepatic Functional Anatomy
- The liver has a dual blood supply, receiving blood from the hepatic artery and hepatic portal vein.
- The hepatic portal vein is the major supplier of blood, containing food-borne xenobiotic agents absorbed from the gastrointestinal (GI) tract, and is poorly oxygenated.
- The liver is organized into hexagonal lobules, with each lobule having a central vein (terminal hepatic venule) and portal triads at the corners.
Blood Flow and Liver Lobule Structure
- Blood from the hepatic artery and portal vein mixes as it enters the sinusoids, and then leaves the sinusoids to enter central veins that drain into the vena cava.
- The liver lobule has three regions: periportal (nearest portal triad), centrilobular (surrounding the central vein), and midzonal (between periportal and centrilobular).
- The acinus concept describes the liver lobule structure, with three zones: zone 1 (closest to the entry of blood), zone 3 (abutting the central vein), and zone 2 (in between).
Liver Injury and Toxicants
- Chemical-induced liver injury is typically initiated by one or more critical events, such as formation of a toxic metabolite, which triggers intracellular responses that can progress to dysfunction or death of hepatic parenchymal cells.
- These intrahepatocellular events can prompt secondary events involving activation of nonparenchymal cells that magnify or attenuate the initial injury.
Liver Functions and Anatomy
- The liver performs critical life functions, including processing of foods and substances absorbed from the intestinal tract and delivering processed nutrients to other organs.
- The liver contributes to immunity, protecting mammals from harmful pathogens.
- It is the main organ where exogenous chemicals are metabolized for eventual excretion into bile and urine.
Hepatic Functional Anatomy
- The liver has a dual blood supply, receiving blood from the hepatic artery and hepatic portal vein.
- The hepatic portal vein is the major supplier of blood, containing food-borne xenobiotic agents absorbed from the gastrointestinal (GI) tract, and is poorly oxygenated.
- The liver is organized into hexagonal lobules, with each lobule having a central vein (terminal hepatic venule) and portal triads at the corners.
Blood Flow and Liver Lobule Structure
- Blood from the hepatic artery and portal vein mixes as it enters the sinusoids, and then leaves the sinusoids to enter central veins that drain into the vena cava.
- The liver lobule has three regions: periportal (nearest portal triad), centrilobular (surrounding the central vein), and midzonal (between periportal and centrilobular).
- The acinus concept describes the liver lobule structure, with three zones: zone 1 (closest to the entry of blood), zone 3 (abutting the central vein), and zone 2 (in between).
Liver Injury and Toxicants
- Chemical-induced liver injury is typically initiated by one or more critical events, such as formation of a toxic metabolite, which triggers intracellular responses that can progress to dysfunction or death of hepatic parenchymal cells.
- These intrahepatocellular events can prompt secondary events involving activation of nonparenchymal cells that magnify or attenuate the initial injury.
Liver Functions and Anatomy
- The liver performs critical life functions, including processing of foods and substances absorbed from the intestinal tract and delivering processed nutrients to other organs.
- The liver contributes to immunity, protecting mammals from harmful pathogens.
- It is the main organ where exogenous chemicals are metabolized for eventual excretion into bile and urine.
Hepatic Functional Anatomy
- The liver has a dual blood supply, receiving blood from the hepatic artery and hepatic portal vein.
- The hepatic portal vein is the major supplier of blood, containing food-borne xenobiotic agents absorbed from the gastrointestinal (GI) tract, and is poorly oxygenated.
- The liver is organized into hexagonal lobules, with each lobule having a central vein (terminal hepatic venule) and portal triads at the corners.
Blood Flow and Liver Lobule Structure
- Blood from the hepatic artery and portal vein mixes as it enters the sinusoids, and then leaves the sinusoids to enter central veins that drain into the vena cava.
- The liver lobule has three regions: periportal (nearest portal triad), centrilobular (surrounding the central vein), and midzonal (between periportal and centrilobular).
- The acinus concept describes the liver lobule structure, with three zones: zone 1 (closest to the entry of blood), zone 3 (abutting the central vein), and zone 2 (in between).
Liver Injury and Toxicants
- Chemical-induced liver injury is typically initiated by one or more critical events, such as formation of a toxic metabolite, which triggers intracellular responses that can progress to dysfunction or death of hepatic parenchymal cells.
- These intrahepatocellular events can prompt secondary events involving activation of nonparenchymal cells that magnify or attenuate the initial injury.
Dietary Nutrients and Hepatotoxicity
- Certain dietary nutrients like essential amino acids, lipids, S-adenosylmethionine, zinc, and antioxidants can prevent hepatotoxicity.
- Excess consumption of essential nutrients like iron can exacerbate hepatotoxicity, especially when combined with alcohol.
Idiosyncratic, Drug-Induced Liver Injury (IDILI)
- IDILI is a rare but severe adverse reaction to certain drugs, requiring liver transplantation or causing death in some cases.
- It occurs unexpectedly in a small number of patients, making it difficult to diagnose and predict.
- Conventional preclinical safety testing often fails to detect IDILI liability of drug candidates.
- Antibiotics are the most common cause of IDILI in Western countries, while dietary and herbal supplements are more common causes in Asia.
Modes of Action of IDILI
- The multiple determinant hypothesis proposes that IDILI occurs due to the intersection of several genetic and environmental susceptibility factors.
- Each factor has a finite probability of occurrence, making IDILI reactions rare.
- The failure-to-adapt hypothesis suggests that therapeutic doses of some drugs cause modest liver injury, which most patients adapt to, but a few fail to adapt and progress to serious liver injury.
Inflammatory Stress Hypothesis
- Drug exposure can interact with a modest, non-injurious inflammatory episode, resulting in liver damage.
- This scenario can account for the bizarre characteristics of idiosyncratic reactions.
Mechanisms of IDILI
- Drugs can be metabolically bioactivated by cytochromes P450 (CYPs) to reactive metabolites, initiating an adaptive immune response.
- Activation of adaptive or innate immune systems leads to the production of cytokines, which can activate cell death pathways.
- Some drugs can interfere with the liver's ability to adapt to modest injury, leading to injury progression.
Diagnostic Markers of Liver Injury
- Gamma-glutamyl transferase (GGT) and 5'-nucleotidase (5NT) are enzymes that can be used in the diagnosis of biliary injury and to help confirm a liver source of ALP increase.
Intrinsic vs. Idiosyncratic Responses
- Intrinsic toxic responses (Type A responses or "toxic hepatitis") have a well-defined dose response relationship and occur in all individuals.
- Idiosyncratic drug reactions (Type B reactions) occur in a minority of patients, have a unclear dose relationship, and are associated with variable liver pathology.
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Description
Learn about the critical life functions of the liver, including processing nutrients, contributing to immunity, and metabolizing exogenous chemicals. Understand the hepatic functional anatomy of this vital organ.
