Liver Anatomy and Functions

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.