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Liver toxicity
The liver is susceptible to toxins because of the following reasons:
Most bio-transformations of xenobiotics act as detoxification reactions and many oxidative reactions produce reactive metabolites that can induce lesions within the liver. Most of the damage is done to the centrilobular region because it has a high concentration of cytochrome p
Types of liver toxicity
Types of injury to the liver depend upon
The hallmarks of hepatotoxicity are
Most xenobiotics enter through our GI tract and after absorption get transported by the hepatic portal vein
High concentration of xenobiotic metabolizing enzymes especially cytochrome P450-dependent monooxygenase system.
Bile formation and bile movement can cause a concentration of xenobiotics in the GI tract. Xenobiotics and most of the bile released into the intestines are reabsorbed and transported back to the liver by the hepatic portal circulation, which can increase the concentration of xenobiotics in hepatocytes.
Intrinsic hepatotoxicants- broad incidence, dose-dependent relationship, and usually similar toxicities are seen in human and animal models. Idiosyncratic hepatotoxicants - limited toxicity was seen in selective individuals and results from hypersensitivity or unusual metabolic conversions that may occur due to polymorphisms (two or more variations in genetic material) in drug- metabolizing genes.
Type of toxic agent The severity of intoxication The type of exposure is acute or chronic.
steatosis (fatty liver)
Damaged liver cells release liver-specific enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase into the blood. Eenzymes ALT and AST are used as biomarkers of injured hepatocytes, while alkaline phosphatase indicates bile duct epithelial damage.
Abnormal accumulation of lipids in hepatocytes especially triglycerides due to an imbalance between the uptake of extrahepatic triglycerides and the hepatic secretion of triglyceride-containing lipoproteins and fatty acid catabolism.
Lipid accumulation is due to the disturbance of the synthesis or secretion of lipoproteins. Excess of lipids is due is an oversupply of free fatty acids from adipose tissue or impaired release of triglycerides from the liver into plasma
cholestasis fibrosis necrosis apoptosis
1. Fatty liver/steatosis
Cholestasis
Fibrosis and Cirrhosis
CIRRHOSIS
Necrosis
leads to stoppage of bile flow Intrahepatic or extrahepatic causes Inflammation or blockage of the bile ducts results in the retention of bile salts and/or bilirubin, which leads to jaundice. Other factors causing cholestasis include changes in membranes permeability of either hepatocytes or biliary canaliculi Bile formation depends upon ATP dependent transport of bile into the canalicular lumen Chemicals that affect the membrane permeability and Na+^ and K+^ pump can cause cholestasis by their impact upon ATP-dependent reaction
Part of the wound-healing response Deposition of collagen, proteoglycans, glycoproteins, and chronic fibrosis After a toxicant exposure, hepatic stellate cells (HSC) proliferate and differentiate into fibroblast-like cells that secrete the components of the Extracellular Matrix Extensive fibrosis can disrupt the structure of the liver and blood flow
Deposition of collagen is found throughout the liver and results in the formation of scar tissue Results from chronic chemical injury, which results in the accumulation of ECM which results in a decrease in blood flow and the liver's normal metabolic and detoxification process This can lead to liver failure can be caused due to ethanol consumption and/or nutrient deficiency
Irreversible loss of cell viability occurs due to loss of normal cellular function. May be localized (local necrosis) or involve the whole lobe (massive necrosis) This leads to cell death Cell death occurs along with rupture of the plasma membrane, and is followed by several morphologic changes
Biochemical events that may lead to these changes
large parts of the liver going through liver necrosis can cause liver damage
Apoptosis
Hepatitis
- Cytoplasmic oedema (swelling due to fluid)
- Dilation of the endoplasmic reticulum
- Disaggregation of polysomes
- Accumulation of triglycerides
- Swelling of mitochondria with disruption of cristae
- Dissolution of organelles and nucleus
Binding of reactive metabolites to proteins and unsaturated lipids (inducing lipid peroxidation)
Subsequent membrane destruction
Disturbance of cellular Ca+2^ homeostasis,
Inference with metabolic pathways
Shifts in Na+^ and K+^ balance
Inhibition of protein synthesis.
A controlled form of cell death This “ ordered ” mechanism of cell death, unlike necrosis, is particularly active during development and senescence it can be produced by xenobiotic chemicals, oxidative stress, anoxia, and radiation Apogen is the agent which causes apoptosis sometimes, apoptosis is stopped causing cell accumulation sign of apoptosis is the absence of inflammation infiltration apoptosis and necrosis can also occur at the same time
Inflammation of liver usually viral drugs can also produce the same effect as the viral infection immune cells increases and associated with idiosyncratic hepatotoxicants like diclofenac only found in a susceptible population
