L13. Toxic Response of Liver Flashcards
What are the major functions of the liver?
- Metabolic Functions (nutrient homeostasis): Maintaining glucose levels
- Hematological Regulation: Plasma proteins (clotting factors Factors II, VII, IX, X)
- Detoxification of Xenobiotics
- Bile Production: to get proper absorption of dietary lipids
What is a consequence of the impairment of each major function of the liver?
- Metabolic Functions (nutrient homeostasis): Hypoglycemia
- Hematological Regulation: Excess bleeding
- Detoxification: Diminished drug metabolism & Inadequate detoxification
- Bile Production: Diarrhea, malnutrition
Explain the blood flow to and from the liver.
The liver has a double blood supply: – ~ 70% of blood comes from hepatic portal vein • Drains stomach & intestines • Is oxygen-poor but nutrient-rich – ~ 30% blood comes from hepatic artery: • Is oxygen-rich (stems from aorta)
The blood leaves the liver via the hepatic vein and enters the heart through the inferior vena cava.
What is the Hepatic portal system?
Hepatic Portal System
– Portal system- two capillary beds connected by a vein (begins and ends in capillaries)
What is the basic unit of the liver? Explain the physiology of it. For image see S8 L13.
The liver lobule (looks like a hexagon).
In the middle of the lobule there is a central vein which takes all of the blood coming into the lobule and send it out to the inferior vena cava via the hepatic vein.
Surrounding the central vein there are “hepatic (portal) triads” which are composed of the portal venule (coming from portal vein from digestive system), portal arteriole (from hepatic artery), and the bile duct. It is said to look like spokes on a wheel. The blood enters and exits the hepatic triads and the central vein via the sinusoids (specialized capillaries of the liver) which span the space in between them throughout the hepatocytes. The liver lobules are separated by the interlobular septum (the connective tissue between each one).
Explain how blood flows into and out of liver lobules.
- Blood into hepatic triads
- Blood percolates towards central vein via sinusoids
- Central vein to hepatic vein
- Hepatic vein to heart
What are the main (most abundant) cells in the liver lobule?
- Hepatocytes
– Make 65% of liver
– One cell layer thick that are separated by liver sinusoids (channels between chords of hepatocytes where blood percolates on way to hepatic vein) - Endothelial cells
– Line sinusoids
– 16% of liver
What are the “other” cells that make up the liver lobule (excluding the hepatocytes and endothelial cells)? What is the Space of Disse?
- Kupffer cells (12%)
– Hepatic macrophages engulf pathogens, cell debris and damaged blood cells. Located within the sinusoids. They guard against infection. - Ito cells (8%)
– a.k.a. hepatic stellate cells
– Store vitamin A
• Space of Disse – named after German anatomist Joseph Disse – Space between hepatocyte and the endothelial cells that line the sinusoids – Contains: • Ito cells • Blood plasma • Lymph • ECM (collagen)
What is a bile canaliculus?
Interspersed between the hepatocytes are the bile canaliculus, which will eventually enter the bile duct for delivery to the digestive system.
What is a liver acinus? See S12 L13.
• The hepatic acinus is the smallest functional unit of the liver
• Oriented around the vascular system
– Located between 2 central veins and 2 portal triads
What are the zones of the liver acinus? and what are their functions?
• Acinus is divided into zones that correspond to distance from blood supply (increasing distance from blood supply)
– Zone 1 (periportal): Closest to the arterioles; best oxygenated; higher glutathione (GSH).
Functions: Ammonia detoxification, oxidative metabolism, gluconeogenesis
– Zone 2: Intermediate/mid-lobular
Functions: mixture of zone 1&2
– Zone 3 (perivenous/pericentral): Farthest from arterioles; least oxygenated; higher cytochrome P450s (CYP2E1 and 3A4)
Functions: glycolysis, lipogenesis, xenobiotic metabolism
The synthesis of serum proteins is not zone specific
In what acinus zone is CYP3A4 and CYP2E1 concentrated in and why?
- CYP3A4 is more concentrated in zone 3 therefore that is where xenobiotic metabolism takes place.
- CYP2E1 is more concentrated in zone 3 which is important when we talk about the metabolism of ethanol and carbon tetrachloride (CCl4).
What are the factors that influence liver toxicity?
• Zones can be differently affected by toxicants
– Zone 1 versus Zone 3: Zone 3 = more P450s for bioactivation of toxicants so this region can have more damage
• Uptake and concentration
• Activation of sinusoidal cells (Kupffer cells)
– Inflammatory and immune responses
What does the damage to the liver by a toxicant depend on?
(1) intensity of insult
(2) population of cells affected
(3) if exposure is chronic or acute
What are the possible outcomes of toxicant exposure to the liver?
- Dysfunction without cell damage
• toxicant blocks uptake, secretion or bioactivation
(Intracellular biochemical functions perturbed)
2. Acute damage kills hepatocytes by disrupting: • membrane integrity • mitochondrial functions • cytoskeleton • transporters & enzymes
- Chronic damage (repeated insults):
• Scar tissue in damaged area
What is hepatocyte cell death a consequence of and where is it most common?
Apoptosis and necrosis is caused by exposure to a number of different toxicants. Zone 3 necrosis is the most common type of zonal necrosis.
What chemical(s) cause these types of injury/damage to the liver?
- Fatty liver (steatosis)
- Hepatocyte death
- Canalicular cholestasis
- Bile duct damage
- Immune-mediated response
- Fibrosis & cirrhosis
- Tumors
- Fatty liver (steatosis): Carbon tetrachloride (CCl4), ethanol
- Hepatocyte death: Acetaminophen, ethanol
- Canalicular cholestasis: Chlorpromazine
- Bile duct damage: paraquat
- Immune-mediated response: ethanol
- Fibrosis & cirrhosis: ethanol, vinyl chloride
- Tumors: vinyl chloride
What is the physiological definition of Cholestasis? What about 2 specific types? What does it consist of?
• Cholestasis is defined physiologically as:
– a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile
– Hepatocellular cholestasis (bile accumulation in the cytoplasm of liver cells)
– Canalicular cholestasis (bile accumulation in the canaliculi)
• Consists of elevated serum level of compounds that are normally concentrated in bile:
– bile salts
– bilirubin (product of the catabolic process that breaks down heme):
- bilirubin (yellowish) accumulates in skin and eyes, causing jaundice
- spills into urine- bright yellow-dark brown
What is Chlorpromazine?
It is a Psychiatric medication used to treat Schizophrenia & Bipolar disorder. It causes cholestasis in 1-2% of patients.
Explain the mechanism of hepatobiliary transport.
- Canalicular excretion of bile acids is the rate limiting step of bile formation.
- Some of the bile acid production is done by CYP7A1 in the hepatocytes which convert cholesterol into bile acids. This replaces the daily loss of bile acids.
- The majority of bile acids come from the enterohepatic circulation (95%). So bile acids that return to the liver through the blood supply, enter the hepatocytes through the NTCP transporter (sodium-taurochlorate co-transporter), the OATP is another important transporter involved in this process indirectly. Once inside the hepatocytes, they are released into the canaliculus through exporters (BSEP-bile salt export pump, MRP2, MDR3) where they will eventually be released into the intestine through the canaliculus and bile duct. The cycle restarts.
What are the potential mechanisms for cholestasis?
- Impaired uptake of bile acids into hepatocyte
- Diminished transcytosis of bile acids through the hepatocyte
- Impaired secretion of bile acids into canaliculus
- Diminished contractility of canaliculus
- Leaky paracellular junctions
- Concentration of reactive species (increase in ROS=oxidative damage)
