Toxic responses of liver & kidney Flashcards
The liver has numerous functions, mention three.
- Metabolic homeostasis: Control of synthesis and utilization of carbohydrates, lipids and proteins. Strategically placed between the intestines and rest of the body, venous blood from the intestines goes through the liver via the portal vein and then out into the systemic circulation, so the liver act as a first “filter” for everything from the stomach and intestines.
- Metabolism of xenobiotics and bioactivation
- Vascular functions such as formation of lymph and the hepatic
phagocytic functions. - Secretory and excretory functions, particularly with respect to the
synthesis and secretion of bile.
What are the sources of hepatic blood and how much do they each account for?
About 70% of hepatic blood flow is from the portal vein (from the stomach and intestine) and about 30% from the hepatic artery (from the heart via the aorta).
Xenobiotics may be extensively metabolized by the liver so that little of the parent xenobiotic enters the systemic circulation (first pass effect)
There are two concepts for classifying the basic functioning unit of the liver, which? Explain them.
- Lobule (classic): Hexagonal lobules with a clear boundary surrounding a central vein, with portal triads in each corner consisting of a portal vein, a hepatic arteriole, and a bile duct. Divided into three zones; centrilobular, midzonal, and periportal. In this classification the middle is where blood flows out.
- Acinus: (preferred): The acinus extends over two lobules, with adjacent portal triads in the base and top, and the central vein of each lobule on the sides. In an acinus, the entry of blood from the portal vein and hepatic arteriole is central, zone 1; then comes the intermediate zone (zone 2) and the blood flows out in the terminal hepatic vein (central vein) and this part is zone 3. This means that the concentration of oxygen, hormones, nutrients, and xenobiotics is highest in zone one and lowest in zone 3 and the hepatocytes in these zones also contain different constituents because of the different environments. In this classification the blood flows in in the middle.
Explain how the blood flows in the liver.
The blood from the portal triads goes into sinusoids (unique capillaries in the liver with pores/fenestrations) and pass sheets of hepatocytes (parenchymal cells) in which biotransformation happens. The blood from all the sinusoids then collect in the central veins and go to the heart.
What types of cells are found in the liver? explain their function.
- Hepatocytes: parenchymal cells that are rich in enzymes that facilitate biotransformation of substances. (78% of liver volume)
- Sinusoidal cells: (6% of the liver volume)
- Endothelial cells that build up the sinusoids (capillaries)
- Kupffer cells: Fixed macrophages situated in the sinusoidal lumen of the liver (80% of the body’s fixed macrophages are kupffer cells!!) that ingest and degrade particulate matter. They are also antigen presenting cells that can be recognized by T-cells in the immune system.
- Stellate cells: (Ito cells; fat-storing cells) are found in the perisinusoidal space (space of Disse). They store vitamin A and fat and produce extracellular matrix and collagen. (The stellate cells (Ito cell) is the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage.)
The remaining 16% of volume of the liver is just space, sinusoidal and ECM.
The regional expression (zone 1-3) of xenobiotic-metabolizing enzymes determines the zone-specific localization of damage by reactive toxicants. which two enzymes are notably expressed in zone 1 and 3 of the acinus? What consequence of zone specific damage does this have?
- High levels of glutathione in zone 1: antioxidant, so it protects from oxidative stress.
- high levels of CYP450 in zone 3: Produce reactive electrophile metabolites.
The combination of high reactive electrophile metabolites and low antioxidants result in zone 3 being more vulnerable/susceptible to oxidative stress.
Bile formation is a specialized function of the liver. How is bile formed?
Bile consist of bile salts, bilirubin, cholesterol, phospholipids, water and soluble xenobiotic metabolites and other waste products and is formed in the hepatocytes from enzymatic reactions. The bile components are actively transported out of the hepatocytes into canaliculi (small channels in between the hepatocytes) that merge into the common hepatic duct leading to the gallbladder, where the bile is stored and gets concentrated. When needed, the bile goes through the common bile duct to the small intestine where it facilitates the digestion and absorption of fats.
What is meant by “hepatotoxicity”?
Hepatotoxicity is chemical-derived damage to the liver. Can be drugs or toxins.
There are many sorts of hepatotoxicity, name three.
- Steatosis (fatty liver)
- Cholestasis
- Fibrosis
- Hepatocyte necrosis
- Tumors
What is fatty liver (steatosis) caused by?
Fatty liver or steatosis is a condition caused by accumulation of lipids (triglycerides or phospholipids), and is diagnosed when lipids make up greater than 5% of the total liver weight. The accumulation occurs due to an imbalance in the uptake of fatty acids and their secretion as very low density lipoproteins (VLDL), typically associated with acute exposure to many hepatotoxins.
Name two hepatotoxins that can cause fatty liver.
Ethanol, carbon tetrachloride, tributyl tin (TBT).
Can steatosis (fatty liver) be treated?
Yes, in early stages it’s fully reversible. If alcohol abuse is the cause, stopping drinking can make you fully recover.
Prolonged exposure can lead to cell death, apoptosis or necrosis, which can be focal (random spots of dead hepatocytes), zonal (death in certain functional regions) or panacinar (widespread). in order from least to most detrimental.
What condition do you have if you have a decreased bile flow? How is it clinically defined?
Cholestasis.
The clinical definition of cholestasis is any condition in which substances normally excreted into bile are retained.
What three causes can lead to cholestasis?
- Impaired secretion by hepatocytes (can either be impaired influx into them, impaired transport inside the cell, or impaired efflux out in canaliculi)
- Obstruction of bile flow through intra- or extrahepatic bile ducts (can be due to impaired contractility of the canaliculi or leaky paracellular junctions)
- Decreased bile formation
Toxicant-induced cholestasis can be transient or chronic; when substantial, it is associated with cell swelling, cell death, and inflammation.
What substance is commonly measured in plasma to diagnose cholestasis?
Conjugated bilirubin (bilirubin+glucuronic acid). Bilirubin is a byproduct of the breakdown of red blood cells, and is normally excreted in bile. If something is causing bile to be retained, the serum levels of bilirubin is heightened.
Name two hepatotoxins that can cause cholestasis.
Chlorpromazine (antipsycotic medicine), estrogens, phalloidins (toxin in death cap mushroom) and penicillin/antifungals such as erythromcyin, ampicillin.
What symptom is caused by excess bilirubin levels? How does it manifest?
Jaundice. Jaundice is characterized by eyes and skin turning yellow and urine becoming bright yellow or brown due to the yellow pigment of bilirubin. Liver and inside of mouth and nose also turns yellow.
