L15 Structure and Function of the Liver Flashcards
What is the Sphincter of Oddi?
Flow of secretions into the duodenum is regulated by the Sphincter of Oddi. This sphincter opens when food is present. When it is closed, the bile – constantly synthesised by the liver – ‘backs up’ the common bile duct and overflows down the cystic duct into the gall bladder – where it is stored and concentrated. During meals the gall bladder is stimulated to contract, forcing stored bile down the common bile duct.
What is the Ampulla of Vater?
The point at which the common bile duct and the pancreatic duct to form a common passage way that drains into the duodenum.
What is the internal structure of the liver?
The liver is very spongy. It is made up of lobules separated from each other via connective tissue. At each apices of the hexagonal lobule is the portal triad: Hepatic artery proper, HPV, bile duct. There is a lot of contact between the cells and the blood. Sinusoids on either side carry a mixture of arterial blood and blood from HPV. Blood flows past these cells. The blood flows to the centre of the hexagon where it goes out through the central vein which ultimately goes to the hepatic vein. The hepatocytes have endothelial cells on either side of them. The endothelial cells do not form a complete barrier between the blood supply and the hepatocytes. There are pores and fenestra through which material can flow. The space of disse is the space between the endothelial cells and the hepatocytes. This contains stellate cells and collagen fibres. The stellate cells produce collagen found in the space. Along two sides of each cell is the sinusoids. Along the other two sides is the bile canniculi. The bile runs in the opposite direction to the blood supply. These are ducts into which bile is actively excreted. There is therefore two absorptive surfaces and a surface where bile is excreted.
What are the cell types found in the liver?
- Hepatocytes
- Kupffer cells
- Endothelial cells
- Pit cells - (liver-associated lymphocytes) Natural killer cells – help protect liver from viruses/tumour cells
- Hepatic stellate cells - Found in the space of Disse. Lipid-filled cells. Primary site of vitamin A storage. Also control turnover of connective tissue, synthesise collagen & regulate contractility of sinusoids. They are contractile and probably regulate blood flow in sinusoids.
What are the functions of the liver?
- Delivery e.g. fats, cholesterol and storage such as vitamins (particularly the fat soluble vitamins A,D,K - but also B12), minerals (iron, copper) and glycogen.
- Control of blood glucose levels (and other substances)
- Treating hazardous material such as detoxification of xenobiotics
- Immunological functions bacteria/antigens from the GI tract via Kupffer cells and pit cells
Removal of internal waste such as degradation of bilirubin - Nitrogen metabolism
- Lipid metabolism
Synthesis of blood components such as albumin, clotting factors, red cells synthesis in the liver and lipoproteins
How is are bile salts formed?
Bile salts formed in hepatocytes from cholesterol – by hydroxylation. Primary bile acids such as cholic acid are produced by the liver from cholesterol. These are worked on in the gut by gut bacteria to produce other sets of bile acids such as deoxycholic acid. Bile acids are conjugated, covalently attached to amino acids, mainly glycine and taurine.
How is bile recirculated?
Most bile is recirculated. It enters the duodenum from the liver or gall bladder. When you have a meal the gall bladder contracts and sends more bile down into the duodenum. These then emulsify fats and are reabsorbed back into tcirculation at the ileum and go back into the liver. An individual bile salt can go around this cycle 6-8 a day. Over a day you lose around 10-20% of bile secreted a day.
What are gallstones?
Bile contains free cholesterol. Too much cholesterol in the bile, or if the bile becomes dehydrated and the concentration increases, cholesterol will precipitate out in the gall bladder. This leads to gall stones. Occasionally one of the gall stones will go out of the gall bladder and enter the cystic duct or common bile duct. This causes considerable pain and is dealt with removal of the gall bladder. Biliary colic or acute cholecystitis can result.
What are the two stages of the digestion of xenobiotics?
There are 2 basic steps in the removal of a xenobiotics. Phase 1 reactions can involve a range of different chemical reactions including oxidation, hydroxylation, hydrolysis and reduction. Phase 2 reactions are additional reactions with a variety of different chemicals - addition of glucuronaly groups, sulphates, This ensures that whatever is reactive becomes pharmacologically unreactive. They are also made more hydrophilic so they can be easily excreted. They are then excreted by the kidney or by the liver in bile and excreted in faeces.
What is required for phase 1 metabolism? How are these reactions effected by other drugs?
These are catabolic and often yield more reactive species. Cytochrome P450 Enzymes (CYP) perform phase 1 metabolism. These are all proteins which contain haem. They are mono-oxygenases. Found in smooth endoplasmic reticulum.
These enzymes are inducible by other drugs e.g. carbamazepine (treat epilepsy) is inducilble by alcohol which increase the synthesis of these drugs, this effects the tolerance.
What are prodrugs?
If a drug is given orally, a drug may not reach its therapeutic target due to high first pass metabolism.
Sometimes drugs may not be absorbed in its active form. Giving prodrugs will get around this. The enzymes in the liver will convert it to an active drug. This also can be used in drugs you want to be absorbed in a different way such as kin patches.
How is tamoxifen activated?
Tamoxifen is a prodrug used in the treatment of hormone-sensitive breast cancer. It is activated to produce endoxifen which is 100x more potent than tamoxifen (TAM).
It is a 2 stage process. The main pathway is using CYP.
How is alcohol metabolised?
Alcohol is converted to ethanal by Ethanol dehydrogenase, using NAD (cytosol). Ethanal, an acetaldehyde is converted to acetate using acetaldehyde dehydrogenase and NAD. Acetate can then enter then Kreb’s cycle (mitochondria).
How is bilirubin produced?
Erythrocytes last around 120 days before needing replacing. Erythrocytes are taken up by phagocytosis by Kupffer cells in the liver as similar cells in the spleen and bone marrow. Broken down in 2 stages first to biliverdin (greenish), then to bilirubin (yellow/orange). This can be seen in the changing colours of a developing bruise.
What is prehepatic jaundice?
Prehepatic jaundice: Something in the body causes an increase in the rate of breakdown of erythrocytes. Too much haem is being produced for the liver to handle e.g. haemolytic anaemia in sickle cell.
