Case 10- function of biliary system Flashcards
Function of the liver?
- Protein and clotting factor production
- Glucose storage
- Immune factors and filters blood
- Drug and nutrient metabolism
- Clears nitrogenous waste
- Iron storage- Ferratin binds to iron within the liver, it then binds to Transferrin which is an iron carrier for protein within the blood
- Produces bile
Liver- carbohydrate metabolism
Glycolysis, Gluconeogenesis, Glycogenolysis and Glycogenesis
Liver- protein metabolism
Catabolism of amino acids, conversion of amino acids, production of almost all circulating proteins
Liver- lipid metabolism
Catabolism of fatty acids, production of fatty acids, cholesterol, phospholipids and lipoproteins, Ketogenesis.
Liver- Albumin synthesis
A major plasma protein synthesised in the liver. It transports steroid hormones, some ions, drugs, fatty acids, vitamins and bilirubin as well as maintaining plasma oncotic pressure. When albumin is reduced it suggests liver disease or a poor nutritional state, below 30gL indicates chronic liver disease.
Liver- synthesis of clotting proteins
Most clotting factors are synthesised by hepatocytes, some clotting factors require vitamin K-dependent modification. In the liver Kupffer cells clear and remove clotting factors. If liver function is compromised then there is ineffective clearing and Disseminated Intravascular Coagulation (DIC) may occur. DIC involves clot formation inside blood vessels.
Liver- detoxification
Detoxification is used in the metabolism of endogenous factors such as hormones and bile pigment as well as xenobiotics such as drugs, toxins and their metabolites. They are metabolised via biotransformation in 3 stages.
Phase 1 drug and hormone metabolism
Metabolism- can result in more toxic substances or activate some drugs. It is catalysed by cytochrome P450 mixed function oxygenase system in the ER
Phase 2 drug and hormone metabolism
Conjugation- increases the negative charge of the substrate so that they are more hydrophilic. It is catalysed by the UDP-glucuronyl transferase enzyme producing glucuronide derivatives. Makes the drug inactive and ready for excretion
Phase 3 drug and hormone metabolism
Secretion- involves transport of the drug out of the hepatocytes and into the canaliculi, it is mediated by ABC (ATP-binding cassete) which is a super family of transport proteins
Bile functions
- Ingestion of fat soluble vitamins- A,D,E,K.
- Neutralising stomach acid- so enzymes can work.
- Excretion of waste- bile contains bilirubin, drugs and cholesterol.
Components of bile
The primary bile acid is cholic acid (58%) and chenodeoxycholic acid (26%) which are converted by gut bacteria into secondary bile acids through dihydroxylation (16%). The bile acids are made from cholesterol. The liver then chemically modifies these bile acids to the conjugated form, the bile salts.
How is bile transported across the canalicular membrane?
By specific transporters i.e. the BSEP transporter
Problems associated with bile transporters
Impairment of the transporters can lead to cholestasis or retention of bile components within the hepatocytes
Mechanism of action of bile- Lipid emulsification
Lipids are broken down into smaller parts by the mechanical contraction of muscles and emulsification of bile salts on the surface of lipid droplets. Bile molecules have a polar and non-polar side, the non-polar side bonds to the fat molecules with the hydrophilic side facing outwards. The polar bile stops the lipid from re-aggregating in the jejunum. This gives the fat a larger surface area for the lipase to act on. When broken down the Monoglyceride fatty acids can now be absorbed.
Bile secretion
Hepatocytes actively secrete bile into bile canaliculi. The intrahepatic and extrahepatic bile ducts transport bile and also add a watery HCO3- rich fluid.
Volume of bile used a day
Hepatic bile secretions are 900ml/day, between meals 450ml/day of the bile is stored in the gallbladder where it is concentrated by 10-20 fold through isosmotic removal of salt and water. The 500ml/day of bile that reaches the duodenum is a mix of relatively “dilute” Hepatic bile and “concentrated” gall bladder bile.
Bile acid independent flow
When organic compounds (non bile acids) are secreted generating an osmotic driving force for canalicular bile formation. Bile acid dependent flow is directly related to bile acid concentration
How the enzymes in bile control bile flow
The accumulation of bile acids causes a decrease in the transcription of the cholesterol 7α-hydroxylase gene. So, enzymes form a rate limiting step in the synthesis of bile from cholesterol. Conversely, the loss of bile acids results in increased transcription of this gene and increased bile acid formation. Bile acids are detected by the FXR (farnesoid X receptor) acts as a “bile acid sensor”.
Excretion of bile salts
95% of bile salts are reabsorbed in the intestinal capillaries and returned to the liver. 5% of bile salts are lost in faeces. The amount of bile salts recycled may increase after a high fat meal. The terminal ileum is the main site of bile acid reabsorption. Malabsorption of fats and fat soluble vitamins may therefore occur if the terminal ileum is inflamed or surgically resected.
Enterohepatic recycling of drugs
Drugs are absorbed across the intestinal wall and into portal circulation. When transported to the liver some drugs will be taken up by hepatocytes. The drugs and conjugated metabolites will be secreted into the bile and returned to the intestine and into the circulation, increasing the drugs half-life. Examples include NSAIDS, hormones, opioids, digoxin and warfarin. When the liver is damaged the drugs will more quickly enter the tissues, this may be in a toxic amount and cause overdose.
Capacity of the gallbladder
50ml
