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
When is bile released?
When chime reaches the duodenum
Bile release- Cholecystokinin (CCK)
Causes contraction of the gallbladder and biliary tree releasing bile into the duodenum. CCK is released when there is fat in the duodenum. CCK causes the sphincter of ODDI to relax.
Bile release= Secretin
Is secreted in response to acid in the duodenum, it stimulates duct cells to secrete bicarbonate and water
Bile release- Vagus nerve
Parasympathetic nerve supply stimulates the gallbladder to contract and release bile
Mictroanatomy of the gallbladder
The gallbladder wall is surrounded by Absorptive epithelial cells which allow water to be removed from the bile. Folds increase the surface area and there are blood vessels within the lamina propria. There is also a smooth muscle layer. There is an outer layer of fibrous tissue with a serosal surface. There is mucosa between each fold and then the Submucosa near the lamina propria. The brush border cells contain microvilli which can absorb water from the bile.
The 2 components of Pancreatic secretions
- Within the Acinar cells you have the RER which produces proteins and the Zymogen granules which are precursor proteins for the digestive enzymes. The Zymogen granules are then released into the pancreatic ducts. The Acinar cells also produce a relatively small volume of isotonic fluid secretion.
- The Ductular cells line the pancreatic duct. They produce a relatively large volume of isotonic fluid secretion. There is secretion of HCO3- and absorption of Cl-.
Digestive hormone secretion in Acinar cells (1st method)
- The hormone VIP binds to the VIP receptor on the basolateral membrane of the Acinar cells.
- This stimulates the G protein complex which activates the enzymes Adenyl Cyclase (AC).
- cAMP is produced which is a second messenger molecules.
- This switches on protein kinase-A (PKA)
- PKA changes the phosphorylation state of the transporters on the Zymogen vesicles.
- The Zymogen vesicles fuse with the Apical membrane and release their contents via exocytosis into the duct lumen.
How parasympathetic nerves cause the release of digestive enzymes in the Acinar (2nd method)
- Ach binds to the Muscarinic receptor on the basolateral membrane of the Acinar cells.
- This stimulates a G protein complex which activates Phospholipase C (PLC).
- The produces DAG which switches on protein kinase-C (PKC).
- PKC changes the phosphorylation state of the transporters on the Zymogen vesicles.
- The Zymogen vesicles fuse with the Apical membrane and release their contents via exocytosis into the duct lumen.
Digestive hormone secretion in Acinar cells (3rd method)
Via parasympathetic nerves. PLC can also increase the amount of IP3 in the cytoplasm. IP3 binds to Ryanodine receptors which are found on the surface of the ER. This causes Ca+2 to leak out of the ER. The Ca+2 can switch on CaM which switches on protein kinases. PK changes the phosphorylation state of the transporters on the Zymogen vesicles. The Zymogen vesicles fuse with the Apical membrane and release their contents via exocytosis into the duct lumen.
Why is fluid produced in Acinar cells
Only produces 20% of the fluid. It helps moves digestive hormones away so that they are not activated too close to the pancreas
How fluid is produced in Acinar cells
1) On the basolateral membrane the Na+/2Cl-/K+ symporter moves Cl- and K+ into the cell using the energy of Na+ moving into the cell down its electrochemical gradient
2) The Na+/K+ ATPase pump pumps sodium out of the cell to maintain the electrochemical gradient for sodium.
3) The K+ balance can be maintained by removing K+ through the K+ channel.
4) This leaves a lot of Cl- within the Acinar cell. The Cl- leaves the cell through Cl- channels on the apical membrane. When the Cl- moves into the ductal lumen there is a movement of negative charge into the ductal lumen. This attracts Na+ molecules which move paracellulary into the ductal lumen from the interstitium. The water follows the Na+.
Controlling fluid secretion within the Acinar cell
ACh can bind to the M3 receptor on the basolateral membrane. This increase Ca+2 levels in the cytoplasm which switches on Protein kinases, this activates Cl- channels so more Cl- enter the ductal lumen. This will increase the volume of fluid produced. So ACh can control the volume of fluid produced.
Pancreas- How fluid is secreted in the ducts
- On the basolateral membrane the Na+/2HCO3- cotransporter moves Na+ into the cell down its electrochemical gradient which provides the energy to move 2 bicarbonate molecules.
- The Na+/K+ ATPase pump moves K+ into the cell and removes sodium from the cell. This sets up the electrochemical gradient for Na+. K+ channels then remove the K+ from the cells.
- CO2 and H2O diffuse into the cell and are converted by carbonic anhydrase into carbonic acid which is then converted to bicarbonate and protons. This is the majority of bicarbonate in the Pancreatic juice.
- The H+ is removed using a H+/Na+ exchanger, Na+ enters the cell
- On the Apical surface there is a Cl-/HCO3- antiporter which removes bicarbonate into the ductal lumen and transports Cl- into the cell.
- The Cl- then exits the cell using a CFTR transporter on the apical membrane.
- The Cl- in the lumen then attracts Na+ and H2O with it.
What fluid is created in the ductal cells of the pancreas
A fluid rich in bicarbonate
Pancreas- how fluid secretion is controlled in the ducts?
1) The hormone secretin can bind to receptors increasing cAMP which increases the opening time of CFTR, so more fluid and Cl- enter the ductal lumen.
2) Parasympathetic stimulation can cause ACh to bind to muscarinic receptors increasing Ca+2 concentration which increases the opening time of CFTR so more Cl- enters the ductal lumen.
Cephalic phase
Seeing food, this acts on your digestive track preparing you for the meal
The gastric phase
The lining of the stomach wall is covered in stretch receptors which are activated when the stomach fills with food
How the cephalic and gastric phase influences Pancreatic secretion
The cephalic and gastric phases turn on the vagus nerve in the brain, this switches on the parasympathetic mechanisms. So ACh will bind to M3 receptor in the ductal and Acinic cells increasing fluid and digestive enzyme production.
How the gastric phase influences Pancreatic secretion
When food is broken down, petides and amino acids are released, this can stimulate G cells to release Gastrin which is a hormone. Gastrin enters the circulation and activates CCKA receptors on the Acini cells increasing enzyme production. Has a lesser effect.
What drives Pancreatic secretions?
30-40% of Pancreatic stimulation is during the cephalic and gastric phases
60% of pancreatic secretion is driven by endocrine factors in the intestinal phase
Hormones which effect Pancreatic secretion
Secretin and Cholecteystokinin- pancrezymin produce a strong stimuli and induce long term secretion
What stimulates the hormone release in the Pancreas (digestion)
After a meal H+, protein and fat moves into the intestine. In the duodenum H+ binds to S cells lining the duodenum which release Secretin which binds to Secretin receptors on ductal cells, this activates ductal cells increasing fluid production. The proteins and fats bind to I cells in the lining of the duodenum. This increases CCK production which binds to CCK receptors on the Acini cells. This activates the Acini cells increasing production of the digestive enzymes
How much pancreatic fluid is secreted each day
1.5L
What is in the pancreatic juice
There are around 20 zymogens that are inactive digestive enzymes whose role is, once activated in the GI tract, to digest the major foodstuffs e.g. carbohydrates, proteins. The secretion also contains fluid and HCO3- this will help wash out the enzymes from the pancreas and neutralise the stomach acid.
Composition of pancreatic juice in low flow rates
It is similar to plasma, when the flow rate increases the concentration of bicarbonate increases and chloride ions decrease
When is malabsorption observed
80-90% of the pancreatic tissue can be lost before malabsorption is observed. The first signs of malabsorption is fat malabsorption as there are fewer fat digesting enzymes compared to other digestive enzymes.
The Pancreatic enzymes
1) Amylolytic enzymes
2) Lipolytic enzymes
3) Nucleolytic enzymes
4) Proteolytic enzymes
Pancreatic enzymes- Amylolytic enzymes
Includes Amylase, is used in carbohydrate metabolism
Pancreatic enzymes- Lipolytic enzymes
Includes lipase and phospholipase, used in fat digestion
Pancreatic enzymes- Nucleolytic enzymes
Includes DNAse and RNAse, used in nucleic acid digestion
Pancreatic enzymes- Proteolytic enzymes
Includes Trypsin, chymotrypsin and elastase, used in protein digest
How enzymes cause pancreatitis
A blockage at the Sphincter of Oddi causes backflow of pancreatic juices which could then digest the pancreas. This causes inflammation
Mechanisms to prevent autodigestion in the Pancreas
The enzymes are stored in Zymogens (inactive proenzymes), they are packages in granules to prevent interaction with other cell compartments. The Acinar cells also produce protease inhibitors to block the activity of prematurely activated enzymes. The zymogens and any other activated enzymes are then flushed out of the pancreas by the secretion of fluid, so the enzymes do not linger in the Pancreas for long.
How Pancreatic enzymes are activated
In the lumen of the small intestine. The proenzyme Trypsinogen is activated to Trypsin by the Enteropeptidase found on the duodenal wall. Trypsin then activates the other proteolytic proenzymes by cleaving off the inactive part
• Chyrmotrypsinogen -> Chymotrypsin
• Prosphospholipase -> Prospholipase
Role of Secretin, CCK and Gastrin
Secretin- bicarbonate and fluid released due to acid in the duodenum
CCK- enzymes released because of fat in the duodenum
Gastrin- promotes production of stomach acid
