S2: Bile, Gallbladder and Stones Flashcards
Why is the gall bladder important?
- It stores and concentrates bile which is synthesised by the liver
- Modifies fats so they can be digested
- Secretions of gall bladder and pancreas come together and go into the duodenum to neutralise the acidic chyme from the stomach - especially HCO3-
How is bile concentrated in the gallbladder?
How does it get more acidic?
It is concentrated because of active Na+ transport from the gallbladder and H2O follows.
The bile becomes more acidic as Na+ is exchanged for H+, but [Na+] increases as more Cl- and HCO3- are lost. Note that by acidic we are talking about it relative to the bile that would have been in the hepatic duct, the gall bladder bile is around pH 7.
What does pancreatic juice contain?
Bile salts
Bile pigments
Dissolved substances in alkaline electrolytes
List substances that are secreted into bile across the bile canalicular membrane
- Bile acids
- Phosphatidylcholine (phospholipid)
- Conjugated bilirubin
- Cholesterol
- Xenobiotics
There are specific transporters to ferry the above substances into the bile. Substances such as water, glucose, Ca2+, GSH (glutathione), amino acids and urea enter the bile by diffusion.
What can deviation of bile acids: phosphatidylcholine: cholesterol in the canalicular bile ratio lead to?
Cholesterol gallstones (as cholesterol precipitates out)
Describe bile formation
- Bile is formed in the liver from bile acids
- Bile moves through larger ductules and ducts and as they go through their composition is modified by movement of Na+ and H+
- Water may be added at specific tight junctions within ductules lined with cells called cholangiocytes
- Ductules scavenge (remove) glucose, AA and GSH is hydrolysed. This is because too much glucose could result in bacteria.
- Ductules also secrete IgA for mucosal protection and HCO3- in response to secretin in the postprandial period (after a meal).
What are cholangiocytes?
Cells which line tight junctions within ductules that allow water to be added to bile
Flow of bile from hepatocytes to bile duct
Hepatocytes –> Bile canaliculi (merge to form ductules) –> terminal bile ducts –> hepatic ducts (L and R) –> Common bile duct
What two cells secretes components of bile?
- Hepatocytes: secretes cholesterol, lecithin, bile acids, bile pigments (bilirubin, biliverdin, urobilin).
- Epithelial cells of bile ducts: bicarbonate rich salt solution
When is secretion of bile greatest?
Secretion of bile is greatest during and after a meal
This is for a good reason as we want to digest the food, particularly if we have taken a fatty meal
How does increased concentration of bile salt affect bile salt secretion and flow?
Increased [bile salt]blood → ↑ bile salt secretion into bile canaliculi
Increased secretion →↑flow of bile
When does the sphincter of oddi contract and relax?
- Sphincter of Oddi contracts during periods of fasting (interdigestive periods)
- Sphincter of Oddi relaxes during and after meals (digestive periods)
What are the major bile acids found in humans?
- Cholic acid
- Chonedeoxycholic acid
- Deoxycholic acid
- Lithocholic acid
What happens to bile acids in intestine?
Bacteria deconjugate these bile acids. Deconjugated bile acids are excreted or reabsorbed.
This is important because bile acids on their own can be very cytotoxic and conjugating them also enhances their solubility.
Formation of secondary bile acids
How are they bile acids secreted into bile?
- Cholesterol is made into primary bile acids in liver
- Anaerobic bacteria in the colon can modify the primary bile acids
- Bile acids are important in the GIT, they are made from cholesterol and secreted into bile conjugated to glycine or taurine.
How are primary and secondary bile acids removed by intestine into liver?
They travel via portal circulation
List some primary and secondary bile acids
Cholic acid -> Deoxycholic acid
Chenodeoxycholic acid -> Lithocholic acid and ursodeoxycholic acid
Function of bile acids
- Bile acids can be used to eliminate cholesterol
- It also reduces precipitation of cholesterol in the gallbladder, bile acids and phospholipids to help solubilise cholesterol in the bile
- Facilitate the absorption of fat soluble vitamins (A, D, E, K)
- Regulate their own transport and metabolism via enterohepatic circulation
- They regulate lipid and glucose metabolism
How is bile concentrated in the gallbladder?
With NaCl and some H2O loss
Difference in composition of hepatic bile and gallbladder bile
Hepatic bile is roughly 97% water, it also contains cholesterol, lecithin, bile acids, bile pigments etc.
Gallbladder bile is about 87% water, contains HCO3-, Cl-, Ca2+, Mg2+, Na+, cholesterol, bilirubin etc
Is bile essential for life?
We know people have their gall bladders removed. In general cholecystomised patients can have a good quality of life, so long as they don’t take too much fatty foods etc. They also have to lose weight.
Describe the control of gallbladder contraction and bile secretion
The gallbladder contracts when we are feeding which allows bile to be released.
It seems what causes bile acid release is similar to that what causes acid release in the stomach.
In the cephalic phase we have taste, smell and presence of food in the mouth which can lead to initiation of impulses via the vagus nerve.
In the gastric phase, distension of the stomach also initiates impulses via the vagus nerve.
Finally in the intestinal phase we have the period of most gallbladder emptying, there are certain signals that are also important here in emptying the gallbladder (motility) like CCK and secretin.
What causes the release of CCK and secretin?
- CCK is released in response to fat which allows sphincter of oddi to relax, contractions of gallbladder
- Secretin is released in response to acidic chyme (acid needs to be neutralised). This causes duct cells in liver (epithelial) to be stimulated which release bicarbonate
Describe role of sphincter of oddi in bile secretion
Sphincter of Oddi which relaxes as the gallbladder contracts and the pancreatic/gall bladder secretions will occur into the duodenum.
There will be neutralisation of acids and digestion will occur.
Distension of the duodenum will send signals via vagal afferents to the dorsal vagal complex. Signals return via efferents, the relaxation of sphincter of Oddi occurs via NO and VIP (and CCK).
What two substances cause the gall bladder to contract?
The gallbladder contracts under stimulation of Ach and CCK. All of this is mediated by distension, the neuronal signals and hormonal.
Effect of motillin on galllbladder
Motillin may influence gallbladder motility and volume.
Describe mechanism of CCK secretion and function
Distension of duodenum and fatty acids in food causes CCK secretion.
There is an increase in plasma CCK levels.
This causes gallbladder contractions which increases flow of bile into common bile duct.
This also causes the sphincter of oddi to relax which causes increased flow of bile to duodenum
How are bile salts mostly reabsorbed by?
What is this pathway called?
Most bile salts are reabsorbed by Na+-bile salt coupled transporters (after being deconjugated in intestine).
The bile salts are returned to the liver and again secreted into bile.
This recycling pathway from intestine to liver and back to intestine is called the enterohepatic circulation.
The liver also secretes cholesterol in bile and this is excreted in faeces.
What can interruption of the enterohepatic circulation (e.g. after ileal resection) cause?
- Excess synthesis of bile salts by liver (as you would be losing bile salts)
- Kidneys will excrete the synthesised bile salts (and some cholesterol)
What are bile salts?
Bile salts (bile compounded with a cation e.g. Na+), cholesterol and phospholipids
What risk factors are associated with gallstones?
- Fat
- Female
- Fourty +
- Fertile
- Fair
Why may there be increased cholesterol in bile?
Consequence of this
- Maybe the liver is secreting more into bile
- Maybe there is too much reabsorption of salt and water, producing an environment for them to form
The higher the cholesterol content of bile, the greater the concentrations of phospholipids and bile salts (as tries to balance ratio).
Changes in the compositions of bile, it may cause cholesterol to precipitate out and form gallstones. There may also be precipitation of bile pigments.
What are the two types of gallstones?
- Calcium bilirubinate stones - if enviroment changes
- Cholesterol stones - due to low levels of bile acids in the gallbladder (bile acids are important in reducing precipitation of cholesterol)
Factors involved in gallstone formation
- Bile stasis - stones form in bile that is sequestered in gallbladder rather than bile flowing through bile ducts
- Decreased amount of bile acids due to malabsorption - this occurs in CF where there is dehydration
- Chronic infection as bacteria helps in formation of pigment stones
- Supersaturation of bile with cholesterol
- Presence of nucleation factors or glycoprotein
What did ex vivo studies of bile from gallstone sufferes show?
- Bile taken from gallstones sufferers tend to form stones more quickly than normal individuals (a few days vs weeks).
Consequences of gallstones
- Small gallstones have an easy passage via the bile duct, so there are no problems (asymptomatic)
- Larger gallstones may lodge in the opening of the gallbladder, blocking the cystic duct or even the common hepatic duct.
Lodging of gallstones where the pancreas joins the bile duct before it joins the duodenum will cause stoppage of bile and pancreatic secretions.
This can result in nutritional deficiency (as food not digested properly, may also get ulcers), further pressure build up also decreases secretion of bile.
There can also be a jaundice, due to increased accumulation of bilirubin in blood
- Stones lodged in neck of cystic duct will cause pain (acute cholescystitis). Gallbladder will secrete mucus if inflamed and this may rupture.
What colours bile, urine and faeces?
Bile and urine is yellow because of bilirubin.
Stercobilirubin colours faeces.
Diagnosis of Gallstones: Visualising the Gallbladder
Ultrasonography and computer tomography can be used to explore the upper right quadrant of the gallbladder to detect gallstones.
Cholescintigraphy, is where we administer technetium 99m – labelled derivative of iminodiacetic acid (this ends up within gallbladder, we can inject CCK to see the behaviour of gallbladder)
Endoscope retrograde cholangiopancreatography (ERCP), this is to visualize the biliary tree by injecting contrast media from an endoscope channel.
