S2: Bile, Gallbladder and Stones

Question 1

Why is the gall bladder important?

Answer 1

• 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-

Question 2

How is bile concentrated in the gallbladder?

How does it get more acidic?

Answer 2

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.

Question 3

What does pancreatic juice contain?

Answer 3

Bile salts
Bile pigments
Dissolved substances in alkaline electrolytes

Question 4

List substances that are secreted into bile across the bile canalicular membrane

Answer 4

• 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.

Question 5

What can deviation of bile acids: phosphatidylcholine: cholesterol in the canalicular bile ratio lead to?

Answer 5

Cholesterol gallstones (as cholesterol precipitates out)

Question 6

Describe bile formation

Answer 6

• 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).

Question 7

What are cholangiocytes?

Answer 7

Cells which line tight junctions within ductules that allow water to be added to bile

Question 8

Flow of bile from hepatocytes to bile duct

Answer 8

Hepatocytes –> Bile canaliculi (merge to form ductules) –> terminal bile ducts –> hepatic ducts (L and R) –> Common bile duct

Question 9

What two cells secretes components of bile?

Answer 9

1. Hepatocytes: secretes cholesterol, lecithin, bile acids, bile pigments (bilirubin, biliverdin, urobilin).
2. Epithelial cells of bile ducts: bicarbonate rich salt solution

Question 10

When is secretion of bile greatest?

Answer 10

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

Question 11

How does increased concentration of bile salt affect bile salt secretion and flow?

Answer 11

Increased [bile salt]blood → ↑ bile salt secretion into bile canaliculi

Increased secretion →↑flow of bile

Question 12

When does the sphincter of oddi contract and relax?

Answer 12

• Sphincter of Oddi contracts during periods of fasting (interdigestive periods)
• Sphincter of Oddi relaxes during and after meals (digestive periods)

Question 13

What are the major bile acids found in humans?

Answer 13

• Cholic acid
• Chonedeoxycholic acid
• Deoxycholic acid
• Lithocholic acid

Question 14

What happens to bile acids in intestine?

Answer 14

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.

Question 15

Formation of secondary bile acids

How are they bile acids secreted into bile?

Answer 15

1. Cholesterol is made into primary bile acids in liver
2. Anaerobic bacteria in the colon can modify the primary bile acids
3. Bile acids are important in the GIT, they are made from cholesterol and secreted into bile conjugated to glycine or taurine.

Question 16

How are primary and secondary bile acids removed by intestine into liver?

Answer 16

They travel via portal circulation

Question 17

List some primary and secondary bile acids

Answer 17

Cholic acid -> Deoxycholic acid

Chenodeoxycholic acid -> Lithocholic acid and ursodeoxycholic acid

Question 18

Function of bile acids

Answer 18

• 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

Question 19

How is bile concentrated in the gallbladder?

Answer 19

With NaCl and some H2O loss

Question 20

Difference in composition of hepatic bile and gallbladder bile

Answer 20

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

Question 21

Is bile essential for life?

Answer 21

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.

Question 22

Describe the control of gallbladder contraction and bile secretion

Answer 22

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.

Question 23

What causes the release of CCK and secretin?

Answer 23

• 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

Question 24

Describe role of sphincter of oddi in bile secretion

Answer 24

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).

Question 25

What two substances cause the gall bladder to contract?

Answer 25

The gallbladder contracts under stimulation of Ach and CCK. All of this is mediated by distension, the neuronal signals and hormonal.

Question 26

Effect of motillin on galllbladder

Answer 26

Motillin may influence gallbladder motility and volume.

Question 27

Describe mechanism of CCK secretion and function

Answer 27

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

Question 28

How are bile salts mostly reabsorbed by?

What is this pathway called?

Answer 28

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.

Question 29

What can interruption of the enterohepatic circulation (e.g. after ileal resection) cause?

Answer 29

• Excess synthesis of bile salts by liver (as you would be losing bile salts)
• Kidneys will excrete the synthesised bile salts (and some cholesterol)

Question 30

What are bile salts?

Answer 30

Bile salts (bile compounded with a cation e.g. Na+), cholesterol and phospholipids

Question 31

What risk factors are associated with gallstones?

Answer 31

• Fat
• Female
• Fourty +
• Fertile
• Fair

Question 32

Why may there be increased cholesterol in bile?

Consequence of this

Answer 32

• 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.

Question 33

What are the two types of gallstones?

Answer 33

1. Calcium bilirubinate stones - if enviroment changes
2. Cholesterol stones - due to low levels of bile acids in the gallbladder (bile acids are important in reducing precipitation of cholesterol)

Question 34

Factors involved in gallstone formation

Answer 34

1. Bile stasis - stones form in bile that is sequestered in gallbladder rather than bile flowing through bile ducts
2. Decreased amount of bile acids due to malabsorption - this occurs in CF where there is dehydration
3. Chronic infection as bacteria helps in formation of pigment stones
4. Supersaturation of bile with cholesterol
5. Presence of nucleation factors or glycoprotein

Question 35

What did ex vivo studies of bile from gallstone sufferes show?

Answer 35

• Bile taken from gallstones sufferers tend to form stones more quickly than normal individuals (a few days vs weeks).

Question 36

Consequences of gallstones

Answer 36

• 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.

Question 37

What colours bile, urine and faeces?

Answer 37

Bile and urine is yellow because of bilirubin.

Stercobilirubin colours faeces.

Question 38

Diagnosis of Gallstones: Visualising the Gallbladder

Answer 38

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.