Bile, Gall Bladder and Gall Stones

Question 1

What is the Ampulla of Vater?

Answer 1

• The Ampulla of Vater (hepatopancreatic duct/ampulla) is formed out of the union of the pancreatic duct and the common bile duct.
• It is found near the duodenal papilla.

Question 2

What is the general function of the gallbladder?

Answer 2

• It stores and concentrates bile.
• The bile is concentrated because of active Na+ transport (and H₂O) from the gallbladder.
• The pH of the bile drops (becomes ‘acidic’ [even though its still around pH 7-7.4 it is much more acidic than 7.8-8.6)] as Na+ is exchanged for H+.
• Pancreatic juice contains bile salts, bile pigments and dissolved substances in alkaline electrolytes.

Question 3

Describe how bile is modified.

Answer 3

• Bile coming from the liver goes into larger ductules and then through ducts (its composition is modified as and when necessary).
• Water may be added or removed via specific tight junctions within ductules. This are done by speciallised cells called cholangiocytes.
• The ductules will scavenge glucose, amino acids; and glutathione (GSH) is hydrolysed to become glutathione disulfide (GSSG).
• Ductules secrete IgA (for mucosal protection), HCO3- and H2O in response to secretin in the postprandial period.

Question 4

Describe bile flow (as in what structures it goes through).

Answer 4

Hepatocytes —-> Bile Canaliculi (these merge to form ductules) —-> Terminal Bile ducts —-> Hepatic ducts (there are 2: left and right) —-> Common Bile duct.

Question 5

What do bile salts consist of?

Answer 5

• Bile.
• A cation (e.g. Na+).

Question 6

What two cells secrete bile salts (and what else)?

Answer 6

1. HEPATOCYTES: cholesterol, lecithin (it is a phospholipid that helps to dissolve cholesterol), bile acids, bile pigments [bilirubin (it makes your eyes yellow when you have jaundice), biliverdin (it is what makes the skins tone blue when you are bruised), urobilin (it colours the urine), etc.].
2. EPITHELIAL CELLS OF BILE DUCTS: They secrete bicarbonate-rich salt solution [secretin influences the secretion of bicarbonate-rich salt solutions and H2O].

Question 7

When is bile secretion the greatest and why?

Answer 7

• Secretion of bile is greatest during and after a meal.
• When there is increased bile salts in the blood, there is increased bile salt secretion into the canaliculi (this is because of the presence of a system called enterohepatic circulation. So after a while at least 95% of the bile in the duct tends to get reabsorbed into portal circulation. If you can deetct it there the chances are that yoy can detect more in the bile canaliculi because its recycled).
• So an increased secretion leads to an increased flow of bile.
• Sphincter of Oddi contracts during periods of fasting.
• Sphincter of Oddi relaxes during and after meals.

Question 8

Can cholecystomised patients have a good quality of life?

Answer 8

Yes, as long as they don’t eat too much fatty food.

Question 9

What substances are secreted across the canalicular membrane?

Answer 9

• Bile acids.
• Phosphatidylcholine.
• Conjugated bilirubin - cholesterol.
• Xenobiotics (foreign chemical/ substance, e.g. drugs).

Specific transporters ferry the above into bile. Substances such as water, glucose, Ca2+, GSH (glutathione), amino acids, and urea enter the bile by diffusion.

Question 10

Describe the composition of hepatic and gallbladder bile.

Answer 10

• Hepatic bile: 97% water; cholesterol, lecithin, bile acids, bile pigments, etc.
• Gallbladder bile: 89% water; HCO₃^-, Cl^-, Ca²⁺, Mg²⁺, Na⁺, cholesterol, bilirubin, bile salts, etc. Bile is more concentrated in the gallbladder (NaCl and H₂O loss means increased solid content). Bile goes to the gallbladder between meals when the Sphincter of Oddi is closed.

Question 11

What are the 2 primary bile acids?

Answer 11

1. Chenodeoxycholic acid.
2. Cholic acid.

Question 12

Briefly describe bile acids.

Answer 12

• Bile acids are important in the GIT.
• They’re made from cholesterol and secreted into bile and conjugated to glycine or taurine.
• Conjugation helps to increase the ability of bile acids to be secreted or reabsorbed and also decrease their cytotoxicity.

Question 13

List and describe the 4 major bile acids found in humans.

Answer 13

• PRIMARY BILE ACIDS: - (formed in the liver)
  
  1. Cholic Acid: 50% - quantitatively more important.
  2. Chenodeoxycholic Acid: 30%.
• SECONDARY BILE ACIDS: - (formed in the colon)
  
  1. Deoxycholic Acid: 15%.
  2. Lithocholic Acid: 5%
• Cholesterol is converted to primary bile acids, then to secondary bile acids.
• Something happens in the intestines (there is anaerobic intestinal bacteria) which will convert the primary bile acids into secondary bile acids.

Cholic acid → deoxycholic acid.

Chenodeoxycholic acid → lithocholic acid and ursodeoxycholic acid.

Question 14

List the main functions of bile/bile acids as metabolic regulators.

Answer 14

1. The elimination of cholesterol to bile acids (5% of bile acids are excreted in faeces. (95% is recirculated) [excess cholesterol is synthesised into bile acids which can then be excreted].
2. It reduces the precipitation of cholesterol in the gallbladder (bile acids and phospholipids help solubilise cholesterol in bile).
3. It facilitate the absorption of fat-soluble vitamins (ADEK).
4. Regulate their own transport and metabolism via enterohepatic circulation (through the activation of various signalling pathways).
5. Facilitate the digestion of triglycerides (work in cohort with phospholipids (lecithin) and monoglycerides to ensure the emulsification of fats) [they act as emulsifying agents that render fats accessible to pancreatic lipase].

Question 15

Describe the contraction of the gallbladder to control the release of bile.

Answer 15

1. Cephalic phase: taste, smell and presence of food in the mouth will initate vagal nerve impulses via vagus nerve and initate secretion.
2. Gastric phase: distension of stomach generates impulses in vagus nerve.
3. Intestinal phase: period of most gallbladder emptying (at this time the enteric nervous system is detecting that somethung needs to happen); key mediators for the increased release are CCK and secretin.

Question 16

What are CCK and secretin released in response to?

Answer 16

• CCK is released in response to lipids/fats.
• Secretin is released in response to HCl in the duodenum. It will then go to stimulate duct cells in the liver (to release a bicarbonate-rich solution).

Question 17

Describe the mechanisms controlling the secretion of bile into the duodenum.

Answer 17

• When the nutrients (lipids) are sensed in the duodenum, they trigger the release of CCK, which acts directly and indirectly.
• Directly, it contracts the gallbladder.
• Indirectly, it sends a signal to the dorsal vagal complex, which then sends a signal back down to contract the gallbladder (via ACh) and relax the Sphincter of Oddi (via NO/VIP).
• There are also other levels of control - motilin, for example, induces gallbladder emptying and antral contractions in the fasting state of humans.
• All this is mediated by distention, the neuronal signals and hormonal signals.

Question 18

In a near all-embracing manner, explain the release of bile into the duodenum.

Answer 18

1. Chyme enters the duodenum causing the release of cholecystokinin (CCK) and secretin from the duodenal enteroendocrine cells.
2. CCK and secretin enter the bloodstream, absorbed by the intestinal mucosa.
3. CCK induces the secretion of enzyme-rich pancreatic juice. Secretin causes the secretion of bicarbonate-rich pancreatic juice.
4. Bile salts and, to a lesser extent, secretin, is transported via the bloodstream and stimulates the liver to produce bile more rapidly.
5. CCK (via the bloodstream) causes the gallbladder to contract and the hepatopancreatic sphincter to relax; bile enters the duodenum.
6. During the cephalic and gastric phases, vagal nerve stimulation causes weak contractions of the gallbladder.

[note, the role of ACh, NO, VIP, etc. are omitted here]

Question 19

Describe how bile salts are ‘recycled’.

Answer 19

• Most of the bile salts are reabsorbed (95%) by Na+-bile salt coupled transporters within the intestines.
• The bile salts are returned to the liver and secreted again into the bile.
• The recycling pathway from the intestine to the liver and back to the intestine is the enterohepatic circulation (via the hepatic portal vein).
• Body’s content of bile acid pool (~ 3.5g) may be recycled ~ twice per meal

Question 20

What will interruption of the enterohepatic circulation cause?

Answer 20

Interruption of enterohepatic circulation (e.g. after ileal resection) will cause the following:-

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

Question 21

Describe the formation of gallstones.

Answer 21

• The liver excretes cholesterol in excess.
• There is the reabsorption of salt and water (this provides an environment for gallstones to form).
• The cholesterol crystallises and forms gallstones.
• The ratio of incidence of gallstones is higher in women then men, and incidence increases with age.
• The higher the cholesterol content of bile, the greater the concentrations of phospholipid and bile salts.

Question 22

What are the two types of gallstones?

Answer 22

1. Cholesterol stones (85%):- (they are usually associated with high cholesterol obesity, decreased bile acids compared to phospholipids).
2. Calcium bilirubinate stones (15%):- (they are formed due to increased conjugated bilirubin. It is usually associated with haemolytic anaemia).

Question 23

List some factors involved in gallstone formation.

Answer 23

1. Bile Stasis: stones form in bile that is sequestered in the gallbladder rather than bile that is flowing in the bile ducts into the duodenum.
2. Decreased amount of bile acids due to malabsorption [in cystic fibrosis (the GI tract is blocked by a lot of mucus) - dehydrated and acidic; 10% incidence]; problems with bile production.
3. Chronic infection - bacteria help in the formation of pigment stones.
4. Super-saturation of bile with cholesterol.
5. Presence of nucleation factors or glycoprotein (possibly?)

Question 24

How would you visualise the gallbladder in a case of gallstones?

Answer 24

• Ultrasonography and computer tomography: explore the upper right quadrant of the gallbladder to detect gallstones.
• Cholescintigraphy: administer technetium-99m-labelled derivative of iminodiacetic acid (radioactive tracer), to show images of the gallbladder and its ducts (we can then inject CCK to see how the gallbladder behaves).
• Endoscope retrograde cholangiopancreatography (ERCP): can visualise the biliary tree by injecting contrast media from an endoscope channel.

Question 25

What symptoms will you end up with if a gallstone got stuck in each of the three possible places it could form?

Answer 25

1. Gallstone in the cystic bile duct: -
   
   • Painful gallbladder contractions.
   • Inflammation of the gallbladder (acute cholecystitis).
2. Gallstone blocking the common bile duct: -
   
   • Pain and nausea.
   • Lack of bile release.
   • Failure to excrete bilirubin leads to jaundice.
   • Can cause bacterial infection (cholangitis).
3. Gallstone blocking the duodenal papilla :-
   
   • Inappropriate activation of pancreatic enzymes.
   • Acute pancreatitis.

Gallbladder will secrete mucus if inflamed and rupture (mucocele or hydrops).