Bile, Gallbladder and Stones Flashcards
Describe the gross anatomy of the biliary system
- Liver
- Gallbladder
- Common hepatic duct and cystic duct anastomose, form common bile duct
- Oesophagus
- Stomach
- Pancreatic duct
- Major duodenal papilla
- Pancreas
- Duodenum portion of small intestine
How is the Ampulla of Vater formed?
Also called hepatopancreatic duct or ampulla
Formed out of union of pancreatic duct and common bile duct neart major duodenal papilla. Sphincter of oddi b/w major duodenal papilla and duct, controls bile secretion. When relaxed, allows bile secretion into duodenum
From the liver, bile moves to where?
Bile canaliculi cells which join the bile ductules and then the bile ducts; following food intake bile acids secreted by gallbladder into duodenum by CCK, which mediates the release of bile acids, key to emulsification of fats
Describe the physiology and functions of the gallbladder. What does hepatopancreatic juice consist of?
- Storage and concentration of bile. B/w meals bile goes to the gallbladder
- Concentrated bcs of active Na+ transport (and H2O) from gallbladder
- pH of bile drops (acidic) as Na+ exchanged for H+
- Hepatopancreatic juice - Bile salts, bile pigments, enzymes, dissolved substances in alkaline electrolytes
Describe the components of bile
Secreted by 2 different cell types:
- Hepatocytes: Cholesterol, lecithin, bile acids, bile pigments (bilirubin, biliverdin, urobilin etc)
- Epithelial cells of bile ducts: bicarbonate-rich salt solution
- Secretin influences secretion of bicarbonate-rich salt solutions and H2O
- Secretion of bile greatest during and after meal
- Sphincter of Oddi contracts during periods of fasting, bile not secreted
- Sphincter of Oddi relaxes during and after meals, bile secreted
What substances are secreted across the bile canalicular membrane?
- Bile acids
- Phosphatidylcholine
- Conjugated bilirubin
- Cholesterol
- Xenobiotics
Specific transporters ferry these into bile.
Substances such as water, glucose, Ca2+, amino acids and urea enter bile by diffusion
The liver converts bilirubin into a form the body is able to get rid of, this is conjugated/direct bilirubin. It travels from the liver into the small intestine, and a very small amount passes into the kidneys and is excreted in urine
Describe the composition of hepatic and gallbladder bile
- Hepatic bile = 97% water; cholesterol; lecithin; bile acids, bile pigments
- After synthesis, bile acids are transported across the canalicular membrane into bile canaliculi and then to the gallbladder
- Gallbladder bile: 89% water; HCO3-, Cl-, Ca2+, Mg2+, Na+, cholesterol, bilirubin, bile salts
- Bile concentrated in gallbladder (NaCl and H2O loss → increased solid content)
- Bile goes to the gallbladder b/w meals when sphincter of Oddi is closed
Describe main functions of bile and the role of bile/bile acids as metabolic regulators
- Elimination of cholesterol to bile acids (5% excreted in faeces)
- Synthesis and subsequent excretion of bile acids in faeces represent significant mechanisms for elimination of excess cholesterol
- Reduce precipitation of cholesterol in gallbladder; bile acids and phospholipids help solubilise cholesterol in bile
- Facilitate the absorption of fat-soluble vitamins (ADEK)
- Regulate their own transport and metabolis via enterohepatic circulation
- Facilitate digestion of triglycerides - work in concert with phospholipids (licithin) and monoglycerides to ensure emulsification of fats
- Facilitate digestion of dietary fats by acting as emulsifying agents that render fats accessible to pancreatic lipases
Describe bile and how it flows
Secretion of bile is greatest during and after a meal
- Bile → Larger ductules and ducts
- Water may be added via specific tight junctons within ductules (cholangiocytes)
- Ductules scavenge glucose, amino acids; GSH hydrolysed
- Ductules secrete IgA (muscosal protection), HCO3- and H2O in response to secretin in postprandial period
Bile flows as follows:
- Hepatocytes → bile canaliculi (merge to form ductules) → terminal bile ducts → hepatic ducts (left and right) → common bile duct
Describe the contraction of the gallbladder
Control of release of bile/bile salts
- Cephalic phase - taste, smell, presence of food in mouth → impulses via vagus nerve
- Gastric phase - Distensio of stomach gnerates impulses in vagus nerve
- Intestinal phase - Period of most gallbladder emptying; key mediators for inceased release are CCK (stimulated in response to FAs and proteins) and secretin (stimulated by the presence of acidic chyme in the duodenum)
What are the mechanisms controlling the secretion of bile into the duodenum?
- Motilin (secreted by enteroendocrine M cells)→ Induces gallbladder emptying and antral contractions in faster states, gallbladder motility and volume of gallbladder secretions
- Dorsal vagal complex, receives vagal afferent signals when lipids etc enter dudoenum and CCK is secreted, fire efferent signals down vagus nerve inducing release of Ach, this acts on I cells and S cells inducing release of CCK and secretin respectively, as well as NO/VIP which relaxes the sphincter of Oddi, also inducing release of bile
Explain the release of bile into the duodenum
ROLE OF ACH, NO AND VIP OMITTED
- Chyme entering duodenum causes release of CCK and secretin from duodenal enteroendocrine cells
- CCK and secretin enter bloodstream
- CCK induces secretion of enzyme-rich pancreatic juice. Secretin causes secretion of HCO3- rich pancreatic juice
- Bile salts to lesser extent, secretin transported via bloodstream stimulate liver to produce bile more rapidly
- CCK via bloodstream) causes gallbladder to contract, hepatopancreatic sphincter to relax; bile enters duodenum
- During cephalic and gastric phases, vagal nerve stimulation weakens contractions of gallbladder
Describe the events stimulated by CCK and secretin
- Stimulate liver to synthesise and release bile into common bile duct
- CCK stimulates gallbladder to contract, ejecting concentrated bile into cystic duct and common bile duct
- Hepatopancreatic sphincter (sphincter Oddi) relaxes, allowing bile to flow from common bile duct into dudodenum
Describe bile secretion and enterohepatic circulation
- Bile salts, lecithin (phospholipids) - Synthesised in liver
- HCO3-, other ions - neutralise acids in duodenum
- Most bile salts reabsorbed by Na+ bile salt coupled transporters
- Bile salts returned to liver and secreted again into bile
- Recycling pathways from intestine → liver → intestine = eneterohepatic circulation
- Liver also secretes cholesterol in bile, some of this excreted in faeces
- Interruption of enterohepatic circulation (e.g. after ileal resection) can cause following:
- Excess synthesis of bile salts by liver
- Kidneys will excrete synthesised bile salts (and some cholesterol)
Describe cholelithiasis and its consequences
Cholelithiasis = Gallstone formation
Gallstones form when bile in the gallbladder is supersaturated with substances such as cholesterol or bilirubin, they precipitate and form stones
Bile salts (bile compounded with cation e.g. Na+), cholesterol and phospholipids
- Higher cholesterol content of bile, greater the concentrations of phospholipid and bile salts
Increased cholesterol caused by:
- Excess cholesterol secreted by liver
- Reabsorption of salt and water
- Cholesterol crystallises and forms gallstones - precipitation of bile pigments
Small gallstones easy passage via bile duct
Larger gallstones lodge in the opening of the gallbladder
Duct from pancreas joins bile duct before joins duodenum.
Lodging at this point causes stoppage of bile and pancreatic secretions, increasing pressure, resulting in nutrient deficiency
Further pressure build up causes decreased secretion of bile, jaundice as a result of the increased accumulation of bilirubin in blood
Describe the types of gallstones and the factors involved in gallastone formation
2 types:
- Cholesterol stones (85%): Obesity, decreasedbile acids vs decreased phospholipids
- Calcium bilirubinate stones: Due to increased lvls of unconjugated bilirubin
Factors:
- Bile stasis - Stones form in bile that is sequestered in gallbladder rather than bile that’s flowing in bile ducts into duodenum
- Decreased amount of bile acids due to malabsorption (in cystic fibrosis - dehydrated and acidic; 10% higher incidence); problems with bile production
- Chronic infection - Bacteria help in formation of pigment stones
- Super-saturation of bile with cholesterol
- Presence of nucleation factors or glycoprotein??
How can gallstones be diagnosed?
- X-ray biliary tree by injecting contrast media fro an endoscope channel:
- Endoscope retrograde cholangiopancreotography (ERCP)
- Explore RUQ of gallbladder to detect gallstones:
- Ultrasound
- CT
- Image gallbladder and ducts:
- Cholescintigraphy: administer tecnetium-99m-labelled derivative of iminodiacetic acid (radioactive tracer)
- Insert devices and remove gallstone fragments that may be obstructing bile flow, pancreatic juice or both
What are the clinical features of gallstones?
- 85% asymptomatic (gallstones remain in gallbladder)
- If neck of cystic duct impaired → biliary pain ensures (acue cholecystitis)
- Gallstones that impact common bile duct → obstruction bile flow and cholestatic jaundice which can cause bacterial infections (cholangitis)
- Gallbladder secretes mucus if inflamed or ruptures (mucocele or hydrops)
- Referred pain (due to convergence of visceral nociceptors onto somatic afferent pathways) in right scapula as well as local pain
- Biliary colic:
- Usually felt as severe gripping or gnawing pain in RUQ. May radiate to epigastrium, or around lower ribs, or directly through to back.
- Gallstone in cystic bile duct - Painful gallbladder contractions
- Gallstone blocking common bile duct - Pain and nausea, lack of bile release, jaundice as bilirubin can’t be excreted
- Gallstone blocking duodenal papilla - Inappropriate activation of pancreatic zymogens, acute pancreatitis
Describe how bile acids are synthesised
DON’T NEED TO MEMORISE NAMES OR ENZYMES
Classic/neutral pathway: End product is Cholic acid, 90% of cholesterol is metabolised via this pathway
- Cholesterol converted into 7 alpha-hydroxycholesterol via cholesterol 7 alpha-hydoxylase
- 7 alpha hydroxycholesterol converted into 7 alpha-hydroxy-4cholesten-3-one via 3 B-hydroxysteroid dehydrogenase
- This is converted into 7 alpha,12alpha - dihydroxy-4-cholesten-3-one
- This is converted into 5B-cholestane-3a, 7a, 12a- triol
- This is then converted into 3a, 7a, 12a-trihydroxy-5B-cholestanoic acid via sterol 27-hydroxylase
- This is then converted into cholic acid 😪
Basically, the double bond of the sterol nucleus is saturated, the 3B hydroxyl group is epimerised and hydroxylysed. Shortening of side chains to 3C-atoms. Carboxylation of last C atom of side chain. Both cholic and chenodeoxycholic acid arre formed in equal amounts in the neutral pathway
Alternative (Acidic Pathway): End product is chenodeoxycholic acid, less common pathway for cholesterol metabolism
- Side chain modification by 27-hydroxylase
- Modification of sterol ring of oxysterols
- 7alpha-hydroxylation by CYP7B1
- Cholesterol first converted into 27-hydroxycholesterol bby CYP27A1
- Oxysterol 7α-hydroxylase (CYP7B1) catalyses hydroxylation of 27-hydroxycholesterol to 3 ,7α-dihydroxy-5-cholestenoic acid, which is eventually converted to chenodeoxycholic acid.
Describe the role of bile acids and what they’re composed of?
- Made from cholesterol - helps reduce cholesterol lvls
- Secreted into bile into bile and conjugated to glycine or taurine
- Conjugated bile acids are major acids in human bile
Glycine and taurine conjugated cholic acid
- Glycine conjugated cholic acid: glycocholic acid (G-CA)
- Taurine conjugated cholic acid: taurocholic acid (T-CA)
Glycine and taurine conjugated chenodeoxycholic acid
- Glycine conjugated chenodeoxycholic acid: glycochenodeoxycholic acid (G-CDCA)
- Taurine conjugated chenodeoxycholic acid: taurochenodeoxycholic acid (T-CDA)
If it’s called a salt, the conjugated forms would be glycochenodeoxycholate and taurochenodeoxycholate
Conjugation → Increases amphipathic nature of bile acids, helps to increase ability of bile acids to be secreted and also decreases their cytotoxcicity.
Bile acids conjugated with taurine or glycline also called bile salts
Compare primary and secondary bile acids
4 major bile acids found in humans:
- Cholic acid: 50%
- Chenodeoxycholic acid: 30%
- Deoxycholic acid: 15%
- Litocholic acid: 5%
Principal primary bile acids are formed in the liver
**Secondary bile acids are formed in the colon they’re made by bacteria acting on primary bile acids
Cholesterol is metabolised into primary bile acids via CYP7A1, CYP8B1, CYP27A1 and CYP7B1. The primary acids can be either chenodeoxycholic acid (CDCA) which is conjugated with G/T-CDCA (glycine or taurine)
They can also be conjugated with cholic acid, G/T-CA.
Secondary bile acids can be chenodeoxycholic or cholic. Chenodeoxycholic is converted into litocholic acid and ursodeoxycholic acid. Cholic acid is converted into deoxycholic acid. Once in the intestine, bacteria deconjugate bile acids. Secondary bile acids are deconjugated by 7 alpha- dehydroxylase, a deoconjugating enzyme
Deconjugated bile acids are excreted (most of LCA) or reabsorbed (CDCA, CA, deoxycholic acid). If too much deconjugated bile acids reach the colon, water enters the colon and causes gut motility and diarrhoea (bile acid diarrhoea)
How is the contraction of the gallbladder and the release of bile into the duodenum controlled?
CCK released from I cells in the duodenum - Stimulates gallbladder contraction and relaxation of sphincter of Oddi. Leads to increase flow of bile into common duct, and when sphincter Oddi relaxes, increased flow of bile into duodenum
The presence of fatty meals stimulates the secretion of CCK
