Gall Bladder function and bile production

Question 1

Hepatic blood supply

Answer 1

Liver receives blood from two sources:
1 a. Hepatic artery (25%): Arterial blood which provides the liver’s O2 supply and metabolites for hepatic processing
b. Hepatic portal vein (75%): venous blood draining the stomach, digestive tract, pancreas, and spleen for processing and storage of newly absorbed nutrients
2. Hepatic vein: Blood leaves the liver via hepatic vein

Question 2

Functions of the liver

Answer 2

metabolism of major nutrients
synthesis of plasma proteins, albumin, glucose, cholesterol, fatty acids, lipoproteins, etc.
Storage: glycogen, fats, irons, copper, vitamins

Detoxification: endogenous compounds (e.g., steroids and other hormones) exogenous compounds (e.g., drugs and toxins)

Inactivation: removes foreign particulate matter by phagocytes (macrophage Kupffer’s cells), bacteria, endotoxins, parasites, aging red blood cells

Activation: convert hormones and vitamins into more active form hydroxylation of vitamin D deiodination
of thyroid hormone thyroxine T4 to
triiodothyronine T3
Bile production: (complex secretory product) elimination of endogenous & exogenous waste products

Question 3

Bile definition and relationship to bilirubin

Answer 3

Bileis notbilirubinbut bilirubin is one of the many
constituents of bile

also called gall, gets its greenish-yellow color from bilirubin
bitter, neutral or slightly alkaline fluid synthesized by the liver
consists of salts, proteins, cholesterol, hormones, enzymes and bilirubin

Question 4

bilirubin

Answer 4

Bilirubin is the breakdown product of hemoglobin

heme breakdown takes place in the liver
it is excreted by the liver in the bile
jaundice is caused by abnormally high levels of bilirubin in the blood

Question 5

Liver lobules

Answer 5

functional units of liver, hexagonal arrangements surrounding a central vein.
At each of the 6 corners of the lobule there are 3 vessels (hepatic artery, hepatic portal vein, bile duct)

Question 6

Liver sinusoids

Answer 6

expanded capillary spaces between rows of hepatocytes

hepatic artery & portal vein flows blood from sinusoids to central veins to hepatic veins

Question 7

bile canaliculus

Answer 7

bile carrying channels runs between sinusoids and within each hepatic plate
Each hepatocyte is in contact with a sinusoid on one side and bile cannaliculus on other side

Question 8

Flow of bile

Answer 8

Hepatocytes –> bile canaliculus –> bile duct (periphery of lobule)–> common bile duct –> duodenum

Question 9

Difference between classic lobule and portal lobule

Answer 9

A. The classic lobule includes all hepatocytes drained by a single central vein. At each corner of the hexagon are triads composed of branches of the hepatic artery, portal vein, and bile duct.
B. The portal lobule includes all hepatocytes drained by a bile ductule.
C. This organization emphasizes the arterial blood supply to the hepatocytes and oxygenation gradient between a branch of the hepatic artery and branches of the hepatic vein (i.e., central vein). Boron

Question 10

Structure of biliary tree

Answer 10

A. Bile canaliculi merge with terminal bile ductules into perilobular ducts, and then interlobular ducts.
B. The interlobular ducts merge into septal ducts, lobar ducts, and the right and left hepatic ducts, combine as common hepatic duct
Common hepatic and cystic ducts gives rise to common bile duct
Common bile duct may merge with pancreatic duct and form ampulla of Vater before entering the duodenum
Common sphincter - sphincter of Oddi-regulates flow out of common bile duct and pancreatic duct.
(Boron, Walter F.., 2nd Edition.)

Question 11

Overview of bile secretion and transport

Answer 11

Bile secretion:

• Bile is actively secreted by liver and actively diverted to gallbladder between meals
• Stored and concentrated in gallbladder
• Sphincter of Oddi-prevents bile from entering duodenum
• After meal, bile enters duodenum

The biliary tract transports bile, formed in hepatocytes and secreted into bile caniliculi, to its eventual destination, the duodenum.

Question 12

Liver secretes bile in 2 stages:

Answer 12

1. Hepatocytes: large amounts of: (bile acids,
   cholesterol, and other organic constituents)
   - hepatic cells - minute bile canaliculi -
   interlobular septa – terminal bile ducts –
   larger ducts – hepatic and common bile duct – duodenum or via cystic duct into gallbladder.
2. Secretory epithelial cells (ductules & ducts)
   (watery solution of sodium & bicarbonate ions
   - into bile ducts and added to initial bile.
   - secretion equal amount to bile.
   - secretin stimulates this secondary secretion

Question 13

Two important words to describe the secretion of canalicular bile

Answer 13

active and isotonic

Question 14

Bile formation: 3 discrete steps

Answer 14

1. Hepatocytes actively secrete bile into the bile canaliculi
2. Intrahepatic and extrahepatic bile ducts not only transport this bile but also secrete into it a watery, HCO3−-rich fluid
   These first two steps may produce ∼1000 mL/day of so-called hepatic bile.
3. Half the hepatic bile-(500 mL/day) is diverted to the gallbladder, which stores the bile and iso-osomotically removes salts and water

Question 15

2 red boxes about bile production and metabolism

Answer 15

blood bilirubin into the liver –> increased cholesterol, lipid soluble bilirubin

Gall bladder: active transport of Na+ out into the enterohepatic circulation, K+, Cl-, H20 follow the salt.

Question 16

Bile salts and micelles, plus other constituents

Answer 16

Bile salts and micelles: bile salts are actively secreted by the liver
- Micelle formation: when bile salts become concentrated, they form micelles
Bile pigments
- Bilirubin gives a golden yellow color to bile
- Stercobilin gives a brown color to the stool
Phospholipids (mainly lecithin)
Cholesterol

Question 17

bile synthesis

Answer 17

The liver converts cholesterol to the primary bile acids—cholic acid and chenodeoxycholic.
Action of bacteria in terminal ileum and colon may dehydroxylate bile acids, yielding the secondary bile acids deoxycholic acid and lithocholic acid.
The hepatocytes conjugate most of primary bile acids to small molecules such as glycine and taurine before secreting them into the bile. The liver may also conjugate some primary and secondary bile acids to sulfate or glucuronate

Question 18

What Choudhury has in red about bile composition

Answer 18

67% bile acid, 22% phospholipid, 4% cholesterol, 4.5% protein, .3% bilirubin.

Total bile secretion: 1000 ml/day
Gallbladder holds about 50 ml concentrated bile/ day

biliary bile acids are 95% cholic, 5% lithocholic and ursodeoxycholic

Question 19

Four major components of bile

Answer 19

Bile salts (cholates, chenodeoxycholate, deoxycholate)- act as detergents
Cholesterol and phospholipids
bilirubin
protein and miscellaneous components: HCO3-

Question 20

Bile functions

Answer 20

Fat digestion and absorption

waste product excretion (bilirubin, cholesterol, lipophilic drugs, trace minerals, etc.)

Question 21

Bile salts: 2 important actions in intestinal tract

Answer 21

1. Detergent action or Emulsification on fat particles.
   -decreases the S/A
   -increase agitation in intestinal tract to break fat globules
2. Absorption of:
   - Fatty acids, monoglycerides, cholesterol and other lipids by formation of
   small complexes called micelles (semi-soluble in chyme)

Question 22

Canalicular flow vs. ductular flow

Answer 22

Canalicular flow:
Independent flow (constant component)
+ dependent flow (rising component that
increases with bile secretion)

Ductular flow: Constant

Independent flow depends on the presence of organic compounds and osmotic force, e, g, Glutathione – increases osmotic driving force for canalicular bile formation.

Dependent flow depends on negatively charged bile salts – in micellar form and out of solution and have low osmotic force

Question 23

What stimulates cholangiocytes? (4-5 things)

Answer 23

Secretin, glucagon, VIP, and gastrin-releasing peptide (GRP) all are choleretics. Somatostatin either enhances fluid absorption or inhibits secretion.

Question 24

Actions of Secretin, glucagon and Vasoactive Intestinal peptide

Answer 24

increases secretion:

Stimulates the cholangiocytes of ductules and ducts to secrete a watery, HCO−3-rich fluid
These hormones raise [cAMP]i and thus stimulate apical Cl− channels and the Cl-HCO3 exchanger.
A Ca2+-activated Cl− channel is also present in the apical membrane.

Question 25

actions of somatostatin

Answer 25

inhibits bile flow by lowering [cAMP]i, an effect opposite that of secretin.
This inhibition may be caused by enhancing fluid reabsorption by bile ducts.

Question 26

Mucus and the gallbladder

Answer 26

secretion by gallbladder epithelial cells protects the apical surface of the gallbladder epithelium from the potentially toxic effects of bile salts.

However, excessive mucin synthesis can be deleterious. 
Cholesterol cholelithiasis (i.e., formation of gallstones made of cholesterol), a marked 
increase in mucin release precedes crystal and stone formation.

Question 27

CCK and the gallbladder

Answer 27

presence of fatty food in the duodenum
 releases CCK 
 causes contraction of the gallbladder
 causes relaxation of the sphincter of Oddi 
 increases bile flow into the duodenum

Question 28

acetylcholine and the gallbladder

Answer 28

secreted from vagus and intestinal enteric NS

stimulates gallbladder less strongly than CCK

Question 29

where are bile salts reabsorbed?

Answer 29

reabsorbed by active transport in terminal Ileum and returned through the hepatic portal vein to the liver, which resecretes them in the bile
Less than 5% of bile salts are lost each day in the stool

Question 30

Circulation of bile acids (nothing is in red)

Answer 30

94 % bile salts are reabsorbed into the blood from the small intestine.
47% by diffusion through the mucosa in the early portions of the small intestine .
47% by an active transport process through the intestinal mucosa in the distal ileum.
They then enter the portal blood and pass back to the liver.
On reaching liver, on first passage through venous sinusoids these salts are absorbed
almost entirely back into the hepatic cells and then are resecreted into the bile.
94 % of all the bile salts are recirculated into the bile.
This recirculation of the bile salts is called the enterohepatic circulation of bile salts.
The quantity of bile secreted by liver each day is highly dependent on availability of bile salts
The greater the quantity of bile salts in enterohepatic circulation (usually a total of only about
2.5 grams), the greater the rate of bile secretion.
Ingestion of supplemental bile salts can increase bile secretion by several hundred milliliters
per day.

Question 31

Obstruction of bile can result in…

Answer 31

• can result in severe pain and lead to reflux of bile into liver parenchyma and eventually systemic circulation. Abnormalities of intestinal function can alter secretion of bile that undergo enterohepatic circulation:

Question 32

if the terminal ileum is diseased or removed

Answer 32

bile salt absorption is reduced
- this decreases bile salt pool (and hence bile salt secretion) and increases synthesis of bile acids by the liver In addition, bile acids that enter the colon induce water secretion by the colonic mucosa and cause diarrhea.

Question 33

Typhoid Mary (why this is in red I have no idea)

Answer 33

asymptomatic carrier of Salmonella typhi

offered choice of:
1 no longer working as a cook or
2 undergoing a cholecystectomy.
She agreed to quit working as cook and was released.

She changed her name and worked again as a household cook. Four family members developed typhoid and 1 died.
She was again arrested, convicted at a public trial, sentenced to lifetime quarantine and lived in isolation for her last 26 years.

Question 34

Cholestasis (nothing in red)

Answer 34

• suppression of bile secretion
• biliary constituents may be retained within the hepatocyte and regurgitated into the systemic circulation.
• causes three major groups of negative effects:
  1. regurgitation of bile components (bile acids, bilirubin) into the systemic
  circulation gives rise to the symptoms of jaundice and pruritus (itching).
  
  2. cholestasis damages hepatocytes, as evidenced by the release of liver
     enzymes (e.g. alkaline phosphatase) into the plasma.
  3. because the bile acids do not arrive in the duodenum, lipid digestion and
     absorption may be impaired.

Question 35

Many acute and chronic liver diseases produce cholestasis by…

Answer 35

mechanically obstructing the extrahepatic bile ducts or by impairing bile flow at the level of the hepatocytes or intrahepatic bile ducts.

Question 36

Gallbladder disorders (3)

Answer 36

a. Cholelithiasis: formation of stones (calculi) within the gallbladder or biliary duct system
b. Cholecystitis: inflammation of gall bladder
c. Cholangitis: inflammation of the biliary ducts

Question 37

pathophysiology of gallbladder disorders (what causes gallstones to form)

Answer 37

Pathophysiology
    Gallstones form due to
 1   Abnormal bile composition
 2   Biliary stasis
 3   Inflammation of gallbladder

causes: 
too much absorption of water from bile
too much absorption of bile acids from bile
too much cholesterol in bile
inflammation of epithelium

Question 38

risk factors for cholesterol stones

Answer 38

Europeans, native americans, mexican americans
age, female sex hormones, obesity and metabolic syndrome, rapid weight redution, gallbladder stasis, inborn disorders of bile acid metabolism, hyperlipidemia syndromes

Question 39

risk factors for pigment stones

Answer 39

asians, rural
chronic hemolytic syndromes
biliary infection
GI disorders (ileal disease, resection/ bypass, cystic fibrosis with pancreatic insufficiency)

Question 40

Cholelithiasis

Four Contributing Factors

Answer 40

Supersaturation
Gallbladder hypomotility
Crystal nucleation
Accretion within mucous layer

Question 41

Cholelithiasis stuff from UptoDate, nothing in red

Answer 41

Gallstones but without symptoms: Unlikely to develop symptoms and when they do occur they are generally mild

Typical biliary symptoms and gallstones
Patients generally undergo treatment (cholecystectomy) since they are likely to develop recurrent symptoms which can be severe.

National Cooperative Gallstone Study (definitive study) demonstrated 70 % increase in risk of recurrence of further symptoms and complications within 2 years in patients who experiences an episode of typical biliary symptoms and gallstones

Atypical symptoms and gallstones
Should search for non-gallstone-related causes of symptoms

If investigation unrevealing, treatment can be considered with the understanding that rate of persistent symptoms is high

Typical biliary symptoms but without gallstones: Clinical suspicion for gallstone disease should be maintained in such patients.

Question 42

Asymptomatic cholelithiasis

Answer 42

Gallstones may be present for decades before symptoms develop; 70 - 80% patients remain asymptomatic throughout their lives.

Asymptomatic patients convert to symptomatic ones at rate of 1- 4% per year and risk diminishes with increasing age

Symptomatic patients have biliary (colic) pain – next slide.

The larger the calculi, the less likely they are to enter the cystic or common ducts to produce complete obstruction; the very small stones, or “gravel,” are the more dangerous.

Cholelithiasis confers increased risk for carcinoma of the gallbladder

Question 43

What do symptomatic cholelithiasis patients have?

Answer 43

biliary (colic) pain. (this was in red)