1-16 Bile Production and Gallbladder Function

Question 1

Is bile bilirubin? What are the characteristics of bile

Answer 1

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 2

Where does bilirubin come from? How is it made? What causes jaundice?

Answer 2

Bilirubin is the breakdown product of RBCs

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 3

What 5 structures help with hepatocyte secreting bile?

Answer 3

Hepatocytes
bile canaliculus
bile duct
common bile duct
duodenum

Question 4

What is a lobule?

Answer 4

Lobules: 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 5

What is a sinusoid?

Answer 5

Sinusoids: expanded capillary spaces between rows of hepatocytes

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

Question 6

What is a bile canaliculus?

Answer 6

Bile canaliculus: 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 7

What makes up the liver parenchyma?

Answer 7

95% Hepatocytes

Question 8

What are some things that sinusoidal spaces contain?

Answer 8

Sinusoidal spaces contain:
 ~   2% Kupffer cells (phagocytic)
 ~   1% Stellate cells or Ito cells 
      (fat or vitamin A storing)
 ~   2% Endothelial cells

Question 9

What are sinusoids? How big are they, what are they lined with, and what do they do?

Answer 9

Sinusoids:

• spaces between hepatocytes
• filled with blood
• wider than capillaries, fenestrated
• lined with endothelial cells and
• Kupffer cells (macrophages)
• blood filtered by kupffer’s cells

Question 10

What is the Space of Disse? What are the contents? Function?

Answer 10

Space of Disse:
-stella cells and plasma solutes present, not blood cells

-cleansed blood passes through liver into systemic circulation

Question 11

What is the layout of a classic lobule?

Answer 11

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.

Question 12

What is the layout of a portal lobule?

Answer 12

The portal lobule includes all hepatocytes drained by a bile ductule.

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).

Question 13

What is the path of bile secretion?

Answer 13

Bile canaliculi
terminal bile ductules
perilobular ducts
interlobular ducts
septal ducts
lobar ducts
right and left hepatic ducts
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.

Question 14

What is the path of blood flow through the sinusoids?

Answer 14

Deoxygenated blood from stomach or small intestine
Hepatic Portal Vein
venules
sinusoids
cental vein
hepatic vein

Question 15

What is the path of bile produced in hepatocytes?

Answer 15

Bile produced in hepatocytes
secreted into canalicul
bile ductules
common duct
gall bladder
bile duct
small intestine

Question 16

What is the fxn of the biliary tract?

Answer 16

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

Question 17

How is bile stored between meals?

Answer 17

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

Question 18

What is the hepatocyte stage of bile secretion? What is the path?

Answer 18

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.

Question 19

What is the secretory stage of bile secretion?

Answer 19

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 20

What hormones act on the liver to stimulate secretion? What else can work on the liver? What do they stimulate?

Answer 20

1. Secretin - stimulates liver ductal secretion
2. Bile acids stimulate parenchymal secretion
3. Vagal stimulation causes weak contraction of gallbladder
4. CCK cause gallbladder contraction and relaxation of sphincter of Oddi

Question 21

What are the 3 steps of bile formation?

Answer 21

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 22

Is bile secreted continuously? Where is it stored? Is bile released into the duodenum dilute or concentrated?

Answer 22

bile is secreted continously by the liver cells and stored in gallbladder

gallbladder concentrates bile 5-20 fold, with max vol held in gallbladder is 30-60 ml

the 500 mL/day of bile that reaches the duodenum through the ampulla of Vater is thus a mixture of relatively “dilute” hepatic bile and “concentrated” gallbladder bile

Question 23

What are micelles a result of?

Answer 23

Micelle formation: when bile salts become concentrated, they form micelles

Bile salts and micelles: bile salts are actively secreted by the liver

Question 24

What forms bile pigments?

Answer 24

Bilirubin gives a golden yellow color to bile

Stercobilin gives a brown color to the stool

Question 25

What are 4 components of bile?

Answer 25

Bile salts/micelles
Bile pigments
Phosopholipids (mostly lecithin)
Cholesterol

Question 26

How are the primary bile acids created?

Answer 26

The liver converts cholesterol to the primary bile acids—cholic acid and chenodeoxycholic

Question 27

How are secondary bile acids created?

Answer 27

Action of bacteria in terminal ileum and colon may dehydroxylate bile acids, yielding the secondary bile acids deoxycholic acid and lithocholic acid

Question 28

How do hepatocytes act on many bile acids?

Answer 28

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 29

What is the bile composition for hepatic, gall bladder, and fecal bile acids for a healthy adult?

Answer 29

See slide 15

Question 30

Bile salts come from what precursor and do what?

Answer 30

Bile Salts (cholates, chenodeoxycholate, deoxycholate): produced by hepatic metabolism of cholesterol and excreted into bile

Bile salts in bile act as detergents to dissolve dietary fat for absorption

Question 31

What does a disruption in bile secretion cause?

Answer 31

Disruption bile excretion disrupts fat absorption & causes malabsorption

Patients develop diarrhea because of the resultant steatorrhea and then develop associated deficiencies of fat-soluble vitamins (A, D, E, & K)

Question 32

What percentage of bile is cholesterol? What is the body’s major route of excretion for cholesterol?

Answer 32

Cholesterol and phospholipids: Only 4% of bile is cholesterol.

However, hepatic secretion of cholesterol and its metabolites (bile salts) into bile is the body’s major route of cholesterol elimination.

Bile phospholipids enhance cholesterol solubilizing properties of bile salts

Inefficient excretion cholesterol can cause an increased serum cholesterol

Question 33

What percentage of bile is bilirubin? What is the clinical significance?

Answer 33

Bilirubin: Comprises only 0.3% bile; responsible for bile’s green-black color.

Obstruction of bile flow leads to jaundice

Question 34

What are the 2 functions of bile?

Answer 34

1. Fat digestion and absorption

2. Waste product excretion

Question 35

What is the process that bile acids do to help with fat digestion? Are all bile acids used at one time in this process?

Answer 35

Bile acids formed in the liver are stored in gallbladder between meals

After eating, gallbladder contracts & releases bile acids into intestines

Digests/absorbs lipids by emulsifying and assisting through intestinal mucosa

Some bile is “recycled” in process via reabsorption, returned to liver and reused (enterohepatic circulation of bile)

Question 36

What products are excreted with the help of bile?

Answer 36

Bilirubin (end product of hemoglobin breakdown)

Cholesterol (excess cholesterol)

lipophilic drugs, trace minerals, etc.

Question 37

What 2 important actions does bile have in the intestinal tract?

Answer 37

1. Detergent action or emulsification of 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 38

What 2 components make up total bile flow?

Answer 38

Canalicular flow (includes independent and dependent flow)
Ductal flow

Question 39

What is the location of canalicular flow?

Answer 39

hepatocytes into canaliculi

Question 40

What is the location of ductal flow?

Answer 40

Cholangiocytes into bile ducts

Question 41

What makes up independent flow?

Answer 41

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

Question 42

What makes up dependent flow?

Answer 42

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

Question 43

What does secretin stimulate?

Answer 43

Secretin stimulates the cholangiocytes of ductules and ducts to secrete a watery, HCO−3-Rich Fluid

Question 44

How is bicarbonate secreted by the cholangiocytes?

Answer 44

Cl-HCO3 exchanger on apical side
Cl- sent back to lumen via Cl- channels

Na-HCO3 cotransport on basolateral side
Uptake of CO2 with H+ extrusion from Na/H+ with carbonic anhydrase
(see slide 19)

Question 45

What are cholerectics?

Answer 45

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

Question 46

What is the effect of secretin, glucagon, and VIP on bile? How?

Answer 46

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 47

What is the effect of somatostatin?

Answer 47

Somastosatin 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 48

What is the effect of mucous on bile flow? What are some deleterious things associated with it?

Answer 48

Mucus: 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 49

What is the effect of acetylcholine on bile flow?

Answer 49

secreted from vagus and intestinal enteric NS

Stimulates gallbladder less strongly than CCK

Question 50

What are the 5 steps of bile release?

Answer 50

1. Acidic, fatty chyme entering duodenum causes release of CCK and secretin from duodenal wall and enteroendocrine cells.
2. CCK and secretin enter bloodstream.
3. Bile salts and secretin transported via bloodstream stimulate liver to produce bile more rapidly.
4. Vagal stimulation causes weak contractions of gallbladder.
5. CCK (via bloodstream) causes gallbladder to contract and hepatopancreatic sphincter to relax - bile enters duodenum.
6. Bile salts reabsorbed into blood.

Question 51

What is enterohepatic circulation of bile acids? Why is it necessary? How are bile salts returned to the liver?

Answer 51

Liver makes a small amount of total bile pool

The majority of bile salts are recycled between the liver and small intestine through the enterohepatic circulation

After participating in fat digestion and absorption, half of bile salts are reabsorbed by active transport in terminal Ileum (important!) and returned through the hepatic portal vein to the liver, which resecretes them in the bile. The other half is reabsorbed passively (diffusion) in early portions of small intestine.

Less than 5% of bile salts are lost each day in the stool

Question 52

What are the 4 steps of enterohepatic circulation?

Answer 52

1. Secretion of bile salts (95% are recycled)
2. 95% of bile salts reabsorped by terminal ilium
3. Reabsorbed salts enter portal vein circulation
4. 5% of bile salts lost in feces

Question 53

Where are bile salts reabsorbed in the liver?

Answer 53

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

Question 54

What affects the secretion of bile?

Answer 54

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 55

How does bile flow change between eating and not eating?

Answer 55

Bile flow between periods of digestion.

Bile is secreted continuously by the liver and flows toward the duodenum. In the interdigestive period the gallbladder is readily distensible, and the sphincter of Oddi is contracted. Therefore, bile flows into the gallbladder rather than the duodenum.

On eating, both hormonal (e.g., cholecystokinin [CCK]) and neural stimuli cause contraction of the gallbladder and relaxation of the sphincter of Oddi. Thus, bile flows into the bowel. Bile secretion from the liver increases as bile acids are returned via the enterohepatic circulation

Question 56

What can obstruction of bile cause?

Answer 56

can result in severe pain and lead to reflux of bile into liver parenchyma and eventually systemic circulation

Question 57

What intestinal abnormalities can affect bile secretion?

Answer 57

if the terminal ileum is diseased or removed, 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 58

What is the reservoir for Salmonella typhi?

Answer 58

Salmonella typhi was first cultured in 1894 from gallbladder. The gallbladder serves as “safe harbor” in the healthy carrier state for typhoid (enteric) fever.

In endemic areas, 0.15% of individuals are chronic carriers of Salmonella typhi
(all carriers have cholelithiasis). Carrier state abolished by cholecystectomy.

Question 59

What is cholestasis? What can happen to the bile materials?

Answer 59

suppression of bile secretion

• biliary constituents may be retained within the hepatocyte and regurgitated into the systemic circulation

Question 60

What are 3 negative effects of cholestasis?

Answer 60

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 61

How does liver disease cause cholestasis?

Answer 61

Many acute and chronic liver diseases produce cholestasis by mechanically obstructing the extrahepatic bile ducts or by impairing bile flow at the level of the hepatocytes or intrahepatic bile ducts.

Question 62

What is cholelithiasis? Cholecystitis? Cholangitis?

Answer 62

Cholelithiasis: formation of stones (calculi) within the gallbladder or biliary duct system

Cholecystitis: inflammation of gall bladder

Cholangitis: inflammation of the biliary ducts

Question 63

What is cholelithiasis? Cholecystitis? Cholangitis?

Answer 63

Cholelithiasis: formation of stones (calculi) within the gallbladder or biliary duct system

Cholecystitis: inflammation of gall bladder

Cholangitis: inflammation of the biliary ducts

Question 64

What causes gallstones to form?

Answer 64

Gallstones form due to:

1. Abnormal bile composition
2. Biliary stasis
3. Inflammation of gallbladder
4. Too much absorption of water from bile
5. Too much absorption of bile acids from bile
6. Too much cholesterol in bile
7. Inflammation of epithelium

Question 65

What is the natural history and complications of gallstones?

Answer 65

1. Asymptomatic - 75%
2. Intermittent biliary pain due to intermittent blockage of cystic duct - 20%
3. Cholecystitis - stone impacting duct (10%)
4. Mirizzi’s syndrome - stone in cystic duct compressing or fistulizing into bile duct (<0.1%)

Question 66

What are the risk factors for gall stones?

Answer 66

Five F’s

Rapid weight loss
gallbladder stasis
Inborn disorders of bile acid metabolism, GI disorders
hyperlipidemia syndromes

Question 67

What are 4 contributing factors to cholelithiasis?

Answer 67

Supersaturation
Gallbladder hypermotility
Crystal nucleation
Accretion within mucous layer

Question 68

What does UpToDate have to say about cholelithiasis?

Answer 68

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 69

What is more problematic, large or small gall stones?

Answer 69

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.

Question 70

What does cholelithiasis increase risk for?

Answer 70

carcinoma of the gallbladder

Question 71

Summary slide 1:

Answer 71

Bile is secreted by the liver as a vehicle to excrete lipid-soluble waste products of metabolismas well as xenobiotics, and it also aids in fat digestion and absorption.

The major solutes driving the primary secretion of bile are the bile acids, which are
amphipathic molecules synthesized from cholesterol in the hepatocyte.

Bile acids can be modified by intestinal bacteria to yield compounds known as secondary bile acids.
One of these, lithocholic acid, is relatively toxic, and so mechanisms exist to promote its
elimination from the body.

Bile acids are actively secreted into the bile canaliculus in conjugated forms by an energy-dependent transporter.

Bile also contains cholesterol and phosphatidylcholine, which are actively transported into the primary secretion, as well as solutes filtered from the plasma, such as calcium and glucose.

Glucose is actively reabsorbed from the bile as it passes through the biliary ductules, which also add IgA and render the bile alkaline.

Bile acids recycle several times daily from the intestine to the liver in the enterohepatic circulation; in their conjugated forms, they are actively reabsorbed in the terminal ileum,
thereby generating a recycling pool of bile acids.

Bile flow can be deficient because of injury to or an absence of bile ducts, a deficiency of
canalicular transporters, or physical obstructions such as gallstones or tumors.

Cholestasis is associated with malabsorption of fat soluble vitamins, as well as with other symptoms.

When bile flow is interrupted, biliary lipids accumulate in the plasma and the only route for cholesterol excretion is the urinary excretion of bile acids.

Question 72

Summary slide 2.

Answer 72

The gallbladder serves to store bile between meals and to coordinate the release of a
concentrated bolus of bile with the presence of the meal in the duodenum.

Gallbladder storage of bile results in changes in its composition, such that bile acids become the dominant anions.

Bile remains isotonic during this process as bile acid monomers are rapidly incorporated into mixed micelles.

The relative proportion of biliary lipids is largely unchanged, although the high concentration of cholesterol in human bile makes us vulnerable to cholesterol precipitation and thus to gallstones.

Concentration of bile results from active transport processes taking place in the lining epithelial cells.

Gallbladder filling and emptying are dynamic processes that depend on the pressure existing in the biliary tree and are regulated by neurohumoral cues.

Cholesterol gallstones are common in humans, and may cause pain and cholestasis.

The gallbladder is not essential to normal digestion, and symptomatic gallstone disease can often be cured by removal of the gallbladder.