1-16 Bile Production and Gallbladder Function Flashcards Preview

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Flashcards in 1-16 Bile Production and Gallbladder Function Deck (72):

Is bile bilirubin? What are the characteristics of bile

Bile is not bilirubin but 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


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

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


What 5 structures help with hepatocyte secreting bile?

bile canaliculus
bile duct
common bile duct


What is a lobule?

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)


What is a sinusoid?

Sinusoids: expanded capillary spaces between rows of hepatocytes

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


What is a bile canaliculus?

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


What makes up the liver parenchyma?

95% Hepatocytes


What are some things that sinusoidal spaces contain?

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


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

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


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

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

-cleansed blood passes through liver into systemic circulation


What is the layout of a classic lobule?

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.


What is the layout of a portal lobule?

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).


What is the path of bile secretion?

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.


What is the path of blood flow through the sinusoids?

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


What is the path of bile produced in hepatocytes?

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


What is the fxn of the biliary tract?

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


How is bile stored between meals?

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


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

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.


What is the secretory stage of bile secretion?

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


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

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


What are the 3 steps of bile formation?

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


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

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


What are micelles a result of?

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

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


What forms bile pigments?

Bilirubin gives a golden yellow color to bile

Stercobilin gives a brown color to the stool


What are 4 components of bile?

Bile salts/micelles
Bile pigments
Phosopholipids (mostly lecithin)


How are the primary bile acids created?

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


How are secondary bile acids created?

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


How do hepatocytes act on many bile acids?

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


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

See slide 15


Bile salts come from what precursor and do what?

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


What does a disruption in bile secretion cause?

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)


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

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


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

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

Obstruction of bile flow leads to jaundice


What are the 2 functions of bile?

1. Fat digestion and absorption

2. Waste product excretion


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

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)


What products are excreted with the help of bile?

Bilirubin (end product of hemoglobin breakdown)

Cholesterol (excess cholesterol)

lipophilic drugs, trace minerals, etc.


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

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)


What 2 components make up total bile flow?

Canalicular flow (includes independent and dependent flow)
Ductal flow


What is the location of canalicular flow?

hepatocytes into canaliculi


What is the location of ductal flow?

Cholangiocytes into bile ducts


What makes up independent flow?

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


What makes up dependent flow?

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


What does secretin stimulate?

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


How is bicarbonate secreted by the cholangiocytes?

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)


What are cholerectics?

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


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

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


What is the effect of somatostatin?

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.


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

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.


What is the effect of acetylcholine on bile flow?

secreted from vagus and intestinal enteric NS
Stimulates gallbladder less strongly than CCK


What are the 5 steps of bile release?

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.


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

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


What are the 4 steps of enterohepatic circulation?

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


Where are bile salts reabsorbed in 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


What affects the secretion of bile?

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


How does bile flow change between eating and not eating?

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


What can obstruction of bile cause?

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


What intestinal abnormalities can affect bile secretion?

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


What is the reservoir for Salmonella typhi?

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.


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

suppression of bile secretion

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


What are 3 negative effects of cholestasis?

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


How does liver disease cause cholestasis?

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.


What is cholelithiasis? Cholecystitis? Cholangitis?

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

Cholecystitis: inflammation of gall bladder

Cholangitis: inflammation of the biliary ducts


What is cholelithiasis? Cholecystitis? Cholangitis?

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

Cholecystitis: inflammation of gall bladder

Cholangitis: inflammation of the biliary ducts


What causes gallstones to form?

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


What is the natural history and complications of gallstones?

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%)


What are the risk factors for gall stones?

Five F's

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


What are 4 contributing factors to cholelithiasis?

Gallbladder hypermotility
Crystal nucleation
Accretion within mucous layer


What does UpToDate have to say about cholelithiasis?

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.


What is more problematic, large or small gall stones?

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.


What does cholelithiasis increase risk for?

carcinoma of the gallbladder


Summary slide 1:

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.


Summary slide 2.

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.