16. Bile Secretion and Gall Bladder Function (DSA + Lecture)

What are the 3 ways to organize liver lobules

*A*: Classic lobule (hepatocytes drained by 1 central vein w/triads at each corner) *B*: Portal lobule (drains bile from hepatocytes to bile duct) *C*: Emphasizes arterial blood supply to hepatocytes (& O2 gradient b/w branches of hepatic artery & vein)

What 2 major waste products are excreted with bile?

- Bilirubin (end product of Hb destruction) - Excess Cholesterol

7 functions of the liver?

1) *Metabolism* (carbs, proteins, lipids) 2) *Synthesis* (proteins, albumin, glucose, cholesterol, FAs, lipoproteins, clotting factors) 3) *Storage* (glycogen, fats, irons, copper, vitamins) 4) *Detox* (endogenous [steroids & other hormones] & exogenous [drugs & toxins]) 5) *Inactivation* (remove foreigners by phagocytes [Kupffer's cells] - bacteria, endotoxins, parasites, aging RBCs) 6 *Activation* (convert hormones & vitamins into more active form [eg vitamin D]) 7 *Bile production*

1) In addition to bile acids causing bile secretion, what hormone also causes bile secretion? (by how much?) 2) How is this increase in secretion accomplished?

1) *Secretin* (sometimes more than doubling its secretion for several hours after a meal) 2) Almost entirely secretion of sodium bicarbonate-rich watery solution by ET cells of bile ductules & ducts (not by increased secretion by hepatocytes)

*Composition of Bile*: 1) 4 major constituents of bile? 2) By far, the most abundant substance secreted in bile are?

1) *bile salts*, *lecithin* (phospholipids), *cholesterol* & *bilirubin* (bile pigments) 2) bile salts (account for 1/2 of total solutes in bile)

Bile salts are formed in the hepatic cells from cholesterol in the blood plasma: 1) In process of secreting bile salts, about how much cholesterol are removed from blood plasma & secreted into bile each day? 2) With what does this cholesterol combine (2)? 3) What do these combine to form?

1) 1 to 2 grams of cholesterol 2) Bile salts & Lecithin 3) Ultramicroscopic micelles (in the form of a colloidal solution)

1) Liver cells make ≈ __ grams of bile salts daily. 2) The precursor of bile salts is ______? (where do we get that from (2))

1) 6 grams 2) cholesterol (from diet or made in liver during fat metab)

1) In addition to CCK, the GB is stimulated less strongly by?2) What is GB emptying like when fat's not in the food? 3) When fat is present, how long does it take for the GB to empty completely?

1) Ach (Vagus & Enteric) 2) GB empties poorly 3) ≈1 hr

Bile formation: 1) Cholesterol + Bilirubin = ? 2) What do you add to (1) for conjugation to primary bile salts?

1) Cholic acid / Chenodeoxycholic acid 2) Glycine / Taurine

Bile salts have what 2 important actions in intestinal tract?

1) Detergent/Emulsifying action on fat particles in food 2) Absorption of fatty acids, monoglycerides, cholesterol, & other lipids from intestinal tract

What 2 things do bile salts do (to assist in fat digestion & absorption)?

1) Emulsify large fat particles of food into many minute particles (the surface of which can then be attacked by lipase enzymes from pancreas) 2) Aid in absorption of digested fat end products through intestinal mucosal membrane

1) Where do reabsorbed bile salts go after reabsorption? 2) On average, bile salts make the entire circuit some ___ times before being carried out in poop (This recirculation of the bile salts is called?)

1) Enter portal blood and pass back to liver (& back into hepatocytes → re-secreted into bile) 2) 17 times (enterohepatic circulation of bile salts)

1) When food begins to be digested in the upper GI, GB begins to empty, especially when? 2) The mechanism of GB emptying is (2)?

1) Especially when fatty foods reach duodenum (≈30 minutes after meal) 2) Rhythmical contractions of GB wall *and* relaxation of sphincter of Oddi

1) What substance, absorbed by GI tract, does not pass through the liver? 2) Why not? 3) What vessel does it travel through?

1) Fat 2) "It will plug up your blood vessels" 3) Lymphatics (lacteals) → R atrium of heart

What are liver: 1) Lobules? 2) Sinusoids? 3) Bile canaliculus?

1) Functional units of liver (hexagon surrounding central vein w/portal triad at each of 6 corners) 2) Wide bore capillaries b/w rows of hepatocytes 3) Bile carrying channels b/w sinusoids & w/in each hepatic plate

Review of stuff you already know: 1) Common cause of pancreatitis? 2) Is the bile is continuously secreted by liver or secreted by liver on demand? 4) Bile actively diverted to __?__ between meals 5) What prevents bile from entering duodenum?

1) Gall stone blocking pancreatic duct 2) Continuously secreted by liver (why we need GB) 4) gallbladder 5) Sphincter of Oddi

Liver receives blood from what two sources *& what %*?

1) Hepatic artery (25%): Arterial blood (O2 & metabolites rich) 2) Hepatic portal vein (75%): Venous blood (from GI tract - processing & storage of newly absorbed nutrients)

Bile is secreted in *two stages* by the liver: 1) The initial portion is secreted by? a) Initial secretion contains large amounts of (3ish)? b) It is secreted into what structure from initial production?

1) Hepatocytes a) bile acids, cholesterol, + other organic stuff b) minute bile canaliculi (originate b/w hepatic cells)

Review: What are the 2 stages of bile secretion?

1) Hepatocytes (bile acids, cholesterol, other organics) 2) Secretory ET cells in ductules/ducts (watery Na & bicarb) [this release is stimulated by *secretin*]

(Not on exam, just for fun) Quick review of humerotheory: 1) What are the 4 humors? 2) What if you had an imbalance of humor?

1) Image 2) bloodletting & such

1) Does bile digest fat? 2) What do we need to reabsorb bile salts? 3) What do we need to digest cholesterol?

1) NO! Just emulsifies it. 2) Colipase (leaving cholesterol) 3) Lipase (from pancreas)

1) Are micelles soluble? 2) The intestinal lipids are "ferried" in this form to where? 3) w/o bile salts in GI tract, up to ___ % of ingested fats are lost in poop (person often develops a metabolic deficit due to nutrient loss)

1) Semi-soluble in chyme (b/c of electrical charges of bile salts) 2) Intestinal mucosa → then absorbed into blood 3) 40%

1) Which zone has the most O2 supply? 2) Which zone has the least O2 supply? 3) Which zone does the most liver detox?

1) Zone 1 (healthy) 2) Zone 3 (unhealthy) 3) Zone 3 (even though zone 1 gets hit first, it can handle it better b/c it's healthy)

1) What is the "blood garbage"? 2) Is bile the same a bilirubin? 3) What given bile is gorgeous green-yellow hue?

1) bilirubin 2) bilirubin is a constituent of bile 3) bilirubin

2 functions of bile?

1) fat digestion and absorption 2) excretion of waste products from blood

More stuff you already know: 1) What are the 3 discreet steps of bile formation?

1) hepatocyte formation → ET modification → GB concentration

What makes up the liver parenchyma (4)?

1) hepatocytes (95%) Sinusoidal spaces: 2) Kupffer cells (2%) 3) Endothelial cells (2%) 4) Stellate/Ito cells (fat/vitamin A storing) (1%)

1) What is the *Space of Disse* again? 2) What is found in this space?

1) space b/w hepatocyte & sinusoids 2) Stellate cells & plasma solutes (no RBC)

1) In its course thru bile ducts, a *2nd* portion of liver secretion is added to initial bile. What is it? 2) What secretes this secretion?

1) watery solution of sodium & bicarbonate ions (can double volume of initial bile secretion) 2) Secretory ET cells that line ductules & ducts

1) Are liver sinusoids filled with blood? 2) What are they lined with? 3) What do these do?

1) yes, but wider than capillaries 2) fenestrated (holy) ET & Kupffer cells 3) Cleanse blood of bacteria, toxins, parasites, aging RBCs (cleansed blood passes thru liver into systemic circulation)

1. The max volume that the gallbladder can hold is?. 2. How does the GB fit all bile continuously secreted by liver?

1. 30 to 60 ml 2. Water, sodium, chloride, & most other small electrolytes are absorbed thru GB mucosa (concentrating remaining bile constituents)

Bile is secreted in *two stages* by the liver: 2) Bile flows in canaliculi toward? a) Canaliculi empty into? and then into? Finally reaching what? b) From these, bile can go what 2 places?

2) Interlobular septa a) terminal bile ducts and then into progressively larger ducts, finally reaching hepatic duct & common bile duct b) empties directly into duodenum *or* diverted thru cystic duct into gallbladder

3) By far the most potent stimulus for causing the GB contractions is? 4) Review: do you remember what effect this peptide hormone had on pancreas?

3) *Cholecystokinin (CCK)* 4) ↑ secretion of digestive enzymes by acinar cells

3) What stimulates this 2nd secretion? 4) What is the purpose of this 2nd secretion?

3) *Secretin* 4) additional bicarb ions supplement bicarb ions in pancreatic secretion (for neutralizing acid that empties into duodenum from stomach)

3) Cholesterol is first converted to what 2 products? 4) These products combine with what 2 things? 5) These products combine to form what 2 things?

3) *cholic acid* or *chenodeoxycholic acid* 4) *glycine* & some *taurine* 5) *glyco-* & *tauroconjugated* bile acids → sodium bile salts

3) The quantity of bile secreted by liver each day is highly dependent on? 4) How might one increase the secretion of bile?

3) Availability of bile salts (more bile salts in the enterohepatic circulation = greater rate of bile secretion) 4) Ingestion of supplemental bile salts

3) In concentrating process (in GB), water & large portions of electrolytes are reabsorbed by? 4) What ion is not reabsorbed by GB?

3) GB mucosa 4) Ca++

3) The bicarbonate in turn passes into where? 4) Explain the *Secretin feedback mechanism*

3) Into small intestine & joins pancreas bicarb. 4) Neutralizing duodenal acid thru *Secretin* effects on *pancreatic* secretion (increases this) =and= thru *liver* ductule/duct secretion

Bile formation: 3) When bile salts become concentrated, they form? 4) Recall: what gives golden yellow color to bile? 5) What gives a brown color to the stool

3) Micelles 4) bilirubin 5) Stercobilin

3. What are the remaining bile constituents (after reabsorption of all the electrolytes & such)? 4. Most GB absorption is caused by what kind of transport thru GB ET? 5. How much is bile normally concentrated? What's its max conc?

3. Bile salts, cholesterol, lecithin, & bilirubin. 4. Secondary active transport (after active transport of Na) 5. Normally concentrated ≈ 5x Max conc ≈ 20x

When bile becomes concentrated in GB, bile salts & lecithin concentrate along w/cholesterol (keeps cholesterol in solution) 4) Under abnormal conditions, what can happen with the cholesterol? 5) What are 4 reasons one might get gallstones?

4) Cholesterol may precipitate in the GB (→ formation of *cholesterol gallstones*) 5) - Cholesterol precipitation via (1) too much water absorption from bile, (2) too much absorption of bile acid from bile, (3) too much cholesterol in bile (4) Inflammation of ET

4) In which zone is cytochrome p450 found? 5) What are the implications of this? 6) what about p450 independent ones?

4) Zone 3 5) Drugs that are p450 dependent will do damage to liver in zone 3 6) p450 independent drugs will do most damage to zone 1

4) What is bilirubin made of? 5) Why might a person be jaundiced?

4) hemoglobin breakdown product (in liver) 5) Too much bilirubin in the blood

4) What does fat absorbed by lacteals combine with (in the R atrium)? 5) What do these combine to form (and transported through the body as)?

4) lipoproteins from the liver (mixed up "like a chocolate factory") 5) LDL

5) What will happen if a bile fistula empties bile salts to exterior for several days/weeks (can't be reabsorbed from the ileum)?

5) Liver ↑ production of bile salts 6x-10x → ↑ rate of bile secretion

5) Stimulus for CCK entry into blood is mainly the presence of? 6) Where does CCK come from (where's it made?)

5) fatty foods in duodenum 6) duodenal mucosa

6) The amount of cholesterol in bile is determined partly by what (bit ambiguous, sorry)?

6) By quantity of fat in diet (b/c liver cells synthesize cholesterol as 1 products of fat metab) → too much fat in diet over years can get gallstones

7) Which zone does viral hepatitis & phosphorus poisoning attack? 8) Which zone does alcohol, ischemia, paracetamol attack?

7) Zone 1 8) Zone 3

7) Inflammation of GB ET often result from what? 8) Why might this cause gallstones?

7) low-grade chronic infection 8) Change absorptive characteristics of GB mucosa → excessive absorption of H2O & bile salts (leaving behind cholesterol) → cholesterol begins to precipitate (1st forming small crystals on surface of inflamed mucosa → progressing to large gallstones)

About ___% of the bile salts are reabsorbed into blood from small intestine? How?

94%: 1/2 by diffusion thru mucosa in early bits of small intestine *&* 1/2 by active transport thru intestinal mucosa in distal ileum

Hormone stuff: A) What is released when acidic chyme enters the duodenum? B) What influence does this hormone have?

A) S cells secrete *secretin* B) Stimulates pancreas to release bicarb

How does bile digest & absorb fat (via bile enzymes or bile salts)?

Bile salts

Hormone stuff: C) What if there is protein & fat content in the chyme (what is released)? D) What influence does this hormone have? E) What receptor does CCK act on?

C) I cells release *CCK* D) Stimulates pancreas to release pancreatic juice (lipases, proteases, nucleases) *AND* Stimulates Liver & GB to release Bile *AND* Relax Sphincter of Oddi E) CCKB

What does the detergent/emuslifying action of bile salts do?

Decreases surface tension of fat particles (allows agitation in GI tract to break fat globules into minute sizes)

Hormone stuff: F) Other than CCK, what else causes GB contraction & Oddi relaxation?

F) Ach

How do bile salts help absorb fatty acids, monoglycerides, cholesterol, & other lipids from GI tarct?

Form very small physical complexes (*micelles*) with these lipids

Liver loses blood from where?

Hepatic vein

PW of bile from formation to final dumping ground?

Hepatocytes → bile canaliculus → bile duct (periphery of lobule)→ common bile duct → duodenum

Recall: What can happen if you chronically take antacids?

It raises the pH of the stomach so secretin & CCK are not stimulated for release → duodenal ulcer

The secretion of canalicular bile is {active OR passive?} and {hypertonic OR hypotonic OR isotonic?}

The secretion of canalicular bile is *active* & *isotonic*

What causes liver fibrosis?

When stellate/ito cells become irritate they turn fibrotic ("don't make them angry or uncomfortable")