Phys Pancreas/Liver/Bile (34/35)
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- cells of the pacreas that SECRETE enzymes & ions (which are iso-osmotic w/ plasma during rest)
- not just a conduit to acinar cells, they actually modify contents secreted by adding bicarbonate
- are the only cells that have the CFTR protein (cystic fibrosis transmembrane receptor) on their surface - if there’s dysfunction then there’s a dysregulation of bicarb secretion → duct cloggage by mucus & the like
- acinar = dots, duct = blue
What can clogged ducts lead to?
- Pancreatitis, inflammation, fibrosis
- this happens in CF patients - most ΔF508 patients are pancreatic insufficient & need to take pancreatic enzyme supplements to prevent malabsorption from happening
What is the fundamental different between pancreatic & salivary glands + ducts?
- Salivary: acini → ducts, which empty into the mouth
- Pancreatic: acini ‘INTERRUPT’ the ductal structures (so it can go acini → duct → acini, etc.)
- functioning of both remain extremely similar
What happens if there ISN’T enough bicarbonate secreted from ductal pancreas cells?
- b/c pancreatic digestive enzymes are pH sensitive, they won’t be able to function in/on the acidic material from the stomach → WON’T be able to digest food that’s been eaten
- in addition, no neutralization of this material → duodenal + other SI epithelial cell damage
What drives the majority of gradients within ductal cells?
- Na+/K+ ATPase
- [most bicarb comes from carbonic anhydrase (CO2 + H2O → HCO3- + H+)]
- [most H+ ions move out of ductal cells through Na+/H+ exchanger]
What happens to ion concentrations in pancreatic ducts (not the cells, just the structures) when enzyme secretory rate (rate at which acinar cells secrete digestive enzymes) INCREASES?
- at rest, ion (HCO3- & Cl-) are iso-osmotic w/ plasma
- ↑ secretory rate → bicarb/Cl- exchanger is running quickly; which means that Cl- levels drop, & HCO3- levels rise
- relevant b/c if you take a sample of pancreatic fluid & see a high HCO3- concentration, you know it must’ve been taken around meal time (digestion is happening)
Why does it appear there is a drop in amylase X minutes after digestion begins?
- there appears to be a drop in digestive enzyme b/c as all these ions & enzymes are being secreted by the pancreas into the duodenum, WATER is being secreted along with them
- this water DILUTES the enzyme, decreasing its concentration in the solution even though more is actually being secreted after digestion starts
Which puts out more material during digestion, acinar or ductal cells?
DUCTAL - even though you increase enzyme production drastically during digestion, the volume of material put out by acinar cells is maybe ~1/2 of that put out by ductal cells
What is the ratio of material secreted from the pancreatic acinar & ductal cells under basal flow vs. stimulated flow (i.e. during digestion)?
- under low flow, both types of cells produce basically equivalent amounts of their respective products volume-wise
- however under HIGH stimulated flow, ductal cells produce WAY more material than acinar cells
- you don’t see a drastic change in volume of acinar secretions b/c while the volume may stay the same, the ENZYME component does actually increase
How are all pancreatic proteases secreted?
- in a PRO (inactive) form
- 5 - trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase A, procarboxypeptidase B
- NO digestion should happen in pancreatic ducts; they don’t become active (cleaved) until they get into the SI
How are all the OTHER pancreatic enzymes secreted?
- ACTIVELY - only the proteolytic enzymes are inactive when secreted
- includes amylolytic, lipolytic, nucleases, & other enzymes
Why are is the Nucleases DNAse released by the pancreas during digestion?
- b/c when DNA is released from cells it creates a GEL - last thing we want in watery enzyme mix is something congealing these pancreatic products
- these enzymes break DNA & RNA into simpler structures, getting rid of undesired gel-like consistency
- a pancreatic enzyme that guards against accidental activation of trypsinogen IN the pancreatic ducts
- only a small amount is madedon’t need OTHER proteolytic enzyme inhibitors b/c it’s TRYPSIN that cleaves the majority of these other enzymes → activating them
- membrane-bound INTESTINAL enzyme that cleaves trypsinogen → trypsin
- this activating enzyme is geographically SEPARATED from the pancreas so trypsinogen doesn’t get prematurely cleaved & digest the pancreas; it isn’t free floating, it stays attached to SI cell membranes
What happens if there’s a deletion of the trypsin gene?
- significantly less protein digestion in the SI will occur (will make it a slow & difficult process) b/c pancreatic proteolytic pro-enzymes (chymotrypsin, elastase, carboxypeptidase A & B) will not be cleaved
- (never all or none but just to prove a point)
Phases of Digestion
- 1. Cephalic: corresponds to saliva formation in response to the sight/smell of food
- 2. Gastric: food IN the stomach
- 3. Intestinal: happening in the stomach
What initiates the Intestinal phase of digestion?
Amino Acids & Fatty Acids - these are positive regulators that stimulate exocrine pancreatic secretion
- peptide hormone released from enterochromaffin cells in the duodenum that stimulates the release of zymogens from pancreatic Acinar cells
- it’s produced in response to protein & fat in the duodenum
- it also stimulates gallbladder contraction & emptying
- secreted by S cells of the duodenum & stimulates ductal secretion - if you want more bicarbonate, secretin will accomplish that
- it also has an effect on gastric emptying: the more H+ ions that get into the SI from the stomach → secretin secretion → ↓gastric emptying + bicarb secretion (as usual)
- in response to H+, FAs, AAs, & peptides, Vagus nerves in the SI send afferent signals to the brain which signals ACh release in the pancreas
- ACh is a positive regulator of acinar cell secretion
- end result: ↑ pancreatic enzyme & ↑ HCO3- secretion
What is the outcome of all stimuli & resulting CCK, vago-vagal reflex, + secretin release?
- ↑ pancreatic enzyme & ↑ HCO3- secretion
- VV reflex is activated & CCK is released in response to all 3 stimuli (AAs, FAs, & H+)
- Secretin is released only in response to FAs & H+
- (acid load = amount of H+ ions entering the SI)
Why does CCK only function to increase output of acinar cells, not ductal cells?
- b/c ductal cells have no receptors for CCK, instead they have secretin receptors
- CCK works on acinar cells via phospholipase C
- Secretin works on ductal cells via adenylate cyclase
• bile production & excretion
• excretion of bilirubin, cholesterol, hormones, & drugs (modifies them so they’re more soluble & can be excreted)
• fat, protein, & mineral metabolism
• glycogen, vitamin (D), & mineral storage
• plasma protein (eg. albumin, globulin) & clotting factor synthesis
• blood detoxification & purification
How do all the components of digestion leave the GI tract?
- through the PORTAL SYSTEM which takes them to the liver
- the liver has a dual blood supply: 75% of blood gets to it through the Portal v. & the remaining 25% is from the Hepatic a.
- portal vein carries nutrient rich, O2-poor blood to liver while the hepatic artery carries nutrient poor, O2-rich blood to liver
- the hepatic vein leaves the liver w/ a high glucose concentration
What type of blood passes through the liver lobule & is dumped into the central vein?
Arterial & Venous blood
- liver macrophages that phagocytose particulates
- they are attached to the luminal surface of sinusoidal endothelial cells
the process where glucose, fructose, & galactose (breakdown products of CHO) are converted to glycogen & stored in the liver & muscle
when the liver breaks down stored glycogen to maintain blood glucose levels when there is a decrease in CHO intake
when the liver synthesizes glucose from proteins or fats to maintain blood glucose levels
What protein produced by the liver is the most abundant plasma protein & is important for maintaing osmotic pressure?
- it can also transport steroids & other hormones through the circulation
Where is the only place in the body that can dispose of ammonia (ammonia)?
- the Liver - it’s the breakdown product of proteins
- ammonia → urea → kidneys for excretion
- it’s the only organ in the body that has a complete urea cycle (w/o it, high levels of ammonia would become extremely toxic)
- if liver function is LOST you’d expect NH3 levels to start rising
- any substance produced by linking glucuronic acid to another substance via a glycosidic bond
- are small additions often conjugated to toxins or drugs to increase their solubility for excretion
What are the major organic compounds produced (or processed) by the liver & found in the bile?
- 1. bile acids (cholic + chenodeoxycholic acid): are VERY important for fat digestion
- 2. phospholipids (lecithins)
- 3. cholesterol (1 of the most insoluble materials the body makes, has very little charge)
- 4. bile pigments (are not produced but processed by the liver): major 1 = bilirubin
Cholesterol is used as the starting material for production of which bile acid in the liver?
- all of them:
- cholesterol → Cholic or Chenodeoxycholic acid
- Cholic acid → Deoxycholic acid
- Chenodeoxycholic acid → Lithocholic acid
- the difference between cholesterol & bile acids is that the acids are CHARGED while the cholesterol is basically uncharged except for a single -OH group
- also the primary bile acids are made in the liver, while the secondary bile acids are modified from the primary ones by bacteria in the intestine
is an AMPHOTERIC molecule, meaning 1 portion of it is charged & the other is not
What happens to bile acids between meals?
- most of the bile secreted by the liver is STORED in the gallbladder
- this is b/c between meals the sphincter of oddi is closed - bile will be flowing but won’t be able to enter the 2nd part of the duodenum
- gallbladder concentrates the bile, removing water so it can hold as much acid produced as possible
What happens to bile flow during digestion?
- eating causes release of CCK which:
- 1. relaxes the sphincter of oddi
- 2. causes the musculature around the gallbladder to CONTRACT
- (also happens via neural stimulation)
What do reticuloendothelial cells do?
- they breakdown hemoglobin from RBCs into Bilirubin, which is then released into the circulation
- they’re a type of phagocyte
What does bilirubin do as it’s secreted into the plasma?
- it binds to ALBUMIN
- albumin transports it to the liver, which takes it up & processes (conjugates) it
- conjugated bilirubin is secreted from the liver into the intestine w/ bile
- an issue w/ the liver (i.e. it can’t process bilirubin) → it will BUILD UP → jaundice (sclera of eye)
What are everyday things that tell us we’re producing bilirubin?
1. color of urine: would be clear w/o bilirubin pigmentation (from this we know some bilirubin is secreted through the kidneys)
2. feces color: would be grey w/o bilirubin
What would be expected with a massive amount of RBC breakdown?
if the liver is working correctly, the products of excretion would appear DARKER (chocolatey urine, black feces)
What is the gallbladder excreting out its basolateral surface?
- large amounts of IONS + WATER move through the endothelial cells (cholangiocyte) that make up the gallblader
- ions move in through the apical surface w/ water following through AQUAPORIN channels
- as the ions exit, water does as well → this is how bile salts are CONCENTRATED
What are dark gallstones rich in & what are light gallstones rich in?
- dark: bilirubin
- light: cholesterol
- form when crystals in the ‘sludge’ layer of the gallbladder grow larger than normal
- are not problematic in the gallbladder, but are problematic when they cause obstruction by getting lodged in say the gallbladder neck or common bile duct
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