Exopancreatic, Intestinal, Liver Secretions - Fan 2/22/16 Flashcards
pancreatic secretions
1500 mL/day
fx
-
acinar cells: produce digestive enzymes for digestion of all macronutrient
- enzymes typically produced in excess ⇒ amt of digestion is actually limited by gastric emptying
- most of these enzymes are secreted as inactive zymogens, need trypsin to activate (…stymied by secretion of trypsin inhibitor)
-
ductular cells: produce HCO3-rich fluid
- fluid transports enzymes to duodenum, establishes pH ideal for enzyme function
- protects cells via H neutralizatoin
dumping syndrome
conseq of widened pyloric sphincter: everything gets dumped into duodenum
symptoms
- GI: watery, painless diarrhea; gassy
- systemic: weakness, diaphoresis, tachycardia
how? pathophysiology
- carb/protein digesting enzymes in duodenum go to work on everything dumped → sudden increase in osmotic pressure pulls a ton of water into GI lumen
- distention of lumen : watery diarrhea
- bacterial fermentation of nutrients : gas
- loss of blood volume (bc all of water that was pulled into GI tract) : weakness, tachycardia
- loss of blood volume → “hyperglycemia” → insulin oversecretion → reactive hypoglycemia : diaphoresis, tachycardia
majority of pancreatic enzymes are secreted as zymogens
how are they activated?
require trypsinogen → trypsin
via enterokinase (brush border in duodenum)
- if zymogens are activated early/in pancreas…pancreatitis.
- reason why you have trypsin inhibitor
pancreatitis
results from early maturation of pancreatic trypsinogen into trypsin
- congenital trypsin inhibitor deficiency
- abdominal trauma: injured pancreas cells release protease that ends up accidentally activating trypsin
why shouldnt you feed a newborn adult food?
exopancreas is only partially developed at birth…don’t have the amylases and proteases needed to digest!
ionic properties of pancreatic juice
- pH increases at higher secretion rates
- [bicarb] inversely proportional to [Cl]
- [Na} and [K] same as anywhere else
ductular fluid secretion: resting condition
basal secretion state, mechanisms
- serosal side: H/K exchanging ATPase (proton pump) pushes H out of cell → H combines with bicarb → carbonic acid, which dissociates → water + CO2
- CO2 diffuses into cell, combines with H2O → carbonic acid → H and HCO3
- HCO3 pumped out of cell into lumen via HCO3/Cl exchanger
- i.e. [bicarb] inversely prop to [Cl]!
- jx between cells are loose enough to allow Na and K to move from serosal side to lumen
- Cl moves into lumen via Cl channel CFTR (cystic fibrosis transmembrane conductance regulator)
ductular fluid secretion: response to feeding
H stimulates secretion of secretin
- stimulates CFTR - gets it open, longer
- provides gradient for more bicarb secretion into lumen
- stimulates translocation of H/K ATPase into basolateral membrane via cAMP
CCK and Ach supplement action of secretion via basolateral K channel via Ca
- increased K efflux means negative cell environment → more HCO3 and Cl pushed out
control of pancreatic secretion
- phases
- % of secretion occuring in phase
- main mediators
interdigestive : 10%
- motilin?
cephalic : 10%
- vagal
gastric : 10%
- vagal
intestinal : 70%
- CCK: acinar cell enzyme secretion for fat/protein/carb breakdown (in small intestine, once activated by trysin)
- vagal
-
secretin (H): generates lots of bicarb
- potentiated by CCK and Ach/vagal action
intestinal secretion
1500 mL/day
- mainly mucus, other fluids
fx
- protection (bicarb-rich)
- maintenance of luminal isotonicity
- aiding digestion/abs
active secretions from small intestine
- HCO3/Cl exchanger in duodenum only
- both prox and distal intestine have CFTR Cl pump → Cl into lumen, Na follows, water follows ions
duodenum
- apical: DRA/AE1 (HCO3/Cl exchanger), CFTR
- basolateral: NHE (Na-H exchanger), NBC (Na-bicarb cotransporter), Na/K ATPase
jejunum/ileum
- apical: CFTR
- basolateral: NKCC1 (Na, K, 2Cl transporter), Na/K ATPase
mediation of CFTR activity: normal
CFTR activated by PKA-mediated phosphorylation
- presence of H → secretin secretion → adenylate cyclase activity
- ATP → cAMP
- cAMP activates PKA
- PKA phosphorylates CFTR and ramps up its activity
mediation of CFTR activity: pathological state
enterotoxins act as cyclases: go ahead and convert all available ATP to cAMP
- effective constitutive activation of PKA-dep activation of CFTR
- Cl pumped out like crazy, Na follows, water follows ions
- diarrhea, dehydration
external fluid circuit (of intestine)
normal state, disease state
normally, at basal portion of intestinal crypt…
- secretion of Cl, Na, water
at apical portion of int crypt (the tip)…
- mature enterocytes do not have CFTR, and so don’t secrete - absorb instead!!!
- maintain a balance (basal cell secretion ~ apical cell reabs)
in disease state (cholera, other toxins)…
- excess basal secretion via constitutively activated CFTR in basal cells : exceeds capacity of apical cells to reabs
treatment for diarrhea/dehydration due to excess secretion
excess secretion of Cl (followed by Na followed by water) by int crypt basal cells (overactive CFTR) : overwhelms apical cells capacity to reabs
- treat with glucose and NaCl!!!
- will spur SGLT (sodium glucose cotransporter) into action : pull in Na and glucose
- passive reabs of Cl, water (follow Na, glucose!)
- will spur SGLT (sodium glucose cotransporter) into action : pull in Na and glucose
- want to hit pt with equal amt of Na and glucose so as to let SGLT do its 1:1 reabs
- has dramatically reduced deaths due to diarrheal dehydration
hepatic secretions and excretions
500 mL/day
- hepatocyte secretions (bile)
- organic substances (bile acid-dependent)
- water, electrolytes (bile acid-indep)
- ductular secretions
- alkaline fluid rich in bicarb
fx
- emulsification of lipids/lipid digestion pdts
- keeping cholesterol in solution (jt action of bile salts, PLs)
- excretion (chol, bile pigments, steroles, heavy metals, etc)
overview of hepatic organic substance secretion
bile acid dependent
[no BA, no secretion - includes BS, PL, chol]
where does BA come from?
- primary BA: approx 10% made by liver
- secondary BA: 90% secreted BS modified by gut bacteria back to BA, reabs in ileum
in liver, BA converted to BS via conjugation before secretion
secreted BS can go either to gallbladder for conc/storage or straight into intestine
bile acids vs bile salts
BA converted to BS in liver through conjugation with Gly or Tau
- drops the pKa of both molecules, makes them amphipathic
- allows them to solubilize better in lumen → better form micelles that will emulsify/solubilize lipids
hepatocyte secretion of BS, organic ions, PL
- how recycled sinusoidal stuff gets into hepatocytes
- how secreted stuff gets out into bile canaliculus
recycled stuff (sinusoidal blood into hepatocyte)
- bile salts : NTCP (Na-dep taurocholate transporter)
- BS/BA, organic anions : OATP
- organic cations : OCT1 (organic cation transporter 1)
secretion (hepatocyte into bile can)
- bile salts : BSEP (bile salt exporting protein)
- organic cations : MDR1
- organic anions : MRP2
- PLs : MDR3
overview of hepatic water/electrolyte secretion
- hepatocytes: water, Na, Ca, K, Cl
- ductal cells: HCO3-rich fluid
- gallbladder: bile
concentration and storage of bile
bile enters gallbladder in interdigestive period
secrete approx 500mL of bile daily, but the gallbladder is only big enough to handle approx 30mL…
- gallbladder concentrates it via reabs of water, free Na, Cl, bicarb
- also leads to acidification of bile
BA/BS enterohepatic circulation
- as BS moves down the intestine, bacteria go to work deconjugating it
- most reabs of BS takes place in distal ileum
- 90% reabs (10% excreted); of the 90, most actively taken up by hepatocytes, trace amt excreted in urine
- once in colon, bacteria convert the 10% to BA
- no transporters in this region, but some BA is still reabs bc its super hydrophobic and can passively diffuse through pl mem of cells
control of bile synth and degradation
during digetion…
- secondary BS inhibits de novo synth of primary BA so that recycled BS can make up the majority of secreted BS
- secretin triggers ductal release of HCO3
- CCK triggers contraction of gallbladder, relaxation of sphincter of Oddi
interdigestive period…
- CCK levels drop - secreted BS are stored in gallbladder
- no reabs of BS in distal ileum - de novo synth of primary BA takes over
