GI secretions: Salivary/Gastric/Pancreatic/Hepatobiliary

Question 1

Describe the composition of saliva. What is the tonicity of saliva relative to the plasma and how is this tonicity maintained? (hint: think of water and ion solubility in acinar/duct cells)

Answer 1

High in K+, HCO3-

Low in Na+ and Cl-

Enzymes: ptyalin (amylase), lingual lipase

The final saliva is hypotonic relative to plasma

In acinar cells: NaCl secreted, water follows and solution is isotonic to plasma

In duct cells (site of final secretion): NaCl reabsorbed, K+ and HCO3- secreted, water not reabsorbed as much b/c duct cells are impermable to water; with increasing rate of flow/secretion, reabsorption of NaCL decreases

Question 2

Describe the movement of ions in the duct cells

Answer 2

Question 3

At all flow rates, saliva is ___ to the plasma. There is a higher concentration of __ and __, while more __ and __ are absorbed.

Answer 3

Hypotonic

K+, HCO3-

Na+ and Cl-

Question 4

Between the sympathetic and parasympathetic systems, which one is the most important for regulation of saliva secretion? Compare the saliva output, temporal responses, saliva content and response to denervation of the 2 systems.

Answer 4

Parasympathetic is the most important for salivary secretion

Question 5

Unlike other systems, the sympathetic and parasympathetic systems both act to __ saliva secretion. Draw the pathway each system uses to do this. What are the conditioned reflexes that influence saliva secretion? Under which conditions is saliva stimulation inhibited?

Answer 5

Both systems stimulate secretion

Question 6

Describe Sjogren’s syndrome

Answer 6

Autoimmune disease that causes xerostomia aka dry mouth

Question 7

What are the components of parietal cell secretions? What about non parietal cell secretions?

What is the major anion at all flow rates?

T/F: K+ concentration is always higher in gastric secretion than in plasma

Answer 7

Chlorine = major anion at all flow rates

T: K+ = always higher in gastric juice than in plasma

Question 8

Name the functions of the following parts of the stomach:

Fundus

Body

Antrum

Pyloric sphincter

Answer 8

Fundus: receptive relaxation

Body (and fundus): glands for hormone and acid secretion

Antrum: tituration

Pyloric sphincter: separates stomach from duodenum; allows passage of small food particles

Question 9

Contrast the components of gastric juice in parietal and non parietal cells. What is the significance of Intrinsic factor?

T/F: At all flow rates, bicarbonate is the major anion and K+ is always less in the gastric secretion than in the plasma.

What is the clinical significance of K+?

Answer 9

Parietal cell secretion: Intrinsic factor, H+, water

Non-parietal cell secretion: Pepsinogen, mucus, bicarbonate, sodium, potassium, chloride

Intrinsic factor >> needed for VitB12 absorption

Falsehood: Cl- major anion at all flow rates, and K+ is always higher in gastric secretion than in plasma

In vomiting, patients can become hypokalemic so treatment would require replacement of K+ more than any other ion

Question 10

Describe the activation process of pepsin. What environment (acidic/alkaline) is needed for pepsin activation? Which cells secrete pepsinogen?

Which important process that occurs in pepsin activation separates pepsin activation from the activation of other enzymes?

How is pepsin activation regulated?

Answer 10

Pepsinogen (has catalytic site with Arg and inhibitory peptide) >> H+ environment >> Pepsin activated via autocatalysis (pepsin clips off inhibitory peptide in the presence of H+,which makes it active)

Pepsinogen secreted by chief cells

Regulation = vagus nerve >> ACh >> M1 and M3 receptors on chief cells >> +cAMP >> pepsinogen secreted >> H+ env >> cleaved to pepsin

Question 11

Describe the phases of gastric secretion

Answer 11

Inderdigestive phase: basal Na+ absorption, baseline histamine levels, neutral ion transport

Cephalic phase: Stimulated by conditioned reflexes (taste, smell, chewing, swallowing, hypoglycemia); parasympathetic activation of acid secretion via vagus nerve

Gastric phase: stimulated by stretch of stomach due to presence of food (local reflex = stretch receptors); vago-vagal reflex : Vagus n >> Ach >> G cells >> Gastrin >>Parietal cell >> H+ secretion

Intestinal phase: slowing of gastric acid secretion and gastric emptying (secretin, CCK, GIP inhibit gastric acid secretion/emptying)

Question 12

Specifically, draw a diagram summarizing what happens in the cephalic and gastric phases. Include the stimuli, the response from the vagus n/neurotransmitters and subsequent acid secretion. Which cells are involved in acid secretion?

Question 13

Draw and describe the feedback regulation of gastric acid secretion

Answer 13

Question 14

T/F: The primary method of gastrin-mediated acid secretion is by gastrin’s direct effect on parietal cells

Answer 14

Falsehood. Gastrin’s primary effect is not directly on parietal cells. It’s actually its activation of ECL cells to secrete histamine, which then stimulates acid secretion via H2 receptor binding on the parietal cell

Question 15

Draw and describe the mechanism of acid secretion in parietal cells (so what is the direction of ion movement between the circulation and the lumen?

Answer 15

Co2 and water are converted to H+/HCO3- viacarbonic anhydrase

H+ secreted into lumen via H+/K+ ATPase

Cl- diffuses out via Cl- channels

HCO3- absorbed into bloodstream in exchange for Cl- (increased bicarbonate in the bloodstream = alkaline tide)

K+ recirculates via luminal K+ channels

Question 16

Which two components are essential for the gastric mucosal barrier?

What is the role of tight junctions in the mucosal barrier? What happens to mucosal blood flow during acid secretion?

Answer 16

HCO3- (neutralizes stomach acid); Mucus (acts as a protective barrier)

Tight junctions serve as a barrier to H+, cell can neutralize intracellular H+)

Mucosal blood flow is increased during acid secretion (e.g. in ENS damage, increasing blood flow is a protective reflex)

Question 17

Explain the significance of Helicobacter pylori in the formation of gastric ulcers.

What is the difference between antral-dominant gastritis and pangastritis?

Answer 17

H. pyloricauses chronic superficial gastritis and gastric lymphoma/carcinoma; alters acid secretion

Antral dominant gastritis: increased acid secretion, results in ulcers

Pangastritis: results in atrophy of epithelial lining; causes reduced acid secretion, results in cancer

Question 18

Describe Zollinger-Ellison syndrome (ZES)

Is the negative feedback regulation of acid secretion able to mitigate the effects of this disease?

T/F: Most ZES tumors are located in the pancreas

Answer 18

ZES - gastrin secreting tumor of the pancreas; causes increased H+ secretion, which results in ulcers

Falsehood. Tumor location = 50% pancreas, 50% duodenum

Question 19

How do NSAIDS impact the gastric mucosal barrier?

Answer 19

NSAIDS inhibit cyclooxygenase enzymes >> no prostaglandin synthesis

Results in decreased HCO3- secretion, decreased mucin production and mucosal blood flow

Question 20

Describe the absorption of Vitamin B12. What are the effects of gastrectomy, pernicious anemia and pancreatitis on B12 absorption?

Answer 20

Haptocorins in the stomach bind B12

B12 freed by pancreatic enzymes

Intrinsic factor binds B12 in the proximal ileum

Allows for B12 absorption

If gastrectomy and pernicious anemia, haptocorins can’t bind B12

If pancreatitis, pancreatic enzymes can’t free B12 from haptocorins (enzymes don’t get secreted?)

Question 21

Describe the exocrine and endocrine function of the pancreas. T/F: Most of the cells in the pancreas are devoted to endocrine function

Answer 21

Endocrine: islet cells of Langerhans (insulin, glucagon, somatostatin secretion)

Exocrine: HCO3- and digestive enzyme secretion

Question 22

Describe the composition of pancreatic juice. Which ions are in high/low concentrations? (also, which ones are high/low relative to plasma?)

Which ions are affected by changes in flow rate?

Between the acinar and the duct cells, which ones secrete HCO3-? Digestive enzymes?

Answer 22

Cl-, HCO3- high

K+, Na+ low

Cl- < plasma; HCO3- > plasma

K+/Na+ don’t change much

Duct cells: HCO3- secretion; pancreatic cancer arises from here

Acinar cells – digestive enzyme release

Question 23

Draw and describe the secretion of bicarbonate

Answer 23

Question 24

What’s the first step in digestive enzyme secretion? What are the 3 classes of zymogens/enzymes released by the pancreas and the enzyme/zymogens in each class?

(hint: for one of the categories - ENside the pancreas is ELASTic and CHYM is TRYPIN!

The exos are 3 pros, the rest are fat carbs)

Answer 24

Cleavage of trypsinogen into trypsin by enterokinase

Question 25

Draw and describe the regulation of pancreatic secretions (hint: draw the thing showing all the peptides and the receptors they bind to and the pathway leading to secretion). Describe the role of secretin, VIP, cholecystokinin and the vagal eneteropancreatic reflex. (for the peptides, include which cells they are secreted from)

Answer 25

Secretin - released from S cells; stimulated by H+\*\*\* and stomach distension; increases bicarbonate and water secretion VIP - similar to secretin but not as potent **CholecystokInin** released from I cells; stimulates acinar enzyme release and gall bladder contraction Vagal enteropancreatic reflex - food in duodenum \>\> vagal afferents \>\> vagal efferents \>\> fluid and enzyme secretion

Question 26

What are the phases of pancreatic secretion? Which hormones and neurotransmitters are active at each stage and what do they do? At which phase does most of pancreatic secretion take place?

Answer 26

**Basal** phase: low level enzyme release **Cephalic** phase (vagus): **ACh** (enzyme secretion) and **VIP** (weak HCO3- secretion) **Gastric phase**: **Gastrin** \>\> enzyme release (augments effects of vagus n); **Vagus n** (effects thru VIP and ACh continue) **Intestinal** phase: (70% of pancreatic secretion): **CCK** (enzyme secretion); **Secretin** (increased HCO3- secretion); **Enteropancreatic reflex** (ACh, VIP)

Question 27

What are the organic and inorganic components of bile? What is the concern of having cholesterol in bile? Describe the role of bile acids and cholesterol in bile

Answer 27

_**Organic** components:_ Bilirubin Bile acids (50% or more) Cholesterol **(can crystallize, forms gallstones)** Phospholipids **(Bile acids and phospholipids keep bile in solution)** _**Inorganic** components:_ Na+, K+, Cl-

Question 28

Describe the process of bilirubin production

Answer 28

Hemoglobin \>\> heme \>\> biliverdin (via heme oxygenase, CO byproduct) \>\> Bilirubin (via bilirubin reductase); bound to albumin \>\> Indirect/Unconjugated \>\> Hepatocytes in liver

Question 29

Describe the process of bilirubin conjugation. What's the key determinant of whether a bile acid will be soluble/more abundant? What are the primary and secondary bile acids? Of these, which is the most soluble/least soluble? Describe Gilbert's syndrome.

Answer 29

Biilirubin \>\> Bilirubin diglucoronate (via UDP glucoronyltransferase) Hydroxylation. CYP7A1 takes cholesterol and makes it into bile acids by hydroxylating at C3, C7 and C12 Primary bile salts: Cholic acid and chenodeoxycholic acid 2ndary bile acids: Deoxycholic acid and lithocholic acid Cholic acid = most soluble, Lithocholic acid = least soluble

Question 30

Draw and describe the process of bile formation. What is the difference between bile acid dependent and independent flow? Describe the hormonal/neural regulation of either process, if any.

Answer 30

Bile independent flow: driven by secretions from duct cells (HCO3-), and absorption of Na+, Cl-; hormonal regulation by secretin (opposed by somatostatin) Bile dependent flow: osmotic gradient created by bile acids drags ions and water with the bile acids into the canaliculus. Independent of nerves or hormonal regulation.

Question 31

Draw and describe the bile acid transport in the ileum and the liver. Describe the roles of NTCP, BSEP, OSTalpha/beta and OTAP transporters on the hepatocyte. What are the roles of ASBT and OSTalpha/beta on the enterocyte? What is the significance of the MDR3 transporter?

Answer 31

MDR3 – multi drug resistant NTCP – major transporter of bile acids from blood to hepatocytes BSEP - major transporter of bile acids into bile ASBT – transports bile acids back into the liver OSTalpha/beta - returns bile acids back into portal circulation

Question 32

Draw and describe the enterohepatic feedback regulation of bile synthesis What is the significance of FGF19? How is this feedback loop changed in patients with irritable bowwl syndrome w/ diarrhea?

Answer 32

In the enterocyte: cholesterol \>\> bile acid \>\> ASBT transport into enterocyte \>\> bile acid binding to FXR receptor \>\> stimulation of FGF19 production In the hepatocyte: FGF19 binding to receptor complex \>\> upregulation of SHP \>\> inhibition of Cyp7A1 Alt pathway: In the enterocyte: cholesterol \>\> bile acid \>\> ASBT transport into enterocyte \>\> export by OSTa/b into portal circulation In the liver: bile acid binding to liver FXR \>\> upregulation of SHP \>\> inhibition of Cyp7A1 IBS w/ diarrhea: bile acids beyond ASBT's transport capacity \>\> secreted into colon \>\> diarrhea develops; FGF19 also lacking FGF19: suppresses bile acid production

Question 33

What is the effect of bacterial deconjugation of bile acids in the small intestine? Describe the mechanism through which bacteria form secondary bile acids

Answer 33

Bacterial deconjugation of bile acids \>\> enhanced motility \>\> diarrhea Bile acids that escape the enterohepatic circulation get converted to 2ndary bile acids

Question 34

Describe the function of the gall bladder and its contraction/relaxation processes. Which hormones/neurotransmitters regulate these processes? Explain the difference between cholesterol and pigment gall stones. What is each type of stone made up of? What conditions, if any, can exacerbate the formation of these stones?

Answer 34

Storage + concentration of bile Contraction of gallbladder prompted by CCK in response to a meal Relaxation of Sphincter of Oddi stimulated by vagus via ACh Cholesterol stones (cholesterol, Ca2+, bilirubin): cause cholecystitis, large and can obstruct the cystic duct or the common bile duct Pigment/bilirubin stones: smaller thus obstruction of the ducts is less likely; conditions that increase hemolysis e.g. sickle cell disease can increase formation of pigment stones