Pancreatic Physiology and Pathophysiology

Question 1

Breast milk lipases

Answer 1

• Present in human breast milk
• Only active once they reach the duodenum
• Important due to pancreatic lipase hypofunction in the first year of life

Question 2

Post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis

Answer 2

ERCP is a technique in which an endoscopist places an endoscope into the duodenum, and then uses special instruments (catheters, stone retrievers or even endoscopic knives) to enter the bile ducts or pancreatic ducts through the Ampulla of Vater.

About 5% of patients will have pancreatitis after an ERCP. The thought is that edema in the ampulla or pressure in the pancreatic duct causes abnormal egress of pancreatic fluid (whose composition may be balanced towards too much trypsin activation), predisposing to pancreatitis.

Question 3

Cholecystokinin

Answer 3

Hormone that activates acinar cell secretion. Released from I cells in the duodenum when contact occurs with fatty acids and certain amino acids.

Question 4

Gallstones in pancreatitis

Answer 4

When gallstones migrate out of gall bladder, into cystic duct, into common duct, and then get lodged in the ampulla, they can cause pancreatitis or cholangitis (bile duct infection).

This makes sense because the major means by which pancreatic fluid emerges has been blocked. Accessory pancreatic ducts are often inadequate to handle the normal flow of secretions.

Question 5

What regulates secretin levels?

Answer 5

pH! Secretin cells possess chemoreceptors for pH. When they detect a pH of 4-5 (indicating buffered stomach acid in the duodenum), they will release secretin, which will then bring the pH up by mixing the solution with bicarbonate. As the pH rises in duodenal lumen, the stimulus for secretin abates

The secretin is released out the basolateral membrane of the S cells into circulation to act as an endocrine hormone.

Question 6

What is going on in this pancreas biopsy?

Answer 6

Cystic fibrosis

Question 7

Pancreatic enzyme and cytoprotection summary

Answer 7

Question 8

Most common causes of pancreatitis in children vs adults

Answer 8

Children: Idiopathic or genetic

Adults: Alcohol or gall stone

Question 9

Signs of steatorrhea

Answer 9

• Oil droplets visible on surface of water after bowel movement
• Floating stool
• Stool sticking to the side of the toilet bowl

Question 10

Cross-Sectional anatomy of the pancreas

Answer 10

Question 11

Malabsorption in the case of gastrinoma or general hypergastrinemia

Answer 11

If too much acid is being produced, the pancreas can’t keep up in terms of bicarbonate production, and so pancreatic enzymes get denatured in the duodenum by stomach acid.

Question 12

Hereditary Pancreatitis

Answer 12

Mutations in the PRSS1 gene that encodes the most common trypsinogen made in the pancreas account for about 80% of hereditary pancreatitis unrelated to cystic fibrosis.

The most common mutation replaces arginine with a histidine at position 122 (R122H), causing activated trypsin in the cell or gland to be resistant to degradation. This autosomal dominant mutation is ~80% penetrant

Question 13

Mechanisms of protecting the pancreas from the enzymes it produces (aka cytoprotection)

Answer 13

• Enzymes with potential substrates in the pancreas are secreted as proenzymes
• They require activation by enterokinase, which is in the duodenum
• The pH of the pancreatic lumen is an inefficient environment for their activity
• They are secreted with enough inhibitors such that the mixture would need to be diluted before they can be active, as it is in the small intestine
• Chymotrypsinogen C is present in pancreatic cells. This enzyme, when calcium levels are low, complexes with trypsin and makes it degrade other trypsin molecules seletively.
• Efficient and coordinate flushing ensures that enzymes are moved away from the pancreatic cells rapidly.

Question 14

The many roles of cholecystokinin

Answer 14

Question 15

What would the presentation, labs, ultrasound findings, and treatment recommendation be for a gall stone at each of these locations?

Answer 15

Question 16

Cellular mechanisms of bicarbonate secretion from duct cells

Answer 16

Secretin uses cAMP to induce cytosolic events resulting in the opening of CFTR in duct apical membranes. CFTR results in increased Cl- flux out of cells. Adjacent bicarbonate/Cl- antiporters then increases activity, resulting in vectoral accumulation of bicarbonate in the duct lumen. CFTR can also conduct bicarbonate directly.

Water and sodium follow paracellularly, down electrochemical gradients set up by local ion concentrations and Cl- efflux.

Question 17

Production of bicarbonate-rich pancreatic fluid

Answer 17

Secretin made in duodenal S cells stimulates production. Subsidiary roles for vagus and CCK.

Sodium bicarbonate-rich fluid that is produced by duct cells (lining the ducts and ductules) which washes the enzymes through to the duodenum. Once in the duodenum, the fluid neutralizes acidic chyme for optimal enzyme function

Question 18

Impaired pathways for fluid emerging from the major papilla

Answer 18

Tumors, inflammation, stones, and unusual anatomy can result in impaired fluid flushing, which usually means some kind of stasis or back up in the gland.

The longer the dwell time in the gland, the more chance there is to be excessive trypsin activation. There may be other explanations as well that increase trypsin activation in the context of stasis.

Question 19

What do you do about a gall stone in the gall baldder?

Answer 19

Nothing, if it’s asymptomatic. If it is producing symptoms, cholecystectomy is indicated, but this is rarely necessary. They are often found incidentally and left alone.

Question 20

When do you need to do a cholecystectomy?

Answer 20

If a patient presents with a symptomatic gall stone within the gall bladder or cystic duct, then immediate cholecystectomy is indicated.

If a patient presents with a symptomatic gall stone within the common bile duct or ampule of Vater, immediate removal of just the stone is preferred over cholecystectomy. However, these patients should get an elective cholecystectomy later in order to prevent recurrence.

Question 21

Where does most of the bicarbonate utilized by the pancreatic duct cells come from?

Answer 21

From the alkaline tide in the stomach! This bicarbonate is taken from the blood and effectively pumped into the lumen in the reverse of the mechanism utilized by the parietal cells of the stomach.

So, the bicarbonate and hyrdrogen ions are split up by the parietal cells as sodium bicarbonate and HCl in the pancreas and stomach respectively, then re-convene to form neutral bicarbonate and sodium chloride in the intestine!

How efficient.

Question 22

Impaired trypsin degradation

Answer 22

A major cause of familial pancreatitis is a gain of function mutation in the PRSS1 gene, which encodes the predominant form of trypsinogen secreted by the pancreas. These trypsins are resistant to auto-degradation, and therefore patients are prone to sustaining injurious amounts of trypsin activity in acini/acinar cells, which can cause recurrent damage.

Loss-of-function in chymotrypsinogen C has been impliacted in similar contexts.

Question 23

Cyst gastrotomy

Answer 23

Acute pancreatitis sometimes causes a large, fluid-filled cyst to form within the lesser sac. This produces substantial epigastric discomfort and may compress the stomach and other abdominal structures, leading to nausea, emesis, and dysphagia.

This is corrected by creating a hole in the posterior wall of the stomach so that the GI system may continuously drain the fluid (since draining it surgically would only be a temporary fix).

Question 24

CCK and secretin timing

Answer 24

CCK controls release of enzymes and secretin controls release of pancreatic flushing fluid.

It is important that these be well timed with one another in order to achieve an efficient flush and protect the pancreatic cells from their own enzymes. Impairment of this flushing (anatomically or functionally) may precipitate pancreatitis.

Question 25

Broad symptoms of pancreatitis

Answer 25

• Intense epigastric pain
• Emesis
• Hypovolemia (may be so severe that it causes hypovolemic and distributive shock leading to death within days)

Question 26

Go-to diagnostic test for gall stone

Answer 26

RUQ ultrasound

Even more sensitive than a CT with contrast for detecting gall stones.

On ultrasound gall stones are detectable as echogenic shadow-casting structures within the anechoic gall bladder.

Question 27

The portal triad

Answer 27

The major structures which enter the liver underneath the hepatoduodenal ligament. These structures are very important to know, as this is a common area of surgery.

From left to right (your perspective): Common bile duct, portal vein, proper hepatic artery

From front to back: Common bile duct, proper hepatic artery, portal vein

Question 28

Non-pro-enzymes secreted from the pancreas

Answer 28

Amykase and lipase are secreted from the pancreas in their active forms, since there is no substrate for them within the pancreas or pancreatic ducts anyway.

There is no evolutionary reason for them to be pro-enzymes.

Question 29

Ductules

Answer 29

Convey pancreatic fluid in larger and larger channels to the main pancreatic duct. Are lined with cells that modify the primary secretions, most importantly by secreting significant amounts of bicarbonate and fluid, in effect ‘washing’ the enzymes out of the pancreas.

Question 30

Effectors that stimulate pancreatic enzyme release from acinar cells

Answer 30

• CCK from I cells
• Vagal effectors (Ach) at M3 receptors (stimulated by CCK)
• Other ENS effectors –ascinus cells have receptors for VIP and GRP (stimulated by CCK)

Question 31

These are the results from an experiment done to determine the cause of a patient’s malabsorption. What is the additional substance that was added?

Answer 31

Enterokinase!

Question 32

Surgical dictum on the pancreas

Answer 32

Don’t mess with the pancreas.

Question 33

Acinar cells

Answer 33

Pancreatic cells which synthesize, store and release digestive proenzymes, enzymes, and certain enzyme inhibitors.

Contain zymogen granules near the apical pole.

Question 34

Pancreatic development

Answer 34

• There is pancreatic hypofunction in the first year of life.
• This is most apparent for pancreatic lipase, and so elevated lipid content of stool is expected
• This is compensated for by gastric lipases and breast milk lipases

Question 35

Due to the close approximation between pancreatic anatomy and ___ anatomy, pancreatitis may also cause ___.

Answer 35

Due to the close approximation between pancreatic anatomy and the splenic vein anatomy, pancreatitis may also cause splenic vein thrombosis.

Question 36

“First and second hits” in pancreatitis

Answer 36

Genetic predisposition and acquiring trigger

Theoretical model for pancreatitis development

Question 37

Treating the GI aspect of CF

Answer 37

• Give supplemental pancreatic enzymes
• May need to give a PPI (since CF patients cannot always overcome stomach acid production with endogenous bicarbonate production, you may need to tune the stomach acid down to achieve neutral duodenal pH)

Question 38

Patient presents with crescendo-decrescendo RUQ pain that appears ~1 hr after eating. What is the likely diagnosis?

Answer 38

Gall stone! The pain pattern is very consistent with gall baldder contraction in response to cholecystokinin release.

Question 39

Pancreatic embryology (minor variant)

Answer 39

In 10% of individuals, fusion of the dorsal and ventral pancreatic ducts does not occur. This variant, called pancreas divisum. In these individuals, secretions from the dorsal and ventral ducts drain separately into the duodenum at the minor and major papilla, respectively.

Individuals with pancreas divisum may be at higher risk for pancreatitis, but note that most people with divisum (>95%) will be asymptomatic.

Question 40

Leading cause of pancreatitis in adults

Answer 40

Alcohol

By far.

Question 41

Enterokinase

Answer 41

Brush border enzyme present on the luminal side of the duodenum.Activates trypsinogen to trypsin.

Activated trypsin then serves to activate all other pro-forms of pancreatic enzymes (including itself!).

Question 42

Coronal anatomy of the pancreas

Answer 42

Question 43

Impaired secretion of the flushing fluid

Answer 43

The striking and sobering disease is cystic fibrosis, caused by mutations in the CFTR chloride channel. Patients with the most severe CFTR dysfunction generally don’t get painful clinical pancreatitis because their pancreases at birth are so scared and damaged.

What is interesting is that patients with less severe CFTR mutations or even heterozygous mutations may be at higher risk for clinical pancreatitis.

Question 44

Structures hiding in the hepatoduodenal ligament

Answer 44

Question 45

Pancreatic embryology (major variant)

Answer 45

The pancreas begins as two separate buds which then fuse together. These originally have separated ducts, then these fuse and both drain into the main pancreatic duct and emerge via the ampulla of Vater in the major duodenal papilla. A branch of the dorsal pancreatic duct, utilized by the dorsal embryologic pancreas, persists, and may drain a small amount of pancreatic secretion as well at the minor duodenal papilla.

Question 46

Excessive trypsin activation in acinar cells

Answer 46

This could occur if there is excess intracellular calcium or a defect in SPINK-1

Intracellular hypercalcemia is one mechanism for ethanol’s injurious effects on the pancreas.

Question 47

There is a decreased pancreatic enzyme secretion in the first year of life, but clinical malabsorption does not occur due to compensation . . .

Answer 47

There is a decreased pancreatic enzyme secretion in the first year of life, but clinical malabsorption does not occur due to compensation from salivary, gastric, and breast milk enzymes.