Pancreatic Physiology and Pathophysiology Flashcards
Breast milk lipases
- Present in human breast milk
- Only active once they reach the duodenum
- Important due to pancreatic lipase hypofunction in the first year of life
Post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis
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.
Cholecystokinin
Hormone that activates acinar cell secretion. Released from I cells in the duodenum when contact occurs with fatty acids and certain amino acids.
Gallstones in pancreatitis
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.
What regulates secretin levels?
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.
What is going on in this pancreas biopsy?
Cystic fibrosis
Pancreatic enzyme and cytoprotection summary
Most common causes of pancreatitis in children vs adults
Children: Idiopathic or genetic
Adults: Alcohol or gall stone
Signs of steatorrhea
- Oil droplets visible on surface of water after bowel movement
- Floating stool
- Stool sticking to the side of the toilet bowl
Cross-Sectional anatomy of the pancreas
Malabsorption in the case of gastrinoma or general hypergastrinemia
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.
Hereditary Pancreatitis
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
Mechanisms of protecting the pancreas from the enzymes it produces (aka cytoprotection)
- 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.
The many roles of cholecystokinin
What would the presentation, labs, ultrasound findings, and treatment recommendation be for a gall stone at each of these locations?
Cellular mechanisms of bicarbonate secretion from duct cells
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.
Production of bicarbonate-rich pancreatic fluid
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
Impaired pathways for fluid emerging from the major papilla
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.
What do you do about a gall stone in the gall baldder?
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.
When do you need to do a cholecystectomy?
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.
Where does most of the bicarbonate utilized by the pancreatic duct cells come from?
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.
Impaired trypsin degradation
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.
Cyst gastrotomy
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).
CCK and secretin timing
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.
