Secretions of the pancrea Flashcards
The pancreas
The pancreas is an elongated gland located behind the stomach.
It has both endocrine and exocrine functions. The exocrine function is directly involved in gastrointestinal function.
The exocrine part of the pancreas secretes digestive enzymes and fluid rich in bicarbonate ions- about 1.5 L of juices in a day!
The bicarbonate ions in the pancreatic fluid help to neutralise the acidity of the chyme coming from the stomach. This prepares the chyme for entry into the small intestine.
Exocrine pancreas structure
Morphologically, the pancreas is divided into lobules, which drain into ductular network (intralobular duct, interlobular ducts and then into a main duct) that connects the entire gland to the lumen of the gastrointestinal tract.
The major pancreatic duct merges with the common bile duct to form a swelling in the duodenal wall called the ampulla of Vater. The muscular wall is thickened, forming the sphincter of Oddi.
Function of Oddi- regulate and prevent reflux
Pancreatic acinus
Within the lobules reside the functional secretory units of the gland.
Each secretory unit is composed of an acinus (latin for grape/berry) and a small intercalated duct.
Pancreatic acinar cells secrete a plethora of zymogens (inactive enzyme precursors), digestive enzymes and an isotonic, plasma-like fluid that accompanies the secretory proteins.
Function of the pancreatic cell types
Acinar
specialised/polarised for the production and export of large quantities of protein as predicted by cellular architecture (RER, secretory granules, exocytosis at apical pole).
Duct
show a level of morphological heterogeneity along the ductal tree. These are predominantly specialized for the transport of electrolytes.
Centroacinar
the very first cells of the intercalated duct and thus are located at the junction of the pancreatic acinar cells and duct cells, function questioned!
Goblet
produce mucus important for lubrication, hydration, protection and immunological role
exocrine secretion of the pancreas -
digestive enzymes - digests all food types - protease , lipase , nuclease , carbohydrase
alkaline juice - numerous functions - neutralise acid , prevent ulcer
fed vs fasted state
Pancreatic juice which is Protein-Rich is embedded within an alkaline fluid.
The rate of pancreatic secretion is dependent on whether you are fed or fasted.
Fasted state/Post absorptive state- low level release of pancreatic enzymes.
Fed state/Absorptive state- Pancreatic secretion increases to levels that are 5- to 20-fold over basal levels.
The composition of the pancreatic fluid will also alter with stimulation.
Secretion of the acinar cell
Acinar cells secrete digestive proteins
In an unstimulated state acinar cells secrete low levels of digestive proteins via a constitutive secretory pathway.
Stimulation is predominantly mediated through CCK receptors and the muscarinic acetylcholine (ACh) receptors located on the basolateral cell membrane.
These receptors signal through a common pathway-the phospholipase C (PLC/PKC)/Ca2+ signal-transduction pathway, leading to increased enzyme secretion from the acinar cell.
CCK
CCK from duodenal I cells stimulates pancreatic acinar cells to increase protein secretion.
In response to a fatty meal, plasma CCK levels increase 5- to 10-fold within minutes. Likely to be both direct through a CCKA receptor or indirectly through the parasympathetic nervous system.
CCK secretion is also stimulated by CCK-releasing factors e.g., LCRF (Luminal CCK Releasing Factor), which are endogenously produced proteins secreted into the gut lumen, and which stimulate CCK.
In the fasting state, LCRFs are degraded by digestive enzymes so no CCK stimulation. However, during a meal, the digestive enzymes act on the chyme and LCRFs stimulate I –cells to release CCK and pancreatic secretion.
Secretion of the duct cell
The principal function of the pancreatic duct cell is to secrete an HCO3–rich fluid that alkalinises and hydrates the protein-rich primary secretions of the acinar cell.
This fluid is also important for enzymatic optimal pH, micelle formation and neutralising acid
Cl- HCO3 exchanger; Carbonic anhydrase generated
Secretin is the most powerful stimulus for HCO3. This induces CFTR and Na-HCO3
Ach activation also impacts on HCO3 secretion
When open, the CFTR allows Cl- to diffuse from the cytoplasm into the lumen, after which the Cl- cycles back into the cell via the Cl-HCO3 exchanger. This process is termed Cl- recycling.
Secretin
Secretin from S cells in the small bowel mucosa stimulates HCO3- and Fluid Secretion by the Ducts, predominantly in response to duodenal acidification. Thus, levels increase in the fed state
Secretin is the most important humoral regulator of ductal secretion. Activation of the secretin receptor on the duct cell stimulates adenylyl cyclase, which raises [cAMP]i and triggers PKA
Ultimately stimulating the apical CFTR Cl- channel and the basolateral Na/HCO3- cotransporter.
HCO3- secretion is also regulated by acetylcholine and the muscarinic receptors on the duct cell causes increased [Ca2+]i and activation of Ca2+ -dependent protein kinases (i.e PKC) in pancreatic duct cells.
Cystic fibrosis
Disease results from mutations in the CF gene that alter the function of its product CFTR
Represents one of the most common lethal genetic diseases affecting ~1 in 2000
In CF, mutant CFTR is prematurely degraded. Subsequent loss of CFTR expression at the plasma membrane disrupts the apical transport processes of the duct cell and results in decreased secretion of HCO3 and water by the ducts.
Results in a protein-rich primary secretion which thickens within the duct lumen and lead to ductal obstruction and eventual pancreatic tissue destruction.
The subsequent deficiency of pancreatic enzymes that occurs leads to the maldigestion of nutrients i.e. steatorrhea and diabetes……!
Diabetes is seen in 9% of CF children, 26% of adolescents, 35% of adults aged 20-29, and 43% of adults aged 30 and older.
Phases of pancreatic secretion
Cephalic phase
*Stimulated by smell, taste, chewing and swallowing
*Mediated by Ach through vagus nerve (acinar cells)
*25% of pancreatic enzymes
Gastric phase
*Stimulated by proteins, gastric distention, gastrin à CCK receptors on acinar cells
*Mediated by vago-vagal reflex
*10-20% of pancreatic enzymes
Intestinal phase
*Stimulated by acid in chyme and fatty acids
*Mediated by secretin, CCK and vago-vagal reflex
*70-75% of pancreatic enzymes and fluid
pattern of pancreatic enzymatic secretion is going to depend on the relative composition of the chyme (e.g. High carb vs fats!)
lipids stimulate CCK and vago vagal reflex
Inhibitor of pancreatic secretions
Somatostatin (present in various places) including D-cells in the islets of Langherhans of the pancreas.
Pancreatic somatostatin is in S-14 form (has 14 amino acids). It inhibits the release of CCK and Secretin.
Analogues of somatostatin (octreotide-longer half life) used clinically to inhibit pancreatic secretions
Preventing autodigestion of the pancreas
Autodigestion is prevented by storing proteases in precursor form and synthesizing protease inhibitors
Enzyme inhibitors such as pancreatic trypsin inhibitor SPINK1 (serine protease inhibitor Kazal type 1) are co-packaged in the secretory granule.
Zymogens become activated only after coming into contact with the small bowel brush border enzyme enterokinase
This converts trypsinogen to trypsin which in turn initiates the conversion of all other zymogens to their active forms
Acute pancreatitis
Loss of protective mechanisms in the pancreas leads to acute pancreatitis.
The diagnosis of acute pancreatitis requires two of the following three features:
characteristic abdominal pain (located generally in the epigastrium and radiates to the back). The pain is often associated with nausea and vomiting
2) serum amylase and/or lipase ≥3 times the upper limit of normal, and
3) characteristic findings of acute pancreatitis on CT scan.
pathophysiology of acute pancreatitis
Premature activation of trypsin within pancreatic acinar cells (hyperstimulation- inhibits/block acinar secretion with maturation in cell)
Intra-pancreatic inflammation (activation of inflammatory and endothelial cells).
Extra-pancreatic inflammation including systemic sepsis and multi-organ failure
treatment of acute pancreatitis
Mild form (80% of cases) of disease: supportive therapy. i) Resting the pancreas (IV fluids to combat dehydration), ii) Hourly fluid balance (input and output (urinary catheter) due to severe hypovolemia iii) Pain relief
Severe form: require intensive care and multi-organ support!
Ultrasound scan (gall stones) or CT scan if still unwell after 48hrs admission
Results of which may require Therapeutic Endoscopic Retrograde Cholangiopancreatography (ERCP)
Therapeutic ERCP is a technique used to treat complications of pancreatitis—gallstones, narrowing or blockage of the pancreatic duct or bile ducts, leaks in the bile ducts, and pseudocysts
Chronic pancreatitis
Chronic pancreatitis is inflammation of the pancreas that does not heal or improve—it gets worse over time and leads to permanent damage.
Most common cause of chronic pancreatitis is chronic alcohol abuse.
Other causes of chronic pancreatitis are hereditary disorders of the pancreas, Cystic fibrosis—the most common inherited disorder leading to chronic pancreatitis, hypercalcemia, hyperlipidemia
treatment for chronic pancreatitis
May require hospitalization for pain management, IV hydration, and nutritional support.
When a normal diet is resumed, this may be supplemented with synthetic pancreatic enzymes if the pancreas does not secrete enough of its own.
Plan a nutritious diet that is low in fat and includes small, frequent meals.
As with acute pancreatitis, ERCP is used to identify and treat complications associated with chronic pancreatitis
Chronic pancreatitis also can lead to calcification of the fibrotic pancreas, which means the pancreatic tissue hardens from deposits of insoluble calcium salts. (of use in diagnosis-imaging)
When pancreatic tissue is destroyed in chronic pancreatitis this can lead to diabetes.
