UW Division of Gastroenterology - Gut Course Syllabus (HuBio 551)

	Updated: 03/13/08 11:26 AM

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Authors: G. Leinbach, B.J. Reid, D.R. Saunders, and T.D. Nguyen
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C. Histologic Structure and Function
Figure 4
Endocrine pancreas: islets of Langerhans Exocrine pancreas: acini and ducts		The endocrine function of the pancreas is mediated by islets of Langerhans scattered irregularly throughout the organ and containing the cells responsible for secreting the endocrine hormones, insulin and glucagon, somatostatin, and pancreatic polypeptide. The exocrine pancreas is divided into many lobules, each containing multiple acini, which comprise >80% of the gland. Each acinus is lined with wedge-shaped acinar cells, the apical portions of which all face the acinar lumen. This lumen opens into terminal ductules, which in turn open into progressively larger ducts until the main pancreatic duct is reached.
1. Acinar Cells and Digestive Enzymes
All acinar cells make all the types of digestive enzymes.		Acinar cells are the site of production and secretion of the digestive enzymes. Each acinar cell makes all of the pancreatic digestive enzymes. The enzymes are synthesized on the ribosomes of the rough endoplasmic reticulum, then stored in the apical portions of the cell within "zymogen" granules in either active (enzyme) or precursor (proenzyme) form. These enzymes or proenzymes are secreted into the ductules in response to hormonal command (i.e., CCK). Protein turnover in the pancreas, relative to the size of this small gland, is greater than that of any other organ in man.
Digestive enzymes are all released together over minutes to hours after CCK stimulation. However, over many hours to days, the mixture of released digestive enzymes, changes due to diet or hormonal changes.		In response to hormonal stimulation, over minutes to hours, individual enzymes are secreted from the acinar cell in parallel. However, over longer periods of time (hours to days) the mixture of pancreatic enzymes may change in response to changes in the diet or hormonal stimulation. For example, it has been demonstrated that under conditions of protein deficiency, proteases (trypsinogen, chymotrypsinogen, proelastase and procarboxypeptidases A and B) increased markedly, but amylase and lipase were markedly diminished despite high levels of carbohydrate in the diet. This response of the pancreas to a zero protein diet appears to be an adaptation for survival during periods of protein deprivation by seeking maximal proteolytic enzyme release. Ultimately, production of adequate enzyme proteins depends upon an adequate supply of protein in the food. Therefore in severe, prolonged dietary protein deficiency, pancreatic acini atrophy and digestive enzyme production almost ceases. The pancreas secretes a number of proteins, most of which are digestive enzymes. They include proteases, for digestion of proteins, amylase, for digestion of carbohydrates, lipases for digestion of fats, and nucleases, for digestion of DNA and RNA. The major digestive enzymes function optimally in the intestinal lumen at neutral pH. Amylase and lipase are secreted into the pancreatic duct in an "active" form. To guard against autodigestion, the proteolytic enzymes (trypsinogen, chymo-trypsinogen, procarboxypeptidases) and prophospholipase are only activated within the intestinal lumen.
		a. Amylase:
Polysaccharide → maltose or oligosaccharide		- Amylase hydrolyzes (splits) the 1,4-glycoside linkages of polysaccharides in starch and glycogen. The resulting products, containing 1,6 glycoside linkages such as maltose (glucose-glucose) and other small oligosaccharides, are then cleaved to glucose by brush border enzymes in the small intestinal mucosa. Besides the pancreas, salivary glands are another source for amylase.
		b. Lipases:
Triglyceride → two free-fatty acids & one 2- monoglyceride		- Lipase hydrolyzes the fatty acids off the 1 and 3 positions of food triglycerides to produce free fatty acids and 2-monoglycerides. Co-lipase is activated from pro-co-lipase in the small intestine. Co-lipase prevents bile salts from inhibiting lipolysis of triglycerides.
Lecithin → fatty acid and lysolecithin		- Prophospholipase A is activated by trypsin within the intestinal lumen to form phospholipase A which then hydrolyzes the fatty acid off the 2 position of lecithin and phosphatidyl ethanolamine.
		c. Proteases:
		- Trypsinogen: Trypsinogen, the precursor form of trypsin, is activated following cleavage inside the small intestinal lumen by an "enterokinase". Enterokinase appears to be principally located in the brush border of the upper small intestinal epithelial cell and cleaves a specific bond within the trypsinogen molecule to yield activated trypsin and trypsinogen activation peptide (TAP). In pancreatitis, the pathologic activation of trypsin through cleaving trypsinogen is sometimes monitored through blood levels of TAP. Activated trypsin then serves as the common activator of other pancreatic enzymes including more trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidases and, prophospholipase. Trypsin is an endopeptidase which hydrolyzes specific peptide bonds within the polypeptide chain of proteins. In contrast, carboxypeptidases are exopeptidases that cleave peptide bonds at the carboxyl ends of proteins
Trypsin Inhibitor within ducts to protect duct cells from activated trypsinogen.		The pancreas protects itself from its own proteolytic enzymes by secreting them as inactive precursors that are only activated at their site of action, the intestinal lumen. However, trypsin may also be "autoactivated" in the pancreatic acinar cell. Should this occur, two additional mechanisms can neutralize this trypsin, a trypsin inhibitor that can inactivate trypsin and proteases that can cleave trypsin. We will see later how a mutation in the trypsin molecule in hereditary pancreatitis renders it resistant to this latter cleavage and leads to pancreatic autodigestion.
		d. Nucleotidases:
ribo- & deoxyribo- nuclease.		Other proteins elaborated by the human pancreas include two nucleolytic enzymes, ribonuclease and deoxyribonuclease that digest, respectively, RNA and DNA. Luminal digestion of carbohydrate, protein and fat reduces them to smaller molecules which can be absorbed by the intestinal cells, either directly or following digestion by enzymes on the brush border of these cells.
2. Duct Cells and Bicarbonate Secretion
Secretin stimulates HCO₃- secretion		The function of pancreatic duct cells is to secrete sufficient sodium bicarbonate to neutralize the gastric acid which enters the duodenum. This bicarbonate can either be derived within the pancreatic duct cell from carbon dioxide and water, a reaction catalyzed by carbonic anhydrase (H₂0 + CO₂ → H₂CO₃^- → H⁺ + HCO₃^-), or it can be transported into the duct cells by a Na⁺ , HCO₃- co-transporter located on the basolateral membrane of these cells. HCO₃- is then transported into the duct lumen by a HCO₃^- /Cl^- exchanger. In cystic fibrosis, impaired function of the cystic fibrosis transmembrane regulator (CFTR) Cl^- channel results in decreased HCO₃^- secretion. This Cl^- channel may recycle the Cl^- imported into the cell by the HCO₃^- /Cl^- exchanges; alternatively, it may also conduct HCO3-. The major stimulant for pancreatic bicarbonate secretion is secretin from endocrine cells in the duodenal mucosa. When liberated into the blood, secretin stimulates the pancreas to produce voluminous juice with increased bicarbonate concentration, from a basal concentration of 40 mM to a maximal of up to 160 mM. The normal pancreas secretes about 2000 cc of juice per day containing some 9 - 18 grams of bicarbonate. Most of this secretion is reabsorbed by the intestine. Secretin, characterized by Bayliss and Starling in 1902, was the first hormone to be discovered.
3. Testing of Pancreatic Exocrine Function
Testing pancreatic exocrine function: Examination of pancreatic juice or assessment of digestive function.		There are at present no simple and easy to perform tests of true exocrine pancreatic function. There are two categories of tests: examination of the pancreatic juice and assessment of the pancreatic digestive function. In general, examination of the pancreatic juice is accurate but cumbersome and invasive while assessment of pancreatic digestive function is simple but insensitive.
		a. Examination of pancreatic juice
Aspirate duodenal contents to examine pancreatic juice		Pancreatic exocrine function can be evaluated by measuring pancreatic concentrations of enzymes (trypsin and lipase) and bicarbonate in aspirated duodenal contents. Both the stomach and duodenum are intubated: stomach intubation is required to remove gastric secretions while the duodenal tube is used for infusion of a nonabsorbable marker and for collection of pancreatic secretions. Pancreatic secretion is stimulated either with an IV infusion of secretin and CCK or with a meal of fat, protein and carbohydrate into the stomach (Lundh test).
		b. Assessment of pancreatic digestive function
Steatorrhea by Sudan Test or quantitatively. Poor sensitivity and Specificity.		Steatorrhea (the excretion of excess fat in the stools) may be determined qualitatively by Sudan stain or quantitatively. Abnormal stool fat lacks sensitivity (in general becoming positive only when there is loss of greater than 80 90% of exocrine pancreatic function) and specificity (because steatorrhea may occur with other conditions, including small intestinal disease).
PABA in urine is very insensitive, but specific		An artificial compound is being used to screen for pancreatic insufficiency: benzoyl-L-tyrosyl-p-amino-benzoic acid is hydrolyzed, after ingestion, by chymotrypsin. The released para amino benzoic acid (PABA) is absorbed and is subsequently excreted in the urine where it is quantified. Pancreatic insufficiency is not reliably detected by the PABA test until the output of pancreatic chymotrypsin is less than 5% of normal, so the test is insensitive but specific.
4. Islet Cells and Endocrine Secretions
Islet cell hormones: Insulin Glucagon Somatostatin Pancreatic Polypeptide		The endocrine cells are scattered irregularly throughout the pancreas in the islets of Langerhans demarcated from the surrounding acinar tissue by reticulin fibers. Four different hormone-secreting cells are present in the islets. The insulin-secreting cells comprise 60 - 80% of the islet. They are surrounded by a mantle of glucagon-secreting, somatostatin-secreting, and pancreatic polypeptide-secreting cells. The various cells of the islets look alike with the usual histological fixatives and stains and are usually arranged in irregular cords separated from one another by a rich capillary network.
Paracrine regulation		Arterioles supply acinar, ductular, and islet vascular beds. The acinar capillary plexus receives blood from vessels draining the islets. The ductular plexus receives blood from the acini and islets. Such a vascular arrangement allows hormones secreted by the endocrine portion of the pancreas (islets) to reach the exocrine acinar and ductular cells, and to control exocrine secretion. Insulin enhances the synthesis and release of amylase. Somatostatin inhibits water and bicarbonate secretion, and enzyme output.
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