IV.

PANCREAS
Theory helps us to bear our ignorance of facts - George Santayana

A. Objectives Know the anatomic relationships to be able to understand pancreas divisum; jaundice and pancreatitis from a common duct stone; how patients with pancreatitis may present with retroperitoneal collections of blood, or plasma; how pancreatitis may cause duodenal or colonic ileus; how pancreatic carcinoma can cause hepatic, and pulmonary metastases. Know the intimate functional relationship between pancreatic islets and acini although histological relations appeared separated. Understand the autoregulation of pancreatic exocrine and endocrine secretion during the digestion of a meal. Learn the major causes of acute pancreatitis, theories about pathogenesis, the protean clinical manifestations, the difficulties of diagnosis, and the rationale of treatment. Be able to plan treatment for patients with pancreatic insufficiency. Know about the basic genetic defects in cystic fibrosis, and in hereditary pancreatitis.

B. Structure Parts of pancreas: Head Body Tail The pancreas is a 10 - 15 cm long organ of about 100 g which lies in the retroperitoneal space on the posterior wall of the abdomen. The head" or right portion of the organ is broad and flat, and fits snugly into the loop of the duodenum. The "body" goes to the left across the spine and behind the stomach, eventually tapering into the "tail" which lies on the hilus of the spleen. Protected safely by a layer of peritoneum, and hiding behind numerous abdominal organs, it defies the attempts of the examining hand to find it under normal and often under abnormal conditions. The pancreas mediates both endocrine (insulin, glucagon) and exocrine (digestive enzymes) functions; it delivers its hormones into the draining venous system and its enzymes into the intestine. The hormones are essential for the regulation of carbohydrate metabolism and the enzymes facilitate the digestion of food in the intestinal lumen. Capillaries arranged in an insuloacinar portal system allow hormones from the islet cells to reach the acinar cells. Although the nature and function of its enzymes are well described, the smooth regulation of its responses after eating is not completely understood.

Endocrine and exocrine functions are interrelated

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Organ

Pancreas

Function

Endocrine

Exocrine

Cell type

Islet

Acinar

Ductal

Secretion

Insulin Glucagon Somatostatin Pancreatic polypeptide

Digestive Enzyme

Water Bicarbonate

Compartment Blood

Pancreatic duct -> Duodenum

Figure 1 Overview of Pancreatic Secretion

1. Embryology
Body, tail, and part of head of pancreas derived from dorsal bud. Uncinate process of head derived from ventral bud. Rotation of pancreatic buds The pancreas arises as ventral (anterior) and dorsal (posterior) buds from the primitive duodenum. The dorsal bud forms the body, tail and part of the head of the pancreas. The ventral bud ultimately develops into the hepatobiliary system, but at the same time gives off a small bud from the bile duct close to the duodenum. This is the ventral pancreatic bud, which eventually forms the remainder of the head of the pancreas and its uncinate process. As the stomachs posteriorly located greater curvature rotates anteriorly to the left, the posterior pancreatic bud ends up along the left posterior abdominal wall and becomes retroperitoneal while the anterior pancreatic bud is carried posteriorly around to the right to end up in the C-loop of the duodenum. The anterior and posterior pancreatic buds then fuse, and their ducts unite to form the major pancreatic excretory duct. Thus, exocrine secretions from the body and tail of the pancreas drain initially into the ductal system of the posterior pancreatic bud, and then through the duct of the anterior bud (duct of Wirsung) into the duodenum. The proximal portion of the duct originally draining the posterior pancreatic bud into the duodenum may or may not remain functional as the accessory duct of Santorini.

Fusion of pancreatic ducts from dorsal and ventral buds

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Figure 2

2. Developmental Anomalies
Annular pancreas If the ventral bud fails to rotate completely, a band of remaining pancreatic tissue may encircle the second portion of the duodenum and produce an annular pancreas. This anomaly may cause duodenal obstruction. Ectopic pancreatic tissue is a developmental anomaly in which small islands of pancreatic tissue are found in the stomach, duodenum or upper jejunum. Such ectopic tissue presumably arises from embryonic tissue similar to that which gave rise to pancreatic buds. These ectopic islands of pancreatic tissue are usually asymptomatic but may occasionally cause symptoms related to their position or size (ulceration, obstruction). In about 10% of the population, the ventral pancreatic duct fails to fuse with the dorsal pancreatic duct so that pancreatic juice from the body and tail drain via the accessory duct (Santorini) and accessory papilla while juice from the pancreatic head drains via the duct of Wirsung and the papilla of Vater (Pancreas divisum). These people may have an increased incidence of pancreatitis, either in the ventral or dorsal pancreas or both. As a result of its embryological development, the terminal portion of the common bile duct, which rotated with the ventral bud posterior to the duodenum, now travels to a variable extent within the pancreatic head to empty into the duodenum either as a common channel with the pancreatic duct or separately. Therefore, tumors or inflammatory conditions of the pancreatic head 64

Ectopic pancreatic tissue

10% incidence of failure of ventral and dorsal ducts to fuse incidence of pancreatitis The common bile duct and pancreatic duct are joined at the ampulla of Vater. Pancreatic tumors

or pancreatitis may cause biliary obstruction and jaundice. Gallstones may cause pancreatitis.

can obstruct the biliary flow from the liver and can distend the gallbladder until it becomes palpable to the examining hand. At the same time, jaundice (yellowing of the skin and the sclerae of the eyes) may occur because of a failure to excrete bilirubin. If a gallstone lodges in and obstructs the distal common duct the patient will become jaundiced. If, in addition, pancreatic drainage is blocked, the pancreas may become inflamed leading to pancreatitis.

3. Anatomic Relations
Lesser omental sac As the gut rotates, it and its mesenteries form the lesser omental sac. The lesser omental sac is bounded posteriorly by the pancreas, anteriorly by the stomach, and relations. and mesenteric connections between the stomach and liver, inferiorly by the transverse colon and mesocolon, on the left by mesenteric connections between the diaphragm, spleen and greater curvature of the stomach, and on the right by the liver and the epiploic foramen by which it communicates with the general peritoneal cavity.

Figure 3 Perforation of lesser sac few symptoms; however, if pus Perforations into the lesser sac by a posterior gastric ulcer or a pancreatic abscess usually produce few abdominal physical findings if the perforation remains confined to the area. But if pus spills through the foramen into the

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enters peritoneal cavity, peritonitis.

general peritoneal cavity, the dramatic findings of peritonitis ensue (painful abdomen with boardlike rigidity).

It's hard to detect masses (blood, serum, tumor, cyst) in or around pancreas. Head: At L2-L3 in "C" of duodenum. Anterior to renal veins, rt renal artery, rt kidney, and IVC. Body: Anterior to aorta Tail: hilus of spleen Effects on contiguous organs

Because of its location, a severely inflamed pancreas may cause large unsuspected volumes of blood or serum to be lost into the retroperitoneal space. These fluid losses may only become apparent when the patient goes into shock from depletion of circulating blood volume. Tumors and cysts may grow quite large before they are detectable by physical examination. The head of the pancreas lies in the bend of the second portion of the duodenum at approximately the level of the second and third lumbar vertebrae. Behind it are the renal veins, the right kidney and renal artery and the vena cava. The pancreatic body crosses the aorta, portal vein, superior mesenteric vessels, splenic vein, left kidney and left adrenal. The pancreatic tail lies at the hilus of the spleen. Anterior to the pancreas lie the liver, transverse colon, duodenal bulb, gastric antrum and loops of proximal small bowel. Enlarging lesions in the head of the pancreas may widen the normal duodenal loop. Posterior antral or duodenal ulcers may penetrate into the pancreas. Inflammation of the pancreas may result in inflammation and stasis of a contiguous loop of bowel producing a local segment of dilated gas-filled intestine (sentinel loop) detectable on X-ray of the abdomen. Contiguous inflammation of the kidneys may be reflected as proteinuria or hematuria. In motor vehicle accidents, sudden deceleration may crush the pancreas against the vertebral column, resulting in pancreatic injury such as pancreatic duct rupture.

4. Vascular Supply and Lymphatics

The arterial supply of the pancreas comes from the aorta via the celiac and superior mesenteric arteries and their branches. The gastroduodenal artery, a branch of the hepatic branch of the celiac artery, courses down behind the first portion of the duodenal bulb and anastomoses there with branches of the superior mesenteric artery to form a rich arcade of vessels supplying the head of the pancreas and the duodenum. A duodenal ulcer which erodes into this vasculature can cause massive bleeding. The splenic artery (from the celiac) and its branches supply the principal portion of the body and tail. Blood from the pancreas drains entirely into the portal vein, either by the superior mesenteric or splenic veins. Thus, a usual site of metastases from pancreatic carcinoma is the liver (where the portal system ends). Lymph drains from the pancreas into local nodes around the gland, into nodes near the hili of the liver and spleen, and generally follows the vascular supply, ultimately draining by way of the superior mesenteric and celiac nodes into the thoracic duct which drains into the systemic venous system. This drainage pathway is responsible for lymph node metastases from pancreatic

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carcinoma that may be felt in the left supraclavicular fossa where the thoracic duct joins the venous system. This lymph node is called the sentinel node or Virchow's node. Because venous blood is then pumped into the lungs, one may see multiple lung metastases from pancreatic cancer.

Sympathetic splanchnic innervates vessels & acini. Parasym vagus acinar & islet cells and ductal smooth muscle

5. Nerve Supply
The pancreas is supplied by both sympathetic splanchnic nerves and parasympathetic vagus nerves. Sympathetic nerves enter the pancreas with the arteries to innervate blood vessels and acini. Vagal fibers innervate acinar and islet cells and ductal smooth muscle. The exact functions of all these nerves are not precisely understood, but clearly vagal stimulation in animals increases pancreatic secretion of a "juice" relatively low in volume but rich in enzymes. Vagal innervation also potentiates the secretory effects of CCK and secretin. Afferent splanchnic nerves of the pancreas mediate pain and account for the constant severe pain felt in the upper two-thirds of the abdomen during attacks of pancreatic inflammation. Both inhibitory and stimulatory sympathetic fibers are probably present, but the functional significance of these is not known. The parietal peritoneum anterior to the pancreas and the posterior abdominal wall behind the pancreas are supplied by somatic nerves from spinal cord levels thoracic-10 to lumbar-2, and account for the back pain commonly seen with pancreatitis. vagal stimulation 1) pancreatic secretions. 2) potentiation of a. CCK stimulates output of enzymes, stimulates gallbladder contraction. b. Secretin stimulates pancreatic HCO3; Also, stimulates bile HCO3-.

Somatic nerves of peritoneum and post abdominal wall account for back pain associated with pancreatitis

C. Histologic Structure and Function

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Figure 4 Endocrine pancreas: The endocrine function of the pancreas is mediated by islets of Langerhans 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 Exocrine pancreas: many lobules, each containing multiple acini, which comprise >80% of the acini and ducts 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 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 all the types of are synthesized on the ribosomes of the rough endoplasmic reticulum, then digestive enzymes. 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.

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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 2monoglyceride Lecithin fatty acid and lysolecithin - 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. - 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 69

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- & deoxyribonuclease. 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 cotransporter 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) Clchannel results in decreased HCO3 secretion. This Cl channel may recycle the Cl imported into the cell by the HCO3 /Cl exchanges; alternatively, it may 70
-

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 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). 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.

Aspirate duodenal contents to examine pancreatic juice

PABA in urine is very insensitive, but specific

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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.

Arterioles supply acinar, ductular, and islet vascular beds. The acinar capillary Paracrine regulation 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. D. Regulation of Exocrine Function Timing, pH, quantity The pancreas must deliver an appropriate quantity of enzymes, at the appropriate time, and at the optimal pH for the efficient digestion of nutrients are crucial delivered from the stomach to the duodenum. The acidic gastric chyme must be neutralized by pancreatic bicarbonate so that pancreatic enzymes can operate at their pH optima of 6-7, acid-peptic damage to small bowel mucosa is prevented, and solubility of bile salts is favored. Hormones and the nervous system participate in the three phases of pancreatic exocrine regulation, the cephalic, gastric, and intestinal phases. a. Cephalic Phase: Mainly cholinergic fibers Abolished by vagotomy The cephalic phase, provoked by smell or taste of food, is exemplified by sham feeding (chewing food and spitting out the chewed food) which can stimulate about 25% of maximal pancreatic secretion. Stimuli reach the dorsal vagal complex to activate efferent vagal fibers. Acinar secretion is mainly stimulated in this phase. Acetylcholine is the major neurotransmitter involved. b. Gastric Phase: The gastric phase is initiated by gastric distension and by peptides and amino acids in the gastric lumen which activate vagovagal reflexes. This phase accounts for about 10% of meal-stimulated pancreatic secretion. c. Intestinal Phase: 72

Chief stimulants are H+, amino acids, fatty acids

The intestinal phase is most important, and it is the most complex. Gastric chyme in the small intestinal lumen stimulates vagal afferents, and initiates the release of CCK and secretin from specific mucosal endocrine cells. Digestion products of fats (fatty acids containing more than twelve carbon atoms, mono-glycerides) and protein (amino acids and peptides) and, to a smaller extent, glucose promote CCK release. Gastric H+ (low pH) and to a lesser extent, fatty acids, and bile acids promote release of secretin. While secretin mainly stimulates ductal secretion of bicarbonate, and CCK mainly stimulates acinar secretion of enzymes, potentiation between these two hormones occurs so than an enzyme and bicarbonate-rich juice is secreted.

CCK promotes pancreatic secretion by stimulating vagal and intra-pancreatic nerves

Until recently, because CCK receptors are present on rat pancreatic acini, it was presumed that CCK, released into the bloodstream, circulates to the pancreatic acinar cells and affects these cells directly through CCK receptors. However, it appears that CCK receptors may not be expressed on human acinar cells. In a still controversial model, CCK may interact with afferent vagal neurons to stimulate secretion through efferent vagal neurons. This model is consistent with the finding that the effects of physiologic concentrations of CCK on pancreatic enzyme secretion are blocked by atropine. Diversion of pancreatic juice from the intestine increases pancreatic secretion, an effect mediated by removing feedback inhibition of trypsin. During a meal, trypsin is occupied with ingested proteins and is not available for feedback inhibition. However, after dietary protein has been digested, trypsin then digests a peptide CCK-releasing factor, which is elaborated by endocrine cells in the duodenum. Less CCK is released as the amount of CCK-releasing factor in the lumen decreases.

One inhibitory feedback loop involves trypsin

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Figure 5
Feedback Regulation of Pancreatic Exocrine Secretion This figure summarizes the intestinal phase of stimulation of pancreatic secretion and the major pathways for regulation of pancreatic bicarbonate and enzyme secretion. Duodenal pH, determined by a balance of pancreatic HCO3 -and gastric HCl regulates the secretion, by intestinal endocrine S cells, of secretin. Secretin then circulates to the pancreas to stimulate, in an endocrine manner, HCO3-secretion from pancreatic duct cells. CCKreleasing factor (CCK-RF), present in the intestinal lumen, stimulates other intestinal endocrine cells to secrete CCK. In the fasting state, trypsin degrades CCK-RF to control pancreatic secretion; after a meal, trypsin binds to ingested proteins and does not attack CCK-RF as efficiently. CCK, originally believed to act as a hormone to directly stimulate enzyme secretion by acinar cells, may act through vagal afferent nerve endings, the CNS, and vagal efferent pathways. Synergism also exists between CCK and secretin in stimulating ductal and acinar secretion. (+) = upregulation/ stimulation (-) = downregulation/ inhibition

Another loop involves circulating hormones.

Nutrient molecules (glucose, amino acids, fatty acids) in the lower ileum, and proximal colon can inhibit CCK or meal-stimulated pancreatic secretion. This inhibition may be mediated by circulating hormones (such as PYY), or by vagal reflexes involving pancreatic polypeptide. You can judge that we have much to learn about pancreatic physiology. An emerging concept emphasizes the importance of the dorsal vagal complex with its sensory receptive area, its motor nucleus, and its area postrema whose fenestrated capillaries breach the blood-brain barrier. Signals from blood-borne hormones and nutrients can be integrated with nervous afferent impulses so that the motor vagal response is appropriate for the phase of digestion and absorption.

Frontiers of pancreatic physiology

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E. Regulation of Pancreatic Endocrine Function GLP-1 is derived from enteroglucagoncontaining cells The gut plays a role in the regulation of insulin release after glucose ingestion. Following orally administered glucose, the rise in blood insulin is greater and the clearance of glucose from the blood faster than after intravenous administration of the same amount of glucose. Thus, there appears to be a "hormone" released from the intestine by glucose which stimulates the pancreas islet cells to release insulin. Of the insulinotropic hormones in the gut, glucagon-like polypeptide-1 (GLP-1), and glucose insulinotropic polypeptide (GIP, known formerly as gastric inhibitory polypeptide) are the most active during a meal. These "incretins" cause a rapid release of insulin which suggests that their primary effect is releasing stored insulin. Somatostatin from gastric D cells, and from small intestinal nerve cells is also released during a meal. Somatostatin, by down-regulating the release of insulin, modulates the action of the incretins. In summary, food in the upper intestine stimulates insulin release from the stored insulin pool in the islet cells of the pancreas. Intestinal somatostatin down-regulates the secretion of insulin.

Summary

F. Diseases of the Pancreas Inflammation of the pancreas is called pancreatitis. Because of potentially confusing nomenclature, many international meetings have been convened and it is the current consensus that the distinction between acute and chronic pancreatitis should be based on the reversibility of pancreatic injury rather than on its time course. Acute pancreatitis is defined as being a reversible process once the inciting cause of the pancreatitis is removed whereas chronic pancreatitis implies some irreversible damage.

Acute pancreatitis: Reversible changes Chronic pancreatitis: Irreversible changes

1. Acute Pancreatitis
Causes of pancreatitis: biliary stones, alcoholism Acute pancreatitis is an auto-digestive disease in which pancreatic enzymes are inappropriately activated within the pancreas with resulting digestion of tissue. The exact cause of acute pancreatitis is not well understood, but 2/3 of patients will either have stones in the biliary tract or alcoholism. Of the remaining 1/3, predisposing factors, such as recent surgery near the pancreas or pancreatic trauma, will be found in most. In some cases the cause is idiopathic, i.e., no underlying reason is found. However, the triggering event for this autodigestive process is unknown. Perhaps in some cases a combination of acinar hypersecretion in the face of blocked pancreatic drainage causes acini to rupture and release activated enzymes which digest pancreatic tissue. For example, stones in the common bile duct may obstruct the pancreatic duct. In other cases, there may be a direct metabolic effect on the pancreas, such as in alcoholism. 75

Histology

Importance of ischemia

A clear histologic picture of the early changes in human pancreatitis is understandably hard to come by, except in experimental animals -- and the exact relation of experimental pancreatitis to the naturally occurring variety is uncertain. In any case the resultant inflammatory changes in the pancreas may vary widely. At one extreme there may be only spotty areas of mild interstitial edema. Variable parenchymatous necrosis involving the ducts, acinar cells, and to a lesser extent the islet cells, may be seen. There may be leukocytic infiltration. In more severe cases, interstitial hemorrhage is seen, along with areas of fat necrosis in the pancreas itself and in the omentum. In patients who die of acute pancreatitis, the gross appearance of the pancreas is a mixture of grey-white areas of necrotic tissue, blue-black areas of hemorrhage, and chalkywhite areas of fat necrosis. Ischemia seems to transform mild edematous pancreatitis into a hemorrhagic, necrotic process. The characteristic clinical finding of acute pancreatic inflammation is midline upper abdominal and/or back pain. Would the pain be colicky or steady? With disease of what other organs might the pain of pancreatitis be confused? Why? Would eating aggravate or relieve pancreatic pain? Why?

Retroperitoneal fluid Blood or serum often oozes in large quantities (up to 2 liters in hemorrhagic pancreatitis) into the retroperitoneal space or into the peritoneal cavity. Fluid in loss the abdominal cavity may be aspirated with a needle; and if its amylase content is high this is almost diagnostic of pancreatitis. Retroperitoneal losses may go undetected until shock appears. Inflammation of contiguous loops of small bowel may result in localized or generalized dilatation and paralysis of the bowel. What findings might you expect therefore on physical examination of the abdomen?

Remote effects of pancreatic enzymes

The liberation of digestive enzymes from the pancreas into the neighboring tissues and the blood stream may explain many manifestations of the disease. Lipase released into the pancreas, mesentery and omentum may result in areas of fat necrosis. Hydrolysis of tissue triglycerides results in release of fatty acids which interact with serum calcium to form "soaps" which are deposited throughout the fatty tissue. This may account for acute decreases in serum calcium and occasional tetany (muscle spasms associated with low blood calcium levels) in pancreatitis. Rarely, lipase can be carried by the blood stream to cause fat necrosis and inflammation in the bone marrow, mediastinum, pericardium, joints and skin. This can result in aseptic necrosis of the femur, pericarditis, arthritis and necrotic skin nodules. Amylase found circulating in the blood stream under normal conditions is derived principally from the salivary glands, with a smaller contribution from the pancreas. Elevated levels of blood amylase (pancreatic) may be detected early in acute pancreatitis, and if sufficiently high (over 3 times normal), may 76

Serum amylase

be diagnostic. However, it is important to remember that such elevated levels of circulating amylase may be seen in a number of other conditions: mumps (combination of increased salivary amylase and associated viral pancreatitis), perforated ulcer (?entry of enzymes into the blood via peritoneal absorption), small bowel obstruction or infarction, acute cholecystitis (mechanism unknown), renal failure (decreased enzyme excretion), salpingitis and ectopic pregnancy (Fallopian tubes manufacture amylase), and opiates administered for any type of pain (increased pancreatic ductal pressure). Furthermore, there may be moderate elevations of serum amylase associated with non-pancreatic abdominal pain. Such cases can be confused with mild attacks of pancreatitis. In some of these conditions the total serum amylase may be elevated to levels identical with those obtained in acute pancreatitis. Such confusion may be overcome by measuring serum lipase. Autodigestion Trypsin has been postulated to be the primary auto-digestive enzyme in pancreatic inflammation, but it is likely that all pancreatic enzymes contribute to the severe destruction and hemorrhage which may be seen in the gland. For example, elastase can digest blood vessel walls. In pancreatitis, autodigestion leads to edema and liquefactive necrosis as pancreatic enzymes seep into the parenchyma, and, sometimes, into adjacent tissue planes. Early in the course, these areas of necrosis (previously known as phlegmons) are identified on computed tomographic (CT) imaging as areas without discrete borders, less dense and less perfused than normal pancreatic parenchyma. Patients who, genetically, have a reduced ability to combat inflammation-induced oxidative stress seem to be more likely to progress from mild to severe pancreatitis. Necrosis is an important factor in the severity of the acute pancreatitis episode because it is associated with multisystem organ failure (shock, pulmonary insufficiency, renal failure, disseminated intravascular coagulation, and gastrointestinal bleeding), and because the necrotic area can become secondarily infected. While the hypotension may be partially explained by the intravascular depletion associated with fluid loss into the peritoneal cavity or retroperitoneal space, the multisystem organ failure appears to be mediated by different cytokines and chemokines, such as IL-1, IL-6, IL-8, and tumor necrosis factor, which are released into the circulation by the injured pancreas and the associated monocytes and macrophages. Secondary infection of the necrotic areas results mainly from bacterial translocation from the gut lumen. Overall, the mortality from interstitial edematous pancreatitis is <2%, with necrosis, it raises to 10%, while with infected necrosis, it is further increased to 30%. Later on, as these necrotic areas become homogenously liquefied and acquire distinct boundaries of connective tissue and surviving parenchyma, they are called pseudocysts because they are not lined by epithelium which is a characteristic of a true cyst. These areas may also become secondarily infected, and become abscesses. 77

Liquefactive necrosis -early: pancreatic necrosis -late: pseudocysts -secondary infection: abscess

cytokines

The hypotension seen with pancreatitis is usually due to fluid loss. However, hypotension may be aggravated by release of "cytokines" into the circulation. How would you plan rational treatment for a patient with severe, acute pancreatitis? Take into consideration the following data obtained from patients with a cannulated pancreatic duct: a. Pancreatic secretion in a fasting subject is approximately 300 cc/day (about 12 ml/hr). b. If gastric acid is continuously removed from the stomach of such a fasting subject, pancreatic secretion is about 75 cc/day (or about 3 ml/hr). c. Pancreatic secretion in a subject who is eating normally is about 2000 cc/day (about 85 ml/hr). d. Intravenous nutrients have little effect on pancreatic exocrine function.

treatment

Of the steps in the treatment plan you have devised, which would be the most important in preventing pancreatic stimulation? Which would be the most important in maintaining circulating blood and fluid volume? Ultrasound scanning and computed tomography are useful techniques in patients with acute pancreatitis to detect gallstones, pancreatic swelling, abscess, or cyst formation. In the past, surgery during the course of acute pancreatitis has been felt to be contraindicated. However, there are now a number of reports which indicate that surgery on appropriate patients with acute pancreatitis does not carry a higher mortality. Surgical debridement is usually necessary for patients with infected pancreatic necrosis.

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Figure 6
An Outline of Possible Sequelae of Acute Pancreatitis.

2. Chronic Pancreatitis and Insufficiency

Pancreatic calcification Recurrent attacks of pancreatic inflammation may lead to variable degrees of focal or diffuse destruction of acinar cells, islets and ducts along with lymphocytic and plasma cell infiltration and scarring. Dilated ducts secondary to multiple stenoses commonly occur. Calcium may be deposited both within the ducts as stones and within the parenchyma in areas of fat necrosis. Such calcium deposition may be seen on abdominal X-ray films, either as focal collections of calcium, or as a diffuse stippled density outlining the pancreas. This process is known as chronic calcific pancreatitis. In some cases this designation is a misnomer because there may be no inflammation. All that may be present is a gland which is carved up by bands of connective tissue. Patients who have the histologic features of chronic pancreatitis may be asymptomatic or may suffer from recurrent inflammatory attacks. Would the serum and urinary amylase be elevated during such attacks? Why? Other patients may suffer from chronic pain either due to a complication within the pancreas (obstructed duct or pseudocyst) or to ongoing inflammation of peripancreatic nerve fibers.

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Endocrine and exocrine insufficiency

Some patients develop so much glandular destruction that endocrine and exocrine secretions become insufficient to meet the daily demands of carbohydrate metabolism and food digestion. Such patients are said to have "chronic pancreatitis with pancreatic insufficiency". These patients may or may not have pain. Endocrine insufficiency results in diabetes mellitus because of inadequate insulin production. Exocrine insufficiency occurs when approximately 80% of the functioning pancreas is destroyed. Impaired digestion of carbohydrates, proteins, and fats diminishes absorption of food and weight loss is frequent. An excessive amount of unabsorbed fat appears in the stool (steatorrhea), and often leads to bulky, frequent, foul-smelling, lightcolored stools which may be greasy and have a characteristic odor of rancid fat. In steatorrhea the stool always shows an excessive number of fat globules when stained with lipophilic dyes and examined microscopically. Small fatty droplets are often present normally, and thus, this finding is not always diagnostic. A quantitative estimate of steatorrhea demands a chemical fat analysis of stools collected in a standardized manner. Direct studies of pancreatic function such as the secretin test show marked reduction in volume and concentration of bicarbonate in all patients who have had sufficient destruction of the pancreas to develop exocrine insufficiency with steatorrhea. The treatment of chronic pancreatic exocrine insufficiency is by giving pancreatic enzymes with each meal. If necessary, deficient insulin secretion can be replaced with the use of insulin injections. Thus, diabetes can be controlled and malabsorption can be reduced. Occasionally, however, patients with proven pancreatic insufficiency fail to respond to pancreatic enzyme replacement given with meals. Why? How might you approach this problem? As noted above, some patients with chronic pancreatitis suffer severe pain. This may be uncontrollable by medical measures and may occasionally result in addiction to the pain-relieving narcotics prescribed by the physician. Such patients sometimes require one or more operations designed to decrease their pain. What sort of operative procedures might you consider, should you be the surgical consultant on such a case? A diagnostic procedure endoscopic retrograde cholangiopancreatography (ERCP) can visualize the ductal system and confirm the presence of a potentially correctable abnormality such as localized resectable disease. ERCP is done by passing an endoscope to the papilla of Vater, inserting a catheter through the endoscope into the papilla, and injecting radio-opaque contrast material through the catheter and into the pancreatic and common bile ducts. The ducts can then be visualized radiographically. ERCP may be useful in determining whether a surgically correctable lesion (obstructed pancreatic duct) is present in either patients with chronic pain or in those having recurrent acute attacks of pain.

Steatorrhea

Treatment

Investigation

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3. Carcinoma of the Pancreas

Carcinoma of the pancreas is increasingly prevalent and is now the fourth commonest cancer causing death in the United States. (Only cancers of the lung, colon, and breast are more common.) It usually occurs in patients over 50 years of age. Virtually all pancreatic tumors (other than those of the islet cells) arise from the ductal epithelium, and are most commonly adenocarcinomas growing in a well-differentiated glandular pattern. Steatorrhea and jaundice Sixty to 70% of pancreatic cancers involve the head of the pancreas. They may produce pancreatic insufficiency and steatorrhea. How? They may also cause jaundice. How? Carcinoma of the body (20 - 30%) or tail (5 - 10%) of the pancreas, on the other hand, may grow to large size and be widely invasive before being detected, often by virtue of a metastatic lesion. Involvement of nerve endings within the pancreas itself gives persistent upper abdominal pain, and involvement of somatic retroperitoneal nerves gives severe back pain. Obstruction of pancreatic and biliary flow can markedly impair digestion of the food with resultant weight loss and steatorrhea. Physical examination of the spleen is of value in diagnosing carcinoma of the pancreas because neoplastic involvement of the splenic vein can cause splenic vein thrombosis and splenomegaly. The presence of a mass in the pancreas may be suggested by displacement of the stomach or widening of the duodenal loop upon X-ray examination of these organs after ingesting barium. Such a mass could be a benign cyst or a cancer. Radiographic diagnosis of carcinoma of the pancreas depends primarily upon cross-sectional imaging techniques such as ultrasound and computed tomography. Pancreatic masses larger than 1-2 cm in diameter may be detected in approximately 80-90% of cases. Barium upper GI series and angiography are secondary studies, not frequently used to establish the diagnosis. ERCP can show ductal obstruction suggestive of cancer, but differentiation from benign obstruction caused by pancreatitis may be difficult. Definitive diagnosis of cancer requires recovery of malignant tissue. This is most efficiently done by percutaneous biopsy guided either by endoscopic ultrasound or CT. Cytologic demonstration of malignant cells may also be accomplished in pancreatic juice or in an operative biopsy of a metastatic nodule. Direct operative biopsy of the lesion in the pancreas may be hazardous (postoperative fistula or pancreatitis) and still misleading (only fibrous tissue adjacent to the cancer may be sampled). Many surgeons thus prefer to remove a peripancreatic node for histological examination.

Pain

Splenomegaly

Diagnosis

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Survival

Pancreatic cancer is extremely difficult to diagnose clinically and usually impossible to treat effectively. Surgical treatment usually involves an extensive resection of the pancreas and surrounding area, and five-year survivals are uncommon. Death usually occurs within 6 to 12 months after the appearance of symptoms.

4. Cystic Fibrosis (CF)

Impaired function of CFTR, a cAMPactivated Clchannel CF is an autosomal recessive disorder. Among people of Northern European origin, approximately 1 in 2,500 live births is affected. It is extremely rare in people of Asian or African origin. The CF gene has been cloned; it encodes a protein, the CF transmembrane conductance regulator (CFTR) which is a cAMP-dependent chloride channel which may also regulate other ion channels. CFTR is expressed in the pancreatic duct epithelial cell and impaired function of this Cl- channel leads to decreased bicarbonate secretion. It has been postulated that decreased bicarbonate and fluid secretion by pancreatic duct cells results in hyperconcentrated pancreatic juice that then inspissates, resulting in pancreatic ductal obstruction. A more recent theory postulates that the acid microenvironment in the periacinar region due to decreased bicarbonate results in the precipitation of GP2, a protein that is excreted by pancreatic acinar cells in conjunction with pancreatic enzymes. These GP2 precipitates result in ductal obstruction. There are now about 900 known mutations of CFTR that result in different types of defects (impaired protein synthesis, impaired protein processing, impaired regulation of the channel, impaired function of the channel, low abundance of the channel). A deletion of a phenylalamine at amino acid position 508 is the most common mutation, accounting for 70% of the alleles in patients with CF; it results in a protein exhibiting both impaired processing and function. Mutations resulting in impaired protein synthesis or processing are severe mutations that, in the homozygous state, produce pancreatic insufficiency. Milder mutations may not produce pancreatic insufficiency but may be associated with chronic pancreatitis. CF is the major cause of pancreatic insufficiency in children and the majority of adult patients with CF have pancreatic insufficiency. Pancreatic insufficiency in adult CF is becoming more a problem now that 35% of the patients live past the age of 20.

5. Hereditary Pancreatitis
Arginine to histidine mutation in the cationic trypsinogen renders it resistant to catalytic cleavage following autoactivation Hereditary pancreatitis (HP) is an autosomal dominant disease with 80% penetrance characterized by recurrent episodes of pancreatitis since childhood and a familial occurrence. The gene for HP has recently been cloned and encodes cationic trypsinogen. Mutations may render this trypsin resistant to catalytic cleavage by trypsin and other proteases. In this manner, when trypsinogen is auto-activated in the pancreatic acinar cell, it can no longer be inactivated by proteases, so that pancreatic autodigestion can result.

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6. Abnormalities of Islet Cells

Hyperplasia, adenoma, or adenocarcinoma of the beta cells of the islets may cause excessive insulin production and profound hypoglycemia. Hyperplasia or neoplasia of the non-beta cells of the islets can cause excessive gastrin secretion. The persistent gastrin stimulation causes excessive HC1 and pepsin secretion by parietal and chief cells of the stomach and can lead to severe, unrelenting peptic ulcer disease and diarrhea (Zollinger-Ellison syndrome). An unusual non-beta cell tumor of the islets produces a humoral substance which causes severe diarrhea with marked fluid and electrolyte loss. This hormone has been identified as vasoactive intestinal peptide (VIP). Symptoms are related to water loss and marked hypokalemia (reduction in blood potassium). These patients do not have gastric hypersecretion. VIP, acting via specific receptors on crypt cells of small and large intestines, stimulates cAMP production to activate the CFTR Cl- channel, resulting in marked luminal electrolyte and fluid loss. G. Key Points The pancreas has three main functions: to secrete sodium bicarbonate to neutralize gastric acid; to secrete digestive enzymes; and to secrete endocrine hormones to regulate intermediary metabolism. In pancreatitis, it is believed that digestive enzymes become activated within acinar cells. Autodigestion, inflammatory mediators, ischemia, and secondary infection account for pathological and clinical consequences. More than 75% of pancreatic tissue must be destroyed before features of pancreatic insufficiency become obvious. Pancreatic cancer is now the fourth leading cause of deaths in the U.S. Patients with cystic fibrosis have defective secretory chloride channels.

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H. Case Histories

Case I
A 60-year old woman presents with vomiting and gnawing epigastric pain which has radiated to her back for 8 hours. She denies taking prescription medicines or abusing alcohol. Three years ago, she had an evaluation for fleeting episodes of right upper quadrant pain; an ultrasound of her right upper quadrant revealed gallstones, but she refused further investigation. On examination, she is a healthy-appearing lady, but in obvious distress. She has tenderness to deep palpation in the epigastrium which appears to be disproportionately distended in relationship to the rest of her abdomen. Her radial pulse is 110 per minute, and her blood pressure is 90/60. The initial laboratory evaluation includes hematocrit of 40 and serum amylase ten times normal. How would you explain the following phenomena if they occurred during an attack of acute pancreatitis? 1. 2. 3. 4. 5. 6. 7. 8. 9. Fluid in the abdomen Radiation of pain to the back Jaundice Left pleural effusion Hypotension Hyperglycemia Hypocalcemia Respiratory distress Painful subcutaneous nodules

10. A toxic course with fever developing over the next four days? Over the next 14 days? 11. A dilated section of transverse colon seen on abdominal x-ray 12. Pancreatic enzymes in peripheral venous blood Based on your knowledge of pancreatic secretion, how would you propose to treat this patient?

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Case II
Our patient is a 56-year old chronic alcoholic who has complained of bouts of severe epigastric pain over the past five years. Now he is complaining of losing weight although his appetite is reasonably good. His fasting blood sugar is twice normal, and his stools contain excessive amounts of triglyceride. What is your diagnosis and how would you support your hypothesis? How would you treat him?

Case III
This 67-year old man began to experience dull, epigastric pain which radiated to his mid-back three months ago. At first, lumbar arthritis was thought to be the cause, and the discomfort was lessened by taking an NSAID (ibuprofen). His appetite diminished, and one month ago, his friends thought that his eyes were yellow. The patient remarked that his stools were lighter in color and more bulky; his urine was darker. How would you proceed?

Question Based on your knowledge of pancreatic pathophysiology, explain why you would or would not use each of the following interventions as therapy in acute pancreatitis: a. intravenous infusion of secretin b. intravenous infusion of Ca2+ c. intraduodenal infusion of trypsin d. intraduodenal infusion of amino acids and fatty acids

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