Medical Physiology, 3rd Edition

Composition, Function, and Control of Pancreatic Secretion

Pancreatic juice is a protein-rich, alkaline secretion

Humans produce ~1.5 L of pancreatic fluid each day. The pancreas has the highest rates of protein synthesis and secretion of any organ in the body. Each day the pancreas delivers between 15 and 100 g of protein into the small intestine. The level of pancreatic secretion is determined by a balance between factors that stimulate secretion and those that inhibit it.

The human pancreas secretes >20 proteins, some of which are listed in Table 43-1. Most of these proteins are either inactive digestive enzyme precursors—zymogens—or active digestive enzymes. The secretory proteins responsible for digestion can be classified according to their substrates: proteases hydrolyze proteins, amylases digest carbohydrates, lipases and phospholipases break down lipids, and nucleases digest nucleic acids. The functions of other secretory proteins—such as glycoprotein II (GP2), lithostathine, and pancreatitis-associated protein—are less well defined.

TABLE 43-1

Secretory Products of the Pancreatic Acinar Cell

 

FUNCTION

Zymogens

Trypsinogens

Digestion

Chymotrypsinogen

Digestion

Proelastase

Digestion

Proprotease E

Digestion

Procarboxypeptidase A

Digestion

Procarboxypeptidase B

Digestion

Active Enzymes

α-Amylase

Digestion

Carboxyl ester lipase

Digestion

Lipase

Digestion

RNAase

Digestion

DNAase

Digestion

Colipase

Digestion

Others

Trypsin inhibitor

Block of trypsin activity

Lithostathine

Constituent of protein plugs

Glycoprotein 2 (GP2)

Formation of protein plugs

Pancreatitis-associated protein

Pancreatic growth, bacteriostasis

Na+, Cl, H2O

Hydration of secretions

Ca2+

Stone formation in pancreatitis

GP2 is an unusual protein with an N-terminal glycosylphosphatidylinositol moiety that links it to the inner leaflet of the zymogen granule membrane. GP2 has been implicated in the regulation of endocytosis. After exocytosis, luminal cleavage of the GP2 linkage to the zymogen granule membrane seems to be necessary for proper trafficking of the zymogen granule membrane back into the cell from the plasma membrane. Under certain circumstances, the released GP2—and also lithostathine—may form protein aggregates in the pancreatic juice. This finding is not surprising inasmuch as GP2 is structurally related to the Tamm-Horsfall protein, which is secreted by the renal thick ascending limb (see pp. 729–730). The tendency of GP2 and lithostathine to form aggregates may have detrimental clinical consequences in that both proteins have been implicated in the pathological formation of protein plugs that can obstruct the lumen of acini in patients with cystic fibrosis (see Box 43-1) and chronic pancreatitis.

Pancreatitis-associated protein is a secretory protein that is present in low concentrations in the normal state. However, levels of this protein may increase up to several hundred-fold during the early phases of pancreatic injury. Pancreatitis-associated protein is a bacteriostatic agent that may help to prevent pancreatic infection during bouts of pancreatitis.

Pancreatic juice is also rich in Ca2+ and imageCalcium concentrations are in the millimolar range inside the organelles of the secretory pathway of the acinar cells, but lower in pancreatic secretions after dilution by Ca2+-free duct secretions. These high levels of Ca2+ in the vesicles may be required to induce the aggregation of secretory proteins and to direct them into the secretory pathway. Bicarbonate secreted by duct cells neutralizes the acidic gastric secretions that enter the duodenum and allows digestive enzymes to function properly; image also facilitates the micellar solubilization of lipids and mucosal cell function. The [image] in pancreatic juice increases with increases in the secretory flow rate (Fig. 43-7). In the unstimulated state, the flow is low, and the electrolyte composition of pancreatic juice closely resembles that of blood plasma. As the gland is stimulated and flow increases, exchange of Cl in the pancreatic juice for image across the apical membrane of the duct cells produces a secretory product that is more alkaline (pH of ~8.1) and has a lower [Cl]. Concentrations of Na+ or K+, however, are not significantly altered by changes in flow.

image

FIGURE 43-7 Flow dependence of the electrolyte composition of pancreatic fluid. Increasing secretin levels not only increases the secretory rate, but also changes the composition of the fluid. (Data from Case RM, Harper AA, Scratcherd T: The secretion of electrolytes and enzymes by the pancreas of the anaesthetized cat. J Physiol 201:335–348, 1969.)

In the fasting state, levels of secreted pancreatic enzymes oscillate at low levels

Pancreatic secretion is regulated in both the fasted and fed states. Under basal conditions, the pancreas releases low levels of pancreatic enzymes (Fig. 43-8). However, during the digestive period (eating a meal), pancreatic secretion increases in sequential phases to levels that are 5- to 20-fold higher than basal levels. The systems that regulate secretion appear to be redundant; if one system fails, a second takes its place. These mechanisms ensure that the release of pancreatic enzymes corresponds to the amount of food in the small intestine.

image

FIGURE 43-8 Time course of pancreatic secretion during fasting and feeding. The interdigestive output of secretory products (e.g., trypsin) by the pancreas varies cyclically and in rough synchrony with the four phases of motor activity (migrating motor complexes) of the small intestine, shown by the colored vertical bands. Feeding causes a massive and sustained increase in trypsin release and switches small-intestinal motility to the fed state. (Data from DiMagno EP, Layer P: In Go VLW, DiMagno EP, Gardner JD, et al [eds]: The Pancreas: Biology, Pathobiology and Disease, 2nd ed. New York, Raven Press, pp 275–300, 1993.)

Like other organs in the upper gastrointestinal tract, the pancreas has a basal rate of secretion even when food is not being eaten or digested. During this interdigestive (fasting) period, pancreatic secretions vary cyclically and correspond to sequential changes in the motility of the small intestine (see p. 861). Pancreatic secretion is minimal when intestinal motility is in its quiescent phase (phase I); biliary and gastric secretions are also minimal at this time. As duodenal motility increases (phase II), so does pancreatic secretion. During the interdigestive period, enzyme secretion is maximal when intestinal motility—the migrating motor complexes (MMCs; see Fig 41-6)—is also maximal (phase III). However, even this maximal interdigestive secretory rate is only 10% to 20% of that stimulated by a meal. The peak phases of interdigestive intestinal motor activity and pancreatic secretory activity are followed by a declining period (phase IV). Fluid and electrolyte secretion rates during the interdigestive phase are usually <5% of maximum levels.

The cyclic pattern of interdigestive pancreatic secretion is mediated by intrinsic and extrinsic mechanisms. The predominant mechanism of pancreatic regulation is through parasympathetic pathways. Telenzepine, an antagonist of the M1 muscarinic ACh receptor, reduces interdigestive enzyme secretion by >85% during phases II and III. Although cholinergic pathways are the major regulators of interdigestive pancreatic secretion, CCK and adrenergic pathways also play a role. CCK appears to stimulate pancreatic enzyme secretion during phases I and II. In contrast, basal α-adrenergic tone appears to suppress interdigestive pancreatic secretion. Although human and canine pancreas denervated during transplantation exhibits cyclic secretion, this secretion is no longer synchronous with duodenal motor activity. These observations support a role for the autonomic nervous system in regulating basal (resting) pancreatic secretion.

CCK from duodenal I cells stimulates acinar enzyme secretion, and secretin from S cells stimulates image and fluid secretion by ducts

CCK plays a central role in regulating pancreatic secretion. CCK is released from neuroendocrine cells (I cells; see Table 41-1) present in the duodenal mucosa (see Fig. 43-4). In response to a meal, plasma CCK levels increase 5- to 10-fold within 10 to 30 minutes.

The most potent stimulator of CCK release from I cells is lipid in the duodenal lumen. Protein digestive products (i.e., peptones, amino acids) also increase CCK release, but carbohydrate and acid have little effect. CCK secretion may also be stimulated by CCK-releasing factors, which are peptides released by mucosal cells of the duodenum or secreted by the pancreas. The level of these releasing factors may reflect a balance between the relative amounts of nutrients and digestive enzymes that are present in the gut lumen at any one time, so the level of the factors reflects the digestive milieu of the duodenum. In the fasting state, luminal CCK-releasing factors are degraded by digestive enzymes that accompany basal pancreatic secretion, so little releasing factor remains to stimulate the I cells. However, during a meal, the digestive enzymes are diverted to the digestion of ingested nutrients entering the gut lumen, and the CCK-releasing factors are spared degradation. Hence, the relative level of proteins to proteases in the small intestine determines the amount of CCK-releasing factor available to drive CCK release and thus pancreatic secretion.

Three lines of evidence show that CCK is a physiological mediator of pancreatic protein secretion: (1) CCK levels increase in the serum in response to a meal, (2) administration of exogenous CCK at the same levels produced by a meal stimulates pancreatic protein secretion to higher levels than those generated by a meal (the meal may also stimulate the release of inhibitory factors in addition to CCK), and (3) a specific CCK inhibitor reduces pancreatic protein secretion by >50%.

CCK may act on the acinar cell through both direct and indirect pathways: it can directly stimulate enzyme secretion through a CCK1 receptor on the acinar cell (see Fig. 43-4), and it may indirectly stimulate enzyme secretion by activating the parasympathetic (cholinergic) nervous system. However, whether human acinar cells have CCK1 receptors remains unclear. As we see below (see pp. 890–892), the parasympathetic pathway plays a major role in mediating the intestinal phase of pancreatic secretion. Vagal stimulation can drive pancreatic secretion to nearly maximum levels. Atropine, an antagonist of muscarinic ACh receptors (see pp. 341–342), reduces the secretion of enzymes and image during the intestinal phase of a meal. Atropine also inhibits secretion in response to stimulation by physiological levels of exogenous CCK. Together, these findings suggest that CCK somehow stimulates the parasympathetic pathway, which in turn stimulates muscarinic receptors on the acinar cell but may have little direct effect on human acinar cells.

Like CCK, GRP—which is structurally related to bombesin—may also be a physiological regulator of pancreatic enzyme secretion. Stimulation of acinar cells with GRP leads to enzyme secretion. In contrast to the hormone CCK, the major source of GRP appears to be the vagal nerve terminals.

Secretin is the most potent humoral stimulator of fluid and image secretion by the pancreas (see Fig. 43-6). Secretin is released from neuroendocrine cells (S cells) in the mucosa of the small intestine in response to duodenal acidification and, to a lesser extent, bile acids and lipids. To stimulate secretin secretion, duodenal pH must fall to <4.5. Like CCK levels, secretin levels increase after the ingestion of a meal. However, when these levels are reached experimentally by administration of exogenous secretin, pancreatic image secretion is less than that generated by a meal. These findings suggest that secretin is acting in concert with CCK, ACh, and other agents to stimulate image secretion.

In addition to hormones of intestinal origin, insulin and other hormones secreted by the islets of Langerhans within the pancreas (see p. 1035) may also influence pancreatic exocrine secretion. Blood flow from the pancreatic islets moves to the exocrine pancreas through a portal system. This organization allows high concentrations of islet hormones to interact with pancreatic acinar cells. One result of this arrangement may be that insulin modifies the composition of digestive enzymes within the acinar cell and increases the relative levels of amylase. Islet hormones may also have trophic effects on the exocrine pancreas and stimulate its growth. As a reflection of this function, the mass of the exocrine pancreas is substantially reduced in individuals with diabetes.

Regulation of exocrine pancreatic secretion is complex, and understanding this process has been made difficult by the following: (1) tissue levels of an exogenously infused hormone may not match those generated physiologically; (2) because several neurohumoral factors are released in response to a meal, the infusion of a single agent may not accurately reflect its physiological role; (3) specific neurohumoral inhibitors are often unavailable; and (4) pancreatic responses may differ depending on the species.

A meal triggers cephalic, gastric, and intestinal phases of pancreatic secretion

The digestive period has been divided into three phases (Table 43-2) based on the site at which food acts to stimulate pancreatic secretion, just as for gastric secretion (see pp. 870–872). These three phases (cephalic, gastric, and intestinal) are sequential and follow the progression of a meal from its initial smell and taste to its movement through the gastrointestinal tract (Fig. 43-9). These phases act in a coordinated fashion to maximize efficiency of the digestive process. For example, stimulation of secretion before the entry of food into the small intestine during the cephalic and gastric phases ensures that active enzymes are present when food arrives. Conversely, suppression of secretion during the late digestive phase suppresses the release of pancreatic enzymes when nutrients are no longer present in the proximal end of the small intestine.

TABLE 43-2

Three Phases of Pancreatic Secretion

PHASE

STIMULANT

REGULATORY PATHWAY

% OF MAXIMUM ENZYME SECRETION

Cephalic

Sight
Smell
Taste
Mastication

Vagal pathways

25

Gastric

Distention
Gastrin?

Vagal-cholinergic

10–20

Intestinal

Amino acids
Fatty acids
H+

CCK
Secretin
Enteropancreatic reflexes

50–80

image

FIGURE 43-9 Three phases of pancreatic secretion.

Cephalic Phase

During the cephalic phase, the sight, taste, and smell of food usually generates only a modest increase in fluid and electrolyte secretion (see Fig. 43-9A). However, these factors have prominent effects on enzyme secretion. In most animal species, enzyme secretion increases to 25% to 50% of the maximum rate evoked by exogenous CCK. In humans, the cephalic phase is short-lived and dissipates rapidly when food is removed. The cephalic phase is mediated by neural pathways. In the dog, stimulation of several regions of the hypothalamus (the dorsomedial and ventromedial nuclei and the mammillary body) enhances pancreatic secretion. The efferent signal travels along vagal pathways to stimulate pancreatic secretion via ACh, an effect blocked by atropine. The cephalic phase does not depend on gastrin or CCK release, but it is probably mediated by the stimulation of muscarinic receptors on the acinar cell.

Gastric Phase

During the gastric phase (see Figure 43-9A), the presence of food in the stomach modulates pancreatic secretion by (1) affecting the release of hormones, (2) stimulating neural pathways, and (3) modifying the pH and availability of nutrients in the proximal part of the small intestine. The presence of specific peptides or amino acids (peptones) stimulates gastrin release from G cells in the antrum of the stomach and, to a much lesser extent, G cells in the proximal part of the duodenum. The gastrin/CCK2 receptor and the CCK1 receptor are closely related (see p. 867). Although in some species the gastrin/CCK2 receptor is not present on the pancreatic acinar cell, gastrin can still act—albeit not as well—through the CCK1 receptor. Although physiological concentrations of gastrin can stimulate pancreatic secretion in some species, the importance of gastrin in regulating secretion in the human pancreas remains unclear. As far as local neural pathways are concerned, gastric distention stimulates low levels of pancreatic secretion, probably through a vagovagal gastropancreatic reflex. Although the presence of food in the stomach affects pancreatic secretion, the most important role for chyme in controlling pancreatic secretion occurs after the gastric contents enter the small intestine.

Intestinal Phase

During the intestinal phase, chyme entering the proximal region of the small intestine stimulates a major pancreatic secretory response by three major mechanisms (see Fig. 43-9B). First, gastric acid entering the duodenum—and to a lesser extent, bile acids and lipids—stimulate duodenal S cells to release secretin, which stimulates duct cells to secrete image and fluid. A threshold duodenal pH of <4.5 is needed to activate S-cell secretion. The acid stimulates fluid and electrolyte secretion to a greater extent than it stimulates protein secretion. Second, lipids and, to a lesser degree, peptones stimulate duodenal I cells to release CCK, which stimulates acinar cells to release digestive enzymes. Finally, the same stimuli that trigger I cells also activate a vagovagal enteropancreatic reflex that predominantly stimulates acinar cells.

The pattern of enzyme secretion—mediated by the CCK and vagovagal pathways—depends on the contents of the meal. For example, a liquid meal elicits a response that is only ~60% of maximal. In contrast, a solid meal, which contains larger particles and is slowly released from the stomach, elicits a prolonged response. Meals rich in calories cause the greatest response.

The chemistry of the ingested nutrients also affects pancreatic secretion via the CCK and vagovagal pathways. For example, perfusion of the duodenum with carbohydrates has little effect on secretion, whereas lipids are potent stimulators of pancreatic enzyme secretion. As far as lipids are concerned, triglycerides do not stimulate pancreatic secretion, but their hydrolytic products—monoglycerides and fatty acids—do. The longer the chain length of the fatty acid, the greater the secretory response; C-18 fatty acids generate protein secretion that is near the maximum produced by exogenous CCK. Some fatty acids also stimulate pancreatic image secretion. Because fatty acids also reduce gastric acid secretion and delay gastric emptying, they may play an important role in modulating pH conditions in the proximal part of the small intestine. Protein breakdown products are intermediate in their stimulatory effect. Nonessential amino acids have little effect on protein secretion, whereas some essential amino acids (see Table 58-2) stimulate secretion. The most potent amino-acid stimulators are phenylalanine, valine, and methionine. Short peptides containing phenylalanine stimulate secretion to the same extent as the amino acid itself. Because gastric digestion generates more peptides than amino acids, it is likely that peptides provide the initial pancreatic stimulation during the intestinal phase.

The relative potency of the different nutrients in stimulating secretion is inversely related to the pancreatic reserves of digestive enzymes. Thus, the pancreas needs to release only a small portion of its amylase to digest the carbohydrate in a meal and to release only slightly greater portions of proteolytic enzymes to digest the proteins. However, a greater fraction of pancreatic lipase has to be released to efficiently digest the fat in most meals. The exocrine pancreas has the ability to respond to long-term changes in dietary composition by modulating the reserves of pancreatic enzymes. For example, a diet that is relatively high in carbohydrates may lead to a relative increase in pancreatic amylase content.

The pancreas has large reserves of digestive enzymes for carbohydrates and proteins, but not for lipids

The exocrine pancreas stores more enzymes than are required for digesting a meal. The greatest pancreatic reserves are those required for carbohydrate and protein digestion. The reserves of enzymes required for lipid digestion—particularly for triglyceride hydrolysis—are more limited. Even so, nutrient absorption studies after partial pancreatic resection show that maldigestion of dietary fat does not occur until 80% to 90% of the pancreas has been removed. Similar reserves exist for pancreatic endocrine function. These observations have important clinical implications because they indicate that individuals can tolerate large pancreatic resections for tumors without fear of developing maldigestion or diabetes postoperatively. When fat maldigestion or diabetes does develop because of pancreatic disease, the gland must have undergone extensive destruction. imageN43-6

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Chronic Pancreatitis and Pancreatic Insufficiency

Contributed by Fred Gorelick

Chronic pancreatitis is a localized and chronic inflammation of the pancreas. The most common causes are many years (10 to 20) of alcohol abuse or smoking. The clinical manifestations of chronic pancreatitis usually begin with chronic epigastric pain that radiates into the back, then progress to include calcification of the pancreas and progressive loss of the endocrine and exocrine tissues. The destruction of pancreatic tissues leads to diabetes and loss of nutrients (malabsorption). A distinct pattern of malabsorption is seen with chronic pancreatitis: individuals lose large amounts of dietary fat but have little loss of protein or carbohydrates. This type of malabsorption can cause fat droplets to appear in the patient's stool; this symptom is a strong clinical clue that a patient is not absorbing dietary lipids. An important reason for the selective loss of lipids is the shortage of lipase and its cofactors compared to other classes of digestive enzymes. This happens because the pancreatic reserves of lipase are very limited and because lipase is very sensitive to an acid environment. Lipase is the only major pancreatic enzyme that become irreversibly inactive at pH < 4.0.

Although the pain of chronic pancreatitis can be difficult to treat, the malabsorption of lipids is very amenable to therapy. This involves giving exogenous pancreatic enzymes (usually extracted from porcine pancreas) by mouth with each meal. However, the critical lipase in these preparations must be protected from an acidic environment. This is done by either raising the pH of the stomach using inhibitors of acid secretion (see pp. 865–866) or encasing the enzyme in a coating that dissolves only when the preparation has reached the high-pH environment of the small intestine.

Fat in the distal part of the small intestine inhibits pancreatic secretion

Once maximally stimulated, pancreatic secretion begins to decrease after several hours. Nevertheless, the levels of secretion remain adequate for digestion. Regulatory systems only gradually return secretion to its basal (interdigestive) state. The regulatory mechanisms responsible for this feedback inhibition are less well characterized than those responsible for stimulating pancreatic secretion. The presence of fat in the distal end of the small intestine reduces pancreatic secretion in most animals, including humans. This inhibition may be mediated by peptide YY (PYY), which is present in neuroendocrine cells in the ileum and colon. PYY may suppress pancreatic secretion by acting on inhibitory neural pathways as well as by decreasing pancreatic blood flow. Somatostatin (particularly SS-28; see pp. 993–994), released from intestinal D cells, and glucagon, released from pancreatic islet α cells, may also be factors in returning pancreatic secretion to the interdigestive state after a meal.

Several mechanisms protect the pancreas from autodigestion

Premature activation of pancreatic enzymes within acinar cells may lead to autodigestion and could play a role in initiating pancreatitis. imageN43-1 To avoid such injury, the acinar cell has mechanisms for preventing enzymatic activity (Table 43-3). First, many digestive proteins are stored in secretory granules as inactive precursors or zymogens. Under normal conditions, zymogens become activated only after entering the small intestine. There, the intestinal enzyme enterokinase converts trypsinogen to trypsin (see pp. 921–922), which initiates the conversion of all other zymogens to their active forms. Second, the secretory granule membrane is impermeable to proteins. Thus, the zymogens and active digestive enzymes are sequestered from proteins in the cytoplasm and other intracellular compartments. Third, enzyme inhibitors such as pancreatic trypsin inhibitor, co-packaged in the secretory granule, block the activity of trypsin aberrantly activated within the granule. However, sufficient pancreatic trypsin inhibitor is present in the secretory granules to block <5% of the potential trypsin activity. Fourth, the condensation of zymogens, the low pH, and the ionic conditions within the secretory pathway may further limit enzyme activity. Fifth, enzymes that become prematurely active within the acinar cell may themselves be degraded by other enzymes or be secreted before they can cause injury.

TABLE 43-3

Mechanisms that Protect the Acinar Cell from Autodigestion

PROTECTIVE FACTOR

MECHANISM

Packaging of many digestive proteins as zymogens

Precursor proteins lack enzymatic activity

Selective sorting of secretory proteins and storage in zymogen granules

Restricts the interaction of secretory proteins with other cellular compartments

Protease inhibitors in the zymogen granule

Block the action of prematurely activated enzymes

Condensation of secretory proteins at low pH

Limits the activity of active enzymes

Nondigestive proteases

Degrade active enzymes

Degradation of prematurely active enzymes may be mediated by other enzymes that are present within the secretory granule or by the mixing of secretory granule contents with lysosomal enzymes that can degrade active enzymes. Three mechanisms lead to the mixing of digestive proteases and lysosomal enzymes: (1) lysosomal enzymes may be co-packaged in the secretory granule; (2) secretory granules may selectively fuse with lysosomes (a process called crinophagy); and (3) secretory granules, as well as other organelles, may be engulfed by lysosomes (a process called autophagy). Failure of these protective mechanisms may result in the premature activation of digestive enzymes within the pancreatic acinar cell and may initiate pancreatitis (Box 43-2). imageN43-7

Box 43-2

Genetic Causes of Acute and Chronic Pancreatitis

Single genetic factors rarely cause pancreatitis but can work in combination with other genetic or environmental factors to increase disease risk. Most of the genetic factors associated with pancreatitis involve digestive enzymes. Of these, the majority are thought to lead to an increase in trypsin activity in the acinar cell. The first described was hereditary pancreatitis, in which mutations in a single gene are sufficient to cause the syndrome. imageN43-7 In hereditary pancreatitis, various mutations in cationic trypsinogen are thought to enhance either the sensitivity of the zymogen (cationic trypsinogen) to activation or the resistance of the active form (trypsin) to degradation.

Predisposing factors for pancreatitis include a high degree of trypsin activation, a low level of pancreatic trypsin inhibitor, and low activity of enzymes that degrade trypsin. All three factors determine the levels of active trypsin in the acinar cell, and mutations are known in proteins that regulate the latter two mechanisms. Mutations of a secretory pancreatic trypsin inhibitor—serine protease inhibitor Kazal-type 1, or SPINK1—which is co-packaged with trypsinogen in the secretory pathway, increase the risk of developing pancreatitis, but alone do not cause disease. Mutations in chymotrypsin C, a protease that degrades aberrantly activated trypsin in the pancreatic acinar cell, also predisposes to disease. It appears to particularly sensitize those who abuse alcohol.

Although classic cystic fibrosis generally results in pancreatic insufficiency at birth and not pancreatitis, mild mutations in CFTR that result in mild defects in Cl conductance (10% to 20% of normal) are a risk factor for developing pancreatitis. These can act in concert with alcohol abuse and SPINK mutations to increase disease risk further. One feature of alcohol-associated pancreatitis is the low risk of developing disease (5% to 10%) in abusers, which is consistent with the idea that other genetic or environmental factors must contribute to the disease risk.

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Hereditary Pancreatitis

Contributed by Fred Gorelick

A rare form of pancreatitis that provides insights into the mechanisms of disease is hereditary pancreatitis. This is an autosomal dominant disease with incomplete penetrance: only about 80% of those carrying disease mutations have clinical disease. Symptoms of pancreatitis often begin in childhood but may be delayed until early adulthood. Often individuals first experience bouts of pain and then develop the other features of chronic pancreatitis, especially pancreatic calcifications, early in the course of disease. There are no treatments that prevent disease progression. One of the unfortunate features of this disease is the increased risk of developing pancreatic cancer (35% to 55% lifetime risk versus 1.5% in the general population, or about a 30-fold increase). The genetic defect in hereditary pancreatitis is found in the gene encoding for cationic trypsinogen. Although a number of genetic defects, including those in CFTR and the pancreatic secretory trypsin inhibitor, can predispose to developing pancreatitis, the mutations in cationic trypsinogen found in hereditary pancreatitis are the only ones that alone cause disease. Although mutations at several sites within the gene have been described, the most common involve a mutation that exchanges a histidine for an arginine residue. This removes a potential cleavage site for serine proteases. Cleavage of cationic trypsin at this site would eliminate the catalytic activity of the enzyme. Such proteolysis of activated enzymes within the acinar cell likely represents a major protective mechanism. Indeed, inactivating mutations in several proteases that degrade trypsin, including chymotrypsin C, increase the risk of developing pancreatitis. Other mutations in cationic trypsinogen can also cause pancreatitis and may have this damaging effect by either increasing the efficiency of cationic trypsinogen activation or causing the enzyme to misfold and trigger an ER stress response.