Physiology 5th Ed.


Secretion is the addition of fluids, enzymes, and mucus to the lumen of the gastrointestinal tract. These secretions are produced by salivary glands (saliva), the cells of the gastric mucosa (gastric secretion), the exocrine cells of the pancreas (pancreatic secretion), and the liver (bile) (Table 8-3).

Table 8–3 Summary of Gastrointestinal Secretions


Salivary Secretion

Saliva, which is produced by the salivary glands at the rate of 1 L per day, is secreted into the mouth. The functions of saliva include initial digestion of starches and lipids by salivary enzymes; dilution and buffering of ingested foods, which may otherwise be harmful; and lubrication of ingested food with mucus to aid its movement through the esophagus.

Structure of the Salivary Glands

The three major salivary glands are the parotid glands, the submandibular glands, and the sublingual glands. Each gland is a paired structure that produces saliva and delivers it to the mouth through a duct. The parotid glands are composed of serous cells and secrete an aqueous fluid composed of water, ions, and enzymes. The submaxillary and sublingual glands are mixed glands and have both serous and mucous cells. The serous cells secrete an aqueous fluid, and the mucous cells secrete mucin glycoproteins for lubrication.

Each salivary gland has the appearance of a “bunch of grapes,” where a single grape corresponds to a single acinus (Fig. 8-12). The acinus is the blind end of a branching duct system and is lined with acinar cells. The acinar cellsproduce an initial saliva composed of water, ions, enzymes, and mucus. This initial saliva passes through a short segment, called an intercalated duct, and then through a striated duct, which is lined with ductal cells. The ductal cellsmodify the initial saliva to produce the final saliva by altering the concentrations of various electrolytes. Myoepithelial cells are present in the acini and intercalated ducts. When stimulated by neural input, the myoepithelial cells contract to eject saliva into the mouth.


Figure 8–12 Mechanism of salivary secretion. Initial saliva is produced by acinar cells (1) and subsequently modified by ductal epithelial cells (2). ATP, Adenosine triphosphate.

Salivary acinar cells and ductal cells have both parasympathetic and sympathetic innervation. Although many organs have such dual innervation, the unusual feature of the salivary glands is that saliva production is stimulated by both parasympathetic and sympathetic nervous systems (although parasympathetic control is dominant).

The salivary glands have an unusually high blood flow that increases when saliva production is stimulated. When corrected for organ size, maximal blood flow to the salivary glands is more than 10 times the blood flow to exercising skeletal muscle!

Formation of Saliva

Saliva is an aqueous solution whose volume is very high considering the small size of the glands. Saliva is composed of water, electrolytes, α-amylase, lingual lipase, kallikrein, and mucus. When compared with plasma, saliva is hypotonic (i.e., has a lower osmolarity), has higher K+ and bicarbonate (HCO3) concentrations, and has lower Na+ and chloride (Cl) concentrations. Saliva, therefore, is not a simple ultrafiltrate of plasma, but it is formed in a two-step process that involves several transport mechanisms. The first step is the formation of an isotonic plasma-like solution by the acinar cells. The second step is modification of this plasma-like solution by the ductal cells.

The acinar and ductal steps in saliva production are shown in Figure 8-12. The circled numbers in the figure correspond to the following steps:

1.          The acinar cells secrete the initial saliva, which is isotonic and has approximately the same electrolyte composition as plasma. Thus, in initial saliva, osmolarity, Na+, K+, Cl, and HCO3 concentrations are similar to those in plasma.

2.          The ductal cells modify the initial saliva. The transport mechanisms involved in this modification are complex, but they can be simplified by considering events in the luminal and basolateral membranes separately and then by determining the net result of all the transport mechanisms. The luminal membrane of the ductal cells contains three transporters: Na+-H+ exchange, Cl-HCO3 exchange, and H+-K+exchange. The basolateral membrane contains the Na+-K+ ATPase and Cl channels. The combined action of these transporters working together is absorption of Na+ and Cl and secretion of K+ and HCO3. Net absorption of Na+ and Cl causes the Na+ and Clconcentrations of saliva to become lower than their concentrations in plasma, and net secretion of K+ and HCO3 causes the K+ and HCO3concentrations of saliva to become higher than those in plasma. Because more NaCl is absorbed than KHCO3 is secreted, there is net absorption of solute.

  A final question is How does saliva, which was initially isotonic, become hypotonic as it flows through the ducts? The answer lies in the relative water impermeability of the ductal cells. As noted, there is net absorption of solute because more NaCl is absorbed than KHCO3 is secreted. Because ductal cells are water impermeable, water is not absorbed along with the solute, making the final saliva hypotonic.

The acinar cells also secrete organic constituents such as α-amylase, lingual lipase, mucin glycoproteins, IgA (immunoglobulin A), and kallikrein. α-Amylase begins the initial digestion of carbohydrates, andlingual lipase begins the initial digestion of lipids. The mucus component serves as a lubricant. Kallikrein is an enzyme that cleaves high-molecular-weight kininogen into bradykinin, a potent vasodilator. During periods of high salivary gland activity, kallikrein is secreted and produces bradykinin. Bradykinin then causes local vasodilation, which accounts for the high salivary blood flow during periods of increased salivary activity.

Effect of Flow Rate on Composition of Saliva

The ionic composition of saliva changes as the salivary flow rate changes (Fig. 8-13). At the highest flow rates (4 mL/min), the final saliva most closely resembles plasma and the initial saliva produced by the acinar cells. At the lowest flow rates (<1 mL/min), the final saliva is most dissimilar to plasma (it has lower concentrations of Na+ and Cl and a higher concentration of K+). The mechanism of the flow-rate–dependent changes in concentration is based primarily on the amount of time saliva is in contact with the ductal cells. At high flow rates, the ductal cells have less time to modify the saliva; at low flow rates, they have more time to modify the saliva. Under conditions of low flow rate, where there is the greatest contact time, more Na+ and Cl are reabsorbed, which decreases their concentrations relative to the initial saliva, and more K+ is secreted, which increases its concentration.


Figure 8–13 Relationship between the composition of saliva and the salivary flow rate. The ionic composition of saliva is compared with that of plasma.

The only electrolyte that is not described by this “contact-time” explanation is HCO3. According to the contact time explanation, because HCO3 is secreted by ductal cells, its concentration should be highest at low flow rates. However, as shown in Figure 8-13, the HCO3 concentration of saliva is lowest at low flow rates and highest at high flow rates. This occurs because HCO3 secretion is selectively stimulated when saliva production is stimulated (e.g., by parasympathetic stimulation). Thus, as the flow rate of saliva increases, the HCO3 concentration also increases.

Regulation of Salivary Secretion

There are two unusual features in the regulation of salivary secretion. (1) Salivary secretion is exclusively under neural control by the autonomic nervous system, whereas the other gastrointestinal secretions are under both neural and hormonal control. (2) Salivary secretion is increased by both parasympathetic and sympathetic stimulation, although parasympathetic stimulation is dominant. (Usually, the parasympathetic and sympathetic nervous systems have opposite actions.)

Regulation of saliva secretion by the autonomic nervous system is summarized in Figure 8-14. As illustrated, there is parasympathetic and sympathetic innervation of acinar and ductal cells. Stimulation of salivary cells results in increased saliva production, increased HCO3 and enzyme secretions, and contraction of myoepithelial cells.


Figure 8–14 Regulation of salivary secretion by the autonomic nervous system. ACh, Acetylcholine; β, β receptor; cAMP, cyclic adenosine monophosphate; CN, cranial nerve; M, muscarinic receptor; NE, norepinephrine; T1–T3, thoracic segments.

image Parasympathetic innervation. The parasympathetic input to the salivary glands is carried on the facial (CN VII) and glossopharyngeal (CN IX) nerves. Postganglionic parasympathetic neurons release ACh, which interacts with muscarinic receptors on the acinar and ductal cells. At the cellular level, activation of muscarinic receptors leads to production of inositol 1,4,5-triphosphate (IP3) and increased intracellular calcium (Ca2+) concentration, which produce the physiologic action of increased saliva secretion, primarily increasing the volume of saliva and the enzymatic component. Several factors modulate the parasympathetic input to the salivary glands. Parasympathetic activity to the salivary glands is increased by food, smell, and nausea and by conditioned reflexes (e.g., as demonstrated by Pavlov’s salivating dogs). Parasympathetic activity is decreased by fear, sleep, and dehydration.

image Sympathetic innervation. The sympathetic input to the salivary glands originates in thoracic segments T1 to T3 with preganglionic nerves that synapse in the superior cervical ganglion. The postganglionic sympathetic neurons release norepinephrine, which interacts with β-adrenergic receptors on the acinar and ductal cells. Activation of β-adrenergic receptors leads to stimulation of adenylyl cyclase and production of cyclic adenosine monophosphate (cAMP). The physiologic action of cAMP, like that of the parasympathetic IP3/Ca2+ mechanism, is to increase saliva secretion. Sympathetic stimulation also activates α-adrenergic receptors on acinar cells, although the activation of β-adrenergic receptors is considered more important.

Gastric Secretion

The cells of the gastric mucosa secrete a fluid called gastric juice. The four major components of gastric juice are hydrochloric acid (HCl), pepsinogen, intrinsic factor, and mucus. Together, HCl andpepsinogen initiate the process of protein digestion. Intrinsic factor is required for the absorption of vitamin B12 in the ileum, and it is the only essential component of gastric juice. Mucus protects the gastric mucosa from the corrosive action of HCl and also lubricates the gastric contents.

Structure and Cell Types of the Gastric Mucosa

The anatomic divisions of the stomach (fundus, body, and antrum) have been discussed in the section on motility. In addition to these gross anatomic divisions, the gastric mucosa contains several cell types that secrete the various components of gastric juice. The cell types and their secretory products are illustrated in Figure 8-15.


Figure 8–15 Secretory products of various gastric cells.

The body of the stomach contains oxyntic glands that empty their secretory products, via ducts, into the lumen of the stomach (Fig. 8-16). The openings of the ducts on the gastric mucosa are called pits, which are lined with epithelial cells. Deeper in the gland are mucous neck cells, parietal (oxyntic) cells, and chief (peptic) cells. The parietal cells have two secretory products, HCl and intrinsic factor. Thechief cells have one secretory product, pepsinogen.


Figure 8–16 Structure of a gastric oxyntic gland showing the various cell types lining the gland. The ducts open into pits on the surface of the gastric mucosa.

The antrum of the stomach contains the pyloric glands, which are configured similar to the oxyntic glands but with deeper pits. The pyloric glands contain two cell types: the G cells and the mucous cells. TheG cells secrete gastrin, not into the pyloric ducts but into the circulation. The mucous neck cells secrete mucus, HCO3, and pepsinogen. Mucus and HCO3 have a protective, neutralizing effect on the gastric mucosa.

HCl Secretion

A major function of the parietal cells is secretion of HCl, which acidifies the gastric contents to between pH 1 and 2. Physiologically, the function of this low gastric pH is to convert inactive pepsinogen, which is secreted by the nearby chief cells, to its active form, pepsin, a protease that begins the process of protein digestion. The cellular mechanism of HCl secretion by parietal cells will be described first, followed by discussion of the mechanisms that regulate HCl secretion and the pathophysiology of H+ secretion.


The cellular mechanism of HCl secretion by gastric parietal cells is illustrated in Figure 8-17. As in renal cells, the cell membranes facing the lumen of the stomach are called the apical or luminal membranes and the cell membranes facing the bloodstream are called the basolateral membranes. The apical membranes contain H+-K+ ATPase and Cl channels, and the basolateral membranes contain Na+-K+ATPase and Cl-HCO3 exchangers. The cells contain carbonic anhydrase.


Figure 8–17 Mechanism of HCl secretion by gastric parietal cells. ATP, Adenosine triphosphate.

HCl secretion is illustrated in Figure 8-17 and is described as follows:

1.          In intracellular fluid, carbon dioxide (CO2) produced from aerobic metabolism combines with H2O to form H2CO3, catalyzed by carbonic anhydrase. H2CO3 dissociates into H+ and HCO3. The H+ is secreted with Cl into the lumen of the stomach, and the HCO3 is absorbed into the blood, as described in steps 2 and 3, respectively.

2.          At the apical membrane, H+ is secreted into the lumen of the stomach via the H+-K+ ATPase. The H+-K+ ATPase is a primary active process that transports H+ and K+ against their electrochemical gradients (uphill). H+-K+ATPase is inhibited by the drug omeprazole, which is used in the treatment of ulcers to reduce H+ secretion. Cl follows H+ into the lumen by diffusing through Clchannels in the apical membrane.

3.          At the basolateral membrane, HCO3 is absorbed from the cell into the blood via a Cl-HCO3 exchanger. The absorbed HCO3 is responsible for the “alkaline tide” (high pH) that can be observed in gastric venous blood after a meal. Eventually, this HCO3 will be secreted back into the gastrointestinal tract in pancreatic secretions.

4.          In combination, the events occurring at the apical and basolateral membranes of gastric parietal cells result in net secretion of HCl and net absorption of HCO3.


Three substances stimulate H+ secretion by gastric parietal cells: histamine (a paracrine), ACh (a neurocrine), and gastrin (a hormone). Each substance binds to a different receptor on the parietal cell and has a different cellular mechanism of action (Fig. 8-18). In addition, there are indirect effects of ACh and gastrin via stimulation of histamine release.


Figure 8–18 Agents that stimulate and inhibit H+ secretion by gastric parietal cells. ACh, Acetylcholine; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; ECL, enterochromaffin-like; IP3, inositol 1,4,5-triphosphate; M, muscarinic.

image Histamine is released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuses via a paracrine mechanism to the nearby parietal cells, where it binds to H2 receptors. The second messenger for histamine is cAMP. Histamine binds to H2 receptors, which are coupled to adenylyl cyclase by a Gs protein. When adenylyl cyclase is activated, there is increased production of cAMP. cAMP activates protein kinase A, leading to secretion of H+ by the parietal cells. Cimetidine blocks H2 receptors and blocks the action of histamine on parietal cells.

image ACh is released from vagus nerves innervating the gastric mucosa and binds directly to muscarinic (M3receptors on the parietal cells. The second messengers for ACh are IP3/Ca2+. When ACh binds to muscarinic receptors, phospholipase C is activated. Phospholipase C liberates diacylglycerol and IP3 from membrane phospholipids, and IP3 then releases Ca2+ from intracellular stores. Ca2+ and diacylglycerol activate protein kinases that produce the final physiologic action: H+ secretion by the parietal cells. Atropine blocks muscarinic receptors on parietal cells and, accordingly, blocks the action of ACh.

ACh also increases H+ secretion indirectly by stimulating ECL cells to release histamine, which then acts on the parietal cells as described earlier.

image Gastrin is secreted into the circulation by G cells in the stomach antrum. Gastrin reaches the parietal cells by an endocrine mechanism, not by local diffusion within the stomach. Thus, gastrin is secreted from the stomach antrum into the systemic circulation and then delivered back to the stomach via the circulation. Gastrin binds to cholecystokinin B (CCKB) receptors on the parietal cells. (The CCKB receptor has equal affinity for gastrin and CCK, whereas the CCKA receptor is specific for CCK.) Like ACh, gastrin stimulates H+ secretion through the IP3/Ca2+ second messenger system. The stimuli that trigger gastrin secretion from the G cells are discussed in detail subsequently. Briefly, these stimuli are distention of the stomach, presence of small peptides and amino acids, and stimulation of the vagus nerves.

Like ACh, gastrin also stimulates H+ secretion indirectly by causing release of histamine from ECL cells.

The rate of H+ secretion is regulated by the independent actions of histamine, ACh, and gastrin, as well as by interactions among the three agents. The interaction is called potentiation, which refers to the ability of two stimuli to produce a combined response that is greater than the sum of the individual responses. One explanation for potentiation in the parietal cells is that each agent stimulates H+ secretion via a different receptor and, in the case of histamine, a different second messenger. Another explanation derives from the fact that both ACh and gastrin stimulate histamine release from ECL cells and thereby induce H+ secretion by a second, indirect, route. This phenomenon of potentiation has consequences for the actions of the various drugs that inhibit H+ secretion. For example, because histamine potentiates the actions of ACh and gastrin, H2 receptor–blocking agents such as cimetidinehave a greater effect than expected: They block the direct action of histamine and they also block the histamine-potentiated effects of ACh and gastrin. In another example, ACh potentiates the actions of histamine and gastrin. A consequence of this potentiation is that muscarinic-blocking agents such as atropine block the direct effects of ACh and the ACh-potentiated effects of histamine and gastrin.


Having established that histamine, ACh, and gastrin all stimulate HCl secretion by parietal cells, the control of HCl secretion in response to a meal now can be discussed in an integrated fashion. Figure 8-19depicts the gastric parietal cells, which secrete HCl, and the G cells, which secrete gastrin. Vagus nerves innervate parietal cells directly, where they release ACh as the neurotransmitter. Vagus nerves also innervate G cells, where they release GRP as the neurotransmitter.


Figure 8–19 Regulation of HCl secretion during cephalic and gastric phases. ACh, Acetylcholine; GRP, gastrin-releasing peptide (bombesin).

As shown in Figure 8-19, the second path, the G cell path, provides an indirect route for vagal stimulation of the parietal cells: Vagal stimulation releases gastrin from the G cells, and gastrin enters the systemic circulation and is delivered back to the stomach to stimulate H+ secretion by the parietal cells. One consequence of this dual action of vagal stimulation is that muscarinic-blocking agents such asatropine do not block HCl secretion completely. Atropine will block the direct vagal effects on the parietal cells, which are mediated by ACh, but it will not block the vagal effects on gastrin secretion because the neurotransmitter at the synapses on G cells is GRP, not ACh.

Gastric HCl secretion is divided into three phases: cephalic, gastric, and intestinal. The cephalic and gastric phases are illustrated in Figure 8-19.

image The cephalic phase accounts for approximately 30% of the total HCl secreted in response to a meal. The stimuli for HCl secretion in the cephalic phase are smelling and tasting, chewing, swallowing, andconditioned reflexes in anticipation of food. Two mechanisms promote HCl secretion in the cephalic phase. The first mechanism is direct stimulation of the parietal cell by vagus nerves, which release ACh. The second mechanism is indirect stimulation of the parietal cells by gastrin. In the indirect path, vagus nerves release GRP at the G cells, stimulating gastrin secretion; gastrin enters the circulation and stimulates the parietal cells to secrete HCl.

image The gastric phase accounts for approximately 60% of the total HCl secreted in response to a meal. The stimuli for HCl secretion in the gastric phase are distention of the stomach and the presence of breakdown products of protein, amino acids and small peptides. Four physiologic mechanisms are involved in the gastric phase. The first two mechanisms, which are initiated by distention of the stomach, are similar to those utilized in the cephalic phase: Distention causes direct vagal stimulation of the parietal cells and indirect stimulation of the parietal cells via gastrin release. The third mechanism is initiated by distention of the stomach antrum and involves local reflexes that stimulate gastrin release. The fourth mechanism is a direct effect of amino acids and small peptides on the G cells to stimulate gastrin release. In addition to these physiologic mechanisms, alcohol and caffeine also stimulate gastric HCl secretion.

image The intestinal phase accounts for only 10% of HCl secretion (not shown in Figure 8-19) and is mediated by products of protein digestion.


HCl secretion is inhibited when HCl is no longer needed for the activation of pepsinogen to pepsin (i.e., when chyme has moved to the small intestine). Logically, the major inhibitory control of HCl secretion is decreased pH of the gastric contents. The question arises, though: Why does the pH of the gastric contents decrease when chyme moves to the small intestine? The answer lies in the fact that food is itself a buffer for H+. With food in the stomach, as H+is secreted, much of it is buffered; the gastric contents are acidified, but not as much as they would be if there were no buffers. When the food moves to the small intestine, the buffering capacity is reduced, and further H+ secretion reduces gastric pH to even lower values. This lower pH then inhibits gastrin secretion, which decreases H+ secretion.

The major inhibitory mechanism for H+ secretion by parietal cells involves somatostatin. Somatostatin inhibits gastric H+ secretion through both a direct pathway and indirect pathways (see Fig. 8-18). In thedirect pathway,, somatostatin binds to receptors on parietal cells that are coupled to adenylyl cyclase via a Gi protein. When somatostatin binds to its receptor, Gi is activated, adenylyl cyclase is inhibited, and cAMP levels are reduced; in this way, somatostatin antagonizes the stimulatory effect of histamine on H+ secretion. In the indirect pathways, somatostatin inhibits both histamine release from ECL cells and gastrin release from G cells; the net result of these indirect actions is to reduce the stimulatory actions of histamine and gastrin. In similar fashion to somatostatin, prostaglandins also antagonize histamine’s stimulatory action on H+ secretion by activating a Gi protein and inhibiting adenylyl cyclase (see Fig. 8-18).


It seems that the gastric mucosal epithelium would be in direct contact with potentially damaging gastric luminal contents—the gastric contents are very acidic and contain the digestive enzyme pepsin. What prevents the gastric contents from eroding and digesting the mucosal epithelial cells? First, mucous neck glands secrete mucus, which forms a gel-like protective barrier between the cells and the gastric lumen. Second, gastric epithelial cells secrete HCO3, which is trapped in the mucus. Should any H+ penetrate the mucus, it is neutralized by HCO3 before reaching the epithelial cells. Furthermore, should any pepsin penetrate the mucus, it is inactivated in the relatively alkaline (high HCO3) environment.

Peptic ulcer disease is an ulcerative lesion of the gastric or duodenal mucosa. The ulceration is caused by the erosive and digestive action of H+ and pepsin on the mucosa (normally protected by the layer of mucus and HCO3). Thus, for a peptic ulcer to be created there must be (1) loss of the protective mucous barrier, (2) excessive H+ and pepsin secretion, or (3) a combination of the two. Stated differently, peptic ulcer disease is caused by an imbalance between the factors that protect the gastroduodenal mucosa and the factors that damage it (Fig. 8-20). Protective factors, in addition to mucus and HCO3, are prostaglandins, mucosal blood flow, and growth factors. Damaging factors, in addition to H+ and pepsin, are Helicobacter pylori (H. pylori) infection, nonsteroidal anti-inflammatory drugs (NSAIDs), stress, smoking, and alcohol consumption. Peptic ulcers are classified as either gastric or duodenal, depending on their location. The features of gastric ulcers, duodenal ulcers, and Zollinger-Ellison syndrome are summarized in Table 8-4.


Figure 8–20 Balance of protective and damaging factors on gastroduodenal mucosa. H. pylori, Helicobacter pylori; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 8–4 Disorders of Gastric H+ Secretion


image Gastric ulcers. Gastric ulcers form primarily because the mucosal barrier is defective, which allows H+ and pepsin to digest a portion of the mucosa. A major causative factor in gastric ulcers is the gram-negative bacterium H. pylori. In producing gastric ulcer, the causation is fairly direct: H. pylori colonizes the gastric mucus (often in the antrum), attaches to gastric epithelial cells, and releases cytotoxins (e.g., cagA toxin) that break down the protective mucous barrier and the underlying cells. H. pylori is allowed to colonize the gastric mucus because it contains the enzyme urease, which converts urea to NH3. The NH3 generated alkalinizes the local environment, permitting the bacteria to survive in the otherwise acidic gastric lumen. Because the local environment is hospitable, the bacteria bind to the gastric epithelium instead of being shed. An additional damaging factor is NH4+, which is in equilibrium with NH3. A diagnostic test for H. pylori is based on its urease activity. In the test, the patient drinks a solution containing 13C-urea, which is converted to 13CO2 and NH3 in the stomach; the 13CO2 is absorbed into blood, expired by the lungs, and measured in a breath test. Surprisingly, in persons with gastric ulcers, net H+ secretory rates are lower than normal because some of the secreted H+ leaks into the damaged mucosa. In gastric ulcer disease, the secretion rate of gastrin is increased as a result of the reduced net H+ secretion. (Recall that gastrin secretion is inhibited by H+.)

image Duodenal ulcers. Duodenal ulcers are more common than gastric ulcers and form because H+ secretory rates are higher than normal. If excess H+ is delivered to the duodenum, it may overwhelm the buffering capacity of HCO3in pancreatic juice. Acting with pepsin, this excess H+ digests and damages the duodenal mucosa. H. pylori infection also causes duodenal ulcer, but its role is indirect. (If the bacteria colonize gastric mucosa, how do they cause duodenal ulcer?) (1) As described previously, H. pylori colonizes gastric mucus. One consequence of this colonization is to inhibit somatostatin secretionfrom D cells in the gastric antrum. Because somatostatin normally inhibits gastrin secretion from G cells, “inhibition of inhibition” results in increased gastrin secretion, which leads to increased H+ secretion by gastric parietal cells. In this way, there is an increased H+ load delivered to the duodenum. (2) The gastric H. pylori infection spreads to the duodenum and inhibits duodenal HCO3 secretion. Normally, duodenal HCO3 is sufficient to neutralize the H+ load delivered from the stomach. However, in this case, not only is excess H+ delivered to the duodenum, but less HCO3 is secreted to neutralize it. In summary, neutralization of H+ in the duodenum is insufficient, the duodenal contents become abnormally acidic, and there is an erosive action of H+ and pepsin on the duodenal mucosa. In persons with duodenal ulcers, baseline gastrin levels may be normal, but gastrin secretion in response to a meal is increased. The increased gastrin levels also exert a trophic effect on the stomach, which increases parietal cell mass.

image Zollinger-Ellison syndrome (gastrinoma). The highest rates of H+ secretion are those seen in Zollinger-Ellison syndrome, in which a tumor (usually in the pancreas) secretes large quantities of gastrin. The high levels of gastrin have two direct effects: increased H+ secretion by parietal cells and increased parietal cell mass. The delivery of excessive amounts of H+ to the duodenum overwhelms the buffering capacity of HCO3 in pancreatic juices, erodes the mucosa, and produces an ulcer. Delivery of increased amounts of H+ to the duodenum also causes steatorrhea because low duodenal pH inactivates the pancreatic lipases necessary for fat digestion. Because gastrin secretion by the tumor is not feedback-inhibited by H+ (as is physiologic gastrin secretion by G cells), it continues unabated. Treatment of Zollinger-Ellison syndrome includes inhibitors of H+ secretion such as cimetidine and omeprazoleand surgical removal of the tumor.

Pepsinogen Secretion

Pepsinogen, the inactive precursor to pepsin, is secreted by chief cells and by mucous cells in the oxyntic glands. When the pH of gastric contents is lowered by H+ secretion from parietal cells, pepsinogen is converted to pepsin, beginning the process of protein digestion. In the cephalic and gastric phases of H+ secretion, vagal stimulation is the most important stimulus for pepsinogen secretion. H+ also triggers local reflexes, which stimulate the chief cells to secrete pepsinogen. These complementary reflexes ensure that pepsinogen is secreted only when the gastric pH is low enough to convert it to pepsin.

Intrinsic Factor Secretion

Intrinsic factor, a mucoprotein, is the “other” secretory product of the parietal cells. Intrinsic factor is required for absorption of vitamin B12 in the ileum, and its absence causes pernicious anemia. Intrinsic factor is the only essentialsecretion of the stomach. Thus, following gastrectomy (removal of the stomach), patients must receive injections of vitamin B12 to bypass the absorption defect caused by the loss of gastric intrinsic factor.

Pancreatic Secretion

The exocrine pancreas secretes approximately 1 L of fluid per day into the lumen of the duodenum. The secretion consists of an aqueous component that is high in HCO3 and an enzymatic component. TheHCO3-containing aqueous portion functions to neutralize the H+ delivered to the duodenum from the stomach. The enzymatic portion functions to digest carbohydrates, proteins, and lipids into absorbable molecules.

Structure of the Pancreatic Exocrine Glands

The exocrine pancreas constitutes approximately 90% of the pancreas. The rest of the pancreatic tissue is the endocrine pancreas (2%), blood vessels, and interstitial fluid. (The endocrine pancreas is discussed in Chapter 9.)

The exocrine pancreas is organized much like the salivary glands: It resembles a bunch of grapes, with each grape corresponding to a single acinus (Fig. 8-21). The acinus, which is the blind end of a branching duct system, is lined with acinar cells that secrete the enzymatic portion of the pancreatic secretion. The ducts are lined with ductal cells. Ductal epithelial cells extend into a special region ofcentroacinar cells in the acinus. The centroacinar and ductal cells secrete the aqueous HCO3-containing component of the pancreatic secretion.


Figure 8–21 Mechanism of pancreatic secretion. The enzymatic component is produced by acinar cells, and the aqueous component is produced by centroacinar and ductal cells. ATP, Adenosine triphosphate.

The exocrine pancreas is innervated by both parasympathetic and sympathetic nervous systems. Sympathetic innervation is provided by postganglionic nerves from the celiac and superior mesenteric plexuses. Parasympathetic innervation is provided by the vagus nerve; parasympathetic preganglionic fibers synapse in the enteric nervous system, and postganglionic fibers synapse on the exocrine pancreas.Parasympathetic activity stimulates pancreatic secretion, and sympathetic activity inhibits pancreatic secretion. (Contrast the exocrine pancreas with the salivary glands, in which both parasympathetic and sympathetic activity are stimulatory.)

Formation of Pancreatic Secretion

The enzymatic and aqueous components of pancreatic secretion are produced by separate mechanisms. Enzymes are secreted by the acinar cells, and the aqueous component is secreted by the centroacinar cells and then modified by the ductal cells.

Pancreatic secretion occurs in the following steps and is illustrated in Figure 8-21:

1.          Enzymatic component of pancreatic secretion (acinar cells). Most of the enzymes required for digestion of carbohydrates, proteins, and lipids are secreted by the pancreas (Table 8-5). Pancreaticamylase and lipases are secreted as active enzymes. Pancreatic proteases are secreted in inactive forms and converted to their active forms in the lumen of the duodenum; for example, the pancreas secretes trypsinogen, which is converted in the intestinal lumen to its active form, trypsin. The functions of the pancreatic enzymes are discussed later in the chapter in the section on digestion of nutrients.

Table 8–5 Sources of Digestive Enzymes


The pancreatic enzymes are synthesized on the rough endoplasmic reticulum of the acinar cells. They are transferred to the Golgi complex and then to condensing vacuoles, where they are concentrated in zymogen granules. The enzymes are stored in the zymogen granules until a stimulus (e.g., parasympathetic activity or CCK) triggers their secretion.

2.          Aqueous component of pancreatic secretion (centroacinar and ductal cells). Pancreatic juice is an isotonic solution containing Na+, Cl, K+, and HCO3 (in addition to the enzymes). The Na+ and K+concentrations are the same as their concentrations in plasma, but the Cl and HCO3 concentrations vary with pancreatic flow rate.

  Centroacinar and ductal cells produce the initial aqueous secretion, which is isotonic and contains Na+, K+, Cl, and HCO3. This initial secretion is then modified by transport processes in the ductal epithelial cells as follows: The apical membrane of ductal cells contains a Cl-HCO3 exchanger, and the basolateral membrane contains Na+-K+ ATPase and an Na+-H+ exchanger. In the presence of carbonic anhydrase, CO2 and H2O combine in the cells to form H2CO3. H2CO3 dissociates into H+ and HCO3. The HCO3 is secreted into pancreatic juice by the Cl-HCO3 exchanger in the apical membrane. The H+ is transported into the blood by the Na+-H+exchanger in the basolateral membrane. The net result, or sum, of these transport processes is net secretion of HCO3 into pancreatic ductal juice and net absorption of H+; absorption of H+ causes acidification of pancreatic venous blood.

Effect of Flow Rate on Composition of Pancreatic Juice

When the pancreatic flow rate changes, the Na+ and K+ concentrations in pancreatic juice remain constant, whereas the concentrations of HCO3 and Cl change (Fig. 8-22). (Recall that a similar, but not identical, relationship is observed between saliva composition and salivary flow rate.) In pancreatic juice, there is a reciprocal relationship between the Cl and HCO3 concentrations, which is maintained by the Cl-HCO3 exchanger in the apical membrane of ductal cells (see Fig. 8-21). At the highest pancreatic flow rates (more than 30 µL/min • g), the HCO3 concentration of pancreatic juice is highest (and much higher than plasma HCO3) and the Cl concentration is lowest. At the lowest flow rates, HCO3 is lowest and Cl is highest.


Figure 8–22 Relationship between the composition of pancreatic juice and the pancreatic flow rate. The ionic composition of pancreatic juice is compared with that of plasma.

The relationship between flow rate and the relative concentrations of Cl and HCO3 is explained as follows: At low (basal) rates of pancreatic secretion, the pancreatic cells secrete an isotonic solution composed mainly of Na+Cl, and H2O. However, when stimulated (e.g., by secretin), the centroacinar and ductal cells secrete even greater amounts of an isotonic solution with a different composition, mainly Na+HCO3, and H2O.

Regulation of Pancreatic Secretion

Pancreatic secretion has two functions: (1) to secrete the enzymes necessary for digestion of carbohydrates, proteins, and lipids; the enzymatic portion of pancreatic secretion performs these digestive functions; and (2) to neutralize H+ in the chyme delivered to the duodenum from the stomach. The aqueous portion of pancreatic secretion contains HCO3, which performs the neutralizing function. Therefore, it is logical that the enzymatic and aqueous portions are regulated separately: The aqueous secretion is stimulated by the arrival of H+ in the duodenum, and the enzymatic secretion is stimulated by products of digestion (small peptides, amino acids, and fatty acids).

Like gastric secretion, pancreatic secretion is divided into cephalic, gastric, and intestinal phases. In the pancreas, the cephalic and gastric phases are less important than the intestinal phase. Briefly, thecephalic phase is initiated by smell, taste, and conditioning and is mediated by the vagus nerve. The cephalic phase produces mainly an enzymatic secretion. The gastric phase is initiated by distention of the stomach and is also mediated by the vagus nerve. The gastric phase produces mainly an enzymatic secretion.

The intestinal phase is the most important phase and accounts for approximately 80% of the pancreatic secretion. During this phase, both enzymatic and aqueous secretions are stimulated. The hormonal and neural regulation of the acinar and ductal cells in the intestinal phase is shown in Figure 8-23.


Figure 8–23 Regulation of pancreatic secretion. ACh, Acetylcholine; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; IP3, inositol 1,4,5-triphosphate.

image Acinar cells (enzymatic secretion). The pancreatic acinar cells have receptors for CCK (CCKA receptors) and muscarinic receptors for ACh. During the intestinal phase, CCK is the most important stimulant for the enzymatic secretion. The I cells are stimulated to secrete CCK by the presence of amino acids, small peptides, and fatty acids in the intestinal lumen. Of the amino acids stimulating CCK secretion, phenylalanine, methionine, and tryptophan are most potent. In addition, ACh stimulates enzyme secretion and potentiates the action of CCK by vagovagal reflexes.

image Ductal cells (aqueous secretion of Na+, HCO3, and H2O). The pancreatic ductal cells have receptors for CCK, ACh, and secretin. Secretin, which is secreted by the S cells of the duodenum, is the major stimulant of the aqueous HCO3-rich secretion. Secretin is secreted in response to H+ in the lumen of the intestine, which signals the arrival of acidic chyme from the stomach. To ensure that pancreatic lipases will be active (because they are inactivated at low pH), the acidic chyme requires rapid neutralization by the HCO3-containing pancreatic juice. The effects of secretin are potentiated by both CCK and ACh.

Bile Secretion

Bile is necessary for the digestion and absorption of lipids in the small intestine. Compared with carbohydrates and proteins, lipids pose special problems for digestion and absorption because they are insoluble in water. Bile, a mixture of bile salts, bile pigments, and cholesterol, solves this problem of insolubility. Bile is produced and secreted by the liver, stored in the gallbladder, and ejected into the lumen of the small intestine when the gallbladder is stimulated to contract. In the lumen of the intestine, bile salts emulsify lipids to prepare them for digestion and then solubilize the products of lipid digestion in packets called micelles.

Overview of the Biliary System

The components of the biliary system are the liver, gallbladder and bile duct, duodenum, ileum, and portal circulation, as illustrated in Figure 8-24. An overview of the system is presented in this section, with detailed descriptions of the steps in later sections.


Figure 8–24 Secretion and enterohepatic circulation of bile salts. Light blue arrows show the path of bile flow; yellow arrows show the movement of ions and water. CCK, Cholecystokinin.

The hepatocytes of the liver continuously synthesize and secrete the constituents of bile (Step 1). The components of bile are the bile salts, cholesterol, phospholipids, bile pigments, ions, and water. Bile flows out of the liver through the bile ducts and fills the gallbladder, where it is stored (Step 2). The gallbladder then concentrates the bile salts by absorption of water and ions.

When chyme reaches the small intestine, CCK is secreted. CCK has two separate but coordinated actions on the biliary system: It stimulates contraction of the gallbladder and relaxation of the sphincter of Oddi, causing stored bile to flow from the gallbladder into the lumen of the duodenum (Step 3). In the small intestine, the bile salts emulsify and solubilize dietary lipids.

When lipid absorption is complete, the bile salts are recirculated to the liver via the enterohepatic circulation (Step 4). The steps involved in the enterohepatic circulation include absorption of bile salts from the ileum into the portal circulation, delivery back to the liver, and extraction of bile salts from the portal blood by the hepatocytes (Step 5). The recirculation of bile salts to the liver reduces the demand to synthesize new bile salt. The liver must replace only the small percentage of the bile salt pool that is excreted in feces.

Composition of Bile

As noted previously, bile is secreted continuously by the hepatocytes. The organic constituents of bile are bile salts (50%), bile pigments such as bilirubin (2%), cholesterol (4%), and phospholipids (40%). Bile also contains electrolytes and water, which are secreted by hepatocytes lining the bile ducts.

image Bile salts (including bile acids) constitute 50% of the organic component of bile. The total bile salt pool is approximately 2.5 g, which includes bile salts in the liver, bile ducts, gallbladder, and intestine. As shown in Figure 8-25, the hepatocytes synthesize two primary bile acids from cholesterol: cholic acid and chenodeoxycholic acid. When these primary bile acids are secreted into the lumen of the intestine, a portion of each is dehydroxylated at C-7 by intestinal bacteria to produce two secondary bile acids, deoxycholic acid and lithocholic acid. Thus, a total of four bile acids are present in the following relative amounts: Cholic acid > chenodeoxycholic acid > deoxycholic acid > lithocholic acid.


Figure 8–25 Biosynthetic pathways for bile acids. The liver conjugates primary and secondary bile acids with glycine or taurine to their respective bile salts. The resulting bile salt is named for the bile acid and the conjugating amino acid (e.g., glycodeoxycholic acid is deoxycholic acid conjugated with glycine).

The liver conjugates the bile acids with the amino acids glycine or taurine to form bile salts. Consequently, there are a total of eight bile salts, each named for the parent bile acid and the conjugating amino acid (e.g., glycocholic acid, taurocholic acid). This conjugation step changes the pKs of bile acids and causes them to become much more water soluble, which is explained as follows: The pH of duodenal contents ranges between pH 3 and 5. Bile acids have pKs of approximately 7. Thus, at duodenal pH, most bile acids will be in their nonionized form, HA, which is insoluble in water. On the other hand, bile salts have pKs ranging between 1 and 4. At duodenal pH, most bile salts will be in their ionized form, A, which is soluble in water. It follows from this discussion that bile salts are more soluble than bile acids in the aqueous duodenal contents. (See Chapter 7 for a discussion of pH and pK.)

The critical property of bile salts is that they are amphipathic, meaning the molecules have both hydrophilic (water-soluble) and hydrophobic (lipid-soluble) portions. Hydrophilic, negatively charged groups point outward from a hydrophobic steroid nucleus such that, at an oil-water interface, the hydrophilic portion of a bile salt molecule dissolves in the aqueous phase and the hydrophobic portion dissolves in the oil phase.

The function of bile salts, which depends on their amphipathic properties, is to solubilize dietary lipids. Without the bile salts, lipids would be insoluble in the aqueous solution in the intestinal lumen and less amenable to digestion and absorption. In this regard, the first role of bile salts is to emulsify dietary lipids. The negatively charged bile salts surround the lipids, creating small lipid droplets in the intestinal lumen. The negative charges on the bile salts repel each other, so the droplets disperse, rather than coalesce, thereby increasing the surface area for digestive enzymes. (Without emulsification, dietary lipids would coalesce into large “blobs,” with relatively little surface area for digestion.) The second role of bile salts is to form micelles with the products of lipid digestion including monoglycerides, lysolecithin, and fatty acids. The core of the micelle contains these lipid products, and the surface of the micelle is lined with bile salts. The hydrophobic portions of the bile salt molecules are dissolved in the lipid core of the micelle, and the hydrophilic portions are dissolved in the aqueous solution in the intestinal lumen. In this way, hydrophobic lipid digestion products are dissolved in an otherwise “unfriendly” aqueous environment. The primary bile salts, having more hydroxyl groups than the secondary bile salts, are more effective at solubilizing lipids.

image Phospholipids and cholesterol also are secreted into bile by the hepatocytes and are included in the micelles with the products of lipid digestion. Like the bile salts, phospholipids are amphipathic and aid the bile salts in forming micelles. The hydrophobic portions of the phospholipids point to the interior of the micelle, and the hydrophilic portions dissolve in the aqueous intestinal solution.

image Bilirubin, a yellow-colored byproduct of hemoglobin metabolism, is the major bile pigment. The cells of the reticuloendothelial system degrade hemoglobin, yielding bilirubin, which is carried in blood bound to albumin. The liver extracts bilirubin from blood and conjugates it with glucuronic acid to form bilirubin glucuronide, which is secreted into bile and accounts for bile’s yellow color. Bilirubin glucuronide, or conjugated bilirubin, is secreted into the intestine as a component of bile. In the intestinal lumen, bilirubin glucuronide is converted back to bilirubin, which is then converted to urobilinogenby the action of intestinal bacteria. A portion of the urobilinogen is recirculated to the liver, a portion is excreted in the urine, and a portion is oxidized to urobilin and stercobilin, the compounds that give stool its dark color.

image Ions and water are secreted into bile by epithelial cells lining the bile ducts. The secretory mechanisms are the same as those in the pancreatic ductal cells. Secretin stimulates ion and water secretion by the bile ducts just as it does in the pancreatic ducts.

Function of the Gallbladder

The gallbladder serves the following three functions: It stores bile, it concentrates bile, and when stimulated to contract, it ejects bile into the lumen of the small intestine.

image Filling of the gallbladder. As previously described, the hepatocytes and ductal cells produce bile continuously. As bile is produced by the liver, it flows through the bile ducts into the gallbladder, where it is stored for later release. During the interdigestive periods, the gallbladder can fill because it is relaxed and the sphincter of Oddi is closed.

image Concentration of bile. The epithelial cells of the gallbladder absorb ions and water in an isosmotic fashion, similar to the isosmotic reabsorptive process in the proximal tubule of the kidney. Because the organic components of bile are not absorbed, they become concentrated as the isosmotic fluid is removed.

image Ejection of bile. Ejection of bile from the gallbladder begins within 30 minutes after a meal is ingested. The major stimulus for ejection of bile is CCK, which is secreted by the I cells in response to amino acids, small peptides, and fatty acids. As noted, CCK has two simultaneous effects that result in ejection of bile from the gallbladder: (1) contraction of the gallbladder and (2) relaxation of the sphincter of Oddi (a thickening of the smooth muscle of the bile duct at its entrance to the duodenum). Bile is ejected in pulsatile “spurts,” not in a steady stream. The pulsatile pattern is caused by the rhythmic contractions of the duodenum. When the duodenum is relaxed and duodenal pressure is low, bile is ejected; when the duodenum is contracting and duodenal pressure is higher, bile is not ejected against the higher pressure.

Enterohepatic Circulation of Bile Salts

Normally, most of the secreted bile salts are recirculated to the liver via an enterohepatic circulation (meaning circulation between the intestine and the liver), rather than being excreted in feces. The steps involved in the enterohepatic circulation are as follows (see Fig. 8-24):

1.          In the ileum, the bile salts are transported from the intestinal lumen into the portal blood by Na+-bile salt cotransporters (Step 4, Fig. 8-24). Significantly, this recirculation step is located in the terminalsmall intestine (ileum), so bile salts are present in high concentration for the entire length of small intestine to maximize lipid digestion and absorption.

2.          The portal blood carries bile salts to the liver (Step 5, Fig. 8-24).

3.          The liver extracts the bile salts from portal blood and adds them to the hepatic bile salt/bile acid pool. Therefore, the liver must replace, by synthesis, only the small percentage of the bile salts that is not recirculated (i.e., excreted in feces); the fecal loss is about 600 mg/day (out of the total bile salt pool of 2.5 g). The liver “knows” how much new bile acid to synthesize daily because bile acid synthesis is under negative feedback control by the bile salts. The rate-limiting enzyme in the biosynthetic pathway, cholesterol 7α-hydroxylase, is inhibited by bile salts. When greater quantities of bile salts are recirculated to the liver, there is decreased demand for synthesis and the enzyme is inhibited. When smaller quantities of bile salts are recirculated, there is increased demand for synthesis and the enzyme is stimulated. Recirculation of bile salts to the liver also stimulates biliary secretion, which is called a choleretic effect.

In persons who have had an ileal resection (removal of the ileum), the recirculation of bile salts to the liver is interrupted and large quantities of bile salts are excreted in feces. Excessive fecal loss diminishes the total bile salt/bile acid pool because synthesis of new bile acids, even though it is strongly stimulated, cannot keep pace with the loss. One consequence of decreased bile salt content of bile is impaired absorption of dietary lipids and steatorrhea (Box 8-1).

BOX 8–1 Clinical Physiology: Resection of the Ileum

DESCRIPTION OF CASE. A 36-year-old woman had 75% of her ileum resected following a perforation caused by severe Crohn disease (chronic inflammatory disease of the intestine). Her postsurgical management included monthly injections of vitamin B12. After surgery, she experienced diarrhea and noted oil droplets in her stool. Her physician prescribed the drug cholestyramine to control her diarrhea, but she continues to have steatorrhea.

EXPLANATION OF CASE. The woman’s severe Crohn disease caused an intestinal perforation, which necessitated a subtotal ileectomy, removal of the terminal portion of the small intestine. Consequences of removing the ileum include decreased recirculation of bile acids to the liver and decreased absorption of the intrinsic factor–vitamin B12 complex.

In normal persons with an intact ileum, 95% of the bile acids secreted in bile are returned to the liver, via the enterohepatic circulation, rather than being excreted in feces. This recirculation decreases the demand on the liver for the synthesis of new bile acids. In a patient who has had an ileectomy, most of the secreted bile acids are lost in feces, increasing the demand for synthesis of new bile acids. The liver is unable to keep pace with the demand, causing a decrease in the total bile acid pool. Because the pool is decreased, inadequate quantities of bile acids are secreted into the small intestine and both emulsification of dietary lipids for digestion and micelle formation for absorption of lipids are compromised. As a result, dietary lipids are excreted in feces, seen as oil droplets in the stool (steatorrhea).

This patient has lost another important function of the ileum, the absorption of vitamin B12. Normally, the ileum is the site of absorption of the intrinsic factor–vitamin B12 complex. Intrinsic factor is secreted by gastric parietal cells, forms a stable complex with dietary vitamin B12, and the complex is absorbed in the ileum. The patient cannot absorb vitamin B12 and must receive monthly injections, bypassing the intestinal absorptive pathway.

The woman’s diarrhea is caused, in part, by high concentrations of bile acids in the lumen of the colon (because they are not recirculated). Bile acids stimulate cAMP-dependent Cl secretion in colonic epithelial cells. When Cl secretion is stimulated, Na+ and water follow Cl into the lumen, producing a secretory diarrhea (sometimes called bile acid diarrhea).

TREATMENT. The drug cholestyramine, used to treat bile acid diarrhea, binds bile acids in the colon. In bound form, the bile acids do not stimulate Cl secretion or cause secretory diarrhea. However, the woman will continue to have steatorrhea.