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The first secretion encountered when food is ingested is saliva. Saliva is produced by three pairs of salivary glands (the parotid, submandibular, and sublingual glands) that drain into the oral cavity. It has a number of organic constituents that serve to initiate digestion (particularly of starch, mediated by amylase) and which also protect the oral cavity from bacteria (such as immunoglobulin A and lysozyme). Saliva also serves to lubricate the food bolus (aided by mucins). Secretions of the three glands differ in their relative proportion of proteinaceous and mucinous components, which results from the relative number of serous and mucous salivary acinar cells, respectively. Saliva is also hypotonic compared with plasma and alkaline; the latter feature is important to neutralize any gastric secretions that reflux into the esophagus.
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The salivary glands consist of blind end pieces (acini) that produce the primary secretion containing the organic constituents dissolved in a fluid that is essentially identical in its composition to plasma. The salivary glands are actually extremely active when maximally stimulated, secreting their own weight in saliva every minute. To accomplish this, they are richly endowed with surrounding blood vessels that dilate when salivary secretion is initiated. The composition of the saliva is then modified as it flows from the acini out into ducts that eventually coalesce and deliver the saliva into the mouth. Na+ and Cl− are extracted and K+ and bicarbonate are added. Because the ducts are relatively impermeable to water, the loss of NaCl renders the saliva hypotonic, particularly at low secretion rates. As the rate of secretion increases, there is less time for NaCl to be extracted and the tonicity of the saliva rises, but it always stays somewhat hypotonic with respect to plasma. Overall, the three pairs of salivary glands that drain into the mouth supply 1000–1500 mL of saliva per day.
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Salivary secretion is almost entirely controlled by neural influences, with the parasympathetic branch of the autonomic nervous system playing the most prominent role (Figure 25–3). Sympathetic input slightly modifies the composition of saliva (particularly by increasing proteinaceous content), but has little influence on volume. Secretion is triggered by reflexes that are stimulated by the physical act of chewing, but is actually initiated even before the meal is taken into the mouth as a result of central triggers that are prompted by thinking about, seeing, or smelling food. Indeed, salivary secretion can readily be conditioned, as in the classic experiments of Pavlov where dogs were conditioned to salivate in response to a ringing bell by associating this stimulus with a meal. Salivary secretion is also prompted by nausea but inhibited by fear or during sleep.
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Saliva performs a number of important functions: it facilitates swallowing, keeps the mouth moist, serves as a solvent for the molecules that stimulate the taste buds, aids speech by facilitating movements of the lips and tongue, and keeps the mouth and teeth clean. The saliva also has some antibacterial action, and patients with deficient salivation (xerostomia) have a higher than normal incidence of dental caries. The buffers in saliva help maintain the oral pH at about 7.0.
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Food is stored in the stomach; mixed with acid, mucus, and pepsin; and released at a controlled, steady rate into the duodenum (Clinical Box 25–1).
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ANATOMIC CONSIDERATIONS
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The gross anatomy of the stomach is shown in Figure 25–4. The gastric mucosa contains many deep glands. In the cardia and the pyloric region, the glands secrete mucus. In the body of the stomach, including the fundus, the glands also contain parietal (oxyntic) cells, which secrete hydrochloric acid and intrinsic factor, and chief (zymogen, peptic) cells, which secrete pepsinogens (Figure 25–5). These secretions mix with mucus secreted by the cells in the necks of the glands. Several of the glands open onto a common chamber (gastric pit) that opens in turn onto the surface of the mucosa. Mucus is also secreted along with HCO3− by mucus cells on the surface of the epithelium between glands.
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The stomach has a very rich blood and lymphatic supply. Its parasympathetic nerve supply comes from the vagi and its sympathetic supply from the celiac plexus.
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ORIGIN & REGULATION OF GASTRIC SECRETION
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The stomach also adds a significant volume of digestive juices to the meal. Like salivary secretion, the stomach readies itself to receive the meal before it is actually taken in, during the so-called cephalic phase that can be influenced by food preferences. Subsequently, there is a gastric phase of secretion that is quantitatively the most significant, and finally an intestinal phase once the meal has left the stomach. Each phase is closely regulated by both local and distant triggers.
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The gastric secretions (Table 25–1) arise from glands in the wall of the stomach that drain into its lumen, and also from the surface cells that secrete primarily mucus and bicarbonate to protect the stomach from digesting itself, as well as substances known as trefoil peptides that stabilize the mucus-bicarbonate layer. The glandular secretions of the stomach differ in different regions of the organ. The most characteristic secretions derive from the glands in the fundus or body of the stomach. These contain the distinctive parietal cells, which secrete hydrochloric acid and intrinsic factor; and chief cells, which produce pepsinogens and gastric lipase (Figure 25–5). The acid secreted by parietal cells serves to sterilize the meal and also to begin the hydrolysis of dietary macromolecules. Intrinsic factor is important for the later absorption of vitamin B12, or cobalamin. Pepsinogen is the precursor of pepsin, which initiates protein digestion. Lipase similarly begins the digestion of dietary fats.
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There are three primary stimuli of gastric secretion, each with a specific role to play in matching the rate of secretion to functional requirements (Figure 25–6). Gastrin is a hormone that is released by G cells in the antrum of the stomach both in response to a specific neurotransmitter released from enteric nerve endings, known as gastrin-releasing peptide (GRP) or bombesin, and also in response to the presence of oligopeptides in the gastric lumen. Gastrin is then carried through the bloodstream to the fundic glands, where it binds to receptors not only on parietal (and likely, chief cells) to activate secretion, but also on so-called enterochromaffin-like cells (ECL cells) that are located in the gland, and release histamine. Histamine is also a trigger of parietal cell secretion, via binding to H2-receptors. Finally, parietal and chief cells can also be stimulated by acetylcholine, released from enteric nerve endings in the fundus.
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CLINICAL BOX 25–1 Peptic Ulcer Disease
Gastric and duodenal ulceration in humans is related primarily to a breakdown of the barrier that normally prevents irritation and autodigestion of the mucosa by the gastric secretions. Infection with the bacterium Helicobacter pylori disrupts this barrier, as do aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the production of prostaglandins and consequently decrease mucus and HCO3− secretion. The NSAIDs are widely used to combat pain and treat arthritis. An additional cause of ulceration is prolonged excess secretion of acid. An example of this is the ulcers that occur in the Zollinger–Ellison syndrome. This syndrome is seen in patients with gastrinomas. These tumors can occur in the stomach and duodenum, but most of them are found in the pancreas. The gastrin causes prolonged hypersecretion of acid, and severe ulcers are produced.
THERAPEUTIC HIGHLIGHTS Gastric and duodenal ulcers can be given a chance to heal by inhibition of acid secretion with drugs such as omeprazole and related drugs that inhibit H+–K+ ATPase (“proton pump inhibitors”). If present, H. pylori can be eradicated with antibiotics, and NSAID-induced ulcers can be treated by stopping the NSAID or, when this is not advisable, by treatment with the prostaglandin agonist misoprostol. Gastrinomas can sometimes be removed surgically.
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Gastric secretion that occurs during the cephalic phase is defined as being activated predominantly by vagal input that originates from the brain region known as the dorsal vagal complex, which coordinates input from higher centers. Vagal outflow to the stomach then releases GRP and acetylcholine, thereby initiating secretory function. However, before the meal enters the stomach, there are few additional triggers and thus the amount of secretion is limited. Once the meal is swallowed, on the other hand, meal constituents trigger substantial release of gastrin and the physical presence of the meal also distends the stomach and activates stretch receptors, which provoke a “vago-vagal” as well as local reflexes that further amplify secretion during the gastric phase. The presence of the meal also buffers gastric acidity that would otherwise serve as a feedback inhibitory signal to shut off secretion secondary to the release of somatostatin, which inhibits both G and ECL cells as well as secretion by parietal cells themselves (Figure 25–6). This probably represents a key mechanism whereby gastric secretion is terminated after the meal moves from the stomach into the small intestine.
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Gastric parietal cells are highly specialized for their unusual task of secreting concentrated acid (Figure 25–7). The cells are packed with mitochondria that supply energy to drive the apical H+, K+-ATPase, or proton pump, that moves H+ ions out of the parietal cell against a concentration gradient of more than a million-fold. At rest, the proton pumps are sequestered within the parietal cell in a series of membrane compartments known as tubulovesicles. When the parietal cell begins to secrete, on the other hand, these vesicles fuse with invaginations of the apical membrane known as canaliculi, thereby substantially amplifying the apical membrane area and positioning the proton pumps to begin acid secretion (Figure 25–8). The apical membrane also contains potassium channels, which supply the K+ ions to be exchanged for H+, and Cl− channels that supply the counterion for HCl secretion (Figure 25–9). The secretion of protons is also accompanied by the release of equivalent numbers of bicarbonate ions into the bloodstream, which are later used to neutralize gastric acidity once its function is complete (Figure 25–9).
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The three agonists of the parietal cell—gastrin, histamine, and acetylcholine—each bind to distinct receptors on the basolateral membrane (Figure 25–8). Gastrin and acetylcholine promote secretion by elevating cytosolic free calcium concentrations, whereas histamine increases intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). The net effects of these second messengers are the transport and morphologic changes described above. However, it is important to be aware that the two distinct pathways for activation are synergistic, with a greater than additive effect on secretion rates when histamine plus gastrin or acetylcholine, or all three, are present simultaneously. The physiologic significance of this synergism is that high rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli. Synergism is also therapeutically significant because secretion can be markedly inhibited by blocking the action of only one of the triggers (most commonly that of histamine, via H2-antagonists that are widely used therapies for adverse effects of excessive gastric secretion, such as reflux).
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Gastric secretion adds about 2.5 L/day to the intestinal contents. However, despite their substantial volume and fine control, gastric secretions are dispensable for the full digestion and absorption of a meal, with the exception of cobalamin absorption. This illustrates an important facet of gastrointestinal physiology, namely that digestive and absorptive capacities are markedly in excess of normal requirements. On the other hand, if gastric secretion is chronically reduced, individuals may display increased susceptibility to infections acquired via the oral route.
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The pancreatic juice contains enzymes that are of major importance in digestion (see Table 25–2). Its secretion is controlled in part by a reflex mechanism and in part by the gastrointestinal hormones secretin and cholecystokinin (CCK).
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ANATOMIC CONSIDERATIONS
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The portion of the pancreas that secretes pancreatic juice is a compound alveolar gland resembling the salivary glands. Granules containing the digestive enzymes (zymogen granules) are formed in the cell and discharged by exocytosis (see Chapter 2) from the apexes of the cells into the lumens of the pancreatic ducts (Figure 25–10). The small duct radicles coalesce into a single duct (pancreatic duct of Wirsung), which usually joins the bile duct to form the ampulla of the bile duct (also known as the ampulla of Vater) (Figure 25–11). The ampulla opens through the duodenal papilla, and its orifice is encircled by the sphincter of Oddi. Some individuals have an accessory pancreatic duct (duct of Santorini) that enters the duodenum more proximally.
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COMPOSITION OF PANCREATIC JUICE
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The pancreatic juice is alkaline (Table 25–3) and has a high HCO3− content (approximately 113 mEq/L vs 24 mEq/L in plasma). About 1500 mL of pancreatic juice is secreted per day. Bile and intestinal juices are also neutral or alkaline, and these three secretions neutralize the gastric acid, raising the pH of the duodenal contents to 6.0–7.0. By the time the chyme reaches the jejunum, its pH is nearly neutral, but the intestinal contents are rarely alkaline.
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The pancreatic juice also contains a range of digestive enzymes, but most of these are released in inactive forms and only activated when they reach the intestinal lumen (see Chapter 26). The enzymes are activated following proteolytic cleavage by trypsin, itself a pancreatic protease that is released as an inactive precursor (trypsinogen). The potential danger of the release into the pancreas of a small amount of trypsin is apparent; the resulting chain reaction would produce active enzymes that could digest the pancreas. It is therefore not surprising that the pancreas also normally secretes a trypsin inhibitor.
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Another enzyme activated by trypsin is phospholipase A2. This enzyme splits a fatty acid off phosphatidylcholine (PC), forming lyso-PC. Lyso-PC damages cell membranes. It has been hypothesized that in acute pancreatitis, a severe and sometimes fatal disease, phospholipase A2 is activated prematurely in the pancreatic ducts, with the formation of lyso-PC from the PC that is a normal constituent of bile. This causes disruption of pancreatic tissue and necrosis of surrounding fat.
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Small amounts of pancreatic digestive enzymes normally leak into the circulation, but in acute pancreatitis, the circulating levels of the digestive enzymes rise markedly. Measurement of the plasma amylase or lipase concentration is therefore of value in diagnosing the disease.
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REGULATION OF THE SECRETION OF PANCREATIC JUICE
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Secretion of pancreatic juice is primarily under hormonal control. Secretin acts on the pancreatic ducts to cause copious secretion of a very alkaline pancreatic juice that is rich in HCO3− and poor in enzymes. The effect on duct cells is due to an increase in intracellular cAMP. Secretin also stimulates bile secretion. CCK acts on the acinar cells to cause the release of zymogen granules and production of pancreatic juice rich in enzymes but low in volume. Its effect is mediated by phospholipase C (see Chapter 2).
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The response to intravenous secretin is shown in Figure 25–12. Note that as the volume of pancreatic secretion increases, its Cl− concentration falls and its HCO3− concentration increases. Although HCO3− is secreted in the small ducts, it is reabsorbed in the large ducts in exchange for Cl− (Figure 25–13). The magnitude of the exchange is inversely proportional to the rate of flow.
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Like CCK, acetylcholine acts on acinar cells via phospholipase C to cause discharge of zymogen granules, and stimulation of the vagi causes secretion of a small amount of pancreatic juice rich in enzymes. There is evidence for vagally mediated, conditioned reflex secretion of pancreatic juice in response to the sight or smell of food.
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An additional secretion important for gastrointestinal function, bile, arises from the liver. The bile acids contained therein are important in the digestion and absorption of fats. In addition, bile serves as a critical excretory fluid by which the body disposes of lipid soluble end products of metabolism as well as lipid soluble xenobiotics. Bile is also the only route by which the body can dispose of cholesterol—either in its native form, or following conversion to bile acids. In this chapter and the next, the role of bile as a digestive fluid will be emphasized. In Chapter 28, a more general consideration of the transport and metabolic functions of the liver will be presented.
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Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice. About 500 mL is secreted per day. Some of the components of the bile are reabsorbed in the intestine and then excreted again by the liver (enterohepatic circulation).
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The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. The formation of these breakdown products of hemoglobin is discussed in detail in Chapter 28.
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When considering bile as a digestive secretion, it is the bile acids that represent the most important components. They are synthesized from cholesterol and secreted into the bile conjugated to glycine or taurine, a derivative of cysteine. The four major bile acids found in humans are listed in Figure 25–14. In common with vitamin D, cholesterol, a variety of steroid hormones, and the digitalis glycosides, the bile acids contain the steroid nucleus (see Chapter 20). The two principal (primary) bile acids formed in the liver are cholic acid and chenodeoxycholic acid. In the colon, bacteria convert cholic acid to deoxycholic acid and chenodeoxycholic acid to lithocholic acid. In addition, small quantities of ursodeoxycholic acid are formed from chenodeoxycholic acid. Ursodeoxycholic acid is a tautomer of chenodeoxycholic acid at the 7-position. Because they are formed by bacterial action, deoxycholic, lithocholic, and ursodeoxycholic acids are called secondary bile acids.
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The bile acids have a number of important actions: they reduce surface tension and, in conjunction with phospholipids and monoglycerides, are responsible for the emulsification of fat preparatory to its digestion and absorption in the small intestine (see Chapter 26). They are amphipathic, that is, they have both hydrophilic and hydrophobic domains; one surface of the molecule is hydrophilic because the polar peptide bond and the carboxyl and hydroxyl groups are on that surface, whereas the other surface is hydrophobic. Therefore, the bile acids tend to form cylindrical disks called micelles (Figure 25–15). Their hydrophilic portions face out and their hydrophobic portions face in. Above a certain concentration, called the critical micelle concentration, all bile salts added to a solution form micelles. Ninety to 95% of the bile acids are absorbed from the small intestine. Once they are deconjugated, they can be absorbed by nonionic diffusion, but most are absorbed in their conjugated forms from the terminal ileum (Figure 25–16) by an extremely efficient Na+–bile salt cotransport system (ABST) whose activity is secondarily driven by the low intracellular sodium concentration established by the basolateral Na+, K+ ATPase. The remaining 5–10% of the bile salts enter the colon and are converted to the salts of deoxycholic acid and lithocholic acid. Lithocholate is relatively insoluble and is mostly excreted in the stools; only 1% is absorbed. However, deoxycholate is absorbed.
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The absorbed bile acids are transported back to the liver in the portal vein and reexcreted in the bile (enterohepatic circulation) (Figure 25–16). Those lost in the stool are replaced by synthesis in the liver; the normal rate of bile acid synthesis is 0.2–0.4 g/day. The total bile acid pool of approximately 3.5 g recycles repeatedly via the enterohepatic circulation; it has been calculated that the entire pool recycles twice per meal and 6–8 times per day.
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INTESTINAL FLUID & ELECTROLYTE TRANSPORT
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The intestine itself also supplies a fluid environment in which the processes of digestion and absorption can occur. Then, when the meal has been assimilated, fluid used during digestion and absorption is reclaimed by transport back across the epithelium to avoid dehydration. Water moves passively into and out of the gastrointestinal lumen, driven by electrochemical gradients established by the active transport of ions and other solutes. In the period after a meal, much of the fluid reuptake is driven by the coupled transport of nutrients, such as glucose, with sodium ions. In the period between meals, absorptive mechanisms center exclusively around electrolytes. In both cases, secretory fluxes of fluid are largely driven by the active transport of chloride ions into the lumen, although absorption still predominates overall.
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Overall water balance in the gastrointestinal tract is summarized in Table 25–4. The intestines are presented each day with about 2000 mL of ingested fluid plus 7000 mL of secretions from the mucosa of the gastrointestinal tract and associated glands. Ninety-eight percent of this fluid is reabsorbed, with a daily fluid loss of only 200 mL in the stools.
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In the small intestine, secondary active transport of Na+ is important in bringing about absorption of glucose, some amino acids, and other substances such as bile acids (see above). Conversely, the presence of glucose in the intestinal lumen facilitates the reabsorption of Na+. In the period between meals, when nutrients are not present, sodium and chloride are absorbed together from the lumen by the coupled activity of a sodium/hydrogen exchanger (NHE) and chloride/bicarbonate exchanger in the apical membrane, in a so-called electroneutral mechanism (Figure 25–17). Water then follows to maintain an osmotic balance. In the colon, moreover, an additional electrogenic mechanism for sodium absorption is expressed, particularly in the distal colon. In this mechanism, sodium enters across the apical membrane via an ENaC (epithelial sodium) channel that is identical to that expressed in the distal tubule of the kidney (Figure 25–18). This underpins the ability of the colon to desiccate the stool and ensure that only a small portion of the fluid load used daily in the digestion and absorption of meals is lost from the body. Following a low-salt diet, increased expression of ENaC in response to aldosterone increases the ability to reclaim sodium from the stool.
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Despite the predominance of absorptive mechanisms, secretion also takes place continuously throughout the small intestine and colon to adjust the local fluidity of the intestinal contents as needed for mixing, diffusion, and movement of the meal and its residues along the length of the gastrointestinal tract. Cl− normally enters enterocytes from the interstitial fluid via Na+–K+–2Cl− cotransporters in their basolateral membranes (Figure 25–19), and the Cl− is then secreted into the intestinal lumen via channels that are regulated by various protein kinases. The cystic fibrosis transmembrane conductance regulator (CFTR) channel that is defective in the disease of cystic fibrosis is quantitatively most important, and is activated by protein kinase A and hence by cAMP (Clinical Box 25–2).
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Water moves into or out of the intestine until the osmotic pressure of the intestinal contents equals that of the plasma. The osmolality of the duodenal contents may be hypertonic or hypotonic, depending on the meal ingested, but by the time the meal enters the jejunum, its osmolality is close to that of plasma. This osmolality is maintained throughout the rest of the small intestine; the osmotically active particles produced by digestion are removed by absorption, and water moves passively out of the gut along the osmotic gradient thus generated. In the colon, Na+ is pumped out and water moves passively with it, again along the osmotic gradient. Saline cathartics such as magnesium sulfate are poorly absorbed salts that retain their osmotic equivalent of water in the intestine, thus increasing intestinal volume and consequently exerting a laxative effect.
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CLINICAL BOX 25–2 Cholera
Cholera is a severe secretory diarrheal disease that often occurs in epidemics associated with natural disasters where normal sanitary practices break down. Along with other secretory diarrheal illnesses produced by bacteria and viruses, cholera causes a significant amount of morbidity and mortality, particularly among the young and in developing countries. The cAMP concentration in intestinal epithelial cells is increased in cholera. The cholera bacillus stays in the intestinal lumen, but it produces a toxin that binds to GM-1 ganglioside receptors on the apical membrane of intestinal epithelial cells, and this permits part of the A subunit (A1 peptide) of the toxin to enter the cell. The A1 peptide binds adenosine diphosphate ribose to the α subunit of Gs, inhibiting its GTPase activity (see Chapter 2). Therefore, the constitutively activated G-protein produces prolonged stimulation of adenylyl cyclase and a marked increase in the intracellular cAMP concentration. In addition to increased Cl− secretion, the function of the mucosal NHE transporter for Na+ is reduced, thus reducing NaCl absorption. The resultant increase in electrolyte and water content of the intestinal contents causes the diarrhea. However, Na+, K+ ATPase and the Na+/glucose cotransporter are unaffected, so coupled reabsorption of glucose and Na+ bypasses the defect.
THERAPEUTIC HIGHLIGHTS Treatment for cholera is mostly supportive, since the infection will eventually clear, although antibiotics are sometimes used. The most important therapeutic approach is to ensure that the large volumes of fluid, along with electrolytes, lost to the stool are replaced to avoid dehydration. Stool volumes can approach 20 L per day. When sterile supplies are available, fluids and electrolytes can most conveniently be replaced intravenously. However, this is often not possible in the setting of an epidemic. Instead, the persistent activity of the Na+/glucose cotransporter provides a physiologic basis for the treatment of Na+ and water loss by oral administration of solutions containing NaCl and glucose. Cereals containing carbohydrates to which salt has been added are also useful in the treatment of diarrhea. Oral rehydration solution, a prepackaged mixture of sugar and salt to be dissolved in water, is a simple remedy that has dramatically reduced mortality in epidemics of cholera and other diarrheal diseases in developing countries.
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Some K+ is secreted into the intestinal lumen, especially as a component of mucus. K+ channels are present in the luminal as well as the basolateral membrane of the enterocytes of the colon, so K+ is secreted into the colon. In addition, K+ moves passively down its electrochemical gradient. The accumulation of K+ in the colon is partially offset by H+–K+ ATPase in the luminal membrane of cells in the distal colon, with resulting active transport of K+ into the cells. Nevertheless, loss of ileal or colonic fluids in chronic diarrhea can lead to severe hypokalemia. When the dietary intake of K+ is high for a prolonged period, aldosterone secretion is increased and more K+ enters the colonic lumen. This is due in part to the appearance of more Na+, K+ ATPase pumps in the basolateral membranes of the cells, with a consequent increase in intracellular K+ and K+ diffusion across the luminal membranes of the cells.