Review of Medical Physiology - William F. Ganong 2002

Functions of the Digestive System
Mechanisms of Regulation of Gastrointestinal Functions
The Stomach

In the Stomach, food is accumulated and mixed with Hydrochloric acid, mucus, and Pepsin before being delivered in controlled portions into the duodenum; this is a tightly regulated process.

Anatomical Features

The macroanatomy of the stomach is shown in Fig. 26-8. The gastric mucosa contains numerous deep glands. In the pyloric and cardiac regions, the glands secrete mucus. The Glands of the gastric body and fundus contain parietal (oxyntic) Cells, which secrete hydrochloric acid and intrinsic factor, as well as chief (zymogenic, peptic) cells, which release pepsinogens (Fig. 26-9). Their secretions mix with the mucus secreted by the cells located in the necks of the glands. Several glands often open onto the mucosal surface together, forming a depression known as the gastric pit. Mucus is secreted onto the mucosal surface along with HCO₃ by surface mucous cells (mucocytes) located between the glands.

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Fig. 26-8. Anatomy of the stomach. Major substances are listed in parentheses beneath the respective Regions of the stomach where they are secreted. The dashed line indicates the boundary between the body and the antrum.

Fig. 26-9. Schematic representation of glands in the human gastric body mucosa (reproduced with permission from Bell GH, Davidson N, Scarboryugh G: Textbook of Physiology and Biochemistry, 6th ed. Livingstone, 1965).

The stomach has a well-developed Blood and Lymphatic supply. Its parasympathetic innervation is provided by the Vagus nerve, and its sympathetic innervation originates from the celiac ganglion.

Gastric Secretion

The Cells of the gastric glands secrete over 2,500 mL of gastric juice per day. This juice contains various substances (Table 26-5). Gastric Enzymes are described in Chapter 25. Hydrochloric acid, secreted by the glands of the gastric body, destroys most ingested Bacteria, AIDS in Protein Digestion, and stimulates the release of Bile AND PANCREATIC juice. Its concentration is high enough to damage cells; however, in normal individuals, the gastric mucosa is neither damaged nor digested because the gastric juice contains mucus. The mucus secreted by the neck and surface mucous cells of the body and fundus, as well as similar cells throughout the stomach, consists of Glycoproteins called mucins. Each mucin comprises four subunits linked by disulfide bridges. The mucus forms a flexible gel that coats the mucosal membrane.

Surface mucous cells also secrete HCO₃, which is trapped within the mucous gel, establishing a pH gradient that ranges from 1-2 at the luminal surface to 6-7 at the epithelial Cell surface. Hydrochloric acid, secreted by the parietal cells of the gastric glands, traverses this barrier through finger-like channels, leaving the rest of the gel layer intact.

The surface membranes of mucous cells and tight junctions between cells also form an integral part of the mucosal barrier that protects the gastric epithelium from injury. Substances known to compromise this barrier and cause gastric irritation include alcohol, vinegar, bile salts, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs). Prostaglandins stimulate mucus secretion, whereas aspirin and related drugs inhibit prostaglandin synthesis.

Part of the stomach's resistance to autodigestion is conferred by the presence of trefoil Peptides in the mucosa. There are several types of these acid-resistant peptides. They are also found in other regions of the gastrointestinal tract, the Hypothalamus and Pituitary gland, and rapidly proliferating Tissues. These compounds are characterized by a three-loop Structure near their amino termini held together by Disulfide Bonds, resembling a three-leaf clover. In knockout mice lacking the Gene for one of these peptides, the gastric and intestinal epithelia exhibit histological abnormalities, along with a significantly increased risk of developing benign and malignant mucosal tumors.

The electrolyte content of gastric juice varies According to the rate of secretion. At low secretory rates, the Na⁺ concentration is high and the H⁺ concentration is low, whereas with an increase in acid secretion, the Na⁺ concentration decreases.

Table 26-5. Composition of normal gastric juice (fasting)

Pepsinogen Secretion

Chief cells secrete pepsinogens, which are the inactive precursors of pepsins in gastric juice (see Chapter 25); they contain zymogen granules. The secretory process is similar to that of trypsinogen and other pancreatic enzymes. Pepsinogen activity can be measured in plasma and urine, where it is referred to as uropepsinogen.

Hydrochloric Acid Secretion

It is difficult to obtain secretions from parietal glands free from contamination by other gastric secretions; however, the purest samples analyzed are notably isotonic. The H⁺ concentration in these secretions is equivalent to 0.17 N HCl with a pH as low as 0.87. Therefore, parietal cell secretion as an isotonic solution can be significant for pure HCl containing 150 mEq of Cl^- and 150 mEq of H⁺ per liter. Despite this, the cytoplasmic pH of parietal cells is comparable to that of other cells (7.0–7.2), whereas the comparative concentration per liter of plasma is about 100 mEq for Cl^- and 0.00004 mEq for H⁺. Located on the apical membrane of parietal cells is the H⁺-K⁺-ATPase, which pumps H⁺ against its concentration gradient (Fig. 26-10). Parietal cells are polarized: their apical membranes face the lumen of the gastric glands, and their basolateral membranes contact the interstitial fluid. Canaliculi extend inward from the apical surface into The Cell (Fig. 26-11). Abundant tubulovesicular structures containing H⁺-K⁺-ATPase molecules in their walls are also present throughout the rest of the cell. The K⁺ level inside the vesicles is low, and the ATPase molecules are inactive. Upon stimulation of parietal cells, the tubulovesicular structures migrate to the apical surface and fuse with it, thereby delivering A large number of ATPase molecules to the membrane. This increases the secretory surface area and promotes The formation of numerous microvilli projecting into the canaliculi. The ATPase molecules are then exposed to K⁺ in the extracellular fluid, and H⁺-K⁺ exchange is initiated.

Fig. 26-10. Secretion of HCl by gastric parietal cells. Active Transport MECHANISMS involving ATP are indicated by arrows within circles. H⁺ ions are secreted into the canalicular lumen in exchange for K⁺ via the H⁺-K⁺-ATPase. HCO₃^- is exchanged for Cl^- in the interstitial fluid by an antiporter, and the Na⁺-K⁺-ATPase maintains a low intracellular Na⁺ level. Dashed lines indicate the direction of diffusion. Compare with Fig. 38-20.

Fig. 26-11. Composite diagram of a parietal cell, depicting the cell in a resting state (bottom left) and an active state (top right). The resting cell features intracellular secretory canaliculi (IC) opening onto the apical cell membrane, and a system of tubulovesicular structures (TV) in the Cytoplasm. Upon cell activation, the TV structures fuse with The cell membrane, and microvilli (MV) extend into the canaliculi, greatly increasing the surface area of the cell membrane in contact with the gastric lumen; M - mitochondrion, G - Golgi apparatus (reproduced with permission from Junqueira LC, Carneiro J, Kelley RO: Basic Histology, 9th ed. McGraw-Hill, 1998).

The Pumping of H⁺ out of parietal cells in exchange for K⁺ requires energy supplied by ATP Hydrolysis. Cl^- ions are also driven against an electrochemical gradient through cAMP-activated channels in the apical membrane. Although the concentration gradient is directed inward, an electrical gradient directed outward is significantly greater. K⁺ ions are also driven out. The released H⁺ ions combine with HCO₃^-, which in turn is generated by Hydration (see Fig. 26-10). This reaction is catalyzed by Carbonic anhydrase, an enzyme exceptionally abundant in parietal cells.

As H₂CO₃ dissociates, it generates HCO_3-, which is driven by an antiporter onto the basolateral membrane of parietal cells, exchanging HCO₃ for another anion in the interstitial fluid—mostly Cl. Due to the efflux of HCO₃ into the blood, the stomach exhibits a negative respiratory quotient, meaning The amount of CO₂ in arterial blood becomes greater than that in gastric venous blood. Following a meal, hydrochloric acid secretion increases, and sufficient H⁺ may be secreted to raise blood and urine pH, rendering the urine more alkaline (a transient decrease in urinary acidity postprandially).

Acid secretion is stimulated by histamine via H₂ receptors, acetylcholine via M₃ muscarinic receptors, and presumably gastrin via gastrin receptors on the parietal cell membranes (Fig. 26-12). H₂ receptors increase intracellular cAMP content via Gs, whereas muscarinic and gastrin receptors act by elevating intracellular free Ca²⁺ levels. Intracellular effects interact in such a way that the activation of one receptor potentiates the response of another to stimulation. Prostaglandins, particularly those of the E class, inhibit acid secretion by activating Gi. This partly accounts for the increased incidence of ulcers in patients taking anti-inflammatory drugs that inhibit prostaglandin synthesis.

Fig. 26-12. Regulation of acid secretion by gastric parietal cells. Acid secretion is enhanced by the action of acetylcholine on M₃ muscarinic receptors, leading to an increase in intracellular Ca²⁺. In addition, gastrin stimulates histamine secretion by enterochromaffin-like (ECL) cells, which represents the major pathway by which gastrin stimulates H⁺ secretion. Histamine binds to H₂ receptors, and via G_s, increases The activity of adenylate cyclase (AC) and intracellular cAMP. PGE₂ acts via G1 to decrease adenylate cyclase activity and intracellular cAMP content; cAMP and Ca²⁺, via protein Kinases, increase The transport of H⁺ into the gastric lumen mediated by H⁺-K⁺-ATPase.

ECL cells

Gastrin also stimulates histamine secretion by enterochromaffin-like (ECL) cells. These vesicle- or granule-containing cells belong to the hyperdominant type of endocrine cells within the acid-secreting region of the stomach. The principal pathway through which gastrin stimulates hydrochloric acid secretion via these cells is now well established. In addition to gastrin receptors, ECL cells possess acetylcholine receptors, although the relative importance of acetylcholine in stimulating their secretion remains to be fully elucidated. Somatostatin inhibits their activity. ECL cells undergo hypertrophy when gastric hydrochloric acid secretion is suppressed for prolonged periods.

Gastric Motility and Gastric Emptying

Upon food entry into the stomach, the fundus and upper portion of the stomach relax to accommodate the volume with only a minimal rise in pressure (receptive relaxation or adaptive relaxation). Peristalsis then begins in the distal part of the body, facilitating food mixing and trituration. Small, semiliquid portions pass through the pyloric region into the duodenum.

Vagal stimulation promotes receptive relaxation, which is initiated by pharyngeal and esophageal movements. Peristaltic movements, regulated by gastric BER, begin rapidly and propagate swiftly toward the pylorus. Each wave causes a contraction of the distal stomach—sometimes referred to as antral systoles—which may last over 10 s. Such waves occur three to four times per minute.

In the mechanisms regulating gastric emptying, the antrum, pylorus, and proximal duodenum apparently function as a single integrated unit. Antral contractions are followed by sequential contractions of the pylorus and duodenum. Particularly strong contractions in the antrum propel gastric contents forward while preventing solid masses from entering the duodenum (where they are remixed and triturated). The more liquid gastric contents are propelled in spurts into the Small Intestine. Normally, duodenal regurgitation does not occur because pyloric contractions tend to last slightly longer than those in the duodenum. Prevention of content regurgitation may also result from the stimulatory effects of CCK and secretin on the pyloric sphincter.

Hunger Contractions

Gastric contractions during interdigestive periods are believed to be associated with the MMC; occasionally, they can be perceived and may even cause moderate discomfort. These hunger contractions elicit a sensation of pain and were once thought to play a major role in appetite regulation, although experimental studies indicate that feeding behavior remains normal in animals following vagal denervation of the stomach and intestine (Chapter 14).

Cerebral Influences

The presence of food in the Oral Cavity reflexively stimulates gastric secretion, with the vagus nerve serving as the efferent pathway for this reflex. Conditioned Reflexes are mediated through vagal effects that increase gastric secretion. In humans, for instance, the sight, smell, or even thoughts of food enhance gastric secretion. This effect stems from cephalic conditioned reflexes established early in life.

The formation of conditioned reflexes and their underlying neuromechanisms are described in Chapter 16. Stimulation of the anterior hypothalamus and adjacent regions of the orbital gyri of the frontal lobe increases vagal efferent activity and gastric secretion. Cerebral influences account for one-third (and sometimes up to one-half) of the acid secretion elicited in response to normal meals.

Effects of Emotions

Psychological states influence gastric secretion and motility, primarily acting via the vagus nerve. William Beaumont made landmark observations on Alexis St. Martin in Canada, who had a permanent gastric fistula resulting from a penetrating gunshot wound, and noted that anger and hostility were accompanied by turgor, hyperemia, and hypersecretion in the gastric mucosa. Subsequent observations in other patients with gastric fistulas revealed that fear and depression decrease gastric secretion and blood flow while inhibiting gastric motility.

Gastric Influences

Ingested food entering the stomach enhances the gastric secretion triggered by the sight and smell of food as well as its presence in the Mouth (Fig. 26-13). Receptors in the gastric wall and mucosa respond to distension and chemical stimulation, chiefly by Amino Acids and related digestion products. Fibers from these receptors project to the submucosal plexus, which houses the cell bodies of the receptor Neurons. They form synapses on postganglionic parasympathetic neurons terminating on parietal cells, thereby stimulating secretion. Thus, the response (acid production) is generated by a local reflex whose arc is entirely contained within the stomach wall. The postganglionic neurons of this local reflex arc are identical to those innervated by descending vagal preganglionic neurons originating from the Brain, which drive the cephalic phase of secretion. Protein digestion products also stimulate gastrin release and enhance acid production.

Fig. 26-13. Time course of human gastric acid secretion following a meat meal (reproduced with permission from Brooks FP: Integrative lecture: Response of the GI tract to a meal. Undergraduate Teaching Project. American Gastroenterological Association, 1974).

REGULATION OF GASTRIC Secretion

The regulation of gastric motility and secretion involves neurohumoral mechanisms. Neural control is mediated through local autonomic reflexes—including cholinergic neurons—and the transmission of Central Nervous system (CNS) impulses via the vagus nerve. Humoral components are provided by the aforementioned Hormones. Vagal stimulation increases gastrin secretion through the release of gastrin-releasing peptide (see above). Other vagal fibers release acetylcholine, which acts directly on the cells of the body and fundus glands to enhance the secretion of hydrochloric acid and pepsins. Stimulation of the cervical or thoracic vagus nerve increases acid and pepsin secretion; however, vagotomy does not abolish the secretory response to local stimuli.

For convenience, the physiological regulation of gastric secretion is typically described in terms of cephalic, gastric, and intestinal phases, although they overlap considerably. The cephalic phase represents vagally mediated responses resulting from CNS activity. The gastric phase comprises primary local reflex responses and the response to gastrin. The intestinal phase encompasses reflex and hormonal feedback effects on gastric secretion initiated from the mucosa of the small intestine.

Intestinal Influences

Although gastrin-producing cells are present in the mucosa of the small intestine as well as the stomach, administering amino acids directly into the duodenum does not increase circulating gastrin levels. Fats, CARBOHYDRATES, and acid in the duodenum inhibit gastric acid and pepsin secretion and gastric motility via neurohumoral mechanisms. The Role of enterogastrone—an intestinal hormone responsible for inhibiting gastric acid—remains unclear. It may possibly be peptide YY (see above). Gastric acid secretion increases following subsequent resection of a large portion of the small intestine. This hypersecretion, which is proportional to the extent of the intestinal resection, likely results from the removal of the source of acid-inhibiting hormones.

Other Influences

Hypoglycemia acts via the brain and the efferent vagus nerve to stimulate acid and pepsin secretion. Other stimulants include alcohol and caffeine, which exert a direct effect on the mucosa. Small amounts of alcohol have a beneficial effect on digestion by stimulating gastric secretion, a fact known since ancient times.

Regulation of Gastric Motility and Emptying

Gastric emptying occurs depending on the composition of ingested food. Carbohydrate-rich meals leave the stomach within a few hours, protein meals empty more slowly, and the gastric emptying of fatty meals is even slower (Fig. 26-14). The emptying rate also depends on the Osmotic Pressure of the chyme entering the duodenum. The hyperosmolarity of duodenal contents is detected by duodenal osmoreceptors, which initiate neural mechanisms that slow gastric emptying.

Protein digestion products and hydrogen ions bathing the duodenal mucosa trigger gastric motility via the enterogastric reflex. Duodenal distension also initiates this reflex. Peptide YY inhibits gastric motility. In humans, vagotomy can frequently cause marked atonia and gastric distension. Excitement or agitation accelerates gastric emptying, whereas fear slows it.

Because fats are particularly effective in delaying gastric emptying, some individuals drink milk, cream, olive oil, or butter before consuming alcoholic beverages. Fats retain alcohol in the stomach for a longer period, thereby delaying its Absorption in the small intestine. Intoxicating substances enter the small intestine slowly and in steady portions. Thus, at least theoretically, a sudden spike in blood alcohol concentration—and the resulting burdensome intoxication—can be avoided.

Fig. 26-14. Effect of Proteins and fats on The rate of human gastric emptying. Subjects ingested 300 mL of liquid meal (reproduced with permission from Brooks FP: Integrative lecture: Response of the GI tract to a meal. Undergraduate Teaching Project. American Gastroenterological Association, 1974).

PEPTIC ULCER DISEASE

The Development of gastric and duodenal ulcers and erosions in humans is primarily associated with a disruption of the barrier that normally protects the mucosa from irritation and autodigestion by gastric secretions. Infection with Helicobacter pylori causes The breakdown of this barrier, as do aspirin and other NSAIDs, which are widely used as analgesics and for treating Arthritis. An additional cause of ulceration is prolonged acid excess. An example of this type is the ulcers observed in Zollinger-Ellison syndrome, which is characteristic of patients with gastrinomas. These tumors occur in the stomach and duodenum, but most commonly in the Pancreas. Gastrin causes acid hypersecretion and severe ulceration. Typically, increased acid secretion is present in all patients with duodenal and prepyloric ulcers (no acid, no ulcer).

Drugs used for the symptomatic Treatment of ulcers act by inhibiting acid secretion and increasing mucosal resistance to acid. A variety of distinct antacids are available, most of which contain aluminum hydroxide, magnesium hydroxide, or calcium bicarbonate. Blockade of H₂ histamine receptors using H₂ receptor antagonists such as cimetidine, ranitidine, nizatidine, and famotidine effectively reduces acid secretion by eliminating the potential stimulatory effect of these receptors in response to other stimuli (see above). Muscarinic receptors can be blocked by atropine or newer, more specific anticholinergic agents. Gastric H⁺-K⁺-ATPase can be inhibited by omeprazole. Sucralfate, a basic aluminum salt of sucrose octasulfate, increases mucosal resistance to acid primarily by forming adherent protein and other complexes at the ulcer site, and it is also effective in treating ulcers.

The Use of H₂ receptor blockers and omeprazole has reduced The Need for Surgical treatment of ulcers. Additionally, severe duodenal and prepyloric ulcers are sometimes treated with vagotomy combined with the resection of the gastrin-secreting antral mucosa. Long-term treatment with omeprazole induces ECL cell carcinoid tumors in rats. In humans, only a slight increase in plasma gastrin occurs, but no carcinomas have been found.

Current research into the causes of peptic ulcers focuses on elucidating the pivotal role of H. pylori infection. Eradication of H. pylori is achieved through antibiotic therapy. Patients with gastric and duodenal ulcers who take NSAIDs should discontinue them or, if that is not possible, continue treatment with long-acting PGE agonists such as misoprostol. Gastrinomas must be surgically removed.

Other Functions of the Stomach

In addition to storing food and regulating its delivery to the duodenum, the stomach performs several other functions.

In addition to hydrochloric acid, the parietal cells of the gastric mucosa secrete intrinsic factor, a 49 kDa glycoprotein that binds cyanocobalamin (vitamin B₁₂), which is required for absorption in the small intestine. Cyanocobalamin (Fig. 26-15) is a complex cobalt-containing vitamin synthesized by microorganisms. Inadequate absorption of this vitamin causes anemia characterized by the appearance in the bloodstream of large, primitive red blood cell precursors called megaloblasts, as well as damage to specific sensory pathways in the central nervous system. Complete remission of the deficiency syndrome occurs with parenteral administration of cyanocobalamin, but not with oral (per os) intake, because intrinsic factor is secreted by the gastric mucosa. Deficiency resulting from inadequate Dietary intake of cyanocobalamin is rare because the daily requirement is low and the vitamin is found in most animal-derived foods. When deficiency states are clinically detected, a defect in cyanocobalamin absorption must be suspected first. Inadequate absorption may result from primary intestinal diseases, such as sprue, or from intrinsic factor deficiency, which occurs after gastrectomy or when parietal cells are destroyed by disease. In pernicious anemia, parietal cells are targets for autoimmune destruction (autoimmune gastritis) or are damaged by chronic bacterial infection of the mucosa (non-autoimmune gastritis).

Fig. 26-15. Cyanocobalamin (vitamin B₁₂). Empirical formula C₆₃H₈₈O₁₄N₁₄PCo

The intrinsic factor-cyanocobalamin complex then binds to specific receptors in the ileum and is absorbed via endocytosis. Within enterocytes, cyanocobalamin is transferred from intrinsic factor to transcobalamin II, another cyanocobalamin-binding protein that transports it into the plasma.

In patients with total gastrectomy, intrinsic factor deficiency can be avoided by parenteral administration of cyanocobalamin. Protein digestion remains normal in the absence of pepsins, and Nutrition can be maintained. However, these patients are prone to developing iron-deficiency anemia (see Chapter 25) and other abnormalities, so they should eat frequent, small meals. Because rapid intestinal Glucose Absorption and resulting hyperglycemia sharply increase Insulin secretion, gastrectomized patients sometimes develop hypoglycemic symptoms 2 hours after a meal (see Chapter 19).

Weakness, dizziness, and sweating after meals, which are components of hypoglycemia, constitute dumping syndrome—a distress syndrome that occurs in patients who have undergone partial gastrectomy or who have had a jejunal-gastric anastomosis. Another cause of these symptoms is the rapid entry of hypertonic chyme into the intestine, which triggers a large fluid shift into the intestinal lumen, resulting in significant hypovolemia and hypotension.