Chapter 7 THE GASTROINTESTINAL TRACT
The gastrointestinal (GI) tract is one of the vital organ systems and a site of many human diseases. The clinical significance of GI diseases in the United States may be illustrated by the following statistics from the National Institutes of Health Web site:
Gastrointestinal diseases belong to the most common human diseases. For example close to 100 million cases of diarrhea are registered yearly in the United States. Some 30 to 50 million Americans have lactose intolerance. Approximately 10 million adults have hemorrhoids, and 4.5 million people suffer from constipation. Estimates are that 3% to 7% of all Americans have gastroesophageal reflux disease. Approximately 3.5 million physician office visits are for diagnosis, treatment, and follow-up of irritable colon disease.
Absorption Uptake of nutrients and fluid from the intestinal lumen into the circulation. Most of the absorption of nutrients occurs in the small intestine, but some nutrients are absorbed in the stomach and the large intestine as well.
Enteroendocrine cells Neuroendocrine cells found into the small and large intestine. They secrete various polypeptide hormones (e.g., cholecystokinin, gastrin) and can be impregnated with silver stains (thus called “argentaffin”). These cells contain membrane-bound cytoplasmic granules, which can be seen by electron microscopy. In microscopic sections they are best demonstrated by immunohistochemistry using antibodies to chromogranin or synaptophysin (staining all neuroendocrine cells) or antibodies to specific polypeptide hormones. These cells give rise to tumors known as carcinoids or neuroendocrine carcinomas.
Large intestine (colon) Part of the lower gastrointestinal tract connecting the ileum and the anus. It consists of several parts: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.
Mucosa-associated lymphoid tissue (MALT) Lymphoid tissue organized into follicles that are found inside the mucosa of the gastrointestinal or respiratory system. These aggregates may be seen microscopically or macroscopically, as in the small intestine where they form Payer’s patches.
Stomach Part of the gastrointestinal tract between the esophagus and the duodenum. It begins at the cardia and ends at the pylorus. The main part of the stomach is called the body. The upper part of the stomach is called the fundus, and the lower the pyloric antrum. The stomach contributes to digestion by secreting hydrochloric acid, pepsin, and several gastroenteric hormones such as gastrin.
Diarrhea Increase in stool frequency or volume. In Western countries it usually means that the stool weighs more than 300 g/day and contains more water than normal. It is said that the stool takes the form of its container.
Endoscopy Examination of the inside of a hollow organ using a flexible or rigid endoscopic instrument. Depending on the organ examined the endoscopic procedures are called esophagoscopy, rectoscopy, colonoscopy, and so on.
Melena Passing of black stools, typically due to bleeding from the upper gastrointestinal tract. The black color results from the interaction of the hydrochloric acid with the blood in the stomach or the small intestines.
Vomiting Forceful expulsion of the upper gastrointestinal contents through the mouth. It is typically associated with nausea. It is mediated by involuntary spasmodic contractions of the abdominal and chest musculature and the relaxation of the lower esophageal sphincter. If no gastrointestinal contents are expulsed the process is called retching or dry heaves. Rumination is effortless regurgitation of the swallowed food without nausea and spasmodic contractions.
Colitis Inflammation of the large intestine. It may be acute or chronic, diffuse or segmental. It may be caused by infection or toxins or it may be idiopathic, as in ulcerative colitis and Crohn’s disease.
Dumping syndrome Syndrome caused by rapid passage of food from the stomach into the small intestine, most often encountered in persons who have partial gastric resection of gastrointestinal anastomoses. Clinically it is characterized by dizziness, sweating, nausea, tachycardia, and subsequent diarrhea.
Enteritis Inflammation of the small intestine that may involve the entire small intestine or only some of its parts (e.g., duodenitis, ileitis). It is often associated with colitis and thus called enterocolitis. It is typically associated with diarrhea or, if chronic, with malabsorption. It may be infectious or autoimmune (e.g., celiac disease) or idiopathic (e.g., Crohn’s disease).
Gastritis Inflammation of the mucosa of the stomach. It may be acute or chronic, atrophic or hypertrophic, erosive or nonerosive. It may be caused by infections (e.g., Helicobacter pylori), chemicals and drugs (e.g., alcohol and nonsteroidal anti-inflammatory drugs), or autoimmune mechanisms.
Gastroesophageal reflux disease (GERD) Set of clinical symptoms related to the reflux of gastric acid into the esophagus due to inadequate function of the lower esophageal sphincter, diaphragmatic hernia, or increased intra-abdominal pressure compressing the stomach.
Gastrointestinal stromal tumor (GIST) Benign or malignant tumor composed of undifferentiated stromal cells. Such tumors may be found anywhere in the gastrointestinal tract from the esophagus to the anus and even in the mesentery and extraintestinal sites of the abdomen.
Gastrointestinal tumors Tumors originating in the gastrointestinal tract, including benign tumors (tubular and villous adenomas); adenocarcinomas of the esophagus, stomach, and intestines; squamous cell carcinoma of the esophagus; carcinoids and neuroendocrine carcinomas; lymphomas and various benign and malignant stromal tumors.
Hereditary nonpolyposis colorectal carcinoma (HNPCC) Autosomal dominant condition characterized by the appearance of adenocarcinomas of the large intestine. It is related to the mutation of the mismatch repair genes and microsatellite genetic instability.
Ischemic bowel disease Intestinal changes related to acute or chronic ischemia, usually related to atherosclerotic narrowing of intestinal arteries or thrombi and emboli. May manifest in the form of minor functional disturbances (e.g., pain, colic, diarrhea, or constipation), hematochezia, or catastrophic extensive intestinal necrosis.
Malabsorption syndrome Gastrointestinal syndrome characterized by incomplete absorption of nutrients and fluids from the intestinal lumen. It may be caused by intestinal, pancreatic, biliary, or gastric diseases.
Obstruction Failure of passage or caudal progression of food in the upper alimentary tract or intestinal contents due to a mechanical barrier. May be caused by tumors; fecal impaction; foreign bodies; or intestinal adhesions, hernia, volvulus, and intussusception.
The GI, or alimentary, tract includes the hollow organs stretching from the mouth to the anus, that is, the GI tract proper; and the solid organs, such as the salivary glands, the liver, and pancreas, that are attached to them (Fig. 7-2). In this chapter we deal only with the GI tract proper, whereas the liver and the pancreas are described in subsequent chapters.
The gastrointestinal tract can be divided for practical purposes into two parts: the upper and the lower GI tract.
The upper GI tract includes the mouth, pharynx, esophagus, stomach, and duodenum. These organs are involved in the ingestion and initial digestion of food. The mouth and pharynx can be inspected with the naked eye. The esophagus, stomach, and duodenum can be visualized by upper GI endoscopy using fiberoptic gastroscope. The mouth and the pharynx are located in the head and neck areas, whereas the esophagus extends from the neck through the thoracic region to the diaphragm. The stomach and duodenum are located in the abdomen.
The lower GI tract includes the small intestine (jejunum and ileum), appendix, large intestine, and anus. The small intestine is the primary site for the final stages of digestion and the place where nutrients are absorbed into the circulation. The anus can be inspected during routine physical examination. Rectoscopy and colonoscopy are used to visualize the large intestine. The terminal part of the ileum can be seen during colonoscopy as well, but the remainder of the small intestine cannot be visualized by routine endoscopy.
The wall of the gastrointestinal tract consists of several distinct histologic layers arranged in a similar manner from the pharynx to the anus.
Mucosa. The mucosa consists of an epithelial lining and the connective tissue lamina propria mucosae. The mouth and esophagus are covered with squamous epithelium that provides protection against the coarse particles found in ingested food. In the stomach and the intestines the mucosa is composed of secretory or absorptive glandular cells that are important for digestion and absorption of food. The lamina propria consists of connective tissue, vessels, and scattered cells of the mucosa-associated lymphoid tissue (MALT).
Submucosa. It is composed of loose connective tissue containing numerous blood and lymphatic vessels, cells of the MALT, and submucosal (Meissner’s) nerve plexus. The submucosa is an important passageway for the blood and lymph entering or exiting the mucosa.
Muscle layer (muscularis propria). The muscle layer of the esophagus and small and large intestines consists of an internal circular sublayer and an external layer containing smooth muscle cells arranged longitudinally. The stomach has an additional oblique middle layer of smooth muscles. The myenteric (Auerbach’s) nerve plexus is located between the muscle sublayers of the intestines.
Serosa. The external surface of the stomach and the intestines is covered with a layer of mesothelium lying on loose connective tissue that separates it from the muscle layer. The esophagus does not have a serosa and is instead enveloped by a connective tissue adventitia. In the abdominal cavity the serosa allows smooth movement of the intestines as they glide over each other’s surface during peristalsis and contraction.
The gastrointestinal tract is subdivided into several functional units by smooth muscular sphincters that regulate the passage of contents from one part of the tract to another.
Sphincters are thickened parts of the muscle layer located in critical sites of the GI tract. Sphincters separate one part of the GI tract from another, thereby regulating the orderly forward passage of food and chyme and preventing regurgitation. The most important sphincters are as follows:
Upper esophageal sphincter. It is located at the upper end of the esophagus and is composed of striated muscle. Its tone is maintained by impulses from vagal postganglionic neurons. This sphincter participates in the swallowing reflex and prevents the reflux of swallowed food from the esophagus into the pharynx.
Lower esophageal sphincter. Located at the esophagogastric junction, its relaxation during peristalsis allows the passage of food from the esophagus into the stomach. It also prevents gastroesophageal reflux. It is under the control of intrinsic nervous plexus, which is influenced by the vagus nerve.
Pyloric sphincter. This sphincter is located at the end of the pylorus. It represents the thickened middle layer of the gastric muscularis propria. Opening of this sphincter allows the passage of chyme from the stomach into the duodenum.
Ileocecal sphincter (valve). The small intestine does not have any sphincters, and the first sphincter the chyme encounters after leaving the stomach is the ileocecal valve. It regulates the passage of chyme from the small into the large intestine. It opens on distention of the terminal ileum by chyme and closes on dilatation of the cecum.
The internal and external anal sphincters. These sphincters prevent involuntary passage of feces but relax during defecation, allowing the passage of stools. The external sphincter, which is composed of skeletal muscle, can be contracted or relaxed at will. If the sphincter is relaxed, defecation occurs. The internal sphincter is involved in the defecation reflex, regulating the entry of feces into the anal canal.
The mucosal lining of the stomach and the intestines contains several highly specialized cells arranged in an anatomic site-specific manner.
The mouth and esophagus on one end and the anus on the other end of the GI tract are lined by squamous epithelium. All other parts of the GI tract are lined by mucosa that contains, with some minor site-specific modifications, five cell types: (1) protective cells, (2) absorptive cells, (3) exocrine secretory cells, (4) endocrine secretory cells, and (5) stem cells considered to be the precursors of all the other more differentiated cells. Obviously some cells have more than one function and could belong to more than one of these categories. These five cells types seen in the small intestine are shown diagrammatically in Figure 7-4.
Figure 7-4 Cells of the small intestinal mucosa. This drawing shows the five cell types in the small intestine. Other parts of the intestine and stomach have slightly different cells, but they also can be classified as protective, exocrine, endocrine, absorptive, or stem cells.
Protective cells. The mouth and the esophagus are lined by squamous epithelium, the primary function of which is the protection of the body from the adverse effects of ingested material. In the stomach and the intestine the main epithelial protective cells are the mucus-secreting cells. One should not forget that the GI system contains immune cells, lymphocytes, and plasma cells, forming the so-called mucosa-associated lymphoid tissue (MALT). These nonepithelial cells interact with the epithelial cells and contribute to their protective function.
Absorptive cells. Since most of the absorption occurs in the small intestine, it is obvious that surface absorptive cells (enterocytes) predominate in this part of the GI tract. Surface absorptive cells are on their luminal surface lined by microvilli, which increase the absorptive surface of the cell membrane. The glycocalyx covering the microvilli is rich in digestive enzymes such as disaccharidases and dipeptidases that facilitate the absorption of carbohydrates. The large intestine contains absorptive cells whose main function is the passive reabsorption of water, which follows the active transport of sodium from the lumen.
Endocrine cells. These cells are part of the diffuse enteroendocrine system and are scattered throughout the GI tract. Similar cells are found in the respiratory tract and in the islets of Langerhans. Enteroendocrine cells secrete biogenic amines, such as histamine and serotonin, and polypeptide hormones that can be classified as (1) true hormones, (2) paracrine hormones, and (3) neurocrine hormones (Table 7-1).
The innervation of the gastrointestinal tract comprises an intrinsic and an extrinsic component interacting with one another and the neuroendocrine cells.
The intrinsic innervation includes the autonomous nervous system ganglia arranged into the myenteric and submucosal plexus, and the so-called GI interstitial cells of Cajal, which act as internal pacer cells. Gastrointestinal plexuses contain both sensory and motor neurons. The sensory cells respond to the local stimuli, such as dilatation of the intestines by food, by transmitting these impulses to the motor neurons or intestinal neuroendocrine cells that regulate the autonomous contraction and relaxation of the smooth muscle cells.
The extrinsic innervation includes a sympathetic and a parasympathetic component. The sympathetic nerves release adrenalin, which inhibits the contraction of smooth muscle cells. The parasympathetic nerves are cholinergic and stimulate contraction of smooth muscle cells.
The sympathetic innervation stems from four ganglia: celiac, superior mesenteric, inferior mesenteric, and hypogastric. Adrenergic stimuli from these ganglia act on the nerve cells of the myenteric and submucosal plexus, or directly on the smooth muscle cells and endocrine and exocrine cells of the GI mucosa (Fig. 7-5).
The parasympathetic innervation is derived from the vagus nerve, which innervates the upper GI tract, and the pelvic nerve, which innervates the colon and anus. The parasympathetic system has long preganglionic fibers that extend to the ganglia in the wall of the GI tract. The intrinsic intestinal ganglion cells process the external stimuli and transmit them to the smooth muscle cells but also to other effector cells, such as the neuroendocrine cells and exocrine mucosal cells. It is important to remember that the vagus nerve is composed of 75% afferent fibers and only 25% efferent fibers. It is the main conduit for pain and other sensory stimuli that reach the central nervous system from the mechanoreceptors and chemoreceptors in the GI system. It is also important for the so-called vasovagal reflexes, accounting for some clinically important symptoms such as nausea and vomiting and paralytic ileus.
The GI tract has two main functions: to provide nutrients for the rest of the body and to eliminate the undigested food and waste products. These two main functions can be accomplished only by coordination of several basic physiologic processes, including the following:
Motility. The musculature of the GI tract consists predominantly of smooth muscle cells, and thus it is not surprising that most of its movements are involuntary. These movements are under the control of the autonomic nervous system and intramural nerve plexus and are often coordinated into reflexes controlled by the autonomic centers in the medulla and the pons.
Secretion. Different parts of the GI tract have different functions, and so the secretions in the stomach differ from those of the small intestine. Keep in mind that the salivary glands, the liver, and the pancreas secrete copious amounts of digestive juices that are essential for normal digestion.
Chewing (mastication). Breakdown of solid food into smaller morsels is accomplished by coordinated movements of the jaws, known as chewing. It is in part based on voluntary movements and in part on a chewing reflex coordinated from the centers in the brainstem. It involves a coordinated action of masticatory muscles such as the masseter, medial pterygoid, and temporalis muscle.
Swallowing (deglutition). Food that has been reduced to smaller morsels is swallowed. Swallowing has three phases: an initial voluntary phase (oral phase), followed by two involuntary phases (pharyngeal and esophageal phases) (Fig. 7-6).
Figure 7-7 Esophageal phase of swallowing. It begins with the opening of the upper esophageal sphincter, followed by peristaltic contractions of the esophageal muscles and the opening of the lower esophageal sphincter. At the end of the passage of food the lower esophageal sphincter closes, preventing the reflux of gastric juice into the esophagus. Manometric recordings of the sequential changes of the esophageal tone are shown graphically.
Gastric processing of the food involves several processes, all of which depend on the proper motility of the muscle layers and the functioning of the mucosal cells. Several distinct processes can be recognized as follows:
Filling. The swallowing of food initiates a vasovagal reflex that leads to the relaxation of the lower esophageal reflex in the proximal part of the stomach. This process is called receptive relaxation. The entry of food into the stomach evokes active dilatation of the fundus, known as gastric accommodation. This dilatation is believed to be mediated by intrinsic gastric innervation and is modulated by the vagus nerve (Fig. 7-8).
Mixing. The gastric contractions needed for the mixing of food are initiated by a pacemaker that is located on the greater curvature and composed of interstitial cells of Cajal. Under the influence of hydrochloric acid the food is broken down into small morsels and transformed into a coarse mixture. This mush is propelled into the antrum, where it is churned. The food hitting the closed pyloric sphincter initiates a contraction of the antrum, which returns the food into the proximal stomach. This propulsion, grinding, and retropulsion are repeated several times, mincing the food into smaller and smaller particles until it is transformed into a semifluid material called chyme. Expulsion of food leads to gastric emptying, as follows.
Gastric emptying. During food mixing the pyloric sphincter is closed as tightly as possible. Nevertheless small amounts of chyme escape into the duodenum. The entry of acid chyme, and especially if it contains lipids and proteins, evokes an enterogastric reflex, which slows down gastric emptying. The purpose of this reflex is to prevent premature emptying of the stomach and overly rapid filling of the duodenum. Nevertheless, as the mixing progresses, more and more food accumulates in the pyloric antrum, causing its gradual dilatation. The relaxation of the pyloric sphincter permits the outflow of food into the duodenum. It should be noticed that gastric emptying is also under hormonal control. Gastrin enhances the contraction of the pyloric sphincter, thereby diminishing gastric emptying. Cholecystokinin and secretin released from the duodenum filling with acid chyme also reduce the rate of gastric emptying.
The processing of food in the stomach is accomplished primarily through the action of hydrochloric acid.
Hydrochloric acid and pepsin are the main components of gastric juice. Hydrochloric acid (HCl) acts by dissociating and lysing cells and the extracellular matrix of animal and plant tissues. It is also essential for acidifying the luminal contents, thus providing the optimal conditions for the action of pepsin. Approximately 10% of the total protein is broken down completely in the stomach through the action of pepsin.
Proteins are not the only food component broken down in the stomach. Gastric lipase breaks down short-chain fatty acids, but in principle most lipids are not digested in the stomach. Carbohydrates continue to be digested by the salivary amylase, which is, however, soon inactivated by acid. Thus, most of the components of a food bolus are only partially digested in the stomach, and very little of these are absorbed. Most absorption involves water-soluble small molecules, which pass freely with the water into the blood.
Cephalic phase. It accounts for approximately 30% of the total gastric secretory response. The cephalic phase involves a central nervous system (CNS) reflex that can be initiated by thinking about food, or by seeing, smelling, or tasting it. The stimuli are transmitted through the vagus nerve. Acetylcholine (ACh) released from the nerve endings of the vagus nerve acts directly on parietal cells to secrete HCl (Fig. 7-9). Acetylcholine released from the vagus nerve also stimulates the enteroendocrine cells, indirectly evoking both stimulatory and, to a lesser degree, inhibitory stimuli. These indirect effects on parietal cells include the action of ACh on the following cells:
Gastric phase. It is initiated by the mechanical stimuli created by the bolus of food as it enters the stomach. This phase accounts for most of the gastric secretory activity. The distention of the stomach provokes vasovagal reflexes, resulting in the release of ACh like in the cephalic phase. Acid pH stimulates the release of pepsin from the chief cells. Pepsin cleaves proteins to amino acids, some of which, notably tryptophan and phenylalanine, stimulate enteroendocrine G cells to release gastrin; this further promotes HCl production. When the acidity of gastric contents drops below pH 3 the secretion of gastrin stops. The acidity of the contents also has an inhibitory effect on the parietal cells, and when it drops below pH 2, HCl secretion stops entirely.
Intestinal phase. This phase begins with the chyme reaching the duodenum. It accounts for only 10% of the gastric output. Initially, as long as the acidity of chyme entering the duodenum is above pH 3, the intestinal phase is characterized by prevailing stimulation of the gastric secretion. Later on, as the acidity of the chyme entering the duodenum drops below pH 3, the inhibitory effects predominate. These inhibitory stimuli include the vasovagal reflex, stimulating somatostatin release in the stomach, and inhibitory hormones, such as secretin, CKK, somatostatin, and gastric inhibitory polypeptide (GIP) released from the duodenum. Collectively these hormones inhibit gastric acid secretion and slow down gastric emptying. Secretin is considered to be the main inhibitor of HCl production: it acts directly on parietal cells, inhibits gastrin release, and stimulates the production of somatostatin in the duodenum and the stomach. Somatostatin released from gastric D cells is the most potent paracrine inhibitor of parietal cells. Distention of the ileum by chyme leads to the release of peptide YY, which slows down gastric emptying.