Chapter 7: Gastrointestinal Physiology

Overview

The gastrointestinal system consists of the gastrointestinal tract and the accessory exocrine glands. The gastrointestinal tract includes the mouth, the esophagus, the stomach, the small intestine, and the large intestine. The major accessory glands are the salivary glands, the liver, the gallbladder, and the pancreas.

The major functions of the gastrointestinal system are assimilation of nutrients and excretion of waste products via the biliary system. Movement of food through the gastrointestinal system (motility) is carefully coordinated with the delivery of appropriate fluid and enzyme solutions (secretion) so that the macromolecules in food can be hydrolyzed (digestion) and the nutrient molecules, which are liberated, can be transported into the circulatory system (absorption). Coordinating multiple organs and physiologic processes is a significant challenge that must be solved to achieve the overall functions of the gastrointestinal system. Elaborate control mechanisms are provided by the enteric nervous system (ENS), a large intrinsic network of neurons in the wall of the gastrointestinal tract, and by several hormones.

Figure 7-1 provides an overview of the main functions of each area of the gastrointestinal system during the passage of food. The following sequence of events results in the efficient assimilation of nutrients from food:

1. Chewing (mastication) of food breaks down the food to create a bolus that is suitable for swallowing. Saliva lubricates food and provides enzymes for digestion. It takes about 10 seconds for swallowed food to travel down the esophagus to the stomach.

2. Depending on its composition, food can remain in the stomach for about 1–4 hours. Stomach motility mixes and grinds food into small particles suitable for delivery to the small intestine via the pyloric sphincter. Exocrine secretions from the stomach mucosa help to dilute and dissolve food; gastric acid assists in dissolving and denaturing the components of food.

3. Entry of food into the small intestine is coordinated with the delivery of major exocrine secretions from the biliary system and the pancreas. The pancreas is essential for digestion because it produces numerous enzymes. The pancreas also secretes HCO₃⁻, which neutralizes acid from the stomach. Contractions of the gallbladder deliver stored bile to the intestine. Bile acids are the major organic component of bile and are important for lipid assimilation.

4. Food moves through the small intestine within 7–10 hours. Motility patterns in the fed state mix food with digestive enzymes and distribute nutrients throughout the absorptive surface. All significant absorption of nutrients occurs in the small intestine.

5. Transit through the large intestine, from the cecum to the sigmoid colon, usually occurs over a period of 12–24 hours. The functions of the large intestine include fluid and electrolyte transport and fermentation of undigested carbohydrates (e.g., cellulose). Storage of fecal waste occurs in the distal large intestine; elimination of fecal waste typically occurs within 1–3 days after ingestion of a meal.

Gastric emptying is a key control point in the gastrointestinal tract to ensure the orderly delivery of nutrients in a form that can be digested and to give appropriate signals of fullness (satiety). Gastroparesis (“weak stomach”) is a common complication of poorly controlled diabetes mellitus and significantly slows gastric emptying. Gastroparesis causes early satiety and erratic stomach emptying, which can result in poor nutrient assimilation, making it more difficult to control blood glucose levels.

Structural Features of the Gastrointestinal Tract

There are four major histologic layers in the gastrointestinal tract, starting from the gut lumen and moving outward: mucosa, submucosa, muscularis externa, and serosa (Figure 7-2).

1. The mucosa is the most variable zone and consists of an epithelium, which is a single cell layer from the stomach to the anus. In most areas, the epithelium is highly folded to increase its surface area (e.g., for absorption) and is frequently invaginated to form the tubular exocrine glands. Exocrine secretions include mucus, electrolytes, water, and digestive enzymes. Numerous endocrine cells are also scattered among epithelial cells. Endocrine cells release gastrointestinal hormones into the blood in response to changes in the luminal environment; for example, the hormone cholecystokinin is released in response to fat and protein in the gut lumen. The epithelium is supported by a connective tissue lamina propria, which contains microvasculature and nerves, and by a thin smooth muscle layer, the muscularis mucosae.

2. The submucosa is a layer of connective tissue that contains the major blood and lymphatic vessels that serve the gastrointestinal tract. This area also contains numerous ganglion cells organized to form the submucosal (Meissner) nerve plexus.

3. The muscularis externa contains the two major smooth muscle layers responsible for mixing and moving food along the gastrointestinal tract: the inner circular layer and the outer longitudinal layer. The myenteric (Auerbach) nerve plexus lies between the two layers of muscle.

4. The serosa is a thin connective tissue layer that is continuous with the peritoneal mesentery in most locations. Several major structures enter through the serosa, including blood vessels, extrinsic nerves, and the ducts of the large accessory exocrine glands.

The peritoneal organs are covered by a serosa, whereas extraperitoneal or retroperitoneal organs are covered by an adventitia (loose connective tissue). The thoracic esophagus is an extraperitoneal structure and is therefore covered by an adventitia. The lack of a serosal covering of the esophagus is thought to facilitate early spread of esophageal cancer.

Successful assimilation of nutrients requires the coordination of multiple organs, and is achieved by a series of overlapping controls that are applied through neural, hormonal, and paracrine mechanisms. The major regulated processes that can generate change (effectors) in the gastrointestinal physiology are gut motility, epithelial secretion, and blood flow. Each of these processes has a level of intrinsic activity, referred to as gastrointestinal tone. Inputs from nerves and hormones are integrated with intrinsic tone to produce a final integrated response.

The control of gastrointestinal smooth muscle underlies gut motility. Gastrointestinal smooth muscle is classified as the visceral type and is composed of bundles of small cells that are electrically coupled via gap junctions (see Chapter 1). Most gastrointestinal smooth muscle cells exhibit spontaneous electrical activity called slow waves, which facilitate the rhythmic muscle contractions that occur in the gastrointestinal tract. Action potentials occur when voltage-operated Ca²⁺ channels open, resulting in Ca²⁺ entry and contraction. Ca²⁺ release from the intracellular stores may also trigger contraction.

Paralytic ileus is a temporary cessation of gut motility that is most commonly caused by abdominal surgery. Other common causes that result in an ileus are infection or inflammation in the abdominal cavity (e.g., appendicitis), electrolyte abnormalities (e.g., hypokalemia), and drug ingestion (e.g., narcotics). Signs and symptoms of paralytic ileus include nausea and vomiting, abdominal distension, and absent bowel sounds.

Enteric Nervous System

The ENS is a division of the autonomic nervous system (see Chapter 2). It is a large neural network located within the wall of the gastrointestinal tract, and can be viewed as a displaced part of the central nervous system (CNS) that is concerned with regulating gastrointestinal function. The ENS can be thought of as a “minibrain” with independent information processing capability. It contains a “program library” that initiates patterns of gastrointestinal activity (e.g., interdigestive, digestive, and emetic activity). The ENS is responsible for much of the moment-to-moment control of gut motility and secretion.

The ENS is arranged as myenteric and submucosal nerve plexuses (Figure 7-3A).

• The myenteric plexus is mainly involved with control of gut motility and innervates the longitudinal and circular smooth muscle layers.

• The submucosal plexus coordinates intestinal absorption and secretion through its innervation of the glandular epithelium, intestinal endocrine cells, and submucosal blood vessels.

Hirschsprung's disease is a congenital absence of the myenteric plexus, usually involving a portion of the distal colon. The pathologic aganglionic section of large bowel lacks peristalsis and undergoes continuous spasm, leading to a functional obstruction. The normally innervated proximal bowel dilates as a result of the obstruction and can lead to the most feared complication of Hirschsprung's disease, toxic megacolon!

In addition to its anatomic complexity, the ENS utilizes many different neurotransmitters, including acetylcholine, adenosine triphosphate (ATP), nitric oxide, and numerous peptides.

• Acetylcholine is the primary neurotransmitter involved in the stimulation of secretion and motility.

• ATP and nitric oxide function as inhibitory neurotransmitters.

• Numerous peptide neurotransmitters are found in both the ENS and the CNS and are referred to as gut-brain peptides. An example of a peptide neurotransmitter is vasoactive intestinal polypeptide (VIP), which is a potent stimulator of intestinal fluid and electrolyte secretion but inhibits motility.

Anticholinergic drugs such as amitriptyline, a tricyclic antidepressant, inhibit the effects of acetylcholine systemically, resulting in a myriad of side effects. Gastrointestinal side effects include xerostomia (dry mouth), constipation, ileus, and nausea and vomiting.

Gut-Brain Axis

Although the ENS can function without other connections, it is linked with the CNS via the parasympathetic and sympathetic nerves, giving rise to the concept of a gut-brain axis (see Figure 7-3B). The CNS may send “command signals” to the ENS, which link gastrointestinal activity with behavior; for example, salivation and gastric secretion occur in response to the thought or smell of food. Emotions can also have a profound effect on gut physiology via the gut-brain axis (e.g., diarrhea induced by anxiety). The link between the gut and the brain also conveys sensory input to the CNS, giving rise to the conscious sensations of fullness, satiety, nausea, and pain. The link between the ENS and the CNS is through the parasympathetic and sympathetic divisions of the autonomic nervous system.

• Parasympathetic innervation to the gastrointestinal system is via the vagus nerve and the sacral (S2–S4) spinal outflow. Long preganglionic axons arise from nerve cell bodies in the brainstem and the sacral spinal cord. Most fibers exert their effect by ending on ganglia within the ENS. Efferent innervation generally causes excitation (more secretion, more propulsive motility). The vagus nerve is particularly important in the control of the activity of the upper gastrointestinal tract during the fed state, with the stimulation of motility in the stomach and upper small intestine. It also stimulates gastric secretion, pancreatic secretion, and contraction of the gallbladder to deliver bile to the small intestine. Parasympathetic nerves contain sensory afferent fibers from the gastrointestinal tract, which convey nonpainful distension and nausea. Vagovagal reflexes are responses that involve the afferent and efferent signals confined to the vagus nerve; for example, distension of the stomach during a meal gives rise to an afferent signal, which results in stimulation of gastric acid secretion via the vagal efferents.

• The gut-brain axis includes the sympathetic nerves; preganglionic fibers arise in the spinal cord and terminate in the prevertebral ganglia. A rich supply of postganglionic sympathetic fibers innervates the vascular smooth muscle, which results in vasoconstriction. Other postganglionic fibers end within the ENS to direct inhibitory responses in the gastrointestinal tract; propulsive motility is decreased and the tone of the sphincters is increased. Sensory afferent signals within the sympathetic nerves convey the sensations of pain and nausea to the CNS.

Role of the Immune System

Communication via the gut-brain axis involves the immune system. Neuroimmune regulation in the intestines includes the mast cells, which are sensitive to a range of neurotransmitters and therefore can process information from the brain. The participation of mast cells in response to foreign antigens, through the release of mediators such as histamine, also provides a means of directly linking sensory information from the gut lumen to responses of the epithelial cells and smooth muscle.

Gastrointestinal Hormones

Hormones play a prominent role in the control of gastrointestinal function, and in most cases these hormones are secreted by the gastrointestinal mucosa itself. Figure 7-4 summarizes the sites of secretion, the stimuli for secretion, and the actions of the major gastrointestinal hormones. Gastrointestinal hormones are peptides, most of which are also found as neurotransmitters in the ENS and CNS, giving rise to the term gut-brain peptides. The release of hormones is influenced by the chemical environment in the lumen of the gastrointestinal tract; enteroendocrine cells have microvilli-bearing receptors that “taste” the gut lumen, allowing the cells to secrete hormone at the appropriate time. The timing of hormone secretion is also guided by “crosstalk” with the ENS. Gastrointestinal hormones are first secreted into the capillary blood in the gastrointestinal tract and must pass through the portal venous system and liver before entering the systemic circulation, a process known as first-pass metabolism.

First-pass metabolism is an important concept that spans many topics, particularly pharmacology. Orally administered drugs that are absorbed in the gastrointestinal tract must enter the hepatic portal circulation prior to becoming systemically available to other areas of the body. The hepatic portal vein carries nutrients, gastrointestinal hormones, and absorbed drugs directly from the gut to the liver. Many drugs are significantly metabolized by the liver enzymes, which reduces the amount of drug that is “bioavailable” to other areas of the body.

Paracrine Control

Paracrine control is exerted when a hormone diffuses locally to affect target cells (see Chapter 8). Three major examples of paracrine mediators in gastrointestinal physiology are serotonin, somatostatin, and histamine.

1. Serotonin is produced by enterochromaffin (EC) cells in the intestinal mucosa in response to distension of the gut wall. It exerts most of its effects indirectly through interactions with the ENS. The effects of serotonin are generally excitatory and result in increased intestinal motility and secretion.

   Carcinoid tumors arise from the EC cells. Because these cells originate as neuroendocrine cells, they often secrete hormones, most commonly serotonin. Systemic release of serotonin results in carcinoid syndrome with clinical manifestations of flushing, diarrhea, bronchospasm, and cardiac valvular disease. When carcinoid tumors arise in the gastrointestinal tract, they are most commonly seen in the ileum; the serotonin is secreted into the hepatic portal circulation, which undergoes first-pass metabolism. Serotonin is rapidly metabolized in the liver, resulting in very little systemic serotonin. Carcinoid syndrome will manifest once the tumor has metastasized to the liver and can release serotonin directly into the systemic circulation.

2. Somatostatin is a peptide produced by D cells and is a potent inhibitor substance in the gastrointestinal system. It may be released both into the blood to act in an endocrine fashion and also as a paracrine mediator. Somatostatin inhibits pancreatic and gastric secretion, relaxes the stomach and gallbladder, and decreases nutrient absorption in the small intestine. These actions result partly from inhibition of several other stimulatory gut hormones, including gastrin, secretin, gastric inhibitory peptide (GIP), and motilin.

   Ruptured esophageal varices can cause severe bleeding into the gastrointestinal tract. Somatostatin analogues (e.g., octreotide) are used to reduce bleeding from ruptured esophageal varices, and are effective because somatostatin is a potent gastrointestinal vasoconstrictor.

3. Local release of histamine in the stomach has a potent stimulatory effect on acid secretion. Enterochromaffin-like (ECL) cells are the source of histamine released as a paracrine mediator in the stomach.

Cimetidine is a histamine (H₂)-receptor blocker. H₂-receptors are found on the parietal cells and stimulate gastric acid secretion. When the H₂-receptors are blocked, the volume and acidity of gastric juice are reduced.

Mastication

Chewing (mastication) reduces the particle size of food and increases its exposure to saliva. This process lubricates food for swallowing and also aids in carbohydrate digestion by the enzyme salivary amylase. The distribution of foodstuffs around the mouth during chewing stimulates the taste receptors. Although chewing is a voluntary act, it is largely coordinated by the reflex centers in the brainstem.

Salivary Secretion

Saliva secreted from each of several salivary glands is mixed together in the mouth to produce a composite juice that is mildly alkaline. The volume of saliva produced is approximately 1.5 L per day.

• The submandibular glands secrete approximately 70% of saliva.

• The parotid glands secrete 25%.

• The sublingual glands secrete 5%.

Although located at different sites, each of the salivary glands is histologically similar. A salivon is the functional unit of a salivary gland and consists of clusters of acinar cells that drain via a duct system (Figure 7-5A). Acinar cells secrete proteins (e.g., the enzyme salivary amylase) in an isotonic electrolyte solution. Duct cells modify the primary saliva by absorbing NaCl (see Figure 7-5B).

Functions of Saliva

The three major functions of saliva are lubrication, protection, and digestion.

1. Lubrication includes moistening the mouth as well as lubricating the food to aid swallowing. Saliva facilitates movements of the mouth and tongue for speech and helps to dissolve chemicals within food for its presentation to the taste receptors.

2. Protection relates to reducing the adverse effects of oral bacteria (e.g., dental caries). The alkalinity of fresh saliva neutralizes acid produced by oral bacteria; the flow of saliva across the teeth also helps to wash away bacteria. Saliva contains additional substances that reduce bacterial growth.

   • Lysozyme attacks bacterial cell walls.

   • Lactoferrin chelates iron, which is needed by many bacteria for replication.

   • Immunoglobin A (IgA)-binding protein is required for the immunologic activity of IgA.

3. The digestive function of saliva is to begin the breakdown of carbohydrates and fats via the enzymes α-amylase and lingual lipase.

   • α-Amylase hydrolyzes starches. It has a pH optimum of 7, but remains active in the stomach because a high proportion of a meal remains unmixed for many minutes in the stomach. α-Amylase can break down up to 75% of the starch in a meal before the enzyme is denatured by gastric acid.

   • Lingual lipase hydrolyzes triglycerides and is secreted by the small salivary glands present on the surface of the tongue. It has an acidic pH optimum and remains active in the stomach.

Sjögren's syndrome is an autoimmune disease that destroys the exocrine glands and most commonly affects tear and saliva production. The hallmark manifestations of Sjögren's syndrome are dry eyes and dry mouth, known as sicca symptoms. Patients with xerostomia (dry mouth) lack adequate saliva. They typically have dental caries and halitosis due to bacterial overgrowth and have difficulty speaking or swallowing solid food due to inadequate lubrication.

Mechanism of Saliva Secretion

An isotonic primary secretion is formed by salivary acini. The contraction of myoepithelial cells moves fluid into the striated ducts via a short, narrow structure called the intercalated duct.

Saliva becomes hypotonic because the striated duct cells reabsorb NaCl, but not water. Figure 7-6 shows the relationship between the composition of final saliva and the rate of saliva collection at the mouth (salivary flow rate). At low flow rates, the duct cells reduce saliva osmolarity to about 100 mOsm/L; at high flow rates, there is less time for the ducts to absorb NaCl, and final saliva more closely resembles the primary isotonic solution produced by the acini.

Salivation is stimulated by the thought, smell, or taste of food by conditioned reflexes and by nausea. Sleep, dehydration, fatigue, and fear all inhibit salivation. Stimuli are integrated by the salivary nuclei in the pons, and salivation is determined by the resulting parasympathetic tone. Efferent nerves reach the salivary glands via the glossopharyngeal and facial nerves. Acinar secretion is stimulated by the release of acetylcholine, which acts via the muscarinic receptors. The only hormonal effect on saliva secretion is from aldosterone, which increases ductal Na⁺ absorption and K⁺ secretion.

Swallowing

Swallowing (deglutition) carries food from the pharynx into the esophagus. There is a voluntary stage when food is shaped into a bolus, collected on the tongue, and pushed into the pharynx. The tongue is then raised against the hard palate to create a pressure gradient that forces the bolus into the pharynx and beyond. When food enters the pharynx, the following involuntary events of the swallowing reflex occur:

• The nasopharynx is closed by the soft palate.

• Food is prevented from entering the airway by elevation and forward displacement of the larynx and deflection of the food bolus by the epiglottis.

• The upper esophageal sphincter relaxes to allow the bolus to enter the esophagus. The upper esophageal sphincter tone prevents the aspiration of the esophageal contents into the airway. It also prevents the entry of air into the esophagus, since the esophageal body exists at below atmospheric pressure in the thorax.

The above events are coordinated by a center in the reticular formation, which also inhibits breathing until food is in the esophagus. The oral and pharyngeal component of swallowing is controlled solely by extrinsic nerves. Neurologic damage (e.g., the result of a stroke) can adversely affect this phase of swallowing.

Esophagus

The function of the esophagus is to move food and liquid to the stomach and to keep it there. The esophagus has three functional zones:

1. The upper zone, which is 6–8 cm long, is closely related to the pharyngeal musculature and consists of striated muscle.

2. The middle zone (main body), which is 12–14 cm long, consists of smooth muscle.

3. The lower zone, which is 3–4 cm long, consists of smooth muscle and corresponds with the lower esophageal sphincter.

The area of the esophagus between the upper and lower esophageal sphincters remains quiescent until called upon to transport gas, fluids, or solids. Swallowing induces a wave of peristalsis in the esophagus known as primary peristalsis. If this wave is insufficient to move a bolus all the way to the stomach, distension of the esophageal wall by a remaining bolus induces secondary peristalsis, which is repeated until the bolus enters the stomach.

The technique of esophageal manometry, in which pressures are simultaneously measured at several locations along the esophagus, is used to assess swallowing and esophageal function (Figure 7-7). The resting esophagus has several notable features, including:

• Resting pressures are high at the upper and lower esophageal sphincters because both sphincters exhibit continuous resting smooth muscle tone.

• In the lumen of the body of the esophagus above the diaphragm, pressure is subatmospheric because the esophagus is passing through the intrathoracic space.

A different pattern of esophageal pressures is observed upon swallowing:

• The upper esophageal sphincter briefly relaxes, allowing the food bolus to pass into the esophagus.

• A contractile (peristaltic) wave sweeps down the esophagus.

• The lower esophageal sphincter and the proximal stomach relax to allow the bolus to enter the stomach.

Gastroesophageal reflux disease (GERD) occurs when the lower esophageal sphincter is incompetent, allowing the flow of gastric juices and contents back into the esophagus. Factors that reduce the lower esophageal sphincter tone and predispose to GERD include smoking, obesity, pregnancy, hiatal hernia, and smooth muscle relaxants (e.g. nitroglycerin, β blockers, and calcium channel blockers). Systemic diseases such as scleroderma can also affect the lower esophageal sphincter. GERD presents clinically as “heartburn” (substernal chest pain) and a sour taste in the mouth. However, reflux of acid is a common trigger for cough and asthma-like symptoms or more rarely a cause of aspiration pneumonitis.

Recurrent reflux of gastric acids damages the esophageal mucosa causing esophagitis, esophageal ulcers, and strictures. Chronic esophagitis can induce a metaplastic change in the esophageal mucosa. Barrett's esophagus is a gastrointestinal metaplasia of the lower esophagus that results from chronic GERD-induced esophagitis. This is the body's attempt to protect the esophagus from further damage. However, the transformation from squamous epithelium to intestinal epithelium (metaplasia) predisposes the cells to undergo dysplasia and eventual development of adenocarcinoma. As such, Barrett's esophagus is the main risk factor for adenocarcinoma of the lower esophagus. (Note: carcinoma of the upper esophagus is typically squamous cell carcinoma and is related to smoking and alcohol consumption.)

The control of swallowing and esophageal peristalsis involves interaction between the extrinsic nerves and the ENS.

• The upper esophageal sphincter is part of the pharyngeal musculature and is controlled by the extrinsic cranial nerves.

• The peristaltic wave is coordinated by the ENS and involves a wave of relaxation preceding a wave of contraction. Relaxation is mediated by the neurotransmitter nitric oxide, and contraction is mediated by the release of acetylcholine.

• Relaxation of the lower esophageal sphincter requires an intact ENS.

Patients with achalasia have a defect in the esophageal ENS. Esophageal manometry shows disruption of esophageal peristalsis and sustained high pressure at the lower esophageal sphincter because the sphincter fails to relax properly. Upper esophageal function is normal in patients with achalasia because it is controlled by the extrinsic nerves, not by the ENS. Swallowed food is retained in the esophagus, causing dilation of the esophageal body and eventually resulting in a reduction in peristalsis.

Overview of the Anatomy of the Stomach

The stomach has five main anatomic areas (Figure 7-8):

1. The cardia is the area where the esophagus enters the stomach.

2. The fundus is the rounded area above the cardiac area.

3. The body of the stomach is below the cardiac region.

4. The gastric antrum is the distal part of the stomach.

5. The pyloric sphincter guards the exit of the stomach into the small intestine.

From a functional perspective, the cardia, the fundus, and the body of the stomach comprise the oxyntic (parietal) gland area, which occupies roughly the proximal 80% of the stomach. The major exocrine secretions are all derived from this area. The pyloric gland area is the major source of gastric hormones, and comprises the distal 20% of the stomach.

The stomach mucosa consists of gastric pits and gastric glands (Figure 7-8). The surface mucosa and pits are lined by mucous cells. The oxyntic glands project downward and are composed of the oxyntic (parietal) cells, which secrete hydrochloric acid (HCl) and intrinsic factor, and the peptic (chief) cells, which secrete pepsinogen. Gastric glands in the antrum and pyloric area consist of endocrine cells, which secrete gastrin and somatostatin.

Gastritis (inflammation of the gastric mucosa) has many causes, but it is most commonly caused by an infection by the bacteria Helicobacter pylori. Other common causes include smoking, use of alcohol and nonsteroidal anti-inflammatory drugs (NSAIDs), and chronic stress. Regardless of the cause, if the surface epithelium of the stomach is acutely damaged, it rapidly regenerates in a process called restitution. This repair results from rapid division of stem cells, which are located in the neck of gastric glands.

Overview of Gastric Functions

The stomach is an important control point in the gastrointestinal tract because it must regulate the delivery of ingested food to the small intestine and present it at an appropriate rate and in a form that can be digested. This is achieved by integration of the following gastric motor and exocrine functions:

• The motor (motility) functions of the stomach include acting as a reservoir for ingested food, followed by mixing and grinding of food prior to its regulated delivery into the small intestine.

• The five main exocrine secretions of the stomach are:

  1. Water, to dissolve and dilute ingested food.

  2. Acid (HCl), to denature dietary proteins and to kill ingested microorganisms.

  3. Enzymes (pepsin and gastric lipase), to contribute to protein and fat digestion.

  4. Intrinsic factor, a glycoprotein that is necessary for vitamin B₁₂ absorption in the ileum.

  5. A mucus-bicarbonate barrier at the mucosal surface, to protect against the corrosive properties of gastric juice.

Autoimmune atrophic gastritis is an antibody-mediated destruction of gastric parietal cells, which causes hypochlorhydria (insufficient acid secretion) and a deficiency of intrinsic factor. The loss of intrinsic factor results in vitamin B₁₂ malabsorption and pernicious anemia.

• Endocrine functions of the stomach include the secretion of the hormones gastrin, somatostatin, and ghrelin. Gastrin and somatostatin are produced in the gastric antrum and regulate gastric acid secretion. Ghrelin is produced in the body of the stomach and is a factor involved in the regulation of hunger and satiety (see Chapter 2).

Gastric Motility

Patterns of stomach motility that occur in the fed state differ from those that occur in the fasting state (Figure 7-9).

• During fasting, the stomach is almost always in a quiescent state. It is interrupted at approximately 90-minute intervals by a series of peristaltic waves called the migrating motor complex. During these intervals, the larger indigestible components of food remaining in the stomach after a meal are flushed out into the small intestine.

• Ingestion of a meal requires transient relaxation of the proximal stomach with the arrival of each bolus of food, which is known as receptive relaxation. As a large amount of food accumulates in the stomach, there is gradual relaxation and dilation of the entire stomach, called accommodation, which allows storage of the food without an increase in intragastric pressure. Vagovagal reflexes are important in mediating both receptive relaxation and accommodation.

• Once food is ingested, the proximal stomach exhibits slow, sustained tonic contractions that gradually press food into the distal stomach. Tonic contraction of the proximal stomach determines intragastric pressure, which is the main determinant of gastric emptying of liquids.

• The distal stomach contracts rhythmically in a phase called antral systole, when food is mixed with gastric juice to reduce the particle size. Food is broken down by retropulsion, when food is forcefully reflected back from the pyloric sphincter into the stomach. The meal then becomes a suspension of partially dissolved particles called chyme. Peristaltic waves occur at a rate of 3–4 per minute in the distal stomach during antral systole. Each peristaltic wave pushes about 1 mL of chyme through the pyloric sphincter, which, at this stage of digestion, only allows small particles (about 0.5–2 mm) to pass through.

Mechanism of Gastric Acid Secretion

Inhibitors of gastric acid secretion are among the most commonly used drugs, including both prescription and over-the-counter drugs. To understand the action of antacids, it is necessary to have a knowledge of the cellular mechanism of acid secretion and of the neuroendocrine control processes that stimulate acid secretion. The oxyntic cells produce and secrete acid, described as follows (Figure 7-10):

• H⁺ is produced through the action of carbonic anhydrase, which produces carbonic acid from CO₂ and H₂O.

• The H⁺/ K⁺-ATPase is used to pump H⁺ from the cytoplasm into the stomach lumen in exchange for K⁺. K⁺ used in this exchange process is available from food or saliva, but it is also secreted via a luminal membrane K⁺ channel.

• Cl⁻ must be secreted to yield HCl. Cl⁻ uptake into oxyntic cells from the extracellular fluid occurs via the Cl⁻/HCO₃⁻ exchange at the basolateral cell membrane. HCO₃⁻ exits the cell in such a large quantity that the gastric venous blood becomes alkaline; this is known as the postprandial alkaline tide.

• Cl⁻ is secreted into the lumen via a Cl⁻ channel in the luminal membrane, which results in the generation of a large lumen-negative transepithelial potential difference across the stomach mucosa. H⁺ is transported against a large electrochemical gradient, which is reduced by a lumen-negative voltage.

Proton pump inhibitors (e.g., omeprazole) are very potent inhibitors of the H⁺/K⁺-ATPase pump on the luminal surface of oxyntic (parietal) cells. Omeprazole binds irreversibly to the H ⁺/K⁺-ATPase pump, thereby inhibiting H ⁺ secretion until new H ⁺/K⁺-ATPase protein is synthesized.

Two-Component Model of Acid Secretion

Approximately 1–2 L of gastric juice composed of mixed secretions from several cell types is produced per day. The composition of gastric juice changes with the overall secretion rate; at low secretion rates, it resembles interstitial fluid, but at high secretion rates, gastric juice becomes a solution composed primarily of HCl. The change in composition with the secretion rate is explained, as follows, by the two-component model:

1. The oxyntic component is the exocrine fluid secreted by the oxyntic cells and contains approximately 140 mM H⁺, 20 mM K⁺, 5 mM Na⁺, and 165 mM Cl⁻.

2. The nonoxyntic component is the collective secretions from all the other cell types present. Nonoxyntic secretion is a mildly alkaline fluid of constant composition and low volume.

When the stomach is stimulated, gastric juice is dominated by oxyntic cell secretion.

Stimulation of Gastric Acid Production

There are several pathways that function together to stimulate gastric acid secretion. There is neural stimulation by the vagus nerve (which releases the neurotransmitter acetylcholine), endocrine stimulation from gastrin, and paracrine stimulation from histamine. Oxyntic cells express receptors for acetylcholine, gastrin, and histamine, and each individual agonist is able to stimulate acid secretion.

• Gastrin and acetylcholine stimulate secretion via an increase in intracellular Ca²⁺.

• Histamine stimulates secretion via an increase in cyclic adenosine monophosphate (cAMP).

• Prostaglandin E₂, which is produced locally in the stomach, is a physiologic antagonist of histamine at the oxyntic cell and acts by inhibiting the production of cAMP. NSAIDs inhibit prostaglandin formation and increase gastric acid secretion.

There is strong cooperativity between acetylcholine, gastrin, and histamine. When histamine occupies its receptor at the oxyntic cell, there is potentiation of the stimulatory action of acetylcholine and gastrin upon the secretion of H⁺. Both gastrin and acetylcholine stimulate histamine release from the ECL cells; a large proportion of H⁺ secretion caused by gastrin is mediated via histamine secretion. This explains why H₂-receptor antagonists, sold as over-the-counter antacid agents, are effective at reducing gastric acid production. However, because proton pump inhibitors block acid secretion at the final common pathway of all agonists (the H ⁺/K⁺-ATPase pump), these drugs are much more effective at blocking acid secretion than are the H₂-receptor antagonists.

Phases of the Gastrointestinal Response

The terms cephalic, gastric, and intestinal are used when describing the phases that control the gastrointestinal responses to a meal. The cephalic phase is characterized by the anticipation and the sight, smell, and taste of food. The gastric and intestinal phases overlap and refer to the period when food is present in the stomach and intestines, respectively. Significant stimulation of gastric secretion occurs during the cephalic and gastric phases, whereas there is inhibition of secretion in the stomach during the intestinal phase.

During the cephalic phase, several stimuli result in vagal stimulation, including the thought of a food and the smell and taste of food during chewing and swallowing. There are two ways in which vagal innervation stimulates H⁺ secretion (Figure 7-11):

1. Direct release of acetylcholine by the postganglionic nerve terminals at the oxyntic cells.

2. Release of the neurotransmitter gastrin-releasing peptide (GRP) from the postganglionic nerves ending on the antral G cells. However, the response of gastrin secretion at this stage is relatively small because it is inhibited by low pH in the gastric lumen.

At least 50% of the acid secretion in response to a meal occurs during the gastric phase. Food entering the stomach neutralizes the acidity, which can cause the pH to increase to as high as six. At this point, the tonic suppression of gastrin secretion by low gastric pH is removed. The following two stimuli actively promote gastrin secretion:

1. Distension of the stomach triggers vagovagal and ENS reflexes, which stimulate G cells.

2. Breakdown products of protein digestion directly stimulate the G cells.

In Zollinger-Ellison syndrome, there is hypersecretion of gastric acid and peptic ulceration. Zollinger-Ellison syndrome is caused by a gastrin-producing tumor (gastrinoma) that is usually located in the pancreas. The sine quo non of gastrinoma is ulceration located distal to the duodenal bulb. About half of all patients with a gastrinoma have multiple endocrine neoplasia syndrome.

The period between meals is referred to as the interdigestive phase. During the interdigestive phase, the stomach contains a small volume of very acidic gastric juice due to a continued oxyntic cell secretion at about 10% of the maximal rate.

Inhibition of Stomach Secretion and Motility

The mechanisms that inhibit gastric secretion are an important counterbalance to stimulatory mechanisms and are necessary because of the corrosive nature of gastric juices. The level of acidity in the stomach and negative feedback from the small intestinal hormones are the main ways in which gastric activity is inhibited. Gastric acid secretion is maximal about 1–2 hours after the ingestion of a balanced meal. The buffering capacity of the meal eventually becomes saturated, and the gastric pH begins to decrease; at this stage, a significant proportion of the meal has entered the small intestine. There are two ways in which a decreasing gastric pH inhibits gastrin secretion:

1. Direct inhibition of G cells by H⁺ when the pH is reduced below 3.

2. Paracrine inhibition of G cells by somatostatin; the secretion of somatostatin from D cells is stimulated by low gastric pH.

Feedback inhibition of gastric H ⁺ secretion by the small intestine occurs due to hormones that are collectively known as enterogastrones. The luminal factors that trigger the release of enterogastrones include H⁺, fatty acids, and hypertonicity. Secretin is the primary enterogastrone and is released in response to the low pH in the duodenum. Figure 7-12 illustrates the enterogastrone concept and some mechanisms that are thought to be involved in this process.

Pepsins

Pepsins are proteolytic enzymes that attack the internal peptide bonds in proteins. They are secreted as two types of inactive pepsinogens in the stomach:

• Type I pepsinogen is secreted in the oxyntic gland area.

• Type II pepsinogen is secreted in the pyloric gland area.

The conversion of pepsinogen to pepsin occurs spontaneously when the pH is below 5; once active pepsin is present, it autocatalyses the conversion of pepsinogen to pepsin in a positive feedback manner. Pepsinogen secretion is stimulated by acetylcholine from the vagal and ENS efferent neurons. Stimuli include a local acid-sensitive reflex that ensures that pepsinogen is released when H⁺ is available for its conversion to pepsin.

Gastric Mucosal Protection

A layer of mucus located at the mucosal surface serves as a barrier mechanism that prevents acid erosion of the mucosa. This layer is effective in neutralizing acid because HCO₃⁻ secreted from the surface cells is trapped in the mucus (Figure 7-13). There is no mucus layer inside the gastric glands to protect cells in this area from high levels of luminal acidity. The oxyntic cells have a thick plasma membrane for protection, and the tight junctions between oxyntic cells have a very high resistance to prevent H⁺ back-diffusion into the submucosa.

Erosive gastritis can occur as a result of chronic use of NSAIDs. The mechanism by which NSAIDS cause gastritis involves the inhibition of prostaglandin synthesis in the stomach. Prostaglandins normally maintain the physicochemical barrier on the gastroduodenal mucosal surface by stimulating the secretion of mucus and bicarbonate. Loss of the protective mucus and bicarbonate barrier renders the gastric mucosa susceptible to damage by the acidic environment.

Pancreatic Function

The main digestive function of the pancreas is to secrete the enzymes that break down the macromolecules in food and to produce smaller nutrient molecules for intestinal absorption. Pancreatic enzymes are essential for digestion. The pancreas also secretes an alkaline fluid that neutralizes the acidic chyme that enters the small intestine from the stomach. This fluid is necessary because pancreatic enzymes have a neutral pH optimum. The pancreas has a separate endocrine function to secrete the hormones insulin and glucagon (see Chapter 8).

Structure of the Exocrine Pancreas

Most of the pancreas is comprised of epithelial cells, which produce an exocrine secretion of digestive enzymes in a HCO₃⁻ -rich solution. Digestive enzymes are synthesized and secreted by grape-like acini, which consist of 20–50 pyramidal cells that surround a small luminal space. Pancreatic acini produce a low-volume, enzyme-rich fluid that drains via a series of ducts into the main pancreatic duct. Pancreatic duct epithelial cells produce a copious amount of HCO₃ ⁻-rich fluid, which is added to the acinar secretion. The main pancreatic duct joins the common bile duct to form a common excretory duct, which is guarded by the Sphincter of Oddi. Exocrine pancreatic secretions and bile enter the duodenum when the Sphincter of Oddi is relaxed. About 1–2 L of pancreatic juice, consisting of a mixture of secretions from the acini and ducts, is secreted per day (Figure 7-14).

Acinar Cell Secretion

Acinar cells produce hydrolytic enzymes to aid in the digestion of fats, proteins, carbohydrates, and nucleic acids. The apical region of acinar cells is packed with secretory granules awaiting a stimulus to bring about their release by exocytosis (Figure 7-15). Several hormones and neurotransmitters, called secretagogues, stimulate pancreatic enzyme secretion. The two most important secretagogues are acetylcholine, secreted from vagal efferents, and the hormone cholecystokinin; both of these agonists act by causing an increase in cytosolic Ca²⁺ concentration.

Prevention of Pancreatic Autodigestion

Several features of enzyme synthesis and activation help to prevent autodigestion of the pancreas, including:

• Most enzymes are produced as inactive precursors called zymogens.

• Enzymes are sequestered in membrane-limited vesicles throughout synthesis to the point of exocytosis, avoiding contact with the acinar cell cytoplasm.

• Activation of zymogens occurs in the small intestine. The process depends on the conversion of the proenzyme trypsinogen to the active proteolytic enzyme trypsin. Trypsinogen is cleaved by the enzyme enterokinase, which is bound to the apical cell membranes of enterocytes lining the small intestine. Once trypsin is activated, it cleaves and activates all other zymogens.

• The pancreas produces a trypsin inhibitor to prevent activation of zymogens within the pancreas if trypsin is inappropriately activated inside the gland.

Pancreatitis occurs when pancreatic enzymes are activated within the pancreas (and surrounding tissues), resulting in autodigestion of the tissues. The most common causes of pancreatitis are gender specific and include gallstones in women and alcohol use in men. Pancreatitis is a painful condition, and is classically described as an epigastric pain radiating from the epigastrium to the back and is often relieved by leaning forward.

Pancreatic Duct

The mechanism of Na⁺ and HCO₃⁻ secretion by the pancreatic duct cells occurs via the following steps (Figure 7-16):

• HCO₃⁻ secretion from the cell cytoplasm into the lumen occurs via the Cl⁻/HCO₃⁻ exchange in the luminal cell membrane.

• To supply enough intracellular Cl⁻ to sustain the rate of Cl⁻/HCO₃⁻ exchange, Cl⁻ is recycled from the lumen into the cell via the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel.

• Na⁺ is secreted into the duct lumen following HCO₃⁻ secretion; water follows by osmosis to produce fluid secretion.

Pancreatic duct cells are stimulated to secrete HCO₃⁻ in response to the hormone secretin, which acts via cAMP and opens the CFTR channels.

Patients with cystic fibrosis lack a functional Cl⁻ channel in the luminal membrane, which results in defective ductal fluid secretion. The ducts become blocked with precipitated enzymes and mucus and the pancreas undergoes fibrosis (hence the name of the disease). Blocked ducts impair secretion of needed pancreatic enzymes for digestion of nutrients, resulting in malabsorption. Treatment of this type of malabsorption includes oral pancreatic enzyme supplements taken with each meal.

The composition of pancreatic juice varies with the rate of fluid secretion (Figure 7-17). The pancreatic flow-rate curves reflect changing proportions of acinar and ductal secretions in the pancreatic juice. Acini secrete a small volume of NaCl-rich solution, whereas duct cells produce a larger volume of a NaHCO₃⁻-rich solution. When the pancreas is stimulated, there is a predomination of duct cell fluid and the overall composition of pancreatic juice becomes rich in HCO₃⁻. The Na⁺ concentration does not change with the secretory rate because the primary acinar and duct secretions both have a similar Na⁺ concentration.

Control of Pancreatic Secretion

During the interdigestive state, there is only minimal secretion of pancreatic juice. Stimulation of pancreatic secretion begins during the cephalic phase of gastric acid production with the anticipation and sight, smell, and taste of food. Stimulation of the cephalic phase is mediated via the vagus nerve and the release of acetylcholine. There is minimal additional stimulation of the pancreas during the gastric phase. Most pancreatic stimulation occurs in the intestinal phase so that secretion is coordinated when chyme enters the small intestine.

• CCK stimulates acinar enzyme secretion; the secretion of CCK is stimulated by long-chain fatty acids and protein digestive products in the small intestine.

• Secretin stimulates ductal HCO₃⁻ secretion; acid entering the duodenum from the stomach stimulates the secretion of secretin.

• Acetylcholine and CCK both potentiate the effect of secretin on ductal HCO₃⁻ and fluid secretion. This potentiation is necessary because food buffers gastric acidity so that the pH of the duodenum may not be low enough to produce high secretin levels.

As food moves beyond the duodenum, the stimuli for pancreatic secretion gradually diminish and the pancreas returns to its resting condition, with a low secretory rate.

Liver Function

The digestive and excretory functions of the liver are associated with the secretion of bile via the biliary tract. Bile is a complex fluid that contains organic and inorganic secretions from the liver, which are important in the digestion of fats. The liver also serves many other functions, some of which are:

• Carbohydrate metabolism. The liver is both a source and a “sink” for glucose, and is a key effector in control of the blood glucose concentration. Glycogenolysis and gluconeogenesis add glucose to the blood. Glycogen synthesis, glycolysis, oxidative metabolism, and fat synthesis all consume blood glucose.

One of the key pathogenic mechanisms in patients with diabetes mellitus is an inappropriately high output of hepatic glucose. The antidiabetic drug metformin has many mechanisms of action, one of which is to reduce hepatic glucose output, thereby decreasing plasma glucose levels.

• Fat metabolism. Dietary lipids circulating in the form of chylomicrons (see fat absorption) are partially broken down during passage through the microcirculation by the enzyme endothelial lipoprotein lipase. The glycerol and fatty acids that are produced then enter the adipose and muscle cells. Remnant chylomicrons containing cholesterol, as well as long-chain fatty acids, are taken up by the liver. The liver uses fatty acids for energy metabolism via beta oxidation or for the synthesis of ketones.

• Cholesterol metabolism. The major sources of cholesterol are found in the diet plus de novo synthesis of cholesterol by the liver. The major elimination pathway for cholesterol is in bile, as native cholesterol, and via hepatic synthesis of bile acids. Bile acids are subsequently excreted in feces.

• Amino acid and protein synthesis. The liver expresses a wide range of amino acid uptake carriers. A large amount of amino acid is consumed for synthesis of serum proteins (e.g., albumin, clotting factors, and hormone-binding proteins). Amino acids can also be used for oxidative metabolism. Urea is formed as the final amino acid breakdown product.

The assessment of liver function in a patient with suspected liver disease includes determination of hepatocyte damage and synthetic function.

• Hepatocyte damage is indicated by elevated serum levels of the marker enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

• Synthetic function can be determined by measuring the serum albumin concentration. The adequacy of hepatic blood clotting factor production can also be assessed using the prothrombin time (see Chapter 3).

• Storage functions. The liver is the main storage site for the fat-soluble vitamins A, D, E, and K, and vitamin B₁₂, iron, and copper. Pathologic iron overload, a condition known as hemochromatosis, can cause liver damage due to excessive iron deposition in the liver.

• Detoxification and biotransformation. Removal of the bioactivity of many organic molecules, including steroids and hydrophobic drugs, occurs in the liver, generally in two phases:

  • Phase I biotransformation involves the cytochrome P450 enzymes.

  • Phase II biotransformation involves conjugation to generate products that are more soluble for excretion. Conjugation reactions involve the addition of glucuronate, sulfate, or glutathione to the parent molecule.

In the setting of liver failure, accumulating toxins can cause a myriad of clinical signs and symptoms. For example, accumulation of estrogen is thought to be responsible for gynecomastia, testicular atrophy, spider hemangiomas, and palmar erythema.

• Immune function. Kupffer cells in the liver are the largest group of fixed macrophages in the body. These cells are responsible for ingesting foreign bodies entering the blood via the gastrointestinal tract.

Functional Anatomy of the Liver

The liver is composed of histologically defined lobules (Figure 7-18). Chains of hepatocytes, usually composed of a single cell layer, separate the large blood-filled sinusoids, which are lined by very permeable fenestrated endothelia. The sinusoids of a single lobule drain into a central vein. The central veins of neighboring lobules unite to form the hepatic veins, which drain into the inferior vena cava. The portal vein provides 75% of hepatic blood flow, and the hepatic artery contributes to the other 25%. Blood from both the portal vein and the hepatic artery is mixed in the sinusoids. Because a large proportion of the blood supply is portal venous blood, hepatocytes are forced to function under low oxygen conditions.

Although the liver lobule is a convenient structure to visualize on histologic sections, it is not regarded as the functional unit of the liver. The function of hepatocytes is strongly influenced by the cellular microenvironment, which is mainly a function of the blood supply. The liver acinus is the smallest functional unit of the liver and consists of those hepatocytes that all receive a blood supply from the same hepatic arteriole and portal venule. An acinus is a three-dimensional ball of cells spanning more than one lobule. The vascular anatomy of the liver results in a “zonal” relationship between hepatocytes in an acinus and their arteriole. Different cellular microenvironments give rise to differences in cellular function.

• Zone I is closest to the arteriole, where cells receive the greatest delivery of oxygen and nutrients. Cells in zone I preferentially undertake oxidative metabolism, ureagenesis, and bile acid production.

• Zone II is a transitional zone between zones I and III.

• Zone III is furthest away from the arteriole, where the concentration of oxygen and nutrients is the lowest. Zone III cells undertake glycolysis, ketogenesis, and detoxification reactions.

Chronic passive congestion of the liver secondary to congestive heart failure results in centrilobular edema (edema around the central hepatic veins), a condition known as “nutmeg liver.”

Biliary System

Bile is a complex fluid secreted by the liver and consists of organic molecules in an alkaline solution. The biliary tract consists of a series of ducts that convey bile from the liver to the duodenum. Bile has three functions:

1. It facilitates the assimilation of dietary lipid; approximately 50% of dietary lipid appears in feces if bile is excluded from the small intestine. Bile facilitates fat digestion by promoting its emulsification and solubilization. This is achieved through the formation of mixed micelles, which enhance lipase action and then assist in the delivery of the digestive products to be absorbed by the enterocytes.

2. It provides a pathway to excrete hydrophobic molecules that may not be readily excreted by the kidney.

3. It assists in neutralizing gastric acid because it is an alkaline solution.

Hepatocytes secrete bile into the canaliculi, which are small 1-µm spaces bounded by neighboring hepatocytes. Canaliculi join together and convey hepatic bile toward small terminal ductules at the periphery of the liver lobules. Bile moves through a sequence of progressively larger ducts in each lobe of the liver and emerges in a hepatic duct. The hepatic ducts from each lobe join outside the liver to form the common hepatic duct. The cystic duct from the gallbladder joins the common hepatic duct to form the common bile duct. This network of ducts is known as the biliary tree (Figure 7-19).

Bile is stored between meals in the gallbladder, where it is concentrated. The integrated response to a meal includes contraction of the gallbladder during the intestinal phase. Bile, along with pancreatic secretions, reaches the small intestine via the common bile duct.

Gallbladder disease is common and occurs in several forms, ranging from asymptomatic cholelithiasis (gallstones) to biliary colic (blockage of the cystic duct). Different areas of the biliary tract can be involved in gallbladder disease. For example:

• Cholecystitis is blockage of the cystic duct with associated infection of the gallbladder.

• Choledocholithiasis is blockage of the common bile duct.

• Ascending cholangitis is blockage of the common bile duct with associated infection of the bile ducts.

• Gallstone pancreatitis occurs if the ampulla of Vater becomes blocked.

Bile Formation

Bile that emerges from the liver in the hepatic ducts is called hepatic bile and is a combination of canalicular bile and ductular bile. Hepatocytes secrete canalicular bile, an isotonic fluid containing NaCl, together with organic molecules that include bile salts, cholesterol, phospholipids, and bile pigments. The organic molecules may be synthesized by hepatocytes or taken up by hepatocytes from the sinusoidal blood. Canalicular bile flows into the biliary tree, where ductular bile is added by epithelial cells called cholangiocytes, which line the biliary ducts. Cholangiocytes resemble pancreatic duct cells and produce a HCO₃⁻-rich fluid in response to the hormone secretin.

Organic Molecules in Bile

Bile acids are the most abundant organic molecules in bile and comprise approximately 70% of the organic constituents of bile. Bile acids are amphipathic molecules with a hydrophobic nucleus on one side and several polar groups on the other. Hepatocytes synthesize and secrete the primary bile acids cholic acid and chenodeoxycholic acid, which are mostly conjugated with either glycine or taurine to produce, for example, glycocholate and taurocholate. Conjugation causes bile acids to ionize more readily into bile salts, which are more soluble in water (Figure 7-20). When bile acids are exposed to the small intestinal lumen, some of the primary bile salts undergo bacterial modification. About 10–20% of bile salts undergo deconjugation, returning them to native bile acids. Native bile acids are reabsorbed in the small intestine and reconjugated in the liver prior to being secreted again. Dehydroxylation may also occur to create secondary bile acids (cholic → deoxycholic acid; chenodeoxycholic acid → lithocholic acid). Because of the loss of a polar –OH group, secondary bile acids become less soluble than the parent molecule.

When the bile acid concentration exceeds a “critical micellar concentration,” bile salts interact to form aggregates known as micelles. The micelle provides a polar outer shell, which interacts with water, and a hydrophobic inner region. Long-chain fatty acids, cholesterol, and other hydrophobic molecules readily dissolve inside the micelles. The primary bile produced in the liver includes phospholipids, which are secreted by hepatocytes and constitute about 20% of the organic molecules in bile. Phospholipid molecules readily align with bile salts to form mixed micelles, which have a greater capacity to dissolve other hydrophobic molecules than do bile salts alone.

Cholesterol, which is secreted by hepatocytes into canalicular bile, normally constitutes about 4% of the biliary solids. Cholesterol is very hydrophobic and must be at the center of a micelle to be dissolved in aqueous solutions. Other organic components of bile include bile pigments and a range of proteins.

There are two types of gallstones:

1. Cholesterol gallstones are the most common type of gallstone. The main risk factor for cholesterol gallstone formation is excessive excretion of cholesterol, which is common in obese patients.

2. Pigment gallstones are mainly composed of calcium bilirubinate. Patients with chronic hemolytic diseases are most at risk of developing this type of gallstone due to the high levels of bilirubin excretion (bilirubin is a breakdown product of hemoglobin). The presence of calcium causes the radiopacity of pigment gallstones.

Enterohepatic Circulation of Bile Acids

The enterohepatic circulation is a circuit in which solutes are secreted by the liver only to be returned to the liver via intestinal reabsorption. Molecules in the enterohepatic circulation are:

• Secreted into bile by hepatocytes.

• Delivered to the small intestine via the biliary tract.

• Reabsorbed from the small intestine.

• Returned to the liver via the portal venous system to become available again for uptake and secretion by hepatocytes.

Many hydrophobic drugs (e.g., acetaminophen) are deactivated by the liver and excreted into bile; enterohepatic recycling frequently occurs, slowing the rate of drug elimination.

Enterohepatic recycling is physiologically important for bile salts and bile acids because the bile acid pool is not large enough to assimilate the lipid content of a typical meal (Figure 7-21). Bile salts and bile acids are recycled approximately two times during each meal, and about six to eight times each day via the enterohepatic circulation. About 95% of the bile salts that arrive in the intestine are reabsorbed. Bile salts that become deconjugated revert to bile acids, which are mostly undissociated and are reabsorbed by simple diffusion in the jejunum. Most primary and secondary bile salts are reabsorbed via Na⁺-bile salt cotransport when they reach the distal ileum. A small amount of bile acid (mostly as lithocholic acid) is lost in fecal excretion each day. The rate of bile acid loss in feces is matched by the rate of hepatic bile acid synthesis, thereby maintaining the bile acid pool.

The enterohepatic circulation of bile acids can be intentionally disrupted as a treatment for high blood cholesterol levels (hypercholesterolemia). Disruption can be achieved by ingestion of bile-binding resins (e.g., cholestyramine), which prevent bile acid reabsorption in the distal ileum, thereby causing fecal bile acid excretion. When bile acids fail to return to the liver, the hepatic synthesis of new primary bile acids is stimulated, which requires an increased supply of cholesterol. The increased demand for cholesterol is met in two ways:

1. Increased uptake of low-density lipoproteins (LDLs) from the blood, which has the desired therapeutic effect of reducing plasma LDL levels.

2. Increased new cholesterol synthesis via stimulation of the enzyme HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzymeA reductase) in the liver.

The additional cholesterol is converted into bile acids and is secreted into the biliary tract. In the setting of impaired enterohepatic circulation, the bile acids and bile salts will eventually be excreted in feces.

Choleresis

Choleresis is the secretion of bile fluid by the liver. Choleretics are substances that stimulate choleresis. Fluid secretion into bile occurs by osmosis following the secretion of solutes:

• Bile salts are the most important choleretics. Fluid secretion into the canaliculi is bile salt-dependent, demonstrated by the increase in bile fluid flow as bile salt secretion increases (Figure 7-22). This occurs physiologically when bile salts return to the liver in the enterohepatic circulation and are taken up again by hepatocytes. Choleresis can also be stimulated pharmacologically by administering bile salts (e.g., ursodiol).

• Canalicular bile contains several other solutes, which are secreted by hepatocytes and grouped together as “nonbile acids.” These solutes entrain a fairly constant background of bile fluid secretion, described as the non–bile salt-dependent fraction (Figure 7-22).

• Hepatic bile includes additional fluid secreted as ductular bile. Secretion of fluid by the cholangiocytes is driven by active NaHCO₃ secretion.

Gallbladder

The gallbladder is a blind outpouching of the biliary tree. It is a distensible muscular organ with a capacity of only 20–50 mL. The function of the gallbladder is to store and concentrate bile between meals and to eject bile into the duodenum during the digestion of a meal. During the interdigestive phase, the gallbladder is relaxed and the sphincter of Oddi is contracted, promoting storage of hepatic bile in the gallbladder. Contraction of the gallbladder during the intestinal phase of a meal delivers the maximum amount of bile into the small intestine at the time when nutrients are present. Therefore, the control of the gallbladder has several components (Figure 7-23A):

• During the cephalic phase, there is gradual rhythmic contraction of the gallbladder, mediated by the cholinergic vagal neurons.

• The entry of a meal into the small intestine stimulates CCK secretion. CCK is the most powerful signal for gallbladder contraction and also mediates the relaxation of the sphincter of Oddi, allowing biliary and pancreatic secretions to enter the duodenum.

• During the intestinal phase, increasing levels of secretin stimulate cholangiocyte secretion, providing additional HCO₃⁻ to neutralize acidic chyme.

• Once enterohepatic recycling of the bile acids begins, choleresis occurs and hepatic bile secretion accelerates.

Bile is secreted at a fairly constant rate between meals, with more than 50% of the daily hepatic bile produced entering the gallbladder during this interdigestive period. This volume of hepatic bile far exceeds the volume of bile in the gallbladder, and the excess fluid volume must be absorbed by epithelial cells lining the gallbladder. Concentrated bile is more effective for promoting fat digestion. The mechanism of salt and fluid absorption is shown in Figure 7-23B. The surface epithelium of the gallbladder secretes mucins and H⁺ for protection against the alkaline bile in the gallbladder lumen.

Bile Pigments

The major bile pigment is bilirubin, which is a breakdown product of hemoglobin. The pathway from the formation of bile pigments to their final excretion is complex, and is responsible for the normal coloration of both feces and urine (Figure 7-24).

• The process begins with ingestion of senescent red blood cells by macrophages. Heme oxygenase is the key enzyme in macrophages that is required to break down the heme moiety from hemoglobin; bilirubin is the end product of this pathway.

• Bilirubin is released from macrophages and bound to albumin in the plasma because of its low solubility in water. This protein-bound form of bilirubin is referred to as unconjugated (or indirect) bilirubin.

• Hepatocytes take up free bilirubin from plasma and convert it to bilirubin diglucuronide via the enzyme glucuronyl transferase; this form of bilirubin is called conjugated (or direct) bilirubin and is water soluble.

• Hepatocytes secrete conjugated bilirubin into bile canaliculi.

• About half the conjugated bilirubin delivered to the intestine is excreted unaltered in feces. The action of intestinal bacteria metabolizes the remaining conjugated bilirubin to the colorless molecule urobilinogen.

• About 80% of urobilinogen passes to the colon, where it is metabolized by bacteria and colors feces with the brown pigment stercobilin.

• The remaining 20% of intestinal urobilinogen enters the enterohepatic recycling pathway; however, some urobilinogen escapes hepatic reuptake and enters the systemic circulation. Urobilinogen in blood is filtered at the kidney and colors the urine yellow when it is oxidized to the pigment urobilin.

Jaundice is a disease that manifests with yellowing of the sclera, the mucous membranes, and the skin, and occurs when plasma bilirubin concentration (unconjugated or conjugated) exceeds about 2 mg/dL. Excess production of bilirubin, or a failure of the hepatocytes to take up or conjugate bilirubin, results in an accumulation of the unconjugated form in blood. If the hepatocytes fail to adequately secrete bilirubin, or if the bile duct is obstructed, then there is an accumulation of the conjugated form of bilirubin. The different types of hyperbilirubinemias that can lead to jaundice are outlined in Table 7-1 and classified as follows:

1. Prehepatic jaundice is caused by conditions that present an excessive bilirubin load to the liver.

2. Hepatic jaundice results from an inability to take up, metabolize, or excrete bilirubin.

3. Posthepatic jaundice is caused by an obstruction to the biliary tract.

Obstructive jaundice, such as occurs with a malignant tumor of the head of the pancreas, results in suppression of hepatic bile flow and reabsorption of conjugated bile into the circulation. Suppressed bile flow results in acholic (light or clay-colored) stool, whereas reabsorbed bile is excreted in urine, causing dark urine (bilirubinuria).

Structure of the Small Intestine

The small intestine is several meters long and extends from the pyloric sphincter of the stomach to the junction with the large intestine at the ileocecal sphincter. It has three regions: the short duodenum proximally and the jejunum and the ileum distally. Exocrine secretions from the salivary glands, the stomach, and the pancreas and liver, plus secretions of the small intestine itself, are mixed with food for digestion and absorption. Several anatomic features of the small intestine amplify the surface area for absorption, including transverse folds in the mucosa (plicae circulares), the arrangement of the mucosa into villi, and the presence of microvilli on the enterocytes that line the small intestine (Figure 7-25).

The villus is the functional unit of the intestine. The villus epithelium consists of enterocytes, mucous-secreting goblet cells, and endocrine cells. Three regions of a villus form a functional continuum: the crypt, the maturation zone, and the villus tip.

1. The crypt contains rapidly dividing stem cells that force migration of cells up the side of a villus. The cells initially produced in the intestinal crypts are immature and do not express enzymes or membrane transporters for nutrient absorption. Crypt cells are the source of intestinal fluid secretion.

2. The maturation zone is an intermediate zone where cells are moving toward the tip of the villus and are beginning to expresses enzymes and absorptive membrane transport proteins.

3. At the villus tip, enterocytes are fully differentiated and undertake the absorption of nutrients, electrolytes, and fluid. After 3–4 days, the cells are sloughed off the villus tip as a defense mechanism against insults from the luminal contents.

Celiac sprue is a malabsorption syndrome caused by hypersensitivity to wheat gluten and gliadin, resulting in immune-mediated destruction and denudation of the small intestinal villi. The denuded small intestine results in malabsorption of nutrients, causing diarrhea (excess fecal fluid) and steatorrhea (excess fecal fat), with associated abdominal bloating and flatulence. Removal of gluten from the diet will resolve the condition. However, resolution of the malabsorption will not occur immediately upon dietary change because the crypt cells require a few days to mature and rebuild the absorptive intestinal villi.

Motility

During the fed state, there is a great deal of motor activity in the small intestine. The three functions of small intestinal motility during the fed state are:

1. Mixing of foodstuffs with digestive secretions and enzymes.

2. Distribution of the luminal contents around the mucosa for absorption.

3. Propulsion of the luminal contents in the aboral direction (away from the mouth).

When nutrients enter the small intestine, transit is initially fast and chyme is spread along the small bowel; transit then slows to promote absorption. There are two major types of motility that occur in the small intestine during the fed state (Figure 7-26):

1. Segmentation contractions produce a string of segments that constantly form and reform. The main function of segmentation contractions is mixing of the luminal contents.

2. Peristalsis consists of a wave of contractions that moves a bolus aborally. The function of peristalsis is propulsion of luminal material. Peristalsis is a reflex, and the main stimulus is moderate distension of the gut wall. The circular muscle contracts in the upstream contracting segment, forcing the bolus forward; receptive relaxation of the circular muscle in the downstream segment reduces the force needed to move the bolus aborally.

The numerous contractions of the small intestine in the presence of food appear chaotic, and there is overlap in the function between peristaltic and segmenting contractions. Most peristaltic contractions travel less than 2 cm and thus contribute to mixing. Segmenting patterns are faster in the upper small intestine than in more distal areas; this gradient of segmentation rate creates a pressure gradient that assists aboral propulsion (Figure 7-26). An alternative classification of intestinal movements defines three variations:

1. Tonic contraction of sphincters.

2. Rhythmic phasic contractions (small peristaltic contractions and segmentation).

3. Giant migrating contractions (powerful peristaltic contractions).

Fluid Absorption

The intestine receives a large daily fluid load that must be absorbed. A typical daily fluid load to the jejunum is 7–10 L per day, consisting of about 1–2 L each of dietary water, saliva, gastric juice, pancreatic juice, and intestinal secretion, and about 0.5 L of bile. The small intestine reabsorbs about 6–8 L per day of fluid by isosmotic transport, with a maximum possible absorption rate of approximately 12 L per day. The rate of absorption of small intestinal fluid is not subject to significant physiologic regulation by the mechanisms that govern the extracellular fluid volume (e.g., renin-angiotensin-aldosterone system).

Because of the high epithelial water permeability of the small intestine, there is rapid osmotic equilibration between the duodenal chyme and plasma. If food has a high water content and is hypotonic to plasma, there is rapid water uptake. More frequently, a meal is hypertonic and water initially enters the small intestine from the extracellular fluid by osmosis. Subsequent absorption of fluid depends on the active transport of nutrients and electrolytes (Figure 7-27). Na⁺ uptake at the luminal membrane is driven by low intracellular Na⁺ concentration. The driving force for Na⁺ uptake is maintained by active Na⁺ extrusion at the basolateral membrane by the Na⁺/K⁺-ATPase. Fluid absorption in the upper small intestine is mainly coupled to Na⁺/nutrient uptake, although Na⁺/H⁺ exchange is also present in this area of the gut. By the time the food reaches the ileum, most sugars have been absorbed and fluid absorption is more dependent on NaCl reabsorption.

Approximately 2 L per day of fluid is delivered to the large intestine, which is roughly the initial dietary fluid load. The colon absorbs approximately 1.9 L, leaving about 0.1 L per day in feces. The maximum reabsorptive capacity of the colon is approximately 5 L per day; diarrhea results if the total fluid delivery to the colon exceeds 5 L per day.

Fluid Secretion

Both the small intestine and the large intestine secrete fluid from the crypt cells. Secretion is necessary for lubrication, as evidenced by the high incidence of obstruction of the gut when secretion is impaired in diseases such as cystic fibrosis. Fluid secretion also provides a source of Na⁺ for coupling to nutrient absorption, which is needed when a meal contains insufficient Na⁺ for sugar and amino acid uptake. Antibodies secreted in the area of the intestinal crypts also require fluid secretions to reach the lumen in the gut.

The mechanism of intestinal fluid secretion is clinically important because it is activated by a number of bacterial enterotoxins that cause secretory diarrhea. The key step in the mechanism of fluid secretion from the crypt enterocytes is opening of the Cl⁻ channels in the luminal cell membrane (Figure 7-28). There are two types of Cl⁻ channels present:

1. cAMP-activated Cl⁻ channels, for which the ENS neurotransmitter VIP is an important secretagogue.

2. Ca²⁺-activated Cl⁻ channels, for which acetylcholine from ENS neurons and serotonin from the EC cells are both secretagogues.

Enterotoxic Escherichia coli (traveler's diarrhea due to E coli) and Vibrio cholera (cholera due to V cholera) both produce enterotoxins that utilize cAMP to induce secretory diarrhea. Cholera, for example, irreversibly activates adenylyl cyclase, causing continuous production of cAMP and a severe Cl⁻-rich watery diarrhea. There can be a significant fluid loss, and death can occur if there is a delay in rehydration and electrolyte replacement.

Intestinal Ca²⁺ Absorption

Ca²⁺ is reabsorbed in the duodenum and upper jejunum; about 30–80% of dietary Ca²⁺ typically is absorbed. About one third of the net Ca²⁺ uptake occurs passively via the paracellular route across the tight junctions. The remaining fraction occurs actively through regulated Ca²⁺ transport pathways in the enterocytes (Figure 7-29):

• Ca²⁺ enters the enterocytes down a steep electrochemical gradient via the Ca²⁺ channels.

• To prevent an increase in intracellular free Ca²⁺ concentration, Ca²⁺ binds to the protein calbindin within the cytoplasm.

• Extrusion of Ca²⁺ from the cells occurs by primary active transport (Ca²⁺-ATPase) and secondary active transport (3Na⁺/Ca²⁺ exchange), against a large electrochemical gradient.

The Ca²⁺uptake mechanism is stimulated by vitamin D (see Chapter 8).

Sarcoidosis is a systemic disease of unknown etiology. It produces noncaseating granulomas that secrete a vitamin D-like substance, resulting in increased intestinal Ca²⁺ absorption and hypercalcemia in some patients.

Iron Homeostasis

The regulation of iron homeostasis is unusual compared to other minerals because it centers on the control of dietary uptake rather than on renal excretion. Tight regulation of iron levels is important because iron is highly reactive due to its redox chemistry and alternates between Fe^3 + (ferric, oxidized iron) and Fe²⁺ (ferrous, reduced iron). About 70% of total body iron is associated with hemoglobin, and an additional 3% is associated with the muscle oxygen-binding protein myoglobin. Most of the remainder of total body iron is in a tissue storage form bound to the protein ferritin.

Iron is transported in blood plasma using a binding protein called transferrin. The iron bound to transferrin is in equilibrium with the very small amounts of free Fe²⁺ in the extracellular fluid and with iron that is bound to ferritin in the tissues. The total amount of iron in the body is subject to negative feedback regulation (Figure 7-30A). When the iron ferritin store in the liver is full, the liver releases an iron regulatory factor called hepcidin. Increased hepcidin inhibits Fe²⁺ uptake by the intestinal enterocytes, preventing iron overload.

Normal daily losses of iron are small, with only 0.6 mg per day in men and about double this amount in women (due to variable menstrual loss). Iron intake generally exceeds 20 mg per day in the typical Western diet, so only a small fraction of ingested iron needs to be absorbed. However, in the developing world, dietary iron deficiency is the most common cause of anemia. Intestinal iron absorption occurs through several mechanisms (see Figure 7-30B):

• In a typical nonvegetarian diet, most dietary iron arrives associated with heme, which has its own intestinal transport protein; iron is released by the action of heme oxygenase within the enterocyte.

• Other sources of dietary iron only become available following exposure to the low pH gastric environment. This accounts for the high incidence of iron deficiency anemia in patients who have had a gastrectomy.

• Most free dietary iron is presented in the Fe³⁺ form and must be converted to Fe²⁺ prior to uptake via the enzyme Fe³⁺ reductase in the brush-border membrane.

• Most Fe²⁺ absorption occurs via a divalent cation transporter (DCT1). Uptake of Fe²⁺ also occurs by endocytosis of transferrin, which is secreted by enterocytes into the intestinal lumen, where it binds free Fe²⁺.

• Once inside the enterocyte, iron can either bind to ferritin or is transported across the basolateral cell membrane via the transport protein ferroportin.

Hemochromatosis is an autosomal recessive disease caused by mutations in a gene referred to as HFE. The abnormal HFE gene is unable to regulate iron absorption, resulting in toxic iron overload. Although the pathogenesis is not completely understood, the hepcidin system becomes less effective, which results in loss of negative feedback to stop excess iron absorption. The most common tissues (and toxic manifestations) affected by the iron toxicity are the liver (cirrhosis), the skin (bronze discoloration), and the pancreas (diabetes). Changes in the skin and pancreas illustrate why hemochromatosis is said to cause “bronze diabetes.”

Nutrient Digestion and Absorption

The major classes of nutrients are carbohydrates, proteins, and fats. Most nutrients are large molecules that must be broken down into smaller molecules that can be absorbed. Digestion is the chemical breakdown of food by enzymes and can occur at three sites (Figure 7-31A):

1. Luminal digestion occurs within the lumen of the gastrointestinal tract and is mediated by enzymes from the salivary glands, the stomach, and the pancreas.

2. Membrane digestion is the action of enzymes fixed to the brush-border membrane of enterocytes. Such enzymes are synthesized by enterocytes and inserted into the membrane.

3. Intracellular digestion is mediated by cytoplasmic enzymes within enterocytes.

Nutrient absorption occurs in the small intestine (see Figure 7-31B). The proximal small intestine absorbs almost all of the iron and Ca²⁺ that is assimilated from food.

Carbohydrates can be absorbed along all parts of the small intestine, but their absorption is usually completed in the proximal small intestine. Absorption of other nutrients (including protein, fat, salts, and water) is spread more uniformly along the small intestine. Bile acids and vitamin B₁₂ are absorbed specifically in the distal ileum.

Carbohydrate Digestion

Carbohydrates are the major source of calories in the Western diet, with about 400 g per day consumed. Approximately 60% is starch, about 30% is sucrose, and about 10% is lactose. Digestion reduces carbohydrates to their component monosaccharides: glucose, galactose, and fructose. Figure 7-32A summarizes the main dietary carbohydrates, the specific enzymes that break down the carbohydrates, and the final products of digestion.

Starch is a polymer of glucose; its luminal digestion begins with salivary amylase and is completed by pancreatic amylase. Although salivary amylase has a neutral pH optimum, it remains active for a long time in the stomach within a food bolus, where it is buffered from gastric acidity. Amylase breaks the α-1,4 glucose linkages to produce oligosaccharides of various lengths, known as dextrins. Much of the oligosaccharide and disaccharide digestion occurs by membrane digestion. The enzymes glucoamylase and isomaltase break down oligosaccharides; the disaccharides sucrose, lactose, and maltose are broken down by sucrase, lactase, and maltase, respectively.

Lactase deficiency is common in adults from nonwhite populations and results in milk intolerance, with manifestations of osmotic diarrhea and bloating due to fermentation of lactose in the colon.

Carbohydrate Absorption

The small intestine has a very large capacity for absorption of sugars, which are all absorbed as monosaccharides (see Figure 7-32B).

• Glucose and galactose uptake from the gut lumen occur, with equal affinity, by secondary active transport via the Na⁺-coupled cotransporter SGLT-1. Oral rehydration therapy is effective at restoring body fluid volume because the ingested fluid contains Na⁺ and glucose, and their uptake drives fluid absorption.

• Fructose is taken up by facilitated diffusion across the brush border membrane via GLUT5. Fructose, glucose, and galactose all exit enterocytes via the facilitated diffusion carrier GLUT2 in the basolateral cell membranes. A small number of patients do not express functional SGLT-1 and are unable to reabsorb glucose; these patients can survive with adequate dietary fructose because it can be absorbed via GLUT5 and converted into glucose by the liver.

Protein Digestion

Dietary protein is assimilated either as amino acids or small peptides. A combination of luminal digestion, membrane digestion, and intracellular digestion is used to break down proteins. Luminal digestion begins with pepsin in the stomach. The partially digested proteins that enter the small intestine are hydrolyzed by three pancreatic endopeptidases (acting on internal peptide bonds): elastase, chymotrypsin, and trypsin. The oligopeptides produced by endopeptidases are further broken down by ectopeptidases, which act from the carboxy terminus of a peptide to remove one amino acid at a time. Carboxypeptidase A digests the products produced by the actions of chymotrypsin and elastase, and carboxypeptidase B acts on the products of trypsin digestion. The enzyme aminooligopeptidase is anchored to the enterocyte brush-border membrane and acts at the amino terminus of short peptides to release amino acids.

Amino Acid and Peptide Absorption

Amino acids are a chemically diverse group of molecules, and several transport systems are needed for their absorption. Most of the systems are cotransporters that couple amino acid entry to that of Na⁺; others are facilitated diffusion carriers, which are Na⁺ independent. The normal mixture of amino acids and small peptides produced by enzyme digestion are absorbed faster than the same quantity of only amino acids. This phenomenon is called kinetic advantage and is explained by the mechanism of H⁺-linked cotransport systems for dipeptides and tripeptides, which operate independent of amino acid carriers (Figure 7-33). Short peptides that are absorbed by enterocytes are quickly broken down inside the cell to amino acids and are transported across the basolateral membrane into the blood. Each transport cycle of a dipeptide or a tripeptide carrier transports the equivalent of two or three amino acids into the enterocyte, accounting for rapid net uptake of protein products from the lumen through this pathway.

Fat Digestion

Triglycerides are the most abundant dietary form of lipid. Other lipids include phospholipids, sphingolipids, sterols, and the fat-soluble vitamins A, D, E, and K. Nondietary sources of fats include lecithins and cholesterol from bile, sloughed enterocytes, and microbes. Lipid digestion involves a mechanical phase and a chemical phase.

The mechanical phase includes chewing and grinding peristalsis in the stomach, which together create an emulsion with large fat droplets being sheared into smaller droplets. When chyme enters the small intestine, bile is added. Bile salts reduce surface tension at the fat droplet and water interface and further aid the formation of a fine emulsion.

The chemical phase of fat digestion occurs when lipases remove fatty acids from the triglyceride molecules. Lipases are termed as acid or alkaline lipases, based on their pH optimum. Lingual lipase from the salivary glands and gastric lipase from the fundus of the stomach are acid lipases with a pH optimum between 3.5 and 5.5. In adults, acid lipases account for about 20% of total lipolysis, but in neonates this can be over 50% of the total lipolytic activity. Alkaline lipase is secreted by the pancreas and has a pH optimum between 6 and 8. The action of pancreatic lipase on triglycerides produces a monoglyceride and two free fatty acids. Pancreatic lipase requires colipase to effectively hydrolyze fats. Colipase is secreted by the pancreas and acts at the surface of a micelle by displacing a bile salt molecule, thereby providing a binding site for pancreatic lipase. Long-chain fatty acids produced by the action of pancreatic lipase are insoluble in water and must enter the core of a micelle to be dissolved. Other lipases include phospholipase A₂ , which degrades lecithins and other phospholipids, and carboxyl ester lipase (nonspecific lipase), which is able to hydrolyze cholesterol esters.

Because the pancreas normally oversecretes lipase, ingested fats can be hydrolyzed with only 10% of the lipase secreted. A patient with chronic pancreatic insufficiency is likely to have experienced very extensive destruction of the gland by the time the clinical signs of maldigestion become apparent (e.g., steatorrhea, bloating, colonic distension, gas, and nutrient excretion in feces).

Fat Absorption

Medium-chain fatty acids are able to freely diffuse from the intestinal lumen into the blood without modification; however, most triglyceride digestion produces long-chain fatty acids. Absorption occurs via the following steps (Figure 7-34):

• Long-chain fatty acids dissolve in micelles, which provide a means for hydrophobic molecules to diffuse through an unstirred fluid layer at the intestinal surface (Figure 7-34A).

• The unstirred fluid layer has a lower pH than the neutralized chyme, which destabilizes micelles as they approach surface cells; long-chain fatty acids escape the micelle and enter the enterocyte by diffusion through the plasma membrane.

• Enterocytes convert long-chain fatty acids back into triglycerides within the smooth endoplasmic reticulum.

• Triglycerides are complexed with apoproteins within the smooth endoplasmic reticulum.

• The Golgi apparatus delivers the lipoprotein complexes in large vesicles called chylomicrons, which are transported across the basolateral membrane by exocytosis. Chylomicrons are too large to pass across the capillary endothelia and instead enter the lymphatic vessels.

• Chylomicrons enter the systemic blood when lymph drains into the venous system.

• The action of the enzyme endothelial lipoprotein lipase liberates fatty acids from chylomicrons, primarily for uptake by adipose tissue and muscle cells; the remnant chylomicrons are processed by the liver.

Fat malabsorption results in increased levels of fecal fat excretion. Steatorrhea is the presence of more than 7 g per day of fatty acids in the stool. There are many potential causes of fat malabsorption, including:

• Fat emulsification is poor in patients who have had a gastrectomy and who experience rapid dumping of ingested food into the small intestine.

• Patients with hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome) may have an acidic duodenal environment that inhibits pancreatic lipase.

• Biliary obstruction or cholecystectomy (removal of the gallbladder) reduces the availability of bile.

• Patients with pancreatic insufficiency (e.g., cystic fibrosis) have inadequate pancreatic lipase secretion.

• Abetalipoproteinemia is a rare condition in which the assembly of triglyceride and apoproteins is defective.

Vitamin Absorption

Vitamins are organic molecules that are required for metabolism but cannot be synthesized in the body; therefore vitamins must be present in the diet. Table 7-2 lists recognized vitamins, summarizes their major functions, and describes the main features of vitamin deficiencies. Vitamins A, D, E, and K are fat-soluble; a meal must contain fat if these vitamins are to be assimilated from food. Fat-soluble vitamins enter micelles and are absorbed into enterocytes by simple diffusion; they appear in chylomicrons unaltered by metabolic processes in the enterocyte. Fat malabsorption is associated with a deficiency of fat-soluble vitamins because the vitamins are excreted along with excess fecal fat.

The water-soluble group of vitamins includes the B vitamins, vitamin C, folate, biotin, and pantothenic acid. Intestinal absorption of these water-soluble molecules by simple diffusion is slow. Although not yet fully understood, separate carrier-mediated transport mechanisms have recently been identified for each of the water-soluble vitamins.

Vitamin B₁₂ Uptake

Vitamin B₁₂ deficiency may take months to manifest clinically because the liver stores a significant amount of the vitamin. Untreated vitamin B₁₂ deficiency results in anemia.

The following steps are involved in vitamin B₁₂ uptake (Figure 7-35):

• When vitamin B₁₂ is ingested, it is bound to the proteins in food and must be released in the stomach by the action of pepsin.

• Vitamin B₁₂ forms a complex with a glycoprotein called haptocorrin, which is secreted into the saliva and gastric juice.

• Pancreatic proteases hydrolyze haptocorrin to liberate vitamin B₁₂, which is then available to bind to intrinsic factor within the small intestine.

• The vitamin B₁₂-intrinsic factor complex is required for vitamin B₁₂ absorption via a specific receptor-mediated mechanism in the distal ileum.

• Vitamin B₁₂ encounters the binding protein transcobalamin in blood, which carries it to the liver for storage.

The mechanism for assimilation of vitamin B₁₂ requires normal function in several gastrointestinal organs. As a result, there are multiple etiologies that lead to vitamin B₁₂ deficiency, including:

• Dietary deficiency.

• Lack of intrinsic factor (known as pernicious anemia), which may be caused, for example, by autoimmune destruction of the parietal cells or by gastric atrophy.

• Pancreatic insufficiency (e.g., cystic fibrosis).

• Surgical resection of the ileum.

• Terminal ileum disease (e.g., Crohn's ileitis); the ileum is the most common location of Crohn's disease.

• Intestinal organisms (e.g., Diphyllobothrium latum, a fish tapeworm).

Regardless of its cause, vitamin B₁₂ deficiency manifests as megaloblastic anemia and neurologic degeneration caused by demyelination of the peripheral nerves, the spinal cord, and the cerebrum. Treatment of vitamin B₁₂ deficiency with only supplemental folic acid should never be attempted; the folic acid will resolve the anemia but without vitamin B₁₂ replacement, the patient will have irreversible neurologic dysfunction.

The large intestine is wider than the small intestine and begins beyond the ileocecal sphincter and ends at the anus. The large intestine consists of the cecum; the ascending colon, transverse colon, descending colon, and sigmoid colon; the rectum; and the anal canal. The longitudinal layer of smooth muscle is arranged in three discrete strips called teniae coli. Contractions of this discontinuous muscle layer cause the wall of the large intestine to form bulges known as haustra. The colon is lined with transporting epithelial cells called colonocytes, which absorb fluid and transport electrolytes but do not express digestive enzymes.

Nutrient absorption should be completed by the time the luminal contents reach the large intestine. The main functions of the large intestine are completion of fluid absorption and the storage and elimination of fecal waste. Most water absorption occurs in the right colon (the cecum, the ascending colon, and the first half of the transverse colon). Prior to defecation, fecal waste is stored in the left colon (i.e., the distal half of the transverse colon, the descending colon, and the sigmoid colon) (Figure 7-36). By the time fecal material reaches the rectum, it consists of a small volume of K⁺-rich fluid containing undigested plant fibers, bacteria, and inorganic material.

Colonic Motility

Both segmentation and peristalsis in the colon produce motility patterns that facilitate fluid and electrolyte absorption and allow the storage and orderly evacuation of feces (Figure 7-37A). The segmenting contractions (“haustral shuttling”) occur most often in the large intestine and function to gradually turn over the fecal contents. Segmenting contractions are more rapid in the left colon than in the right colon, which tends to slow the movement of feces toward the rectum, allowing more time to complete fluid absorption (see Figure 7-37B). Peristaltic contractions occur infrequently and act to forcefully propel feces into the rectum prior to defecation. Peristaltic contractions are giant migrating-type contractions called mass movements. These peristaltic waves typically occur 3–5 times per day, and each wave moves the fecal contents aborally 20 cm or more.

Colonic Fluid Transport

Colonic fluid absorption reduces the 2 L per day of fluid that enters from the small intestine to about 0.1 L of fluid excretion in feces. The mechanisms for Na⁺ absorption that function in the right and left colon are as follows (Figure 7-38):

• In the right (proximal) colon, most Na⁺ uptake occurs via the Na⁺/H⁺ exchange, via a mechanism that resembles Na⁺ uptake in the ileum.

• In the left (distal) colon, Na⁺ absorption occurs via a Na⁺ channel, and K⁺ secretion occurs at the same time via K⁺ channels. The transport model in the distal colon resembles that of the cortical collecting duct in the kidney (see Chapter 6). In both locations, the hormone aldosterone stimulates Na⁺ absorption and K⁺ secretion.

The colon is also capable of fluid secretion, which is produced from the colonic crypts by the same mechanism as described above for the small intestine.

Although rare, villous adenomas of the rectosigmoid colon can cause a secretory diarrhea syndrome, which results in hypokalemia and hypovolemia.

Diarrhea

Diarrhea is defined as an increase in stool fluid volume of more than 200 mL within 24 hours. In general terms, diarrhea may result from the delivery of more fluid to the colon than the colon can absorb, or it may result if feces move too rapidly through the colon to allow the colon to adequately absorb fluid. The general causes of diarrhea are:

• Osmotic diarrhea occurs when there is an agent in the intestine that causes water to be retained in the lumen. The agent may be a malabsorbed nutrient or an exogenous agent such as saline laxatives.

• Secretory diarrhea occurs when there is excess endogenous fluid secretion by enterocytes and colonocytes. Bacterial food poisoning is a common cause of secretory diarrhea (e.g., traveler's diarrhea caused by enterotoxic E coli). Rare causes of secretory diarrhea include hormone-secreting tumors that release secretagogues such as VIP or serotonin.

• Rapid intestinal motility may cause diarrhea due to transit times that are too brief to complete fluid and electrolyte absorption.

• Inflammation of the bowel may cause diarrhea as a result of increased fluid secretion and motility (e.g., inflammatory bowel disease).

Diarrhea may cause excessive loss of K⁺ and HCO₃⁻ in feces, resulting in hypokalemia and metabolic acidosis. The principles underlying K⁺ loss in diarrhea are the same as those that explain urinary K⁺ loss from diuretic use (see Chapter 6). In this case, diarrhea causes large amounts of fluid and Na⁺ delivery to the distal colon, which drives more Na⁺ uptake via the Na⁺ channels (Figure 7-38). This depolarizes the colonocyte apical membrane potential and increases the driving force for K⁺ secretion. The diarrheal fluid entering the distal colon also has a low K⁺ concentration and presents a more favorable diffusion gradient for K⁺ secretion into the colon. Increased loss of HCO₃⁻ in feces occurs because of the Cl⁻/HCO₃⁻ exchange in the apical cell membranes along the ileum and the colon. Luminal fluid contains NaCl; as more fluid flows past surface epithelial cells, there is more Cl⁻ available to drive HCO₃⁻ secretion.

Dietary Fiber

The main undigested material in feces is nonstarch polysaccharides, including cellulose, hemicellulose, lignin, pectin, gums, and algal polysaccharides, which are collectively called dietary fiber.

A high-fiber diet improves colonic motility and reduces the incidence of constipation. Health benefits in other body systems are also associated with high-fiber diets, including reduced incidence of coronary heart disease and improved control of blood glucose concentration in type 2 diabetes mellitus, also called non–insulin-dependent diabetes mellitus, or NIDDM.

Dietary fiber undergoes fermentation by bacteria in the colon, which produces the short-chain fatty acids acetate, propionate, and butyrate. Short-chain fatty acids create a more acidic colonic fluid, which prevents bacterial overgrowth. Fermentation reactions also produce gases (e.g., hydrogen, methane, carbon dioxide, and hydrogen sulfide), which are excreted as flatus.

The functions of different motility patterns include propulsion (i.e., aboral movement of luminal material), mixing of luminal contents, or the creation of reservoirs for temporary storage of material (e.g., distal colon). The gastrointestinal tract is involved in a great deal of rhythmic contraction, which is facilitated by spontaneous electrical activity in gastrointestinal smooth muscle, known as the basic electrical rhythm. The sphincters along the gastrointestinal tract separate the gut into functional segments (Table 7-3). Sphincters are characterized as zones of high resting pressure that relax in response to an appropriate stimulus. Distention of the gut segment immediately distal to a sphincter causes it to contract, preventing retrograde flow. The actions of enteric nerves and hormones integrate motility behavior in each region of the gastrointestinal tract to promote digestion and absorption of nutrients.

Slow Waves

The phasic contractions that underlie mixing and propulsion of the intestinal contents are facilitated by the presence of a basic electrical rhythm (slow waves) in the gastrointestinal smooth muscle (Figure 7-39).

• Slow waves in the gastrointestinal smooth muscle are spontaneous oscillations in the membrane potential. The distal stomach is the first location in the smooth muscle to exhibit slow waves.

• Spike potentials are triggered if the peak of a slow wave depolarizes the membrane to a threshold potential. Spike potentials are slow action potentials caused by the opening of Ca²⁺ channels.

• Ca²⁺ entry into smooth muscle cells occurs during spike potentials and triggers muscle contraction; this explains why the amount of force developed by muscle contraction correlates with the appearance of spike potentials.

If spike potentials occur with every slow wave, a rhythmic contraction occurs with the same frequency as the slow wave. The maximum frequency of rhythmic contraction in a given region of the gut, therefore, is set by the local rate of slow wave generation. The observed pattern of gut motility (e.g., segmentation) is programmed by the ENS, which determines when slow waves will produce spike potentials and give rise to a contraction. Excitatory transmitters often cause nonselective cation channels in the smooth muscle cells to open; the resting membrane potential is depolarized and more slow waves cross the threshold for the generation of a spike potential. Inhibitory transmitters often act by opening the K⁺ channels in smooth muscle cells, hyperpolarizing the membrane potential and preventing the slow waves from reaching threshold.

Interstitial Cells of Cajal

The origin of the basic electrical rhythm is a network of fibroblast-like cells called the interstitial cells of Cajal, which are positioned between the longitudinal and the circular smooth muscle layers. The interstitial cells of Cajal have multiple processes, many of which are electrically coupled to the smooth muscle cells via gap junctions and conduct the pacemaker currents to smooth muscle cells. Slow waves propagate down the gastrointestinal tract for variable distances via the extensive network of cell-to-cell contacts between the interstitial cells of Cajal.

Motility Patterns Along the Gastrointestinal Tract

Each of the areas of the gastrointestinal tract, as defined by the presence of sphincters (Table 7-3), shows patterns of motility that are distinct from other areas. In most cases, the observed motility patterns are strongly influenced by the characteristics of the locally generated slow waves.

Esophagus and Stomach

There are no slow waves in the esophagus, which remains quiescent unless stimulated by swallowing or by the presence of a bolus in the lumen.

The proximal stomach does not exhibit rhythmic contraction nor does it produce slow waves. A steady tone in the proximal stomach presses on the gastric contents, pushing the contents toward the pylorus. Slow waves are first encountered in the distal stomach, and are driven by a pacemaker of the interstitial cells of Cajal in the greater curvature of the stomach. Slow waves occur at about 3–4 per minute and underlie the rhythmic contractions of antral systole that are observed when food is present.

Small Intestinal Motility

A pacemaker in the duodenum produces about 12 slow waves per minute. The rate of pacemaker activity declines progressively along the small bowel to about six to eight cycles per minute in the ileum. This pattern of slow waves produces a gradient of segmenting contraction rates, which is more rapid proximally than distally and promotes gradual aboral movement of food along the intestine.

The terminal ileum participates in reflexes that regulate intestinal motility and emptying of the stomach. If nutrients reach the terminal ileum, this reflects inadequate absorption at more proximal sites. The ileal brake is a mechanism that reduces stomach emptying and intestinal motility, and is mediated by the release of the hormones glucagon-like peptide-1 and peptide YY. A neuronal pathway operating through the ENS and the extrinsic nerves, known as the ileogastric reflex, augments the ileal brake when there is distension of the terminal ileum. The distal ileum is also able to sense inappropriate retrograde flow of colonic material into the small intestine. The distal ileum reacts to short-chain fatty acids derived from the colon by increasing peristalsis and quickly returning material to the colon. If the distal ileum is surgically removed, a common effect is disrupted small intestinal motility.

Large Intestinal Motility

Most contractions of the large intestine are segmenting contractions that continually mix the fecal contents. Occasional giant peristaltic contractions (mass movements) propel fecal material into the rectum. Mass movements are increased in frequency and intensity by the gastrocolic reflex, which is triggered by the entry of food into the stomach and duodenum. The neuronal pathway includes both the ENS and the autonomic nerves. Fecal continence is maintained by the action of several anal sphincters.

• The internal anal sphincter is a thickening of smooth muscle around the anal canal and is controlled by the autonomic nerves.

• The external anal sphincter is distal to the internal sphincter and is composed of skeletal muscle around the anal canal.

• The pelvic diaphragm is also important in the maintenance of fecal continence and is a sling of skeletal muscle, originating from the bony pelvis that forms the acute anorectal angle.

Rectal distension initiates the rectosphincteric reflex, in which the internal anal sphincter initially relaxes and the intraluminal pressure recorded in the anal canal decreases (Figure 7-40). As fecal material moves down into the upper part of the anal canal, it initiates the urge to defecate. Voluntary contraction of the external anal sphincter can override the rectosphincteric reflex. Voluntary contraction of the external sphincter causes the internal sphincter to regain tone; the rectal wall relaxes to reduce rectal pressure, and feces are temporarily accommodated in the rectum. If the defecation reflex is allowed to continue, the internal and external anal sphincters both relax. Coordinated voluntary acts of straining occur in conjunction with propulsive involuntary contractions of the left colon and rectum to expel feces.

Migrating Motor Complex

The migrating motor complex is a pattern of motility that occurs about every 90 minutes between meals. It involves an interval of strong propulsive contractions, which pass down the distal stomach and small intestine (Figure 7-41). The function of migrating motor complexes is to sweep the stomach and small intestine of indigestible materials. During a meal, the stomach only allows small particles to pass into the small intestine, leaving behind larger particles (e.g., dietary fiber). The migrating motor complex is an intrinsic property of the gastrointestinal tract that does not require external innervation. The appearance of migrating motor complexes in infants indicates the developmental maturity of the intestines and can be absent in premature neonates.

Migrating motor complexes rarely disappear as a person ages or in pathologic states; however, they have been found to disappear, for example, in patients after treatment of cancer with radiotherapy. Loss of the migrating motor complex can cause bacterial overgrowth in the small intestine, suggesting that it normally prevents bacterial colonization of the upper intestine.

The clock that sets the regular 90-minute intervals of contraction is found within the ENS. The motor program that is initiated includes secretion of the hormone motilin, which stimulates propulsive contractions of the intestine. The migrating motor complexes continue until a meal is ingested. The length of time from the end of a meal to the next migrating motor complex is linearly related to the caloric content of the meal rather than to ingestion of a specific nutrient. The start of an interdigestive period is defined by the first migrating motor complex that occurs after a meal.

Gastrointestinal distress (i.e., nausea, vomiting, and diarrhea) is the most common adverse effect of erythromycin, a macrolide antibiotic. Erythromycin binds to motilin receptors, causing increased gastrointestinal motility, which is responsible for the unfavorable adverse effects of this drug.

Vomiting Vomiting removes noxious or harmful irritants from the gastrointestinal tract and can be initiated by several mechanisms, including:

• Noxious stimuli in the gut lumen (e.g., infected food) stimulate sensory receptors in the gut wall, resulting in the subjective sensation of nausea carried by autonomic nerves to the CNS.

• Higher brain centers can induce nausea and vomiting in the absence of noxious stimuli in the gut (e.g., as a result of seeing a disturbing image, smelling a nauseating odor, or by motion sickness).

• Chemicals in the circulation can induce vomiting by acting on a region of the area postrema on the lateral wall of the fourth ventricle, called the chemoreceptor trigger zone. The dopamine agonist apomorphine is an example of a stimulant of the chemoreceptor trigger zone that may be used in patients who have Parkinson's disease. Antiemetics must be given prophylactically to prevent vomiting when apomorphine is used.

The CNS vomiting center integrates stimuli and coordinates the act of vomiting, which involves reverse peristalsis in the small intestine and stomach, together with sequential relaxation of the pyloric, the lower esophageal, and the upper esophageal sphincters. Serotonin (5-HT) and dopamine (D) are important transmitters in the central vomiting pathway; antagonists at the 5-HT₃ (e.g., ondansetron) and the D₂ receptors (e.g., prochlorperazine) are effective antiemetics.

Splanchnic Circulation

The splanchnic circulation is the largest regional circulation at rest and receives about 30% of the cardiac output. The splanchnic circulation is also the largest reservoir of blood that can be redirected to other vascular beds (e.g., during exercise). Most of the blood in the splanchnic circulation is distributed to the gastrointestinal organs via the celiac and superior mesenteric arteries. Most of the venous drainage from the digestive system passes to the liver via the hepatic portal vein.

The sympathetic nervous system is a dominant effector that controls splanchnic vascular resistance. The release of norepinephrine by the postganglionic nerves causes vasoconstriction and venoconstriction. Norepinephrine is responsible for the decrease in splanchnic blood flow associated with the general cardiovascular stressors that activate the sympathetic nervous system, including reduced blood pressure, reduced blood volume, and fear and pain. The gastrointestinal system is vulnerable to low blood flow and ischemia in states of shock, which can result in the release of toxins or the entry of pathogens.

Mesenteric ischemia results from low blood flow to the bowel. The most common cause of this disorder is due to the rupture of an atheroma (plaque in the arterial wall) with associated blockage of blood vessels. Clinically, this condition is most common in elderly people and presents as unremitting abdominal pain that is out of proportion to physical findings and is associated with bloody diarrhea. Bacterial migration across the injured bowel wall quickly results in potentially fatal peritonitis. The mortality rate in patients with mesenteric ischemia is over 50%.

The period of increased splanchnic blood flow after a meal is called postprandial hyperemia. Splanchnic vasodilation results from several factors, including the hormonal environment (e.g., high levels of CCK) and the action of enteric nerves (e.g., VIPergic neurons). In addition, the generalized increase in parasympathetic nerve activity after a meal stimulates gastrointestinal secretion and motility, which indirectly increases splanchnic blood flow as a result of increased local metabolism (see Chapter 4).