PHS 212_GIT_102100.ppt

PHS 212/214: HUMAN PHYSIOLOGY II (GASTROINTESTINAL PHYSIOLOGY) By DR. OYEYEMI, A. W. Department of Physiology Osun State University, Osogbo 1  INTRODUCTION The gastrointestinal s...

PHS 212/214: HUMAN PHYSIOLOGY II (GASTROINTESTINAL PHYSIOLOGY) By DR. OYEYEMI, A. W. Department of Physiology Osun State University, Osogbo 1  INTRODUCTION The gastrointestinal system (Fig. 1) consists: Gastrointestinal tract - Mouth, esophagus, stomach, small and large intestine Accessory exocrine glands – Salivary gland, liver, gallbladder and pancreas. 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). 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. 2  INTRODUCTION The following sequence of events results in the efficient assimilation of nutrients from food (Fig 1): Chewing (mastication) allows bolus to be 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. Fod 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  INTRODUCTION  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. 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. 4  INTRODUCTION 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. 5  INTRODUCTION Figure 1: Functions of the gastrointestinal organs 6  ANATOMY-PHYSIOLOGIC OF GASTROINTESTINAL TRACT There are four major histologic layers in the gastrointestinal tract (Fig 2):  Mucosa,  submucosa,  muscularis externa, and  serosa. The mucosa is consists of a single cell epithelium 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 that secrete mucus, electrolytes, water, and digestive enzymes. Numerous endocrine cells are also scattered among epithelial cells of mucosa. 7 ANATOMY-PHYSIOLOGIC OF GASTROINTESTINAL TRACT Figure 2: Structural features of the gastrointestinal tract 8  ANATOMY-PHYSIOLOGIC OF GASTROINTESTINAL TRACT 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. 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. 9  ANATOMY-PHYSIOLOGIC OF GASTROINTESTINAL TRACT 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. 10  CONTROL MECHANISMS IN GASTROINTESTINAL PHYSIOLOGY The controls mechanisms are through neural, hormonal, and paracrine. The major regulated processes that can generate change (effectors) in the gastrointestinal physiology are gut motility, epithelial secretion, and blood flow. The enteric nervous system (ENS) (Fig 3) is a division of the autonomic nervous system. It is a large neural network located within the wall of the gastrointestinal tract and it is concerned with regulating gastrointestinal function. 11  CONTROL MECHANISMS IN GASTROINTESTINAL PHYSIOLOGY Figure 3: A. The enteric nervous system. B. The gut-brain axis. The ENS is linked to the central nervous system (CNS) via the sensory and motor nerves of the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS). 12  CONTROL MECHANISMS IN GASTROINTESTINAL PHYSIOLOGY The controls mechanisms are through neural, hormonal, and paracrine. The major regulated processes that can generate change (effectors) in the gastrointestinal physiology are gut motility, epithelial secretion, and blood flow. The enteric nervous system (ENS) (Fig 3) is a division of the autonomic nervous system. It is a large neural network located within the wall of the gastrointestinal tract and it is concerned with regulating gastrointestinal function. 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. 13  CONTROL MECHANISMS IN GASTROINTESTINAL PHYSIOLOGY 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. 14  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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. 15  GASTROINTESTINAL TRACT MOTILITY AND SECRETION SALIVARY SECRETION Salivary gland produce saliva that is mildly alkaline. The volume of saliva produced is approximately 1.5 L per day. The salivary glands consist of: The submandibular glands secrete approximately 70% of saliva. The parotid glands secrete 25%. The sublingual glands secrete 5%. 16  GASTROINTESTINAL TRACT MOTILITY AND SECRETION SALIVARY SECRETION A salivon is the functional unit of a salivary gland and consists of clusters of acinar cells that drain via a duct system (Fig 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 Fig 5B). 17  GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 5: A) The salivon. B) Primary saliva secreted by the acinus is an isotonic solution resembling interstitial fluid 18  GASTROINTESTINAL TRACT MOTILITY AND SECRETION The three major functions of saliva are lubrication, protection, and digestion. 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. Protection relates to reducing the adverse effects of oral bacteria.  The alkalinity of fresh saliva neutralizes acid produced by oral bacteria;  The flow of saliva across the teeth also helps to wash away bacteria.  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. 19  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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. 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. 20  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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. 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. 21  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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. 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. 22  GASTROINTESTINAL TRACT MOTILITY AND SECRETION MECHANISM OF SALIVA SECRETION 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. 23  GASTROINTESTINAL TRACT MOTILITY AND 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. 24  GASTROINTESTINAL TRACT MOTILITY AND SECRETION SWALLOWING 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. 25  GASTROINTESTINAL TRACT MOTILITY AND SECRETION ESOPHAGUS The function of the esophagus is to move food and liquid to the stomach. The esophagus has three functional zones (Fig 6): The upper zone, which is 6–8 cm long, is closely related to the pharyngeal musculature and consists of striated muscle. The middle zone (main body), which is 12–14 cm long, consists of smooth muscle. The lower zone, which is 3–4 cm long, consists of smooth muscle and corresponds with the lower esophageal sphincter. Swallowing induces a wave of peristalsis in the esophagus known as primary peristalsis. 26 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 6: Esophageal manometry 27  GASTROINTESTINAL TRACT MOTILITY AND SECRETION ESOPHAGUS 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. 28  GASTROINTESTINAL TRACT MOTILITY AND SECRETION ESOPHAGUS Gastroesophageal reflux disease (GERD) occurs when the lower esophageal sphincter is incompetent, allowing the flow of gastric juices and contents back into the esophagus. 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. Recurrent reflux of gastric acids damages the esophageal mucosa causing esophagitis, esophageal ulcers, and strictures. 29  GASTROINTESTINAL TRACT MOTILITY AND SECRETION ESOPHAGUS Achalasia is a defect in the esophageal ENS. There is 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. Swallowed food is retained in the esophagus, causing dilation of the esophageal body and eventually resulting in a reduction in peristalsis. 30  GASTROINTESTINAL TRACT MOTILITY AND SECRETION STOMACH The stomach has five main anatomic areas (Figure 7): The cardia is the area where the esophagus enters the stomach. The fundus is the rounded area above the cardiac area. The body of the stomach is below the cardiac region. The gastric antrum is the distal part of the stomach. The pyloric sphincter guards the exit of the stomach into the small intestine. 31  GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 7: Cell types and secretory products of gastric glands 32  GASTROINTESTINAL TRACT MOTILITY AND SECRETION STOMACH The cardia, the fundus, and the body of the stomach (80%) comprise the oxyntic (parietal) gland. The major exocrine secretions are all derived from this area. The pyloric gland area (20%) is the major source of gastric hormones. The stomach mucosa consists of gastric pits and gastric glands (Fig 7). 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 The peptic (chief) cells, which secrete pepsinogen. 33  GASTROINTESTINAL TRACT MOTILITY AND SECRETION STOMACH Gastric glands in the antrum and pyloric area consist of endocrine cells, which secrete gastrin and somatostatin. The stomach regulates 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. 34  GASTROINTESTINAL TRACT MOTILITY AND SECRETION STOMACH The five main exocrine secretions of the stomach are: Water, to dissolve and dilute ingested food. Acid (HCl), to denature dietary proteins and to kill ingested microorganisms. Enzymes (pepsin and gastric lipase), to contribute to protein and fat digestion. Intrinsic factor, a glycoprotein that is necessary for vitamin B12 absorption in the ileum. A mucus-bicarbonate barrier at the mucosal surface, to protect against the corrosive properties of gastric juice. 35  GASTROINTESTINAL TRACT MOTILITY AND SECRETION GASTRIC MOTILITY Patterns of stomach motility is shows in Fig 8. 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 (storage of the food). 36  GASTROINTESTINAL TRACT MOTILITY AND SECRETION GASTRIC MOTILITY 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. 37  GASTROINTESTINAL TRACT MOTILITY AND SECRETION GASTRIC MOTILITY 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. 38 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 8: Gastric motility. 1.The stomach is quiescent most of the time between meals. 2.Receptive relaxation of the proximal stomach facilitates the entry of food from the esophagus after swallowing. Accommodation is progressive relaxation of the entire stomach as it fills to prevent increased intragastric pressure during a meal. 3.Peristalsis begins in the midstomach. 4.Antral systole is the vigorous peristaltic rhythm in the distal stomach. Retropulsion is forceful reflection of food off the closed pyloric sphincter. 39  GASTROINTESTINAL TRACT MOTILITY AND SECRETION GASTRIC ACID SECRETION The oxyntic cells produce and secrete acid (Fig 9): 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+. 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. 40  GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 9: The mechanism of gastric acid secretion by the oxyntic (parietal) cells 41  GASTROINTESTINAL TRACT MOTILITY AND SECRETION GASTRIC ACID SECRETION 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. 42  GASTROINTESTINAL TRACT MOTILITY AND SECRETION STIMULATION OF GASTRIC ACID SECRETION Gastrin and acetylcholine stimulate secretion via an increase in intracellular Ca 2+. 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. In Zollinger-Ellison syndrome, there is hypersecretion of gastric acid and peptic ulceration. It is caused by a gastrin-producing tumor (gastrinoma) that is usually located in the pancreas. 43  GASTROINTESTINAL TRACT MOTILITY AND SECRETION INHIBITION OF GASTRIC SECRETION AND MOTILITY 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. There are two ways in which a decreasing gastric pH inhibits gastrin secretion:  Direct inhibition of G cells by H+ when the pH is reduced below 3.  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 (Secretin). 44  GASTROINTESTINAL TRACT MOTILITY AND SECRETION PEPSINS Pepsins are proteolytic enzymes that attack the internal peptide bonds in proteins. They are secreted as two types of inactive pepsinogens:  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. Pepsinogen secretion is stimulated by acetylcholine from the vagal and ENS efferent neurons. 45  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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. 46  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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  the jejunum  the ileum distally. Several anatomic features of the small intestine amplify the surface area for absorption, including transverse folds in the mucosa, the arrangement of the mucosa into villi, and the presence of microvilli on the enterocytes that line the small intestine (Fig 10). 47 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 10: A) Amplification of the absorptive area of the small intestine. Plicae circulares are transverse folds of intestinal mucosa. B) The crypt-villus unit. 48  GASTROINTESTINAL TRACT MOTILITY AND SECRETION THE SMALL INTESTINE 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 - are the source of intestinal fluid secretion the maturation zone - expresses enzymes and absorptive membrane transport proteins. The villus tip - enterocytes are fully differentiated and undertake the absorption of nutrients, electrolytes, and fluid. 49  GASTROINTESTINAL TRACT MOTILITY AND SECRETION THE SMALL INTESTINE 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:  Mixing of foodstuffs with digestive secretions and enzymes.  Distribution of the luminal contents around the mucosa for absorption.  Propulsion of the luminal contents in the aboral direction (away from the mouth). There are two major types of motility that occur in the small intestine during the fed state (Fig 11):  Segmentation contractions produce a string of segments that constantly form and reform for mixing luminal contents.  Peristalsis consists of a wave of contractions that moves a bolus aborally. The function of peristalsis is propulsion of luminal material. 50 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 11: Patterns of small intestinal motility 51  GASTROINTESTINAL TRACT MOTILITY AND SECRETION THE SMALL INTESTINE FLUID SECRETION Both the small intestine and the large intestine secrete fluid from the crypt cells. Secretion is necessary for lubrication. Fluid secretion also provides a source of Na+ for coupling to nutrient absorption. Antibodies secreted in the area of the intestinal crypts also require fluid secretions to reach the lumen in the gut. The key step in the mechanism of fluid secretion from the crypt enterocytes is opening of the Cl− channels in the luminal cell membrane (Fig 12). 52 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 12: Mechanism of intestinal fluid secretion. 53  GASTROINTESTINAL TRACT MOTILITY AND SECRETION THE SMALL INTESTINE FLUID SECRETION There are two types of Cl− channels present: cAMP-activated Cl− channels, for which the ENS neurotransmitter (vasoactive intestinal peptide is an important secretagogue. Ca2+-activated Cl− channels, for which acetylcholine from ENS neurons and serotonin from the EC cells are both secretagogues. 54  GASTROINTESTINAL TRACT MOTILITY AND SECRETION THE LARGE INTESTINE The large intestine (Fig 13) 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. 55 GASTROINTESTINAL TRACT MOTILITY AND SECRETION Figure 13: Areas and functions of the large intestine. 56  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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 The segmenting contractions (“haustral shuttling”) occur most often in the large intestine and function to gradually turn over the fecal contents. 57  GASTROINTESTINAL TRACT MOTILITY AND SECRETION 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.  Secretory diarrhea occurs when there is excess endogenous fluid secretion by enterocytes and colonocytes. 58  GASTROINTESTINAL TRACT MOTILITY AND SECRETION DIARRHEA Bacterial food poisoning is a common cause of secretory diarrhea (e.g., traveler’s diarrhea caused by enterotoxic E coli). 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). 59 DIGESTION OF CARBOHYDRATES 60  DIGESTION OF CARBOHYDRATES Digestion of starch starts in the oral cavity via the activity of salivary amylase. Salivary and pancreatic amylase hydrolyze internal α-1,4 bonds in both amylose and amylopectin. The digestion of starch by amylase is of necessity incomplete and results in short oligomers of glucose (maltose, maltotriose, and α-limit dextrins). Further digestion occur at the brush border by the hydrolases glucoamylase, sucrase, or isomaltase (Table 1, Fig 14). All yield free glucose monomers, which can then be absorbed. isomaltase activity is critical for α-limit dextrins digestion, because it is the only enzyme that can cleave α-1,6 bonds that make up the branch points as well as α-1,4 bonds. 61  DIGESTION OF CARBOHYDRATES Brush border hydrolases critical to the digestion of dietary carbohydrates include sucrase, isomaltase, glucoamylase, and lactase (Table 1). Table 1: Brush border carbohydrate hydrolases Enzymes Substrates Products Sucrase α-1,4 bond maltose, maltotriose, and sucrose Glucose, fructose Isomaltase α-1,4 bond maltose, maltotriose, α limit dextrins Glucose Glucoamylase α-1,4 bonds of maltose, maltotriose Glucose Lactase Lactose Glucose, galactose 62 DIGESTION OF CARBOHYDRATES Figure 14: Digestion of carbohydrate 63  DIGESTION OF CARBOHYDRATES Lactose intolerance is relatively common in adults. It results from the absence of brush border lactase and, thus, the inability to hydrolyze lactose to glucose and galactose for absorption. The disorder reflects a normal developmental decline in the expression of lactase by enterocytes. In such individuals, consumption of foods containing large quantities of lactose (e.g., milk, ice cream) can result in abdominal cramping, gas, and diarrhea. These symptoms reflect a relative inability to digest lactose; thus, it remains in the lumen, and water is retained. 64  ABSORPTION OF CARBOHYDRATE Water-soluble monosaccharides resulting from digestion must be absorpbed across the hydrophobic plasma membrane of the enterocyte. The sodium/glucose transporter 1 (SGLT1) is a symporter that takes up glucose (and galactose) against its concentration gradient by coupling its transport to that of Na+ (Fig 15). Once inside the cytosol, glucose and galactose can be retained for the epithelium’s metabolic needs or can exit the cell across its basolateral pole via a transporter known as GLUT2. Fructose, in contrast, is taken up across the apical membrane by GLUT5 and facilitated diffusion. 65  ABSORPTION OF CARBOHYDRATE Figure 15: Absorption of glucose, galactose, and fructose in the small intestine 66  PROTEIN DIGESTION Proteins can be hydrolyzed to long peptides simply by virtue of the acidic pH that exists in the gastric lumen. Three phases of enzymatically mediated protein digestion (Fig 16). The first phase takes place in the gastric lumen and is mediated by pepsin. Pepsin is highly specialized to act in the stomach, since it is activated by low pH. It is not capable of digesting protein fully into a form that can be absorbed by the intestine. Instead, it yields a mixture of intact protein, large peptides (the majority), and a limited number of free amino acids. 67  PROTEIN DIGESTION Figure 16: Protein digestion 68  PROTEIN DIGESTION The partially digested protein in small intestine encounters the proteases provided in pancreatic juice. Enterokinase (Fig 17) cleaves trypsinogen to yield active trypsin. Trypsin in turn cleaves all the other protease precursors to form an active enzymes that can almost completely digest the majority of dietary proteins. Trypsin is an endopeptidase that cleaves proteins only at internal bonds within the peptide chain. The chymotrypsin and elastase (endopeptidase) have a similar mechanism of action but cleave at sites of neutral amino acids. The peptides that result from endopeptidase activity are then acted on by pancreatic ectopeptidases. 69  PROTEIN DIGESTION AND ABSORPTION Figure 17: Conversion of the inactive proenzymes of pancreatic juice to active enzymes by the action of trypsin. 70  PROTEIN DIGESTION Carboxypeptidase A and B cleave neutral and basic amino acid situated at the C- terminus. The majority of peptides taken up into the enterocyte in their intact form are then subjected to a final stage of digestion in the cytosol of the enterocyte to liberate their constituent amino acids for use in the cell (Fig 18). However, some di- and tripeptides may also be transported into the blood in their intact form. 71  PROTEIN DIGESTION AND ABSORPTION Figure 18: A wide variety of dipeptides and tripeptides are taken up across the brush border membrane by the proton-coupled symporter known as peptide transporter 1 (PepT1). 72  ABSORPTION OF PEPTIDES AND AMINO ACIDS The small intestine is notable for its ability to take up short peptides (Fig 18). The primary transporter responsible for such uptake is called peptide transporter 1 (PepT1) and is a symporter that transports peptides in conjunction with protons. Amino acids liberated from these peptides are exported across the basolateral membrane and enter blood capillaries to be transported to the liver via the portal vein. 73  LIPDS DIGESTION Lipids is defined as substances that are more soluble in organic solvents than in water. Lipids are the third major class of macronutrients making up the human diet. The fat-soluble vitamins (A, D, E, K) are essential nutrients that should be supplied in the diet to avoid disease. In the stomach, mixing breaks lipids into droplets to increase the surface area for digestion by pancreatic enzymes. Lingual lipases digest some of the ingested triglycerides to monoglycerides and fatty acids. However, most of the ingested lipids are digested in the intestine by pancreatic lipases. 74  LIPDS DIGESTION Cholecystokinin slows gastric emptying. Thus, delivery of lipids from the stomach to the duodenum is slowed to allow adequate time for digestion and absorption in the intestine. Bile acids emulsify lipids in the small intestine, increasing the surface area for digestion. Pancreatic lipases hydrolyze lipids to fatty acids, monoglycerides, cholesterol, and lysolecithin. The enzymes are pancreatic lipase, cholesterol ester hydrolase, and phospholipase A2. The hydrophobic products of lipid digestion are solubilized in micelles by bile acids. 75  ABSORPTION OF LIPDS Micelles bring the products of lipid digestion into contact with the absorptive surface of the intestinal cells. Then, fatty acids, monoglycerides, and cholesterol diffuse across the luminal membrane into the cells. In the intestinal cells, the products of lipid digestion are re-esterified to triglycerides, cholesterol ester, phospholipids and, with apoproteins form chylomicrons. Chylomicrons are transported out of the intestinal cells by exocytosis. Because chylomicrons are too large to enter the capillaries, they are transferred to lymph vessels and are added to the bloodstream via the thoracic duct. 76  ABSORPTION OF LIPDS Malabsorption of lipids—steatorrhea It can be caused by any of the following: Pancreatic disease (e.g., pancreatitis, cystic fibrosis), in which the pancreas cannot synthesize adequate amounts of the enzymes (e.g., pancreatic lipase) needed for lipid digestion. Hypersecretion of gastrin, in which gastric H+ secretion is increased and the duodenal pH is decreased. Low duodenal pH inactivates pancreatic lipase. Ileal resection, which leads to a depletion of the bile acid pool because the bile acids do not recirculate to the liver. 77  ABSORPTION OF LIPDS Malabsorption of lipids—steatorrhea Bacterial overgrowth, which may lead to deconjugation of bile acids and their “early” absorption in the upper small intestine. In this case, bile acids are not present throughout the small intestine to aid in lipid absorption. Decreased number of intestinal cells for lipid absorption (tropical sprue). Failure to synthesize apoprotein B, which leads to the inability to form chylomicrons. 78  LIVER FUNCTIONAL ANATOMY OF THE LIVER The liver is composed of histologically defined lobules (Fig 19). Chains of hepatocytes 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. 79  LIVER Figure 19: Anatomy of liver lobules 80  LIVER LIVER FUNCTION The digestive and excretory functions of the liver are associated with the secretion of bile via the biliary tract. The liver serves many functions, some of which are: Carbohydrate metabolism: Glycogenolysis & gluconeogenesis add glucose to the blood. Glycogen synthesis, glycolysis, oxidative metabolism, and fat synthesis all consume blood glucose. Fat metabolism: 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. 81  LIVER Cholesterol metabolism: de novo synthesis of cholesterol occur in the liver. Cholesterol is eliminate via hepatic synthesis of bile acids. Bile acids are subsequently excreted in feces. Amino acid and protein synthesis 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. Detoxification and biotransformation  Phase I biotransformation involves the cytochrome P450 enzymes.  Phase II biotransformation involves conjugation to generate products that are more soluble for excretion. Immune function: Kupffer cells in the liver are the largest group of fixed macrophages in the body. 82  LIVER 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. 83  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: It facilitates the assimilation of dietary lipid through emulsification and solubilization. It provides a pathway to excrete hydrophobic molecules that may not be readily excreted by the kidney. It assists in neutralizing gastric acid because it is an alkaline solution. 84  LIVER BILIARY SYSTEM Hepatocytes secrete bile into the canaliculi. Canaliculi join together and convey hepatic bile toward small terminal ductules at the periphery of the liver lobules. 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 (Fig 20). Bile is stored between meals in the gallbladder, where it is concentrated. Bile, along with pancreatic secretions, reaches the small intestine via the common bile duct. 85  LIVER Figure 20: The biliary tract. 86  LIVER BILIARY SYSTEM Gallbladder disease is common and occurs in several forms, ranging from asymptomatic cholelithiasis (gallstones) to biliary colic (blockage of the cystic duct). There are two types of gallstones: Cholesterol gallstones are the most common type of gallstone due to excessive excretion of cholesterol, which is common in obese patients. Pigment gallstones are mainly composed of calcium bilirubinate common in Patients with chronic hemolytic diseases due to the high levels of bilirubin excretion. 87  LIVER 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. 88  LIVER Figure 21: Enterohepatic circulation of bile acids. Most bile acids are reabsorbed in the distal ileum and are returned to the liver, via the portal vein, for recycling. 89  LIVER ENTEROHEPATIC CIRCULATION OF BILE ACIDS 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 (Fig 21). 90  LIVER Bilirubin production and excretion (Fig 22). Hemoglobin is degraded to bilirubin by the reticuloendothelial system. Bilirubin is carried in the circulation bound to albumin. In the liver, bilirubin is conjugated with glucuronic acid via the enzyme uridine diphosphate glucuronyl transferase. A portion of conjugated bilirubin is excreted in the urine, and a portion is secreted into bile. In the intestine, conjugated bilirubin is converted to urobilinogen, which is returned to the liver via the enterohepatic circulation, and urobilin and stercobilin, which are excreted in feces. 91  LIVER Figure 6.15 Bilirubin metabolism. UDP = uridine diphosphate 92