476 PART VII GASTROINTESTINAL PHYSIOLOGY where it is retained for about 24 hours. This suggests that the transverse colon is the primary location for the removal of water and electrolytes and the storage of solid feces in the large intestine. A segmental pattern of motility programmed by the ENS accounts for the ultraslow forward movement of feces in the transverse colon. Ring-like contractions of the circular mus- cle divide the colon into pockets called haustra (Fig. 26.37). The motility pattern, called haustration, differs from seg- mental motility in the small intestine, in that the contracting segment and the receiving segments on either side remain in their respective states for longer periods. In addition, there is uniform repetition of the haustra along the colon. The con- tracting segments in some places appear to be fixed and are marked by a thickening of the circular muscle. Haustrations are dynamic, in that they form and reform at different sites. The most common pattern in the fasting individual is for the contracting segment to propel the con- tents in both directions into receiving segments. This mechanism mixes and compresses the semiliquid feces in the haustral pockets and probably facilitates the absorption of water without any net forward propulsion. Net forward propulsion occurs when sequential migration of the haustra occurs along the length of the bowel. The con- Colonic transit revealed by radioscintigra- Haustra in the large intestine. This X-ray FIGURE 26.36 FIGURE 26.37 phy. Successive scintigrams reveal that the film shows haustral contractions in the ascend- longest dwell-time for intraluminal markers injected initially into ing and the transverse colon. Between the haustral pockets are the cecum is in the transverse colon. The image is faint after 48 segments of contracted circular muscle. Ongoing activity of in- hours, indicating that most of the marker has been excreted with hibitory motor neurons maintains the relaxed state of the circular the feces. muscle in the pockets. Inactivity of inhibitory motor neurons per- mits the contractions between the pockets.
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 477 tents of one haustral pocket are propelled into the next re- sphincter muscles in a continuous sheet from the bottom gion, where a second pocket is formed, and from there to the margins of the pelvis to the anal verge (the transition zone next segment, where the same events occur. This pattern re- between mucosal epithelium and stratified squamous ep- sults in slow forward progression and is believed to be a ithelium of the skin). After defecation, the levator ani con- mechanism for compacting the feces in storage. tract to restore the perineum to its normal position. Fibers Power propulsion is another programmed motor event of the puborectalis join behind the anorectum and pass in the transverse and the descending colon. This motor be- around it on both sides to insert on the pubis. This forms a havior fits the general pattern of neurally coordinated peri- U-shaped sling that pulls the anorectal tube anteriorly, staltic propulsion and results in the mass movement of fe- such that the long axis of the anal canal lies at nearly a right ces over long distances. Mass movements may be triggered angle to that of the rectum (Fig. 26.38). Tonic pull of the by increased delivery of ileal chyme into the ascending puborectalis narrows the anorectal tube from side to side at colon following a meal. The increased incidence of mass the bend of the angle, resulting in a physiological valve that movements and generalized increase in segmental move- is important in the mechanisms that control continence. ments following a meal is called the gastrocolic reflex. Irri- The puborectalis sling and the upper margins of the in- tant laxatives, such as castor oil, act to initiate the motor ternal and external sphincters form the anorectal ring, program for power propulsion in the colon. The presence which marks the boundary of the anal canal and rectum. of threatening agents in the colonic lumen, such as para- Surrounding the anal canal for a length of about 2 cm are sites, enterotoxins, and food antigens, can also initiate the internal and external anal sphincters. The external anal power propulsion. sphincter is skeletal muscle attached to the coccyx posteri- Mass movement of feces (power propulsion) in the orly and the perineum anteriorly. When contracted, it healthy bowel usually starts in the middle of the transverse compresses the anus into a slit, closing the orifice. The in- colon and is preceded by relaxation of the circular muscle ternal anal sphincter is a modified extension of the circular and the downstream disappearance of haustral contrac- muscle layer of the rectum. It is comprised of smooth mus- tions. A large portion of the colon may be emptied as the cle that, like other sphincteric muscles in the digestive contents are propelled at rates up to 5 cm/min as far as the tract, contracts tonically to sustain closure of the anal canal. rectosigmoid region. Haustration returns after the passage of the power contractions. Sensory Innervation and Continence. Mechanorecep- tors in the rectum detect distension and supply the enteric neural circuits with sensory information, similar to the in- The Descending Colon Is a Conduit Between nervation of the upper portions of the GI tract. Unlike the the Transverse and Sigmoid Colon rectum, the anal canal in the region of skin at the anal verge Radioscintigraphic studies in humans show that feces do is innervated by somatosensory nerves that transmit signals not have long dwell-times in the descending colon. La- to the CNS. This region has sensory receptors that detect beled feces begin to accumulate in the sigmoid colon and touch, pain, and temperature with high sensitivity. Pro- rectum about 24 hours after the label is instilled in the ce- cessing of information from these receptors allows the in- cum. The descending colon functions as a conduit without long-term retention of the feces. This region has the neural program for power propulsion. Activation of the program is responsible for mass movements of feces into the sigmoid colon and rectum. Left pubic Symphysis pubis tubercle The Physiology of the Rectosigmoid Region, Anal Canal, and Pelvic Floor Musculature Maintains Fecal Continence The sigmoid colon and rectum are reservoirs with a capac- ity of up to 500 mL in humans. Distensibility in this region is an adaptation for temporarily accommodating the mass Rectum Puborectalis muscle movements of feces. The rectum begins at the level of the third sacral vertebra and follows the curvature of the Anorectal angle sacrum and coccyx for its entire length. It connects to the Anal canal anal canal surrounded by the internal and external anal sphincters. The pelvic floor is formed by overlapping sheets of striated fibers called levator ani muscles. This Anus muscle group, which includes the puborectalis muscle and the striated external anal sphincter, comprise a functional FIGURE 26.38 Structural relationship of the anorectum and puborectalis muscle. One end of the pu- unit that maintains continence. These skeletal muscles be- borectalis muscle inserts on the left pubic tubercle, and the other have in many respects like the somatic muscles that main- inserts on the right pubic tubercle, forming a loop around the tain posture elsewhere in the body (see Chapter 5). junction of the rectum and anal canal. Contraction of the pub- The pelvic floor musculature can be imagined as an in- orectalis muscle helps form the anorectal angle, believed to be verted funnel consisting of the levator ani and external important in the maintenance of fecal continence.
478 PART VII GASTROINTESTINAL PHYSIOLOGY dividual to discriminate consciously between the presence Defecation Involves the Neural Coordination of of gas, liquid, and solids in the anal canal. In addition, Muscles in the Large Intestine and Pelvic Floor stretch receptors in the muscles of the pelvic floor detect changes in the orientation of the anorectum as feces are Distension of the rectum by the mass movement of feces or propelled into the region. gas results in an urge to defecate or release flatus. CNS pro- Contraction of the internal anal sphincter and the pub- cessing of mechanosensory information from the rectum is orectalis muscles blocks the passage of feces and maintains the underlying mechanism for this sensation. Local process- continence with small volumes in the rectum (see Clinical ing of the mechanosensory information in the enteric neural Focus Box 26.3). When the rectum is distended, the rec- circuits activates the motor program for relaxation of the in- toanal reflex or rectosphincteric reflex is activated to relax ternal anal sphincter. At this stage of rectal distension, vol- the internal sphincter. Like other enteric reflexes, this one untary contraction of the external anal sphincter and the pu- involves a stretch receptor, enteric interneurons, and exci- borectalis muscle prevents leakage. The decision to defecate at this stage is voluntary. When the decision is made, com- tation of inhibitory motor neurons to the smooth muscle mands from the brain to the sacral cord shut off the excita- sphincter. Distension also results in the sensation of rectal tory input to the external sphincter and levator ani muscles. fullness, mediated by the central processing of information Additional skeletal motor commands contract the abdominal from mechanoreceptors in the pelvic floor musculature. muscles and diaphragm to increase intra-abdominal pressure. Relaxation of the internal sphincter allows contact of the Coordination of the skeletal muscle components of defeca- rectal contents with the sensory receptors in the lining of tion results in a straightening of the anorectal angle, descent the anal canal, providing an early warning of the possibility of the pelvic floor, and opening of the anus. of a breakdown of the continence mechanisms. When this Programmed behavior of the smooth muscle during occurs, continence is maintained by voluntary contraction defecation includes shortening of the longitudinal muscle of the external anal sphincter and the puborectalis muscle. layer in the sigmoid colon and rectum, followed by strong The external sphincter closes the anal canal, and the pub- contraction of the circular muscle layer. This behavior cor- orectalis sharpens the anorectal angle. An increase in the responds to the basic stereotyped pattern of peristaltic anorectal angle works in concert with increases in intra-ab- propulsion. It represents terminal intestinal peristalsis, in dominal pressure to create a “flap” valve. The flap valve is that the circular muscle of the distal colon and rectum be- formed by the collapse of the anterior rectal wall onto the comes the final propulsive segment while the outside envi- upper end of the anal canal, occluding the lumen. ronment receives the forwardly propelled luminal contents. Whereas the rectoanal reflex is mediated by the ENS, A voluntary decision to resist the urge to defecate is synaptic circuits for the neural reflexes of the external anal eventually accompanied by relaxation of the circular mus- sphincter and other pelvic floor muscles reside in the sacral cle of the rectum. This form of adaptive relaxation accom- portion of the spinal cord. The mechanosensory receptors modates the increased volume in the rectum. As wall ten- are muscle spindles and Golgi tendon organs similar to sion relaxes, the stimulus for the rectal mechanoreceptors is those found in skeletal muscles elsewhere in the body. Sen- removed, and the urge to defecate subsides. Receptive re- sory input from the anorectum and pelvic floor is transmit- laxation of the rectum is accompanied by a return of con- ted over dorsal roots to the sacral cord, and motor outflow tractile tension in the internal anal sphincter, relaxation of to these areas is in sacral root motor nerve fibers. The spinal tone in the external sphincter, and increased pull by the circuits account for the reflex increases in contraction of puborectalis muscle sling. When this occurs, the feces re- the external sphincter and pelvic floor muscles by behav- main in the rectum until the next mass movement further iors that raise intra-abdominal pressure, such as coughing, increases the rectal volume and stimulation of mechanore- sneezing, and lifting weights. ceptors again signals the neural mechanisms for defecation. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (B) Longitudinal muscle → myenteric (A) Enteric neurons items or incomplete statements in this plexus → circular muscle (B) Inhibitory motor neurons section is followed by answers or by (C) Myenteric plexus → circular (C) Enterochromaffin cells completions of the statement. Select the muscle → longitudinal muscle (D) Interstitial cells of Cajal ONE lettered answer or completion that is (D) Network of interstitial cells of (E) Enteroendocrine cells BEST in each case. Cajal → longitudinal muscle → 3. A patient with chronic intestinal circular muscle pseudoobstruction has action 1. A surgeon makes an incision in the (E) Longitudinal muscle → network of potentials and large- amplitude jejunum starting at the serosal surface interstitial cells of Cajal → submucous contractions of the circular muscle and ending in the lumen. What is the plexus associated with every electrical slow sequential order of bisected structures 2. A mouse with a new genetic mutation wave at all levels of the intestine in the as the scalpel passes through the is discovered not to have electrical interdigestive state. Dysplasia of which intestinal wall? slow waves in the small intestine. What cell type most likely explains this (A) Circular muscle → longitudinal cell type is most likely affected by the patient’s condition? muscle → submucous plexus mutation? (A) Unitary-type smooth muscle (continued)
CHAPTER 26 Neurogastroenterology and Gastrointestinal Motility 479 (B) Interstitial cells of Cajal propulsion in real time with magnetic neurons decrease the amplitude of the (C) Inhibitory motor neurons resonance imaging shows the plateau phase of the gastric action (D) Sympathetic postganglionic stereotyped formation of propulsive potential neurons and receiving segments. What is the (C) Frequency of the gastric action (E) Vagal efferent neurons normal sequence of events in enteric potential increases beyond 3/min 4. A neural tracer technique labels the neural programming of the propulsive (D) The pyloric sphincter opens axon and cell body when it is applied and receiving segments? (E) Excitatory motor neurons to the to any part of a neuron. Where are (A) Relaxation of the longitudinal and musculature of the gastric reservoir are labeled cell bodies most likely to be circular muscles in the propulsive activated found after the tracer substance is segment 14.When elevated in an ingested meal, injected into the wall of the stomach? (B) Relaxation of the circular and the factor with the greatest effect in (A) Prefrontal cortex longitudinal muscles in the receiving slowing gastric emptying is (B) Intermediolateral horn of spinal segment (A) pH cord (C) Contraction of the longitudinal (B) Carbohydrate (C) Dorsal vagal complex and circular muscles in the receiving (C) Protein (D) Hypothalamus segment (D) Lipid (E) Gray matter of sacral spinal cord (D) Relaxation of the circular muscle (E) H 2 O 5. An electrophysiological study of a and contraction of the longitudinal 15.On a return visit after receiving a neuron in the ENS detects a fast EPSP. muscle in the receiving segment diagnosis of functional dyspepsia, a 35- Which is the most likely property (E) Contraction of the longitudinal year-old woman reports sensations of associated with the EPSP? muscle and relaxation of the circular early satiety and discomfort in the (A) Acetylcholine (ACh) receptors muscle in the propulsive segment epigastric region after a meal. These (B) Suppression of hyperpolarizing 10.Examination of the properties of a symptoms are most likely a result of after-potentials normal sphincter in the digestive tract (A) Malfunction of adaptive relaxation (C) Receptor activation of adenylyl will show that in the gastric reservoir cyclase (A) Primary flow across the sphincter is (B) Elevated frequency of contractions (D) Hyperpolarization of the unidirectional in the antral pump membrane potential (B) The lower esophageal sphincter is (C) An incompetent lower esophageal (E) Mediation by a metabotropic relaxed at the onset of a migrating sphincter receptor motor complex in the stomach (D) Premature onset of the 6. The application of norepinephrine (C) Blockade of the sphincteric interdigestive phase of gastric motility (NE) to the ENS suppresses innervation by a local anesthetic causes (E) Bile reflux from the duodenum cholinergically mediated EPSPs but has the sphincter to relax 16.A 46-year-old university professor with no effect on depolarizing responses to (D) The manometric pressure in the an allergy to shellfish must be cautious applied acetylcholine (ACh). This lumen of the sphincter is less than the when eating in restaurants because a finding is best interpreted as pressure detected in the lumen on trace of shrimp in any form of food (A) Postsynaptic excitation either side of the sphincter triggers an allergic reaction, including (B) Slow synaptic inhibition (E) The inhibitory motor neurons to abdominal cramping and diarrhea. (C) Presynaptic inhibition the sphincter muscle stop firing during Which kind of contractile behavior is (D) Postsynaptic facilitation a swallow the most likely intestinal motility (E) Inhibitory junction potential 11.The absence of intestinal motility in pattern during the professor’s allergic 7. A 10-cm segment of small intestine is the normal small intestine is best reaction to shellfish? removed surgically and placed in a described as (A) Physiological ileus 37C physiological solution containing (A) A migrating motor complex (B) Migrating motor complex tetrodotoxin. A stimulus at one end of (B) An interdigestive state (C) Retrograde peristaltic propulsion the segment evokes an action potential (C) Segmentation (D) Segmentation and an accompanying contraction that (D) Physiological ileus (E) Power propulsion travels to the opposite end of the (E) Power propulsion 17.The instillation of markers in the large segment. This finding is best explained 12.The best description of the lag phase intestine is used to evaluate transit time by of gastric emptying is the time required in the large intestine and diagnose (A) Electrical slow waves for motility disorders. In healthy subjects, (B) Varicose motor nerve fibers (A) Conversion from the interdigestive dwell-times for instilled markers in the (C) Interstitial cells of Cajal to the digestive enteric motor program large intestine are greatest in the (D) Functional electrical syncytial (B) Maximal stimulation of gastric (A) Ascending colon properties secretion (B) Sigmoid colon (E) Release of neurotransmitters (C) Return of the emptying curve to (C) Descending colon 8. A disease that results in the loss of baseline (D) Transverse colon enteric inhibitory motor neurons to the (D) Reduction of particle size to occur (E) Anorectum musculature of the digestive tract will (E) Emptying of half of a liquid meal 18.An 86-year-old woman has complaints most likely be expressed as 13.Increased strength of the trailing of a compromised lifestyle because of (A) Rapid intestinal transit component of the contractile complex fecal incontinence. Examination of this (B) Accelerated gastric emptying in the gastric antral pump is most patient will most likely reveal the (C) Gastroesophageal reflux likely to occur when underlying cause of the incontinence (D) Diarrhea (A) Excitatory motor neurons are to be (E) Achalasia of the lower esophageal activated to release ACh at the antral (A) Absence of the rectoanal reflex sphincter musculature (B) Elevated sensitivity to the presence 9. The viewing of intestinal peristaltic (B) Sympathetic postganglionic of feces in the rectum (continued)
480 PART VII GASTROINTESTINAL PHYSIOLOGY (C) Loss of the ENS in the distal large clinics. Z Gastroenterol (Suppl 2) book for Clinicians. London: Harcourt intestine (adult Hirschsprung’s disease) 1997;:3–68. Brace, 1998;19–42. (D) Weakness in the puborectalis and Kunze WA, Furness JB. The enteric nerv- Wood JD. Physiology of the enteric nerv- external anal sphincter muscles ous system and regulation of intestinal ous system. In: Johnson LR, Alpers DH, (E) A myopathic form of chronic motility. Annu Rev Physiol Christensen J, Jacobson ED, Walsh JH, pseudoobstruction in the large 1999;61:117–142. eds. Physiology of the Gastrointestinal intestine Makhlouf GM. Smooth muscle of the gut. Tract. 3rd Ed. New York: Raven, In: Yamada T, Alpers DH, Owyang C, 1994;423–482. SUGGESTED READING Powell DW, Silverstein FE, eds. Text- Wood JD, Alpers DH, Andrews PLR. Fun- Costa M, Glise H, Sjödal R. The enteric book of Gastroenterology. 2nd Ed. damentals of neurogastroenterology. nervous system in health and disease. Philadelphia: Lippincott, 1995;86–111. Gut 1999;45:1–44. Gut 2000;47:1–88. Sanders KM. A novel pacemaker mecha- Wood JD, Alpers DH, Andrews PLR. Gershon MD. The Second Brain. New nism drives gastrointestinal rhythmic- Fundamentals of neurogastroenterol- York: Harper Collins, 1998. ity. News Physiol Sci ogy: Basic science. In: Drossman Costa M, Hennig GW, Brookes SJ. Intesti- 2000;15:291–298. DA, Talley NJ, Thompson WG, nal peristalsis: A mammalian motor pat- Szurszewski JH. A 100-year perspective on Corazziari E, eds. The Functional tern controlled by enteric neural cir- gastrointestinal motility. Am J Physiol Gastrointestinal Disorders: Diagno- cuits. Ann N Y Acad Sci 1998;274:G447–G453. sis, Pathophysiology and Treatment: 1998;16:464–466. Wood JD. Enteric neuropathobiology. In: A Multinational Consensus. McLean, Krammer HJ, Enck P, Tack L. Neurogas- Phillips SF, Wingate DL, eds. Func- VA: Degnon Associates, troenterology—From the basics to the tional Disorders of the Gut: A Hand- 2000;31–90.
Gastrointestinal CHAPTER 27 Secretion, Digestion, 27 and Absorption Patrick Tso, Ph.D. CHAPTER OUTLINE ■ GASTROINTESTINAL SECRETION ■ DIGESTION AND ABSORPTION OF ■ SALIVARY SECRETION CARBOHYDRATES ■ GASTRIC SECRETION ■ DIGESTION AND ABSORPTION OF LIPIDS ■ PANCREATIC SECRETION ■ DIGESTION AND ABSORPTION OF PROTEINS ■ BILIARY SECRETION ■ ABSORPTION OF VITAMINS ■ INTESTINAL SECRETION ■ ELECTROLYTE AND MINERAL ABSORPTION ■ DIGESTION AND ABSORPTION ■ ABSORPTION OF WATER KEY CONCEPTS 1. The major function of the GI tract is the digestion and ab- 11. Pancreatic secretion neutralizes the acids in chyme and sorption of nutrients. contains enzymes involved in the digestion of carbohy- 2. Saliva assists in the swallowing of food, carbohydrate di- drates, fat, and protein. gestion, and the transport of immunoglobulins that com- 12. Secretin stimulates the pancreas to secrete a bicarbonate- bat pathogens. rich fluid, neutralizing acidic chyme. 3. Salivary secretion is mainly under the control of the auto- 13. CCK stimulates the pancreas to secrete an enzyme-rich fluid. nomic nervous system. Parasympathetic and sympathetic 14. Pancreatic secretion is under neural and hormonal control nerves innervate the blood supply to the salivary glands. and consists of three phases: cephalic, gastric, and intes- The parasympathetic nervous system increases the flow of tinal. saliva significantly, but the sympathetic nervous system 15. Bile salts play an important role in the intestinal absorption only increases saliva flow marginally. of lipids. 4. The stomach prepares chyme to aid in the digestion of 16. Carbohydrates, when digested, form maltose, maltotriose, food in the small intestine. and -limit dextrins, which are cleaved by brush border en- 5. The gastric mucosa contains surface mucous cells that se- zymes to monosaccharides and taken up by enterocytes. crete mucus and bicarbonate ions, which protect the stom- 17. Lipids absorbed by enterocytes are packaged and secreted ach from the acid in the stomach cavity. as chylomicrons into lymph. 6. Parietal cells secrete hydrochloric acid and intrinsic factor, 18. Protein is digested to form amino acids, dipeptides, and and chief cells secrete pepsinogen. tripeptides that are taken up by enterocytes and trans- 7. Gastrin plays an important role in stimulating gastric acid ported in the blood. secretion. 19. The GI tract absorbs water-soluble vitamins and ions by 8. The acidity of gastric juice provides a barrier to microbial different mechanisms. invasion of the GI tract. 20. Calcium-binding protein is involved in calcium absorption. 9. Gastric secretion is under neural and hormonal control and 21. Heme and nonheme iron is absorbed in the small intestine consists of three phases: cephalic, gastric, and intestinal. by different mechanisms. 10. Gastric inhibitory peptide (GIP), secreted by intestinal en- 22. Most of the salt and water entering the intestinal tract, docrine cells, is a potent inhibitor of gastric acid secretion whether in the diet or in GI secretions, is absorbed in the and enhances insulin release. small intestine. 481
482 PART VII GASTROINTESTINAL PHYSIOLOGY he major function of the GI tract is the digestion and Tabsorption of nutrients. Some absorption occurs in the stomach, including that of medium-chain fatty acids and some drugs, but most digestion and absorption of nutrients takes place in the small intestine. Secretions from the sali- vary glands, stomach, pancreas, and liver aid in the diges- tion and absorption process and protect the GI mucosa from the harmful effects of noxious agents. This chapter discusses the relevant anatomy, mechanism, composition, and regulation of GI secretion and the role the GI tract plays in the absorption of carbohydrate, fat, protein, fat- soluble and water-soluble vitamins, electrolytes, bile salts, and water. GASTROINTESTINAL SECRETION Secretions of the GI tract share several common features. A given secretion originates from individual groups of cells (e.g., acinar cells in the salivary gland) before pooling with other secretions. Secretions often empty into small ducts, which in turn empty into larger ducts, which empty into the lumen of the GI tract. Such a ductal system serves as a conduit for secretions from the salivary glands, pancreas, and liver, and modifies the primary secretion. Carbonic an- FIGURE 27.1 An acinus and associated ductal system from the human submandibular gland. (Modified hydrase, an enzyme present in gastric, pancreatic, and in- from Johnson LR, Christensen J, Jackson MJ, et al. eds. Physiology testinal cells, is involved in the formation of GI secretions. of the Gastrointestinal Tract. New York: Raven, 1987.) SALIVARY SECRETION tory (collecting) duct. The acinus is a blind sac containing Salivary secretion is unique in that it is regulated almost ex- mainly pyramidal cells. Occasionally, there are stellate- clusively by the nervous system. Saliva is produced by a shaped myoepithelial cells surrounding the large pyramidal heterogeneous group of exocrine glands called the salivary cells. The cells of the acinus are not homogeneous. Serous glands. Saliva performs several functions. It facilitates cells secrete digestive enzymes, and mucous cells secrete chewing and swallowing by lubricating food, carries im- mucin. Serous cells contain an abundance of rough endo- munoglobulins that combat pathogens, and assists in car- plasmic reticulum (ER), reflecting active protein synthesis, bohydrate digestion. and numerous zymogen granules. Salivary amylase is an The parotid, submandibular (submaxillary), and sublin- important digestive enzyme synthesized and stored in the gual glands are the major salivary glands. They are drained zymogen granules and secreted by the serous acinar cells. by individual ducts into the mouth. The sublingual gland Numerous mucin droplets are stored in the mucous aci- also has numerous small ducts that open into the floor of nar cells. Mucin is composed of glycoproteins of various the mouth. The secretions of the major glands differ signif- molecular weights. icantly. The parotid glands secrete saliva that is rich in wa- The intercalated ducts are lined with small cuboidal cells. ter and electrolytes, whereas the submandibular and sublin- The function of these cells is unclear, but they may be in- gual glands secrete saliva that is rich in mucin. There are volved in the secretion of proteins, since secretory granules also minor salivary glands located in the labial, palatine, are occasionally observed in their cytoplasm. The interca- buccal, lingual, and sublingual mucosae. lated ducts are connected to the striated duct, which eventu- The salivary glands are endowed with a rich blood supply ally empties into the excretory duct. The striated duct is and are innervated by both the parasympathetic and sympa- lined with columnar cells. Its major function is to modify the thetic divisions of the autonomic nervous system. Although ionic composition of the saliva. The large excretory ducts, hormones may modify the composition of saliva, their phys- lined with columnar cells, also play a role in modifying the iological role is questionable, and it is generally believed that ionic composition of saliva. Although most proteins are syn- salivary secretion is mainly under autonomic control. thesized and secreted by the acinar cells, the duct cells also synthesize several proteins, such as epidermal growth factor, ribonuclease, -amylase, and proteases. The Salivary Glands Consist of a Network of Acini and Ducts Saliva Contains Various Electrolytes and Proteins A diagram of the human submandibular gland is shown in Figure 27.1. The basic unit, the salivon, consists of the aci- The electrolyte composition of the primary secretion pro- nus, the intercalated duct, the striated duct, and the excre- duced by the acinar cells resembles that of plasma. Microp-
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 483 Osmolality (mOsm/kg H 2 O) 240 lining of the duct is not permeable to water, so water does in place of two K ions taken up by the cell. The epithelial not follow the absorbed salt. The two major proteins present in saliva are amylase and mucin. Salivary -amylase (ptyalin) is produced predomi- 160 nantly by the parotid glands and mucin is produced mainly by the sublingual and submandibular salivary glands. Amy- lase catalyzes the hydrolysis of polysaccharides with -1,4- 80 glycosidic linkages. It is a hydrolytic enzyme involved in the digestion of starch. It is synthesized by the rough ER 160 and transferred to the Golgi apparatus, where it is packaged Na + into zymogen granules. The zymogen granules are stored Ionic concentrations (mEq/L) 80 HCO 3 - Cl - acids in the stomach can inactivate the amylase, a substan- at the apical region of the acinar cells and released with ap- 120 propriate stimuli. Because some time usually passes before + Na tial amount of the ingested carbohydrate can be digested before reaching the duodenum. (The action of amylase is described later in the chapter.) - Cl Mucin is the most abundant protein in saliva. The term 40 different amounts of different sugars. Mucin is responsible K + HCO 3 - describes a family of glycoproteins, each associated with K + for most of saliva’s viscosity. Also present in saliva are small 0 amounts of muramidase, a lysozyme that can lyse the mu- 0 123 4 5 Plasma Rate of secretion (mL/min) ramic acid of certain bacteria (e.g., Staphylococcus); lactofer- rin, a protein that binds iron; epidermal growth factor, The osmolality and electrolyte composition FIGURE 27.2 which stimulates gastric mucosal growth; immunoglobulins of saliva at different secretion rates. (Modi- (mainly IgA); and ABO blood group substances. fied from Granger DN, Barrowman JA, Kvietys PR. Clinical Gas- trointestinal Physiology. Philadelphia: WB Saunders, 1985.) Saliva Has Protective Functions Saliva’s pH is almost neutral (pH 7), and it contains uncture samples have revealed that there is little modifica- HCO 3 that can neutralize any acidic substance entering tion of the electrolyte composition of the primary secretion the oral cavity, including regurgitated gastric acid. Saliva in the intercalated duct. However, samples from the excre- plays an important role in the general hygiene of the oral tory (collecting) ducts are hypotonic relative to plasma, in- cavity. The muramidase present in saliva combats bacteria dicating modification of the primary secretion in the striated by lysing the bacterial cell wall. The lactoferrin binds iron and excretory ducts. As shown in Figure 27.2, there is less strongly, depriving microorganisms of sources of iron vital sodium (Na ), less chloride (Cl ), more potassium (K ), to their growth. and more bicarbonate (HCO 3 ) in saliva than in plasma. Saliva lubricates the mucosal surface, reducing the fric- This is because Na is actively absorbed from the lumen by tional damage caused by the rough surfaces of food. It helps the ductal cells, whereas K and HCO 3 ions are actively small food particles stick together to form a bolus, which secreted into the lumen. Chloride ions leave the lumen either makes them easier to swallow. Moistening of the oral cav- in exchange for HCO 3 ions or by passive diffusion along ity with saliva facilitates speech. Saliva can dissolve flavor- the electrochemical gradient created by Na absorption. ful substances, stimulating the different taste buds located The electrolyte composition of saliva depends on the on the tongue. Finally, saliva plays an important role in wa- rate of secretion (see Fig. 27.2). As the secretion rate in- ter intake; the sensation of dryness of the mouth due to low creases, the electrolyte composition of saliva approaches salivary secretion urges a person to drink. the ionic composition of plasma, but at low flow rates it dif- fers significantly. At low secretion rates, the ductal epithe- Autonomic Nerves Are the Chief Modulators lium has more time to modify and, thus, reduce the osmo- lality of the primary secretion, so the saliva has a much of Saliva Output and Content lower osmolality than plasma. The opposite is true at high As mentioned, salivary secretion is predominantly under secretion rates. the control of the autonomic nervous system. In the resting Although the absorption and secretion of ions may ex- state, salivary secretion is low, amounting to about 30 plain changes in the electrolyte composition of saliva, these mL/hr. The submandibular glands contribute about two processes do not explain why the osmolality of saliva is thirds to resting salivary secretion, the parotid glands about lower than that of the primary secretion of the acinar cells. one fourth, and the sublingual glands the remainder. Stim- Saliva is hypotonic to plasma because of a net absorption of ulation increases the rate of salivary secretion, most notably ions by the ductal epithelium, a result of the action of a in the parotid glands, up to 400 mL/hr. The most potent Na /K -ATPase in the basolateral cell membrane. The stimuli for salivary secretion are acidic-tasting substances, Na /K -ATPase transports three Na ions out of the cell such as citric acid. Other types of stimuli that induce sali-
484 PART VII GASTROINTESTINAL PHYSIOLOGY vary secretion include the smell of food and chewing. Se- cretion is inhibited by anxiety, fear, and dehydration. TABLE 27.1 Effects of Parasympathetic and Sympa- Parasympathetic stimulation of the salivary glands re- thetic Stimulation on Salivary Secretion sults in increased activity of the acinar and ductal cells and Responses increased salivary secretion. The parasympathetic nervous Responses Parasympathetic Sympathetic system plays an important role in controlling the secretion Saliva output Copious Scant of saliva. The centers involved are located in the medulla Temporal response Sustained Transient oblongata. Preganglionic fibers from the inferior salivatory Composition Protein poor, high Protein-rich, low nucleus are contained in cranial nerve IX and the synapse in K and HCO 3 K and HCO 3 the otic ganglion. They send postganglionic fibers to the Response to Decreased secretion, Decreased secretion parotid glands. Preganglionic fibers from the superior sali- denervation atrophy vatory nucleus course with cranial nerve VII and synapse in the submandibular ganglion. They send postganglionic fibers to the submandibular and sublingual glands. and blood vessels. Sympathetic stimulation tends to result Blood flow to resting salivary glands is about 50 mL/min in a short-lived and much smaller increase in salivary secre- per 100 g tissue and can increase as much as 10-fold when tion than parasympathetic stimulation. The increase in sali- salivary secretion is stimulated. This increase in blood flow vary secretion observed during sympathetic stimulation is is under parasympathetic control. Parasympathetic stimula- mainly via -adrenergic receptors, which are more in- tion induces the acinar cells to release the protease volved in stimulating the contraction of myoepithelial kallikrein, which acts on a plasma globulin, kininogen, to cells. Although both sympathetic and parasympathetic release lysyl-bradykinin, which causes dilation of the blood stimulation increases salivary secretion, the responses pro- vessels supplying the salivary glands (Fig. 27.3). Atropine, duced are different (Table 27.1). an anticholinergic agent, is a potent inhibitor of salivary se- Mineralocorticoid administration reduces the Na con- cretion. Agents that inhibit acetylcholinesterase (e.g., pilo- centration of saliva with a corresponding rise in K con- carpine) enhance salivary secretion. Some parasympathetic centration. Mineralocorticoids act mainly on the striated stimulation also increases blood flow to the salivary glands and excretory ducts. Arginine vasopressin (AVP) reduces directly, apparently via the release of the neurotransmitter the Na concentration in saliva by increasing Na reab- vasoactive intestinal peptide (VIP). sorption by the ducts. Some GI hormones (e.g., VIP and The salivary glands are also innervated by the sympa- substance P) have been experimentally demonstrated to thetic nervous system. Sympathetic fibers arise in the upper evoke salivary secretory responses. thoracic segments of the spinal cord and synapse in the su- perior cervical ganglion. Postganglionic fibers leave the superior cervical ganglion and innervate the acini, ducts, GASTRIC SECRETION The major function of the stomach is storage, but it also ab- sorbs water-soluble and lipid-soluble substances (e.g., alco- hol and some drugs). An important function of the stomach is to prepare the chyme for digestion in the small intestine. Chyme is the semi-fluid material produced by the gastric digestion of food. Chyme results partly from the conver- sion of large solid particles into smaller particles via the combined peristaltic movements of the stomach and con- traction of the pyloric sphincter. The propulsive, grinding, and retropulsive movements associated with antral peristal- sis are discussed in Chapter 26. A combination of the squirting of antral content into the duodenum, the grinding action of the antrum, and retropulsion provides much of the mechanical action necessary for the emulsification of di- etary fat, which plays an important role in fat digestion. Numerous Cell Types in the Stomach Contribute to Gastric Secretions The fundus of the stomach is relatively thin-walled and can be expanded with ingested food (see Fig. 26.24). The main body (corpus) of the empty stomach is composed of many longitudinal folds called rugae gastricae. The stomach’s mu- The effect of parasympathetic innervation cosal lining, the glandular gastric mucosa, contains three FIGURE 27.3 on blood flow to the salivary glands. (Mod- main types of glands: cardiac, pyloric, and oxyntic. These ified from Sanford PA. Digestive System Physiology. Baltimore: glands contain mucous cells that secrete mucus and HCO 3 University Park Press, 1982.) ions, which protect the stomach from the acid in the stom-
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 485 ach lumen. The cardiac glands are located in a small area ad- jacent to the esophagus and are lined by mucus-producing columnar cells. The pyloric glands are located in a larger area adjacent to the duodenum. They contain cells similar to mu- cous neck cells but differ from cardiac and oxyntic glands in having many gastrin-producing cells called G cells. The oxyntic glands, the most abundant glands in the stomach, a) are found in the fundus and the corpus. The oxyntic glands contain parietal (oxyntic) cells, chief cells, mucous neck cells, and some endocrine cells (Fig. 27.4). Surface mucous cells occupy the gastric pit (foveola); in the gland, most mucous cells are located in the neck region. The base of the oxyntic gland contains mostly chief cells, along with some parietal and endocrine cells. Mucous neck cells secrete mucus, parietal cells principally secrete hydrochloric acid (HCl) and intrinsic factor, and chief cells secrete pepsinogen. (Intrinsic factor and pepsinogen are discussed later in the chapter.) Parietal cells are the most distinctive cells in the stom- ach. The structure of resting parietal cells is unique in that they have intracellular canaliculi as well as an abundance of mitochondria (Fig. 27.5A). This network consists of clefts and canals that are continuous with the lumen of the oxyn- tic gland. There is also an extensive smooth ER referred to as the tubulovesicular membranes. In active parietal cells (Fig. 27.5B), the tubulovesicular system is greatly dimin- ished with a concomitant increase in the intracellular canaliculi. The mechanism for these morphological changes is not well understood. Hydrochloric acid is se- creted across the parietal cell microvillar membrane and A simplified diagram of the oxyntic gland FIGURE 27.4 flows out of the intracellular canaliculi into the oxyntic in the corpus of a mammalian stomach. One to several glands may open into a common gastric pit. gland lumen. As mentioned, surface mucous cells line the (Modified from Ito S. Functional gastric morphology. In: Johnson entire surface of the gastric mucosa and the openings of the LR, Christensen J, Jackson MJ, et al. eds. Physiology of the Gas- cardiac, pyloric, and oxyntic glands. These cells secrete trointestinal Tract. New York: Raven, 1987.) mucus and HCO 3 to protect the gastric surface from the Golgi Golgi apparatus apparatus Tubulovesicular membrane Mitochondria Intracellular canaliculus Tubulovesicular Mitochondria membrane Basal folds Basal folds Intracellular canaliculus Basement lamina Basement lamina A B Parietal cells of the stomach. A, A nonsecret- the most striking difference is the abundance of long microvilli and FIGURE 27.5 ing parietal cell. The cytoplasm is filled with the paucity of the tubulovesicular system, making the mitochondria tubulovesicular membranes, and the intracellular canaliculi have be- appear more numerous. (From Ito S. Functional gastric morphology. come internalized, distended, and devoid of microvilli. B, An ac- In: Johnson LR, Christensen J, Jackson MJ, et al. eds. Physiology of tively secreting parietal cell. Compared to the resting parietal cell, the Gastrointestinal Tract. New York: Raven, 1987.)
486 PART VII GASTROINTESTINAL PHYSIOLOGY acidic environment of the stomach. The distinguishing K entering the cell. The H /K -ATPase is inhibited by characteristic of a surface mucous cell is the presence of nu- omeprazole. Omeprazole, an acid-activated prodrug that is merous mucus granules at its apex. The number of mucus converted in the stomach to the active drug, binds to two granules in storage varies depending on synthesis and se- cysteines on the ATPase, resulting in an irreversible inacti- cretion. The mucous neck cells of the oxyntic glands are vation. Although the secreted H is often depicted as be- similar in appearance to surface mucous cells. ing derived from carbonic acid (see Fig. 27.6), the source of Chief cells are morphologically distinguished primarily H is probably mostly from the dissociation of H 2O. Car- by the presence of zymogen granules in the apical region bonic acid (H 2CO 3) is formed from carbon dioxide (CO 2) and an extensive ER. The zymogen granules contain and H 2O in a reaction catalyzed by carbonic anhydrase. pepsinogen, a precursor of the enzyme pepsin. Carbonic anhydrase is inhibited by acetazolamide. The Also present in the stomach are various neuroendocrine CO 2 is provided by metabolic sources inside the cell and cells, such as G cells, located predominantly in the antrum. from the blood. These cells produce the hormone gastrin, which stimulates For the H /K -ATPase to work, an adequate supply of acid secretion by the stomach. An overabundance of gas- K ions must exist outside the cell. Although the mecha- trin secretion, a condition known as Zollinger-Ellison syn- nism is still unclear, there is an increase in K conductance drome, results in gastric hypersecretion and peptic ulceration. (through K channels) in the apical membrane of the pari- D cells, also present in the antrum, produce somatostatin, an- etal cells simultaneous with active acid secretion. This other important GI hormone. surge of K conductance ensures plenty of K in the lu- men. The H /K -ATPase recycles K ions back into the cell in exchange for H ions. As shown in Figure 27.6, the Gastric Juice Contains Hydrochloric Acid, basolateral cell membrane has an electroneutral Electrolytes, and Proteins Cl /HCO 3 exchanger that balances the entry of Cl into entering the The important constituents of human gastric juice are HCl, the cell with an equal amount of HCO 3 electrolytes, pepsinogen, and intrinsic factor. The pH is bloodstream. The Cl inside the cell then leaks into the lu- low, about 0.7 to 3.8. This raises a question: How does the men through Cl channels, down an electrochemical gra- gastric mucosa protect itself from acidity? As mentioned dient. Consequently, HCl is secreted into the lumen. earlier, the surface mucous cells secrete a fluid containing A large amount of HCl can be secreted by the parietal mucus and HCO 3 ions. The mucus forms a mucus gel cells. This is balanced by an equal amount of HCO 3 layer covering the surface of the gastric mucosa. Bicarbon- added to the bloodstream. The blood coming from the ate trapped in the mucus gel layer neutralizes acid, pre- stomach during active acid secretion contains much venting damage to the mucosal cell surface. HCO 3 , a phenomenon called the alkaline tide. The os- motic gradient created by the HCl concentration in the gland lumen drives water passively into the lumen, thereby, Hydrochloric Acid Is Secreted by the Parietal Cells maintaining the iso-osmolality of the gastric secretion. The HCl present in the gastric lumen is secreted by the parietal cells of the corpus and fundus. The mechanism of Gastric Juice Contains Various Electrolytes HCl production is depicted in Figure 27.6. An H /K - Figure 27.7 depicts the changes in the electrolyte composi- ATPase in the apical (luminal) cell membrane of the pari- tion of gastric juice at different secretion rates. At a low se- etal cell actively pumps H out of the cell in exchange for cretion rate, gastric juice contains high concentrations of Na and Cl and low concentrations of K and H . When the rate of secretion increases, the concentration of Na Plasma Parietal cell Lumen decreases while that of H increases significantly. Also coupled with this increase in gastric secretion is an increase in Cl concentration. To understand the changes in elec- CO + H O CO 2 2 2 trolyte composition of gastric juice at different secretion Carbonic anhydrase H + rates, it is important to remember that gastric juice is de- H CO 3 H + rived from the secretions of two major sources: parietal 2 HCO 3 - ATP cells and nonparietal cells. Secretion from nonparietal cells HCO 3 - + is probably constant; therefore, it is parietal secretion (HCl ADP+Pi K secretion) that contributes mainly to the changes in elec- trolyte composition with higher secretion rates. - K + K + Cl Cl - Cl - Cl - + Na + Na ATP Gastric Secretion Performs Digestive, Protective, and Other Functions ADP+Pi Gastric juice contains several proteins: pepsinogens, K + K + pepsins, salivary amylase, gastric lipase, and intrinsic factor. The chief cells of the oxyntic glands release inactive The mechanism of HCl secretion by the pepsinogen. Pepsinogen is activated by acid in the gastric FIGURE 27.6 gastric parietal cell. lumen to form the active enzyme pepsin. Pepsin also cat-
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 487 160 Cl - Vagal Gastric juice stimulation 140 H + ACh 2+ K + Ionic concentrations (mEq/L) 120 Gastrin Adenylyl cAMP hydrogen H + Ca Gastric 100 ion pump 80 60 40 Histamine cyclase ATP The stimulation of parietal cell acid secre- FIGURE 27.8 20 tion by histamine, gastrin, and acetyl- K + choline (ACh), and potentiation of the process. Na + 0 0 123 Rate of secretion (mL/min) The concentration of electrolytes in the occur when the effect of two stimulants is greater than the FIGURE 27.7 gastric juice of a healthy, young adult man effect of either stimulant alone. For example, the interac- as a function of the rate of secretion. (Modified from Daven- tion of gastrin and ACh molecules with their respective re- port HW. Physiology of the Digestive Tract. Chicago: Year ceptors results in an increase in intracellular Ca 2 concen- Book, 1977.) tration, and the interaction of histamine with its receptor results in an increase in cellular cAMP production. The in- creased intracellular Ca 2 and cAMP interact in numerous alyzes its own formation from pepsinogen. Pepsin, an en- ways to stimulate the gastric H /K -ATPase, which brings dopeptidase, cleaves protein molecules from the inside, re- about an increase in acid secretion (see Fig. 27.8). Exactly sulting in the formation of smaller peptides. The optimal how the increase in intracellular Ca 2 and cAMP greatly pH for pepsin activity is 1.8 to 3.5; therefore, it is extremely enhances the effect of the other in stimulating gastric acid active in the highly acidic medium of gastric juice. secretion is not well understood. The acidity of gastric juice poses a barrier to invasion of the GI tract by microbes and parasites. The intrinsic factor, produced by stomach parietal cells, is necessary for absorp- Acid Secretion Is Increased During a Meal tion of vitamin B 12 in the terminal ileum. The stimulation of acid secretion resulting from the ingestion of food can be divided into three phases: the cephalic phase, Gastric Secretion Is Under Neural and the gastric phase, and the intestinal phase (Table 27.2). The Hormonal Control cephalic phase involves the central nervous system. Smelling, chewing, and swallowing food (or merely the thought of Gastric acid secretion is mediated through neural and hor- food) send impulses via the vagus nerves to the parietal and G monal pathways. Vagus nerve stimulation is the neural ef- cells in the stomach. The nerve endings release ACh, which fector; histamine and gastrin are the hormonal effectors directly stimulates acid secretion from parietal cells. The (Fig. 27.8). Parietal cells possess special histamine recep- nerves also release gastrin-releasing peptide (GRP), which tors, H 2 receptors, whose stimulation results in increased stimulates G cells to release gastrin, indirectly stimulating acid secretion. Special endocrine cells of the stomach, parietal cell acid secretion. The fact that the effect of GRP is known as enterochromaffin-like (ECL) cells are believed to atropine-resistant indicates that it works through a non- be the source of this histamine, but the mechanisms that cholinergic pathway. The cephalic phase probably accounts stimulate them to release histamine are poorly understood. for about 40% of total acid secretion. The importance of histamine as an effector of gastric acid The gastric phase is mainly a result of gastric distension secretion has been indirectly demonstrated by the effec- and chemical agents such as digested proteins. Distension tiveness of cimetidine, an H 2 blocker, in reducing acid se- of the stomach stimulates mechanoreceptors, which stimu- cretion. H 2 blockers are commonly used for the treatment late the parietal cells directly through short local (enteric) of peptic ulcer disease or gastroesophageal reflux disease. reflexes and by long vago-vagal reflexes. Vago-vagal re- The effects of each of these three stimulants (ACh, gas- flexes are mediated by afferent and efferent impulses trav- trin, and histamine) augment those of the others, a phe- eling in the vagus nerves. Digested proteins in the stomach nomenon known as potentiation. Potentiation is said to are also potent stimulators of gastric acid secretion, an ef-
488 PART VII GASTROINTESTINAL PHYSIOLOGY TABLE 27.2 The Three Phases of Stimulation of Acid Secretion After Ingesting a Meal Stimulus to Phase Stimulus Pathway Parietal Cell Cephalic Thought of food, smell, taste, chewing, Vagus nerve to and swallowing Parietal cells ACh G cells Gastrin Gastric Stomach distension Local (enteric) reflexes and vago-vagal reflexes to Parietal cells ACh G cells Gastrin Digested peptides G cells Gastrin Intestinal Protein digestion products in duodenum Amino acids in blood Amino acids Distension Intestinal endocrine cell Enterooxyntin fect mediated through gastrin release. Several other chem- tant only during the digestion of food. Second, excess acid icals, such as alcohol and caffeine, stimulate gastric acid se- can damage the gastric and the duodenal mucosal surfaces, cretion through mechanisms that are not well understood. causing ulcerative conditions (see Clinical Focus Box 27.1). The gastric phase accounts for about 50% of total gastric The body has an elaborate system for regulating the amount acid secretion. of acid secreted by the stomach. Gastric luminal pH is a sen- During the intestinal phase, protein digestion products sitive regulator of acid secretion. Proteins in food provide in the duodenum stimulate gastric acid secretion through buffering in the lumen; consequently, the gastric luminal pH the action of the circulating amino acids on the parietal is usually above 3 after a meal. However, if the buffering ca- cells. Distension of the small intestine, probably via the re- pacity of protein is exceeded or if the stomach is empty, the lease of the hormone enterooxyntin from intestinal en- pH of the gastric lumen will fall below 3. When this happens, docrine cells, stimulates acid secretion. The intestinal phase the endocrine cells (D cells) in the antrum secrete somato- accounts for only about 10% of total gastric acid secretion. statin, which inhibits the release of gastrin and, thus, gastric acid secretion. Another mechanism for inhibiting gastric acid secretion Gastric Acid Secretion Is Inhibited by is acidification of the duodenal lumen. Acidification stimu- Several Mechanisms lates the release of secretin, which inhibits the release of The inhibition of gastric acid secretion is physiologically im- gastrin, and several peptides, collectively known as entero- portant for two reasons. First, the secretion of acid is impor- gastrones, which are released by intestinal endocrine cells. CLINICAL FOCUS BOX 27.1 Acid Secretion and Duodenal Ulcer ease is the finding of a possible correlation between Heli- Ulcerative lesions of the gastroduodenal area are classi- cobacter pylori (H. pylori) infection and the incidence of fied as peptic ulcer disease. Peptic ulcer disease is as- gastric and duodenal ulcers. The role of H. pylori infection sociated with a high rate of recurrence. The saying, “no in the genesis of peptic ulcers is unclear, but in a significant acid, no ulcer,” has withstood the test of time and is still number of patients, eradication of the bacteria reduces the accepted by most physicians and researchers as generally rate of ulcer recurrence. H. pylori produces large quantities true. One possible cause of gastric and duodenal ulcers is of the enzyme urease, which hydrolyzes urea to produce reduced mucosal defense mechanisms. Human and ani- ammonia. The ammonia neutralizes acid in the stomach, mal data, however, have demonstrated that duodenal ul- protecting the bacteria from the injurious effects of hy- cers do not occur with reduced mucosal defense mecha- drochloric acid. nisms alone but also require the presence of sufficient Although the mechanism has not been elucidated, the amounts of acid. In one study, patients suffering from presence of H. pylori in the stomach enhances the secre- duodenal ulcer had a significantly increased mean num- tion of gastrin by the gastric mucosa. Whether increased ber of gastric parietal cells and appeared to have in- gastrin release by the presence of H. pylori is responsible creased sensitivity to gastrin when compared with healthy for the increased recurrence of gastric and duodenal ulcers subjects. Although the reason is unknown, the stomach in patients has yet to be proven. It has been demonstrated emptying rate may be greatly increased in duodenal ulcer that H 2 receptor antagonists (cimetidine and ranitidine) patients. Another abnormality in duodenal ulcer patients have no effect on H. pylori infection. In contrast, omepra- is decreased inhibition of gastrin release by acid and a re- zole (an inhibitor of the H /K -ATPase) appears to be bac- duced rate of duodenal bicarbonate secretion. It should be teriostatic. A combined therapy using omeprazole and the emphasized, however, that a significant number of pa- antibiotic amoxicillin appears to be effective in the eradi- tients with duodenal ulcer do not have excessive secretion cation of H. pylori in 50 to 80% of patients with peptic ulcer of acid. disease, resulting in a significant reduction of duodenal ul- An exciting development in the field of peptic ulcer dis- cer recurrence.
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 489 Acid, fatty acids, or hyperosmolar solutions in the duode- with increases in secretion rate and reaches a maximal con- num stimulate the release of enterogastrones, which inhibit centration of about 140 mEq/L, yielding a solution with a gastric acid secretion. Gastric inhibitory peptide (GIP), an pH of 8.2. A reciprocal relationship exists between the enterogastrone produced by the small intestinal endocrine Cl and HCO 3 concentration in pancreatic juice. As the cells, inhibits parietal cell acid secretion. There are also sev- concentration of HCO 3 increases with secretion rate, the eral currently unidentified enterogastrones. Cl concentration falls accordingly, resulting in a com- bined total anion concentration that remains relatively constant (150 mEq/L) regardless of the pancreatic secre- PANCREATIC SECRETION tion rate. Two separate mechanisms have been proposed to ex- One of the major functions of pancreatic secretion is to plain the secretion of a HCO 3 -rich juice by the pan- neutralize the acids in the chyme when it enters the duo- creas and the HCO 3 concentration changes. The first denum from the stomach. This mechanism is important be- mechanism proposes that some cells, probably the acinar cause pancreatic enzymes operate optimally near neutral cells, secrete a plasma-like fluid containing predomi- pH. Another important function is the production of en- nantly Na and Cl , while other cells, probably the cen- zymes involved in the digestion of dietary carbohydrate, troacinar and duct cells, secrete a HCO 3 -rich solution fat, and protein. when stimulated. Depending on the different rates of se- cretion from these three different cell types, the pancre- atic juice can be rich in either HCO 3 or Cl . The sec- The Pancreas Consists of a Network of ond mechanism depicts the primary secretion as rich in Acini and Ducts HCO 3 . As the HCO 3 solution moves down the ductal The human pancreas is located in close apposition to the system, HCO 3 ions are exchanged for Cl ions. When duodenum. It performs both endocrine and exocrine func- the flow is fast, there is little time for this exchange, so tions, but here we discuss only its exocrine function. (The the concentration of HCO 3 is high. The opposite is endocrine functions are discussed in Chapter 35.) true when the flow is slow. The exocrine pancreas is composed of numerous small, The secretion of electrolytes by pancreatic duct cells is sac-like dilatations called acini composed of a single layer depicted in Figure 27.11. A Na /H exchanger is located of pyramidal acinar cells (Fig. 27.9). These cells are actively in the basolateral cell membrane. The energy required to involved in the production of enzymes. Their cytoplasm is drive the exchanger is provided by the Na /K -ATPase- filled with an elaborate system of ER and Golgi apparatus. generated Na gradient. Carbon dioxide diffuses into the Zymogen granules are observed in the apical region of aci- cell and combines with H 2 O to form H 2 CO 3 , a reaction nar cells. A few centroacinar cells line the lumen of the ac- catalyzed by carbonic anhydrase, which dissociates to H inus. In contrast to acinar cells, these cells lack an elaborate and HCO 3 . The H is extruded by the Na /H ex- ER and Golgi apparatus. Their major function seems to be changer, and HCO 3 is exchanged for luminal Cl via a modification of the electrolyte composition of the pancre- Cl /HCO 3 exchanger. Also located in the luminal cell atic secretion. Because the processes involved in the secre- membrane is a protein called cystic fibrosis transmem- tion or uptake of ions are active, centroacinar cells have nu- brane conductance regulator (CFTR). CFTR is an ion merous mitochondria in their cytoplasm. channel belonging to the ABC (ATP-binding cassette) fam- The acini empty their secretions into intercalated ducts, ily of proteins. Regulated by ATP, its major function is to which join to form intralobular and then interlobular ducts. secrete Cl ions out of the cells, providing Cl in the lu- The interlobular ducts empty into two pancreatic ducts: a men for the Cl /HCO 3 exchanger to work. The Na /K - major duct, the duct of Wirsung, and a minor duct, the duct ATPase removes cell Na that enters through the Na /H of Santorini. The duct of Santorini enters the duodenum antiporter. Sodium from the interstitial space follows se- more proximally than the duct of Wirsung, which enters creted HCO 3 by diffusing through a paracellular path the duodenum usually together with the common bile duct. (between the cells). Movement of H 2 O into the duct lumen A ring of smooth muscle, the sphincter of Oddi, surrounds is passive, driven by the osmotic gradient. The net result of the opening of these ducts in the duodenum. The sphincter pancreatic HCO 3 secretion is the release of H into the of Oddi not only regulates the flow of bile and pancreatic plasma; thus, pancreatic secretion is associated with an acid juice into the duodenum but also prevents the reflux of in- tide in the plasma. testinal contents into the pancreatic ducts. Pancreatic Secretions Neutralize Luminal Pancreatic Secretions Are Rich in Acids and Digest Nutrients Bicarbonate Ions As mentioned, one of the primary functions of pancreatic The pancreas secretes about 1 L/day of HCO 3 -rich fluid. secretion is to neutralize the acidic chyme presented to the The osmolality of pancreatic fluid, unlike that of saliva, is duodenum. The enzymes present in intestinal lumen work equal to that of plasma at all secretion rates. The Na and best at a pH close to neutral; therefore, it is crucial to in- K concentrations of pancreatic juice are the same as crease the pH of the chyme. As described above, pancreatic those in plasma, but unlike plasma, pancreatic juice is en- juice is highly basic because of its HCO 3 content. Thus, riched with HCO 3 and has a relatively low Cl concen- the acidic chyme presented to the duodenum is rapidly tration (Fig. 27.10). The HCO 3 concentration increases neutralized by pancreatic juice.
490 PART VII GASTROINTESTINAL PHYSIOLOGY Intercalated duct cell Basement membrane Centroacinar cell Acinar cell Fenestrated capillary Nerve fiber The structure of a pancreatic acinus. (From Krstic RV. General Histology of the Mam- FIGURE 27.9 mal. New York: Springer-Verlag, 1984.)
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 491 8.2 pH 340 similar to secretin, stimulates the secretion of HCO 3 and H 2O. However, because VIP is much weaker than secretin, Osmolality (mOsm/kg H 2 O) it produces a weaker pancreatic response when given to- gether with secretin than when secretin is given alone. Sim- pH ilarly, gastrin can stimulate pancreatic enzyme secretion Osm 7.8 300 it is a weak agonist for pancreatic enzyme secretion. 7.4 260 because of its structural similarity to CCK, but unlike CCK, 160 Pancreatic Secretion Is Phasic Na Na The regulation of pancreatic secretion by various hormonal Ionic concentrations (mEq/L) 80 Cl food results in the secretion of a pancreatic juice rich in en- HCO 3 and neural factors is summarized in Table 27.4. Seeing, 120 smelling, tasting, chewing, swallowing, or thinking about zymes. In this cephalic phase, stimulation of pancreatic se- cretion is mainly mediated by direct efferent impulses sent by vagal centers in the brain to the pancreas and, to a mi- nor extent, by the indirect effect of parasympathetic stimu- lation of gastrin release. The gastric phase is initiated when 40 food enters the stomach and distends it. Pancreatic secre- HCO 3 Cl tion is then stimulated by vago-vagal reflex. Gastrin may K K 0 also be involved in this phase. 0 100 200 300 400 500 Plasma During the most important phase, the intestinal phase, Rate of secretion (mL/h) the entry of acidic chyme from the stomach into the small intestine stimulates the release of secretin by the S cells (a The pH, osmolality, and electrolyte com- FIGURE 27.10 type of endocrine cell) in the intestinal mucosa. When the position of pancreatic juice at different se- cretion rates. Plasma electrolyte composition is provided for pH of the lumen in the duodenum decreases, the secretin comparison. (Adapted from Granger DN, Barrowman JA, Kvi- concentration in plasma increases. This response is fol- etys PR. Clinical Gastrointestinal Physiology. Philadelphia: WB lowed by an increase in HCO 3 output by the pancreas. Saunders, 1985.) The secretion of pancreatic enzymes is increased by circu- lating CCK and by parasympathetic stimulation through a vago-vagal reflex. The release of CCK by the I cells (a type The other major function of pancreatic secretion is the of endocrine cell) in the intestinal mucosa is stimulated by production of large amounts of pancreatic enzymes. exposure of the intestinal mucosa to long-chain fatty acids Table 27.3 summarizes the various enzymes present in (lipid digestion products) and free amino acids. pancreatic juice. Some are secreted as proenzymes, which are activated in the duodenal lumen to form the active enzymes. (The digestion of nutrients by these en- Duct zymes is discussed later in the chapter.) Interstitial + H + lumen space Na Na + Pancreatic Secretion Is Under Neural H + and Hormonal Control K + ATP Pancreatic secretion is stimulated by parasympathetic ADP+Pi fibers in the vagus nerve that release ACh. Stimulation of the vagus nerve results predominantly in an increase in en- CO 2 CO + H O H CO 3 HCO 3 - HCO 3 - 2 2 2 zyme secretion—fluid and HCO 3 secretion are margin- Carbonic ally stimulated or unchanged. Sympathetic nerve fibers anhydrase - - mainly innervate the blood vessels supplying the pancreas, Cl Cl causing vasoconstriction. Stimulation of the sympathetic Na + nerves neither stimulates nor inhibits pancreatic secretion, probably because of the reduction in blood flow. K + The secretion of electrolytes and enzymes by the pan- creas is greatly influenced by circulating GI hormones, par- ticularly secretin and cholecystokinin (CCK). Secretin + + H O 2 tends to stimulate a HCO 3 -rich secretion. CCK stimu- Na , K , H O 2 lates a marked increase in enzyme secretion. Both hor- mones are produced by the small intestine, and the pan- A model for electrolyte secretion by pan- creas has receptors for them. FIGURE 27.11 creatic duct cells. The luminal membrane Structurally similar hormones have effects similar to Cl channel is CFTR (cystic fibrosis transmembrane conduc- those of secretin and CCK. For example, VIP, structurally tance regulator).
492 PART VII GASTROINTESTINAL PHYSIOLOGY TABLE 27.3 Characteristics of Pancreatic Enzymes Pancreatic acinar cell Enzyme Specific Hydrolytic Activity ATP Proteolytic Secretin Adenylyl cyclase VIP cAMP Endopeptidases Trypsin(ogen) Cleaves peptide linkages in which the carboxyl group is either arginine or ? GRP lysine Chymotrypsin(ogen) Cleaves peptides at the carboxyl end of Enzymes hydrophobic amino acids, e.g., tyrosine or phenylalanine ? ACh (Pro)elastase Cleaves peptide bonds at the carboxyl Ca 2 terminal of aliphatic amino acids Exopeptidase Ca 2 (Pro)carboxypeptidase Cleaves amino acids from the carboxyl CCK stores end of the peptide Amylolytic 2 -Amylase Cleaves -1,4-glycosidic linkages of Ca glucose polymers Substance P Lipases Lipase Cleaves the ester bond at the 1 and 3 The stimulation of pancreatic secretion by FIGURE 27.12 positions of triglycerides, producing hormones and neurotransmitters. free fatty acids and 2-monoglyceride (Pro)phospholipase A 2 Cleaves the ester bond at the 2 2 position of phospholipids intracellular stores. The increase in intracellular Ca re- Carboxylester hydrolase Cleaves cholesteryl ester to free lease and cAMP formation results in an increase in pancre- cholesterol (cholesterol esterase) atic enzyme secretion. The mechanism by which this takes Nucleolytic place is not well understood. Ribonuclease Cleaves ribonucleic acids into mononucleotides Deoxyribonuclease Cleaves deoxyribonucleic acids into mononucleotides BILIARY SECRETION The suffix -ogen or prefix pro- indicates the enzyme is secreted in an in- The human liver secretes 600 to 1,200 mL/day of bile into active form. the duodenum. Bile contains bile salts, bile pigments (e.g., bilirubin), cholesterol, phospholipids, and proteins and performs several important functions. For example, bile Potentiation, as previously described for gastric secre- salts play an important role in the intestinal absorption of tion, also exists in the pancreas. Its effect in pancreatic se- lipid. Bile salts are derived from cholesterol and, therefore, cretion is a result of the different receptors used for ACh, constitute a path for its excretion. Biliary secretion is an im- CCK, and secretin. Secretin binding triggers an increase in portant route for the excretion of bilirubin from the body. adenylyl cyclase activity, which, in turn, stimulates the for- Bile canaliculi are fine tubular canals running between mation of cAMP (Fig. 27.12). Acetylcholine (ACh), CCK, the hepatocytes. Bile flows through the canaliculi to the and the neuropeptides GRP and substance P bind to their bile ducts, which drain into the gallbladder. During the in- respective receptors and trigger the release of Ca 2 from terdigestive state, the sphincter of Oddi, which controls TABLE 27.4 Factors Regulating Pancreatic Secretion After a Meal Phase Stimulus Mediators Response Cephalic Thought of food, smell, taste, Release of ACh and gastrin by Increased secretion, with greater effect on chewing, and swallowing vagal stimulation enzyme output Gastric Protein in food Gastrin Increased secretion, with greater effect on enzyme output Gastric distension Vago-vagal reflex Increased secretion, with a greater effect on enzyme output Intestinal Acid in chyme Secretin Increased H 2 O and HCO 3 secretion Long-chain fatty acids CCK and vago-vagal reflex Increased secretion, with greater effect on enzyme output Amino acids and peptides CCK and vago-vagal reflex Increased secretion, with greater effect on enzyme output
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 493 Electrolyte Composition of Human He- primary bile acids and convert them to secondary bile acids TABLE 27.5 by dehydroxylation. Cholic acid is converted to deoxycholic patic Bile acid and chenodeoxycholic acid to lithocholic acid. Bile Plasma At a neutral pH, the bile acids are mostly ionized and are Concentration Concentration referred to as bile salts. Conjugated bile acids ionize more Constituent (mEq/L) (mEq/L) readily than the unconjugated bile acids and, thus, usually Na 140–170 145 exist as salts of various cations (e.g., sodium glycocholate). K 4.0–6.0 4.5 Bile salts are much more polar than bile acids, and have Ca 2 1.2–5.0 4.6 greater difficulty penetrating cell membranes. Conse- Mg 2 1.5–3.0 1.6 quently, bile salts are absorbed much more poorly by the Cl 95–125 105 small intestine than bile acids. This property of bile salts is HCO 3 15–60 24 important because they play an integral role in the intes- tinal absorption of lipid. Therefore, it is important that bile salts are absorbed by the small intestine only after all of the the opening of the duct that carries biliary and pancreatic lipid has been absorbed. secretions, is contracted and the gallbladder is relaxed. The major lipids in bile are phospholipids and choles- Thus, most of the hepatic bile is stored in the gallbladder terol. Of the phospholipids, the predominant species is during this period. After the ingestion of a meal, CCK is re- phosphatidylcholine (lecithin). The phospholipid and cho- leased into the blood, causing contraction of the gallblad- lesterol concentrations of hepatic bile are 0.3 to 11 mmol/L der and resulting in the delivery of bile into the duodenum. and 1.6 to 8.3 mmol/L, respectively. The concentrations of these lipids in the gallbladder bile are even higher because of the absorption of water by the gallbladder. Cholesterol in The Major Components of Bile Are bile is responsible for the formation of cholesterol gallstones. Electrolytes, Bile Salts, and Lipids The electrolyte composition of human bile collected from Total Bile Secretion Consists of Three the hepatic ducts is similar to that of blood plasma, except Components, One of Which Depends on the HCO 3 concentration may be higher, resulting in an al- Bile Acids kaline pH (Table 27.5). Bile acids are formed in the liver from cholesterol. During the conversion, hydroxyl groups The total bile flow is composed of the ductular secretion and and a carboxyl group are added to the steroid nucleus. Bile the canalicular bile flow (Fig. 27.14). The ductular secretion acids are classified as primary or secondary (Fig. 27.13). The is from the cells lining the bile ducts. These cells actively se- primary bile acids are synthesized by the hepatocytes and in- crete HCO 3 into the lumen, resulting in the movement of clude cholic acid and chenodeoxycholic acid. Bile acids are water into the lumen of the duct. Another mechanism that secreted as conjugates of taurine or glycine. When bile en- may contribute to ductular secretion of fluid is the presence ters the GI tract, bacteria present in the lumen act on the of a cAMP-dependent Cl channel that secretes Cl into the The formation of bile acids. Bile acids are conjugated with the amino acids glycine and FIGURE 27.13 taurine in the liver.
494 PART VII GASTROINTESTINAL PHYSIOLOGY Bile acid dependent flow Bile acid independent flow Total bile flow Ductular Free bile Na + CO 2 secretion salts Canalicular bile flow Bile acid– salts 2 Na + Na + 4 H + CO + H O Bile 2 2 Bile flow dependent Total Conjugation anhydrase Carbonic flow with taurine canalicular or glycine H CO bile flow 2 3 Bile acid– 3 Bile salt independent Cholesterol - flow Phospholipid HCO 3 Bile acid secretion rate Bilirubin - HCO 3 5 Components of total bile flow: canalicular Na + FIGURE 27.14 bile flow and ductular secretion. Total canalicular bile flow is composed of bile acid–dependent flow ATP ADP+Pi and bile acid–independent flow. (Modified from Scharschmidt Na + K + BF. In: Zakim D, Boyer T, eds. Hepatology. Philadelphia: WB Saunders, 1982.) 1 Hepatocyte Na + Na + K + The mechanism of bile salt secretion and FIGURE 27.15 bile flow. (1) Na /K -ATPase. (2) Bile ductule lumen. Canalicular bile flow can be conceptually di- salt–sodium symport. (3) Canalicular bile salt carrier. (4) Na /H vided into two components: bile acid–dependent secretion exchanger. (5) HCO 3 transport system. and bile acid–independent secretion. Canalicular Bile Acid–Dependent Flow. Hepatocyte up- take of free and conjugated bile salts is Na -dependent and Bile Secretion Is Primarily Regulated by a mediated by bile salt–sodium symport (Fig. 27.15). The energy required is provided by the transmembrane Na Feedback Mechanism, With Secondary gradient generated by the Na /K -ATPase. This mecha- Hormonal and Neural Controls nism is a type of secondary active transport because the en- The major determinant of bile acid synthesis and secretion ergy required for the active uptake of bile acid, or its con- by hepatocytes is the bile acid concentration in hepatic por- jugate, is not directly provided by ATP but by an ionic tal blood, which exerts a negative-feedback effect on the gradient. The free bile acids are reconjugated with taurine synthesis of bile acids from cholesterol. The concentration or glycine before secretion. Hepatocytes also make new of bile acids in portal blood also determines bile acid–de- bile acids from cholesterol. Bile salts are secreted by hepa- pendent secretion. Between meals, the portal blood concen- tocytes by a carrier located at the canalicular membrane. tration of bile salts is usually extremely low, resulting in in- This secretion is not Na -dependent; instead, it is driven creased bile acid synthesis but reduced bile acid–dependent by the electrical potential difference between the hepato- flow. After a meal, there is increased delivery of bile salts in cyte and the canaliculus lumen. the portal blood, which not only inhibits bile acid synthesis Other major components of bile, such as phospholipid but also stimulates bile acid–dependent secretion. and cholesterol, are secreted in concert with bile salts. CCK is secreted by the intestinal mucosa when fatty Bilirubin is secreted by hepatocytes via an active process. acids or amino acids are present in the lumen. CCK causes Although the secretion of cholesterol and phospholipid is contraction of the gallbladder, which, in turn, causes in- not well understood, it is closely coupled to bile salt secre- creased pressure in the bile ducts. As the bile duct pressure tion. The osmotic pressure generated as a result of the se- rises, the sphincterof Oddi relaxes (another effect of CCK), cretion of bile salts draws water into the canaliculus lumen and bile is delivered into the lumen. through the paracellular pathway. When the mucosa of the small intestine is exposed to acid in the chyme, it releases secretin into the blood. Se- Canalicular Bile Acid–Independent Flow. As the name cretin stimulates HCO 3 secretion by the cells lining the implies, this component of canalicular flow is not depend- bile ducts. As a result, bile contributes to the neutralization ent on the secretion of bile acids (see Figs. 27.14 and of acid in the duodenum. 27.15). The Na /K -ATPase plays an important role in Gastrin stimulates bile secretion directly by affecting the bile acid-independent bile flow, a role that is clearly liver and indirectly by stimulating increased acid produc- demonstrated by the marked reduction in bile flow when an tion that results in increased secretin release. Steroid hor- inhibitor of this enzyme is applied. Another mechanism re- mones (e.g., estrogen and some androgens) are inhibitors sponsible for bile acid-independent flow is canalicular of bile secretion, and reduced bile secretion is a side effect HCO 3 secretion. associated with the therapeutic use of these hormones.
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 495 During pregnancy, the high circulating level of estrogen Liver can reduce bile acid secretion. The biliary system is supplied by parasympathetic and Conjugation sympathetic nerves. Parasympathetic (vagal) stimulation results in contraction of the gallbladder and relaxation of Primary Secondary ~500 mg bile the sphincter of Oddi, as well as increased bile formation. bile salts bile salts acids lost Bilateral vagotomy results in reduced bile secretion after a Bile daily in feces meal, suggesting that the parasympathetic nervous system salts plays a role in mediating bile secretion. By contrast, stimu- Portal lation of the sympathetic nervous system results in reduced circulation bile secretion and relaxation of the gallbladder. Gallbladder Bile Differs From Hepatic Bile Gallbladder Colon Bile Gallbladder bile has a very different composition from he- storage Bile patic bile. The principal difference is that gallbladder bile is salts Bile more highly concentrated. Water absorption is the major acids mechanism involved in concentrating hepatic bile by the 1 2 gallbladder. Water absorption by the gallbladder epithe- lium is passive and is secondary to active Na transport via Conjugated Free Deoxycholic a Na /K -ATPase in the basolateral membrane of the ep- bile 3 bile 4 acid ithelial cells lining the gallbladder. As a result of isotonic salts acids Lithocholic acid fluid absorption from the gallbladder bile, the concentra- Small tion of the various unabsorbed components of hepatic bile intestine Terminal Cecum ileum increases dramatically—as much as 20-fold. The enterohepatic circulation of bile salts. FIGURE 27.16 Bile salts are recycled out of the small intestine The Enterohepatic Circulation Recycles Bile Salts in four ways: (1) passive diffusion along the small intestine (plays Between the Small Intestine and the Liver a relatively minor role); (2) carrier-mediated active absorption in the terminal ileum (the most important absorption route); (3) de- The enterohepatic circulation of bile salts is the recycling conjugation to primary bile acids before being absorbed either of bile salts between the small intestine and the liver. The passively or actively; (4) conversion of primary bile acids to sec- total amount of bile acids in the body, primary or second- ondary bile acids with subsequent absorption of deoxycholic acid. ary, conjugated or free, at any time is defined as the total bile acid pool. In healthy people, the bile acid pool ranges from 2 to 4 g. The enterohepatic circulation of bile acids in Although bile salt and bile acid absorption is extremely ef- this pool is physiologically extremely important. By cy- ficient, some salts and acids are nonetheless lost with every cling several times during a meal, a relatively small bile acid cycle of the enterohepatic circulation. About 500 mg of bile pool can provide the body with sufficient amounts of bile acids are lost daily. They are replenished by the synthesis of salts to promote lipid absorption. In a light eater, the bile new bile acids from cholesterol. The loss of bile acid in feces acid pool may circulate 3 to 5 times a day; in a heavy eater, is, therefore, an efficient way to excrete cholesterol. it may circulate 14 to 16 times a day. The intestine is nor- Absorbed bile salts are transported in the portal blood mally extremely efficient in absorbing the bile salts by car- bound to albumin or high-density lipoproteins (HDLs). The riers located in the distal ileum. Inflammation of the ileum uptake of bile salts by hepatocytes is extremely efficient. In can lead to their malabsorption and result in the loss of just one pass through the liver, more than 80% of the bile salts large quantities of bile salts in the feces. Depending on the in the portal blood is removed. Once taken up by hepato- severity of illness, malabsorption of fat may result. cytes, bile salts are secreted into bile. The uptake of bile salts Bile salts in the intestinal lumen are absorbed via four is a primary determinant of bile salt secretion by the liver. pathways (Fig. 27.16). First, they are absorbed throughout the entire small intestine by passive diffusion, but only a The Liver Secretes Bile Pigments small fraction of the total amount of bile salts is absorbed in this manner. Second, and most important, bile salts are ab- The major pigment present in bile is the orange compound sorbed in the terminal ileum by an active carrier-mediated bilirubin, an end-product of hemoglobin degradation in process, an extremely efficient process in which usually less the monocyte-macrophage system in the spleen, bone mar- than 5% of the bile salts escape into the colon. Third, bac- row, and liver (Fig. 27.17). Hemoglobin is first converted teria in the terminal ileum and colon deconjugate the bile to biliverdin with the release of iron and globin. Biliverdin salts to form bile acids, which are much more lipophilic is then converted into bilirubin, which is transported in than bile salts and, thus, can be absorbed passively. Fourth, blood bound to albumin. The liver removes bilirubin from these same bacteria are responsible for transforming the the circulation rapidly and conjugates it with glucuronic primary bile acids to secondary bile acids (deoxycholic and acid. The glucuronide is secreted into the bile canaliculi lithocholic acids) by dehydroxylation.. Deoxycholic acid through an active carrier-mediated process. may be absorbed, but lithocholic acid is poorly absorbed. In the small intestine, bilirubin glucuronide is poorly ab-
496 PART VII GASTROINTESTINAL PHYSIOLOGY point that it cannot be solubilized, it starts to crystallize, forming gallstones. Eventually, calcium deposits form in the stones, increasing their opacity and making them easily detectable on X-ray images of the gallbladder. INTESTINAL SECRETION The small intestine secretes 2 to 3 L/day of isotonic alkaline fluid. This secretion is derived mainly from cells in the crypts of Lieberkühn, tubular glands located at the base of intestinal villi. Of the three major cell types in the crypts of Lieberkühn—argentaffin cells, Paneth cells, and undiffer- entiated cells—the undifferentiated cells are responsible for intestinal secretions. Intestinal secretion probably helps maintain the fluidity of the chyme and may also play a role in diluting noxious agents and washing away infectious microorganisms. The HCO 3 in intestinal secretions protects the intestinal mu- cosa by neutralizing any H present in the lumen. This is important in the duodenum and also in the ileum where bacteria degrade certain foods to produce acids (e.g., di- etary fibers to short-chain fatty acids). The fluid and electrolytes from intestinal secretions are usually absorbed by the small intestine and colon, but if secretion surpasses absorption (e.g., in cholera), watery diarrhea may result. If uncontrolled, this can lead to the loss of large quantities of fluid and electrolytes, which can result in dehydration and electrolyte imbalances and, ulti- mately, death. Several noxious agents, such as bacterial toxins (e.g., cholera toxin), can induce intestinal hyper- secretion. Cholera toxin binds to the brush border mem- brane of crypt cells and increases intracellular adenylyl cyclase activity. The result is a dramatic increase in intra- cellular cAMP, which stimulates active Cl and HCO 3 secretion into the lumen. Also present in intestinal secretions are various mucins (mucoproteins) secreted by goblet cells. Mucins are glyco- proteins high in carbohydrate, and they form gels in solution. They are extremely diverse in structure and are usually very large molecules. The mucus lubricates the mucosal surface and protects it from mechanical damage by solid food parti- cles. It may also provide a physical barrier in the small intes- tine against the entry of microorganisms into the mucosa. It is well documented that tactile stimulation, or an in- The metabolism and excretion of bile pig- crease in intraluminal pressure, stimulates intestinal secre- FIGURE 27.17 ment (bilirubin). tion. Other potent stimuli are certain noxious agents and the toxins produced by microorganisms. With the excep- tion of toxin-induced secretion, our understanding of the sorbed. In the colon, however, bacteria deconjugate it, and normal control of intestinal secretion is meager. Vasoactive part of the bilirubin released is converted to the highly solu- intestinal peptide is known to be a potent stimulator of in- ble, colorless compound called urobilinogen. Urobilinogen testinal secretion. This is demonstrated by a form of en- can be oxidized in the intestine to stercobilin or absorbed by docrine tumor of the pancreas that results in the secretion the small intestine. It is excreted in either urine or bile. Ster- of large amounts of VIP into the circulation. In this condi- cobilin is responsible for the brown color of the stool. tion, intestinal secretion rates are high. Cholesterol Gallstones Form When Cholesterol DIGESTION AND ABSORPTION Supersaturates the Bile To ensure the optimal absorption of nutrients, the GI tract Bile salts and lecithin in the bile help solubilize cholesterol. has several unique features. For instance, after a meal, the When the cholesterol concentration in bile increases to the small intestine undergoes rhythmic contractions called seg-
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 497 mentations (see Chapter 26), which ensure proper mixing of the small intestinal contents, exposure of the contents to digestive enzymes, and maximum exposure of digestion products to the small intestinal mucosa. The rhythmic seg- mentation has a gradient along the small intestine, with the highest frequency in the duodenum and the lowest in the ileum. This gradient ensures slow but forward movement of intestinal contents toward the colon. Another unique feature of the small intestine is its archi- tecture. Spiral or circular concentric folds increase the sur- face area of the intestine about 3 times (Fig. 27.18). Finger- like projections of the mucosal surface called villi further increase the surface area of the small intestine about 30 times. To amplify the absorptive surface further, each ep- ithelial cell, or enterocyte, is covered by numerous closely packed microvilli. The total surface area is increased to 600 times. The various nutrients, vitamins, bile salts, and water are absorbed by the GI tract by passive, facilitated, or ac- tive transport. (The site and mechanism of absorption will be discussed below.) The GI tract has a large reserve for the digestion and absorption of various nutrients and vitamins. Malabsorption of nutrients is usually not detected unless a large portion of the small intestine has been lost or dam- aged because of disease (see Clinical Focus Box 27.2). Most nutrients and vitamins are absorbed by the duode- num and jejunum, but because bile salts are involved in the intestinal absorption of lipids, it is important that they not be absorbed prematurely. For effective fat absorption, the Surface area amplification by the special- small intestine has adapted to absorb the bile salts in the FIGURE 27.18 ized features of the intestinal mucosa. terminal ileum through a bile salt transporter. The entero- (Modified from Schmidt RF, Thews G. Human Physiology. cytes along the villus that are involved in the absorption of Berlin: Springer-Verlag, 1993, p. 602). nutrients are replaced every 2 to 3 days. CLINICAL FOCUS BOX 27.2 Celiac Sprue (Gluten-Sensitive Enteropathy) digestion of gluten results in the production of a toxic sub- Celiac sprue, also called gluten-sensitive enteropa- stance, which injures the intestinal mucosa. This idea is thy, is a common disease involving a primary lesion of the probably incorrect, however, because the intestinal brush intestinal mucosa. It is caused by the sensitivity of the border peptidases revert to normal after the healing of small intestine to gluten. This disorder can result in the damaged intestinal mucosa. Another hypothesis is that im- malabsorption of all nutrients as a result the shortening or mune mechanisms are involved. This is supported by the a total loss of intestinal villi, which reduces the mucosal fact that the number and activity of plasma cells and lym- enzymes for nutrient digestion and the mucosal surface for phocytes increase during the active phase of celiac sprue absorption. Celiac sprue occurs in about 1 to 6 of 10,000 in- and that antigluten antibodies are usually present. It has dividuals in the Western world. The highest incidence is in been demonstrated that the small intestine makes a lym- western Ireland, where the prevalence is as high as 3 of phokine-like substance, which inhibits the infiltration of 1,000 individuals. Although the disease may occur at any leukocytes into the lamina propria of the intestinal mucosa age, it is more common during the first few years and the when exposed to gluten. Unfortunately, it is not clear third to fifth decades of life. whether these immunological manifestations are primary In patients with celiac sprue, the water-insoluble pro- or secondary phenomena of the disease. tein gluten (present in cereal grains such as wheat, barley, The elimination of dietary gluten is a standard treat- rye, and oats) or its breakdown product interacts with the ment for patients with celiac sprue. Occasionally, intestinal intestinal mucosa and causes the characteristic lesion. Pre- absorptive function and intestinal mucosal morphology of cisely how the binding of gluten to the intestinal mucosa patients with celiac sprue are improved with glucocorti- causes mucosal injury is unclear. One hypothesis is that coid therapy. Presumably, such treatment is beneficial be- patients prone to celiac sprue may have a brush border cause of the immunosuppressive and anti-inflammatory peptidase deficiency and that the consequent incomplete actions of these hormones.
498 PART VII GASTROINTESTINAL PHYSIOLOGY DIGESTION AND ABSORPTION OF CARBOHYDRATES The digestion and absorption of dietary carbohydrates takes place in the small intestine. These are extremely ef- ficient processes, in that essentially all of the carbohy- drates consumed are absorbed. Carbohydrates are an ex- tremely important component of food intake, since they constitute about 45 to 50% of the typical Western diet and provide the greatest and least expensive source of en- ergy. Carbohydrates must be digested to monosaccha- rides before absorption. The Diet Contains Both Digestible and Nondigestible Carbohydrates Humans can digest most carbohydrates; those we cannot di- gest constitute the dietary fiber that forms roughage. Car- The structure of glycogen. bohydrate is present in food as monosaccharides, disaccha- FIGURE 27.19 rides, oligosaccharides, and polysaccharides. The monosaccharides are mainly hexoses (six-carbon sugars), and glucose is by far the most abundant of these. Glucose is obtained directly from the diet or from the digestion of dis- Carbohydrates Are Digested in Different Parts of accharides, oligosaccharides, or polysaccharides. The next the GI Tract most common monosaccharides are galactose, fructose, and sorbitol. Galactose is present in the diet only as milk lactose, The digestion of carbohydrates starts when food is mixed a disaccharide composed of galactose and glucose. Fructose with saliva during chewing. The enzyme salivary amylase is present in abundance in fruit and honey and is usually acts on the -1,4-glycosidic linkage of amylose and amy- present as disaccharides or polysaccharides. Sorbitol is de- lopectin of polysaccharides to release the disaccharide rived from glucose and is almost as sweet as glucose, but sor- maltose and oligosaccharides maltotriose and -limit dex- bitol is absorbed much more slowly and, thus, maintains a trins (Fig. 27.20). Because salivary amylase works best at high blood sugar level for a longer period when similar neutral pH, its digestive action terminates rapidly after the amounts are ingested. It has been used as a weight-reduction bolus mixes with acid in the stomach. However, if the food aid to delay the onset of hunger sensations. is thoroughly mixed with amylase during chewing, a sub- The major disaccharides in the diet are sucrose, lactose, stantial amount of complex carbohydrates is digested be- and maltose. Sucrose, present in sugar cane and honey, is composed of glucose and fructose. Lactose, the main sugar in milk, is composed of galactose and glucose. Maltose is composed of two glucose units. The digestible polysaccharides are starch, dextrins, and Amylose glycogen. Starch, by far the most abundant carbohydrate in the human diet, is made of amylose and amylopectin. Amy- lose is composed of a straight chain of glucose units; amy- α-Amylase lopectin is composed of branched glucose units. Dextrins, formed from heating (e.g., toasting bread) or the action of Maltotriose Maltose the enzyme amylase, are intermediate products of starch di- gestion. Glycogen is a highly branched polysaccharide that stores carbohydrates in the body. The structure of glyco- Amylopectin gen is illustrated in Figure 27.19. Normally, about 300 to 1,6 Link 400 g of glycogen is stored in the liver and muscle, with more stored in muscle than in the liver. Muscle glycogen is 1,4 Link used exclusively by muscle, and liver glycogen is used to α-Amylase provide blood glucose during fasting. Dietary fiber is made of polysaccharides that are usually poorly digested by the enzymes in the small intestine. They Maltotriose α-Limit dextrin Maltose have an extremely important physiological function in that they provide the “bulk” that facilitates intestinal motility and function. Many vegetables and fruits are rich in fibers, The digestion products of starch after ex- and their frequent ingestion greatly decreases intestinal FIGURE 27.20 posure to salivary or pancreatic -amylase. transit time. Sugar units are indicated by hexagons.
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 499 fore this point. Pancreatic amylase continues the digestion of the remaining carbohydrates. However, the chyme must first be neutralized by pancreatic secretions, since pancre- atic amylase works best at neutral pH. The products of pan- creatic amylase digestion of polysaccharides are also malt- ose, maltotriose, and -limit dextrins. The digestion products of starch and glycogen, to- gether with disaccharides (sucrose and lactose), are fur- ther digested by enzymes located at the brush border membrane. Table 27.6 lists the enzymes involved in the digestion of disaccharides and oligosaccharides and the products of their action. The final products are glucose, fructose, and galactose. Enterocytes Play an Important Role in Carbohydrate Absorption and Metabolism Monosaccharides are absorbed by enterocytes either ac- tively or by facilitated transport. Glucose and galactose are absorbed via secondary active transport by a symporter (see The enterocyte Na -dependent carrier system Chapter 2) that transports two Na ions for every molecule FIGURE 27.21 for glucose and galactose. of monosaccharide (Fig. 27.21). The movement of Na into the cell, down concentration and electrical gradients, effects the uphill movement of glucose into the cell. The low intracellular Na concentration is maintained by the The sugars absorbed by enterocytes are transported by basolateral membrane the portal blood to the liver where they are converted to Na /K -ATPase. The osmotic effects of sugars increase glycogen or remain in the blood. After a meal, the level of the Na /K -ATPase activity and the K conductance of blood glucose rises rapidly, usually peaking at 30 to 60 min- the basolateral membrane. Sugars accumulate in the cell at utes. The concentration of glucose can be as high as 150 a higher concentration than in plasma and leave the cell by mg/dL. Although enterocytes can use glucose for fuel, glu- Na -independent facilitated transport or passive diffusion tamine is preferred. Both galactose and glucose can be used through the basolateral cell membrane. Glucose and galac- in the glycosylation of proteins in the Golgi apparatus of tose share a common transporter at the brush border mem- the enterocytes. brane of enterocytes and, thus, compete with each other during absorption. Fructose is taken up by facilitated transport. Although fa- The Lack of Some Digestive Enzymes cilitated transport is carrier-mediated, it is not an active Impairs Carbohydrate Absorption process (see Chapter 2). Fructose absorption is much slower than glucose and galactose absorption and is not Na -de- Impaired carbohydrate absorption caused by the absence pendent. Although in some animal species both galactose of salivary or pancreatic amylase almost never occurs be- and fructose can be converted to glucose in enterocytes, this cause these enzymes are usually present in great excess. mechanism is probably not important in humans. However, impaired absorption due to a deficiency in membrane disaccharidases is rather common. Such defi- ciencies can be either genetic or acquired. Among con- genital deficiencies, lactase deficiency is, by far, the most common. Affected individuals suffer from lactose intoler- ance, a condition in which the ingestion of milk products The Digestion of Disaccharides and results in severe osmotic (watery) diarrhea. The mecha- TABLE 27.6 Oligosaccharides by Brush Border En- nism responsible is depicted in Figure 27.22. Undigested zymes lactose in the intestinal lumen increases the osmolality of Enzyme Substrate Site of Action Products the luminal contents. Osmolality is further increased by Sucrase Sucrose -1,2-glycosidic Glucose and lactic acid produced from the action of intestinal bacteria linkage fructose on the lactose. Increased luminal osmolality results in net Lactase Lactose -1,4-glycosidic Glucose and water secretion into the lumen. The accumulation of fluid linkage galactose distends the small intestine and accelerates peristalsis, Isomaltase -Limit -1,6-glycosidic Glucose, eventually resulting in watery diarrhea. dextrins linkage maltose, and Congenital sucrase deficiency results in symptoms simi- oligosaccharides lar to those of lactase deficiency. Sucrase deficiency can be Maltase Maltose, -1,4-glycosidic Glucose inherited or acquired through disorders of the small intes- maltotriose linkage tine, such as tropical sprue or Crohn’s disease.
500 PART VII GASTROINTESTINAL PHYSIOLOGY Lactase deficiency The Luminal Lipid Consists of Both Exogenous and Endogenous Lipids Lipids are comprised of several classes of compounds that Accumulation of Lactic acid lactose in intestinal lumen are insoluble in water but soluble in organic solvents. By far production the most abundant dietary lipids are triacylglycerols, or by bacteria triglycerides. They consist of a glycerol backbone esteri- Increased luminal fied in the three positions with fatty acids (Fig. 27.23A). osmolality More than 90% of the daily dietary lipid intake is in the form of triglycerides. The other lipids in the human diet are cholesterol and Fluid accumulation in lumen phospholipids. Cholesterol is a sterol derived exclusively from animal fat. Humans also ingest a small amount of plant sterols, notably -sitosterol and campesterol. The phos- Luminal distension pholipid molecule is similar to a triglyceride with fatty acids occupying the first and second positions of the glyc- Enhanced peristalsis erol backbone (Fig. 27.23B). However, the third position of the glycerol backbone is occupied by a phosphate group coupled to a nitrogenous base (e.g., choline or Watery diarrhea ethanolamine), for which each type of phospholipid mole- The mechanism for osmotic diarrhea result- cule is named. FIGURE 27.22 ing from lactase deficiency. Bile serves as an endogenous source of cholesterol and phospholipids. Bile contributes about 12 g/day of phos- pholipid to the intestinal lumen, most in the form of phos- phatidylcholine, whereas dietary sources contribute 2 to 3 g/day. Another important endogenous source of lipid is Dietary Fiber Plays an Important Role desquamated intestinal villus epithelial cells. in GI Motility Dietary fiber includes indigestible carbohydrates and car- bohydrate-like components mainly found in fruits and veg- Different Lipases Carry Out Lipid Hydrolysis etables. The most common are cellulose, hemicellulose, Lipid digestion mainly occurs in the lumen of the small in- pectins, and gums. Cellulose and hemicellulose are insolu- testine. Humans secrete an overabundance of pancreatic li- ble in water and are poorly digested by humans, thus, pro- pase. Depending on the substrate being digested, pancre- viding the bulkiness of stool. atic lipase has an optimal pH of 7 to 8.0, allowing it to work Dietary fiber imparts bulk to the bolus and, therefore, well in the intestinal lumen after the acidic contents from greatly shortens transit time. It has been proposed that di- the stomach have been neutralized by pancreatic HCO 3 etary fiber reduces the incidence of colon cancer by short- secretion. Pancreatic lipase hydrolyzes the triglyceride ening GI transit time, which, in turn, reduces the formation molecule to a 2-monoglyceride and two fatty acids (Fig. of carcinogenic bile acids (e.g., lithocholic acid). Because 27.24). It works on the triglyceride molecule at the oil-wa- dietary fiber also binds bile acids, which are formed from ter interface; thus, the rate of lipolysis depends on the sur- cholesterol, fiber consumption can result in a lowering of face area of the interface. The products from the partial di- blood cholesterol by promoting excretion. DIGESTION AND ABSORPTION OF LIPIDS Lipids are a concentrated form of energy. They provide 30 to 40% of the daily caloric intake in the Western diet. Lipids are also essential for normal body functions, as they form part of cellular membranes and are precursors of bile acids, steroid hormones, prostaglandins, and leukotrienes. The human body is capable of synthesizing most of the lipids it requires with the exception of the es- sential fatty acids linoleic acid (C 18:2, an 18-carbon long fatty acid with two double bonds) and arachidonic acid (C 20:4). Both of these acids belong to the family of omega-6 fatty acids. Recently, researchers have provided FIGURE 27.23 Dietary lipids. A, A triglyceride molecule. R 1, R 2, and R 3 belong to different fatty acids. B, A convincing evidence that eicosapentaenoic acid (C 20:5) phospholipid molecule. The fatty acid occupying the first posi- and docosahexaenoic acid (C 22:6) are also essential for tion (R 1) is usually a saturated fatty acid and that in the second the normal development of vision in newborns. Both of position (R 2 ) is usually an unsaturated or polyunsaturated fatty these acids are omega-3 fatty acids and are abundant in acid. The third position after the phosphate group is occupied by seafood and algae. a nitrogenous base (N), such as choline or ethanolamine.
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 501 gestion of dietary triglyceride by gastric lipase and the unstirred water layer (Fig. 27.25B). The lipid digestion churning action of the stomach produce a suspension of oil products are then absorbed by enterocytes, mainly by pas- droplets (an emulsion) that help increase the area of the oil- sive diffusion. Fatty acid and monoglyceride molecules are water interface. Pancreatic juice also contains the peptide taken up individually. Similar mechanisms seem to operate colipase, which is necessary for the normal digestion of fat for cholesterol and lysolecithin. by pancreatic lipase. Colipase binds lipase at a molar ratio Bile salts are derived from cholesterol, but they are dif- of 1:1, thereby allowing the lipase to bind to the oil-water ferent from cholesterol in that they are water-soluble. They interface where lipolysis takes place. Colipase also counter- are essentially detergents—molecules that possess both hy- acts the inhibition of lipolysis by bile salt, which, despite its drophilic and hydrophobic properties. Because bile salts are importance in intestinal fat absorption, prevents the at- polar molecules, they penetrate cell membranes poorly. tachment of pancreatic lipase to the oil-water interface. This is significant because it ensures their minimal absorp- Phospholipase A 2 is the major pancreatic enzyme for tion by the jejunum where most fat absorption takes place. digesting phospholipids, forming lysophospholipids and At or above a certain concentration of bile salts, the critical fatty acids. For instance, phosphatidylcholine (lecithin) is micellar concentration, they aggregate to form micelles; hydrolyzed to form lysophosphatidylcholine (lysolecithin) the concentration of luminal bile salts is usually well above and fatty acid (see Fig. 27.24). the critical micellar concentration. When bile salts alone Dietary cholesterol is presented as a free sterol or as a are present in the micelle, it is called a simple micelle. Sim- sterol ester (cholesterol ester). The hydrolysis of choles- ple micelles incorporate the lipid digestion products— terol ester is catalyzed by the pancreatic enzyme car- monoglyceride and fatty acids—to form mixed micelles. boxylester hydrolase, also called cholesterol esterase (see This renders the lipid digestion products water-soluble by Fig. 27.24). The digestion of cholesterol ester is important incorporation into mixed micelles. Mixed micelles diffuse because cholesterol can be absorbed only as the free sterol. across the unstirred water layer and deliver lipid digestion products to the enterocytes for absorption. Bile Salt Plays an Important Role in Lipid Absorption Enterocytes Process Absorbed Lipid to Form Lipoproteins A layer of poorly stirred fluid called the unstirred water layer coats the surface of the intestinal villi (Fig. 27.25A). After entering the enterocytes, the fatty acids and mono- The unstirred water layer reduces the absorption of lipid di- glycerides migrate to the smooth ER. A fatty acid–binding gestion products because they are poorly soluble in water. protein may be involved in the intracellular transport of They are rendered water-soluble by micellar solubilization fatty acids, but whether or not a protein carrier is involved by bile salts in the small intestinal lumen. This mechanism in the intracellular transport of monoglycerides is un- greatly enhances the concentration of these products in the known. In the smooth ER, monoglycerides and fatty acids The digestion of dietary FIGURE 27.24 lipids by pancreatic en- zymes in the small intestine. Solid circles represent oxygen atoms.
502 PART VII GASTROINTESTINAL PHYSIOLOGY A Brush border Lumen Interstitial space Monoglyceride Diglyceride Triglyceride Fatty acid Acyl CoA Enterocyte Enterocyte Lysolecithin Lecithin Cholesterol Cholesterol ester Free cholesterol Chylo- micron Unstirred water layer Monoglyceride and fatty acid Exocytosis Bile salt The intracellular metabolism of absorbed FIGURE 27.26 lipid digestion products to form chylomi- B Brush border crons. Micelle Micelle exported from the enterocytes. The intestine produces two major classes of lipoproteins: chylomicrons and very low density lipoproteins (VLDLs). Both are triglyceride- rich lipoproteins with densities less than 1.006 g/mL. Chylomicrons are made exclusively by the small intestine, Enterocyte and their primary function is to transport the large amount of dietary fat absorbed by the small intestine from the enterocytes to the lymph. Chylomicrons are large, spherical lipoproteins with diameters of 80 to 500 nm. They contain less protein and phospholipid than VLDLs and are, therefore, less dense than VLDLs. VLDLs are made continuously by the small intestine during both fast- Unstirred water ing and feeding, although the liver contributes signifi- layer cantly more VLDLs to the circulation. Apoproteins—apo A-I, apo A-IV, and apo B—are The micellar solubilization of lipids. Micel- FIGURE 27.25 among the major proteins associated with the production lar solubilization enhances the delivery of lipid to the brush border membrane. A, In the absence of bile salts. B, of chylomicrons and VLDLs. Apo B is the only protein In the presence of bile salts. that seems to be necessary for the normal formation of in- testinal chylomicrons and VLDLs. This protein is made in the small intestine. It has a molecular weight of 250,000 are rapidly reconstituted to form triglycerides (Fig. 27.26). and it is extremely hydrophobic. Apo A-I is involved in a Fatty acids are first activated to form acyl-CoA, which is reaction catalyzed by the plasma enzyme lecithin choles- then used to esterify monoglyceride to form diglyceride, terol acyltransferase (LCAT). Plasma LCAT is responsi- which is transformed into triglyceride. The lysolecithin ab- ble for the esterification of cholesterol in the plasma to sorbed by the enterocytes can be reesterified in the smooth form cholesterol ester with the fatty acid derived from the ER to form lecithin. 2-position of lecithin. After the chylomicrons and VLDLs Cholesterol can be transported out of the enterocytes enter the plasma, apo A-I is rapidly transferred from chy- as free cholesterol or as esterified cholesterol. The en- lomicrons and VLDLs to high-density lipoproteins zyme responsible for the esterification of cholesterol to (HDLs). Apo A-I is the major protein present in plasma form cholesterol ester is acyl-CoA cholesterol acyltrans- HDLs. Apo A-IV is made by the small intestine and the ferase (ACAT). liver. Recently, it was shown that apo A-IV, secreted by the small intestine, may be an important factor contribut- Enterocytes Secrete Chylomicrons and Very Low ing to anorexia after fat feeding. Density Lipoproteins Newly synthesized lipoproteins in the smooth ER are transferred to the Golgi apparatus, where they are pack- The reassembled triglycerides, lecithin, cholesterol, and aged in vesicles. Chylomicrons and VLDLs are released cholesterol esters are then packaged into lipoproteins and into the intercellular space by exocytosis (Fig. 27.27). From
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 503 Pancreatic deficiency significantly reduces the ability of the exocrine pancreas to produce digestive enzymes. Be- cause the pancreas normally produces an excess of digestive enzymes, enzyme production has to be reduced to about 10% of normal before symptoms of malabsorption develop. One characteristic of pancreatic deficiency is steatorrhea (fatty stool), resulting from the poor digestion of fat by the pancreatic lipase. Normally about 5 g/day of fat are ex- creted in human stool. With steatorrhea, as much as 50 g/day can be excreted. Fat absorption subsequent to the action of pancreatic li- pase requires solubilization by bile salt micelles. Acute or chronic liver disease can cause defective biliary secretion, resulting in bile salt concentrations lower than necessary for micelle formation. The normal absorption of fat is thereby inhibited. Exocytosis of chylomicrons. The exocytosis FIGURE 27.27 of chylomicrons is evident in this electron mi- Abetalipoproteinemia, an autosomal recessive disor- crograph. The nascent chylomicrons in the secretory vesicle (V) der, is characterized by a complete lack of apo B, which is are similar in size and morphology to those already present in the required for the formation and secretion of chylomicrons intercellular space (IS). (From Sabesin SM, Frase S. Electron mi- and VLDLs. Apo B–containing lipoproteins in the circula- croscopic studies of the assembly, intracellular transport, and se- tion—including chylomicrons, VLDLs, and low-density cretion of chylomicrons by rat intestine. J Lipid Res lipoproteins (LDLs)—are absent. Plasma LDLs are absent 1977;18:496–511.) because they are derived mainly from the metabolism of VLDLs. Since individuals with abetalipoproteinemia do not produce any chylomicrons or VLDLs in the small in- there, they are transferred to the central lacteals (the be- testine, they are unable to transport absorbed fat, result- ginnings of lymphatic vessels) by a process that is not well ing in an accumulation of lipid droplets in the cytoplasm understood. Experimental evidence seems to indicate that of enterocytes. They also suffer from a deficiency of fat- the transfer probably occurs mostly by diffusion. Intestinal soluble vitamins. lipid absorption is associated with a marked increase in lymph flow called the lymphagogic effect of fat feeding. This increase in lymph flow plays an important role in the DIGESTION AND ABSORPTION OF PROTEINS transfer of lipoproteins from the intercellular spaces to the central lacteal. Proteins form the fundamental structure of cells and are the Fatty acids can also travel in the blood bound to albu- most abundant of all organic compounds in the body. Most min. While the most of the long-chain fatty acids are trans- proteins are found in muscle, with the remainder in other ported from the small intestine as triglycerides packaged in cells, blood, body fluids, and body secretions. Enzymes and chylomicrons and VLDLs, some are transported in the por- many hormones are proteins. Proteins are composed of tal blood bound to serum albumin. Most of the medium- amino acids and have molecular weights of a few thousand chain (8 to 12 carbons) and all of the short-chain fatty acids to a few hundred thousand. More than 20 common amino are transported by the hepatic portal route. acids form the building blocks for proteins (Table 27.7). Of these, nine are considered essential and must be provided by the diet. Although the nonessential amino acids are also The Lack of Pancreatic Lipases or Bile Salts Can required for normal protein synthesis, the body can syn- Impair Lipid Absorption thesize them from other amino acids. In several clinical conditions, lipid digestion and absorp- Complete proteins are those that can supply all of the tion are impaired, resulting in the malabsorption of lipids essential amino acids in amounts sufficient to support nor- and other nutrients and fatty stools. Abnormal lipid ab- mal growth and body maintenance. Examples are eggs, sorption can result in numerous problems because the body poultry, and fish. The proteins in most vegetables and requires certain fatty acids (e.g., linoleic and arachidonic grains are called incomplete proteins because they do not acid, precursors of prostaglandins) to function normally. provide all of the essential amino acids in amounts suffi- These are called essential fatty acids because the human cient to sustain normal growth and body maintenance. body cannot synthesize them and is, therefore, totally de- Vegetarians need to eat a variety of vegetables and soy pro- pendent on the diet to supply them. Recent studies suggest tein to avoid amino acid deficiencies. that the human body may also require omega-3 fatty acids in the diet during development. These include linolenic, Luminal Protein Is Derived From the Diet, docosahexaenoic, and eicosapentaenoic acids. Linolenic GI Secretions, and Enterocytes acid is abundant in plants, and docosahexaenoic and eicos- apentaenoic acids are abundant in fish. Docosahexaenoic The average adult American takes in 70 to 110 g/day of acid is an important fatty acid present in the retina and protein. The minimum daily protein requirement for adults other parts of the brain. is about 0.8 g/kg body weight (e.g., 56 g for a 70-kg person.
504 PART VII GASTROINTESTINAL PHYSIOLOGY The Amino Acids polypeptides to release the smaller peptides. The three en- TABLE 27.7 dopeptidases present in pancreatic juice are trypsin, chy- Found in Proteins motrypsin, and elastase. Trypsin splits off basic amino acids Essential Nonessential from the carboxyl terminal of a protein, chymotrypsin at- tacks peptide bonds with an aromatic carboxyl terminal, Histidine Alanine Isoleucine Arginine and elastase attacks peptide bonds with a neutral aliphatic Leucine Asparagine carboxyl terminal. The exopeptidases in pancreatic juice Lysine Aspartic acid are carboxypeptidase A and carboxypeptidase B. Like the Methionine Cysteine endopeptidases, the exopeptidases are specific in their ac- Phenylalanine Glutamic acid tion. Carboxypeptidase A attacks polypeptides with a neu- Threonine Glutamine tral aliphatic or aromatic carboxyl terminal. Carboxypepti- Tryptophan Glycine dase B attacks polypeptides with a basic carboxyl terminal. Valine Hydroxyproline The final products of protein digestion are amino acids and Proline small peptides. Serine Tyrosine Specific Transporters in the Small Intestine Take Up Amino Acids and Peptides Amino acids are taken up by enterocytes via secondary ac- Pregnant or lactating women require 20 to 30 g above the tive transport. Six major amino acid carriers in the small in- recommended daily allowance to meet the extra demand testine have been identified; they transport related groups for protein. A lactating woman can lose as much as 12 to 15 of amino acids. The amino acid transporters favor the L g of protein per day as milk protein. Children need more form over the D form. As in the uptake of glucose, the up- protein for body growth; the recommended daily al- take of amino acids is dependent on a Na concentration lowance for infants is about 2 g/kg body weight. gradient across the enterocyte brush border membrane. While most of the protein entering the GI tract is di- The absorption of peptides by enterocytes was once etary protein, there are also proteins derived from endoge- thought to be less efficient than amino acid absorption. nous sources such as pancreatic, biliary, and intestinal se- However, subsequent studies in humans clearly demon- cretions, and the cells shed from the intestinal villi. About strated that dipeptides and tripeptide uptake is significantly 20 to 30 g/day of protein enters the intestinal lumen in pan- more efficient than the uptake of amino acids. Dipeptides creatic juice and about 10 g/day in bile. Enterocytes of the and tripeptides use different transporters than those used intestinal villi are continuously shed into the intestinal lu- by amino acids. The peptide transporter prefers dipeptides men, and as much as 50 g/day of enterocyte proteins enter and tripeptides with either glycine or lysine residues. Fur- the intestinal lumen. An average of 150 to 180 g/day of to- thermore, tetrapeptides and more complex peptides are tal protein is presented to the small intestine, of which only poorly transported by the peptide transporter. These more than 90% is absorbed. peptides can be further broken down to dipeptides and tripeptides by the peptidases (exopeptidases) located on Proteins Are Digested in the GI Tract, the brush border of the enterocytes. Dipeptides and tripep- Yielding Amino Acids and Peptides tides are given to individuals suffering from malabsorption because they are absorbed more efficiently and are more Most of the protein in the intestinal lumen is completely di- palatable than free amino acids. Another advantage of pep- gested into either amino acids or dipeptides or tripeptides tides over amino acids is the smaller osmotic stress created before it is taken up by the enterocytes. Protein digestion as a result of delivering them. starts in the stomach with the action of pepsin, which is se- In adults, a negligible amount of protein is absorbed as creted as a proenzyme and activated by acid in the stomach. undigested protein. In some individuals, however, intact or Pepsin hydrolyzes protein to form smaller polypeptides. It partially digested proteins are absorbed, resulting in ana- is classified as an endopeptidase because it attacks specific phylactic or hypersensitivity reactions. The pulmonary and peptide bonds inside the protein molecule. This phase of cardiovascular systems are the major organs involved in protein digestion is normally not important other than in in- anaphylactic reactions. For the first few weeks after birth, dividuals suffering from pancreatic exocrine deficiency. the newborn’s small intestine absorbs considerable amounts Most of the digestion of proteins and polypeptides takes of intact proteins. This is possible because of low prote- place in the small intestine. Most proteases are secreted in olytic activity in the stomach, low pancreatic secretion of the pancreatic juice as inactive proenzymes. When the pan- peptidases, and poor development of intracellular protein creatic juice enters the duodenum, trypsinogen is con- degradation by lysosomal proteases. verted to trypsin by enteropeptidase (also known as en- The absorption of immunoglobulins (predominantly terokinase), an enzyme found on the luminal surface of IgG) plays an important role in the transmission of passive enterocytes. The active trypsin then converts the other immunity from the mother’s milk to the newborn in several proenzymes to active enzymes. animal species (e.g., ruminants and rodents). In humans, The pancreatic proteases are classified as endopepti- the absorption of intact immunoglobulins does not appear dases or exopeptidases (Table 27.3). Endopeptidases hy- to be an important mode of transmission of antibodies for drolyze certain internal peptide bonds of proteins or two reasons. First, passive immunity in humans is derived
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 505 almost entirely from the intrauterine transport of maternal ABSORPTION OF VITAMINS antibodies. Second, human colostrum, the thin, yellowish, milky fluid secreted by the mammary glands a few days be- Vitamins are organic substances from both animal and fore or after parturition, contains mainly IgA, which is plant sources needed in small quantities for normal meta- poorly absorbed by the small intestine. The ability to ab- bolic function and the growth and maintenance of the sorb intact proteins is rapidly lost as the gut matures—a body. Because most of these organic compounds are not process called closure. Colostrum contains a factor that manufactured in the body, adequate dietary intake and ef- promotes the closure of the small intestine. ficient intestinal absorption are important. Vitamins are After dipeptides and tripeptides are taken up by the ente- classified in many ways, but in terms of absorption, they are rocytes, they are further broken down to amino acids by pep- classified according to whether they are lipid-soluble or tidases in the cytoplasm. The amino acids are transported in water-soluble. the portal blood. The small amount of protein that is taken up by the adult intestine is largely degraded by lysosomal proteases, although some proteins escape degradation. The Fat-Soluble Vitamins Include A, D, E, and K The only feature shared by the fat-soluble vitamins is their lipid solubility. Otherwise, they are structurally very differ- Defects in Digestion and Transport Can Impair Protein Absorption ent. Most are absorbed passively. The fat-soluble vitamins are summarized in Table 27.8. Although pancreatic deficiency has the potential to affect protein digestion, it only does so in severe cases. Pancreatic Vitamin A. The principal form of vitamin A is retinol; the deficiency seems to affect lipid digestion more than protein aldehyde (retinal) and the acid (retinoic acid) are also ac- digestion. There are several extremely rare genetic disor- tive forms of vitamin A. Retinol can be derived directly ders of amino acid carriers. In Hartnup’s disease, the mem- from animal sources or through conversion from - brane carrier for neutral amino acids (e.g., tryptophan) is carotene (found abundantly in carrots) in the small intes- defective. Cystinuria involves the carrier for basic amino tine. Vitamin A is rendered water-soluble by micellar solu- acids (e.g., lysine and arginine) and the sulfur-containing bilization and is absorbed by the small intestine passively. amino acids (e.g., cystine). Cystinuria was once thought to It is converted in the small intestinal mucosa to an ester, involve only the kidneys because of the excretion of amino retinyl ester, which is incorporated in chylomicrons and acids such as cystine in urine, but the small intestine is in- taken up by the liver. Vitamin A is stored in the liver and volved as well. released to the circulation bound to retinol-binding pro- Because the peptide transport system remains unaf- tein only when needed. fected, disorders of some amino acid transporters can be Vitamin A is important in the production and regenera- treated with supplemental dipeptides containing these tion of rhodopsin of the retina and in the normal growth of amino acids. However, this treatment alone is not effective the skin. Vitamin A–deficient individuals develop night if the kidney transporter is also involved, as in cystinuria. blindness and skin lesions. TABLE 27.8 Fat-Soluble Vitamins Vitamin RDA Sources Site and Mode of Absorption Role A 1,000 RE Liver, kidney, butter, whole milk, Small intestine; passive Vision, bone development, cheese, and -carotene (yields epithelial development, two molecules of retinol) and reproduction D 200 IU Liver, butter, cream, vitamin D Small intestine; passive Growth and development, fortified milk, conversion from formation of bones and 7-dehydrocholesterol by UV light teeth, stimulation of i intestinal Ca 2 and phosphate absorption, mobilization of Ca 2 from bones E 10 mg Wheat germ, green plants, egg Small intestine; passive Antioxidant yolk, milk, butter, meat K 70–100 g Green vegetables, intestinal Phylloquinones from green Blood clotting flora vegetables are absorbed actively from the proximal small intestine; menaquinones from gut flora are absorbed passively RDA, recommended daily allowances; RE, retinol equivalent; IU, international unit: 1 IU 0.025 g
506 PART VII GASTROINTESTINAL PHYSIOLOGY Vitamin D. Vitamin D is a group of fat-soluble com- many oxidative processes by acting as a coenzyme or co- pounds collectively known as the calciferols. Vitamin D 3 factor. It is absorbed mainly by active transport in the (also called cholecalciferol or activated dehydrocholes- ileum. Vitamin C deficiency is associated with scurvy, a terol) in the human body is derived from two main sources: disorder characterized by weakness, fatigue, anemia, and the skin, which contains a rich source of 7-dehydrocholes- bleeding gums. terol that is rapidly converted to cholecalciferol when ex- posed to UV light, and dietary vitamin D 3 . Like vitamin A, Vitamin B 1 . Vitamin B 1 (thiamine) plays an important vitamin D 3 is absorbed by the small intestine passively and role in carbohydrate metabolism. Thiamine is absorbed by is incorporated into chylomicrons. During the metabolism the jejunum passively as well as by an active, carrier-medi- of chylomicrons, vitamin D 3 is transferred to a binding pro- ated process. Thiamine deficiency results in beriberi, char- tein in plasma called the vitamin D–binding protein. acterized by anorexia and disorders of the nervous system Unlike vitamin A, vitamin D is not stored in the liver but is and heart. distributed among the various organs depending on their lipid content. In the liver, vitamin D 3 is converted to 25-hydroxyc- Vitamin B 2 . Vitamin B 2 (riboflavin) is a component of holecalciferol, which is subsequently converted to the active the two groups of flavoproteins—flavin adenine dinu- hormone 1,25-dihydroxycholecalciferol in the kidneys. The cleotide (FAD) and flavin mononucleotide (FMN). Ri- latter enhances Ca 2 and phosphate absorption by the small boflavin plays an important role in metabolism. Riboflavin intestine and mobilizes Ca 2 and phosphate from bones. is absorbed by a specific, saturable, active transport system Vitamin D is essential for normal development and located in the proximal small intestine. Riboflavin defi- growth and the formation of bones and teeth. Vitamin D ciency is associated with anorexia, impaired growth, im- deficiency can result in rickets, a disorder of normal bone paired use of food, and nervous disorders. ossification manifested by distorted bone movements dur- ing muscular action. Niacin. Niacin plays an important role as a component of the coenzymes NAD(H) and NADP(H), which participate Vitamin E. The major dietary vitamin E is -tocopherol. in a wide variety of oxidation-reduction reactions involving Vegetable oils are rich in vitamin E. It is absorbed by the H transfer. small intestine by passive diffusion and incorporated into At low concentrations, niacin is absorbed by the small chylomicrons. Unlike vitamins A and D, vitamin E is trans- intestine by Na -dependent, carrier-mediated facilitated ported in the circulation associated with lipoproteins and transport. At high concentrations, it is absorbed by passive erythrocytes. diffusion. Niacin has been used to treat hypercholes- Vitamin E is a potent antioxidant and therefore prevents terolemia, for the prevention of coronary artery disease. It lipid peroxidation. Tocopherol deficiency is associated decreases plasma total cholesterol and LDL cholesterol, yet with increased red cell susceptibility to lipid peroxidation, increases plasma HDL cholesterol. which may explain why the red cells are more fragile in vi- Niacin deficiency is characterized by many clinical symp- tamin E–deficient individuals than in healthy individuals. toms, including anorexia, indigestion, muscle weakness, and skin eruptions. Severe deficiency leads to pellagra, a disease Vitamin K. Vitamin K can be derived from green vegeta- characterized by dermatitis, dementia, and diarrhea. bles in the diet or the gut flora. The vitamin K derived from green vegetables is in phylloquinones. Vitamin K derived Vitamin B 6 . Vitamin B 6 (pyridoxine) is involved in from bacteria in the small intestine is in menaquinones. amino acid and carbohydrate metabolism. Vitamin B 6 is ab- Phylloquinones are taken up by the small intestine via an sorbed throughout the small intestine by simple diffusion. energy-dependent process from the proximal small intes- A deficiency of this vitamin is often associated with anemia tine. In contrast, menaquinones are absorbed from the and CNS disorders. small intestine passively, dependent only on the micellar solubilization of these compounds by bile salts. Vitamin K Biotin. Biotin acts as a coenzyme for carboxylase, tran- is incorporated into chylomicrons. It is rapidly taken up by scarboxylase, and decarboxylase enzymes, which play an the liver and secreted together with VLDLs. No carrier pro- important role in the metabolism of lipids, glucose, and tein for vitamin K has been identified. amino acids. At low luminal concentrations, biotin is ab- Vitamin K is essential for the synthesis of various clot- sorbed by the small intestine by Na -dependent active ting factors by the liver. Vitamin K deficiency is associated transport. At high concentrations, biotin is absorbed by with bleeding disorders. simple diffusion. Biotin is so common in food that defi- ciency is rarely observed. The Water-Soluble Vitamins Are C, B 1 , B 2 , B 6 , B 12 , Folic Acid. Folic acid is usually found in the diet as polyg- Niacin, Biotin, and Folic Acid lutamyl conjugates (pteroylpolyglutamates). It is required Most of the water-soluble vitamins are absorbed by the for the formation of nucleic acids, the maturation of red small intestine by both passive and active processes. The blood cells, and growth. An enzyme on the brush border water-soluble vitamins are summarized in Table 27.9. degrades pteroylpolyglutamates to yield a monoglutamyl- folate, which is taken up by enterocytes by facilitated trans- Vitamin C. The major source of vitamin C (ascorbic acid) port. Inside enterocytes, the monoglutamylfolate is re- is green vegetables and fruits. It plays an important role in leased directly into the bloodstream or converted to
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 507 TABLE 27.9 Water-Soluble Vitamins Vitamin RDA Sources Site and Mode of Absorption Role C 60 mg/day Fruits, vegetables, organ (liver Active transport by the ileum Coenzyme or cofactor and kidney) meat in many oxidative processes B 1 (thiamine) 1 mg/day Yeast, liver, cereal grains At low luminal concentrations, Carbohydrate metabolism by active, carrier-mediated process; at high luminal concentrations by passive diffusion B 2 (riboflavin) 1.7 mg/day Dairy products Active transport in proximal Metabolism small intestine Niacin 19 mg/day Brewer’s yeast, meat At low luminal concentrations, Component of coenzymes by Na -dependent, carrier- NAD(H) and NADP(H); mediated, facilitated transport metabolism of carbohydrates, fats, and proteins; synthesis of fatty acid and steroid B 6 (pyridoxine) 2.2 mg/day Brewer’s yeast, wheat germ, By passive diffusion in small Amino acid and carbohy- meat, whole grain cereals, intestine drate metabolism dairy products Biotin 200 g /day Brewer’s yeast, milk, liver, At low luminal concentrations, Coenzyme for carboxylase, egg yolk by Na -dependent active transport; transcarboxylase, and at high luminal concentrations, by carboxylase enzymes, simple diffusion metabolism of lipids, glucose, and amino acids Folic acid 0.5 mg/day Liver, beans, dark green By Na -dependent facilitated Nucleic acid biosynthesis, leafy vegetables transport maturation of red blood cells, promotion of growth 3 g/day Liver, kidney, dairy products, Absorbed in terminal ileum Normal cell division; bone B 12 eggs, fish by active transport involving marrow and intestinal binding to intrinsic factor mucosa most affected in deficiency state, characterized by pernicious anemia 5-methyltetrahydrofolate before exiting the cell. A folate- intestine are absorbed. The absorption of electrolytes and binding protein binds the free and methylated forms of minerals involves both passive and active processes, result- folic acid in plasma. Folic acid deficiency causes a fall in ing in the movement of electrolytes, water, and metabolic plasma and red cell folic acid content and, in its most severe substrates into the blood for distribution and use through- form, the development of megaloblastic anemia, dermato- out the body. logical lesions, and poor growth. Sodium. The GI system is well equipped to handle the Vitamin B 12 . The discovery of vitamin B 12 (cobalamin) large amount of Na entering the GI lumen daily—on av- followed from the observation that patients with perni- erage, about 25 to 35 g of Na every day. Around 5 to 8 g cious anemia who ate large quantities of raw liver recov- are derived from the diet, and the rest from salivary, gastric, ered from the disease. Subsequent analysis of liver compo- biliary, pancreatic, and small intestinal secretions. The GI nents isolated the cobalt-containing vitamin, which plays tract is extremely efficient in conserving Na : only 0.5% of an important role in the production of red blood cells. A intestinal Na is lost in the feces. The jejunum absorbs glycoprotein secreted by the parietal cells in the stomach more than half of the total Na , and the ileum and colon called the intrinsic factor binds strongly with vitamin B 12 to absorb the remainder. The small intestine absorbs the bulk form a complex that is then absorbed in the terminal ileum of the Na presented to it, but the colon is most efficient in through a receptor-mediated process (Fig. 27.28). Vitamin conserving Na . B 12 is transported in the portal blood bound to the protein Sodium is absorbed by several different mechanisms op- transcobalamin. Individuals who lack the intrinsic factor erating at varying degrees in different parts of the GI tract. fail to absorb vitamin B 12 and develop pernicious anemia. When a meal that is hypotonic to plasma is ingested, con- siderable absorption of water from the lumen to the blood takes place, predominantly through tight junctions and in- tercellular spaces between the enterocytes, resulting in the ELECTROLYTE AND MINERAL ABSORPTION absorption of small solutes such as Na and Cl ions. This Nearly all of the dietary nutrients and approximately 95 to mode of absorption, called solvent drag, is responsible for 98% of the water and electrolytes that enter the upper small a significant amount of the Na absorption by the duode-
508 PART VII GASTROINTESTINAL PHYSIOLOGY Stomach most of the monosaccharides and amino acids have already Parietal cell been absorbed by the small intestine (Fig. 27.29B). Sodium chloride is transported via two exchangers located at the brush border membrane. One is a Cl /HCO 3 exchanger, and the other is a Na /H exchanger. The downhill move- ment of Na into the cell provides the energy required for Vitamin B 12 the uphill movement of the H from the cell to the lumen. Similarly, the downhill movement of HCO 3 out of the cell provides the energy for the uphill entry of Cl into the Intrinsic enterocytes. The Cl then leaves the cell through facili- factor Intrinsic factor/ tated transport. This mode of Na uptake is called Na /H -Cl /HCO 3 countertransport. vitamin B 12 complex In the colon, the mechanisms for Na absorption are mostly similar to those described for the ileum. There is no sugar- or amino acid–coupled Na transport because most Ileum Lumen sugars and amino acids have already been absorbed. Sodium is also absorbed here via Na -selective ion channels in the apical cell membrane (electrogenic Na absorption). Potassium. The average daily intake of K is about 4 g. Absorption takes place throughout the intestine by passive + H + HCO - H CO CO + H O Blood Vitamin B 12 released into blood 3 2 3 2 2 Cl - Transcobalamin/ Glucose, Na + Na + H + Transcobalamin amino vitamin B 12 complex acids H CO 3 Cl - 2 The intestinal absorption of vitamin B 12 . HCO 3 - FIGURE 27.28 CO 2 + H O 2 Na + Metabolism ATP K + num and jejunum, but it probably plays a minor role in Na A absorption by the ileum and colon because more distal re- gions of the intestine are lined by a “tight” epithelium (see Blood Chapter 2). In the jejunum, Na is actively pumped out of the baso- CO + H O H CO 3 2 2 2 lateral surface of enterocytes by a Na /K -ATPase (Fig. + - - 27.29A). The result is low intracellular Na concentration, H HCO 3 Cl and the luminal Na enters enterocytes down the electro- chemical gradient, providing energy for the extrusion of H into the lumen (via a Na /H exchanger). The H + - - then reacts with HCO 3 in bile and pancreatic secretions Cl - Na + Na + H HCO 3 Cl in the intestinal lumen to form H 2CO 3. Carbonic acid dis- sociates to form CO 2 and H 2O. The CO 2 readily diffuses H CO across the small intestine into the blood. Another mode of 2 3 Cl - Na uptake is via a carrier located in the enterocyte brush CO + H O border membrane, which transports Na together with a 2 2 Na + Na + monosaccharide (e.g., glucose) or an amino acid molecule Metabolism ATP (a symport type of transport). K + K + In the ileum, the presence of a Na /K -ATPase at the B basolateral membrane also creates a low intracellular Na concentration, and luminal Na enters enterocytes down Blood the electrochemical gradient. Sodium absorption by Na - FIGURE 27.29 A, Na absorption by the jejunum. B, Na ab- coupled symporters is not as great as in the jejunum because sorption by the ileum.
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 509 diffusion through the tight junctions and lateral intercellu- increased by 1,25-dihydroxy vitamin D 3 . Once inside the lar spaces of the enterocytes. The driving force for K ab- cell, the Ca 2 ions are sequestered in the ER and Golgi sorption is the difference between luminal and blood K membranes by binding to the CaBP in these organelles. concentration. The absorption of water results in an in- Calcium absorption by the small intestine is regulated by crease in luminal K concentration, resulting in K ab- the circulating plasma Ca 2 concentration. Lowering of the sorption by the intestine. In the colon, K can be absorbed Ca 2 concentration stimulates the release of parathyroid or secreted depending on the luminal K concentration. hormone, which stimulates the conversion of vitamin D to With diarrhea, considerable K can be lost. Prolonged di- its active metabolite—1,25-dihydroxy vitamin D 3 —in the arrhea can be life-threatening, because the dramatic fall in kidney. This in turn stimulates the synthesis of CaBP and 2 extracellular K concentration can cause complications the Ca -ATPase by the enterocytes (Fig. 27.30). Because such as cardiac arrhythmias. protein synthesis is involved in the stimulation of Ca 2 up- take by parathyroid hormone, a lapse of a few hours usually Chloride. Most of the Cl ions added to the GI tract from occurs between the release of parathyroid hormone and the the diet and from the various secretions of the GI system increase in Ca 2 absorption by the enterocytes. are absorbed. Intestinal chloride absorption involves both passive and active processes. In the jejunum, active Na ab- Magnesium. Humans ingest about 0.4 to 0.5 g/day of 2 sorption generates a potential difference across the small Mg . The absorption of Mg 2 seems to take place along intestinal mucosa, with the serosal side more positive than the entire small intestine, and the mechanism involved the lumen. Chloride ions follow this potential difference seems to be passive. and enter the bloodstream via the tight junctions and lat- eral intercellular spaces. In the ileum and colon, Cl is Zinc. The average daily zinc intake is 10 to 15 mg, about taken up actively by enterocytes via Cl /HCO 3 ex- half of which is absorbed primarily in the ileum. A carrier lo- change, as discussed above. This absorption of Cl is in- cated in the brush border membrane actively transports zinc hibited by the presence of other halides. from the lumen into the cell, where it can be stored or trans- ferred into the bloodstream. Zinc plays an important role in Bicarbonate. Bicarbonate ions are absorbed in the je- several metabolic activities. For example, a group of metal- junum together with Na . In humans, the absorption of HCO 3 by the jejunum stimulates the absorption of Na and H 2 O (see Fig. 27.29A). Through a Na /H exchanger, H is secreted into the intestinal lumen where H and Plasma Ca 2+ HCO 3 react to form H 2 CO 3 , which then dissociates to form CO 2 and H 2 O. The CO 2 diffuses into the entero- cytes, where it reacts with H 2 O to form H 2 CO 3 (catalyzed Parathyroid hormone release by carbonic anhydrase). H 2 CO 3 dissociates into HCO 3 and H and the HCO 3 then diffuses into the blood. In the ileum and colon, HCO 3 is actively secreted into 25-hydroxy 1,25-dihydroxy vitamin D 3 Kidney vitamin D 3 the lumen in exchange for Cl . This secretion of HCO 3 is important in buffering the decrease in pH resulting from the short-chain fatty acids produced by bacteria in the dis- tal ileum and colon. Stimulates synthesis of calcium-binding protein 2+ Calcium. The amount of Ca 2 entering the GI tract is and Ca -ATPase in enterocyte about 1 g/day, approximately half of which is derived from the diet. The most of dietary Ca 2 is derived from meat and dairy products. Of the Ca 2 presented to the GI tract, about 40% is absorbed. Several factors affect Ca 2 absorp- Endoplasmic tion. For instance, the presence of fatty acid can retard Ca 2+ reticulum Ca 2 absorption by the formation of Ca 2 soap. In con- CaBP trast, bile salt molecules form complexes with Ca 2 ions, Ca 2+ CaBP which facilitates Ca 2 absorption. channel Ca 2+ Golgi Ca 2+ Calcium absorption takes place predominantly in the apparatus Ca - 2+ duodenum and jejunum, is mainly active, and involves three ATPase steps: (1) Calcium is taken up by enterocytes by passive dif- fusion through a Ca 2 channel, since there is a large Ca 2 concentration gradient; the luminal Ca 2 is about 5 to 10 mM, whereas free intracellular Ca 2 is about 100 nM. (2) Once inside the cell, Ca 2 is complexed with Ca 2 -binding FIGURE 27.30 Calcium absorption by enterocytes. Parathy- roid hormone stimulates the conversion of vita- protein, calbindin D (CaBP). (3) At the basolateral mem- min D 3 in the kidney to its active metabolite 1,25-dihydroxy vita- 2 brane, Ca 2 is extruded from the enterocyte via the Ca - min D 3 (1,25-dihydroxycholecalciferol), which stimulates Ca 2 ATPase pump. Calcium uptake by enterocytes, the level of uptake via the Ca 2 channels. It also stimulates the synthesis of 2 CaBP in the cells, and transport by Ca -ATPase pumps are both Ca -binding protein (CaBP) and the Ca -ATPase. 2 2
510 PART VII GASTROINTESTINAL PHYSIOLOGY loenzymes (e.g., alkaline phosphatase, carbonic anhydrase, Lumen Enterocyte Blood and lactic dehydrogenase) requires zinc to function. Fe Sloughed with cell Iron. Iron plays an important role not only as a compo- nent of heme but also as a participant in many enzymatic re- Normal actions. About 12 to 15 mg/day of iron enter the GI tract, where it is absorbed mainly by the duodenum and upper je- Fe for junum (Fig. 27.31). There are two forms of dietary iron: enzymes heme and nonheme. The heme iron is absorbed intact by enterocytes. Nonheme iron absorption depends on both pH 3 and concentration. Ferric (Fe ) salts are not soluble at pH 2 7, whereas ferrous (Fe ) salts are. Consequently, in the duodenum and upper jejunum, unless Fe 3 ion is chelated, it forms a precipitate. Several compounds, such as tannic acid in tea and phytates in vegetables, form insoluble complexes with iron, preventing absorption. Iron is absorbed by an ac- tive process via a carrier(s) located in the brush border mem- brane. One such transporter, the divalent metal transporter (DMT-1), is expressed abundantly in the duodenum. Iron Once inside the cell, heme iron is released by the action deficient of heme oxygenase and mixed with the intracellular free iron pool. Iron is either stored in the enterocyte cytoplasm bound to the storage protein apoferritin to form ferritin, or transported across the cell bound to transport proteins, which carry the iron across the cytoplasm and release it into the intercellular space. Iron is bound and transported in the blood by transferrin, a -globulin synthesized by the liver. Iron absorption is closely regulated by iron storage in en- terocytes and iron concentration in the plasma. Enterocytes are continuously shed into the lumen, and the ferritin con- tained within is also lost. Normally, iron in enterocytes is derived from the lumen and the blood (Fig. 27.32). The amount of iron absorbed is regulated by the amount stored Iron loaded Lumen Enterocyte Blood Heme Heme Heme oxygenase Transport protein Iron Ferritin Apoferritin Transferrin Transferrin Fe Fe FIGURE 27.32 The regulation of iron absorption in the intestinal mucosa. In healthy subjects, the DMT-1 amount of iron that enters enterocytes is regulated by the Ferritin Transferrin- amount of iron in the cells and circulating in the plasma. In Fe iron-deficient subjects, little iron is incorporated into entero- cytes and less is circulating in the plasma; therefore, absorption is increased and excretion is decreased. In iron-loaded subjects, the mucosal cells and transferrin are more highly saturated, lim- = Facilitated transport iting absorption and increasing excretion. (Modified from Krause MV, Mahan LK, eds. Food, Nutrition, and Diet Ther- apy. Philadelphia: WB Saunders, 1984.) DMT-1 = Divalent metal transporter Iron absorption. FIGURE 27.31
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 511 in enterocytes. In iron deficiency, the circulating plasma ABSORPTION OF WATER iron concentration is low, which stimulates the absorption of iron from the lumen and the transport of iron into the In human adults, the average daily intake of water is about blood. Moreover, in a deficient state, less iron is stored as 2 L. As shown in Table 27.10, secretions from the salivary ferritin in the enterocytes, so the loss of iron through this glands, pancreas, liver, and GI tract make up the most of means is significantly reduced. In iron-loaded patients, there the fluid entering the GI tract (about 7 L). Despite this large is less absorption of iron because of the large amount of mu- volume of fluid, only 100 mL are lost in the feces. There- cosal iron storage, which increases iron loss as a result of en- fore, the GI tract is extremely efficient in absorbing water. terocyte shedding. Furthermore, because of the high level of Water absorption by the GI tract is passive. The rate of ab- circulating plasma iron, the transfer of iron from enterocytes sorption depends on both the region of the intestinal tract to the blood is reduced. Through a combination of various and the luminal osmolality. The duodenum, jejunum, and mechanisms, body iron homeostasis is maintained. ileum absorb the bulk of the water that enters the GI tract daily. The colon normally absorbs about 1.4 L of water and excretes about 100 mL. It is capable of absorbing consider- ably more water (about 4.5 L), however, and watery diar- rhea occurs only if this capacity is exceeded. Water Intake, Absorption, Because water absorption is determined by the osmolal- TABLE 27.10 and Excretion by the GI Tract ity difference of the lumen and the blood, water can move both ways in the intestinal tract (i.e., secretion and absorp- Water added to GI tract tion). The osmolality of blood is about 300 mOsm/kg Food and beverages 2,000 mL Salivary secretion 1,000 mL H 2 O. The ingestion of a hypertonic meal (e.g., 600 Biliary secretion 1,000 mL mOsm/kg H 2 O) initially leads to net water movement from Gastric secretion 2,000 mL blood to lumen; however, as the various nutrients and elec- Pancreatic secretion 1,000 mL trolytes are absorbed by the small intestine, the luminal os- Intestinal mucosal secretion 2,000 mL molality falls, resulting in the net water movement from lu- Water absorbed or lost in feces men to blood. The water of a hypertonic meal is therefore Water absorbed absorbed mainly in the ileum and colon. In contrast, if a Duodenum and jejunum 4,000 mL hypotonic meal is ingested (e.g., 200 mOsm/kg H 2 O), net Ileum 3,500 mL water movement is immediately from the lumen to the Colon 1,400 mL Water loss in feces 100 mL blood, resulting in the absorption of the most of the water in the duodenum and jejunum. REVIEW QUESTIONS DIRECTIONS: Each of the numbered protein crucial for the absorption of (D) Hydrochloric acid items or incomplete statements in this vitamin B 12 by the ileum. What is this (E) Hypochlorous acid section is followed by answers or by protein? 6. Parasympathetic stimulation induces completions of the statement. Select the (A) Intrinsic factor salivary acinar cells to release the ONE lettered answer or completion that is (B) Gastrin protease BEST in each case. (C) Somatostatin (A) Bradykinin (D) Cholecystokinin (CCK) (B) Kallikrein 1. Most of the following GI secretions (E) Chylomicrons (C) Kininogen have a basal output during the 4. Gastric acid secretion is stimulated (D) Kinin interdigestive period (between meals). during several phases associated with (E) Aminopeptidase However, the sight and smell of a tasty the ingestion and digestion of a meal. 7. Which protein is absent in saliva? meal stimulates GI secretions. Of the Which phase is associated with the (A) Lactoferrin various GI secretions, which is the bulk of acid secretion? (B) Amylase most stimulated? (A) Cephalic (C) Mucin (A) Gastric secretion (B) Esophageal (D) Intrinsic factor (B) Intestinal secretion (C) Gastric (E) Muramidase (C) Pancreatic secretion (D) Intestinal 8. After the ingestion of a meal, the pH (D) Salivary secretion (E) Colonic in the stomach lumen increases in (E) Biliary secretion 5 Carbonic anhydrase is an enzyme that response to the dilution and buffering 2. Bile acid uptake by hepatocytes is occurs in plants, bacteria, and animals of gastric acid by the arrival of food. dependent on and is involved in the formation of The pH in the stomach lumen in the (A) Calcium which chemical? fasting state is usually between (B) Iron (A) Carbon dioxide from carbon and 0.1 to 0.5 (C) Sodium oxygen (A) 1 to 2 (D) Potassium (B) Carbonic acid from carbon dioxide (B) 4 to 5 (E) Chloride and water (C) 6 to 7 3. Parietal cells in the stomach secrete a (C) Bicarbonate ion from carbonic acid (D) 9 to 10 (continued)
512 PART VII GASTROINTESTINAL PHYSIOLOGY 9. Unlike other GI secretions, salivary (A) Glucose protein has been digested and secretion is controlled almost (B) Glucose and galactose absorbed by the GI tract? exclusively by the nervous system and (C) Glucose and fructose (A) Free amino acids is significantly inhibited by (D) Galactose and fructose (B) Dipeptides and tripeptides (A) Atropine (E) Fructose (C) Free amino acids and dipeptides (B) Pilocarpine 16.Maltase hydrolyzes maltose to form (D) Free amino acids and tripeptides (C) Cimetidine (A) Glucose (E) Free amino acids, dipeptides, and (D) Aspirin (B) Glucose and galactose tripeptides (E) Omeprazole (C) Glucose and fructose 22.Which vitamin is water-soluble? 10.The chief cells of the stomach secrete (D) Galactose and fructose (A) Vitamin A (A) Intrinsic factor (E) Galactose (B) Vitamin D (B) Hydrochloric acid 17.Which sugar is taken up by (C) Vitamin K (C) Pepsinogen enterocytes by facilitated diffusion? (D) Vitamin B 1 (D) Gastrin (A) Glucose (E) Vitamin E (E) CCK (B) Galactose 23.Which one of the following vitamins 11.The interaction of histamine with its (C) Fructose stimulates calcium absorption by the H 2 receptor in the parietal cell results (D) Xylose GI tract? in (E) Sucrose (A) Vitamin E (A) An increase in intracellular sodium 18.Dietary triglyceride is a major source (B) Vitamin D concentration of nutrient for the human body. It is (C) Vitamin A (B) An increase in intracellular cAMP digested mostly in the intestinal lumen (D) Vitamin K production by pancreatic lipase to release (E) Vitamin C (C) An increase in intracellular cGMP (A) Lysophosphatidylcholine and fatty 24.Which vitamin is transported in production acids chylomicrons as an ester? (D) A decrease in intracellular calcium (B) Glycerol and fatty acids (A) Vitamin E concentration (C) Diglyceride and fatty acids (B) Vitamin D (E) A decrease in intracellular cAMP (D) 2-Monoglyceride and fatty acids (C) Vitamin A production (E) Lysophosphatidylcholine and (D) Vitamin K 12.When the pH of the stomach lumen diglyceride (E) Vitamin B 12 falls below 3, the antrum of the 19.After a meal of pizza, dietary lipid is 25.Potassium is absorbed in the jejunum stomach releases a peptide that acts absorbed by the small intestine and by locally to inhibit gastrin release. This transported in the lymph mainly as (A) Active transport peptide is (A) VLDLs (B) Facilitated transport (A) Enterogastrone (B) Free fatty acids bound to albumin (C) Passive transport (B) Intrinsic factor (C) Chylomicrons (D) Active and passive transport (C) Secretin (D) LDLs (E) Coupling to sodium absorption (D) Somatostatin (E) HDLs 26.Ascorbic acid is a potent enhancer of (E) CCK 20.Hartnup’s disease is an inherited iron absorption because it 13.Which hormone stimulates pancreatic autosomal recessive disorder involving (A) Enhances the absorption of heme secretion that is rich in bicarbonate? the malabsorption of amino acids, iron (A) Somatostatin particularly tryptophan, by the small (B) Enhances the activity of heme (B) Secretin intestine. Feeding dipeptides and oxygenase (C) CCK tripeptides containing tryptophan to (C) Is a reducing agent, thereby (D) Gastrin patients with this disease improves helping to keep iron in the ferrous (E) Insulin their clinical condition because state 14.A patient suffering from Zollinger- (A) Dipeptides and tripeptides, unlike (D) Decreases the production of Ellison syndrome would be expected to free amino acids, can be taken up ferritin by enterocytes have passively by enterocytes in the small (E) Stimulates production of (A) Excessive acid reflux into the intestine transferrin esophagus, resulting in esophagitis (B) Peptides, unlike free amino acids, (B) Excessive secretion of CCK, can be taken up by defective amino SUGGESTED READING causing continuous contraction of the acid transporters Alpers DH. Digestion and absorption of gallbladder (C) Dipeptides and tripeptides use carbohydrates and proteins. In: John- (C) A gastrin-secreting tumor of the transporters that are different from the son LR, ed. Physiology of the Gastroin- pancreas, causing excessive stomach defective amino acid transporters testinal Tract. 3rd Ed. New York: acid secretion and peptic ulcers (D) The presence of dipeptides and Raven, 1994;1723–1749. (D) Low plasma lipid levels, due to tripeptides in the intestinal lumen Boyer JL, Graf J, Meier PJ. Hepatic trans- failure of the liver to secrete VLDLs enhances the uptake of amino acids by port systems regulating pH, cell vol- (E) Inadequate secretion of bicarbonate the transporters ume and bile secretion. Annu Rev by the pancreas (E) Dipeptides and tripeptides, unlike Physiol 1992;54:415–438. 15.Lactase is a brush border enzyme amino acids, can be taken up passively Choudari CP, Lehman GA, Sherman S. involved in the digestion of lactose. by the colon Pancreatitis and cystic fibrosis gene The digestion product or products of 21.What would you expect to find in a mutations. Gastroenterol Clin North lactose are sample of hepatic portal blood after Am 1999;28:543–549. (continued)
CHAPTER 27 Gastrointestinal Secretion, Digestion, and Absorption 513 Davenport HW. Physiology of the Diges- Ito S. Functional gastric morphology. In: Rose RC. Intestinal absorption of tive Tract. 5th Ed. Chicago: Year Book, Johnson LR, ed. Physiology of the Gas- water-soluble vitamins. In: Johnson 1982. trointestinal Tract. 2nd Ed. New York: LR, ed. Physiology of the Hagenbuch B, Stieger B, Foguet M, Lub- Raven, 1987;817–851. Gastrointestinal Tract. 2nd Ed. bert H, Meier PJ. Functional expression Johnson LR. Gastrointestinal Physiology. New York: Raven 1987; cloning and characterization of the he- 6th Ed. St. Louis: CV Mosby, 2001. 1581–1596. patocyte Na /bile acid cotransport sys- Phan CT, Tso P. Intestinal lipid absorption Scott D, Weeks D, Melchers K, Sachs G. tem. Proc Natl Acad Sci U S A and transport. Front Biosci The life and death of Helicobacter pylori. 1991;88:10,629–10,633. 2001;6:D299–D319. Gut 1998;43:S56–S60.
The Physiology CHAPTER 28 of the Liver 28 Patrick Tso, Ph.D. James McGill, M.D. CHAPTER OUTLINE ■ THE ANATOMY OF THE LIVER ■ PROTEIN AND AMINO ACID METABOLISM IN THE ■ THE METABOLISM OF DRUGS AND XENOBIOTICS LIVER ■ ENERGY METABOLISM IN THE LIVER ■ THE LIVER AS A STORAGE ORGAN ■ ENDOCRINE FUNCTIONS OF THE LIVER KEY CONCEPTS 1. The liver sinusoid is lined with sinusoidal cells (endothelial 5. The liver synthesizes glucose from noncarbohydrate cells), Kupffer cells, and fat storage cells (also called stel- sources, a process called gluconeogenesis. late or Ito cells), which perform important metabolic func- 6. The liver is the first organ to experience and respond to tions and defend the liver. changes in plasma insulin levels. 2. The liver plays an important role in maintaining blood 7. The liver is one of the main organs involved in fatty acid glucose levels and in metabolizing drugs and toxic sub- synthesis. stances. 8. The liver aids in the elimination of cholesterol from the body. 3. The liver has a remarkable capacity to regenerate. 9. The liver is a storage area for fat-soluble vitamins and iron. 4. The liver is extremely important in maintaining an ade- 10. The liver modifies the action of hormones released by quate supply of nutrients for metabolism. other organs. he liver is the largest internal organ in the body, consti- stances into the GI tract, and it stores, degrades, and detox- Ttuting about 2.5% of an adult’s body weight. During ifies many substrates. rest, it receives 25% of the cardiac output via the hepatic portal vein and hepatic artery. The hepatic portal vein car- ries the absorbed nutrients from the GI tract to the liver, The Arrangement of Hepatocytes Along Liver which takes up, stores, and distributes nutrients and vita- Sinusoids Aids the Rapid Exchange of Molecules mins. The liver plays an important role in maintaining blood glucose levels. It also regulates the circulating blood lipids Hepatocytes are highly specialized cells. The bile canalicu- by the amount of very low density lipoproteins (VLDLs) it lus is usually lined by two hepatocytes and is separated secretes. Many of the circulating plasma proteins are syn- from the pericellular space by tight junctions, which are im- thesized by the liver. In addition, the liver takes up numer- permeable and, thus, prevent the mixing of contents be- ous toxic compounds and drugs from the portal circulation. tween the bile canaliculus and the pericellular space It is well equipped to deal with the metabolism of drugs and (Fig. 28.1). The bile from the bile canaliculus drains into a toxic substances. The liver also serves as an excretory organ series of ducts, and it may eventually join the pancreatic for bile pigments, cholesterol, and drugs. Finally, it performs duct near where it enters the duodenum. Drainage of bile important endocrine functions. into the duodenum is partly regulated by a sphincter lo- cated at the junction between the bile duct and the duode- num, the sphincter of Oddi (see Chapter 27). The pericellular space, the space between two hepato- THE ANATOMY OF THE LIVER cytes, is continuous with the perisinusoidal space (see Fig. The liver is essential to the normal physiology of many or- 28.1). The perisinusoidal space, also known as the space of gans and systems of the body. It interacts with the cardio- Disse, is separated from the sinusoid by a layer of sinu- vascular and immune systems, it secretes important sub- soidal endothelial cells. Hepatocytes possess numerous, 514
CHAPTER 28 The Physiology of the Liver 515 The hepatic portal vein provides about 70 to 80% of the liver’s blood supply, and the hepatic artery provides the Stellate cell rest. Hepatic portal blood is poorly oxygenated unlike that from the hepatic artery. The portal vein branches repeat- Pericellular space edly, forming smaller venules that eventually empty into the sinusoids. The hepatic artery branches to form arteri- Tight junction oles and then capillaries, which also drain into the sinu- Bile canaliculus soids. Liver sinusoids can be considered specialized capil- laries. As mentioned earlier, the hepatic sinusoid is Hepatocyte extremely porous and allows the rapid exchange of materi- Perisinusoidal space als between the perisinusoidal space and the sinusoid. The sinusoids empty into the central veins, which subsequently join to form the hepatic vein, which then joins the inferior Kupffer cell vena cava. Hepatic blood flow varies with activity, increasing af- Sinusoid ter eating and decreasing during sleep. Blood flow to the intestines and spleen and, in turn, in the portal vein is predominantly regulated by the splanchnic arterioles. In Sinusoidal this way, eating results in increased blood flow to the in- endothelial cells testines followed by increased liver blood flow. Portal The relationship between hepatocytes, the vein pressure is normally low. Increased resistance to por- FIGURE 28.1 perisinusoidal space, and the sinusoid. tal blood flow results in portal hypertension. Portal hy- pertension is the most common complication of chronic liver disease and accounts for a large percentage of the finger-like projections that extend into the perisinusoidal morbidity and mortality associated with chronic liver space, greatly increasing the surface area over which hepa- diseases (see Clinical Focus Box 28.1). tocytes contact the perisinusoidal fluid. Endothelial cells of the liver, unlike those in other parts of the cardiovascular system, lack a basement membrane. The Liver Has an Important Lymphatic System Furthermore, they have sieve-like plates that permit the ready exchange of materials between the perisinusoidal The hepatic lymphatic system is present in three main ar- space and the sinusoid. Electron microscopy has demon- eas: adjacent to the central veins, adjacent to the portal strated that even particles as big as chylomicrons (80 to 500 veins, and coursing along the hepatic artery. As in other or- nm in diameter) can penetrate these porous plates. Al- gans, it is through these channels that fluid and proteins are though the barrier between the perisinusoidal space and drained. The protein concentration is highest in lymph the sinusoid is permeable, it does have some sieving prop- from the liver. erties. For example, the protein concentration of hepatic In the liver, the largest space drained by the lymphatic lymph, assumed to derive from the perisinusoidal space, is system is the perisinusoidal space. Disturbances in the bal- lower than that of plasma by about 10%. ance of filtration and drainage are the primary causes of as- Kupffer cells also line the hepatic sinusoids. These are cites, the accumulation of serous fluid in the peritoneal cav- resident macrophages of the fixed monocyte-macrophage ity. Ascites is another common cause of morbidity in system that play an extremely important role in removing patients with chronic liver disease. unwanted material (e.g., bacteria, virus particles, fibrin-fib- rinogen complexes, damaged erythrocytes, and immune complexes) from the circulation. Endocytosis is the mech- The Liver Can Regenerate anism by which these materials are removed. Of the solid organs, the liver is the only one that can re- Some perisinusoidal cells contain distinct lipid droplets generate. There appears to be a critical ratio between func- in the cytoplasm. These fat-storage cells are called stellate tioning liver mass and body mass. Deviations in this ratio cells or Ito cells. The lipid droplets contain vitamin A. trigger a modulation of either hepatocyte proliferation or Through complex and typically inflammatory processes, apoptosis, in order to maintain the liver’s optimal size. Pep- stellate cells become transformed to myofibroblasts, which tide growth factors—such as transforming growth factor- then become capable of both secreting collagen into the (TGF-), hepatocyte growth factor (HGF), and epidermal space of Disse and regulating sinusoidal portal pressure by growth factor (EGF)—have been the best-studied stimuli of their contraction or relaxation. Stellate cells may be in- hepatocyte DNA synthesis. After these peptides bind to volved in the pathological fibrosis of the liver. their receptors on the remaining hepatocytes and work their way through myriad transcription factors, gene tran- The Liver Receives Venous Blood Through scription is accelerated, resulting in increased cell number the Portal Vein and Arterial Blood Through and increased liver mass. Alternatively, a decrease in liver volume is achieved by the Hepatic Artery enhanced hepatocyte apoptosis rates. Apoptosis is a care- Circulation to the liver is discussed in detail in Chapter 17; fully programmed process by which cells kill themselves here, we will briefly describe some of its unique features. while maintaining the integrity of their cellular membranes.
516 PART VII GASTROINTESTINAL PHYSIOLOGY CLINICAL FOCUS BOX 28.1 Esophageal Varices, a Common Manifestation pressure increases are least opposed in the esophagus of Portal Hypertension because of the limited connective tissue support at the Chronic liver injury can lead to a sequence of changes base of the esophagus. This structural condition, along that terminates with fatal bleeding from esophageal with the negative intrathoracic pressure, favors the for- blood vessels. In most forms of chronic liver injury, stel- mation and rupture of esophageal varices. Approxi- late cells are transformed into collagen-secreting myofi- mately 30% of patients who develop an esophageal broblasts. These cells deposit collagen into the sinusoids, variceal hemorrhage die during the episode of bleeding, interfering with the exchange of compounds between the making it one of the most lethal medical illnesses. blood and hepatocytes and increasing resistance to por- Currently there are no well-recognized treatments to re- tal venous flow. The resistance appears to be further in- verse cirrhosis, but numerous strategies are employed to creased when stellate cells contract. The increased resist- reduce portal hypertension and bleeding. Chief among ance results in increased hepatic portal pressure and these is the use of nonselective beta blockers, which en- decreased liver blood flow. This disorder is seen in ap- hance splanchnic arteriolar vasoconstriction and thereby proximately 80% of patients with cirrhosis. In a compen- reduce portal venous pressure. Bleeding esophageal satory effort, new channels are formed or dormant ve- varices are frequently treated by endoscopic ligation of the nous tributaries are expanded, resulting in the formation varices. Shunts can be placed radiologically or surgically of varicose (unnaturally swollen) veins in the abdomen. between the portal venous system and the systemic ve- Although varicose veins develop in many areas, portal nous to reduce the portal pressure. In contrast, cell death that results from necroinflammatory conversion of alcohol to acetaldehyde. It may also play a processes is characterized by a loss of cell membrane in- role in the dehydrogenation of steroids. tegrity and the activation of inflammatory reactions. Liver The enzymes involved in phase I reactions of drug bio- cell suicide is mediated by proapoptotic signals, such as tu- transformation are present as an enzyme complex composed mor necrosis factor (TNF). of the NADPH-cytochrome P450 reductase and a series of hemoproteins called cytochrome P450 (Fig. 28.2). The drug combines with the oxidized cytochrome P450 3 to form the 3 THE METABOLISM OF DRUGS cytochrome P450 -drug complex. This complex is then re- 2 AND XENOBIOTICS duced to the cytochrome P450 -drug complex, catalyzed by the enzyme NADPH-cytochrome P450 reductase. The Hepatocytes play an extremely important role in the me- reduced complex combines with molecular oxygen to form an tabolism of drugs and xenobiotics—compounds that are oxygenated intermediate. One atom of the molecular oxygen foreign to the body, some of which are toxic. Most drugs and xenobiotics are introduced into the body with food. The kidneys ultimately dispose of these substances, but for effective elimination, the drug or its metabolites must be made hydrophilic (polar, water-soluble). This is because re- absorption of a substance by the renal tubules is dependent on its hydrophobicity. The more hydrophobic (nonpolar, lipid-soluble) a substance is, the more likely it will be reab- sorbed. Many drugs and metabolites are hydrophobic, and the liver converts them into hydrophilic compounds. The Liver Converts Hydrophobic Drugs and Xenobiotics to Hydrophilic Compounds Two reactions (phase I and II), catalyzed by different en- zyme systems, are involved in the conversion of xenobi- otics and drugs into hydrophilic compounds. In phase I re- actions, the parent compound is biotransformed into more polar compounds by the introduction of one or more polar groups. The common polar groups are hydroxyl (OH) and carboxyl (COOH). Most phase I reactions involve oxida- tion of the parent compound. The enzymes involved are mostly located in the smooth ER; some are located in the cytoplasm. For example, alcohol dehydrogenase is located Phase I reactions in the metabolism of in the cytoplasm of hepatocytes and catalyzes the rapid FIGURE 28.2 drugs.
CHAPTER 28 The Physiology of the Liver 517 then combines with two H and two electrons to form water. volatile fatty acids), whereas cellulose is not well digested The other oxygen atom remains bound to the cytochrome by the bacteria. Only a small amount of long-chain fatty 3 P450 -drug complex and is transferred from the cy- acids, bound to albumin, is transported by the portal blood; tochrome P450 3 to the drug molecule. The drug product the most is transported in intestinal lymph as triglyceride- with an oxygen atom incorporated is released from the com- rich lipoproteins (chylomicrons). plex. The cytochrome P450 3 released can then be recycled for the oxidation of other drug molecules. In phase II reactions, the phase I reaction products un- The Liver Is Important in dergo conjugation with several compounds to render them Carbohydrate Metabolism more hydrophilic. Glucuronic acid is the substance most The liver is extremely important in maintaining an ade- commonly used for conjugation, and the enzymes involved quate supply of nutrients for cell metabolism and regulating are the glucuronyltransferases. Other molecules used in blood glucose concentration (Fig. 28.3). After the ingestion conjugation are glycine, taurine, and sulfates. of a meal, the blood glucose increases to a concentration of 120 to 150 mg/dL, usually in 1 to 2 hours. Glucose is taken up by hepatocytes by a facilitated carrier-mediated process Aging, Nutrition, and Genetics and is converted to glucose 6-phosphate and then UDP- Influence Drug Metabolism glucose. UDP-glucose can be used for glycogen synthesis, The enzyme systems in phase I and II reactions are age-de- or glycogenesis. It is generally believed that blood glucose pendent. These systems are poorly developed in is the major precursor of glycogen. However, recent evi- human newborns because their ability to metabolize dence seems to indicate that the lactate in blood (from the any given drug is lower than that of adults. Older adults also peripheral metabolism of glucose) is also a major precursor have a lower capacity than young adults to metabolize drugs. of glycogen. Amino acids (e.g., alanine) can supply pyru- Nutritional factors can also affect the enzymes involved vate to synthesize glycogen. in phase I and II reactions. Insufficient protein in the diet to Glycogen is the main carbohydrate store in the liver, and sustain normal growth results in the production of fewer of may amount to as much as 7 to 10% of the weight of a nor- the enzymes involved in drug metabolism. mal, healthy liver. The glycogen molecule resembles a tree It is well known that drug-metabolizing enzymes can be with many branches (see Fig. 27.19). Glucose units are linked induced by certain factors, such as polycyclic aromatic hy- via -1,4- (to form a straight chain) or -1,6 (to form a drocarbons. Persons who smoke inhale polycyclic aromatic branched chain) glycosidic bonds. The advantage of such a hydrocarbons, increasing the metabolism of certain drugs, configuration is that the glycogen chain can be broken down such as caffeine. at multiple sites, making the release of glucose much more ef- The role of genetics in the regulation of drug metabo- ficient than would be the case with a straight-chain polymer. lism by the liver is less well understood. Briefly, drug me- During fasting, glycogen is broken down by glyco- tabolism by the liver can be controlled by a single gene or genolysis. The enzyme glycogen phosphorylase catalyzes several genes (polygenic control). Careful study of the me- the cleavage of glycogen into glucose 1-phosphate. Glyco- tabolism of a certain drug by the population can provide gen phosphorylase acts only on the -1,4-glycosidic bond, important clues as to whether its metabolism is under sin- gle gene or polygenic control. Genetic variability com- bined with the induction or inhibition of P450 enzymes by other drugs or compounds can have a profound effect on what is a safe and effective dose of a medicine. Blood Glucose (present in high concentration after ENERGY METABOLISM IN THE LIVER Facilitated transport a meal) The liver is pivotal in regulating the metabolism of carbo- hydrates, lipids, and proteins. It also helps to maintain a UDP-glucose constant blood glucose concentration by converting other substances, such as amino acids, into glucose. Glucose 1-phosphate Glycogen Glucose 6-phosphate Glucose The Intestine Supplies Nutrients to the Liver The most of water-soluble nutrients and water-soluble vita- Pyruvate Glucose mins and minerals absorbed from the small intestine are (to be used transported via the portal blood to the liver. The nutrients Liver peripherally) transported in portal blood include amino acids, monosac- Lactate charides, and fatty acids (predominantly short- and medium-chain forms). Short-chain fatty acids are largely Amino acids derived from the fermentation of dietary fibers by bacteria (e.g., alanine) in the colon. Some dietary fibers, such as pectin, are almost The regulation of carbohydrate metabolism completely digested to form short-chain fatty acids (or FIGURE 28.3 in the liver.
518 PART VII GASTROINTESTINAL PHYSIOLOGY and the enzyme -1,6-glucosidase is used to break the - acids, and lactate. The process is energy-dependent, and 1,6-glycosidic bonds. the starting substrate is pyruvate. The energy required Glucose 1-phosphate is converted to glucose 6-phos- seems to be derived predominantly from the -oxidation of phate by the enzyme phosphoglucomutase. The enzyme fatty acids. Pyruvate can be derived from lactate and the glucose-6-phosphatase, which is present in the liver but metabolism of glucogenic amino acids—those that can not in muscle or brain, converts glucose 6-phosphate to contribute to the formation of glucose. The two major or- glucose. This last reaction enables the liver to release glu- gans involved in the production of glucose from noncarbo- cose into the circulation. Glucose 6-phosphate is an impor- hydrate sources are the liver and the kidneys. However, be- tant intermediate in carbohydrate metabolism because it cause of its size, the liver plays a far more important role can be channeled either to provide blood glucose or for than the kidney in the production of sugar from noncarbo- glycogen formation. hydrate sources. Both glycogenolysis and glycogenesis are hormonally Gluconeogenesis is important in maintaining blood glu- regulated. The pancreas secretes insulin into the portal cose concentrations especially during fasting. The red blood. Therefore, the liver is the first organ to respond to blood cells and renal medulla are totally dependent on changes in plasma insulin levels, to which it is extremely blood glucose for energy, and glucose is the preferred sub- sensitive. For instance, a doubling of portal insulin concen- strate for the brain. Most amino acids can contribute to the tration completely shuts down hepatic glucose production. carbon atoms of the glucose molecule, and alanine from About half the insulin in portal blood is removed in its first muscle is the most important. The rate-limiting factor in pass through the liver. Insulin tends to lower blood glucose gluconeogenesis is not the liver enzymes but the availabil- by stimulating glycogenesis and suppressing glycogenoly- ity of substrates. Gluconeogenesis is stimulated by epi- sis and gluconeogenesis. Glucagon, in contrast, stimulates nephrine and glucagon but greatly suppressed by insulin. glycogenolysis and gluconeogenesis, raising blood sugar Thus, in type 1 diabetics, gluconeogenesis is greatly stimu- levels. Epinephrine stimulates glycogenolysis. lated, contributing to the hyperglycemia observed in these The liver regulates the blood glucose concentrations patients (see Chapter 35). within a narrow limit, 70 to 100 mg/dL. Although one might expect patients with liver disease to have difficulty regulating blood glucose, this is usually not the case be- The Liver Plays an Important Role cause of the relatively large reserve of hepatic function. in the Metabolism of Lipids However, those with chronic liver disease occasionally The liver plays a pivotal role in lipid metabolism (Fig. 28.4). have reduced glycogen synthesis and reduced gluconeoge- It takes up free fatty acids and lipoproteins (complexes of nesis. Some patients with advanced liver disease develop lipid and protein) from the plasma. Lipid is circulated in the portal hypertension, which induces the formation of por- plasma as lipoproteins because lipid and water are not mis- tosystemic shunting, resulting in elevated arterial blood levels of insulin and glucagon. The Metabolism of Monosaccharides. Monosaccharides are first phosphorylated by a reaction catalyzed by the en- zyme hexokinase. In the liver (but not in the muscle), there is a specific enzyme (glucokinase) for the phosphorylation of glucose to form glucose 6-phosphate. Depending on the energy requirement, the glucose 6-phosphate is channeled to glycogen synthesis or used for energy production by the - glycolytic pathway. Fructose is taken up by the liver and phosphorylated by fructokinase to form fructose 1-phosphate. This molecule is either isomerized to form glucose 6-phosphate or metabo- lized by the glycolytic pathway. Fructose 1-phosphate is used by the glycolytic pathway more efficiently than glu- cose 6-phosphate. Galactose is an important sugar used not only to provide energy but also in the biosynthesis of glycoproteins and glycolipids. When galactose is taken up by the liver, it is phosphorylated to form galactose 1-phosphate, which then reacts with uridine diphosphate-glucose, or UDP-glucose, to form UDP-galactose and glucose 1-phosphate. The UDP-galactose can be used for glycoprotein and glycolipid biosynthesis or converted to UDP-glucose, which can then be recycled. FIGURE 28.4 The regulation of lipid metabolism in the liver. LDL, low-density lipoprotein; VLDL, Gluconeogenesis. Gluconeogenesis is the production of very low density lipoprotein; TG, triglycerides; TCA, tricar- glucose from noncarbohydrate sources such as fat, amino boxylic acid.
CHAPTER 28 The Physiology of the Liver 519 cible; the lipid droplets coalesce in an aqueous medium. lipase to yield fatty acids, which can be metabolized to The protein and phospholipid on the surface of the provide energy. The human liver normally has a consider- lipoprotein particles stabilize the hydrophobic triglyceride able capacity to produce VLDLs, but in acute or chronic center of the particle. liver disorders, this ability is significantly compromised. During fasting, fatty acids are mobilized from adipose Liver VLDLs are associated with an important class of tissue and are taken up by the liver. They are used by the proteins, the apo B proteins. The two forms of circulating hepatocytes to provide energy via -oxidation, for the gen- apo B are B 48 and B 100 . The human liver makes only apo eration of ketone bodies, and to synthesize the triglyceride B 100 , which has a molecular weight of about 500,000. Apo necessary for VLDL formation. After feeding, chylomi- B 100 is important for the hepatic secretion of VLDL. In crons from the small intestine are metabolized peripherally, abetalipoproteinemia, apo B synthesis and, therefore, the and the chylomicron remnants formed are rapidly taken up secretion of VLDLs is blocked. Large lipid droplets can be by the liver. The fatty acids derived from the triglycerides seen in the cytoplasm of the hepatocytes of abetalipopro- of the chylomicron remnants are used for the formation teinemic patients. VLDLs or for energy production via -oxidation. Although considerable amounts of circulating plasma LDLs and HDLs are produced in the plasma, the liver also Fatty Acid Oxidation and Synthesis. Fatty acids derived produces a small amount of these two cholesterol-rich from the plasma can be metabolized in the mitochondria of lipoproteins. LDLs are denser than VLDLs, and HDLs are hepatocytes by -oxidation to provide energy. Fatty acids denser than LDLs. The function of LDLs is to transport are broken down to form acetyl-CoA, which can be used in cholesterol ester from the liver to the other organs. HDLs the tricarboxylic acid cycle for ATP production, in the syn- are believed to remove cholesterol from the peripheral tis- thesis of fatty acids, and in the formation of ketone bodies. sue and transport it to the liver. Because fatty acids are synthesized from acetyl-CoA, any The formation and secretion of lipoproteins by the liver substances that contribute to acetyl-CoA, such as carbohy- is regulated by precursors and hormones, such as estrogen drate and protein sources, enhance fatty acid synthesis. and thyroid hormone. For instance, during fasting, the fatty The liver is one of the main organs involved in fatty acid acids in VLDLs are derived mainly from fatty acids mobi- synthesis. Palmitic acid is synthesized in the hepatocellular lized from adipose tissue. In contrast, during fat feeding, cytosol; the other fatty acids synthesized in the body are fatty acids in VLDLs produced by the liver are largely de- derived by shortening, elongating, or desaturating the rived from chylomicrons. palmitic acid molecule. As noted earlier, the fatty acids taken up by the liver can be used for -oxidation and ketone body formation. The rel- Lipoprotein Synthesis. One of the major functions of the ative amounts of fatty acid channeled for these various pur- liver in lipid metabolism is lipoprotein synthesis. The four poses are largely dependent on the individual’s nutritional major classes of circulating plasma lipoproteins are chy- and hormonal status. More fatty acid is channeled to keto- lomicrons, very low density lipoproteins (VLDLs), low- genesis or -oxidation when the supply of carbohydrate is density lipoproteins (LDLs), and high-density lipoproteins short (during fasting) or under conditions of high circulating (HDLs) (Table 28.1). These lipoproteins, which differ in glucagon or low circulating insulin (diabetes mellitus). In chemical composition, are usually isolated from plasma ac- contrast, more of the fatty acid is used for synthesis of cording to their flotation properties. triglyceride for lipoprotein export when the supply of carbo- Chylomicrons are the lightest of the four lipoprotein hydrate is abundant (during feeding) or under conditions of classes, with a density of less than 0.95 g/mL. They are made low circulating glucagon or high circulating insulin. only by the small intestine and are produced in large quanti- ties during fat ingestion. Their major function is to transport Lipoprotein Catabolism. The importance of the liver in the large amount of absorbed fat to the bloodstream. lipoprotein metabolism is exemplified by familial hyperc- Very low density lipoproteins (VLDLs) are denser and holesterolemia, a disorder in which the liver fails to pro- smaller than chylomicrons. The liver synthesizes about 10 duce the LDL receptor. When LDL binds its receptor, it is times more circulating VLDLs than the small intestine. internalized and catabolized in the hepatocyte. Conse- Like chylomicrons, VLDLs are triglyceride-rich and carry quently, the LDL receptor is crucial for the removal of LDL most of the triglyceride from the liver to the other organs. from the plasma. Individuals suffering from familial hyper- The triglyceride of VLDLs is broken down by lipoprotein cholesterolemia usually have very high plasma LDLs, TABLE 28.1 Characteristics of Human Plasma Lipoproteins Lipoprotein Source Density (g/mL) Size (nm) Protein Lipid Chylomicron Intestine 0.95 80–500 1% 99% VLDL Intestine and liver 0.95–1.006 30–80 7–10% 90–93% LDL Chylomicron and VLDL 1.019–1.063 18–28 20–22% 78–80% HDL Chylomicron and VLDL 1.063–1.21 5–14 35–60% 40–65% VLDL, very low density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
520 PART VII GASTROINTESTINAL PHYSIOLOGY which predisposes them to early coronary heart disease. The Liver Produces Most of the Often the only effective treatment is a liver transplant. Circulating Plasma Proteins The liver also plays an important role in the uptake of chylomicrons after their metabolism. After the chylomi- The liver synthesizes many of the circulating plasma pro- crons produced by the small intestine enter the circulation, teins, albumin being the most important (Fig. 28.5). It syn- lipoprotein lipase on the endothelial cells of blood vessels thesizes about 3 g of albumin a day. Albumin plays an im- acts on them to liberate fatty acids and glycerol from the portant role in preserving plasma volume and tissue fluid triglycerides. As metabolism progresses, the chylomicrons balance by maintaining the colloid osmotic pressure of shrink, resulting in the detachment of free cholesterol, plasma. This important function of plasma proteins is illus- phospholipid, and proteins, and the formation of HDL. trated by the fact that both liver disease and long-term star- Chylomicrons are converted to chylomicron remnants dur- vation result in generalized edema and ascites. Plasma albu- ing metabolism, and chylomicron remnants are rapidly min plays a pivotal role in the transport of many substances taken up by the liver via chylomicron remnant receptors. in blood, such as free fatty acids and certain drugs, includ- ing penicillin and salicylate. The Production of Ketone Bodies. Most organs, except the The other major plasma proteins synthesized by the liver, can use ketone bodies as fuel. For example, during pro- liver are components of the complement system, compo- longed fasting, the brain shifts to use ketone bodies for en- nents of the blood clotting cascade (fibrinogen and pro- ergy, although glucose is the preferred fuel for the brain. The thrombin), and proteins involved in iron transport (trans- two ketone bodies are acetoacetate and -hydroxybutyrate. ferrin, haptoglobin, and hemopexin) (see Chapter 11). Their formation by the liver is normal and physiologically im- portant. For instance, during fasting a rapid depletion of the glycogen stores in the liver occurs resulting in a shortage of The Liver Produces Urea substrates (e.g., oxaloacetate) for the citric acid cycle. There Ammonia, derived from protein and nucleic acid catabo- is also a rapid mobilization of fatty acids from adipose tissues lism, plays a pivotal role in nitrogen metabolism and is to the liver. Under these circumstances, the acetyl-CoA needed in the biosynthesis of nonessential amino acids and formed from -oxidation is channeled to ketone bodies. nucleic acids. Ammonia metabolism is a major function of The liver is efficient in producing ketone bodies. In hu- the liver. The liver has an ammonia level 10 times higher mans, it can produce half of its equivalent weight of ketone than the plasma ammonia level. High circulating ammonia bodies per day. However, it lacks the ability to metabolize levels are highly neurotoxic, and a deficiency in hepatic the ketone bodies formed because it lacks the necessary en- function can lead to several distinct neurological disorders, zyme ketoacid-CoA transferase. including coma in severe cases. The level of ketone bodies circulating in the blood is The liver synthesizes most of the urea in the body. The usually low, but during prolonged starvation and in dia- enzymes involved in the urea cycle are regulated by protein betes mellitus it is highly elevated, a condition known as intake. In humans, starvation stimulates these enzymes. ketosis. In patients with diabetes, large amounts of -hy- droxybutyric acid can make the blood pH acidic, a state called ketoacidosis. Cholesterol Metabolism. The liver plays an important role in cholesterol homeostasis. Liver cholesterol is derived from both de novo synthesis and the lipoproteins taken up by the liver. Hepatic cholesterol can be used in the formation of bile acids, biliary cholesterol secretion, the synthesis of VLDLs, and the synthesis of liver membranes. Because the absorption of biliary cholesterol and bile acids by the GI tract is incom- plete, this method of eliminating cholesterol from the body is essential and efficient. However, patients with high plasma cholesterol levels might be given additional drugs, such as statins, to lower their plasma cholesterol levels. Statins act by inhibiting enzymes that play an essential role in cholesterol synthesis. VLDLs secreted by the liver provide cholesterol to organs that need it for the synthesis of steroid hormones (e.g., the adrenal glands, ovaries, and testes). PROTEIN AND AMINO ACID METABOLISM IN THE LIVER The liver is one of the major organs involved in synthesiz- ing nonessential amino acids from the essential amino acids. The body can synthesize all but nine of the amino The regulation of protein and amino acid FIGURE 28.5 acids necessary for protein synthesis. metabolism in the liver.
CHAPTER 28 The Physiology of the Liver 521 The Liver Plays an Important Role in the Synthesis and Interconversion of Amino Acids Retinyl Amino acid ester The essential amino acids (see Table 27.7) must be sup- plied in the diet. The liver can form nonessential amino acids from the essential amino acids. For instance, tyrosine Rough ER can be synthesized from phenylalanine and cysteine can be Retinol synthesized from methionine. Glutamic acid and glutamine play an important role in Retinol- the biosynthesis of certain amino acids in the liver. Glu- Hydrolysis binding protein tamic acid is derived from the amination of -ketoglutarate Retinyl (RBP) by ammonia. This reaction is important because ammonia ester is used directly in the formation of the -amino group and constitutes a mechanism for shunting nitrogen from waste- ful urea-forming products. Glutamic acid can be used in the amination of other -keto acids to form the corresponding Retinol/RBP amino acids. It can also be converted to glutamine by cou- complex pling with ammonia, a reaction catalyzed by glutamine Chylomicron remnant containing retinyl ester synthetase. After urea, glutamine is the second most im- Chylo- portant metabolite of ammonia in the liver. It plays an im- micron Lipoprotein lipase portant role in the storage and transport of ammonia in the blood. Through the action of various transaminases, gluta- The metabolism of vitamin A (retinol) by mine can be used to aminate various keto acids to their cor- FIGURE 28.6 the hepatocyte. responding amino acids. It also acts as an important oxida- tive substrate, and in the small intestine it is the primary substrate for providing energy. A store (Fig. 28.6). Retinol (an alcohol) is transported in chylomicrons mainly as an ester of long-chain fatty acids (see Chapter 27). When chylomicrons enter the circula- THE LIVER AS A STORAGE ORGAN tion, the triglyceride is rapidly acted on by lipoprotein li- pase; the triglyceride content of the particles is signifi- Another important role of the liver is the storage and me- tabolism of fat-soluble vitamins and iron. Some water-solu- cantly reduced, while the retinyl ester content remains ble vitamins, particularly vitamin B 12 , are also stored in the unchanged. Receptors in the liver mediate the rapid uptake liver. These stored vitamins are released into the circulation of chylomicron remnants, which are degraded, and the when a need for them arises. retinyl ester is stored. When the vitamin A level in blood falls, the liver mobi- lizes the vitamin A store by hydrolyzing the retinyl ester The Liver Has a Central Role in (see Fig. 28.6). The retinol formed is bound with retinol- Regulating Coagulation binding protein (RBP), which is synthesized by the liver before it is secreted into the blood. The amount of RBP se- Liver cells are important both in the production and the creted into the blood is dependent on vitamin A status. Vi- clearance of coagulation proteins. Most of the known clot- tamin A deficiency significantly inhibits the release of RBP, ting factors and inhibitors are secreted by hepatocytes, whereas vitamin A loading stimulates its release. some of them exclusively. In addition, several coagulation Hypervitaminosis A develops when massive quantities and anticoagulation proteins require a vitamin K–depend- of vitamin A are consumed. Since liver is the storage organ ent modification following synthesis, specifically factors II, for vitamin A, hepatotoxicity is often associated with hy- VII, IX, and X and proteins C and S, to make them effective. pervitaminosis A. The continued ingestion of excessive The monocyte-macrophage system of the liver, pre- amounts of vitamin A eventually leads to portal hyperten- dominantly Kupffer cells, is an important system for clear- sion and cirrhosis. ing clotting factors and factor-inhibitor complexes. Distur- Vitamin D is thought to be stored mainly in skeletal bances in liver perfusion and function result in the muscle and adipose tissue. However, the liver is responsible ineffective clearance of activated coagulation proteins, so for the initial activation of vitamin D by converting vitamin patients with advanced liver failure may be predisposed to D 3 to 25-hydroxy vitamin D 3 , and it synthesizes vitamin D- developing disseminated intravascular coagulation. binding protein. Vitamin K is a fat-soluble vitamin important in the he- patic synthesis of prothrombin. Prothrombin is synthesized Fat-Soluble Vitamins Are Stored in the Liver as a precursor that is converted to the mature prothrombin, Vitamin A comprises a family of compounds related to a reaction that requires the presence of vitamin K retinol. Vitamin A is important in vision, growth, the main- (Fig. 28.7). Vitamin K deficiency, therefore, leads to im- tenance of epithelia, and reproduction. The liver plays a paired blood clotting. pivotal role in the uptake, storage, and maintenance of cir- The largest vitamin K store is in skeletal muscle, but the culating plasma vitamin A levels by mobilizing its vitamin physiological significance of this and other body stores is
522 PART VII GASTROINTESTINAL PHYSIOLOGY Amino acid Precursor of prothrombin CO 2 Vitamin K Rough ER Prothrombin Prothrombin The formation and secretion of prothrom- FIGURE 28.7 The possible pathways following phagocy- bin by the hepatocyte. FIGURE 28.8 tosis of damaged red blood cells by Kupf- fer cells. (Modified from Young SP, Aisen P. The liver and iron. In: Arias I, Jakoby WB, Popper H, et al., eds. The Liver: Biology and Pathobiology. New York: Raven, 1988.) unknown. The dietary vitamin K requirement is extremely small and is adequately supplied by the average North American diet. Bacteria in the GI tract also provide vitamin K. This appears to be an important source of vitamin K be- genase releases iron from the heme, which then enters the cause prolonged administration of wide-spectrum antibi- free iron pool and is stored as ferritin or released into the otics sometimes results in hypoprothrombinemia. Because bloodstream (bound to apotransferrin). Some of the ferritin vitamin K absorption is dependent on normal fat absorp- iron may be converted to hemosiderin granules. It is un- tion, any prolonged malabsorption of lipid can result in its clear whether the iron from the hemosiderin granules is ex- deficiency. The vitamin K store in the liver is relatively lim- changeable with the free iron pool. ited, and therefore, hypoprothrombinemia can develop It was long believed that Kupffer cells were the only within a few weeks. Vitamin K deficiency is not uncommon cells involved in iron storage, but recent studies suggest in the Western world. Parenteral administration of vitamin that hepatocytes are the major sites of long-term iron stor- K usually provides a cure. age. Transferrin binds to receptors on the surface of hepa- tocytes, and the entire transferrin-receptor complex is in- ternalized and processed (Fig. 28.9). The apotransferrin The Liver Is Important in the Storage (not containing iron) is recycled back to the plasma, and and Homeostasis of Iron the released iron enters a labile iron pool. The iron from transferrin is probably the major source of iron for the he- The liver is the major site for the synthesis of several pro- patocytes, but they also derive iron from haptoglobin-he- teins involved in iron transport and metabolism. The pro- moglobin and hemopexin-heme complexes. When hemo- tein transferrin plays a critical role in the transport and globin is released inside the hepatocytes, it is degraded in homeostasis of iron in the blood. The circulating plasma the secondary lysosomes, and heme is released. Heme is transferrin level is inversely proportional to the iron load of processed in the smooth ER and free iron released enters the body—the higher the concentration of ferritin in the the labile iron pool. A significant portion of the free iron in hepatocyte, the lower the rate of transferrin synthesis. Dur- the cytosol probably combines rapidly with apoferritin to ing iron deficiency, liver synthesis of transferrin is signifi- form ferritin. Like Kupffer cells, hepatocytes may transfer cantly stimulated, enhancing the intestinal absorption of some of the iron in ferritin to hemosiderin. iron. Haptoglobin, a large glycoprotein with a molecular Iron is absolutely essential for survival, but iron overload weight of 100,000, binds free hemoglobin in the blood. The can be extremely toxic, especially to the liver where it can hemoglobin-haptoglobin complex is rapidly removed by cause hemochromatosis, a condition characterized by ex- the liver, conserving iron in the body. Hemopexin is an- cessive amounts of hemosiderin in the hepatocytes. The other protein synthesized by the liver that is involved in the hepatocytes in patients with hemochromatosis are defec- transport of free heme in the blood. It forms a complex with tive and fail to perform many normal functions. free heme, and the complex is removed rapidly by the liver. The spleen is the organ that removes red blood cells that are slightly altered. Kupffer cells of the liver also have the ENDOCRINE FUNCTIONS OF THE LIVER capacity to remove damaged red blood cells, especially those that are moderately damaged (Fig. 28.8). The red The liver is important in regulating the endocrine functions of cells taken up by Kupffer cells are rapidly digested by sec- hormones. It can amplify the action of some hormones. It is ondary lysosomes to release heme. Microsomal heme oxy- also the major organ for the removal of peptide hormones.
CHAPTER 28 The Physiology of the Liver 523 The Liver Can Modify or Amplify Hormone Action As discussed before, the liver converts vitamin D 3 to 25-hy- droxy vitamin D 3 , an essential step before conversion to the active hormone 1,25-hydroxy vitamin D 3 in the kidneys. The liver is also a major site of conversion of the thyroid hormone thyroxine (T 4 ) to the biologically more potent hormone triiodothyronine (T 3 ). The regulation of the he- patic T 4 to T 3 conversion occurs at both the uptake step and the conversion step. Due to the liver’s relatively large reserve in converting T 4 to T 3 , hypothyroidism is uncom- mon in patients with liver disease. In advanced chronic liver disease, however, signs of hypothyroidism may be evident. The liver modifies the function of growth hormone (GH) secreted by the pituitary gland. Some growth hor- mone actions are mediated by insulin-like growth factors made by the liver (see Chapter 32). The Liver Removes Circulating Hormones The liver helps to remove and degrade many circulating hormones. Insulin is degraded in many organs, but the liver and kidneys are by far most important. The presence of in- sulin receptors on the surface of hepatocytes suggests that the binding of insulin to these receptors results in degrada- tion of some insulin molecules. There is also degradation of insulin by proteases of hepatocytes that do not involve the insulin receptor. The possible pathways followed by iron in Glucagon and growth hormone are degraded mainly by FIGURE 28.9 the hepatocyte. (Modified from Young SP, the liver and the kidneys. The liver may also degrade vari- Aisen P. The liver and iron. In: Arias I, Jakoby WB, Popper H, et al., ous GI hormones (e.g., gastrin), but the kidneys and other eds. The Liver: Biology and Pathobiology. New York: Raven, 1988.) organs probably contribute more significantly to inactivat- ing these hormones. REVIEW QUESTIONS DIRECTIONS: Each of the numbered 3. Both the liver and muscle contain liver secretes only items or incomplete statements in this glycogen, yet, unlike liver, muscle is (A) Chylomicrons section is followed by answers or by not capable of contributing glucose to (B) VLDLs completions of statements. Select the the circulation because muscle (C) LDLs ONE lettered answer or completion that is (A) Does not have the enzyme (D) HDLs BEST in each case. glucose-6-phosphatase (E) Chylomicron remnants (B) Glycolytic activity consumes all of 6. Because free ammonia in the blood is 1. The first step in alcohol metabolism by the glucose it generates toxic to the body, it is transported in the liver is the formation of (C) Does not have the enzyme which of the following non-toxic acetaldehyde from alcohol, a chemical glucose-1-phosphatase forms? reaction catalyzed by (D) Does not have the enzyme (A) Histidine and urea (A) Cytochrome P450 glycogen phosphorylase (B) Phenylalanine and methionine (B) NADPH-cytochrome P450 (E) Is not as capable of (C) Glutamine and urea reductase gluconeogenesis as is the liver (D) Lysine and glutamine (C) Alcohol oxygenase 4. The hepatocyte is compartmentalized (E) Methionine and urea (D) Alcohol dehydrogenase to carry out specific functions. In 7. In patients with a portacaval shunt (E) Glycogen phosphorylase which subcellular compartment does (connection between the portal vein 2. The arterial blood glucose fatty acid synthesis occur? and vena cava), the circulating concentration in normal humans after a (A) Cytoplasm glucagon level is extremely high meal is in the range of (B) Mitochondria because the (A) 30 to 50 mg/dL (C) Nucleus (A) Pancreas produces more glucagon (B) 50 to 70 mg/dL (D) Endosomes in these patients (C) 120 to 150 mg/dL (E) Golgi apparatus (B) Kidney is less efficient in removing (D) 220 to 250 mg/dL 5. The small intestine secretes various the circulating glucagon in these (E) 300 to 350 mg/dL triglyceride-rich lipoproteins, but the patients (continued)
524 PART VII GASTROINTESTINAL PHYSIOLOGY (C) Liver normally is the major site for (B) Conjugation of drugs with glycine (B) HDL receptors and then the removal of glucagon or taurine internalizing them (D) Small intestine produces more (C) Introduction of one or more polar (C) The albumin present on LDLs and glucagon in these patients groups to the drug molecule then internalizing them (E) Blood flow to the small intestine is (D) Introduction of one or more (D) The transferrin present on LDL compromised hydrophobic groups to the drug and then internalizing them 8. Which protein is made by the liver and molecule (E) The ceruloplasmin on LDLs and carries iron in the blood? (E) Conjugation of drugs with sulfate then internalizing them (A) Hemosiderin 11.The level of circulating 1,25- (B) Haptoglobin dihydroxycholecalciferol is SUGGESTED READING (C) Transferrin significantly reduced in patients with Arias IM. The Liver: Biology and Pathobi- (D) Ceruloplasmin chronic liver disease because ology. 3rd Ed. New York: Lippincott- (E) Lactoferrin (A) The liver can no longer efficiently Raven, 1994. 9. The level of drug metabolizing convert 25-hydroxycholecalciferol to Black ER. Diagnostic strategies and test al- enzymes in the liver determines how 1,25-dihydroxycholecalciferol gorithms in liver disease. Clin Chem fast a drug is removed from the (B) The liver can no longer efficiently 1997;43:1555–1560. circulation. Therefore, it would be convert vitamin D to cholecalciferol Chang EB, Sitrin MD, Black DD. Gas- expected to find drug metabolizing (C) The liver can no longer efficiently trointestinal, Hepatobiliary, and Nutri- enzymes convert vitamin D to 25- tional Physiology. Philadelphia: Lip- (A) Higher in smokers than in hydroxycholecalciferol pincott-Raven, 1996. nonsmokers (D) The liver can no longer efficiently Liska DJ. The detoxification enzyme sys- (B) Similar in smokers and nonsmokers convert cholecalciferol to 1,25- tems. Altern Med Rev 1998;3:187–198. (C) Lower in smokers than in dihydroxycholecalciferol MacMathuna PM. Mechanisms and conse- nonsmokers (E) The intestine has impaired quences of portal hypertension. Drugs (D) Stimulated by malnutrition absorption of 1,25- 1992;44(Suppl 2):1–13, 70–72. (E) Higher in newborns than in adults hydroxycholecalciferol Oka K, Davis AR, Chan L. Recent ad- 10.Phase I reactions of drug metabolism 12.The liver removes LDLs in the blood vances in liver-directed gene therapy: refer to the by the LDLs binding to Implications for the treatment of dys- (A) Conjugation of drugs with (A) LDL receptors and then lipidemia. Curr Opin Lipidol glucuronic acid internalizing them 2000;11:179–186. CASE STUDIES FOR PART VII • • • CASE STUDY FOR CHAPTER 26 macological approaches include calcium channel blockers (e.g., nifedipine) to relax the smooth muscle of the sphinc- Dysphagia ter, and local endoscopic injection of botulinum toxin, an in- A 51-year-old woman is evaluated for difficulty in swal- hibitor of ACh release from nerve terminals. lowing solid foods. She experiences chest pain while at- Reference tempting to eat and often regurgitates swallowed food. Richter JE. Motility disorders of the esophagus. In: Yamada T, Fluoroscopic examination of a barium swallow reveals a Alpers DH, Owyang C, Powell DW, Silverstein FE, eds. Text- dilated lower esophagus with considerable residual bar- book of Gastroenterology. 2nd Ed. Philadelphia: Lippincott, ium remaining after the swallow. A manometric motility 1995;1174–1213. study of esophageal motility following a swallow reveals an absence of primary peristalsis in the distal third, with- CASE STUDY FOR CHAPTER 27 out relaxation of contractile tone in the lower esophageal sphincter. Lactose Intolerance Questions A 9-year-old Chinese American boy regularly complains 1. What is the explanation for the woman’s dysphagia? of abdominal cramps, abdominal distension, and diar- 2. What is the most likely explanation for the failure of the rhea after drinking milk. A gastroenterologist adminis- lower esophageal sphincter relaxation during the swallow? ters 50 g of lactose by mouth to the child and measures 3. What are the possible treatments for the woman’s condi- an increase in the boy’s expired hydrogen gas. tion? Questions Answers to Case Study Questions for Chapter 26 1. How is lactose digested and absorbed in the small intes- 1. The best explanation for the patient’s dysphagia is failure of tine? the lower esophageal sphincter to relax (achalasia). 2. Explain the symptoms that accompany lactose intolerance. 2. Loss of the ENS in the region of the lower esophageal 3. Why was the lactose breath test done? sphincter and gastric cardia is the histoanatomic hallmark of 4. How common is lactose intolerance? lower esophageal sphincter achalasia. Failure of the sphinc- 5. What can be done about lactose intolerance? ter to relax reflects the loss of inhibitory motor innervation Answers to Case Study Questions for Chapter 27 of the sphincteric muscle. 1. Lactose is hydrolyzed by a brush border enzyme called lac- 3. There are several possible treatments. The time-tested treat- tase to glucose and galactose. The monosaccharides are ment is pneumatic dilation of the lower esophageal sphinc- then absorbed by sodium-dependent secondary active ter, by placing a balloon in the lumen of the sphincter. Phar- transport.
CHAPTER 28 The Physiology of the Liver 525 2. If the lactase enzyme is deficient, lactose will not be broken crease renal excretion of sodium and water) and inter- down and will remain in the intestinal lumen. The osmotic mittent paracentesis (insertion of a needle into the peri- activity of the lactose draws water into the intestinal lumen toneal space, evacuating fluid, which relieves the ab- and results in a watery diarrhea. In the colon, bacteria me- dominal distension and discomfort). She subsequently tabolize the lactose to lactic acid, carbon dioxide, and hy- undergoes placement of a transjugular intrahepatic por- drogen gas. The extra fluid and gas in the intestine result in tosystemic shunt (TIPS), which serves to lower portal distension and increased motility (cramps). pressure by shunting blood into systemic veins. She is 3. The child might have had an allergy to proteins in milk. The also given warfarin, an anticoagulant. lactose breath test results indicate lactose intolerance. Questions 4. In the most of the world’s population, intestinal lactase ac- 1. What is the probable explanation for her abdominal pain, tivity is high during childhood, but falls after ages 5 to 7 to distension, and weight gain over 6 months? low adult levels. The prevalence of lactose intolerance in 2. What is the rationale for giving an anticoagulant, and how adults is about 100% in Asian Americans, 95% in Native does warfarin work? Americans, 81% in African Americans, 56% in Mexican Americans, and 24% in white Americans. Lactose intoler- Answers to Case Study Questions for Chapter 28 ance is common (about 50 to 70%) in adult Americans of 1. A common explanation for abdominal discomfort, disten- Mediterranean descent, but is low (0 to only a few %) in sion, and weight gain in women is pregnancy. Her age those of northern European ancestry. makes this unlikely but not impossible. Any disorder that re- 5. Avoiding foods that contain lactose (milk, dairy products) is sults in fluid retention may present with these symptoms. recommended for persons who are lactose-intolerant; how- Common causes of marked abdominal fluid retention are ever, calcium and caloric intake should not be compro- nephrotic syndrome (the kidneys fail to adequately remove mised. Milk can be pretreated with an enzyme obtained excess water), congestive heart failure (the heart fails to ad- from bacteria or yeasts that digests lactose, or lactase pills equately pump blood to the kidneys, reducing their ability can be taken with meals. to remove excess water), and liver dysfunction (usually from an excess pressure in the sinusoids resulting in in- creased fluid loss into the abdomen). The general term to CASE STUDY FOR CHAPTER 28 describe excess fluid in the abdominal cavity is ascites. Al- ternatively, symptoms may be due to intraabdominal malig- Budd-Chiari Syndrome nancies, such as malignant ascites or large tumors. In a A 51-year-old woman complained of 4 days of epigastric woman of this age, ovarian cancer would be considered a abdominal pain. She reported having been healthy all likely cause. her life. She admitted to having gained approximately 9 2. The anticoagulant warfarin was given to treat the patient’s kg (20 lb) over the preceding 6 months, which was un- hypercoagulable disorder and to maintain shunt patency. usual. Upon examination by her physician, she is found Clotting factors, mostly produced in the liver, have a series to have a distended abdomen that is tender in the area of glutamic acid residues that must be carboxylated by a vi- between her ribs at the top of her abdomen. tamin K–dependent carboxylase in order for them to bind to An exploratory laparotomy reveals an enlarged liver endothelial cells and activate platelets necessary for clot for- and no other disease. A liver biopsy is taken and report- mation. The reduced form of vitamin K is a necessary cofac- edly shows no significant abnormalities. For unstated tor for the carboxylation. During carboxylation of the clot- reasons, the patient is later taken for a venogram and ting factor, vitamin K becomes an epoxide. Warfarin is was found to have thrombosis of her hepatic veins, thought to disrupt the vitamin K cycle, thereby preventing Budd-Chiari syndrome. She is subsequently referred to a the necessary carboxylation of clotting factors. The liver tertiary hospital. Initially, the patient is treated with di- continues to synthesize these factors, but they lack effect uretic medication (spironolactone and furosemide to in- and therefore clotting is limited.
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