Physiology_Levy

Physiology_Levy. Pancreatic juice also contains two additional enzymes that are important in fat digestion. The first of these is phospholipase A2, which hydrolyzes phospholipids such as those present in cell membranes. Predictably this enzyme would be quite toxic in the absence of dietary substrates, and thus it is secreted as an inactive pro-form that is activated only when it reaches the small intestine. Furthermore, pancreatic juice contains a relatively nonspecific cholesterol esterase that can break down esters of cholesterol, as its name implies, as well as esters of fat-soluble vitamins and even triglycerides. Interestingly this enzyme requires bile acids for activity (contrast with lipase, discussed earlier), and it is related to an enzyme produced in breast milk that plays an important role in lipolysis in neonates.


Physiology_Levy

Physiology_Levy. As lipolysis proceeds, the products are abstracted from the lipid droplet, first into a lamellar (membrane) phase and subsequently into mixed micelles composed of lipolytic products as well as bile acids. The amphipathic (meaning they have both a hydrophobic and hydrophilic face) bile acids serve to shield the hydrophobic regions of lipolytic products from water while presenting their own hydrophilic faces to the aqueous environment (


Physiology_Levy

Physiology_Levy. Fig. 30.15 ). Micelles are truly in solution and thus markedly increase lipid solubility in the intestinal contents. This increases the rate at which molecules such as fatty acids diffuse to the absorptive epithelial surface. Nevertheless, given the very large surface area of the small intestine and the appreciable molecular solubility of the products of triglyceride hydrolysis, micelles are not essential for the absorption of triglyceride. Thus patients who have insufficient output of bile acids (caused, for example, by a gallstone that obstructs bile output) do not normally show fat malabsorption. On the other hand, cholesterol and the fat-soluble vitamins are almost totally insoluble in water and accordingly require micelles to be absorbed even after they have been digested. Thus if luminal bile acid concentrations fall below the critical micellar concentration, patients can become deficient in fat-soluble vitamins.


Physiology_Levy

Physiology_Levy. •Fig. 30.15 Schematicdepictionofbileacids(A)andmixedmicelles(B).Bileacidsinsolutionareamphipathic.Mixedmicellesarecylindricalassemblagesofbileacidswithotherdietarylipids. Uptake of Lipids and Subsequent Handling


Physiology_Levy

Physiology_Levy. The products of fat digestion are believed to be capable of crossing cell membranes readily because of their lipophilicity. However, recent evidence suggests that their uptake may alternatively or additionally be regulated via the activity of specific membrane transporters. A microvillus membrane fatty acid–binding protein (MVM-FABP) provides for the uptake of long-chain fatty acids across the brush border. Likewise, Niemann-Pick C1–like 1 (NPC1L1) has recently been identified as an uptake pathway for cholesterol in enterocytes and may be a therapeutic target in patients who suffer from pathological increases in circulating cholesterol (hypercholesterolemia). However, uptake of cholesterol overall is relatively inefficient because this molecule, along with plant sterols, can also be actively effluxed from enterocytes back into the cytosol by a heterodimeric complex of two ATP-binding cassette (ABC) transporters termed ABC G5 and G8. Finally, the glycerol backbone of triglycerides may


Physiology_Levy

Physiology_Levy. effluxed from enterocytes back into the cytosol by a heterodimeric complex of two ATP-binding cassette (ABC) transporters termed ABC G5 and G8. Finally, the glycerol backbone of triglycerides may be transported into intestinal epithelial cells by a number of different aquaglyceroporins.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Lipids also differ from carbohydrates and proteins in terms of their fate after absorption into the enterocyte. Unlike monosaccharides and amino acids, which leave the enterocyte in molecular form and enter the portal circulation, the products of lipolysis are reesterified in the enterocyte to form triglycerides, phospholipids, and cholesterol esters. These metabolic events take place in the smooth endoplasmic reticulum. Concurrently the enterocyte synthesizes a series of proteins known as apolipoproteins in the rough endoplasmic reticulum. These proteins are then combined with the resynthesized lipids to form a structure known as a chylomicron, which consists of a lipid core (predominantly triglyceride with much less cholesterol, phospholipid, and fat-soluble vitamin esters) coated by the apolipoproteins. The chylomicrons are then exported from the enterocyte by a process of exocytosis. However, on entering the lamina propria, they are too large (≈750–5000 Å in diameter) to permeate


Physiology_Levy

Physiology_Levy. apolipoproteins. The chylomicrons are then exported from the enterocyte by a process of exocytosis. However, on entering the lamina propria, they are too large (≈750–5000 Å in diameter) to permeate through the intercellular spaces of the mucosal capillaries. Instead they are taken up into lymphatics in the lamina propria and therefore bypass the portal circulation and, at least for their first pass, the liver. Eventually, chylomicrons in the lymph enter the bloodstream via the thoracic duct and then serve as the vehicle to transport lipids around the body for use by cells in other organs. The only exception to this chylomicron-mediated transport is for medium-chain fatty acids. These acids are relatively water soluble and can also permeate enterocyte tight junctions appreciably, which means that they bypass the intracellular processing steps described earlier and are not packaged into chylomicrons. They therefore enter the portal circulation and are more readily available to other


Physiology_Levy

Physiology_Levy. means that they bypass the intracellular processing steps described earlier and are not packaged into chylomicrons. They therefore enter the portal circulation and are more readily available to other tissues. A diet rich in medium-chain triglycerides may be of particular benefit in patients with inadequate bile acid pools.


Physiology_Levy

Physiology_Levy. The foregoing description of digestion has stressed that these processes take place in the small intestine in an aqueous •Fig. 30.16 OverallfluidbalanceinthehumanGItract.About1to2Lofwaterisingested,and8LofvarioussecretionsenterstheGItract.Ofthistotal,mostisabsorbedinthesmallintestine.About2Lispassedontothecolon,thevastmajorityofwhichisabsorbedinhealth.(FromVanderAJetal.Human Physiology. 6thed.NewYork:McGraw-Hill;1994.) milieu. The fluidity of intestinal contents, especially in the small intestine, is important in allowing the meal to be propelled along the length of the intestine and to permit digested nutrients to diffuse to their site of absorption. Part of this fluid is derived from oral intake, but in most adults this consists of only about 1 to 2 L/day derived from both food and drink (Fig. 30.16 ). Additional fluid is supplied by the stomach and the small intestine themselves, as well as the organs that drain into the GI tract. In total, these secretions add another 8 L, which


Physiology_Levy

Physiology_Levy. (Fig. 30.16 ). Additional fluid is supplied by the stomach and the small intestine themselves, as well as the organs that drain into the GI tract. In total, these secretions add another 8 L, which means that the intestine is presented with approximately 9 to 10 L of fluid on a daily basis. However, in health only about 2 L of this load is passed to the colon for reabsorption, and eventually only 100 to 200 mL exits in stool. Thus the intestine absorbs water overall. During the postprandial period, such absorption is promoted in the small intestine predominantly via the osmotic effects of nutrient absorption. An osmotic gradient is established across the intestinal epithelium that simultaneously drives movement of water across the tight junctions. The generic mechanism for nutrient-driven Na+ and water absorption in the small intestine is diagrammed in


Physiology_Levy

Physiology_Levy. Fig. 30.17 . Moreover, in the period between meals, when nutrients are absent, fluid absorption can still occur via the coupled uptake of Na+ and Cl− mediated by the cooperative interaction of a Na+/H+ antiporter (NHE-3) and a Cl−/ HCO3 − antiporter (see Fig. 30.17


Physiology_Levy

Physiology_Levy. Even though net water and electrolyte transport in the small intestine is predominantly absorptive, this does not imply that the tissue fails to participate in electrolyte secretion. Secretion is regulated in response to signals derived from the luminal contents and in response to deformation of the mucosa and intestinal distention. Critical secretagogues include acetylcholine, VIP, prostaglandins, and serotonin. Secretion ensures that the intestinal contents are appropriately fluid while digestion and absorption are ongoing and is important to lubricate the passage of food particles along the length of the intestine. For example, some clinical evidence suggests that constipation and intestinal obstruction, the latter observed in cystic fibrosis, can result when secretion is abnormally low. The majority of the intestinal •Fig. 30.17


Physiology_Levy

Physiology_Levy. evidence suggests that constipation and intestinal obstruction, the latter observed in cystic fibrosis, can result when secretion is abnormally low. The majority of the intestinal •Fig. 30.17 MechanismsofNaClabsorptioninthesmallintestine.DRA,downregulatedinadenoma;GLUT2,glucosetransporter2;KCC1,potassium/chloridecotransporter1;NHE-3,sodium/hydrogenexchanger3;PAT1,putativeaniontransporter1;SGLT1,sodium/glucosetransporter1.SGLT1H˜2K˜KCC1NHE 3DRA?PAT1?ATPHCO3°GLUT2Glucose secretory flow of fluid into the lumen is driven by active secretion of chloride ions via the mechanism diagrammed in


Physiology_Levy

Physiology_Levy. Fig. 30.18 . In cystic fibrosis the loss of CFTR Cl channels can partially be compensated for by accessory chloride channels, such as the TMEM16A channel that is activated by elevations in cytoplasmic calcium. Some segments of the intestine may engage in additional secretory mechanisms, such as secretion of bicarbonate ions via the mechanisms shown in Fig. 30.19. Bicarbonate secretion protects the epithelium, particularly in the most proximal portions of the duodenum immediately downstream from the pylorus, from damage caused by acid and pepsin. Absorption of Minerals and Water-Soluble Vitamins


Physiology_Levy

Physiology_Levy. Absorption of Minerals and Water-Soluble Vitamins The small intestine is also an important site for absorption of water-soluble vitamins (e.g., vitamin C, cobalamin) and minerals such as calcium, magnesium, and iron. In general these substances are taken up from the luminal contents via the activity of specific transporters. Their uptake is •Fig. 30.18 MechanismofCl−secretioninthesmallandlargeintestines.CFTR,cysticfibrosistransmembraneconductanceregula-tor;NKCC1,sodium/potassium/2chloridecotransporter1.Notethatadditionalchloridechannels(notshown),suchasthoseregulatedbyintracellularcalciumconcentration,mayalsoexistintheapicalmembraneandcontributetooveralltransport.˜Ca˜˜Cl°2K˜˜˜cAMPNKCC1ATP˜ also controlled by feedback mechanisms that sense the concentration of the relevant substrate in the circulation and adjust the expression of transporters and accessory molecules accordingly. Motor Patterns of the Small Intestine


Physiology_Levy

Physiology_Levy. Motor Patterns of the Small Intestine The smooth muscle layers in the small intestine produce motility patterns that mix chyme with the various digestive secretions and propel fluid along the length of the intestine so that nutrients (along with water and electrolytes) can be absorbed. Motor patterns of the small intestine during the postprandial period are directed predominantly toward mixing and consist largely of segmenting and retropulsive contractions that retard the meal while digestion is still ongoing. Segmentation is a stereotypical pattern of rhythmic contractions that is displayed in


Physiology_Levy

Physiology_Levy. Fig. 30.20 and presumably reflects programmed activity of the enteric nervous system superimposed on the basic electrical rhythm. Hormonal mediators of this fed pattern of motility are poorly defined, although CCK contributes. CCK also plays important roles in slowing gastric emptying when the meal is in the small intestine, as described at the beginning of this chapter. This makes sense as a mechanism to match nutrient delivery to the available capacity to digest and absorb the components of the meal. •Fig. 30.19 Mechanismsofbicarbonatesecretionintheduodenum.CA,carbonicanhydrase;CFTR,cysticfibrosistransmembranecon-ductanceregulator;DRA,downregulatedinadenoma;NBC-1,sodium/bicarbonatecotransporter1;NHE-1,sodium/hydrogenexchanger-1;PAT1,putativeaniontransporter1.3Na˜Na˜Na˜H˜Cl°Cl°K˜NBC-1 NHE-1 DRA? PAT1? CFTR ATP CO2 + H2O CA HCO3 °HCO3 °


Physiology_Levy

Physiology_Levy. After the meal has been digested and absorbed, it is desirable to clear any undigested residues from the lumen to prepare the intestine for the next meal. Such clearance is effected by peristalsis ( Fig. 30.21 ), a coordinated sequence of contraction occurring above the intestinal contents and relaxation below that permits the contents to be conveyed over considerable distances. Peristalsis reflects the action of acetylcholine and substance P released orad to a site of intestinal distention, which serves to contract the circular muscle, as well as the inhibitory effects of VIP and nitric oxide on the caudad side. Like segmentation, peristalsis originates when action potentials generated by intrinsic innervation are superimposed on sites of cellular depolarization dictated by the basic electrical rhythm. The peristaltic motor patterns that occur during fasting, moreover, are organized into a sequence of phases known as the migrating motor complex (


Physiology_Levy

Physiology_Levy. Fig. 30.22 ). Phase I of the MMC is characterized by relative quiescence, whereas small disorganized contractions begin to occur during phase II. During phase III, which lasts about 10 minutes, large contractions that •Fig. 30.20 A,Radiographicviewshowingthestomachandsmallintestinefilledwithbariumcontrastmediuminanormalindividual.Notethesegmentationoftheintestine.B,Sequenceofsegmentalcontractionsinthesmallintestine.Lines1to4representsequentialtimepoints.Thedottedlinesindicatewherecontractionswilloccurnext;thearrowsdepictthedirectionofmovementoftheintestinalcontents.(A,FromGardenerEMetal.Anatomy: A Regional Study of Human Structure. 4thed.Philadelphia:Saunders;1975;B,redrawnfromCannonWB. Am J Physiol 1902;6:251.) •Fig. 30.21 Peristalticmotilityintheintestinepropelsintestinalcontentsalongthelengthofthesmallintestine.


Physiology_Levy

Physiology_Levy. propagate along the length of the intestine are stimulated by the hormone motilin and sweep any remaining gastric and intestinal contents out into the colon. The pylorus and ileocecal valve open fully during this phase, so even large undigested items can eventually pass from the body. Motility of the intestine then reverts to phase I of the MMC, with the entire cycle taking about 90 minutes in adults unless a meal is ingested, in which case the MMC is suspended. After the meal, motilin levels fall, and the MMC cannot be resumed until they rise again. 1. On leaving the stomach, the meal enters the small intestine, which consists (sequentially) of the duodenum, jejunum, and ileum. The principal function of the small intestine is to digest and absorb the nutrients contained in the meal. 2. The presence of chyme in the duodenum retards additional gastric emptying, thus helping match nutrient delivery to the ability of the small intestine to digest and absorb such substances. 3.


Physiology_Levy

Physiology_Levy. 2. The presence of chyme in the duodenum retards additional gastric emptying, thus helping match nutrient delivery to the ability of the small intestine to digest and absorb such substances. 3. Digestion and absorption in the small intestine are aided by two digestive juices derived from the pancreas (pancreatic juice) and liver (bile). These secretions are triggered by hormonal and neural signals activated by the presence of the meal in the small intestine. 4. Pancreatic secretions arise from the acini and contain various proteins capable of digesting the meal or acting as important cofactors. The secretion is diluted and alkalinized as it passes through the pancreatic ducts. 5. Bile is produced by the liver and stored in the gallbladder until needed in the postprandial period. Bile acids, important components of bile, are biological detergents that solubilize the products of lipid digestion.


Physiology_Levy

Physiology_Levy. •Fig. 30.22 Migratingmotorcomplexesintheduodenumandjejunumasrecordedfromafastinghumansubjectbymanometry.D1,D2,J1,J2,andJ3indicatesequentialrecordingpointsalongthelengthoftheduodenumandjejunum.Theintensecontractions(phaseIII)propagateaborally.(RedrawnfromSofferEEetal. Am J Gastroenterol 1998;93:1318.) 6. Carbohydrates and proteins, water-soluble macromolecules, are digested and absorbed by broadly analogous mechanisms. Lipids, the third macronutrient, require special mechanisms to transfer the products of lipolysis to the epithelial surface where they can be absorbed. The small intestine also absorbs fatand water-soluble vitamins, as well as minerals such as calcium, magnesium, and iron. 7. The small intestine transfers large volumes of fluid into and out of the lumen on a daily basis to facilitate digestion and absorption of nutrients, driven by active transport of ions and other electrolytes. 8.


Physiology_Levy

Physiology_Levy. 8. The motor patterns of the small intestine vary depending on whether a meal has been ingested. Immediately after a meal, motility is directed to retaining the meal in the small intestine, mixing it with digestive juices, and providing sufficient time for absorption of nutrients. During fasting, a “housekeeper” complex of intense contractions (the migrating motor complex) sweeps periodically along the length of the stomach and small intestine to clear them of undigested residues. Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol Rev. 2012;92:1061-1085. Argent BE, et al. Cell physiology of the pancreatic ducts. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Barrett KE, Keely SJ. Electrolyte secretion and absorption in the small intestine and colon. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015.


Physiology_Levy

Physiology_Levy. Bharucha AE, Hasler WL. Motility of the small intestine and colon. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. Ganapathy V. Protein digestion and absorption. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Liddle RA. Regulation of pancreatic secretion. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Wright EM, Sala-Rabanal M, Loo DDF, Hirayama BA. Sugar absorption. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Upon completion of this chapter the student should be able to answer the following questions: 1. What are the structures of the anatomy of the colon and rectum, and what is the role of the large intestine in storing and desiccating the residues of a meal? 2.


Physiology_Levy

Physiology_Levy. What are the structures of the anatomy of the colon and rectum, and what is the role of the large intestine in storing and desiccating the residues of a meal? 2. What are the motility patterns of the colon that provide for its storage function, and what reflexes signal to the colon from more proximal portions of the GI tract? 3. What is the role of intestinal microorganisms in metabolism and host defense? 4. What are the mechanisms that provide for defecation, and how it can be delayed until convenient? Overview of the Large Intestine The most distal segment of the gastrointestinal (GI) tract, the large intestine, comprises the cecum; ascending, transverse, and descending portions of the colon; rectum; and anus (


Physiology_Levy

Physiology_Levy. Fig. 31.1 ). The primary functions of the large intestine are to digest and absorb components of the meal that cannot be digested or absorbed more proximally, reabsorb the remaining fluid that was used during movement of the meal along the GI tract, and store the waste products of the meal until they can conveniently be eliminated from the body. In fulfilling these functions, the large intestine uses characteristic motility patterns and expresses transport mechanisms that drive the absorption of fluid, electrolytes, and other solutes from the stool. The large intestine also contains a unique biological ecosystem known as the microbiota, consisting of many trillions of commensal bacteria and other microorganisms that engage in a lifelong symbiotic relationship with their human host. These microorganisms can metabolize components of the meal that are not digested by host enzymes and make their products available to the body via a process known as fermentation. Colonic bacteria also


Physiology_Levy

Physiology_Levy. microorganisms can metabolize components of the meal that are not digested by host enzymes and make their products available to the body via a process known as fermentation. Colonic bacteria also metabolize other endogenous substances such as bile acids and bilirubin, thereby influencing their disposition. There is emerging evidence that the colonic microbiota is critically involved in promoting development of the normal colonic epithelium and in stimulating its differentiated functions.


Physiology_Levy

Physiology_Levy. In addition the microbiota can detoxify xenobiotics (substances originating outside the body, such as drugs) and protect the colonic epithelium from infection by invasive pathogens. Finally, the colon is both the recipient and the source of signals that allow it to communicate with other GI segments to optimally integrate function. For example, when the stomach is filled with freshly masticated food, the presence of the meal triggers a long reflex arc that results in increased colonic motility (the gastrocolic reflex) and eventually evacuation of the colonic contents to make way for the residues of the next meal. Similarly the presence of luminal contents in the colon causes release of both endocrine and neurocrine mediators that slow propulsive motility and decrease electrolyte secretion in the small intestine. This negative feedback mechanism matches the rate of delivery of colonic contents to the segment’s capacity to process and absorb the useful components. Details of the signals


Physiology_Levy

Physiology_Levy. in the small intestine. This negative feedback mechanism matches the rate of delivery of colonic contents to the segment’s capacity to process and absorb the useful components. Details of the signals that mediate this crosstalk between the colon and other components of the GI system are reviewed in the next section.


Physiology_Levy

Physiology_Levy. The colon is regulated primarily, though not exclusively, by neural pathways. Colonic motility is influenced by local reflexes that are generated by filling of the lumen, thereby initiating distention and the activation of stretch receptors. These regulatory pathways exclusively involve the enteric nervous system. Local reflexes triggered by distortion of the colonic epithelium and produced, for example, by passage of a bolus of fecal material stimulate short bursts of Cl− and fluid secretion mediated by 5-hydroxytryptamine (5-HT) from enteroendocrine cells and acetylcholine from enteric secretomotor nerves. On the other hand, colonic function and motility responses in particular are also regulated by long reflex arcs originating more proximally in the GI tract or in other body systems. One example is the gastrocolic reflex. Distention of the stomach activates a generalized increase in colonic motility and mass movement of fecal material, as described in more detail later. This reflex


Physiology_Levy

Physiology_Levy. example is the gastrocolic reflex. Distention of the stomach activates a generalized increase in colonic motility and mass movement of fecal material, as described in more detail later. This reflex has both chemosensitive and mechanosensitive components at its site of origin and involves release of 5-HT and acetylcholine. Similarly the orthocolic reflex is activated on rising from bed and promotes a morning urge to defecate in many individuals.


Physiology_Levy

Physiology_Levy. The colon is relatively poorly supplied with cells that release bioactive peptides and other regulatory factors. Exceptions are enterochromaffin cells, which release 5-HT, and cells that synthesize peptide YY, so named because its sequence contains two adjacent tyrosine residues. Peptide YY is synthesized by enteroendocrine cells localized in the terminal ileum and colon and is released in response to lipid in the lumen. It decreases gastric emptying and intestinal propulsive motility. Peptide YY also reduces Cl− and thus fluid secretion by intestinal epithelial cells. Thus peptide YY has been characterized as an “ileal brake” in that it is released if nutrients, especially fat, are not absorbed by the time the meal reaches the terminal ileum and proximal part of the colon. By reducing propulsion of the intestinal contents, in part by limiting their fluidity and distention-induced motility, peptide YY provides more time for the meal to be retained in the small intestine where its


Physiology_Levy

Physiology_Levy. propulsion of the intestinal contents, in part by limiting their fluidity and distention-induced motility, peptide YY provides more time for the meal to be retained in the small intestine where its constituent nutrients can be digested and absorbed.


Physiology_Levy

Physiology_Levy. Patterns of Colonic Motility To appreciate colonic motility the functional anatomy of the colonic musculature will be reviewed first, followed by a discussion of the regulation of colonic motility. Functional Anatomy of the Colonic Musculature


Physiology_Levy

Physiology_Levy. Functional Anatomy of the Colonic Musculature As in other segments of the intestine, the colon consists of functional layers, with a columnar epithelium most closely apposed to the lumen, which is then underlaid by the lamina propria, serosa, and muscle layers. Similarly the colonic mucosa is surrounded by continuous layers of circular muscle that can occlude the lumen. Indeed, at intervals •Fig. 31.1 Majoranatomicsubdivisionsofthecolon.Sigmoid colon Cecum Rectum Ileocecal valve Terminal ileum •Fig. 31.2 Radiographshowingaprominenthaustralpatterninthecolonofanormalindividual.(FromKeatsTE.An Atlas of Normal Roentgen Variants. 2nded.StLouis:Mosby–YearBook;1979.) the circular muscle contracts to divide the colon into segments called haustra. These haustra are readily appreciated if the colon is viewed at laparotomy or by x-ray imaging as shown in


Physiology_Levy

Physiology_Levy. Fig. 31.2 . The arrangement of the majority of the longitudinal muscle fibers, however, is distinct from •Fig. 31.3 Anatomyoftherectumandanalcanal. that in the small intestine. Three nonoverlapping bands of longitudinal muscle known as the taeniae coli extend along the length of the colon. Although the circular and longitudinal muscle layers of the colon are electrically coupled, this process is less efficient than in the small intestine. Thus propulsive motility in the colon is less effective than in the small intestine. Activity of the enteric nervous system also provides for the segmenting contractions that form the haustra. Contents can be moved back and forward between haustra, which is a means of retarding passage of the colonic contents and maximizing their contact time with the epithelium. In contrast, when rapid propulsion is called for, the contractions forming the haustra relax and the contour of the colon is smoothened.


Physiology_Levy

Physiology_Levy. The colon terminates in the rectum, which is joined to the colon at an acute angle (the rectosigmoid junction ) (Fig.


Physiology_Levy

Physiology_Levy. 31.3 ). The rectum lacks circular muscle and is surrounded only by longitudinal muscle fibers. It is a reservoir wherein feces can be stored before defecation. Muscular contractions also form functional “valves” in the rectum that retard movement of feces and are important in delaying the loss of feces until it is convenient, at least in adults. The rectum in turn joins the anal canal, distinguished by the fact that it is surrounded not only by smooth muscle but also by striated (skeletal) muscle. The combination of these muscle layers functionally accounts for two key sphincters that control evacuation of solid waste and flatus from the body. The internal anal sphincter is composed of a thickened band of circular muscle, whereas the external anal sphincter is made up of three different striated muscle structures in the pelvic cavity that wrap around the anal canal. These latter muscles are distinctive because they maintain a significant level of basal tone and can be contracted


Physiology_Levy

Physiology_Levy. striated muscle structures in the pelvic cavity that wrap around the anal canal. These latter muscles are distinctive because they maintain a significant level of basal tone and can be contracted further either voluntarily or reflexively when abdominal pressure increases abruptly (e.g., when lifting a heavy object).


Physiology_Levy


Physiology_Levy

Physiology_Levy. Contraction of the smooth muscle layers in the proximal part of the colon is stimulated by vagal input as well as by the enteric nervous system. On the other hand, the remainder of the colon is innervated by the pelvic nerves, which also control the caliber of the internal anal sphincter. Voluntary input from the spinal cord via branches of the pudendal nerves regulates contraction of the external anal sphincter and muscles of the pelvic floor. The ability to control these structures is learned during toilet training. This voluntary control distinguishes the anal canal from most of the GI system, with the exception of the striated muscle in the esophagus that regulates swallowing.


Physiology_Levy

Physiology_Levy. Consistent with its primary function, the two predominant motility patterns of the large intestine are directed not to propulsion of the colonic contents but rather to mixing of the contents and retarding their movement, thereby providing them with ample time in contact with the epithelium. Two distinctive forms of colonic motility have been identified. The first is referred to as short-duration contractions, which are designed to provide for mixing. These contractions originate in the circular muscle and are stationary pressure waves that persist for 8 seconds on average. Long-duration contractions, in contrast, are produced by the taeniae coli, last for 20 to 60 seconds, and may propagate over short distances. Notably, however, propagation may move orally as well as aborally, particularly in the more proximal segments of the colon. Both motility patterns are thought to originate largely in response to local conditions such as distention. Note that the basal electrical rhythm that


Physiology_Levy

Physiology_Levy. in the more proximal segments of the colon. Both motility patterns are thought to originate largely in response to local conditions such as distention. Note that the basal electrical rhythm that governs the rate and origination sites of smooth muscle contraction in the small intestine does not traverse the ileocecal valve to continue into the colon.


Physiology_Levy

Physiology_Levy. On the other hand, probably as a result of both local influences and long reflex arcs, approximately 10 times per day in healthy individuals the colon engages in a motility pattern that is of high intensity and sweeps along the length of the large intestine from the cecum to the rectum. Such contractions, called high-amplitude propagating contractions, move exclusively in an aboral direction and are designed to clear the colon of its contents. However, although such a motility pattern can clearly be associated with defecation, it does not necessarily result in defecation for reasons discussed later.


Physiology_Levy

Physiology_Levy. It is also important to note that there is considerable variability among individuals with respect to the rate at which colonic contents are transported from the cecum to the rectum. Although small intestinal transit times are relatively constant in healthy adults, the contents may be retained in the large intestine anywhere from hours to days without signifying dysfunction. This also accounts for significant variation among individuals in their normal patterns of defecation and mandates careful elicitation of a patient’s history before diagnosing bowel dysfunction. Transport Mechanisms in the Colon


Physiology_Levy

Physiology_Levy. Transport Mechanisms in the Colon The major role of the colonic epithelium is to either absorb or secrete electrolytes and water rather than nutrients. Secretion, which is confined to the crypts, maintains the sterility of the crypts, which might otherwise become stagnant. This is important because the stem cells that renew the epithelium are located at the base of the crypt. The stem cells give rise to daughter cells that migrate out of the crypts and acquire the differentiated properties of surface cells that are responsible for water and electrolyte absorption. The colonic epithelium also absorbs short-chain fatty acids salvaged from nonabsorbed carbohydrates by colonic bacteria. Indeed, one such short-chain fatty acid, butyrate, is a critical energy source for colonocytes. A reduction in butyrate levels in the lumen (as a result of changes in colonic microbiota caused by administration of broad-spectrum antibiotics) may induce epithelial dysfunction.


Physiology_Levy

Physiology_Levy. The colon receives 2 L of fluid each day and absorbs 1.8 L, thus leaving 200 mL of fluid to be lost in stool. The colon has a considerable reserve capacity for fluid absorption and can absorb up to three times its normal fluid load without loss of excessive fluid in the stool. Therefore any illness that results in stimulation of active fluid secretion in the small intestine will cause diarrhea only when the reserve capacity of 4 to 6L is exceeded. Absorption and secretion of water by the colon are passive processes driven by absorption or secretion of electrolytes and other solutes. Quantitatively, fluid absorption by the


Physiology_Levy

Physiology_Levy. colon is driven by three transport processes. The first is electroneutral NaCl absorption, which is mediated by the same mechanism that drives NaCl absorption in the intestine (see Fig. 30.17 ). NaCl absorption is stimulated by various growth factors, such as epidermal growth factor, and is inhibited by hormones and neurotransmitters that increase levels of cyclic adenosine monophosphate (cAMP) in colonic surface epithelial cells. •Fig. 31.4 Mechanismofshort-chainfattyacid(SCFA)uptakebycolonocytes.ATP,adenosinetriphosphate;SMCT1,sodium/monocarboxylatecotransporter1.3Na˜SMCT1 SCFA used by colonocyte for intracellular metabolism ATP


Physiology_Levy

Physiology_Levy. The second transport process that drives fluid absorption in the colon is absorption of short-chain fatty acids, including acetate, propionate, and butyrate. These molecules are absorbed from the lumen by surface (and perhaps crypt) epithelial cells in an Na+-dependent fashion by a family of symporters related to the Na+-glucose symporter in the small intestine, and known as sodium-monocarboxylate transporters (SMCTs). Uptake of short-chain fatty acids by SMCTs located in the apical plasma membrane is driven by the low intracellular [Na+] established by the basolateral Na+,K+-ATPase ( Fig. 31.4 ). These short-chain fatty acids are used for energy by colonocytes. In addition, butyrate regulates expression of specific genes in colonic epithelial cells and may suppress development of a malignant phenotype. Expression of SMCT1 (also identified as SLC5A8) is reduced in some colon cancers, thereby leading to a reduction in butyrate uptake, which may contribute to malignant transformation.


Physiology_Levy

Physiology_Levy. The third absorptive process of major significance in the colon is absorption of Na+ ( Fig. 31.5 ). This transport process is predominantly localized to the distal part of the colon and is driven by the epithelial Na+ channel (ENaC), which is also involved in reabsorption of Na+ in the kidney. When the channel is opened in response to activation by neurotransmitters or hormones, or both, Na+ flows into the colonocyte cytosol and is then transported across the basolateral membrane by Na+,K+-ATPase. Cl− ions follow passively via the intercellular tight junctions to maintain electrical neutrality. Water is absorbed across the tight junctions as a result of the transepithelial osmotic gradient due to solute absorption. This mode of Na+ absorption is the •Fig. 31.5 ElectrogenicNa+ absorptioninthecolon.ENaC,epithelialsodiumchannel.


Physiology_Levy

Physiology_Levy. last line of defense to prevent excessive loss of water in stool, given its strategic location in the distal part of the colon. Indeed, patients suffering from bowel inflammation often show markedly diminished expression of ENaC, perhaps accounting for their diarrheal symptoms. We also know that expression of ENaC can be acutely regulated in response to whole-body Na+ balance. Thus in situations of reduced Na+ intake, the hormone aldosterone increases ENaC expression in both the colon and kidney, thereby promoting retention of Na+ . Adequate hydration of the colonic contents is determined by the balance between water absorption and secretion. Fluid secretion in the colon is driven by Cl− ion secretion, by the same mechanism driving fluid secretion in the small intestine, and is subject to the same regulation (see Fig. 30.18).


Physiology_Levy

Physiology_Levy. Fig. 30.18). Indeed, some cases of constipation may reflect abnormalities in epithelial transport, and constipation that results from abnormally slow motility can be treated by agents that stimulate Cl− secretion. Conversely, excessive Cl− secretion can be one mechanism underlying diarrhea.


Physiology_Levy

Physiology_Levy. The remnants of the meal entering the colon interact with a vast assortment of bacteria and other microorganisms. This enteric microbial ecosystem is established shortly after birth, matures as the child grows, and fluctuates in predictable ways in healthy individuals depending on factors such as diet or circadian rhythms. More drastic perturbations in the microbiota can be provoked by antibiotics or introduction of an aggressive pathogen and may then take considerable time to resolve. The enteric bacterial ecosystem contributes to GI physiology in a surprising number of ways. Indeed, the large intestine (and to a lesser extent the distal portion of the small intestine) is an unusual organ in that it maintains a symbiotic relationship with such an extensive microbiota, whereas other body compartments are largely sterile.


Physiology_Levy

Physiology_Levy. The colonic microbiota is not essential to life because animals raised in germ-free conditions apparently develop normally and are able to reproduce. However, in such animals the mucosal immune system is immature, and intestinal epithelial cells differentiate more slowly. Importantly the colonic microbiota provides benefits to the host in that the constituent microbes are capable of performing metabolic reactions that do not take place in mammalian cells. Bacterial enzymes act on both endogenous and exogenous substrates. They form secondary bile acids and deconjugate bile acids that have escaped uptake in the terminal ileum, so they can be reabsorbed. They convert bilirubin into urobilinogen (see ) and salvage nutrients that are resistant to pancreatic and brush border hydrolases, such as dietary fiber. A summary of the metabolic contributions of the colonic microbiota is provided in


Physiology_Levy

Physiology_Levy. Table 31.1 . Microbial metabolism can also be exploited for pharmacological purposes. A drug targeted to the colon, for example, can be conjugated in such a way that it will become bioavailable only after it is acted on by bacterial enzymes. Bacterial enzymes may also detoxify some dietary carcinogens, but equally they may generate toxic or carcinogenic compounds from dietary substrates.


Physiology_Levy

Physiology_Levy. Commensal microorganisms also play a critical role in limiting the growth or invasion (or both) of pathogenic microorganisms. They fulfill this antimicrobial role via a number of different mechanisms—by synthesizing and secreting compounds that inhibit the growth of competitor organisms or that are microbicidal, by functioning as a physical barrier to prevent attachment of pathogens and their subsequent entry into colonic epithelial cells, and by triggering patterns of gene expression in the epithelium that counteract the adverse effects of pathogens on epithelial function. These mechanisms provide a basis for understanding why patients who have received broad-spectrum antibiotics, which temporarily disrupt the colonic microbiota, are susceptible to overgrowth of pathogenic organisms and associated intestinal and systemic infections. They may also shed light on the efficacy of probiotics, commensal bacteria selected for their resistance to gastric acid and proteolysis that are


Physiology_Levy

Physiology_Levy. and associated intestinal and systemic infections. They may also shed light on the efficacy of probiotics, commensal bacteria selected for their resistance to gastric acid and proteolysis that are intentionally ingested to prevent or treat a variety of digestive disorders.


Physiology_Levy

Physiology_Levy. Atoxinknownasheat-stable toxin of E. coli, orSTa,isamajorcausativeagentoftraveler’sdiarrhea,whichcanbecontractedbyconsumptionofinfectedfoodorwater.Thistoxinbindstoareceptorontheapicalsurfaceofintestinalepithelialcellsknownasguanylyl cyclase C (GC-C).Inturnthisenzymegenerateslargequantitiesofintracellularcyclicguanosinemonophosphate(cGMP)thattriggerincreasedCl− secretionviaactivationofthecysticfibrosistransmembraneconductanceregulator(CFTR)Cl−


Physiology_Levy


Physiology_Levy

Physiology_Levy. The colonic microbiota is also notable for its contribution to formation of intestinal gas. Although large volumes of air may be swallowed in conjunction with meals, the majority of this gas returns up the esophagus via belching. However, during fermentation of unabsorbed dietary components, the microbiota generates large volumes of nitrogen, hydrogen, and carbon dioxide. Approximately 1 L of these nonodorous gases is excreted on a daily basis via the anus in all individuals, even those who do not complain of flatulence. Some individuals may generate appreciable concentrations of methane. Trace amounts of odorous compounds are also present, such as hydrogen sulfide, indole, and skatole.


Physiology_Levy

Physiology_Levy. The final stage in the journey taken by a meal after its ingestion is expulsion of its indigestible residues from the body in the process known as defecation. The feces also contain the remnants of dead bacteria, dead and dying epithelial cells that have been desquamated from the lining of the intestine, biliary metabolites specifically targeted for excretion (e.g., conjugates of xenobiotics [see ]), and a small amount of water. In health, the stool contains few if any useful nutrients. The presence of nutrients in stool, particularly lipid (known as steatorrhea), signifies maldigestion, malabsorption, or both. Fat in the stool is a sensitive marker of small intestinal dysfunction because it is poorly used by the colonic microbiota, but loss of carbohydrate and protein in stool can also be seen if the underlying condition worsens.


Physiology_Levy

Physiology_Levy. The process of defecation requires coordinated action of the smooth and striated muscle layers in the rectum and anus, as well as surrounding structures such as the pelvic floor muscles. During the mass movement of feces produced by high-amplitude propagating contractions, the rectum fills with fecal material. Expulsion of this material from the body is controlled by the internal and external anal sphincters, which contribute approximately 70% to 80% and 20% to 30% of anal tone at rest, respectively. Filling of the rectum causes relaxation of the internal anal sphincter via release of vasoactive intestinal polypeptide and generation of nitric oxide. Relaxation of the inner sphincter permits the anal sampling mechanism, which can distinguish whether the rectal contents are solid, liquid, or gaseous in nature. After toilet training, sensory nerve endings in the anal mucosa then generate reflexes that initiate appropriate activity of the external sphincter to either retain the rectal


Physiology_Levy

Physiology_Levy. or gaseous in nature. After toilet training, sensory nerve endings in the anal mucosa then generate reflexes that initiate appropriate activity of the external sphincter to either retain the rectal contents or permit voluntary expulsion (e.g., of flatus). If defecation is not convenient, the external sphincter contracts to prevent the loss of stool. Then with time the rectum accommodates to its new volume, the internal anal sphincter contracts again, and the external anal sphincter relaxes (


Physiology_Levy

Physiology_Levy. Fig. 31.6 When defecation is desired, on the other hand, adoption of a sitting or squatting position alters the relative orientation of the intestine and surrounding muscular structures by straightening the path for exit of either solid or liquid feces. Relaxation of the puborectalis muscle likewise increases the rectoanal angle. After voluntary relaxation of the external anal sphincter, rectal contractions move the fecal material out of the body, sometimes followed by additional mass movements of feces from more proximal segments of the colon ( Fig. 31.7 ). Evacuation is assisted by simultaneous contraction of muscles that increase abdominal pressure, such as the diaphragm. Voluntary expulsion of flatus, on the other hand, involves a similar sequence of events, except that there is no relaxation of the puborectalis muscle. This permits flatus to be squeezed past the acute rectoanal angle while retaining fecal material.


Physiology_Levy

Physiology_Levy. Cooperative activity of the external anal sphincter, puborectalis muscle, and sensory nerve endings in the anal canal is required to delay defecation until it is appropriate, even if the rectum is acutely distended with stool or intraabdominal pressure rises sharply. This explains why incontinence can develop in individuals in whom the integrity of such structures has been compromised, such as after trauma, surgical or obstetrical injuries, prolapse of the rectum, or neuropathic diseases such as long-standing diabetes. Surgical intervention may be necessary to correct muscle abnormalities in patients with the distressing condition of fecal incontinence, although many can be helped to increase external anal sphincter tone with the use of biofeedback exercises.


Physiology_Levy

Physiology_Levy. •Fig. 31.6 Responsesoftheinternalandexternalanalsphincterstoprolongeddistentionoftherectum.Notethattheresponsesofthesphinctersaretransientbecauseofaccommodation.(RedrawnfromShusterMMetal.Bull Johns Hopkins Hosp 1965;116:79.) •Fig. 31.7 Motilityoftherectumandanalsphinctersinresponsetorectalfillingandduringdefecation.Notethatfillingoftherectumcausesaninitialdecreaseininternalsphinctertonethatiscounterbalancedbycontractionoftheexternalsphincter.Theinternalsphincterthenaccommodatestothenewrectalvolume,therebyallowingtheexternalsphinctertorelax.Finally,defecationoccurswhentheexternalanalsphincterisrelaxedvoluntarily.(DatafromChangEBetal.Gastrointestinal, Hepatobiliary and Nutritional Physiology. Philadelphia:Lippincott-Raven;1996.) 1.


Physiology_Levy

Physiology_Levy. The final segment of the intestine through which the meal traverses is the large intestine, which is composed of the cecum, colon, rectum, and anus. The primary role of the large intestine is to reclaim water used during the process of digestion and absorption and to store the residues of the meal until defecation is socially convenient. 2. Colonic motility primarily serves to mix and delay passage of the luminal contents, other than during periodic large-amplitude contractions that convey fecal material to the rectum. Bharucha AE, Brookes SJR. Neurophysiologic mechanisms of human large intestinal motility. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Bharucha AE, Hasler WL. Motility of the small intestine and colon. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. 3.


Physiology_Levy

Physiology_Levy. Bharucha AE, Hasler WL. Motility of the small intestine and colon. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. 3. The colon is highly active in transporting water and electrolytes as well as products salvaged from undigested components of the meal by colonic bacteria. 4. The colon maintains a lifelong mutually beneficial relationship with a vast microbial ecosystem that metabolizes endogenous substances, nutrients, and drugs and protects the host from infection with pathogens. 5. Defecation involves both involuntary and voluntary relaxation of muscle structures surrounding the anus and reflex pathways that control these structures. Kau AL, et al. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474:327-336. Kendig DM, Grider JR. Serotonin and colonic motility. Neurogastroenterol Motil. 2015;27:899-905.


Physiology_Levy

Physiology_Levy. Kau AL, et al. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474:327-336. Kendig DM, Grider JR. Serotonin and colonic motility. Neurogastroenterol Motil. 2015;27:899-905. Koren A, Ley RE. The human intestinal microbiota and microbiome. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. Upon completion of this chapter the student should be able to answer the following questions: 1. How does the liver contribute metabolic, detoxification, and excretory functions that are vital to life? 2. What cell types make up the liver, what is their unusual arrangement, and what is the liver’s unique portal blood supply? 3. What is the function of bile as an excretory fluid, what are the mechanisms that underlie its formation, and what is the role of the enterohepatic circulation? 4.


Physiology_Levy

Physiology_Levy. 3. What is the function of bile as an excretory fluid, what are the mechanisms that underlie its formation, and what is the role of the enterohepatic circulation? 4. How is bile is stored and concentrated in the gallbladder, and what are the mechanisms that coordinate gallbladder emptying with ingestion of a meal? 5. How are ammonia and bilirubin eliminated from the body? Overview of the Liver and Its Functions


Physiology_Levy

Physiology_Levy. The liver is a large multilobed organ located in the abdominal cavity whose function is intimately associated with that of the gastrointestinal system. The liver serves as the first site of processing for most absorbed nutrients and also secretes bile acids, which as we learned in , play a critical role in absorption of lipids from the diet. In addition the liver is a metabolic powerhouse, critical for disposing of a variety of metabolic waste products and xenobiotics from the body by converting them to forms that can be excreted. The liver stores or produces numerous substances needed by the body, such as glucose, amino acids, and plasma proteins. In general, key functions of the liver can be divided into three areas: (1) contributions to whole-body metabolism, (2) detoxification, and (3) excretion of protein-bound/lipid-soluble waste products. In this chapter we discuss the structural and molecular features of the liver and biliary system that subserve these functions, as well as


Physiology_Levy

Physiology_Levy. (3) excretion of protein-bound/lipid-soluble waste products. In this chapter we discuss the structural and molecular features of the liver and biliary system that subserve these functions, as well as their regulation. Although the liver contributes in a pivotal way to the maintenance of whole-body biochemical status, a complete discussion of all the underpinning reactions is beyond the scope of this chapter. We will confine our discussion primarily to hepatic functions that relate to gastrointestinal physiology.


Physiology_Levy

Physiology_Levy. Metabolic Functions of the Liver Hepatocytes contribute to metabolism of the major nutrients: carbohydrates, lipids, and proteins. Thus the liver plays an important role in glucose metabolism by engaging in gluconeogenesis, conversion of other sugars to glucose. The liver also stores glucose as glycogen at times of glucose excess (e.g., postprandial period) and then releases stored glucose into the bloodstream as it is needed. This process is referred to as the glucose buffer function of the liver. When hepatic function is impaired, glucose concentrations in blood may rise excessively after ingestion of carbohydrate; conversely, between meals, hypoglycemia may be seen because of an inability of the liver to contribute to carbohydrate metabolism and interconversion of one sugar to another.


Physiology_Levy

Physiology_Levy. Hepatocytes also participate in lipid metabolism. They are a particularly rich source of the metabolic enzymes engaged in fatty acid oxidation to supply energy for other body functions. Hepatocytes also convert products of carbohydrate metabolism to lipids that can be stored in adipose tissue and synthesize large quantities of lipoproteins, cholesterol, and phospholipids, the latter two being important in the biogenesis of cell membranes. In addition, hepatocytes convert a considerable portion of synthesized cholesterol to bile acids, which will be discussed in more detail later in this chapter.


Physiology_Levy

Physiology_Levy. The liver also plays a vital role in protein metabolism. The liver synthesizes all the nonessential amino acids (see ) that do not need to be supplied in the diet, in addition to participating in interconverting and deaminating amino acids so the products can enter biosynthetic pathways for carbohydrate synthesis. With the exception of immunoglobulins, the liver synthesizes almost all the proteins present in plasma (especially albumin, which determines plasma oncotic pressure) as well as most of the important clotting factors. Patients suffering from liver disease may develop peripheral edema secondary to hypoalbuminemia and are also susceptible to bleeding disorders. Finally, the liver is the critical site for disposal of the ammonia generated from protein catabolism. This is accomplished by converting ammonia to urea, which is •Fig. 32.1 Typicalbloodflowthroughthesplanchniccirculationinafastingadulthuman.


Physiology_Levy

Physiology_Levy. excreted by the kidneys. The details of this process will be discussed later in this chapter. The Liver and Detoxification The liver serves both as a gatekeeper, by limiting entry of toxic substances into the bloodstream, and as a garbage disposal, by extracting potentially toxic metabolic products produced elsewhere in the body and converting them to chemical forms that can be excreted. The liver fulfills these functions in part because of its unusual blood supply. Unlike all other organs, the majority of blood arriving at the liver is venous in nature and is supplied via the portal vein from the intestine (


Physiology_Levy

Physiology_Levy. Fig. 32.1 ). As such, the liver is strategically located to receive both absorbed nutrients and potentially harmful absorbed molecules such as drugs and bacterial toxins. Depending on the efficiency with which these molecules are extracted by hepatocytes and subjected to first-pass metabolism, little or none of the absorbed substance may make it into the systemic circulation. This is a major reason why not all pharmaceutical agents can achieve therapeutic concentrations in the bloodstream if administered orally. CHAPTER 32 Transport and Metabolic Functions of the Liver


Physiology_Levy

Physiology_Levy. The liver has two levels at which it removes and metabolizes/detoxifies substances originating from the portal circulation. The first of these is physical. Blood arriving in the liver percolates among cells of the macrophage lineage, known as Kupffer cells. These cells are phagocytic and particularly important in removing particulate material from portal blood, including bacteria that may enter blood from the colon even under normal conditions. The second level of defense is biochemical. Hepatocytes are endowed with a broad array of enzymes that modify both endogenous and exogenous toxins so the products are in general more water soluble and less susceptible to reuptake by the intestine. The metabolic reactions involved are broadly divided into two classes. Phase I reactions (oxidation, hydroxylation, and other reactions catalyzed by cytochrome P450 enzymes) are followed by phase II reactions that conjugate the resulting products with another molecule (e.g., glucuronic acid, sulfate,


Physiology_Levy

Physiology_Levy. and other reactions catalyzed by cytochrome P450 enzymes) are followed by phase II reactions that conjugate the resulting products with another molecule (e.g., glucuronic acid, sulfate, amino acids, glutathione) to promote their excretion. The products of these reactions are then excreted into bile or returned to the bloodstream to ultimately be excreted by the kidneys. We will return to the precise mechanisms involved in detoxification of some key metabolic waste products later in this chapter.


Physiology_Levy

Physiology_Levy. Role of the Liver in Excretion The kidneys play an important role in excretion of water-soluble catabolites, as discussed in the renal section. Only relatively small water-soluble catabolites can be excreted by the process of glomerular filtration. However, larger water-soluble catabolites and molecules bound to plasma proteins, including lipophilic metabolites and xenobiotics, steroid hormones, and heavy metals, cannot be filtered by the glomerulus. All these substances are potentially harmful if allowed to accumulate, so a mechanism must exist for their excretion. The mechanism involves the liver, which excretes these substances in bile. Hepatocytes take up these substances with high affinity by virtue of an array of basolateral membrane transporters, and the substances are subsequently metabolized at the level of microsomes and in the cytosol (


Physiology_Levy

Physiology_Levy. Table 32.1 ). Ultimately, substances destined for excretion in bile are exported across the canalicular membrane of hepatocytes via a different array of transporters. The features of bile allow solubilization of even lipophilic substances, which can then be excreted into the intestine and ultimately leave the body in feces. Structural Features of the Liver and Biliary System Hepatocytes, the major cell type in the liver, are arranged in anastomosing cords that form plates around which large volumes of blood circulate (


Physiology_Levy

Physiology_Levy. Hepatocytes, the major cell type in the liver, are arranged in anastomosing cords that form plates around which large volumes of blood circulate ( Fig. 32.2 ). The liver receives a high blood flow that is disproportionate to its mass, which ensures that hepatocytes receive high quantities of both O2 and nutrients. Hepatocytes receive more than 70% of their •Fig. 32.2 Diagrammaticrepresentationofahepaticlobule.Platesofhepatocytesarearrayedradiallyaroundacentralvein.Branchesoftheportalveinandhepaticarteryarelocatedontheperipheryofthelobuleandformthe“portaltriad”togetherwiththebileduct.Bloodfromtheportalveinandhepaticarterypercolatesaroundthehepatocytesviathesinusoidsbeforedrainingintothecentralvein.(ModifiedfromBloomW,FawcettDW.A Textbook of Histology. 10thed.Philadelphia:Saunders;1975.) blood supply at rest via the portal vein (rising to more than 90% in the postprandial period).


Physiology_Levy

Physiology_Levy. The plates of hepatocytes that constitute the liver parenchyma are supplied by a series of sinusoids, which are low-resistance cavities supplied by branches of both the portal vein and hepatic artery. The sinusoids are unlike the capillaries that perfuse other organs. During fasting, many sinusoids are collapsed, but more can gradually be recruited as portal blood flow increases during the period after a meal when absorbed nutrients are transported to the liver. The low resistance of the sinusoidal cavities means that blood flow through the liver can increase considerably without •Fig. 32.3 Interrelationshipsofthemajorcelltypesintheliver. a concomitant increase in pressure. Eventually the blood drains into central branches of the hepatic vein. The sinusoids are also unusual in terms of the endothelial cells that line their walls (


Physiology_Levy

Physiology_Levy. The sinusoids are also unusual in terms of the endothelial cells that line their walls ( Fig. 32.3 ). Hepatic endothelial cells contain specialized openings known as fenestrations that are large enough to permit passage of molecules as big as albumin. Sinusoidal endothelial cells also lack a basement membrane, which might otherwise pose a diffusion barrier. These features allow access of albumin-bound substances to the hepatocytes that will eventually take them up. The sinusoids also contain Kupffer cells. Beneath the sinusoidal endothelium and separating the endothelium from the hepatocytes is a thin layer of loose connective tissue called the space of Disse, which in health likewise poses little resistance to the movement of molecules even as large as albumin. The space of Disse is also the location of another important hepatic cell type, the stellate cell. Stellate cells serve as storage sites for retinoids and in addition are the source of key growth factors for hepatocytes.


Physiology_Levy

Physiology_Levy. Under abnormal conditions, stellate cells are activated to synthesize large quantities of collagen, which contributes to the hepatic dysfunction.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Hepatocytes are also the origination point for the biliary system. Although hepatocytes are considered to be epithelial cells with basolateral and apical membranes, the spatial arrangement of these two cell domains differs from that seen in simple columnar epithelium, such as that lining the gastrointestinal tract. Rather, in the liver the apical surface of the hepatocyte occupies only a small fraction of the cell membrane, and the apical membranes of adjacent cells oppose each other to form a channel between the cells known as the canaliculus (see


Physiology_Levy

Physiology_Levy. Fig. 32.3 ). The role of canaliculi is to drain bile from the liver, and these canaliculi drain into biliary ductules that are lined by classic columnar epithelial cells known as cholangiocytes. Ultimately the biliary ductules drain into large bile ducts that coalesce into the right and left hepatic ducts to permit exit of bile from the liver. These in turn form the common hepatic duct, from which bile can flow into either the gallbladder (via the cystic duct) or the intestine (via the common bile duct; Fig. 32.4 ) on the basis of prevailing pressure relationships.


Physiology_Levy

Physiology_Levy. One other feature of the structural organization of the liver bears emphasis because of its clinical significance. Branches of the hepatic vein, hepatic artery, and bile ducts run in parallel in the so-called hepatic triad. Hepatocytes lying closest to this triad are referred to as periportal, or zone 1, and have the greatest supply of oxygen and nutrients. In contrast, hepatocytes lying closest to branches of the hepatic vein are referred to as pericentral, or zone 3. The latter cells are more sensitive to ischemia, whereas the former are more sensitive to oxidative injury. Thus the location of damaged cells on biopsy may provide clues to the cause of a given case of liver injury. Zone 1 cells are most active in detoxification functions in normal circumstances, but •Fig. 32.4 Functionalanatomyofthebiliarysystem.Right and left hepatic ducts from liver Common hepatic duct Common bile duct Cystic duct Sphincter of Oddi Duodenum Gallbladder zone 2 (intermediate between zones 1 and 3) and


Physiology_Levy

Physiology_Levy. and left hepatic ducts from liver Common hepatic duct Common bile duct Cystic duct Sphincter of Oddi Duodenum Gallbladder zone 2 (intermediate between zones 1 and 3) and zone 3 cells can progressively be recruited in cases of liver disease. Conversely, zone 3 cells are thought to be most active in bile acid synthesis.


Physiology_Levy

Physiology_Levy. Bile is the excretory fluid of the liver that plays an important role in lipid digestion. Bile formation begins in hepatocytes, which actively transport solutes into bile canaliculi across their apical membranes. Bile is a micellar solution in which the major solutes are bile acids, phosphatidylcholine, and cholesterol in an approximate ratio of 10:3:1, respectively. Secretion of these solutes drives concomitant movement of water and electrolytes across the tight junctions that link adjacent hepatocytes to form canalicular bile. The majority of bile flow is driven by the secretion of bile acids across the apical membrane of hepatocytes via an adenosine triphosphatase (ATPase) transporter known as the bile salt export pump (BSEP; see


Physiology_Levy

Physiology_Levy. Table 32.1 ). The composition of the resulting fluid can be modified further as it flows through the biliary ductules (resulting in hepatic bile) and still further on storage in the gallbladder (gallbladder bile). Ultimately bile becomes a concentrated solution of biological detergents that aids in solubilization of the products of lipid digestion in the aqueous environment of the intestinal lumen, thereby enhancing the rate at which lipids are transferred to the absorptive epithelial surface. It also serves as a medium in which metabolic waste products are exported from the body.


Physiology_Levy

Physiology_Levy. Bile acids are produced by hepatocytes as end products of cholesterol metabolism. Cholesterol is selectively metabolized by a series of enzymes that result in formation of bile acid ( Fig. 32.5 ). The initial and rate-limiting step is addition of a hydroxyl group to the 7 position of the steroid nucleus by the enzyme cholesterol 7α-hydroxylase. The side chain of the product of this reaction is then shortened and a carboxylic acid function added by C27 dehydroxylase to yield chenodeoxycholic acid, a dihydroxy bile acid. Alternatively the product is further hydroxylated at the 12 position and then acted on by C27 dehydroxylase to yield cholic acid, a trihydroxy bile acid. Bile acid synthesis can be up-or downregulated depending on the body’s requirements (Fig.


Physiology_Levy

Physiology_Levy. 32.6 ). For example, if bile acid levels are reduced in the blood flowing to the liver, synthesis can be increased up to 10-fold. Conversely, feeding of bile acids profoundly suppresses new synthesis of bile acids by hepatocytes. The mechanisms underlying these changes in bile acid synthesis relate to changes in expression of the enzymes involved. Bile acids activate a variety of cell surface and nuclear receptors in hepatocytes, leading ultimately to activation of specific transcription factors that regulate enzyme abundance. Chenodeoxycholic acid and cholic acid are defined as primary bile acids because they are synthesized by the hepatocyte (see


Physiology_Levy

Physiology_Levy. Chenodeoxycholic acid and cholic acid are defined as primary bile acids because they are synthesized by the hepatocyte (see Fig. 32.5 ). However, each can be metabolized in the colonic lumen by bacterial enzymes to yield ursodeoxycholic and deoxycholic acid, respectively. Chenodeoxycholic acid is also converted by bacterial enzymes to form lithocholic acid, which is relatively cytotoxic. Collectively these three products of bacterial metabolism are referred to as secondary bile acids. One additional important biochemical modification occurs for both primary and secondary bile acids in the hepatocyte (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 32.5 ). These molecules are conjugated with either glycine or taurine, which significantly depresses their pKa. The result is that conjugated bile acids are almost totally ionized at the pH prevailing in the small intestinal lumen and thus cannot passively traverse cell membranes. Consequently the conjugated bile acids are retained in the intestinal lumen until they are actively absorbed in the terminal ileum via the apical sodium-dependent bile salt transporter (asbt). Conjugated bile acids that escape this uptake step are deconjugated by bacterial enzymes in the colon, and the resulting unconjugated forms are passively reabsorbed across the colonic epithelium because they are no longer charged. Hepatic Aspects of Enterohepatic Circulation of Bile Acids


Physiology_Levy

Physiology_Levy. Hepatic Aspects of Enterohepatic Circulation of Bile Acids Bile acids assist in digestion and absorption of lipids by acting as detergents rather than enzymes, and thus a significant mass of these molecules is required to solubilize all dietary lipids. Via the enterohepatic circulation, actively reabsorbed conjugated bile acids travel through the portal blood back to the hepatocyte, where they are efficiently taken up by basolateral transporters that may be Na+ dependent or independent (see Table 32.1 ). Similarly, bile acids that are deconjugated in the colon also return to the hepatocyte, where they are reconjugated to be secreted into bile. In this way a pool of circulating primary and secondary


Physiology_Levy

Physiology_Levy. Cholesterol Major bile acids Cholic acid HO Primary Secondary OH OH COOH C27 dehydroxylase 7˜-Hydroxylase (12˜-hydroxylase) HO HO OH COOH Chenodeoxycholic acid Deoxycholic acid Conjugation of bile acids HO OH COOH HO OH 3 7 12 OH C O O OH C O–H CH2N H Glycine, pKa˜3.7 Taurine, pKa˜1.5 or SO2O–HN CH2CH2 H HO OH COOH Ursodeoxycholic acid HO COOH Lithocholic acid Liver Colon (bacteria) •Fig. 32.5 Structuresofthemajorprimaryandsecondarybileacidsofbile.Primarybileacidsaresynthesizedintheliver.Secondarybileacidsareproducedwhenintestinalbacteriaactonprimarybileacids.Atthebottomofthefiguretheconjugationofcholicacidwithglycineortaurineisshown. bile acids is produced, and daily synthesis is then equal only to the minor fraction (≈10%/day, or 200–400 mg) that escapes uptake and is lost in stool (


Physiology_Levy

Physiology_Levy. bile acids is produced, and daily synthesis is then equal only to the minor fraction (≈10%/day, or 200–400 mg) that escapes uptake and is lost in stool ( Fig. 32.7 ). The only exception to this rule is lithocholic acid, which is preferentially sulfated in the hepatocyte rather than being conjugated with glycine or taurine. The majority of the sulfate conjugates are lost from the body after each meal because they are not substrates for asbt, thereby avoiding accumulation of a potentially toxic molecule. Some comment should also be made with respect to the role of bile acids in whole-body cholesterol homeostasis. The pool of cholesterol in the body reflects its daily synthesis as well as the relatively minor component derived from inefficient dietary uptake, balanced against loss from the body, which can only occur in health via bile (


Physiology_Levy

Physiology_Levy. Fig. 32.8 ). Cholesterol can be excreted in two forms, either as the native molecule or after its conversion to bile acids. The latter account for up to a third of the cholesterol excreted per day despite enterohepatic recycling. Thus one strategy for treating hypercholesterolemia is to interrupt the enterohepatic circulation of bile acids, which drives increased conversion of cholesterol to bile acids; the bile acids are then lost from the body in feces.


Physiology_Levy

Physiology_Levy. As noted earlier, bile also contains cholesterol and phosphatidylcholine. Cholesterol transport across the canalicular membrane is mediated at least in part by a heterodimer of the active transporters we discussed in as participating in the efflux of cholesterol from the small intestinal epithelial cells, namely, ABC G5 and ABC G8 (see 32.1 ). Phosphatidylcholine derives from the inner leaflet of the canalicular membrane and is specifically “flipped” across the membrane by another ABC family transporter called multidrug resistance protein 3 (MDR3). Furthermore, 5.0


Physiology_Levy

Physiology_Levy. Limit of intestinal absorption 0.5 30 0.0 0.25 0.5 0.75 1.0 1.25 Diet Hepatic and extra-hepatic synthesis To bile As bile acids As cholesterol In health, input = output Cholesterol (g/day) 0.5 •Fig. 32.6 Relationshipbetweenratesofbileacidsynthesisandsecretion.Thebileacidsecretionratenormallyaverages30g/24h,whereasthesynthesisrateaverages0.5g/24h.Thepairsofverticalandhorizontaldottedlinesdepictthenormalrangeforbileacidsecretionandsynthesis,respectively.Increasedsecretion(simulatedbybileacidfeeding)increasestherateofreturnofbileacidstotheliverviaportalblood,whichexertsanegativefeedbackonsynthesis.Conversely,interruptionoftheenterohepaticcirculation,suchasafterilealresection,canincreasesynthesistovaluesmorethan10-foldhigherthannormal.(FromCareyMC,CahalaneMJ.In:AriasIMetal.[eds].The Liver: Biology and Pathobiology. 2nded.NewYork:RavenPress;1988.) •Fig. 32.8 Dailycholesterolbalanceinhealthyadulthumans.


Physiology_Levy

Physiology_Levy. •Fig. 32.9 Pathwaysforentryofsolutesintobile.(ModifiedfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.) because mixed micelles composed of bile acids, phosphatidylcholine, and cholesterol are osmotically active and the tight junctions that link adjacent hepatocytes are relatively leaky, water is drawn into the canalicular lumen, as well as other plasma solutes (e.g., Ca++, glucose, glutathione, amino acids, urea) at concentrations essentially approximating •Fig. 32.7 Relativeamountsofbileacidsindifferentbodypoolsand theenterohepaticcirculation.Therelativeamountsareindicatedbythe widthofthegreenlines.Thusthefigureillustratesthatthemajorityof thebileacidpoolcirculatesbetweentheliver,gallbladder,andsmall Fig. 32.9 ). Finally, conjugated bilirubin, which is water soluble, and a variety of additional organic and xenobiotics are secreted into bile across the apical intestine,ratherthanbeinginthesystemiccirculation.membrane of the hepatocyte.


Physiology_Levy

Physiology_Levy. •Fig. 32.10 Themajortransportprocessesofcholangiocytesthatsecreteanalkaline-richfluidandreclaimusefulsubstances.AQP,aquaporin;CFTR,cysticfibrosistransmembraneconductanceregulator;GGT,γ-glutamyltranspeptidase;NKCC1,sodium/potassium/2chloridecotransporter1;NBC,sodium/bicarbonatecotransporter;NHE1,sodium/hydrogenexchanger1,SGLT-1,sodium-glucosecotransporter1;GLUT1,glucosetransporter1. The cholangiocytes lining the biliary ductules are specifically designed to modify the composition of bile (


Physiology_Levy

Physiology_Levy. The cholangiocytes lining the biliary ductules are specifically designed to modify the composition of bile ( Fig. 32.10 ). Useful solutes (e.g., glucose, amino acids) are reclaimed by the activity of specific transporters. Chloride ions in bile are also exchanged for HCO3 − , rendering the bile slightly alkaline and reducing the risk of precipitation of Ca++ . Glutathione is broken down on the surface of cholangiocytes into its constituent amino acids by the enzyme γ-glutamyl transpeptidase (GGT), and the products are reabsorbed. Bile is also diluted at this site, in concert with ingestion of a meal, in response to hormones such as secretin that increase HCO3 − secretion and stimulate insertion of aquaporin water channels into the cholangiocyte’s apical membrane. Flow of bile is thereby increased during the postprandial period when bile acids are needed to aid in assimilation of lipid. Role of the Gallbladder


Physiology_Levy

Physiology_Levy. Role of the Gallbladder Finally, bile enters the ducts and is conveyed toward the intestine. However, in the period between meals, outflow is blocked by constriction of the sphincter of Oddi, and thus bile is redirected to the gallbladder. The gallbladder is a muscular sac lined with high-resistance epithelial cells. During gallbladder storage, bile becomes concentrated because sodium ions are actively absorbed in exchange for protons, and bile acids, as the major anions, are too large to exit across the gallbladder epithelial tight junctions (Fig. 32.11 ). However, although the concentration of bile acids can rise more than 10-fold, bile remains isotonic because a •Fig. 32.11 Mechanismsaccountingforconcentrationofbileduringstorageinthegallbladder.NHE,sodium/hydrogenexchanger;BA−,bileacidanion;AQP1,aquaporin1.


Physiology_Levy

Physiology_Levy. single micelle acts as only one osmotically active particle. Any additional bile acid monomers that become available as a result of concentration are thus immediately incorporated into existing mixed micelles. This also reduces to some extent the risk that cholesterol will precipitate from bile. However, cholesterol is supersaturated in the bile of many adults, with precipitation normally being inhibited by the presence of antinucleating proteins. Prolonged storage of bile increases the chance that nucleation can occur, thus making a good case for never skipping breakfast and perhaps explaining why gallstone disease is relatively prevalent in humans.


Physiology_Levy

Humansareunusuallysusceptibletogallstones, whichrepresentprecipitatedbileconstituentsthataccumulateinthegallbladderorelsewhereinthebiliarytree.GallstonesarecomposedpredominantlyofcholesterolorCa++


Physiology_Levy


Physiology_Levy

Physiology_Levy. Bile is secreted from the gallbladder in response to signals that simultaneously relax the sphincter of Oddi and contract the smooth muscle that encircles the gallbladder epithelium ( Fig. 32.12 ). A critical mediator of this response is cholecystokinin. In addition, intrinsic neural reflexes and vagal pathways, some of which themselves are stimulated by the ability of cholecystokinin to bind to vagal afferents, also contribute to gallbladder contractility. The net result is ejection of a concentrated bolus of bile into the duodenal lumen, where the constituent mixed micelles can aid in lipid uptake. Then, when no longer needed, the bile acids are reclaimed and reenter the enterohepatic circulation to begin the cycle again. However, the other components of bile are largely lost in stool, thus providing for their excretion from the body. Bilirubin Formation and Excretion by the Liver


Physiology_Levy

Physiology_Levy. Bilirubin Formation and Excretion by the Liver The liver is also important for excretion of bilirubin, which is a metabolite of heme that is potentially toxic to the body. Bilirubin is an antioxidant and also serves as a way to eliminate the excess heme released from the hemoglobin of senescent red blood cells. Indeed, red blood cells account for 80% of bilirubin production, with the remainder coming from additional heme-containing proteins in other tissues such as skeletal muscle and the liver. Bilirubin can cross the blood-brain barrier and, if present in excessive levels, results •Fig. 32.12 Neurohumoralcontrolofgallbladdercontractionandbiliarysecretion.ThepathwayalsoinvolvesrelaxationofthesphincterofOdditopermitoutflowofbileintotheduodenum.ACh,acetylcholine;CCK,cholecystokinin;NO,nitricoxide;VIP,vasoactiveintestinalpolypeptide.


Physiology_Levy

Physiology_Levy. in brain dysfunction secondary to neuronal cell death and the activation of astrocytes and microglia; it can be fatal if left untreated. Bilirubin and its metabolites are also notable for the fact that they provide color to bile, feces, and to a lesser extent urine. By the same token, when bilirubin accumulates in the circulation as a result of liver disease, it is responsible for the common symptom of jaundice, or yellowing of the skin and conjunctiva. Bilirubin is synthesized from heme by a two-stage reaction that takes place in phagocytic cells of the reticuloendothelial system, including Kupffer cells and cells in the spleen (


Physiology_Levy

Physiology_Levy. Bilirubin is synthesized from heme by a two-stage reaction that takes place in phagocytic cells of the reticuloendothelial system, including Kupffer cells and cells in the spleen ( Fig. 32.13 ). The enzyme heme oxygenase that is present in these cells liberates iron from the heme molecule and produces the green pigment biliverdin. This in turn can be reduced to form yellow bilirubin. Because bilirubin is essentially insoluble in aqueous solutions at neutral pH, it is transported through the bloodstream bound to albumin. When this complex reaches the liver, it enters the space of Disse, where bilirubin is selectively taken up across the basolateral membrane of hepatocytes via an OATP transporter (see


Physiology_Levy

Physiology_Levy. Table 32.1 ). In the microsomal compartment, bilirubin is then conjugated with one or two molecules of glucuronic acid to enhance its aqueous solubility. The reaction is catalyzed by UDP glucuronyl transferase (UGT). This enzyme is synthesized only slowly after birth, which explains why mild jaundice is relatively common in •Fig. 32.13 Conversionofhemetobilirubin.Thereactionsinsidethedashedboxoccurincellsofthereticuloendothelialsystem.NADP+,oxidizedformofnicotinamideadeninedinucleotidephosphate;NADPH,reducedformofnicotinamideadeninedinucleotidephosphate.


Physiology_Levy

Physiology_Levy. newborn infants. The bilirubin conjugates are then secreted into bile by a multidrug resistance–associated protein (MRP2) located in the canalicular membrane. Notably the conjugated forms of bilirubin cannot be reabsorbed from the intestine, thereby ensuring they can be excreted. However, transport of bilirubin across the hepatocyte (and indeed its initial uptake from the bloodstream) is relatively inefficient, so some conjugated and unconjugated bilirubin is present in plasma even under normal conditions. Both circulate bound to albumin, but the conjugated form is bound more loosely and thus can enter the urine. In the colon, bilirubin conjugates are deconjugated by bacterial enzymes, whereupon the bilirubin liberated is metabolized by bacteria to yield urobilinogen, which is reabsorbed, and urobilins and stercobilins, which are excreted. Absorbed urobilinogen in turn can be taken up by hepatocytes and reconjugated, thus giving the molecule yet another chance to be excreted.


Physiology_Levy

Physiology_Levy. Measurement of bilirubin in plasma, as well as assessment of whether it is unconjugated or conjugated, is an important tool in the evaluation of liver disease. The presence of unconjugated bilirubin, which is essentially fully albumin bound and cannot be excreted in urine, reflects either loss of UGT (or a normal temporary delay in its maturation in infants) or a sudden oversupply of heme that overwhelms the conjugation mechanism (such as occurs in transfusion reactions or in Rhesus-incompatible newborns). Conjugated bilirubinemia on the other hand is characterized by the presence of bilirubin in urine, to which it imparts a dark coloration. This is indicative of genetic defects in the transporter that mediates bilirubin glucuronide/diglucuronide secretion into the canaliculus, or it may be due to blockage to the flow of bile, perhaps


Physiology_Levy

Physiology_Levy. CHAPTER 32 Transport and Metabolic Functions of the Liver caused by an obstructing gallstone. In both cases, bilirubin conjugates are formed in the liver, but with no means of exit they regurgitate back into plasma for urinary excretion.


Physiology_Levy

Physiology_Levy. Ammonia Handling by the Liver Ammonia (NH3) is a small neutral metabolite that arises from protein catabolism and bacterial activity and is highly membrane permeant. The liver is a critical contributor to prevention of ammonia accumulation in the circulation, which is important because like bilirubin, ammonia is toxic to the central nervous system. The liver eliminates ammonia from the body by converting it to urea via a series of enzymatic reactions known as the urea, or Krebs-Henseleit, cycle (Fig. 32.14 ). The liver is the only tissue in the body that can convert ammonia to urea.


Physiology_Levy

Physiology_Levy. Ammonia is derived from two major sources. Approximately 50% is produced in the colon by bacterial ureases. Because the colonic lumen is normally slightly acidic, some of this ammonia is converted to the ammonium ion (NH4 +), which renders it impermeant to the colonic epithelium and therefore allows it to be excreted in stool. However, the remainder of the ammonia generated crosses the colonic epithelium passively and is transported to the liver via the portal circulation. The other major source of ammonia (≈40%) is the kidney (see ). A small amount of ammonia (≈10%) is derived from deamination of amino acids in the liver, by metabolic processes in muscle cells, and via release of glutamine from senescent red blood cells. The “mass balance” for ammonia handling in a healthy adult is presented in


Physiology_Levy

Physiology_Levy. The “mass balance” for ammonia handling in a healthy adult is presented in Fig. 32.15 . As just noted, ammonia is a small neutral molecule that readily crosses cell membranes without the benefit of a specific transporter, although some membrane proteins transport ammonia, including certain aquaporins. Whatever the mechanism for transport, the physicochemical properties of ammonia ensure that it is efficiently extracted from portal and systemic circulation •Fig. 32.14 Theureacycle.ADP,adenosinediphosphate;ATP,adenosinetriphosphate.


Physiology_Levy

Physiology_Levy. If the metabolic capacity of the liver is compromised acutely, coma and death can rapidly ensue. In chronic liver disease, patients may experience a gradual decline in mental function that reflects the action of both ammonia and other toxins that cannot be cleared by the liver, in a condition known as hepatic encephalopathy. Development of confusion, dementia, and eventually coma in a patient with liver disease is evidence of significant progression, and these symptoms can prove fatal if left untreated. Clinical Assessment of Liver Function


Physiology_Levy

Physiology_Levy. Clinical Assessment of Liver Function Given the importance of the liver for homeostasis, tests of liver function are a mainstay of clinical diagnosis. Such tests have several goals: (1) to assess whether hepatocytes have been injured or are dysfunctional, (2) to determine whether bile excretion has been interrupted, and (3) to evaluate whether cholangiocytes have been injured or are dysfunctional. Liver function tests are also used to monitor responses to therapy or rejection reactions after liver trans •Fig. 32.15 Ammoniahomeostasisinhealth.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.) by hepatocytes, where it then enters the urea cycle to be converted to urea (see


Physiology_Levy

Physiology_Levy. Fig. 32.14 ) and is subsequently transported back into the systemic circulation. Urea is a small neutral molecule that is readily filtered at the glomerulus, and it is reabsorbed by the kidney tubules such that approximately 50% of the filtered urea is excreted in urine (see ). Urea that enters the colon is either excreted or metabolized to ammonia via colonic bacteria, with the resulting ammonia being reabsorbed or excreted. plantation. However, not all such tests measure function directly. Nevertheless, liver function tests are discussed briefly because of their link to hepatic physiology.


Physiology_Levy

Physiology_Levy. plantation. However, not all such tests measure function directly. Nevertheless, liver function tests are discussed briefly because of their link to hepatic physiology. Tests for hepatocyte injury rely on markers that are specific for this cell type. When hepatocytes are killed by necrotic responses to inflammation or infection, for example, they release enzymes that include alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These enzymes, which are essential to interconvert amino acids, are easily measured in serum and indicate hepatocyte injury, although AST may also be released after injury to other tissues, including the heart. Two other tests are markers of injury to the biliary system. Alkaline phosphatase is expressed in the canalicular membrane, and elevations of this enzyme in plasma suggest localized obstruction to bile flow. Similarly, increased levels of GGT are seen when there is damage to cholangiocytes.


Physiology_Levy

Physiology_Levy. Measurement of bilirubin in the circulation or in urine also provides insight into liver function. In addition, measurement of any of the other characteristic secreted products of the liver can be used to diagnose liver disease. Clinically the most common tests are measurements of serum albumin and a blood clotting parameter, the prothrombin time. If results of these tests are abnormal, when considered together with other aspects of the clinical picture, a diagnosis of liver CHAPTER 32 Transport and Metabolic Functions of the Liver disease may be established. Blood glucose and ammonia levels are frequently monitored in patients with chronic liver disease. Finally, imaging tests and histological examination of biopsy specimens of liver parenchyma, usually obtained percutaneously, are also important in evaluating and monitoring patients with suspected or proven liver disease. 1.


Physiology_Levy

Physiology_Levy. 1. Vital functions of the liver include carbohydrate, lipid, and protein metabolism and synthesis; detoxification of unwanted substances; and excretion of circulating substances that are lipid soluble and carried in the bloodstream bound to albumin. The liver also synthesizes the majority of plasma proteins, including albumin. 2. Liver function depends on its unique anatomy, its constituent cell types (especially hepatocytes), and the unusual arrangement of its blood supply. 3. Substances are excreted from the liver in bile. Bile flow is driven by the presence of bile acids, which are Feranchak AP. Bile secretion and cholestasis. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. Kanel GC. Liver: anatomy, microscopic structure, and cell types. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015.


Physiology_Levy

Physiology_Levy. Kanel GC. Liver: anatomy, microscopic structure, and cell types. In: Podolsky DK, et al., eds. Yamada’s Textbook of Gastroenterology. 6th ed. Hoboken, NJ: Wiley Blackwell; 2015. amphipathic end products of cholesterol metabolism that are produced by hepatocytes. Bile acids circulate between the liver and intestine to conserve their mass, and water-insoluble metabolites (e.g., cholesterol) are carried in bile in the form of mixed micelles. 4. Bile is stored in the gallbladder between meals, where it is concentrated and released when hormonal and neural signals simultaneously contract the gallbladder and relax the sphincter of Oddi. 5. The liver is critical for disposing of certain substances that would be toxic if allowed to accumulate in the bloodstream, including bilirubin and ammonia. Parekh PJ, Balart LA. Ammonia and its role in the pathogenesis of hepatic encephalopathy. Clin Liver Dis. 2015;19:529-537.


Physiology_Levy

Physiology_Levy. Parekh PJ, Balart LA. Ammonia and its role in the pathogenesis of hepatic encephalopathy. Clin Liver Dis. 2015;19:529-537. Wolkoff AW. Organic anion uptake by hepatocytes. Compr Physiol. 2014;4:1715-1735. Wu T, et al. Gut motility and enteroendocrine secretion. Curr Opin Pharmacol. 2013;13:928-934. SECTION 7The Renal System BRUCE A. STANTON AND BRUCE M. KOEPPEN Chapter 36 Potassium, Calcium, and Phosphate Homeostasis Elements of Renal Function Chapter 34 Solute and Water Transport Along the Nephron: Tubular Function Chapter 35 Control of Body Fluid Osmolality and Volume Chapter 37 Role of the Kidneys in the Regulation of Acid-Base Balance Upon completion of this chapter the student should be able to answer the following questions: 1. Which structures in the glomerulus are filtration barriers to plasma proteins? 2. What is the physiological significance of the juxtaglomerular apparatus? 3. What blood vessels supply the kidneys? 4. What nerves innervate the kidneys? 5.


Physiology_Levy

Physiology_Levy. 2. What is the physiological significance of the juxtaglomerular apparatus? 3. What blood vessels supply the kidneys? 4. What nerves innervate the kidneys? 5. What is the location of the kidneys, and what are their gross anatomical features? 6. What are the different parts of the nephron, and what is their locations within the cortex and medulla? 7. What are the major components of the glomerulus, and what are the cell types located in each component? 8. How can the concepts of mass balance be used to measure the glomerular filtration rate (GFR)? 9. Why can inulin clearance and creatinine clearance be used to measure GFR? 10. Why is plasma creatinine concentration used clinically to monitor GFR? 11. What are elements of the glomerular filtration barrier, and how do they determine how much protein enters Bowman’s space? 12. What Starling forces are involved in formation of the glomerular ultrafiltrate, and how do changes in each force affect GFR? 13.


Physiology_Levy

Physiology_Levy. 12. What Starling forces are involved in formation of the glomerular ultrafiltrate, and how do changes in each force affect GFR? 13. What is autoregulation of renal blood flow and GFR, and which factors and hormones are responsible for autoregulation? 14. Which hormones regulate renal blood flow? 15. Why do hormones influence renal blood flow despite autoregulation? Overview of Renal Function The kidney presents in the highest degree the phenomenon of sensibility, the power of reacting to various stimuli in a direction, which is appropriate for the survival of the organism; a power of adaptation which almost gives one the idea that its component parts must be endowed with intelligence. E. STARLING—1909 Certainly, mental integrity is a sine qua non of the free and independent life. But let the composition of our internal environment suffer change, let our kidneys fail for even a short time to fulfill their tasks, and our mental integrity, or personality is destroyed.


Physiology_Levy

Physiology_Levy. HOMER W. SMITH—1939 As both Starling and Smith recognized, the kidneys are more appropriately considered regulatory rather than excretory organs. The kidneys regulate (1) body fluid osmolality and volumes, (2) electrolyte balance, and (3) acid-base balance. In addition the kidneys excrete metabolic products and foreign substances and produce and secrete hormones.


Physiology_Levy

Physiology_Levy. Control of body fluid osmolality is important for maintenance of normal cell volume in all tissues of the body. Control of body fluid volume is necessary for normal function of the cardiovascular system. The kidneys are also essential in regulating the amount of several important inorganic ions in the body, including Na+, K+, Cl−, bicarbonate (HCO3 −), hydrogen (H+), Ca++ , and inorganic phosphate (Pi). Excretion of these electrolytes must be equal to daily intake to maintain appropriate total body balance. If intake of an electrolyte exceeds its excretion, the amount of this electrolyte in the body increases and the individual is in positive balance for that electrolyte. Conversely if excretion of an electrolyte exceeds its intake, its amount in the body decreases and the individual is in negative balance for that electrolyte. For many electrolytes the kidneys are the sole or principal route for excretion from the body.


Physiology_Levy

Physiology_Levy. Another important function of the kidneys is regulation of acid-base balance. Many metabolic functions of the body are exquisitely sensitive to pH. Thus the pH of body fluids must be maintained within narrow limits. Normal pH is maintained by buffers within body fluids and by the coordinated action of the lungs, liver, and kidneys. The kidneys excrete a number of the end products of metabolism. These waste products include urea (from amino acids), uric acid (from nucleic acids), creatinine (from muscle creatine), end products of hemoglobin metabolism, and metabolites of hormones. The kidneys eliminate these substances from the body at a rate that matches their production. Thus the kidneys regulate hormone concentrations within body fluids. The kidneys also represent an important route for elimination of foreign substances such as drugs, toxins (e.g., pesticides), and other chemicals from the body.


Physiology_Levy

Physiology_Levy. Finally, the kidneys are important endocrine organs that produce and secrete renin, calcitriol, and erythropoietin. Renin is not a hormone but an enzyme that activates the renin-angiotensin-aldosterone system, which helps regulate blood pressure and Na+ and K+ balance. Calcitriol, a metabolite of vitamin D3, is necessary for normal absorption of Ca++ by the gastrointestinal tract and for its deposition in bone (see ). In patients with renal disease the kidneys’ ability to produce calcitriol is impaired and levels of this hormone are reduced. As a result, Ca++ absorption by the intestine is decreased, which over time contributes to the bone formation abnormalities seen in patients with chronic renal disease. Another consequence of many kidney diseases is a reduction in erythropoietin production and secretion. Erythropoietin stimulates red blood cell formation by bone marrow. Decreased erythrocyte production contributes to the anemia that occurs in chronic kidney disease (CKD), a


Physiology_Levy

Physiology_Levy. production and secretion. Erythropoietin stimulates red blood cell formation by bone marrow. Decreased erythrocyte production contributes to the anemia that occurs in chronic kidney disease (CKD), a progressive loss in kidney function over a period of months or years.