Gastroenterologists require detailed knowledge regarding theanatomy of the GI system in order to understand thedisturbances caused by diseases they diagnose and treat. Gastrointestinal Anatomy and Physiology will bring together theworld's leading names to present a comprehensive overview ofthe anatomical and physiological features of the gastrointestinaltract. Full colour and with excellent anatomical and clinical figuresthroughout, it will provide succinct, authoritative and didacticanatomic and physiologic information on all the key areas,including GI motility, hepatic structure, GI hormones, gastricsecretion and absorption of nutrients. GI trainees will enjoy the self-assessment MCQs, writtento the level they will encounter during their Board exams,and the seasoned gastroenterologist will value it as a handyreference book and refresher for re-certification exams
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CHAPTER 1 : Structure and innervation of hollow viscera
The muscularis propria
Serosa or adventitia
Colon and rectum
Multiple choice questions
CHAPTER 2 : Gastrointestinal hormonesin the regulation of gut function in health and disease
Gut peptide classification and function
Multiple choice questions
CHAPTER 3 : Gastrointestinal motility
Enteric nervous system
Small bowel motility
Multiple choice questions
CHAPTER 4 : Gastrointestinal immunology and ecology
The anatomy of the mucosal immune system
Sites of mucosal immune–microbial interactions
Cells of the mucosal immune system
Immunosuppression in the GI tract: Oral tolerance
The enteric ecosystem
Multiple choice questions
CHAPTER 5 : Gastric physiology
Regulation of gastric acid secretion
Measurement of gastric acid secretion
Regulation of pepsinogen secretion
Multiple choice questions
CHAPTER 6 : Structure and functionof the exocrine pancreas
Cellular mechanisms of secretion
Regulation of pancreatic secretion
Multiple choice questions
CHAPTER 7 : Absorption and secretion of fluid and electrolytes
Principles of transepithelial transport
Regional transport properties of the intestine
Regulation of transport
Multiple choice questions
CHAPTER 8 : Absorption of nutrients
Multiple choice questions
CHAPTER 9 : Hepatic structure and function
Assessment of liver function
Multiple choice questions
CHAPTER 10 : The splanchnic circulation
Multiple choice questions
CHAPTER 11 : Composition and circulation of the bile
Mechanism of bile formation
Chemistry of bile acids
Bile acid transport and the enterohepatic circulation
Functions of bile acids
Multiple choice questions
CHAPTER 12 : Bilirubin metabolism
Sources of bilirubin
Transport and metabolism of bilirubin
Extrahepatic fate of excreted bilirubin
Clinical laboratory determination of serum bilirubin
Evaluation of the patient with hyperbilirubinemia
Multiple choice questions
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Table 2.1 GI hormone families.
Table 2.2 Clinical application of GI hormones.
Table 3.1 Putative neurotransmitters of the ENS.
Table 3.2 Prokinetic therapies used in GI motility disorders.
Table 3.3 Inhibitory pharmacologic therapies used in GI motility disorders.
Table 6.1 Sites of action of pancreatic digestive enzymes.
Table 6.2 Protective mechanisms to prevent pancreatic autodigestion.
Table 7.1 Some transport proteins of the intestine.
Table 7.2 Luminal substances causing secretion.
Table 7.3 Endogenous agents that can alter intestinal transport from the basolateral surface.
Table 8.1 Schemes for lipid digestion and absorption.
Table 8.2 Schemes for protein digestion and absorption.
Table 8.3 Schemes for carbohydrate digestion and absorption.
Table 9.1 Causes of serum aminotransferase elevationsaa.
Table 9.2 Causes of conjugated hyperbilirubinemia.
Table 12.1 Comparison of inheritable disorders characterized by unconjugated or conjugated hyperbilirubinemia.
Figure 1.1 Normal histology of the esophagus. (a) Low-power image (H&E stain) of normal esophagus illustrating the characteristic layers of the wall – mucosa, submucosa, muscularis propria, and adventitia/serosa. A submucosal gland can be seen at the right side of the image. (b) Medium-power image (H&E stain) of the esophageal mucosa, with stratified squamous epithelium, lamina propria, and muscularis mucosae. Note the rich vascularity in the lamina propria. (c) High-power image (H&E stain) of an esophageal submucosal gland. (d) High-power image (PAS-AB stain) of an esophageal submucosal gland with characteristic dark blue color.
Figure 1.2 Normal histology of the stomach. (a) Low-power image (H&E stain) of normal stomach (body) illustrating the characteristic layers of the wall – mucosa, submucosa, muscularis propria, and serosa. (b) Medium-power image (H&E stain) of transitional gastric epithelium. On the right, oxyntic epithelium consists of surface foveolar cells overlying oxyntic glands with parietal and chief cells. On the left, antral epithelium consists of foveolar cells overlying mucin-producing antral glands. (c) Medium-power image (PAS-AB stain) of antral epithelium, illustrating the bright pink staining of both the foveolar cells and the antral glands. (d) Medium-power image (PAS-AB) stain of oxyntic epithelium, with bright pink staining of foveolar cells but lack of staining in the parietal and chief cells of the oxyntic glands. (e) Antral mucosa (gastrin immunohistochemical stain), illustrating the presence of gastrin-producing G cells in the antral glands. Gastrin immunohistochemical stain is negative in oxyntic mucosa and in cardiac mucosa.
Figure 1.3 Normal histology of the small bowel. (a) Low-power image (H&E stain) of normal small bowel with plicae circulares and epithelial villi. The small bowel contains the same layers as the other organs of the tubular GI tract – mucosa, submucosa, muscularis propria, and serosa. (b) Medium-power image (H&E stain) of the duodenal mucosa and submucosa, illustrating the presence of Brunner’s glands in the lamina propria and submucosa. Strictly speaking, Brunner’s glands should be restricted to the submucosa, but most adult patients have Brunner’s glands in the duodenal lamina propria, presumably a reparative change. (c) Medium-power image (PAS-AB stain) of the duodenal mucosa and submucosa, illustrating the bright pink staining of Brunner’s glands. Note that the goblet cells contain alcianophilic purple-colored mucin, whereas the absorptive cells lack mucin.
Figure 1.4 Normal histology of the colon. (a) Low-power image (H&E stain) of normal colon illustrating the characteristic layers – mucosa, submucosa, muscularis propria, and serosa. Large vessels are apparent in the submucosa but not the lamina propria. (b) Medium-power image (H&E stain) of normal colonic mucosa, with regular crypts lined by mucin-producing goblet cells arranged like “test tubes in a rack” and abuting on the muscularis mucosae. (c) Muscularis propria of the colon (CD117 immunohistochemical stain), illustrating the presence of numerous ICCs scattered throughout the muscularis propria. (d) Lamina propria of the colon (CD117 immunohistochemical stain), illustrating the (normal) presence of mast cells in the lamina propria – these cells should not be confused with ICCs, which are also positive for CD117.
Figure 1.5 Normal histology of the anus. (a) Low-power image (H&E stain) of anus with dilated hemorrhoidal blood vessels in the submucosa. The mucosa consists of colonic (right), transitional (center), and squamous (left) regions. The anus consists of the characteristic layers, with an adventitia due to its retroperitoneal location. (b) High-power image (H&E stain) of a submucosal anal gland. (c) Medium-power image (H&E stain) of dilated hemorrhoidal vessels in the submucosa of the anus.
Figure 2.1 EEC of the GI tract. (a) Image of canine antral mucosa immunostained with a SST-specific antibody. Somatostatin cells are shown as the dark brown staining cells. This image depicts the small number and diffuse distribution of a typical EEC. (b) Electron micrograph of a gastrin and Somatostatin cell revealing the numerous secretory granules and the proximity of these cells to each other and to a capillary bed.
Figure 2.2 Diagram depicting the steps involved in the synthesis and processing of GI hormones. The process is initiated in the nucleus through gene transcription of the corresponding DNA into mRNA which in turn is translocated to the cytoplasm where it is translated into the corresponding precursor hormone, the preprohormone polypeptide chain. The precursor molecule is then processed through several steps in the rough endoplasmic reticulum (RER) and Golgi apparatus, resulting in the biologically active molecule which is stored in the secretory granule from which it is released to its target cell after a specific stimulus.
Figure 2.3 Pathways by which GI hormones mediate their actions. Once released, gut hormones can lead to subsequent target cell activation through either an endocrine (peptide reaches its target via the circulation), a paracrine (peptide traverses the paracellular environment to reach its target), or an autocrine (peptide acts upon its cell of origin).
Figure 2.4 Receptor activation and postreceptor signaling. Diagram of a GPCR. As in the case of the gastrin receptor, GPCRs traverse the lipid bilayer of the cell membrane seven times. Upon ligand (gastrin) binding, the receptor undergoes conformational change which leads to binding of the corresponding G-protein, which, in turn, activates downstream effectors essential for the ultimate biological action (secretion, contraction, growth). From Reference .
Figure 3.1 Schematic depiction of the neurologic control of GI motility. The central, autonomic, and enteric nervous systems work in concert on the smooth muscle effector system of the GI tract. Disorders at each level of neurologic control or at the visceral smooth muscle end organ level may result in motility disorders. Specific examples of disorders are listed to the right side of the schematic. Adapted from Reference .
Figure 3.2 Isobaric color contour plot of normal esophageal manometry. Color denotes the amplitude of esophageal contractile activity. A swallow is associated with brief relaxation of the upper esophageal sphincter followed by sequential contractions of the esophageal body comprising primary peristalsis. Relaxation of the LES corresponds with the onset of swallowing.
Figure 3.3 Isobaric color contour plot of achalasia. Complete esophageal aperistalsis is event with failure of deglutitive relaxation of the LES.
Figure 3.4 Isobaric color contour plot of phase 3 of the MMC. Phasic contractions of the gastric antrum occur at a slower frequency than clustered contractions of the duodenum and jejunum.
Figure 3.5 Isobaric color contour plots of anorectal manometric responses to attempted defecation. (a) Normal pattern: There is an appropriate increase in intrarectal pressure (black parenthesis; >45 mm Hg) with reflexive relaxation of the anal sphincters (red parenthesis). (b) Type I dyssynergia: There is an appropriate increase in intrarectal pressure but paradoxical contraction of the anal sphincters. (c) Type II dyssynergia: There is an insufficient increase in intrarectal pressure with paradoxical contraction of the anal sphincters. This is also known as inadequate defecatory propulsion. (d) Type III dyssynergia: There is an appropriate increase in intrarectal pressure with a lack of anal sphincter relaxation.
Figure 3.6 Isobaric color contour plots of normal and abnormal recto-anal inhibitory reflexes (RAIRs). (a) As the intrarectal pressure increases (black arrow), the internal anal sphincter reflexively relaxes (red arrow). This is a normal response. (b) As the intrarectal pressure increases (black arrow), there is no relaxation of the internal anal sphincter (red arrow). This is an inappropriate response.
Figure 3.7 Wireless motility capsule tracing depicting simultaneous recordings of intraluminal temperature, pH, and pressure. (a) Gastric transit time: This is measured from the time the capsule is ingested until the time it enters the duodenum. This is best evaluated via the pH tracings (green lines). Entry into the duodenum is characterized by a large increase in pH, indicating a shift from the acidic milieu of the stomach to the alkalinized small intestine. (b) Small intestinal transit time: This is measured from the time the capsule enters the duodenum to the time it enters the cecum. This occurs when there is a decrease of at least 1 pH unit lasting more than 10 min and occurring greater than 30 min after entry of the capsule into the small intestine. The decrease in pH is believed secondary to acidic fermentation of digestive matter by colonic flora. This is best assessed by the pH tracings (green lines). (c) Colon transit time: This is measured from the time the capsule enters the cecum to the time it exits the body. The exit time can be determined using the blue lines. The temperature will remain stable throughout the study until the capsule is expelled from the body which will be characterized by a precipitous decrease in temperature correlating to the temperature of the water in the toilet basin. (d) Whole gut transit time: This is calculated from the time of ingestion until the capsule is passed as represented by the rapid decrease in temperature which correlates to passage of the capsule.
Figure 4.1 The gut immune system. Interactions between commensal bacteria, antigens, and immune cells occur at PPs and isolated follicles, where M cells in the follicle-associated epithelium translocate bacterial antigens from the lumen to the dome region beneath the follicle-associated epithelium. Immature myeloid DCs and macrophages encounter and process antigen, differentiate into mature DCs, and migrate to T-cell zones in PP or to mesenteric lymph nodes to activate T cells. The organized GALT serves as the source of the activated effector cells, which populate the intervening mucosa; cells leave via efferent lymph, enter the blood stream, and migrate back to the lamina propria. Lymphocyte trafficking to the intestine is directed by adhesion receptors.
Figure 4.2 Modulating the immune system in IBD. Therapies for IBD are tailored to specifically target an immune mediator of disease. (a) Current therapies that target immune cell trafficking to inflamed intestinal mucosa include corticosteroids and natalizumab (antibody that blocks interaction between integrin α4 on the leukocyte and MAdCAM1 on the endothelial cell). Emerging therapies include inhibition of integrin α4β7 and MAdCAM1 that occurs specifically in the vascular endothelium of the intestines and other small molecules, for example, silencing RNAs targeting adhesions molecules in the vascular endothelium(b) T-cell activation is the target of widely used immunomodulator therapy in IBD that includes azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus. Clinical trials for antibodies directed toward T cells (CD3) and subset populations (CD23, Tregs) are being conducted; (c) the monoclonal antibodies to tumor necrosis factor (TNF) (infliximab, a mouse–human chimeric antibody; adalimumab, a humanized recombinant antibody to TNF; and certolizumab pegol, a Fab fragment of a humanized anti-TNF alpha monoclonal antibody that is attached to polyethylene glycol to increase its half-life in circulation) are FDA-approved biological therapies for IBD. Future therapies target the IL-12 and IL-23 axis.
Figure 5.1 Functional gastric anatomy. The stomach consists of three anatomic (fundus, corpus or body, and antrum) and two functional (oxyntic and pyloric gland) areas. The hallmark of the oxyntic gland area is the parietal cell, whereas that of the pyloric gland area is the G or gastrin cell. SST-containing D cells are present in both functional areas. Their cytoplasmic processes terminate in the vicinity of acid-secreting parietal cells and histamine-secreting ECL cells in the oxyntic gland area (fundus and corpus) and gastrin-secreting G cells in the pyloric gland area (antrum). The functional correlate of this anatomic coupling is a tonic restraint exerted by SST on acid secretion that is exerted directly on the parietal cell as well as indirectly by inhibiting histamine and gastrin secretion. From Reference . Reproduced with permission of Elsevier.
Figure 5.2 Model illustrating the receptors and transduction pathways regulating acid secretion by the parietal cell. The principal stimulants of acid secretion at the level of the parietal cell are histamine (paracrine), gastrin (hormonal), and ACh (neurocrine). Histamine, released from ECL cells, binds to H2 receptors that activate AC and convert adenosine-5'-triphosphate (ATP) to adenosine 3′,5′-cyclic monophosphate (cAMP). Increases in cAMP activate cAMP-dependent protein kinases (PKA) to phosphorylate intracellular proteins that ultimately elicit acid secretion. Gastrin, released from G cells, binds to CCK2 receptors that activate phospholipase C (PLC) with conversion of phosphatidylinositol bisphosphate (PIP2) to inositol trisphosphate (IP3). IP3, in turn, induces release of cytosolic calcium (Ca++) with activation of calcium-dependent enzymes, such as calmodulin kinases, that ultimately elicit acid secretion. The acid stimulatory effects of gastrin, however, are currently thought to be mediated primarily by release of histamine from ECL cells (thick arrow). ACh, released from postganglionic intramural neurons, binds to M3 receptors that are coupled to an increase in intracellular Ca++ via similar pathways described previously for gastrin. The intracellular cAMP- and calcium-dependent signaling systems activate downstream kinases that ultimately lead to fusion and activation of H+K+-ATPase, the proton pump. SST, released from oxyntic D cells, is the principal inhibitor of acid secretion. Acting via the SSTR2 receptor, SST inhibits parietal cell secretion directly as well as indirectly by inhibiting histamine release from ECL cells. +, stimulatory; −, inhibitory. From Reference . Reproduced with permission of Elsevier.
Figure 5.3 Model illustrating the neural, paracrine, and hormonal regulation of gastric acid secretion. Vagal efferent fibers synapse with intramural gastric cholinergic (ACh) and peptidergic (GRP, VIP, and PACAP) neurons. In the fundus and corpus (oxyntic mucosa), ACh neurons stimulate acid secretion directly (via M3 receptors) as well as indirectly by inhibiting SST secretion (via M2 and M4 receptors), thus eliminating its restraint on parietal and histamine-containing ECL cells. In the antrum (pyloric mucosa), ACh neurons stimulate gastrin secretion directly (via M3 receptors) as well as indirectly by inhibiting SST secretion (via M2 and M4 receptors). GRP neurons, activated by luminal protein, stimulate gastrin secretion directly. VIP neurons, activated by low-grade distension, stimulate SST (via VPAC-1 receptors) and thus inhibit gastrin secretion. PACAP neurons, acting via PAC-1 receptors, stimulate histamine secretion and, acting via VPAC-1 receptors, stimulate SST secretion; the net effect of PACAP on acid secretion will depend upon the relative contribution of these pathways. Dual paracrine pathways link SST-containing D cells to parietal and ECL cells in the fundus/body. Histamine released from ECL cells acts via H3 receptors to inhibit SST secretion; this pathway serves to accentuate the decrease in SST secretion induced by cholinergic stimuli and thus augments acid secretion. In the antrum, dual paracrine pathways link SST and gastrin secretion. Release of acid into the lumen of the stomach restores SST secretion in both the fundus/body and antrum; the latter is mediated by release of CGRP from extrinsic sensory neurons.
Figure 5.4 Model illustrating the generation and secretion of hydrochloric acid (HCl) by the parietal cell. Acid secretion requires a functional H+K+-ATPase as well as apical K+ (KCNQ1, KCNJ15, and/or KCNJ10) and Cl− (CFTR, CLIC-6, and/or CLC26A9) channels and basolateral Cl− channels (SLC26A7), exchangers (Cl−/HCO3− anion exchanger 2 (AE2 or SLC4A2)), and transporters (NKCCl or Na+-2Cl−K+ cotransporter). Acid is produced by the hydration of CO2 to form H+ + HCO3−, a reaction catalyzed by cytoplasmic carbonic anhydrase CA. For each H+ secreted, a HCO3− exits the cell via the basolateral AE2.
Figure 5.5 Gastroduodenal offense and defense. Mucosal integrity depends upon a delicate balance between aggressive and defensive factors. When mucosal defense mechanisms are overwhelmed, ulceration may occur. NSAIDs, nonsteroidal anti-inflammatory drugs; ROS, reactive oxygen species; HCO3, bicarbonate; H2S, hydrogen sulfide; CA, carbonic anhydrase; CGRP, calcitonin gene-related peptide; NO, nitric oxide; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2. From Reference . Reproduced with permission of Elsevier.
Figure 6.1 (a) Anterior and (b) posterior views of the pancreas and some surrounding structures. A, artery; B, body; H, head; T, tail; V, vein. From Reference . Reproduced with permission of Elsevier.
Figure 6.2 Diagrammatic view of the pancreas showing the main and accessory ducts, common bile duct, and major and minor duodenal papillae. From Reference . Reproduced with permission of Elsevier.
Figure 6.3 Histologic organization of the pancreatic acinus and its relationship to surrounding capillaries and nerves. From Reference . Reproduced with permission of Elsevier.
Figure 6.4 Concentrations of the major ions in pancreatic juice. The concentrations of Na+ and K+ are similar to those in plasma and do not change with increasing rates of secretion. However, as the rate of secretion rises, the concentration of HCO3− increases substantially coupled with a reciprocal decrease in the concentration of Cl−. From Reference . Reproduced with permission of Morgan & Claypool Life Sciences.
Figure 6.5 Cellular mechanisms involved in the secretion of HCO3− by the pancreatic duct cell. HCO3− enters the cell via cotransport with Na+ on the basolateral surface of the cell and is formed by the action of CA on H2O and CO2. Secretion is mediated by secretin which increases intracellular cAMP and ACh which increases intracellular Ca2+. Cl− enters the duct lumen through conductance channels provided by CFTR (mediated by cAMP) and a Ca+-mediated channel. HCO3− is secreted into the duct lumen in exchange for Cl−. HCO3− may also pass into the duct lumen via CFTR and the Ca+-mediated conductance, at least under some circumstances. Na+ travels into the duct lumen by electrodiffusion through paracellular tight junction channels, and water enters through aquaporin water channels (not shown). From Reference . Reproduced with permission of Morgan & Claypool Life Sciences.
Figure 7.1 Basic arrangement of the gastrointestinal epithelium. Epithelial cells are polarized with distinct apical and basolateral cell membrane domains separated by tight junctions.
Figure 7.2 Channels are pores in the cell membrane which are specific for a particular ion with gates that open and close rapidly allowing ions to diffuse down their electrochemical gradients.
Figure 7.3 Carriers are protein complexes which facilitate the movement of specific solutes across the membrane. The solute may move in response to its own concentration gradient (facilitated diffusion) (panel a) or by using the energy inherent in concentration gradients of other solutes produced by other transporters (secondary active transport). Subtypes include cotransporters (panel b), carriers which move two substances in the same direction across a membrane, and exchangers (panel c), carriers that move ions in opposite directions across a membrane.
Figure 7.4 Pumps are transport proteins that move solutes against electrochemical gradients by directly linking energy production (i.e., ATP hydrolysis) to transport.
Figure 7.5 Active transport requires production of energy to move solute across the mucosa. Primary active transport involves pumps that directly couple energy creation from hydrolysis of ATP to movement of solute (e.g., sodium–potassium ATPase on basolateral membrane). The ion gradients produced by active transport can power secondary active transport at the apical membrane (e.g., glucose–sodium cotransport).
Figure 7.6 Passive transport involves passage of solute down its concentration through carriers (transcellular pathway) or through tight junctions (paracellular pathway).
Figure 7.7 Solvent drag involves entrainment of solute in the stream of water passing through the tight junctions. It can only occur in the duodenum and jejunum where tight junctions are loose enough to produce large paracellular water fluxes.
Figure 7.8 Fluid flow through the lumen and mixing of contents are optimal in the center of the lumen and decrease at the mucosal surface where water movement is very slow, producing an “unstirred water layer” that can serve as a diffusion barrier for large molecular arrays like mixed micelles.
Figure 7.9 Glucose-stimulated sodium absorption in the jejunum likely involves solvent drag since most sodium that is absorbed transcellularly leaks back into the lumen through the paracellular pathway.
Figure 7.10 The bulk of water absorption occurs in the jejunum and ileum due to vigorous nutrient and sodium absorption in these regions of the intestine. Adapted from Reference . Reproduced with permission of Elsevier.
Figure 7.11 Colonic absorption removes almost all remaining water from the lumen as sodium is reduced to very low levels (~10 mmol/l). Adapted from . Reproduced with permission of Elsevier.
Figure 9.1 Drawing of the abdomen with the anterior abdominal wall cut away. The right and left lobes of the liver are separated by the falciform ligament. From Reference . Reproduced with permission of Wolters Kluwer Health.
Figure 9.2 Drawing of the posterior aspect of the liver with depiction of the liver segments. The quadrate lobe is demarcated by the gallbladder, porta hepatis, and ligamentum teres. The caudate lobe is demarcated by the IVC, porta hepatis, and ligamentum venosum. The solid black line represents the “Cantlie line,” which separates the functional right and left lobes. The dotted black line shows the divisions between the anterior and posterior segments of the functional right lobe and the lateral and medial segments of the functional left lobe. From Reference . Reproduced with permission of Elsevier.
Figure 9.3 Schematic drawing of liver architecture. At the left is the classic hepatic lobule, with the central vein as its center and portal tracts at three corners. In the middle toward the bottom is the portal lobule, with the portal tract at its center and central veins and nodal points at its periphery. At the right is the liver acinus, the center of which is the terminal afferent vessel (in the portal tract) and the periphery of which is drained by the terminal hepatic venule, or central vein. Zones 1, 2, and 3 extending from the portal tract to the terminal hepatic venule are shown. CV, central vein; N, nodal point; P, portal tract; TVH, terminal hepatic venule. From Reference . Reproduced with permission of Elsevier.
Figure 9.4 Drawing that compares liver blood flow in the three zones of the acinus model with Matsumoto’s concept of liver architecture. According to the model by Matsumoto, sinusoids that abut portal tracts and terminal afferent vessels (septal branches) form a hemodynamically equipotential sickle-shaped perfusion front (dotted lines). This model conforms to the concept of the classic lobule rather than to the acinus. Zones 1, 2, and 3 of the hepatic acinus are labeled. PT, portal tract; THV, terminal hepatic venule. From Reference . Reproduced with permission of Elsevier.
Figure 9.5 Radial distribution of the liver cell (hepatocyte) plates and sinusoids around the terminal hepatic venule, or central vein. A bile duct, branches of the portal vein hepatic artery, and bile canaliculi are shown. From Reference . Reproduced with permission of Hodder Education.
Figure 9.6 Drawing of liver cell plates and adjoining sinusoids. DS, space of Disse; E, endothelial cell; F, stellate (fat-storing, Ito) cell; H, hepatocyte; K, Kupffer cell; P, pit cell. From Reference . Reproduced with permission of S. Karger AG, Basel.
Figure 10.1 NO-mediated relaxation of VSM in splanchnic arterioles. The endothelial cell enzyme NO synthase generates NO following activation with either ACh, substance P, or VIP. The NO diffuses into the underlying smooth muscle cells to activate guanylate cyclase and consequently produce cyclic GMP (cGMP), which lowers intracellular calcium and elicits VSM relaxation.
Figure 10.2 Oxygen consumption is better maintained than blood flow in digestive organs when blood pressure is reduced. The recruitment (opening) of more perfused capillaries at low pressures minimizes the distance that oxygen must diffuse between blood and parenchymal cells, thereby facilitating O2 exchange and maintaining O2 consumption.
Figure 10.3 Changes in the balance of hydrostatic (capillary, Pc, and interstitial, Pt) and oncotic (capillary, πc, and interstitial, πt) forces enable capillaries to absorb or filter water (Jv) in accordance with the transport function of epithelial cells in digestive organs. In the absence of epithelial transport (resting state), capillaries filter at a low rate. When water enters the interstitium as a result of epithelial water absorption, the capillaries assume an absorptive phenotype due to the rise in Pt and Kf (a measure of the number of capillaries open to perfusion) and a reduction in πt. When epithelial cells are stimulated to secrete fluid from interstitium to lumen (gut or duct), interstitial volume falls, which leads to a fall in Pt and an increase in πt. These changes in interstitial forces are accompanied by increases in Pc and Kf. These changes promote capillary hyperfiltration, which provides the fluid needed for the secretory pump.
Figure 10.4 (a) Microvascular transport of HCO3− from acid-secreting portion of the gastric pit to the surface epithelium. The surface epithelial cells, in turn, transport HCO3− into the adherent mucus layer creating a pH gradient decreasing from the epithelium to the gastric lumen. Adapted from Gastroenterology, 1984, pp. 866–875. Reproduced with permission from Elsevier. (b) Proposed mechanism by which interstitial H+ activates a neural reflex that induces a hyperemia to (i) deliver additional HCO3− to epithelial cells for transport into the mucus layer and (ii) neutralize the excess H+ in the interstitium. CGRP, calcitonin gene-related peptide; NO, nitric oxide.
Figure 10.5 The dependency of portal pressure on portal blood flow when portal vascular resistance is normal (solid line) or increased (broken line). Increasing blood flow leads to an increased portal pressure when vascular resistance is either normal (point A to point B) or elevated (point C to point D). When both blood flow and vascular resistance are increased (e.g., portal hypertension), a more substantial increase in portal pressure occurs (point A to point D).
Figure 11.1 Synthesis of bile acids: cholic and chenodeoxycholic acids are synthesized in hepatocytes from cholesterol and are known as primary bile acids. They differ from cholesterol through shortening of the side chain and hydroxylation patterns of the ring structure. The 3-OH group of cholesterol is in the β configuration, as indicated by a solid line, and becomes epimerized to the α configuration, indicated by a dashed line, during the biosynthetic process. The α and β designations refer to whether the hydroxyl group is below or above the plane of the steroid ring, respectively. Hydroxylation at the 7 and 12 positions results in formation of cholic acid, while addition of a hydroxyl group at the 7 position alone in addition to that at the 3 position results in formation of chenodeoxycholic acid. All of these hydroxyl groups are in the α configuration. Within the intestine, there are bacteria that 7-dehydroxylate the primary bile acids cholic and chenodeoxycholic acids resulting in formation of the secondary bile acids deoxycholic and lithocholic acids, respectively. In addition, a small amount of ursodeoxycholic acid is formed from chenodeoxycholic acid by epimerization of the 7-α hydroxyl group to 7-β. These bile acids can be absorbed from the intestine and added to the bile acid pool, although the poor aqueous solubility of lithocholic acid limits its availability.
Figure 11.2 Conjugation of bile acids: within the hepatocyte, all bile acids are conjugated with the amino acids glycine or taurine at the carboxyl side chain. In humans, glycine is the predominant conjugate. Conjugation serves to increase the solubility of the bile acids at physiologic pH. Although most conjugated bile acids are reabsorbed from the small intestine, the small amount that reaches the colon can be deconjugated by bacteria and reabsorbed passively through the intestinal lumen into the portal circulation. They can then be extracted by hepatocytes and reconjugated.
Figure 11.3 The enterohepatic circulation of bile acids: bile acids within the portal circulation are taken up avidly by hepatocytes via the NTCP that mediates their predominant Na+-dependent uptake or an organic anion transport protein (OATP) that mediates their Na+-independent uptake in exchange for an anion such as HCO3−. Bile acids are subsequently pumped out of the hepatocyte into bile by an ATP-dependent pump termed BSEP. Bile acids in bile flow into the small intestine where they are efficiently recovered. The major transporters for bile acid recovery are located in the ileal enterocyte of the terminal ileum. They are taken up into the cell by a Na+-dependent protein called the ASBT that resides on the brush border membrane of the enterocytes. This transporter is related to but distinct from NTCP, the Na+-dependent hepatocyte bile acid transporter. Bile acids within the ileal enterocytes are exported into the portal circulation by a heteromeric protein termed OST that is composed of two subunits, OST-α and OST-β. The cycle can then repeat. The enterohepatic circulation of bile acids is highly efficient recovering approximately 95% per day of bile acids that are secreted into the intestine.
Figure 12.1 Pathway of bilirubin formation from heme: bilirubin is a degradation product of heme that is released from senescent red blood cells as well as other heme proteins such as cytochromes. The first step in this process is opening of the tetrapyrollic heme ring at its α-methene bridge. This process is catalyzed by the enzyme heme oxygenase and results in release of an atom of iron and a molecule of carbon monoxide (CO) and formation of the green compound, biliverdin. This reaction is the only endogenous source of CO, a gas that may have important biological signal transduction effects. Biliverdin is converted to the yellow compound bilirubin, catalyzed by the enzyme biliverdin reductase.
Figure 12.2 Schematic diagram of the liver as it relates to bilirubin transport and metabolism: bilirubin has very low aqueous solubility and circulates in the blood stream bound tightly to albumin. Fenestrations in the sinusoidal endothelium (SE) permit the albumin–bilirubin complex to enter the space of Disse and come into proximity of hepatocyte microvilli that contain a bilirubin transporter (T) that facilitates entry into the hepatocyte of the unbound bilirubin that is in equilibrium with albumin-bound bilirubin. Within the hepatocyte, bilirubin binds to GSTs as a nonsubstrate ligand and is conjugated with glucuronic acid in a reaction catalyzed by the enzyme UGT1A1 and requiring UDP-GA . Conjugation of bilirubin with glucuronic acid renders it water soluble, and it is then pumped out of the cell into the bile canalicular space by an ATP-dependent pump (MRP2). The bile canaliculus represents a specialized area of the hepatocyte plasma membrane. It is isolated from the sinusoidal plasma membrane by junctional complexes including tight junctions (TJ).
Table of Contents
John F. Reinus, MD
Chief of Clinical Hepatology
Division of Gastroenterology and Liver Diseases
Montefiore Medical Center
Professor of Clinical Medicine
The Albert Einstein College of Medicine
Bronx, NY, USA
Douglas Simon, MD, FACG
Chief of Gastroenterology and Hepatology
Jacobi Medical Center
Professor of Clinical Medicine
The Albert Einstein College of Medicine
Bronx, NY, USA
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