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Surgery_Schwartz. cells of Cajal (ICC), also are present.The outer layer of the stomach is the serosa, also known as the visceral peritoneum. This layer provides significant tensile strength to gastric anastomoses. When tumors originating in the mucosa penetrate and breach the serosa, microscopic or gross peritoneal metastases are common, presumably from shedding of tumor cells that would not have occurred if the serosa had not been penetrated. In this way, the serosa may be thought of as an outer envelope of the stomach.PHYSIOLOGYThe stomach stores food and facilitates digestion through a variety of secretory and motor functions. Important secretory functions include the production of acid, pepsin, intrinsic factor, mucus, and a variety of GI hormones. Important motor func-tions include food storage (receptive relaxation and accommo-dation), grinding and mixing, controlled emptying of ingested food, and periodic interprandial “housekeeping.”Acid SecretionHydrochloric acid in the stomach hastens both


Surgery_Schwartz

Surgery_Schwartz. relaxation and accommo-dation), grinding and mixing, controlled emptying of ingested food, and periodic interprandial “housekeeping.”Acid SecretionHydrochloric acid in the stomach hastens both the physical and (with pepsin) the biochemical breakdown of ingested food. In an acidic environment, pepsin and acid facilitate proteolysis. Gastric acid also inhibits the proliferation of ingested patho-gens, which protects against both infectious gastroenteritis and intestinal bacterial overgrowth and helps to maintain a healthy gastrointestinal microbiome.21 Long-term acid suppression with proton pump inhibitors (PPIs) has been associated with an Surface mucous cellsParietal cellsMucous neck cellsArgentaffin cellChief cellsGastric pitIsthmusNeckBaseFigure 26-8. Mammalian gastric gland from the body of the stom-ach. (Reproduced with permission from Ito S, Winchester RJ: The fine structure of the gastric mucosa in the bat, J Cell Biol. 1963 Mar;16(3):541-577.)Brunicardi_Ch26_p1099-p1166.indd


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Surgery_Schwartz. of the stom-ach. (Reproduced with permission from Ito S, Winchester RJ: The fine structure of the gastric mucosa in the bat, J Cell Biol. 1963 Mar;16(3):541-577.)Brunicardi_Ch26_p1099-p1166.indd 110501/03/19 7:11 PM 1106SPECIFIC CONSIDERATIONS PART IIincreased risk of community-acquired Clostridium difficile coli-tis and other gastroenteritis, presumably because of the absence of this protective germicidal barrier.22,23Parietal Cell. The parietal cell is stimulated to secrete acid (Fig. 26-12) when one or more of three membrane receptor types is stimulated by acetylcholine (from vagally stimulated enteric neurons), gastrin (from G cells), or histamine (from ECL cells).7,24,25 The enzyme H+/K+-ATPase is the parietal cell proton pump. It is stored within the intracellular tubulovesicles and is the final common pathway for gastric acid secretion. When the parietal cell is stimulated, there is a cytoskeletal rearrangement and fusion of the tubulovesicles with the apical membrane


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Surgery_Schwartz. and is the final common pathway for gastric acid secretion. When the parietal cell is stimulated, there is a cytoskeletal rearrangement and fusion of the tubulovesicles with the apical membrane of the secretory canaliculus. The heterodimer assembly of the enzyme subunits into the microvilli of the secretory canalicu-lus results in acid secretion, with extracellular potassium being exchanged for cytosolic hydrogen. Although electroneutral, this is an energy-requiring process because the hydrogen is secreted against a gradient of at least 1 million-fold, which explains why the parietal cell is packed with energy producing mito-chondria. During acid production, potassium and chloride are also secreted into the apical secretory canaliculus through sepa-rate channels, providing potassium to exchange for H+ via the H+/K+-ATPase, and chloride to accompany the secreted hydrogen. At the basolateral membrane, the combined activity of various SCMTVFigure 26-9. Ultrastructural features of the


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Surgery_Schwartz. exchange for H+ via the H+/K+-ATPase, and chloride to accompany the secreted hydrogen. At the basolateral membrane, the combined activity of various SCMTVFigure 26-9. Ultrastructural features of the parietal (oxyntic) cell. SC = secretory canaliculus; M = mitochondria; TV = tubulovesicle. (Reproduced with permission from Ming S-C, Goldman H: Pathol-ogy of the Gastrointestinal Tract, 2nd ed. Baltimore, MD: Williams & Wilkins; 1998.)ZGGAGERFigure 26-10. Ultrastructural features of the chief (zymogenic) cell. GA = Golgi apparatus; GER = granular endoplasmic reticu-lum; ZG = zymogen granule. (Reproduced with permission from Ming S-C, Goldman H: Pathology of the Gastrointestinal Tract, 2nd ed. Baltimore, MD: Williams & Wilkins; 1998.)Table 26-2Epithelial cells of the stomachCELL TYPEDISTINCTIVE ULTRASTRUCTURAL FEATURESMAJOR FUNCTIONSSurface-foveolar mucous cellsApical stippled granules up to 1 μm in diameterProduction of neutral glycoprotein and bicarbonate to form a gel on the gastric


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Surgery_Schwartz. ULTRASTRUCTURAL FEATURESMAJOR FUNCTIONSSurface-foveolar mucous cellsApical stippled granules up to 1 μm in diameterProduction of neutral glycoprotein and bicarbonate to form a gel on the gastric luminal surface; neutralization of hydrochloric acidaMucous neck cellHeterogeneous granules 1–2 μm in diameter dispersed throughout the cytoplasmProgenitor cell for all other gastric epithelial cells; glycoprotein production; production of pepsinogens I and IIOxyntic (parietal) cellSurface membrane invaginations (canaliculi); tubulovesicle structures; numerous mitochondriaProduction of hydrochloric acid; production of intrinsic factor; production of bicarbonateChief cellModerately dense apical granules up to 2 μm in diameter; prominent supranuclear Golgi apparatus; extensive basolateral granular endoplasmic reticulumProduction of pepsinogens I and II, and of lipaseCardiopyloric mucous cellMixture of granules like those in mucous neck and chief cells; extensive basolateral granular endoplasmic


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Surgery_Schwartz. reticulumProduction of pepsinogens I and II, and of lipaseCardiopyloric mucous cellMixture of granules like those in mucous neck and chief cells; extensive basolateral granular endoplasmic reticulumProduction of glycoprotein; production of pepsinogen IIEndocrine cellsSee Figure 26-11 aBicarbonate is probably produced by other gastric epithelial cells in addition to surface-foveolar mucous cells.Reproduced with permission from Ming S-C, Goldman H: Pathology of the Gastrointestinal Tract, 2nd ed. Baltimore, MD: Williams & Wilkins; 1998.Brunicardi_Ch26_p1099-p1166.indd 110601/03/19 7:11 PM 1107STOMACHCHAPTER 26cotransporters and ion exchangers accomplishes intracellular pH regulation and electrolyte homeostasis.24The normal human stomach contains approximately 1 billion parietal cells, and total gastric acid production is pro-portional to parietal cell mass. Almost all of the parietal cells are in the proximal 2/3 stomach, though there are some parietal cells found in gastric antral


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Surgery_Schwartz. total gastric acid production is pro-portional to parietal cell mass. Almost all of the parietal cells are in the proximal 2/3 stomach, though there are some parietal cells found in gastric antral glands. The potent acid-suppressing PPI drugs irreversibly interfere with the function of the H+/K+-ATPase molecule. These agents must be incorporated into the activated enzyme to be effective and thus work best when taken before or during a meal (when the parietal cell is stimulated). When PPI therapy is stopped, acid secretory capability gradu-ally returns (within days) as new H+/K+-ATPase is synthesized.Gastrin, acetylcholine, and histamine stimulate the parietal cell to secrete hydrochloric acid (see Fig. 26-12). Gastrin binds to type B cholecystokinin (CCK2) receptors on ECL cells and stimulates ECL cell histamine release, which binds to H2 recep-tors on the parietal cell. This stimulates adenylatecyclase (via a G-protein–linked mechanism) and increases cAMP which acti-vates protein


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Surgery_Schwartz. ECL cell histamine release, which binds to H2 recep-tors on the parietal cell. This stimulates adenylatecyclase (via a G-protein–linked mechanism) and increases cAMP which acti-vates protein kinases, leading to increased levels of phospho-proteins and activation of the proton pump. Gastrin also binds to CCK2 receptors on the parietal cell, but this is less important for acid secretion than the gastrin effect on ECL cells. Acetyl-choline from intrinsic neurons binds to M3 muscarinic recep-tors on the parietal cell, which (like gastrin binding to CCK2 receptors) stimulates phospholipase C via a G-protein–linked mechanism leading to increased production of inositol trispho-sphate from membrane bound phospholipids. Inositol trisphos-phate stimulates the release of calcium from intracellular stores, which leads to activation of protein kinases and activation of H+/K+-ATPase. Somatostatin released from mucosal D cells in the antral and oxcyntic mucosa in response to luminal acid binds to


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Surgery_Schwartz. stores, which leads to activation of protein kinases and activation of H+/K+-ATPase. Somatostatin released from mucosal D cells in the antral and oxcyntic mucosa in response to luminal acid binds to SSTR2 receptors on parietal cells and inhibits acid release directly. Somatostatin also inhibits acid secretion in a paracrine fashion, binding to nearby ECL cells in the oxcyntic mucosa and decreasing histamine release, and binding to nearby antral G cells to inhibit gastrin release.26Physiologic Acid Secretion.27 Food ingestion is the physi-ologic stimulus for acid secretion (Fig. 26-13). The acid secre-tory response that occurs after a meal is traditionally described Oxyntic mucosaOther3%D19%G49%EC29%Other14%D26%EC25%ECL35%Pyloric mucosaFigure 26-11. Endocrine cells of the stomach—proportion by site. D = d cell (somatostatin); EC = enterochromaffin cell; ECL = enterochromaffin-like cell (histamine); G = g cell (gastrin). (Repro-duced with permission from Feldman M, Friedman LS,


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Surgery_Schwartz. by site. D = d cell (somatostatin); EC = enterochromaffin cell; ECL = enterochromaffin-like cell (histamine); G = g cell (gastrin). (Repro-duced with permission from Feldman M, Friedman LS, Sleisenger MH, et al: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 7th ed. Philadelphia, PA: Elsevier/Saunders; 2002.)Adenylate cyclaseATPHistamineInterstitiumLumenSomatostatinGi proteinGs proteinIP3PIP2Ca++K+ channelK+ClchannelCl-H+K+CCK8 receptorM3 receptorH+/K+-ATPaseGs proteinActivation ofother kinasescAMPActivatesprotein kinasesGastrinAcetylcholinePLCSomatostatinreceptorH2 receptorGs proteinFigure 26-12. Control of acid secretion in the parietal cell. ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; H2 = histamine 2; IP3 = inositol trisphosphate; PIP2 = phosphatidylinositol 4,5-bisphosphate; PLC = phospholipase C. (Reproduced with permission from Zuidema GD, Yeo CJ: Shackelford’s Surgery of the Alimentary Tract, 5th ed. Vol. II.


Surgery_Schwartz

Surgery_Schwartz. PIP2 = phosphatidylinositol 4,5-bisphosphate; PLC = phospholipase C. (Reproduced with permission from Zuidema GD, Yeo CJ: Shackelford’s Surgery of the Alimentary Tract, 5th ed. Vol. II. Philadelphia, PA: Elsevier/Saunders; 2002.)Brunicardi_Ch26_p1099-p1166.indd 110701/03/19 7:11 PM 1108SPECIFIC CONSIDERATIONS PART IIin three phases: cephalic, gastric, and intestinal.28,29 The cephalic or vagal phase begins with the thought, sight, smell, and/or taste of food. These stimuli activate several cortical and hypotha-lamic sites (e.g., tractus solitarius, dorsal motor nucleus, and dorsal vagal complex), and signals are transmitted to the stom-ach by the vagal nerves which stimulate enteric submucosal neurons. Acetylcholine is released, leading to stimulation acid secretion from parietal cells. Vagal stimulation also leads to gas-trin release from antral G cells via CGRP, and sensitizes ECL cells to gastrin.30,31 Although the acid secreted per unit of time in the cephalic phase is


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Surgery_Schwartz. cells. Vagal stimulation also leads to gas-trin release from antral G cells via CGRP, and sensitizes ECL cells to gastrin.30,31 Although the acid secreted per unit of time in the cephalic phase is greater than in the other two phases, the cephalic phase is shorter. Thus, the cephalic phase accounts for no more than 30% of total acid secretion in response to a meal. Sham feeding (chewing and spitting) stimulates gastric acid secretion only via the cephalic phase, and it results in acid secretion that is about half of that seen in response to IV penta-gastrin or histamine.When food reaches the stomach, the gastric phase of acid secretion begins. This phase lasts until the stomach is empty and accounts for about 60% of the total acid secretion in response to a meal. The gastric phase of acid secretion has several compo-nents. Amino acids and small peptides directly stimulate antral G cells to secrete gastrin, which is carried in the bloodstream to the ECL and parietal cells, stimulating


Surgery_Schwartz

Surgery_Schwartz. secretion has several compo-nents. Amino acids and small peptides directly stimulate antral G cells to secrete gastrin, which is carried in the bloodstream to the ECL and parietal cells, stimulating acid secretion in an endo-crine fashion. In addition, proximal gastric distention stimulates acid secretion via a vagovagal reflex arc, which is mitigated by truncal or highly selective vagotomy (HSV). Antral disten-tion also stimulates antral gastrin secretion. Finally, ongoing cephalic vagal input stimulates gastrin release, which in turn stimulates histamine release from ECL cells and acid secretion.The intestinal phase of gastric secretion is poorly under-stood. It is thought to be mediated by a hormone released from the proximal small bowel mucosa in response to luminal chyme. This phase starts when gastric emptying of ingested food begins, and it continues as long as nutrients remain in the proximal small intestine. It accounts for about 10% of meal-induced acid


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Surgery_Schwartz. chyme. This phase starts when gastric emptying of ingested food begins, and it continues as long as nutrients remain in the proximal small intestine. It accounts for about 10% of meal-induced acid secretion.Interprandial basal acid secretion is 2 to 5 mEq hydrochlo-ric acid per hour, about 10% of maximal acid output (MAO), and it is greater at night. Basal acid secretion probably contrib-utes to the relatively low bacterial counts found in the stomach. Basal acid secretion is reduced 75% to 90% by vagotomy or continuous H2-receptor blockade.The pivotal role that ECL cells play in the regulation of gastric acid secretion is emphasized in Fig. 26-13. The acid stimulatory effect of gastrin is largely mediated by histamine released from mucosal ECL cells. H2-receptor knockout mice do not secrete acid in response to gastrin.24 This explains why the H2-receptor antagonists (H2RAs) are effective inhibitors of acid secretion, even though histamine is only one of three parietal cell


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Surgery_Schwartz. not secrete acid in response to gastrin.24 This explains why the H2-receptor antagonists (H2RAs) are effective inhibitors of acid secretion, even though histamine is only one of three parietal cell stimulants. The mucosal D cell, which releases somatosta-tin, is also an important regulator of acid secretion. Somatostatin inhibits histamine release from ECL cells and gastrin release from antral G cells. The function of D cells can be inhibited by Helicobacter pylori infection, resulting in an exaggerated acid secretory response (see “Helicobacter pylori Infection”).Proton pump inhibitors are potent suppressors of gastric acid secretion. This results in hypergastrinemia and conse-quent ECL stimulation. In patients on long-term PPI (median 5.5 years), the degree of hypergastrinemia does not appear to correlate with the length of treatment.32 Chronic PPI use has been associated with ECL hyperplasia and type 1 gastric neuro-endocrine tumor, but so far there has been no evidence linking


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Surgery_Schwartz. appear to correlate with the length of treatment.32 Chronic PPI use has been associated with ECL hyperplasia and type 1 gastric neuro-endocrine tumor, but so far there has been no evidence linking these agents to malignant gastric epithelial or neuroendocrine tumors. Gastrin levels return to normal within a few days of PPI cessation, but during this time, some patients may experience gastric hyperacidity and dyspeptic symptoms, which may lead to difficulty in getting patients off the medication.33,34 This is less likely to occur with short-term PPI use and may be amelio-rated by PPI dose tapering and/or initiation of H2 blockers prior to PPI cessation.Pepsinogen SecretionThe most potent physiologic stimulus for pepsinogen secre-tion from chief cells is food ingestion; acetylcholine is the most important mediator. Somatostatin inhibits pepsinogen secre-tion. Pepsinogen I is produced by chief cells in acid producing glands, whereas pepsinogen II is produced by chief cells and by SECs in


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Surgery_Schwartz. most important mediator. Somatostatin inhibits pepsinogen secre-tion. Pepsinogen I is produced by chief cells in acid producing glands, whereas pepsinogen II is produced by chief cells and by SECs in both acid producing and gastrin producing (i.e., antral) glands. Pepsinogen is cleaved to the active pepsin enzyme in an acidic environment and is maximally active at pH 2.5, and inactive at pH >5, although pepsinogen II may be activated over a wider pH range than pepsinogen I. Pepsin catalyzes the hydro-lysis of proteins and is denatured at alkaline pH. Serum levels of pepsinogen I and II are increased in helicobacter gastritis, so elevated pepsinogen I and II levels and positive helicobacter serology are presumptive evidence of active helicobacter infec-tion. Longstanding helicobacter infection may lead to atrophic gastritis, suggested by decreased pepsinogen I/II ratio (from chief cell loss) and hypergastriemia (from parietal cell loss and hypochlorhydria).35Intrinsic FactorActivated


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Surgery_Schwartz. may lead to atrophic gastritis, suggested by decreased pepsinogen I/II ratio (from chief cell loss) and hypergastriemia (from parietal cell loss and hypochlorhydria).35Intrinsic FactorActivated parietal cells secrete intrinsic factor in addition to hydrochloric acid. Presumably the stimulants are similar, but MealVagusD-cellECLcellParietal cellGastrinSomatostatinHistamine++++–––++++AcetylcholineG-cellFigure 26-13. Physiologic control of acid secretion. ECL = enterochromaffin-like. (Reproduced with permission from Zuidema GD, Yeo CJ: Shackelford’s Surgery of the Alimentary Tract, 5th ed. Vol. II. Philadelphia, PA: Elsevier/Saunders; 2002.)Brunicardi_Ch26_p1099-p1166.indd 110801/03/19 7:11 PM 1109STOMACHCHAPTER 26acid secretion and intrinsic factor secretion may not be linked. Intrinsic factor binds to luminal vitamin B12, and the complex is absorbed in the terminal ileum via mucosal receptors. Vitamin B12 deficiency can be life threatening, and patients with total gastrectomy or


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Surgery_Schwartz. factor binds to luminal vitamin B12, and the complex is absorbed in the terminal ileum via mucosal receptors. Vitamin B12 deficiency can be life threatening, and patients with total gastrectomy or pernicious anemia (i.e., patients with no pari-etal cells) require B12 supplementation by a nonenteric route. Some patients develop vitamin B12 deficiency following gastric bypass, presumably because there is insufficient intrinsic fac-tor present in the small proximal gastric pouch and oral B12 intake may be decreased. Under normal conditions, a signifi-cant excess of intrinsic factor is secreted, and acid-suppressive medication does not appear to inhibit intrinsic factor production and release.Gastric Mucosal BarrierThe stomach’s durable resistance to autodigestion by caustic hydrochloric acid and active pepsin is intriguing. Some of the important elements of gastric barrier function and cytoprotection are listed in Table 26-3.36,37 When these defenses break down, ulceration occurs. A


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Surgery_Schwartz. acid and active pepsin is intriguing. Some of the important elements of gastric barrier function and cytoprotection are listed in Table 26-3.36,37 When these defenses break down, ulceration occurs. A variety of factors are important in maintain-ing an intact gastric mucosal layer.38 The mucus and bicarbonate secreted by SECs form an unstirred mucous gel with a favorable pH gradient. Cell membranes and tight junctions prevent hydro-gen ions from gaining access to the interstitial space. Hydrogen ions that do break through are buffered by the alkaline tide cre-ated by basolateral bicarbonate secretion from stimulated pari-etal cells. Any sloughed or denuded SECs are rapidly replaced by migration of adjacent cells, a process known as restitution. Mucosal blood flow plays a crucial role in maintaining a healthy mucosa, providing nutrients and oxygen for the cellular func-tions involved in cytoprotection. During acid secretion, there is a tremendous gradient favoring the movement of


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Surgery_Schwartz. in maintaining a healthy mucosa, providing nutrients and oxygen for the cellular func-tions involved in cytoprotection. During acid secretion, there is a tremendous gradient favoring the movement of hydrogen ions from the lumen to the interstitium. This “back-diffused” hydrogen is buffered and rapidly removed by the rich blood supply. When “barrier breakers” such as bile or aspirin lead to increased back-diffusion of hydrogen ions from the lumen into the lamina propria and submucosa, there is a protective increase in mucosal blood flow. If this protective response is blocked, gross ulceration can occur. Important mediators of these protec-tive mechanisms include prostaglandins, nitric oxide, intrinsic nerves, and peptides (e.g., calcitonin gene-related peptide, gas-trin-releasing peptide [GRP], gastrin, and heat shock proteins). Sucralfate acts locally to enhance mucosal defenses. Protec-tive reflexes involve afferent sensory neurons, and they can be blocked by the application of


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Surgery_Schwartz. [GRP], gastrin, and heat shock proteins). Sucralfate acts locally to enhance mucosal defenses. Protec-tive reflexes involve afferent sensory neurons, and they can be blocked by the application of topical anesthetics to the gastric mucosa, or the experimental destruction of the afferent sensory nerves. In addition to these local defenses, there are important protective factors in saliva, duodenal secretions, and pancreatic or biliary secretions.Gastric Hormones13,39The stomach is quite an elegant endocrine organ. It is the source of important peptides which work in an autocrine (EGF and surface epithelial cells, TGF and parietal cells), paracrine (somatostatin), endocrine (gastrin), and/or neurocrine (ghrelin) fashion.Gastrin. Gastrin is produced by antral G cells and is the major hormonal stimulant of acid secretion during the gastric phase predominantly via an endocrine effect on histamine generating ECL cells and to a lesser extent via a direct effect on parietal cells. A variety of


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Surgery_Schwartz. stimulant of acid secretion during the gastric phase predominantly via an endocrine effect on histamine generating ECL cells and to a lesser extent via a direct effect on parietal cells. A variety of molecular forms exist: big gastrin (34 amino acids; G34), little gastrin (17 amino acids; G17), and mini-gastrin (14 amino acids; G14). The large majority of gastrin released by the human antrum is G17. The biologically active pentapeptide sequence at the C-terminal end of gastrin is identical to that of CCK. Luminal peptides and amino acids are the most potent stimulants of gastrin release, and luminal acid is the most potent inhibitor of gastrin secretion. The latter effect is predominantly mediated in a paracrine fashion by somatostatin released from antral D cells. Gastrin-stimulated acid secretion is significantly blocked by H2 antagonists, suggesting that the principal media-tor of gastrin-stimulated acid production is histamine from mucosal ECL cells and not direct stimulation of


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Surgery_Schwartz. secretion is significantly blocked by H2 antagonists, suggesting that the principal media-tor of gastrin-stimulated acid production is histamine from mucosal ECL cells and not direct stimulation of parietal cells by gastrin (see Fig. 26-13). In fact, chronic hypergastrinemia is associated with hyperplasia of gastric ECL cells and, rarely, gastric type I gastric neuroendocrine tumors (type I gastric car-cinoid). Gastrin is trophic to gastric parietal cells and to other GI mucosal cells including gastric stem cells. It also is a regulator of gastric cellular proliferation, migration, invasion, apoptosis and angiogenesis.40 Mucosal biopsies of the gastric body from patients with gastrinoma show a thick mucosa with excess pari-etal cells, while similar biopsies in patients years after antrec-tomy (i.e., low gastrin state) show thin mucosa and decreased parietal cells. In animal studies, gastrin administration has been shown to stimulate the growth of established colon cancers and to cause


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Surgery_Schwartz. (i.e., low gastrin state) show thin mucosa and decreased parietal cells. In animal studies, gastrin administration has been shown to stimulate the growth of established colon cancers and to cause pancreatic acinar cell hyperplasia.41 Important causes of hypergastrinemia include pernicious anemia, acid-suppressive medication, gastrinoma, retained antrum following distal gas-trectomy and Billroth II surgery, and vagotomy.42,43Ghrelin. Ghrelin, first described in 1999, is a small peptide that is produced mainly in the stomach.44,45 It is produced by specialized P/D1 endocrine cells in gastric oxyntic glands. Ninety percent of the body’s ghrelin stores are in the stomach and duodenum. Ghrelin is a potent secretagogue of pituitary growth hormone and a weak secretogogue for ACTH and pro-lactin. It appears to be a major orexigenic regulator of appetite. Ghrelin crosses the blood brain barrier and stimulates appetite via hypothalamic receptors. It also stimulates appetite periph-erally by


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Surgery_Schwartz. It appears to be a major orexigenic regulator of appetite. Ghrelin crosses the blood brain barrier and stimulates appetite via hypothalamic receptors. It also stimulates appetite periph-erally by stimulating vagal afferent fibers in the gastric wall. Table 26-3Important components and mediators of mucosal defenses in the stomachComponentsMucous barrierBicarbonate secretionEpithelial barrier Hydrophobic phospholipids Tight junctions RestitutionMicrocirculation (reactive hyperemia)Afferent sensory neuronsMediatorsProstaglandinsNitric oxideEpidermal growth factorCalcitonin gene-related peptideHepatocyte growth factorHistamineGastrin-releasing peptideBrunicardi_Ch26_p1099-p1166.indd 110901/03/19 7:11 PM 1110SPECIFIC CONSIDERATIONS PART IIWhen ghrelin is elevated, appetite is stimulated, and when it is suppressed, appetite is decreased. Typically, ghrelin levels are elevated before a meal and decreased postprandially. Levels are high during starvation and decreased during


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Surgery_Schwartz. stimulated, and when it is suppressed, appetite is decreased. Typically, ghrelin levels are elevated before a meal and decreased postprandially. Levels are high during starvation and decreased during hyperglycemia. Obesity and insulin resistance is associated with low ghrelin levels, but resection of the primary source of this hormone (i.e., the stomach) may partly account for the anorexia and weight loss seen in some patients following gastric resection including sleeve gastrectomy (Fig. 26-14).46-48 The effect of RYGBP on ghrelin physiology is controversial. This very effective weight loss procedure has been shown by some investigators to be asso-ciated with suppression of plasma ghrelin levels (and appetite) in humans (Fig. 26-15A).49,50Other groups have failed to show a significant decrease in ghrelin levels following gastric bypass but have found such decreases following sleeve gastrectomy, another effective weight loss operation (Fig. 26-15B).50 Possibly, subtle differ-ences in


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Surgery_Schwartz. in ghrelin levels following gastric bypass but have found such decreases following sleeve gastrectomy, another effective weight loss operation (Fig. 26-15B).50 Possibly, subtle differ-ences in operative technique, patient selection, or experimental (including assay) conditions account for the disparate results of studies on the effect of bariatric surgery on ghrelin levels in obese patients. Interestingly the two common metabolites of ghrelin have different physiologic effects: acyl-ghrelin increases gastric emptying and appetite while deacyl ghrelin decreases gastric emptying and induces satiety.51 Obviously appetite con-trol is complex with redundant and overlapping orexigenic and anorexigenic pathways and signals.39,52Somatostatin. Somatostatin is produced by D cells located throughout the gastric mucosa. The predominant form in humans is somatostatin 14, though somatostatin 28 is present as well. The major stimulus for somatostatin release is antral acidification; acetylcholine


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Surgery_Schwartz. the gastric mucosa. The predominant form in humans is somatostatin 14, though somatostatin 28 is present as well. The major stimulus for somatostatin release is antral acidification; acetylcholine from vagal nerve fibers inhibits its release. Somatostatin inhibits acid secretion from parietal cells and gastrin release from G cells. It also decreases histamine release from ECL cells. The proximity of the D cells to these target cells suggests that the primary effect of somatostatin is mediated in a paracrine fashion, but an endocrine (i.e., blood-stream) effect also is possible.Gastrin-Releasing Peptide. GRP is the mammalian equiva-lent of bombesin, a hormone discovered more than two decades ago in an extract of skin from a frog. In the antrum, GRP stimu-lates both gastrin and somatostatin release by binding to recep-tors on the G and D cells. There are nerve terminals ending near the mucosa in the gastric body and antrum, which are rich in GRP immunoreactivity. When GRP is given


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Surgery_Schwartz. release by binding to recep-tors on the G and D cells. There are nerve terminals ending near the mucosa in the gastric body and antrum, which are rich in GRP immunoreactivity. When GRP is given peripherally, it stimulates acid secretion, but when it is given centrally into the cerebral ventricles of animals, it inhibits acid secretion, appar-ently via a pathway involving the sympathetic nervous system.Leptin. Leptin is a protein primarily synthesized in adipocytes. It is also made by chief cells in the stomach, the main source of leptin in the GI tract.39,53 Leptin works at least in part via vagally mediated pathways to decrease food intake in animals. Not surprisingly, leptin, a satiety signal hormone, and ghrelin, a hunger signal hormone, are both synthesized in the stomach, an organ increasingly recognized as central to the mechanisms of appetite control.39,52Autocrine Proteins. Gastric surface epithelial cells secrete a variety of proteins that are important regulators of SEC


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Surgery_Schwartz. increasingly recognized as central to the mechanisms of appetite control.39,52Autocrine Proteins. Gastric surface epithelial cells secrete a variety of proteins that are important regulators of SEC health, including trefoil factor family proteins and heat shock pro-teins.38 Parietal cells may also be influenced by molecules they secrete including transforming growth factor-α.Gastric Motility and EmptyingGastric motor function has several purposes.43,54-56 Interprandial motor activity clears the stomach of undigested debris, sloughed cells, and mucus. When feeding begins, the stomach relaxes to accommodate the meal. Regulated motor activity then breaks down the food into small particles and controls the output into the duodenum. The stomach accomplishes these functions by coordinated smooth muscle relaxation and contraction of the various gastric segments (proximal, distal, and pyloric). Smooth muscle myoelectric potentials are translated into muscular activity, which is modulated by


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Surgery_Schwartz. muscle relaxation and contraction of the various gastric segments (proximal, distal, and pyloric). Smooth muscle myoelectric potentials are translated into muscular activity, which is modulated by extrinsic and intrinsic innerva-tion and hormones. The mechanisms by which gastric distention is translated into a neurohormonal satiety signal have only been partially elucidated.39,52Intrinsic Gastric Innervation. The extrinsic parasympa-thetic and sympathetic gastric innervation was discussed pre-viously in “Innervation.” The intrinsic innervation consists of ganglia and nerves that constitute the enteric nervous system (Fig. 26-16).57 There are a variety of neurotransmitters that effect gastric smooth muscle; these are generally grouped as excitatory (augment muscular activity) and inhibitory (decrease muscular activity). Important excitatory neurotransmitters include acetylcholine, the tachykinins, substance P, and neu-rokinin A. Important inhibitory neurotransmitters include nitric


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Surgery_Schwartz. (decrease muscular activity). Important excitatory neurotransmitters include acetylcholine, the tachykinins, substance P, and neu-rokinin A. Important inhibitory neurotransmitters include nitric oxide (NO) and vasoactive intestinal peptide (VIP). Serotonin has been shown to modulate both contraction and relaxation. A variety of other molecules affect motility, including GRP, hista-mine, neuropeptide Y, norepinephrine, and endogenous opioids.Specialized cells in the muscularis propria also are impor-tant modulators of GI motility. These cells, called interstitial cells of Cajal, are distinguishable histologically from neurons and myocytes and appear to amplify both cholinergic excitatory 300200Plasma ghrelin (fmol/mL)100NormalcontrolsGastrectomizedpatients0*Figure 26-14. Ghrelin levels are decreased after gastrectomy. (Reproduced with permission from Ariyasu H, Takaya K, Tagami T, et al: Stomach is a major source of circulating ghrelin, and feed-ing state determines plasma ghrelin-like


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Surgery_Schwartz. decreased after gastrectomy. (Reproduced with permission from Ariyasu H, Takaya K, Tagami T, et al: Stomach is a major source of circulating ghrelin, and feed-ing state determines plasma ghrelin-like immunoreactivity levels in humans, J Clin Endocrinol Metab. 2001 Oct;86(10):4753-4758.)Brunicardi_Ch26_p1099-p1166.indd 111001/03/19 7:11 PM 1111STOMACHCHAPTER 26Figure 26-15. A and B. Ghrelin secretion after bariatric surgery. Some investigators have suggested that ghrelin secretion is dramatically decreased after gastric bypass. Other groups have shown statistically insig-nificant changes in ghrelin levels after gastric bypass, (RYGBP) but significant decreases after sleeve gastrectomy (SG). A. green = gastric bypass; blue = obese controls; red = normal weight controls; B. blue = fasting; pink = postprandial. B. Top = RYGBP; B bottom = SG. (A, Repro-duced with permission from Cummings DE, Weigle DS, Frayo RS, et al: Plasma ghre-lin levels after diet-induced weight loss or gastric


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Surgery_Schwartz. pink = postprandial. B. Top = RYGBP; B bottom = SG. (A, Repro-duced with permission from Cummings DE, Weigle DS, Frayo RS, et al: Plasma ghre-lin levels after diet-induced weight loss or gastric bypass surgery, N Engl J Med. 2002 May 23;346(21):1623-1630. B, Reproduced with permission from Karamanakos SN, Vagenas K, Kalfarentzos F, et al: Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: A prospec-tive, double blind study, Ann Surg. 2008 Mar;247(3):401-407.)Plasma ghrelin level (pg/mL)Detection limitTime6 a.m.8 a.m.10 a.m.noon2 p.m.4 p.m.6 p.m.8 p.m.10 p.m.080100200300400500600700800BreakfastLunchDinnerA1200P = 0.06P = 0.15P = 0.16P = 0.13P = 0.01P = 0.03P = 0.01P = 0.0310008006004002000PreGhrelin (pg/mL)Ghrelin (pg/mL)3Time (months)Time (months)612Pre36129008007006005004003002001000Band nitrergic inhibitory input to the smooth muscle of the stom-ach and intestine.58 They are


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Surgery_Schwartz. (pg/mL)Ghrelin (pg/mL)3Time (months)Time (months)612Pre36129008007006005004003002001000Band nitrergic inhibitory input to the smooth muscle of the stom-ach and intestine.58 They are thought to be the cell of origin for gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal neoplasms in the GI tract.Segmental Gastric Motility.13,58,59 In general, the proximal stomach serves a short-term food storage function and helps regulate basal intragastric tone, and the distal stomach mixes and grinds the food. The pylorus helps the latter process when Brunicardi_Ch26_p1099-p1166.indd 111101/03/19 7:11 PM 1112SPECIFIC CONSIDERATIONS PART IIclosed, facilitating retropulsion of the solid food bolus back into the body of the stomach for additional breakdown. The pylorus opens intermittently to allow metered emptying of liquids and small solid particles into the duodenum.Most of the motor activity of the proximal stomach con-sists of slow tonic contractions and


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Surgery_Schwartz. opens intermittently to allow metered emptying of liquids and small solid particles into the duodenum.Most of the motor activity of the proximal stomach con-sists of slow tonic contractions and relaxations, lasting up to 5 minutes. This activity is the main determinant of basal intra-gastric pressure, an important determinant of liquid empty-ing. Rapid phasic contractions may be superimposed on the slower tonic motor activity. When food is ingested, intragastric pressure falls as the proximal stomach relaxes. This proximal relaxation is mediated by two important vagovagal reflexes: receptive relaxation and gastric accommodation. Receptive relaxation refers to the reduction in gastric tone associated with the act of swallowing. This occurs before the food reaches the stomach and can be reproduced by mechanical stimulation of the pharynx or esophagus. Gastric accommodation refers to the proximal gastric relaxation associated with distention of the stomach.60 Accommodation is mediated


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Surgery_Schwartz. by mechanical stimulation of the pharynx or esophagus. Gastric accommodation refers to the proximal gastric relaxation associated with distention of the stomach.60 Accommodation is mediated through stretch recep-tors in the gastric wall and does not require esophageal or pha-ryngeal stimulation. Initially, as the meal enters the stomach, there is a drop in intragastric pressure mediated by nitric oxide. As the meal progresses, the intragastric pressure rises, parallel with the onset of satiety. Interestingly, satiety does not seem to be associated with any specific level of intragastric pressure. Obese patients have a delayed onset of satiety, so an obvious hypothesis to be tested is that a pharmacologic-induced increase in gastric tone leads to increased satiety and decreased food intake in this patient group.60 Because receptive relaxation and accommodation are mediated by afferent and efferent vagal fibers, they are significantly altered by truncal and highly selec-tive vagotomy.


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Surgery_Schwartz. in this patient group.60 Because receptive relaxation and accommodation are mediated by afferent and efferent vagal fibers, they are significantly altered by truncal and highly selec-tive vagotomy. Both these operations result in decreased gastric compliance, shifting the volume/pressure curve to the left. Pre-sumably for any given amount of food ingested, the intragastric pressure is higher, and perhaps in some patients the onset of satiety is sooner. This may be one explanation for weight loss associated with vagotomy,61 and it also helps explain acceler-ated liquid gastric emptying postvagotomy, which likely con-tributes to dumping symptoms in some patients.NO and VIP are the principal mediators of proximal gas-tric relaxation. But a variety of other agents increase proximal gastric relaxation and compliance, including dopamine, gastrin, CCK, secretin, GRP, and glucagon. Proximal gastric tone also is decreased by duodenal distention, colonic distention, and ileal perfusion with


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Surgery_Schwartz. relaxation and compliance, including dopamine, gastrin, CCK, secretin, GRP, and glucagon. Proximal gastric tone also is decreased by duodenal distention, colonic distention, and ileal perfusion with glucose (ileal brake).The distal stomach breaks up solid food and is the main determinant of gastric emptying of solids. Slow waves of myo-electric depolarization sweep down the distal stomach at a rate of about three per minute. These waves originate from the proxi-mal gastric pacemaker, high on the greater curvature.62 The pac-ing cells appear to be the interstitial cells of Cajal, which have been shown to have a similar function in the small intestine and colon. Most of these myoelectric waves are below the thresh-old for smooth muscle contraction in the quiescent state and thus are associated with negligible changes in pressure. Neural and/or hormonal input, which increases the plateau phase of the action potential, can trigger muscle contraction, resulting in a peristaltic wave


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Surgery_Schwartz. with negligible changes in pressure. Neural and/or hormonal input, which increases the plateau phase of the action potential, can trigger muscle contraction, resulting in a peristaltic wave associated with the electrical slow wave and of the same frequency (three per minute) (Fig. 26-17). There are measurable abnormalities in gastric slow wave activity in disor-ders of gastric motility such as gastroparesis, but reliable elec-trogastrogaphy to aid in the diagnosis and management of these problems is not yet a clinical reality. It is likely that implantable gastric pacemakers benefit some patients with gastroparesis by favorably impacting this myoelectric coupling, normalizing gas-tric slow wave patterns.During fasting, distal gastric motor activity is controlled by the migrating motor complex (MMC), the “gastrointesti-nal housekeeper” (Fig. 26-18). The purported function of the MMC is to sweep along any undigested food, debris, sloughed cells, and mucus after the fed phase of


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Surgery_Schwartz. complex (MMC), the “gastrointesti-nal housekeeper” (Fig. 26-18). The purported function of the MMC is to sweep along any undigested food, debris, sloughed cells, and mucus after the fed phase of digestion is complete. The MMC lasts approximately 100 minutes (longer at night, shorter during daytime) and is divided into four phases. Phase I (about half the length of the entire cycle) is a period of relative motor inactivity. High-amplitude muscular contractions do not occur in phase I of the MMC. Phase II (about 25% of the entire MMC cycle) consists of some irregular, high-amplitude, gener-ally nonpropulsive contractions. Phase III, a period of intense, Figure 26-16. Enteric nervous sys-tem. (Reproduced with permission from Friedman SL, McQuaid KR, Grendell JH: Current Diagnosis and Treatment in Gastroenterology, 2nd ed. New York, NY: McGraw-Hill Education; 2003.)Parasympathetic (vagal) nerveMesenteryPerivascular sympathic nerveMuscularis externa (longitudinal)Muscularis externa


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Surgery_Schwartz. in Gastroenterology, 2nd ed. New York, NY: McGraw-Hill Education; 2003.)Parasympathetic (vagal) nerveMesenteryPerivascular sympathic nerveMuscularis externa (longitudinal)Muscularis externa (circular)Subepethelial plexusMuscularis mucosaSubmucosaVillusIntestinal lumenDeep muscularis plexusSerosaTertiary branchSecondary branchGanglionSubmucosal plexusMyenteric plexusBrunicardi_Ch26_p1099-p1166.indd 111201/03/19 7:11 PM 1113STOMACHCHAPTER 26regular (about three per minute), propulsive contractions, only lasts about 5 to 10 minutes. Most phase III complexes of the GI MMC begin in the stomach, and the frequency approximates that of the myoelectric gastric slow wave. Phase IV is a transi-tion period.Neurohormonal control of the MMC is poorly understood, but it appears that different phases are regulated by different mechanisms. For example, vagotomy abolishes phase II of the gastric MMC but has little influence on phase III that persists even in the


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Surgery_Schwartz. but it appears that different phases are regulated by different mechanisms. For example, vagotomy abolishes phase II of the gastric MMC but has little influence on phase III that persists even in the autotransplanted stomach, totally devoid of extrinsic neural input. This suggests that phase III is regulated by intrin-sic nerves and/or hormones. Indeed, the initiation of phase III of the MMC in the distal stomach corresponds temporally to elevation in serum levels of motilin, a hormone produced in the duodenal mucosa. Resection of the duodenum abolishes dis-tal gastric phase III in dogs, and resection of the duodenum in humans (e.g., with pancreaticoduodenectomy, the Whipple pro-cedure) commonly results in early postoperative delayed gastric emptying. There are clearly motilin receptors on gastric smooth muscle and nerves. Other modulators of gastric MMC activ-ity include NO, endogenous opioids, intrinsic cholinergic and adrenergic nerves, and duodenal pH. The onset of MMC phase III


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Surgery_Schwartz. gastric smooth muscle and nerves. Other modulators of gastric MMC activ-ity include NO, endogenous opioids, intrinsic cholinergic and adrenergic nerves, and duodenal pH. The onset of MMC phase III signals the return of hunger in humans, but oddly ghrelin, a major orexigenic hormone, appears to have little to do with phase III.63Feeding abolishes the MMC and leads to the fed motor pattern. The fed motor pattern of gastric activity starts within 10 minutes of food ingestion and persists until all the food has left the stomach. The neurohormonal initiator of this change is unknown, but CCK and the vagus appear to play some role since sham feeding transiently induces antral motor activity resembling the fed motor pattern which is blocked by the CCK receptor antagonist loxiglumide. Gastric motility during the fed pattern resembles phase II of the MMC, with irregular but con-tinuous phasic contractions of the distal stomach. During the fed state, about half of the myoelectric slow waves


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Surgery_Schwartz. motility during the fed pattern resembles phase II of the MMC, with irregular but con-tinuous phasic contractions of the distal stomach. During the fed state, about half of the myoelectric slow waves are associated with strong higher frequency distal gastric contractions. Some are prograde and some are retrograde, serving to mix and grind the solid components of the meal. The magnitude of gastric con-tractions and the duration of the pattern are influenced by the consistency and composition of the meal.The pylorus functions as an effective regulator of gastric emptying and an effective barrier to duodenogastric reflux. Bypass, transection, or resection of the pylorus may lead to uncontrolled gastric emptying of food and the dumping syn-drome (see “Postgastrectomy Problems”). Pyloric dysfunction IntracellularrecordingTensionQuiescentStimulated0 mv0 5 g -70 1122Figure 26-17. The relationship between intracellular electrical activity and muscle cell contraction. Note that contractile


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Surgery_Schwartz. IntracellularrecordingTensionQuiescentStimulated0 mv0 5 g -70 1122Figure 26-17. The relationship between intracellular electrical activity and muscle cell contraction. Note that contractile activity is always associated with electrical activity, but the converse is not so. During mechanical quiescence, there are regular depolarizations that do not reach threshold. In the stimulated state, the threshold for contraction is reached, and motor activity is demonstrable. (Reproduced with permission from Kim CH, Malagelada JR: Electrical activity of the stomach: clinical implications, Mayo Clin Proc. 1986 Mar;61(3):205-210.)Figure 26-18. Migrating motor complex, the fasting pattern of GI activity. During phase III of the migrating motor complex, effective peri-staltic waves progress from the stomach to the distal small intestine. (Reproduced with permis-sion from Rees WD, Malagelada JR, Miller LJ, et al: Human interdigestive and postprandial gas-trointestinal motor and gastrointestinal


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Surgery_Schwartz. stomach to the distal small intestine. (Reproduced with permis-sion from Rees WD, Malagelada JR, Miller LJ, et al: Human interdigestive and postprandial gas-trointestinal motor and gastrointestinal hormone patterns, Dig Dis Sci. 1982 Apr;27(4):321-329.)AntrumProximal duodenumDistal duodenumJejunum1 min100 mm Hg100 mm Hg100 mm Hg100 mm HgPhase IIPhase IIIPhase IVPhase IBrunicardi_Ch26_p1099-p1166.indd 111301/03/19 7:11 PM 1114SPECIFIC CONSIDERATIONS PART IIor disruption may also result in uncontrolled entry of duode-nal contents into the stomach. Perfusion of the duodenum with lipids, glucose, amino acids, hypertonic saline, or hydrochloric acid results in closure of the pylorus and decreased transpylo-ric flow. Ileal perfusion with fat has the same effect. A variety of neurohumoral pathways are involved with these physiologic responses, and there is evidence that different pathways may be involved for different stimuli.The pylorus is readily apparent grossly as a


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Surgery_Schwartz. neurohumoral pathways are involved with these physiologic responses, and there is evidence that different pathways may be involved for different stimuli.The pylorus is readily apparent grossly as a thick ring of muscle and connective tissue. The density of nerve tissue in the pyloric smooth muscle is several folds higher than in the antrum, with increased numbers of neurons staining positive for substance P, neuropeptide Y, VIP, and galanin. Interstitial cells of Cajal are closely associated with pyloric myocytes, and the myoelectric slow wave of the pylorus has the same frequency as that seen in the distal stomach. The motor activity of the pylo-rus is both tonic and phasic. During phase III of the MMC, the pylorus is open as gastric contents are swept into the duodenum. During the fed phase, the pylorus is closed most of the time. It relaxes intermittently, usually in synchronization with lower-amplitude, minor antral contractions. The higher-amplitude, more major antral


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Surgery_Schwartz. the fed phase, the pylorus is closed most of the time. It relaxes intermittently, usually in synchronization with lower-amplitude, minor antral contractions. The higher-amplitude, more major antral contractions are usually met with a closed pylorus, facilitating retropulsion and further grinding of food.Modulation of pyloric motor activity is complex. There is evidence for both inhibitory and excitatory vagal pathways. Some contractile vagal effects are mediated by opioid pathways because they are blocked by naloxone. Electrical stimulation of the duodenum causes the pylorus to contract, whereas electrical stimulation of the antrum causes pyloric relaxation. Nitric oxide is an important mediator of pyloric relaxation. Other molecules that may play a physiologic role in controlling pyloric smooth muscle include serotonin, VIP, prostaglandin E1, and galanin (pyloric relaxation); and histamine, CCK, and secretin (pyloric contraction).Gastric Emptying.13 The control of gastric emptying is


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Surgery_Schwartz. smooth muscle include serotonin, VIP, prostaglandin E1, and galanin (pyloric relaxation); and histamine, CCK, and secretin (pyloric contraction).Gastric Emptying.13 The control of gastric emptying is com-plex. In general, liquid emptying is faster than solid emptying. Osmolarity, acidity, caloric content, nutrient composition, and particle size are important modulators of gastric emptying. Stimulation of duodenal osmoreceptors, glucoreceptors, and pH receptors clearly inhibits gastric emptying by a variety of neurohumoral mechanisms. CCK has been consistently shown to inhibit gastric emptying at physiologic doses (Fig. 26-19). Recently, it has been noted that the anorexigenic hormone leptin, secreted largely by fat but also by gastric mucosa, inhib-its gastric emptying, perhaps through the same pathway as CCK (which also has properties of a satiety hormone). The orexigenic hormone ghrelin has the opposite effect.Liquid Emptying. The gastric emptying of water or isotonic saline follows


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Surgery_Schwartz. same pathway as CCK (which also has properties of a satiety hormone). The orexigenic hormone ghrelin has the opposite effect.Liquid Emptying. The gastric emptying of water or isotonic saline follows first-order kinetics, with a half emptying time around 12 minutes. Thus, if one drinks 200 mL of water, about 100 mL enters the duodenum by 12 minutes, whereas if one drinks 400 mL of water, about 200 mL enters the duodenum by 12 minutes. This emptying pattern of liquids is modified consid-erably as the caloric density, osmolarity, and nutrient composi-tion of the liquid changes (Fig. 26-20). Up to an osmolarity of about 1 M, liquid emptying occurs at a rate of about 200 kcal per hour. Duodenal osmoreceptors and hormones (e.g., secretin and VIP) are important modulators of liquid gastric emptying. Generally, liquid emptying is delayed in the supine position.Traditionally, liquid emptying has been attributed to the activity of the proximal stomach, but it is probably more complicated than


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Surgery_Schwartz. Generally, liquid emptying is delayed in the supine position.Traditionally, liquid emptying has been attributed to the activity of the proximal stomach, but it is probably more complicated than previously thought. Clearly, receptive relax-ation and gastric accommodation play a role in gastric empty-ing of liquids. Patients with a denervated (e.g., vagotomized), resected, or plicated (e.g., fundoplication) proximal stomach have decreased gastric compliance and may show accelerated gastric emptying of liquids.Some observations suggest an active role for the distal stomach in liquid emptying. For instance, even if the proximal intragastric pressure is lower than duodenal pressure, normal gastric emptying of liquids can occur. Also, diabetic patients CCK (µg/kg)0.25Low-fat dietHight-fat diet0102030405060700.51.02.0% Suppression of gastric emptyingFigure 26-19. Cholecystokinin (CCK) inhibits gastric emptying. (Reproduced with permission from Covasa M, Ritter RC: Adapta-tion to high-fat


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Surgery_Schwartz. Suppression of gastric emptyingFigure 26-19. Cholecystokinin (CCK) inhibits gastric emptying. (Reproduced with permission from Covasa M, Ritter RC: Adapta-tion to high-fat diet reduces inhibition of gastric emptying by CCK and intestinal oleate, Am J Physiol Regul Integr Comp Physiol. 2000 Jan;278(1):R166-R170.)7006005004003001002000Residual gastric volume (mL)Time (min)806040200Figure 26-20. Nutrient composition and caloric density affect liquid gastric emptying. Glucose solution (purple circles), the least calorically dense, emptied the fastest. Other more calorically dense solutions, such as milk protein (green triangles) and pep-tide hydrolysates (red circles and blue triangles), emptied slower. (Reproduced with permission from Calbet JA, MacLean DA. Role of caloric content on gastric emptying in humans, J Physiol. 1997 Jan 15;498 (Pt 2):553-559.)Brunicardi_Ch26_p1099-p1166.indd 111401/03/19 7:11 PM 1115STOMACHCHAPTER 26may have normal proximal gastric motor function and


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Surgery_Schwartz. emptying in humans, J Physiol. 1997 Jan 15;498 (Pt 2):553-559.)Brunicardi_Ch26_p1099-p1166.indd 111401/03/19 7:11 PM 1115STOMACHCHAPTER 26may have normal proximal gastric motor function and pro-foundly delayed gastric emptying of liquids. Indeed, antral contractile activity does correlate with liquid gastric emptying, and this distal gastric activity appears to vary with the nutrient composition and caloric content of the liquid meal. Depend-ing on the circumstances, distal gastric motor activity can pro-mote or inhibit gastric emptying of liquids. Distal gastrectomy and pyloric stenting both obviously interfere with distal gastric motor activity, and both accelerate the initial rapid phase of liq-uid gastric emptying.Solid Emptying. Normally, the half-time of solid gastric emp-tying is less than 2 hours. Unlike liquids, which display an initial rapid phase followed by a slower linear phase of emptying, sol-ids have an initial lag phase during which little emptying of sol-ids


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Surgery_Schwartz. is less than 2 hours. Unlike liquids, which display an initial rapid phase followed by a slower linear phase of emptying, sol-ids have an initial lag phase during which little emptying of sol-ids occurs. It is during this phase that much of the grinding and mixing occurs. A linear emptying phase follows, during which the smaller particles are metered out to the duodenum. Solid gastric emptying is a function of meal particle size, caloric con-tent, and composition (especially fat). When liquids and solids are ingested together, the liquids empty first. Solids are stored in the fundus and delivered to the distal stomach at constant rates for grinding. Liquids also are sequestered in the fundus, but they appear to be readily delivered to the distal stomach for early emptying. The larger the solid component of the meal, the slower the liquid emptying. Patients bothered by dumping syn-drome are advised to limit the amount of liquid consumed with the solid meal, taking advantage of this


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Surgery_Schwartz. solid component of the meal, the slower the liquid emptying. Patients bothered by dumping syn-drome are advised to limit the amount of liquid consumed with the solid meal, taking advantage of this effect. Three prokinetic (metoclopramide, erythromycin, domperidone) may be used to treat delayed gastric emptying. Typical doses and mechanism of action are shown in Table 26-4.DIAGNOSIS OF GASTRIC DISEASESigns and SymptomsThe most common symptoms of gastric disease are pain, weight loss, early satiety, and anorexia. Nausea, vomiting, bloating, and anemia also are frequent complaints. Several of these symptoms (pain, bloating, nausea, and early satiety) are often described by physicians as dyspepsia, synonymous with the common nonmedical term indigestion. Common causes of dyspepsia include gastroesophageal reflux disease (GERD), helicobacter gastritis, and other disorders of the stomach, gallbladder, and pancreas. Although none of the aforementioned symptoms alone is specific for gastric


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Surgery_Schwartz. reflux disease (GERD), helicobacter gastritis, and other disorders of the stomach, gallbladder, and pancreas. Although none of the aforementioned symptoms alone is specific for gastric disease, when elicited in the con-text of a careful history and physical examination, they point to a differential diagnosis, which can be refined with certain tests. Early endoscopy should be considered in patients present-ing with recent onset of alarm symptoms (weight loss, anemia, dysphagia, vomiting) particularly those over 55 years of age (Table 26-5).Diagnostic TestsEsophagogastroduodenoscopy. Esophagogastroduodenos-copy (EGD) is a safe and accurate outpatient procedure per-formed under conscious sedation.64 Smaller flexible scopes with excellent optics and a working channel are easily passed trans-nasally in the unsedated patient. Following an 8-hour fast, the flexible scope is advanced under direct vision into the esopha-gus, stomach, and duodenum. The fundus and GE junction are inspected by


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Surgery_Schwartz. in the unsedated patient. Following an 8-hour fast, the flexible scope is advanced under direct vision into the esopha-gus, stomach, and duodenum. The fundus and GE junction are inspected by retroflexing the scope. To rule out cancer with a high degree of accuracy, all patients with gastric ulcer diag-nosed on upper GI series or found at EGD should have multiple biopsy specimens of the base and rim of the lesion. Brush cytol-ogy also should be considered. Gastritis should be biopsied both for histologic examination and assessment (see discussion on gastritis in “Helicobacter Pylori Infection”) and for a tissue ure-ase test and histologic evaluation to rule out the presence of H pylori. If Helicobacter infection is detected, it should be treated because of the etiologic association with peptic ulcers, mucosa-associated lymphoid tissue (MALT), and gastric cancer; in addition, eradication may ameliorate symp-toms. The most serious complications of EGD are perforation (which is rare, but


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Surgery_Schwartz. ulcers, mucosa-associated lymphoid tissue (MALT), and gastric cancer; in addition, eradication may ameliorate symp-toms. The most serious complications of EGD are perforation (which is rare, but can occur anywhere from the cervical esoph-agus to the duodenum), aspiration, and respiratory depression from excessive sedation. Although EGD is a more sensitive test than double-contrast upper GI series, these modalities should be considered complementary rather than mutually exclusive.Barium Upper GI Study. Plain abdominal X-rays may be helpful in the diagnosis of gastric perforation (pneumoperi-toneum) or delayed gastric emptying (large air-fluid level). Double-contrast upper GI series may be better than EGD at elucidating gastric diverticula, fistula, tortuosity, stricture loca-tion, and size or morphology of hiatal hernia.65 Although there are radiologic characteristics of ulcers that suggest the pres-ence or absence of malignancy, gastric ulcers always require adequate biopsy.Computed


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Surgery_Schwartz. or morphology of hiatal hernia.65 Although there are radiologic characteristics of ulcers that suggest the pres-ence or absence of malignancy, gastric ulcers always require adequate biopsy.Computed Tomographic Scanning and Magnetic Resonance Imaging. Usually, significant gastric disease can be diag-nosed without these sophisticated imaging studies. However, one or the other should be part of the routine staging work-up for patients with a malignant gastric tumor. Magnetic resonance imaging (MRI) may prove clinically useful as a quantitative test for gastric emptying, and it may even hold some promise for the 1Table 26-4Drugs that accelerate gastric emptyingAGENTTYPICAL ADULT DOSEMECHANISM OF ACTIONMetoclopramide10 mg PO four times a dayDopamine antagonistErythromycin250 mg PO four times a dayMotilin agonistDomperidone10 mg PO four times a dayDopamine antagonistTable 26-5Alarm symptoms that indicate the need for upper endoscopyAge >55 years with new onset dyspepsiaUnintentional weight


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Surgery_Schwartz. dayMotilin agonistDomperidone10 mg PO four times a dayDopamine antagonistTable 26-5Alarm symptoms that indicate the need for upper endoscopyAge >55 years with new onset dyspepsiaUnintentional weight lossPersistent or recurrent vomitingProgressive dysphagiaRecent onset odynophagiaUnexplained iron deficiency anemia or GI bleedingPalpable abdominal mass or lymphadenopathyFamily history of upper gastrointestinal cancerBrunicardi_Ch26_p1099-p1166.indd 111501/03/19 7:11 PM 1116SPECIFIC CONSIDERATIONS PART IIanalysis of myoelectric derangements in patients with gastropa-resis. Virtual gastroscopy using multi detector CT scan or MRI is not yet widely used, but these techniques may prove useful for screening and staging of gastric disease66-68 (Fig. 26-21). CTA or MRA is useful in evaluating the blood supply to the stomach after endovascular treatment of aortic and/or visceral arterial disease or in patients with previous upper abdominal operation in whom gastric conduit construction


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Surgery_Schwartz. the blood supply to the stomach after endovascular treatment of aortic and/or visceral arterial disease or in patients with previous upper abdominal operation in whom gastric conduit construction is contemplated, e.g., with esophagectomy.Arteriography can be helpful in the occasional poor-risk patient with exsanguinating gastric hemorrhage, in the patient with occult gastric bleeding, or when CTA or MRA is inconclu-sive in delineating vascular anatomy.Endoscopic Ultrasound. Endoscopic ultrasound (EUS) is useful in the evaluation and management of gastric mass lesions.69-71 Local staging of gastric adenocarcinoma with EUS is quite accurate, and this modality can be used to plan therapy. At many centers, patients with transmural and/or node positive adenocarcinoma of the stomach are considered for preoperative (neoadjuvant) chemoradiation therapy. EUS is the best way to clinically stage these patients locoregion-ally. Suspicious nodes can be sampled with EUS-guided endoscopic needle


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Surgery_Schwartz. for preoperative (neoadjuvant) chemoradiation therapy. EUS is the best way to clinically stage these patients locoregion-ally. Suspicious nodes can be sampled with EUS-guided endoscopic needle biopsy. Malignant tumors that are confined to the mucosa on EUS may be amenable to endoscopic muco-sal resection (EMR). EUS also can be used to assess tumor response to chemotherapy. Submucosal masses are commonly discovered during routine EGD. Large submucosal masses should be resected unless benign pathology is a certainty, but observation may be appropriate for some small submucosal masses (e.g., lipoma or leiomyoma). There are endoscopic characteristics of benign and malignant mesenchymal tumors, and thus, EUS can provide reassurance, but no guarantee, that small lesions under observation are probably benign. Thus, EUS-guided needle biopsy should be considered. Submucosal varices also can be assessed by EUS.Gastric Secretory Analysis. Analysis of gastric acid output requires gastric


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Surgery_Schwartz. are probably benign. Thus, EUS-guided needle biopsy should be considered. Submucosal varices also can be assessed by EUS.Gastric Secretory Analysis. Analysis of gastric acid output requires gastric intubation, and it is performed infrequently nowadays. This test may be useful in the evaluation of patients with hypergastrinemia, including the Zollinger-Ellison syn-drome (ZES), patients with refractory ulcer or GERD, and patients with recurrent ulcer after operation. Historically, gas-tric analysis was performed most commonly to test for the ade-quacy of vagotomy in postoperative patients with recurrent or persistent ulcer. Now this can be done by assessing peripheral ABCDFigure 26-21. Conventional double-contrast barium study (A) shows a focal protruding mass (arrow) on the gastric fundus. Axial com-puted tomographic scan (B) also shows a protruding polyp (arrow). The three-dimensional computed tomographic gastrographic images in the transparent (C) mode shows an elevated lesion on the


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Surgery_Schwartz. Axial com-puted tomographic scan (B) also shows a protruding polyp (arrow). The three-dimensional computed tomographic gastrographic images in the transparent (C) mode shows an elevated lesion on the gastric fundus (arrow). Photograph of the total gastrectomy specimen (D) shows a well-demarcated polypoid mass (arrow); this lesion was confirmed as early gastric carcinoma type I on microscopic examination (not shown). (Reproduced with permission from Shin KS, Kim SH, Han JK, et al: Three-dimensional MDCT gastrography compared with axial CT for the detection of early gastric cancer, J Comput Assist Tomogr. 2007 Sep-Oct;31(5):741-749.)Brunicardi_Ch26_p1099-p1166.indd 111601/03/19 7:11 PM 1117STOMACHCHAPTER 26pancreatic polypeptide levels in response to sham feeding.72 A 50% increase in pancreatic polypeptide within 30 minutes of sham feeding suggests intact vagal function.Normal basal acid output (BAO) is greater than 5 mEq/h. MAO is the average of the two final stimulated 15-minute


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Surgery_Schwartz. polypeptide within 30 minutes of sham feeding suggests intact vagal function.Normal basal acid output (BAO) is greater than 5 mEq/h. MAO is the average of the two final stimulated 15-minute periods and is usually 10 to 15 mEq/h. Peak acid output is defined as the highest of the four stimulated periods. Patients with a gastrinoma commonly have a high BAO, often above 30 mEq/h, but consistently above 15 mEq/h unless there has been previous vagotomy or gastric resection. In patients with gastrinoma, the ratio of BAO to MAO exceeds 0.6. Normal acid output in the patient prescribed acid-suppressive medica-tion usually means that the patient is noncompliant. To assess acid-secretory capacity in the absence of medication effect, H2 blockers and PPIs should be withheld for several days before gastric analysis.Scintigraphy. The standard scintigraphic evaluation of gastric emptying involves the ingestion of a test meal with one or two isotopes and scanning the patient under a gamma camera. A


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Surgery_Schwartz. analysis.Scintigraphy. The standard scintigraphic evaluation of gastric emptying involves the ingestion of a test meal with one or two isotopes and scanning the patient under a gamma camera. A curve for gastric emptying is plotted, and the half-time is calcu-lated. Normal standards exist at each facility. Duodenogastric reflux can be quantitated by the IV administration of hepato-biliary iminodiacetic acid (HIDA scan), which is concentrated and excreted by the liver into the duodenum. Software allows a semiquantitative assessment of how much of the isotope refluxes into the stomach. Positron emission tomography (PET) scan or CT/PET scan is useful in staging certain patients with gastric malignancy.Tests for Helicobacter pylori. A variety of tests can help the clinician to determine whether the patient has active H pylori infection.73 The predictive value (positive and negative) of any of these tests when used as a screening tool depends on the prevalence of H pylori infection in the


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Surgery_Schwartz. the patient has active H pylori infection.73 The predictive value (positive and negative) of any of these tests when used as a screening tool depends on the prevalence of H pylori infection in the screened population. A positive test is quite accurate in predicting H pylori infection, but a negative test can be unreliable. Thus, in the appropriate clinical setting, treatment for H pylori should be initiated on the basis of a positive test, but not necessarily withheld if the test is negative. Helicobacter infection should be treated when the diagnosis is made and eradication is confirmed.A positive serologic test is presumptive evidence of active infection if the patient has never been treated for H pylori. Histologic examination of gastric mucosal biopsy using special stains is the gold standard test for helicobacter infection. Other sensitive tests include commercially available rapid urease tests, which assay for the presence of urease in mucosal biopsy speci-mens (strong


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Surgery_Schwartz. the gold standard test for helicobacter infection. Other sensitive tests include commercially available rapid urease tests, which assay for the presence of urease in mucosal biopsy speci-mens (strong presumptive evidence of infection). Urease is an omnipresent enzyme in H pylori strains that colonize the gas-tric mucosa. The carbon labeled urea breath test has become the standard test to confirm eradication of H pylori following appropriate treatment.74 In this test, the patient ingests urea labeled with nonradioactive 13C or 14C. The labeled urea is acted upon by the urease present in the H pylori and converted into ammonia and carbon dioxide. The radiolabeled carbon dioxide is excreted from the lungs and can be detected in the expired air (Fig. 26-22). It also can be detected in a blood sample. The fecal antigen test also is quite sensitive and specific for active H pylori infection and may also be used to confirm cure after treatment. Helicobacter culture may be useful to assess


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Surgery_Schwartz. sample. The fecal antigen test also is quite sensitive and specific for active H pylori infection and may also be used to confirm cure after treatment. Helicobacter culture may be useful to assess antimi-crobial resistance in persistently recalcitrant cases.Antroduodenal Motility Testing and Electrogastrography. Antroduodenal motility testing and electrogastrography (EGG) are performed in specialized centers and may be useful in the evaluation of the occasional patient with dyspeptic symptoms. EGG consists of the transcutaneous recording of gastric myo-electric activity. Antroduodenal motility testing is done with a tube placed transnasally or transorally into the distal duodenum. There are pressure-recording sensors extending from the stom-ach to the distal duodenum. The combination of these two tests together with scintigraphy provides a thorough assessment of gastric motility.HELICOBACTER PYLORI INFECTIONOver 50% of people worldwide are infected with Helicobacter pylori.75,76


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Surgery_Schwartz. of these two tests together with scintigraphy provides a thorough assessment of gastric motility.HELICOBACTER PYLORI INFECTIONOver 50% of people worldwide are infected with Helicobacter pylori.75,76 Infection with H pylori is a chronic disease and does not resolve spontaneously without specific treatment. World-wide, H pylori–induced gastritis accounts for 80% to 90% of all gastritis. Chronic gastritis associated with H pylori is the most important risk factor for peptic ulcer and gastric adeno-carcinoma. Successful H pylori treatment largely eliminates recurrent peptic ulcer in infected patients, and eradication of H pylori worldwide would eliminate most cases of gastric Figure 26-22. Labeled urea breath test to detect Helicobacter infection. (Repro-duced with permission from Walsh JH, Peterson WL. The treatment of Helico-bacter pylori infection in the management of peptic ulcer disease, N Engl J Med. 1995 Oct 12;333(15):984-991.)[13C] urea13CO2 (µmol)Positive breathurea


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Surgery_Schwartz. Walsh JH, Peterson WL. The treatment of Helico-bacter pylori infection in the management of peptic ulcer disease, N Engl J Med. 1995 Oct 12;333(15):984-991.)[13C] urea13CO2 (µmol)Positive breathurea testUreaseBloodHours1213CO2 in breathNH2NH22NH3+CO2H2O + 13C = 0Negative breathurea testBrunicardi_Ch26_p1099-p1166.indd 111701/03/19 7:11 PM 1118SPECIFIC CONSIDERATIONS PART IIadenocarcinoma, a major cause of cancer death worldwide.77 Helicobacter pylori infection is also associated with MALT lymphoma, dyspepsia, hyperplastic gastric polyps, and even immune thrombocytopenic purpura.Human beings are the only reservoir for H pylori. Infection is presumed to occur by oral ingestion of the bacterium, which dramatically alters the gastric microbiome.78 In helicobacter-infected individuals, 90% of gastric bacteria are helicobacter, whereas in helicobacter-negative patients 90% of gastric bac-teria are a combination of firmicutes, actinobacteria, bacte-roidetes, proteobacteria, and


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Surgery_Schwartz. 90% of gastric bacteria are helicobacter, whereas in helicobacter-negative patients 90% of gastric bac-teria are a combination of firmicutes, actinobacteria, bacte-roidetes, proteobacteria, and fusobacteria. The prevalence of H pylori infection varies among populations and is strongly cor-related with socioeconomic conditions. In developing countries, H pylori infection usually occurs in childhood, and over 80% of adults are infected. Reinfection after curative treatment is common. Infection rates are lower in industrialized countries, and the prevalence of infection in the United States has been declining since the second half of the 19th century as hygiene and sanitation have improved. Nonetheless, H pylori infection is predicted to remain endemic in the United States for the next century. Family members of infected individuals and healthcare workers are at increased risk of infection.With specialized flagella and a rich supply of urease, H pylori is uniquely equipped for survival


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Surgery_Schwartz. Family members of infected individuals and healthcare workers are at increased risk of infection.With specialized flagella and a rich supply of urease, H pylori is uniquely equipped for survival in the hostile envi-ronment of the stomach.[79-81] Helicobacter strains that lack either flagella or urease are nonpathogenic. The pathogenesis of helicobacter infection involves survival in the acidic gastric lumen, flagellated movement from the lumen across the mucus layer to the surface epithelial cell, adhesion to the surface epi-thelial cell, and toxin production. Up to 15% of the protein in a Helicobacter organism is composed of cytoplasmic urease that converts periplasmic urea into CO2 and ammonia. This buffers the surrounding acid, allowing the bacteria to survive the inimical luminal environment until it can burrow deeply into the surface mucus, propelled by its flagella (Fig. 26-23). H pylori typically does not invade the surface epithelial cell layer. Rather, it triggers a host


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Surgery_Schwartz. environment until it can burrow deeply into the surface mucus, propelled by its flagella (Fig. 26-23). H pylori typically does not invade the surface epithelial cell layer. Rather, it triggers a host immune response by attach-ing to gastric epithelial cells. Important Helicobacter adhesins mediating surface cell injury include neutrophil activating pro-tein A, heat shock protein 60, and sialic acid–binding adhesin. Helicobacter-produced toxins include vacuolating cytotoxin A and cag A (cytotoxin-associated gene A). The initial inflammatory response to Helicobacter infection is characterized by recruit-ment of neutrophils, followed sequentially by T and B lympho-cytes, plasma cells, and macrophages (Fig. 26-24). The resultant chronic gastric inflammation in affected individuals is charac-terized by enhanced mucosal expression of multiple cytokines and the presence of reactive oxygen and nitrogen species, and long-term infection is associated with mucosal cell DNA damage and


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Surgery_Schwartz. charac-terized by enhanced mucosal expression of multiple cytokines and the presence of reactive oxygen and nitrogen species, and long-term infection is associated with mucosal cell DNA damage and chromosomal instability and increased apopto-sis (Fig. 26-25).80,81 The net effect is a weakening of mucosal defenses. The mechanism by which the helicobacter organism avoids recognition and destruction by the mucosal immune sys-tem is a topic of interest and active research.82Acute H pylori infection causes a nonerosive pangastritis that is invariably followed by the development of chronic gastritis. Chronic antral gastritis with sparing of the proximal stomach occurs in about 10% of infected patients, and this pre-disposes to peptic ulcer disease (PUD). The other 90% of Heli-cobacter-infected patients develop chronic inflammation of the proximal stomach (corpus dominant gastritis), which can lead to gastric cancer in about 1% to 3% of this group.Figure 26-23. Helicobacter pylori closely


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Surgery_Schwartz. patients develop chronic inflammation of the proximal stomach (corpus dominant gastritis), which can lead to gastric cancer in about 1% to 3% of this group.Figure 26-23. Helicobacter pylori closely adherent to the cell membrane (top), and spiral-shaped H pylori attached to epithelial surface and surrounding microvilli (bottom). In the image on the bottom, the bacterial flagella can be seen arising from the upper pole of the bacterium. (Reproduced with permission from Mertz HR, Walsh JH: Peptic ulcer pathophysiology, Med Clin North Am. 1991 Jul;75(4):799-814.)H pylori infection is the major cause of peptic ulceration. Patients with H pylori infection and antral gastritis are three and one-half times more likely to develop PUD than patients without H pylori infection. Up to 90% of patients with duode-nal ulcers, and at least 70% of patients with gastric ulcers, have H pylori infection. It is clear from multiple randomized prospec-tive studies that curing H pylori infection dramatically


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Surgery_Schwartz. with duode-nal ulcers, and at least 70% of patients with gastric ulcers, have H pylori infection. It is clear from multiple randomized prospec-tive studies that curing H pylori infection dramatically alters the natural history of PUD, decreasing the recurrent ulcer rate from more than 75% in patients treated with a course of acid-suppressive therapy alone (in whom H pylori is not eradicated) to less than 20% in patients treated with a course of antibacterial therapy (Fig. 26-26).83In patients with duodenal ulcer caused by helicobacter, the associated antral gastritis leads to relative hypergastrinemia by depleting antral somatostatin, the primary inhibitor of antral gastrin release. H pylori infection is associated with decreased Brunicardi_Ch26_p1099-p1166.indd 111801/03/19 7:11 PM 1119STOMACHCHAPTER 26levels of somatostatin, decreased somatostatin messenger RNA production, and fewer somatostatin-producing D cells. The mechanism of decreased antral somatostatin synthesis and


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Surgery_Schwartz. PM 1119STOMACHCHAPTER 26levels of somatostatin, decreased somatostatin messenger RNA production, and fewer somatostatin-producing D cells. The mechanism of decreased antral somatostatin synthesis and release may be related to (a) antral alkalinization due to heli-cobacter urease (acid in the antrum releases somatostatin); (b) toxic cytokine effect on antral D cells; and/or (c) Helicobacter production of N-α-methylhistamine, an H3 receptor agonist, which binds H3 receptors on the antral D cell and decreases somatostatin release.84 Since the gastritis does not involve the oxcyntic mucosa, hypergastrinemia leads to hyperacidity and parietal cell hyperplasia. The acid hypersecretion and the antral gastritis are thought to lead to antral epithelial metaplasia in the postpyloric duodenum. This duodenal metaplasia allows H pylori to colonize the duodenal mucosa, and this is where the duodenal ulcer occurs. In fact, in patients with gastric metapla-sia of the duodenum, the risk of developing


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Surgery_Schwartz. duodenal metaplasia allows H pylori to colonize the duodenal mucosa, and this is where the duodenal ulcer occurs. In fact, in patients with gastric metapla-sia of the duodenum, the risk of developing a duodenal ulcer increases 50-fold. When H pylori colonizes the duodenum, there is a significant decrease in acid-stimulated duodenal bicarbonate release. When H pylori infection is successfully treated, acid secretory physiology tends to normalize. Relapse of duodenal ulcer after eradication of H pylori may signal reinfection of the gastric mucosa by the organism.Many patients with antral dominant helicobacter gastritis never develop duodenal ulcer, and some patients with peptic ulcer do not have Helicobacter. This obviously suggests that there are other important pathogenetic factors involved in peptic ulcer. And even in the presence of active H pylori infection, strong acid suppression usually heals peptic ulcer, an observa-tion consistent with the old dictum “no acid, no ulcer.” But


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Surgery_Schwartz. in peptic ulcer. And even in the presence of active H pylori infection, strong acid suppression usually heals peptic ulcer, an observa-tion consistent with the old dictum “no acid, no ulcer.” But suc-cessful helicobacter treatment eliminates ulcer recurrence and the need for long-term PPI. And long-term PPI in patients with active Helicobacter infection may lead to corpus predominant gastritis, which leads to atrophic gastritis and increases the risk of gastric cancer. Thus, Helicobacter infection should be treated and eradication confirmed.Testing for H pylori infection should be performed in patients with peptic ulcer, gastritis, significant dyspepsia, MALT lymphoma, and early gastric cancer.85 Noninvasive methods for diagnosis of H pylori infection include the urea breath test, serology, and detection of stool antigen. The urea breath test has a sensitivity and specificity of greater than 90% and is useful for initial diagnosis of infection and for follow-up after eradication


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Surgery_Schwartz. and detection of stool antigen. The urea breath test has a sensitivity and specificity of greater than 90% and is useful for initial diagnosis of infection and for follow-up after eradication therapy since it is positive only in the presence of active infection. The stool antigen test is another noninvasive test to detect active H pylori infection, but it is recommended that only locally validated tests be used.86 Because H pylori induces a strong immunologic response, serological testing is useful but may not be as accurate as the urea breath test or the stool antigen test, and a positive serology persists after eradica-tion of H pylori infection, so serology is not useful to confirm successful treatment of Helicobacter infection. H pylori infec-tion can also be diagnosed by histologic evaluation of gastric biopsies and/or the rapid urease test on fresh biopsies. Culture of H pylori is not routine and is usually reserved for recurrent infection and for antibiotic sensitivity testing


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Surgery_Schwartz. of gastric biopsies and/or the rapid urease test on fresh biopsies. Culture of H pylori is not routine and is usually reserved for recurrent infection and for antibiotic sensitivity testing when second-line therapy has failed. All tests for H pylori have a false negative rate. Empiric Helicobacter treatment can be considered despite negative tests if clinical likelihood of infection is high, e.g., a compliant nonsmoking, non–NSAID-consuming patient facing operation for nonhealing peptic ulcer or a patient with unex-plained gastritis.Patients with a positive test should be treated and eradi-cation confirmed. Spontaneous cure without treatment is very rare. It is important to note that none of the therapeutic regimens reported to date cure H pylori infection in 100% of patients. To be effective, antimicrobial drugs must be combined with gas-tric acid secretion inhibitors or bismuth salts. The Maastricht V/Florence Consensus Report87 provides current recommenda-tions for diagnosis and


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Surgery_Schwartz. antimicrobial drugs must be combined with gas-tric acid secretion inhibitors or bismuth salts. The Maastricht V/Florence Consensus Report87 provides current recommenda-tions for diagnosis and treatment of H pylori infection in various clinical scenarios, including recommendations for areas with high metronidazole and clarithromycin resistance.87,88 Ideally, a treatment regimen is chosen with 90% effectiveness. Treat-ment failure requires an alternative course of therapy. Failure to eradicate infection after two tries should prompt Helicobacter culture and sensitivity testing and referral to a specialist. With assiduous treatment, Helicobacter eradication can be achieved in nearly every patient. Patients with atrophic gastritis require endoscopic surveillance (see discussion of gastritis later in this Figure 26-24. Model of Helico-bacter effects on duodenal ulcer pathogenesis. (Reproduced with per-mission from Feldman M, Friedman LS, Sleisenger MH, et al: Sleisenger and Fordtran’s


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Surgery_Schwartz. later in this Figure 26-24. Model of Helico-bacter effects on duodenal ulcer pathogenesis. (Reproduced with per-mission from Feldman M, Friedman LS, Sleisenger MH, et al: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 7th ed. Philadelphia, PA: Elsevier/Saunders; 2002.)Multiple factors (smoking, ageat acquisition of infection)Somatostatin/gastrindysregulationAcquisition of H pyloriDuodenum ulcerationIncreased acidsecretionGastric metaplasiain duodenumDuodenum bicarbonate secretionInflammation (Duodenitis)Chronic H pyloriinfection in stomachH pylori colonization in duodenumBrunicardi_Ch26_p1099-p1166.indd 111901/03/19 7:11 PM 1120SPECIFIC CONSIDERATIONS PART IIchapter) because the same sequence of inflammation to meta-plasia to dysplasia to carcinoma, that is well known to occur in the esophagus from reflux-induced inflammation (and in the colon from inflammatory bowel disease), is now increasingly well recognized to occur in the stomach with Helicobacter-induced


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Surgery_Schwartz. to occur in the esophagus from reflux-induced inflammation (and in the colon from inflammatory bowel disease), is now increasingly well recognized to occur in the stomach with Helicobacter-induced gastritis. Helicobacter also clearly has an etiologic role in the development of gastric lymphoma.PEPTIC ULCER DISEASEPeptic ulcers are focal defects in the gastric or duodenal mucosa that extend into the submucosa or deeper. They may be acute or chronic and, ultimately, are caused by an imbalance between mucosal defenses and acid/peptic injury (Fig. 26-27).89,90 Peptic ulcer remains a common outpatient diagnosis, but the number of Figure 26-25. Pathogen-host interactions in the pathogenesis of Helicobacter pylori infection. ICAM = intercellular adhesion molecule-1; IFN-γ = interferon-γ; LPS = lipopolysaccharide; NF-κB = nuclear factor κB; PAI = pathogenicity island; PMN = polymorphonuclear neutrophil; TNF-α = tumor necrosis factor-α; VCAM = vascular cell adhesion molecule. (Used with


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Surgery_Schwartz. = lipopolysaccharide; NF-κB = nuclear factor κB; PAI = pathogenicity island; PMN = polymorphonuclear neutrophil; TNF-α = tumor necrosis factor-α; VCAM = vascular cell adhesion molecule. (Used with permission from Manuel Amieva, Stanford University.)cag+H pyloristraincag-PAI-encodedsecretoryapparatusMultiple adhesions:BabA (binds tolewis B), AIpA,AlpB, HopZPhospholipaseA2Alterationsin mucousglycoproteinsGastricepithelialcellFlagellaMucusActinpolymerizationCagAphosphorylationVacAApoptosisDisruption of epithelialbarrierFasexpressionUreaseLPSPorinsInterleukin-8CagAMacrophageInterleukin-12Th 1 cellTh 2 cellB cellCytokine-inducedchanges in gastric physiologyTh 0 cellICAM and VCAMexpressionPMN recruitmentInterleukin-8Chemotacticinterleukin-8 gradienton proteoglycanscaffoldingNeutrophilT cellB cellBlood vesselNF-˜ B AP-1 GRO-°ENA-78T-cell and B-cellextravasationINF-˛ TNF-°Interleukin-1˙MHC II, B7-1,and


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Surgery_Schwartz. gradienton proteoglycanscaffoldingNeutrophilT cellB cellBlood vesselNF-˜ B AP-1 GRO-°ENA-78T-cell and B-cellextravasationINF-˛ TNF-°Interleukin-1˙MHC II, B7-1,and B7-2expressionAnti-H+/K+-ATPaseantibodiesBrunicardi_Ch26_p1099-p1166.indd 112001/03/19 7:11 PM 1121STOMACHCHAPTER 26physician visits, hospital admissions, and elective operations for PUD has decreased steadily and dramatically over the past four decades. Interestingly, the start of these trends all predated the widespread use of acid suppression, or highly selective vagot-omy. The incidence of emergency surgery and the death rate associated with peptic ulcers has not decreased nearly so dra-matically. These epidemiologic changes probably represent the net effect of several factors, including (beneficially) decreased prevalence of H pylori infection, better medical therapy, and increased outpatient management and (detrimentally) the use of NSAIDs and aspirin (with and without ulcer prophylaxis)


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Surgery_Schwartz. decreased prevalence of H pylori infection, better medical therapy, and increased outpatient management and (detrimentally) the use of NSAIDs and aspirin (with and without ulcer prophylaxis) in an aging population with multiple risk factors.Figure 26-26. Helicobacter treatment dramatically decreases the recurrence rate of duodenal and gastric ulcer. (Reproduced with permission from Peek RM, Blaser MJL: Pathophysiology of Helico-bacter pylori-induced gastritis and peptic ulcer disease, Am J Med. 1997 Feb;102(2):200-207.)Figure 26-27. Balance of aggressive and defensive factors in the gastric mucosa. (Reproduced with permission from Suerbaum S, Michetti P: Helicobacter pylori infection, N Engl J Med. 2002 Oct 10;347(15):1175-1186.)PUD is one of the most common GI disorders in the United States with a prevalence of about 2%, and a lifetime cumulative prevalence of about 10%, peaking around age 70 years.91 The costs of PUD, including lost work time and productivity, are estimated to be


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Surgery_Schwartz. with a prevalence of about 2%, and a lifetime cumulative prevalence of about 10%, peaking around age 70 years.91 The costs of PUD, including lost work time and productivity, are estimated to be above $8 billion per year in the United States. In 1998, approximately 1.5% of all Medicare hospital costs were spent treating PUD, and the crude mortal-ity rate for peptic ulcer was 1.7 per 100,000 individuals. Using the National Inpatient Sample, it can be estimated that the mortality rate in patients hospitalized in 2006 with duodenal ulcer was 3.7% compared to 2.1% for gastric ulcer,92 and the age adjusted hospitalization rate was 56.5 per 100,000, down 21% from the previous decade. Recent studies have shown an increase in the rates of hospitalization and mortality in elderly patients for the peptic ulcer complications of bleeding and perforation.93 This may be due in part to the increasingly com-mon use of NSAIDs and aspirin in this elderly cohort, many of whom also have H pylori


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Surgery_Schwartz. for the peptic ulcer complications of bleeding and perforation.93 This may be due in part to the increasingly com-mon use of NSAIDs and aspirin in this elderly cohort, many of whom also have H pylori infection.Pathophysiology and EtiologyA variety of factors may contribute to the development of PUD. Although it is now recognized that the large majority of duode-nal and gastric ulcers are caused by H pylori infection (see previ-ous discussion on H pylori) and/or NSAID use20,94 (Fig. 26-28), the final common pathway to ulcer formation is acid-peptic injury of the gastroduodenal mucosal barrier. Acid suppression heals both duodenal and gastric ulcers and prevents recurrence if continued. In general, H pylori predisposes to ulceration, both by acid hypersecretion and by compromise of mucosal defense mechanisms. NSAID use causes ulcers predominantly by com-promise of mucosal defenses. Duodenal ulcer was traditionally viewed as a disease of increased acid-peptic action on the duo-denal


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Surgery_Schwartz. defense mechanisms. NSAID use causes ulcers predominantly by com-promise of mucosal defenses. Duodenal ulcer was traditionally viewed as a disease of increased acid-peptic action on the duo-denal mucosa, whereas gastric ulcer was viewed as a disease of weakened mucosal defenses. An increased understanding of peptic ulcer pathophysiology has blurred this overly simplistic distinction. Clearly, weakened mucosal defenses play a role in both duodenal and gastric ulcers, and acid hypersecretion may result in a duodenal or gastric ulcer in the setting of normal mucosal defenses.Elimination of H pylori infection or NSAID use is important for optimal ulcer healing, and perhaps is even more important in preventing ulcer recurrence and/or complications. A variety of other diseases are known to cause peptic ulcer, including ZES (gastrinoma), antral G-cell hyperfunction and/or hyperplasia, systemic mastocytosis, trauma, burns, and major physiologic stress. Other causative agents include drugs


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Surgery_Schwartz. peptic ulcer, including ZES (gastrinoma), antral G-cell hyperfunction and/or hyperplasia, systemic mastocytosis, trauma, burns, and major physiologic stress. Other causative agents include drugs (all NSAIDs, aspirin, and cocaine), smoking, and psychologic stress. In the United States, probably more than 90% of serious peptic ulcer complications can be attributed to H pylori infec-tion, NSAID use, and/or cigarette smoking.Acid Secretion and Peptic Ulcer. A variety of abnormalities related to mucosal acid exposure have been described in patients with duodenal ulcer (Fig. 26-29).95 Although duodenal ulcer patients as a group have a higher mean BAO and mean MAO compared to normal controls, many duodenal ulcer patients have basal and peak acid outputs in the normal range, and there is no correlation between acid secretion and the severity of the ulcer disease. As a group, duodenal ulcer patients produce more acid than normal controls in response to any known acid secre-tory stimulus.


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Surgery_Schwartz. correlation between acid secretion and the severity of the ulcer disease. As a group, duodenal ulcer patients produce more acid than normal controls in response to any known acid secre-tory stimulus. Although they usually have normal fasting serum gastrin levels, DU patients often produce more gastric acid at AcidPepsinNSAIDsH pyloriAggressionDefenseRepairBicarbonateBlood flowMucusCell junctionsApical resistanceRestitutionMucoid capProliferationGrowth factors0%10%20%30%40%50%60%70%80%90%100%Duodenal ulcerrecurrenceGastric ulcerrecurrenceRanitidine +antibioticsRanitidine aloneBrunicardi_Ch26_p1099-p1166.indd 112101/03/19 7:11 PM 1122SPECIFIC CONSIDERATIONS PART IIany given dose of gastrin than controls. Considering that many duodenal ulcer patients do produce excessive gastric acid, it has been argued that a “normal” fasting gastrin level in these patients is inappropriately high, and that there is an impaired feedback mechanism, especially in light of the apparently increased