Stomach

Divisions

The stomach is derived from the tubular embryonic foregut and begins as a dilation during the fifth week of gestation in the caudal portion. The embryonic stomach is invested by two mesenteries: dorsal (which becomes the gastrosplenic, gastrocolic, and gastrophrenic ligaments) and ventral (which becomes the hepatoduodenal and gastrohepatic ligaments of the lesser omentum and the falciform ligament). By the seventh week of gestation, the stomach descends, rotates, and further dilates with a disproportionate elongation of the greater curvature into its normal anatomic shape and position.

The most proximal region of the stomach is called the cardia and attaches to the esophagus. Immediately proximal to the cardia is the physiologically competent lower esophageal sphincter. The stomach is fixed at the gastroesophageal (GE) junction and pylorus, but its large midportion is mobile. The fundus represents the superior-most part of the stomach and is floppy and distensible. The angle of His is an important anatomic angle formed by the fundus with the left margin of the esophagus. The body of the stomach represents the largest portion and is also referred to as the corpus. The body is bounded on the right by the relatively straight lesser curvature and on the left by the longer greater curvature. At the angularis incisura, the lesser curvature abruptly angles to the right. The body of the stomach ends here and the antrum begins. Distally, the pylorus connects the distal stomach (antrum) to the proximal duodenum ( Fig. 49.1 ).

The left lateral segment of the liver covers a large portion of the stomach anteriorly. Posteriorly, the stomach is bounded by the diaphragm, left kidney, pancreas, aorta, and celiac trunk. Inferiorly, the stomach is attached to the transverse colon via the gastrocolic ligament. Superiorly, the GE junction is found approximately 2 to 3 cm below the diaphragmatic esophageal hiatus in the horizontal plane of the seventh chondrosternal articulation, a plane only slightly cephalad to the plane containing the pylorus. The gastrosplenic ligament attaches the proximal greater curvature to the spleen.

Blood Supply

The celiac artery provides the majority of the blood supply to the stomach ( Fig. 49.2 ). There are four main arteries—the left and right gastric arteries along the lesser curvature and the left and right gastroepiploic arteries along the greater curvature, with the left gastric artery being the largest. In addition, a substantial quantity of blood may be supplied to the proximal stomach by the inferior phrenic arteries and by the short gastric arteries from the spleen. Approximately 15% to 20% of patients have an aberrant left hepatic artery originating from the left gastric artery. Consequently, proximal ligation of the left gastric artery can result in acute left-sided hepatic ischemia. The right gastric artery arises from the hepatic artery (or sometimes the gastroduodenal artery). The left gastroepiploic artery originates from the splenic artery, and the right gastroepiploic artery originates from the gastroduodenal artery. The extensive anastomotic connections between these major vessels ensures that, in most cases, the stomach will survive if three out of four arteries are ligated, provided that the arcades along the greater and lesser curvatures are not disturbed. In general, the veins of the stomach parallel the arteries. The left gastric (coronary) and right gastric veins usually drain into the portal vein. The right gastroepiploic vein drains into the superior mesenteric vein, and the left gastroepiploic vein drains into the splenic vein.

Lymphatic Drainage

The lymphatic drainage of the stomach parallels the vasculature and drains into four zones of lymph nodes ( Fig. 49.3 ). The superior gastric group drains lymph from the upper lesser curvature into the left gastric and paracardial nodes. The suprapyloric group of nodes drains the antral segment on the lesser curvature of the stomach into the right suprapancreatic nodes. The pancreaticolienal group of nodes drains lymph high on the greater curvature into the left gastroepiploic and splenic nodes. The inferior gastric and subpyloric group of nodes drains lymph along the right gastroepiploic vascular pedicle. All four zones of lymph nodes drain into the celiac nodes and eventually into the thoracic duct. Although these lymph nodes drain different areas of the stomach, gastric cancers may metastasize to any of the four nodal groups, regardless of the cancer location. In addition, the extensive submucosal plexus of lymphatics accounts for the fact that there is frequently microscopic evidence of malignant cells several centimeters from gross disease.

Innervation

As shown in Fig. 49.4 , the extrinsic innervation of the stomach is both parasympathetic (via the vagus nerve) and sympathetic (via the celiac plexus). The vagus nerve originates in the vagal nucleus in the floor of the fourth ventricle and traverses the neck in the carotid sheath to enter the mediastinum, where it divides into several branches around the esophagus. These branches coalesce above the esophageal hiatus to form the left and right vagus nerves. It is not uncommon to find more than two vagal trunks at the distal esophagus. At the GE junction, the left vagus is anterior, and the right vagus is posterior.

The left vagus gives off the hepatic branch to the liver and continues along the lesser curvature as the nerve of Latarjet. The so-called criminal nerve of Grassi is the first branch of the right posterior vagus nerve; it is recognized as a potential cause of recurrent ulcers when left undivided. The right vagus nerve gives a branch off to the celiac plexus and continues posteriorly along the lesser curvature. A truncal vagotomy is performed above the celiac and hepatic branches of the vagi, whereas a selective vagotomy is performed below. A highly selective vagotomy is performed by dividing the crow’s feet to the proximal stomach while preserving the innervation of the antral and pyloric parts of the stomach. Most (90%) of the vagal fibers are afferent, carrying stimuli to the brain. Efferent vagal fibers originate in the dorsal nucleus of the medulla and synapse with neurons in the myenteric and submucosal plexuses. These neurons influence gastric motor function and gastric secretion. In contrast, the sympathetic nerve supply comes from T5 to T10, traveling in the splanchnic nerve to the celiac ganglion. Postganglionic fibers travel with the arterial system to innervate the stomach.

The intrinsic or enteric nervous system of the stomach consists of neurons in Auerbach and Meissner autonomic plexuses. In these locations, cholinergic, serotoninergic, and peptidergic neurons are present. The exact function of these neurons is poorly understood. Nevertheless, numerous neuropeptides have been localized to these neurons, including acetylcholine, serotonin, substance P, calcitonin gene–related peptide, bombesin, cholecystokinin (CCK), and somatostatin.

Gastric Morphology

The stomach is covered by peritoneum, which forms the outer serosa of the stomach. Below this is the thicker muscularis propria, or muscularis externa, which is composed of three layers of smooth muscles. The middle layer of smooth muscle is circular and is the only complete muscle layer of the stomach wall. At the pylorus, this middle circular muscle layer becomes progressively thicker and functions as a true anatomic sphincter. The outer muscle layer is longitudinal and predominates in the distal two thirds of the stomach. Within the layers of the muscularis externa is a rich plexus of autonomic nerves and ganglia, called Auerbach myenteric plexus. The submucosa lies between the muscularis externa and the mucosa and is a collagen-rich layer of connective tissue that forms the strongest layer of the gastric wall. In addition, it contains the rich anastomotic network of blood vessels and lymphatics as well as the Meissner plexus of autonomic nerves. The mucosa consists of surface epithelium, lamina propria, and muscularis mucosae. The muscularis mucosae is on the luminal side of the submucosa and is probably responsible for the rugae that greatly increases the stomach’s epithelial surface area. It also marks the microscopic boundary for invasive and noninvasive gastric carcinoma. The lamina propria represents a small connective tissue layer and contains capillaries, vessels, lymphatics, and nerves necessary to support the surface epithelium.

Gastric Microscopic Anatomy

Gastric mucosa consists of simple columnar epithelia interrupted by gastric pits containing one or more gastric glands. The cellular populations (and functions) of the cells forming this glandular epithelium vary based on their location in the stomach ( Table 49.1 ). The glandular epithelium is divided into cells that secrete products into the gastric lumen for digestion (parietal cells, chief cells, mucus-secreting cells) and cells that control function (gastrin-secreting G cells, somatostatin-secreting D cells). In the cardia, the mucosa is arranged in branched glands, and the pits are short. In the fundus and body, the glands are more tubular, and the pits are longer. In the antrum, the glands are more branched. The luminal ends of the gastric glands and pits are lined with mucus-secreting surface epithelial cells, which extend down into the necks of the glands for variable distances. In the cardia, the glands are predominantly mucus-secreting. In the body, the glands are mostly lined from the neck to the base with parietal and chief cells ( Fig. 49.5 ). There are a few parietal cells in the fundus and proximal antrum, but none in the cardia or prepyloric antrum. The endocrine G cells are present in greatest quantity in the antral glands.

Gastrin

Gastrin is produced by G cells located in the gastric antrum and is the primary endocrine regulator of the secretory phase of a protein meal (see Table 49.1 ). It is synthesized as a prepropeptide and undergoes posttranslational processing by enzymatic cleavage in the rough endoplasmic reticulum and secretory vesicles to produce biologically reactive gastrin peptides. Several molecular forms of gastrin exist. The two major forms are G34 (big gastrin) and G17 (little gastrin). Ninety percent of antral gastrin is released as the 17–amino acid peptide, although G34 predominates in the circulation because its metabolic half-life is longer. The pentapeptide sequence contained at the carboxy terminus of gastrin is the biologically active component and is identical to that found on another gut peptide, CCK. CCK and gastrin differ by their tyrosine sulfation sites. Gastrin initiates its biologic actions by activation of surface membrane receptors. These receptors are members of the classic G protein–coupled receptor family and are classified as type A or B CCK receptors. The gastrin or CCK-B receptor has high affinity for gastrin and CCK, whereas type A CCK receptors have an affinity for sulfated CCK analogues and a low affinity for gastrin.

The release of gastrin is stimulated mostly by gastric distension, gastrin-releasing peptide (bombesin), and protein digestion products. Luminal acid inhibits the release of gastrin, specifically when the intragastric pH is below 3.0, via somatostatin release. In the antral location, somatostatin and gastrin release are functionally linked, and an inverse reciprocal relationship exists between these two peptides.

Gastrin is the major hormonal regulator of the gastric phase of acid secretion. Gastrin primarily does this by stimulating enterochromaffin-like (ECL) cells to synthesize and release histamine. However, gastrin also exerts direct actions on the parietal cell to stimulate acid release. Gastrin also has considerable trophic effects on both parietal cells and ECL cells. Prolonged hypergastrinemia from any cause leads to mucosal hyperplasia and an increase in the number of ECL cells and, under some circumstances, is associated with the development of gastric carcinoid tumors.

The detection of hypergastrinemia may suggest a pathologic state of acid hypersecretion but most commonly is the result of treatment with agents to reduce acid secretion, such as proton pump inhibitors (PPIs). Table 49.2 lists common causes of chronic hypergastrinemia. Hypergastrinemia that results from the administration of acid-reducing drugs is an appropriate response caused by loss of feedback inhibition of gastrin release by luminal acid. Lack of acid causes a reduction in somatostatin release, which causes increased release of gastrin from antral G cells. Hypergastrinemia can also occur in the setting of pernicious anemia, uremia, or after surgical procedures such as vagotomy. In contrast, gastrin levels increase inappropriately in patients with gastrinoma (Zollinger-Ellison syndrome [ZES]). These gastrin-secreting tumors are not located in the antrum and secrete gastrin autonomously.

Somatostatin

Somatostatin is produced by delta cells and exists endogenously as either a 14–amino acid peptide or 28–amino acid peptide. The predominant molecular form in the stomach is somatostatin-14. It is produced by diffuse neuroendocrine cells located in the fundus and antrum. The principal stimulus for somatostatin release is antral acidification as well as gastrin-releasing peptide, whereas acetylcholine from vagal fibers inhibits its release. Somatostatin inhibits parietal cell acid secretion directly but also indirectly decreases acid secretion through inhibition of gastrin release from G cells and downregulation of histamine release from ECL cells.

Somatostatin receptors are also G protein–coupled receptors. Binding of somatostatin with its receptors is coupled to one or more inhibitory guanine nucleotide–binding proteins. Parietal cell somatostatin receptors appear to be a single subunit of glycoproteins with a molecular weight of 99 kDa, with equal affinity for somatostatin-14 and somatostatin-28. Somatostatin can inhibit parietal cell secretion through G protein–dependent and G protein–independent mechanisms. However, the ability of somatostatin to exert its inhibitory actions on cellular function is primarily thought to be mediated through the inhibition of adenylate cyclase, with a resultant reduction in cyclic adenosine monophosphate (cAMP) levels.

Histamine

Histamine (H ₂ ) plays a prominent role in parietal cell stimulation. Administration of H ₂ -receptor antagonists almost completely abolishes gastric acid secretion in response to gastrin and acetylcholine, suggesting that histamine may be a necessary intermediary of these pathways. Histamine is stored in the acidic granules of ECL cells and in resident mast cells. ECL cells are located in the oxyntic mucosa in direct proximity to the parietal cell. Histamine release is stimulated by gastrin, vasoactive intestinal peptide, ghrelin, acetylcholine, and epinephrine through receptor-ligand interactions on ECL cells. In contrast, somatostatin inhibits gastrin-stimulated histamine release through interactions with somatostatin receptors located on the ECL cell, with other inhibitors including peptide YY and prostaglandins. The ECL cell plays an essential role in parietal cell activation, possessing stimulatory and inhibitory feedback pathways that modulate the release of histamine.

Ghrelin

Ghrelin is a 28–amino acid peptide predominantly produced by endocrine cells of the oxyntic glands in the stomach. Ghrelin appears to be under both endocrine and metabolic control, has a diurnal rhythm, and likely plays a major role in the neuroendocrine and metabolic responses to changes in nutritional status. Ghrelin has been shown to stimulate growth hormone release as well. Ghrelin levels are high during fasting and increases shortly before meals, with decreased levels after meals. Decreased ghrelin levels have been associated with gastritis. Within the stomach, ghrelin increases gastric emptying and motility and increases gastric acid secretion.

In human volunteers, ghrelin administration enhances appetite and increases food intake. In patients who have undergone a gastric bypass or sleeve gastrectomy, ghrelin levels are lower. Although the mechanism responsible for suppression of ghrelin levels after bariatric surgery is unknown, it is suggested that ghrelin may be responsive to the normal flow of nutrients across the stomach. Other studies have suggested that ghrelin leads to a switch toward glycolysis and away from fatty acid oxidation, which would favor fat deposition. Ghrelin appears to be upregulated in times of negative energy balance and downregulated in times of positive energy balance. Ghrelin may come to have a role in the treatment and prevention of obesity.

Stimulated Acid Secretion

Ingestion of food is the physiologic stimulus for acid secretion. Three phases of the acid secretory response to a meal have been described—cephalic, gastric, and intestinal. These three phases are interrelated and occur concurrently.

Activation and Secretion by the Parietal Cell

The two second messengers principally involved in stimulation of acid secretion by parietal cells are intracellular cAMP and calcium. These two messengers activate protein kinases and phosphorylation cascades. The intracellular events following ligand binding to receptors on the parietal cell are shown in Fig. 49.7 . Histamine causes an increase in intracellular cAMP, which initiates a cascade of phosphorylation events that culminates in activation of proton pump (H ⁺ , K ⁺ -ATPase). In contrast, acetylcholine and gastrin stimulate phospholipase C, which converts membrane-bound phospholipids into inositol triphosphate to mobilize calcium from intracellular stores. Increased intracellular calcium activates other protein kinases that ultimately activate H ⁺ , K ⁺ -ATPase in a similar fashion to initiate the secretion of hydrochloric acid.

H ⁺ , K ⁺ -ATPase is the final common pathway for gastric acid secretion by the parietal cell. It is composed of two subunits, a catalytic α-subunit (100 kDa) and a glycoprotein β-subunit (60 kDa). During the resting state, gastric parietal cells store H ⁺ , K ⁺ -ATPase intracellularly. Cellular relocation of the proton pump subunits through cytoskeletal rearrangements must occur for acid secretion to increase in response to stimulatory factors. The subsequent heterodimer assembly of the H ⁺ , K ⁺ -ATPase subunits and insertion into the microvilli of the secretory canaliculus causes an increase in gastric acid secretion. A potassium chloride efflux pathway must exist to supply potassium to the extracytoplasmic side of the pump. Cytosolic hydrogen is secreted by H ⁺ , K ⁺ -ATPase in exchange for extracytoplasmic potassium (see Fig. 49.7 ), which is an electroneutral exchange and does not contribute to the transmembrane potential difference across the parietal cell. Secretion of chloride is accomplished through a chloride channel moving chloride from the parietal cell cytoplasm to the gastric lumen. The exchange of hydrogen for potassium requires energy in the form of adenosine triphosphate because hydrogen is being secreted against a gradient of more than a million fold. Because of this large energy requirement, the parietal cell has a mitochondrial compartment representing about one third of its cellular volume. In response to a secretagogue, the parietal cell undergoes a conformational change, and a several-fold increase in the canalicular surface area occurs ( Fig. 49.8 ). In contrast to stimulated acid secretion, cessation of acid secretion requires endocytosis of H ⁺ , K ⁺ -ATPase, with regeneration of cytoplasmic tubulovesicles containing the subunits, and this occurs through a tyrosine-based signal. The tyrosine-containing sequence is located on the cytoplasmic tail of the β-subunit and is highly homologous to the motif responsible for internalization of the transferrin receptor.

More than 1 billion parietal cells are found in the normal human stomach and are responsible for secreting approximately 20 mmol/hr of hydrochloric acid in response to a protein meal. There is a linear relationship between maximal acid output and parietal cell number. However, gastric acid secretory rates may be altered in patients with upper gastrointestinal (GI) disease. For example, gastric acid is often increased in patients with duodenal ulcer or gastrinoma, whereas it is decreased in patients with pernicious anemia or gastric atrophy. Patients with proximal gastric ulcers have lower secretory rates, whereas distal, antral, or prepyloric ulcers are associated with acid secretory rates similar to rates in patients with duodenal ulcers.

Gastric acid plays a critical role in the digestion of a meal. It is required to convert pepsinogen into pepsin, elicits the release of secretin from the duodenum, and limits colonization of the upper GI tract with bacteria.

Pharmacologic Regulation

Given the role stomach acid plays in many disease pathologies and the diversity of mechanisms that stimulate acid secretion, there has been much interest in the development of many site-specific drugs aimed at decreasing acid output by the parietal cell. The best-known site-specific antagonists are the group collectively known as the H ₂ - receptor antagonists , which inhibit the H ₂ -receptor on the parietal cell. The most potent of the H ₂ -receptor antagonists is famotidine, followed by ranitidine, nizatidine, and cimetidine.

PPIs block acid secretion more completely than H ₂ -receptor antagonists because of their irreversible inhibition of the H ⁺ , K ⁺ -ATPase proton pump. After oral administration, these agents are absorbed into the bloodstream as prodrugs and selectively concentrate in the secretory canaliculus of the parietal cell. At low pH, they become ionized and activated, with the formation of an active sulfur group. The cysteine residues on the α-subunit of the H ⁺ , K ⁺ -ATPase form a covalent disulfide bond with activated PPIs, which irreversibly inhibits the proton pump. Because of the covalent nature of this bond, these PPIs have more prolonged inhibition of gastric acid secretion than H ₂ blockers. For recovery of acid secretion to occur, new protein pumps must be synthesized.

Antacids and sucralfate are two other medications with effects on gastric acid; however, they are both less potent. Antacids typically contain aluminum hydroxide, calcium carbonate, or magnesium trisilicate and can be used to neutralize gastric acid and decrease acid delivery to the duodenum, although the exact mechanism is unclear. Sucralfate is a sucrose octasulfate complexed with aluminum hydroxide and has been shown to bind to injured gastric tissue and stimulate angiogenesis and granulation tissue formation. Given the lower potency, the indications for antacids and sucralfate are limited to treatment of mild GE reflux disease.

Other Gastric Secretory Products

Fasting Gastric Motility

The electrical basis of gastric motility begins with the depolarization of pacemaker cells located in the mid-body of the stomach along the greater curvature. Once initiated by the interstitial of Cajal, slow waves travel at 3 cycles/minute in a circumferential and antegrade fashion toward the pylorus. In addition to these slow waves, gastric smooth muscle cells are capable of producing action potentials, which are associated with larger changes in membrane potential than slow waves. Compared with slow waves, which are not associated with gastric contractions, action potentials are associated with actual muscle contractions. During fasting, the stomach goes through a cyclical pattern of electrical activity composed of slow waves and electrical spikes, which has been termed the migrating myoelectric complex. Each cycle of the migrating myoelectric complex lasts 90 to 120 minutes. The net effects of the myoelectric migrating complex are frequent clearance of gastric contents during periods of fasting. The exact regulatory mechanisms of myoelectric migrating complex activities are unknown, but these activities remain intact after vagal denervation.

Postprandial Gastric Motility

Ingestion of a meal results in a decrease in the resting tone of the proximal stomach and fundus, referred to as receptive relaxation and gastric accommodation, respectively. Because these reflexes are mediated by the vagus nerves, interruption of vagal innervation to the proximal stomach, such as by truncal vagotomy or proximal gastric vagotomy, can eliminate these reflexes, with resultant early satiety and rapid emptying of ingested liquids. In addition to its storage function, the stomach is responsible for the mechanical mixing of ingested solid food particles. This activity involves repetitive forceful contractions of the midportion and antral portion of the stomach, causing food particles to be propelled against a closed pylorus, with subsequent retropulsion of solids and liquids. The net effect is a thorough mixing of solids and liquids and sequential shearing of solid food particles to smaller than 1 mm prior to passage through the pylorus to the proximal duodenum.

The emptying of gastric contents is influenced by coordinated neural and hormonal mediators. Additionally, the chemical and mechanical properties and temperature of the intraluminal contents can influence the rate of gastric emptying. In general, liquids empty more rapidly than solids, and carbohydrates empty more readily than fats. In addition, hot and cold liquids tend to empty at a slower rate than ambient temperature fluids. These responses to luminal stimuli are regulated by the enteric nervous system. Osmoreceptors and pH-sensitive receptors in the proximal small bowel have also been shown to be involved in the activation of feedback inhibition of gastric emptying. Inhibitory peptides proposed to be active in this setting include CCK, vasoactive intestinal peptide, glucagon, and gastric inhibitory polypeptide.

Abnormal Gastric Motility

Symptoms of abnormal gastric motility are nausea/vomiting, postprandial fullness, early satiety, abdominal pain, and bloating. In the most severe cases, patients can suffer weight loss. The first steps in evaluating patients with suspected abnormal gastric motility after history and physical examination should be to exclude a mechanical obstruction with upper endoscopy and either a computed tomographic (CT) or magnetic resonance (MR) enterography or barium follow-through. The most common cause of gastroparesis is idiopathic, accounting for approximately half of patients. Other common causes include diabetes mellitus, viral infection (i.e., cytomegalovirus and Epstein-Barr virus), neurologic disease (i.e., multiple sclerosis, stroke, Parkinson disease), autoimmune disease, and certain medications such as tricyclic antidepressants, calcium channel blockers, and cyclosporine. Additionally, gastric motility can also be impaired after surgery due to either intentional or accidental vagotomy. Vagotomy results in loss of receptive relaxation and gastric accommodation in response to meal ingestion, with resultant early satiety, postprandial bloating, accelerated emptying of liquids, and delay in emptying of solids. Delayed gastric emptying is also seen after pancreatic surgery, most notably pancreaticoduodenectomy, where it is reported in 10% to 40% of patients postoperatively.

Clinical manifestations of diabetic gastropathy, which can occur in insulin-dependent or non–insulin-dependent patients, are thought to be related to a variety of factors. Impaired neural control via the vagus nerve, myenteric nervous system, interstitial cells of Cajal, and the underlying smooth muscle have been implicated. Additionally, hyperglycemia itself has been shown to cause a decrease in contractility of the gastric antrum, increase in pyloric contractility, relax the proximal stomach, and suppress the migrating myoelectric complexes. Hyperinsulinemia, which is often associated with non–insulin-dependent diabetes, may play a role in the gastroparesis seen in non–insulin-dependent diabetes because it also leads to suppression of migrating myoelectric complex activity.

Gastric-Emptying Studies

There are numerous ways to assess gastric emptying. The most common is a radionucleotide scan. This nuclear scintigraphy study is performed using a meal of radiolabeled food. Scans are obtained immediately after ingestion of the meal and at 1, 2, and 4 hours after the meal. Measurement of residual gastric contents at 4 hours provides the most sensitive means for diagnosing gastroparesis. At 4 hours, retention of 10% to 15% signifies mild gastroparesis, 15% to 35% is moderate, and greater than 35% is severe. More recently, some institutions include a clear liquid gastric-emptying study to detect patients with normal solid food emptying but delayed liquid emptying. There are multiple other diagnostic options; however, they are utilized less frequently. An upper abdominal x-ray series after barium swallow can provide information on gastric emptying and may reveal mechanical causes that could contribute to a delay, such as gastric outlet obstruction. An electrogastrogram or antroduodenal motility study assesses for nerve and muscle abnormalities; however, neither evaluates the actual functional significance. Wireless motility capsules have also been investigated as an alternative to scintigraphy, which can measure the pH, temperature, and pressure during its transit.

Treatment

Regardless of the cause of gastroparesis, initial first-line treatment of mild gastroparesis involves dietary modification. Patients should be encouraged to eat multiple, small meals with little fat or insoluble fiber. Acidic and spicy foods should also be avoided. Medications that affect gastric motility, such as opioids, calcium channel blockers, tricyclic antidepressants, and dopamine agonists, should be stopped when possible. Glycemic control should be optimized in diabetic patients.

Pharmacologic therapy is necessary for persistent symptoms despite the above nonpharmacologic modifications. First-line medical therapy is metoclopramide (Reglan), a dopamine 2 receptor antagonist that stimulates antral contractions and decreases postprandial relaxation of the fundus. Outside of the United States, domperidone, another dopamine 2 antagonist, is available for patients who do not respond to metoclopramide or who experience side effects. Macrolide antibiotics (erythromycin and azithromycin) are motilin agonists that act by stimulating fundal contraction and have also shown benefit; they can be considered for second-line therapy.

Surgery for gastroparesis is rarely required and only indicated for refractory symptoms despite maximal medical therapy, partly because poor improvement in symptoms was observed historically after traditional open operations including gastrojejunostomy and subtotal gastrectomy. Surgical venting gastrostomy tubes can be placed (if unable to place endoscopically) for venting and jejunostomy tubes can be placed if needed for nutrition. Pyloromyotomy and pyloroplasty are options for the surgical management of gastroparesis that function by lowering outflow resistance at the pylorus and enhancing any remaining gastric contractility. Surgical implantation of gastric electrostimulators has also been used as a treatment for refractory idiopathic and diabetic gastroparesis. In this technique, electrical leads are placed onto the antrum laparoscopically and connected to a subcutaneously positioned simulator that delivers high-frequency, low-energy current. A recent systematic review reported that pyloric surgery improved nausea and abdominal pain more than gastric electrical stimulation ; however, robust comparative trials are lacking. Endoscopic therapies, such as the gastric peroral endoscopic myotomy, are also being explored. Retrospective series have shown durable improvement up to 1 year; however, prospective clinical trials are needed. Endoscopic pyloric dilation and stenting can also be considered in select settings.

Helicobacter pylori Infection

It is estimated that half of the world’s population is affected by H. pylori. While, previously, 80% to 95% of duodenal ulcers and approximately 75% of gastric ulcers were associated with H. pylori infection, its prevalence in peptic ulcers has fallen to 50% to 75% in developed countries more recently with improved diagnosis, treatment, and prevention. Infection with H. pylori has been shown to temporally precede ulcer formation, and when this organism is eradicated as part of ulcer treatment, ulcer recurrence is extremely rare. These observations have secured the place of H. pylori as a primary causative factor in the pathogenesis of PUD.

The interplay between bacterial and host factors determines the clinical outcome of H. pylori infection. H. pylori is a spiral-shaped, flagellate, gram-negative bacteria that resides in gastric-type epithelium within or beneath the mucus layer. Its shape and flagella aid its movement through the mucous layer, and it produces enzymes that help it adapt to this hostile environment. Mucolytic enzymes both facilitate passage through the mucus layer and protect the bacteria from mucin’s antibiotic effects. Most notably, H. pylori is a potent producer of urease, which is capable of splitting urea into ammonia and bicarbonate, creating an alkaline microenvironment in the setting of an acidic gastric milieu, allowing for the bacteria’s survival in the stomach. The bacteria attach to the gastric epithelial cells by binding to surface adhesions. H. pylori organisms are microaerophilic and can live only in gastric epithelium. Thus, H. pylori can also be found in heterotopic gastric mucosa in the proximal esophagus, in Barrett esophagus, in gastric metaplasia in the duodenum, within a Meckel diverticulum, and in heterotopic gastric mucosa in the rectum. The host response to H. pylori is at least partially determined genetically, with associations shown with interleukin 1β and toll-like receptors, both components of the inflammatory response.

The exact mechanisms responsible for H. pylori –induced GI injury are still not fully understood, but the following four potential mechanisms have been proposed (and likely interact) to cause a derangement of normal gastric and duodenal physiology that leads to subsequent ulcer formation:

• 1.

  Production of toxic products that cause local tissue injury. Locally produced toxic mediators include breakdown products from urease activity (e.g., ammonia), cytotoxins, mucinase (which degrades mucus and glycoproteins), phospholipases that damage both epithelial and mucus cells, and platelet-activating factor (which is known to cause mucosal injury and thrombosis in the microcirculation).

• 2.

  Induction of a local mucosal immune response. H. pylori can cause a local inflammatory reaction in the gastric mucosa, attracting neutrophils and monocytes, which then produce numerous proinflammatory cytokines and reactive oxygen metabolites.

• 3.

  Increased gastrin levels and changes in acid secretion. In patients with antral H. pylori infection, basal and stimulated gastrin levels are significantly increased, presumably secondary to a reduction in somatostatin release from antral D cells because of infection with H. pylori. During the acute phase of H. pylori infection, acid secretion is decreased. With chronic infection, H. pylori has trophic effects on ECL and G cells, which can result in acid hypersecretion. A decrease in serum levels of somatostatin could also contribute to the gastric hyperacidity. However, if oxyntic glands are destroyed by the chronic infection, hypoacidity will result.

• 4.

  Gastric metaplasia occurring in the duodenum. Metaplastic replacement of areas of duodenal mucosa with gastric epithelium likely occurs as a protective response to decreased duodenal pH, resulting from the above-described acid hypersecretion; this allows for H. pylori to colonize these areas of the duodenum, which causes duodenitis and likely predisposes to duodenal ulcer formation. The presence of H. pylori in the duodenum is more common in patients with ulcer formation compared with patients with asymptomatic infections isolated to the stomach.

Peptic ulcers are also strongly associated with antral gastritis. Studies performed before the H. pylori era demonstrated that almost all patients with peptic ulcers have histologic evidence of antral gastritis. It is now known that most cases of histologic gastritis are caused by H. pylori infection. Of patients with NSAID-associated ulcers, 25% have evidence of a histologic antral gastritis compared with 95% of patients with non–NSAID-associated ulcers. In most cases, the infection tends to be confined initially to the antrum and results in antral inflammation. The causative role of H. pylori infection in the pathogenesis of gastritis and PUD was first elucidated by Marshall and Warren in Australia in 1984. To prove this connection, Marshall himself ingested inocula of H. pylori after first confirming that he had normal gross and microscopic gastric mucosa. Within days, he developed abdominal pain, nausea, and halitosis as well as histologically confirmed presence of gastric H. pylori infection. Acute inflammation was observed histologically on days 5 and 10. By 2 weeks, acute inflammation had been replaced by chronic inflammation with evidence of a mononuclear cell infiltration. For their pioneering work, Marshall and Warren were jointly awarded the Nobel Prize in Medicine in 2005.

Evidence of infection is seen in childhood in developing countries and in adulthood in developed countries. Spontaneous remission is rare. There is an inverse relationship between infection rates and socioeconomic status. The reasons for this relationship are poorly understood, but it seems to be the result of factors such as sanitary conditions, familial clustering, lack of running water, and overcrowding. Such factors likely also explain why developing countries have a comparatively higher rate of H. pylori infection, especially in children. In the United States, H. pylori prevalence is higher in African Americans and Hispanics.

H. pylori infection is associated with many common upper GI disorders, but most infected individuals are asymptomatic. Healthy U.S. blood donors have an overall prevalence anywhere from 20% to 55%. H. pylori infection is almost always present in the setting of active chronic gastritis. In addition, most patients with gastric cancer have current or past H. pylori infection. Although the association between H. pylori and gastric cancer is strong, no causal relationship has been proven. However, H. pylori –induced chronic gastritis and intestinal metaplasia are thought to play a role. A meta analysis of case-control studies comparing H. pylori –positive and H. pylori –negative individuals found that infection was associated with a twofold increased risk of developing gastric cancer. There is also a strong association between mucosa-associated lymphoid tissue (MALT) lymphoma and H. pylori infection. Regression of these lymphomas has been demonstrated after eradication of H. pylori .

Invasive Tests

Noninvasive Tests

Nonsteroidal Antiinflammatory Drugs

NSAIDs, including aspirin, are absorbed through the stomach and small intestine and function as inhibitors of the cyclooxygenase enzymes. Cyclooxygenase enzymes form the rate-limiting step of prostaglandin synthesis in the GI tract. Prostaglandins (including thromboxane A2) promote gastric and duodenal mucosal protection from luminal acid and pepsin via numerous mechanisms, including increasing mucin and bicarbonate secretion and increasing blood flow to the mucosal endothelium and promoting epithelial cell proliferation and migration to the luminal surface. The presence of NSAIDs disrupts these naturally protective mechanisms, increasing the risk of peptic ulcer formation in the stomach and the duodenum.

The Food and Drug Administration estimates that NSAIDs are associated with a 1% to 4% risk per year of a clinically significant GI event, including bleeding, pyloric obstruction, and perforation. The risk for mucosal injury or ulceration is roughly proportional to the anti-inflammatory effect associated with each NSAID. Compared with H. pylori ulcers, which are more frequently found in the duodenum, NSAID-induced ulcers are more often found in the stomach. H. pylori ulcers are also almost always associated with chronic active gastritis, whereas gastritis is not frequently found with NSAID-induced ulcers. When NSAID use is discontinued, the ulcers usually do not recur.

Clinical Manifestations

One clinical challenge of gastric ulcer management is the differentiation between gastric carcinoma and a benign ulcer. This is in contrast to duodenal ulcers, in which malignancy is extremely rare. Similar to duodenal ulcers, gastric ulcers are also characterized by recurrent episodes of quiescence and relapse. They also cause pain, bleeding, and obstruction and can perforate. Occasionally, benign ulcers have also been found to result in spontaneous gastrocolic fistulas. Surgical intervention is required in patients who develop complications from gastric ulcer disease. Patients who develop significant bleeding from gastric ulcers usually are older, are less likely to stop bleeding spontaneously, and have higher morbidity and mortality rates than patients with bleeding from a duodenal ulcer. The most frequent complication of gastric ulceration is perforation. Most perforations occur along the anterior aspect of the lesser curvature. In general, older patients have increased rates of perforations, and larger ulcers are associated with higher morbidity and mortality. Similar to duodenal ulcers, gastric outlet obstruction can also occur in patients with type II or III gastric ulcers. However, one must carefully differentiate between benign obstruction and obstruction secondary to carcinoma.

Diagnosis and Treatment

The diagnosis and treatment of gastric ulceration generally mirror the diagnosis and treatment of duodenal ulcer disease. The significant difference is the possibility of malignancy in a gastric ulcer. This critical difference demands that cancer be ruled out in acute and chronic presentations of gastric ulcer disease. Acid suppression and H. pylori eradication are important aspects of any treatment.

As with duodenal ulcers, intractable nonhealing ulcers are becoming increasingly less common. It is important to ensure that adequate time has elapsed and appropriate therapy has been administered to allow healing of the ulcer to occur; this includes confirmation that H. pylori has been eradicated and that NSAIDs have been eliminated. The presentation of a nonhealing gastric ulcer in the H. pylori era should raise serious concerns about the presence of an underlying malignancy. These patients should undergo a thorough evaluation with multiple biopsies to exclude malignancy ( Fig. 49.9 ). The approach for a complicated gastric ulcer varies depending on the type of ulcer and its association with pathophysiologic acid levels. Types I and IV ulcers, which are not associated with increased acid levels, do not require acid-reducing vagotomy. Fig. 49.10 is an algorithm for managing complicated gastric ulcers.