TOPIC 6: STOMACH STRUCTURE AND FUNCTION

Steps to diagnosis: gastroparesis and pseudo-obstruction

1. Suspect and exclude mechanical obstruction. 2. Assess gastric and small bowel motility. 3. Identify the pathogenesis. 4. Identify complications of the motility disorder, including bacterial overgrowth, dehydration, and malnutrition.

Histamine H1 and muscarinic M1 receptors and emesis

Histamine H1 and muscarinic M1 receptors, which are abundant in the vestibular center and solitary nucleus, constitute the preferred pharmacologic targets for inhibiting motion sickness, vestibular nausea, and pregnancy-related emesis.

Outline the diagnostic usefulness of features associated with a history of vomiting.

-"Certain clinical features may be characteristic of specific causes of nausea and vomiting. -Nausea and vomiting that occur in the morning or on an empty stomach and with emission of mucoid material (swallowed saliva) or gastroenteric secretions are characteristic of direct activation of the emetic center or CTZ. -This type of emesis is most typical of pregnancy, drugs, toxins (e.g., alcohol), or metabolic disorders (e.g., diabetes mellitus, uremia). -Psychogenic vomiting may also exhibit these characteristics. -Vomiting that occurs outside the immediate postprandial period and is characterized by evacuation of retained and partially digested food is typical of slowly developing gastric outlet obstruction or gastroparesis. -Pseudovomitus, in which totally undigested food that has not been exposed to gastric juice is expelled, may occur in long-standing achalasia or with a large Zenker's diverticulum. -Bilious vomiting is commonly seen after multiple vomiting episodes occur in close succession because of retrograde entry of intestinal material into the stomach. -It is also characteristic of patients with a surgical enterogastric anastomosis, in whom the gastric contents normally include bile-stained enteric refluxate. -Vomitus with a feculent odor suggests intestinal obstruction, ileus associated with peritonitis, or long-standing gastric outlet obstruction. -Vomiting that develops abruptly without preceding nausea or retching (projectile vomiting) is characteristic of, but not specific for, direct stimulation of the emetic center, as may occur with intracerebral lesions (tumor, abscess) or increased intracranial pressure."

Celiac phase of gastric secretion

-(~30% of response) -The cephalic phase of secretion is initiated by the sight, smell, taste, and swallowing of food. -can be influenced by food preferences -These stimuli activate the dorsal motor nucleus of the vagal nerve in the medulla and result in vagal discharge and parasympathetic motor nerves. -Stimulation has several consequences. -In the corpus, postganglionic nerves release ACh, which directly activates parietal cells by M3 receptors. -ACh also induces histamine release from enterochromaffin cells, which stimulates H+ ion secretion by parietal cells. -In the antrum, vagal stimulation induces release of the peptide, GRP, from postganglionic fibers, which stimulates gastrin release and thus indirectly stimulates secretion of H+ ion secretion. -ACh also inhibits somatostatin release from D cells in the corpus and pylorus to stimulate secretion of H+ ions.

Hiatal Hernia

-A hiatal hernia is a protrusion of part of the stomach into the mediastinum through the esophageal hiatus of the diaphragm. -The hernias occur most often in people after middle age, possibly because of weakening of the muscular part of the diaphragm and widening of the esophageal hiatus. -Although clinically there are several types of hiatal hernia, the two main types are paraesophageal hiatal hernia and sliding hiatal hernia -In the less common para-esophageal hiatal hernia, the cardia remains in its normal position -However, a pouch of peritoneum, often containing part of the fundus of the stomach, extends through the esophageal hiatus anterior to the esophagus. -In these cases, usually no regurgitation of gastric contents occurs because the cardial orifice is in its normal position -In the common sliding hiatal hernia, the abdominal part of the esophagus, the cardia, and parts of the fundus of the stomach slide superiorly through the esophageal hiatus into the thorax, especially when the person lies down or bends over -Some regurgitation of stomach contents into the esophagus is possible because the clamping action of the right crus of the diaphragm on the inferior end of the esophagus is weak.

Posterior gastric ulcer

-A posterior gastric ulcer may erode through the stomach wall into the pancreas, resulting in referred pain to the back. -In such cases, erosion of the splenic artery results in severe hemorrhage into the peritoneal cavity. -Pain impulses from the stomach are carried by visceral afferent fibers that accompany sympathetic nerves -pain of a recurrent peptic ulcer may persist after complete vagotomy, whereas patients who have had a bilateral sympathectomy may have a perforated peptic ulcer and experience no pain

Mamillated areas (Stomach)

-A view of the stomach's surface with a hand lens shows that smaller regions of the mucosa are formed by grooves or shallow trenches that divide the stomach surface into bulging irregular areas called mamillated areas. -These grooves provide a slightly increased surface area for secretion.

Gastric pits (foveolae)

-At higher magnification, numerous openings can be observed in the mucosal surface. -These are the gastric pits or foveolae. -They can be readily demonstrated with the SEM -The gastric glands open into the bottom of the gastric pits.

Vagotomy

-B/c the secretion of acid by parietal cells of the stomach is largely controlled by the vagus nerves, vagotomy is performed in some people with chronic or recurring ulcers to reduce the production of acid. -Vagotomy may also be performed in conjunction with resection of the ulcerated area (antrectomy, or resection of the pyloric antrum) to reduce acid secretion. -A truncal vagotomy (surgical section of the vagal trunks) is rarely performed because the innervation of other abdominal structures is also sacrificed -In selective gastric vagotomy, the stomach is denervated but the vagal branches to the pylorus, liver and biliary ducts, intestines, and celiac plexus are preserved -A selective proximal vagotomy attempts to denervate even more specifically the area in which the parietal cells are located, hoping to affect the acid-producing cells while sparing other gastric function (motility) stimulated by the vagus nerve

Basal acid output (BAO)

-Basal acid output (BAO) is gastric acid output in the fasted state. -It is estimated from samples drawn at 15 min intervals for 1 hour during the unstimulated (fasting) state. -BAO is normally about 2-3 mmol/h.

CCK

-CCK either produced by I cells in the intestine, or released by nerve endings in the brain, inhibits further food intake and thus is defined as a satiety factor or anorexin. -CCK and other similar factors have attracted great interest from the pharmaceutical industry in the hopes that derivatives might be useful as aids to dieting, an objective that is lent greater urgency given the current epidemic of obesity in Western countries

Cardiac Glands of the Gastric Mucosa

-Cardiac glands are composed of mucus-secreting cells. -Cardiac glands are limited to a narrow region of the stomach (the cardia) that surrounds the esophageal orifice. -Their secretion, in combination with that of the esophageal cardiac glands, contributes to the gastric juice and helps protect the esophageal epithelium against gastric reflux. -The glands are tubular, somewhat tortuous, and occasionally branched -mainly composed of mucus-secreting cells, with occasional interspersed enteroendocrine cells. -The mucus-secreting cells are similar in appearance to the cells of the esophageal cardiac glands. -They have a flattened basal nucleus, and the apical cytoplasm is typically filled with mucin granules. -A short duct segment containing columnar cells with elongate nuclei is interposed between the secretory portion of the gland and the shallow pits into which the glands secrete. -The duct segment is the site at which the surface mucous cells and the gland cells are produced.

Vomiting initiated by chemoreceptors

-Chemoreceptor cells in the medulla can also initiate vomiting when they are stimulated by certain circulating chemical agents. -The chemoreceptor trigger zone in which these cells are located is in the area postrema, a V-shaped band of tissue on the lateral walls of the fourth ventricle near the obex. -This structure is one of the circumventricular organs and is not protected by the blood-brain barrier. -Lesions of the area postrema have little effect on the vomiting response to GI irritation or motion sickness, but abolish the vomiting that follows injection of apomorphine and a number of other emetic drugs. -Such lesions also decrease vomiting in uremia and radiation sickness, both of which may be associated with endogenous production of circulating emetic substances.

Chief cells

-Chief cells are located in the deeper part of the fundic glands. -Chief cells are typical protein-secreting cells -The abundant rER in the basal cytoplasm gives this part of the cell a basophilic appearance, whereas the apical cytoplasm is eosinophilic owing to the presence of the secretory vesicles, also called zymogen granules because they contain enzyme precursors. -The basophilia, in particular, allows easy identification of these cells in H&E sections. -The eosinophilia may be faint or absent when the secretory vesicles are not adequately preserved. -Chief cells secrete pepsinogen and a weak lipase. -ACh is the main stimulant of pepsinogen secretion -On contact with the acid gastric juice, pepsinogen is converted to pepsin, a proteolytic enzyme.

Enteric and Intrinsic Neuropathic Disorders

-Disorders of the enteric nervous system or interstitial cells of Cajal are usually the result of an infectious, degenerative, immune, or inflammatory process. -Virus-induced gastroparesis (e.g., rotavirus, Norwalk virus, cytomegalovirus, or Epstein-Barr virus is associated with infiltration of the myenteric plexus with inflammatory cells. -In idiopathic chronic intestinal pseudo-obstruction, in which there is no disturbance of the extrinsic neural control, degeneration of the interstitial cells of Cajal, inflammation, or herpesvirus infection may contribute.

Smooth Muscle Disorders (GI dysmotility)

-Disturbances of smooth muscle may result in significant disorders of gastric emptying and of transit through the small bowel and colon. -These disturbances include, in decreasing order of prevalence, systemic sclerosis , amyloidosis , dermatomyositis, myotonic dystrophy , and metabolic muscle disorders -Motility disturbances may be the result of metabolic disorders, such as hypothyroidism and hyperparathyroidism but these patients more commonly present with constipation. -Scleroderma may result in focal or general dilation, wide-mouthed diverticula, and delayed transit in the stomach, small bowel, and colon. -The amplitude of contractions is reduced, and bacterial overgrowth may result in steatorrhea or pneumatosis intestinalis. -Mitochondrial neurogastrointestinal encephalomyopathy, or familial visceral myopathy type II, is an autosomal recessive condition that may be manifested with hepatic failure in neonates, seizures or diarrhea in infants, and hepatic failure or chronic intestinal pseudo-obstruction in adults

Dumping Syndrome and Accelerated Gastric Emptying

-Dumping syndrome and accelerated gastric emptying typically follow truncal vagotomy and gastric drainage procedures or fundoplication for GERD -With the widespread use of highly selective vagotomy and the advent of effective antacid secretory therapy, these problems are becoming rare. -A high calorie (usually carbohydrate) content of the liquid phase of the meal evokes a rapid insulin response with secondary hypoglycemia. -These patients may also have impaired antral contractility and gastric stasis of solids, which paradoxically may result in a clinical picture of gastroparesis (for solids) and dumping (for liquids) -The management of dumping syndrome and accelerated gastric emptying emphasizes dietary maneuvers, such as avoidance of high-nutrient liquid drinks and possibly addition of guar gum or pectin to retard gastric emptying of liquids. -Rarely, pharmacologic treatment with octreotide, 25 to 100 µg subcutaneously before meals, is needed to retard intestinal transit and to inhibit the hormonal responses that lead to hypoglycemia.

Duodenal Development

-During the 5th and 6th weeks epithelial proliferation closes off the lumen; it recanalizes by 8 weeks. -There is posterior rotation, so the bile duct empties posteriorly at the ampulla of Vater. -The first two portions (I, II) of the duodenum are foregut, retroperitoneal, and supplied by the celiac artery -the last two portions (III, IV) are midgut derivatives supplied by the superior mesenteric artery. -The last portion beyond the ligament of Treitz is intraperitoneal. -for the IMAGE, the echo recording focuses on the spatial relationship between the abdominal organs

Intestinal phase of gastric secretion

-During the intestinal phase, the products of protein digestion, on entering the small intestine, can stimulate gastrin release from G cells in the duodenum. -Many substances, most notably fat and acid, stimulate the secretion of hormones from the small intestine that inhibit gastric acid secretion. -Examples include secretin and cholecystokinin.

Enteroendocrine cells

-Enteroendocrine cells secrete their products into either the lamina propria or underlying blood vessels. -Enteroendocrine cells are found at every level of the fundic gland, although they tend to be somewhat more prevalent in the base -In general, two types of enteroendocrine cells can be distinguished throughout the GI tract. -Most of them represent small cells that rest on the basal lamina and do not always reach the lumen; they are known as enteroendocrine "closed" cells -Some, however, have a thin cytoplasmic extension bearing microvilli that are exposed to the gland lumen; these are referred to as enteroendocrine "open" cells. -open cells serve as primary chemoreceptors that sample the contents of the gland lumen and release hormones based on the information obtained from those samples. -The taste receptors, similar to those found in taste buds of the specialized oral mucosa, detect sweet, bitter, and umami sensations and have now been characterized on the free surface of the open enteroendocrine cells. -They belong to the T1R and T2R families of G protein-coupled receptors -Secretion from closed cells, however, is regulated by luminal content

HCO3- (Gastric secretions)

-Epithelial cells of the corpus and antrum secrete HCO3- ions. -Although the secretion of HCO3- is minor compared with H+ ion secretion, HCO3- plays a major role in epithelial defense. -HCO3- ions are trapped in the mucous gel to form an "unstirred layer" in proximity to the epithelium, where the pH is 7.0 compared with 1.0-3.0 in the lumen. -ACh and intraluminal acid stimulate HCO3- secretion.

Extrinsic Neuropathic Disorders

-Extrinsic neuropathic processes include vagotomy, trauma, Parkinson disease, diabetes, amyloidosis , and a paraneoplastic syndrome usually associated with small cell carcinoma of the lung -Another common "neuropathic" problem in clinical practice results from the effect of medications, such as α 2 -adrenergic agonists, glucagon-like peptide 1 analogues, opiates, and anticholinergics, on neural control. -Damage to the autonomic nerves by trauma, infection, neuropathy, and neurodegeneration may lead to motor, secretory, and sensory disturbances, most frequently resulting in constipation. -Patients with spinal cord injury above the level of the sacral segments have delayed proximal and distal colonic transit attributable to parasympathetic denervation. -In these patients, fasting colonic motility and tone are normal, but the response to feeding generally is reduced or absent. -Spinal cord lesions involving the sacral segments and damage to the efferent nerves from these segments disrupt the neural integration of rectosigmoid expulsion and anal sphincter control. -In patients with these injuries, there is loss of contractile activity in the left colon and decreased rectal tone and sensitivity, which may lead to colorectal dilation and fecal impaction. -Parkinson disease and MS frequently are associated with constipation.

Fluid reabsorption and GI transit

-Fluid reabsorption influences GI transit. -Approximately 9 L of fluid enters the gut from oral intake and endogenous secretions. -The small intestine delivers about 1.5 L of fluid to the colon, where most is reabsorbed, leaving a maximum of 200 mL of water excreted in normal stool. -Up to 3 L of fluid can be reabsorbed by the colon in a 24-hour period, unless the rate of ileocolonic flow or colonic motility overwhelms the colon's capacity or reabsorptive ability

Composition of fundic glands

-Fundic glands are composed of four functionally different cell types. -The cells that constitute the fundic glands are of four functional types. -Each has a distinctive appearance. -In addition, undifferentiated cells that give rise to these cells are also present. -These are the various cells that constitute the gland: (1) Mucous neck cells (2) Chief cells (3) Parietal cells, also called oxyntic cells (3) Enteroendocrine cells (4) Undifferentiated adult stem cell

Ghrelin

-Ghrelin is a predominantly fast-acting orexin that stimulates food intake. -produced mainly by the stomach, as well as other tissues such as the pancreas and adrenal glands in responses to changes in nutritional status —circulating ghrelin levels increase preprandially, then decrease after a meal. -It is believed to be involved primarily in meal initiation - the effects of ghrelin are produced mostly via actions in the hypothalamus. -increases synthesis and/or release of central orexins, including neuropeptide Y and cannabinoids, and suppresses the ability of leptin to stimulate the anorexigenic factors discussed above. -Loss of the activity of ghrelin may account in part for the effectiveness of gastric bypass procedures for obesity. -Its secretion may also be inhibited by leptin, underscoring the reciprocity of these hormones. -There is some evidence to suggest, however, that the ability of leptin to reduce ghrelin secretion is lost in the setting of obesity.

Diseases of Slow Transit through the Stomach and Small Bowel

-GI motility disturbances result from disorders of the extrinsic nervous system, ENS, interstitial cells of Cajal, or smooth muscle. -Neuropathic patterns are characterized by normal amplitude but incoordinated contractions, whereas myopathies are characterized by low-amplitude contractions (average of less than 40 mm Hg in the antrum and less than 10 mm Hg in the small bowel). -Combined disorders occur in systemic sclerosis, amyloidosis, and mitochondrial cytopathy, which can be manifested initially with neuropathic patterns and later display myopathic characteristics with disease progression. -Genetic defects that result in congenital dysmotilities include abnormalities of RET , the gene that encodes the tyrosine kinase receptor, and abnormalities in the endothelin B system. -Neural crest cells migrate from the vagal and sacral crest to the developing gut and, over time, colonize the entire developing alimentary canal and its appendages. -Endothelin B serves to retard maturation of migrating neural crest cells, thus facilitating colonization of the entire gut with nerve cells. -Other abnormalities resulting in congenital dysmotility involve other transcription factors, such as Sox10, which enhances maturation of neural precursors, and Kit, a marker for the interstitial cells of Cajal. -Defects of RET , endothelin B, and Sox10 are associated with the phenotypic picture recognized in Hirschsprung disease, whereas KIT defects have been associated with idiopathic hypertrophic pyloric stenosis and congenital megacolon. -c- KIT mutations are associated with gastrointestinal stromal tumors

Gastric Acid Output

-Gastric acid output equals the product of volume of gastric juice and concentration of H ions in it. -It is quantified by aspirating gastric juice through a nasogastric tube placed in the stomach. -The clinical utility of gastric acid analysis, especially the estimation of BAO, is limited to identifying the mechanism of hypergastrinemia (an individual with elevated fasting serum gastrin concentration). -Rarely, hypergastrinemia due to a gastrin-secreting tumor is the cause of an elevation in BAO, MAO, gastric, and duodenal ulcers (Zollinger-Ellison syndrome). -But individuals with achlorhydria secondary to a disease process selectively destroying parietal cells in the stomach or secondary to sustained pharmacologic inhibition of gastric acid secretion also have hypergastrinemia as a result of disinhibition of the release of gastrin. -in evaluating individuals with hypergastrinemia that analysis of BAO is helpful. -Some individuals with duodenal ulcers typically have elevated BAO and MAO, without considerable elevation in gastrin concentration, whereas some individuals with duodenal ulcers have normal serum gastrin concentration and BAO. -This is why gastric acid output analysis is unhelpful in the routine diagnosis of acid-peptic disease.

Gastric emptying

-Gastric emptying of solids is characterized by an initial lag period followed by a linear postlag emptying phase. -Secretion of hormones that mediate the motor and digestive process (e.g., gastrin for acid secretion; cholecystokinin for gallbladder contraction and bile and pancreatic secretion; and insulin, glucagon, and incretins such as glucagon-like peptide 1 for glucose regulation) is integrated with the arrival of food or chyme at different levels of the gut to ensure optimal digestion.

Gastric ulcer

-Gastric ulcers are open lesions of the mucosa of the stomach -Most ulcers of the stomach and duodenum are associated with an infection of H. pylori -If the ulcer erodes into the gastric arteries, it can cause life threatening bleeding.

Gastrin

-Gastrin is a hormone -released by G cells in the antrum of the stomach both in response to a specific neurotransmitter released from enteric nerve endings, known as gastrin-releasing peptide (GRP) or bombesin -also released in response to the presence of oligopeptides in the gastric lumen. -Gastrin is then carried through the bloodstream to the fundic glands, where it binds to receptors not only on parietal (and likely, chief cells) to activate secretion, but also on enterochromaffin-like cells (ECL cells) that are located in the gland, and release histamine.

Gastritis

-Gastritis is a mucosal inflammatory process. -When neutrophils are present, the lesion is referred to as acute gastritis. -When inflammatory cells are rare or absent, the term gastropathy is applied; it includes a diverse set of disorders marked by gastric injury or dysfunction. -Agents that cause gastropathy include NSAIDs, alcohol, bile, and stress induced injury. -Acute mucosal erosion or hemorrhage, such as Curling ulcers or lesions following disruption of gastric blood flow, for example, in portal hypertension, can also cause gastropathy that typically progress to gastritis. -Both gastropathy and acute gastritis may be asymptomatic or cause variable degrees of epigastric pain, nausea, and vomiting. -In more severe cases there may be mucosal erosion, ulceration, hemorrhage, hematemesis, melena, or, rarely, massive blood loss.

Causes of disruption in protective mechanisms of gastric mucosa

-Gastropathy, acute gastritis, and chronic gastritis can occur following disruption of any of these protective mechanisms. -NSAIDs inhibit COX dependent synthesis of prostaglandins E2 and I2, which stimulate mucus, HCO3-, and phospholipid secretion, mucosal blood flow, and epithelial restitution while reducing acid secretion. -Although COX-1 plays a larger role than COX-2, both isoenzymes contribute to mucosal protection. -while the risk of NSAID-induced gastric injury is greatest with nonselective inhibitors, for example, aspirin, ibuprofen, and naproxen, selective COX-2 inhibition, for (celecoxib), can also result in gastropathy or gastritis. -The gastric injury that occurs in uremic patients and those infected with urease-secreting H. pylori may be due to inhibition of gastric HCO3- transporters by ammonium ions. -Reduced mucin and HCO3- secretion have been suggested as factors that explain the increased susceptibility of older adults to gastritis. -Decreased oxygen delivery may account for an increased incidence of acute gastritis at high altitudes. -Ingestion of harsh chemicals, particularly acids or bases, either accidentally or as a suicide attempt, also results in severe gastric injury, predominantly as a result of direct injury to mucosal epithelial and stromal cells. -Direct cellular damage also contributes to gastritis induced by excessive alcohol consumption, NSAIDs, radiation therapy, and chemotherapy. -Agents that inhibit DNA synthesis or the mitotic apparatus, including those used in cancer chemotherapy, may cause generalized mucosal damage due to insufficient epithelial renewal.

Helicobacter pylori

-H. pylori is a bacterium that lives in the mucous layer of the stomach where the enzyme urease is active, converting urea to CO2 and ammonia. -Ammonia buffers luminal acid and protects the organism. -H pylori also secretes proteins, such as CagA and VacA, that modulate immune responses and directly alter mucosal cell signaling pathways. -More than half of the world's population is infected with H pylori. -In most cases, the infection, though chronic, is mild and does not cause symptoms. -In some individuals, the infection leads to increased acid secretion and symptomatic inflammation that causes ulceration of the stomach or duodenum. -Almost all duodenal peptic (i.e., acid-associated) ulcers and about half of gastric peptic ulcers have H. pylori infection as a root cause; the remaining gastric ulcers are caused by medications (such as aspirin and NSAIDs). -In some pts, chronic H pylori infection can lead to atrophy of parietal cells, chronic inflammation, and altered mucosal differentiation patterns (metaplasias) that increase the risk of progression to gastric cancer. -In certain geographical regions (eg, East Asia and parts of Central and South America), due to environmental and/or lifestyle factors that have not yet been elucidated, risk for progression to gastric cancer is much higher than in other regions (eg, US and Canada).

Production of HCl

-HCl is produced in the lumen of the intracellular canaliculi. -Parietal cells have three different types of membrane receptors for substances that activate HCl secretion: gastrin receptors, histamine H2 receptors, and acetylcholine M3 receptor. -Activation of the gastrin receptor by gastrin, a GI peptide hormone, is the major path for parietal cell stimulation -After stimulation, several steps occur in the production of HCl: -Production of H+ ions in the parietal cell cytoplasm by the enzyme carbonic anhydrase. -This enzyme hydrolyzes carbonic acid (H2CO3) to H+ and HCO3−. -CO2, necessary for synthesis of carbonic acid, diffuses across the basement membrane into the cell from the blood capillaries in the lamina propria. -Transport of H+ ions from the cytoplasm, across the membrane to the lumen of the canaliculus by the H+/K+-ATPase proton pump. -Simultaneously, K+ from the canaliculus is transported into the cell cytoplasm in exchange for the H+ ions. -Transport of K+ and Cl− ions from the parietal cell cytoplasm into the lumen of the canaliculus through activation of K+ and Cl− channels (uniporters) in the plasma membrane. -Formation of HCl from the H+ and Cl− that were transported into the lumen of the canaliculus.

Histamine (role in gastric secretion)

-Histamine is a trigger of parietal cell secretion, via binding to H2-receptors.

Morphology Gastritis

-Histologically, gastropathy and mild acute gastritis may be difficult to recognize, since the lamina propria shows only moderate edema and slight vascular congestion. -The surface epithelium is intact, but foveolar cell hyperplasia, with characteristic corkscrew profiles and epithelial proliferation are typically present. -Neutrophils are not abundant, but a few may be found among the epithelial cells or within mucosal glands in gastritis. -There are few lymphocytes and plasma cells. -The presence of neutrophils above the basement membrane in direct contact with epithelial cells is abnormal in all parts of the GI tract and signifies active inflammation, or, in this case, gastritis (rather than gastropathy). -The term active inflammation is preferred over acute inflammation, since active inflammation may be present in both acute and chronic disease states. -With more severe mucosal damage, erosions and hemorrhage develop. -Erosion denotes loss of the epithelium, resulting in a superficial mucosal defect. -It is accompanied by a pronounced mucosal neutrophilic infiltrate and a fibrin-containing purulent exudate in the lumen. -Hemorrhage may occur and cause dark punctae in hyperemic mucosa. -Concurrent erosion and hemorrhage is termed acute erosive hemorrhagic gastritis. -Large areas of the gastric surface may be denuded, although the involvement is typically superficial. When erosions extend deeply, they may progress to ulcers, as described later.

How does irritation of the Upper GI tract mucosa trigger vomiting

-Impulses are relayed from the mucosa to the medulla over visceral afferent pathways in the sympathetic nerves and vagi.

Accommodation of food by the stomach

-In response to food ingestion, the proximal stomach accommodates food by a vagally mediated reduction in tone, thereby facilitating the ingestion of food without an increase in pressure. -Liquids empty from the stomach in an exponential manner, and the rate of emptying varies with calorie content and viscosity. -The half-emptying time for non-nutrient liquids in healthy individuals is usually < 20 minutes. -Solids are retained selectively in the stomach, where they undergo acid and peptic digestion as well as "churning" or trituration by high liquid shearing forces in the antrum. -Digestible food particles are emptied after their size is reduced by trituration to less than 2 mm.

Movement during postprandial period

-In the postprandial period, the interdigestive migrating motor complex is replaced by an irregular pattern of variable amplitude and frequency. -This pattern, which enables mixing, digestion, and absorption, is observed in the gastrointestinal regions in contact with food. -The maximum frequency of contractions is lower than during phase III of the interdigestive motor complex, and the duration of this postprandial contractile activity is proportional to the number of calories consumed (about 1 hour for each 200 kcal ingested). -Segments of the small intestine that are not in contact with food continue with interdigestive motor patterns.

Intrinsic factor

-Intrinsic factor, a glycoprotein secreted by parietal cells that binds to vitamin B12. -It is essential for its absorption, which occurs in the distal part of the ileum. -Lack of intrinsic factor leads to pernicious anemia and vitamin B12 deficiency -its secretion is stimulated by the same receptors that stimulate gastric acid secretion -In the stomach, acid and pepsin release B12 from dietary carrier proteins. -The acid environment permits binding of B12 to haptocorrin (R factor), a glycoprotein produced by salivary glands and gastric glands. -The B12-haptocorrin complex enters the duodenum, where pancreatic proteases digest the haptocorrin. -Free intrinsic factor also enters the duodenum. Intrinsic factor combines with B12 in the less acidic environment of the small intestine, forming a degradation-resistant complex for transport to the ileum. -Specific receptors on epithelial cells lining the ileum bind the vitamin B12-intrinsic factor complex, which is taken into cells by endocytosis. -The absorbed complex dissociates within the epithelial cells, and then vitamin B12 binds to transcobalamin II, a protein required for exocytosis and transport to the liver. -In autoimmune gastritis, parietal cells are destroyed, leading to loss of intrinsic factor secretion, which can result in vitamin B12 deficiency and pernicious anemia. -This anemia is caused by impaired synthesis of purines and thymine for which vitamin B12 is required. -The only reliable therapy is regular intramuscular injections of vitamin B12.

Leptin

-Leptin is produced by adipose tissue, and signals the status of the fat stores therein. -As adipocytes increase in size, they release greater quantities of leptin and this tends to decrease food intake, in part by increasing the expression of other anorexigenic factors in the hypothalamus such as pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), neurotensin, and corticotropin-releasing hormone (CRH). -Leptin also stimulates the metabolic rate. -Animal studies have shown that it is possible to become resistant to the effects of leptin, however, and in this setting, food intake persists despite adequate (or even growing) adipose stores —obesity therefore results.

Rugae of stomach

-Longitudinal submucosal folds, rugae, allow the stomach to distend when filled. -the inner surface of the empty stomach reveals a number of longitudinal folds or ridges called rugae. -They are prominent in the narrower regions of the stomach but poorly developed in the upper portion -When the stomach is fully distended, the rugae, composed of the mucosa and underlying submucosa, virtually disappear. -The rugae do not alter total surface area; rather, they serve to accommodate expansion and filling of the stomach.

Maximal acid output (MAO)

-Maximal acid output (MAO) used to be estimated with a standard intravenous dose of pentagastrin (a gastrin receptor agonist). -MAO reflects the functional capacity of parietal cell mass. -MAO ranges from 20-30 mmol/h.

Disorders of GI Motility

-Motility disorders result from impaired control of the neuromuscular apparatus of the GI tract. -Associated symptoms include recurrent or chronic nausea, vomiting, bloating, abdominal discomfort, and constipation or diarrhea in the absence of intestinal obstruction

Neuroendocrine control of GI motility

-Motor function of the gastrointestinal tract depends on the contraction of smooth muscle cells and their integration and modulation by enteric and extrinsic nerves as well as the interstitial cells of Cajal. -The ENS is an independent nervous system comprising approximately 100 million neurons organized into ganglionated plexuses. -The interstitial cells of Cajal are spontaneously active pacemaker cells that coordinate muscle contraction and sense distortion.

Mechanisms of protection of gastric mucosa

-Mucin secreted by surface foveolar cells forms a thin layer of mucus and phospholipids that prevents large food particles from directly touching the epithelium. -The mucus covering also promotes formation of an "unstirred" layer of fluid over the epithelium that protects the mucosa and has a neutral pH as a result of bicarbonate ion secretion by surface epithelial cells. -Beneath the mucus, a continuous layer of gastric epithelial cells forms a physical barrier that limits back diffusion of acid and leakage of other luminal materials, including pepsin, into the lamina propria. -Complete replacement of the surface foveolar cells every 3 to 7 days is essential for both the maintenance of the epithelial layer and the secretion of mucus and bicarbonate from these cells. -In acid-secreting parts of the stomach, a capillary "alkaline tide" is generated as parietal cells secrete HCl into the gastric lumen and HCO3- into the vessels. -In addition to delivering HCO3-, the rich mucosal vasculature delivers oxygen and nutrients while washing away acid that has back-diffused into the lamina propria

Mucins

-Mucins are high-molecular-weight glycoproteins secreted by mucous cells of gastric glands in the corpus and antrum. -The peptide backbone of mucins is densely populated with carbohydrate side chains enriched with sulfate groups. -Mucins combine with phospholipids, bicarbonate, and water to form the mucus gel layer that adheres to the surface of epithelial cells of the stomach. -This layer forms physical protection for epithelial cells from damage by contractile grinding of food as well as noxious substances such as acid, pepsin, and bile acids. -Acetylcholine and mucosal irritation stimulate secretion of mucin.

Mucus (gastric juice)

-Mucus, an acid-protective coating for the stomach secreted by several types of mucus-producing cells. -The mucus and bicarbonates trapped within the mucous layer maintain a neutral pH and contribute to the so-called physiologic gastric mucosa barrier. -In addition, mucus serves as a physical barrier between the cells of the gastric mucosa and the ingested material in the lumen of the stomach.

Neurokinin-1 (NK-1) receptors and emesis

-Neurokinin-1 (NK-1) receptors in the area postrema and the solitary nucleus bind to substance P and are part of the final common emetic pathway. -Activation of NK-1 receptors by substance P constitutes the basis of chemotherapy-induced emesis (i.e., emesis 24 to 72 hours after administration of chemotherapeutic drugs). -NK-1 antagonists (example, aprepitant) reduce emesis induced by peripherally and centrally acting emetogens.

Defecation and Continence

-Normal defecation requires a series of coordinated actions of the colon, rectum, pelvic floor, and anal sphincter muscles -Filling of the rectum by a volume of 10 mL may be sensed, although the rectum can accommodate 300 mL before a sense of fullness and urge to defecate develop. -Distention of the rectum results in the relaxation of the internal anal sphincter (rectoanal inhibitory reflex) and simultaneous contraction of the external anal sphincter to maintain continence. -The anal transition zone can sense the difference between solid or liquid stool and gas.

Central causes of vomiting

-Other causes of vomiting can arise centrally. -afferents from the vestibular nuclei mediate the nausea and vomiting of motion sickness. -Other afferents presumably reach the vomiting control areas from the diencephalon and limbic system, because emetic responses to emotionally charged stimuli also occur. -Thus, we speak of "nauseating smells" and "sickening sights."

Visceral Referred Pain

-Pain is an unpleasant sensation associated with actual or potential tissue damage and mediated by specific nerve fibers to the brain, where its conscious appreciation may be modified. -Organic pain arising from an organ such as the stomach varies from dull to severe; however, the pain is poorly localized. -It radiates to the dermatome level, which receives visceral afferent fibers from the organ concerned. -Visceral referred pain from a gastric ulcer, for example, is referred to the epigastric region because the stomach is supplied by pain afferents that reach the T7 and T8 spinal sensory ganglia and spinal cord segments through the greater splanchnic nerve -The brain interprets the pain as though the irritation occurred in the skin of the epigastric region, which is also supplied by the same sensory ganglia and spinal cord segments. -Pain arising from the parietal peritoneum is of the somatic type and is usually severe. -The site of its origin can be localized. -The anatomical basis for this localization of pain is that the parietal peritoneum is supplied by somatic sensory fibers through thoracic nerves, whereas a viscus such as the appendix is supplied by visceral afferent fibers in the lesser splanchnic nerve. -Inflamed parietal peritoneum is extremely sensitive to stretching. -When digital pressure is applied to the anterolateral abdominal wall over the site of inflammation, the parietal peritoneum is stretched. -When the fingers are suddenly removed, extreme localized pain is usually felt, known as rebound tenderness.

Parietal cells

-Parietal cells secrete HCl and intrinsic factor. -Parietal (oxyntic) cells are found in the neck of the fundic glands, among the mucous neck cells, and in the deeper part of the gland. -They tend to be most numerous in the upper and middle portions of the neck. -They are large cells, sometimes binucleate, and appear somewhat triangular in sections, with the apex directed toward the lumen of the gland and the base resting on the basal lamina. -The nucleus is spherical, and the cytoplasm stains with eosin and other acidic dyes. -Their size and distinctive staining characteristics allow them to be easily distinguished from other cells in the fundic glands. -When examined with the TEM, parietal cells are seen to have an extensive intracellular canalicular system that communicates with the lumen of the gland. -Numerous microvilli project from the surface of the canaliculi, and an elaborate tubulovesicular membrane system is present in the cytoplasm adjacent to the canaliculi. -In an actively secreting cell, the number of microvilli in the canaliculi increases, and the tubulovesicular system is reduced significantly or disappears. -The membranes of the tubulovesicular system serve as a reservoir of plasma membrane containing active proton pumps. -This membrane material can be inserted into the plasma membrane of the canaliculi to increase their surface area and the number of proton pumps available for acid production. -Numerous mitochondria with complex cristae and many matrix granules supply the high levels of energy necessary for acid secretion. -In humans, intrinsic factor is secreted by the parietal cells

Pepsin

-Pepsin, a potent proteolytic enzyme. -It is converted from pepsinogen produced by the chief cells by HCl at a pH lower than 5. -Pepsin hydrolyzes proteins into small peptides by splitting interior peptide bonds. -Peptides are further digested into amino acids by enzymes in the small intestine. -Pepsin has a pH optimum of 3.0 and is thus active in the stomach. -It is an endopeptidase that begins the degradation of dietary proteins to peptides. -However, pepsin accounts for only 10% of the total protein digestion.

Pyloric Glands of the Gastric Mucosa

-Pyloric gland cells are similar to surface mucous cells and help protect the pyloric mucosa. -Pyloric glands are located in the pyloric antrum (the part of the stomach between the fundus and the pylorus). -They are branched, coiled, tubular glands -The lumen is relatively wide, and the secretory cells are similar in appearance to the surface mucous cells, suggesting a relatively viscous secretion. -Enteroendocrine cells are found interspersed within the gland epithelium along with occasional parietal cells. -The glands empty into deep gastric pits that occupy about half the thickness of the mucosa

Pyloric region (Stomach)

-Pyloric region (pylorus), the part proximal to the pyloric sphincter, which contains the pyloric glands

Rapid Transit Dysmotility of the Small Bowel

-Rapid transit of material through the small bowel may occur in the setting of the IBS-diarrhea predominant subtype,, postvagotomy diarrhea, short bowel syndrome, diabetic diarrhea, and carcinoid diarrhea. -With the exception of irritable bowel syndrome, these conditions may cause severe diarrhea and result in significant losses of fluid and electrolytes. -Ileal resection or disease and idiopathic bile acid malabsorption may represent an inability of the distal ileum to reabsorb bile acids because of rapid transit and reduced contact time with the ileal mucosa; this condition may induce colonic secretion and secondary diarrhea. -Accelerated transit may be confirmed by scintigraphic studies

Receptive Relaxation

-Receptive relaxation is, in part, vagally mediated and triggered by movement of the pharynx and esophagus. -Intrinsic reflexes also lead to relaxation as the stomach wall is stretched. -Peristaltic waves controlled by the gastric BER begin soon thereafter and sweep toward the pylorus. -The contraction of the distal stomach caused by each wave is sometimes called antral systole and can last up to 10 s. -Waves occur 3-4 times per minute.

Colonic transit of digested substances

-Residue may be retained for prolonged periods in the right colon, and a mass movement may deliver the contents to the sigmoid colon in seconds. -Feeding stimulates movement of colonic content (referred to as the gastrocolonic response). -In health, the average mouth-to-cecum transit time is about 6 hours, and transit times through the right colon, left colon, and sigmoid colon are about 12 hours each. -As the ingestion of dietary fiber increases, mean colonic transit time decreases, stool frequency increases, and stool consistency is softer. -Decreased calorie intake slows colonic transit, whereas a meal (typically >500 kcal, especially a fat-rich meal) stimulates colonic motor function and propulsion of colonic content. -Outlet obstruction in patients with pelvic floor dysfunction or voluntary suppression of defecation often is associated with slow colonic transit and decreased motor response to feeding.

Reverse peristalsis (vomiting)

-Reverse peristalsis empties material from the upper part of the small intestine into the stomach. -The glottis closes, preventing aspiration of vomitus into the trachea. -The breath is held in mid inspiration. -The muscles of the abdominal wall contract, and because the chest is held in a fixed position, the contraction increases intra-abdominal pressure. -The LES and the esophagus relax, and the gastric contents are ejected. -The "vomiting center" in the reticular formation of the medulla consists of various scattered groups of neurons in this region that control the different components of the vomiting act

Seretonin induced vomiting

-Serotonin (5-HT) released from enterochromaffin cells in the small intestine appears to initiate impulses via 5-HT3 receptors that trigger vomiting. -In addition, there are dopamine D2 receptors and 5-HT3 receptors in the area postrema and adjacent nucleus of the solitary tract. -5-HT3 antagonists such as ondansetron and D2 antagonists such as chlorpromazine and haloperidol are effective antiemetic agents. -Corticosteroids, cannabinoids, and benzodiazepines, alone or in combination with 5-HT3 and D2 antagonists, are also useful in treatment of the vomiting produced by chemotherapy. -The mechanisms of action of corticosteroids and cannabinoids are unknown, whereas the benzodiazepines probably reduce the anxiety associated with chemotherapy.

Stimulation of brain 5-HT3 receptors and emesis

-Stimulation of brain 5-HT3 receptors provokes release of dopamine, which in turn stimulates D2 receptors in the emetic center, thereby activating the emetic response. -This is the basis for the use of 5-HT3 receptor antagonists (example, ondansetron), and D2 receptor blockers (metaclopramide) as anti-emetic agents. -5HT-3 receptors on vagal afferents in the gut may also respond to 5-HT released by enteroendocrine cells that release 5-HT.

Renewal of surface mucosal cells

-Surface mucous cells are renewed approximately every 3 to 5 days. -The short lifespan of the surface mucous cells is accommodated by mitotic activity in the isthmus, the narrow segment that lies between the gastric pit and the fundic gland -The isthmus of the fundic gland contains a reservoir of tissue stem cells that undergo mitotic activity, providing for continuous cell renewal. -Most of the newly produced cells at this site become surface mucous cells. -They migrate upward along the wall of the pit to the luminal surface of the stomach and are ultimately shed into the stomach lumen.

enteric nervous system

-The ENS is an independent nervous system comprising approximately 100 million neurons organized into ganglionated plexuses. -The larger myenteric or Auerbach plexus is situated between the longitudinal and circular muscle layers of the muscularis externa; this plexus contains neurons responsible for GI motility. -The submucosal or Meissner plexus controls absorption, secretion, and mucosal blood flow. -The ENS also plays an important role in visceral afferent function.

cardia of stomach

-The cardia surrounds the esophageal orifice

Clinical features: gastroparesis and pseudo-obstruction

-The clinical features of gastroparesis and chronic intestinal pseudo-obstruction are similar and include nausea, vomiting, early satiety, abdominal discomfort, distention, bloating, and anorexia. -Severe cases, which occur mostly in patients with disorders of smooth muscle, may be accompanied by considerable dilation as well as by weight loss, with depletion of mineral and vitamin stores. -Diarrhea and constipation indicate that the motility disorder extends beyond the stomach. -Vomiting may result in aspiration pneumonia or Mallory-Weiss esophageal tears, and patients with a generalized motility disorder may have abnormal swallowing or delayed colonic transit -On physical examination, a succussion splash indicates stasis, typically in the stomach. -A motility disorder of the stomach or small bowel should be suspected whenever large volumes are aspirated from the stomach, particularly after an overnight fast, or when undigested solid food or large volumes of liquids are observed during esophagogastroduodenoscopy.

Epithelium of gastric pits

-The epithelium that lines the surface and the gastric pits of the stomach is simple columnar. -The columnar cells are designated surface mucous cells. -Each cell possesses a large, apical cup of mucinogen granules, creating a glandular sheet of cells -The mucous cup occupies most of the volume of the cell. -It typically appears empty in routine H&E sections because the mucinogen is lost in fixation and dehydration. -When the mucinogen is preserved by appropriate fixation, however, the granules stain intensely with toluidine blue and with the PAS procedure. -The toluidine blue staining reflects the presence of many strongly anionic groups in the glycoprotein of the mucin, among which is bicarbonate -The nucleus and Golgi of the surface mucous cells are located below the mucous cup. -The basal part of the cell contains small amounts of rER that may impart a light basophilia to the cytoplasm when observed in well-preserved specimens

Muscularis mucosa of the stomach

-The muscularis mucosae is composed of two relatively thin layers, usually arranged as an inner circular and outer longitudinal layer. -In some regions, a third layer may be present; its orientation tends to be in a circular pattern. -Thin strands of smooth muscle cells extend toward the surface in the lamina propria from the inner layer of the muscularis mucosae. -These smooth muscle cells in the lamina propria are thought to help outflow of the gastric gland secretions.

Gastric phase of gastric secretion

-The gastric phase (~70% of response) of secretion is induced by stimuli within the stomach. -Vagal sensory nerves detect gastric distension with food and trigger a vago-vagal reflex during which vagal motor nerves release ACh in the stomach to promote acid secretion. -Partially digested proteins and AAs stimulate gastrin release from G cells in the pylorus. -G cells, like D cells, are open-type endocrine cells that directly sense the contents of the stomach. -Gastrin then further stimulates acid secretion. -Acidification of the pylorus stimulates somatostatin release, which inhibits acid secretion by a negative-feedback loop

Control of Food Intake

-The intake of nutrients is under complex control involving signals from both the PNS and the CNS -Complicating the picture, higher functions also modulate the response to both central and peripheral cues that either trigger or inhibit food intake. - food preferences, emotions, environment, lifestyle, and circadian rhythms may all have profound effects on whether food is sought, and the type of food that is ingested. -Many of the hormones and other factors that are released coincident with a meal, and may play other important roles in digestion and absorption are also involved in the regulation of feeding behavior -CCK either produced by I cells in the intestine, or released by nerve endings in the brain, inhibits further food intake and thus is defined as a satiety factor or anorexin. -Leptin and ghrelin are peripheral factors that act reciprocally on food intake

interstitial cells of Cajal

-The interstitial cells of Cajal are spontaneously active pacemaker cells that coordinate muscle contraction and sense distortion. -They form a non-neural pacemaker system predominantly at the interface of the circular and longitudinal muscle layers of the intestine as well as within the muscle layers themselves and function as intermediaries between the neurogenic enteric nervous system and the myogenic control system. -Electrical control activity spreads through interneurons in the contiguous segments of the gut through neurochemical activation by transmitters that may be excitatory (e.g., acetylcholine, substance P) or inhibitory (e.g., nitric oxide, somatostatin).

lamina propria of the stomach

-The lamina propria of the stomach is relatively scant and restricted to the limited spaces surrounding the gastric pits and glands. -The stroma is composed largely of reticular fibers with associated fibroblasts and sm. muscle cells. -Other components include cells of the immune system, namely, lymphocytes, plasma cells, macrophages, and some eosinophils. -When inflammation occurs, as is often the case, neutrophils may also be prominent. -Occasional lymphatic nodules are also present, usually intruding partially into the muscularis mucosae.

Absorptive capacity of the lining of the stomach

-The lining of the stomach does not function in an absorptive capacity. -However, some water, salts, and lipid-soluble drugs may be absorbed. -For instance, alcohol and certain drugs such as aspirin or NSAIDs enter the lamina propria by damaging the surface epithelium. -Even small doses of aspirin suppress the production of protective prostaglandins by the gastric mucosa. -In addition, aspirin's direct contact with the wall of the stomach interferes with the hydrophobic properties of the gastric mucosa.

Gastric and Small Bowel Motility

-The motor functions of the stomach and small intestine are characterized by distinct patterns of motor activity in the fasting and postprandial periods -In response to food ingestion, the proximal stomach accommodates food by a vagally mediated reduction in tone, thereby facilitating the ingestion of food without an increase in pressure. -Gastric emptying of solids is characterized by an initial lag period followed by a linear postlag emptying phase. -The small intestine transports solids and liquids at approximately the same rate as the stomach -In the postprandial period, the interdigestive MMC is replaced by an irregular pattern of variable amplitude and frequency. -Vomiting is characterized by a stereotypic sequence of motor events, including contractions of the stomach, abdominal muscles, and diaphragm.

Motor functions of the stomach

-The motor functions of the stomach and small intestine are characterized by distinct patterns of motor activity in the fasting and postprandial periods -The fasting or interdigestive period is characterized by a cyclic motor phenomenon, the interdigestive migrating motor complex. -In healthy individuals, one cycle of this complex is completed every 60 to 90 minutes. -The complex has three phases: (1) a period of quiescence (phase I) (2) a period of intermittent pressure activity (phase II) (3) an activity front (phase III) during which the stomach and small intestine contract at highest frequencies (3/min in the stomach, 12/min in the duodenum, 8/min in the ileum). -Another characteristic motor pattern in the distal small intestine is the giant migrating complex, or power contraction, which empties residue from the ileum into the colon in bolus transfers.

Mucous secretions from surface mucous cells (stomach and gastric pits)

-The mucous secretion from the surface mucous cells is described as visible mucus because of its cloudy appearance. -It forms a thick, viscous, gel-like coat that adheres to the epithelial surface; thus, it protects against abrasion from rougher components of the chyme. -Additionally, its high bicarbonate and potassium concentration protects the epithelium from the acidic content of the gastric juice. -The bicarbonate that makes the mucus alkaline is secreted by the surface cells but is prevented from mixing rapidly with the contents of the gastric lumen by its containment within the mucous coat.

Gastric Muscularis Externa

-The muscularis externa of the stomach is traditionally described as consisting of an outer longitudinal layer, a middle circular layer, and an inner oblique layer. -This description is somewhat misleading, as distinct layers may be difficult to discern. -As with other hollow, spheroidal organs (e.g., gallbladder, urinary bladder, and uterus), the smooth muscle of the muscularis externa of the stomach is somewhat more randomly oriented than the term layer implies. -the longitudinal layer is absent from much of the anterior and posterior stomach surfaces, and the circular layer is poorly developed in the periesophageal region. -The arrangement of the muscle layers is functionally important, as it relates to its role in mixing chyme during the digestive process as well as to its ability to force the partially digested contents into the small intestine. -Groups of ganglion cells and bundles of unmyelinated nerve fibers are present between the muscle layers. -Collectively, they represent the myenteric (Auerbach's) plexus, which provides innervation of the muscle layers.

Colonic Motility

-The normal colon displays short-duration (phasic) contractions and a background contractility or tone. -Colonic transit is a discontinuous process, slow most of the time and rapid at other times. -Fluid reabsorption influences gastrointestinal transit.

Physiology of acid secretion

-The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (M3) -When ACh (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic Ca 2+, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+-ATPase (the proton pump) on the canalicular surface. -In close proximity to the parietal cells are gut endocrine cells called ECL cells. -ECL cells also have receptors for gastrin and ACh, which stimulate histamine release. -Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cAMP and activates protein kinases that stimulate acid secretion by the H+/K+-ATPase. -In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. -In contrast, ACh provides potent direct parietal cell stimulation

Clinical features of Gastritis

-The presentation of gastropathy and acute gastritis varies according to etiology, and the two cannot be distinguished on clinical grounds. -Patients with NSAID-induced gastropathy may be asymptomatic or have persistent epigastric pain that responds to antacids or PPIs. -In contrast, pain associated with bile reflux is typically refractory to such therapies and may be accompanied by occasional bilious vomiting.

REGULATION OF GASTRIC MOTILITY & EMPTYING

-The rate at which the stomach empties into the duodenum depends on the type of food ingested. -Food rich in carbohydrate leaves the stomach in a few hours. -Protein-rich food leaves more slowly, and emptying is slowest after a meal containing fat -The rate of emptying also depends on the osmotic pressure of the material entering the duodenum. -Hyperosmolality of the duodenal contents is sensed by "duodenal osmoreceptors" that initiate a decrease in gastric emptying, which is probably neural in origin. -Fats, carbohydrates, and acid in the duodenum inhibit gastric acid and pepsin secretion and gastric motility via neural and hormonal mechanisms. -The messenger involved is probably peptide YY. -CCK has also been implicated as an inhibitor of gastric emptying

Gastric Serosa

-The serosa is continuous with the parietal peritoneum of the abdominal cavity via the greater omentum and with visceral peritoneum of the liver at the lesser omentum. -Otherwise, it exhibits no special features

small intestine transport of digested substances

-The small intestine transports solids and liquids at approximately the same rate. -As a result of the lag phase for the transport of solids from the stomach, liquids typically arrive in the colon before solids. -Chyme moves from ileum to colon intermittently in boluses propelled by contractions.

What are the protective reflexes activated as part of the vomiting response?

-The soft palate is raised, and this prevents the vomitus from entering the nasopharynx. -Respiration is momentarily inhibited, and the glottis is closed to prevent pulmonary aspiration, which is a potentially serious complication of vomiting.

Stomach Development

-The stomach enlarges and rotates so that the greater curvature lies on the left and a small portion of peritoneal cavity called the omental bursa (lesser peritoneal sac) comes to lie behind (posterior to) the stomach -The left diaphragmatic leaf is just above and the pancreas behind (posterior to) the stomach -mesenteries start as mesogastrium which is mesodermal in origin (pink in the figure)-serve to support intra-abdominal structures -omental bursa will begin to invaginate (D) and eventually create omental foramen (F) -stomach will rotate 90 degrees, and as seen in (G) will create a potential space behind the stomach

stomach

-The stomach is an expanded part of the digestive tube that lies beneath the diaphragm. -It receives the bolus of macerated food from the esophagus. -Mixing and partial digestion of the food in the stomach by its gastric secretions produce a pulpy fluid mix called chyme. -The chyme then passes into the small intestine for further digestion and absorption. -The stomach is divided histologically into three regions based on the type of gland that each contains (1) cardiac region (2) pyloric region (3) fundic region

Gastric Submucosae

-The submucosa is composed of a dense CT containing variable amounts of adipose tissue and blood vessels, as well as the nerve fibers and ganglion cells that compose the submucosal (Meissner's) plexus. -The latter innervates the vessels of the submucosa and the smooth muscle of the muscularis mucosae

Pyloric Stenosis

-There is prominent hypertrophied muscle with elongation and narrowing of the pylorus at the gastric outlet. -This uncommon condition is a cause for "projectile" vomiting in an infant about 3 to 6 weeks of age. -the pyloric sphincter usually controls gastric emptying -with stenosis, anything swallowed will accumulate and eventually be vomited out -Males >females. -overall incidence is approximately 3 per 1000 livebirths. -treatment involves surgically splitting the muscle

Gastrectomy and lymph node resection

-Total gastrectomy (removal of the entire stomach) is uncommon. -Partial gastrectomy (removal of part of the stomach) may be performed to remove a region of the stomach involved by a carcinoma, for example. -b/c the anastomoses of the arteries supplying the stomach provide good collateral circulation, one or more arteries may be ligated during this procedure without seriously affecting the blood supply to the part of the stomach remaining in place. -When removing the pyloric antrum, for example, the greater omentum is incised parallel and inferior to the right gastro-omental artery, requiring ligation of all the omental branches of this artery. -The omentum does not degenerate, however, because of anastomoses with other arteries, such as the omental branches of the left gastro-omental artery, which are still intact. -Partial gastrectomy to remove a carcinoma usually also requires removal of all involved regional lymph nodes. -B/c cancer frequently occurs in the pyloric region, removal of the pyloric lymph nodes as well as the right gastro-omental lymph nodes also receiving lymph drainage from this region is especially important. -As stomach cancer becomes more advanced, the lymphogenous dissemination of malignant cells involves the celiac lymph nodes, to which all gastric nodes drain

Treatment: Rapid Transit Dysmotility of the Small Bowel

-Treatment goals are to restore hydration and nutrition and to slow small bowel transit. -Dietary interventions include avoiding hyperosmolar drinks and replacing them with iso-osmolar or hypo-osmolar oral rehydration solutions. -The fat content in the diet should be reduced to approximately 50 g/day to avoid delivery of unabsorbed fat to the colon. -All electrolyte and nutritional deficiencies of calcium, magnesium, potassium, and water-soluble and fat-soluble vitamins should be corrected. -In patients with less than 1 m of residual small bowel, it may be impossible to maintain fluid and electrolyte homeostasis without parenteral support. -In patients with a longer residual segment, oral nutrition, pharmacotherapy, and supplements are almost always effective. -The opioid agent loperamide suppresses the motor response to feeding and improves symptoms but may be ineffective or cause side effects (e.g., hypotension). -Bile acid binding, such as with cholestyramine or colesevelam, is indicated for patients with suspected or proven bile acid malabsorption. -Verapamil, clonidine, or a 5-HT 3 antagonist is used rarely in addition to loperamide. -Octreotide may be used in patients for whom the oral agents are ineffective or poorly tolerated. -5-HT 3 antagonists may be efficacious in the treatment of carcinoid diarrhea and diarrhea-predominant IBS, but it should be reserved for patients with severe, unresponsive diarrhea, and the dose should be titrated to avoid constipation.

Motor events in vominting

-Vomiting is characterized by a stereotypic sequence of motor events, including contractions of the stomach, abdominal muscles, and diaphragm. -This sequence is followed immediately in the proximal small bowel by a propagated, rhythmic contractile response similar to the migrating motor complex.

Vomiting

-Vomiting starts with salivation and the sensation of nausea. -Reverse peristalsis empties material from the upper part of the small intestine into the stomach. -Irritation of the mucosa of the upper gastrointestinal tract is one trigger for vomiting. -Chemoreceptor cells in the medulla can also initiate vomiting when they are stimulated by certain circulating chemical agents. -Serotonin (5-HT) released from enterochromaffin cells in the small intestine appears to initiate impulses via 5-HT3 receptors that trigger vomiting.

Gastric Motility and Emptying

-When food enters the stomach, the fundus and upper portion of the body relax and accommodate the food with little if any increase in pressure (receptive relaxation). -Peristalsis then begins in the lower portion of the body, mixing and grinding the food and permitting small, semiliquid portions of it to pass through the pylorus and enter the duodenum. -Receptive relaxation is, in part, vagally mediated and triggered by movement of the pharynx and esophagus. -In the regulation of gastric emptying, the antrum, pylorus, and upper duodenum apparently function as a unit. -Contraction of the antrum is followed by sequential contraction of the pyloric region and the duodenum. -In the antrum, partial contraction ahead of the advancing gastric contents prevents solid masses from entering the duodenum, and they are mixed and crushed instead. -The more liquid gastric contents are squirted a bit at a time into the small intestine. -Normally, regurgitation from the duodenum does not occur, because the contraction of the pyloric segment tends to persist slightly longer than that of the duodenum. -The prevention of regurgitation may also be due to the stimulating action of cholecystokinin (CCK) and secretin on the pyloric sphincter.

Carcinoma of stomach

-When the body or pyloric part of the stomach contains a malignant tumor, the mass may be palpable. -Using a gastroscope, physicians can inspect the mucosa of the air-inflated stomach, enabling them to observe gastric lesions and take biopsies -The extensive lymphatic drainage of the stomach and the impossibility of removing all the lymph nodes create a surgical problem. -The nodes along the splenic vessels can be excised by removing the spleen, gastrosplenic and splenorenal ligaments, and the body and tail of the pancreas. -Involved nodes along the gastro-omental vessels can be removed by resecting the greater omentum; however, removal of the aortic and celiac nodes and those around the head of the pancreas is difficult.

Gastric secretions

-arise from glands in the wall of the stomach that drain into its lumen, and also from the surface cells that secrete primarily mucus and HCO3- to protect the stomach from digesting itself, as well substances known as trefoil peptides that stabilize the mucus-HCO3- layer -parietal cells secrete HCl and intrinsic factor -chief cells: produce pepsinogens and gastric lipase -acid secreted by the parietal cells serves to sterilize the meal and also to begin the hydrolysis of dietary macromolecules -intrinsic factor is important for later absorption of B12 and cobalamin -pepsinogen is the precursor of pepsin (initiates protein digestion) -lipase: begins digestion of dietary fats

Pathogenesis of Gastritis/Gastropathy

-gastric lumen has a pH close to 1 -the harsh environment of the gastric lumen contributes to digestion but also has the potential to damage the gastric mucosa -multiple mechanisms protect the gastric mucosa -gastropathy/acute gastritis/chronic gastritis can occur following disruption of protection mechanisms (NSAIDs, H.pylori, reduced mucin and HCO3- secretion and decreased O2 delivery) -Ingestion of harsh chemicals, particularly acids or bases, either accidentally or as a suicide attempt, also results in severe gastric injury, predominantly as a result of direct injury to mucosal epithelial and stromal cells.

Three agonists of gastric secretion

-gastrin -histamine -ACh -Gastrin and ACh promote secretion by elevating cytosolic free Ca 2+ concentrations, whereas histamine increases intracellular cAMP - it is important to be aware that the two distinct pathways for activation are synergistic, with a greater than additive effect on secretion rates when histamine plus gastrin or acetylcholine, or all three, are present simultaneously. -The physiologic significance of this synergism is that high rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli. -Synergism is also therapeutically significant b/c secretion can be markedly inhibited by blocking the action of only one of the triggers (most commonly that of histamine, via H2-antagonists that are widely used therapies for adverse effects of excessive gastric secretion, such as reflux).

Mucous neck cells

-located in the neck region of the fundic gland. -Parietal cells are usually interspersed b/t groups of these cells. -The mucous neck cell is much shorter than the surface mucous cell and contains considerably less mucinogen in the apical cytoplasm. - these cells do not exhibit a prominent mucous cup. -the nucleus tends to be spherical compared with the more prominent, elongated nucleus of the surface mucous cell. -The mucous neck cells secrete less alkaline soluble mucus compared with the high-alkaline insoluble or cloudy mucus produced by the surface mucous cell. -Release of mucinogen granules is induced by vagal stimulation; thus, secretion from these cells does not occur in the resting stomach. -These mucous neck cells differentiate from stem cells, which reside in the neck region of the fundic gland. -They are considered immature precursors of the surface mucous cells.

Vago-vagal reflex

-once the meal is swallowed, meal constituents trigger substantial release of gastrin and the physical presence of the meal causes the stomach to distend and activate stretch receptors (which promote a vago-vagal' reflex and other local reflexes that further amplify secretion during the gastric phase -The presence of the meal also buffers gastric acidity that would otherwise serve as a feedback inhibitory signal to shut off secretion secondary to the release of somatostatin, which inhibits both G and ECL cells as well as secretion by parietal cells themselves. -This probably represents a key mechanism whereby gastric secretion is terminated after the meal moves from the stomach into the small intestine.

ACh (role in gastric secretion)

-parietal and chief cells can also be stimulated by acetylcholine, released from enteric nerve endings in the fundus

peptic ulcer

-peptic ulcers are lesions of the mucosa of the pyloric canal or, more often, the duodenum. -Most ulcers of the stomach and duodenum are associated with an infection of H. pylori -People experiencing severe chronic anxiety are most prone to the development of peptic ulcers. -They often have gastric acid secretion rates that are markedly higher than normal between meals. -It is thought that the high acid in the stomach and duodenum overwhelms the bicarbonate normally produced by the duodenum and reduces the effectiveness of the mucous lining, leaving it vulnerable to H. pylori. -The bacteria erode the protective mucous lining of the stomach, inflaming the mucosa and making it vulnerable to the effects of the gastric acid and digestive enzymes (pepsin) produced by the stomach. -If the ulcer erodes into the gastric arteries, it can cause life threatening bleeding.

Fundic Glands of the Gastric Mucosa

-produce the gastric juice of the stomach. -present throughout the entire gastric mucosa except for the relatively small regions occupied by cardiac and pyloric glands. -The fundic glands are simple, branched, tubular glands that extend from the bottom of the gastric pits to the muscularis mucosae -Located between the gastric pit and the gland below is a short segment known as the isthmus. -Isthmus of the fundic gland is a site of stem cell location (stem cell niche) in which stem cells replicate and differentiate. -Cells destined to become mucous surface cells migrate upward in the gastric pits to the stomach surface. -Other cells migrate downward, maintaining the population of the fundic gland epithelium. -Typically, several glands open into a single gastric pit. -Each gland has a narrow, relatively long neck segment and a shorter and wider base or fundic segment. -The base of the gland usually divides into two and sometimes three branches that become slightly coiled near the muscularis mucosae. -The cells of the gastric glands produce gastric juice (about 2 L/day), which contains a variety of substances. In addition to water and electrolytes, gastric juice contains four major components: HCL, Pepsin, mucus, and intrinsic factor -In addition, gastrin and other hormones and hormone-like secretions are produced by enteroendocrine cells in the fundic glands and secreted into the lamina propria, where they enter the circulation or act locally on other gastric epithelial cells.

Hydrochloric acid (HCl)

-produced by the fundic glands as a component of gastric juice -HCl in a concentration ranging from 150 to 160 mmol/L, which gives the gastric juice a low pH (<1.0 to 2.0). -It is produced by parietal cells and initiates digestion of dietary protein (it promotes acid hydrolysis of substrates). -converts inactive pepsinogen into the active enzyme pepsin. -B/c HCl is bacteriostatic, most of the bacteria entering the stomach with the ingested food are destroyed. -some bacteria can adapt to the low pH of the gastric contents. -H. pylori contains large amounts of urease, the enzyme that hydrolyzes urea, in its cytoplasm and on its plasma membrane. -This highly active enzyme creates a protective basic "ammonia cloud" around the bacterium, allowing it to survive in the acidic environment of the stomach

Role of prostaglandins in protective roles of gastric mucosa

-prostaglandins (PGE2) appear to play an important role in protecting gastric mucosa. -They stimulate secretion of bicarbonates and increase thickness of the mucous layer with accompanied vasodilatation in the lamina propria. -This action improves supply of nutrients to any damaged area of gastric mucosa, thus optimizing conditions for tissue repair.

Life span of fundic gland cells

-some cells from the isthmus migrate down into the gastric glands to give rise to the parietal cells, chief cells, mucous gland cells, and enteroendocrine cells that constitute the gland epithelium. -These cells have a relatively long lifespan. -The parietal cells have the longest lifespan, approximately 150 to 200 days. -The chief and enteroendocrine cells are estimated to live for about 60 to 90 days before they are replaced by new cells migrating downward from the isthmus. -The mucous neck cell, in contrast, has a much shorter lifespan, approximately 6 days.

Fundus of the stomach

-the fundus lies above the level of a horizontal line drawn through the esophageal (cardiac) orifice

Pyloric part of the stomach

-the pyloric part is the funnel-shaped region that leads into the pylorus, the distal, narrow sphincteric region between the stomach and duodenum.

Cardiac region (stomach)

Cardiac region (cardia), the part near the esophageal orifice, which contains the cardiac glands

Fundic region (Stomach)

Fundic region (fundus), the largest part of the stomach, which is situated between the cardia and pylorus and contains the fundic or gastric glands

Body of the stomach

central portion of the stomach