INTRODUCTION

INTRODUCTION

1.PEPTIC ULCER: Peptic ulcer is a major health hazard both in terms of morbidity and mortility. It occurs due to imbalance between the offensive (acid-pepsin secretion, bile and H.pylori) versus impaired mucosal resistance

(mucus,bicarbonate secretion, prostaglandin, blood flow and the process of restitution and regeneration after cellular injury.(Gastroprotective etal 2007). peptic ulcers are usually solidary lesion less than 4cm located in the following sites Stomach usually in antrum Duodenum, first portion At the gastroesophageal junction, in the setting of gastroesophageal reflux or Barrett esophagus Within the margins of a gastrojejunostomy In the duodenum, stomach and are jejunum of patients with Zollinger Ellison syndrome (Kumar et al 2004) in diameter,

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Fig no: 1 Gastric ulcer

1.2 ACUTE PEPTIC ULCERS Acute peptic ulcers are multiple, small mucosal erosions, seen most commonly in the stomach but occasionally involving in the duodenum.

PATHOLOGIC CHANGES: Acute ulcers are multiple they are more common anywhere in the stomach, decreasing frequency in the first part of duodenum. They may be oval or circular in shape, with a smooth base and perpendicular borders.

Microscopically the stress ulcers are shallow and do not invade the muscular layer. The margin and the base may show some inflammatory reaction depending upon the duration of the ulcer.

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1.3 CHRONIC PEPTIC ULCERS: It means gastric and duodenal ulcers, the two major forms of peptic ulcer diseases of the gasterointestinal(GI) tract in which the acid-pepsin secretions are implicated in their pathogenesis.

PATHOLOGIC CHANGES: Gross and microscopic changes in gastric and duodenal ulcers are similar and quite characteristic. Gastric ulcers are found predominantly along the lesser curvature in the region of pyloric antrum, more commonly on the posterior wall. Most duodenal ulcers are found in the first of duodenum, usually immediate post-pyloric than the anterior. Microscopically, chronic peptic ulcers have 4 histological zones from within outside, they are Necrotic zone, Superficial exudative zone, Granulation tissue zone, Zone of cicatrisation (Francesca Borrelli etal 2000).

1.4 EPIDEMIOLOGY Peptic ulcer occurs in the oesophagus, in the stomach, and in the upper part of the duodenum. About 10 percent of persons suffer, some time in their lives from a chronic gastric or duodenal ulcer. Males are afflicted about four times more frequently than females. At autopsy, gastric ulcer is more frequent than duodenal. In a life time the peptic ulcer develops about 10% for American males and 4% for females.
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Ulcers affect about 5.5 million people each year. More than 50,000 people a year have surgery because of persistent symptoms or problems from ulcers. Each year about 7,000 people die of ulcer-related complications. Ulcers can develop at any age, but they are rare among teenage people and even more uncommon in childrens. Peptic ulcers occur for the first time usually between the ages of 35 and 50. Peptic ulcers occur more frequently in men than women. Stomach ulcers will develops in people over age 60. Stomach ulcers develops more often in women than men. Mostly womens often affected at or after menopause.( Edwin etal 1962),(Digestive Disorders2008). 1.5 PHYSIOLOGY OF GASTRIC ACID SECRETION GASTRIC SECRETION

Function of Gastric Mucosa The gastric mucosa has two functional regions: They are Oxyntic area Pyloric area Oxyntic area: It begins at the lower esophageal sphincter and ends at the antropyloric area. There are several types of cells that are found in this area. Peptic (chief) cells are those which produce pepsinogen. Pepsinogen is an inactive enzyme that is converted into pepsin by HCl. Pepsin is a proteolytic enzyme that is responsible for digesting proteins in the stomach. Oxyntic (parietal) cells are responsible for producing HCl and intrinsic factor like vitamin B12. Enterochromaffin-like cells (ECL) are histamine releasing endocrine cells were
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found in the gastric fundus. Histamine are responsible for the activation of H 2 receptors in the parietal cells to stimulate acid secretion. Mucus neck cells will secrete mucus. The mucus is rich in bicarbonate it also important in neutralization of acid in the gastriclumen. (Scharschmidt et al1987) (Kumar, et al 7th ed. )

1.6 Production of HCl in the Parietal Cells: The production of hydrogen ions in the cytoplasm of parietal cell from the enzyme carbonic anhydrase will catalyses the reaction between the carbon dioxide and water, in which the carbonic acid were produced. This acid immediately will be dissociates in to hydrogen ions and hydrogen carbonate ions. The hydrogen ions will leaves the cell by the aid of H+/K+ ATPase or proton pump inhibitor. Chloride ions and sodium ions get secreted actively from cytoplasm of parietal cell into lumen of canaliculus. Bicarbonate will

transported out of basolateral membrane in the exchange for chloride ions .At the same time sodium ions were actively reabsorbed. This means that the largest amount of secreted K+ ions and Na+ ions will return in to the cytoplasm. In the canaliculus,the secreted hydrogen and chloride ions will combine into HCl and then secreted into the lumen of the oxyntic glands.(Michael etal 1998:).

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Fig no: 2 secretion of HCl from parietal cell

Fig no: 3 Gastric acid secretion

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These second messengers activate luminal Cl-- and K+-channels. Cl- and K+ pass into the lumen, whereby their cellular concentrations decrease (Fig. 22-10 left). The luminal [K+] activates the K+-H+-pump. in cellular [bicarbonate], stimulates the basolateral Cl --bicarbonate exchanger, The fall in cellular [H+] and [bicarbonate] stimulates formation of H+ and bicarbonate, under the influence of carboanhydrase . Cellular [H+] is a substrate for the luminal gastric proton pump (the K+-H+-pump), already activated by K+. The net result is H+secretion to the lumen in a balanced relationship to Cl --secretion. The HCl secretion requires ATP.

The cellular concentration of cations is maintained by the basolateralNa+-K+pump.(GastrointestinalFunction And Disorders.)

Pyloric area: The gastric mucosa will makes up to about 15% of the glandular region. This region will produces its own pepsins. The G-cells of the pyloric area secrete the gastrin after they are stimulated by either by protein digestion products or vagal innervation. Gastrin enters the bloodstream and then passes through the circulation until it reaches the gastric oxyntic cells to stimulate them to produce acids. Gastrin will also stimulates the release of pepsinogen and promotes growth of gastric mucosal lining. The antral D-cells produces somatostatin. It is inhibitory of gastricacid and pancreatic secretions. ( Scharschmidt et al 1987.)

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1.7 REGULATION OF ACID SECRETION Various substances are known to stimulate the parietal cell to secrete acid. These include gastrin, acetylcholine and histamine .The current evidence suggest that each parietal cell has separate receptor for each of the secretagogues. Gastrin which is produced in the G cells of the antrum stimulates the oxyntic cells to produce acid. Histamine is released from the ECL cells of the fundus. It stimulates acid secretion directly and potentiates Ach or gastrin effects by stimulating cAMP levels of the cell. In turns, cAMP activates cAMP-dependent protein kinase which phosphorylates H+ / K+ ATPase in the apical membrane of the cell phosphorylation of exchange activates extrusion of H+ from the parietal cell into the gastric lumen. Acetylcholine enhances gastric secretion by different intracellular messenger system and to increases the concentration of calcium in the cytoplasm of the parietal cell. This in turn stimulates protein kinases that stimulate acid secretion from an H+/K+ ATPase (the proton pump) on the canalicular surface.(Mitchell Schubert etal 2008) ( Stephen etal. 2006)

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Fig no: 4 - Regulation of Acid secretion ( Yeomans etal 2000)

1.8 Integrated regulation of Gastric acid Secretion: There are three phases of gastric acid secretion. They are Cephalic phase Gastric phase Intestinal phase

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Fig no: 5 Phases of Gastric acid secretion

The cephalic phase accounts for 30% of the total secretion in the stomach. When a person sees and smells food, this stimulates vagal afferents to the stomach to increase secretion. This phase depends on the integrity of the vagal fibers innervating the stomach and has a direct effect on the G-cells of the pyloric cells via gastrin releasing peptide (GRP) and on oxyntic cells via Ach. The release of somatostatin is inhibited by vagal stimulation. More gastric secretion occurs when eating a meal that is pleasing than when eating an unappetizing meal. The gastric phase accounts for most of the gastric acid

production/secretion 50% and occurs when food is in the stomach. It occurs mainly due to gastrin. During the gastric phase, the G cells are acted on in several manners. There is a direct stimulation of the G-cells, Ach acting on the G-cells, stimulation of the G-cells by GRP, stimulation of the G cells by protein

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digestive products in the antropyloric area, and stimulation of the nerves innervating the oxyntic cells by stomach distension and releasing Ach.

The intestinal phase is responsible for about 5% of the total gastric acid secretion. It occurs after the meals moves into intestine. Several mechanisms are involved in it. Intestinal gastrin in the duodenum will stimulates the oxyntic cells use to release acids. A hypothetical substances called entero-oxyntin were produced by the intestine to stimulate gastric acid secretions. Finally amino acids absorbed it and can be directly use to enhance the gastric acid secretion by stimulating the oxyntic cells.( Stephen et al 2006)

Other Factors Involved in Secretions Pepsins are also involved in secretion. Pepsinogen is an inactive enzyme produced by the peptic cells. Pepsinogen secretion is increased when there is stomach distension or vagal stimulation. The speed at which pepsinogen is converted to pepsin by gastric acid increases as more acid is secreted.

1.9 GASTRIC MUCOSAL BARRIER: Gastric mucosal barrier are somatostatin D cells and prostaglandins Somatostatin: It decreases acid secretion via three mechanisms Inhibition of gastrin release from G cells by a paracrine mechanism, Inhibition of histamine release by ECL cells and mast cells, Direct inhibition of parietal cells and acid secretion.( Ari Hirsch etal 2003) Prostaglandins: Its one series of the group of compounds collectively known as "eicosanoids" they are synthesized from the dietary essential fatty acids, that are primarily linoleic acid, which are later metabolized to the arachidonic acid
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(AA). Prostaglandins (PGS) and related groups are the unique. In that they are synthesized upon demand from the fatty acid precursors stored in the

phospholipids pools within the lipid bilayer in the cell membranes. In addition, prostaglandins act locally and they are locally metabolized. The two major pathways of the arachidonic metabolism are throygh the cyclooxygenase

pathway,then it leads to the formation of "prostanoids", and lipoxygenase pathways,then leads to leukotrienes and hydroxylated derivatives. A unique characteristic of prostaglandins is that they prevent gastric mucosal damage caused by a variety of diverse noxious agents, including the presence of acid to cause damage, such as NSAIDS, bile acids and stress, and those that will damage the mucosa directly, such as ethanol, caustic solutions and thermal damage.The factors contributing to this "gastric mucosal barrier" are multiple, they include anatomical "tight junctions" between the cells, the intracellular pumps, surface phospholipids, mucus, bicarbonate secretion and the mucosal blood flow into the lumen of the stomach.( Parthasarathy etal 1995) (Ireneusz etal, 2005.)

Fig no: 6 Effect of NSAIDs on gastric mucosal barrier

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1.10 Continuous generation of PGE2 and PGI2 The Continuous generation of PGE2 and PGI2 by the mucosa is a crucial for maintening of mucosal integrity. Almost all of the mucosal defense mechanisms will be stimulated by PGs. PGs will inhibit acid secretion, and thus stimulate mucus, bicarbonate, phospholipid secretion and will Increase mucosal blood flow and accelerate epithelial restitution and mucosal healings. PGs alsowill inhibit the mast cell activation and leukocyte and platelet E-type

adherence to the vascular endothelium. Endogenous and exogenous

PGs and their analogs exert the biologic actions through EP receptors like EP1, EP-2, EP-3, EP-4. The mucosal protective action of PGs is mainly mediated through EP-1 receptors, which also increase the bicarbonate secretion and mucosal blood flow in damaged mucosa and decrease gastric motility. EP-3 and EP-4 receptors will affect the acid and mucus secretion, respectively. (Songul et al 2000)

1.11 Components of the mucosal barrier The Secretion of mucus, and The Secretion of bicarbonate and The Mucosal cell which will regenerate and restitution in the response to injury part. Mucosal blood flow.

These are Gastric Mucos were used for defense Mechanisms.

Thus the Mucus-bicarbonate to the phospholipid barrier. The mucus-bicarbonate to phospholipid were the barrier

constitutes the first line of the mucosal defense.This barrier is formed by the mucus gel, and bicarbonate, and the surfactant phospholipids, which are used to cover the mucosal surfaces. This
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unstirred layer will be retains the bicarbonate secreted by the surface epithelial cells to maintain the neutral microenvironment pH 7.0 at the surface of the epithelial cells and thus prevents

penetration of pepsin and thus proteolytic digestion of the surface epithelium. Mucus gel is secreted by apical expulsion from the surface of the epithelial cells and thus contains 95% of water and 5% of mucin glycoproteins, thus products of mucin (MUC) genes. The gel

forming to the mucin units to polymerize into the larger mucin multimers are essential for the gel formation. The structure of each of the gels forming the mucins, MUC2, MUC5AC, MUC5B, and MUC6, have been elucidated. In the stomach, MUC5AC is expressed by the surface epithelial cells of cardia, fundus, and antrum ; and the MUC6 is expressed in the neck cells of the fundus and in antral glands. Alternating the layers of MUC5AC and MUC6 have been demonstrated in the mucus layer in human gastric mucosa. The Mucus gel is cosecreted with the low-molecular-weight trefoil factor family peptides (TFFs). TFFs are an the integral part of the intracellular mucus

secretory vesicles and may play a role in the intracellular assembly and/or packaging of the mucins. TFF2 increases the viscosity of the gastric mucin and stabilizes the gel network. Mucus secretion is stimulated by the gastrointestinal hormones, including gastrin and secretin, as well as PGE2 and cholinergic agents. (Loren etal 2008) The secretion of HCO3 into a stable, adherent mucus gel layer creates a pH gradient at the epithelial surface of the stomach and duodenum and provides the first line of the mucosal defense against luminal acid. pH gradient are studies were provided experimental evidence for the existence of the mucusbicarbonate barrier in vivo and the presence of a nearly neutral pH at the epithelial surface. The surface epithelium in the acid secreting of gastric
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mucosa will exports HCO3 at rates only 10% of the acid secretion rate the Mucus gel minimizes the luminal loss of HCO3sufficiently to maintain the neutral pH at the apical cell surfaces. The mucus bicarbonate barrier is the only prepithelial barrier between the lumen and epithelium. When it is overwhelmed or breaks the down in the disease, the next series of the protective mechanisms come into play, including the intracellular neutralization of acids,the rapid epithelial repair, and maintenance and distribution of mucosal blood flow. ( Loren Laine etal 2008) 1.12 Surface epithelial cells The next line of mucosal defense is formed by a continuous layer of surface epithelial cells, which secrete mucus and bicarbonate and generate PGs, heat shock proteins, TFFs. Because of the presence of phospholipids on the surfaces, these cells are the hydrophobic, repelling acid- and water-soluble damaging agents. Interconnected by the tight junctions, the surface of the epithelial cells form a barrier preventing back the diffusion of acid and pepsin. The surface epithelial cells are metabolically and electrically coupled by the gap junctions. Heat shock proteins are generated by the gastric epithelial cells in response to the stress, such as increased the temperature, oxidative stress, and the cytotoxic agents. They prevent the protein denaturation and protect the cells against injury. Cathelicidin and the defensins are the cationic peptide that plays major roles in the innate defensive systems at the mucosal surfaces by preventing the bacterial colonization. They have been demonstrated in the gastric epithelial cells, and they accelerate the ulcer healing. Surface epithelial cells will secrete TFFs that regulate the reepithelialization and exert the mucosal protective action.

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1.13 Continuous cell renewal from mucosal progenitor cells Continuous cell will renewal from the mucosal progenitor cells maintains the structural integrity of the mucosa. The epithelium is continually renewed by the well-coordinated and controlled proliferation of the progenitor cells that enables the replacement of damaged or aged surface epithelial cells. The

Complete replacement of the gastric surface epithelium usually takes 37 days, whereas months are required to replace the glandular cells. In gastric glands, are the single stem cells that undergoes division to produce committed by progenitor cells, which further differentiate into an adult epithelial cell types.

1.14 Mucosal microcirculation Mucosal microcirculation is the essential for delivery of oxygen and nutrients and the removal of toxic substances. At the level of the muscularis mucosae, most gastric arteries branchs into the capillaries, which enter the lamina propria and travel upwards in proximity to gastric glandular epithelial cells. At the base of the surface epithelial cells, capillaries converge into collecting venules. The endothelial cells lining the microvessels generate potent vasodilators such as nitric oxide (NO) and prostacyclin (PGI2), which protect the gastric mucosa against injury and oppose the mucosal damaging action of vasoconstrictors such as leukotriene C4, thromboxane A2, and endothelin. (Loren Laine etal 2008) ( Rebecca Darlinget al 2004)

1.15 PATHOPHYSIOLOGY The pathophysiology of peptic ulcer disease has been compromised mucosal defense mechanisms. Peptic ulceration in the stomach or duodenum can be viewed as an imbalance between the aggressive acid and peptic factors and the mucosal defense factors. It has long been recognized that many patients
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with peptic ulcer are not acid hypersecretors. Supposedly, in these individuals, a normal amount of luminal acid and pepsin is sufficient to overcome compromised mucosal defenses. Important mucosal defense mechanisms include: 1) an intact layer of the surface epithelial cells, 2) rapid restitution of this layers when surface epithelial cells were lost, 3) the mucus, 4)the luminal bicarbonate, 5) an alkaline tide of bicarbonate on the serosal side of the mucosal to buffer back-diffusing to the hydrogen ions, 6) the mucosal blood flows, 7) the growth factors, 8) the angiogenesis factors, and 9) finally motility. The Important mediators of this complexs process of thecytoprotection include the prostaglandins (particularly PGE2),the nitric oxide, calcitonin generelated peptides, and a variety of gastrointestinal (GI) hormones. Some the important protective reflexes are mediated by the gastric afferent sensory neurons. In addition to these local factors, these are important protective factors in swalloes saliva, duodenal secretions, and pancreaticobiliary secretions. (Sean Harbison et al .2005) H.pylori infection causes gastritis in all infected individuals and is causally linked to peptic ulcer diseases however about only 20% of infected persons development of symptomatic peptic ulcer diseases. The H.pylori bacteria is uniquely equipped for survival in the hostile environment of the stomach,. It possesses the urease enzyme, which converts urea into ammonia and bicarbonate. This creates an environment around the bacteria which buffers the acid secreted by the stomach. Mutant strains of H.pylori that do not produce urease are unable to colonize the stomach, emphasizing the importance of this enzyme in stabilizing the microenvironment for the Helicobacter organism. The organism lives in the mucus layer atop the gastric surface epithelial cells, propelled by its flagellum, and some attach to the surface epithelial cells. There are a variety of possible mechanisms whereby H.pylori produces mucosal injury. One fundamental mechanism appears to be a disturbance in acid secretion. When patients are first infected by H. pylori, there
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is an initial period of hypochlorhydria or achlorhydria, followed by the development of acid hypersecretion and hypergastrinemia. This is due at least in part to the inhibitory effect that H. pylori exerts on antral D cells, which secrete somatostatin, a potent inhibitor of antral G cell gastrin production. In the gastric mucosa, H.pylori infection is associated with decreased levels of somatostatin, decreased somatostatin mRNA production, and fewer somatostatin producing D cells. These effects are probably mediated (inter alia) by Helicobacter-induced local alkalinization of the antrum (antral acidification is the most potent turnoff mechanism for antral gastrin secretion) and Helicobacter-mediated increases in other local mediators and cytokines. The end result is hypergastrinemia and acid hypersecretion. (Jia-Qing Huang etal 2002)

NSAIDS (including aspirin) causes gastric mucosal damage by two mechanism 1) direct or tropical irritation of gastric epithelium 2) systemic inhibition of the cyclooxygenase-1(COX 1) enzyme which results in decreases synthesis of protective prostaglandins. Uses of corticosteroids alone does not increases the risk of ulcer (or)complication but ulcer risk in doubled in corticosteroids uses taking NSAIDS concurrently. (Barbare etal 2006)

Epidemiologic studies suggest that smokers are approximately twice as likely to develop peptic ulcer disease as nonsmokers. Smoking increases gastric acid secretion and duodenogastric reflux. Smoking decreases both

gastroduodenal prostaglandin production and pancreaticoduodenal bicarbonate production.Although clinical observation suggests that ulcer patients are adversely affected by stress full events, controlled studies fail to document a causes and effects relationship. Coffee, tea, milk and bear may cause dyspepsia but do not increases Peptic ulcer diseases risk.
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Ethanol ingestion in high concentration is associated with acute gastric mucosal damage and upper GI bleeding. Alcoholic cirrhosis is associated with an increased incidence of peptic ulcer.Finally, the Zollinger-Ellison syndrome. This is associated with multiple peptic ulcerations in the stomach, duodenum, and even jejunum, owing to excess gastrin secretion by a tumor and hence the excess of gastric acid production.( Barbare wells etal. 2006)

1.16 SYMPTOMS The great majority of peptic ulcers causes epigastric gnawing, burning, or aching pain. A significant minority first comes to light with complications such as iron-deficiency anemia, frank hemorrhage, or perforation. The pain tends to be the worse at night and occurs usually 1 to 3 hours after meals during the day. Classically, the pain is relieved by the alkalis or food, but there are many exceptions. Nausea, vomiting, bloating, bleching, and a significant weight loss are additional manifestations. With penetrating ulcers, the pain is occasionally referred to the back, the left upper quadrant or chest. This type of pain may be misinterpreted as being of cardiac origin. Peptic ulcers are the notoriously chronic, recurring lesions. They more often impairs the quality of life than shorten it. When untreated, it takes an average of 15 years for healing a duodenal or gastric ulcer. (Kumar etal 2004)

1.17 COMPLICATION OF PEPTIC ULCER: Bleeding Occurs in 15% to 20% of patients Most frequent complication May be life-threatening Accounts for 25% of ulcer deaths May be the first indication of an ulcer
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Perforation Occurs in about 5% of patients Accounts for two thirds of ulcer deaths Rarely, is the first indication of an ulcer Obstruction from edema or scarring Occurs in about 2% of patients Most often due to pyloric channel ulcers May also occur with duodenal ulcers Causes incapacitating, cramp abdominal pain Rarely, may lead to total obstruction with intractable vomiting.

1.18 DIAGNOSIS The treatment protocols may be different for different types of ulcers, it is important to adequately diagnose the ulcer diseases and H. pyloris before starting the treatment. Diagnosis methods are Upper GI series Endoscopy Blood, breath, and stomach tissue tests

1.19 Treatment for Ulcer Along with the reducing stress and modifying lifestyle, doctors treats gastric,peptic and duodenal ulcers with several types of medicines. (Tripathi K D ) (Rang 2003 5th ed) They are H2-blockers(ranitidine, famotidine, cimetidine) Adverse effects: Diarrhoea, dizziness, gynaecomastia in men, headache, dry mouth, bowel upset, rashes, CNS effects like confusion state.
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Proton-pump inhibitors ( omeprazole, lansoprazole, pantoprazole, rabeprazole, Esomeprazole ) Adverse effects: Nausea, vomiting, headache, abdominal pain, pain in muscles and joint pain. Mucosal protective agents(sucralfate, misoprostol, bismuth subsalicylate) Adverse effects: Abdominal cramps, uterine contraction, constipation. Antacids (magnesium hydroxide, aluminium hydroxide gel, sodium bicarbonate) Adverse effects: chronic renal failure Antibiotics(amoxicillin, tetracycline, clarythromycin) Adverse effects: GI disturbances, bone deformities

1.20 SURGERY People who do not responds to medications or who develop the complications may requires surgery. At present, laproscopic surgery is performed to treat all type of ulcers. Types include.(Sharon Gillson et al 2008. )

Vagotomy - a procedure that involves cutting parts of the vagus nerves (a nerve that transmits messages from the brain to the stomach) to interrupt messages sent via it, therefore, reducing acid secretion. Antrectomy - an operation to remove the lower part of the stomach (antrum), which produces a hormone that stimulates the stomach to secrete the digestive juices. Sometimes a surgeon may also remove an adjacent parts of the stomach Sthat secretes pepsin and acid. A vagotomy is usually done in conjunction with antrectomy. Pyloroplasty an surgical procedure that may be performed along with the vagotomy, in which the opening into duodenum and small intestine (pylorus) wer enlarged, enabling contents to pass more freely from the stomach.
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1.21 Complication of surgical treatment: Recurrent ulcer (marginal ulcer). Gastro-jejuno-colic and gastro-colic fistula. Dumping syndrome. Alkaline gastritis. Anemia. Post-vagotomy diarrhoea.( Ulcer Surgery and its Complications)

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