Peptic Ulcer Disease and GERD Lecture Notes PDF

Peptic ulcer disease. Esophageal reflux disease. Oleg Osadchiy 1 Learning objectives ✓ Outline different types of peptic ulcers. ✓ Explain the concept of imbalance between the factors that damage the gastric mucosa and the factors that protect it. ✓ Explain pathogenesis of the peptic ulcer disease....

Peptic ulcer disease. Esophageal reflux disease. Oleg Osadchiy 1 Learning objectives ✓ Outline different types of peptic ulcers. ✓ Explain the concept of imbalance between the factors that damage the gastric mucosa and the factors that protect it. ✓ Explain pathogenesis of the peptic ulcer disease. ✓ Explain the mechanisms by which the Helicobacter pylori and non-steroid anti-inflammatory drugs may promote peptic ulcer disease. 2 Learning objectives ✓ Describe clinical manifestations of the peptic ulcer disease. ✓ Compare and contrast pathogenesis and clinical manifestations of gastric ulcers vs. duodenal ulcers. ✓ Explain pathogenesis and clinical manifestations of the Zollinger-Elison syndrome. ✓ Explain pathogenesis and clinical manifestation of the gastroesophageal reflux disease. 3 Overview ✓ Peptic ulcer disease refers to disorders of the upper GI tract caused by the action of hydrochloric acid and pepsin. ✓ These disorders are characterized by injury to the mucosa of the stomach, duodenum, or esophagus. ✓ The disorders may range from slight irritation to severe ulceration of the mucosa. 4 Lesions caused by peptic ulcer disease. Peptic ulcer disease ✓ Peptic ulcers can be acute and chronic, and superficial or deep. ✓ Superficial defects of the GIT lining that involve mucosa, but do not affect the submucosal layer are called erosions. They usually heal without therapeutic interventions. ✓ Deeper defects of the GIT lining are called ulcers. ✓ Penetrating ulcers may damage the blood vessels, causing hemorrhage, or may perforate the wall of the stomach (so the acid may leak to the abdominal cavity). 6 Peptic gastric ulcer. Typical localization of the peptic ulcers in GIT. Localization of peptic ulcers in GIT ✓ The most frequent site for the peptic ulcer is in the duodenum, within a few centimeters of the pylorus. ✓ The ulcers may also occur along the lesser curvature of the antral part of the stomach. ✓ More rarely, ulcers may be found in the lower end of the esophagus, where the gastric acid may reflux. ✓ Marginal ulcers of the stomach can be found in patients that had a surgical operation of the gastrojejunostomy. 9 Pathogenesis ✓ Peptic ulcer develops due to imbalance between the factors that protect gastric mucosa and factors that produce an injury. ✓ Damaging factors – (i) Hydrochloric acid. (ii) Pepsin. Protective factors – (i) Mucosal diffusion barrier. (ii) Growth factors. 10 Pathogenesis ✓ Peptic ulcer develops due to imbalance between the factors that protect gastric mucosa and factors that produce an injury. ✓ Damaging factors – (i) Hydrochloric acid. (ii) Pepsin. Protective factors – (i) Mucosal diffusion barrier. (ii) Growth factors. 11 Mucosal diffusion barrier (i) Mucus (ii) Bicarbonates (iii) Mucosal lining itself. 12 Mucus and bicarbonates are secreted by the mucous cells of the gastric gland. Secretion Oxyntic glands Pyloric glands Gastrin (hormone) Mucous cells are present both in oxyntic glands and pyloric glands. Balance of damaging and protective factors in gastric mucosa. The mucus and bicarbonates protect gastric mucosa form acid and pepsin. Mucous layer ✓ Mucus (secreted by mucous cells in the neck of the gastric gland) is made of glycoproteins called mucins, phospholipids, and water. Secretion of mucus is increased upon vagal stimulation, and upon irritation of the stomach, e.g. ingestion of aspirin or alcohol. ✓ Mucus has a high viscosity, so it forms a gel layer, which separates the acidic content of the gastric lumen from the bicarbonate-rich fluid on the surface of mucosal cells. ✓ It forms a physical barrier that slows diffusion of the acid and pepsin to the mucosal cell surface. ✓ This allows to keep the pH at the surface of mucosal cells close to neutral (pH 7), even though the pH of the gastric content in the lumen of the stomach is highly acidic (pH 2). 17 Bicarbonate layer ✓ Mucous cells in the gastric gland also secrete bicarbonates. ✓ Bicarbonates accumulate in the fluid that covers the surface of the mucosal cells, just underneath the mucus. ✓ Bicarbonates form a chemical barrier that protects mucosal cells from the acid. ✓ Bicarbonates act as a buffer that neutralizes H+ ions, thus preventing their destructive effect on the mucosal cells. ✓ As bicarbonates neutralize the acid, pepsin becomes inactive and cannot damage the mucosal cells. 18 Mucosal diffusion barrier (i) Mucus (ii) Bicarbonates (iii) Mucosal lining itself. 19 Neither the thick luminal membrane of the mucosal cells nor the intercellular clefts (equipped with tight junctions) are permeable to acid. 20 Pathogenesis ✓ Peptic ulcer develops due to imbalance between the factors that protect gastric mucosa and factors that produce an injury. ✓ Damaging factors – (i) Hydrochloric acid. (ii) Pepsin. Protective factors – (i) Mucosal diffusion barrier. (ii) Growth factors. 21 Rapid regeneration of mucosal cells ✓ The entire mucosal lining is replaced every three days. ✓ Consequently, even if the mucosal cells were affected by the acid and pepsin, the induced structural derangements may not progress to the serious damage, because the affected cells are rapidly replaced with the new ones. 22 What happens when the mucosal protective barrier is damaged? 23 24 Pathogenesis of peptic ulcers ✓ Once H+ penetrates to deeper layers of the wall of the stomach, it produces two effects – (i) H+ stimulates conversion of pepsinogen to pepsin, which causes further destruction of mucosa. (ii) H+ stimulates release of histamine, which then stimulates acid secretion, production of pepsinogen, and increases blood flow and capillary permeability. Gastric mucosa becomes inflamed and edematous. 25 Histamine: effect 1. 26 Previous slide When the mucous barrier is damaged, gastric acid and pepsin can penetrate into the submucosal layer, and stimulate the mast cells to release histamine. Histamine promotes gastric acid secretion by the parietal cells. This forms a positive feedback mechanism (when more acid is secreted, more histamine is released, and then even more acid is secreted). 27 Histamine: effect 2. Histamine also causes inflammation of the gastric mucosa, by inducing vasodilation and increasing capillary permeability. 28 Pathogenesis of the peptic ulcer ✓ Gastric or duodenal ulcers are caused by factors that impair the balance between the mechanisms that can damage GIT mucosa and the mechanisms that can protect it. ✓ Therefore, peptic ulcers can be induced due to – (i) Increased secretion of gastric acid and pepsin. (ii) Reduced secretion of mucus and bicarbonates. (iii) Impaired integrity of the mucosal lining (e.g. in inflammation, such as chronic gastritis). (iv) Reduced ability of mucosal cells to regenerate. 29 Causes of peptic ulcer disease Precipitating factors (i) Helicobacter pylori (causes 80% of all peptic ulcers). (ii) Non-steroid anti-inflammatory drugs, e.g. aspirin (cause 20% of all peptic ulcers). Facilitating factors (i) Stressful lifestyle. (ii) Irritating diet (spicy foods, alcohol, caffeine). (iii) Smoking. (iv) Genetics. 30 H.pylori exploits several strategies to survive in acidic environment. (i) It has flagella, which allow to escape from the gastric lumen, and to take up residence under the layer of alkaline mucus. Why H.pylori is not killed by the gastric acid, like any other bacteria? (ii) It preferentially settles in the antrum of the stomach, which contains no parietal cells that secrete acid. 31 H.pylori exploits several strategies to survive in acidic environment. (iii) It produces an enzyme urease, which splits urea into ammonia and CO2. Ammonia serves as a buffer that neutralizes gastric acid locally in the vicinity of the H. pylori. Why H.pylori is not killed by the gastric acid, like any other bacteria? 32 Helicobacter pylori ✓ H. pylori also produces catalase, an enzyme that protects the microbe from phagocytosis by neutrophils. ✓ Ammonia produced by H.pylori damages the protective mucous layer of the stomach, making it thinner. This facilitates migration of the microbe through the mucous layer. ✓ Once H. pylori has reached the gastric mucosal cells, it produces several adhesion proteins that allow the microbe to attach itself to mucosal cells, or to lodge in between the cells. 33 Helicobacter pylori can penetrate through the GI mucosal layer, and then attach to mucosal cells. Helicobacter pylori ✓ H. pylori secretes toxins that cause a persistent inflammation of the gastric mucosa (chronic gastritis). ✓ This impairs structural integrity of the mucosal cells, making them permeable for gastric acid. ✓ Overall, the mucosal lining becomes extremely leaky, and loses its protective properties. 35 NSAIDs and peptic ulcer ✓ Chronic use of NSAIDs suppresses prostaglandin synthesis in GIT mucosa. ✓ Prostaglandin E2 normally inhibits secretion of gastric acid, and increase secretion of bicarbonates and mucin. ✓ Hence inhibition of prostaglandin secretion by NSAIDs causes the opposite – secretion of gastric acid is increased, and secretion of bicarbonates and mucin (that normally protect mucosa) is reduced. ✓ These changes promote the development of peptic ulcer. 36 E2 NSAIDs (e.g. aspirin) act by inhibiting enzyme cyclooxygenase. This blocks synthesis of prostaglandins. 37 Facilitating factors ✓ Stressful lifestyle – glucocorticoids released from adrenal cortex in response to stress stimulate gastric acid secretion and reduce gastric mucosal defenses. ✓ Smoking – the incidence of the peptic ulcer disease is twice as high in smokers compared to non-smokers. ✓ Heredity – certain patterns of gastrin release and pepsin secretion can be determined by genetic factors. There are families with increased incidence of the peptic ulcer disease. 38 Clinical manifestations of the peptic ulcer disease ✓ Epigastric burning pain that is relieved by the intake of food (especially diary products) or antacids. ✓ Nausea. ✓ Abdominal upset (dyspepsia). ✓ Significant proportion of ulcers is asymptomatic. 39 Epigastric pain in peptic ulcer disease ✓ The pain of gastric ulcers typically occurs on an empty stomach. ✓ The pain of duodenal ulcer occurs 30 min to 2-3 hours after eating. The pain may occur in the middle of the night, and disappear by morning. ✓ Epigastric pain results from sensorineural stimulation by gastric acid, or muscle spasm, or both. ✓ “Pain-food-relief” pattern. 40 Complications of peptic ulcer (i) GIT hemorrhage resulting from the damage of blood vessels in the submucosal layer caused by gastric acid and pepsin. (ii) Perforation of the stomach wall, resulting in the leak of the gastric content into the abdominal cavity. 41 Characteristics of patients with gastric vs. duodenal ulcers 42 Gastric ulcers ✓ Primarily localized in the antral region of the stomach. ✓ Pathogenesis is related to weak mucous barrier that normally protects the mucosal cells from damage by the hydrochloric acid. ✓ Surprisingly, gastric acid secretion may be normal or even less than normal. This is because part of H+ ions secreted into the lumen of the stomach may leak back through the damaged mucosa (so their amount in the sample of gastric juice becomes smaller). 43 Duodenal ulcers ✓ More common than gastric ulcers. ✓ Pathogenesis is related to increased secretion of gastric acid and pepsin. The chyme becomes more acidic, which is leading to the duodenal ulceration. ✓ Weak protective mucus barrier is another contributing factor. ✓ H. pylori reduces secretion of somatostatin by D-cells in the gastric antrum. Somatostatin normally inhibits release of gastrin by G-cells. When lesser somatostatin is secreted, more gastrin is released, which increases gastric acid secretion by the parietal cells. Hence more acid is delivered to the duodenum, causing ulcerations. 44 Somatostatin inhibits secretion of gastrin. Hence when lesser somatostatin is produced due to effects of H. pylori, secretion of gastrin is increased. This stimulates acid secretion by the parietal cells. Patients with duodenal ulcers present with high serum levels of gastrin, as well as high gastric acid secretion (both basal and stimulated). 46 Zollinger-Elison syndrome ✓ Is associated with increased secretion of gastrin, a hormone that increases gastric acid secretion by stimulating the parietal cells in stomach. ✓ Gastrin is secreted by gastrinoma, a neuroendocrine tumor of the pancreas or duodenum. ✓ This causes gastric and duodenal ulcers, as well as gastroesophageal reflux. ✓ On top of that, gastric acid inactivates pancreatic lipase secreted into the duodenum. As a result, fat is not properly digested, and excreted into the stool (steatorrhea). 47 Zollinger-Elison syndrome ✓ Clinical manifestations include abdominal pain, diarrhea, and steatorrhea. ✓ Diagnosis is aided by measuring plasma gastrin levels. 48 Diagnosis of peptic ulcer disease (i) Barium contrast radiography. (ii) Endoscopy. During endoscopy, a biopsy can be taken for histology in order to exclude malignancy. 49 Radiograph of an ulcer in the lesser curvature of the stomach. Endoscopy in a patient with peptic ulcer disease. 52 Endoscopy reveals association of Helicobacter pylori with gastric mucosa. 53 Treatment ✓ The goals of the treatment – a) Eradicate H. pylori. a) Reduce gastric acidity b) Encourage healing of the injured mucosa. ✓ Medications that block gastric acid secretion (proton pump inhibitors, histamine H2 receptor blockers). ✓ Oral antacids (to buffer the gastric acid). ✓ Agents that form a protective coating over the injured mucosa (e.g. sucralfate). ✓ Antibiotics to eradicate Helicobacter pylori. 54 Gastro-esophageal reflux disease 55 Esophagus has an upper sphincter and a lower sphincter. Lower esophageal sphincter Upon completing the swallowing, the lower esophageal sphincter closes, which prevents reflux of gastric acid. Gastro-esophageal reflux ✓ In normal conditions, the gastric content may not go back from the stomach to esophagus due to the closure of the lower esophageal sphincter. ✓ In some individuals, closing of this sphincter is incomplete, which allows reflux of gastric content to the esophagus. ✓ Esophagitis is an inflammation of the mucosa in esophagus, which is caused by the reflux of acid and pepsin from the stomach (gastroesophageal reflux disease). 58 In GERD (right), acidic content from stomach produces a damage of the esophageal mucosa, which causes a burning sensation (dyspepsia). 59 Gastro-esophageal reflux ✓ The risk factors for gastroesophageal reflux disease (GERD) include – (i) Obesity (ii) Hiatal hernia (iii) Drugs that relax the lower esophageal sphincter (anticholinergics, nitrates, calcium channel blockers). 60 Hiatal hernia occurs when upper part of the stomach pushes up into the chest through a small opening in the diaphragm. 61 Pathophysiology of GERD ✓ GERD develops in persons with weak lower esophageal sphincter (low resting tone). ✓ Gastroesophageal reflux is precipitated by increased abdominal pressure caused by vomiting, coughing, lifting weight, bending, or obesity. ✓ Another contributing factor is a delayed gastric emptying. This can be seen in patients with narrow pylorus. Narrowing of the pylorus can develop as a consequence of gastric or duodenal ulcers, which cause pyloric edema and scarring. 62 Clinical manifestations of GERD ✓ Clinical symptoms result from the gastric acid regurgitation, and include – (i) Chest pain (usually occurs within 1 hour of eating). Can mimick pain in angina pectoris. (ii) Chronic cough. (iii) Laryngitis. 63 Heartburn in GERD ✓ This is a substernal burning sensation that may radiate to the neck or throat. ✓ Two mechanisms contribute to heartburn – (i) Gastric acid is noxious stimulant to sensory nerve endings in the esophageal mucosa. (ii) Pain is caused by the spasm of the esophageal muscle induced directly by the gastric acid. 64 Treatment ✓ Gastroesophageal reflux can be reduced by avoiding large meals, especially just before the bedtime. ✓ Elevation of the head of the bed may prevent reflux. ✓ Reduce caffeine intake. ✓ Reduce smoking, alcohol consumption, and intake of specific foods which promote reflux. ✓ Manage excess body weight. 65 Treatment of GERD ✓ Drugs that increase the muscle tone of the lower esophageal sphincter. Metoclopramide is doing so through a local release of acetylcholine. It also improves emptying of the stomach to the duodenum, which reduces the chance for reflux. ✓ Drugs that reduce gastric acidity – (i) Proton pump inhibitors (ii) Histamine H2 receptor antagonists (iii) Antacids ✓ Protection of the esophageal mucosa (alginates). 66 Alginate is a mixture of alkaline aluminium, magnesium, and sodium carbonate or hydroxide. When dissolved in water, it forms a foamy gel uppermost in stomach, which prevents reflux of the acid to esophagus. 67 After this lecture you are able to ✓ Explain pathophysiology of the peptic ulcer disease. ✓ Compare and contrast pathogenesis and clinical manifestations of gastric ulcers vs. duodenal ulcers. ✓ Explain pathogenesis of the Zollinger-Elison syndrome. ✓ Explain pathophysiology and clinical manifestation of the gastroesophageal reflux disease. 68