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GI Barrett's esophagus and gastric ulcers
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GI Barrett's esophagus and gastric ulcers
Barrett’s esophagus and gastric ulcers both involve the acid-producing apparatus of the stomach. In this project, you will examine the mechanisms underlying these two conditions.
1. Describe, in detail, the mechanism for acid production in the stomach (cell type and histological appearance by LM and EM, molecular mechanism, and regulation of acid production).
The stomach is divided into several regions: cardia, fundus, corpus/body, antrum, and pylorus. The fundus and corpus/body of the stomach is the principal site of acid production/secretion while the cardiac, antral, and pyloric regions contain more endocrine cells than others.
The gastric mucosa is folded into visible folds called rugae that increase its surface area. The gastric surface is opened with gastric pits that are lined with surface columnar epithelial cells. They are responsible for secreting bicarbonate to prevent acid digestion of stomach itself. Upon entering the region of the gland, there are low columnar mucous neck cells that secrete mucus to protect the epithelial layer. Also, they can migrate upward to become surface epithelial cells or migrate downward to become specialized gland cells (parietal/oxyntic, chief/peptic, or G cells).
Figure 1: LM image showing parietal cells in relation to mucous neck cells
Figure 2: LM image showing parietal cells in relation to chief cells
The principal cells involved with acid production/secretion (HCl) are the parietal cells. They are spread throughout the gastric gland (isthmus, neck, basal regions). They are differentiated from the neighboring chief cells by their “fried-egg” appearance (large, polygonal shape with centrally-located nuclei and highly acidophilic cytoplasm). The apical surface is extensively folded, and the cells have intracellular canalicular system that additionally increases the surface area of individual cells. They generally live for about a year and are replaced with differentiating mucous neck cells.
Figure 3: Another LM image showing parietal cells in relation to chief cells
Figure 4: Schematic showing the arrangment of intracellular canalicular system in a parietal cell
Acid production/secretion in parietal cells is quite complex, involving both molecular and morphological changes in the cell. Upon stimulation to release acid, cytoplasmic tubulovesicles, which contain the H+-pump (H+-K+ ATPase), and potassium and chloride channels in their intracellular membranes, disappear by fusing with the apical/mucosal canalicular membrane. At the same time, the cell contains large amounts of hydrogen ions due to dissociation of carbonic acid (by the action of carbonic anhydrase) into a hydrogen ion and a bicarbonate molecule. Bicarbonate is transported out of the cell by HCO3-/Cl- antiport exchanger located at the basal/serosal membrane. The hydrogen ions are secreted out from the cell by the apical H+-K+ ATPase that transports one hydrogen ion out and brings one potassium ion into the cell. The excess potassium and chloride ions accumulated inside the cell are secreted out from the cell through the potassium and chloride channels located at the apical membrane. There are additional exchangers at the basal membrane such as Na+-K+ ATPase and Na+-H+ exchanger that maintain the correct balance of ions in the cell.
Figure 5: EM image of a parietal cell showing canalicus (C), tubulovesicles (TV) and many mitochondria
Figure 6: A parietal cell with prominent nucleus and many mitochondria (M)
Acid secretion is promoted by three gastric molecules: gastrin, acetylcholine, and histamine. Gastrin is produced from the G cells of the stomach and released into the splanchnic circulation. It binds to a surface receptor within the basal membrane of the cell and increases intracellular calcium level. Acetylcholine binds to a muscarinic receptor at the basal membrane and in turn stimulates phospholipase C (PLC). PLC acts on phosphatidylinositol-4,5-bisphosphate in the membrane to release inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases calcium ions from endoplasmic reticulum and elevates calcium level while DAG directly stimulates the actions of protein kinase C (PKC). Histamine is released from mast cells in the gastric mucosa following stimulation by mechanical distention (arrival of food). It binds to an H2 receptor at the basal membrane and activates adenylate cyclase to produce more cAMP, which in turn also stimulates more protein kinase A (PKA). Increased calcium level due to the effects of both gastrin and acetylcholine and increased activity of PKA and PKC by histamine and acetylcholine respectively stimulate more regulatory proteins responsible for canalicular fusion with the mucosal membrane. This fusion is the beginning of acid secretion in parietal cells, allowing more hydrogen ions to be pumped out into the lumen of the stomach through the H+-K+ ATPase pump.
Acid secretion is inhibited by somatostatin. It directly blocks gastrin secretion from the G cells and acid secretion from the parietal cells (the molecular mechanisms are unclear).
The parietal cells also secrete intrinsic factor, which aids in absorption of vitamin B12.
2. Describe the normal anatomy and histology of the gastroesophageal junction, the development of Barrett’s esophagus, the histological appearance, the principal reason why this condition is so dangerous, and the most common form of treatment.
Figure 7: Schematic of gastroesophageal junction
Figure 8: LM image of lower esophagus with characteristic stratified squamous epithelium (SSE) and cardiac glands
The esophagus is a relatively long muscular tube that is covered with non-keratinized, stratified squamous epithelium. At the gastroesophageal junction, the epithelium gradually changes into columnar epithelium, a characteristic of the stomach epithelium. By this point, the muscularis mucosa is mostly smooth muscle in nature. Moreover, esophageal cardiac glands become more prominent in the lamina propria. The presence of this gland is important since it secretes mucus that protects the junctional lining from possible acid reflux from the stomach. The esophageal muscular layer also thickens at this junction, forming the lower esophageal sphincter.
Figure 9: LM image showing normal gastroesophageal junction
Figure 10: LM image of lower esophagus showing gradual increase in thickness of muscular wall
Barrett’s esophagus arises as a common complication of gastroesophageal reflux disease (GERD). About 8-20% of patients who suffer from GERD develop Barret’s esophagus. It is known to affect males more frequently than females and is more common among whites. The major histological change involves the replacement of the normal stratified sqaumous epithelium by metaplastic columnar epithelium containing goblet cells. Prolonged exposure to acidic content from the stomach damages the stratified sqaumous epithelium and slowly changes the epithelium into that of a columnar layer with mucus-secreting goblet cells.
Figure 11: Endoscopic view of lower esophagus with Barrett's disease
Figure 12: LM image of Barrett's esophagus showing the region of dysplasia
The reason why Barrett’s esophagus is very dangerous is that it may develop into adenocarcinoma, Patients with Barrett’s esophagus are 30x-100x more likely to develop this cancer, initially located close to the gastroesophageal junction. Adenocarcinoma is characterized by large nodular masses that invade nearby gastric cardia. About 90% of patients diagnosed with adenocarcinoma die within five years.
Figure 13: LM image of adenocarcinoma
Currently, patients who have GERD are encouraged to change their lifestyle (more exercise, stop smoking, take antacids, avoid foods that aggravate heartburn) in order to prevent progression into Barrett’s esophagus or possible esophageal cancer. There are also medications that lessen acid production by stomach such as omeprazole (Prilosec®) that irreversibly block H+-K+ ATPase pump in the apical lining of stomach. Other treatment options just for Barrett's esophagus include photodynamic therapy, esophagectomy, thermal ablation, and endoscopic muscosal resection.
3. Our understanding of gastric ulcers has increased dramatically with the discovery of the causative organism Helicobacter pylori. Describe the normal appearance of the stomach mucosa (gastric glands, and the LM appearance of the cell types of those glands). Describe the mechanism by which ulcers develop due to infection with H. pylori; show the gross and histological appearance of typical ulcers. Describe the most commonly used treatment.
The stomach’s mucosa is lined with a columnar epithelium containing many openings called gastric pits. In the base of each of these pits are openings to several gastric glands located in the fundus, which contain cells specialized for the pepsinogen and HCl production. The stomach wall has rugae, which are longitudinal folds designed to allow the stomach to distend during a meal.
Figure 14: Stomach mucosa
Figure 15: Cells of the gastric glands
There are four cell types present in fundic glands. Surface mucous cells and mucous neck cells are present respectively on the surface and neck of the gastric glands. Parietal cells, which release HCl and intrinsic factor, are located in the neck and basal regions of the glands and look like “fried eggs.” Chief cells, which secrete pepsinogen and lipase, are located primarily at the base of the gastric glands. These cells can be identified by their zymogen granuoles. Stem cells are also present in gastric glands and are located in the middle third of the glands. In addition to the fundic gland cells, enteroendocrine cells are present at the base of the gastric glands.
Figure 16: Cells of the gastric glands
Figure 17: Surface mucous cells
Two other glands are present as well: cardiac glands, which produce alkaline mucus to protect the esophagus from stomach acid, and pyloric glands, which produce an alkaline mucus to protect the duodenum.
Figure 18: Enteroendocrine cells
Figure 19: Pyloric glands
is a bacteria which weakens the protective mucous coating of the stomach and duodenum allowing acid to come in contact with the sensitive lining beneath. The bacteria is present in 70 to 90% of people with gastric ulcers. The combination of the acid and the bacteria together irritate and inflame the lining leading to a sore, or ulcer (wrongdiagnosis.com).
has the ability to live in the acidic conditions of the stomach by secreting enzymes that neutralize the acid. This mechanism allows
to make its way to the protective mucous lining where is releases proteases and phospholipases which break down and weaken the first mucosal lining.
also enhances gastric acid secretion and blocks bicarbonate production in the duodenum. This decreases the pH within the stomach which contributes to the creation of the ulcer (Robbins).
Figure 20: Peptic ulcer. Notice the mucosa is gone and some of the submucosa is affected as well.
peptic ulcers are treated by administering drugs that kill the bacteria, reduce stomach acid, and protect the stomach lining. Antibiotics are used to kill the bacteria and there are two possible types of acid-suppressing drugs that might be used: H2 blockers and proton pump inhibitors. H2 blockers block histamine, which stimulates acid secretion. Proton pump inhibitors prevent low pH in the stomach by suppressing protons entering the lumen of the stomach. But these drugs do not remove the
and therefore do not cure
-related ulcers. Bismuth subsalicylate, which is found in Pepto-Bismol, is commonly used to protect the lining of the stomach from acid and, more importantly, it kills
needs to be killed in addition to decreasing the acidity of the stomach, treatment usually involves antibiotics, acid suppressors, and stomach protectors (wrongdiagnosis.com).
Presently, the most effective treatment is a 2-week treatment called "triple therapy." This method involves taking two antibiotics to kill the bacteria and either an acid suppressor or stomach-lining shield to prevent increased ulceration. Another option is using a 2-week dual therapy method where two drugs are used: an antibiotic and an acid suppressor. However, this treatment is not as effective as triple therapy (wrongdiagnosis.com).
Histology Digestive Lecture II
"Gastrointestinal Secretion" (Dr. Sackin)
Robbins Basic Pathology
. Boston: W.B. Saunders Company, 2002.
Kasper, Dennis L., Eugene Braunwald, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, and J. Larry Jameson.
Harrison's Manual of Medicine
. New York: McGraw-Hill Professional, 2005.
Figure 2: RFUMS Virtual Microscope Slide Even-012
Figure 3: RFUMS Virtual Microscope Slide Odd-013
Figure 4: RFUMS Histology Digestive Lecture II Figure 20
Figure 7: RFUMS Histology Digestive Lecture II Figure 6
Figure 8: RFUMS Virtual Microscope Slide Odd-012
Figure 10: RFUMS Virtual Microscope Slide Odd-012
Figure 12: RFUMS Virtual Microscope Pathology Slide HD085
Figure 14: RFUMS Histology Digestive Lecture II Figure 12
Figure 15: RFUMS Histology Digestive Lecture II Figure 14
Figure 16: RFUMS Histology Digestive Lecture II Figure 16
Figure 17: RFUMS Histology Digestive Lecture II Figure 19
Figure 18: RFUMS Histology Digestive Lecture II Figure 27
Figure 19: RFUMS Histology Digestive Lecture II Figure 30
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