GASTRIC ULCER

What is a gastric ulcer? Gastric ulcer, also known as peptic ulcer, is a localized area of erosion in the stomach lining, resulting inabdominal pain, possible bleeding, and other gastrointestinal symptoms. The most common cause of gastric ulcer is a stomach infection associated with the Helicobacter pylori (H pylori) bacteria. The spread of H pylori among humans is not completely understood; it may spread through contaminated food and water. Many people become infected with H pylori at a young age, but symptoms most commonly occur in adulthood. In some people, the H pylori bacteria cause an infection in the lining of the stomach, which may lead to gastric ulcers. Damage to the stomach lining from stomach acid increases the likelihood that H pylori infection will result in a gastric ulcer. Other risk factors for gastric ulcer include alcohol use, tobacco use, and prolonged use of medications such nonsteroidal anti-inflammatory drugs (NSAIDs). Severe illness has also been associated with developing a gastric ulcer. The signs and symptoms of gastric ulcer can be constant or sporadic, and the disease course varies among individuals. If H pylori is the cause, the symptoms will remain as long as the infection is untreated. Some people with gastric ulcers have no symptoms at all, while others may have burning pain, severe nausea, and vomiting. In the case of H pylori-related gastric ulcers, the infection can be treated successfully with antibiotics. For gastric ulcer not related to H pylori, antacids or other medications are an effective treatment. You can reduce your risk of H pylori bacteria infection by following commonsense hygiene practices such as washing your hands with soap and water prior to preparing food and after handling dirty diapers or using the bathroom. Seek immediate medical care (call 911) for serious symptoms such as severe abdominal pain, bloody or black tarry stools, or bloody or black vomit. Seek prompt medical care if you are being treated for gastric ulcer but mild symptoms recur or are persistent. What are the symptoms of a gastric ulcer? Gastric ulcer causes inflammation and damage to the stomach lining that may result in a number of symptoms. The symptoms can vary in intensity among individuals. Common symptoms of a gastric ulcer You may experience gastric ulcer symptoms daily or just once in a while. At times any of these common symptoms can be severe: Abdominal bloating Abdominal burning Abdominal pain Belching Feeling of fullness Loss of appetite Nausea with or without vomiting Unexplained weight loss Serious symptoms that might indicate a life-threatening condition In some cases, gastric ulcer can be life threatening. Seek immediate medical care (call 911) if you, or someone you are with, have any of these life-threatening symptoms including: Bloody stool (blood may be red, black, or tarry in texture) Severe abdominal pain Vomiting blood or black material (resembling coffee grounds) What causes a gastric ulcer? Other causes of gastric ulcer include agents that can cause inflammation of the stomach lining, including alcohol, tobacco, and medications such as nonsteroidal anti-inflammatory drugs (NSAIDs). Severe illness and radiation therapy have also been associated with gastric ulcers.

What are the risk factors for a gastric ulcer? A number of factors increase the risk of developing a gastric ulcer. Not all people with risk factors will get gastric ulcer. Risk factors for gastric ulcers include: Alcohol abuse H pylori infection History of radiation therapy Regularly taking NSAIDs, such as ibuprofen (Advil, Motrin), naproxen (Aleve), or aspirin Stress or severe illness Tobacco use How is a gastric ulcer treated? Treatment for gastric ulcer begins with seeking medical care from your health care provider. To determine if you have a gastric ulcer, your health care provider may ask you to undergo diagnostic tests. Antibiotic treatments for a gastric ulcer If your gastric ulcer is caused by H pylori infection, antibiotic therapy is the mainstay of treatment. It is important to follow your antibiotic regimen precisely to avoid re-infection or recurrence. Most commonly, two antibiotics are given for 14 days. Examples of antibiotic treatments include: Amoxicillin Clarithromycin (Biaxin) Metronidazole (Flagyl) Tetracycline Other medications for treating a gastric ulcer Medications such as proton pump inhibitors and histamine H2-receptor antagonists, which decrease the amount of acid in the stomach, can also be effective treatments for gastric ulcers. Proton pump inhibitors that are effective in the treatment of gastric ulcer include: Esomeprazole (Nexium) Lansoprazole (Prevacid) Omeprazole (Prilosec) Pantoprazole (Protonix) Rabeprazole (Aciphex) Histamine H2-receptor antagonists that are effective in the treatment of gastric ulcers include: Cimetidine (Tagamet) Famotidine (Pepcid) Nizatidine (Axid) Ranitidine (Zantac) If you have diarrhea and vomiting, fluid and electrolyte replenishment is also a component of successful treatment. What are the potential complications of a gastric ulcer? You can help minimize your risk of serious complications by following the treatment plan you and your health care professional design specifically for you. Complications of gastric ulcer include: Internal hemorrhaging Perforated gastric ulcer, which can lead to bleeding Severe discomfort or pain Spread of infection References: Peptic ulcer. PubMed Health. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001255/. Accessed May 6, 2011. Helicobacter pylori and peptic ulcer disease. Centers for Disease Control and Prevention.http://www.cdc.gov/ulcer/. Accessed May 6, 2011. http://www.localhealth.com/article/gastric-ulcer/symptoms

Gastric Ulcer

Peptic ulcer disease, intestinal disease; also see duodenal ulcer

ulcer, just

ulcer

Normal

Abnormal

Peptic ulcers are areas of weakness or "depressions" that develop in the wall of the stomach or intestines, causing pain or discomfort. In a few cases they can bleed, tear open, or cause a blockage. Treatment is usually done with medicines, so surgery is very rarely needed. Peptic Ulcer Disease is a broad description of any process that causes an ulcer to form in the stomach or intestines. If the ulcer is in the stomach, it is known as a Gastric Ulcer. If it is in the first part of the intestines, then it is called a duodenal ulcer. There are over half a million new cases diagnosed each year and up to 4 million people have a flare up of the disease each year. About 1 out of every 10 people will at some time in life have an ulcer. Ulcers are found in the intestines 5 times as often as they are in the stomach. Ulcers occur more often in men, in smokers, and in those using medications that weaken the lining of the stomach and intestines. Duodenal ulcers usually occur in younger people, while Gastric Ulcers occur in older age groups. It is still not clear what, if any, role stress plays in the development of ulcers. Alcohol and diet are not felt to play a very important role in the formation of ulcers. Some ulcers are caused by an organism called Helicobacter pylori, some are due to medications, and a few are caused by stomach or intestinal cancer. Therefore, treatment and longterm outcome depends on the cause of the ulcer.

Almost all people will have pain in the upper, central part of the abdomen (just under the breastbone). The pain can be a dull ache, throbbing, sharp, burning, "gas-like," cramping, etc. However, the pain can occur in almost any part of the abdomen. Often the pain associated with Peptic Ulcer Disease comes and goes. Some people notice that the pain gets worse after eating spicy foods. Also, many will notice that over the counter antacids help relieve their symptoms. Some people will feel better after eating, while, in others, the pain may increase after meals. Many will complain of stomach pain that wakes them up in the middle of the night -- usually between 2 and 4 am. Nausea and vomiting Because of the stomach pain, some lose their appetite and lose weight. In a few cases where the ulcers are more severe, the pain may radiate or move to the back. Not all people with these symptoms have a true ulcer. In fact, of all the people who have upper abdominal pain, only a minority has real ulcers. Most have a condition known as Gastritis or dyspepsia. Some will have chest pain or back pain If the ulcer causes a lot of inflammation, a blockage may develop. Please see the "Complications" section below. A few will have intestinal or stomach bleeding as their first symptom. There can be vomiting of blood or coffee-grounds like material. Others may complain of passing stools that are either red or black. In people with ulcers due to NSAIDs, up to half may not have any symptoms at all.

There are many things that can cause Peptic Ulcer Disease. The major causes of Peptic Ulcer Disease are Helicobacter pylori, NSAIDs, acid hypersecretion, and cancer. Stress, diet, and alcohol are not felt to directly cause ulcers. Helicobacter pylori -- this is a bacteria that is felt to cause many ulcers. 1. H. pylori is a bacterium that lives in the stomach 2. H. pylori is involved in the development of

3.

4.

5.

6.

the majority of duodenal and Gastric Ulcers not caused by NSAIDs. Destroying this bacterium with antibiotics leads to a much higher success rate in the treatment of ulcers. People who are treated for this infection also have much lower rates of the ulcer's returning. When the organism is not destroyed, up to 80% of people will have a recurrence of their ulcer. When the organism is treated and destroyed, only about 10-20% of people will have a recurrence of the ulcer. However, only one out of every six people who have these bacteria in the stomach will ever develop an ulcer. for nonsteroidal anti-

leads to excess acid production. This can overwhelm the protective layer in the stomach and intestines and lead to ulcers. Please look up the section on Zollinger-Ellison Syndromefor more information. In a few cases, the ulcer is actually due to a cancer in the stomach or intestine.

NSAIDs-this stands inflammatory drugs.

1. This is a group of medicines that includes things such as ibuprofen, naproxen, indomethacin, etc. These drugs are most often used to treat arthritis, headaches, back pain, and other conditions that cause pain and inflammation. 2. It is felt that NSAIDs cause ulcers by decreasing the protective lining of the stomach and intestines. 3. NSAIDs dramatically increase the risk ofGastric Ulcers. 4. People who take NSAIDs for a prolonged period are 40 times more likely to developGastric Ulcers compared to those who do not take NSAIDS. 5. People who take NSAIDs have a higher chance of developing complications such a bleeding or perforation. 6. The risk of developing ulcers is higher in those over 70 years, those taking higher doses of NSAIDs, those with a previous history of ulcers, in those people who are on blood thinners or steroids, and in those with severe medical problems. 7. Aspirin is the worst of all of the NSAIDs with respect to causing ulcers. 8. There are newer NSAIDs that are being used, such as etodolac and celecoxib, that have a lower risk of developing ulcers. These medicines help reduce pain and inflammation, but do not weaken the stomach lining as much as other NSAIDs. Though they are safer, there is still a risk of developing ulcers.

The best way to diagnose ulcers is by an endoscopy. In this test, a camera is used to look into the stomach. The doctor can look at the lining of the stomach and intestines to see if an ulcer is present. The doctor can also do a biopsy if needed and, in some cases, stop any bleeding that may be present. All Gastric Ulcers must be biopsied. This is because there is a high risk of Gastric Ulcers' being caused by cancer. If there is any suspicion of cancer, then people with Gastric Ulcers need to have a repeat endoscopy within about 12 weeks after starting treatment to make sure that the ulcer has completely healed. Duodenal ulcers are almost never due to cancer. Therefore, they are usually not biopsied for cancer testing purposes. However, biopsies are often done on all ulcers in order to test for H. pylori. If H. pylori is present then treatment is different. Therefore, this is a very important diagnostic test. Another test that can be done to diagnose an ulcer is an upper GI series. In this test, the person is given barium and then X-Rays are taken to see if there is an ulcer. This test is not as accurate as an endoscopy, but it is less invasive. If a Gastric Ulcer is detected, the patient is treated, and after about 12 weeks to make sure that the ulcer has healed, an endoscopy done. All people with ulcers need to be tested for H. pylori. There are many ways to test for this infection. 1. If an endoscopy is performed, then a biopsy is done, and the sample is tested for the presence of H. pylori. 2. If the ulcer is detected by an upper GI, then a breath test can be done to see if the organism is present. 3. Blood tests are also available that detect the presence of antibodies to the bacteria. This is a very convenient test, but it is not the best option because it can be abnormal even if the organism is not causing an active infection. However, in some cases,

Zollinger-Ellison Syndrome is a condition that

antibody levels are followed over a long period of time to see if the infection has been fully treated.

Blood tests are usually normal in most cases of ulcer disease in which there is no complication. If there is a complication, then you may see abnormal blood tests. For example, if the person develops a bleeding ulcer, they may be anemic. If the ulcer tears a hole through the stomach, then the person will be very ill with a high white blood count. X-Rays may show air in the abdominal cavity. In cases where Zollinger-Ellison Syndromeis suspected, a Gastrin level can be measured. In people with this disease, the Gastrin level will be elevated. Physical examination may only reveal some tenderness of the upper part of the abdomen. Testing of the stool may show the presence of blood if the ulcer is bleeding.

used. Basically, they very effectively reduce acid production by the stomach. They are more potent than H2 receptor blockers but they are usually only used for short-term therapy. They can help cure up to 80-90% of ulcers. These medicines are usually taken 30 minutes before a meal. They help to relieve symptoms and allow healing to take place faster than H2 blockers, but the overall cure rate for ulcers is not much different between the two groups. 2. H2 receptor blockers -- Cimetidine, Ranitidine, Famotidine, and Nizatidine are the 4 most commonly used medicines in this category. These medicines also reduce acid production and they can be used for longer periods of time. They are not as potent as the proton pump inhibitors, but they can be just as effective at curing ulcers. They also can cure about 80-90% of ulcers. Ulcer symptoms usually get better within about 2 weeks, but treatment is usually continued for 6-8 weeks.

Use of NSAIDs. The higher the dose, the higher the risk of developing ulcers. Also, some NSAIDs have a lower risk of ulcer formation. Infection with H. pylori. Diseases such as Zollinger-Ellison Syndrome that lead to increased production of acid. Increased stress may be a risk factor. Smoking increases the risk of ulcers and slows ulcer healing. In countries other than the U.S., lower socioeconomic status is a risk factor because those people have a higher rate of infection with H. pylori.

Certain medicines are available that basically protect and preserve the lining of the stomach and duodenum. These include: 1. Sucralfate -- this is a medicine that basically coats ulcers and forms a protective layer. It is very good at treating duodenal ulcers. It is not as good for treatment of Gastric Ulcers. 2. Bismuth -- this is a medicine that causes increased production of the substances that normally protect the stomach and intestines. It also helps destroy H. pylori. 3. Misoprostol -- this is a medicine that increases the production of the substances that normally protect the stomach and intestines. It is not as effective as the other medicines in treating an active ulcer. It is used mainly to help prevent the formation of ulcers in people who are on long-term treatment with NSAIDs. 4. Antacids -- these are available over-thecounter. These medicines help protect the wall of the stomach and intestines. They do not reduce the formation of acid. They are no longer used as initial treatment for ulcers because more effective medicines are available. However, they do work very quickly and can be use to rapidly control symptoms.

There are several different medicines available to treat ulcers. The type of treatment and the medicines used depend on the cause of the ulcer. There are three main types of medicines that can be used: 1) medicines that reduce the amount of acid produced, 2) medicines that protect the lining of the stomach and intestines, and 3) medicines that destroy the bacterium, H. pylori. Medicines that reduce acid production are broken down into two categories. Generally, with these medicines, duodenal ulcers heal within 4-6 weeks and gastric ulcers heal within 6-8 weeks. 1. Proton pump inhibitors -- Omeprazole and Lansoprazole are the most commonly

Treatment depends on the cause of the ulcer. For ulcers caused by H. pylori, there are several treatment options. 1. Metronidazole (500 mg twice a day) and clarithromycin (500 mg twice a day) and a proton pump inhibitor (such as omeprazole 20 mg twice a day) for 14 days. 2. Amoxicillin (1 gram twice a day) and clarithromycin (500 mg twice a day) and a proton pump inhibitor (such as omeprazole 20 mg twice a day) for 14 days. 3. Amoxicillin (1 gram twice a day) and metronidazole (500 mg twice a day) and a proton pump inhibitor (such as omeprazole 20 mg twice a day) for 14 days. 4. Bismuth subsalicylate (2 tablets 4 times a day) and tetracycline (500 mg 4 times a day) and either metronidazole (250 mg 4 times a day) or clarithromycin (500 mg 3 times a day) for 14 days. Some are now recommending using ranitidine along with this regimen. 5. After the person has completed one of the above regimens, they need to be continued on a proton pump inhibitor, an H2 antagonist, or sucralfate for an additional 46 weeks. This will help allow the ulcer to heal completely. 6. This course of therapy should destroy the bacterium in more than 85% of people. 7. Newer combinations are constantly being tested. Therefore, it is best to discuss treatment options with your doctor. 8. There are increasing reports of H. pylori being resistant to metronidazole. Therefore, in areas where there is a lot of resistance to this antibiotic, the other treatment options are being used first. 9. In the past, most people with ulcers used to be continued on some sort of ulcer treatment for very long periods of time. However, now that we have found out that many of these ulcers are due to an infection, most people no longer need prolonged anti-ulcer treatment if their infection is cured. Therefore, only those who have recurrent ulcers, those in whom the infection could not be cured, and people with H. pylori infections who keep getting ulcers even though the infection was treated will need to be on long-term anti-ulcer treatment. 10. If the person is treated for H. pylori and the ulcer does not come back, no further evaluation or treatment is needed. If the

ulcer does come back, then they need testing to see if the H. pylori has truly been destroyed. For ulcers caused by NSAIDs, treatment is a little different. 1. The first step is to stop using the NSAIDs. 2. Proton pump inhibitors (such as omeprazole, lansoprazole) should be started as soon as possible. These are the most effective medicines. 3. You can also use H2 receptor antagonists or sucralfate, but these are not as effective. 4. If the person is on NSAIDs but tests also show the presence of H. pylori, then the best option is to stop the NSAIDs but also to go ahead and treat the H. pylori infection. 5. In people with ulcers, NSAIDs can be continued along with one of the above medicines if there is absolutely no other alternative. However, healing of the ulcer will be delayed.

Recurrent ulcers or ulcers that do not heal with normal treatments are fairly rare these days. If this is truly the case, then other diagnoses must be considered. The most common cause of ulcers not healing is because people do not take all the medicines as prescribed by the doctor or they resume use of NSAIDs. Another common cause is H. pylori infections that are not adequately treated. Another cause is a missed cancer, especially with stomach ulcers that do not heal despite adequate therapy. Therefore, all Gastric Ulcers need to be followed by repeat endoscopy to confirm that they have healed. If they have not, then repeat biopsies should be done after 2-3 months of treatment. Repeat endoscopies should be done periodically until the ulcer has completely healed. A much rarer cause of non-healing or recurrent ulcers is Zollinger-Ellison Syndrome. Therefore, all people with continued ulcers should be checked for this condition. If all else fails and the person continues to have recurrent ulcers, then he or she may need surgery. This is the last treatment option that should only be considered after all other options are exhausted.

Stomach or intestinal bleeding Stomach or intestinal rupture Bowel obstruction or blockage

Cancer Anemia Inflammation of the Pancreas, liver, or bile ducts

http://ecureme.com/emyhealth/data/Gastric_Ulcer.a sp

Seek medical attention. Some people will first try over-the-counter medications as listed above. However, if this does not help or if the symptoms persist, then you must seek medical attention. Also, if you have severe abdominal pain, if you vomit up blood or coffee-grounds looking material, have fever or chills, or if you have red or black stools, this is a medical emergency and you must go to the hospital immediately.

Avoid prolonged NSAID use if possible. There are newer drugs such as celecoxib, salsalate, and nabumetone that are associated with fewer ulcers. If possible, one of these medications can be used. Using misoprostol (200 micrograms 3-4 times a day) in people on chronic NSAID treatment may help reduce the formation of ulcers. Proton pump inhibitors may also be effective in preventing ulcers caused by NSAIDs. At the present time, it is not felt that using H2 blockers help much. Those individuals who are at increased risk of developing NSAID associated ulcers should be given either misoprostol or a proton pump inhibitor while taking NSAIDs. There are now combination drugs available that combine the NSAID with misoprostol. Smokers should stop smoking.

Dyspepsia Gastroesophageal Reflux Disease Pancreatitis Cholelithiasis Cholecystitis Choledocholithiasis Esophageal rupture Constipation Gastric or intestinal volvulus Abdominal aortic aneurysm Esophagitis Myocardial Infarction Gastric or intestinal perforation Gastritis Dyspepsia

Gastric Ulcer A gastric ulcer is a break in the normal tissue that lines the stomach. REFERENCE FROM A.D.A.M. Alternative Names Ulcer - stomach; Peptic disease; Stomach ulcer Causes Non-cancerous (benign) gastric ulcers are caused by an imbalance between stomach acid, an enzyme called pepsin, and the natural defenses of the stomach''s lining. This imbalance leads to inflammation, which can be made worse by aspirin and nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen. Risk factors for benign gastric ulcers include:

Use of aspirin and NSAIDs Helicobacter pylori (H. pylori) infection Chronic gastritis Smoking Increasing age Mechanical ventilation (being put on a breathing machine) Certain blood clotting problems Stress does not cause or worsen gastric ulcers. Symptoms

Abdominal pain o May wake you at night o May be relieved by antacids or milk o May occur 2 to 3 hours after a meal o May be worse if you don''t eat Nausea Abdominal indigestion Vomiting, especially vomiting blood Blood in stools or black, tarry stools Unintentional weight loss Fatigue Note: There may be no symptoms. Signs and Tests

EGD (esophagogastroduodenoscopy) and biopsy showing a benign gastric ulcer Upper GI series showing a gastric ulcer

Treatment For people with Helicobacter pylori infection, the main goal is to get rid of the bacteria that causes the infection. Many different medicines work. They usually include either an H2 receptor antagonist such as famotidine (Pepcid) or nizatidine (Axid) or a proton pump inhibitor such as omeprazole (Prilosec) or esomeprazole (Nexium) to suppress acid, combined with two antibiotics. After you finish your medicines, your doctor will likely order a test to make sure that the H. pylori infection is gone. Those who do not have an H. pylori infection may be prescribed ulcer-healing medications such as antacids, H2 receptor antagonists, or proton pump inhibitors. Long-term treatment may be needed. If the ulcer bleeds, endoscopy can control bleeding in most cases. Surgery may be recommended for persons who do not respond to medicines or endoscopy. Surgical procedures for gastric ulcers include:

Vagotomy -- cuts the vagus nerve, which controls the stomach''s production of gastric acid Partial gastrectomy -- removes part of the stomach Self-help measures include eating several small meals a day at regular time periods and avoiding the following:

Smoking Tea, coffee, and soft drinks containing caffeine Alcohol Aspirin and NSAIDs Expectations (prognosis) Most ulcers heal with medication in 6 to 8 weeks. Recurrence is common, but is less likely if H. pylori infection is treated and acid-blocking medications are continued. Complications

Bleeding from the ulcer Perforation (hole) in the stomach Blockage in the stomach that prevents movement of stomach contents Complications can often be corrected by medication, endoscopy, or (in rare cases) with surgery. Calling Your Health Care Provider Call your health care provider if symptoms of gastric ulcer develop. Prevention If you are at risk for ulcers, use caution when taking aspirin and NSAIDs.

http://health.nytimes.com/health/guides/disease/gastric-ulcer/overview.html

PATHOPHYSIOLOGY Gastric and duodenal ulcers are lumped together under the general heading of peptic ulcer disease. Basically an ulcer forms when the capacity of the gastric mucosa to protect itself is overwhelmed by the existing level of gastric juice production. Gastric ulcers (see GASTRIC ULCER ) are frequently due to reduced defensive capacity, whereas, duodenal ulcers are frequently the result of increased exposure of the duodenal mucosa to gastric juice. Normal subjects secrete about 25 mEq H+/hr in response to a maximal dose of histamine. The highest rates of gastric acid secretion are seen in cases of gastrinoma (Zollinger-Ellison syndrome), and can be as high as 80 mEq H+/hr. Factors that may play a role in maintaining mucosal resistance are blood flow, mucus production, cellular renewal, chemical factors (i.e. gastrin, prostaglandins, EGF). Prostaglandins have been shown to dramatically increase the resistance of cells to toxic conditions. NSAID work by inhibiting prostaglandin synthesis. Chronic use of NSAID is a common cause of gastric ulceration. Recent studies have shown that the major acquired factor responsible for both gastric and duodenal ulcers is the bacterium Helicobacter Pylori. H. pylori infections are present in 95% of patients with duodenal ulcers and 100% of patients with gastric ulcers. However, 50% of patients with H. pylori infections do not have peptic ulcer disease, suggesting that this is one of multiple contributing factors. H. pylori have high urease activity and metabolize urea into NH4+ that is secreted to neutralize gastric acid. This may be the major cause of H. pylori cytotoxicity because NH4+ directly damages epithelial cells and weakens the mucosal barrier. H. pylori may also increase gastric acid production by unknown mechanism. Treatment of ulcers with H2-receptor blockers or omeprazole is very effective and have essentially replaced surgical and other forms of treatment. However, the ulcer frequently returns when treatment is discontinued unless the patient is also treated with oral antibiotics.

GASTRIC ULCER

http://physioweb.uvm.edu/gi_physiology/stomach/pathophysiology.htm

BMJ. 2001 October 27; 323(7319): 980982. Copyright 2001, BMJ ABC of the upper gastrointestinal tract Pathophysiology of duodenal and gastric ulcer and gastric cancer John Calam and J H Baron This article has been cited by other articles in PMC.

PMCID: PMC1121510

Duodenal and gastric ulcers and gastric cancer are common and serious diseases but occur in only a minority of people infected with Helicobacter pylori. Mass eradication of H pylori is impractical because of the cost and the danger of generating antibiotic resistance, so we need to know how to target prophylaxis. Knowledge of the mechanisms that lead to ulcer formation or to gastric cancer in the presence of H pylori infection is therefore valuable. Various factors affect the outcome of H pylori infection, including the host response and particularly the extent and severity of gastric inflammation and thus the amount of acid secreted by parietal cells. H pylori can elevate acid secretion in people who develop duodenal ulcers, decrease acid through gastric atrophy in those who develop gastric ulcers or cancer, and leave acid secretion largely unchanged in those who do not develop these diseases. Regulation of gastric acid secretion Several specialised cells in the gastric mucosa contribute to the control of acid secretion. G cells in the gastric antrum release the hormone gastrin. Gastrin acts on the enterochromaffin-like cells in the gastric corpus to release histamine, which stimulates parietal cells to secrete acid. Gastrin also stimulates parietal cells directly and promotes growth of enterochromaffin-like and parietal cells. Histamine H2 receptor antagonists act by blocking the effect of histamine on parietal cells. Proton pump inhibitors act by inhibiting the enzyme in parietal cells that catalyses acid production for release into the gastric lumen. G cells, enterochromaffin-like cells, and parietal cells are all regulated by release of the inhibitory peptide somatostatin from somatostatin cells, which are distributed throughout the stomach. The effect of H pylori infection on acid secretion depends on which part of the stomach is most inflamed because this determines which of these cells are affected most. H pylori related acid secretion Hypersecretion in duodenal ulcer disease Before the discovery of H pylori it was known that patients with duodenal ulcers secrete about twice as much acid as controls because they have twice as many parietal cells. Patients with gastric ulcer and those with functional dyspepsia have normal acid output and parietal cell count. Thus there was good evidence that acid played a major role in ulcer formation. Duodenal ulcers did not occur in achlorhydric people or in those secreting <15 mmol/h of acid. Duodenal ulcers can be healed, but not cured, by pharmacological suppression of acid secretion below this threshold. Causes of duodenal ulcer

Helicobacter pylori antral gastritis Non-steroidal anti-inflammatory drugs

Rare causes Crohn's disease HypergastrinaemiaIdiopathicGastrinoma Hyperparathyroidism

Areas of gastric metaplasia in the duodenum can be colonised by H pylori, causing inflammation (duodenitis) and leading to further damage of the mucosa. The extent of gastric metaplasia is related to the amount of acid entering the duodenumlowest in patients with pernicious anaemia who secrete no acid and highest in patients with acid hypersecretion due to gastrin-secreting tumours (Zollinger-Ellison syndrome). Acid hypersecretion in duodenal ulcer disease is virtually always due to H pyloriinfection because secretion returns to normal after the infection is eradicated. The predominantly antral gastritis in duodenal ulcer disease leads to acid hypersecretion by suppressing somatostatin cells and increasing gastrin release from the G cells in the gastric antrum. Hyposecretion in patients at risk of gastric cancer H pylori infection predisposes to distal gastric cancer, but patients who develop this complication have diminished acid secretion. Low acid secretion in gastric cancer was, until recently, thought to be predominantly due to gastric corpus gastritis, the associated gastric atrophy leading to loss of parietal cells. However, H pyloriassociated acid hyposecretion can in part be reversed by eradicating H pylori, suggesting that hyposecretion is due to inflammation rather than to permanent loss of cells. H pylori associated acid hyposecretion may also be due to incomplete recovery from the loss of acid secretion that occurs with acute infection or may be in part genetically determined because it is more common in the first degree relatives of patients with gastric cancer. Low acid secretion predisposes to gastric cancer by several mechanisms, including impaired absorption of vitamin C and overgrowth of salivary and intestinal bacteria within the stomach. By contrast, proximal gastric cancer (at the gastro-oesophageal junction) is associated with normal acid output. The rising incidence of this type of gastric cancer may reflect the decreasing prevalence of H pylori infection in Western societies. Relation between distribution of gastritis and acid secretion Thus distribution of H pylori gastritis determines acid secretion and the clinical outcome of H pylori infection, be that duodenal ulcer, gastric ulcer, gastric cancer, or asymptomatic infection. Positive feedback may perpetuate the different patterns of gastritis; for example, suppression of acid with a proton pump inhibitor diminishes antral gastritis but allows H pylori to colonise the corpus, which then becomes inflamed. This shows that acid secretion normally protects the corpus from H pyloriinfection. This effect has several important consequences:

High acid secretion in people with duodenal ulcers may be self perpetuating because it restricts gastritis to the antrum, leaving a healthy corpus to continue secreting acid Low acid secretion may be self perpetuating because it increases corpus gastritis, which further depresses acid secretion Proton pump inhibitors may be more effective in patients with H pylori infection than in those without because they promote corpus gastritis, which further inhibits acid secretion. Aspects of the environment, bacterium, or host that affect acid output or the severity of corpus gastritis might steer a person infected with H pylori to a state of high acid secretion (predominantly antral gastritis) or to low acid secretion (predominantly corpus gastritis). This model is attractive because it allows studies of gastric physiology to be integrated with other equally important determinants of disease outcome. Other factors that might affect gastric physiology and disease outcome

The pathogenic importance of H pylori depends on the interaction between bacterial virulence, the host, and the environment. Host Studies of identical and non-identical twins have shown that host factors are important in determining the outcome of infection. Duodenal ulcer is twice as common in those who are blood group O nonsecretors. Studies in the mouse model of Helicobacter infection have shown that different strains of mice developed either severe gastritis or hardly any gastritis when infected with the same strain ofHelicobacter. The genes responsible for the different outcomes are not known, but preliminary evidence suggests that a variety of genes involved in the inflammatory response affect the likelihood of H pylori infection progressing to duodenal ulcer disease. Bacterium In contrast, some investigators believe that H pylori is mainly responsible for disease because gastric mucosal inflammation is always present and fully resolves only when infection is successfully treated. Most strains of H pylori can be divided into two distinct phenotypes based on the presence or absence of a vacuolating toxin (Vac A toxin) and the products of the cag pathogenicity island (cagPI), a large chromosomal region that encodes virulence genes and is similar to that found in other enteric pathogens such as Escherichia coli and Salmonella typhi. People infected with strains of H pylori with the cagPI have more severe mucosal damage and are more likely to have duodenal ulcers or gastric cancer. However, research has not so far identified H pylori genes that predispose to either duodenal ulcer or gastric cancer. Furthermore, in developing countries, where H pylori infects most of the population, cagPI strains of H pylori are present in almost all infected people but only a few develop clinical disease. Summary points

Both duodenal ulcer and gastric ulcer are essentially gastric ulcers They occur in gastric mucosa in the stomach or in gastric metaplasia mucosa in the duodenum The mucosa may be attacked bySecretagogues (excess gastrin, histamine, or calcium producing excess of acid)Bacteria (H pylori)Drugs (non-steroidal anti-inflammatory drugs)

Identifying these and other bacterial virulence factors associated with more severe disease may allow screening tests to be developed. These may then permit identification of patients infected with bad bacteria so that eradication treatment can be targeted to them. Environment Gastric cancer is epidemiologically linked with diets high in salt and low in fresh fruit. Salt may change acid secretion because it suppresses parietal cells, and salty diets cause gastric atrophy. Conversely, the antioxidant vitamins in fresh fruit might protect specialised gastric cells from the reactive oxygen species released by inflammatory cells. A diet high in salt and lacking antioxidant vitamins might thus promote low acid secretion with corpus gastritis. Cigarette smoking strongly predisposes to both duodenal ulcer and gastric cancer. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121510/