PEPTIC ULCER DISEASE: A CURABLE INFECTION?
Edward L. Cattau, Jr. M.D.


INTRODUCTION


What is a peptic ulcer?
A peptic ulcer is like an open wound that occurs in the lining of the stomach or in the duodenum (the first part of the small intestine just below the stomach). Peptic ulcer disease is very common with one in every ten Americans developing an ulcer at some time during his or her life. For many years it was thought that the main risk factors for developing ulcers were stress and spicy foods. It is now clear that the two major risk factors are: 1) nonsteroidal anti-inflammatory (NSAID) medications such as aspirin, ibuprofen and other arthritis medications or 2) an infection with a bacteria Heliocobactor pylori (H. pylori). In fact, it is estimated that 80 to 90% of all ulcers that develop in patients who are not on NSAIDs are a direct consequence of H. pylori infection.

What is H. pylori?
H. pylori is a bacteria that has probably been in our environment for a very long time. However, it was not until the 1970s that it was suspected that bacteria in the stomach may be related to ulcer disease. In 1983 experiments were done that confirmed the cause and effect of this infection. At that time, Drs. Marshall and Warren in Australia were able to grow the bacteria in the laboratory and subsequently ingested cultures of this bacteria resulting in gastritis (inflammation of the stomach) similar to that seen in the patients with peptic ulcers. Since that time there has been a huge amount of research showing that eradication of H. pylori can dramatically decrease the risk of recurrent ulcer disease.

H. pylori is a very common infection in the United States. About 20% of people over the age of 40 and nearly half the people over the age of 60 are infected. However, most infected people do not develop ulcers. The exact reason H. pylori does not cause ulcers in every infected person is unknown. However, it appears that there are different strains of H. pylori, some of which produce substances that are toxic to the stomach and intestinal lining.

It is not certain how people become infected with H. pylori although there is growing evidence that it may be through contaminated food or water. Researchers have found H. pylori in some infected peoples saliva, so the bacteria may also be spread through mouth to mouth contact such as kissing. The infection rate is much higher in under developed countries and in some segments of the U.S. population where there are crowded living conditions.

How does H. pylori cause a peptic ulcer?
One of the purposes of the acid produced in the stomach is to kill any bacteria that are ingested before they can grow and cause further problems to the intestinal tract. H. pylori cannot only withstand the stomach acid but it is unique in its ability to grow in the stomach lining. It does this by producing a variety of different chemical protectants. The most well known of these is urease, which allows the bacteria to set up an environment around itself that is "safe" and acid-free. The presence of urease is also a foundation for one of the tests to detect H. pylori that will be discussed later. Once the bacteria has colonized the stomach, it produces a variety of toxins that damage the stomach and intestinal lining cells, resulting in an ulcer.

What are the symptoms of an ulcer?
Pain is the most common symptom. Although the pain can vary significantly from person to person, the most common description is of a dull, gnawing ache in the upper abdomen. It most commonly occurs two to three hours after a meal and in the middle of the night and is relieved by food. Other symptoms may include weight loss, poor appetite, bloating, burping, nausea or vomiting. Some people may experience very little symptoms or none at all.

There are additional symptoms that may suggest the possibility of a complication of ulcer disease. These complications include perforation (when an ulcer makes a hole all the way through the stomach or intestinal wall); bleeding (when the ulcer breaks through a blood vessel); or obstruction (when the ulcer blocks the passage of food trying to leave the stomach). Symptoms that suggest the possibility of one of these complications include sharp, sudden, persistent stomach pain; black or bloody stools; or bloody vomit or vomit that looks like coffee grounds.

HOW IS AN H. PYLORI RELATED ULCER DIAGNOSED?

Diagnosing An Ulcer
If you have symptoms suggesting an ulcer, your doctor may order an upper gastrointestinal series (UGI). This is an x-ray done by having the patient drink a chalky liquid called barium to take x-ray pictures of the upper intestine.

If you have atypical symptoms, symptoms suggesting a complication, or symptoms refractory to therapy, your doctor is more likely to order an endoscopy. This is an examination using a thin, lighted tube with a tiny camera at the end. The patient is lightly sedated and is then able to swallow this tube so that the doctor can get a direct look at the lining of the upper intestinal tract. The endoscopy is more accurate and more detailed than the UGI series. In addition, during this examination the physician can take biopsies (small pieces of tissue to examine under the microscope) or can treat bleeding ulcers. Since endoscopy is more involved and expensive, it is usually not the first test ordered except in those situations just mentioned.

Diagnosing H. Pylori
If an ulcer is found, your doctor should do a test to see if you have H. pylori. If the ulcer is found on UGI series, the most cost effective way to make the diagnosis is by a simple serology blood test. This serology which can often be performed in a doctor’s office detects the presence of antibodies against H. pylori.

If the ulcer is diagnosed by endoscopy, tissue tests are usually done using biopsies. There are three types of tissue tests:

Rapid urease test detects the enzyme urease, which is uniquely produced by H. pylori. This test takes less than 24 hours, is the least expensive and most commonly performed tissue test.

Histology allows the physician to look under the microscope to find the bacteria. This is more expensive but slightly more accurate than the rapid urease test.

A culture test involves growing H. pylori in culture media. This is the most expensive test and is used only in the evaluation of patients who have not responded to standard treatments.

Breath tests are relatively new and used mainly after treatment to see if the treatment has been effective. The test is called a urea breath test (UBT). While in the doctor’s office, the patient drinks a solution of urea that contains a special carbon atom. If H. pylori is present it breaks down the urea releasing this carbon, which is subsequently absorbed into the bloodstream and then carried to the lungs where it is exhaled. The test is 96 to 98% accurate. Since it is more expensive than the blood test, it is not routinely performed to make the initial diagnosis. But since the blood test remains positive even after successful treatment, the UBT test appears to be the best test to confirm eradication of the bacteria.

The newest test made available is a stool antigen test, which detects the presence of an H. pylori protein called an antigen. This test potentially could be used to make both the initial diagnosis as well as to document eradication of disease. Although it appears to have the same accuracy as the UBT and is somewhat less expensive, the cumbersome need to collect stool has prevented it from becoming commonly used.

How are H. pylori peptic ulcers treated?
Acid suppressing medications are the mainstay of therapy to heal ulcers. The two main classes of medications in this category are H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). Cimetidine (Tagamet) was the first H2RA, which became available in the late 1970s. Subsequently other H2RAs have become available and include ranitidine (Zantac), famotidine (Pepcid) and nizatidine (Axid). These medications are routinely used for six to eight weeks, depending on the ulcer location.

The PPIs are the newest class of acid suppressive medicines and they include, (in order that they became available) omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (AcipHex), and pantoprazole (Protonix). PPIs are much stronger medications and usually require only four to six weeks of therapy. Although they are more expensive, because they can be used for a shorter period of time, they are generally more cost effective. The exception to this would be the use of generic H2RAs, which are now available.

Although acid suppressive medications will heal H. pylori associated ulcers, the benefit of adding H. pylori eradicating medications include more rapid healing of the ulcer and a dramatic decrease in the risk of recurrent ulcer. Unless the H. pylori is eradicated, patients who have H. pylori associated ulcers have a 50 to 80% chance of having a recurrent ulcer within one year. With eradication, that risk of recurrent ulcer is usually less than 10%. The obvious explanation for this "cure" is elimination of the underlying risk factor.

Treatment regimens to eradicate H. pylori include acid suppressing medications, antibiotics, and a stomach lining protector (bismuth subsalicylate). There are a variety of combinations of these medications that have been tried with several being approved that have eradication rates of approximately 85 to 95%. Unfortunately, there is no combination that is 100% effective. The standard regimens include two weeks of therapy although one of the most commonly used regimens using a PPI and two antibiotics has been shown to be equally efficacious if given for only ten days. Unfortunately, all of these regimens using antibiotics have potential side effects including nausea, abdominal pain and diarrhea.

Patient Testing After Treatment
There is some controversy about which patients should be tested to document eradication of the infection. Some experts suggest that everybody who has been treated should be tested to document eradication. Others feel that testing should only be done in selected patient populations. The groups that they suggest should be tested include those with: 1) complicated ulcer disease such as perforation or bleeding; 2) recurrent ulcers 3) family or personal history of stomach cancer; 4) the need for treatment with NSAIDs. These later two groups we will discuss later.


H. Pylori Prevention
Although work is underway toward a vaccine, there is none currently available. Good personal hygiene including washing of hands before eating may be of benefit.

Other issues in H. pylori related disease include:

Gastric Cancer
Adenocarcinoma of the stomach is one of the most common malignancies in the world although it is relatively uncommon in the United States with approximately 24,000 new cases per year. There is evidence that H. pylori infection is associated with adenocarcinoma of the stomach. However, gastric cancer occurs in some individuals with no evidence of H. pylori and fewer than 1% of H. pylori – infected individuals will ever develop gastric cancer. But, because of this association and because of the increased risk of H. pylori among family members, it is recommended that all family members of patients with H. pylori positive gastric adenocarcinoma be tested for H. pylori. And, if H. pylori is found it should be treated and eradication documented.

There is a very rare type of cancer of the stomach called mucosa associated lymphoid tissue lymphoma (MALToma). There is some evidence that some patients with MALToma and H. pylori may have complete eradication of the lymphoma by eradication of H. pylori without the need for traditional chemotherapy.


Non-ulcerative Dyspepsia
There are a large number of patients who have ulcer type symptoms but who do not have ulcers. Their symptoms can be secondary to a host of abnormalities including inflammation of the stomach (gastritis) without ulceration; abnormal contraction patterns of the stomach including slow emptying (gastroparesis) and intestinal spasm. In the absence of a specific disorder, many patients are diagnosed as having a functional disorder, irritable bowel syndrome. In patients who have non ulcerative dyspepsia and in whom H. pylori are found, there is a great debate whether or not the H. pylori is a coincidental finding or actually the cause of the patients symptoms. Remember that many patients with H. pylori have no symptoms so merely finding the H. pylori does not prove a cause and effect relationship with non ulcerative dyspepsia. However, it appears that some patients with H. pylori will have H. pylori gastritis that has caused the patient’s symptoms. The optimal strategy for evaluating and treatment of patients in this group is not agreed upon. However, the majority of the current data would suggest that if patients have typical dyspeptic symptoms, and H. pylori serology is positive, treatment with an H. pylori eradicating regimen would be appropriate before considering any other tests including an upper GI or endoscopy. However, if patients do not respond to this therapy, further evaluation is clearly indicated. However, it is not appropriate to treat for H. pylori without getting a serology to initially confirm the diagnosis of infection.

NSAID Induced Ulcer
As previously mentioned, NSAIDs alone are a risk factor for the development of ulcers. However, if patients are H. pylori positive the risk of NSAID induced ulcers is even greater. For that reason, some experts recommend testing all patients who are going to be on NSAIDs for H. pylori and treating those who are positive. It has not been determined if this is cost effective in the management of patients who are going to taking NSAIDs for a short period of time. However, it would seem prudent to follow this recommendation for patients who will be on chronic therapy.


H. pylori and Gastroesophageal Reflux Disease (GERD)
Since chronic infection with H. pylori causes a gastritis resulting in decreased acid production by the stomach, patients who are H. pylori positive may actually be somewhat protected against GERD. There are studies that support the contention that the prevalence of symptomatic GERD increases after the eradication of H. pylori. While this may be true, because of the significance of H. pylori, no one recommends withholding treatment for H. pylori because of this phenomena. However, patients should be aware of the possibility that they will develop GERD symptoms after eradication of the bacteria.


Future Developments
There are currently tests available that identify strains of H. pylori that produce some of the chemicals that make certain strains virulent. In the near future this test will become clinically available so that only those patients who have "dangerous" H. pylori will need to be treated saving the expense of unnecessary treatment, avoiding side effects of medical treatment for H. pylori and preventing the risk of precipitating GERD by unnecessary treatment of "benign" H. pylori infection.

References

•  Anderson J, Gonzalez J. H. Pylori Infection - Review of the Guidelines for Diagnosis and Treatment. Geriatrics 2000;55:44-9.

•  Arakawa T, et al. Heliocobactor pylori: Criminal or Innocent Bystander? J. Gastroenterology 2000;35 (suppl 12):42-6.

•  Bateson MC. Heliocobactor Pylori: Post Grad Med J 2000; 76:141-4.

•  NIH Consensus Statement 1994; 12:(#1): 1-23.

•  Ofman JJ, et al. Management Strategies for Heliocobactor Pylori – Seropositive Patients with Dyspepsia: Clinical and Economic Consequences. Ann Intern Med 1997; 126: 280-91.

•  Soll A H. Medical Treatment of Peptic Ulcer Disease: Practice Guidelines. JAMA 1996; 275:622-8.

•  Proceedings of the American Digestive Health Foundation International Update Conference on H. pylori. Gastroenterology 1997;113:S1-S169.


Symptoms of Severe Peptic Ulcer Disease

•  Sharp, sudden persistent stomach pain.
•  Bloody or black stools.
•  Vomit that is bloody or like coffee grounds.


 Who Should Be Tested for H. Pylori

•  Active or previous peptic ulcers.
•  Personal or family history of gastric cancer.
•  Non-ulcer dyspepsia.
•  Long-term NSAID therapy.

Tests Used to Diagnosed H. Pylori

•  Non-Invasive
•  Serology – Simple blood test. First live test to make initial diagnosis.
•  Not useful in documenting eradication (90 – 98% accurate).
Urea Breath Test (UBT) – Simple office test that is first choice to
•  Document eradication (96 – 98% accurate).
•  Fecal Antigen Test – Stool test to document active disease. May be as reliable as UBT.
•  Tissue Testing
•  Rapid Urease Test (RUT) – Most cost-efficient tissue test (92 – 99% accurate).
•  Histology – More expensive than the RUT and more operator dependent (95 –99% accurate).
•  Culture – Slowest method, useful in patients who have refractory disease.

COMMON REGIMENS USED TO TREAT H.PYLORI


REGIMEN MEDICATION (5) FREQUENCY DURATIO

(1) PPI – PPI (4) + b.i.d.


•  Triple Therapy Clarithromycin (Biaxin) 500 mg + b.i.d
•  10-14 day Amoxicillin 500 mg or b.i.d.
•  Metronidazole (Flagyl) 500 mg b.i.d

(2) RBC/C RBC 400 mg + b.i.d. 28 days


•  Clarithromycin (Biaxin) 500 mg t.i.d. 14 days

(3) BMT Bismuth subsalicylate (Pepto-Bismol)


•  525 mg + q.i.d.
•  Metronidazole (Flagyl) 250 mg + q.i.d. 14 days
•  Tetracycline 500 mg + q.i.d.
•  H2 receptor antagonist q.d.

 

1. A prepackaged system with each day of medicine is available with lansoprazole (Prevpac).
2. RBC – Ranitadine – bismuth-citrate (Tritec)
3. A prepackaged system with each day of medicine (without H2RA) is available (Helidac).
4. Omeprazole 20 mg, Lansoprazole 30 mg, Rabeprazole 20 mg, or Pantoprazole 40 mg.
5. Frequency abbreviations: q.d.- once daily; b.i.d. – twice daily; t.i.d. – three times daily; q.i.d. – four times daily.

 

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