1. What is a peptic ulcer?
A peptic ulcer is a wound in the stomach lining, or duodenum, which is the beginning of the small intestine. Peptic ulcers are common: one in every 10 Americans develops an ulcer at some point in their life.
Most gastric ulcers and duodenal ulcers (peptic ulcers) are caused by a bacteria, Helicobacter Pylori, but some ulcers are caused by prolonged use of a nonsteroidal anti-inflammatory drug (NSAID), such as aspirin (acetylsalicylic acid) and ibuprofen.
2. What causes these ulcers?
Until the ’80s of the 20th century, peptic ulcers were considered to be the result of acid hypersecretion produced by a disorder in the specialized gastric cells. However, in 1983, scientists identified a bacteria, Helicobacter pylori (H. pylori), that colonizes the gastric mucosa and has since been associated with gastroduodenal pathology (gastritis, peptic ulcer, especially duodenal ulcers, and gastric carcinoma).
Although we believed that spiced food, spices, acid, and stress were the main causes of ulcers, we now know that nine out of ten ulcers are caused by H. pylori. Medications that reduce stomach acid can make you feel better by relieving the symptoms, but they will not cure the ulcer.
The good news is: since most ulcers are caused by this bacterial infection, they may then be cured with the right antibiotics.
3. What are the symptoms of an ulcer?
The most common symptom is pain with a burning sensation or burning in the abdomen between the sternum and the navel.
The pain often occurs when the stomach is empty, between meals and in the early hours of the day, but can occur at any other time. It may last from a few minutes to several hours and maybe relieved by eating or by taking antacids.
Less common symptoms may include:
- Loss of appetite.
Sometimes ulcers bleed. If the bleeding goes on for an extended period, it can lead to anemia, weakness and fatigue. If the bleeding is heavy, blood can be found in vomit or evacuation of bloody or black stools.
4. What is Helicobacter pylori?
Helicobacter pylori is a Gram-negative bacterium, approximately 2.5mm in length and 4 to 6 unipolar flagella which allow the microorganism to move in a helical corkscrew-like movement.
The very name Helicobacter pylori reflects its helical or spiralled (S-shaped) morphology and the most common site for its isolation, the stomach pylorus. Identified in 1983, H. pylori colonizes the gastric mucosa and has been associated with gastroduodenal pathology, namely chronic gastritis, peptic ulcer disease (especially duodenal ulcers) and also gastric adenocarcinoma and primary gastric lymphoma (MALT).
Recently, there have been investigations regarding its association with some extra-gastrointestinal diseases, such as iron deficiency anemia, stunting, or chronic urticaria.
5. How is H. pylori transmitted?
H. pylori infection typically begins in childhood, as an inflammatory process of the stomach. The acquisition of the bacteria follows a 10% rate in children between two and eight years old, so most teenagers are infected. Although the transmission of the microorganism appears to happen from one person to another, the mode of transmission is not fully known.
It is believed that H. pylori is transmitted by the oral-oral or fecal-oral route. Many researchers think that it is transmitted by contaminated food or water. In addition, it is possible that aerophagia and gastroesophageal reflux, highly common in gastritis, enable its fixation in the mouth, making oral contact a means of transmission of infection. The organism has been cultivated in both vomiting and diarrheal stools.
6. What enables the adaptation of H. pylori to the gastric environment?
Most microorganisms are inactivated by the acid gastric environment. However, H. pylori is well adapted to the acidic environment of the human stomach. A number of special features ensure successful colonization. These include the microorganism’s ability to adhere to the gastric wall, the production of urease, and the presence of flagella that confer mobility.
H. pylori typically gathers around the tight intercellular junctions of epithelial cells, below the mucous layer, although 1/5 of the microorganisms are found adhering to the mucosal surface. The dhesion is specific for gastric mucin-producing cells. The motility is an important feature that allows microorganisms to penetrate the viscous mucus layer of the stomach and colonize the gastric mucosa.
H. pylori is the most potent urease producer of all known microbes. The active urease is present in the cytoplasm as well as on the surface and in the extracellular space of the bacteria. This enzyme hydrolyzes the urea to CO2 and ammonia. The microorganism envelops itself in a cloud of ammonia, which has a significant role in the colonization and adaptation by buffering the gastric acid of the multi-bacterial microenvironment. The elevation of the resulting pH creates a favourable microenvironment for the bacteria.
Another adaptive mechanism which enables the bacteria to colonize the human gastric tract is the outer membrane, or lipopolysaccharide envelope (LPS). This LPS envelope does not trigger from the host the same vigorous immune response as with other Gram-negative microorganisms. This diminished reactivity may be due to the high concentration of Lewis blood group antigens in LPS, enabling H. pylori to mimic glycoproteins or glycolipids on the surface of the human cells.
This molecular mimicry can explain how this microorganism can evade the host’s defence mechanisms and induce the formation of autoantibodies with cross-reactivity, found in some patients. This permanent state of chronic inflammation maintained at a low level, with the concomitant increase of mutations and deregulated apoptosis may also partially lead to most gastric cancers associated with H. pylori.
7. Incidence and implications of H. pylori infection.
H. pylori infection is very common. It has been postulated that H. pylori infection is the most common chronic infection worldwide. It is estimated that over 50% of the world’s population is infected with this stomach bacteria. In developed countries (USA) approximately 20% of people under 40 and 50% of people over 60 are infected. In developing countries the majority of adults (2/3) is infected.
The prevalence of the infection increases with age, most likely reflecting the so-called cohort effect, in which the variation in the age at which H. pylori is acquired will influence the risk of peptic ulcer disease. Specifically, the infections acquired early in life increase the risk of distal gastric cancer and gastric ulcer, but decrease the risk of duodenal ulcer.
On the contrary, the late acquisition of H. pylori increases the risk of duodenal ulcer but reduces the risk of gastric ulcers and stomach cancer. The socio-economic status varies inversely with the prevalence of infection, with individuals of lower socioeconomic strata showing the highest rates of infection.
H. pylori can exist for decades in the gastric mucosa without any apparent symptoms or diseases. However, histopathology speaking, all individuals infected with H. pylori exhibit evidence of active chronic gastritis. The gastritis is generally more obvious in the antrum, but can extend to the rest of the body and cardia.
8. What are the consequences of H. pylori infection?
H. pylori colonization may lead to chronic active gastritis (chronic inflammation of the stomach mucosa), the first stage of development of an ulcer. The transition into ulcer can be facilitated by unhealthy activities and habits like smoking, drinking alcohol and being subjected to stress. H. pylori infection is also associated with 3 to 12 times increased risk of gastric cancer.
9. Do all patients infected with H. pylori develop the disease associated with this bacteria?
No. Most people infected do not contract an ulcer. Epidemiological data show that the incidence of diseases associated with H. pylori in infected individuals varies between 1 and 10%
The most likely justifications for the selective development of gastritis or peptic ulcer disease in people infected with H. pylori include differences in the virulence of H. pylori strains, genetic differences in human susceptibility and environmental and behavioural factors.
Most gastric adenocarcinomas occurring in the gastric body and antrum are due to H. pylori infection, however, less than 1% of those infected will develop adenocarcinoma.
The diet has also been studied as an environmental co-factor that plays an important role in carcinogenesis related to H. pylori. Salting, smoking and other types of meat preparations are associated with an increased risk of gastric cancer, while fresh fruit and vegetables are protective.
10. Is it important to perform tests to detect H. pylori infection?
Yes, for several reasons. The diagnosis of H. pylori infection is impossible based exclusively on clinical assessment, as there are no characteristic clinical symptoms associated with this condition. Once detected, H. pylori infection can be effectively treated with antibiotics in double, triple and even quadruple regimens, which pair the use of antibiotics and antisecretory drugs.
As suggested in the Maastricht 2-2000 Consensus Report, the first line of therapy should be a triple therapy using a proton-pump inhibitor such as Omeprazole (or ranitidine bismuth citrate) combined with Clarithromycin and Amoxicillin or, alternatively, Clarithromycin and Metronidazole, for at least 7 days.
The importance of detecting and eradicating H. pylori infection is reflected not only in the patient’s healing but also in the probability of subsequent relapses. It has been shown that H. pylori eradication reduces the relapse rate to only 3%, while the conventional treatment without antibiotics is accompanied by relapse rates of up to 67%.
11. Which tests are available to detect H. pylori infection?
Helicobacter pylori infection can be detected by invasive and non-invasive methods.
11.1. Invasive Methods
Based on gastric biopsy during an endoscopic examination. The presence of H. pylori in a biopsy fragment is further confirmed either by direct microscopic examination, by a rapid urease test or by the bacteriological culture of the microorganism from the biopsy material.
The culture is relatively insensitive for the diagnosis of H. pylori, but may be required to determine antimicrobial sensitivity in patients who do not respond to antibiotic therapy.
The invasive tests are not without difficulties, as they can be painful, with some risk and discomfort to the patient. They are time-consuming and not always sensitive, due to the tendency that H. pylori has to distribute itself in islands or colonies in the gastric mucosa, in its un-colonized areas.
11.2. Non-invasive Methods
These include the urea breath test and stool antigen test, which can detect the presence of an active infection and are called active testing; and the serological tests, which detect antibodies specific to H. pylori, which are markers of exposure to H. pylori but do not indicate whether there is an active infection and are called passive tests.
Serology (anti-H. Pylori antibodies)
Serological tests are the main non-invasive tests used in Portugal and are far less accurate than the urea breath test. They rely on the detection of anti-H. pylori IgG antibodies in serum or plasma. Serology enables the quantitative determination of antibodies. The level of antibodies is expressed in arbitrary units, which differ from one mark to another.
The immunoenzymatic analysis (ELISA) is the favoured test, as it is sensitive and user-friendly. While these tests are relatively inexpensive, they are unable to distinguish active infections from prior exposure to H. pylori.
A positive result in serology can mean one of three things: the patient is infected at the time of testing; the patient was once infected, but, at the time of testing, the infection was resolved by either specific therapy or natural course; or the test has detected non-specific crossed antibodies.
Antibody levels may persist for a long time in the patient’s blood after the eradication of the H. pylori infection, decreasing very slowly over time. Therefore, for the follow-up treatment, serological tests are less useful since it is necessary to compare the titers of antibodies pre and post-treatment, separated by a long period of time.
Nevertheless, several studies in the literature suggest that a decrease in the IgG antibody level over 25% six months after therapy predicts with relative accuracy the successful cure of H. pylori infection.
Urea Breath Test
Helicobacter pylori produces urease an enzyme which hydrolyzes urea into ammonia and carbon dioxide. The microorganism can use the urease activity to regulate the pH in its microenvironment. The urea breath test is based on the principle that there is urease activity in the stomach of patients infected with H. pylori.
After ingesting a urea solution labelled with 13C, this is then hydrolyzed by the urease produced by the bacteria in the gastric mucosa, releasing ammonia and labelled CO2. The CO2 is then diffused through the gastric mucosa to the epithelial blood vessels and into the general circulation and within a few minutes is eliminated by the exhaled air.
The labelled urea is usually given to the patient with a drink, to delay gastric emptying and increase the contact time with the mucosa. 20 minutes after ingesting the urea, exhaled air samples are collected in a tube containing an agent which retains CO2 (hyamine).
Detection of 13C (which is a non-radioactive isotope from 12C) is performed using costly equipment, such as mass spectrometry.
Fecal Antigen Test
This is an enzyme immunoassay test capable of detecting the presence of H. pylori antigens in stool samples. The first available tests used polyclonal antibodies, and have been used in thousands of patients across Europe; it almost as specific (91.2%) and sensitive (92.4%) as the urea breath test. However, some centres have reported a significant variability between different batches.
Recently, an ELISA test of monoclonal antibodies has shown excellent results and avoids this variability. The monoclonal test currently available has shown to be as accurate as the urea breath test (97.5% sensitivity, 94.7% specificity). While equivalent to the urea breath test in performance, the fecal antigen test is considerably less expensive and less time-consuming.
In contrast to serology, the fecal antigen test is useful for confirming the eradication of the infection 4 weeks after the end of therapy. When compared with the urea breath test, the fecal antigen test is more convenient, particularly in paediatrics, since stool samples can be obtained from children without their active collaboration.
Stool samples can be stored up to 5 days at room temperature or at -20 °C which
12. When do antibodies against H. pylori appear during the infection? Is it important to quantify the antibodies’ levels?
Generally, antibodies against H. pylori can be detected within 10 to 20 days after the infection has set in and persist all throughout. These antibodies do not provide protection against H. pylori nor do they help eliminate it. Quantification of antibody titers is an important tool because:
- The level of antibody titers adequately reflects the severity of H. pylori gastric colonization.
- The successful eradication of H. pylori with antibiotic treatment leads to a significant decrease in antibody levels within the following 6 months.
- The recurring rise in antibody titers can be a warning sign to consider the possibility of relapse.
13. Testing and treating dyspepsia – which test to choose?
The recent European guidelines recommend the use of non-invasive tests for the detection of Helicobacter pylori infection in the context of primary health care, in patients with persistent or recurrent, uncomplicated recurrent dyspepsia, and if the test result is positive, administer triple therapy.
With a policy requiring non-invasive testing and treatment, we need to use a highly accurate test, so that patients receive the correct treatment.
The Urea Breath Test and Serology were the first non-invasive tests available; the urea breath test is the most accurate, but it has not been widely used in a primary care setting in Portugal, most likely because it is expensive and time-consuming as it requires two breath samples, taken 20 minutes apart.
Serological tests have been the main non-invasive tests performed in Portugal and are less accurate than the urea breath test, although they have the advantage of being significantly cheaper.
Another non-invasive test currently available and accurate is the fecal antigen test, which detects the presence of H. pylori antigens in stool samples. This test has been widely appraised and it has shown to be as accurate as the urea breath test. It uses similar laboratory methods to serological tests and can be introduced easily into the laboratory’s practice routine.
Although equal to the breath test in performance, the fecal antigen test is considerably less expensive and less time-consuming.
For the follow-up treatment, serological tests are less useful since it is necessary to compare the titers of antibodies pre and post-treatment, and their levels decrease very slowly, making it necessary to wait 6 months to confirm healing.
Testing for healing with the breath test or the fecal antigen test should be done 1 month, and preferably 3 months, after completion of treatment. (earlier tests may not be sufficiently accurate, either because any remaining microorganisms have not reached the sufficient development to be detected, or because the dead or dying microorganisms affect the accuracy of the tests).
Serology leads to at least four times more false-positive results than the urea breath test or the fecal antigen test, with an unnecessary associated treatment and increased risk of antibiotic resistance in other bacterial flora. If the “test and treat” guidelines for dyspepsia are widely implemented in Europe, the number of patients receiving treatment to eradicate H. pylori can easily double.
The European Group of Helicobacter pylori study and the European guidelines advise using the urea breath test or the fecal antigen test as opposed to serology. Any additional cost to these tests will be largely offset by improved diagnostic accuracy and reduced use of antibiotics. Moreover, as these tests replace serology, it is likely that their prices will fall.
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