The most common cause of gastric and duodenal ulcers is a spiral-shaped, gram-negative bacterium – genus: Helicobacter, species: pylori – that lives on the gastric mucosa under the mucous layer. This organism was first observed in stomach biopsy specimens by Australian pathologist J. Robin Warren in 1979; it was first cultured by Warren and his colleague Barry Marshall in the early 1980s; it was first described in the medical literature by Warren and Marshall in 1983; and it was first covered in the Medical Sciences Bulletin in 1985. Yet today, 17 years after Warren’s landmark observation, the majority of Americans have never even heard of H pylori. A recent study found that even people who have ulcers themselves are ignorant of the cause; 90% said that stress causes ulcers, 60% blamed dietary indiscretion, and a whopping 90% had never heard of Helicobacter pylori.
Helicobacter pylori is probably the most common infectious disease in the world. In developing nations, 60-70% of children are infected by age 10, probably because of over-crowding and poor sanitation. In some countries, almost the entire population is infected. In the US, more than half of 60-year olds are infected, but younger Americans have an infection rate of only about 20% (with the exception of African- Americans, whose infection rates are 40-50%, and immigrants; infection rates in Hispanics are more than 60%, and Eastern Europeans more than 50%). The incidence of H pylori infection in developed nations is likely to increase – not just in older persons, but in all age groups – as immigration increases and population density rises. Even dogs, cats and other animals have their own Helicobacter species.
In their early studies, Warren and Marshall found H pylori in 65% of patients with gastritis, 85% of gastric ulcer patients, and all of duodenal ulcer patients. The only ulcers they found that were not associated with H pylori were in patients taking nonsteroidal antiinflammatory drugs (NSAIDs). After Warren and Marshall published their results, investigators all over the world confirmed their findings. H pylori was found in association with gastritis and gastric ulcers (more than 80% of gastric ulcer patients were infected, excluding those with gastrinoma or taking NSAIDs), and duodenal ulcers (more than 95% of duodenal ulcer patients were infected). Subsequently, Marshall found that while histamine-2 (H2) blockers help ulcer symptoms, patients relapse as soon as therapy is discontinued; relapse does not occur when Helicobacter pylori is eradicated; and bismuth salts easily kills H pylori, but the infection recurs unless metronidazole is added. Marshall, who still investigates H pylori, is now at the University of Virginia Health Sciences Center.
The primary disease caused by H pylori is gastritis. Not all infected persons have symptoms, but all show changes in the gastric mucosa (“chronic superficial gastritis”). Helicobacter pylori are well adapted to survive in the hostile environment of the stomach. Their spiral shape allows them to corkscrew down through the mucous layer to the gastric mucosa; they attach to mucous-secreting cells that line the stomach; they break down urea to produce ammonia that helps neutralize gastric acid in their immediate vicinity; and they produce various proteins that damage mucosal cells, attracting lymphocytes (which may be their primary source of nutrients) and causing persistent inflammation. After years or even decades of chronic superficial gastritis, carriers develop lesions (“atrophic gastritis”) and eventually the stomach tissue can become abnormal and precancerous.
Peptic ulcer only develops in 1% of infected adults per year, depending on the bacteria (some strains produce toxins that attract certain lymphocytes) and the host (old age or poor health reduce resistance, and smoking or NSAID therapy impair mucosal defense). Helicobacter pylori infection appears to cause the acid hypersecretion seen in duodenal ulcer disease. It also causes intestinal metaplasia (replacement of gastric cells with intestine-type cells) that is associated with gastric cancer, and can cause the growth of lymph tissue that can lead to a type of lymphoma.
The determination that ulcers are an infectious disease that can be treated with antibiotics is a major medical breakthrough. Ulcers are painful at best, and life threatening in the worst case (a bleeding ulcer can result in a fatal hemorrhage, and a perforated ulcer can result in fatal shock when stomach or intestinal contents spill into the abdominal cavity). For more information, write: Helicobacter Foundation. 1500 Avon St. Ext., Charlottesville, VA 22902. Or, American Digestive Health Foundation, 1201 Connecticut Ave., NW, Suite 300, Washington DC. 20036.
Diagnosing Helicobacter pylori Infection
Each year, millions of patients visit their physicians complaining of digestive symptoms, most commonly functional dyspepsia (“indigestion”) or gastroesophageal reflux (“heartburn”). However, many patients with abdominal discomfort are suffering from gastric or duodenal ulcers, which are commonly caused by H pylori and thus are curable. Clearing the infection usually heals the ulcer and prevents relapse, so an accurate diagnosis is important. There are several options for diagnosing Helicobacter pylori infection: serology to detect antibodies against the bacterium; endoscopic biopsy for urease testing ( H pylori produce a urease that breaks down urea to ammonia and carbon dioxide); histology with special stains; or culture. Unfortunately, these procedures are invasive, expensive, or not always accurate. Serological tests require a blood sample and tell only that a patient has been exposed to H pylori at some time in the past, but not whether the patient is currently infected. Endoscopy and biopsy can detect current infection – the CLOtest urease test allows rapid detection of H pylori in gastric biopsy specimens – but endoscopy and biopsy are unpleasant medical procedures and require laboratory work. False negatives with these procedures range from 5 to 15%, so further testing may be required to rule out infection.
One test that is widely available outside the US and under FDA evaluation in this country is the urea breath test, a sensitive, specific, and noninvasive test for Helicobacter pylori. When an infected person swallows a dose of urea labeled with an isotope of carbon – carbon-13 (13C) or carbon-14 (14C) – H pylori in the gastric mucosa break down the labeled urea to form ammonia and labeled carbon dioxide. The carbon dioxide is absorbed into the bloodstream and excreted via the lungs. The patient then exhales into a device that measures the level of carbon dioxide. Of the two isotopes, 13C is safer because it is not radioactive, but it requires expensive instruments to detect it (a new generation of laser detectors may bring down costs). The 14C isotope uses a less expensive detector, but it emits beta radiation (although the amount emitted is a tiny fraction of the beta radiation that the average person is exposed to each year from natural sources). The urea breath test is specific for H pylori (it detects only urease-producing bacteria), it is sensitive (the labeled urea reaches a large area of the stomach and thus reflects total gastric urease activity), and the results can be reproduced.
Ultimately, the urea breath test should be approved and should be available for use in the doctor’s office to provide a rapid diagnosis. In the mean time, doctors must rely on patient history, physical examination, lab tests, and radiography or endoscopy. Duodenal ulcers are usually benign, but gastric ulcers may be caused by a malignancy so endoscopic evaluation and biopsy of gastric ulcers are recommended, with repeat endoscopy to confirm healing.
Helicobacter and Heart Burn
What about diagnosing the patient with benign functional dyspepsia? In the past, lab tests and/or endoscopy were used to rule out ulcers, but dyspepsia is so common and diagnostic costs are so prohibitive that many physicians are managing patients with empirical therapy. And many patients are managing themselves with a trip to the drug store. One concern is that the availability of so many over-the-counter acid suppressants – famotidine (Pepcid AC), cimetidine (Tagamet HB), and ranitidine (Zantac 75), as well as Pepto-Bismol and a large selection of antacids – will allow patients to treat their own indigestion, which could be caused by Helicobacter pylori infection and thus should be treated with antibiotics. When the urea breath test is available and diagnosing H pylori becomes a more routine part of medical care, self-diagnosis and self-treatment will be much less of a problem.
Practice Guidelines: Treating Helicobacter pylori Infection
Medical experts now know that spicy foods and stress do not cause ulcers and that antacids and acid-suppressing drugs alone do not cure ulcers. What cures ulcers and prevents relapse is antibiotic therapy, preferably given in conjunction with an acid-suppressing drug to aid healing. H pylori is difficult to eradicate, so it usually takes two or more antibiotics to do the job. Studies have shown that dual or triple antibiotic therapy plus a histamine-2 (H2) receptor blocker or a proton-pump inhibitor (PPI) cures 85-90% of ulcer patients (H2 blockers inhibit the action of histamine, which normally stimulates acid production, and PPIs block the final step in acid production). Relapse is rare (less than 4% in studies in Europe, Australia, and the US).
Helicobacter pylori is very sensitive to tetracycline and amoxicillin; it is resistant to vancomycin, nalidixic acid, trimethoprim, and sulfonamides; and it readily becomes resistant to metronidazole, and to a lesser extent to clarithromycin, if either drug is used alone. Bismuth salts have topical activity against H pylori; colloidal bismuth blocks bacterial enzymes, disrupts cell walls, prevents the organism from sticking to stomach tissue, and persists in the mucous in antimicrobial concentrations for about two hours following dosing. Bismuth subsalicylate (Pepto-Bismol) is the product available in the US; bismuth citrate is available abroad and under FDA evaluation here.
Recently the American College of Gastroenterology (ACG) published practice guidelines for the management of peptic ulcer disease. These guidelines were formulated by Andrew Soll, MD, reviewed and revised by the ACG, and approved by the American Gastroenterological Association and the American Society for Gastroenterological Endoscopy. According to the ACG guidelines, all H pylori-infected ulcer patients should be treated with antibiotics to clear the infection. Duodenal ulcer patients should also receive conventional antiulcer therapy to relieve symptoms and promote healing. Gastric ulcer patients should undergo endoscopic evaluation to rule out cancer. Endoscopy is also important for patients with anemia, GI bleeding, anorexia, early satiety, weight loss, or age older than 50.
To clear infection, patients should be treated with two antibiotics plus colloidal bismuth (Pepto-Bismol) and/or an antisecretory agent, usually the PPI omeprazole (Prilosec / Astra Merck). The ACG guidelines cautiously endorse three regimens: bismuth-metronidazole-tetracycline plus PPI, clarithromycin-metronidazole-PPI, or clarithromycin- amoxicillin-PPI. Other acid suppressants (H2 blockers, sulcralfate) and even antacids have been shown to heal duodenal ulcers, and PPIs, H2 blockers and sucralfate heal gastric ulcers as well, but not all regimens have been approved by the FDA. Recently the FDA approved the combination of clarithromycin (Biaxin / Abbott) and omeprazole for the treatment of H pylori ulcer disease, and an FDA advisory committee has recommended the approval of clarithromycin in combination with ranitidine bismuth citrate (Tritec / Glaxo).
In patients with refractory ulcers, there are probably other complicating factors involved, such as poor compliance with therapy, poor health, advanced age, smoking, hypersecretory conditions, or use of NSAIDs. For refractory ulcers, physicians are advised to maximize acid inhibition (omeprazole 40 mg/day), extend the duration of therapy, reduce or eliminate NSAID therapy where appropriate, and eradicate H pylori (present in 50% of patients with NSAID- induced ulcers). Omeprazole is probably the drug of choice if NSAIDs must be continued; it may even prevent NSAID-induced ulcers, although only misoprostil is approved for this indication. Sulcralfate, antacids, or bismuth have not proved to be effective for preventing or treating NSAID-induced ulcers, and healing is generally delayed with H2 blockers.
Patients with nonulcer dyspepsia don’t require treatment, although dyspepsia is common and the symptoms can’t be distinguished from ulcers. According to Marshall, a case can be made for treating all patients with dyspepsia (and evidence of Helicobacter pylori) as if they have an ulcer. Treatment is simple, and antibiotics are preferable to endoscopy.
Follow-up: How to Confirm Cure?
Confirming Helicobacter pylori eradication is difficult. Most tests require endoscopy, which is invasive, uncomfortable, time- consuming, and expensive. Urea breath tests are noninvasive and easy to perform, but the 13C test is expensive and the 14C test requires radioisotope handling, and neither are available yet in the US. Given the choices, most patients decline follow-up (unless there is a complication such as bleeding). Recently, Phull et al reported that there may be an easy way to confirm cure: ask the patient.
Phull et al studied 112 duodenal ulcer patients before and after treatment with antibiotics plus omeprazole or lansoprazole and/or colloidal bismuth subcitrate. At one and six months after completion of treatment, urea breath tests were administered and data collected on dyspeptic symptoms (epigastric discomfort, heartburn, nausea, vomiting, and gas). Absence of symptoms was considered indicative of successful eradication. At 6 months, there was a high correlation between dyspeptic symptoms and breath test results. Absence of symptoms was an excellent indicator of successful H pylori eradication; sensitivity was 97.5% and specificity 90.6%.
The Best Time to Take Bismuth
When is the best time to take bismuth? Traditionally, patients have been advised to take colloidal bismuth (PeptoBismol) on an empty stomach to allow the compound to coat the stomach. However, a double-blind study by Webb et al suggests that bismuth compounds may be more effective when taken on a full stomach. The investigators studied the antimicrobial efficacy of ranitidine bismuth citrate in 40 patients with H pylori infection. Ranitidine bismuth citrate (Tritec/Glaxo) is a combination of ranitidine and bismuth citrate (bismuth 32% w/w). The combination has a dual mechanism of action; the bismuth component protects ulcer craters and is toxic to H pylori, while the ranitidine blocks H2 receptors on the acid-secreting parietal cell.
Patients with Helicobacter pylori infection – as indicated by a positive serum test 21 days prior to dosing and a positive urea breath test 60 minutes and 30 minutes prior to dosing – were randomly assigned to ranitidine bismuth citrate (400 mg twice daily for 7 days). Half the patients took the drug combination 30 minutes prior to morning and evening meals (with a matching placebo taken 30 minutes after these meals), and half the patients took the combination 30 minutes after meals (with a matching placebo taken 30 minutes before meals). Food enhanced drug activity: 90% of patients who took the combination on a full stomach tested negative for H pylori on two consecutive 13C-urea breath tests, compared with only 55% of those who took it on an empty stomach. At follow-up in 3- 10 months, 14% of patients who took the combination on a full stomach were clear of H pylori compared with none of those who took the combination without food.The investigators suggest that food delays gastric emptying, prolonging the time that the bismuth component is in contact with the mucosa. Also, digestion mixes stomach contents, enhancing drug dispersal. The results of this study suggest that bismuth-containing preparations may be more effective when administered with food.