Peptic Ulcer Disease in the ’90s: Treatment of Helicobacter pylori
Peptic Ulcer Disease in the ’90s: Treatment of Helicobacter pylori
Author: Russell Yang, MD, PhD, Assistant Professor of Medicine, Division of Gastroenterology and Liver Diseases, University of Southern California School of Medicine; Chief, Gastroenterology and Endoscopy, Los Angeles Veterans Administration Outpatient Clinic.
Peer Reviewers: Mark E. Classen, MD, PhD, Associate Professor, Department of Family Medicine, Wright State University School of Medicine, Dayton, OH; Rajeev Mehta, MD, Assistant Clinical Professor, Wright State University School of Medicine, Dayton, OH.
Editor’s NoteIt seems today that more and more in medicine can be explained by the germ theory. Add to that list peptic ulcer disease. Physicians had become rather dogmati c in assigning the cause of ulcer disease as having "too much acid." Due to very original and exciting research first starting in Australia, we have now established the bacterial etiology of peptic ulcer disease. With this new knowledge comes more precise therapy. Those of us who are seasoned veterans have witnessed the remarkable advances in medicine over the past several decades in regard to ulcer disease. Some remember the bland diet regimens, antiacids, and the development of H2 blockers, sucralfate, and proton-pump inhibitorsall of which have made ulcer surgery almost an anachronism. It is indeed somewhat curious and ironic that we now return to the relatively simple modality of antibiotics.
This issue highlights the appropriate diagnosis and management of patients suffering the ravages of Helicobacter pylori infection and highlights the new FDA guidelines. Perhaps we were right after all in the "old days" when we told patients they had gastritis. The "itis" is more true now than ever.
Helicobacter pylori (H. pylori) is a gram-negative organism named for its spiral shape and predilection for gastric tissue.1 H. pylori infects more than 90% of duodenal ulcer patients and 70% of patients with gastric ulcers.38 As such, eradication of H. pylori represents a major advancement in the treatment of peptic ulcer disease. The exact mechanism by which H. pylori causes ulcers is not known, but its eradication reduces the risk of ulcer recurrence from 60-90% to less than 10%.38 Thus, careful selection of individuals for eradication is cost-effective and can improve the quality of life for those individuals.
With the widespread penetration of managed care, primary care physicians will be increasing their roles in the treatment and management of peptic ulcer disease. Understanding the risk factors and epidemiology as well as the diagnostic methods available for H. pylori is important. Furthermore, knowledge of the current treatment regimens is crucial to render effective eradication of H. pylori.
The epidemiology of H. pylori is well-established.1 (See Table 1.) Individuals from crowded urban living conditions and poor socioeconomic status have a high prevalence of H. pylori infection. Indeed, the H. pylori prevalence is twice as high in persons whose incomes are less than $5000 per year as compared to those who earn more than $25,000 per year.2
H. pylori is an acquired infection, and the mode of transmission is not clear. In developing countries, infection occurs early so that most individuals are infected in their childhood (approaching 80%).39 In developed countries, the infection occurs later, with approximately 50% of individuals becoming infected by the time they reach 60 years of age.3 In the United States, minority populations (black and Hispanic) have an increased rate of H. pylori as compared to whites.4 Furthermore, an individual who has parents or siblings infected with H. pylori is much more likely to harbor H. pylori.5 Although the mode of transmission in these studies has not been established, fecal-oral or person-to-person transmission is suspected.6
The precise mechanisms by which H. pylori causes peptic ulcer disease is not known.7 (See Table 2.) Ammonia production by the bacterial urease may cause injury to gastric tissue. H. pylori also produces a vacuolating cytotoxin which disrupts gastric epithelial cells. In addition, the protective gastric mucous layer may also be destroyed by proteases and lipases elaborated by H. pylori. Stimulation of a mucosal immune response may also cause damage. Furthermore, H. pylori does increase gastrin levels, resulting in enhanced acid production, which eventually leads to ulcer formation.8 Indeed, elevated gastrin levels return to normal following eradication of H. pylori in duodenal ulcer patients.9
Infection with H. pylori is associated with antral gastritis. As noted earlier, a high proportion of duodenal and gastric ulcers in patients not taking nonsteroidal anti-inflammatory drugs (NSAIDs) have H. pylori infection. Conversely, only 15-20% of H. pylori-infected people develop ulcer disease.10 Thus, it is probably a culmination of factors, such as age of acquisition, host’s health status, and the virulence of the H. pylori strain, that leads to ulcer disease.
How Do You Test for H. pylori Infection?
Both invasive and non-invasive methods for confirming the presence of H. pylori are available.11-13 (See Table 3.) Overall, false-negative results occur in about 5-15% of cases using any of these methods.
In patients for whom esophagogastroduodenoscopy (EGD) is indicated, gastric mucosal biopsy specimens can be easily obtained. The specimen can then be tested for the presence of bacterial urease by histological examination or culture. Histologic examination is considered to be the gold standard for the diagnosis of H. pylori.14 Generally, sampling more than one area of the stomach can increase the yield of detection.11,40 Rapid urease testing is quick and inexpensive when compared to histology, and false-positive results are uncommon (90% sensitivity and nearly 100% specificity). Results are usually available within five hours and yield a sensitivity of 85-90% and a specificity of 95-100%.13 Urease testing is performed by placing a gastric biopsy specimen in a well with urea and a pH indicator, which signals the change in pH. Thus, if the biopsy specimen contains H. pylori, then the enzyme urease degrades the urea to ammonia resulting in a color change. Therefore, given the inexpensive cost of rapid urease testing, histologic examination should be performed when H. pylori infection is suspected and the urease test is negative (i.e., when a false-negative rapid urease test is suspected or when histology may yield additional information (e.g., malignancy).11 Cultures for H. pylori are the least sensitive of the invasive testing methods and are primarily a research tool to test for antimicrobial sensitivity.13
The nonendoscopic methods for determining the presence of H. pylori include serologic/whole blood testing and the recently FDA-approved urea breath test. Qualitative serologic/whole blood testing for antibodies (IgG) to H. pylori is inexpensive and about as sensitive (90%) as invasive methods.37 In a comparison of four commercially available serology tests, the sensitivity ranges from 84% to 97%.37 Serologic/whole blood testing is used most commonly since it is simple and can be easily performed. However, this methodology is not reliable in confirming H. pylori status after eradication since antibody levels fall slowly (over months). In addition, serologic tests do not distinguish which patients with dyspepsia actually have ulcer disease.
Urea breath tests offering a 95% sensitivity and specificity are now available and take advantage of urease production by H. pylori. Patients drink a liquid containing a non-radioactive (13C) or radioactive (14C) labelled urea. In the presence of H. pylori, the bacterial urease hydrolyzes the urea, releasing labelled CO2, which is absorbed into the blood and then released though expired air.15 A sample of expired air is sent to the laboratory for examination. The urea breath test is useful to document eradication of H. pylori after antibiotic therapy. Recent treatment with bismuth compounds, antibiotics, or proton pump inhibitors (omeprazole or lanzoprazole) can lead to false negative results. Therefore, it is generally recommended that the urea breath test be performed at least four weeks after therapy has been discontinued.15
In summary, it not always necessary to perform endoscopy to diagnose H. pylori. For the initial diagnosis without endoscopy, serologic testing is the test of choice. When performing endoscopy, the rapid urease assay is less expensive, although histologic examination remains the gold standard. For evaluation after eradication therapy, the urea breath test is preferred. (See Table 4.)
Who Should be Tested for H. pylori?
Primary care physicians should test for H. pylori in all patients with known ulcer disease including current disease, prior history, or those on maintenance therapy. Furthermore, patients with a history of complicated ulcer diseases (bleeding, penetration, etc.) should also be tested.38
H. pylori is associated with gastric adenocarcinoma, and individuals infected with H. pylori do have an increased chance of developing cancer (3-6 fold).16 Furthermore, some gastric non-Hodgkin lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas are also linked to H. pylori infection. In fact, cure of some MALT lymphomas has been reported simply by bacterial eradication.17 Thus, these individuals should be tested for the presence of H. pylori.
It is not known at present if prophylactic eradication of H. pylori will prevent the development of gastric cancer in high-risk individuals (i.e., first-degree relatives).
Dyspepsia without demonstrable ulcer disease is very common and is probably secondary to several etiologies. The role of H. pylori in these patients has not been established; therefore, routine testing of these individuals is not warranted.18
Following the above guidelines, the primary care physician should only treat those individuals who test positive for H. pylori. NSAID-related ulcers should be treated with antibiotics only if H. pylori is present; approximately 50% of patients with NSAID-related ulcers are infected with H. pylori.35
Conventional anti-ulcer therapy is important for symptomatic relief and to enhance ulcer healing. Most studies have examined the role of H2 receptor antagonists and proton pump inhibitors in the treatment of H. pylori. The four H2 blockers (ranitidine, cimetidine, nizatidine, famotidine) are equally effective and are generally well-tolerated.19 Cimetidine has more drug-drug interactions (particularly with warfarin, phenytoin, and theophylline) because of its inhibition of cytochrome p450. The H2 blockers have no intrinsic anti-Helicobacter activity.
The proton pump inhibitors (omeprazole and lanzoprazole) relieve pain and heal ulcers more rapidly than the H2 receptor antagonists.20 These agents are well tolerated and may have some intrinsic anti-microbial activity against H. pylori, but they are more expensive than the other available agents. The role of other anti-ulcer agents such as antacids and sucralfate is not clear.21 Misoprostol, a prostaglandin analogue, is indicated only for ulcer prevention in patients on chronic NSAID therapy.22
At present, no single antibiotic can reliably eradicate H. pylori infection.23 Because H. pylori is a non-invasive organism residing in the mucous layer overlying gastric mucosa, many antibiotics cannot achieve high enough levels of penetration to be effective. Thus, single agent therapy should not be used and can lead to bacterial resistance.
Multiple drug regimens have been studied, and several regimens have received FDA approval. (See Table 5.) Successful eradication of H. pylori is influenced by local resistance patterns and compliance with awkward regimens. In general, high eradication rates are achieved when at least two antimicrobials are combined with either a bismuth compound (e.g., Pepto Bismol), which has topical antimicrobial activity, or an antisecretory agent, such as a proton pump inhibitor or an H2-receptor antagonist (> 80%).25 Regimens containing only one antimicrobial agent are not recommended because of cure rates of less than 70%.23,24
Two dual drug regimens to eradicate H. pylori have been approved by the FDA.24 Initially, omeprazole plus amoxicillin was shown to be effective against H. pylori, but subsequent studies did not confirm its efficacy. More recently, omeprazole plus clarithromycin has resulted in eradication rates of approximately 80%, and this regimen appears to be well-tolerated.25 Combination therapy with ranitidine bismuth subcitrate and clarithromycin may give slightly higher rates of eradication, but this therapy has been less well studied.26 At present, it is recommended to add another antibiotic (e.g., tetracycline or amoxicillin) to achieve acceptable eradication rates.18,24
Standard triple therapy (bismuth, metronidazole, and tetracycline) for 14 days is the original regimen first reported to successfully eradicate H. pylori.27 This regimen is usually given with an H2 receptor antagonist or a proton pump inhibitor and results in greater than 90% eradication rates in compliant patients (i.e., adherence to at least 60% of the treatment regimen).28 Clarithromycin (500 mg bid) can be substituted for metronidazole if nitroimidazole resistance is problematic. Substitution of amoxicillin (500 mg qid) for tetracycline reduces eradication rates to 80%.23 Similarly, doxycycline could not be substituted for tetracycline.23 Thus, standard triple therapy is relatively inexpensive, but taking 15-17 pills per day and a relatively high rate of side effects (> 30%) limit its effectiveness.28 Usually, an H2 receptor antagonist or proton pump inhibitor is added to the treatment regimen to reduce ulcer pain and to ensure ulcer healing.18
Newer triple therapies comprised of a proton pump inhibitor (omeprazole or lanzoprazole) and two antimicrobial agents also provide excellent eradication rates of H. pylori (> 90%). These therapies are better tolerated, leading to greater compliance. (See Table 5.) These regimens are better accepted because they can be given for only one week, do not contain bismuth, and can be administered twice a day. Usually, one of the antibiotics is clarithromycin since it is able to eradicate H. pylori in up to 40% of cases as a monotherapy and because its levels are enhanced in the mucous layer when given with a proton pump inhibitor (omeprazole).29,30
The duration of therapy of these regimens can be varied. Per protocol eradication rates for treatment lengths of seven, 10, and 14 days range from 86%, 91%, and 95%, respectively.31 Thus, patients should be encouraged to adhere to treatment regimens for as long as prescribed, since decreased compliance can render an otherwise acceptable regimen ineffective. The mnemonic "3-2-1" for three drugs given twice a day for one week may be useful in remembering the various drug regimens.
Resistance may occur to metronidazole and to clarithromycin, particularly if either agent is given alone.25 Bacterial resistance occurs rarely to tetracycline and and amoxicillin but not at all to bismuth.32,41 Prior antibiotic exposure predicts individual and regional variation and should be considered in selecting an appropriate regimen.
Non-compliance is a problem due to the side effects and complexity of the available regimens. To minimize compliance problems, shorter courses of therapy are desired (e.g., 1 week). Additionally, two products are available to help patients adhere to their complex regimens. Helidac therapy is supplied as 14 blister cards, each containing eight bismuth salicylate tablets, four metronidazole tablets (250 mg each), and four tetracycline tablets (500 mg each). Tritec is a combination product of ranitidine and bismuth subcitrate. Although convenient, this combination is more expensive than if each agent were purchased separately.
Thus, selection of the appropriate eradication regimen should be done on an individual basis. Penetration of managed care into the practice of medicine has made decision-making more complicated due to restricted formularies. However, if a regimen is not well-tolerated, even if it is less expensive, it may end up costing more because of more returned office visits, further testing (including repeated endoscopy), or additional eradication regimens and decreased customer satisfaction.
Follow-up After H. pylori Eradication
Confirming eradication of H. pylori after completing treatment is not routinely required in uncomplicated and symptom-free patients.33 Confirmation is recommend in patients with a history of refractory or complicated ulcers. Serologic testing is not recommend since slowly declining antibody titers may result in false-positive results. The urea breath test is the test of choice because it is reliable, non-invasive, and should only be performed more than four weeks after the last dose of antibiotics to prevent false-negative results. Endoscopy with biopsy is the most expensive method to confirm eradication.
Management of patients once H. pylori has been eradicated is controversial and should be determined on a case-by-case basis. In general, once the antibiotic regimen has been administered, anti-secretory treatment with an H2 blocker or proton pump inhibitor can be given for a patient with complicated ulcer disease. In these patients, confirmation of H. pylori eradication is useful. Reinfection rates with H. pylori are considered to be low34 and depend upon the prevalence of H. pylori infection, socioeconomic status, age, geographical location, developing vs. developed countries, and timing of follow-up period.42
In patients taking NSAIDs who are also H. pylori-infected, treatment of their ulcer should involve both eradication of the H. pylori and cessation of the NSAID (if possible) since both are independent risk factors for ulcer disease.35,36
The discovery of H. pylori has revolutionized the care of the peptic ulcer disease patient. Eradication of H. pylori greatly reduces the risk of ulcer recurrence and can eliminate the need for chronic anti-ulcer therapy. Current regimens have proven effective but are often complex and associated with many adverse effects. In the future, more effective regimens requiring shorter treatment courses and with more favorable side effect profiles will be developed.
References
1. Graham DY, et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Gastroenterol 1991;100:1495-1501.
2. Fierdorek SC, Malaty HM, Devans DL, et al. Factors influencing the epidemiology of Helicobacter pylori infection in children. Pediatrics 1991;88:578-582.
3. EUROGAST Study Group. Epidemiology of and risk factors for Helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. Gut 1993;34:1672-1676.
4. Veldhuyzen van Zanten SJO, Pollak PT, Best LM, et al. Increasing prevalence of Helicobacter pylori infection with age: Continuous risk of infection in adults rather than a cohort effect. J Infect Dis 1994;169:434-437.
5. Drumm B, Perez-Perez GI, Blaser MJ, et al. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990;322:359-363.
6. Mitchell HM, Lee A, Carrick J. Increased incidence of Campylobacter pylori infection in gastroenterologists: Further evidence to support person-to-person transmission of H. pylori. Scand J Gastroenterol 1989;24:396-400.
7. Dunn BE. Pathogenic mechanisms of Helicobacter pylori. Gastroenterol Clin North Am 1993;22:43-57.
8. El-Omar EM, Penman ID, Ardill JES, et al. Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterol 1995;109:681-691.
9. Moss SF, Calam J. Acid secretion and sensitivity to gastrin in patients with duodenal ulcer: Effect of eradication of Helicobacter pylori. Gut 1993;34:888-892.
10. Hunt RH. The role of Helicobacter pylori in pathogenesis: The spectrum of clinical outcomes. Scand J Gastroenterol 1996;31. Suppl 220:3-9.
11. Cohen H, Laine L. Endoscopic methods for the diagnosis of Helicobacter pylori. Aliment Pharmacol Ther 1997;11 Suppl 1:3-9.
12. Cutler AF, Harstad S, Ma CK, et al. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori. Gastroenterol 1995;109:136-141.
13. Loffeld RJLF, Stobberingh E, Arends JW. A review of diagnostic techniques for Helicobacter pylori infection. Dig Dis Sci 1993;11:173-180.
14. Genta RM, Robason GO, Graham DY. Simultaneous visualization of Helicobacter pylori and gastric morphology: A new stain. Hum Pathol 1994;25:221-226.
15. Brown KE, Peura DA. Diagnosis of Helicobacter pylori infection. Gastroenterol Clinics of North Am 1993;22:105-116.
16. Howden CW. Clinical expressions of Helicobacter pylori infection. Am J Med 1996;100:27S-34S.
17. Rogerrero E, Zucca E, Pinotti G, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma or mucosa-associated lymphoid tissue. Ann Intern Med 1995;122:767-769.
18. Soll AH for the Practice Parameters Committee of the American College of Gastroenterology. Consensus statement: Medical treatment of peptic ulcer disease. Practice guidelines. JAMA 1996;275:622-629.
19. Jones DB, Howden CW, Bruget DW, et al. Acid suppression in duodenal ulcer: A meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28:1120-1127.
20. Valenzuela JE, Berlin RG, Snape WJ, et. al. U.S. experience with omeprazole in duodenal ulcer. Multicenter double-blind comparative study with ranitidine. Dig Dis Sci 1991;36:761-768.
21. Korman MG. Helicobacter pylori eradication: Therapy other than with bismuth or proton-pump inhibitors. Scan J Gastroenterol 1996;31 Suppl 220:41-43.
22. Cryer B, Feldman M. Strategies for preventing NSAID-induced ulcers. Drug Ther 1994;July:26-32.
23. Chiba N, Rao BV, Rademaker JW, et al. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori. Am J Gastroenterol 1992;87:1716-1727.
24. Unge P, Berstad A. Pooled analysis of anti-Helicobacter pylori treatment regimens. Scand J Gastroenterol 1996:31 Suppl 22:27-40.
25. Hunt RH. Eradication of Helicobacter pylori infection. Am J Med 1996;100:42S-51S.
26. Ciociola AA, Webb DD, Turner K. Dual and triple therapy regimens of antisecretory agents and antibiotics for the eradication of Helicobacter pylori: An overview. Scan J Gastroenterol 1996;31 (Suppl 218):3-9.
27. Graham DY, Law GO, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer: A randomized, controlled study. Ann Intern Med 1992;116:705-708.
28. Graham DY, Law GO, Malaty HM, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterol 1992;102:493-496.
29. Goddard AF, Spiller RC. The effect of omeprazole on gastric juice viscosity, pH and bacterial counts. Aliment Pharmacol Ther 1996;10:105-109.
30. Gustavson LE, Kaiser JF, Edmonds AL, et al. Effect of omeprazole on the concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother 1995;39:2078-2083.
31. Laine L, Estrada R, Trujillo E, et al. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:1029-1033.
32. Olson C, Edmonds A. Primary susceptibility of C. pylori to clarithromycin compared to metronidazole in patient with duodenal ulcers associated with H. pylori infection. Gut 1995;37 (Suppl 2):A814.
33. Penston JG. Review article: Clinical aspects of Helicobacter pylori eradication therapy in peptic ulcer disease. Aliment Pharmacol Ther 1996;10:469-486.
34. Penston JG. Helicobacter pylori eradicationUnderstandable caution but no excuse for inertia. Aliment Pharmacol Ther 1994;8:369-389.
35. Laine LA. Helicobacter pylori and complicated ulcer disease. Am J Med 1996;100:52S-59S.
36. Laine I, Comineli F, Sloane R, et al. Interactions of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: A controlled double-blind trial. Aliment Pharmacol Ther 1995;9:127-135.
37. Chey WD, Murthy UK, Linscheer WG, et al. A comparison between four different commercially available serology tests for Helicobacter pylori. Gastroenterol 1996;110:A80 (abstract).
38. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA 1994;272:65-69.
39. Malaty HM, Evans DG, Evans DJ, et al. Helicobacter pylori in Hispanics: Comparison with blacks and whites of similar age and socioeconomic class. Gastroenterol 1992;103:813-816.
40. Genta RM, Graham DY. Comparison of biopsy sites for the histopathologic diagnosis of Helicobacter pylori: A topographic study of H. pylori density and distribution. Gastrointest Endoscopy 1994;40:342-345.
41. Adamek RJ, et al. Primary and acquired H. pylori resistance to clarithromycin, metronidazole, and amoxicillin. Gastroenterol 1996;110:A48.
42. Van der Ende A, Van Der Hulst RWM, Dankert J, et al. Reinfection versus recrudescence in Helicobacter pylori infection. Aliment Pharmacol Ther 1997;11 (Suppl 1):55-61.
Physician CME Questions
36. Compared to persons with an income greater than $25,000, persons with incomes below $5000 have a prevalence of H. pylori that is:
a. three times as high.
b. twice as high.
c. four times as high.
d. half as high.
37. In order to document eradication of H. pylori in a patient who has received antibiotic therapy, how long should you wait after therapy has been discontinued to perform the urea breath test?
a. Ten days
b. Two weeks
c. Three weeks
d. Four weeks
38. Which of the following is the most expensive method used to confirm H. pylori eradication?
a. Serologic testing
b. Urea breath test
c. Endoscopy with biopsy
d. None of the above
39. Which of the following is not a risk factor for H. pylori infection?
a. Living in a developing country
b. Having a relative with H. pylori infection
c. Having an income of less than $5000
d. Being white
40. Which of the following groups should be tested for the presence of H. pylori?
a. Patients with known ulcer disease
b. Patients with a history of complicated ulcer disease
c. Patients with gastric non-Hodgkin lymphomas and MALT lymphomas
d. All of the above.
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