THE INFECTIOUS ETIOLOGY OF PEPTIC ULCER DISEASE

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GASTROENTEROLOGY

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THE INFECTIOUS ETIOLOGY OF PEPTIC ULCER DISEASE Diagnosis and Implications for Therapy Michael J. Brooks, MD, Chester J. Maxson, MD, and Walter Rubin, MD

During the past decade, the diagnosis and treatment of peptic ulcer disease (PUD) have undergone major changes. Previously considered a disorder primarily of mucosal disruption by gastric acid, PUD now is recognized as multifactorial in etiology, with a major factor thought to be the presence in the stomach of a spiral-shaped bacterium known as Helicobacter pylori (HP). Since 1982 when Marshall and Warren38first isolated and cultured this organism, thousands of articles have been written showing associations between HP and most cases of chronic gastritis and gastroduodenal ~ l c e r a t i o n .Etiologic ~ ~ , ~ ~ links between the organism and neoplastic processes such as gastric lymphoma and adenocarcinoma also have been ~ u g g e s t e d . ' ~ , ~ ~article discusses many aspects of HP infecThis tion, its relationship to PUD and other gastrointestinal disorders, methods for detection, and various treatment strategies. BIOLOGIC CHARACTERISTICS OF H. PYLORl

HP is a gram-negative, spiral-shaped bacillus with multiple unipolar flagella.38The organism is found only on gastric epithelium, whether in the stomach or in metaplastic gastric mucosa in the esophagus, duodenum, or r e ~ t u m . ~ Within ~,~~ the, ~stomach, ~ HP is located primarily in the antrum and angularis and less in the body. HP possesses several mechFrom the Division of Gastroenterology, Department of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania

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anisms that allow it to survive the hostile acidic environment of the stomach and to produce inflammation. The bacterium penetrates the mucous layer of the distal stomach with the help of its flagella and comes to rest between this layer and the gastric epithelium. This process often elicits a neutrophilic response that represents the initiation of superficial gastriti^.*^ The presence of HP infection almost always implies that chronic gastritis exists38;HP is rarely present in patients with histologically normal stomachs.8 In addition to its flagella, another potent virulence factor in HP is its production of enzymes such as urease, oxidase, catalase, and several chemotactic substance^.'^ Probably the most important of these compounds is the urease enzyme, which breaks down urea to produce ammonia, which locally neutralizes gastric acid and further disrupts the epithelial layer.23It is the detection of this production of ammonia on which several diagnostic tests for HP are based. Aside from the production of localized inflammation or gastritis, HP also has been shown to cause increased gastrin release in some patients" and significant hypochlorhydria in others.33 In response to these aggressive or virulent factors, the body initiates its own immune response consisting of the production of specific antibodies (mostly IgG) and the proliferation of neutrophils, monocytes, macrophages, and T lymphocytes? Although significant, this response is nevertheless usually inadequate to eradicate the organism; therefore, the majority of patients remain with chronic infection and gastritis. Aside from chronic gastritis, however, several other possible sequelae of HP infection exist: atrophic gastritis, which may predispose to gastric adeno~arcinoma~~; the indolent proliferation of mucosa-associated lymphoid tissue and possible subsequent l y m p h ~ r n a sand ~ ~ ; the common disorder known as PUD. Although these associations exist, the exact cause-andeffect mechanisms for most HP-related.diseases remain unclear. DIAGNOSIS OF H. PYLORl INFECTION

No less than six diagnostic methods have been used to detect human infection with HP. Three require the performance of an endoscopic examination of the upper gastrointestinal tract; the others do not. Each of the available diagnostic tests has relatively high sensitivity and specificity, and each has relative advantages with respect to the others. It is useful to classify these methods of detection into invasive and noninvasive tests, based on whether they require the performance of endoscopy. lnvasive Tests (Requiring Endoscopy) Histology is considered by some the gold standard in diagnosing HP infection. Histologic analysis of endoscopicallyobtained gastric tissue has a diagnostic sensitivity and specificity in excess of 93%.4The more tedious (and more expensive)Warthin-Starry silver stain has been shown superior to standard hematoxylin-eosin staining in detecting HP in gastric biopsy

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specimens.'* An example of this technique for staining the organism is seen in Figure 1.Giemsa staining appears equally as effective as the Warthinstarry stain and is less expensive to perform.12The endoscopy also permits the visualization of the gastric mucosa and the biopsy of suspicious lesions. Disadvantages of the histological approach include the high cost of endoscopy and its attendant risks, the cost of histologic analysis, and a 48-hour to 72-hour processing time that delays diagnosis and initiation of therapy. Culture of HP is a difficult and expensive task because of the fastidiousness of the organism. In addition, the use of antimicrobial drugs (antibiotics) or proton pump inhibitors (omeprazole or lansoprazole) may lead to false-negative results. Multiple biopsy specimens from different sites within the stomach probably increase the chances of a positive culture. Advantages of direct microbiologic culture include the ability to test for bacterial sensitivity and to determine resistance in patients who have failed seemingly adequate antibiotic therapy. Disadvantages again include the high cost and potential risks of an endoscopic procedure, the relatively low sensitivity (around 77%-80?'0)~ relative to other available diagnostic tests, and the long processing time, which ranges from several days to several weeks.12 Urease tests identify the presence in the stomach of this enzyme produced by the HP organism. The prototype of this type of test, the Campylobacter-like organism test (Delta West Pty) (Fig. 2), requires placement of a gastric mucosal biopsy into a mounted gel containing urea and a pH

Figure 1. Photomicrographof HP bacteria highlighted on gastric mucous layer with WarthinStarry silver stain (original magnification, x 128). Spiral shape of organisms is apparent (arrowheads).

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Figure 2. Example of rapid urease (CLO) tests (top one represents positive result).

indicator (phenol red), which changes color as the pH rises above 6. The urease produced by HI', if present, hydrolyzes the urea to ammonia and carbon dioxide, elevating the pH above 6 and changing the initially yellow gel to pink. A positive result may be seen within several minutes, but the test should not be considered negative until 24 hours have elapsed.27Advantages include an excellent sensitivity and specificity (98% and 1009'0, respectively, at 24 hours? timely results (usually in less than 3 hours), and relatively low cost, excluding the endoscopy fee. Minor disadvantages include the need for endoscopy and the fact that false-negativesmay occur with recent use of antibiotics, proton pump inhibitors, or formalin contamination during preparation of the biopsy specimen. Overall, however, easy application and delivery of rapid, accurate results make some form of the urease test the initial invasive diagnostic test of choice at most centers. Noninvasive Tests

Several techniques have been developed to detect the presence of HI' infection without the need for endoscopy.

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Urea breath tests, which are not commercially available, may be the most promising method for the detection of HI'. After ingestion of urea labeled with radioactive carbon (C14)or a heavy isotope of carbon (C13), the urease enzyme generated by HP hydrolyzes the labeled urea to ammonia and labeled carbon dioxide that is expired by the lungs. This labeled carbon dioxide is detected with a Geiger counter or mass spectrometer. Although the sensitivity and specificity of this method are high, recent use of antimicrobial agents may yield false-negative results. The urea breath test also may be used to determine the effectiveness of eradication of HP as early as 8 weeks post-therapyZ6and thus eliminate the need for a second, costly endoscopy and biopsy to assess the effects of treatment. Serologic testing for antibodies (IgG) directed against HP using the ELISA method remains the sole commercially available, noninvasive modality to establish HI' infection. Elevated blood levels of anti-HP IgG are seen in infected individuals and can be considered a marker of active infection. Two caveats are that antibodies to HP persist for many months after eradication therapy and that the rate of IgG decline after treatment A positive serology result in a is variable and not clearly e~tablished.~ patient can be somewhat equivocal; it may represent current (active) or recently treated (and possibly eradicated) HI' infection. The advantages of serologic testing are the low cost, high sensitivity and specificity, and commercial availability. A disadvantage is that antibody titers must be followed for at least 6 months before a decline after treatment may be seen? There also is no established equation that correlates rate of IgG decline with successful eradication. One recent study reported, however, that a 50% decline in IgG titers at 6 months after treatment correlated with successful elimination of HI' at a sensitivity and specificity of 97% and 95%, respe~tive1y.l~ The choice of diagnostic tests to detect HP depends on the modality that is used to detect the presence of gastroduodenal ulceration (see section on Therapy). If endoscopy is used to diagnose PUD, mucosal biopsy with urease testing is the most readily available method of detection. If upper gastrointestinal radiography is used to diagnose PUD, however, serologic testing would be appropriate to establish HP infection.

EPIDEMIOLOGY OF H. PYLORl

HP is a ubiquitous organism found throughout the world. The only known reservoir of HI' is man, although similar spiral organisms are found in animals such as dogs and cats.1° HP likely is transmitted from human to human in a fecal-oral or an oral-oral route. Support for both of these modes of transmission comes from the detection of the organism in stool and saliva of patients with known HP infection.28There appears an inverse relationship between HP infection and the parameters of socioeconomic status, level of education, quality of water supply, and ~anitation.~~

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Prevalence of HI' increases significantly with age, by approximately 1%per year in Western-developed countries. This rate of HP infection is contrasted with that seen in developing countries, where new HP infections of 5% per year have been r e p ~ r t e d .In ~ ,the ~ ~United States, approximately 50% of people are serologically positive for HP by age 50.8

PATHOGENIC CONSIDERATIONS

It is unclear why 10% to 15% of patients infected with HP develop PUD. More than 90% of patients with duodenal ulcers and more than 80% of patients with gastric ulcers are infected with and HP eradication greatly reduces the number of ulcer recurrences of both types.17 Ulcer disease in the absence of HP infection is distinctly unusual and strongly implies the use of nonsteroidal anti-inflammatory agents or the existence of a hypersecretory state (such as gastrinoma).21The exact causal relationship between HP and PUD is unknown; however, one hypothetic model of the pathogenic sequence in the development of gastric metaplasia, duodenitis, and duodenal ulcer disease is discussed (Fig. 3). By this same mechanism, HP also may cause other gastrointestinal diseases such as gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma.

Infection with H.pyfori of gastric antral mucosa

1

Local idammation gastritis

Production of gastrinhncreased production of acid

H. pylori colonizes duodenum in setting of gastric metaplasia

Superficial gastritis

Nonulcer Gastric Gastric dyspepsia ulcer cancer

Duodenal cancer

Genetic factors

Figure 3. Hypothetic scheme of HP-induced gastroduodenal injury.

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THERAPY FOR H. PYLORl INFECTION

Healing of benign gastroduodenal ulceration can be achieved with judicious use of histamine-receptor (H,) blockers and, more recently and more rapidly, with proton pump inhibitors (omeprazole or lansoprazole). Within 8 weeks of starting therapy with H, antagonists, 80% to 90% of ulcers are healed. This duration can be cut in half with pump Unfortunately, unless antisecretory therapy is continued, more than 90% of patients ultimately will experience ulcer r e c ~ r r e n c eBased . ~ ~ on the current understanding of the association of HP with PUD, the National Institutes of Healthz9in 1994 released a consensus statement supporting the then-unconventional strategy that all patients with proven PUD and documented HP infection should receive antimicrobial therapy to eradicate the organism. This major position was adopted after the emergence of solid evidence that eradication of HP almost eliminates the recurrence of gastroduodenal ~1ceration.l~ Preliminary data also suggest that this therapy, as expected, reduces ulcer complications (such as bleeding and perforation) as well.25In most studies, the recurrence rate at 1year is reduced from approximately 80% in patients treated only with H, blockers to about 10%in patients treated with antimicrobial therapy to eliminate the organism.13t51The consensus guidelines adopted by the National Institutes of Health for antimicrobial therapy of HP-infected patients with ulcer disease are depicted in Table 1. HP has proved a difficult organism to eradicate; this is illustrated by the large number of different treatment regimens that have been reported.6 Because HP almost never is eliminated successfully with antisecretory therapy alone, multidrug regimens using a combination of antimicrobials and antisecretory agents have been developed. When evaluating treatment strategies for HP, several factors must be considered. Documented efficacy of the treatment regimen is important, as is the likelhood of patient compliance. In a study of 93 patients who received triple antimicrobial therapy for HP (metronidazole, bismuth, and tetracycline), cure rates were 69% for patients who took less than 60% of the total prescribed medication compared with 96% for those who had taken more than 60% of the prescribed regimen.14The most commonly tested regimens worldwide to eradicate HP combine a bismuth-based compound (bismuth subsalicylate [Pepto-bismol] or colloidal bismuth subcitrate), a macrolide antibiotic (tetracycline) or a penicillin derivative (amoxicillin), Table 1. NATIONAL INSTITUTES OF HEALTH CONSENSUS GUIDELINES FOR ANTIMICROBIAL TREATMENT OF PATIENTS INFECTED WITH H. PYLORl Patient Status Asymptomatic Nonulcer dyspepsia Gastric ulcer Duodenal ulcer

+

H. py/ori ( - )

H. py/ori ( )

No No

No No Yes Yes

No No

Data from NIH Consensus Development Panel Statement: Helicobacterpyloriinpeptic ulcer disease. JAMA 272:65-69,1994.

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and a substituted nitroimidazole (metronidazole or tinidazole) with or without antisecretory therapy (omeprazole). Cure rates with these medications consistently exceed 85?'0.~One major drawback to this type of regimen is the large number of pills that must be taken each day. Recent experience suggests that compliance with this complicated combination is likely to be low. Because of this, simplified two-drug regimens have been developed and tested to improve the chances of adequate compliance without compromise of efficacy. Research has suggested that as the number of antibiotic agents in the regimen is reduced, the need for nearcomplete acid suppression becomes p a r a m o ~ n t . ' ~ Therapies ,~~ combining a single antibiotic (or two) and a proton-pump inhibitor have gained popularity. In a recent study using omeprazole, 40 mg daily for 28 days, and clarithromycin, 500 mg three times daily for 14 days, HP eradication rates reached 83Y0.2~Peptic ulcer recurrence rates at 12 months were 6% in the HP-eradicated group compared with 76% in matched controls who did not receive antibiotic therapy.25 Recent evidence has suggested that metronidazole is the critical antimicrobial agent in preventing resistance to HP. If this agent is incorporated with another antibiotic along with sufficient acid suppression, duration of therapy may be shortened to as little as 1 week.22A variety of well-studied treatment regimens for eradication of HP, including some of very short duration, are shown in Table 2. Table 2. SELECTED MEDICAL REGIMENS FOR THE ERADICATION OF H. PYLORl

H. pylori Eradication Rates Regimen

Double Therapy Clarithromycin, 500 mg tid x 14 days Omeprazole, 40 mg q day x 28 days or Arnoxicillin, 750 rng tid x 14 days Omeprazole, 40 mg tid x 14 days Triple Therapy Bismuth subsalicylate, 2 tabs qid x 14 days Metronidazole, 500 rng tid x 14 days Amoxicillin, 500 rng tid x 14 days or Bismuth subsalicylate, 2 tabs qid x 21 days Metronidazole, 250 mg tid x 14 days Tetracycline, 500 mg tid x 14 days Triple Therapy Plus an Antisecretory Drug (e.g., H, Blocking Agent) Amoxicillin, 500 rng qid x 14 days Bismuth subsalicylate, 2 tabs qid x 14 days Clarithromycin, 250 rng tid x 14 days Triple Therapy-Short Course Orneprazole, 20 rng q day x 7 days Clarithromycin, 250 rng bid x 7 days Metronidazole, 500 mg bid x 7 days or Orneprazole, 20 rng q day x 7 days Clarithromycin, 250 rng bid x 7 days Tinidazole, 500 rng bid x 7 days

("/.I

Reference

83

25

>90

12

90

3

88

36

>90

12

95

22

95

1

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Once treatment has been completed with a particular regimen to cure the HP infection, no further diagnostic or therapeutic intervention is required in most cases because PUD is not likely to recur. The patient simply can be followed clinically and questioned periodically about return of symptoms. If definitive evidence of eradication is desired, pretreatment serum should be drawn and stored. Six-month post-treatment serum then can be obtained, and the paired samples submitted for serologic testing, with a significant decrease in anti-HP IgG antibody titers required to document cure.7The magnitude of antibody titer decrease necessary to predict eradication is still under debate. If an ulcer recurs and the patient is not taking nonsteroidal anti-inflammatory drugs, failure to eradicate HP is the likely cause, not reinfection. Serologic testing (or urea breath testing, if available) may be useful to determine HP status 6 months or more after antibiotic therapy. Even though a positive HP status in a symptomatic patient with previous ulcer disease suggests recurrent PUD,14 documentation of an active peptic ulcer (via barium study or endoscopy) is probably still prudent before retreatment. Many patients (especiallythose with long histories of PUD recurrences) experience ulcer-like symptoms, perhaps caused by transient motility disorders from scarring after successful healing of PUD. If retreatment is chosen, a different combination of drugs is suggested to improve chances of successful HP eradication. ASSOCIATION BETWEEN H. PYLORl AND NONULCER DYSPEPSIA

Nonulcer dyspepsia is defined as the presence of chronic upper abdominal discomfort (ulcer-likesymptoms) in the absence of an identifiable cause. Although HP may be present in patients with NUD, a causal association has not been proven consistently in controlled studies; possibly because disease definition and symptom interpretation differ widely from culture to culture. Most investigators have failed to show that HP is implicated in the pathogenesis of NUD or that antimicrobial therapy of HP infection significantly improves symptoms in NUD when compared with placebo? Because most studies have suffered from methodologic flaws, high placebo-response rates, and widely varied responses, the use of antimicrobial therapy for patients with NUD and HI' infection cannot be recommended. Despite the lack of scientific support, it is tempting to eliminate HP in an HP-positive patient with NUD whose troubling symptoms have failed to respond to other empiric and supportive therapies. Future well-controlled, placebo-based trials ultimately may shed new light on this controversial issue. SUMMARY

Since 1982, our understanding of PUD has been refocused to include an infectious cause. Our attention now is directed toward a ubiquitous spiral bacterium known as HI'. HP has been found to cause most cases of

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chronic gastritis and clearly is involved in the pathogenesis of PUD. It also is implicated in gastric adenocarcinoma and lymphoma, although the association is far from established. Diagnostic techniques (invasive and noninvasive) for HP infection that are available provide excellent sensitivity and specificity. Future diagnostic modalities, including urea breath testing, will be less invasive and can be expected to provide efficacious and cost-effective tests for the presence of HP and its eradication after therapy. Cure of HI' infection is difficult, and multidrug regimens must be used to provide an acceptable elimination rate of 85% or greater. Many of these therapeutic combinations offer excellent cure rates, although expense, poor compliance, increasing bacterial resistance, and untoward side effects may emerge as potential problems. Only patients with documented PUD and HP infection should undergo eradication therapy; however, many questions remain unanswered. How does HP cause PUD? Are there any HP-positive patients with NUD who will benefit from HP eradication? Should any asymptomatic patients with HP be treated empirically with antibiotics to prevent disease? If HP is shown clearly to cause gastric cancer, should its presence not be more aggressively sought and eradicated? What measures can a society take to prevent widespread HP infection (i.e., vaccines)? These and many other questions certainly will be addressed in the future as more is learned about HP and its epidemiology and role in gastrointestinal disease. ACKNOWLEDGMENT The authors acknowledge the invaluable assistance of Ann Gallagher in the preparation of this manuscript.

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Address reprint requests to Chester J. Maxson, MD Division of Gastroenterology Allegheny University of the Health Sciences 3300 Henry Avenue Philadelphia, PA 19129