386
STATE-OF-THE-ART CLINICAL ARTICLE
Helicobacter pylori: Its Role in Disease From the Division of Infectious Diseases. Department of Medicine and Department of Microbiology and Immunology. Vanderbilt University School ofMedicine; and Department of Veterans Affairs Medical Center. Nashville. Tennessee
Since its discovery in 1982, Helicobacter (formerly Campylobacter) pylori has been shown to be an important pathogen of humans. This bacterium colonizes the stomach for years or decades, not days or weeks, as we usually expect for bacterial pathogens. Unlike Mycobacterium tuberculosis, which persists in infected hosts for extended periods but is mostly in a dormant or latent state, H. pylori causes continuous inflammation. It is this longevity and persistent lowgrade gastric inflammation that suggest that H. pylori should be considered the prototypic "slow" bacterium. In this review, I will provide a brief overview of the microbiology, epidemiology, and pathogenesis of H. pylori infection, topics that have been recently reviewed elsewhere [l , 2]. Subsequently, I will outline the relationship of this organism to peptic ulcer disease and gastric cancer, two important clinical consequences of infection, and then concentrate on a clinical approach to H. pylori infection.
nia production is an important conserved survival mechanism for bacteria in the acidic gastric environment. Although fastidious, H. pylori can readily be isolated from gastric biopsy specimens when appropriate methods are used. Diagnosis of H. pylori infection also can be made by visualization of the organisms on stained histologic sections ofbiopsy specimens or by detection of urease activity. Diagnostic techniques that do not require endoscopy include urea breath tests and determination ofserum antibodies. When appropriately performed, each of the major diagnostic techniquesculture, histology, breath tests, and serology-has >95% accuracy.
Microbiology H. pylori organisms are gram-negative curved or spiral bacteria that live in the mucus layer overlaying the gastric epithelium. These bacteria are microaerophilic, befitting their residence in the semipermeable mucus layer. H. pylori organisms possess multiple flagella at one pole and are actively motile. Their outstanding biochemical characteristic is the abundant production of urease, which catalyzes the hydrolysis of urea into ammonia and carbon dioxide. Since the discovery of H. pylori. similar organisms (including Helicobacter mustelae. Helicobacter muridarum. and Helicobacter nemastrinaei have been found in the stomachs ofother mammals; all are strongly urease-positive. suggesting that ammo-
Received 6 May 1992; revised 28 May 1992. Grant support: This work was supported in part by the Department of Veterans Affairs. In accordance with CID policy. the author discloses that he has a royalty interest in serological tests for Helicobacter pylori infection. Reprints or correspondence: Dr. Martin J. Blaser. Vanderbilt University School of Medicine. Division of Infectious Diseases. A-3310 Medical Center North. Nashville. Tennessee 37232-2605. Clinical Infectious Diseases 1992;15:386-93 © 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1503-0001$02.00
Epidemiology H. pylori infection is present throughout the world. In developed countries such as the United States, few infections occur during childhood but the incidence of infection is about 0.5%-1.0% per year; '" 50% of 60-year-old adults are infected. Among Afro-Americans, Hispanics, and native Americans in the United States, the incidence early in life appears to be substantially higher. Infection clusters in families and is associated with low socioeconomic status, independent of ethnicity. In developing countries. most persons are infected with H. pylori by the age of 10 years, a phenomenon that appears related to poor sanitary practices. Thus, it is likely that one-half of the world's population is infected with H. pylori. No nonhuman reservoir has been identified, and it is likely that most transmission is from person to person. However, the specific modes of transmission are not known.
Pathogenesis Once acquired, H. pylori produces chronic superficial gastritis involving both the antrum and the fundus, often resulting in hypergastrinemia. The evidence that H. pylori is a pathogen and not just a common commensal is by now overwhelming and includes data from experimental challenges, treatment studies, and animal models [3]. Thus, the chronic gastritis associated with "normal" aging is in fact due to a bacterial infection; with eradication of H. pylori. the gastric mucosa returns to its pristine state. Although H. pylori does not invade the gastric epithelium per se but remains largely
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
Martin J. Blaser
Table 1. Association of H. pylori infection with gastroduodenal pathology and symptoms. Presence of H. pylori (%) Patient characteristic Normal gastric histology* Chronic gastritis* Duodenal ulcer* Gastric ulcer* Nonulcer dyspepsia"
387
Role of H. pylori in Disease
CID 1992; 15 (September)
No. of studies
15 15 12 12 9
No. of subjects
568 IAII
620 312 1,293
Range
Median
0-14 62-94 60-100 44-90 33-87
4 83 92 69 51
"offshore" within the mucus layer, the host recognizes its presence by mounting a selective immune response. The humoral response involves antibodies ofa sufficiently high titer to permit accurate diagnosis of the infection, as is the case for such diseases as syphilis, human immunodeficiency virus infection, and the lepromatous form ofleprosy. Nevertheless, despite immunologic recognition, the host is unable to eradicate the organism. The mechanisms by which H. pylori produces chronic inflammation are incompletely understood. The ammonia generated by its abundant urease activity is injurious to eukaryotic cells, as is a cytotoxin that produces vacuoles in affected cells. H. pylori components, especially heat shock proteins, are antigenically cross-reactive with host tissues and could form a basis for autoimmunity. H. pylori cells release soluble factors that are absorbed into tissue and recruit and activate inflammatory cells. The inflammatory response may then injure "innocent bystander" epithelial cells and perturb gastrin-hydrochloric acid homeostasis. I have raised the hypothesis that the host attempts to down-regulate this inflammatory response so as to prevent further tissue injury and that the net consequence of the host-bacteria interaction is a persistent low-grade inflammation [2]. Although it is now evident that H. pylori is the major cause of chronic superficial gastritis (table I), in most cases this pathological condition is clinically silent. However, there are several important consequences of this persistent inflammatory process that necessitate consideration of the complexities of H. pylori infection. The first to be discussed is peptic ulcer disease, and the second is gastric cancer.
Role in Peptic Ulcer Disease Well before the discovery of H. pylori, it was recognized that virtually all patients with idiopathic peptic ulcer disease (not induced by aspirin or nonsteroidal antiinflammatory agents or part of the Zollinger-Ellison syndrome) have
Table 2. Effect of eradication of H. pylori on rates of relapse of duodenal ulcers. on the basis of published reports.* Duodenal ulcer relapse H. pvlori
First author of study (y) Coghlan (1987) Marshall ( 1988) Borody ( 1989) Rauws (1990) George (1990) Graham ( I 992)
Follow-up period (rno)
nt
12 12 9-37 12 12-48 12
29 47 4 21 0 36
+
H. pvlori
%t
II
9ft
10 23 54 17 62 40
10 22* 0 0 0 0
76 8 [§
75 81 NA
95
~
NOTE. + = infected; - = uninfected: NA = not applicable. * Table adapted from [9, 10]. t Number of subjects in whom H. pvlori organisms were detected I month after therapy was discontinued. t Percentage of subjects whose ulcer disease relapsed during the prolonged follow-up period. § Includes patients whose symptoms recurred with no endoscopic confirmation of duodenal ulcer.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
* Data adapted from [4], including only studies with> 10 subjects per category. t Compiled from [4-6].
chronic superficial gastritis. Thus, it was not surprising to find a striking association between H. pylori infection and peptic ulcer disease (table I), with infection rates significantly higher among persons with peptic ulcers than among age-matched controls [7]. It is interesting that although gastric and duodenal ulcers differ from one another in a number of characteristics, both are associated with H. pylori infection. It is now known that H. pylori is capable of colonizing islands ofgastric tissue in the duodenum (gastric metaplasia) and that the presence of these organisms in the duodenum is associated with a strikingly increased risk of duodenal ulceration. It is reasonable to ask whether H. pylori plays a causal role in duodenal ulceration or whether the organism has just found a good niche. There are no satisfactory experimental models of peptic ulceration, although longitudinal studies have shown that the presence of chronic superficial gastritis is associated with a 13-fold increase in the risk of duodenal ulceration over a lfl-year period [8]. We know that ulcer disease can be well treated with acid-reducing therapies but that when the therapy ceases the ulcers recur at rates of ~70% per year. Recently. several clinical trials have been performed that have assessed whether antimicrobial therapy affects duodenal ulceration (table 2). In each of the studies reported, treatment with a wide variety of agents to which H. pylori is susceptible resulted in healing of ulcers as well as significant reductions in ulcer recurrence rates. In those cases in which the therapy used eradicated H. pylori, ulcer recurrence rates during the following year were 5%). C. Acquired resistance to metronidazole occurs commonly (>5%). D. H 2 blockers can eradicate H. pylori. H. pylori organisms are A. anaerobes. B. microaerophiles. C. facultative aerobes. D. cryophilic. E. none of the above. The most outstanding biochemical characteristic of H. pylori is A. urease activity. B. nitrate reductase. C. acid phosphatase. D. lactase. E. carbonic anhydrase.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
UCLfI
CIO 1992; 15 (September)
CME Test
A. Infection always leads to upper gastrointestinal symptoms. B. Infection usually is self-limited. C. Development of a host immune response enables eradication of the organism. D. Tissue invasion is the critical pathogenetic step. E. None of the above. 10. Which of the following statements about nonulcer dyspepsia (NUD) is correct? A. The pathophysiology of NUD is now largely understood. B. NUD may coexist with gastric ulceration. C. H. pylori infection is often present in patients with NUD. D. The role of H. pylori infection in NUD pathogenesis is now well established. E. None of the above.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
7. The presence of H. pylori infection can be diagnosed by A. culture. B. serology. C. visualization of the organisms on biopsy. D. urea breath test. E. all of the above. 8. Which of the following statements about H. pylori epidemiology is correct? A. Transmission from contaminated foods is the principal means of spread. B. In the United States, most children are infected. C. Person-to-person transmission is the major means of spread. D. There is no familial association with infection. E. None of the above. 9. Which ofthe following statements about H. pylori pathogenesis is correct?
393
STATE-OF-THE-ART CLINICAL ARTICLE
Helicobacter pylori: Its Role in Disease From the Division of Infectious Diseases. Department of Medicine and Department of Microbiology and Immunology. Vanderbilt University School ofMedicine; and Department of Veterans Affairs Medical Center. Nashville. Tennessee
Since its discovery in 1982, Helicobacter (formerly Campylobacter) pylori has been shown to be an important pathogen of humans. This bacterium colonizes the stomach for years or decades, not days or weeks, as we usually expect for bacterial pathogens. Unlike Mycobacterium tuberculosis, which persists in infected hosts for extended periods but is mostly in a dormant or latent state, H. pylori causes continuous inflammation. It is this longevity and persistent lowgrade gastric inflammation that suggest that H. pylori should be considered the prototypic "slow" bacterium. In this review, I will provide a brief overview of the microbiology, epidemiology, and pathogenesis of H. pylori infection, topics that have been recently reviewed elsewhere [l , 2]. Subsequently, I will outline the relationship of this organism to peptic ulcer disease and gastric cancer, two important clinical consequences of infection, and then concentrate on a clinical approach to H. pylori infection.
nia production is an important conserved survival mechanism for bacteria in the acidic gastric environment. Although fastidious, H. pylori can readily be isolated from gastric biopsy specimens when appropriate methods are used. Diagnosis of H. pylori infection also can be made by visualization of the organisms on stained histologic sections ofbiopsy specimens or by detection of urease activity. Diagnostic techniques that do not require endoscopy include urea breath tests and determination ofserum antibodies. When appropriately performed, each of the major diagnostic techniquesculture, histology, breath tests, and serology-has >95% accuracy.
Microbiology H. pylori organisms are gram-negative curved or spiral bacteria that live in the mucus layer overlaying the gastric epithelium. These bacteria are microaerophilic, befitting their residence in the semipermeable mucus layer. H. pylori organisms possess multiple flagella at one pole and are actively motile. Their outstanding biochemical characteristic is the abundant production of urease, which catalyzes the hydrolysis of urea into ammonia and carbon dioxide. Since the discovery of H. pylori. similar organisms (including Helicobacter mustelae. Helicobacter muridarum. and Helicobacter nemastrinaei have been found in the stomachs ofother mammals; all are strongly urease-positive. suggesting that ammo-
Received 6 May 1992; revised 28 May 1992. Grant support: This work was supported in part by the Department of Veterans Affairs. In accordance with CID policy. the author discloses that he has a royalty interest in serological tests for Helicobacter pylori infection. Reprints or correspondence: Dr. Martin J. Blaser. Vanderbilt University School of Medicine. Division of Infectious Diseases. A-3310 Medical Center North. Nashville. Tennessee 37232-2605. Clinical Infectious Diseases 1992;15:386-93 © 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1503-0001$02.00
Epidemiology H. pylori infection is present throughout the world. In developed countries such as the United States, few infections occur during childhood but the incidence of infection is about 0.5%-1.0% per year; '" 50% of 60-year-old adults are infected. Among Afro-Americans, Hispanics, and native Americans in the United States, the incidence early in life appears to be substantially higher. Infection clusters in families and is associated with low socioeconomic status, independent of ethnicity. In developing countries. most persons are infected with H. pylori by the age of 10 years, a phenomenon that appears related to poor sanitary practices. Thus, it is likely that one-half of the world's population is infected with H. pylori. No nonhuman reservoir has been identified, and it is likely that most transmission is from person to person. However, the specific modes of transmission are not known.
Pathogenesis Once acquired, H. pylori produces chronic superficial gastritis involving both the antrum and the fundus, often resulting in hypergastrinemia. The evidence that H. pylori is a pathogen and not just a common commensal is by now overwhelming and includes data from experimental challenges, treatment studies, and animal models [3]. Thus, the chronic gastritis associated with "normal" aging is in fact due to a bacterial infection; with eradication of H. pylori. the gastric mucosa returns to its pristine state. Although H. pylori does not invade the gastric epithelium per se but remains largely
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
Martin J. Blaser
Table 1. Association of H. pylori infection with gastroduodenal pathology and symptoms. Presence of H. pylori (%) Patient characteristic Normal gastric histology* Chronic gastritis* Duodenal ulcer* Gastric ulcer* Nonulcer dyspepsia"
387
Role of H. pylori in Disease
CID 1992; 15 (September)
No. of studies
15 15 12 12 9
No. of subjects
568 IAII
620 312 1,293
Range
Median
0-14 62-94 60-100 44-90 33-87
4 83 92 69 51
"offshore" within the mucus layer, the host recognizes its presence by mounting a selective immune response. The humoral response involves antibodies ofa sufficiently high titer to permit accurate diagnosis of the infection, as is the case for such diseases as syphilis, human immunodeficiency virus infection, and the lepromatous form ofleprosy. Nevertheless, despite immunologic recognition, the host is unable to eradicate the organism. The mechanisms by which H. pylori produces chronic inflammation are incompletely understood. The ammonia generated by its abundant urease activity is injurious to eukaryotic cells, as is a cytotoxin that produces vacuoles in affected cells. H. pylori components, especially heat shock proteins, are antigenically cross-reactive with host tissues and could form a basis for autoimmunity. H. pylori cells release soluble factors that are absorbed into tissue and recruit and activate inflammatory cells. The inflammatory response may then injure "innocent bystander" epithelial cells and perturb gastrin-hydrochloric acid homeostasis. I have raised the hypothesis that the host attempts to down-regulate this inflammatory response so as to prevent further tissue injury and that the net consequence of the host-bacteria interaction is a persistent low-grade inflammation [2]. Although it is now evident that H. pylori is the major cause of chronic superficial gastritis (table I), in most cases this pathological condition is clinically silent. However, there are several important consequences of this persistent inflammatory process that necessitate consideration of the complexities of H. pylori infection. The first to be discussed is peptic ulcer disease, and the second is gastric cancer.
Role in Peptic Ulcer Disease Well before the discovery of H. pylori, it was recognized that virtually all patients with idiopathic peptic ulcer disease (not induced by aspirin or nonsteroidal antiinflammatory agents or part of the Zollinger-Ellison syndrome) have
Table 2. Effect of eradication of H. pylori on rates of relapse of duodenal ulcers. on the basis of published reports.* Duodenal ulcer relapse H. pvlori
First author of study (y) Coghlan (1987) Marshall ( 1988) Borody ( 1989) Rauws (1990) George (1990) Graham ( I 992)
Follow-up period (rno)
nt
12 12 9-37 12 12-48 12
29 47 4 21 0 36
+
H. pvlori
%t
II
9ft
10 23 54 17 62 40
10 22* 0 0 0 0
76 8 [§
75 81 NA
95
~
NOTE. + = infected; - = uninfected: NA = not applicable. * Table adapted from [9, 10]. t Number of subjects in whom H. pvlori organisms were detected I month after therapy was discontinued. t Percentage of subjects whose ulcer disease relapsed during the prolonged follow-up period. § Includes patients whose symptoms recurred with no endoscopic confirmation of duodenal ulcer.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
* Data adapted from [4], including only studies with> 10 subjects per category. t Compiled from [4-6].
chronic superficial gastritis. Thus, it was not surprising to find a striking association between H. pylori infection and peptic ulcer disease (table I), with infection rates significantly higher among persons with peptic ulcers than among age-matched controls [7]. It is interesting that although gastric and duodenal ulcers differ from one another in a number of characteristics, both are associated with H. pylori infection. It is now known that H. pylori is capable of colonizing islands ofgastric tissue in the duodenum (gastric metaplasia) and that the presence of these organisms in the duodenum is associated with a strikingly increased risk of duodenal ulceration. It is reasonable to ask whether H. pylori plays a causal role in duodenal ulceration or whether the organism has just found a good niche. There are no satisfactory experimental models of peptic ulceration, although longitudinal studies have shown that the presence of chronic superficial gastritis is associated with a 13-fold increase in the risk of duodenal ulceration over a lfl-year period [8]. We know that ulcer disease can be well treated with acid-reducing therapies but that when the therapy ceases the ulcers recur at rates of ~70% per year. Recently. several clinical trials have been performed that have assessed whether antimicrobial therapy affects duodenal ulceration (table 2). In each of the studies reported, treatment with a wide variety of agents to which H. pylori is susceptible resulted in healing of ulcers as well as significant reductions in ulcer recurrence rates. In those cases in which the therapy used eradicated H. pylori, ulcer recurrence rates during the following year were 5%). C. Acquired resistance to metronidazole occurs commonly (>5%). D. H 2 blockers can eradicate H. pylori. H. pylori organisms are A. anaerobes. B. microaerophiles. C. facultative aerobes. D. cryophilic. E. none of the above. The most outstanding biochemical characteristic of H. pylori is A. urease activity. B. nitrate reductase. C. acid phosphatase. D. lactase. E. carbonic anhydrase.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
UCLfI
CIO 1992; 15 (September)
CME Test
A. Infection always leads to upper gastrointestinal symptoms. B. Infection usually is self-limited. C. Development of a host immune response enables eradication of the organism. D. Tissue invasion is the critical pathogenetic step. E. None of the above. 10. Which of the following statements about nonulcer dyspepsia (NUD) is correct? A. The pathophysiology of NUD is now largely understood. B. NUD may coexist with gastric ulceration. C. H. pylori infection is often present in patients with NUD. D. The role of H. pylori infection in NUD pathogenesis is now well established. E. None of the above.
Downloaded from http://cid.oxfordjournals.org/ at Queen Mary, University of London on July 14, 2014
7. The presence of H. pylori infection can be diagnosed by A. culture. B. serology. C. visualization of the organisms on biopsy. D. urea breath test. E. all of the above. 8. Which of the following statements about H. pylori epidemiology is correct? A. Transmission from contaminated foods is the principal means of spread. B. In the United States, most children are infected. C. Person-to-person transmission is the major means of spread. D. There is no familial association with infection. E. None of the above. 9. Which ofthe following statements about H. pylori pathogenesis is correct?
393
