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In 1983, a pair of Australian microbiologists (Warren and Marshall) suggested that gastritis and peptic ulcers were infectious diseases, contradicting long-held beliefs concerning their epidemiology, pathogenesis, and treatment. In the same year, the 10th edition of Harrison's Principles of Internal Medicine described peptic ulcers as due to an unfavorable balance between gastric acid–pepsin secretion and gastric or duodenal mucosal resistance. Underlying causes cited included genetic and lifestyle (smoking) as well as psychologic factors (anxiety, stress). Treatment with bismuth salts, antacids, and inhibitors of acid secretion gave relief but not cure. Relapsing patients (50%-80%) were subjected to surgical treatments (vagotomy, partial gastrectomy), which had their own set of complications (reflux, afferent loop syndrome, dumping syndrome). All of this was logical and supported by clinical observations and research studies, but was simply incorrect. The bacteria now called Helicobacter had been observed but dismissed because they were so common and its urease was once considered a secretory product of the stomach itself. The Nobel Prize-winning studies that stimulated the reversal of this dogma have led to cures using antibacterial agents and new ideas linking Helicobacter infection to cancer. This experience has also left us with a sense that we can never be smug about what we “know” in medicine.
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Almost everything we once knew about ulcers was wrong
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BACTERIOLOGY: HELICOBACTER PYLORI
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Helicobacter pylori has morphologic and growth similarities to the campylobacters, with which they were originally classified. The cells are slender, curved rods with polar flagella. The cell wall structure is typical of other Gram-negative bacteria. Growth requires a microaerophilic atmosphere and is slow (3–5 days). The cells are rapidly motile due to the action of multiple polar flagella.
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Features are similar to Campylobacter
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A number of unique bacteriologic features have been found in H pylori. The most distinctive is a urease whose action allows the organism to persist in low pH environments by the generation of ammonia. The urease is produced in amounts so great (6% of bacterial protein) that its action can be demonstrated within minutes of placing H pylori in the presence of urea. Another secreted protein called the vacuolating cytotoxin (VacA) causes apoptosis in eukaryotic cells it enters generating multiple large cytoplasmic vacuoles (Figure 32–3). The vacuoles are felt to be generated by the toxin's formation of channels in lysosomal and endosomal membranes. Another protein, CagA, induces changes in multiple cellular proteins and has a strong association with virulence. Both VacA and CagA are delivered to cells by injection secretion systems (type IV). The genes for CagA and the components of its secretion system are located in a large PAI.
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Urease raises pH rapidly
VacA injures lysosomal and endosomal membranes
CagA induces multiple changes
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HELICOBACTER GASTRITIS
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CLINICAL CAPSULE
Helicobacter infections are limited to the mucosa of the stomach, and most are asymptomatic even after many years. Burning pain in the upper abdomen, accompanied by nausea and sometimes vomiting, is a symptom of gastritis. Ulcers may cause additional symptoms, depending on their anatomic location. It is common for gastric and duodenal ulcers to be unrecognized by the patient until they cause frank bleeding or rupture.
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Infection with H pylori causes what is perhaps the most prevalent disease in the world. The organism is found in the stomachs of 30% to 50% of adults in developed countries, and it is almost universal in developing countries. The exact mode of transmission is not known, but is presumed to be person to person by the fecal–oral route or by contact with gastric secretions in some way. Colonization increases progressively with age, and children are believed to be the major amplifiers of H pylori in human populations. A declining prevalence in developed countries may be due to decreased transmission because of less crowding and frequent exposure to antimicrobial agents.
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Infection is transmitted by human fecal or gastric secretions
Gastric colonization is prevalent worldwide
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Once established, the same strain persists for years, decades, even for life. Molecular epidemiologic analysis indicates the strains themselves have strong linkages to ethnic origins that can be traced back to the earliest known patterns of human migration. Helicobacter pylori has been called an “accidental tourist,” which was established in the stomachs of humans thousands of years ago and remained bound to the original population as it dispersed from continent to continent.
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Colonization persists indefinitely
Ethnic links are strong
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Helicobacter pylori is the most common precursor of gastritis, gastric ulcer, and duodenal ulcer cases which are not due to drugs. In addition Helicobacter gastritis caused by Cag+ strains is acknowledged to be an antecedent of gastric adenocarcinoma, one of the most common causes of cancer death in the world. It is also linked to a gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which is less common but shows the striking property of regressing with antimicrobial therapy. Helicobacter pylori gained the dubious distinction of being the first bacterium declared a class I carcinogen by the World Health Organization.
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H pylori is the sole nondrug cause of gastritis and ulcers
Adenocarcinoma and lymphoma are preceded by infection
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Helicobacter pylori is exclusive to humans, but other species have been found in the stomachs of a wide range of animals, where they are also associated with gastritis. It is difficult to imagine the old “stress ulcer” theories surviving the discovery of a cheetah with Helicobacter gastritis. Speculation that domestic animals may serve as a reservoir for human infection has not been confirmed.
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Other Helicobacter species occur in animals
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To persist in the hostile environs of the stomach, H pylori uses many mechanisms to adhere to the gastric mucosa and survive the acid milieu of the stomach (Figure 32–4). Motility provided by the flagella allows the organisms to swim to the less acidic locale beneath the gastric mucus, where the urease further creates a more neutral microenvironment by ammonia production. Urease production is regulated in response to changes in the gastric acidity such as rises to a pH as high as 6.0 following the buffering effect of meals. At the mucosa, adherence is mediated by multiple outer membrane proteins which bind to the surface of gastric epithelial cells and certain erythrocyte antigens (Lewis b).
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Urease neutralizes gastric acid
Motility facilitates surface microenvironment
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Helicobacter pylori colonization is almost always accompanied by a cellular infiltrate ranging from minimal mononuclear infiltration of the lamina propria to extensive inflammation with neutrophils, lymphocytes, and microabscess formation. Both gastritis and duodenal ulcers are most strongly associated with colonization of the antrum area of the stomach. The inflammation may be due to toxic effects of the urease or the VacA transported into the gastric epithelial cells by the secretion system. Inside the cell, VacA causes vacuolization of the endosomal compartment and has other effects including altered T-cell function. The CagA protein is injected into the gastric epithelial cell by the secretion system, where it triggers multiple enzymatic reactions including those that cause reorganization of the actin cytoskeleton and stimulation of cytokines. Variations in the genes contained in the PAI generate a mixed population of H pylori cells particularly in relation to the multiple properties of CagA. Added together urease, CagA, and VacA provide ample explanation for the gastritis that is universal in H pylori infection. This prolonged and aggressive inflammatory response could lead to epithelial cell death and ulcers. The progression from gastritis to ulcer remains to be explained although a duodenal ulcer-promoting gene has been identified.
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Multiple factors stimulate inflammation
VacA directly induces cellular changes and death
CagA alters cytoskeleton
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That decades of inflammation and assault by the virulence factors just described could cause metaplasia, and eventually cancer seems logical, but the specific mechanisms of carcinogenesis have only recently been explored. CagA, for example, has been shown to trigger a cascade of interactions leading to growth-promoting oncogenic signals. The gastric lymphomas may represent neoplastic transformation of B-lymphocyte clones proliferating in response to chronic antigenic stimulation. The discovery that H pylori colonization may affect hormones involved in glucose homeostasis has led to other hypotheses involving type 2 diabetes.
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Chronic inflammation leads to metaplasia
CagA can trigger oncogenic signals
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There is obviously little evidence of natural immunity in an infection that typically lasts for decades. The immunosuppressive effect of virulence factors such as VacA may be responsible in combination with yet to be discovered mechanisms.
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HELICOBACTER DISEASE: CLINICAL ASPECTS
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Primary infection with H pylori is either silent or causes an illness with nausea and upper abdominal pain lasting up to 2 weeks. Years later, the findings of gastritis and peptic ulcer disease include nausea, anorexia, vomiting, epigastric pain, and even less specific symptoms such as belching. Many patients are asymptomatic for decades, even up to perforation of an ulcer. Perforation can lead to extensive bleeding and peritonitis due to the leakage of gastric contents into the peritoneal cavity.
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Epigastric pain and nausea are signs of gastritis
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The most sensitive means of diagnosis is endoscopic examination, with biopsy and culture of the gastric mucosa. The H pylori urease is so potent that its activity can be directly demonstrated in biopsies in less than an hour. Noninvasive methods include serology and a urea breath test. For the breath test, the patient ingests 13C- or 14C-labeled urea, from which the urease in the stomach produces products that appear as labeled CO2 in the breath. A number of methods for the detection of antibody directed against H pylori are now available. Because IgG or IgA remains elevated as long as the infection persists, these tests are valuable both for screening and for evaluation of therapy. The advantage of direct detection of the organism is that culture is the most sensitive indicator of cure following therapy.
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Culture or urease detection is diagnostic
Serologic tests demonstrate chronic infection
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TREATMENT AND PREVENTION
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Helicobacter pylori is susceptible to a wide variety of antimicrobial agents. Bismuth salts (eg, Pepto-Bismol), which in the past were believed to act by coating the stomach, also have antimicrobial activity. Cure rates approaching 90% have been achieved with various combinations of bismuth salts and/or a protein pump inhibitor plus two antibiotics. Clarithromycin plus either amoxicillin or metronidazole and metronidazole plus tetracycline have been effective. Relapse rates are low, particularly when acid secretion is also controlled with the use of a proton pump inhibitor. These combination regimens must be continued for at least 2 weeks and may be difficult for some patients to tolerate. Prevention of H pylori disease awaits further understanding of transmission and immune mechanisms. Prophylactic treatment of asymptomatic persons colonized with H pylori is not yet recommended.
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Regimen may be difficult to tolerate