Helicobacter pylori

The Pathogen

H. pylori is a gram-negative, motile, flagellated spiral-shaped bacillus that resides in a unique biological niche, the human gastric mucosa. It is S shaped in-vivo and measures up to 5 μm long and 0.5 μm in width. Numerous studies provide evidence of colonization of the oral cavity, but whether this colonization is transient or persistent remains unclear.

The pattern of H. pylori gastric mucosal colonization and resultant inflammation plays a major role in determining disease phenotype. In 2005, a Nobel Prize in Medicine was awarded for the 1982 discovery of H. pylori (then called Campylobacter pyloridis ) and its association with duodenal and gastric ulcer disease. Helicobacter constitutes group III of the rRNA superfamily VI, which also includes Campylobacter (group I) and Arcobacter (group II). A number of Helicobacter species have been identified, with H. pylori being the most common and the primary pathogen associated with human disease. H. pylori has been isolated from primates (previously called Helicobacter nemestrinae ), but no conclusive evidence exists of animal-to-human transmission.

H. pylori is a microaerophilic bacterium that survives the acidic environment of the gastric mucosa due to its spiral shape, motility, and production of urease. H. pylori urease is a potent stimulus for memory CD8 ⁺ T lymphocytes, which may have important implications for the development of more severe disease outcomes. ^, Other virulence factors include the production of catalase, oxidase, mucinase, and a vacuolating cytotoxin (VacA), but the role of these on disease severity or progression is unclear. The cytotoxin-associated gene pathogenicity island is a portion of the H. pylori genome that contains a large number of the genes responsible for disease outcomes in the infected host. ^, Genetic variability is the rule with H. pylori with the variant strains considered “quasi-species.”

H. pylori infection elicits a variety of phenotypic responses in cultured gastric epithelial cells, including expression of proinflammatory genes and changes in the actin cytoskeleton. Both responses are mediated by the type IV secretion system (TFSS) encoded by the cag pathogenicity island ( cag PAI) that contains over 31 genes. ^{, ,} TFSS is postulated to be a key mechanism in H. pylori -associated carcinogenesis. H. pylori adheres to epithelial cells in the gastric mucosa and expresses several surface proteins, including a blood group antigen-binding adhesin (BabA). BabA-mediated binding of H. pylori to Lewis (Le)-associated antigens on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. Le-associated antigens are related biochemically to the ABO blood groups and also are thought to play a role in H. pylori adhesion to gastric mucosa. Moreover, H. pylori contains a fucosyltransferase gene (α 1,3,4-FUT ) expressed in the bacterial outer membrane as lipopolysaccharide moieties strikingly similar to Lewis ^x and Lewis ^y epitopes, which facilitates the persistence in colonization and immune cell evasion. ^{, , ,}

Epidemiology

H. pylori resides in the stomachs of >50% of the world’s population, making this pathogen the most common chronic infection worldwide. The prevalence varies by geographic area, age, race, and socioeconomic status. In developed countries, the prevalence may be 40% or less. However, in developing countries or populations in developed countries with poor water sanitation and socioeconomic conditions (e.g., Native Canadian and Native Alaskan populations), up to 90% of the population is infected. ^, Socioeconomic status has an inverse relation with the prevalence of infection and is one of the most important risk factors for acquisition. In poor populations, infection usually is acquired early in childhood, with most infections acquired before 10 years of age. Conversely, large seroprevalence studies demonstrate that H. pylori infection has decreased substantially for the last 5 decades, with a <15% prevalence by 10 years of age ( Fig. 174.1 ). ^, Data suggest that acquisition is decreasing in age cohorts born more recently worldwide, and such decreases are more prevalent in developed countries. ^{, ,} The specific reason for declining prevalence is unknown, although better living conditions, less crowding, smaller family size, clean, chlorinated water, and the widespread use of antibiotics may contribute. ^, Some investigators have speculated that not all H. pylori strains are pathogenic, and that at some point during the microbe and/or human evolution H. pylori may have been a constituent of the human gastrointestinal microbiome.

Most new H. pylori infections are acquired during childhood, especially in developing countries, with up to 50% of children infected during their few years of life in some countries. ^, Close contact with children, especially siblings aged <5 years, could be a more important risk factor for recurrent infection than the age at initiation of treatment. Most data suggest that a child’s mother plays the predominant role in infection among infants and young children. ^, Lower socioeconomic status correlates with higher H pylori prevalence. ^{, ,} In the US, African American, Hispanic, and immigrant populations have a 2- to 6-fold increased risk of seropositivity compared with White people of higher socioeconomic status. ^{, , ,} Overall, sex is not associated with the prevalence of H. pylori infection but may play a role in the disease outcome. Increased consumption of fruits, vegetables, and vitamin C supplements reduces the probability of acquisition of H. pylori infection and the severity of disease outcomes. ^, Breastfeeding during infancy has not been found to be protective against H. pylori infection. ^,

H. pylori transmission occurs primarily from person to person, but waterborne and iatrogenic spread through contaminated medical equipment also have been described. Person-to-person transmission includes fecal-oral, gastro-oral, and oral-oral routes, with much higher risks associated with neurologically impaired persons residing in institutionalized settings where close personal contact and exposure to feces and vomitus are frequent. Multiple, large family studies show increased risk of intrafamilial transmission, especially mother to offspring, younger to older sibling, and between spouses. ^, A number of studies demonstrated that H. pylori isolates from family members are homologous by DNA fingerprinting, and the fecal-oral route is the predominant mode of transmission.

The oral-oral transmission also can occur in certain populations and may not be associated solely with the premastication of food by mothers. Saliva, dental plaque, reflux of gastric contents, and vomitus are considered sources of H. pylori . ^, Although transmission through contaminated water is debated, the evidence is compelling. One study showed that children whose water source was outside their homes had infection rates 3-fold higher than those whose homes had an internal water source. Transmission in the healthcare setting also is important, even in the developed world. ^, A meta-analysis spanning 20 years showed that the risks are highest for gastroenterologists, some nurses, and employees caring for persons with mental disabilities. ^, Moreover, the use of improperly disinfected endoscopes increases the risk of infection, whereas disinfection of endoscopes by soaking in glutaraldehyde cleaning agents and cleansing of the channels by vigorous brushing reduces the risk of H. pylori acquisition. ^,

Pathogenesis

H. pylori infection and its long-term effects, including peptic ulcer, MALToma, and gastric adenocarcinoma, result from a complex interaction between the organism’s virulence factors, susceptibility and immunological response of the host, and environmental factors that might modulate susceptibility to infection or disease outcome. ^, Several mechanisms have been elucidated that allow the pathogen to persistently colonize the gastric epithelium, generate mucosal inflammation, and regulate gastric acid output, and subsequently cause a wide spectrum of chronic ailments.

Colonization of gastric mucosa by the motile H. pylori is initiated by a unique and specific tropism for gastric epithelial cells rich in Lewis ^b blood group antigen. ^{, ,} H. pylori uses over half of its energy to produce high quantities of urease enzyme, which converts urea into ammonium and bicarbonate, thereby creating an alkaline microenvironment that permits survival despite gastric acidity. ^, Attachment to the gastric epithelial cell Lewis ^b receptor is mediated by the bacterial BabA. Although other bacterial adhesins may contribute to colonization, expression of BabA has been associated with duodenal ulcer and gastric adenocarcinoma. ^, The vacuolating cytotoxin VacA also is associated with an increased risk for gastroduodenal ulcers and, to a lesser extent, gastric cancer. Polymorphisms, and the two main variable regions of the vacA gene, the signal sequence ( s ) and the mid-region ( m ) properties, facilitate typing of isolated strains. Expression of these regions reflects the production of the vacuolating toxin; s1-m1, s1-m2, and s2-m1 genotypes correspond to high, medium, and low toxin-producing strains, respectively. However, the overall correlation between vacA and disease phenotype remains equivocal.

H. pylori is a potent inducer of gastric mucosal inflammation through various mechanisms, the most important of which is CagA. TFSS are macromolecular assemblies, which are widespread in pathogenic bacteria, and often are used to deliver effectors into host cells. Encoded for in the cag pathogenicity island, H. pylori encodes Cag-TFSS that mediates the injection of the toxin CagA into gastric epithelial cells, where it undergoes tyrosine phosphorylation by host cell kinases. ^, CagA then activates nuclear factor κB (NF-κB), the intracellular signaling pathway that regulates induction of the proinflammatory cytokines interleukin-8 (IL-8) and IL-1β. ^, The relative ability of H. pylori strains to induce epithelial cell inflammation is dependent on the presence of an intact cag pathogenicity island (PAI) containing the picB gene. Strains that possess the complete PAI induce pangastritis, which evolves to gastric ulceration, atrophy, intestinal metaplasia, and eventually, distal gastric cancer. CagA ⁺ variant strains that have an incomplete cag PAI (because of deletions or mutations) induce antral-predominant gastritis, more likely leading to duodenal ulcer than to distal gastric cancer. ^,

H. pylori strains that possess toxigenic vacA s1 allele, a complete cag PAI, cagA alleles containing multiple EPIYA phosphorylation sites, and expression of BabA adhesin, correlates with the development of gastroduodenal disease in adults. In a study of North American children with a variety of gastroduodenal pathologies, the presence of a functional cag PAI had a significant correlation with ulcer disease. Although H. pylori strains that possess the cag PAI and secrete a functional cytotoxin induce more severe gastric injury and further augment the risk for developing distal gastric cancer, carcinogenesis also is influenced by host genetic diversity, particularly involving immune response genes such as IL-1ss and TNF as well as expression of tumor suppressor genes including p53 and c- myc .

H. pylori urease binds to major histocompatibility complex class II molecules expressed on the surface of gastric epithelial cells, which in turn induces apoptosis and thus modulates cell growth. A second mechanism is the induction of Fas-Fas ligand-regulated apoptosis through two different proinflammatory cytokines: (1) production of interferon (IFN)-γ induced by a Th1 immune response triggered by H. pylori colonization; (2) induction of IL-1β by CagA. CagA is one of the primary H. pylori -produced stimuli of production of the proinflammatory cytokine IL-1β, which also is a potent inhibitor of gastric acid secretion. ^{, ,} Gastric acidity may be further reduced in H. pylori -infected individuals with particular polymorphisms of the IL-1β gene promoter, thereby increasing the risk of atrophic gastritis and gastric adenocarcinoma. ^, Another virulence marker of H. pylori is the iceA gene. The gene has two distinct genotypes, iceA1 and iceA2, but the overall relevance of genotypes to disease phenotype remains unclear.

Although >50% of the world’s population is infected, the majority of individuals remain clinically asymptomatic, suggesting that not all H. pylori strains are pathogenic. It remains unclear why 15%–20% develop gastroduodenal ulcer disease, and <1% develop gastric adenocarcinoma. ^, Identifying markers that predict more severe disease outcomes is of great importance to implement cost-effective public health strategies to target eradication treatment efforts. Studies to determine associations between BabA, VacA, CagA, and PicB with peptic ulcer and gastric cancer continue to reveal conflicting results. ^{, , , ,} While cag PAI appears to be a marker of inflammation and clinical disease , other virulence factors appear to be markers of the geographic distribution of organisms rather than predictors of disease outcome ( Fig. 174.2 ). ^,

Clinical Manifestations

Intestinal Disease

H. pylori infection in children is generally asymptomatic. However, once there is persistent colonization, gastritis develops almost universally. Although there are reports of spontaneous elimination of H. pylori infection in children, many of these studies are limited by the methods used to detect infection. ^, The association between H. pylori infection and gastritis and duodenal ulcer disease in children is very strong. Nodular gastritis appears to be observed more commonly in children ( Fig. 174.3 ). However, it is not known how long it takes to develop visible nodules or which children with lymphofollicular gastritis will progress to develop MALToma and over what time period. Studies have demonstrated that eradication of H. pylori in children with MALT lymphoma results in the resolution of both gastric and extragastric mucosal disease. ^,

Although cases of pediatric gastric adenocarcinoma and MALT lymphoma have been reported, these conditions are rare in children. ^, However, early childhood acquisition and persistence of H. pylori significantly increase the risk of gastric malignancies in adults. ^, Atrophic gastritis and intestinal metaplasia, precursor lesions for gastric cancer, occur in H. pylori -infected children. ^, In a study of 173 children from countries with a high incidence of gastric cancer, atrophic gastritis was noted in 16% of those with active H pylori infection.

Landmark studies have demonstrated that IL-1 gene cluster polymorphisms leading to increased IL-1β production are associated with an increased risk of H. pylori -induced hypochlorhydria and gastric cancer. Compared with healthy controls, relatives of patients with gastric cancer had a higher prevalence of hypochlorhydria (27% vs. 3%) despite having a similar prevalence of H. pylori infection (63% vs. 64%). ^, Relatives of cancer patients matched for H. pylori prevalence also had a higher prevalence of atrophy (34%) than patients with non-ulcer dyspepsia (5%). Increased prevalence of precancerous gastric abnormalities in relatives is limited to those with H. pylori infection.

A causal relationship between H. pylori infection and recurrent abdominal pain of childhood has not been established definitively. ^, Symptoms of epigastric pain, abdominal pain causing nocturnal wakening, hematemesis, and recurrent vomiting are not predictive of H. pylori infection. In addition, although a relationship between ulcer disease and abdominal symptoms is apparent, it is unclear whether chronic gastritis causes symptoms in children. Results from studies around the world have been conflicting, precluding a definitive recommendation for treatment of H. pylori found in the child with gastrointestinal symptoms but no demonstrable disease. In one randomized placebo-controlled treatment trial, 20 children with recurrent abdominal pain and H. pylori infection all had evidence of gastritis; 8 of 10 in the treatment group and none in the placebo group had eradication of H. pylori . However, at 52 weeks, bacterial eradication and healing of gastric inflammation did not lead to symptomatic relief of chronic abdominal pain.

The true incidence of gastric and duodenal ulcer disease in children is unknown. However, children with duodenal or gastric ulcers in general have symptoms similar to those of adults, including a sharp, “burning” type of pain, located primarily in the epigastrium that generally occurs with an empty stomach, between meals, and during the early morning hours. In addition, signs of occult, as well as frank bleeding, can occur. Primary ulcers in the pediatric population (the majority of which are H. pylori -associated) occur in the duodenum and are seen in older children. Gastric ulcers are less common and usually due to another disease process, such as Crohn’s disease or chemical irritation of the gastric mucosa caused by aspirin or nonsteroidal anti-inflammatory drugs.

Whether H. pylori infection predisposes to or provides protection against diarrheal diseases in children remains a topic of debate. A number of studies provide compelling evidence that H. pylori -infected children are more at risk for diarrhea due to enteric infections. ^, For example, a study in Peru showed a high incidence of diarrhea in children with H. pylori infection, probably as a result of the transient achlorhydria that occurs during the acute phase of infection. Increased rates of enteric infection in the face of early H. pylori infection likely are due to poor water sanitation and/or poor hygiene resulting in increased exposure to enteric pathogens. Conversely, others studies have shown a protective effect of H pylori infection against diarrheal diseases. These conflicting observations may be related to the age, socioeconomic status, or geographic regions of the population studied, or the stage at which infection is detected, as protection against diarrhea occurs when the pH returns to acid. Furthermore, the presence of H. pylori augments the local and systemic immune response to enteropathogens, as has been demonstrated in Vibrio cholerae . ^,

The controversy surrounding whether H. pylori infection is protective, causative, or unrelated to gastroesophageal reflux disease (GERD) in adults and children has, for the most part, been settled. H. pylori at most is an innocent bystander and is not protective against GERD or its sequelae in both children and adults. ^{, ,} Although there is a reverse prevalence of GERD in countries with a high and low prevalence of H. pylori, the conclusion of causality is overly simplistic. In a study of 95 children and adolescents who were recruited and completed an eradication trial with a mean follow-up of 11.2 months, the distribution of outcomes for each symptom (better, worse, unchanged) was similar before and after eradication and did not depend on prior H. pylori status. When the diagnosis of GERD is made clinically, or by pH monitoring, it is not necessary to screen for H. pylori .