**2. Gastritis and peptic ulcer**

**1. Introduction**

14 Helicobacter Pylori - New Approaches of an Old Human Microorganism

to the animal-associated *Helicobacter* spp. [11].

**Genus Species**

*Wolinella succinogenes*

*Epsilonproteobacteria* is a large group of Gram-negative curved or spiral rods which include the genera *Campylobacter* spp., *Helicobacter* spp., *Arcobacter* spp., and *Wolinella* spp. (**Table 1**) [1]. The bacteria have microaerobic or anaerobic growth requirements, and many of these are difficult to culture from clinical samples [2]. Recent studies with identification of *Epsilonproteobacteria* by PCR have shown that these bacteria cause infections in humans more commonly than previously thought [3, 4]. The most well-known species are *Campylobacter jejuni/coli* causing gastroenteritis [2] and *Helicobacter pylori* causing gastric and extra-gastric manifestations [5]. This chapter will focus on *Helicobacter* spp. and mainly on *H. pylori*. *Helicobacter* spp. can be divided into three groups: (1) gastric *Helicobacter* spp., (2) intestinal *Helicobacter* spp., and (3) hepatobiliary *Helicobacter* spp. [6]. The knowledge about intestinal *Helicobacter* spp. in human diseases is very limited mainly because they are very difficult to culture. In contrast to the intestinal and hepatobiliary *Helicobacter* spp., the gastric *Helicobacter* spp. produce a great amount of urease, which is important for its survival in the stomach by neutralizing acid, thereby creating a neutral microenvironment [7]. Urease is also crucial for the bacteria's survival through antigenic shedding where urease captures human antibodies [8]. The human gastric *Helicobacter* sp., *H. pylori*, is the most intensively investigated *Helicobacter* sp., but gastric *Helicobacter* spp. from animals (*Helicobacter heilmannii*, *Helicobacter bizzozeronii*, *Helicobacter suis*, etc.) have also been found in the human stomach [9]. These bacteria colonize the stomach in very different ways. *H. pylori* colonizes the antrum part of the stomach on the surface between epithelial cells and can actively move down between the epithelial cells [10]. On the other hand, *Helicobacter* sp. from animals colonizes the parietal cell glands in the corpus/fundus part of the stomach which may contribute to other manifestations than those caused by *H. pylori* [11]. Usually, a stronger cellular immune response is seen in *H. pylori* in comparison

*Arcobacter anaerophilus*, *aquimarinus*, *bivalviorum*, *butzleri*, *cibarius*, *cloacae*, *cryaerophilus*, *defluvii*, *ebronensis*,

*Campylobacter avium*, *canadensis*, *coli*, *concisus*, *corcagiensis*, *cuniculorum*, *curvus*, *fetus* subsp. *fetus*, *fetus*

*Helicobacter acinonychis*, *ailurogastricus*, *anseris*, *apri*, *aurati*, *baculiformis*, *bilis*, *bizzozeronii*, *brantae*,

*pacificus*, *suis*, *thereius*, *trophiarum*, *venerupis*

*suis*, *trogontum*, *typhlonius*, *valdiviensis*

**Table 1.** The species belonging to the four largest groups of *Epsilonproteobacteria* [102].

*ellisii*, *haliotis*, *halophilus*, *lanthieri*, *lekithochrous*, *marinus*, *molluscorum*, *mythili*, *nitrofigilis*,

subsp. *testudinum*, *fetus* subsp. *venerealis*, *geochelonis*, *helveticus*, *hepaticus*, *hominis*, *hyoilei*, *hyointestinalis* subsp. *hyointestinalis*, *hyointestinalis* subsp. *lawsonii*, *iguanorium*, *insulaenigrae*, *jejuni* subsp. *doylei*, *jejuni* subsp. *jejuni*, *lanienae*, *lari* subsp. *concheus*, *lari* subsp. *lari*, *mucosalis*, *ornithocola*, *pyloridis*, *pinnipediorum*, *pinnipediorum* subsp. *caledonicus*, *pinnipediorum* subsp. *pinnipediorum*, *rectus*, *showae*, *sputorum*, *subantarcticus*, *upsaliensis*, *ureolyticus*, *volucris*

*canadensis*, *canicola*, *canis*, *cetorum, cholecystus*, *cinaedi*, *cynogastricus*, *equorum*, *felis*, *fennelliae*, *ganmani*, *heilmannii*, *hepaticus*, *himalayensis*, *jaachi*, *japonicus*, *macacae*, *marmotae*, *mastomyrinus*, *mesocricetorum*, *muridarum*, *mustelae*, *pamatensis*, *pullorum*, *pylori*, *rodentium*, *salomonis*, *saguini*, Whenever *H. pylori* is found in the human stomach, there is never just a simple colonization. Instead, there is always a cellular and humoral immune response confirming that *H. pylori* causes infection [10, 19, 20]. Thus, patients with gastritis and *H. pylori* have *H. pylori*-related gastritis. However, if there is no *H. pylori* infection, patients may have functional gastritis but no inflammation. *H. pylori*-related gastritis may benefit from antibiotic treatment, whereas there is no indication for antibiotic treatment for functional gastritis [21].

Peptic ulcers occur in about 10% of patients infected with *H. pylori* where most (80%) are duodenal ulcers [19]. More than 90% of duodenal ulcers are caused by *H. pylori* [19]. The pathogenesis of these ulcers is not clear, but they often occur in the part of the duodenum where the flow from the stomach content is the highest. Duodenal ulcers may be caused by a combination of physical, physiological, and immunologic effects as well as *H. pylori*. Patients with duodenal ulcers almost always benefit from antibiotic treatment. More than 60% of gastric ulcers are caused by *H. pylori*, while the remaining 40% may be caused by different sources such as medication (NSAID, etc.) [21, 22]. Gastric ulcers are often found in the isthmus area of the stomach where the amount of blood flow of the stomach is the lowest. *H. pylori* stimulates the production of platelet-activating factor (PAF) which acts on angiogenesis by contracting blood vessels [23]. *H. pylori* has a direct damaging effect on the epithelium and interferes with the immune system in many ways [24]. However, the mechanisms are very complex, and the pathogenesis is still not completely understood.

If *H. pylori* is treated in the early premalignant stages (atrophic gastritis), further cancer development can be prevented [35]. If intestinal metaplasia has developed, it is believed that antibiotic treatment has no effect [21]. As with gastritis and peptic ulcers, the relationship between *H. pylori* and gastric cancer has many loose ends that need to be explained before we

Idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura (ITP) is an acquired autoimmune disease resulting in the destruction of antibody-covered platelets and decreased platelet production. This results in an increased risk for bruising and bleeding. ITP

The mechanism that leads to ITP in *H. pylori*-infected patients is not entirely established. It is proposed that molecular mimicry may be involved [13]. Cross-reactivity between platelet-associated immunoglobulin G and CagA has been found, which suggests that mimicry

It is well established that *H. pylori* screening may be warranted in patients with ITP. A systematic review from 2009 with 696 evaluable patients found that in patients with *H. pylori* infection, eradication of the bacteria led to a complete treatment response in 43% of the patients and

of 50%. The treatment tended to be more effective in milder forms of thrombocytopenia. The authors found that the predictors of treatment response were quite heterogeneous from study to study. Shorter duration of ITP was consistently found, and response rates tended to be higher in countries with a higher prevalence of *H. pylori* [38]. In the highly *H. pylori* prevalent country of South Korea, a more recent prospective study with 26 patients with persistent or chronic ITP investigated the efficacy of *H. pylori* eradication as a first-line treatment in patients with moderate thrombocytopenia [39]. The study found an eradication rate of 80% and a

The most recent ITP guidelines from the American Society of Hematology (ASH) recommend eradication therapy in adult ITP patients with *H. pylori* infection. They do not define which patients should be screened or at what point in the course of the illness patients should receive treatment [36]. ASH recommends against routine testing in children because of diverging results but rather argues for the consultation with a pediatric gastroenterologist beforehand. Since the publication of the ASH guidelines, a randomized-controlled trial (RCT) with 85 ITP-affected children has been published. Twenty-two children were *H. pylori* infected, and they were randomized to receive either eradication therapy or no therapy. Complete response was achieved in 60% of the treated children compared to 18% of the children who were not treated. The authors suggested that *H. pylori* infection may play a bigger role in the pediatric ITP population than the earlier notions. It is also noted that 86% of the patients had CagA

/L, may be either primary or secondary, and is classi-

Clinical Manifestations of the *Epsilonproteobacteria* (*Helicobacter pylori*)

http://dx.doi.org/10.5772/intechopen.80331

/L and at least a doubling of initial platelet count)

can completely understand the process.

is defined as a platelet count <100 × 10<sup>9</sup>

fied as acute, persistent, or chronic [36].

an overall response (platelet count ≥30 × 10<sup>9</sup>

maximal complete response rate of 65% [39].

**5. Idiopathic thrombocytopenic purpura (ITP)**

through CagA may play a role in the development of ITP [37].

#### **3. Mucosa-associated lymphoid tissue (MALT) lymphomas**

MALT lymphomas are a group of lymphomas which arise in the tissue normally devoid of lymphoid tissue, such as the stomach. These tissues accumulate lymphoid tissue during chronic antigenic stimulation such as chronic infections and autoimmune diseases. *H. pylori* causes about 80% of low-grade MALT lymphomas and 60% of high-grade MALT lymphomas [19]. Eradication of *H. pylori* stops the progression in most cases, and 60–80% of early-state low-grade MALT lymphomas will regress [25]. The mechanism by which *H. pylori* induces MALT lymphomas is unclear, and there is no evident correlation between MALT lymphomas and *H. pylori* virulence factors [26]. One theory is that the development of gastric MALT lymphomas in patients with *H. pylori* could be secondary to chronic antigenic stimulation of the immune system by the pathogen [27]. However, as in many other diseases, antigenic mimicry may also play a role [27]. Finally, it is possible that MALT lymphomas are correlated to nonpylori *Helicobacter* spp. instead of *H. pylori* [28, 29].

## **4. Gastric cancer**

*H. pylori* causes approximately 80% of all gastric cancer cases, and in 1994 *H. pylori* became categorized as a Group 1 carcinogen meaning that *H. pylori* is a definite carcinogen to humans [30].

The development of gastric cancer is a complex process that depends on *H. pylori* virulence factors, host mucosa properties, immunological reactions to infections, as well as environmental factors in the stomach. In *H. pylori*, virulence factors like CagA and VacA have been suggested to influence cancer development. *CagA* gene and the type IV secretion system (T4SS) are encoded by a 40-kb DNA fragment called *cag* pathogenicity island (*cag*PAI) [19, 31]. CagA protein infects host gastric epithelial cells via the T4SS, where it is tyrosine-phosphorylated by host kinases at specific glutamate-proline-isoleucine-tyrosine-alanine (EPIYA) motifs [31, 32]. CagA thereafter interferes with different host cell-signaling pathways causing changes in cell growth, polarity, and motility, thereby increasing the risk for gastric cancer [19, 32]. VacA toxin affects gastric epithelial cells in a similar manner by affecting the host's inflammatory response as well as cellular apoptosis among other ways [19]. Other host factors could be high-salt diets and iron deficiency, which have been proven to increase the risk for gastric cancer [33, 34].

If *H. pylori* is treated in the early premalignant stages (atrophic gastritis), further cancer development can be prevented [35]. If intestinal metaplasia has developed, it is believed that antibiotic treatment has no effect [21]. As with gastritis and peptic ulcers, the relationship between *H. pylori* and gastric cancer has many loose ends that need to be explained before we can completely understand the process.
