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

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

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 non-

*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

pathogenesis is still not completely understood.

16 Helicobacter Pylori - New Approaches of an Old Human Microorganism

pylori *Helicobacter* spp. instead of *H. pylori* [28, 29].

**4. Gastric cancer**

cancer [33, 34].

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

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 is defined as a platelet count <100 × 10<sup>9</sup> /L, may be either primary or secondary, and is classified as acute, persistent, or chronic [36].

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

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 an overall response (platelet count ≥30 × 10<sup>9</sup> /L and at least a doubling of initial platelet count) 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 maximal complete response rate of 65% [39].

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 antibodies and 82% harbored VacA antibodies [40]. The recently updated joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN/NASPGHAN) guidelines recommend testing for *H. pylori* in children with chronic ITP [41].

and thereafter binds to intrinsic factors secreted from parietal cells and finally is absorbed by specific receptors in the terminal ileum. Pernicious anemia is an autoimmune disorder consisting of chronic atrophic gastritis, decreased acid secretion, and antibodies directed against parietal cells and/or intrinsic factors, thereby leading to decreased cobalamin absorption. *H. pylori* possibly stimulates these antibodies directed against parietal cells/intrinsic factors, thereby inducing pernicious anemia. In food-cobalamin malabsorption, there is an inability to absorb food-bound or protein-bound cobalamin in a person that normally can absorb free cobalamin. *H. pylori* infection predisposes to a more severe form of food-cobalamin malab-

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

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

As mentioned above, it has been proposed that B12 deficiency can arise as the result of a late phase of *H. pylori-*induced atrophic gastritis [47]. This theory has been mentioned already in the early 1990s [51]. In a prospective case series with 138 patients with megaloblastic anemia and low cobalamin, it was found that 56% had *H. pylori* infection. Eradication therapy was successful in 40% of the infected patients, and the hematological parameters and B12 levels

The literature regarding the association between *H. pylori* and pernicious anemia shows more heterogeneous results than for ITP and IDA [52]. Therefore, treatment guidelines do not yet recommend screening for *H. pylori* in pernicious anemia. However, the Maastricht V/Florence Consensus Report does recommend that in all three of the abovementioned disorders *H. pylori*

Studies indicate an association between *H. pylori* and cardiovascular disease (CVD) [53, 54]. However, the stratification of patient groups and methods are very heterogeneous which may be the reason for the very diverging results in the studies [53]. *H. pylori* seems to mostly be associated with coronary atherosclerosis [55, 56]. This is in accordance with an unpublished study where we found increased antibodies to *H. pylori*, but not to *Chlamydophila pneumoniae* and *Cytomegalovirus* in patients undergoing surgery for coronary atherosclerosis. *H. pylori* can survive in monocytes, and it might be speculated whether the bacteria could be transferred from the stomach to the coronary vessels. Here, *H. pylori* may stimulate PAF and other factors that may act on angiogenesis [23, 56]. *H. pylori* may also stimulate the atherogenesis through molecular mimicry or vitamin B12 and folate malabsorption [13, 53, 54]. In addition, *H. pylori* may change the lipid profile by increasing LDL levels and decreasing HDL levels as seen in

Studies have shown a correlation between increased antibody levels to *H. pylori* in patients with pancreatitis and pancreatic cancer [60–63]. In an unpublished study, we showed that in more than 50% of patients with pancreatitis *H. pylori* was cultured from the antral part of the

improved in all these patients without complementary cobalamin therapy [52].

many other infections, which leads to atherogenesis [53, 54, 57–59].

**9. Pancreatitis and pancreatic cancer**

should be screened for and eradicated [21].

**8. Cardiovascular disease**

sorption [50].
