**7. Vitamin B12 deficiency anemia**

Vitamin B12 (cobalamin) deficiency is estimated to affect approximately 10–15% of the population older than 60 years. There are several causes where pernicious anemia and food-cobalamin malabsorption are the most common reasons. Cobalamin is obtained primarily from food through a complicated process where an acidic environment releases cobalamin from food 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 malabsorption [50].

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

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* should be screened for and eradicated [21].

### **8. Cardiovascular disease**

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) guide-

*H. pylori* infection has also been linked to iron-deficiency anemia (IDA) [42–44]. Mechanisms that cause IDA may increase iron loss due to hemorrhagic gastritis, gastric cancer, peptic ulcers, iron utilization for bacterial growth, achlorhydria resulting in reduced iron uptake,

A meta-analysis comprising 15,183 patients from 20 studies found an association between *H. pylori* infection and IDA (odds ratio (OR) 2.22) [46]. They also found a greater effect of eradication therapy plus iron than iron supplements alone but with heterogeneous results. Adult IDA patients reacted more strongly to eradication than children and adolescents, and bismuth triple therapy seemed to be more effective than proton pump inhibitor (PPI) triple therapy. The authors do not recommend a population-based screening for *H. pylori* to prevent IDA [46]. On the other hand, Herschko et al. studied 160 patients with autoimmune gastritis, of whom 83 presented with IDA [47]. When stratifying by age, they found a decreasing prevalence of coexistent *H. pylori* infection with increasing age: 88% at age <20 years, 47% at 20–40 years, 38% at 41–60 years, and 13% at age >60 years. A possible explanation, which other authors also have mentioned, is that *H. pylori* demands an acidic environment to survive, which no longer exists in advanced atrophic anemia. This might suggest that *H. pylori* infection in autoimmune gastritis may represent an early phase of the disease in which an infectious process is gradually replaced by an autoimmune disease terminating in a burned-out infection and the irreversible destruction of gastric mucosa. This might explain why younger patients with IDA

The British Society of Gastroenterology recommends noninvasive testing and antibiotic treatment for *H. pylori* in patients with IDA and normal esophagogastroduodenoscopy and colonoscopy [48]. The American College of Gastroenterology also recommends testing for *H. pylori* in patients with unexplained IDA [49]. The association between IDA and *H. pylori* infection in the pediatric population is less studied and with heterogeneous results. ESPGHAN/ NASPGHAN guidelines propose that in children with refractory IDA where there is an indication for upper endoscopy, it might be considered taking biopsies to test for *H. pylori* [41].

Vitamin B12 (cobalamin) deficiency is estimated to affect approximately 10–15% of the population older than 60 years. There are several causes where pernicious anemia and food-cobalamin malabsorption are the most common reasons. Cobalamin is obtained primarily from food through a complicated process where an acidic environment releases cobalamin from food

lines recommend testing for *H. pylori* in children with chronic ITP [41].

**6. Iron-deficiency anemia**

and reduced secretion of ascorbic acid [45].

18 Helicobacter Pylori - New Approaches of an Old Human Microorganism

have a high prevalence of *H. pylori* infection [47].

**7. Vitamin B12 deficiency anemia**

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

#### **9. Pancreatitis and pancreatic cancer**

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 stomach. The interaction leading to pancreatic cancer is unknown, but *H. pylori* infection in the antral part of the stomach decreases the production of somatostatin. This increases pancreatic bicarbonate and secretin which stimulates ductal epithelial cell proliferation [64]. In addition, studies indicate that *H. pylori* increases the risk of autoimmune pancreatitis through molecular mimicry and thereby increases the risk for pancreatic cancer [13, 60, 63–65]. These findings are of great interest and need further intensive research.

**12. Neuromyelitis optica**

**13. Asthma**

rin-4, and thus molecular mimicry could play a role [18].

could inhibit asthma in a multitude of ways.

**14. Hepatobiliary diseases**

Several studies have shown a correlation between *H. pylori* and neuromyelitis optica (NMO) [18]. NMO is a disease where antibodies attack aquaporin-4 on astrocytes in the central nervous system [80]. There is a close relationship between *H. pylori* and antibodies to aquapo-

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

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

The prevalence of asthma is increasing in areas where the prevalence of *H. pylori* is decreasing [81]. Meta-analyses have found an inverse correlation between *H. pylori* and asthma, but the mechanism is unclear [72, 82, 83]. CagA-positive *H. pylori* strains especially have been found to have a greater inverse relationship with asthma than those without *H. pylori* [81]. The longestablished hygiene hypothesis, where a lack of exposure to infectious agents leads to an increased risk for allergens, has been proposed as one way in which an absence of *H. pylori* causes asthma [82]. Th2-mediated immune responses drive allergies, while Th1-mediated immune responses inhibit these reactions. *H. pylori* appears to stimulate Th1-mediated immune responses but inhibit Th2-mediated immune responses through neutrophil-activating protein (HP-NAP), thereby inhibiting asthma development [84]. Another possible mechanism of *H. pylori* is upregulation of Treg cells which can control Th2-mediated immune responses [82]. A mouse study by Arnold et al. proved that *H. pylori* infection protected mice against asthma and an upregulation of Treg cells was found in mice infected with *H. pylori* [85]. Thus, *H. pylori*

Non-pylori *Helicobacter* species have been isolated from the liver of a variety of animals. *H. hepaticus*, *H. bilis*, and *H. cholecystus* are involved in the pathogenesis of chronic liver diseases and liver carcinomas [86–88]. *H. pylori*, *H. hepaticus*, *H. bilis*, and *H. cholecystus* have been detected in the human hepatobiliary tissue mainly by PCR [89–91]. Several studies have shown an increased prevalence of *H. pylori* in patients with hepatocellular carcinomas (HCC), liver encephalopathy (HE), liver fibrosis, cholangiocarcinoma (CCA), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis [92]. Much interest has been linked to HCC and CCA which histologically is characterized as adenocarcinomas. The pathogenesis has been proposed to follow the same pattern as in stomach cancer: hyperplasia, metaplasia, dysplasia, and lastly cancer [92]. Inflammatory cytokines and chemokines may play an important role in the pathogenesis. HE is a frequent complication to liver cirrhosis with a wide variety of neuropsychiatric symptoms, and high levels of ammonia play an important role in the pathogenesis [93]. *H. pylori* produces urease which reacts to ammonium, which might explain a possible mechanism in HE development. Liver fibrosis, among other ways, may be caused by *H. pylori* stimulating

## **10. Obesity and diabetes mellitus type 2**

Obesity is becoming a worldwide problem, and population studies have shown that in the same areas where the prevalence of *H. pylori* is decreasing, the prevalence of obesity is increasing [21, 66]. An implication of obesity could be diabetes mellitus type 2. A possible mechanism in which *H. pylori* affects obesity and thereby also affects type 2 diabetes is persistent damage of gastric mucosa, e.g., chronic gastritis. This might affect ghrelin production, thereby changing food intake and increasing body weight [67, 68].

Ghrelin is a hormone mainly produced by endocrine cells in the gastrointestinal mucosa and is released to the surroundings. This molecule is important for stimulating food intake and weight gain [69]. The damages that *H. pylori* introduce on gastric mucosa reduce the number of ghrelin-producing cells and decrease plasma ghrelin concentrations significantly, thereby reducing the feeling of satiety which can lead to obesity [67, 68, 70].

Ghrelin also seems to play a role in fat metabolism and glucose homeostasis, which can lead to a cross-reaction between lipid and glucose metabolisms that may result in insulin resistance [71]. However, one thing is clear, diabetes mellitus type 2 is a multifactorial disease, and *H. pylori* is only one of the many risk factors. *H. pylori* may also act on leptin or by activating cytokines that together can have an effect on insulin secretion [72, 73].

Although many studies have shown that there could be a correlation between *H. pylori* and obesity and diabetes mellitus type 2, other studies have shown that there are none and the correlation is still uncertain [66, 74].
