The extragastric manifestations represent indeed one of the most fascinating and appealing issues of the whole history of Helicobacter pylori. In fact, several reviews are published on this topic every year, just to prove the high interest of researchers from all over the world. Similarly, there is also a great interest in some bacteria composing the gut microbiota as a possible cause of different gastrointestinal (GI) or extra-GI diseases; H. pylori may indeed represent, in this context, one of the best models of host-bacterial interaction, thus opening the way for new studies on the role of bacteria of the GI tract in different diseases, even outside the gastroduodenal environment. This review article is aimed at summarizing the most relevant studies published on this topic from March 2013 to April 2014.
Several studies have been published on this issue over the last year. Hughes et al. showed the occurrence of a concomitant decline in the prevalence of both heart attacks and duodenal ulcers in a military cohort of subjects born around 1930. The authors speculated that as duodenal ulcer is strongly related to H. pylori infection, the concomitant decline of heart attacks may be due to the interference with H. pylori eradication. While inflammation has been shown to play a key role in the destabilization of atherosclerotic plaques, Nakagawa et al. demonstrated that high serologic IL-6 levels are significantly associated with H. pylori infection, possibly playing a role in ischemic heart disease (IHD). In a similar study, Figura et al. reported high circulating levels of IL-6 and B-type natriuretic peptide, a biomarker of heart failure, in patients with coronary artery disease and infected by CagA-positive strains. To highlight the significant role of CagA-positive strains in this argument, Ikeda et al. recently showed that H. pylori infection in general is not associated with a risk of myocardial infarction or stroke, in contrast to CagA positivity. In fact, the association between myocardial infarction was only a trend (p = .10), and there was no association with stroke. Concerning the possible role of H. pylori on the occurrence of some atherosclerotic risk factors, Vahdat et al.described a positive association between coinfection with Chlamydia pneumoniae and H. pylori and essential hypertension. Taken together, these results highlight the potential role of CagA-positive strains in the occurrence of cardiovascular diseases.
Sealy-Jefferson et al. demonstrated that antibody levels to H. pylori predicted the incidence of strokes in a Mexican–American population (OR: 1.58; 95% CI: 1.09–2.28). On the other hand, Laek et al. studied a possible correlation between positivity to infectious agents, such as C. pneumoni,H. pylori,cytomegalovirus, herpes simplex virus, and hepatitis A virus, and coronary artery calcium (CAC) but with negative findings.
A possible role of H. pylori in diabetes mellitus (DM) has been fully investigated . A study from China reported that chronic H. pylori infection is significantly associated with high levels of glycated hemo-globin A1c and type 2 DM in patients over 65 years old (p = .001) and decreased levels of insulin and insulin sensitivity in subjects under 45 years old (p = .05). Yang et al. also reported a significant association between H. pyloriinfection and DM (OR: 1.42, 95% CI: 1.01–2.01), but not with prediabetes (OR: 1.02, 95% CI: 0.77–1.36). Interestingly, the possible role of H. pylori in complications of DM has been also investigated. A meta-analysis by Wang et al. showed a possible association betweenH. pylori and the risk of nephropathy (RR: 1.35, 95% CI: 1.06–1.73) and neuropathy (RR: 1.73, 95% CI: 1.03–1.40), especially in Asian patients. Similar results were obtained in a similar study showing a positive correlation between H. pylori infection and nephropathy in DM patients. On the other hand, some authors found negative results. Vafaeimanesh et al., in fact, did not find any correlation between H. pylori infection and serum levels of adiponectin, a marker of adipocyte function, in patients with DM, although the degree of insulin resistance was significantly higher in infected patients. Jafarzadeh et al.reported a similar H. pylori infection rate between type 2 DM and nondiabetic controls (76% vs 75%), while the anti-H. pylori IgG titer was significantly higher in nondiabetic subjects compared with DM patients (131.63 ± 11.68 vs 54.43 ± 4.50 U/mL, p < .0001). Haeseker et al. did not demonstrate any positive association between H. pyloriinfection and DM, in contrast to some viruses such as EBV and HHV6, while Vafaeimanesh et al.showed that H. pylori eradication plays no role in the control of glycemia in type 2 DM patients. Similarly, Wada et al.found that H. pylori eradication did not affect glycemic control in Japanese patients with type 2 DM, at least during the 6-month observational period.
A study showed a significant positive predictive value of antibody level against H. pylori and stroke in a Mexican population (OR: 1.58; 95% CI: 1.09–2.28). Similarly, Katan et al. clearly showed that infection burden sustained by C. pneumoniae, H. pylori, CMV, HS1, and HS2 significantly increases the risk of stroke and impairs cognitive performances measured by mini-mental state examination. On the contrary, a prospective cohort analysis performed on 9895 subjects showed an inverse relationship between H. pyloristatus and stroke mortality.
Two studies also evaluated the role of H. pylori on dementia. Huang et al. reported that H. pylori infection may increase the risk of developing non-Alzheimer disease dementia by 1.6-fold. Similarly, Chang et al. showed that H. pylori eradication in patients with Alzheimer disease is associated with a decreased progression of dementia, and Beydoun et al.clearly reported that H. pylori seropositivity is associated with poor cognition among US adults.
Concerning multiple sclerosis (MS), Mohebi et al.found a lower prevalence of MS in patients with H. pylori, thus proposing a protective rather than a negative role of H. pylorion that neurological disease. Similar results were reported by Long et al. concerning MS in Chinese patients, even though a positive association with neuromyelitis optica (NMO) and with higher levels of AQP4, a marker of NMO, has been clearly shown.
Iron Deficiency Anemia
The role of H. pylori infection in unexplained iron deficiency anemia (IDA) has already been confirmed. A study showed that while prevalence of H. pylori in patients with IDA is higher compared with that of the general population, 64–75% of the patients reported a complete disappearance of IDA after H. pylori eradication. A study by Queiroz et al. clearly identified H. pylori infection as a predictor of low ferritin and hemoglobin in children from Latin America, and it was associated with a lower mean corpuscular value (MCV) and mean corpuscular hemoglobin (MCH). Another study performed on adult patients with iron-refractory anemia or IDA showed that H. pylori may be considered as the cause of IDA in 38.1% of the patients, especially in postmenopausal women. An article by Carbotti et al. reported a significant association among pangastritis, iron deficiency, IDA, and levothyroxine malabsorption, thus demonstrating that the type of gastric histologic damage is crucial in discriminating the clinical manifestations of H. pylori-associated diseases. Similarly, a study by Hamed et al.found a difference between infected and noninfected patients concerning the occurrence of dyspepsia and anemia as well as a different distribution of those conditions among patients with different histologic patterns. Interestingly, Nashaat et al.showed that the response to iron therapy in patients with IDA and without H. pylori infection was significantly higher than in patients with active infection. In order to more thoroughly investigate the mechanisms behind this association, Azab et al.studied the role of hepcidin, a systemic iron homeostasis regulator, showing that H. pylori infection upregulates its serum levels, thus attenuating the response to iron therapy in children with IDA. Similar results were also reported by Ozkasap et al.who demonstrated that H. pylori eradication significantly reduces the levels of hepcidin, possibly by increasing the response to iron therapy. On the other hand, Kim et al. did not find any significant association between H. pylori infection and serum levels of prohepcidin, while this biomarker was decreased in patients with atrophic gastritis. Finally, the results of three recent studies did not support any association between H. pylori infection and IDA; however, the occurrence of some biases, such as the exact definition of IDA or the absence of information concerning the specific gastric histologic patterns shown by patients, may, in our opinion, affect the results of studies performed on this important issue.
Idiopathic Thrombocytopenic Purpura
The role of H. pylori on idiopathic thrombocytopenic purpura (ITP), via the modulation of Fcγ-receptor balance of monocytes/macrophages or molecular mimicry mechanisms between platelet and H. pylori peptides, is well defined. A study by Payandeh et al. clearly reported a significant beneficial effect of H. pylori eradication in patients with mild thrombocytopenia, but a poor response in patients with severe thrombo-cytopenia was noted. In a similar study, Teawtrakul et al.showed a significant platelet count response in approximately 80% of adults with ITP after H. pylori eradication within a median time of 4 months. Nevertheless, some authors reported negative findings. Samson et al. did not show any significant difference between infected and noninfected patients concerning the platelet count, while Gan et al. reported a low prevalence of H. pylori infection in patients with ITP and the absence of any significant effect of H. pylori eradication on the platelet count. Differences in the definition of ITP may be the cause of those findings, at least in our opinion.
A meta-analysis by Shi et al.conducted on patients with autoimmune thyroid disease (ATD) reported a significant role of H. pylori in Grave's disease (GD), more than in Hashimoto's thyroiditis (HT), with an additional increased risk in the case of infection sustained by CagA-positive strains. Another study by Aghili et al. reported a significant epidemiological association between H. pylori infection and HT in patients from Iran. Similarly, Zekry et al. demonstrated a significant association between H. pyloriinfection and autoimmune thyroiditis in patients affected by type 1 DM. An additional interesting study clearly showed a significant association between GD, CagA positivity, and negative HLA-DQA1 0201 or positive HLA-DQA1 0501. Finally, Jafarzadeh et al.reported higher serum levels of rheumatoid factor and antinuclear antibodies in H. pylori-infected patients with peptic ulcer disease, thus proposing that this infection possibly contributes to the occurrence or worsening of some autoimmune diseases.
A review article by Li et al. postulated a possible relationship between H. pyloriinfection and nonalcoholic fatty liver disease (NAFLD). On this subject, Jamali et al. investigated the possible role of H. pylori infection on the occurrence and progression of NAFLD; however, the results were negative. On the other hand, Sathar et al.reported a significant association between H. pylori infection and portal hypertensive gastropathy in cirrhotic patients. Interestingly, the administration of the eradicating treatment inH. pylori-positive cirrhotic patients caused a significant improvement in hepatic encephalopathy, even though the results on this topic are not conclusive due to differences among different studies concerning the design and methodology. Nevertheless, Jiang et al.have shown that cirrhotic patients with H. pylori infection have higher blood ammonia levels compared to noninfected subjects.
Sakr et al.reported a higher occurrence of cirrhotic nodules and liver fibrosis in patients coinfected with H. pylori and HCV. Interestingly, H. pylori DNA was identified in liver tissue from patients with hepatocellular carcinoma (HCC). Concerning this issue, Wang et al. reported a significant association between H. pylori infection and an increased risk of death from liver cancer among rural Chinese residents. Nevertheless, García et al. reported a negative association between H. pylori and HCC in a transgenic mouse model of HCV, leaving this topic open to further evaluation.
Some studies also investigated the possible role of H. pylori in biliary tract diseases. Boonyanugomol et al. demonstrated that the cag pathogenicity island (PAI) is able to promote H. pylori internalization in cholangiocarcinoma cells (CCA) with significantly reduced levels of NF-κB activation and IL-8 production by the same cells, thus opening the road for a possible role of H. pylori in some biliary tract diseases. Concerning cholangiocarcinoma, a positive association with some defined conditions, including diabetes, IBD, and peptic ulcer caused by H. pylori, is a well-known risk factor. On this subject, Xiao et al. performed a meta-analysis showing a positive association betweenHelicobacter species and cholangiocarcinoma.
Colonic and Pancreatic Diseases
A recent study showed that the activity of H. pylori-related gastritis is associated with colorectal cancer (CRC) risk. Chen et al., in a meta-analysis demonstrated thatH. pylori infection indeed increases the risk of colorectal adenoma and adenocarcinoma (OR: 1.49; 95% CI: 1.30–1.72). Hsu et al. reported a significant association betweenH. pylori infection and both CRC and gastric cancer risk. Similarly, Nam et al.demonstrated that patients with CRC have a significantly higher H. pylori prevalence compared with controls, even after adjustment for confounding factors such as age, sex, BMI, HbA1c, and total cholesterol. Polyp formation is also influenced not only by H. pyloriinfection, but also by CagA positivity of the strains , even though this data has not been confirmed in all studies. Concerning pathogenic mechanisms behind the association, hypergastrinemia did not increase the risk of any colonic neoplasm, while seropositivity to any of five specific H. pylori proteins, that is, VacA, HP231, HP305, NapA, and HcpC, has been shown to be associated with a 60–80% increase in odds ratio with a specific role for VacA seropositivity, especially for early onset and late-stage cancers.
Concerning pancreatic cancer, a study by Risch et al.reported a decreased risk of pancreatic cancer in case of CagA positivity, while an increased risk was observed in CagA-negative H. pylori seropositive subjects.
H. pylori infection has been recognized as a potential pathogenic factor for pregnancy-related diseases. CagA-positive strains have been found to be more prevalent in women with unexplained, recurrent early pregnancy loss compared with those with a single-missed abortion. A role of H. pylori in hyperemesis gravidarum has also been postulated; Shaban et al. reported a significant association between H. pylori positivity and frequency of vomiting.
Some authors investigated the possible role of H. pylori in respiratory diseases. Siva et al. described a positive association between peptic ulcer disease, H. pylori infection, and chronic obstructive pulmonary disease. Other authors reported an epidemiological association between H. pylori infection and lung cancer, with an estimated relative risk ranging from 1.24 to 17.78. Another study conducted on children undergoing surgery for adenotonsillar hypertrophy showed the presence of H. pylori on almost all samples, with a high prevalence of VacAs1bm2 strains.
Finally, a study by Dang et al. on infected patients with acute idiopathic central serous chorioretinopathy showed a positive effect of H. pylori eradication on the improvement of central retinal sensitivity. Moretti et al. described a significant association between CagA positivity and sperm motility and vitality and the percentage of sperm with normal forms. Concerning chronic urticaria, Yoshimasu et al. described a significant effect ofH. pylori eradication on clinical remission of this dermatological disease.
Over the last year, several extragastric diseases have been studied for a possible association with H. pylori infection and/or CagA-positive strains. A subgroup of ITP, IDA, and vitamin B12 deficiency have already been recognized as being caused by H. pylori. On the other hand, there are several interesting studies on cardiovascular, hepatobiliary, colonic, and pancreatic diseases, which may help us to better understand the role of bacteria in some diseases in which the infectious origin has only previously been marginally considered.