Extragastric Manifestations of Helicobacter pylori Infection


Reprint requests to: Hidekazu Suzuki, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: hsuzuki@a6.keio.jp


In the previous year, some extragastric diseases, possibly linked to Helicobacter pylori infection, have been largely investigated. There are, in fact, several studies concerning cardiovascular diseases, lung diseases, hematologic diseases, eye and skin diseases, hepatobiliary diseases, diabetes mellitus, and neurological disorders. Among them, the relationship between bacterial CagA positivity and coronary heart disease is reportedly emphasized. Concerning normal tension glaucoma, new interesting data are playing in favor of the association with H. pylori infection. For other diseases, there are many interesting results, although more studies are needed to clarify the reality of the proposed association.

The topic of the extragastric manifestations of Helicobacter pylori infection continues to capture the attention of many researchers all over the world, as demonstrated by the number of studies published. Here, we review the results of the studies published last year.

Cardiovascular Diseases

Several studies have been published in the last year on the possible role of H. pylori infection in cardiovascular diseases. Jafarzadeh et al. [1] focused on the prevalence of CagA-positive strains in patients with acute myocardial infarction (MI), unstable angina (UA), and healthy controls. They clearly showed that the seroprevalence of CagA-positive strains was significantly higher in patients with acute MI and UA than controls (86.7, 91.7, and 58.3%, respectively). Another study conducted by our group in Rome on the role of CagA positivity in patients undergoing coronary angiography showed that the titer of anti-CagA antibodies was significantly higher in patients with coronary atherosclerosis than in subjects with normal coronary arteries [2]. Interestingly, a positive correlation between CagA antibody titer and the extent score of the atherosclerotic disease was also found. Moreover, patients infected with CagA-positive strains had a more extensive coronary artery disease (CAD) compared with those infected with CagA-negative strains and, at multivariate analysis, anti-CagA antibody titer was the only predictor of the extent of coronary atherosclerosis [2].

Another study by Agrawal et al. [3] conducted on diabetic patients with or without H. pylori infection reported a higher prevalence of H. pylori infection in patients with diabetes mellitus (DM). Moreover, H. pylori-positive diabetic patients showed a higher prevalence of CAD than H. pylori-negative diabetic subjects. Nevertheless, this is still a debated topic. In fact, these data were not confirmed by the study of Schimke et al. [4], in which CagA positivity was not shown to be a risk factor for chronic vascular complications in patients with type 2 diabetes.

Concerning the pathogenic mechanisms by which H. pylori may eventually concur to the pathogenesis of ischemic heart disease (IHD), two studies were published last year. The first one aimed at investigating whether CagA-positive H. pylori strains may influence serological levels of high sensitivity C-reactive protein, total cholesterol, low-density protein (LDL), oxidized LDL (oxLDL), and apolipoprotein B. Interestingly, the levels of all those markers were significantly increased in CagA-positive patients compared with negative; moreover, CagA-positive patients showed a more severe coronary atherosclerosis [5].

The second study presents a meta-analysis of all studies published in the field of H. pylori infection, platelet aggregation, and thrombosis [6]. Results showed that some H. pylori strains are able to bind to the von Willebrand factor, to interact with glycoprotein Ib, and to induce platelet aggregation in humans. The final hypothesis is that H. pylori may eventually affect IHD by eliciting thrombosis [6].

Diabetes Mellitus

The consistency of a role of H. pylori infection in the pathogenesis of DM as well as in the gastric abnormalities of patients with diabetes has been analyzed and critically discussed. Several controversies emerge from the epidemiological data. The clinical consequence of H. pylori infection in terms of metabolic control seems to be low. Regarding interventional studies, the bacterial eradication rate is significantly lower in patients with DM than in controls [7]. The difference in the H. pylori eradication rate observed between adults and children affected by diabetes could be due to the fact that the latter have no history of repeated infectious diseases and antibiotic treatments, leading to less antibiotic-resistant H. pylori strains. Ojetti et al. showed that a higher H. pylori reinfection rate occurs in patients with DM than in the general population [8].

Lung Diseases

In the last few years, a positive correlation between seroprevalence of H. pylori and lung cancer has been described. A study by Behroozian et al. seems to confirm these findings [9]. In particular, they looked for the prevalence of anti-H. pylori antibodies among 66 patients with lung cancer and 66 controls. Interestingly, they found a higher prevalence of H. pylori in patients with lung cancer compared with controls (73 vs 51%; odds ratio (OR): 2.51; [95% CI: 1.14–5.54]; p <.05). Nevertheless, whether the higher prevalence of H. pylori in patients with lung cancer is casual or causative still remains undetermined. Smoking habits might be confounding in both events.

Interestingly, a case report was published by Riviere et al. showing the disappearance of pulmonary sarcoidosis in a patient after H. pylori eradication [10]. Also in this case, whether H. pylori is the cause or a coincidence is still unknown.

Hematologic Diseases

Helicobacter pylori is a well-recognized cause of idiopathic thrombocytopenic purpura (ITP) [11,12]. Studies published in the last year are in favor of this association. A study by Kikuchi et al., who re-evaluated 11 patients with ITP 8 years after H. pylori eradication, clearly showed the presence of a complete remission in all patients [13]. Fan et al. tested the efficacy of amifostine, a cytoprotective agent reducing reactive oxygen species, in treating patients with refractory ITP. Interestingly, all patients treated with this drug experienced a long-lasting remission, except for two, and one of these two patients relapsed following an H. pylori infection [14]. Matsukawa et al. focused on a peculiar interaction between H. pylori infection and peripheral platelet count in patients without ITP. In particular, the authors reported a significant decrease in peripheral platelet counts in patients with H. pylori infection, after its successful eradication [15]; the clinical significance of such a phenomenon is still unclear. A study conducted by Gursel et al. showed that H. pylori infection may cause dysfunction of platelets in children and can be reversed by H. pylori eradication [16]. Those studies clearly demonstrate the existence of a close interaction between H. pylori and platelets, which surely merits further investigation.

Diamantidis et al. reported a high prevalence of H. pylori infection in Greek patients with myelodysplastic syndromes; nevertheless, there is no evidence for a causal relationship between those conditions so far [17]. Finally, Matsukawa et al. described the case of a patient with H. pylori-positive atrophic gastritis, who showed a significant increase in IgE and eosinophils after successful eradication of the infection [18].

Ophthalmology, Skin, and Mucosal Diseases

Rahbani-Nobar et al. evaluated the effect of H. pylori treatment on remission of idiopathic central serous chorioretinopathy [19]. Twenty-five patients with idiopathic central serous chorioretinopathy who were infected with H. pylori were treated with an anti-H. pylori treatment; another 25 patients with the same clinical symptoms served as the control. The difference between the mean visual acuity at the end of 16 weeks and the time of subretinal fluid reabsorption was compared between the two groups. Subretinal fluid reabsorption time was 9.28 ± 3.20 weeks in the H. pylori eradication group and 11.63 ± 3.18 weeks in the control group, which was statistically significant (p = .015). On the other hand, visual acuity improvement did not represent a statistically significant difference. Helicobacter pylori eradication regimen can be considered as effective in the treatment of patients with idiopathic central serous chorioretinopathy given that it leads to a faster reabsorption of subretinal fluid.

Kim et al. investigated whether H. pylori infection is associated with normal tension glaucoma (NTG) [20]. One hundred consecutive patients with NTG (group 1) from an outpatient glaucoma clinic were enrolled. Medical records of the 88 control participants (control 1) of the outpatient clinic as well as 104 patients with NTG (group 2) and 1116 healthy controls (control 2) (1220 subjects in total) from a primary health care center were reviewed retrospectively to compare the results. The distribution of the results of H. pylori serology of the patients with NTG and controls was compared. Patients with NTG had significantly more positive H. pylori serology than did the healthy controls. There were significant differences between group 1 and control 1 patients (p = .020; OR: 2.05; [95%CI: 1.12–3.75]), group 1 and control 2 patients (p = .016; OR: 1.73; [95%CI: 1.10–2.72]), and group 2 and control 2 patients (p = .008; OR: 1.83; [95%CI: 1.17–2.86]). This study suggests that H. pylori infection may be associated with an increased risk of NTG and that H. pylori may play a role in the development or progression of NTG.

Akashi et al. studied the relationship between H. pylori and chronic urticaria and prurigo chronica multiformis [21]. Eighty-two patients with chronic urticaria and 17 patients with prurigo chronica multiformis were tested with a polyclonal H. pylori stool antigen test. H. pylori antigen was detected in 25 (30.5%) of the 82 patients with chronic urticaria and in 10 (58.8%) of the 17 patients with prurigo chronica multiformis. This H. pylori positivity was not significantly higher than the positivity observed in healthy age-matched controls. The therapeutic efficacy of antibacterial treatment for the chronic urticaria and the prurigo chronica multiformis was examined. The effectiveness of treatment was evaluated by scoring the skin conditions and by using the Skindex-16, a measure of quality of life. Although H. pylori eradication therapy was more effective in treating prurigo chronica multiformis and the skin symptoms started to improve within 3–14 days after the start of treatment, such eradication therapy was not always effective in treating chronic urticaria. Helicobacter pylori may be an important pathogenetic factor, especially for prurigo chronica multiformis, and eradication therapy would be considered to treat intractable cases.

Helicobacter pylori has been found in the oral cavity and stomach. Zou et al. studied whether there might be any associations between isolates of H. pylori in the oral cavity and those in the stomach by meta-analysis [22]. Studies reporting raw data on the prevalence of H. pylori infection in the oral cavity in gastric H. pylori-positive and H. pylori-negative patients, in patients with gastroesophageal diseases (GERD), and in healthy individuals and studies reporting data on the eradication rate in the oral cavity or stomach were identified. The prevalence of H. pylori infection in the oral cavity in gastric H. pylori-positive patients was significantly higher (45.0%) than that in gastric H. pylori-negative patients (23.9%) (OR: 3.61, [95% CI: 1.91–6.82], p <.0001). The 44.8% (91/203) prevalence of H. pylori infection in the oral cavity of patients with clinical and/or histologic GERD was significantly higher than the 13.2% (21/159) prevalence in patients with nonulcer dyspepsia or healthy controls (OR: 5.15, [95% CI: 2.97–8.92], p <.00001). The eradication rate in the stomach was 85.8% (187/218), while it was only 5.7% (9/158) in the oral cavity (OR: 55.59, 95%CI: 8.69–497.46, p <.00001), indicating that the oral cavity may be a source or reservoir of reinfection by H. pylori.

Hepatobiliary Diseases

Ki et al. reported that H. pylori promotes hepatic fibrosis in a murine model [23]. To elucidate the mechanism by which H. pylori accelerates liver fibrosis, they investigated the changes in expression levels of mitogen-activated protein kinases (MAPKs), p53-related proteins, antioxidants, and pro-inflammatory cytokines in liver samples. Helicobacter pylori and/or CCl4-induced MAP kinase activation was investigated. Helicobacter pylori infection enhanced CCl4-induced MAP kinase activation and the p53 signaling pathway as well as Bax- and proliferating-cell nuclear antigen expressions, whereas H. pylori alone induced neither of these expressions nor hepatic fibrosis. Moreover, mRNA expression of inflammatory cytokines, glutathione peroxidase expression, and the proliferative index were strongly augmented in livers with H. pylori in the CCl4-treated group compared with those without H. pylori in the CCl4-treated group, whereas there was no difference in apoptotic index between these two groups. Interestingly, H. pylori treatment increased the number of alpha-fetoprotein-expressing hepatocytes, independent of CCl4 intoxication. In vitro analyses, using an immortalized rat hepatic stellate (Ito) cell line, revealed that H. pylori lysates increased the proliferation of hepatic stellate (Ito) cells, which was boosted by the addition of transforming growth factor-beta1 (TGF-β1). Furthermore, the treatment of H. pylori lysates promoted the translocation of the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) into the nucleus based on an increase in the degradation of NF-κB inhibitor alpha, in the presence of TGF-β1, as did H2O2 treatment. They concluded that H. pylori infection along with an elevated TGF-β1 might accelerate hepatic fibrosis through increased TGF-β1-induced pro-inflammatory signaling pathways in hepatic stellate cells. Moreover, they suggest that H. pylori infection would increase the risk of TGF-β1-mediated tumorigenesis by disturbing the balance between apoptosis and proliferation of hepatocytes.

Bacterial infection is accepted as a precipitating factor in cholesterol gallstone formation, and recent studies have revealed the presence of Helicobacter species in the hepatobiliary system. Lee et al. utilized PCR to establish the presence of bacterial DNA, including from Helicobacter species, in gallstones, bile juice, and gallbladder mucosa from patients with gallstones [24]. At cholecystectomy, 58 gallstones, 48 bile samples, and 46 gallbladder mucosal specimens were obtained and subjected to nested PCR using specific 16S rRNA primers of H. pylori and other bacteria. Bacterial 16S rRNA was detected in 25 of 36 (69.4%) mixed cholesterol gallstones, one of 10 (10%) pure cholesterol gallstones, and 9 of 12 (75%) pigmented stones, and 16S rDNA sequencing identified Escherichia coli, Pseudomonas, Citrobacter, Klebsiella, and Helicobacter species. Helicobacter DNA was detected in 4 of 58 (6.9%) gallstones, 6 of 48 (12.5%) bile samples, and 5 of 46 (10.9%) gallbladder specimens. Direct sequencing of Helicobacter amplicons confirmed H. pylori strains in all four gallstones, in five of 6 (83.3%) bile samples, and in three of 5 (60%) gallbladder specimens. Although almost all mixed cholesterol gallstones appear to harbor bacterial DNA, predominantly E. coli, H. pylori was also found in the biliary system, suggesting that these bacteria play a role in the gallstone formation.

Helicobacter pylori has been suggested to be involved in pancreatic diseases, namely autoimmune pancreatitis and pancreas cancer. Jesnowski et al. investigated the presence of conserved sequences of Helicobacter in pancreatic tissue and pancreatic juice from patients with chronic nonautoimmune and autoimmune pancreatitis as well as pancreatic ductal adenocarcinoma [25]. They collected 35 pancreatic juice samples during routine endoscopic retrograde cholangiopancreatography and 30 pancreatic tissue samples and performed a nested PCR to detect H. pylori in the isolated DNA samples. However, they could detect no H. pylori DNA, suggesting that a direct infection of the microbial agent in the pancreas seems unlikely.

Neurological Disorders

Dobbs et al. examined the effect of eradicating H. pylori in idiopathic parkinsonism by a randomized, placebo-controlled study [26]. Thirty idiopathic parkinsonism patients infected with H. pylori and taking no anti-parkinsonian medication were enrolled. Stride length improved (73 mm/year; [95% CI: 14–131]; p = .01) in favor of successful blinded active over placebo, irrespective of anti-parkinsonian medication. Gait did not deteriorate in years 2 and 3 post-eradication. This study suggested that H. pylori plays a role in the progression of idiopathic parkinsonism.

Kountouras et al. tested the hypothesis that eradication of H. pylori infection could improve survival in a Greek cohort of patients with Alzheimer’s disease, in a 5-year follow-up [27]. Forty-six patients diagnosed with probable Alzheimer’s disease were enrolled in their analysis. The study population was classified into three groups: 1, patients for whom H. pylori eradication therapy was successful; 2, patients for whom eradication therapy of H. pylori had failed, those who refused the treatment, and those who were noncompliant with eradication therapy; and 3, patients who were H. pylori negative at baseline. During the 5-year follow-up, 21 patients died and 25 patients remained alive. Patients who died were older and exhibited lower mean Mini-Mental State Examination scores compared with the patients still alive. Successful eradication of H. pylori infection was associated with a significantly lower mortality risk (HR: 0.287; [95% CI: 0.114–0.725]; p = .008). The results were similar in adjusted and unadjusted models, for age and Mini-Mental State Examination at baseline (HR: 0.29; [95% CI: 0.11–0.765]; p = .012). Helicobacter pylori eradication regimen in patients with Alzheimer’s disease is associated with a higher 5-year survival rate. A limitation of this series was the small number of patients studied. Therefore, these findings were considered rather as preliminary, thereby requiring future confirmation.

In conclusion, in the last year, several diseases have been investigated to possibly be associated with H. pylori infection. For some of those, such as ITP, there is consistent evidence of a causative role, while for the others, further studies are needed to verify the association.

Conflicts of Interest

The authors have declared no conflicts of interest.