Next Article in Journal
Body Composition in Adolescent PKU Patients: Beyond Fat Mass
Next Article in Special Issue
Worldwide Prevalence and Risk Factors of Helicobacter pylori Infection in Children
Previous Article in Journal
Association between Physical Fitness and Low Back Pain: The Pepe Cross-Sectional Study
Previous Article in Special Issue
The Relationship between Anemia and Helicobacter Pylori Infection in Children
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Children
Volume 9
Issue 9
10.3390/children9091352
children-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality

by
Cristian Dan Mărginean
1,
Cristina Oana Mărginean
2,* and
Lorena Elena Meliț
2
1
Department of Pediatrics I, County Emergency Hospital Târgu Mureș, Gheorghe Marinescu Street No. 50, 540136 Târgu Mureș, Romania
2
Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No. 38, 540136 Târgu Mureș, Romania
*
Author to whom correspondence should be addressed.
Children 2022, 9(9), 1352; https://doi.org/10.3390/children9091352
Submission received: 11 August 2022 / Revised: 29 August 2022 / Accepted: 1 September 2022 / Published: 4 September 2022
(This article belongs to the Special Issue Childhood Helicobacter pylori Infection: Treatment and Prevention)
Versions Notes

Abstract

:
It is well documented that Helicobacter pylori (H. pylori) can cause both gastrointestinal and extraintestinal manifestations. The latter one represents a major burden in terms of diagnosis and treatment. H. pylori-associated systemic subclinical inflammation is mostly responsible for the development of extraintestinal manifestations, and its early eradication might result in preventing all adverse events related to their occurrence. Thus, it was suggested that H. pylori might be associated with iron deficiency anemia, thrombocytopenia (immune thrombocytopenic purpura), Schonlein Henoch purpura, failure to thrive, vitamin B12 deficiency, diabetes mellitus, body mass index, cardiovascular diseases, as well as certain neurological conditions. Nevertheless, studies showed both pros and cons in terms of the role of H. pylori in the development of previously mentioned clinical entity underlining the crucial need for further studies on these topics. Although most of these extraintestinal manifestations occur during adulthood, we must not forget that H. pylori infection is acquired mainly during childhood, and thus its early diagnosis and eradication might represent the cornerstone in the prevention of H. pylori-induced inflammatory status and consequently of all related extraintestinal conditions.

1. Introduction

The spectrum of disorders caused by Helicobacter pylori (H. pylori) does not resume to the gastrointestinal tract, resulting in a major burden worldwide in terms of diagnosis and treatment. Thus, aside from the classical damage caused in the host’s stomach resulting in acute or chronic gastritis, peptic ulcer disease, gastric cancer, and gastric-mucosa-associated lymphoid tissue lymphoma, this bacterium has the ability to trigger many other extraintestinal disorders such as iron deficiency anemia, vitamin B12 deficiency, idiopathic thrombocytopenic purpura, or growth retardation [1]. Moreover, recent data suggested a potential relationship between this infection and other less common manifestations such as acute coronary disease, arterial hypertension, diabetes, arterial stiffness in diabetic patients, thyroid disease, glaucoma, stroke, eczema, chronic hives, rosacea, Parkinson’s disease, or Alzheimer disease [1,2]. The most important life-threatening complication of long-term H. pylori persistence within the gastric mucosa is represented by gastric carcinogenesis due to the associated chronic inflammation. H. pylori infection seems to be involved in the etiology of 80% of all gastric cancers and 5.5% of worldwide malignant conditions [3,4]. Colonization of the gastric mucosa occurs usually during childhood and might be life-long if left untreated. The prevalence of this infection varies in different countries worldwide, especially depending on the socioeconomic status, reaching up to 80% in developing countries or even more [1].
Aside from this dark side of H. pylori infection, it was indicated that H. pylori might instead have a protective effect against gastroesophageal reflux disease, atopy, allergy and asthma [1]. Therefore, the gram-negative spiral bacterium H. pylori might be considered a ‘chameleon’ based on the wide spectrum of disorders that it might cause. H. pylori-associated systemic subclinical inflammation seems to be responsible for this wide range of extraintestinal manifestations [2]. In addition, the eradication of this infection was proven to result in the improvement in platelet count and in the efficacy of iron supplementation [5,6]. Although, according to the previously mentioned hypotheses, subclinical inflammation should be related to the long-term persistence of H. pylori infection and it should subsequently occur only during adulthood, it seems in fact that the mechanism involved in the development of this inflammatory status does not require a prolonged time since recent studies pointed out the presence of this low-grade inflammation also in children with H. pylori infection [7,8]. H. pylori virulence factors including flagellin, lipopolysaccharides, cag-pathogenicity island, vacuolating cytotoxin A, pathogen-associated molecular patterns, and adhesins have a major contribution in enabling the long-term persistence of this bacterium and its related harmful effect on the host [9]. The other side of the mechanism involved in the inflammation is represented by the host’s innate and adaptive immune responses, which further trigger the synthesis of a wide range of proinflammatory cytokines and other molecules such as chemokines or chemotactic proteins [10,11]. Innate immunity represented by Toll-like receptors is an important player in the host’s defense mechanisms, but it might also promote H. pylori inflammation [12].
As we already mentioned, acute H. pylori infection usually occurs during childhood, and it might cause unspecific symptoms such as abdominal pain, nausea, vomiting, or even diarrhea, associated with a reduced gastric acid secretion [1]. Although unspecific, epigastric pain seems to be a significant symptom in children with H. pylori-positive gastritis [7,13]. The symptoms usually last for a few days, becoming asymptomatic afterwards in most of the cases, but in time, it becomes a chronic process consisting of the infiltration of a high number of immune cells within the gastric mucosa such as mast cells, macrophages, neutrophils, lymphocytes, dendritic cells, natural killer cells, as well as T and B lymphocytes, along with high levels of chemokines and cytokines [14,15]. Furthermore, around 10–20% of individuals diagnosed with H. pylori infection eventually develop gastric or duodenal ulcer [16]. In spite of increased incidence of gastric cancer within different countries, it seems that this incidence is strongly correlated with the prevalence of H. pylori infection in the same countries [1]. Moreover, effective eradication of this infection was proven to be associated with a significantly reduced risk of gastric cancer [17,18].
The first step for effective eradication is in fact represented by accurate diagnosis based on choosing the most appropriate diagnostic method depending on the geographic area, patient’s age, or other H. pylori-related peculiarities [19]. Additionally, the diagnosis is even more difficult in patients that present only extraintestinal manifestations triggered by this infection.
The aim of this review was to assess the most important extraintestinal manifestations caused by H. pylori in children in order to increase the awareness of practitioners worldwide regarding their relevance for the timely accurate diagnosis of this infection.

2. H. pylori and Iron Deficiency Anemia

Iron deficiency represents the most common nutritional deficiency worldwide, affecting at least 500 million people [20]. Taking into account the well-known fact that H. pylori is the most common bacterial infection worldwide, it is not surprising that researchers focused on assessing if there is a relationship between them. Blecker et al. described for the first time in 1991 the relationship between H. pylori and iron deficiency anemia in a 15-year-old Belgian patient diagnosed with H. pylori-induced chronic active hemorrhagic gastritis and iron deficiency anemia, which completely resolved without iron supplementation after H. pylori eradication [21]. Several hypotheses were stated in order to explain this relationship such as active hemorrhage from erosive gastritis lesions and anemia associated with chronic inflammation and reduced iron absorption due to achlorhydria [22]. Furthermore, other case reports also sustained this association [22]. Harris et al. assessed the relationship between hypochlorhydria and iron deficiency in a sample of 123 children and noticed that H. pylori-positive children associate hypochlorhydria as compared to the uninfected ones sustaining one of the previously mechanisms involved in iron deficiency anemia [23]. Similarly, Soundaravallly et al. [24] compared H. pylori schoolchildren with a non-infected one in terms of ferritin levels and pro-oxidant status and concluded that children with H. pylori infection have significantly higher levels of malondialdehyde and carbonyls, along with significantly decreased levels of ferritin when compared to H. pylori negative group (Table 1).
As we already mentioned, systemic subclinical inflammatory status triggered by the cytokine storm in the setting of H. pylori infection represents the most likely explanation for extraintestinal manifestations. Queiroz et al. [28] also sustained this statement based on their findings, which revealed that interleukin-1β might predict the decreased ferritin and hemoglobin concentrations in children with H. pylori infection. Hepcidin is another inflammatory protein which contributes to iron homeostasis by playing an essential role in macrophage iron retention and therefore enables the development of inflammation-associated anemia [52]. Therefore, the second hypotheses that H. pylori-induced chronic gastritis might cause H. pylori associated iron deficiency anemia was confirmed by Ozkasap et al. [29], who revealed that H. pylori-positive children with iron deficiency anemia have significantly higher levels of prohepcidin before eradication. Moreover, a study that compared the serum hepcidin level and the response to oral iron therapy between H. pylori-positive and H. pylori-negative children proved that serum hepcidin level was associated with a reduced response to the oral iron supplementation in infected children who were associated with iron-deficiency anemia [30]. Other studies also sustained the relationship between H. pylori and iron deficiency anemia, as well as the spontaneous resolution of this deficiency after H. pylori eradication [26,27]. In terms of eradication, the meta-analysis of Hudak et al. also proved that the eradication regimens added to iron supplementation increased both hemoglobin and ferritin levels [136]. These findings were sustained also by the meta-analyses of Yuan et al. and Huang et al. [137,138] (Table 2). Nevertheless, a recent retrospective study involving 508 subjects diagnosed with H. pylori infection and iron deficiency anemia failed in proving the resolution of iron deficiency anemia after H. pylori eradication [20]. Similarly, another study performed recently on Indian children with H. pylori also stated that H. pylori might not, in fact, have an essential role in the development of iron deficiency anemia [36]. Moreover, Emiralioglu N et al. failed in proving a significant difference between prohepcidin level in H. pylori-infected children when compared to uninfected ones, even though the mean level was lower in anemic H. pylori-positive children [37]. The authors found significantly higher initial levels of prohepcidin, ferritin, and interleukin-6 in infected children, but they noticed no improvement in these parameters after H. pylori eradication. Contrarily, another recent study in Egypt pointed out that H. pylori infection was more prevalent in patients with refractory or unexplained iron deficiency anemia, revealing also a significant improvement in hematological parameters in patients receiving iron supplements associated with the standard eradication triple therapy in comparison to those receiving only iron supplements [31]. Similar findings were also reported by a study in 2018 which showed that H. pylori is involved in iron-deficiency anemia and that the eradication of this infection results in improved blood parameters [32]. Sabbagh et al. also sustained the potential relationship between H. pylori infection and iron deficiency anemia, but at the same time stated that H. pylori might not be the only one involved in this relationship since poverty, poor nutritional status, and poor treatment might also be a cause for this effect [33]. Furthermore, the results of Rahat A et al. proved that H. pylori infection represents a frequent cause of iron deficiency anemia in patients with lower education and females and that 37.5% of H. pylori-positive cases presented iron deficiency anemia [25] (Table 1). According to the meta-analysis of Afsar et al., H. pylori infection might be associated with adverse pregnancy outcomes, resulting in an increased risk of iron deficiency anemia in pregnant women [139] (Table 2).
Moreover, it was proven that highly virulent H. pylori strains such as those expressing cytotoxin-associated gene A or the vacuolating cytotoxin A act via molecular mimicry mechanisms in order to produce or augment iron deficiency [34]. Thus, cytotoxin-associated gene A was suggested to act as a facilitator for H. pylori colonization, enhancing iron acquisition and subsequently enabling bacterial survival [35]. International consensus and management guidelines currently recommend that H. pylori should be sought and effectively eradicated in patients presenting iron deficiency anemia [34,182]. However not all patients detected with H. pylori infection present with iron deficiency anemia, and therefore, further studies should focus on elucidating these controversies [38]. Moreover, based on the most recent reports, several controversies emerged regarding the previously well-documented relationship between H. pylori infection and iron deficiency anemia, implying an urgent need for further studies in order to elucidate this mystery (Table 1).

3. H. pylori and Purpura

In 1998, Gasbarrini et al. [39] was the first to notice a significant increase in platelet count after H. pylori eradication. Furthermore, one year later, Garcia Perez et al. [40] also reported the normalization of platelet count in a patient with chronic immune thrombocytopenic purpura after the eradication of this bacterium. Similarly, Stasi et al. [41] noticed that 50% of adults presented a sustained platelet response following H. pylori eradication, especially those with mild forms of immune thrombocytopenic purpura. Thus, studies did not reveal an association between this infection and the severity of immune thrombocytopenic purpura [38]. A more recent study pointed out that patients with immune thrombocytopenia who underwent a successful eradication of H. pylori infection were proven to maintain a higher platelet count thereafter [42]. The host response after eradication therapy was indicated to depend on several factors such as the short length of immune thrombocytopenic purpura, age under 65 at the time of immune thrombocytopenic purpura, no prior therapy for this condition, no prior or concomitant steroid therapy, and higher baseline platelet count [41,45,183,184]. Thus, in patients with thrombocytopenia and no bleeding or mild bleeding it is important to avoid treatment as much as possible until the elucidation of the cause. A recent case report of a 57-year-old male which presented petechial rash and gum bleeding increased awareness regarding this recommendation since he was diagnosed with H. pylori infection based on stool antigen and presented complete resolution of symptoms and thrombocytopenia following H. pylori eradication [43]. Several meta-analyses concluded that H. pylori eradication resulted in the increase in platelet count in patients with immune thrombocytopenic purpura [140,141] (Table 2). These findings were also sustained by a review including 11 controlled studies which revealed a platelet count response in 51% of the patients with H. pylori infection when compared to 8.8% of H. pylori-negative subjects [185]. Therefore, H. pylori is a well-documented cause of secondary immune thrombocytopenic purpura since it was proven that the prevalence of this bacterium is higher in patients with this condition as compared to healthy individuals [44]. Multiple mechanisms were involved in the pathogenesis of immune thrombocytopenic purpura in patients diagnosed with H. pylori infection such as the induction of platelet aggregated through the von Willebrand triggered by certain H. pylori strains, a phenomenon consisting of an activation of monocyte/macrophages with an anti-platelet effect, or molecular mimicry consisting of antibodies formation against H. pylori CagA protein and platelet antigens [186] (Table 1).
Further studies also indicated a relationship between these two clinical entities but not all of them encountered statistical significance. Moreover, it seems that the findings depend on the diagnostic method used for detecting H. pylori infection. Therefore, serology-based studies found a higher seroprevalence of H. pylori infection in patients with immune thrombocytopenic purpura when compared to stool-antigen-based tests [22]. Nevertheless, the results remain controversial since certain stool-antigen-based tests found a considerable higher prevalence in patients with this immune disorders as compared to those without this condition [22]. Aside from the diagnostic method, this relationship was reported to depend on overall H. pylori prevalence. Thus, two studies performed in low prevalence areas such as the United States of America and France failed in identifying any link between H. pylori infection and immune thrombocytopenic purpura [49,50]. In addition, Mubarak et al. revealed that despite the high prevalence of H. pylori infection in pregnant women from Sudan, the study found no association with thrombocytopenia [51]. Surprisingly, H. pylori was proven also to have a certain effect also in subjects with a normal level of platelets based on a recent study which pointed out that patients with H. pylori infection have a higher mean platelet volume as compared to the H. pylori-negative individuals [187]. Based on these findings, the authors hypothesized that in the setting of H. pylori infection, the host develops an ongoing mechanism for compensating the destruction process, and certain conditions related to the host or the H. pylori strain might be disabled, resulting in immune thrombocytopenia. Nevertheless, pediatric patients were not proven to experience the same effect based on the findings of Săsăran et al., who found no significant difference in terms of mean platelet volume in children with H. pylori infection when compared to those with H. pylori-negative gastritis or controls [8]. Corroborating the previously mentioned reports in adult patients with these findings in pediatric patients, we might hypothesize that the effect of H. pylori on platelets might require a certain amount of time (Table 1).
Based on the aforementioned facts, the detection and eradication of H. pylori in patients with immune thrombocytopenic purpura could be extremely useful in clinical practice. Moreover, according to the American Society of Hematology guidelines, eradication therapy should be provided to the patients with immune thrombocytopenic purpura and H. pylori infection [188]. The same recommendations were also stated by the European Helicobacter Study Group Consensus and the Second Asia-Pacific Consensus Guidelines [189,190]. Although current guidelines do not recommend screening of all patients with immune thrombocytopenic purpura for H. pylori infection, recent studies sustain that this screening would be extremely useful, especially in those originating from areas with a high prevalence [191]. Moreover, based on its ease of administration and limited toxicity, the triple standard eradication regimen with amoxicillin, clarithromycin, and a proton pump inhibitor should be administered to patients with this condition who are detected with H. pylori infection in spite of its variable effectiveness [191] (Table 1).
It is worth mentioning that H. pylori seems to contribute as well to the pathogenesis of a different type of purpura, Schonlein Henoch purpura, which is known to have an immunological component, but otherwise, individuals have a normal platelet count. Studies in China, where H. pylori prevalence is high pointed out that infection is extremely high in children diagnosed with this condition. Thus, it was suggested this type of purpura might also be associated with H. pylori infection especially in the setting of gastrointestinal manifestations [46]. The authors concluded that in these endemic areas a screening for H. pylori infection would be of great benefit in children with Schonlein Henoch purpura. Furthermore, another study showed that H. pylori eradication led either to prompt resolution of Schonlein Henoch purpura or to prevention of recurrences [47]. The meta-analysis of Xiong et al. also pointed out that successful eradication might be associated with a decrease in the recurrence rate in children with Schonlein Henoch purpura [46] (Table 2). A recent review pointed out that the immunological events and local injury of the gastric mucosa triggered by H. pylori contribute to the development of Schonlein Henoch purpura [48]. Except for this mechanism, cryoglobulins, elevated serum IgA, C3 levels, proinflammatory molecules, autoimmunity, and molecular mimicry that induce cross-reactive antibodies and immune complexes associated to H. pylori infection were also proven to be involved in the course of this condition [48]. Nevertheless, further studies are required to elucidate the complex link between this pathogen and Schonlein Henoch purpura (Table 1).

4. H. pylori and Growth

The relationship between H. pylori and growth faltering is deeply controversial. This link has been highlighted, especially in countries with poor resources where malnutrition has a considerable high prevalence due to the coexistence in young children between H. pylori and other parasitic/enteropathogen infections [52]. Another possible explanation for this fact is that in these areas, also considered endemic area in terms of H. pylori, the infection occurs shortly after birth, providing a sufficient amount of time for this bacterium to express this negative effect [192]. Moreover, several meta-analyses which assessed the effect of H. pylori infection during pregnancy pointed out a relationship between this infection and gestational diabetes mellitus, preeclampsia, spontaneous abortion, fetal growth restriction, birth defects, and hyperemesis gravidarum [144,145] (Table 2). Jaganath et al. investigated the role of H. pylori infection during infancy (6–11 months) and early childhood (12–23 months) in terms of height in children from Peru [61]. The authors noticed that 77% of the included children acquired the infection before 12 months and age most-likely due to the low socioeconomic status, concluding that H. pylori was not independently related with growth deficits in these children [61]. Contrarily, other findings sustained the association between H. pylori and both growth faltering and malnutrition [53]. More recent studies suggest that mathematical models combining attenuated total reflectance flourier transform infrared spectroscopy and artificial neural networks could be useful in assessing the precise role of this infection in terms of growth failure [193] (Table 1).
The basis of this relationship consists in evidence sustaining that H. pylori is related to decreased ghrelin levels, a gastrointestinal hormone responsible for regulating food intake. Thus, a study including 50 children proved that gastric ghrelin levels returned to normal once the infection was successfully eradicated, but body mass index showed no significant differences [54]. Other studies also pointed out this relationship [62,194]. Aside from ghrelin, certain authors found a low level of leptin in H. pylori-infected children, which improved following eradication [55,56]. The consequences of these pathological findings had a negative effect on growth, but they were also proven to result in short stature and recurrent infection due to decreased immunity [195,196]. A more complex study from the Czech Republic that assessed vital signs and body parameters in H. pylori-positive versus H. pylori-negative subjects with an overall H. pylori prevalence of 5.2% concluded that this infection was associated with short stature in children, but not with body weight, body mass index, and blood pressure either in children and adolescents or in adults [57]. Similarly, a review assessing studies which included children from low- and middle-income areas suggested a potential relationship between H. pylori and growth retardation but concluded that there is not sufficiently strong evidence to justify screening in order to prevent this consequence [58]. Furthermore, Chiu et al., performing a study on a large sample of children, found no association between failure to thrive and H. pylori association [197].
Recent studies underlined the role of gastrointestinal microflora, including H. pylori, in terms of molecular mimicry representing antigens sources, which resemble appetite-regulating peptides [59]. Moreover, certain common sequences were identified between leptin and the intestinal microflora proteins of Lactococcus lactis, Lactobacillus bacteriophage, Escherichia coli, Candida, and Aspergillus [59]. Thus, experimental studies on serum samples from children with growth hormone deficiency and short stature pointed out that certain children that were infected with H. pylori as well as those exposed to Candida albicans present antibodies against leptin, ghrelin, orexin A, and α-MSH, with a potentially negative effect on the physiological functions of these molecules [53,60]. However, based on these multiple controversies, further studies on larger samples should definitely be performed in order to elucidate all mechanisms involved in the relationship between H. pylori and growth retardation in children (Table 1).

5. H. pylori and Vitamin B12 Deficiency

H. pylori-induced gastritis was proven to result in a functional inhibition of parietal cells causing hypochlorhydria. The increase in gastric pH will lead to the malabsorption of several vitamins and other minerals [79].
The relationship between vitamin B12 deficiency and H. pylori infection was reported for the first time in 1984 by O’Connor et al., who identified Campylobacter-like organisms in patients with type A gastritis associated with pernicious anemia [63]. Several studies proved a link between this infection and the malabsorption of vitamin B12, pointing out that this deficiency was present in more than half (67.4%) of the patients with H. pylori infection [64,65]. Moreover, even in the setting of normal serum vitamin B12 levels, studies revealed a higher prevalence of this infection in patients with these levels at the lower end of the normal range [66]. Tsay et al. suggested that studies to follow the effect of eradication therapy on vitamin B12 level would be useful for clearly determining the role of H. pylori infection on vitamin B12 status [198]. Nevertheless, a case report of a 35-yearl-old male with H. pylori infection and vitamin B12 deficiency pointed out that the vitamin B12 level normalized after 1 month of vitamin B12 supplementation and standard triple therapy for H. pylori eradication [67]. In fact, vitamin B12 deficiency is very common worldwide, accounting for 20–60% of incidences in developing countries and up to 20% in developed ones [32]. Thus, a recent study performed on adults with H. pylori infection showed a significant association between the presence of this infection and vitamin B12 deficiency [32]. Moreover, Annibale et al. [73] found H. pylori to be the only pathological elements in 57.1% of patients with macrocytic anemia due to vitamin B12 deficiency (Table 1).
Another potential mechanism for this deficiency might be related to the treatment with antacid drugs [19]. Furthermore, H. pylori might play the role of molecular mimicker since H. pylori expresses an antigen which is similar to H+/K+-adenosine triphosphate protein [199]. Eventually, vitamin B12 deficiency leads to hyperhomocysteinemia, which might be a risk factor for both cerebrovascular and ischemic heart diseases, therefore linking H. pylori infection and vascular disorders [68]. Based on all these findings, the Maastricht IV/Florence Consensus 2012 included unexplained vitamin B12 deficiency in the management guide of H. pylori infection [200]. Based on the major relevance of this vitamin deficiency, further studies to assess the role of H. pylori infection in its occurrence could result in the development of further effective preventive strategies with major impact on also reducing subsequent cardiovascular events (Table 1).

6. H. pylori and Cardiovascular Diseases

Cardiovascular diseases include coronary artery disease, stroke and peripheral artery disease with increased rates of morbidity and mortality worldwide. Studies pointed out that the presence of H. pylori at the level of carotid plaques might result in their instability and eventually lead to ischemic stroke, especially in patients infected with CagA gene positive strains [69]. The authors also underlined an association between H. pylori and acute cerebral ischemia in patients with ischemic cerebrovascular stroke. These findings were also sustained by the meta-analysis of Doheim et al., who emphasized the significant association between H. pylori infection and the increased risk of stroke [149]. Nevertheless, Yu et al. found no association even in those infected with Cag-A positive strains [150] (Table 2). Furthermore, a study from Korea pointed out a positive association between this infection and low HDL, elevated LDL, and cardiovascular disease, reporting that eradication of this bacteria lowered the risk of high LDL and low HDL but had no effect on cardiovascular disease [72]. These findings were sustained by a very recent review, which concluded that H. pylori infection increased the risk of adverse cardiovascular events by 51%, especially in terms of myocardial infarction and cerebrovascular disease [70]. Therefore, clarithromycin-based eradication therapy might lower mortality rate in patients at risk, such as those with arterial hypertension [201]. Two recent meta-analyses revealed that H. pylori infection was positively associated with arterial hypertension representing an essential factor in the development of this condition [76,151] (Table 2). Nevertheless, another study from Japan found no relationship between H. pylori infection and either stroke mortality risk or coronary heart disease [202] (Table 1). The results regarding the effect of H. pylori on coronary heart disease remain controversial because, while several studies sustained an association between these two pathologies [203,204,205,206], other studies failed in identifying any association [207,208,209,210]. A concerning fact is that according to the meta-analysis of Rahmani et al., most of the patients with coronary heart disease acquired the infection during childhood [152]. Another meta-analysis also pointed out that H. pylori infection might augment the risk of coronary heart disease during early life [153]. Coronary instability and acute coronary syndrome might also occur as a result of H. pylori infection [154,155] (Table 2). Moreover, it was suggested that H. pylori eradication might result in an improvement in endothelial function [211], but the findings remain inconsistent [212]. H. pylori-associated inflammation plays a major role in the development of atherosclerosis based on the wide spectrum of pro-inflammatory cytokines associated with this infection [213]. Several meta-analyses pointed out a significant positive association between H. pylori infection and the risk of atherosclerosis, proving that the infection has the ability to promote atherosclerosis development in people below the age of 60 years but also in those without cardiovascular risk factors [146,147,148] (Table 2). In addition, this systemic inflammation induces the synthesis of acute phase coagulation proteins such as fibrinogen, which is particularly important in the development of coronary heart disease [214], thus also suggesting a possible link between H. pylori infection and other thrombotic events, including stroke. Another possible explanation for the relationship between H. pylori infection and coronary heart disease might be related to the ability of this infection to induce platelet aggregation, resulting in instability of atherosclerotic lesions [215]. CagA virulent strains are associated with an increased risk of thrombotic events [213]. Moreover, these strains were reported to play a major role in destabilizing coronary plaques, resulting in acute coronary syndromes [154]. Furthermore, Rahmani et al. highlighted in their meta-analysis a significant association between H. pylori infection and myocardial infarction [158] (Table 2). Although in the meta-analysis of Yan et al., the authors suggested a possible relationship between H. pylori infection and arrhythmia, including atrial fibrillation [156], the results are rather inconsistent [157]. Nevertheless, H. pylori eradication was proven to decrease the incidence of arrhythmia in Asian and African subjects [156] (Table 2).
In terms of risk factors, Kim et al. pointed out that H. pylori infection was a significant and independent predictor or dyslipidemia [71]. Mladenova et al. suggested that host’s genetic susceptibility might represent the response to the question why only certain individuals with H. pylori infection develop adverse cardiovascular events [216]. Based on these controversial reports, and the worldwide mortality due to cardiovascular events, further studies are definitely required in order to clearly determine the role of this infection in the development of cardiovascular diseases.

7. H. pylori Infection, Insulin Resistance, Diabetes Mellitus, and Obesity

H. pylori seems to also be related with insulin resistance, diabetes mellitus, and metabolic syndrome [79]. Nevertheless, while certain studies sustained a higher prevalence of H. pylori in patients with diabetes mellitus, others failed in identifying any association between these two [89,90,91]. Thus, Nasif WA et al. proved that H. pylori prevalence was more increased in type 2 diabetes mellitus patients as compared to non-diabetic individuals [75]. Eradication of H. pylori infection was proven to decrease the risk of diabetes [77]. Additionally, Song et al. recently pointed out that diabetic patients with H. pylori infection might require more aggressive eradication therapies, especially those with poor glycemic control and greater body mass index [78]. Therefore, Mansori et al. concluded in a recent meta-analysis that H. pylori eradication should be considered in patients with diabetes mellitus [160]. Nonetheless, Upala et al. found no improvement in insulin resistance, fasting blood glucose, and metabolism paraments after eradication of H. pylori [159] (Table 2). A more recent study also indicated a significantly higher prevalence of H. pylori infection in patients with diabetes as compared to controls with a more increased chance to be symptomatic [74]. H. pylori infection might also increase the risk of diabetes-related complications, being associated with proteinuria [162] (Table 2). Moreover, it was suggested that there is a relationship between the presence of this infection and insulin resistance in normal-weight subjects [79]. Studies emphasized once more that H. pylori-associated inflammation and subsequent production of cytokines along with hormonal imbalances are responsible for the association between this infection and diabetes mellitus [217] (Table 1).
In diabetic patients, the risk of atherosclerotic vascular disease seems to be linked to the increased levels of serum oxidized low-density lipoprotein associated with H. pylori infection [75]. Furthermore, obesity was not proven to enhance insulin resistance in the setting of H. pylori infection, it being stated that H. pylori is in fact responsible for adverse lipid profile outcomes [92]. In terms of lipid profile parameters, H. pylori eradication was proven to increase the high-density lipoprotein levels [166] (Table 2). However, it was emphasized that the H. pylori eradication rate is lower in obese patients when compared to controls [80]. Similarly, Hamrah et al. pointed out a significant association between H. pylori infection and both diabetes mellitus and increased body mass index in patients from Afghanistan [82]. In terms of obesity, most of the reported meta-analyses sustain a significant positive association between H. pylori and obesity risk [159,165,167] (Table 2). Moreover, a recent study from Douala-Cameron showed that H. pylori and high body mass index, separately or not, were proven to be risk factors for diabetes mellitus [81]. Contrarily, Alzahrani et al. found a relationship only between H. pylori infection and increased body mass index and not with type 2 diabetes mellitus [83]. Likewise, a recent study from China also reported that H. pylori was not significantly associated with diabetes [93]. Alzahrani et al. also failed in identifying any association between H. pylori seropositivity and the risk of developing diabetes even in adults at high risk for this condition [94]. However, even the results in the same population remain controversial since another study from China revealed that H. pylori is significantly associated associated with diabetes [84] (Table 1).
It seems there is an interdependence relationship between H. pylori infection and diabetes since it was proven that not does only H. pylori influence diabetic patients, but diabetes also influences the severity and localization of gastric inflammation induced by H. pylori infection. Yang et al. proved that the severity of corpus gastritis associated to H. pylori infection was more severe in type 2 diabetes mellitus patients when compared to non-diabetic controls [85]. In addition, the authors highlighted that non-insulin users and male gender presented a higher risk for developing corpus-predominant gastritis following H. pylori infection. Therefore, diabetes mellitus and H. pylori infection are two highly prevalent conditions which may share certain common pathogenetic mechanisms affecting each other and may coexist beyond the simple coincidence [87], but further studies are required on different populations in order to elucidate that question (Table 1).
In terms of pediatric age, the evidence is scarce. However, a recent study found no significant association between diabetes and H. pylori infection in children aged between 5 and 15 years [95]. Moreover, the study pointed out no difference in glycemic control between type 1 diabetes mellitus children with or without H. pylori infection. A potential explanation might be related to the insufficient amount of time required for H. pylori to trigger its related systemic complications.
Non-alcoholic fatty liver disease (NAFLD) was recently linked to H. pylori infection [198]. Thus, Kim et al. pointed out that subjects infected with H. pylori had a higher incidence of NAFLD as compared to uninfected controls [86]. Similar findings were reported by Polyzos, who noticed that NAFLD patients had higher circulating levels of anti-H. pylori IgG [87]. A recent meta-analysis performed by Wijarnpreecha et al. also pointed that patients detected with H. pylori infection have a higher risk of NAFLD [88]. Contrarily, studies from Japan and Korea stated exactly the opposite [96,97] (Table 1).

8. H. pylori and Neurological Conditions

Recent evidence pointed out a potential link between H. pylori infection and certain neurological conditions such as Parkinson’s disease, multiple sclerosis, or Alzheimer’s disease, but the results remain controversial.
It was suggested that H. pylori might damage dopaminergic cells in central nervous system contributing to the development of Parkinson’s disease [98]. Furthermore, Tan et al. pointed out that H. pylori might worsen motor severity in patients with Parkinson’s disease [99]. In terms of eradication effects, studies are even more controversial. Thus, certain researchers sustain that H. pylori eradication was associated with an improvement in levodopa action, clinical symptoms, and life quality in patients with Parkinson’s disease [20], while others failed to find any association between bacterial eradication and clinical outcomes of Parkinson’s disease [110]. A recent review pointed out that the host’s innate immunity represented by toll-like receptor 2 might represent the underlying link between this neurological condition and H. pylori infection [100] (Table 1).
In terms of multiple sclerosis, it was highlighted that H. pylori infection was commonly encountered in this group of patients [101]. However, the findings reported in the literature remain conflicting since Long et al. [102] pointed out an increased prevalence of H. pylori infection in patients with multiple sclerosis, while Yaoa et al. found a negative correlation between these two conditions [111]. Oppositely, Gerges et al. found a significantly higher H. pylori seropositivity in Egyptian multiple sclerosis patients, especially those with secondary progressive forms [103]. Moreover, Baj et al. also reported both harmful and protective effects of H. pylori infection on multiple sclerosis [100] (Table 1).
The neurodegenerative diseases called Alzheimer’s disease was related to certain bacterial or viral pathogens such as H. pylori, Chlamydia pneumonia, or Herpes simplex virus-1 [104]. Thus, H. pylori infection was found to increase the risk of Alzheimer’s disease, while its eradication was associated with improvement in Alzheimer’s disease symptoms [106,107]. Other studies found significantly higher levels of anti-H. pylori IgG antibodies in both serum and cerebrospinal fluid of Alzheimer’s disease patients when compared to controls [108]. Moreover, those with increased seropositivity experienced a poorer clinical outcome. A recent systematic review also pointed out a possible association between this neurodegenerative condition and gastrointestinal microbiota, including H. pylori [109]. Thus, bacteria were proven to contribute to neurodegeneration by promoting inflammation, molecular mimicry mechanisms and accumulation of amyloid beta into the brain [218]. Therefore, gastrointestinal disorders, including H. pylori might negatively impact Alzheimer’s disease development and clinical course [105], but further studies are definitely required (Table 1).
The results of several meta-analyses regarding the role of H. pylori infection and Parkinson’s or Alzheimer’s disease remain controversial [105,170,171,172,173] (Table 2).

9. H. pylori and Other Extraintestinal Manifestations

9.1. Dermatological Conditions

Rosacea, a chronic facial dermatitis manifesting as erythema and cutaneous lesions characterized by very dilated red superficial capillaries, also known as teleangiectasia, is the most common dermatological condition associated with H. pylori infection [112]. Although several studies have indicated a potential relationship between this infection and rosacea, the precise role of H. pylori in the pathogenesis of rosacea remains debatable. Thus, it was proven that H. pylori infection is significantly more common in patients with rosacea when compared to control group [219].
H. pylori infection, but not small intestinal bacterial overgrowth, may play a pathogenic role in rosacea [219]. Moreover, the authors proved that the eradication of this infection was associated with either the improvement or total resolution of rosacea cutaneous lesions in 96.9% of the patients. Similar findings were also reported by other studies on this topic [113,114].
Chronic urticaria or itchy rash consisting of wheal-like lesions was also reported to be associated with H. pylori infection [115,116]. Contrarily, other authors failed in identifying a relationship between these two conditions; still, they pointed out a positive effect of eradication therapy on skin lesions [117].
Autoimmune bullous diseases consisting of pemphigus, pemphigoid, dermatitis herpetiformis, epidermolysis bullosa acquisita, and linear immunoglobulin A disease were also suggested to be associated with H. pylori infection [112]. The scarce evidence reported on this topic proved a higher level of IgG anti-H. pylori antibodies in patients with these conditions, revealing a higher prevalence of H. pylori infection in patients with autoimmune bullous diseases [220,221].
Data regarding the association between H. pylori infection and psoriasis or alopecia aerata remain contradictory, calling for further studies on larger samples [112].

9.2. Ophthalmic Disease

Recent evidence pointed out a potential relationship between open-angle glaucoma, a condition that might result in optic nerve damage, and H. pylori infection [118]. A recent meta-analysis performed on 10 studies proved that the prevalence of H. pylori infection was twice as high in patients with this ophthalmic condition as compared to a control group, revealing at the same time a normalization of mean visual field parameters and intraocular pressure as a result of H. pylori eradication [119].
Another ophthalmic condition, central serous chorioretinopathy, which might lead to micropsia, decreased vision acuity, metamorphopsia, and dyschromatopsia, was also suggested to be associated with H. pylori infection [118]. Based on the findings of Cotticelli et al., H. pylori infection prevalence was twice as high in patients with this condition as compared to controls [222]. Other authors highlighted both an improvement of central serous chorioretinopathy and a reduction in the recurrence rate following H. pylori eradication [120,121].

9.3. Autoimmune Conditions

The relationship between rheumatoid arthritis and H. pylori infection raised several controversies. Studies in vitro pointed out that B cells chronically stimulated with H. pylori-produced urease resulted in the production of autoantibodies, including IgM rheumatoid factor [122]. Nevertheless, studies regarding the prevalence of H. pylori in patients with this autoimmune condition failed in proving a significant difference in prevalence rate when compared to healthy controls [15,132]. In fact, studies on this topic revealed a similar prevalence between rheumatoid arthritis patients and healthy controls [223]. The eradication effect on rheumatoid arthritis evolution also remains debatable since both positive [128,129] and null [130,131] findings were reported. The risk of rheumatoid arthritis and lupus erythematosus in the setting of H. pylori infection might be related to the virulence features of this bacterium [123].
In terms of systemic lupus erythematosus, studies on mice proved that exposure to the urease produced by H. pylori might lead to the synthesis of anti-double-stranded DNA antibodies [122]. The contradictions go further since other authors suggested that H. pylori might represent a protective factor against systemic lupus erythematosus development in African-American females [133]. A more recent study performed in Taiwan revealed a 1.63-fold higher risk of systemic lupus erythematosus in infected females below the age of 30 years [124]. Furthermore, it is well-documented that H. pylori infection triggers a Th-17 inflammatory response, which is also involved in the pathophysiology of systemic lupus erythematosus [224,225]. In fact, a recent review concluded that H. pylori might have a dichotomous role acting as both a trigger and a protector for systemic lupus erythematosus depending on age, race, and the affected organs [125].
Sjögren syndrome, a systemic autoimmune disease characterized by lymphoplasmocytic infiltration of the exocrine glands resulting in sicca syndrome was also suggested to be associated with H. pylori infection [125]. H. pylori antibodies were found to be significantly increased in patients with primary Sjögren syndrome as compared to secondary type, other autoimmune diseases, and healthy controls [126]. Similar findings were reported by other authors [226,227,228]. Nevertheless, the benefit of H. pylori eradication in patients with this autoimmune condition remains controversial [134].
Regarding systemic sclerosis, the role of H. pylori infection follows the same pattern of controversies [223]. H. pylori seropositivity is not uncommon in patients with systemic sclerosis [127]. Nevertheless, other studies failed in identifying a significant difference regarding H. pylori prevalence in systemic sclerosis patients and healthy controls but revealed that almost all patients with systemic sclerosis were infected with more virulent H. pylori strains, especially those expressing CagA [135]. Contrarily, Kalabay et al. found an increased prevalence of H. pylori infection in patients with systemic sclerosis [229]. The same authors suggested a potential relationship between H. pylori infection and increased severity of systemic sclerosis. Therefore, H. pylori might be involved in the activity of systemic sclerosis [223].

10. Concluding Remarks

Emerging evidence suggests more and more extraintestinal pathologies to be related with H. pylori infection. Although most of them do not occur during childhood, acknowledging their existence is crucial for eradicating H. pylori infection in children since it is well-documented that H. pylori-associated inflammation is initiated in early life. Therefore, preventing the development of all aforementioned extraintestinal manifestations is possible only in the setting of early diagnosis and eradication of this infection. Moreover, it seems that the development of extraintestinal manifestations as a result of H. pylori infection might depend also on other factors such as age, race, gender, and even geographical areas. Therefore, future perspectives should also focus on elucidating the role of these demographic and host-related factors in the pathogenesis of H. pylori-associated extraintestinal manifestations. Likewise, a more in-depth study of host-related inflammatory response as a result of H. pylori infection should be performed for identifying potential inflammatory pathways that might be used for designing targeted therapies in order to prevent further complications related to this infection, including extraintestinal manifestations. It would add a great value if these studies were performed on pediatric patients for increasing the effectiveness of potential therapies that could be developed.
Indeed, pros and cons exist regarding the involvement of H. pylori in each of these extraintestinal manifestations imposing further studies in order to identify all the mechanisms related to the development of this conditions in which this bacterium might be implicated.

Author Contributions

Conceptualization, C.D.M., C.O.M. and L.E.M.; methodology, C.O.M. and L.E.M.; validation C.O.M. and L.E.M.; investigation, C.D.M., C.O.M. and L.E.M.; writing—original draft preparation, C.D.M., C.O.M. and L.E.M.; writing—review and editing C.O.M. and L.E.M.; supervision C.O.M. and L.E.M. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Robinson, K.; Atherton, J.C. The Spectrum of Helicobacter-Mediated Diseases. Annu. Rev. Pathol. 2021, 16, 123–144. [Google Scholar] [CrossRef] [PubMed]
  2. Dincă, A.L.; Meliț, L.E.; Mărginean, C.O. Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. Children 2022, 9, 1083. [Google Scholar] [CrossRef] [PubMed]
  3. Amieva, M.; Peek, R.M. Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 2016, 150, 64–78. [Google Scholar] [CrossRef] [PubMed]
  4. Parkin, D.M.; Bray, F.; Ferlay, J.; Pisani, P. Global Cancer Statistics, 2002. CA Cancer J. Clin. 2005, 55, 74–108. [Google Scholar] [CrossRef]
  5. Sheema, K.; Ikramdin, U.; Arshi, N.; Farah, N.; Imran, S. Role of Helicobacter pylori Eradication Therapy on Platelet Recovery in Chronic Immune Thrombocytopenic Purpura. Gastroenterol. Res. Pract. 2017, 2017, 9529752. [Google Scholar] [CrossRef]
  6. Gheibi, S.; Farrokh-Eslamlou, H.R.; Noroozi, M.; Pakniyat, A. Refractory Iron Deficiency Anemia and Helicobacter pylori Infection in Pediatrics: A Review. Iran J. Ped. Hematol. Oncol. 2015, 5, 50–64. [Google Scholar]
  7. Meliţ, L.E.; Mărginean, M.O.; Mocan, S.; Mărginean, C.O. The Usefulness of Inflammatory Biomarkers in Diagnosing Child and Adolescent’s Gastritis: STROBE Compliant Article. Medicine 2019, 98, e16188. [Google Scholar] [CrossRef]
  8. Săsăran, M.O.; Meliț, L.E.; Mocan, S.; Ghiga, D.V.; Dobru, E.D. Pediatric Gastritis and Its Impact on Hematologic Parameters. Medicine 2020, 99, e21985. [Google Scholar] [CrossRef]
  9. Săsăran, M.O.; Meliț, L.E.; Dobru, E.D. MicroRNA Modulation of Host Immune Response and Inflammation Triggered by Helicobacter pylori. Int. J. Mol. Sci. 2021, 22, 1406. [Google Scholar] [CrossRef]
  10. Meliț, L.E.; Mărginean, C.O.; Săsăran, M.O.; Mocan, S.; Ghiga, D.V.; Bogliş, A.; Duicu, C. Innate Immunity-the Hallmark of Helicobacter pylori Infection in Pediatric Chronic Gastritis. World J. Clin. Cases 2021, 9, 6686–6697. [Google Scholar] [CrossRef]
  11. Guclu, M.; Faruq Agan, A. Association of Severity of Helicobacter pylori Infection with Peripheral Blood Neutrophil to Lymphocyte Ratio and Mean Platelet Volume. Euroasian J. Hepatogastroenterol. 2017, 7, 11–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Meliț, L.E.; Mărginean, C.O.; Mărginean, C.D.; Mărginean, M.O. The Relationship between Toll-like Receptors and Helicobacter pylori-Related Gastropathies: Still a Controversial Topic. Available online: https://www.hindawi.com/journals/jir/2019/8197048/abs/ (accessed on 9 February 2019).
  13. Rosu, O.-M.; Gimiga, N.; Stefanescu, G.; Anton, C.; Paduraru, G.; Tataranu, E.; Balan, G.G.; Diaconescu, S. Helicobacter pylori Infection in a Pediatric Population from Romania: Risk Factors, Clinical and Endoscopic Features and Treatment Compliance. J. Clin. Med. 2022, 11, 2432. [Google Scholar] [CrossRef]
  14. White, J.R.; Winter, J.A.; Robinson, K. Differential Inflammatory Response to Helicobacter pylori Infection: Etiology and Clinical Outcomes. J. Inflamm. Res. 2015, 8, 137–147. [Google Scholar] [CrossRef] [PubMed]
  15. Yamaoka, Y.; Kita, M.; Kodama, T.; Sawai, N.; Kashima, K.; Imanishi, J. Induction of Various Cytokines and Development of Severe Mucosal Inflammation by CagA Gene Positive Helicobacter pylori Strains. Gut 1997, 41, 442–451. [Google Scholar] [CrossRef]
  16. Malaty, H.M. Epidemiology of Helicobacter pylori Infection. Best Pract. Res. Clin. Gastroenterol. 2007, 21, 205–214. [Google Scholar] [CrossRef]
  17. Kuipers, E.J.; Nelis, G.F.; Klinkenberg-Knol, E.C.; Snel, P.; Goldfain, D.; Kolkman, J.J.; Festen, H.P.M.; Dent, J.; Zeitoun, P.; Havu, N.; et al. Cure of Helicobacter pylori Infection in Patients with Reflux Oesophagitis Treated with Long Term Omeprazole Reverses Gastritis without Exacerbation of Reflux Disease: Results of a Randomised Controlled Trial. Gut 2004, 53, 12–20. [Google Scholar] [CrossRef] [PubMed]
  18. Cai, X.; Carlson, J.; Stoicov, C.; Li, H.; Wang, T.C.; Houghton, J. Helicobacter Felis Eradication Restores Normal Architecture and Inhibits Gastric Cancer Progression in C57BL/6 Mice. Gastroenterology 2005, 128, 1937–1952. [Google Scholar] [CrossRef]
  19. Mărginean, C.O.; Meliț, L.E.; Săsăran, M.O. Traditional and Modern Diagnostic Approaches in Diagnosing Pediatric Helicobacter pylori Infection. Children 2022, 9, 994. [Google Scholar] [CrossRef]
  20. Tseng, D.S.; Li, D.; Cholleti, S.M.; Wei, J.C.; Jodesty, Y.; Pham, H.-V. Effect of Helicobacter pylori Treatment on Unexplained Iron Deficiency Anemia. Perm. J. 2019, 23, 18–195. [Google Scholar] [CrossRef]
  21. Blecker, U.; Renders, F.; Lanciers, S.; Vandenplas, Y. Syncopes Leading to the Diagnosis of a Helicobacter pylori Positive Chronic Active Haemorrhagic Gastritis. Eur. J. Pediatr. 1991, 150, 560–561. [Google Scholar] [CrossRef]
  22. Aye, T.; Win, T.; Tun, M. The Status of Helicobacter pylori Infection Related Extraintestinal Diseases in Myanmar. GastroHep 2021, 3, 344–351. [Google Scholar] [CrossRef]
  23. Harris, P.R.; Serrano, C.A.; Villagrán, A.; Walker, M.M.; Thomson, M.; Duarte, I.; Windle, H.J.; Crabtree, J.E. Helicobacter pylori-Associated Hypochlorhydria in Children, and Development of Iron Deficiency. J. Clin. Pathol. 2013, 66, 343–347. [Google Scholar] [CrossRef] [PubMed]
  24. Soundaravally, R.; Pukazhvandthen, P.; Zachariah, B.; Hamide, A. Plasma Ferritin and Indices of Oxidative Stress in Helicobacter pylori Infection among Schoolchildren. J. Pediatr. Gastroenterol. Nutr. 2013, 56, 519–522. [Google Scholar] [CrossRef] [PubMed]
  25. Rahat, A.; Kamani, L. Frequency of Iron Deficiency Anemia (IDA) among Patients with Helicobacter pylori Infection. Pak. J. Med. Sci. 2021, 37, 776–781. [Google Scholar] [CrossRef] [PubMed]
  26. Qu, X.-H.; Huang, X.-L.; Xiong, P.; Zhu, C.-Y.; Huang, Y.-L.; Lu, L.-G.; Sun, X.; Rong, L.; Zhong, L.; Sun, D.-Y.; et al. Does Helicobacter pylori Infection Play a Role in Iron Deficiency Anemia? A Meta-Analysis. World J. Gastroenterol. 2010, 16, 886–896. [Google Scholar] [CrossRef]
  27. Monzón, H.; Forné, M.; Esteve, M.; Rosinach, M.; Loras, C.; Espinós, J.C.; Viver, J.M.; Salas, A.; Fernández-Bañares, F. Helicobacter pylori Infection as a Cause of Iron Deficiency Anaemia of Unknown Origin. World J. Gastroenterol. 2013, 19, 4166–4171. [Google Scholar] [CrossRef]
  28. Queiroz, D.M.M.; Harris, P.R.; Sanderson, I.R.; Windle, H.J.; Walker, M.M.; Rocha, A.M.C.; Rocha, G.A.; Carvalho, S.D.; Bittencourt, P.F.S.; de Castro, L.P.F.; et al. Iron Status and Helicobacter pylori Infection in Symptomatic Children: An International Multi-Centered Study. PLoS ONE 2013, 8, e68833. [Google Scholar] [CrossRef]
  29. Ozkasap, S.; Yarali, N.; Isik, P.; Bay, A.; Kara, A.; Tunc, B. The Role of Prohepcidin in Anemia Due to Helicobacter pylori Infection. Pediatr. Hematol. Oncol. 2013, 30, 425–431. [Google Scholar] [CrossRef]
  30. Azab, S.F.A.; Esh, A.M.H. Serum Hepcidin Levels in Helicobacter pylori-Infected Children with Iron-Deficiency Anemia: A Case-Control Study. Ann. Hematol. 2013, 92, 1477–1483. [Google Scholar] [CrossRef]
  31. Demerdash, D.M.E.; Ibrahim, H.; Hassan, D.M.; Moustafa, H.; Tawfik, N.M. Helicobacter pylori Associated to Unexplained or Refractory Iron Deficiency Anemia: An Egyptian Single-Center Experience. Hematol. Transfus. Cell Ther. 2018, 40, 219–225. [Google Scholar] [CrossRef]
  32. Rahman, Y.A.; Ahmed, L.A.W.; Hafez, R.M.M.; Ahmed, R.M.M. Helicobacter pylori and Its Hematological Effect. Egypt. J. Intern. Med. 2019, 31, 332–342. [Google Scholar] [CrossRef]
  33. Sabbagh, P.; Javanian, M.; Koppolu, V.; Vasigala, V.R.; Ebrahimpour, S. Helicobacter pylori Infection in Children: An Overview of Diagnostic Methods. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38, 1035–1045. [Google Scholar] [CrossRef] [PubMed]
  34. Campuzano-Maya, G. Hematologic Manifestations of Helicobacter pylori Infection. World J. Gastroenterol. 2014, 20, 12818–12838. [Google Scholar] [CrossRef] [PubMed]
  35. Stein, J.; Connor, S.; Virgin, G.; Ong, D.E.H.; Pereyra, L. Anemia and Iron Deficiency in Gastrointestinal and Liver Conditions. World J. Gastroenterol. 2016, 22, 7908–7925. [Google Scholar] [CrossRef]
  36. Zahmatkeshan, M.; Karimi, M.; Geramizadeh, B.; Eslaminasab, S.; Esmailnejad, A.; Safarpour, A.R. Association between Helicobacter pylori Infection and Iron Deficiency Anemia in School-Aged Iranian Children. Indian Pediatr. 2019, 56, 387–389. [Google Scholar] [CrossRef] [PubMed]
  37. Emiralioglu, N.; Yenicesu, I.; Sari, S.; Egritas, O.; Poyraz, A.; Pasaoglu, O.T.; Celik, B.; Dalgic, B. An Insight into the Relationships between Prohepcidin, Iron Deficiency Anemia, and Interleukin-6 Values in Pediatric Helicobacter pylori Gastritis. Eur. J. Pediatr. 2015, 174, 903–910. [Google Scholar] [CrossRef]
  38. Tan, H.-J.; Goh, K.-L. Extragastrointestinal Manifestations of Helicobacter pylori Infection: Facts or Myth? A Critical Review. J. Dig. Dis. 2012, 13, 342–349. [Google Scholar] [CrossRef]
  39. Gasbarrini, A.; Franceschi, F.; Tartaglione, R.; Landolfi, R.; Pola, P.; Gasbarrini, G. Regression of Autoimmune Thrombocytopenia after Eradication of Helicobacter pylori. Lancet 1998, 352, 878. [Google Scholar] [CrossRef]
  40. García Pérez, A.; Valverde de La Osa, J.; Giménez Samper, M.; Alonso García, I. Resolution of an autoimmune thrombocytopenic purpura after eradicating treatment of Helicobacter pylori. Sangre 1999, 44, 387–388. [Google Scholar]
  41. Stasi, R.; Sarpatwari, A.; Segal, J.B.; Osborn, J.; Evangelista, M.L.; Cooper, N.; Provan, D.; Newland, A.; Amadori, S.; Bussel, J.B. Effects of Eradication of Helicobacter pylori Infection in Patients with Immune Thrombocytopenic Purpura: A Systematic Review. Blood 2009, 113, 1231–1240. [Google Scholar] [CrossRef]
  42. Lee, A.; Hong, J.; Chung, H.; Koh, Y.; Cho, S.-J.; Byun, J.M.; Kim, S.G.; Kim, I. Helicobacter pylori Eradication Affects Platelet Count Recovery in Immune Thrombocytopenia. Sci. Rep. 2020, 10, 9370. [Google Scholar] [CrossRef] [PubMed]
  43. Marques, A.R.; Sousa, L.; Mendes, M.; Apolinário, I. Immune Thrombocytopenia Associated with Helicobacter pylori-Unclear Associative Mechanisms. Hematol. Transfus. Cell Ther. 2019, 41, 272–274. [Google Scholar] [CrossRef] [PubMed]
  44. Papagiannakis, P.; Michalopoulos, C.; Papalexi, F.; Dalampoura, D.; Diamantidis, M.D. The Role of Helicobacter pylori Infection in Hematological Disorders. Eur. J. Intern. Med. 2013, 24, 685–690. [Google Scholar] [CrossRef] [PubMed]
  45. Kuwana, M. Helicobacter pylori-Associated Immune Thrombocytopenia: Clinical Features and Pathogenic Mechanisms. World J. Gastroenterol. 2014, 20, 714–723. [Google Scholar] [CrossRef]
  46. Xiong, L.-J.; Tong, Y.; Wang, Z.-L.; Mao, M. Is Helicobacter pylori Infection Associated with Henoch-Schonlein Purpura in Chinese Children? A Meta-Analysis. World J. Pediatr. 2012, 8, 301–308. [Google Scholar] [CrossRef]
  47. Li, Q.; Lin, X.; Wu, Z.; He, L.; Wang, W.; Cao, Q.; Zhang, J. Immuno-Histochemistry Analysis of Helicobacter pylori Antigen in Renal Biopsy Specimens from Patients with Glomerulonephritis. Saudi J. Kidney Dis. Transpl. 2013, 24, 751–758. [Google Scholar] [CrossRef]
  48. Xiong, L.-J.; Mao, M. Current Views of the Relationship between Helicobacter pylori and Henoch-Schonlein Purpura in Children. World J. Clin. Pediatr. 2016, 5, 82–88. [Google Scholar] [CrossRef]
  49. Michel, M.; Cooper, N.; Jean, C.; Frissora, C.; Bussel, J.B. Does Helicobater Pylori Initiate or Perpetuate Immune Thrombocytopenic Purpura? Blood 2004, 103, 890–896. [Google Scholar] [CrossRef]
  50. Michel, M.; Khellaf, M.; Desforges, L.; Lee, K.; Schaeffer, A.; Godeau, B.; Bierling, P. Autoimmune Thrombocytopenic Purpura and Helicobacter pylori Infection. Arch. Intern. Med. 2002, 162, 1033–1036. [Google Scholar] [CrossRef]
  51. Mubarak, N.; Gasim, G.I.; Khalafalla, K.E.; Ali, N.I.; Adam, I. Helicobacter pylori, Anemia, Iron Deficiency and Thrombocytopenia among Pregnant Women at Khartoum, Sudan. Trans. R. Soc. Trop. Med. Hyg. 2014, 108, 380–384. [Google Scholar] [CrossRef]
  52. Iwańczak, B.; Francavailla, R. Helicobacter pylori Infection in Pediatrics. Helicobacter 2014, 19, 46–51. [Google Scholar] [CrossRef]
  53. Stawerska, R.; Czkwianianc, E.; Matusiak, A.; Smyczyńska, J.; Hilczer, M.; Chmiela, M.; Lewiński, A. Prevalence of Autoantibodies against Some Selected Growth and Appetite-Regulating Neuropeptides in Serum of Short Children Exposed to Candida Albicans Colonization and/or Helicobacter pylori Infection: The Molecular Mimicry Phenomenon. Neuroendocrinol. Lett. 2015, 36, 458–464. [Google Scholar] [PubMed]
  54. Deng, Z.-H.; Chu, B.; Xu, Y.-Z.; Zhang, B.; Jiang, L.-R. Influence of Helicobacter pylori Infection on Ghrelin Levels in Children. World J. Gastroenterol. 2012, 18, 5096–5100. [Google Scholar] [CrossRef]
  55. Ozen, A.; Furman, A.; Berber, M.; Karatepe, H.O.; Mutlu, N.; Sarıçoban, H.E.; Büyükgebiz, B. The Effect of Helicobacter pylori and Economic Status on Growth Parameters and Leptin, Ghrelin, and Insulin-like Growth Factor (IGF)-I Concentrations in Children. Helicobacter 2011, 16, 55–65. [Google Scholar] [CrossRef] [PubMed]
  56. Yang, Y.-J.; Sheu, B.-S.; Yang, H.-B.; Lu, C.-C.; Chuang, C.-C. Eradication of Helicobacter pylori Increases Childhood Growth and Serum Acylated Ghrelin Levels. World J. Gastroenterol. 2012, 18, 2674–2681. [Google Scholar] [CrossRef] [PubMed]
  57. Kopacova, M.; Koupil, I.; Seifert, B.; Fendrichova, M.S.; Spirkova, J.; Vorisek, V.; Rejchrt, S.; Douda, T.; Tacheci, I.; Bures, J. Blood Pressure and Stature in Helicobacter pylori Positive and Negative Persons. World J. Gastroenterol. 2014, 20, 5625–5631. [Google Scholar] [CrossRef]
  58. Poddar, U. Helicobacter pylori: A Perspective in Low- and Middle-Income Countries. Paediatr. Int. Child Health 2019, 39, 13–17. [Google Scholar] [CrossRef]
  59. Chmiela, M.; Gonciarz, W. Molecular Mimicry in Helicobacter pylori Infections. World J. Gastroenterol. 2017, 23, 3964–3977. [Google Scholar] [CrossRef]
  60. Stawerska, R.; Czkwianianc, E.; Matusiak, A.; Smyczyńska, J.; Hilczer, M.; Chmiela, M.; Lewiński, A. Assessment of Ghrelin, Leptin, Orexin A and Alpha-MSH Serum Concentrations and the Levels of the Autoantibodies against the Aforementioned Peptides in Relation to Helicobacter pylori Infections and Candida Albicans Colonization in Children with Short Stature. Pediatr. Endocrinol. Diabetes Metab. 2016, 21, 102–110. [Google Scholar] [CrossRef]
  61. Jaganath, D.; Saito, M.; Gilman, R.H.; Queiroz, D.M.M.; Rocha, G.A.; Cama, V.; Cabrera, L.; Kelleher, D.; Windle, H.J.; Crabtree, J.E.; et al. First Detected Helicobacter pylori Infection in Infancy Modifies the Association between Diarrheal Disease and Childhood Growth in Peru. Helicobacter 2014, 19, 272–279. [Google Scholar] [CrossRef]
  62. Thomas, J.E.; Dale, A.; Bunn, J.E.G.; Harding, M.; Coward, W.A.; Cole, T.J.; Weaver, L.T. Early Helicobacter pylori Colonisation: The Association with Growth Faltering in The Gambia. Arch. Dis. Child. 2004, 89, 1149–1154. [Google Scholar] [CrossRef] [PubMed]
  63. O’Connor, H.J.; Axon, A.T.; Dixon, M.F. Campylobacter-like Organisms Unusual in Type A (Pernicious Anaemia) Gastritis. Lancet 1984, 2, 1091. [Google Scholar] [CrossRef]
  64. Stabler, S.P. Vitamin B12 Deficiency. N. Engl. J. Med. 2013, 368, 2041–2042. [Google Scholar] [CrossRef]
  65. Sarari, A.S.; Farraj, M.A.; Hamoudi, W.; Essawi, T.A. Helicobacter pylori, a Causative Agent of Vitamin B12 Deficiency. J. Infect. Dev. Ctries. 2008, 2, 346–349. [Google Scholar] [CrossRef] [PubMed]
  66. Shuval-Sudai, O.; Granot, E. An Association between Helicobacter pylori Infection and Serum Vitamin B12 Levels in Healthy Adults. J. Clin. Gastroenterol. 2003, 36, 130–133. [Google Scholar] [CrossRef]
  67. Tun, M.; Aye, K.; Aye, T. Helicobacter pylori Infection and Vitamin B12 Deficiency 2019. In Proceedings of the 27th Annual Meeting of the Korean College of Helicobacter and Upper Gastrointestinal Research & The 16th Japan-Korea Joint Symposium on Helicobacter Research, Seoul, Korea, 18–19 March 2019. [Google Scholar]
  68. Franceschi, F.; Annalisa, T.; Teresa, D.R.; Giovanna, D.; Ianiro, G.; Franco, S.; Viviana, G.; Valentina, T.; Riccardo, L.L.; Antonio, G. Role of Helicobacter pylori Infection on Nutrition and Metabolism. World J. Gastroenterol. 2014, 20, 12809–12817. [Google Scholar] [CrossRef]
  69. Sagar, V.; Zafar, K.; Kumar, G. A Study of Helicobacter pylori Infection in Patients of Ischemic Cerebro Vascular Stroke. Int. J. Res. Med. Sci. Sagar V 2016, 4, 589–592. [Google Scholar] [CrossRef]
  70. Wang, B.; Yu, M.; Zhang, R.; Chen, S.; Xi, Y.; Duan, G. A Meta-Analysis of the Association between Helicobacter pylori Infection and Risk of Atherosclerotic Cardiovascular Disease. Helicobacter 2020, 25, e12761. [Google Scholar] [CrossRef]
  71. Kim, T.J.; Lee, H.; Kang, M.; Kim, J.E.; Choi, Y.-H.; Min, Y.W.; Min, B.-H.; Lee, J.H.; Son, H.J.; Rhee, P.-L.; et al. Helicobacter pylori Is Associated with Dyslipidemia but Not with Other Risk Factors of Cardiovascular Disease. Sci. Rep. 2016, 6, 38015. [Google Scholar] [CrossRef]
  72. Nam, S.Y.; Ryu, K.H.; Park, B.J.; Park, S. Effects of Helicobacter pylori Infection and Its Eradication on Lipid Profiles and Cardiovascular Diseases. Helicobacter 2015, 20, 125–132. [Google Scholar] [CrossRef]
  73. Annibale, B.; Capurso, G.; Delle Fave, G. Consequences of Helicobacter pylori Infection on the Absorption of Micronutrients. Dig. Liver Dis. 2002, 34 (Suppl. S2), S72–S77. [Google Scholar] [CrossRef]
  74. Bener, A.; Ağan, A.F.; Al-Hamaq, A.O.A.A.; Barisik, C.C.; Öztürk, M.; Ömer, A. Prevalence of Helicobacter pylori Infection among Type 2 Diabetes Mellitus. Adv. Biomed. Res. 2020, 9, 27. [Google Scholar] [CrossRef]
  75. Nasif, W.A.; Mukhtar, M.H.; Nour Eldein, M.M.; Ashgar, S.S. Oxidative DNA Damage and Oxidized Low Density Lipoprotein in Type II Diabetes Mellitus among Patients with Helicobacter pylori Infection. Diabetol. Metab. Syndr. 2016, 8, 34. [Google Scholar] [CrossRef]
  76. Huang, M.; Zhu, L.; Jin, Y.; Fang, Z.; Chen, Y.; Yao, Y. Association between Helicobacter pylori Infection and Systemic Arterial Hypertension: A Meta-Analysis. Arq. Bras. Cardiol. 2021, 117, 626–636. [Google Scholar] [CrossRef]
  77. Kato, M.; Toda, A.; Yamamoto-Honda, R.; Arase, Y.; Sone, H. Association between Helicobacter pylori Infection, Eradication and Diabetes Mellitus. J. Diabetes Investig. 2019, 10, 1341–1346. [Google Scholar] [CrossRef]
  78. Song, X.; Cai, C.; Jin, Q.; Chen, X.; Yu, C. The Efficacy of Helicobacter pylori Eradication in Diabetics and Its Effect on Glycemic Control: A Systematic Review and Meta-Analysis. Helicobacter 2021, 26, e12781. [Google Scholar] [CrossRef]
  79. Yula, E.; Koksal, F. Autoimmune Extraintestinal Manifestations of Helicobacter pylori Infection: A Bundle of Conflicts. J. Immunol. Clin. Microbiol. 2016, 1, 22. [Google Scholar] [CrossRef]
  80. Abdullahi, M.; Annibale, B.; Capoccia, D.; Tari, R.; Lahner, E.; Osborn, J.; Leonetti, F.; Severi, C. The Eradication of Helicobacter pylori Is Affected by Body Mass Index (BMI). Obes Surg. 2008, 18, 1450–1454. [Google Scholar] [CrossRef]
  81. Kouitcheu Mabeku, L.B.; Noundjeu Ngamga, M.L.; Leundji, H. Helicobacter pylori Infection, a Risk Factor for Type 2 Diabetes Mellitus: A Hospital-Based Cross-Sectional Study among Dyspeptic Patients in Douala-Cameroon. Sci. Rep. 2020, 10, 12141. [Google Scholar] [CrossRef]
  82. Hamrah, M.S.; Hamrah, M.H.; Ishii, H.; Suzuki, S.; Hamrah, M.H.; Hamrah, A.E.; Dahi, A.E.; Takeshita, K.; Hamrah, M.H.; Fotouhi, A.; et al. Association between Helicobacter pylori Infection and Cardiovascular Risk Factors among Patients in the Northern Part of Afghanistan: A Cross-Sectional Study in Andkhoy City. Asian Pac. J. Cancer Prev. 2018, 19, 1035–1039. [Google Scholar] [CrossRef]
  83. Alzahrani, S.; Lina, T.T.; Gonzalez, J.; Pinchuk, I.V.; Beswick, E.J.; Reyes, V.E. Effect of Helicobacter pylori on Gastric Epithelial Cells. World J. Gastroenterol. 2014, 20, 12767–12780. [Google Scholar] [CrossRef]
  84. Wan, Z.; Song, L.; Hu, L.; Hu, M.; Lei, X.; Huang, Y.; Lv, Y. Helicobacter pylori Infection Is Associated with Diabetes among Chinese Adults. J. Diabetes Investig. 2020, 11, 199–205. [Google Scholar] [CrossRef] [Green Version]
  85. Yang, Y.-J.; Wu, C.-T.; Ou, H.-Y.; Lin, C.-H.; Cheng, H.-C.; Chang, W.-L.; Chen, W.-Y.; Yang, H.-B.; Lu, C.-C.; Sheu, B.-S. Male Non-Insulin Users with Type 2 Diabetes Mellitus Are Predisposed to Gastric Corpus-Predominant Inflammation after H. pylori Infection. J. Biomed. Sci. 2017, 24, 82. [Google Scholar] [CrossRef]
  86. Kim, T.J.; Sinn, D.H.; Min, Y.W.; Son, H.J.; Kim, J.J.; Chang, Y.; Baek, S.-Y.; Ahn, S.H.; Lee, H.; Ryu, S. A Cohort Study on Helicobacter pylori Infection Associated with Nonalcoholic Fatty Liver Disease. J. Gastroenterol. 2017, 52, 1201–1210. [Google Scholar] [CrossRef]
  87. Polyzos, S.A.; Kountouras, J.; Papatheodorou, A.; Patsiaoura, K.; Katsiki, E.; Zafeiriadou, E.; Zavos, C.; Anastasiadou, K.; Terpos, E. Helicobacter pylori Infection in Patients with Nonalcoholic Fatty Liver Disease. Metabolism 2013, 62, 121–126. [Google Scholar] [CrossRef]
  88. Wijarnpreecha, K.; Thongprayoon, C.; Panjawatanan, P.; Manatsathit, W.; Jaruvongvanich, V.; Ungprasert, P. Helicobacter pylori and Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. J. Clin. Gastroenterol. 2018, 52, 386–391. [Google Scholar] [CrossRef]
  89. Devrajani, B.R.; Shah, S.Z.A.; Soomro, A.A.; Devrajani, T. Type 2 Diabetes Mellitus: A Risk Factor for Helicobacter pylori Infection: A Hospital Based Case-Control Study. Int. J. Diabetes Dev. Ctries 2010, 30, 22–26. [Google Scholar] [CrossRef]
  90. Bener, A.; Micallef, R.; Afifi, M.; Derbala, M.; Al-Mulla, H.M.; Usmani, M.A. Association between Type 2 Diabetes Mellitus and Helicobacter pylori Infection. Turk. J. Gastroenterol. 2007, 18, 225–229. [Google Scholar]
  91. Anastasios, R.; Goritsas, C.; Papamihail, C.; Trigidou, R.; Garzonis, P.; Ferti, A. Helicobacter pylori Infection in Diabetic Patients: Prevalence and Endoscopic Findings. Eur. J. Intern. Med. 2002, 13, 376. [Google Scholar] [CrossRef]
  92. Gerig, R.; Ernst, B.; Wilms, B.; Thurnheer, M.; Schultes, B. Gastric Helicobacter pylori Infection Is Associated with Adverse Metabolic Traits in Severely Obese Subjects. Obesity 2013, 21, 535–537. [Google Scholar] [CrossRef]
  93. Man, S.; Ma, Y.; Jin, C.; Lv, J.; Tong, M.; Wang, B.; Li, L.; Ning, Y. Association between Helicobacter pylori Infection and Diabetes: A Cross-Sectional Study in China. J. Diabetes Res. 2020, 2020, 7201379. [Google Scholar] [CrossRef]
  94. Alzahrani, S.; Nelson, J.; Moss, S.F.; Paulus, J.K.; Knowler, W.C.; Pittas, A.G.; Diabetes Prevention Program Research Group. H. pylori Seroprevalence and Risk of Diabetes: An Ancillary Case-Control Study Nested in the Diabetes Prevention Program. J. Diabetes Complicat. 2017, 31, 1515–1520. [Google Scholar] [CrossRef]
  95. Esmaeili Dooki, M.R.; Alijanpour Aghamaleki, M.; Noushiravani, N.; Hosseini, S.R.; Moslemi, L.; Hajiahmadi, M.; Pournasrollah, M. Helicobacter pylori Infection and Type 1 Diabetes Mellitus in Children. J. Diabetes Metab. Disord. 2020, 19, 243–247. [Google Scholar] [CrossRef]
  96. Tang, D.M.; Kumar, S. The Association Between Helicobacter pylori Infection and Nonalcoholic Fatty Liver Disease. Curr. Gastroenterol. Rep. 2017, 19, 5. [Google Scholar] [CrossRef]
  97. Okushin, K.; Takahashi, Y.; Yamamichi, N.; Shimamoto, T.; Enooku, K.; Fujinaga, H.; Tsutsumi, T.; Shintani, Y.; Sakaguchi, Y.; Ono, S.; et al. Helicobacter pylori Infection Is Not Associated with Fatty Liver Disease Including Non-Alcoholic Fatty Liver Disease: A Large-Scale Cross-Sectional Study in Japan. BMC Gastroenterol. 2015, 15, 25. [Google Scholar] [CrossRef]
  98. Dobbs, R.J.; Dobbs, S.M.; Weller, C.; Charlett, A.; Bjarnason, I.T.; Curry, A.; Ellis, D.S.; Ibrahim, M.A.A.; McCrossan, M.V.; O’Donohue, J.; et al. Helicobacter Hypothesis for Idiopathic Parkinsonism: Before and Beyond. Helicobacter 2008, 13, 309–322. [Google Scholar] [CrossRef]
  99. Tan, A.H.; Mahadeva, S.; Marras, C.; Thalha, A.M.; Kiew, C.K.; Yeat, C.M.; Ng, S.W.; Ang, S.P.; Chow, S.K.; Loke, M.F.; et al. Helicobacter pylori Infection Is Associated with Worse Severity of Parkinson’s Disease. Parkinsonism Relat. Disord. 2015, 21, 221–225. [Google Scholar] [CrossRef]
  100. Baj, J.; Forma, A.; Flieger, W.; Morawska, I.; Michalski, A.; Buszewicz, G.; Sitarz, E.; Portincasa, P.; Garruti, G.; Flieger, M.; et al. Helicobacter pylori Infection and Extragastric Diseases-A Focus on the Central Nervous System. Cells 2021, 10, 2191. [Google Scholar] [CrossRef]
  101. Gavalas, E.; Kountouras, J.; Boziki, M.; Zavos, C.; Polyzos, S.A.; Vlachaki, E.; Venizelos, I.; Tsiptsios, D.; Deretzi, G. Relationship between Helicobacter pylori Infection and Multiple Sclerosis. Ann. Gastroenterol. 2015, 28, 353–356. [Google Scholar]
  102. Long, Y.; Gao, C.; Qiu, W.; Hu, X.; Shu, Y.; Peng, F.; Lu, Z. Helicobacter pylori Infection in Neuromyelitis Optica and Multiple Sclerosis. Neuroimmunomodulation 2013, 20, 107–112. [Google Scholar] [CrossRef]
  103. Gerges, S.E.; Alosh, T.K.; Khalil, S.H.; El Din, M.M.W. Relevance of Helicobacter pylori Infection in Egyptian Multiple Sclerosis Patients. Egypt. J. Neurol. Psychiatr. Neurosurg. 2018, 54, 41. [Google Scholar] [CrossRef] [PubMed]
  104. Vitale, G.; Barbaro, F.; Ianiro, G.; Cesario, V.; Gasbarrini, G.; Franceschi, F.; Gasbarrini, A. Nutritional Aspects of Helicobacter pylori Infection. Minerva Gastroenterol. Dietol. 2011, 57, 369–377. [Google Scholar] [PubMed]
  105. Fu, P.; Gao, M.; Yung, K.K.L. Association of Intestinal Disorders with Parkinson’s Disease and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. ACS Chem. Neurosci. 2020, 11, 395–405. [Google Scholar] [CrossRef] [PubMed]
  106. Goni, E.; Franceschi, F. Helicobacter pylori and Extragastric Diseases. Helicobacter 2016, 21 (Suppl. S1), 45–48. [Google Scholar] [CrossRef]
  107. Chang, Y.-P.; Chiu, G.-F.; Kuo, F.-C.; Lai, C.-L.; Yang, Y.-H.; Hu, H.-M.; Chang, P.-Y.; Chen, C.-Y.; Wu, D.-C.; Yu, F.-J. Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study. Gastroenterol. Res. Pract. 2013, 2013, 175729. [Google Scholar] [CrossRef]
  108. Santos, C.Y.; Snyder, P.J.; Wu, W.-C.; Zhang, M.; Echeverria, A.; Alber, J. Pathophysiologic Relationship between Alzheimer’s Disease, Cerebrovascular Disease, and Cardiovascular Risk: A Review and Synthesis. Alzheimers Dement. 2017, 7, 69–87. [Google Scholar] [CrossRef]
  109. Doulberis, M.; Kotronis, G.; Gialamprinou, D.; Polyzos, S.A.; Papaefthymiou, A.; Katsinelos, P.; Kountouras, J. Alzheimer’s Disease and Gastrointestinal Microbiota; Impact of Helicobacter pylori Infection Involvement. Int. J. Neurosci. 2021, 131, 289–301. [Google Scholar] [CrossRef]
  110. Tan, A.H.; Lim, S.-Y.; Mahadeva, S.; Loke, M.F.; Tan, J.Y.; Ang, B.H.; Chin, K.P.; Mohammad Adnan, A.F.; Ong, S.M.C.; Ibrahim, A.I.; et al. Helicobacter pylori Eradication in Parkinson’s Disease: A Randomized Placebo-Controlled Trial. Mov. Disord. 2020, 35, 2250–2260. [Google Scholar] [CrossRef]
  111. Yao, G.; Wang, P.; Luo, X.-D.; Yu, T.-M.; Harris, R.A.; Zhang, X.-M. Meta-Analysis of Association between Helicobacter pylori Infection and Multiple Sclerosis. Neurosci. Lett. 2016, 620, 1–7. [Google Scholar] [CrossRef]
  112. Gravina, A.G.; Zagari, R.M.; De Musis, C.; Romano, L.; Loguercio, C.; Romano, M. Helicobacter pylori and Extragastric Diseases: A Review. World J. Gastroenterol. 2018, 24, 3204–3221. [Google Scholar] [CrossRef]
  113. Argenziano, G.; Donnarumma, G.; Iovene, M.R.; Arnese, P.; Baldassarre, M.A.; Baroni, A. Incidence of Anti-Helicobacter pylori and Anti-CagA Antibodies in Rosacea Patients. Int. J. Dermatol. 2003, 42, 601–604. [Google Scholar] [CrossRef] [PubMed]
  114. El-Khalawany, M.; Mahmoud, A.; Mosbeh, A.-S.; Alsalam, F.A.B.D.; Ghonaim, N.; Abou-Bakr, A. Role of Helicobacter pylori in Common Rosacea Subtypes: A Genotypic Comparative Study of Egyptian Patients. J. Dermatol. 2012, 39, 989–995. [Google Scholar] [CrossRef] [PubMed]
  115. Hizal, M.; Tüzün, B.; Wolf, R.; Tüzün, Y. The Relationship between Helicobacter pylori IgG Antibody and Autologous Serum Test in Chronic Urticaria. Int. J. Dermatol. 2000, 39, 443–445. [Google Scholar] [CrossRef] [PubMed]
  116. Galadari, I.H.; Sheriff, M.O. The Role of Helicobacter pylori in Urticaria and Atopic Dermatitis. Skinmed 2006, 5, 172–176. [Google Scholar] [CrossRef]
  117. Campanati, A.; Gesuita, R.; Giannoni, M.; Piraccini, F.; Sandroni, L.; Martina, E.; Conocchiari, L.; Bendia, E.; Di Sario, A.; Offidani, A. Role of Small Intestinal Bacterial Overgrowth and Helicobacter pylori Infection in Chronic Spontaneous Urticaria: A Prospective Analysis. Acta Derm. Venereol. 2013, 93, 161–164. [Google Scholar] [CrossRef]
  118. Gravina, A.G.; Priadko, K.; Ciamarra, P.; Granata, L.; Facchiano, A.; Miranda, A.; Dallio, M.; Federico, A.; Romano, M. Extra-Gastric Manifestations of Helicobacter pylori Infection. J. Clin. Med. 2020, 9, 3887. [Google Scholar] [CrossRef]
  119. Zeng, J.; Liu, H.; Liu, X.; Ding, C. The Relationship Between Helicobacter pylori Infection and Open-Angle Glaucoma: A Meta-Analysis. Invest. Ophthalmol. Vis. Sci. 2015, 56, 5238–5245. [Google Scholar] [CrossRef]
  120. Zavoloka, O.; Bezditko, P.; Lahorzhevska, I.; Zubkova, D.; Ilyina, Y. Clinical Efficiency of Helicobacter pylori Eradication in the Treatment of Patients with Acute Central Serous Chorioretinopathy. Graefes Arch. Clin. Exp. Ophthalmol. 2016, 254, 1737–1742. [Google Scholar] [CrossRef]
  121. Dang, Y.; Mu, Y.; Zhao, M.; Li, L.; Guo, Y.; Zhu, Y. The Effect of Eradicating Helicobacter pylori on Idiopathic Central Serous Chorioretinopathy Patients. Ther. Clin. Risk Manag. 2013, 9, 355–360. [Google Scholar] [CrossRef]
  122. Theander, E.; Nilsson, I.; Manthorpe, R.; Jacobsson, L.T.; Wadström, T. Seroprevalence of Helicobacter pylori in Primary Sjögren’s Syndrome. Clin. Exp. Rheumatol. 2001, 19, 633–638. [Google Scholar]
  123. Youssefi, M.; Tafaghodi, M.; Farsiani, H.; Ghazvini, K.; Keikha, M. Helicobacter pylori Infection and Autoimmune Diseases; Is There an Association with Systemic Lupus Erythematosus, Rheumatoid Arthritis, Autoimmune Atrophy Gastritis and Autoimmune Pancreatitis? A Systematic Review and Meta-Analysis Study. J. Microbiol. Immunol. Infect. 2021, 54, 359–369. [Google Scholar] [CrossRef] [PubMed]
  124. Wu, M.-C.; Leong, P.-Y.; Chiou, J.-Y.; Chen, H.-H.; Huang, J.-Y.; Wei, J.C.-C. Increased Risk of Systemic Lupus Erythematosus in Patients With Helicobacter pylori Infection: A Nationwide Population-Based Cohort Study. Front. Med. 2019, 6, 330. [Google Scholar] [CrossRef] [PubMed]
  125. Etchegaray-Morales, I.; Jiménez-Herrera, E.A.; Mendoza-Pinto, C.; Rojas-Villarraga, A.; Macías-Díaz, S.; Osorio-Peña, Á.D.; Munguía-Realpozo, P.; García-Carrasco, M. Helicobacter pylori and Its Association with Autoimmune Diseases: Systemic Lupus Erythematosus, Rheumatoid Arthritis and Sjögren Syndrome. J. Transl. Autoimmun. 2021, 4, 100135. [Google Scholar] [CrossRef]
  126. Aragona, P.; Magazzù, G.; Macchia, G.; Bartolone, S.; Di Pasquale, G.; Vitali, C.; Ferreri, G. Presence of Antibodies against Helicobacter pylori and Its Heat-Shock Protein 60 in the Serum of Patients with Sjögren’s Syndrome. J. Rheumatol. 1999, 26, 1306–1311. [Google Scholar] [PubMed]
  127. Gasbarrini, A.; Massari, I.; Serricchio, M.; Tondi, P.; De Luca, A.; Franceschi, F.; Ojetti, V.; Dal Lago, A.; Flore, R.; Santoliquido, A.; et al. Helicobacter pylori Eradication Ameliorates Primary Raynaud’s Phenomenon. Dig. Dis. Sci. 1998, 43, 1641–1645. [Google Scholar] [CrossRef] [PubMed]
  128. Meron, M.K.; Amital, H.; Shepshelovich, D.; Barzilai, O.; Ram, M.; Anaya, J.-M.; Gerli, R.; Bizzaro, N.; Nicola, B.; Shoenfeld, Y. Infectious Aspects and the Etiopathogenesis of Rheumatoid Arthritis. Clin. Rev. Allergy Immunol. 2010, 38, 287–291. [Google Scholar] [CrossRef] [PubMed]
  129. Ishikawa, N.; Fuchigami, T.; Matsumoto, T.; Kobayashi, H.; Sakai, Y.; Tabata, H.; Takubo, N.; Yamamoto, S.; Nakanishi, M.; Tomioka, K.; et al. Helicobacter pylori Infection in Rheumatoid Arthritis: Effect of Drugs on Prevalence and Correlation with Gastroduodenal Lesions. Rheumatology 2002, 41, 72–77. [Google Scholar] [CrossRef]
  130. Tanaka, E.; Singh, G.; Saito, A.; Syouji, A.; Yamada, T.; Urano, W.; Nakajima, A.; Taniguchi, A.; Tomatsu, T.; Hara, M.; et al. Prevalence of Helicobacter pylori Infection and Risk of Upper Gastrointestinal Ulcer in Patients with Rheumatoid Arthritis in Japan. Mod. Rheumatol. 2005, 15, 340–345. [Google Scholar] [CrossRef]
  131. Zentilin, P.; Seriolo, B.; Dulbecco, P.; Caratto, E.; Iiritano, E.; Fasciolo, D.; Bilardi, C.; Mansi, C.; Testa, E.; Savarino, V. Eradication of Helicobacter pylori May Reduce Disease Severity in Rheumatoid Arthritis. Aliment. Pharmacol. Ther. 2002, 16, 1291–1299. [Google Scholar] [CrossRef]
  132. Scott, D.L.; Wolfe, F.; Huizinga, T.W.J. Rheumatoid Arthritis. Lancet 2010, 376, 1094–1108. [Google Scholar] [CrossRef]
  133. Sorrentino, D.; Faller, G.; DeVita, S.; Avellini, C.; Labombarda, A.; Ferraccioli, G.; Kahlow-Toussaint, S. Helicobacter pylori Associated Antigastric Autoantibodies: Role in Sjögren’s Syndrome Gastritis. Helicobacter 2004, 9, 46–53. [Google Scholar] [CrossRef] [PubMed]
  134. Raderer, M.; Osterreicher, C.; Machold, K.; Formanek, M.; Fiebiger, W.; Penz, M.; Dragosics, B.; Chott, A. Impaired Response of Gastric MALT-Lymphoma to Helicobacter pylori Eradication in Patients with Autoimmune Disease. Ann. Oncol. 2001, 12, 937–939. [Google Scholar] [CrossRef] [PubMed]
  135. Sulli, A.; Seriolo, B.; Savarino, V.; Cutolo, M. Lack of Correlation between Gastric Helicobacter pylori Infection and Primary or Secondary Raynaud’s Phenomenon in Patients with Systemic Sclerosis. J. Rheumatol. 2000, 27, 1820–1821. [Google Scholar]
  136. Hudak, L.; Jaraisy, A.; Haj, S.; Muhsen, K. An Updated Systematic Review and Meta-Analysis on the Association between Helicobacter pylori Infection and Iron Deficiency Anemia. Helicobacter 2017, 22, e12330. [Google Scholar] [CrossRef] [PubMed]
  137. Huang, X.; Qu, X.; Yan, W.; Huang, Y.; Cai, M.; Hu, B.; Wu, L.; Lin, H.; Chen, Z.; Zhu, C.; et al. Iron Deficiency Anaemia Can Be Improved after Eradication of Helicobacter pylori. Postgrad. Med. J. 2010, 86, 272–278. [Google Scholar] [CrossRef]
  138. Wenzhen, Y.; Yumin, L.; Kehu, Y.; Bin, M.; Quanlin, G.; Donghai, W.; Lijuan, Y. Iron Deficiency Anemia in Helicobacter pylori Infection: Meta-Analysis of Randomized Controlled Trials. Scand. J. Gastroenterol. 2010, 45, 665–676. [Google Scholar] [CrossRef]
  139. Afsar, M.N.A.; Jhinu, Z.N.; Bhuiyan, M.A.I.; Islam, Z.; Siddiqua, T.J. Helicobacter pylori Infection and Micronutrient Deficiency in Pregnant Women: A Systematic Review and Meta-Analysis. BMJ Open Gastroenterol. 2020, 7, e000490. [Google Scholar] [CrossRef]
  140. Kim, B.J.; Kim, H.S.; Jang, H.J.; Kim, J.H. Helicobacter pylori Eradication in Idiopathic Thrombocytopenic Purpura: A Meta-Analysis of Randomized Trials. Gastroenterol. Res. Pract. 2018, 2018, 6090878. [Google Scholar] [CrossRef]
  141. Yu, T.; Wu, D.; Zhao, X.-Y. Infection and Eradication of Helicobacter Pylorus Affecting Etiology and Curative Effect of Idiopathic Thrombocytopenic Purpura: A META Analysis. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2011, 19, 1255–1259. [Google Scholar]
  142. Wei, S.; Dang, Y.; Peng, L.; Li, X.; Tang, L.; Zhang, G. Association between Helicobacter pylori Infection and Delayed Growth in Children: A Meta-Analysis. Exp. Ther. Med. 2020, 19, 3814–3828. [Google Scholar] [CrossRef]
  143. Xu, C.; Wu, Y.; Xu, S. Association between Helicobacter pylori Infection and Growth Outcomes in Children: A Meta-Analysis. Helicobacter 2022, 27, e12861. [Google Scholar] [CrossRef] [PubMed]
  144. Tang, Y.; Yang, Y.; Lv, Z. Adverse Pregnancy Outcomes and Helicobacter pylori Infection: A Meta-Analysis. Int. J. Clin. Pract. 2021, 75, e14588. [Google Scholar] [CrossRef] [PubMed]
  145. Zhan, Y.; Si, M.; Li, M.; Jiang, Y. The Risk of Helicobacter pylori Infection for Adverse Pregnancy Outcomes: A Systematic Review and Meta-Analysis. Helicobacter 2019, 24, e12562. [Google Scholar] [CrossRef] [PubMed]
  146. Shi, H.; Li, Y.; Dong, C.; Si, G.; Xu, Y.; Peng, M.; Li, Y. Helicobacter pylori Infection and the Progression of Atherosclerosis: A Systematic Review and Meta-Analysis. Helicobacter 2022, 27, e12865. [Google Scholar] [CrossRef] [PubMed]
  147. Keikha, M.; Karbalaei, M. A Comprehensive Survey of the Relationship between Helicobacter pylori Infection and Atherosclerosis in the Iranian Population: A Systematic Review and Meta-Analysis. Arch. Iran. Med. 2022, 25, 257–266. [Google Scholar] [CrossRef]
  148. Wang, X.; He, Q.; Jin, D.; Ma, B.; Yao, K.; Zou, X. Association between Helicobacter pylori Infection and Subclinical Atherosclerosis: A Systematic Review and Meta-Analysis. Medicine 2021, 100, e27840. [Google Scholar] [CrossRef]
  149. Doheim, M.F.; Altaweel, A.A.; Elgendy, M.G.; Elshanbary, A.A.; Dibas, M.; Ali, A.A.H.A.; Dahy, T.M.; Sharaf, A.K.; Hassan, A.E. Association between Helicobacter pylori Infection and Stroke: A Meta-Analysis of 273,135 Patients. J. Neurol. 2021, 268, 3238–3248. [Google Scholar] [CrossRef]
  150. Yu, M.; Zhang, Y.; Yang, Z.; Ding, J.; Xie, C.; Lu, N. Association between Helicobacter pylori Infection and Stroke: A Meta-Analysis of Prospective Observational Studies. J. Stroke Cerebrovasc. Dis. 2014, 23, 2233–2239. [Google Scholar] [CrossRef]
  151. Fang, Y.; Xie, H.; Fan, C. Association of Hypertension with Helicobacter pylori: A Systematic Review and Meta-analysis. PLoS ONE 2022, 17, e0268686. [Google Scholar] [CrossRef]
  152. Rahmani, Y.; Mohammadi, S.; Karim, H.; Rezazadeh, M.; Babanejad, M.; Shahmohammadi, A.; Rai, A. Association of Helicobacter pylori and Coronary Heart Disease in Iran: A Meta-Analysis. Med. J. Islam Repub. Iran 2018, 32, 73. [Google Scholar] [CrossRef]
  153. Sun, J.; Rangan, P.; Bhat, S.S.; Liu, L. A Meta-Analysis of the Association between Helicobacter pylori Infection and Risk of Coronary Heart Disease from Published Prospective Studies. Helicobacter 2016, 21, 11–23. [Google Scholar] [CrossRef] [PubMed]
  154. Franceschi, F.; Niccoli, G.; Ferrante, G.; Gasbarrini, A.; Baldi, A.; Candelli, M.; Feroce, F.; Saulnier, N.; Conte, M.; Roccarina, D.; et al. CagA Antigen of Helicobacter pylori and Coronary Instability: Insight from a Clinico-Pathological Study and a Meta-Analysis of 4241 Cases. Atherosclerosis 2009, 202, 535–542. [Google Scholar] [CrossRef] [PubMed]
  155. Fang, Y.; Fan, C.; Xie, H. Effect of Helicobacter pylori Infection on the Risk of Acute Coronary Syndrome: A Systematic Review and Meta-Analysis. Medicine 2019, 98, e18348. [Google Scholar] [CrossRef] [PubMed]
  156. Yan, J.; She, Q.; Zhang, Y.; Cui, C.; Zhang, G. The Association between Arrhythmia and Helicobacter pylori Infection: A Meta-Analysis of Case-Control Studies. Int. J. Environ. Res. Public Health 2016, 13, 1139. [Google Scholar] [CrossRef] [PubMed]
  157. Tetta, C.; Moula, A.I.; Matteucci, F.; Parise, O.; Maesen, B.; Johnson, D.; La Meir, M.; Gelsomino, S. Association between Atrial Fibrillation and Helicobacter pylori. Clin. Res. Cardiol. 2019, 108, 730–740. [Google Scholar] [CrossRef]
  158. Rahmani, Y.; Mohammadi, S.; Babanejad, M.; Rai, A.; Zalei, B.; Shahmohammadi, A. Association of Helicobacter pylori with Presence of Myocardial Infarction in Iran: A Systematic Review and Meta-Analysis. Ethiop. J. Health Sci. 2017, 27, 433–440. [Google Scholar] [CrossRef]
  159. Upala, S.; Sanguankeo, A.; Saleem, S.A.; Jaruvongvanich, V. Effects of Helicobacter pylori Eradication on Insulin Resistance and Metabolic Parameters: A Systematic Review and Meta-Analysis. Eur. J. Gastroenterol. Hepatol. 2017, 29, 153–159. [Google Scholar] [CrossRef]
  160. Mansori, K.; Dehghanbanadaki, H.; Naderpour, S.; Rashti, R.; Moghaddam, A.B.; Moradi, Y. A Systematic Review and Meta-Analysis of the Prevalence of Helicobacter pylori in Patients with Diabetes. Diabetes Metab. Syndr. 2020, 14, 601–607. [Google Scholar] [CrossRef]
  161. Zhou, X.; Zhang, C.; Wu, J.; Zhang, G. Association between Helicobacter pylori Infection and Diabetes Mellitus: A Meta-Analysis of Observational Studies. Diabetes Res. Clin. Pract. 2013, 99, 200–208. [Google Scholar] [CrossRef]
  162. Shi, Y.; Duan, J.-Y.; Liu, D.-W.; Qiao, Y.-J.; Han, Q.-X.; Pan, S.-K.; Tang, L.; Cai, G.-Y.; Chen, X.-M.; Liu, Z.-S.; et al. Helicobacter pylori Infection Is Associated with Occurrence of Proteinuria in Type 2 Diabetes Patients: A Systemic Review and Meta-Analysis. Chin. Med. J. 2018, 131, 2734–2740. [Google Scholar] [CrossRef]
  163. Chen, J.; Xing, Y.; Zhao, L.; Ma, H. The Association between Helicobacter pylori Infection and Glycated Hemoglobin A in Diabetes: A Meta-Analysis. J. Diabetes Res. 2019, 2019, 3705264. [Google Scholar] [CrossRef] [PubMed]
  164. Azami, M.; Baradaran, H.R.; Dehghanbanadaki, H.; Kohnepoushi, P.; Saed, L.; Moradkhani, A.; Moradpour, F.; Moradi, Y. Association of Helicobacter pylori Infection with the Risk of Metabolic Syndrome and Insulin Resistance: An Updated Systematic Review and Meta-Analysis. Diabetol. Metab. Syndr. 2021, 13, 145. [Google Scholar] [CrossRef] [PubMed]
  165. Upala, S.; Jaruvongvanich, V.; Riangwiwat, T.; Jaruvongvanich, S.; Sanguankeo, A. Association between Helicobacter pylori Infection and Metabolic Syndrome: A Systematic Review and Meta-Analysis. J. Dig. Dis. 2016, 17, 433–440. [Google Scholar] [CrossRef] [PubMed]
  166. Watanabe, J.; Hamasaki, M.; Kotani, K. The Effect of Helicobacter pylori Eradication on Lipid Levels: A Meta-Analysis. J. Clin. Med. 2021, 10, 904. [Google Scholar] [CrossRef] [PubMed]
  167. Baradaran, A.; Dehghanbanadaki, H.; Naderpour, S.; Pirkashani, L.M.; Rajabi, A.; Rashti, R.; Riahifar, S.; Moradi, Y. The Association between Helicobacter pylori and Obesity: A Systematic Review and Meta-Analysis of Case-Control Studies. Clin. Diabetes Endocrinol. 2021, 7, 15. [Google Scholar] [CrossRef]
  168. Xu, X.; Li, W.; Qin, L.; Yang, W.; Yu, G.; Wei, Q. Relationship between Helicobacter pylori Infection and Obesity in Chinese Adults: A Systematic Review with Meta-Analysis. PLoS ONE 2019, 14, e0221076. [Google Scholar] [CrossRef]
  169. Jaruvongvanich, V.; Sanguankeo, A.; Jaruvongvanich, S.; Upala, S. Association between Helicobacter pylori Infection and Multiple Sclerosis: A Systematic Review and Meta-Analysis. Mult. Scler. Relat. Disord. 2016, 7, 92–97. [Google Scholar] [CrossRef] [PubMed]
  170. Dardiotis, E.; Tsouris, Z.; Mentis, A.-F.A.; Siokas, V.; Michalopoulou, A.; Sokratous, M.; Dastamani, M.; Bogdanos, D.P.; Deretzi, G.; Kountouras, J.H. Pylori and Parkinson’s Disease: Meta-Analyses Including Clinical Severity. Clin. Neurol. Neurosurg. 2018, 175, 16–24. [Google Scholar] [CrossRef]
  171. Shen, X.; Yang, H.; Wu, Y.; Zhang, D.; Jiang, H. Meta-Analysis: Association of Helicobacter pylori Infection with Parkinson’s Diseases. Helicobacter 2017, 22, e12398. [Google Scholar] [CrossRef]
  172. Liu, N.-Y.; Sun, J.-H.; Jiang, X.-F.; Li, H. Helicobacter pylori Infection and Risk for Developing Dementia: An Evidence-Based Meta-Analysis of Case-Control and Cohort Studies. Aging 2021, 13, 22571–22587. [Google Scholar] [CrossRef]
  173. Shindler-Itskovitch, T.; Ravona-Springer, R.; Leibovitz, A.; Muhsen, K. A Systematic Review and Meta-Analysis of the Association between Helicobacterpylori Infection and Dementia. J. Alzheimers Dis. 2016, 52, 1431–1442. [Google Scholar] [CrossRef] [PubMed]
  174. Jørgensen, A.-H.R.; Egeberg, A.; Gideonsson, R.; Weinstock, L.B.; Thyssen, E.P.; Thyssen, J.P. Rosacea Is Associated with Helicobacter pylori: A Systematic Review and Meta-Analysis. J. Eur. Acad. Dermatol. Venereol. 2017, 31, 2010–2015. [Google Scholar] [CrossRef] [PubMed]
  175. Watanabe, J.; Shimamoto, J.; Kotani, K. The Effects of Antibiotics for Helicobacter pylori Eradication or Dapsone on Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis. Antibiotics 2021, 10, 156. [Google Scholar] [CrossRef] [PubMed]
  176. Gu, H.; Li, L.; Gu, M.; Zhang, G. Association between Helicobacter pylori Infection and Chronic Urticaria: A Meta-Analysis. Gastroenterol. Res. Pract. 2015, 2015, 486974. [Google Scholar] [CrossRef]
  177. Doulberis, M.; Papaefthymiou, A.; Polyzos, S.A.; Bargiotas, P.; Liatsos, C.; Srivastava, D.S.; Zavos, C.; Katsinelos, P.; Kountouras, J. Association between Active Helicobacter pylori Infection and Glaucoma: A Systematic Review and Meta-Analysis. Microorganisms 2020, 8, 894. [Google Scholar] [CrossRef]
  178. Liu, B.; Deng, T.; Zhang, J. RISK FACTORS FOR CENTRAL SEROUS CHORIORETINOPATHY: A Systematic Review and Meta-Analysis. Retina 2016, 36, 9–19. [Google Scholar] [CrossRef]
  179. Chen, Q.; Zhou, X.; Tan, W.; Zhang, M. Association between Helicobacter pylori Infection and Sjögren Syndrome: A Meta-Analysis. Medicine 2018, 97, e13528. [Google Scholar] [CrossRef]
  180. Li, L.; Tan, J.; Liu, L.; Li, J.; Chen, G.; Chen, M.; Xie, J.; Song, Q.; Huang, X.; Xie, S. Association between H. pylori Infection and Health Outcomes: An Umbrella Review of Systematic Reviews and Meta-Analyses. BMJ Open 2020, 10, e031951. [Google Scholar] [CrossRef]
  181. Yong, W.C.; Upala, S.; Sanguankeo, A. Helicobacter pylori Infection in Systemic Sclerosis: A Systematic Review and Meta-Analysis of Observational Studies. Clin. Exp. Rheumatol. 2018, 36 (Suppl. S113), 168–174. [Google Scholar]
  182. Chey, W.D.; Leontiadis, G.I.; Howden, C.W.; Moss, S.F. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am. J. Gastroenterol. 2017, 112, 212–239. [Google Scholar] [CrossRef]
  183. Barbosa, A.M.D.C.; Ribeiro, R.A.; Silva, C.Í.S.M.; Cruz, F.W.S.; de Azevedo, O.G.R.; da Pitombeira, M.H.S.; Braga, L.L.C. Platelet Count Response to Helicobacter pylori Eradication for Idiopathic Thrombocytopenic Purpura in Northeastern Brazil. Rev. Bras. Hematol. Hemoter. 2018, 40, 12–17. [Google Scholar] [CrossRef] [PubMed]
  184. Stasi, R.; Rossi, Z.; Stipa, E.; Amadori, S.; Newland, A.C.; Provan, D. Helicobacter pylori Eradication in the Management of Patients with Idiopathic Thrombocytopenic Purpura. Am. J. Med. 2005, 118, 414–419. [Google Scholar] [CrossRef] [PubMed]
  185. Arnold, D.M.; Bernotas, A.; Nazi, I.; Stasi, R.; Kuwana, M.; Liu, Y.; Kelton, J.G.; Crowther, M.A. Platelet Count Response to H. pylori Treatment in Patients with Immune Thrombocytopenic Purpura with and without H. pylori Infection: A Systematic Review. Haematologica 2009, 94, 850–856. [Google Scholar] [CrossRef]
  186. Wong, F.; Rayner-Hartley, E.; Byrne, M.F. Extraintestinal Manifestations of Helicobacter pylori: A Concise Review. World J. Gastroenterol. 2014, 20, 11950–11961. [Google Scholar] [CrossRef] [PubMed]
  187. Umit, H.; Umit, E.G. Helicobacter pylori and Mean Platelet Volume: A Relation Way before Immune Thrombocytopenia? Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 2818–2823. [Google Scholar] [PubMed]
  188. Neunert, C.; Lim, W.; Crowther, M.; Cohen, A.; Solberg, L.; Crowther, M.A. American Society of Hematology The American Society of Hematology 2011 Evidence-Based Practice Guideline for Immune Thrombocytopenia. Blood 2011, 117, 4190–4207. [Google Scholar] [CrossRef] [PubMed]
  189. Fock, K.M.; Katelaris, P.; Sugano, K.; Ang, T.L.; Hunt, R.; Talley, N.J.; Lam, S.K.; Xiao, S.-D.; Tan, H.J.; Wu, C.-Y.; et al. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori Infection. J. Gastroenterol. Hepatol. 2009, 24, 1587–1600. [Google Scholar] [CrossRef]
  190. Malfertheiner, P.; Selgrad, M.; Bornschein, J. Helicobacter pylori: Clinical Management. Curr. Opin. Gastroenterol. 2012, 28, 608–614. [Google Scholar] [CrossRef]
  191. Vanegas, Y.A.M.; Vishnu, P. Management of Helicobacter pylori in Patients with Immune Thrombocytopenia. Hamostaseologie 2019, 39, 279–283. [Google Scholar] [CrossRef]
  192. Roma, E.; Miele, E. Helicobacter pylori Infection in Pediatrics. Helicobacter 2015, 20 (Suppl. S1), 47–53. [Google Scholar] [CrossRef]
  193. Gonciarz, W.; Lechowicz, Ł.; Urbaniak, M.; Kaca, W.; Chmiela, M. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (FTIR) and Artificial Neural Networks Applied to Investigate Quantitative Changes of Selected Soluble Biomarkers, Correlated with H. pylori Infection in Children and Presumable Consequent Delayed Growth. J. Clin. Med. 2020, 9, 3852. [Google Scholar] [CrossRef]
  194. Mera, R.M.; Correa, P.; Fontham, E.E.; Reina, J.C.; Pradilla, A.; Alzate, A.; Bravo, L.E. Effects of a New Helicobacter pylori Infection on Height and Weight in Colombian Children. Ann. Epidemiol. 2006, 16, 347–351. [Google Scholar] [CrossRef] [PubMed]
  195. Soylu, O.B.; Ozturk, Y. Helicobacter pylori Infection: Effect on Malnutrition and Growth Failure in Dyspeptic Children. Eur. J. Pediatr. 2008, 167, 557–562. [Google Scholar] [CrossRef]
  196. Cherian, S.; Forbes, D.; Sanfilippo, F.; Cook, A.; Burgner, D. Helicobacter pylori, Helminth Infections and Growth: A Cross-Sectional Study in a High Prevalence Population. Acta Paediatr. 2009, 98, 860–864. [Google Scholar] [CrossRef]
  197. Chiu, N.-C.; Lin, C.-Y.; Chi, H.; Yeung, C.-Y.; Ting, W.-H.; Chan, W.-T.; Jiang, C.-B.; Li, S.-T.; Lin, C.-H.; Lee, H.-C. Helicobacter pylori Infection Is Not Associated with Failure to Thrive: A Case Control Study. Ther. Clin. Risk Manag. 2017, 13, 273–278. [Google Scholar] [CrossRef] [PubMed]
  198. Tsay, F.-W.; Hsu, P.-I.H. Pylori Infection and Extra-Gastroduodenal Diseases. J. Biomed. Sci. 2018, 25, 65. [Google Scholar] [CrossRef] [PubMed]
  199. Claeys, D.; Faller, G.; Appelmelk, B.J.; Negrini, R.; Kirchner, T. The Gastric H+,K+-ATPase Is a Major Autoantigen in Chronic Helicobacter pylori Gastritis with Body Mucosa Atrophy. Gastroenterology 1998, 115, 340–347. [Google Scholar] [CrossRef]
  200. Malfertheiner, P.; Megraud, F.; O’Morain, C.A.; Atherton, J.; Axon, A.T.R.; Bazzoli, F.; Gensini, G.F.; Gisbert, J.P.; Graham, D.Y.; Rokkas, T.; et al. Management of Helicobacter pylori Infection--the Maastricht IV/ Florence Consensus Report. Gut 2012, 61, 646–664. [Google Scholar] [CrossRef] [Green Version]
  201. Huh, C.W.; Kim, B.-W. The Pros and Cons of Helicobacter Pylori Treatment: A Focus on Cardiovascular Mortality. Gut Liver 2020, 14, 1–2. [Google Scholar] [CrossRef]
  202. Lin, Y.; Obata, Y.; Kikuchi, S.; Tamakoshi, A.; Iso, H.; JACC Study Group. Helicobacter pylori Infection and Risk of Death From Cardiovascular Disease Among the Japanese Population: A Nested Case-Control Study within the JACC Study. J. Atheroscler. Thromb. 2015, 22, 1207–1213. [Google Scholar] [CrossRef]
  203. Fraser, A.G.; Scragg, R.K.; Cox, B.; Jackson, R.T. Helicobacter pylori, Chlamydia Pneumoniae and Myocardial Infarction. Intern. Med. J. 2003, 33, 267–272. [Google Scholar] [CrossRef] [PubMed]
  204. Tamer, G.S.; Tengiz, I.; Ercan, E.; Duman, C.; Alioglu, E.; Turk, U.O. Helicobacter pylori Seropositivity in Patients with Acute Coronary Syndromes. Dig. Dis. Sci. 2009, 54, 1253–1256. [Google Scholar] [CrossRef] [PubMed]
  205. Khodaii, Z.; Vakili, H.; Ghaderian, S.M.H.; Najar, R.A.; Panah, A.S.T. Association of Helicobacter pylori Infection with Acute Myocardial Infarction. Coron. Artery Dis. 2011, 22, 6–11. [Google Scholar] [CrossRef] [PubMed]
  206. Lai, C.-Y.; Yang, T.-Y.; Lin, C.-L.; Kao, C.-H. Helicobacter pylori Infection and the Risk of Acute Coronary Syndrome: A Nationwide Retrospective Cohort Study. Eur. J. Clin. Microbiol. Infect. Dis. 2015, 34, 69–74. [Google Scholar] [CrossRef]
  207. Murray, L.J.; Bamford, K.B.; O’Reilly, D.P.; McCrum, E.E.; Evans, A.E. Helicobacter pylori Infection: Relation with Cardiovascular Risk Factors, Ischaemic Heart Disease, and Social Class. Br. Heart J. 1995, 74, 497–501. [Google Scholar] [CrossRef]
  208. Folsom, A.R.; Nieto, F.J.; Sorlie, P.; Chambless, L.E.; Graham, D.Y. Helicobacter pylori Seropositivity and Coronary Heart Disease Incidence. Atherosclerosis Risk In Communities (ARIC) Study Investigators. Circulation 1998, 98, 845–850. [Google Scholar] [CrossRef] [PubMed]
  209. Sheehan, J.; Kearney, P.M.; Sullivan, S.O.; Mongan, C.; Kelly, E.; Perry, I.J. Acute Coronary Syndrome and Chronic Infection in the Cork Coronary Care Case-Control Study. Heart 2005, 91, 19–22. [Google Scholar] [CrossRef]
  210. Schöttker, B.; Adamu, M.A.; Weck, M.N.; Müller, H.; Brenner, H. Helicobacter pylori Infection, Chronic Atrophic Gastritis and Major Cardiovascular Events: A Population-Based Cohort Study. Atherosclerosis 2012, 220, 569–574. [Google Scholar] [CrossRef]
  211. Elizalde, J.I.; Pérez-Pujol, S.; Heras, M.; Sionis, A.; Casanovas, N.; Martorell, T.; Lozano, M.; González, J.; Escolar, G.; Sanz, G.; et al. Effects of Helicobacter pylori Eradication on Platelet Activation and Disease Recurrence in Patients with Acute Coronary Syndromes. Helicobacter 2004, 9, 681–689. [Google Scholar] [CrossRef] [PubMed]
  212. Stone, A.F.M.; Mendall, M.A.; Kaski, J.-C.; Edger, T.M.; Risley, P.; Poloniecki, J.; Camm, A.J.; Northfield, T.C. Effect of Treatment for Chlamydia Pneumoniae and Helicobacter pylori on Markers of Inflammation and Cardiac Events in Patients with Acute Coronary Syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 2002, 106, 1219–1223. [Google Scholar] [CrossRef]
  213. Lim, S.H. Extraintestinal Manifestations of H. pylori Infection: Heart Disease. In Helicobacter pylori; Kim, N., Ed.; Springer: Singapore, 2016; pp. 349–360. ISBN 978-981-287-706-2. [Google Scholar]
  214. Meade, T.W.; Mellows, S.; Brozovic, M.; Miller, G.J.; Chakrabarti, R.R.; North, W.R.; Haines, A.P.; Stirling, Y.; Imeson, J.D.; Thompson, S.G. Haemostatic Function and Ischaemic Heart Disease: Principal Results of the Northwick Park Heart Study. Lancet 1986, 2, 533–537. [Google Scholar] [CrossRef]
  215. Fagoonee, S.; De Angelis, C.; Elia, C.; Silvano, S.; Oliaro, E.; Rizzetto, M.; Pellicano, R. Potential Link between Helicobacter pylori and Ischemic Heart Disease: Does the Bacterium Elicit Thrombosis? Minerva Med. 2010, 101, 121–125. [Google Scholar] [PubMed]
  216. Mladenova, I. Helicobacter pylori and Cardiovascular Disease: Update 2019. Minerva Cardioangiol. 2019, 67, 425–432. [Google Scholar] [CrossRef] [PubMed]
  217. Hosseininasab Nodoushan, S.A.; Nabavi, A. The Interaction of Helicobacter pylori Infection and Type 2 Diabetes Mellitus. Adv. Biomed. Res. 2019, 8, 15. [Google Scholar] [CrossRef] [PubMed]
  218. Franceschi, F.; Ojetti, V.; Candelli, M.; Covino, M.; Cardone, S.; Potenza, A.; Simeoni, B.; Gabrielli, M.; Sabia, L.; Gasbarrini, G.; et al. Microbes and Alzheimer’ Disease: Lessons from H. pylori and GUT Microbiota. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 426–430. [Google Scholar] [CrossRef]
  219. Gravina, A.; Federico, A.; Ruocco, E.; Lo Schiavo, A.; Masarone, M.; Tuccillo, C.; Peccerillo, F.; Miranda, A.; Romano, L.; de Sio, C.; et al. Helicobacter pylori Infection but Not Small Intestinal Bacterial Overgrowth May Play a Pathogenic Role in Rosacea. United Eur. Gastroenterol. J. 2015, 3, 17–24. [Google Scholar] [CrossRef]
  220. Sagi, L.; Baum, S.; Agmon-Levin, N.; Sherer, Y.; Katz, B.S.P.; Barzilai, O.; Ram, M.; Bizzaro, N.; SanMarco, M.; Trau, H.; et al. Autoimmune Bullous Diseases the Spectrum of Infectious Agent Antibodies and Review of the Literature. Autoimmun. Rev. 2011, 10, 527–535. [Google Scholar] [CrossRef]
  221. Mortazavi, H.; Hejazi, P.; Khamesipour, A.; Mohebali, M.; Ehsani, A.H.; Mohammadi, Y.; Farahani, I.V.; Amirzargar, A.A. Frequency of Seropositivity against Infectious Agents amongst Pemphigus Vulgaris Patients: A Case-Control Study on Strongyloides Stercoralis, Helicobacter pylori, Toxoplasma Gondii, Leishmania Major, and Epstein-Barr Virus. Int. J. Dermatol. 2015, 54, e458–e465. [Google Scholar] [CrossRef]
  222. Cotticelli, L.; Borrelli, M.; D’Alessio, A.C.; Menzione, M.; Villani, A.; Piccolo, G.; Montella, F.; Iovene, M.R.; Romano, M. Central Serous Chorioretinopathy and Helicobacter pylori. Eur. J. Ophthalmol. 2006, 16, 274–278. [Google Scholar] [CrossRef]
  223. Radić, M. Role of Helicobacter pylori Infection in Autoimmune Systemic Rheumatic Diseases. World J. Gastroenterol. 2014, 20, 12839–12846. [Google Scholar] [CrossRef]
  224. Arachchi, P.S.; Fernando, N.; Weerasekera, M.M.; Senevirathna, B.; Weerasekera, D.D.; Gunasekara, C.P. Proinflammatory Cytokine IL-17 Shows a Significant Association with Helicobacter pylori Infection and Disease Severity. Gastroenterol. Res. Pract. 2017, 2017, 6265150. [Google Scholar] [CrossRef]
  225. Koga, T.; Ichinose, K.; Kawakami, A.; Tsokos, G.C. The Role of IL-17 in Systemic Lupus Erythematosus and Its Potential as a Therapeutic Target. Expert Rev. Clin. Immunol. 2019, 15, 629–637. [Google Scholar] [CrossRef] [PubMed]
  226. Showji, Y.; Nozawa, R.; Sato, K.; Suzuki, H. Seroprevalence of Helicobacter pylori Infection in Patients with Connective Tissue Diseases. Microbiol. Immunol. 1996, 40, 499–503. [Google Scholar] [CrossRef] [PubMed]
  227. Saghafi, M.; Abdolahi, N.; Orang, R.; Hatef, M.R.; Molseghi, M.H. Helicobacter pylori Infection in Sjögren’s Syndrome: Co-Incidence or Causality? Curr. Rheumatol. Rev. 2019, 15, 238–241. [Google Scholar] [CrossRef]
  228. El Miedany, Y.M.; Baddour, M.; Ahmed, I.; Fahmy, H. Sjogren’s Syndrome: Concomitant H. pylori Infection and Possible Correlation with Clinical Parameters. Jt. Bone Spine 2005, 72, 135–141. [Google Scholar] [CrossRef] [PubMed]
  229. Kalabay, L.; Fekete, B.; Czirják, L.; Horváth, L.; Daha, M.R.; Veres, A.; Fónyad, G.; Horváth, A.; Viczián, A.; Singh, M.; et al. Helicobacter pylori Infection in Connective Tissue Disorders Is Associated with High Levels of Antibodies to Mycobacterial Hsp65 but Not to Human Hsp60. Helicobacter 2002, 7, 250–256. [Google Scholar] [CrossRef]
Table
Table 1. H. pylori and extraintestinal manifestations—Pros and Cons.
Table 1. H. pylori and extraintestinal manifestations—Pros and Cons.
DiseasesPros H. pyloriCons H. pylori
Iron deficiency anemia
  • H. pylori infection represents a frequent cause of iron deficiency [25]
  • completely resolved without iron supplementation after H. pylori eradication [21,26,27].
  • interleukin-1β—the decreased ferritin and hemoglobin concentrations in children with H. pylori infection [28]
  • H. pylori-positive children with iron deficiency anemia have significantly higher levels of prohepcidin before eradication [29]
  • serum hepcidin level associated with a reduced response to the oral iron supplementation in infected children [30]
  • H. pylori infection more prevalent in patients with refractory or unexplained iron deficiency anemia → significant improvement in hematological parameters in patients receiving iron supplements associated with the standard eradication triple therapy [31]
  • eradication improves blood parameters [32]
  • Sabbagh et al. → potential relationship between H. pylori infection and iron deficiency anemia, but at the same time stated that H. pylori might not be the only one involved in this relationship [33]
  • highly virulent H. pylori strains produce or augment iron deficiency [34]
  • Cag A → facilitator for H. pylori colonization enhancing iron acquisition [35]
  • Tseng et al. → failed in proving the resolution of iron deficiency anemia after H. pylori eradication [20]
  • Indian study on children → H. pylori might not, in fact, have an essential role in the development of iron deficiency anemia [36]
  • Emiralioglu N et al. → no difference between prohepcidin level in H. pylori infected children when compared to uninfected ones [37]
  • not all patients detected with H. pylori infection associate iron deficiency anemia [38]
Purpura
  • significant increase in platelet count after H. pylori eradication [39]
  • Garcia Perez et al. [40] → normalization of platelet count in a patient with chronic immune thrombocytopenic purpura after the eradication of the bacterium
  • 50% of adults—a sustained platelet response following H. pylori eradication [41]
  • patients with immune thrombocytopenia who underwent a successful eradication of H. pylori → maintain a higher platelet count thereafter [42]
  • complete resolution of symptoms and thrombocytopenia following H. pylori eradication [43]
  • H. pylori → cause of secondary immune thrombocytopenic purpura [44]
  • the pathogenesis of immune thrombocytopenic purpura → induction of platelet aggregated through the von Willebrand triggered by certain H. pylori strains → an activation of monocyte/macrophages with an anti-platelet effect, or antibodies against H. pylori CagA protein and platelet antigens [45]
  • Schonlein Henoch purpura associated with H. pylori infection, especially in the setting of gastrointestinal manifestations [46]
  • H. pylori eradication led either to prompt resolution of Schonlein Henoch purpura or to prevention of recurrences [47]
  • local injury of the gastric mucosa triggered by H. pylori contribute to the development of Schonlein Henoch purpura [48]
  • two studies from United States of America and France → no link between H. pylori infection and immune thrombocytopenic purpura [49,50]
  • other studies no association between this infection and the severity of immune thrombocytopenic purpura [38]
  • Sudan study → no association between H. pylori infection and thrombocytopenia in pregnant women [51]
  • Săsăran et al. → on pediatric patients → no significant difference in terms of mean platelet volume [8]
Growth
  • link between growth faltering and H. pylori → in countries with poor resources [52]
  • correlation between H. pylori and both growth faltering and malnutrition [53]
  • gastric ghrelin levels returned to normal once the infection was successfully eradicated [54]
  • low level of leptin in H. pylori infected children—improved following eradication [55,56]
  • Czech study → H. pylori infection was associated with short stature in children [57]
  • low- and middle-income countries → potential relationship between H. pylori and growth retardation [58]
  • gastrointestinal microflora including H. pylori—molecular mimicry [59]
  • children infected with H. pylori—antibodies against, leptin, ghrelin, orexin A, and α-MSH [53,60]
  • A study in Peru → 77% of the children which acquired the infection before 12 months of age with low socioeconomic status → H. pylori was not independently related with growth deficits in these children [61]
  • body mass index showed no significant differences after eradication [54]
  • Chiu et al.—no association between failure to thrive and H. pylori [62]
Vitamin B12 deficiency
  • in adults with H. pylori infection → significant association between the presence of this infection and vitamin B12 deficiency [32]
  • O’Connor et al. → vitamin B12 deficiency and H. pylori infection [63]
  • this deficiency present in > a half (67.4%) of the patients with H. pylori infection [64,65]
  • a higher prevalence of H. pylori infection in patients with vitamin B12 levels at the lower end of the normal range [66]
  • vitamin B12 level normalized after 1 month of vitamin B12 supplementation and standard triple therapy [67]
  • Annibale et al. [60] → H. pylori the only pathological elements in 57.1% of patients with anemia due to vitamin B12 deficiency
  • vitamin B12 deficiency—link between H. pylori infection and vascular disorders [68]
Cardiovascular diseases
  • H. pylori—carotid plaques instability => ischemic stroke [69]
  • association between H. pylori and acute cerebral ischemia in patients with ischemic cerebrovascular stroke [69]
  • Korea → a positive association between this infection and low HDL, elevated LDL, and cardiovascular disease—eradication lowered the risk of high LDL and low HDL
  • H. pylori infection increased the risk of adverse cardiovascular events by 51% [70]
  • H. pylori infection—a significant and independent predictor of dyslipidemia [71]
  • Korea → H. pylori had no effect on cardiovascular disease [72]
  • Japan → no relationship between H. pylori infection and either stroke mortality risk or coronary heart disease [73]
Insulin resistance, diabetes mellitus and obesity
  • significantly higher prevalence of H. pylori infection in patients with diabetes [74]
  • H. pylori prevalence—more increased in type 2 diabetes mellitus patients [75]
  • H. pylori-associated inflammation + cytokines + hormonal imbalances = → association between this infection and diabetes mellitus [76]
  • eradication → decreases the risk of diabetes [77]
  • Song et al. → diabetic patients with H. pylori infection might require more aggressive eradication therapies [78]
  • relationship between H. pylori infection and insulin resistance in normal-weight subjects [79]
  • eradication rate lower in obese patients [80]
  • H. pylori and high body mass index separately or not—risk factors for diabetes mellitus [81]
  • Hamrah et al. → significant association between H. pylori infection and both diabetes mellitus and increased body mass index [82]
  • Alzahrani et al.—a relationship only between H. pylori infection and increased body mass index [83]
  • China → H. pylori is significantly associated with diabetes [84]
  • Yang et al. → the severity of corpus gastritis associated to H. pylori infection was more severe in type 2 diabetes mellitus patients when compared to non-diabetic controls [85]
  • H. pylori—a higher incidence of NAFLD [86]
  • Polyzos et al.—NAFLD patients higher circulating levels of anti-H. pylori IgG [87]
  • patients detected with H. pylori infection have a higher risk of NAFLD [88]
  • certain studies failed in identifying any association [89,90,91]
  • obesity was not proven to enhance insulin resistance in the setting of H. pylori infection [92]
  • Alzahrani et al.—no relationship between H. pylori infection and type 2 diabetes mellitus [83]
  • China → H. pylori was not significantly associated with diabetes [93]
  • Alzahrani et al. also failed in identifying any association between H. pylori seropositivity and risk of developing diabetes [94]
  • pediatric patients → no significant association between diabetes and H. pylori infection [95]
  • Japan and Korea → no relationship between H. pylori infection and NAFLD [96,97]
Neurological conditions
  • H. pylori might damage dopaminergic cells in central nervous system => Parkinson’s disease [98]
  • Tan et al.—H. pylori might worsen Parkinson’s disease motor severity [99]
  • eradication associated with an improvement of levodopa action, clinical symptoms, and life quality in Parkinson’s disease [20]
  • host’s innate immunity—underlying link between Parkinson’s disease and H. pylori infection [100]
  • multiple sclerosis → H. pylori infection more frequent in these patients [101]
  • Long et al. [102]—an increased prevalence of H. pylori infection in multiple sclerosis
  • Gerges et al.—a significantly higher H. pylori seropositivity in Egyptian multiple sclerosis patients [103]
  • Baj et al.—both harmful and protective effects of H. pylori infection on multiple sclerosis [100]
  • Alzheimer’s disease related to H. pylori [104]
  • H. pylori might negatively impact Alzheimer’s disease development and clinical course [105]
  • H. pylori infection—increased the risk of Alzheimer’s disease, while its eradication—improvement in Alzheimer’s disease symptoms [106,107]
  • significantly higher levels of anti-H. pylori IgG antibodies in both serum and cerebrospinal fluid of Alzheimer’s disease [108]
  • possible association between Alzheimer’s disease and gastrointestinal microbiota including H. pylori [109]
  • no association between bacterial eradication and Parkinson’s disease clinical outcome [110]
  • Yaoa et al.—negative correlation between multiple sclerosis and H. pylori [111]
  • Baj et al. also—both harmful and protective effects of H. pylori infection on multiple sclerosis [100]
Dermatological conditions
  • rosacea, also known as teleangiectasia → associated with H. pylori infection [112]
  • eradication of H. pylori infection → improvement or total resolution of rosacea cutaneous lesions in 96.9% [113,114]
  • chronic urticaria or itchy rash consisting of wheal-like lesions—associated with H. pylori infection [115,116]
  • autoimmune bullous diseases consisting of pemphigus, pemphigoid, dermatitis herpetiformis, epidermolysis bullosa acquisita → associated with H. pylori infection [112]
  • other authors → no relationship between rosacea, chronic urticaria and H. pylori infection, still they pointed out a positive effect of eradication therapy on skin lesions [117]
  • association between H. pylori infection and psoriasis or alopecia aerata remain contradictory [112]
Ophthalmic disease
  • relationship between open-angle glaucoma and H. pylori infection [118]
  • prevalence of H. pylori infection higher in patients with this ophthalmic condition
  • normalization of mean visual field parameters and intraocular pressure as a result of H. pylori eradication [119]
  • central serous chorioretinopathy is associated with H. pylori infection [118]
  • improvement in central serous chorioretinopathy and a reduction in the recurrence rate following H. pylori eradication [120,121]
-
Autoimmune conditions
  • B cells chronically stimulated with H. pylori-produced urease resulted in a production of autoantibodies, including IgM rheumatoid factor [122]
  • the risk of rheumatoid arthritis and lupus erythematosus in the setting of H. pylori infection might be related to the virulence features of this bacterium [123]
  • higher risk of systemic lupus erythematosus in H. pylori infected females <30 years [124]
  • Sjögren syndrome → associated with H. pylori infection [125]
  • H. pylori antibodies → significantly increased in patients with primary Sjögren syndrome [126]
  • Increased prevalence of H. pylori infection in patients with systemic sclerosis [127]
  • the eradication of H. pylori infection effect on rheumatoid arthritis evolution remains also debatable since both positive [128,129] and null [130,131] findings were reported
  • prevalence of H. pylori in patients with this autoimmune condition failed in proving a significant difference in prevalence rate when compared to healthy controls [15,132]
  • H. pylori might represent a protective factor against systemic lupus erythematosus in African-American females [133]
  • H. pylori—dichotomous role acting as both a trigger and a protector for systemic lupus erythematosus depending on age, race, and the affected organs [125]
  • the benefit of H. pylori eradication in patients with this autoimmune condition remains controversial [134]
  • other studies failed in identifying a significant difference regarding H. pylori prevalence in systemic sclerosis patients [135]
  • all patients with systemic sclerosis were infected with more virulent H. pylori strains, especially those expressing CagA [135]
Table
Table 2. Possible association between H. pylori and extra-gastrointestinal diseases—Meta-analysis-based evidence.
Table 2. Possible association between H. pylori and extra-gastrointestinal diseases—Meta-analysis-based evidence.
Type of Extra-Intestinal ManifestationsAuthors, YearStatements
Hematological diseasesIron deficiency anemiaQu et al., 2010 [26]
  • association between H. pylori and iron deficiency anemia
  • in randomized controlled trials, eradication of H. pylori can improve hemoglobin and serum ferritin levels (not significantly)
Hudak et al., 2017 [136]
  • H. pylori—decreased iron stores
  • H. pylori eradication therapy, added to iron therapy → increased ferritin and hemoglobin levels
Yuan et al., 2010 [138]
  • treatment of H. pylori infection could be effective in improving anemia and iron status in iron deficiency anemia
Afsar et al., 2020 [139]
  • H. pylori infection is associated with increased risk of iron deficiency anemia in pregnancy
Huang et al., 2010 [137]
  • H pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of iron deficiency anemia
PurpuraXiong et al., 2012 [46]
  • eradication therapy may reduce the recurrence of Schonlein Henoch purpura in children with H. pylori infection
Kim et al., 2018 [140]
  • H. pylori eradication → therapeutic effect in patients with immune thrombocytopenic purpura
Yu et al., 2011 [141]
  • eradication of H. Pylori increases platelet count in patients with immune thrombocytopenic purpura
GrowthDelayed growth in childrenWei et al., 2020 [142]
  • H. pylori-positive children were prone to delayed linear growth
  • preventing and detecting H. pylori infection in children—critical to ensure normal growth and development during childhood
Xu et al., 2022 [143]
  • H. pylori infection—associated with growth outcomes in children, mainly negative effect on children’s height-for-age
Tang et al., 2021 [144]
  • H. pylori infection during pregnancy was significantly related to a higher rate of preeclampsia, fetal growth restriction, gestational diabetes mellitus, and hyperemesis gravidarum
Zhan et al., 2019 [145]
  • H. pylori infection during pregnancy can increase the risk on adverse pregnancy outcomes (preeclampsia, fetal growth restriction, gestational diabetes mellitus, spontaneous abortion and birth defect)
Cardiovascular diseasesAtherosclerosis (AS)Shi et al., 2022 [146]
  • H. pylori infection can promote the process of atherosclerosis in people <60 years and people without cardiovascular risk factors
Keikha et al., 2022 [147]
  • positive relationship between H. pylori infection and atherosclerosis in the Iranian population, similar to Western countries
Wang et al., 2021 [148]
  • significant association between H. pylori and subclinical atherosclerosis
StrokeDoheim et al., 2021 [149]
  • H. pylori infection—significantly associated with increased risk of stroke
Yu et al., 2014 [150]
  • no strong association between H. pylori infection and stroke, neither in those with cytotoxin-associated gene-A-positive infection
Systemic Arterial HypertensionHuang et al., 2021 [76]
  • H. pylori infection is positively associated with hypertension
Fang et al., 2022 [151]
  • H. pylori is a vital risk factor for hypertension
Coronary heart diseaseRahmani et al., 2018 [152]
  • most of the patients acquired H. pylori infection during childhood
  • personal hygiene promotion and preventive programs for Iranian children may have a role in reducing the risk of the infection and cardiovascular diseases
Sun et al., 2016 [153]
  • H. pylori infection might increase the risk of coronary heart disease events, especially in early life, but weak
Coronary instabilityFranceschi et al., 2009 [154]
  • H. pylori strains might be critical to precipitate coronary instability mediated by antigen mimicry between CagA antigen and a protein contained in coronary atherosclerotic plaques
Acute coronary syndromeFang et al., 2019 [155]
  • H. pylori infection was associated with an increased risk of acute coronary syndrome, especially in developing countries
ArrhythmiaYan et al., 2016 [156]
  • H. pylori infection was a risk factor for atrial fibrillation in Asia and Africa.
  • a possible correlation between H. pylori infection and arrhythmia
  • H. pylori eradication may decrease the occurrence of arrhythmia, especially in Asia and Africa
Atrial fibrillationTetta et al., 2019 [157]
  • no significant correlation between H. pylori infection and atrial fibrillation
Myocardial Infarction Rahmani et al., 2017 [158]
  • H. pylori—associated with higher incidence of myocardial infarction in adults
Metabolic syndromeDiabetes and Insulin resistanceSong et al., 2021 [78]
  • a higher risk of H. pylori eradication failure in type 2 diabetes mellitus (T2DM)
  • H. pylori eradication could improve glycemic control in patients with T2DM
Upala et al., 2017 [159]
  • H. pylori eradication does not improve insulin resistance, lipid metabolism parameters, or fasting blood glucose
Mansori et al., 2020 [160]
  • high prevalence of H. pylori in patients with diabetes
  • eradication of this bacterium should be considered in patients with diabetes
Zhou et al., 2013 [161]
  • H. pylori infection increased in T2DM patients
Shi et al., 2018 [162]
  • H. pylori infection was associated with the occurrence of proteinuria in T2DM patients
Chen et al., 2019 [163]
  • correlation between Helicobacter pylori infection and glycated hemoglobin A levels in diabetes
Azami et al., 2021 [164]
  • a possible relationship between metabolic syndrome, insulin resistance, and H. pylori infection
Upala et al., 2016 [165]
  • H. pylori infection is positively associated with metabolic syndrome
  • infection with H. pylori is associated with higher triglyceride, fasting blood glucose, body mass index (BMI), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), systolic blood pressure and lower high-density lipoprotein (HDL-C)
Nonalcoholic Fatty Liver Disease (NAFLD)Wijarnpreecha et al., 2018 [88]
  • a significantly increased risk of NAFLD among patients with H. pylori infection was demonstrated
Lipid metabolismWatanabe et al., 2021 [166]
  • H. pylori eradication increases the HDL-C levels
ObesityBaradaran et al., 2021 [167]
  • a positive correlation between the risk of H. pylori infection and the prevalence of obesity development
Xu et al., 2019 [168]
  • China—obesity associated with H. pylori infection
  • H. pylori infection may be one of the risk factors for obesity
Neurological diseasesMultiple SclerosisYao et al., 2016 [111]
  • a significant lower prevalence of H. pylori infection in patients with multiple sclerosis
  • H. pylori might be a protective factor for developing multiple sclerosis
Jaruvongvanich et al., 2016 [169]
  • a significant lower prevalence of H. pylori infection in patients with multiple sclerosis
  • H. pylori might be a protective factor for developing multiple sclerosis.
Parkinson’s Disease (PD) and Alzheimer’s Disease (AD):Fu et al., 2020 [105]
  • H. pylori has negative impact on the development of Parkinson and Alzheimer’s disease
Dardiotis et al., 2018 [170]
  • higher prevalence of H. pylori infection in Parkinson disease patients suggesting that H. pylori
Shen et al., 2017 [171]
  • H. pylori infection might be associated with the risk of Parkinson’s disease
Liu et al., 2021 [172]
  • positive association between H. pylori infection and the risk of all-cause dementia, but not Alzheimer’s dementia
Shindler-Itskovitch et al., 2016 [173]
  • H. pylori may play a role in the etiology of Alzheimer’s dementia
Dermatological conditionsRosaceaJørgensen et al., 2017 [174]
  • weak associations between rosacea and H. pylori infection
  • effect of H. pylori therapy on rosacea symptoms → no statistical significance
Chronic urticariaWatanabe et al., 2021 [175]
  • antibiotics, especially those for H. pylori eradication, improved the remission rate and symptoms of chronic urticaria with few adverse events
Gu et al., 2015 [176]
  • H. pylori infection is significantly, though weakly associated with an increased risk of chronic urticaria
Ophthalmic diseaseGlaucomaZeng et al., 2015 [119]
  • significant association between H. pylori infection and open-angle glaucoma
GlaucomaDoulberis et al., 2020 [177]
  • H. pylori infection may be associated with glaucoma with null heterogeneity, as beyond histology, quantified by anti-H. pylori titers and increases with age
Central serous chorioretinopathyLiu et al., 2016 [178]
  • H. pylori infection → possible risk factor for central serous chorioretinopathy
Autoimmune diseasesSystemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis, and autoimmune pancreatitisYoussefi et al., 2021 [123]
  • infection with more virulent strains of H. pylori cagA positive increase the risk of autoimmune diseases
  • H. pylori—prevent the development of atrophic gastritis by stimulating inflammation in the gastric antrum.
Sjögren syndromeChen et al., 2018 [179]
  • Significantly higher H. pylori infection rate in patients with SS
Systemic sclerosisLi et al., 2020 [180]
  • H. pylori infection may be associated with an increased risk of systemic sclerosis.
Yong et al., 2018 [181]
  • Systemic sclerosis patients have an increased prior risk of H. pylori infection
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mărginean, C.D.; Mărginean, C.O.; Meliț, L.E. Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality. Children 2022, 9, 1352. https://doi.org/10.3390/children9091352

AMA Style

Mărginean CD, Mărginean CO, Meliț LE. Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality. Children. 2022; 9(9):1352. https://doi.org/10.3390/children9091352

Chicago/Turabian Style

Mărginean, Cristian Dan, Cristina Oana Mărginean, and Lorena Elena Meliț. 2022. "Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality" Children 9, no. 9: 1352. https://doi.org/10.3390/children9091352

APA Style

Mărginean, C. D., Mărginean, C. O., & Meliț, L. E. (2022). Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality. Children, 9(9), 1352. https://doi.org/10.3390/children9091352

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop