Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality

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.


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 gastricmucosa-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. pyloriassociated 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.

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). • 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]  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. pyloriinduced 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). • treatment of H. pylori infection could be effective in improving anemia and iron status in iron deficiency anemia Table 2. Cont.

Hematological diseases
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    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).

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, serologybased 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).

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. pyloripositive 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 lowand 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).

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).

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 metaanalysis 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.

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).

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).

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].

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].

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. pyloriproduced 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].

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.

Conflicts of Interest:
The authors declare no conflict of interest.