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Extradigestive manifestations of Helicobacter pylori gastric infection
  1. A Gasbarrinia,
  2. F Franceschia,
  3. A Armuzzib,
  4. V Ojettib,
  5. M Candellib,
  6. E Sanz Torreb,
  7. A De Lorenzoc,
  8. M Antib,
  9. S Pretolanib,
  10. G Gasbarrinib
  1. aDepartment of Medical Pathology, Catholic University of Rome, Rome, Italy, bDepartment of Internal Medicine, Catholic University of Rome, Rome, Italy, cDepartment of Neuroscience, Tor Vergata University, Rome, Italy
  1. Dr A Gasbarrini, Istituto di Patologia Medica, Gemelli Hospital, Catholic University, Largo Gemelli 8–00168 Roma, Italy.

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Summary

In the past year, several studies have been carried out on the association between Helicobacter pyloriinfection and a miscellany of extradigestive diseases, such as cardiovascular, immunological, and various other pathologies. In particular, a higher prevalence of H pyloriinfection in patients affected by ischaemic heart disease has been described and there is growing evidence for an association betweenH pylori and some autoimmune diseases. Moreover, recent studies have shown that various helicobacter species have been detected in human bile; if confirmed, this finding could revise the diagnostic and therapeutic approach to diseases of the biliary tract.

It has long been known that some infectious agents which affect specific areas of the body may also have systemic sequelae. A typical example of this phenomenon is infection by β haemolytic streptococcus group A, a frequent determinant of acute or chronic tonsillitis, which can also lead to rheumatic fever, cardiac inflammation, glomerulonephritis, and neurological involvement.1 It has been shown that the extrapharyngeal manifestations of the infection are caused by cross mimicry between bacterial and host antigens.1

H pylori is one of the most frequent causes of gastrointestinal infections worldwide; it is known that the immunological response elicited by the bacterium is an important determinant of gastric mucosal damage.2 In particular, the production of large amounts of various proinflammatory substances, such as cytokines, eicosanoids, and proteins of the acute phase follows gastric colonisation by H pylori (fig1).2 It has also been shown that there is cross mimicry between some bacterial and host antigens which may be responsible, at least in part, for the mucosal damage during the infection.3 On the basis of these observations, some authors have also investigated the role of H pylori as a pathogenic determinant of some extragastroduodenal idiopathic diseases, such as cardiovascular, immunological, skin, liver, biliary tract, and various other disorders, in which an inexplicable increase in cytokines or an autoimmune trait has been involved in the pathogenesis.

Figure 1

Schematic representation of the substances released by the immune system following gastric colonisation by Helicobacter pylori. TNF, tumour necrosis factor; PAF, platelet activating factor; LT, leukotriene; PG, prostaglandin; IL, interleukin; INF, interferon.

Vascular diseases

ISCHAEMIC HEART DISEASE

Over the past 20 years, several studies carried out on the pathogenesis of peripheral vascular diseases have found that diabetes, hyperlipaemia, hypertension, and smoking are important risk factors for the development of atherosclerosis and have made the development of therapeutic approaches for the control of these pathologies possible. Recently, attention has been focused on the possible pathogenic mechanisms involved in the development of atherosclerosis through an association with infectious diseases. Various studies have found that the presence of a chronic infection by some microbial species could act as a risk factor in vascular diseases. In particular, several epidemiological studies have been carried out on the association between ischaemic heart disease (IHD) and H pylori infection.4-11 In spite of this large number of studies, however, whether the association is causal or occasional is still unclear. Since the first report in 1994, at least 25 epidemiological studies have been published on the association between H pylori antibody titre and IHD. In all studies, however, potential confounding factors, such as low socioeconomic status, seem to be strongly associated both withH pylori infection and coronary heart disease. The failure to make appropriate adjustments for potential confounding factors could lead to spurious associations of infection with coronary heart disease. In fact, most of the studies in which controls were opportunistically recruited and not adjusted for confounding factors reported a strong association. Conversely, studies that tried to reduce the effects of selection bias by adjusting for potential confounding factors and by random sampling of controls from roughly the same population tended to report weak associations.12 On balance, studies performed to date do not show a strong association, but they do vary in their results and are consistent with a 10–20% excess risk. Whether or not residual confounding explains such a weak association is open to debate.

With regard to the pathogenic mechanisms proposed in order to link H pylori with IHD, it is of special interest to note that the “infectious hypothesis” has long been supported to explain IHD occurrence. Micro-organisms, such as chlamydia, cytomegalovirus, or other herpes viruses, have been proposed as potential determinants of coronary atheroma.13 14 It has also been shown that immunological mechanisms are implicated in the pathogenesis of atherosclerosis and that there is a relation between serum cytokine concentration and coronary heart disease.15Increased serum concentrations of interleukin (IL) 6 and tumour necrosis factor (TNF) α in particular show a linear correlation with some cardiovascular risk factors15; and cytokines, such as IL-6 and TNF-α, or other phlogosis mediators promote release of some acute phase proteins, such as fibrinogen or C-reactive protein.2 Furthermore, cytokines may amplify the inflammatory response through other mechanisms, as shown in table 1. No definitive data are available on the role of H pylori in influencing the systemic inflammatory response. However, as raised concentrations of cytokines or phlogosis mediators are predictive of a higher risk of acute IHD events,16 and many of these proteins could be released as a result ofH pylori gastric colonisation,2a link with IHD is likely. Furthermore, ascagA positive strains cause greater release of cytokines by gastric epithelial cells,17 a recent study which showed a significantly higher prevalence of H pylori cagA positive strains in patients affected by IHD than in matched controls, is of interest.6 Considering the peculiar ability of these strains to stimulate greater release of cytokines by the inflammatory cells, the authors concluded that only some cytotoxicH pylori strains could be associated with IHD.6 If confirmed, this association with more cytotoxic strains could be extremely important in answering concerns over residual confounding factors such as social class. Other proposed mechanisms that may influence IHD by means of H pylori are the development of cross mimicry between endothelial and bacterial antigens, such as heat shock proteins, and the development of a procoagulant status as a result of the infection.18

Table 1

Action of cytokines released during the acute phase response to infection

ISCHAEMIC CEREBROVASCULAR DISORDERS

Few studies are available. A recent report shows thatH pylori infection affects patients with ischaemic cerebrovascular disease (ICVD) more frequently than controls.19 Moreover, as the study reported that infected patients show a mean carotid stenosis greater than uninfected subjects, the authors concluded that H pyloriinfection may act, at least in part, by increasing atherosclerosis.19 In addition to the mechanisms already proposed for the relation between H pyloriand IHD, another reason that could explain the association could be the reduction of gastric absorption of folate caused by the infection, a well known risk factor for ischaemic vascular disease.8The lack of well designed prospective studies able to show a causal relation between H pylori infection and ICVD, however, still does not make it possible to assess the validity of the association.

FUNCTIONAL VASCULAR DISORDERS

As the release of large amounts of various proinflammatory and vasoactive substances (such as cytokines, eicosanoids, and acute phase proteins) follows gastric colonisation by H pylori, the bacterium may be involved in some functional vascular disorders. It has been shown that H pylori infection is common in two typical functional vascular disorders such as primary Raynaud’s phenomenon and idiopathic migraine. Furthermore, in both cases H pylori eradication resulted in a significant improvement in the clinical manifestation of the disease.20 21 Controlled eradication studies, however, still need to be performed and the exact sequence of events that could link H pyloriinfection to functional vascular diseases remains to be shown.

Immunological diseases

Several clinical observations suggest a role forH pylori infection in various immunological disorders. Some reports have shown healing of some autoimmune diseases (such as Henoch-Schönlein purpura, Sjögren’s syndrome, and autoimmune thrombocytopenia) after eradication of H pylori.22-25 Furthermore, the observation of complete disappearance of some cases of extragastric mucosa associated lymphoid tissue (MALT) lymphoma, such as those localised to the salivary gland, small intestine, and rectum, following treatment forH pylori infection, is of special interest.26-28

Although no definitive data are available on the pathogenesis of these phenomena, it has been shown that antibodies againstH pylori may react with some extragastric tissues, such as glomerular capillary walls, ductal cells of the salivary gland, and renal tubular cells.29 30 Similar mechanisms have been suggested to link H pylori infection with some acute immune polyneuropathies in which there is a molecular mimicry betweenCampylobacter jejuni lipopolysaccharides and GM1 ganglioside.31 On the basis of these observations, it is hypothesised that an antigenic similarity betweenH pylori and host antigens could be responsible for autoimmunity in some infected patients. Further studies are required to clarify this.

Skin diseases

Some studies have suggested a link between idiopathic chronic urticaria and H pyloriinfection.32-34 A recent study in particular showed a significant decrease in the typical symptoms of urticaria, such as wheals, erythema, and pruritus after eradication ofH pylori.33 The reasons behind the phenomenon, however, are unknown. Probably, an increase in mast cell degranulation, which could be induced by peculiarH pylori cytotoxic strains, may act as a trigger in subjects with an individual susceptibility to develop urticaria.

Acne rosacea and alopecia areata have also been associated withH pylori infection.35-37Discordant and not definitive data, however, are available on these topics.

Liver and biliary tract

Recently, a higher prevalence of H pylori infection has been described in patients with liver cirrhosis than in age and sex matched controls.38 Further studies, however, are necessary in order to verify whether the association is causal or occasional. Furthermore, it is unclear whether the association has a clear pathological significance as the available data show no relation between H pyloriinfection status and severity of the liver disease.39However, the fact that infected patients have higher blood concentrations of ammonia and that eradication of the bacterium results in a significant reduction, is interesting.40

A possible link between H pylori infection and some diseases of the biliary tract has been hypothesised. In particular, a recent study showed both the presence ofH pylori sequences in bile samples, and a homology between sequences of CagA protein and those of aminopeptidase N, a well known substance capable of inducing cholesterol aggregation.41 However, whether H pylori is associated with cholelithiasis is not known. Finally, there is emerging evidence of a possible role of other helicobacter species, such as H bilis andH pullorum, in the pathogenesis of chronic cholecystitis.42

Other extragastroduodenal diseases

H pylori infection is reported to be more highly prevalent in patients with sideropenic anaemia compared with healthy controls.43 Furthermore, several case reports showed the resolution of chronic idiopathic sideropenia following eradication of H pylori.44-46The mechanisms behind this phenomenon, however, are still unclear. It is plausible to speculate that direct use of iron by the bacterium or impairment of iron absorption through the release of iron binding substances, such as lactoferrin or siderophores, may lead to sideropenia in some infected patients.44 47

Low growth rate and sudden infant death are other diseases that have been associated with H pyloriinfection.48-50 Data, however, are conflicting and well designed controlled studies are required to clarify the existence of a causal association.

Conclusions

As peculiar H pylori cytotoxic strains may induce a local chronic release of cytokines, or vasoactive or procoagulant substances by the immune cells in susceptible subjects, several studies have been designed to assess a role ofH pylori infection in some extragastric idiopathic diseases. Available epidemiological data are conflicting because of the presence of several confounding factors (socioeconomic status and geographical location, time of acquisition of the infection, presence of different bacterial strains, previous antimicrobial therapy, presence of concominant infections) which may influence the results of these studies. However, as H pylori eradication often leads to the disappearance of or an improvement in some extradigestive pathologies, further well designed in vitro, epidemiological, and controlled intervention studies, with special reference to cagA status of infecting strains, are needed in order to identify whether and by which molecular mechanisms H pylori may cause extragastric manifestations.

References

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Footnotes

  • Abbreviations used in this paper:
    IHD
    ischaemic heart disease
    IL
    interleukin
    TNF
    tumour necrosis factor
    ICVD
    ischaemic cerebrovascular disease
    MALT
    mucosa associated lymphoid tissue

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