Helicobacter pylori and Extradigestive Disorders in the Past 10 Years

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Group: 2009
Subgroup: Volume 11, Issue 2
Date: April 2009
Type: Review Article
Start Page: 123
End Page: 132

Authors:

  • Shohreh Farshad
  • Assistant Professor of Microbiology, Prof. Alborzi Clinical Microbiology Research Center,Nemazee Hospital,Shiraz University of Medical Sciences, Shiraz, Fars, Iran
  • A Japoni1
  • Microbiology, Prof. Alborzi Clinical Microbiology Research Center,Nemazee Hospital,Shiraz University of Medical Sciences, Shiraz, Fars, Iran
  • A Alborzi
  • Professor,Prof.Alborzi Clinical Microbiology Research Center,Shiraz University of Medical Sci-ences, Shiraz, Fars, Iran

      Correspondence:

      Affiliation: Assistant Professor of Microbiology, Prof. Alborzi Clinical Microbiology Research Center,Nemazee Hospital,Shiraz University of Medical Sciences
      City, Province: Shiraz, Fars
      Country: Iran
      Tel: +98-711-6474296
      Fax: +98-711-6474303
      E-mail: s_farshad@yahoo.com

Abstract:


While the association between Helicobacter pylori and other digestive conditions are still under the study, some authors have also investigated an expanding list of the studies on the role of H. pylori as a pathogenic determinant of some extraduodenal idiopathic diseases, such as cardiovascular, immunological, skin, liver, biliary tract, and various other disorders. Although it is still unclear how a localized infection may affect areas distant from the site of infection, it is supposed that H. pylori gastric infection may cause systemic illnesses through immune-mediated mechanisms. This idea is based on the following points: (i) local inflammation can have systemic effects; (ii) gastric H. pylori infection is a chronic process that lasts for decades; (iii) persistent infection induces chronic inflammatory and immune responses that can cause lesions that are local or distant from the site of primary infection. In the past 10 years, an increasing number of studies concerning the association between H. pylori infection and extradigestive conditions have been reported. Most of these studies have documented the H. pylori infection by serology and Urease Breath Test (UBT), and rarely by PCR, and no one could isolate any H. pylori microorganism from samples, using culture method. Of course, the culture of this fastidious organism is extremely difficult; if not impossible. In this study, some of the recent papers are reviewed to find new scopes for the role of H. pylori in some kinds of extradigestive diseases.

 

Keywords: Helicobacter pylori; Extradigestive disorders

Manuscript Body:


Introduction

 

Helicobacter pylori is a gram-negative, microaerophilic bacterium that inhabits various areas of the stomach and duodenum. It causes a chronic low-level inflammation of the stomach lining and is strongly linked to the development of duodenal and gastric ulcers. Multiple studies have demonstrated that inflammation caused by H. pylori infection may contribute to the development of adenocarcinoma of the stomach; moreover, it has been involved in the development of low-grade B-cell lymphoma of gastric mucosa-associated-lymphoid-tissue (MALT lymphoma).1 Over 80% of individuals infected with the bacterium are asymptomatic. H. pylori is a helix-shaped bacterium, about 3 micrometres long with a diameter of about 0.5 micrometres. It contains a hydrogenase which can be used to obtain energy by oxidizing molecular hydrogen (H2) that is produced by intestinal bacteria.2 It produces oxidase, catalase, and urease. It is capable of forming biofilms3 and can convert from spiral to a possibly viable but nonculturable coccoid form,4 both likely to favor its survival and be factors in the epidemiology of the bacterium. The coccoid form can adhere to the gastric epithelial cells in vitro.5 This bacterium lives in the stomach and duodenum (the section of intestine just below stomach). It has a unique way of adapting in the harsh environment of the stomach. The inside of the stomach is bathed in about half a gallon of gastric juice every day. Gastric juice is composed of digestive enzymes and concentrated hydrochloric acid, which can readily tear apart the toughest food or microorganism. It used to be thought that the stomach contained no bacteria and was actually sterile, but H. pylori changed that view. The stomach is protected from its own gastric juice by a thick layer of mucus that covers the stomach lining. H. pylori take advantage of this protection by living in the mucus lining. Once H. pylori is safely ensconced in the mucus, it is able to fight the stomach acid that does reach it with an enzyme it possesses called urease. Urease converts urea, which exists abundantly in the stomach (from saliva and gastric juices), into bicarbonate and ammonia, which are strong bases. This creates a cloud of acid neutralizing chemicals around the H. pylori, protecting it from the acid in the stomach. The reaction of the urea hydrolysis is important for the diagnosis of H. pylori by the breath test.6

 

Urea hydrolysis: urea is broken down to ammonia and carbon dioxide

 

Another defense H. pylori has is that the body's natural defenses can not reach the bacterium in the mucus lining of the stomach. The immune system will respond to an H. pylori infection by sending white cells, killer T cells, and other infection fighting agents. However, these potential H. pylori eradicators can not reach the infection because they can not easily get through the stomach lining. They do not go away either, though, and the immune response grows and grows. The polymorphs die, and spill their destructive compounds (superoxide radicals) on the stomach lining cells. Extra nutrients are sent to reinforce the white cells, and the H. pylori can feed on this. Within a few days, gastritis and perhaps eventually a peptic ulcer will be resulted. It may not be H. pylori itself which causes peptic ulcer, but the inflammation of the stomach lining, i.e. the response to H. pylori.6 On the other hand, this organism produces a wide range of toxins detrimental to the gastric mucosa both in-vivo and in-vitro.7 These include vacuolating toxin A (VacA), cytotoxin A (CagA) urease, catalase, phospholipidases, alcohol dehydrogenase, haemolysin, platelet activating factor and mucolytic factor. The cytotoxin A is a 120-140 KDa protein of unknown function in about 60-70% of H. pylori strains. Of particular interest is vacuolating toxin as it is found in 50% of H. pylori isolates in-vitro.8 Indeed, gastric mucosal cells in proximity to adherent H. pylori have been shown to display severe ultrastructural damage demonstrable by transmission electron microscopy.9 While these toxins are undoubtedly harmful to the stomach and duodenum, they also interact with other tissues in the body. On the basis of these data, while the association between H. pylori and other digestive conditions are still under the study, some authors have also investigated an expanding list of the studies on the role of H. pylori as a pathogenic determinant of some extraduodenal idiopathic diseases, such as cardiovascular, immunological, skin, liver, biliary tract, and various other disorders.10 Although it is still unclear how a localized infection may affect areas distant from the site of infection, it is supposed that H. pylori gastric infection may cause systemic illnesses through immune-mediated mechanisms.11 This idea is based on the following points: (i) local inflammation can have systemic effects; (ii) gastric H. pylori infection is a chronic process that lasts for decades; (iii) persistent infection induces chronic inflammatory and immune responses that can cause lesions that are local or distant from the site of primary infection.12,13

 

 

Transmission

 

H. pylori are believed to be transmitted orally. Many researchers think that H. pylori are transmitted orally by means of fecal matter through the ingestion of waste tainted food or water. In addition, it is possible that H. pylori could be transmitted from the stomach to the mouth through gastro-esophagal reflux (in which a small amount of the stomach's contents is involuntarily forced up the esophagus) or belching, common symptoms of gastritis. The bacterium could then be transmitted through oral contact.6

 

 

Extradigestive Diseases Caused by H. pylori

 

In the past 10 years, an increasing number of studies concerning the association between H. pylori infection and extradigestive conditions have been reported. Most of these studies have documented the H. pylori infection by serology and Urease Breath Test (UBT), and rarely by PCR, and no one has been able to isolate any H. pylori microorganism from samples, using culture method. Of course, the culture of this fastidious organism is extremely difficult; if not impossible.14-17 In this study, we reviewed some of the recent papers to find new scopes for the role of H. pylori in some kinds of extradigestive diseases.

 

 

Hepatobiliary Diseases

 

According to the animal models, it seems that various Helicobacter species and possibly other new bile adapted species which can cause disease in dogs, mice and other rodents, may also invade the human bile tree and liver.18 Several authors have reported that H. pylori DNA has been found in human bile.19-21 It has been concluded that the presence of H. pylori in bile may represent an increased risk of gallstone formation.20 While studies in Taiwan and Korea regularly seem to detect Helicobacter in human bile in chronic cholestatic bile tract diseases, conflicting negative PCR results on bile have been reported.22,23 However, Monstein et al. reported the presence of H. pylori DNA in 55% of cholesterol gallstones.24 On the other hand, recently a correlation between the presence of H. pylori DNA in bile and bile duct malignancies has been shown.25 In two studies done in our lab, we showed the presence of H. pylori DNA in 18.1% (6 from 33) of stone and 12.1% (4 from 33) of bile samples from patients.17,26 In our study, we couldn't isolate Helicobacter from gallstone and bile samples, using culture method. All our positive patients were categorized in the mild chronic cholecystitis group.17 Molecular detection of organisms in bile may simply be due to the enterohepatic circulation of DNA. On the other hand, H. pylori infection may serve as an initiating factor or play other important roles in the development of gallstones. In both situations, H. pylori or its DNA will be more concentrated and captured inside gallstones during the stone formation.26 However, while we are not sure if these organisms are viable, to clarify the clinical role of Helicobacter species in the gallbladder disease studies with accurate tests on larger patient and control groups are needed to be conducted to ascertain whether this microorganism is an innocent bystander or an active participant in gallstone formation.17

Experimental studies have also shown that infection by H. pylori and/or other Helicobacter spp. is associated with the development of chronic hepatitis27 and the production of liver-specific toxins.28 Furthermore, Helicobacter spp. Ribosomal DNA has been demonstrated in the liver of patients with hepatocellular carcinoma (HCC).29,30 In this respect, Giannini et al. confirmed that H. pylori infection is associated with an impairment of cytochrome P-450 liver metabolic activity and that the prevalence of H. pylori infection in anti-HCV positive HCC patients is similar to that in tumor-free cirrhotics.31 Further studies are needed to evaluate whether the influence of H. pylori on the liver metabolic function could be restricted to cytotoxic strains and to determine the mediators of impairment of cytochrome P-450 liver metabolic activity in H. pylori-infected cirrhotic patients.

 

 

Ocular Diseases

 

Only recently has H. pylori attracted the interest of ophthalmologists.32-34 Central Serous Chorioretinopathy (CSC) is a macular serous detachment which typically affects young men in the 25-45 age range and which usually resolves spontaneously with good visual prognosis.14 It has recently been documented that CSC could be an extra-digestive expression of H. pylori.35-38 Asensio-Sanchez et al. in 2008 studied 16 patients with CSC. By using UBT, they could define H. pylori infection in 11 patients (68.75%) and negative in 5 (31.25%). Men were H. pylori positive in 72.73% of cases versus women who were H. pylori positive in 60%. The different prevalence of H. pylori between the CSC (68.75%) and the control groups (30%) was significant (p< 0.05).14 These results are in accordance with those of other studies which also showed a greater prevalence of H. pylori infection in males in general, independently of the ocular involvement.39 From the above studies, it can be considered that H. pylori could be a risk factor in patients with CSC, being involved in their physiopathology the same way it affects vascular, cerebral and dermatological pathologies. Bacterial antigens would be equivalent to proteins expressed by the human body, for example vascular endothelium, producing an attack by the immune system against structures such as the choriocapillary, with blood flow reduction and damages to the EP.32,37 However, important limiting factors for producing CSC by H. pylori in every case could be due to the different H. pylori strains and the genetically determined susceptibility of individuals.40,41 If these findings were confirmed with randomized, multi-centre studies with control cases, the treatment of CSC would be mainly anti-microbial as an extra-gastric expression of H. pylori.

Blepharitis is a very common disease in the elderly patients. Seborrheic dermatitis is the most common cause of anterior lamellar or marginal blepharitis whereas blepharitis of the posterior lamella is due to meibomian gland dysfunction. Eyelid margins have focal or diffuse inflammation, with telangiectasia around the meibomian gland orifices.42 Several other factors play an etiologic role, including exogenous irritants and allergens, staphylococcal infection, and rosacea.43 Patients with rosacea often report digestive disturbances,44-51 which have been considered to be directly related to blepharitis.52 Digestive troubles are related more to rosacea than to seborrhea51 although there is much that binds these two pathologic conditions.53 There seems to be a connection between H. pylori infection and rosacea,54 whereas the association between seborrhea and H. pylori, which has been reported in another study,55 seems to be more uncertain. Moreover, seborrheic dermatitis may be seen in conjunction with other skin diseases, such as rosacea, blepharitis, or ocular rosacea, and acne vulgaris.56 It can, therefore, be claimed, albeit with some uncertainty, that digestive troubles correlate with the presence of blepharitis, or, in any case, that their association is likely. A study coducted by Sacca et al. confirmed that the relation between blepharitis and H. pylori infection is not influenced by its clinical appearance or degree,57 and it seems that the only common factor is chronic inflammation of the eyelid and gastrointestinal tract.15 However, in their study, the clinical improvements were obtained after the eradication of H. pylori infection. H. pylori infection may influence the pathophysiology of glaucoma by releasing various proinflammatory and vasoactive substances, as well as by influencing the apoptotic process, parameters that may also exert their own effects on the induction and/or progression of glaucomatous neuropathy.58 Indeed, H. pylori infection could affect the pathophysiology of glaucoma, by producing oxidative stress and circulating lipid peroxides,59 and may contribute to central serous chorioretinopathy by increasing endothelin 1, nitric oxide,60 and inducible nitric oxide synthase and releasing proinflammatory and vasoactive substances. The latter substances may be involved in the pathophysiology of blepharitis. Therefore, further studies to elucidate the role of H. pylori infection in the pathogenesis of these diseases are indicated.

 

 

Heart Diseases

 

Since the first description by Mendall et al.,61  a number of studies reporting controversial data on the association between Coronary Heart Disease (CHD) and H. pylori infection have appeared in the literature. For at least two decades, numerous observations have linked chronic infections to vascular disease, through inflammatory pattern,62 and the data on the reduction of cardiac events in patients with previous myocardial infarction or angina after antibiotic therapy63,64 have encouraged research in this field.16 On the other hand, older age, low socioeconomic status and being part of specific ethnic groups are all associated with both H. pylori infection and CHD and, thus, would be expected to confound the association. Furthermore, other studies have not supported this hypothesis.65,66 Most reports in the literature have focused on two specific vascular diseases: stroke and Ischemic Heart Diseases (IHD).67 Notwithstanding the number of studies published regarding H. pylori infection and IHD, the relationship between the former and the latter still remains controversial and so does the way in which H. pylori could induce or accelerate atherosclerosis in the coronary arteries, leading to IHD. Since 2000, a number of studies have not shown any positive correlation between serologically68,69 or histologically documented H. pylori infection and the risk for IHD.70,71 Zhu et al., based on the results from a cross-sectional and a longitudinal study, suggested that H. pylori infection could not lead to IHD or AMI.72 Other studies showed no significant association between the titer of antibodies against H. pylori and the risk for MI.73,74 Heider et al. reported that anti- H. pylori IgG seropositivity is not associated with the incidence of cardiovascular disease in a mean follow-up period of 10 years.75 Coles et al. found no association between the serum anti- H. pylori IgG levels and the risk for developing IHD or stroke.76 This lack of association between H. pylori infection and IHD has also been suggested in a study by Schiele et al., who did not find a high risk for restenosis after percutaneous transluminal coronary angioplasty (PTCA) in H. pylori infected patients.77 Moreover, H. pylori seropositivity has been associated with a lower occurrence of venous bypass graft occlusion in patients with IHD who had undergone bypass surgery since the rate of seropositivity in the occlusion-free group was higher than that in the group with occlusion.78 Therefore, the results originating from the studies investigating the relationship between infection with H. pylori and IHD, with focus on many different risk factors, proved to be quite contradictory, thus making it difficult to determine whether there is a link between this microorganism and IHD. Nevertheless, the presence of H. pylori DNA in atherosclerotic lesions, the presence of antibodies against heat shock proteins in patients with IHD, along with the already described cross-reactivity of antibodies against H. pylori with vascular components are the evidence that should not be taken lightly.16 Based on the results from two different studies, Rechcinski et al. proposed the intensive humoral response to H. pylori antigens as a causative mechanism for atherosclerosis.79,80 Grebowska et al. confirmed this intense humoral response and also implicated the host’s predisposition to respond to Lewis determinants that are present in H. pylori lipopolysaccharide (LPS) with the production of IgG, in the atherogenic process.81 The genetic susceptibility of the host has been highlighted in the study of Candore et al., who demonstrated that a specific mutation regarding Toll-like receptor 4 (TLR4) shows a significantly lower frequency in patients affected by MI, compared to controls.82 Thus, it seems that the concept of H. pylori’s implication in the pathogenesis of IHD is still open for discussion and needs to be studied so that a widely accepted mechanism through which H. pylori infection can result in IHD could be determined.

 

 

Respiratory Tract Diseases

 

As noted, H. pylori infection triggers a marked local inflammatory response and a chronic systemic immune response. Many respiratory disorders, such as chronic bronchitis, bronchiectasis, asthma, lung cancer and tuberculosis, feature chronic inflammation and increased immune response. In addition, it is well known that patients with peptic ulcers have higher rates of chronic bronchitis and lung cancer than individuals who are ulcer-free.83-88 Recently, Laheij et al.89 showed that subjects using acid suppressive drugs more often reported clinical manifestations of respiratory tract infections and complications compared with those who did not use acid-suppressive drugs.90 The prevalence of lung cancer in patients with peptic ulcers is two to three times higher than that in people who are ulcer-free.91 Gocky et al.92 found a very high seroprevalence of H. pylori (89.5%) and speculated that this might be involved in lung carcinogenesis. In addition, there were more CagA- and VacA-positive lung cancer cases than controls; however, only VacA seropositivity showed a statistically significant association with occurrence of lung cancer.92 However, Philippou et al.93 could find no significant association between H. pylori infection and lung cancer. H. pylori infection may contribute to lung cancer by upregulating gastrin and COX-2, which could stimulate the tumor growth and angiogenesis.92 Moreover, if H. pylori is inhaled or its exotoxins are aspirated, these substances could accumulate in the lung tissue. However, to date, H. pylori has not been identified in human bronchial tissue or isolated from bronchoalveolar lavage fluid.90

Literature on the link between H. pylori infection and chronic bronchitis has not been identified to date, but it is clear that cigarette smoking is the major factor underlying the association between H. pylori and chronic bronchitis.94,95 A study in Denmark showed that chronic bronchitis was more prevalent in women who were positive for H. pylori serology test than those with negative test.94 In another study, Roussos et al.95 found significantly higher rates of seropositivity for anti-H. pylori and anti-CagA antibodies in chronic bronchitis patients in comparison with control subjects.95 It is well known that virulence factor CagA stimulates the production of cytokines, including IL-1, IL-8 and TNF-α.96,97 On the other hand, these cytokines are involved in the pathogenesis of chronic bronchitis.98-100 So, it could be concluded that infection with CagA-positive strains might lead to a proinflammatory reaction in chronic bronchitis in parallel with the other unknown factors. It seems that for defining any association between H. pylori infection and chronic bronchitis we need to see if the eradication of H. pylori in these patients could affect the process of chronic bronchitis or not.

According to the recent data, a relationship between asthma and H. pylori infection could not be found.101 There are insufficient data to be certain whether or not there is a relationship between H. pylori infection and asthma and further studies are warranted.

While Sanaka et al.102 and Tsang et al.103 could find no differences in seroprevalence of H. pylori between healthy volunteers and patients with tuberculosis, recently Roussos et al. carried out a case-control study and found that the H. pylori seropositivity in the TB group was significantly higher than that in controls. Taken together, data in the literature on the relationship between H. pylori infection and pulmonary TB are still insufficient. The observed frequent coexistence of both infections must be confirmed in a larger number of patients.

 

 

Skin Diseases

 

In some of the recent researches, H. pylori infection has been linked to several skin diseases. Chronic urticaria is a multifactorial disease classified in three main groups: mechanical, autoimmune and idiopathic. So far, the mechanisms that produce it are not clear. Many factors directly and indirectly activating mast cells may be involved including autoimmune mechanisms, and infectious diseases (viral, bacterial, parasitic), especially H. pylori-associated gastritis.104,105 In an attempt to establish the relationship between chronic urticaria and H. pylori through endoscopic and histopatological studies, Pliego Reyes et al. showed an association between chronic urticaria and H. pylori and suggested a routine scan for this microorganism in patients with the disease.106 On the other hand, Sianturi et al. found no significant difference in the seroprevalence of H. pylori infection between CU patients and controls.107 However, as it has been shown that persistent infection caused by H. pylori could be a potential trigger for chronic urticaria, the infection by this organism in these patients should be identified and eradicated, as this is one of the most successful therapeutic approaches.

Scleroderma, which is a collagen disease, causes fibrosis or sclerosing lesions in the skin and internal organs. Esophageal involvement affects 75-90% of the patients with scleroderma.108 According to previous reports, scleroderma patients have an accelerated frequency of H. pylori infection compared to the average incidence of gastric H. pylori in white, healthy, asymptomatic subjects.109-111 Another report showed that scleroderma patients had a higher incidence of IgG antibodies to H. pylori compared to the general population in Japanese people.112 However, there are some controversial data considering the influence of H. pylori infection on reflux esophagitis with scleroderma.113-115 Recently, the data have indicated that H. pylori infection plays an important role in the prevalence of endoscopic reflux esophagitis associated with scleroderma in Japan.116

 

 

Conclusion

 

In summary, the primary evidence for an association between H. pylori infection and extradigestive diseases has come from serology-based case-control studies concerning a relatively small number of patients. Furthermore, studies with sufficient powerful design did not exist. The primary evidence for a causal role of H. pylori infection in a number of extradigestive diseases rests primarily on rather weak associations based on epidemiological investigations usually not performed to address the question regarding H. pylori. The role of genetic predisposition of the infected host or the presence of strain-specific virulence factors also needs further evaluation. It is also necessary to conduct well-designed sets of studies to clarify whether there is an association between the mentioned diseases and H. pylori infection, and to answer questions that have been posed regarding the patterns of histology, genotypes of H. pylori, and the effects of eradication therapy. Future studies should be large enough for moderate-sized effects to be assessed or registered reliably. On the other hand, in many cases inflammatory mediators stimulated by H. pylori infection could be the pathogenetic mechanism underlying the observed associations. Therefore, the role of genetic predisposition of the infected host, the presence of strain-specific virulence factors such as CagA, VacA and the serum concentration of proinflammatory markers in H. pylori infected patients with these diseases needs further evaluation. Further studies using accurate tests on the larger patient and control groups are recommended to ascertain whether this microorganism is an innocent bystander or active participant in the development and natural history of these disorders.

 

Conflict of interest: None declared.

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