Helicobacter pylori
Helicobacter pylori (H. pylori) was first discovered in the stomachs of patients with gastritis and stomach ulcers nearly 25 years ago by Dr Barry J. Marshall and Dr J. Robin Warren of Perth, Western Australia. At the time (1982/83) the conventional thinking was that no bacterium can live in the human stomach as the stomach produced extensive amounts of acid which was similar in strength to the acid found in a car-battery. Marshall and Warren literally “re-wrote” the text-books with reference to what causes gastritis and gastric ulcers. In recognition of their very important discovery, they were awarded the 2005 Nobel Prize for Medicine and Physiology (Helicobacter Foundation, 2006).
Spiral or curved bacilli were found in animal and human gastric mucosa 100 years ago, but until 1980, no clinical significance was attached to the presence of these organisms (Kikuchi, 2005). In vivo, H. pylori is a spiral bacterium, only a few micrometers long and actively motile. It has up to six sheeted flagella projecting from either pole and being of great importance for its mobility. H. pylori is Gram-negative and urease, catalase and oxidase positive. The characteristic high urease activity is used by the bacteria to convert urea to neutralizing ammonia when colonizing the gastric mucosa (Scott et al., 1998).
Prevalence and incidence:
H. pylori is found to be present in the stomach lining of about 3 billion people around the world (i.e. half the world’s population) and is the most common bacterial infection of man (Helicobacter Foundation, 2006).
Torres et al. (2000) stated that in the developing countries, H. pylori infection occurs earlier in life and with a higher frequency than in the developed world (tables 5 and 6). In many developing countries, it was reported that the prevalence of infection with H. pylori exceeds 50% by 5 years of age, and that by adulthood, infection rates exceeding 90% are common (Robert et al., 2003).
The studies on the incidence of H. pylori infection suggest that rates of infection within the developing world are much higher than the 1–2% yearly incidence reported in industrialized countries (Glynn et al., 2002).
An ongoing question regarding infection with H. pylori is whether some infections are transient. There are several studies indicating that while H. pylori infection in adults may be chronic, it appears that children may have repeated cycles of acquiring and losing the infection until the infection eventually becomes chronic, especially in the developing countries. A study on Egyptian children between 6 and 36 months of age declared that 42% of the children turned seronegative during the period of observation suggesting a spontaneous clearance of the infection (Abu-Elyazeed et al .,2000 ).
Modes of transmission:
H. pylori is transmitted from person-to-person through oro-oral, faeco-oral and gastro-oral routs. The nature of the organism, which makes isolation and culture difficult, the lack of accurate serotyping systems and the inability to identify acute infection clinically, has delayed a deeper understanding of the transmission mechanisms. Also, the lack of adequate techniques for detecting the bacteria in materials other than the gastric tissue has delayed the identification of the portals of entry and exit as well as the identification or ruling out of environmental reservoirs (Miranda et al., 2008).
Pathology:
H. pylori infection causes gastritis in both adults and children (Drumm, 1993). The following differences characterize H. pylori infection in children when compared to adults:
The gastric mucosa is still under maturation as regards the immunological aspects.
The effects of injurious substances (tobacco, alcohol, non-steroidal anti-inflammatory drugs) are rarely present.
In children, the most frequent endoscopic finding is antral gastritis whereas only 50% of the adult patients suffer from antral gastritis, they rather have peptic ulcer (Sipponen, 1997).
Gastritis:
Many of those carrying the bacterium have little or no symptoms and are apparently well, but all without exception have inflammation of the stomach lining, a condition which is called "gastritis". Gastritis is the underlying condition which eventually causes ulcers and other digestive complaints (Helicobacter Foundation, 2006). H. pylori causes acute and chronic gastritis in children (Aydin et al., 2003).
Acute gastritis with a diffusely hyperemic gastric mucosa
(The Internet Pathology Laboratory for Medical Education, 2007).
Gastro esophageal reflux:
Because H. pylori infection cause a progressive atrophic gastritis, it has been hypothesized that patients with gastroesophageal reflux might be protected by the hypoacidity resulting from chronic infection (Raghunath et al., 2003).
Peptic ulcer:
H. pylori infection is the most important cause in both duodenal and gastric ulcerogenesis. It appears that 90% to 95% of duodenal and 50% to 70% of gastric ulcer patients harbor the bacterium (Graham, 1991).
Peptic ulcer:
H. pylori infection is the most important cause in both duodenal and gastric ulcerogenesis. It appears that 90% to 95% of duodenal and 50% to 70% of gastric ulcer patients harbor the bacterium (Graham, 1991).
Helicobacter pylori and peptic ulcer (Surgical-tutor.org.uk, 2006).Gastric adenocarcinoma:
H. pylori infection constantly for 20-30 years, it can lead to cancer of the stomach. That is why the World Health Organization’s (WHO) International Agency for Research into Cancer (IARC) has classified H. pylori as a “Class-I-Carcinogen” i.e. in the same category as cigarette smoking is to cancer of the lung and respiratory tract (Helicobacter Foundation, 2006).Infection with H. pylori has been identified as a risk factor in the development of gastric adenocarcinoma. The mechanisms by which H. pylori may result in malignancy are not completely identified (Houghton and Wang, 2005).
Gastric Adenocarcinoma (The Internet Pathology Laboratory for Medical Education, 2006).
Mucosa-associated lymphoid tissue lymphoma:
There is now growing evidences that H. pylori plays a key role in the development of MALT lymphoma. So, the successful eradication of H. pylori helps in complete or partial remission in low grade MALT lymphoma (Santacroce et al., 2008).
Helicobacter associated mucosa-associated lymphoid tissue lymphoma (Bruce et al., 2005).
H. pylori and liver disease:
H. pylori increases the levels of ammonia secondary to bacterial urease action on urea in gastric lumen leading to encephalopathy in chronic liver disease patients (Zullo et al., 2003).
H. pylori and the biliary tract:
It was proved that some helicobacter pylori species could grow in the presence of bile H.hepaticus, H.pallorum, H.billis. They were detected by PCR (Pandey and Shukla, 2009).
Pathogenicity:
H. pylori is able to colonize and persist in a unique biological niche within the gastric lumen. The putative pathogenic determinants of H. pylori can be
divided into two major groups:
1- Virulence factors, which contribute to the pathogenic effects of the bacterium.
2- Maintenance factors, which allow the bacterium to colonize and remain within the host
Virulence factors contribute to the three major pathogenic effects of H. pylori: gastric inflammation, disruption of the gastric mucosal barrier, and alteration of gastric physiology. Virulence factors and maintenance factors are outlined in tables 7 and 8 (Lu et al., 2005).
H. pylori and the biliary tract:
It was proved that some helicobacter pylori species could grow in the presence of bile H.hepaticus, H.pallorum, H.billis. They were detected by PCR (Pandey and Shukla, 2009).
Pathogenicity:
H. pylori is able to colonize and persist in a unique biological niche within the gastric lumen. The putative pathogenic determinants of H. pylori can be
divided into two major groups:
1- Virulence factors, which contribute to the pathogenic effects of the bacterium.
2- Maintenance factors, which allow the bacterium to colonize and remain within the host
Virulence factors contribute to the three major pathogenic effects of H. pylori: gastric inflammation, disruption of the gastric mucosal barrier, and alteration of gastric physiology. Virulence factors and maintenance factors are outlined in tables 7 and 8 (Lu et al., 2005).
Histological section of gastric antral mucosa infected with H. pylori. Abundant microorganisms are observed in the luminal surface and attached to the epithelium (modified Steiner silver stain) (Correa and Piazuelo, 2008).
H. pylori inside the human body:
After being ingested, the bacteria have to evade the bactericidal activity of the gastric luminal contents and enter the mucous layer. Urease hydrolyzes urea into carbon dioxide and ammonia, thereby permitting H. pylori to survive in an acidic medium (Mobley, 2001). Motility is essential for colonization (Josenhans and Suerbaum, 2001).
H. pylori can bind tightly to epithelial cells by BabA, a 78-kD outer-membrane protein that binds to the fucosylated Lewis B blood group antigen. The majority of H. pylori strains have the vacuolating cytotoxin VacA, a secreted exotoxin. After attachment to the epithelial cell, CagA is phosphorylated and binds to SHP-2 tyrosine phosphatase, leading to a growth factor–like cellular response and cytokine production by the host cell. Response initially consists of the recruitment of neutrophils, followed by T and B lymphocytes, plasma cells, and macrophages, along with epithelial-cell damage (Ilver et al., 1998).
Immune response of the human body:
The pathogen can bind to class II major-histocompatibility-complex (MHC) molecules on the surface of gastric epithelial cells, inducing their apoptosis. Further changes in epithelial cells depend on proteins encoded in the CagA-PAI and on the translocation of CagA into gastric epithelial cells (Odenbreit et al., 2000). H. pylori urease and porins may contribute to extravasation and chemotaxis of neutrophils as shown in (figure 17) (Suerbaum and Michtti, 2003).The gastric epithelium of H. pylori- infected persons has enhanced levels of IL-1b, IL-2, IL-6, and TNF. Among these, IL-8 is a potent neutrophil-activating chemokine expressed by gastric epithelial cells, apparently has a central role (Yamaoka et al., 1996).
H. pylori strains carrying the CagA-PAI induce a far stronger IL-8 response than Cag-negative strains, and this response depends on activation of nuclear factor-kB (NF-k), the neutrophil-activating protein, a 150-kD surface protein of H. pylori, may contribute to phagocyte activation, although its relation to clinical outcome remains uncertain (Evans et al., 1995).
H. pylori infection induces a vigorous systemic and mucosal humoral response (Perez-Perez et al., 1988). This antibody production does not lead to eradication of the infection but may contribute to tissue damage. Some H. pylori infected patients have an autoantibody response directed against the H+/K+–ATPase of gastric parietal cells that correlates with increased atrophy of the corpus (Negrini etal.,1997).
After being ingested, the bacteria have to evade the bactericidal activity of the gastric luminal contents and enter the mucous layer. Urease hydrolyzes urea into carbon dioxide and ammonia, thereby permitting H. pylori to survive in an acidic medium (Mobley, 2001). Motility is essential for colonization (Josenhans and Suerbaum, 2001).
H. pylori can bind tightly to epithelial cells by BabA, a 78-kD outer-membrane protein that binds to the fucosylated Lewis B blood group antigen. The majority of H. pylori strains have the vacuolating cytotoxin VacA, a secreted exotoxin. After attachment to the epithelial cell, CagA is phosphorylated and binds to SHP-2 tyrosine phosphatase, leading to a growth factor–like cellular response and cytokine production by the host cell. Response initially consists of the recruitment of neutrophils, followed by T and B lymphocytes, plasma cells, and macrophages, along with epithelial-cell damage (Ilver et al., 1998).
Immune response of the human body:
The pathogen can bind to class II major-histocompatibility-complex (MHC) molecules on the surface of gastric epithelial cells, inducing their apoptosis. Further changes in epithelial cells depend on proteins encoded in the CagA-PAI and on the translocation of CagA into gastric epithelial cells (Odenbreit et al., 2000). H. pylori urease and porins may contribute to extravasation and chemotaxis of neutrophils as shown in (figure 17) (Suerbaum and Michtti, 2003).The gastric epithelium of H. pylori- infected persons has enhanced levels of IL-1b, IL-2, IL-6, and TNF. Among these, IL-8 is a potent neutrophil-activating chemokine expressed by gastric epithelial cells, apparently has a central role (Yamaoka et al., 1996).
H. pylori strains carrying the CagA-PAI induce a far stronger IL-8 response than Cag-negative strains, and this response depends on activation of nuclear factor-kB (NF-k), the neutrophil-activating protein, a 150-kD surface protein of H. pylori, may contribute to phagocyte activation, although its relation to clinical outcome remains uncertain (Evans et al., 1995).
H. pylori infection induces a vigorous systemic and mucosal humoral response (Perez-Perez et al., 1988). This antibody production does not lead to eradication of the infection but may contribute to tissue damage. Some H. pylori infected patients have an autoantibody response directed against the H+/K+–ATPase of gastric parietal cells that correlates with increased atrophy of the corpus (Negrini etal.,1997).
During specific immune responses, different subgroups of T cells emerge. These cells participate in mucosal protection and help distinguishing the pathogenic bacteria from commensals. Immature T helper (Th) 0 cells expressing CD4 can differentiate into two functional subtypes: Th1 cells, IL-2 secreting and Th2 cells, secreting IL-4, IL-5, and IL-10. Whereas Th2 cells stimulate B cells in response to extracellular pathogens, Th1 cells are induced mostly in response to intracellular pathogens. Because H. pylori is non invasive and induces a strong humoral response, a Th2-cell response would be expected. Paradoxically, H. pylori-specific gastric mucosal T cells generally present a Th1 phenotype (Harris et al., 2000).
Pathogenesis of H. pylori (Suerbaum and Michtti, 2002).
Studies in gene-targeted mice have further showed that Th1 cytokines promote gastritis, whereas Th2 cytokines are protective against gastric inflammation (Smythies et al., 2000). This Th1 orientation may be due to increased antral production of IL-8 in response to H. pylori infection. This biased Th1 response, combined with Fas-mediated apoptosis of H. pylori-specific T-cell clones, may favor the persistence of H. pylori (Tomita et al., 2001).
Gastrointestinal effects:
1-Gastritis
Gastritis that accompanies H. pylori infection has both acute and chronic phases. Most patients remain clinically well. There may be occasional symptoms of dyspeptic pain, nausea, and emesis. The acute phase typically subsides over few weeks and progresses to a chronic low grade superficial gastritis that is asymptomatic (Aydin et al., 2003).
2-Peptic Ulcer
It is manifested by recurrent episodes of abdominal pain, nausea, vomiting, nocturnal awaking, hematemesis and melena ((Graham, 1991).
3-Non ulcer dyspepsia
Dyspepsia is recurrent pain in the upper abdomen for which no definite structural or biochemical cause can be identified. Symptom severity can be assessed according to Visick score (Table 9), (Farrell et al., 2005). A recent study demonstrated a highly significant improvement in dyspepsia symptoms after treatment (Moayyedi et al., 2005).
4-Gastroesophageal reflux disease
A recent systematic review of 20 studies of the relationship between H. pylori and GERD by Raghunath and colleagues (2003) has demonstrated decrease prevalence of H. pylori in GERD patients from around the world. In an age-stratified endoscopic study of 507 patients with sliding hiatus hernias, rise in prevalence of H. pylori infection, and a parallel decrease in prevalence of reflux symptoms were noted with advancing age (Manes et al., 2003).
5-Gastric Adenocarcinoma
The clinical manifestations are epigastric pain, anorexia, weight loss, vomiting, hematemesis, and melena (Houghton and Wang, 2005).
6-Mucosa-associated lymphoid tissue lymphoma
The disease clinically manifests as epigastric pain, anorexia, weight loss, and occasional emesis, hematemesis, or melena. A recent study showed an improvement of low-grade MALT lymphoma after a 2 week course of therapy against H. pylori (Santacroce et al., 2008).
7-Liver diseases:
Recently, a higher prevalence of H. pylori infection has been described in patients with liver cirrhosis (Giannini et al., 2003) and hepatic carcinoma (Ito et al., 2004).
8-Billiary tract and H. pylori:
There is a possible link between H. pylori infection and some diseases of the biliary tract as cholelithiasis (Fox et al., 1998) and hepatobiliary tract cancers (Pandey and Shukla, 2009).
Schematic representation of the clinical outcomes following H. pylori infection (Correa and Piazuelo, 2008).
Schematic description of the urea breath test. Radiolabeled urea is ingested by the patient and converted in the stomach to ammonia and radiolabeled carbon dioxide (CO2) in the presence of H. pylori urease. Exhaled radiolabeled (CO2) is then measured (Bruce et al., 2005).
Studies in gene-targeted mice have further showed that Th1 cytokines promote gastritis, whereas Th2 cytokines are protective against gastric inflammation (Smythies et al., 2000). This Th1 orientation may be due to increased antral production of IL-8 in response to H. pylori infection. This biased Th1 response, combined with Fas-mediated apoptosis of H. pylori-specific T-cell clones, may favor the persistence of H. pylori (Tomita et al., 2001).
Gastrointestinal effects:
1-Gastritis
Gastritis that accompanies H. pylori infection has both acute and chronic phases. Most patients remain clinically well. There may be occasional symptoms of dyspeptic pain, nausea, and emesis. The acute phase typically subsides over few weeks and progresses to a chronic low grade superficial gastritis that is asymptomatic (Aydin et al., 2003).
2-Peptic Ulcer
It is manifested by recurrent episodes of abdominal pain, nausea, vomiting, nocturnal awaking, hematemesis and melena ((Graham, 1991).
3-Non ulcer dyspepsia
Dyspepsia is recurrent pain in the upper abdomen for which no definite structural or biochemical cause can be identified. Symptom severity can be assessed according to Visick score (Table 9), (Farrell et al., 2005). A recent study demonstrated a highly significant improvement in dyspepsia symptoms after treatment (Moayyedi et al., 2005).
4-Gastroesophageal reflux disease
A recent systematic review of 20 studies of the relationship between H. pylori and GERD by Raghunath and colleagues (2003) has demonstrated decrease prevalence of H. pylori in GERD patients from around the world. In an age-stratified endoscopic study of 507 patients with sliding hiatus hernias, rise in prevalence of H. pylori infection, and a parallel decrease in prevalence of reflux symptoms were noted with advancing age (Manes et al., 2003).
5-Gastric Adenocarcinoma
The clinical manifestations are epigastric pain, anorexia, weight loss, vomiting, hematemesis, and melena (Houghton and Wang, 2005).
6-Mucosa-associated lymphoid tissue lymphoma
The disease clinically manifests as epigastric pain, anorexia, weight loss, and occasional emesis, hematemesis, or melena. A recent study showed an improvement of low-grade MALT lymphoma after a 2 week course of therapy against H. pylori (Santacroce et al., 2008).
7-Liver diseases:
Recently, a higher prevalence of H. pylori infection has been described in patients with liver cirrhosis (Giannini et al., 2003) and hepatic carcinoma (Ito et al., 2004).
8-Billiary tract and H. pylori:
There is a possible link between H. pylori infection and some diseases of the biliary tract as cholelithiasis (Fox et al., 1998) and hepatobiliary tract cancers (Pandey and Shukla, 2009).
Schematic representation of the clinical outcomes following H. pylori infection (Correa and Piazuelo, 2008).
Extra-gastrointestinal effects:
Helicobacter pylori infection, although confined to the stomach, induces a strong systemic immune host response. It is therefore possible that untoward effects of this response may contribute to the development of diseases in areas other than the gastrointestinal tract (Gasbarrin et al., 2003). The demonstration of a causal relationship is rather difficult, because:
The etiology of most of the disorders in which the organism might be involved is multifactorial, H. pylori being, at best, one of the causative factors.
The organism may not be directly involved, and results of eradication therapy are interpreted with difficulty.
Antibiotics used for eradication therapy may act on other coexisting infections and/or have immunomodulatory effects (Gasbarrin et al., 2004).
Studies dealing with H. pylori related extra-gastric diseases have described observational data assessing H. pylori prevalence in a given patient population, treatment trials evaluating H. pylori eradication effects on the extra-gastric disease, case reports or hypothesis-driven bench research looking inside disease pathogenesis (Carloni et al., 2000).
Mechanisms underlying H. pylori responsibility in extra-gastric diseases are ascribable to direct bacterial effects, systemic effects provoked by soluble inflammatory mediators released by H. pylori, or cross-mimicry between bacterial and host antigens (Gasbarrin et al., 2003).
Ischemic heart 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. Several epidemiological studies have been carried out on the association between ischemic heart disease (IHD) and H. pylori infection (Pasceri et al., 2006).
It has 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. Increased serum concentrations of interleukin-6 (IL-6) and tumor necrosis factor (TNF) showed linear correlations with some cardiovascular risk factors. H. pylori influencing the systemic inflammatory response, raised concentrations of cytokines predictive of a higher risk of acute IHD events. 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 (Franceschi et al., 2009).
Ischemic cerebrovascular disorders
Recent studies show that H. pylori infection are more frequent in patients with ischemic cerebrovascular disease (ICVD) than in controls through the reduction of gastric absorption of folate caused by the infection (Cremonini et al., 2004), but there is still a lack of prospective studies able to show a causal relation between H. pylori infection and ICVD (Coles et al., 2003).
Respiratory diseases:
Chronic bronchitis
Recent epidemiological study in Danish adults suggested that chronic bronchitis might be more prevalent in women who are positive for H. pylori IgG than in women who tested negative for this antibody (Rosenstock et al., 2000). Other study found significantly higher rates of seropositivity for anti-H. pylori and anti-CagA antibodies in chronic bronchitis patients than in control subjects (Roussos et al., 2005). Literature on mechanisms between H. pylori infection and chronic bronchitis has not been identified to date but one possibility is that chronic induction of inflammatory mediators by H. pylori infection leads to the development of chronic bronchitis. Another potential pathogenetic mechanism could be inhalation of H .pylori or aspiration of its exotoxins into the respiratory tract, which might also cause chronic airway inflammation like that, which occurs in chronic bronchitis (Kanbaya et al., 2007).
Bronchiectasis
A study was detecting a high seroprevalence of H. pylori (76%) in patients with bronchiectasis, and found that this rate was significantly higher than rates they observed in healthy volunteers (54.3%) and tuberculosis patients (52.9%). The authors found that the patients with bronchiectasis who were sputum producers had a significantly higher H. pylori seroprevalence (83.1%) than the nonproducers (58.6%) (P ¼ 0:0002) (Tsang et al., 1998).
With regard to the pathogenesis of bronchiectasis in the setting of H. pylori infection, H. pylori-induced chronic activation of inflammatory mediators might lead to the development of this bronchial condition. H. pylori infection causes an extensive recruitment of polymorphs and T lymphocytes into the gastric submucosa, and also causes release of cytokines, IL-8, TNF-α and IL-1. As noted above, it is also possible that inhalation of H. pylori or aspiration of H. pylori exotoxins might lead to chronic airway inflammation, as occurs in bronchiectasis. So, H. pylori is common in patients with chronic bronchiectasis and the mechanism underlying the suggested association between H. pylori infection and bronchiectasis remain unclear (Kanbaya et al., 2007).
Lung Cancer
The prevalence of lung cancer in patients with peptic ulcers is two to three times higher than that in people who are ulcer-free. H. pylori infection may contribute to lung cancer by up regulating gastrin and COX-2, which could stimulate tumor growth and angiogenesis. The lungs develop from the same endodermal cells that form the lining of the gastrointestinal tract, and both systems contain cells that release various hormonal peptides (Kanbaya et al., 2007).
Tuberculosis
It is well known that patients with peptic ulcers are more prone to have tuberculosis than individuals who are ulcer free. Many studies have indicated that patients with tuberculosis may have a higher prevalence of H. pylori infection than the healthy population. But the knowledge about the possible connection between H. pylori infection and tuberculosis and its pathogenetic mechanisms involved remain unclear (Filippou et al., 2002).
Hematologic diseases:
Idiopathic thrombocytopenic purpura (ITP)
ITP has been frequently associated with H. pylori and many authors repeatedly confirmed this link. There are wider reports concerning a case series where ITP remission was achieved in 55% of H. pylori-eradicated patients (Ando et al., 2003). Conversely, a North American study showed low H. pylori prevalence in ITP patients and no ITP amelioration in 14 H. pylori-eradicated patients (Michel et al., 2004).
β-thalassaemia major
Patients with β-thalassaemia major are in greater risk for infectious diseases due to multiple causative factors (Vento et al., 2006).
Iron deficiency anemia
H. pylori infection is known to be a cause of iron deficiency anemia that is unresponsive to iron supplements because H. pylori binds iron to a specific receptor by iron-repressible outer membrane proteins (Lee et al., 2009).
Skin diseases
As for H. pylori and acne rosacea, (Tisma et al., 2003) higher H. pylori seropositivity is described in patients with rosacea and dyspepsia than in patients with rosacea alone (Argenziano et al., 2003).
Diagnosis:
H. pylori infection can be diagnosed in by invasive and noninvasive techniques and the surest one is histopathological biopsy but the ideal test for H. pylori is noninvasive or minimally invasive, highly accurate, inexpensive and readily available (Gold et al., 2000).
Noninvasive Tests
Immunoassay tests to detect H. pylori antibodies
ELISA to detect H. pylori antibodies are relativity inexpensive and easy to implement in the clinical setting. Specific IgG in children was 91% sensitive (Khanna et al., 1998) but antibody test do not work well after H.pylori was treated (Helicobacter foundation, 2006).
Urine and Saliva assay to detect H. pylori antibodies
Similar to serologic tests, saliva-based tests also detect the presence of H. pylori specific IgG antibodies which easy to perform, painless and inexpensive but less sensitive than assay of serum (Fallone et al., 1996).Urine-based assay are easy to perform, require minimal labor for collection and are painless (Alemohammed et al., 1993).However, these assay are highly variable and are not yet commercially available so cannot be recommend (Gold et al., 2000).
Urea breath test
Urea breath tests are noninvasive and have high sensitivity and specificity (>95%) both in adults (cuture et al., 1995) and children (Bode et al., 1998).
The test requires the ingestion of either radio-labeled 14C-urea or urea tagged with the stable isotope 13C.Test results may be influenced by concurrent use of antibiotics and acid suppressing medications and by the presence of other urease producing organisms present in the oral cavity. In addition, urea breath testing is
technically more difficult to perform in small children and infants (Rowland et al., 1997).
Helicobacter pylori infection, although confined to the stomach, induces a strong systemic immune host response. It is therefore possible that untoward effects of this response may contribute to the development of diseases in areas other than the gastrointestinal tract (Gasbarrin et al., 2003). The demonstration of a causal relationship is rather difficult, because:
The etiology of most of the disorders in which the organism might be involved is multifactorial, H. pylori being, at best, one of the causative factors.
The organism may not be directly involved, and results of eradication therapy are interpreted with difficulty.
Antibiotics used for eradication therapy may act on other coexisting infections and/or have immunomodulatory effects (Gasbarrin et al., 2004).
Studies dealing with H. pylori related extra-gastric diseases have described observational data assessing H. pylori prevalence in a given patient population, treatment trials evaluating H. pylori eradication effects on the extra-gastric disease, case reports or hypothesis-driven bench research looking inside disease pathogenesis (Carloni et al., 2000).
Mechanisms underlying H. pylori responsibility in extra-gastric diseases are ascribable to direct bacterial effects, systemic effects provoked by soluble inflammatory mediators released by H. pylori, or cross-mimicry between bacterial and host antigens (Gasbarrin et al., 2003).
Ischemic heart 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. Several epidemiological studies have been carried out on the association between ischemic heart disease (IHD) and H. pylori infection (Pasceri et al., 2006).
It has 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. Increased serum concentrations of interleukin-6 (IL-6) and tumor necrosis factor (TNF) showed linear correlations with some cardiovascular risk factors. H. pylori influencing the systemic inflammatory response, raised concentrations of cytokines predictive of a higher risk of acute IHD events. 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 (Franceschi et al., 2009).
Ischemic cerebrovascular disorders
Recent studies show that H. pylori infection are more frequent in patients with ischemic cerebrovascular disease (ICVD) than in controls through the reduction of gastric absorption of folate caused by the infection (Cremonini et al., 2004), but there is still a lack of prospective studies able to show a causal relation between H. pylori infection and ICVD (Coles et al., 2003).
Respiratory diseases:
Chronic bronchitis
Recent epidemiological study in Danish adults suggested that chronic bronchitis might be more prevalent in women who are positive for H. pylori IgG than in women who tested negative for this antibody (Rosenstock et al., 2000). Other study found significantly higher rates of seropositivity for anti-H. pylori and anti-CagA antibodies in chronic bronchitis patients than in control subjects (Roussos et al., 2005). Literature on mechanisms between H. pylori infection and chronic bronchitis has not been identified to date but one possibility is that chronic induction of inflammatory mediators by H. pylori infection leads to the development of chronic bronchitis. Another potential pathogenetic mechanism could be inhalation of H .pylori or aspiration of its exotoxins into the respiratory tract, which might also cause chronic airway inflammation like that, which occurs in chronic bronchitis (Kanbaya et al., 2007).
Bronchiectasis
A study was detecting a high seroprevalence of H. pylori (76%) in patients with bronchiectasis, and found that this rate was significantly higher than rates they observed in healthy volunteers (54.3%) and tuberculosis patients (52.9%). The authors found that the patients with bronchiectasis who were sputum producers had a significantly higher H. pylori seroprevalence (83.1%) than the nonproducers (58.6%) (P ¼ 0:0002) (Tsang et al., 1998).
With regard to the pathogenesis of bronchiectasis in the setting of H. pylori infection, H. pylori-induced chronic activation of inflammatory mediators might lead to the development of this bronchial condition. H. pylori infection causes an extensive recruitment of polymorphs and T lymphocytes into the gastric submucosa, and also causes release of cytokines, IL-8, TNF-α and IL-1. As noted above, it is also possible that inhalation of H. pylori or aspiration of H. pylori exotoxins might lead to chronic airway inflammation, as occurs in bronchiectasis. So, H. pylori is common in patients with chronic bronchiectasis and the mechanism underlying the suggested association between H. pylori infection and bronchiectasis remain unclear (Kanbaya et al., 2007).
Lung Cancer
The prevalence of lung cancer in patients with peptic ulcers is two to three times higher than that in people who are ulcer-free. H. pylori infection may contribute to lung cancer by up regulating gastrin and COX-2, which could stimulate tumor growth and angiogenesis. The lungs develop from the same endodermal cells that form the lining of the gastrointestinal tract, and both systems contain cells that release various hormonal peptides (Kanbaya et al., 2007).
Tuberculosis
It is well known that patients with peptic ulcers are more prone to have tuberculosis than individuals who are ulcer free. Many studies have indicated that patients with tuberculosis may have a higher prevalence of H. pylori infection than the healthy population. But the knowledge about the possible connection between H. pylori infection and tuberculosis and its pathogenetic mechanisms involved remain unclear (Filippou et al., 2002).
Hematologic diseases:
Idiopathic thrombocytopenic purpura (ITP)
ITP has been frequently associated with H. pylori and many authors repeatedly confirmed this link. There are wider reports concerning a case series where ITP remission was achieved in 55% of H. pylori-eradicated patients (Ando et al., 2003). Conversely, a North American study showed low H. pylori prevalence in ITP patients and no ITP amelioration in 14 H. pylori-eradicated patients (Michel et al., 2004).
β-thalassaemia major
Patients with β-thalassaemia major are in greater risk for infectious diseases due to multiple causative factors (Vento et al., 2006).
Iron deficiency anemia
H. pylori infection is known to be a cause of iron deficiency anemia that is unresponsive to iron supplements because H. pylori binds iron to a specific receptor by iron-repressible outer membrane proteins (Lee et al., 2009).
Skin diseases
As for H. pylori and acne rosacea, (Tisma et al., 2003) higher H. pylori seropositivity is described in patients with rosacea and dyspepsia than in patients with rosacea alone (Argenziano et al., 2003).
Diagnosis:
H. pylori infection can be diagnosed in by invasive and noninvasive techniques and the surest one is histopathological biopsy but the ideal test for H. pylori is noninvasive or minimally invasive, highly accurate, inexpensive and readily available (Gold et al., 2000).
Noninvasive Tests
Immunoassay tests to detect H. pylori antibodies
ELISA to detect H. pylori antibodies are relativity inexpensive and easy to implement in the clinical setting. Specific IgG in children was 91% sensitive (Khanna et al., 1998) but antibody test do not work well after H.pylori was treated (Helicobacter foundation, 2006).
Urine and Saliva assay to detect H. pylori antibodies
Similar to serologic tests, saliva-based tests also detect the presence of H. pylori specific IgG antibodies which easy to perform, painless and inexpensive but less sensitive than assay of serum (Fallone et al., 1996).Urine-based assay are easy to perform, require minimal labor for collection and are painless (Alemohammed et al., 1993).However, these assay are highly variable and are not yet commercially available so cannot be recommend (Gold et al., 2000).
Urea breath test
Urea breath tests are noninvasive and have high sensitivity and specificity (>95%) both in adults (cuture et al., 1995) and children (Bode et al., 1998).
The test requires the ingestion of either radio-labeled 14C-urea or urea tagged with the stable isotope 13C.Test results may be influenced by concurrent use of antibiotics and acid suppressing medications and by the presence of other urease producing organisms present in the oral cavity. In addition, urea breath testing is
technically more difficult to perform in small children and infants (Rowland et al., 1997).
Schematic description of the urea breath test. Radiolabeled urea is ingested by the patient and converted in the stomach to ammonia and radiolabeled carbon dioxide (CO2) in the presence of H. pylori urease. Exhaled radiolabeled (CO2) is then measured (Bruce et al., 2005).
Invasive tests
Testing through endoscopy
Biopsy can be during endoscopy to check to see if you have H. pylori and examination by:
Histopathology: Gram stain, Gimsa stain or silver stain and microscopy (Genta and Graham 1997).
Rapid urease test: poor positive predicative value in children.
Bacterial culture: culture of H. pylori from the gastric mucosa provides an opportunity to obtain a profile of antibiotic sensitivity that could identify potential treatment failure due to antibiotic resistance but it is expensive and success rates for recovery of the organism in many clinical laboratories are low and standardization of culture procedures has not been established (Holton. 1997).
Polymerase chain reaction (PCR): can be used to detect the presence of H. pylori in body fluids (e.g., gastric juice and stool), tissues (e.g., gastric mucosa), and water but is expensive and the assay is difficult to set up, specificity may be compromised by inadvertent contamination, and it is not widely available outside the research laboratory (Westblom, 1997).
Treatment
Since H .pylori is associated with various gastro-duodenal diseases, many discussions about which diseases should be treated by eradication of this organism were provoked (Fischbach et al., 2007).
Challenges in H. pylori treatment:
The goal of H. pylori treatment is the complete elimination of the organism. Once this has been achieved, reinfection rates are low. Thus, the benefit of treatment is durable. Clinically relevant H. pylori eradication regimens must have cure rates of at least 80 % without major side effects and with minimal induction of bacterial resistance (Laine et al., 2000).
Such goals have not been achieved because: Although H. pylori is sensitive to many antibiotics in vitro, no agent is effective in vivo alone, as monotherapy. Combination regimens are needed for eradication. Other factors such as the hostile gastric environment which reduces bioavailability of antibiotics in the stomach, side effects and poor patient compliance were significantly associated with treatment failure (Treiber et al., 2007).
Indication of treatment
The original Maastricht III Consensus Report identified gastric and duodenal ulcer diseases as indications for therapy in children. This panel agreed that there is no specific clinical picture associated with H. pylori in children, and that the benefit of H. pylori eradication in children with dyspepsia has not been established. Therefore, in children, testing for H. pylori is recommended only if the symptoms are severe enough to justify therapy (table 10) (Selgrad and Malfertheiner, 2008; Kanizaj et al., 2009).
Lines of Treatment of H. pylori infection
The Maastricht III Consensus Report reported that the combination of two or more antimicrobial agents increases the rates of cure and reduces the risk of resistance of H. pylori. The chief antimicrobial agents used in these regimens are amoxicillin, clarithromycin, metronidazole, tetracycline, and bismuth. Combinations of antisecretory agents with two antimicrobial agents (triple therapy) are usually tried for 7 to 14 days (Selgrad and Malfertheiner, 2008; Kanizaj et al., 2009).
First-line therapies:
Proton-pump inhibitor-based triple therapies
It is composed of 20 mg of omeprazole, given either with 1 g of amoxicillin and 500 mg of clarithromycin, or with 400 mg of metronidazole and 250 mg of clarithromycin daily for seven days (Cavallaro et al., 2006).
Several comparative trials have demonstrated the equivalence of 30 mg of lansoprazole twice daily, 40 mg of pantoprazole twice daily, 20 mg of rabeprazole daily, and 20 mg of esomeprazole twice daily with omeprazole in these triple therapies (Laine et al., 2000). Increasing the dose of clarithromycin to 1.5 g per day improved rates of cure, but increasing the doses of the other antibiotics did not. In another pooled analysis, no effect of larger doses of proton-pump inhibitors was observed among the triple therapies (Megraud and Lamouliatte, 2003).
The duration of therapy remains controversial: In Europe, 7 day treatment is recommended, whereas in the United States, 14 day courses have been found to be better than shorter courses (Zagari et al., 2007).
Ranitidine bismuth citrate–based therapies
Ranitidine bismuth citrate in dual therapy with clarithromycin for two weeks has been widely approved. Meta-analyses suggest that ranitidine bismuth citrate with clarithromycin and amoxicillin, or with clarithromycin and a nitroimidazole perform as well as corresponding proton-pump-inhibitor–based therapies (McMahon et al., 2003).
Bismuth-Based Triple Therapies:
Bismuth in association with metronidazole and tetracycline compares well in meta-analyses with therapies based on proton-pump inhibitors or ranitidine bismuth citrate; even if the duration of treatment is reduced to seven days .This inexpensive regimen remains an important option. Furazolidone, a nitrofuran derivative, has also been proposed for use in bismuth-based triple therapies (Rodgers and van Zanten 2007).
Triple therapy for two weeks, consisting of 100 mg of furazolidone four times daily, amoxicillin, and bismuth was successful in 86 percent of cases. However, furazolidone, particularly when combined with bismuth for two weeks, is associated with substantial side effects. Standard bismuth-based therapy and its furazolidone-containing alternatives were recommended at the 1999 Latin American Consensus Conference (Coelho et al., 2000).
Three regimens were recommended by the 1998 U.S. Consensus Conference:
A proton-pump inhibitor, clarithromycin, and either amoxicillin or metronidazole are for two weeks.
Ranitidine bismuth citrate, clarithromycin, and amoxicillin, metronidazole or tetracycline for two weeks.
A proton-pump inhibitor, bismuth, metronidazole, and tetracycline for one to two weeks (Howden and Hunt, 1998).
The regimens recommended by the European Maastricht 2-2000 conference are a proton pump inhibitor (or ranitidine bismuth citrate), clarithromycin, and amoxicillin or metronidazole for seven days. Recommended eradication therapies for H. pylori disease in children are presented (Drumm et al., 2000).
Second-line therapies
Eradication is more difficult when a first treatment attempt has failed, usually because of either poor patient compliance or the development of antibiotic resistance. Therefore, a 10-14 days treatment course is advocated for second-line therapies. However, the optimal strategy for re-treatment after the failure of eradication has not yet been established. Because the failure of therapy is often associated with secondary antibiotic resistance, retreatment should ideally be guided by data on susceptibility (Lam and Talley, 1998).
However, such information is often unavailable. So, quadruple therapies in which a proton-pump inhibitor or an H2-receptor antagonist is added to a bismuth-based triple regimen with metronidazole have been suggested as optimal second-line therapy (Hojo et al., 2001).
Another approach to re-treatment without susceptibility testing is to prescribe a second course of proton-pump-inhibitor–based triple therapy, avoiding antimicrobial agents against which prior therapy may have induced resistance and avoiding less effective combinations, such as amoxicillin and tetracycline. If a clarithromycin-based regimen is used first, a metronidazole- based regimen should be used afterwards, or vice versa (Kanizaj et al., 2009).
Vaccination
Immunization with vaccines containing the H. pylori vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), or neutrophil-activating protein (NAP), alone or in combination, have been shown to prevent experimental infection in animals, which have proven that vaccines have a therapeutic effect and that the concept of vaccination is possible (Kabir, 2007). However, the exact mechanism of vaccine-induced protection is so far poorly understood (Agarwal K and Agarwal S, 2008).
Testing through endoscopy
Biopsy can be during endoscopy to check to see if you have H. pylori and examination by:
Histopathology: Gram stain, Gimsa stain or silver stain and microscopy (Genta and Graham 1997).
Rapid urease test: poor positive predicative value in children.
Bacterial culture: culture of H. pylori from the gastric mucosa provides an opportunity to obtain a profile of antibiotic sensitivity that could identify potential treatment failure due to antibiotic resistance but it is expensive and success rates for recovery of the organism in many clinical laboratories are low and standardization of culture procedures has not been established (Holton. 1997).
Polymerase chain reaction (PCR): can be used to detect the presence of H. pylori in body fluids (e.g., gastric juice and stool), tissues (e.g., gastric mucosa), and water but is expensive and the assay is difficult to set up, specificity may be compromised by inadvertent contamination, and it is not widely available outside the research laboratory (Westblom, 1997).
Treatment
Since H .pylori is associated with various gastro-duodenal diseases, many discussions about which diseases should be treated by eradication of this organism were provoked (Fischbach et al., 2007).
Challenges in H. pylori treatment:
The goal of H. pylori treatment is the complete elimination of the organism. Once this has been achieved, reinfection rates are low. Thus, the benefit of treatment is durable. Clinically relevant H. pylori eradication regimens must have cure rates of at least 80 % without major side effects and with minimal induction of bacterial resistance (Laine et al., 2000).
Such goals have not been achieved because: Although H. pylori is sensitive to many antibiotics in vitro, no agent is effective in vivo alone, as monotherapy. Combination regimens are needed for eradication. Other factors such as the hostile gastric environment which reduces bioavailability of antibiotics in the stomach, side effects and poor patient compliance were significantly associated with treatment failure (Treiber et al., 2007).
Indication of treatment
The original Maastricht III Consensus Report identified gastric and duodenal ulcer diseases as indications for therapy in children. This panel agreed that there is no specific clinical picture associated with H. pylori in children, and that the benefit of H. pylori eradication in children with dyspepsia has not been established. Therefore, in children, testing for H. pylori is recommended only if the symptoms are severe enough to justify therapy (table 10) (Selgrad and Malfertheiner, 2008; Kanizaj et al., 2009).
Lines of Treatment of H. pylori infection
The Maastricht III Consensus Report reported that the combination of two or more antimicrobial agents increases the rates of cure and reduces the risk of resistance of H. pylori. The chief antimicrobial agents used in these regimens are amoxicillin, clarithromycin, metronidazole, tetracycline, and bismuth. Combinations of antisecretory agents with two antimicrobial agents (triple therapy) are usually tried for 7 to 14 days (Selgrad and Malfertheiner, 2008; Kanizaj et al., 2009).
First-line therapies:
Proton-pump inhibitor-based triple therapies
It is composed of 20 mg of omeprazole, given either with 1 g of amoxicillin and 500 mg of clarithromycin, or with 400 mg of metronidazole and 250 mg of clarithromycin daily for seven days (Cavallaro et al., 2006).
Several comparative trials have demonstrated the equivalence of 30 mg of lansoprazole twice daily, 40 mg of pantoprazole twice daily, 20 mg of rabeprazole daily, and 20 mg of esomeprazole twice daily with omeprazole in these triple therapies (Laine et al., 2000). Increasing the dose of clarithromycin to 1.5 g per day improved rates of cure, but increasing the doses of the other antibiotics did not. In another pooled analysis, no effect of larger doses of proton-pump inhibitors was observed among the triple therapies (Megraud and Lamouliatte, 2003).
The duration of therapy remains controversial: In Europe, 7 day treatment is recommended, whereas in the United States, 14 day courses have been found to be better than shorter courses (Zagari et al., 2007).
Ranitidine bismuth citrate–based therapies
Ranitidine bismuth citrate in dual therapy with clarithromycin for two weeks has been widely approved. Meta-analyses suggest that ranitidine bismuth citrate with clarithromycin and amoxicillin, or with clarithromycin and a nitroimidazole perform as well as corresponding proton-pump-inhibitor–based therapies (McMahon et al., 2003).
Bismuth-Based Triple Therapies:
Bismuth in association with metronidazole and tetracycline compares well in meta-analyses with therapies based on proton-pump inhibitors or ranitidine bismuth citrate; even if the duration of treatment is reduced to seven days .This inexpensive regimen remains an important option. Furazolidone, a nitrofuran derivative, has also been proposed for use in bismuth-based triple therapies (Rodgers and van Zanten 2007).
Triple therapy for two weeks, consisting of 100 mg of furazolidone four times daily, amoxicillin, and bismuth was successful in 86 percent of cases. However, furazolidone, particularly when combined with bismuth for two weeks, is associated with substantial side effects. Standard bismuth-based therapy and its furazolidone-containing alternatives were recommended at the 1999 Latin American Consensus Conference (Coelho et al., 2000).
Three regimens were recommended by the 1998 U.S. Consensus Conference:
A proton-pump inhibitor, clarithromycin, and either amoxicillin or metronidazole are for two weeks.
Ranitidine bismuth citrate, clarithromycin, and amoxicillin, metronidazole or tetracycline for two weeks.
A proton-pump inhibitor, bismuth, metronidazole, and tetracycline for one to two weeks (Howden and Hunt, 1998).
The regimens recommended by the European Maastricht 2-2000 conference are a proton pump inhibitor (or ranitidine bismuth citrate), clarithromycin, and amoxicillin or metronidazole for seven days. Recommended eradication therapies for H. pylori disease in children are presented (Drumm et al., 2000).
Second-line therapies
Eradication is more difficult when a first treatment attempt has failed, usually because of either poor patient compliance or the development of antibiotic resistance. Therefore, a 10-14 days treatment course is advocated for second-line therapies. However, the optimal strategy for re-treatment after the failure of eradication has not yet been established. Because the failure of therapy is often associated with secondary antibiotic resistance, retreatment should ideally be guided by data on susceptibility (Lam and Talley, 1998).
However, such information is often unavailable. So, quadruple therapies in which a proton-pump inhibitor or an H2-receptor antagonist is added to a bismuth-based triple regimen with metronidazole have been suggested as optimal second-line therapy (Hojo et al., 2001).
Another approach to re-treatment without susceptibility testing is to prescribe a second course of proton-pump-inhibitor–based triple therapy, avoiding antimicrobial agents against which prior therapy may have induced resistance and avoiding less effective combinations, such as amoxicillin and tetracycline. If a clarithromycin-based regimen is used first, a metronidazole- based regimen should be used afterwards, or vice versa (Kanizaj et al., 2009).
Vaccination
Immunization with vaccines containing the H. pylori vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), or neutrophil-activating protein (NAP), alone or in combination, have been shown to prevent experimental infection in animals, which have proven that vaccines have a therapeutic effect and that the concept of vaccination is possible (Kabir, 2007). However, the exact mechanism of vaccine-induced protection is so far poorly understood (Agarwal K and Agarwal S, 2008).
ليست هناك تعليقات:
إرسال تعليق