Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
7
Chronic gastritis e An update Mariya Varbanova, MD, Fellow/Resident at the Department of Gastroenterology, Hepatology and Infectious Diseases a, €ger, Fellow/Resident at the Institute of Katrin Frauenschla Pathology b, Peter Malfertheiner, MD, Professor, Director of the Department of Gastroenterology, Hepatology and Infectious Diseases a, * a
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany b Institute of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
a b s t r a c t Keywords: Gastritis Helicobacter pylori Autoimmune gastritis Pernicious anaemia
Helicobacter pylori is the main aetiologic factor for chronic gastritis worldwide. The degree of inflammation and the evolution of this form of chronic gastritis can vary largely depending on bacterial virulence factors, host susceptibility factors and environmental conditions. Autoimmune gastritis is another cause of chronic inflammation in the stomach, which can occur in all age groups. This disease presents typically with vitamin B12 deficiency and pernicious anaemia. The presence of anti-parietal cell antibodies is highly specific for the diagnosis. The role of H. pylori as a trigger for autoimmune gastritis remains uncertain. Other rare conditions for chronic gastritis are chronic inflammatory conditions such as Crohn's disease or on the background of lymphocytic or collagenous gastroenteropathies. © 2014 Published by Elsevier Ltd.
Introduction Helicobacter pylori (H. pylori) infection is the most common cause of chronic inflammation of the stomach worldwide. The bacterium discovered by Warren and Marshall in 1982 colonizes around half * Corresponding author. Tel.: þ49 391 6713100. E-mail address: [email protected] (P. Malfertheiner).
http://dx.doi.org/10.1016/j.bpg.2014.10.005 1521-6918/© 2014 Published by Elsevier Ltd.
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M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
of the world population. All H. pylori infected individuals develop chronic gastritis; the degree of mucosal inflammation results from the interplay of bacterial virulence factors, host susceptibility genes and environmental factors. Corpuspredominant gastritis, severe gastric atrophy and intestinal metaplasia confine a risk for the development of gastric cancer as shown in large prospective cohorts [1e3]. Autoimmune gastritis (AIG) is another cause of chronic inflammation of the stomach. The term AIG refers to a variety of definitions such as atrophic body gastritis, pernicious anaemia and Morbus Biermer. The clinical presentation can be variable, most typically with vitamin B12 deficiency and manifest pernicious anaemia (PA), but iron deficiency may also be a consequence. At the time of diagnosis, the oxyntic mucosa is usually transformed and shows severe glandular atrophy. The traditional concept of AIG needs to be revisited because of the role of H. pylori infection in the development of AIG through mimicry of the proton pump of parietal cells (Hþ/Kþ-ATPase). The risk for type 1 gastric neuroendocrine neoplasm, as well as the co-occurrence with various autoimmune diseases is reviewed in this article. Besides H. pylori gastritis and AIG, several other chronic inflammatory conditions of the gastric mucosa are discussed. They include collagenous gastritis, lymphocytic gastritis, M. Menetrier and M. Crohn and are rare forms. H pylori gastritis Epidemiology The excusive permanent reservoir of H. pylori is the human stomach. Local prevalence of H. pylori varies greatly from 8% (North America) to 90% (Siberia) depending on geographic region and socioeconomic conditions [4]. A selection of H. pylori prevalence in the adult population from different continents is shown in Table 1. The bacterium is found in feces and the oral cavity of infected individuals [5] but exclusively colonizes and persists in the gastric mucosa. Since the wide-spread use of antibiotic treatment and the improvement of hygiene in industrialized countries, prevalence of H. pylori infection of children and young individuals gradually decreases [6], and lies below 10% in children in western populations [7,8]. Pathogenesis Bacterial factors H. pylori is an obligate pathogen in the human stomach. The bacterium possesses various virulence factors which facilitate survival, cell adhesion, cell damage and evasion from immune response. Table 2 shows a list of the best known virulence factors and their functions, excellently reviewed recently by Posselt et al. [9]. The pathogenicity island cytotoxin-associated gene a (cagA) in particular is expressed by a large number of strains and is considered a potent inductor of inflammation [10]. The cagA gene exhibits strong variations in different geographic locations correlated with incidence of gastric cancer [11,12]. Attention was drawn on variations in the conserved sequence of the cagA gene Glu-Pro-Ile-TyrAla (EPIYA) motifs. Particularly the number of C tyrosine phosphorylations seems to play a decisive role in virulence as reviewed in another chapter of this edition. Two or more EPIYA C motifs point to an
Table 1 Reports of H. pylori prevalence in the largest studies in adults from different continents published between 2010 and 2011 using tests for active infection. Modified from Goh et al [6]. Continent
Country
N
Test
Prevalence
Asia Africa South America North America Europe
Korea Morocco Chile USA Albania, Greece
10,102 755 5664 78,985 101 Albanian 101 Greek
RUT Histology RUT Histology Histology
51% 69% 78% 8% 54% 34%
M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
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Table 2 Selected H. pylori virulence factors and their basic functions. Virulence factor
Description
Function
Association with disease
OipA BabA/B
Outer inflammatory protein A Blood-group-antigen-binding adhesion Sialic acid binding adhesion Urease, functional enzyme
Adhesion, inflammation Adhesion
Gastritis Gastric cancer
Adhesion Colonization, disruption of tight junctions Evasion, inflammation
Gastritis Gastritis
Disruption of tight junctions, translocation of proteins inflammation Cell damage (vacuolization), apoptosis
Gastritis Ucer disease Gastric cancer Ulcer disease Gastric cancer
SabA Ure A/B LPS CagA
Lipopolysaccharides, membrane component Cytotoxin-associated gene A protein
VacA
Vacuole-inducing toxin
Gastritis
increased risk for the development of atrophic gastritis and gastric carcinoma with calculated odds ratio (OR) of 12 and 51, respectively [13]. Host factors Host susceptibility factors such as polymorphisms in genes coding for toll like receptors or specific cytokines have also been reported to influence the progression of chronic gastritis to preneoplastic conditions and gastric cancer [14]. For example, it has been shown that the concurrence of infection with cagA and vacA s1m1 positive strains in subjects with IL-1b-511*T polymorphism increases the risk of chronic gastritis to progress to GC 25-fold [15]. Testing for specific factors is however not recommended in clinical practice, as none can sufficiently predict the clinical outcome of infection [16]. Infiltration of the gastric mucosa with neutrophil granulocytes is a histopathological hallmark for infection. This reaction is an essential part of the immune response against H. pylori triggered by high interleukin 8 (IL-8) levels produced by gastric epithelial cells after contact with the bacterium [17]. IL-8 attracts neutrophils, which release oxyradicals (oxidative burst) leading to cell damage while being tolerated by H. pylori equipped with enzymes to block oxidative stress (catalase, hydrogenase). On the other hand, lymphocyte infiltration is also typically observed, in some cases accompanied by the formation of lymphoid follicles. It represents the cellular response mediated foremost by a Th1- and Th17-response with secretion of proinflammatory cytokines such as IFN-g and IL-17 [18]. New insights into the capacity of H. pylori to overcome the life-long immune response of the host were gained by the discovery of pronounced infiltration of mucosa with immunosuppressive regulatory T cells (Treg) [19]. Neutrophil and lymphocyte infiltration represent the activity and chronicity of H. pylori induced gastritis. Grading of these parameters of inflammation is performed standardized by a visual scale proposed in the Updated Sydney system [20]. Diagnosis and treatment Invasive and non-invasive tests for H. pylori infection are available for clinical practice. Several invasive methods can be used to determine the presence of H. pylori: histological staining (Fig. 1), culture, rapid urease test and molecular detection via PCR, all of which require gastric biopsies obtained during upper endoscopy. High consumption of resources and avoidance of endoscopy give way to non-invasive test modalities for the first diagnostic steps such as urea breath test (13C e UBT), stool faecal antigen test and serology. One essential problem is co-medication with proton pump inhibitors (PPI), which leads to false negative results in the invasive and non-invasive tests for active infection due to suppression of H. pylori density and urease during PPI therapy [21,22]. Serological detection of antibodies against H. pylori can be utilized in such cases; however it does not allow the discrimination between active or past infection. Current recommendations for the clinical management and treatment of H. pylori infection have been stated in the IV Maastricht/ Florence Consensus report [16]. First line treatment is usually a
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M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
Clarithromycin/ PPI based regimen combined with amoxicillin or metronidazole, except in areas with high clarithromycin resistance. Here a quadruple bismuth containing therapy would be the first choice, alternatively non bismuth quadruple therapy. After two eradication failures it is recommended to obtain a culture of H. pylori and test for antibiotic resistance.
Practice points H. pylori is the main etiologic factor for chronic gastritis worldwide Currently there is no biomarker (either host- or bacteria related) which can reliably predict the outcome of the infection H. pylori gastritis therefore whenever detected requires eradication therapy
Research agenda Assessment of genetics and mechanisms of virulence and host factors which determine risk of gastric cancer Monitoring antibiotic resistance in order to select effective eradication therapies
Autoimmune gastritis Epidemiology Due to the frequent asymptomatic nature of disease, the prevalence of AIG in the general population is probably underestimated. A recent epidemiological study in Germany including 9,684 subjects aged 50e74 years revealed the presence of anti-parietal cell antibodies (PCA) in approximately 20%, along with a strong association with gastric atrophy as determined by low pepsinogen I levels [23]. In another epidemiological study on the general population on the Canary Islands, PCA were found in 8% and in 10% of the women [24].
Fig. 1. A Helicobacter pylori gastritis (Warthin-Starry-stain) with a dense inflammatory infiltrate of neutrophiles, lymphocytes and plasma cells in the upper Lamina propria. Furthermore, there is a moderate foveolar hyperplasia, identified by the elongated and contorted foveolae (white arrow heads). B Long lasting Helicobacter pylori gastritis with a lymphoid follicle (black arrow heads). C A close-up view of the comma-shaped Helicobacter pylori bacteria (white arrows) on the surface of the foveolar epithelium.
M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
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A large number of elderly patients with undiagnosed pernicious anaemia (PA) has been reported in a prospective study from the United States (n ¼ 729, age >60 years) [25]. Vitamin B12 deficiency and positive intrinsic factor antibodies were found in 1.9% of the study population and in 4% of the women. An Israeli study suggested a possibly high number of undiagnosed AIG in young patients as well. Notably, 30% of a cohort of asymptomatic PA patients were aged below 40 years [26]. Another important epidemiological aspect is the frequent association of autoimmune gastritis with other autoimmune disorders: the prevalence of AIG in type 1 diabetes mellitus and autoimmune thyroid disease is five- to ten- fold higher than in the general population [27,28]. Pathogenesis Anti-parietal cell antibodies (PCA) and antibodies against intrinsic factor (IFA) were discovered back in the early 1960ies. Almost 30 years later, the Hþ/Kþ-ATPase was identified as the causal antigen [29], which triggers the autoimmune response and the progress of the disease by consecutive destruction of parietal cells and functional loss of the oxyntic gastric mucosa [30]. It is assumed that during epithelial turnover some amount of the Hþ/Kþ-ATPase protein (the main functional component of parietal cells) is accessible for dendritic cells in the gastric mucosa. When presented as an antigen to naïve T cells, a pathogenic clone of CD4þ antigen specific T cells can arise in predisposed individuals [31]. It infiltrates the gastric mucosa providing the stimulus for the eventually observed Th1 driven immune response. By the involvement of B cells on the mucosal level, autoantibody production is initiated and maintained, a process dependent on antigen presentation. The exact mechanisms exerting parietal cell death are not clear. A possible death by Fas ligand induced apoptosis has been suggested based on the observation that gastric epithelial cells express Fas ligand in experimental autoimmune gastritis possibly interacting with Fas ligand on infiltrating T cells [32]. A similar process of tissue loss has been described in other autoimmune diseases [33]. The reduced acid production invokes reactive and ineffective excess of gastrin levels used as a diagnostic criterion of AIG. As an acidic milieu is needed to extract iron from proteins, iron deficiency anaemia caused by hypochlorhydria can be an early sign of disease in 20e37% of AIG patients [34,35]. Another target of the autoimmune response is the intrinsic factor, an essential protein for vitamin B12 (cobalamin) uptake. Vitamin B12 deficiency dominates the clinical picture in PA patients, a condition which probably requires decades from the onset of AIG to develop. The role of H. pylori The classic concept of three types of gastritis (A for autoimmune, B for bacterial and C for chemical) discriminates an infectious from an autoimmune principle cause of inflammation. In a prospective controlled case control trial from 1991 H. pylori infection was reported as a rare finding in the group of patients with pernicious anaemia [36]. However, this concept is challenged by a growing body of literature supporting the idea of H. pylori as an infectious trigger of autoinflammation. Diagnosis of H. pylori by histology or other tests for active infection in severe atrophy can be difficult. However, according to more recent reports, H. pylori can be detected on histology in up to 30% of patients with pernicious anaemia and about a half of them by serology [37]. An even larger proportion of H. pylori seropositive patients (75%) was observed in a cohort of 150 AIG cases [38]. Interestingly, the H. pylori negative patients were 10 years older than the H. pylori positive group and 75% of them had pernicious anaemia vs. 12% in the H. pylori positive group. This trend of H. pylori ‘loss’ with age was demonstrated even more clearly in a prospective study from Israel using UBT. High prevalence of active H. pylori infection (88% positive) was found in very young patients with AIG (age
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
7
Chronic gastritis e An update Mariya Varbanova, MD, Fellow/Resident at the Department of Gastroenterology, Hepatology and Infectious Diseases a, €ger, Fellow/Resident at the Institute of Katrin Frauenschla Pathology b, Peter Malfertheiner, MD, Professor, Director of the Department of Gastroenterology, Hepatology and Infectious Diseases a, * a
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany b Institute of Pathology, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
a b s t r a c t Keywords: Gastritis Helicobacter pylori Autoimmune gastritis Pernicious anaemia
Helicobacter pylori is the main aetiologic factor for chronic gastritis worldwide. The degree of inflammation and the evolution of this form of chronic gastritis can vary largely depending on bacterial virulence factors, host susceptibility factors and environmental conditions. Autoimmune gastritis is another cause of chronic inflammation in the stomach, which can occur in all age groups. This disease presents typically with vitamin B12 deficiency and pernicious anaemia. The presence of anti-parietal cell antibodies is highly specific for the diagnosis. The role of H. pylori as a trigger for autoimmune gastritis remains uncertain. Other rare conditions for chronic gastritis are chronic inflammatory conditions such as Crohn's disease or on the background of lymphocytic or collagenous gastroenteropathies. © 2014 Published by Elsevier Ltd.
Introduction Helicobacter pylori (H. pylori) infection is the most common cause of chronic inflammation of the stomach worldwide. The bacterium discovered by Warren and Marshall in 1982 colonizes around half * Corresponding author. Tel.: þ49 391 6713100. E-mail address: [email protected] (P. Malfertheiner).
http://dx.doi.org/10.1016/j.bpg.2014.10.005 1521-6918/© 2014 Published by Elsevier Ltd.
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M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
of the world population. All H. pylori infected individuals develop chronic gastritis; the degree of mucosal inflammation results from the interplay of bacterial virulence factors, host susceptibility genes and environmental factors. Corpuspredominant gastritis, severe gastric atrophy and intestinal metaplasia confine a risk for the development of gastric cancer as shown in large prospective cohorts [1e3]. Autoimmune gastritis (AIG) is another cause of chronic inflammation of the stomach. The term AIG refers to a variety of definitions such as atrophic body gastritis, pernicious anaemia and Morbus Biermer. The clinical presentation can be variable, most typically with vitamin B12 deficiency and manifest pernicious anaemia (PA), but iron deficiency may also be a consequence. At the time of diagnosis, the oxyntic mucosa is usually transformed and shows severe glandular atrophy. The traditional concept of AIG needs to be revisited because of the role of H. pylori infection in the development of AIG through mimicry of the proton pump of parietal cells (Hþ/Kþ-ATPase). The risk for type 1 gastric neuroendocrine neoplasm, as well as the co-occurrence with various autoimmune diseases is reviewed in this article. Besides H. pylori gastritis and AIG, several other chronic inflammatory conditions of the gastric mucosa are discussed. They include collagenous gastritis, lymphocytic gastritis, M. Menetrier and M. Crohn and are rare forms. H pylori gastritis Epidemiology The excusive permanent reservoir of H. pylori is the human stomach. Local prevalence of H. pylori varies greatly from 8% (North America) to 90% (Siberia) depending on geographic region and socioeconomic conditions [4]. A selection of H. pylori prevalence in the adult population from different continents is shown in Table 1. The bacterium is found in feces and the oral cavity of infected individuals [5] but exclusively colonizes and persists in the gastric mucosa. Since the wide-spread use of antibiotic treatment and the improvement of hygiene in industrialized countries, prevalence of H. pylori infection of children and young individuals gradually decreases [6], and lies below 10% in children in western populations [7,8]. Pathogenesis Bacterial factors H. pylori is an obligate pathogen in the human stomach. The bacterium possesses various virulence factors which facilitate survival, cell adhesion, cell damage and evasion from immune response. Table 2 shows a list of the best known virulence factors and their functions, excellently reviewed recently by Posselt et al. [9]. The pathogenicity island cytotoxin-associated gene a (cagA) in particular is expressed by a large number of strains and is considered a potent inductor of inflammation [10]. The cagA gene exhibits strong variations in different geographic locations correlated with incidence of gastric cancer [11,12]. Attention was drawn on variations in the conserved sequence of the cagA gene Glu-Pro-Ile-TyrAla (EPIYA) motifs. Particularly the number of C tyrosine phosphorylations seems to play a decisive role in virulence as reviewed in another chapter of this edition. Two or more EPIYA C motifs point to an
Table 1 Reports of H. pylori prevalence in the largest studies in adults from different continents published between 2010 and 2011 using tests for active infection. Modified from Goh et al [6]. Continent
Country
N
Test
Prevalence
Asia Africa South America North America Europe
Korea Morocco Chile USA Albania, Greece
10,102 755 5664 78,985 101 Albanian 101 Greek
RUT Histology RUT Histology Histology
51% 69% 78% 8% 54% 34%
M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
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Table 2 Selected H. pylori virulence factors and their basic functions. Virulence factor
Description
Function
Association with disease
OipA BabA/B
Outer inflammatory protein A Blood-group-antigen-binding adhesion Sialic acid binding adhesion Urease, functional enzyme
Adhesion, inflammation Adhesion
Gastritis Gastric cancer
Adhesion Colonization, disruption of tight junctions Evasion, inflammation
Gastritis Gastritis
Disruption of tight junctions, translocation of proteins inflammation Cell damage (vacuolization), apoptosis
Gastritis Ucer disease Gastric cancer Ulcer disease Gastric cancer
SabA Ure A/B LPS CagA
Lipopolysaccharides, membrane component Cytotoxin-associated gene A protein
VacA
Vacuole-inducing toxin
Gastritis
increased risk for the development of atrophic gastritis and gastric carcinoma with calculated odds ratio (OR) of 12 and 51, respectively [13]. Host factors Host susceptibility factors such as polymorphisms in genes coding for toll like receptors or specific cytokines have also been reported to influence the progression of chronic gastritis to preneoplastic conditions and gastric cancer [14]. For example, it has been shown that the concurrence of infection with cagA and vacA s1m1 positive strains in subjects with IL-1b-511*T polymorphism increases the risk of chronic gastritis to progress to GC 25-fold [15]. Testing for specific factors is however not recommended in clinical practice, as none can sufficiently predict the clinical outcome of infection [16]. Infiltration of the gastric mucosa with neutrophil granulocytes is a histopathological hallmark for infection. This reaction is an essential part of the immune response against H. pylori triggered by high interleukin 8 (IL-8) levels produced by gastric epithelial cells after contact with the bacterium [17]. IL-8 attracts neutrophils, which release oxyradicals (oxidative burst) leading to cell damage while being tolerated by H. pylori equipped with enzymes to block oxidative stress (catalase, hydrogenase). On the other hand, lymphocyte infiltration is also typically observed, in some cases accompanied by the formation of lymphoid follicles. It represents the cellular response mediated foremost by a Th1- and Th17-response with secretion of proinflammatory cytokines such as IFN-g and IL-17 [18]. New insights into the capacity of H. pylori to overcome the life-long immune response of the host were gained by the discovery of pronounced infiltration of mucosa with immunosuppressive regulatory T cells (Treg) [19]. Neutrophil and lymphocyte infiltration represent the activity and chronicity of H. pylori induced gastritis. Grading of these parameters of inflammation is performed standardized by a visual scale proposed in the Updated Sydney system [20]. Diagnosis and treatment Invasive and non-invasive tests for H. pylori infection are available for clinical practice. Several invasive methods can be used to determine the presence of H. pylori: histological staining (Fig. 1), culture, rapid urease test and molecular detection via PCR, all of which require gastric biopsies obtained during upper endoscopy. High consumption of resources and avoidance of endoscopy give way to non-invasive test modalities for the first diagnostic steps such as urea breath test (13C e UBT), stool faecal antigen test and serology. One essential problem is co-medication with proton pump inhibitors (PPI), which leads to false negative results in the invasive and non-invasive tests for active infection due to suppression of H. pylori density and urease during PPI therapy [21,22]. Serological detection of antibodies against H. pylori can be utilized in such cases; however it does not allow the discrimination between active or past infection. Current recommendations for the clinical management and treatment of H. pylori infection have been stated in the IV Maastricht/ Florence Consensus report [16]. First line treatment is usually a
1034
M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
Clarithromycin/ PPI based regimen combined with amoxicillin or metronidazole, except in areas with high clarithromycin resistance. Here a quadruple bismuth containing therapy would be the first choice, alternatively non bismuth quadruple therapy. After two eradication failures it is recommended to obtain a culture of H. pylori and test for antibiotic resistance.
Practice points H. pylori is the main etiologic factor for chronic gastritis worldwide Currently there is no biomarker (either host- or bacteria related) which can reliably predict the outcome of the infection H. pylori gastritis therefore whenever detected requires eradication therapy
Research agenda Assessment of genetics and mechanisms of virulence and host factors which determine risk of gastric cancer Monitoring antibiotic resistance in order to select effective eradication therapies
Autoimmune gastritis Epidemiology Due to the frequent asymptomatic nature of disease, the prevalence of AIG in the general population is probably underestimated. A recent epidemiological study in Germany including 9,684 subjects aged 50e74 years revealed the presence of anti-parietal cell antibodies (PCA) in approximately 20%, along with a strong association with gastric atrophy as determined by low pepsinogen I levels [23]. In another epidemiological study on the general population on the Canary Islands, PCA were found in 8% and in 10% of the women [24].
Fig. 1. A Helicobacter pylori gastritis (Warthin-Starry-stain) with a dense inflammatory infiltrate of neutrophiles, lymphocytes and plasma cells in the upper Lamina propria. Furthermore, there is a moderate foveolar hyperplasia, identified by the elongated and contorted foveolae (white arrow heads). B Long lasting Helicobacter pylori gastritis with a lymphoid follicle (black arrow heads). C A close-up view of the comma-shaped Helicobacter pylori bacteria (white arrows) on the surface of the foveolar epithelium.
M. Varbanova et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 1031e1042
1035
A large number of elderly patients with undiagnosed pernicious anaemia (PA) has been reported in a prospective study from the United States (n ¼ 729, age >60 years) [25]. Vitamin B12 deficiency and positive intrinsic factor antibodies were found in 1.9% of the study population and in 4% of the women. An Israeli study suggested a possibly high number of undiagnosed AIG in young patients as well. Notably, 30% of a cohort of asymptomatic PA patients were aged below 40 years [26]. Another important epidemiological aspect is the frequent association of autoimmune gastritis with other autoimmune disorders: the prevalence of AIG in type 1 diabetes mellitus and autoimmune thyroid disease is five- to ten- fold higher than in the general population [27,28]. Pathogenesis Anti-parietal cell antibodies (PCA) and antibodies against intrinsic factor (IFA) were discovered back in the early 1960ies. Almost 30 years later, the Hþ/Kþ-ATPase was identified as the causal antigen [29], which triggers the autoimmune response and the progress of the disease by consecutive destruction of parietal cells and functional loss of the oxyntic gastric mucosa [30]. It is assumed that during epithelial turnover some amount of the Hþ/Kþ-ATPase protein (the main functional component of parietal cells) is accessible for dendritic cells in the gastric mucosa. When presented as an antigen to naïve T cells, a pathogenic clone of CD4þ antigen specific T cells can arise in predisposed individuals [31]. It infiltrates the gastric mucosa providing the stimulus for the eventually observed Th1 driven immune response. By the involvement of B cells on the mucosal level, autoantibody production is initiated and maintained, a process dependent on antigen presentation. The exact mechanisms exerting parietal cell death are not clear. A possible death by Fas ligand induced apoptosis has been suggested based on the observation that gastric epithelial cells express Fas ligand in experimental autoimmune gastritis possibly interacting with Fas ligand on infiltrating T cells [32]. A similar process of tissue loss has been described in other autoimmune diseases [33]. The reduced acid production invokes reactive and ineffective excess of gastrin levels used as a diagnostic criterion of AIG. As an acidic milieu is needed to extract iron from proteins, iron deficiency anaemia caused by hypochlorhydria can be an early sign of disease in 20e37% of AIG patients [34,35]. Another target of the autoimmune response is the intrinsic factor, an essential protein for vitamin B12 (cobalamin) uptake. Vitamin B12 deficiency dominates the clinical picture in PA patients, a condition which probably requires decades from the onset of AIG to develop. The role of H. pylori The classic concept of three types of gastritis (A for autoimmune, B for bacterial and C for chemical) discriminates an infectious from an autoimmune principle cause of inflammation. In a prospective controlled case control trial from 1991 H. pylori infection was reported as a rare finding in the group of patients with pernicious anaemia [36]. However, this concept is challenged by a growing body of literature supporting the idea of H. pylori as an infectious trigger of autoinflammation. Diagnosis of H. pylori by histology or other tests for active infection in severe atrophy can be difficult. However, according to more recent reports, H. pylori can be detected on histology in up to 30% of patients with pernicious anaemia and about a half of them by serology [37]. An even larger proportion of H. pylori seropositive patients (75%) was observed in a cohort of 150 AIG cases [38]. Interestingly, the H. pylori negative patients were 10 years older than the H. pylori positive group and 75% of them had pernicious anaemia vs. 12% in the H. pylori positive group. This trend of H. pylori ‘loss’ with age was demonstrated even more clearly in a prospective study from Israel using UBT. High prevalence of active H. pylori infection (88% positive) was found in very young patients with AIG (age
