Open access peer-reviewed chapter

Current View on Autoimmune Gastritis

Written By

Mila Dimitrova Kovacheva-Slavova, Todor Asenov Angelov, Hristo Yankov Valkov, Hristo Ilianov Iliev and Borislav Georgiev Vladimirov

Submitted: 26 January 2019 Reviewed: 22 May 2019 Published: 14 August 2019

DOI: 10.5772/intechopen.87006

From the Edited Volume

Gastritis - New Approaches and Treatments

Edited by Bruna Maria Roesler

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Abstract

Autoimmune gastritis (AIG) is a chronic inflammatory disease of the gastric corpus and fundus. Although still unclear, genetic and environmental factors, antigenic mimicry or cross-reactivity are proposed pathogenic mechanisms. Parietal cells destruction results in loss of intrinsic factor and increased gastric pH due to hypochlorhydria and G-cell proliferation. Furthermore, atrophy, intestinal, pancreatic and spasmolytic polypeptide-expressing metaplasia are observed. AIG is underdiagnosed, however, proper diagnostic approach, including endoscopic, serological and histopathological assessment, is required. Gastroscopy with corpus and fundus biopsies is a gold standard. A serological combination of anti-parietal cell antibodies, intrinsic factor antibody, anti-Helicobacter pylori IgG, gastrin, pepsinogen I and pepsinogen I/II ratio improves the diagnostic sensitivity and specificity and allows atrophy level prediction. AIG might manifest with multifactorial iron deficiency anemia, vitamin B12 deficiency (pernicious anemia), neurological and neuropsychiatric conditions, small intestinal bacterial overgrowth and gastrointestinal infections. AIG association with other autoimmune diseases is well-established. Gastric cancer and gastric carcinoid are neoplastic transformations of a continuous chronic inflammation. Patients with AIG should be carefully monitored as no specific AIG therapy is available and disease complication could be fatal.

Keywords

  • autoimmune gastritis
  • parietal cells
  • atrophy
  • metaplasia
  • pernicious anemia

1. Introduction

First reported by Thomas Addison (1849) as an atrophic gastritis with autoimmune etiology and co-existing distinctive type of anemia, the autoimmune gastritis (AIG) represents a chronic gastric inflammation with progression to mucosal atrophy, occurring in up to 8% of the general population. Since parietal cells antibodies (PCA) and anti-intrinsic factor antibodies (AIFA) have been first reported by Schwartz (1960) and Irvine (1962), the autoimmune conception of this type of gastritis is recognized. The autoimmune reaction with CD4+ T cells leads to destruction of parietal cells, which are unique cells in the corpus and fundus glands. Therefore, AIG is located in stomach corpus and fundus, which distinguish AIG from other diseases, leading to gastric atrophy (H. pylori infection, drugs etc.). Based on Sydney System, pyloric or intestinal glands replace the oxyntic glands. The consequences of the loss of parietal cells are hypochlorhydria, gastric pH increasement and decreased production of intrinsic factor with concomitant megaloblastic pernicious anemia in the end-stage due to vitamin B12 malabsorption. Patients might suffer from iron deficiency anemia due to hypochlorhydria and inadequate iron uptake. Gastrointestinal symptoms are rarely reported. AIG is often presented with other autoimmune co-morbidities (thyroid autoimmune disease, type 1 diabetes, etc.). Although gastrointestinal symptoms are rarely reported, a malignant transformations, namely intestinal-type gastric cancer and type I gastric carcinoid are observed in respectively 5.3% and ca. 9% of AIG patients [1, 2, 3].

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2. Epidemiology

Nowadays the prevalence of AIG is difficult to obtain, as the disease occurs asymptomatic in early stages, remains undiagnosed for a long period as symptoms arise with atrophy and mucosal dysplasia progression. Further explanations for the underdiagnosed AIG are the inadequate and not from the right location biopsy sampling and the poor identification of the etiology of anemia, which is one of the AIG manifestations. Estimated incidence is ca. 2% in younger and up to 12% in elderly patients. Studies demonstrate increased prevalence of AIG with advancing age and in patients with H. pylori infection (Zhang et al.). Females are more often affected than males (3:1 ratio), although this has not been consistently observed. Cabreta et al. in their randomized study find no age difference. The reported prevalence of pernicious anemia, which is one of the most typical AIG manifestations, is about 0.1% in the general population and about 2% in elderly (older than 60 years). The prevalence of pernicious anemia does not differ between populations (white, African American and non-white Hispanic). A study of Carmel and Johnson elucidate that African American women develop pernicious anemia at significantly younger age. Association with other autoimmune diseases (autoimmune thyroid diseases - Hashimoto’s thyroiditis and Graves’ disease, type 1 diabetes, vitiligo, Addison’s disease etc.) is documented to additionally increase the prevalence to up to 35%. This consequence determines a multiple autoimmune diseases (MAS) type 3B and 4. Pernicious anemia is present in patients with Graves’ disease, Hashimoto’s thyroiditis, type 1 diabetes, autoimmune thyroid disease, Addison’s disease, primary hypoparathyroidism and vitiligo in 2, 4–12%, up to 4, 2–12, 6, 9 and 3–8%, respectively. Recent data direct the attention to the possible association between H. pylori infection and AIG development in respect to molecular mimicry between H. pylori antigens and the gastric H+/K+ adenosine-triphosphate enzyme (ATPase). Few studies evaluate the incidence of AIG (using histology, PCA positive levels) in patients with iron deficiency anemia (IDA) of unknown etiology. The estimated prevalence varies between 15 and 27%. The profile of patients with IDA and positive PCA are younger females with lower hemoglobin and ferritin levels and who suffer more often from restless legs syndrome [1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14].

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3. Pathogenesis

AIG is a chronic inflammation, localized in the gastric corpus and fundus. The inflammatory processes start with lymphocytes and plasma cells infiltration in lamina propria with involvement of deep layers, leading to parietal cells destruction. Because of preservation of relatively normal oxyntic mucosa, a gastric pseudopolyposis appears (also known as “islands in the sea”). The loss of parietal cells results in hypochlorhydria and further in G-cell hyperplasia due to missing negative feedback, leading to higher gastrin secretion in the antrum. A further consequence of the increased gastric pH is the parietal cell pseudohypertrophy. The higher gastrin secretion leads to direct stimulation of enterochromaffin-like (ECL) cells and their proliferation in hyperplastic, dysplastic and neoplastic subtypes that might onset a carcinoid tumor. Pseudopyloric metaplasia (“oxyntic antralization”, spasmolytic polypeptide-expressing metaplasia (SPEM)), intestinal metaplasia (IM) and pancreatic metaplasia can be observed. SPEM can be transformed into IM, which represents the replacement of gastric mucosa with intestinal epithelium (small intestinal and colonic). AIG results in microcytic iron deficiency anemia and megalocytic pernicious anemia due to vitamin B12 deficiency [2, 4].

3.1 Immunogenetic factors

AIG and PCA are observed in 20–30% of the family members of patients with pernicious anemia. However, a genetic predisposition has been proposed. Although the association between pernicious anemia and particular HLA haplo/genotypes is weak, studies evaluate HLA DR4, with DR2 and DR5 haplotypes. A genetic heterogeneity is observed in respect to DR3/DR4 genotype, which is found in patients with pernicious anemia and concomitant endocrinopathy. Using murine models, 4 distinct genetic regions of susceptibility genes for AIG were identified (Gasa1, 2, 3 and 4) on chromosomes 4 and 6 and H2 region. Interestingly, three of these genes are nonmajor histocompatibility complex genes and are located on the same locus with those of type 1 diabetes, which could explain the strong concordance between AIG and type 1 diabetes [2, 15, 16, 17, 18].

3.2 Cell-mediated autoimmunity

Cell-mediated autoimmunity has a key role for the AIG development. The main trigger of autoimmunity are the 100-kd catalytic α-subunit and the 60- to 90-kd glycoprotein β-subunit of the gastric H+/K + -ATPase, which membrane protein is a proton pump. PCA and AIFA are found in both serum and gastric juice. The higher the PCA titer is, the more severe the corpus atrophy is and the lower the parietal cells concentration is. The loss of parietal cells is a consequence of mainly CD4+ CD25− Th1 resting lymphocyte effectors initiated perforin-mediated cytotoxicity (perforin/granzyme B pathway) or Fas–FasL apoptosis. CD4+ CD25− Th1 resting lymphocyte effectors produce IFN-γ and TNF-α. Submucosa, lamina propria and gastric glands are infiltrated by CD4 + CD25− T-cells, together with macrophages and B lymphocytes, leading to loss of parietal (CD4+ T cells react to H+/K+-ATPase α chain and marginally to the β chain), principal and P/D1 ghrelin-producing cells [2, 5, 15, 19, 20, 21].

3.3 Humoral autoimmunity

Two types of antibodies are produced by B cells from activated CD4+ T cells in patients with AIG, namely PCA (antibody to the parietal cells) and AIFA (antibody to the produced by the parietal cells a 60-kDa glycoprotein intrinsic factor). PCA are found in the serum and gastric juice in up to 90% and AIFA in 30–50% of AIG patients. Α catalytic and β subunits of gastric H+/K + -ATPase are bound by PCA. In end-stages of AIG the PCA titer decreases because of parietal cells loss. Researchers have found two types of AIFA from IgG class. Type 1 is present in 70% of patients and acts as a blocking antibody that reacts with the binding site for vitamin B12. Type 2 AIFA is present in 30% of patients and is a precipitating antibody that binds other binding sites from vitamin B12 and impedes binding of intrinsic factor-vitamin B12 to the receptors in the ileal mucosa [5, 22, 23, 24].

3.4 Association with H. pylori

H. pylori, which is well-established etiological factor for atrophic gastritis development, may induce AIG through mechanisms of molecular mimicry at the T-cell level (autoreactive T cells against gastric proton pump), bystander activation and / or epitope spreading. This hypothesis is supported by recent studies as some patients may have AIG with co-existing H. pylori infection (20–50%). H. pylori leads to development of various antibodies, including PCA and anticanalicular antibodies against the H+/K+ ATPase, which are in fact most frequent. Studies show a high homology between the β subunit of H. pylori urease and the subunit β of gastric proton pump, which is a precondition for cross-reactivity against parietal cells and IFN-γ production, resulting in killing or apoptotic suicide. Some patients with PCA and/or AIFA, who underwent H. pylori eradication, demonstrated loss of antigastric antibodies. However, the correlation between AIG and H. pylori still remains controversial. AIG patients with observed gastric atrophy or IM in the course of H. pylori infection do not decrease their risk for gastric cancer development even after H. pylori eradication [2, 5, 25, 26, 27, 28, 29, 30].

3.5 Endocrine factors

AIG is frequently associated with other autoimmune diseases. Emphasized is the link to type 1 diabetes and autoimmune thyroid disease (Hashimoto’s thyroiditis and Graves’ disease). Reported risk factors for patients with AIG and type 1 diabetes are persistent positive islet cell antibody and positive glutamic acid decarboxylase-65 antibody, which is found in the thyroid gland and stomach except in pancreas and brain. Studies demonstrate that type 1 diabetes itself and not hereditary might be a risk factor for AIG development. Positive thyroid peroxidase autoantibody are reported in up to 50%of AIG patients due to possible cross-reaction. As PCA are verified in up to 40% of patients with autoimmune thyroid diseases, screening the patients of this population for AIG should be recommended. Other reported co-existing autoimmune conditions are polyglandular autoimmune syndromes (mainly type 3B), Addison’s disease, vitiligo, perioral cutaneous autoimmune diseases (mainly erosive oral lichen) and myasthenia gravis [2, 4, 7, 31, 32, 33, 34].

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4. Diagnostic approach

4.1 Serological tests

The evaluation of AIG-associated autoantibodies (PCA and AIFA), anti-H. pylori antibodies (anti-HP-IgG) and markers for gastric atrophy (gastrin and pepsinogen levels) is used for serological noninvasive diagnosis of AIG (“serological biopsy”, the so-called GastroPanel test (ELISA test, Biohit, Helsinki, Finland)). AIG-associated autoantibodies are widely used for screening and diagnosis of AIG. They differ according to their sensitivity and specificity as PCA is higher sensitive (80% compared to 50% sensitivity for AIFA) but less specific for pernicious anemia detection. Studies are controversial whether PCA levels correlate with AIG severity or not. Due to low gastric acid output and G-cells stimulation and elevated gastrin secretion in patients with atrophic autoimmune gastritis, it is crucial to evaluate gastrin levels (usually gastrin 17) as gastrin correlates strong with gastric atrophy based on histopathology. Other useful atrophy markers are the produced by the chief cells of oxyntic mucosa of stomach corpus and fundus pepsinogen I and the secreted by the chief cells and mucous neck cells of the whole stomach mucosa pepsinogen II. In patients with atrophic autoimmune gastritis are demonstrated significant decrease of pepsinogen I (low pepsinogen II levels are not commonly observed) and low Pepsinogen I/Pepsinogen II ratio (<3). In respect to diagnosis of pernicious anemia, a panel of vitamin B12, homocysteine and methylmalonic acid measurement is required. In those patients may be observed thrombocytopenia, increased levels of LDH and bilirubin, and rarely schistocytes in the peripheral smear. Iron deficiency anemia, which is often present in patients with AIG, should be identified by levels of hemoglobin, mean corpuscular volume (MCV), serum iron, ferritin, total iron-binding capacity (TIBS) and serum transferrin receptor (TfR). In patients with suspected carcinoid tumor transformation the measurement of chromogranin A, which is secreted by the ECL cells, can be useful, although it shows low specificity (23%) and false-positive results in patients with inflammatory bowel disease, renal insufficiency and other conditions [4, 23, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45].

4.2 Endoscopy

Of a great importance for AIG diagnosis is the performance of gastroscopy with separately collected biopsies - two from the corpus, two from the antrum and one from the incisura angularis (updated Sydney System recommendations). New endoscopic techniques (magnifying endoscopy, autofluorescence and narrow-band imaging) improve the diagnostic accuracy as they provide information for minimal gastric atrophic changes. A number of endoscopic appearances can be present: polyps (hyperplastic or adenomatous), pseudopolyps, flattened rugal folds, visible submucosal vessels, loss of subepithelial capillary network resembling honeycomb, collecting venules in regular shape and appearance and vascular pattern and swelling of areae gastricae. A combination of them improves the sensitivity and specificity of the procedure. In early AIG stages with minimal or no endoscopical and histological changes, gastric acid production is increased due to hypo- or achlorhydria. Thus, gastric acid measurement (simple intragastric pH measurement or volume of acid secretion) might be useful for early AIG diagnosis [1, 4, 46, 47, 48, 49, 50, 51, 52].

4.3 Histopathology

Histopathological assessment of biopsies form gastric corpus and fundus remains gold standard for AIG diagnosis even in early stages of the disease. The correct site of biopsy is of great importance for the proper AIG diagnosis, which could be tested by immunohistochemical staining of G cells (gastrin). Histological characteristics change with disease progression. Typical but non-specific for AIG are lymphoplasmacytic infiltration in lamina propria, which is mainly multifocal with accentuation in the deeper; glandular portion in early stage and diffuse lymphoplasmacytic infiltration of the lamina propria in end-stage; focal to profound atrophy of oxyntic mucosa with disease progression. End-stage AIG is further characterized by distinct reduction or total loss of oxyntic glands with pseudohypertrophy of parietal cells due to fragmentary oxyntic glands destruction in end-stage of AIG; SPEM presence; pancreatic or intestinal metaplasia; ECL cells hyperplasia with additional samples immunohistochemical testing with chromogranin A and synaptophysin [1, 4, 11, 53, 54, 55, 56, 57].

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5. Clinical presentation

Symptoms vary during the course of AIG as patients at early stages are most often asymptomatic, which makes the diagnostic approach only on clinical presentation challenging. With disease progression a wide spectrum of gastrointestinal, hematological and neurological signs and symptoms arises [1, 3, 4].

5.1 Gastrointestinal manifestations

Gastrointestinal symptoms are not the leading presentation of patients with AIG. Carabotti et al. report in their recent study frequency of one or more gastrointestinal symptoms in 56.7% of AIG patients. Female gender, younger age (<55 years) and non-smoking are independent risk factors for gastrointestinal symptoms manifestation. More than half of the patients had upper gastrointestinal complains as most frequent one was vague dyspepsia in respect to post-prandial fullness and/or early satiation. Furthermore, as achlorhydria is a major pathogenetic consequence of AIG, patients may suffer from bloating, delayed gastric emptying, small intestinal bacterial overgrowth, and gastrointestinal infections such as Clostridium difficile. Pain and peptic or duodenic ulcers are not reported. Atrophic glossitis due to vitamin B12 deficiency is an early stage AIG manifestation. Interestingly, heartburn (24%) and acid regurgitation (12%) are presented in a study of Miceli et al., which could develop from nonacidic refluxes. Data exist to support the observation that gastroesophageal reflux disease and its complications like Barrett’s esophagus may develop even in AIG patients [1, 2, 3, 4, 6, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69].

5.2 Hematological manifestations

Typical hematological manifestations of AIG are iron deficiency anemia (IDA) in the early stages and pernicious anemia in the end-stage of the disease.

IDA is the leading hematological manifestation, occurring in 50% of AIG patients as reported by Hershko et al. Several epidemiological studies demonstrate IDA in younger patients prior to pernicious anemia development. Iron metabolism, which is regulated by an uptake, is impaired in AIG mainly due to the presence of achlorhydria. Different mechanisms of IDA with AIG etiology are observed. For the necessary reduction of the ferric form of inorganic iron (the iron type in food) to ferrous as well as for releasing the ferric/ferrous iron from its protein-complex in order to precede to an iron uptake, gastric acid is needed. Another cause for IDA in AIG is the decreased iron absorption due to lack of ascorbic acid, destroyed in AIG. IDA symptoms vary as the commonly reported are fatigue, brittle nails, hair loss, restless legs syndrome, immune dysfunction, ineffective wound healing, while due to anemia itself tachycardia, shortness of breath, dizziness, lightheadedness and cognitive and physical dysfunction may develop. Pregnant women are at risk of early birth and underweight newborns. Of great importance is that IDA with AIG etiology is refractory to iron therapy [1, 4, 6, 13, 20, 58, 59, 60, 70, 71, 72, 73, 74, 75].

Pernicious anemia is usually caused by vitamin B12 deficiency due to loss of intrinsic factor and insufficient releasing of vitamin B12 from the food due to low levels of gastric acid. Vitamin B12 is a key regulator of DNA synthesis. Mostly affected are patients at advanced age due to age-related reduced absorption and minimal turnover with further large stores of vitamin B12. The clinical manifestations vary widely; therefore pernicious anemia is so-called “great pretender”. Reported symptoms of pernicious anemia are fatigue, lightheadedness, palpitations, angina pectoris and congestive heart failure and mental disturbances. Patients are at increased risk of endovascular dysfunction and myocardial infarction and pulmonary embolism due to hyperhomocysteinemia and the related thrombosis. Therefore, untreated pernicious anemia may lead to lethal exit [1, 4, 6, 20, 58, 59, 60, 61, 76, 77, 78, 79, 80].

5.3 Neurological manifestations

Neuronal death due to demyelination and axonal damage leads to the typical neurological manifestation of vitamin B12, which might be present even in patients with no hematological changes. The loss of vibratory and position sensations together with distal paresthesias develop from damages in the lateral and posterior columns of the cervical and upper thoracic segments of the spinal cord. This syndrome is called a subacute combined degeneration and is very specific for pernicious anemia. Other vitamin B12 deficiency presentations are peripheral neuropathy (paresthesia and numbness of the lower extremities), optic neuropathy and neuropsychiatric conditions (dementia, mania, depression, psychosis, obsessive–compulsive disorder, etc.). Proper diagnosis and early vitamin B12 substitution are mandatory to delay progression and for better outcome [1, 4, 81, 82, 83, 84, 85, 86, 87, 88, 89].

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6. Neoplastic transformations

Patients with AIG are at increased risk of gastric cancer development. The estimated prevalence is about 5.3% as recent studies suggest even higher incidence - 14.2 per 1000 person-years with patients with AIG having risk of gastric cancer development 3 to 6-fold higher than the general population. Recent meta-analysis demonstrates 0.27% per person-year with an overall relative risk of 6.8 (95% CI 2.6–18.1) for gastric cancer development. Elderly people, chronic inflammation due to H. pylori infection, achlorhydria, presence of dysplasia and intestinal metaplasia are significantly risk factors for gastric tumorogenesis [1, 57, 90].

6.1 Gastric carcinoid

Gastric carcinoids are verified in 4–9% of patients with AIG and pernicious anemia. 50–85% of all gastric carcinoids develop in patients with AIG. Three types of gastric carcinoids are established, of which type I is found in patients with AIG, type II is associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia I and type III carcinoid is the most aggressive type. Achlorhydria is a key factor for the development of gastric carcinoids in AIG patients. As described, achlorhydria leads to loss of negative feedback and G-cells stimulation in antrum, followed by hypergastrinemia (typical for type I and II carcinoids). The high gastrin levels demonstrate trophic effects on ECL cells hyperplasia, which further may result in dysplasia and transformation into gastric carcinoid. Gastric carcinoids are quite benign lesions with low metastatic potential (less than 10%). Patients with gastric carcinoids are usually asymptomatic. However, they may complain of dyspepsia, abdominal pain, flushing, diarrhea and symptoms of anemia. Classical carcinoid syndrome is seen very rare. Carcinoids are usually diagnosed incidentally during endoscopy in patients with anemia. Gastroscopy with biopsy sampling with further immunostaining for chromogranin A and/or neuron-specific enolase is the best diagnostic approach. The presence of polyps in the stomach body in patients with AIG is significantly associated with type I carcinoid. As long as polyps might be underdiagnosed during endoscopy, serum chromogranin A levels are more accurate for carcinoids diagnosis. Chromogranin A levels correlate strong with gastrin levels and ECL cell density in the corpus and fundus mucosa, representing high specificity (59%) and sensitivity (100%). According to the algorithm of Gilligan et al. based on size and number, gastric carcinoids in AIG patients, which size is <1 cm and the number is 3–5, should be removed endoscopically, and those >1 cm and/or > 5 should be followed by antrectomy. Surveillance at every 6-month is proposed. Another therapeutic option is the administration of octreotide, which leads to lower gastrin levels, improved ECL status and even spontaneous regression (Ferraro et al.) [1, 2, 4, 45, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110].

6.2 Gastric cancer

The chronic inflammation, which is an integral part of the pathogenesis of AIG, increases significantly the risk of malignant transformations. Achlorhydria, high dietary salt intake and bacterial overgrowth are proposed risk factors. Furthermore, the concomitant H. pylori infection additionally increases the risk of precancerous lesions. Current studies suggest that cancer stem cells, which might be exposed on mutations, have an important role in cancerogenesis. This concept is assumed as stem cells are well-known for their longevity and inherent capacity for self-renewal. As a consequence of chronic inflammation, stem cells level and proliferation potential increase, which favors their intestinal metaplasia (possible phenotype of stem cells abnormality) and dysplasia. In 1988, Correa and Piazuelo proposed the so-called “Correa hypothesis/cascade” for gastric cancer development in patients with H. pylori infection: unknown genetic and epigenetic factors lead stepwise to 1. chronic inflammation; 2. atrophy gastritis; 3. intestinal metaplasia; 4. low to high grade dysplasia, which finally results in gastric cancer in some patients. H. pylori factors, associated with higher malignancy potential are CagA-positive strains, VacA gene and s1 m1 [1, 4, 5, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120].

An attention is paid at the role of tumor-associated autoantigens in immunogenicity and immunodiagnosis, which may detect cancer at early stage. Usually these autoantigens are cellular proteins, which can be ectopically expressed or a result from genetic mutations and rearrangements. Additional mutations in the tumor-associated autoantigens lead to new antigenic epitopes and finally increased immunogenicity. According to a current concept of the immunological response of cancer tissue, tumor-associated antigens lead to autoantibodies production. Autoantibodies with potential clinical usefulness are anti-carcinoembryonic antigen (CEA), anti-p53, anti-survivin, anti-mucin, and anti-livin autoantibodies. The autoantibodies are missing in healthy people and non-cancer diseases. Thus, autoantibodies against tumor antigens can serve as biomarkers and may have the potential to verify an early stage cancer, which may significantly improve patients diagnosis and outcome as the majority of patients with gastric cancer are diagnosed late, when are symptomatic and the management is rather palliative. Studies show significant lower levels of biomarkers after radical tumor resection, which suggest their prominent role in patient monitoring [5, 121, 122, 123, 124, 125].

The estimated frequency of detection of anti-carcinoembryonic antigen (CEA) anti-survivin, anti-mucin, and anti-livin autoantibodies is 46–56, 40, 75 and 50%, respectively, as anti-CEA is found in 10% of healthy people. They are present in the early stage of gastric cancer and demonstrate a good prognostic value for survival and postoperative monitoring, especially in patients without anti-p53 antibodies [123, 126, 127, 128, 129, 130, 131].

p53 is a key factor in carcinogenesis. In 46% of patients with p53-positive gastric cancer are found increased anti-p53 antibodies levels. Anti-p53 antibodies, which are first reported in patients with breast cancer, correlate significantly with the tumor suppressor gene p53 protein expression, demonstrating about 96% specificity for neoplastic detection. In contrast to anti-carcinoembryonic antigen (CEA) anti-survivin, anti-mucin, and anti-livin autoantibodies, anti-p53 antibodies are not appropriate markers for early diagnosis and prognosis as they are detected in advanced gastric tumors with regional lymph node involvement [123, 126, 132, 133, 134].

Extracellular protein kinase A (ECPKA) is a cAMP-dependent intracellular enzyme. Anti- ECPKA antibodies are significantly increased in patients with gastric cancer and other malignancies. They have the potential to be future universal screening method for tumors of different origin as their sensitivity and specificity are very high - 90 and 87%, respectively [135].

The presence of substantial number heterogeneous autoantibodies varies widely and demonstrates high specificity but low diagnostic sensitivity. To improve their sensitivity in order to enable their application in clinical practice for screening and diagnosis of gastric cancer; it is reasonable to promote a combination of serological AIG- and tumor biomarkers, microRNAs and/or glycosylation signatures. Using a combination of 5 biomarkers (MAGEA4, CTAG1, TP53, ERBB2_C, and SDCCAG8), Werner et al. demonstrated 32% sensitivity and 87% specificity for diagnosis of early stage gastric adenocarcinoma. In a study of Zhou et al. a combination of 7 markers, namely p53, Koc, p62, c-myc, IMP1, survivin and p16, identified gastric cancer with sensitivity and specificity of 64% and 87%, respectively. Wang et al. verified a panel of 8 biomarkers (IMP1, p62, Koc, p53, c-myc, cyclin B1, survivin and p16), able to detect gastric cancer with 56.1% sensitivity and 86.2% specificity [136, 137, 138, 139, 140, 141, 142, 143, 144].

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7. Treatment

Up-to-date there is no consensus on whom to screen for AIG and how often. The treatment management of AIG with avoiding further complications requires according to the present symptoms, serological results and imaging data proper follow-up. A proper monitoring with testing once a year complete blood count, gastrin, iron and vitamin B12 levels seems to be beneficial. Therapy depends on the stage of AIG, H. pylori infection, current nutrient deficiencies, concomitant autoimmune conditions and (pre)malignant transformation. As described above, H. pylori infection may play a crucial role in AIG pathogenesis. However, screening for H. pylori (serological anti-HP-Ig G and Ig M, fecal HP-antigen, breath tests, histological and cultural methods) in patients with AIG, gastric atrophy, intestinal metaplasia/dysplasia, and hypo- or achlorhydria should be performed. If positive for H. pylori, patients need subsequent treatment and eradication. Studies support H. pylori treatment as H. pylori eradication was associated with decreased levels of PCA and AIFA and AIG early stages healing. Oral supplementation with vitamin B12, iron and folic acid is recommended in early stages of AIG. With neurological symptoms occurring, parenteral vitamin B12 should be applied. As long as various autoimmune diseases are recognized as AIG co-morbidities, attention should be paid at their screening and following treatment. Researchers recommend the routine screening for type 1 diabetes and autoimmune thyroid diseases. On the other hand, in patients, who are diagnosed with type 1 diabetic (positive glutamate decarboxylase-65 antibodies) and autoimmune thyroiditis (positive thyroid peroxidase antibodies), PCA should be investigated at the disease’s onset and thereafter yearly for 3 years and later on a longer intervals if there is no AIG clinical signs. Screening for AIG in those patients’ populations might avoid the development of IDA and pernicious anemia with their above mentioned serious complications. As long as gastric carcinoid is curative, proper diagnosis and radical treatment are essential. According to size, number and location of gastric cancer /carcinoid, polypectomy, antrectomy (gastrin-producing part), surgical eradication of a gastric tumor, with resection of adjacent lymph nodes or medicamentous treatment with further surveillance is performed. Somatostatin analogs are used as they can reduce gastrin and chromogranin A levels in patients with neuroendocrine tumor (carcinoid). Promising therapeutic option is the gastrin receptor antagonist Netazepide, leading to decreased chromogranin A levels together with cancer size and number. A new technique for carcinoid tumors treatment is the peptide receptor radiotherapy, which would be worth to be tested in AIG patients. Whether to perform surveillance program with regular endoscopic and histological examination in patients with AIG or not remains controversial and guidelines according to AIG surveillance are missing. If mild to moderate dysplasia or ECL cell hyperplasia are observed, an endoscopic surveillance every 5 years is proposed. In contrast to the rare and with far better prognosis carcinoids, gastric cancer development might be fatal. According to the American Society for Gastrointestinal Endoscopy recommendations (2006) for monitoring of patients with H. pylori atrophic gastritis, depending on the primary endoscopic finding the follow-up should be in intervals of 3–5 years (patients with simple, linear/micronodular hyperplasia); every 3 years (patients with extensive atrophy/IM) or every year (patients with adenomas/low-grade dysplasia) [1, 2, 11, 90, 103, 109, 113, 145, 146, 147, 148, 149, 150, 151, 152, 153].

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8. Discussion

Although H. pylori is a leading cause for gastritis, AIG frequency is increasing in elderly people and in those with other autoimmune pathology. As AIG is commonly underdiagnosed, AIG should be considered in the differential diagnosis of patients with anemia, dyspepsia and especially in those with concomitant autoimmune thyroid disease and type 1 diabetes and with relatives with gastric neoplasia. H. pylori presence does not exclude AIG in the pathogenesis of an underlying gastritis. Screening of patients with a panel of serological markers pepsinogen I and II, gastrin, and/or H. pylori antibodies as well as the antibodies PCA and AIFA directs to the need of gastroscopy. However, gastroscopy with separately collected biopsies and histopathological assessment of specimens form gastric corpus and fundus remain the gold standard for AIG diagnosis. Asymptomatic in the early stages of the disease, AIG is not recognized in guidelines as an etiological factor for iron deficiency. However, AIG is often leading to iron deficiency anemia, which requires a different treatment strategy. Untreated pernicious anemia, which is a later manifestation of AIG, could cause both neurological complications and letal cardiovascular events. AIG is a precancerosis for the development of gastric cancer and neuroendocrine tumors. An effort is required to identify a biomarker panel with high sensitivity for early-stage gastric malignancy diagnosis. The treatment of AIG still remains challenging due to asymptomatic early stage and complex pathogenesis of the disease.

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9. Conclusion

Proper and early diagnostic approach and prevention, followed by patients’ carefully lifelong monitoring at yearly intervals is mandatory to improve the prognosis and outcome of AIG. New therapeutic strategies are needed to delay disease progression and influence the gastric atrophy, making it a reversible entity. Guidelines of AIG surveillance are awaited.

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Acknowledgments

The publication of this work was supported by Vladimir Jeglov and Valeri Andreev.

Conflict of interest

There is no conflict.

References

  1. 1. Kulnigg-Dabsch S. Autoimmune gastritis. Autoimmungastritis. Wiener Medizinische Wochenschrift. 2016;166(13-14):424-430. DOI: 10.1007/s10354-016-0515-5
  2. 2. De Block CEM, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: A clinically oriented review. The Journal of Clinical Endocrinology & Metabolism. 2008;93(2):363-371. DOI: 10.1210/jc.2007-2134
  3. 3. Carabotti M, Lahner E, Esposito G, Sacchi MC, Severi C, Annibale B. Upper gastrointestinal symptoms in autoimmune gastritis: A cross-sectional study. Medicine. 2017;96(1):e5784. DOI: 10.1097/MD.0000000000005784
  4. 4. Minalyan A, Benhammou JN, Artashesyan A, Lewis MS, Pisegna JR. Autoimmune atrophic gastritis: Current perspectives. Clinical and Experimental Gastroenterology. 2017;10:19-27. DOI: 10.2147/CEG.S109123
  5. 5. Bizzaro N, Antico A, Villalta D. Autoimmunity and gastric cancer. International Journal of Molecular Sciences. 2018;19(2):377. DOI: 10.3390/ijms19020377
  6. 6. Hershko C et al. Variable hematologic presentation of autoimmune gastritis: Age-related progression from iron deficiency to cobalamin depletion. Blood. 2006;107(4):1673-1679
  7. 7. Zhang Y et al. Gastric parietal cell antibodies, helicobacter pylori infection, and chronic atrophic gastritis: Evidence from a large population-based study in Germany. Cancer Epidemiology, Biomarkers & Prevention. 2013;22(5):821-826
  8. 8. Kulnigg-Dabsch S et al. Autoimmune gastritis is common in patients with iron deficiency – Non-invasive evaluation of iron deficiency aside guideline recommendations. Gastroenterology. 2015;148(4):1
  9. 9. Carmel R, Johnson CS. Racial patterns in pernicious anemia. Early age at onset and increased frequency of intrinsic-factor antibody in black women. The New England Journal of Medicine. 1978;298(12):647-650
  10. 10. Lam-Tse WK, Batstra MR, Koeleman BP, et al. The association between autoimmune thyroiditis, autoimmune gastritis and type 1 diabetes. Pediatric Endocrinology Reviews. 2003;1(1):22-37
  11. 11. Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritis – Pathogenesis, pathology and management. Nature Reviews Gastroenterology & Hepatology. 2013;10(9):529-541
  12. 12. Dickey W et al. Gastric as well as duodenal biopsies may be useful in the investigation of iron deficiency anaemia. Scandinavian Journal of Gastroenterology. 1997;32(5):469-472
  13. 13. Annibale B et al. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. The American Journal of Medicine. 2001;111(6):439-445
  14. 14. Kaye PV et al. The clinical utility and diagnostic yield of routine gastric biopsies in the investigation of iron deficiency anemia: A case-control study. The American Journal of Gastroenterology. 2008;103(11):2883-2889
  15. 15. De Block CE, De Leeuw IH, Van Gaal LF. High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 (insulin-dependent) diabetic patients. The Belgian diabetes registry. The Journal of Clinical Endocrinology and Metabolism. 1999;84:4062-4067
  16. 16. Baxter AG, Jordan MA, Silveira PA, Wilson WE, van Driel IR. Genetic control of susceptibility to autoimmune gastritis. International Reviews of Immunology. 2005;24:55-62
  17. 17. van Driel IR, Baxter AG, Laurie KL, Zwar TD, La Gruta NL, Judd LM, et al. Immunopathogenesis, loss of T cell tolerance and genetics of autoimmune gastritis. Autoimmunity Reviews. 2002;1:290-297
  18. 18. van Driel IR, Read S, Zwar T, Gleeson PA. Shaping the T cell repertoire to a bona fide autoantigen: Lessons from autoimmune gastritis. Current Opinion in Immunology. 2005;17:570-576
  19. 19. D’Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, de Pont JJ, et al. H(+),K(+)- ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology. 2001;120:377-386. DOI: 10.1053/gast.2001.21187
  20. 20. Toh BH, Van Driel IR, Gleeson PA. Mechanisms of disease: Pernicious anemia. The New England Journal of Medicine. 1997;337:1441-1448. DOI: 10.1056/NEJM199711133372007
  21. 21. Callaghan JM, Khan MA, Alderuccio F, van Driel IR, Gleeson PA, Toh BH. Alpha and beta subunits of the gastric H+/K+-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis. Autoimmunity. 1993;16:289-295. DOI: 10.3109/08916939309014648
  22. 22. Toh BH, Alderuccio F. Pernicious anaemia. Autoimmunity. 2004;37:357-361. DOI: 10.1080/08916930410001705439
  23. 23. Antico A, Tampoia M, Villalta D, Tonutti E, Tozzoli R, Bizzaro N. Clinical usefulness of the serological gastric biopsy for the diagnosis of chronic autoimmune gastritis. Clinical & Developmental Immunology. 2012;2012:520970. DOI: 10.1155/2012/520970
  24. 24. Tozzoli R, Kodermaz G, Perosa AR, Tampoia M, Zucano A, Antico A, et al. Autoantibodies to parietal cells as predictors of atrophic body gastritis: A five-year prospective study in patients with autoimmune thyroid diseases. Autoimmunity Reviews. 2010;10:80-83. DOI: 10.1016/j.autrev.2010.08.006
  25. 25. Weck MN, Brenner H. Association of helicobacter pylori infection with chronic atrophic gastritis: Meta-analyses according to type of disease definition. International Journal of Cancer. 2008;123:874-881. DOI: 10.1002/ijc.23539
  26. 26. Claeys D, Faller G, Appelmelk B, Negrini R, Kirchner T. The gastric H+/K+ ATPase is a major autoantigen in chronic helicobacter pylori gastritis with body mucosa atrophy. Gastroenterology. 1998;115:340-347. DOI: 10.1016/S0016-5085(98)70200-8
  27. 27. Amedei A, Bergman MP, Appelmelk B, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between helicobacter pylori antigens and H+K+-adenotriphosphatase in human gastric autoimmunity. The Journal of Experimental Medicine. 2003;198:1147-1156. DOI: 10.1084/jem.20030530
  28. 28. D’Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del Prete GF. Gastric autoimmunity: The role of helicobacter pylori and molecular mimicry. Trends in Molecular Medicine. 2004;10:316-323. DOI: 10.1016/j.molmed.2004.06.001
  29. 29. Veijola LI, Oksanen AM, Sipponen PI, Rautelin HIK. Association of autoimmune type atrophic corpus gastritis with helicobacter pylori infection. World Journal of Gastroenterology. 2010;16(1):83-88
  30. 30. Faller G, Steininger H, Eck M, Hensen J, Hann EG, Kirchner T. Anti-gastric autoantibodies in helicobacter pylori gastritis: Prevalence, in-situ binding sites and clues for clinical relevance. Virchows Archiv. 1996;427(5):483-486
  31. 31. Massironi S, Zilli A, Elvevi A, Invernizzi P. The changing face of chronic autoimmune atrophic gastritis: an updated comprehensive perspective. Autoimmunity Reviews. 2019;18(3):215-222. DOI: 10.1016/j.autrev.2018.08.011
  32. 32. Venerito M, Radünz M, Reschke K, Reinhold D, Frauenschläger K, Jechorek D, et al. Autoimmune gastritis in autoimmune thyroid disease. Alimentary Pharmacology & Therapeutics. 2015;41:686-693. DOI: 10.1111/apt.13097
  33. 33. Checchi S, Montanaro A, Ciuoli C, et al. Prevalence of parietal cell antibodies in a large cohort of patients with autoimmune thyroiditis. Thyroid. 2010;20:1385-1389
  34. 34. Castoro C, Le Moli R, Arpi ML, et al. Association of autoimmune thyroid diseases, chronic atrophic gastritis and gastric carcinoid: Experience from a single institution. Journal of Endocrinological Investigation. 2016;39(7):779-784
  35. 35. Rusak E, Chobot A, Krzywicka A, Wenzlau J. Anti-parietal cell antibodies – diagnostic significance. Advances in Medical Sciences. 2016;61(2):175-179
  36. 36. Khan S, Del-Duca C, Fenton E, et al. Limited value of testing for intrinsic factor antibodies with negative gastric parietal cell antibodies in pernicious anaemia. Journal of Clinical Pathology. 2009;62(5):439-441
  37. 37. Phan J, Benhammou JN, Pisegna JR. Gastric hypersecretory states: Investigation and management. Current Treatment Options in Gastroenterology. 2015;13(4):386-397
  38. 38. Carmel R. Pepsinogens and other serum markers in pernicious anemia. American Journal of Clinical Pathology. 1988;90(4):442-445
  39. 39. Noah D, Assoumou M, Bagnaka S, Ngaba G, Alonge I, Paloheimo L, et al. Assessing GastroPanel serum markers as a non-invasive method for the diagnosis of atrophic gastritis and helicobacter pylori infection. Open Journal of Gastroenterology. 2012;2:113-118. DOI: 10.4236/ojgas.2012.23024
  40. 40. Storskrubb T, Aro P, Ronkainen J. Serum biomarkers provide an accurate method for diagnosis of atrophic gastritis in a general population: The Kalixanda study. Scandinavian Journal of Gastroenterology. 2008;43:448-1455
  41. 41. Syrjänen K. Serological biomarker panel (GastroPanel®): A test for non-invasive diagnosis of dyspeptic symptoms and for comprehensive detection of helicobacter pylori infection. Biomark J. 2017;3:1
  42. 42. Väänänen H, Vauhkonen M, Helske T. Non-endoscopic diagnosis of atrophic gastritis with a blood test. Correlation between gastric histology and serum levels of gastrin-17 and pepsinogen I: A multicenter study. European Journal of Gastroenterology & Hepatology. 2003;15:885-891
  43. 43. Syrjänen K. A panel of serum biomarkers (GastroPanel®) in non-invasive diagnosis of atrophic gastritis. Systematic review and meta-analysis. Anticancer Research. 2016;36:5133-5144
  44. 44. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: Unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood. 2005;105(3):978-985
  45. 45. Wu PB, Deng YZ, Shu YX, Tan SY, Li M, Fang G. Increased plasma CgA levels associated with nonalcoholic fatty liver disease. The Turkish Journal of Gastroenterology. 2015;26(5):404-407
  46. 46. Nomura S, Ida K, Terao S, et al. Endoscopic diagnosis of gastric mucosal atrophy: Multicenter prospective study. Digestive Endoscopy. 2014;26(6):709-719
  47. 47. Park YH, Kim N. Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer. Journal of Cancer Prevention. 2015;20(1):25-40
  48. 48. Anagnostopoulos GK, Ragunath K, Shonde A, Hawkey CJ, Yao K. Diagnosis of autoimmune gastritis by high resolution magnification endoscopy. World Journal of Gastroenterology. 2006;12(28):4586-4587
  49. 49. Dai Y-C, Tang Z-P, Zhang Y-L. How to assess the severity of atrophic gastritis. World Journal of Gastroenterology. 2011;17(13):1690-1693
  50. 50. Toh BH. Diagnosis and classification of autoimmune gastritis. Autoimmunity Reviews. 2014;13(4-5):459-462
  51. 51. Okano A, Takakuwa H, Matsubayashi Y. Parietal-cell hyperplasia mimicking sporadic fundic gland polyps in the atrophic mucosa of autoimmune gastritis. Gastrointestinal Endoscopy. 2007;66(2):394-395
  52. 52. Ghosh T et al. Review article: Methods of measuring gastric acid secretion. Alimentary Pharmacology & Therapeutics. 2011;33(7):768-781
  53. 53. Park JY, Lam-Himlin D, Vemulapalli R. Review of autoimmune metaplastic atrophic gastritis. Gastrointestinal Endoscopy. 2013;77(2):284-292
  54. 54. Pittman ME et al. Autoimmune metaplastic atrophic gastritis: Recognizing precursor lesions for appropriate patient evaluation. The American Journal of Surgical Pathology. 2015;39(12):1611-1620
  55. 55. Wong HH, Chu P. Immunohistochemical features of the gastrointestinal tract tumors. Journal of Gastrointestinal Oncology. 2012;3(3):262-284
  56. 56. Sepulveda AR, Patil M. Practical approach to the pathologic diagnosis of gastritis. Archives of Pathology & Laboratory Medicine. 2008;132(10):1586-1593
  57. 57. Joo YE, Park HK, Myung DS, Baik GH, Shin JE, Seo GS, et al. Prevalence and risk factors of atrophic gastritis and intestinal metaplasia: A nationwide multicenter prospective study in Korea. Gut and Liver. 2013;7(3):303-310. DOI: 10.5009/gnl.2013.7.3.303
  58. 58. Lahner E, Carabotti M, Annibale B. Atrophic body gastritis: Clinical presentation, diagnosis, and outcome. EMJ Gastroenterology. 2017;6(1):75-82
  59. 59. Miceli E, Lenti MV, Padula D, Luinetti O, Vattiato C, Monti CM, et al. Common features of patients with autoimmune atrophic gastritis. Clinical Gastroenterology and Hepatology. 2012;10(7):812-814. DOI: 10.1016/j.cgh.2012.02.018
  60. 60. Hershko C, Patz J, Ronson A. The anemia of achylia gastrica revisited. Blood Cells, Molecules & Diseases. 2007;39(2):178-183
  61. 61. Lahner E, Annibale B. Pernicious anemia: New insights from a gastroenterological point of view. World Journal of Gastroenterology. 2009;15(41):5121-5128
  62. 62. Zhu JC, Wang YF, Sheng J, Chen FX, Tang GY. Atrophic glossitis is attributed to cobalamin deficiency. Shanghai J Stomatol. 2013;22(1):58-62
  63. 63. Soykan I, Yakut M, Keskin O, et al. Clinical profiles, endoscopic and laboratory features and associated factors in patients with autoimmune gastritis. Digestion. 2012;86:20-26
  64. 64. Tenca A, Massironi S, Pugliese D, et al. Gastro-esophageal reflux and antisecretory drugs use among patients with chronic autoimmune atrophic gastritis: A study with pH-impedance monitoring. Neurogastroenterology and Motility. 2016;28:274-280
  65. 65. Vakil N, van Zanten SV, Kahrilas P, et al. Global consensus group the Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. The American Journal of Gastroenterology. 2006;101:1900-1920
  66. 66. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;130:1466-1479
  67. 67. Carabotti M, Lahner E, Severi C, et al. A case of Barrett’s oesophagus in pernicious anaemia: Acid is not the only culprit! Therapeutic Advances in Gastroenterology. 2016;9:419-421
  68. 68. Kalkan Ç, Soykan I, Soydal Ç, et al. Assessment of gastric emptying in patients with autoimmune gastritis. Digestive Diseases and Sciences. 2016;61:1597-1602
  69. 69. Iwai W, Abe Y, Iijima K, et al. Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. Journal of Gastroenterology. 2013;48:214-221
  70. 70. Bezwoda W et al. The importance of gastric hydrochloric acid in the absorption of nonheme food iron. The Journal of Laboratory and Clinical Medicine. 1978;92(1):108-116
  71. 71. Cook JD, Brown GM, Valberg LS. The effect of Achylia Gastrica on iron absorption. The Journal of Clinical Investigation. 1964;43:1185-1191
  72. 72. Aditi A, Graham DY. Vitamin C, gastritis, and gastric disease: A historical review and update. Digestive Diseases and Sciences. 2012;57(10):2504-2515
  73. 73. Hershko C, Hoffbrand A, Keret D, et al. Role of autoimmune gastritis, helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica. 2005;90(5):585-595
  74. 74. Gonçalves C, Oliveira ME, Palha AM, Ferrão A, Morais A, Lopes AI. Autoimmune gastritis presenting as iron deficiency anemia in childhood. World Journal of Gastroenterology. 2014;20(42):15780-15786
  75. 75. Annibale B, Capurso G, Delle Fave G. The stomach and iron deficiency anaemia: A forgotten link. Digestive and Liver Disease. 2003;35:288-295
  76. 76. Stabler SP. Clinical practice. Vitamin B12 deficiency. The New England Journal of Medicine. 2013;368(2):149-160
  77. 77. Asimacopoulos PJ, Groves MD, Fischer DK, et al. Pernicious anemia manifesting as angina pectoris. Southern Medical Journal. 1994;87(6):671-672
  78. 78. Tadakamalla AK, Talluri SK, Besur S. Pseudo-thrombotic thrombocytopenic purpura: A rare presentation of pernicious anemia. North American Journal of Medical Sciences. 2011;3(10):472-474
  79. 79. Shamkani WA, Jafar NS, Narayanan SR, Rajappan AK. Acute myocardial infarction in a young lady due to vitamin B12 deficiency induced hyperhomocysteinemia. Heart Views. 2015;16(1):25-29
  80. 80. Whittingham S, Mackay IR. Pernicious anemia and gastric atrophy. In: Rose NR, Mackay IR, editors. The Autoimmune Diseases. New York: Academic Press; 1985. pp. 243-266
  81. 81. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annual Review of Nutrition. 1992;12:59-79
  82. 82. Francis G, Hohol K, Jawad Z, Ayer A, Toth C. Methylmalonic acid accumulation and the development of peripheral neuropathy (IN1-1.010). Neurology. 2012;78(1 suppl):IN1-IN1
  83. 83. Ralapanawa DM, Jayawickreme KP, Ekanayake EM, Jayalath WA. B(12) deficiency with neurological manifestations in the absence of anaemia. BMC Research Notes. 2015;8:458
  84. 84. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. The New England Journal of Medicine. 1988;318(26):1720-1728
  85. 85. Vasconcelos OM, Poehm EH, McCarter RJ, Campbell WW, Quezado ZMN. Potential outcome factors in subacute combined degeneration: Review of observational studies. Journal of General Internal Medicine. 2006;21(10):1063-1068
  86. 86. Saperstein DS, Barohn RJ. Peripheral neuropathy due to cobalamin deficiency. Current Treatment Options in Neurology. 2002;4(3):197-201
  87. 87. Chu C, Scanlon P. Vitamin B12 deficiency optic neuropathy detected by asymptomatic screening. BML Case Reports. 2011;2011:bcr0220113823
  88. 88. Metzler D, Miller WH, Stephen EC. Psychiatric manifestation of vitamin B-12 deficiency: An update. Jefferson Journal of Psychiatry. 1991;9(2)
  89. 89. Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(23):9523-9528
  90. 90. Mahmud N, Stashek K, Katona BW, Tondon R, Shroff SG, Roses R, et al. The incidence of neoplasia in patients with autoimmune metaplastic atrophic gastritis: A renewed call for surveillance. Annals of Gastroenterology. 2018;32(1):67-72. DOI: 10.20524/aog.2018.0325
  91. 91. Kokkola A, Sjöblom SM, Haapiainen R, Sipponen P, Puolakkainen P, Jarvinen H. The risk of gastric carcinoma and carcinoid tumours in patients with pernicious anaemia: A prospective follow-up study. Scandinavian Journal of Gastroenterology. 1998;33:88-92
  92. 92. De Block CE, De Leeuw IH, Pelckmans PA, Michielsen PP, Bogers JJ, Van Marck EA, et al. Autoimmune hepatitis, autoimmune gastritis, and gastric carcinoid in a type 1 diabetic patient: A case report. Journal of Diabetes and its Complications. 2000;14:116-120
  93. 93. De Block CE, Colpin G, Thielemans K, Coopmans W, Bogers JJ, Pelckmans PA, et al. Neuroendocrine tumor markers and enterochromaffin-like cell hyper/dysplasia in type 1 diabetes. Diabetes Care. 2004;27(6):1387-1393
  94. 94. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128:1717-1751
  95. 95. Vannella L et al. Development of type I gastric carcinoid in patients with chronic atrophic gastritis. Alimentary Pharmacology & Therapeutics. 2011;33(12):1361-1369
  96. 96. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: A clinicopathologic study. Gastroenterology. 1993;104:994-1006
  97. 97. Gough DB, Thompson GB, Crotty TB, Donohue JH, Kvols LK, Carney A, et al. Diverse clinical and pathologic features of gastric carcinoid and the relevance of hypergastrinemia. World Journal of Surgery. 1994;18:473-479
  98. 98. Borch K, Stridsberg M, Burman P, Rehfeld JF. Basal chromogranin A and gastrin concentrations in circulation correlate to endocrine cell proliferation in type A gastritis. Scandinavian Journal of Gastroenterology. 1997;32:198-202
  99. 99. Borch K, Renvall H, Liedberg G. Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology. 1985;88:638-648
  100. 100. Peracchi M, Gebbia C, Basilisco G, Quatrini M, Tarantino C, Vescarelli S, et al. Plasma chromogranin A in patients with autoimmune chronic atrophic gastritis, enterochromaffin-like cell lesions and gastric carcinoids. European Journal of Endocrinology. 2005;152:443-448
  101. 101. Sjöblom SM, Sipponen P, Jarvinen H. Gastroscopic follow-up of pernicious anaemia patients. Gut. 1993;34:28-32
  102. 102. Hirschowitz BI, Griffith J, Pellegrin D, Cummings OW. Rapid regression of enterochromaffinlike cell gastric carcinoids in pernicious anemia after antrectomy. Gastroenterology. 1992;102(4 Pt 1):1409-1418
  103. 103. Ferraro G, Annibale B, Marignani M, Azzoni C, D’Adda T, D’Ambra G, et al. Effectiveness of octreotide in controlling fasting hypergastrinemia and related enterochromaffin-like cell growth. The Journal of Clinical Endocrinology and Metabolism. 1996;81:677-683
  104. 104. Zhou K, Ho W. Gastric carcinoids: Classification and diagnosis. In: Pisegna RJ, editor. Management of Pancreatic Neuroendocrine Tumors. New York, NY: Springer New York; 2015. pp. 83-93
  105. 105. Burkitt MD, Pritchard DM. Review article: Pathogenesis and management of gastric carcinoid tumours. Alimentary Pharmacology & Therapeutics. 2006;24(9):1305-1320
  106. 106. Li T-T, Qiu F, Qian ZR, Wan J, Qi X-K, Wu B-Y. Classification, clinicopathologic features and treatment of gastric neuroendocrine tumors. World Journal of Gastroenterology. 2014;20(1):118-125
  107. 107. Creutzfeldt W. The achlorhydria-carcinoid sequence: Role of gastrin. Digestion. 1988;39(2):61-79
  108. 108. Bordi C et al. Hypergastrinemia and gastric enterochromaffin-like cells. The American Journal of Surgical Pathology. 1995;19(Suppl 1):S8-S19
  109. 109. Nikou GC, Angelopoulos TP. Current concepts on gastric carcinoid tumors. Gastroenterology Research and Practice. 2012;2012:287825
  110. 110. Vanoli A, La Rosa S, Luinetti O, Klersy C, Manca R, Alvisi C, et al. Histologic changes in type A chronic atrophic gastritis indicating increased risk of neuroendocrine tumor development: The predictive role of dysplastic and severely hyperplastic enterochromaffin-like cell lesions. Human Pathology. 2013;44:1827-1837. DOI: 10.1016/j.humpath.2013.02.005
  111. 111. Correa P. A human model of gastric carcinogenesis. Cancer Research. 1988;48(13):3554-3560
  112. 112. Vannella L et al. Systematic review: Gastric cancer incidence in pernicious anaemia. Alimentary Pharmacology & Therapeutics. 2013;37(4):375-382
  113. 113. Hirota WK et al. ASGE guideline: The role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointestinal Endoscopy. 2006;63(4):570-580
  114. 114. Schneller J, Gupta R, Mustafa J, Villanueva R, Straus EW, Raffaniello RD. Helicobacter pylori infection is associated with a high incidence of intestinal metaplasia in the gastric mucosa of patients at inner-city hospitals in New York. Digestive Diseases and Sciences. 2006;51(10):1801-1809
  115. 115. Wong BC, Lam SK, Wong WM, et al. China gastric cancer study group helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: A randomized controlled trial. Journal of the American Medical Association. 2004;291(2):187-194
  116. 116. Correa P, Piazuelo MB. The gastric precancerous cascade. Journal of Digestive Diseases. 2012;13(1):2-9
  117. 117. Yong X, Tang B, Li B-S, et al. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Communication and Signaling: CCS. 2015;13(1):1-13
  118. 118. Van Doorn LJ, Figueiredo C, Sanna R, Plaisier A, Schneeberger P, de Boer W, et al. Clinical relevance of the cagA, vacA, and iceA status of helicobacter pylori. Gastroenterology. 1998;115:58-66. DOI: 10.1016/S0016-5085(98)70365-8
  119. 119. Yamaoka Y. Mechanisms of disease: Helicobacter pylorivirulence factors. Nature Reviews Gastroenterology & Hepatology. 2010;7(11):629-641
  120. 120. Wroblewski LE, Peek RM, Wilson KT. Helicobacter pylori and gastric cancer: Factors that modulate disease risk. Clinical Microbiology Reviews. 2010;23(4):713-739
  121. 121. Tan EM. Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis. Journal of Clinical Investigation. 2001;108:1411-1415. DOI: 10.1172/JCI14451
  122. 122. Werner S, Chen H, Tao S, Brenner H. Systematic review: Serum autoantibodies in the early detection of gastric cancer. International Journal of Cancer. 2015;136:2243-2252. DOI: 10.1002/ijc.28807
  123. 123. Macdonald IK, Parsy-Kowalska CB, Chapman CJ. Autoantibodies: Opportunities for early cancer detection. Trends in Cancer. 2017;3:198-213. DOI: 10.1016/j.trecan.2017.02.003
  124. 124. Liu W, Peng B, Lu Y, Xu W, Qian W, Zhang JY. Autoantibodies to tumor-associated antigens as biomarkers in cancer immunodiagnosis. Autoimmunity Reviews. 2011;10:331-335. DOI: 10.1016/j.autrev.2010.12.002
  125. 125. Zaenker P, Ziman MR. Serologic autoantibodies as diagnostic cancer biomarkers—A review. Cancer Epidemiology, Biomarkers & Prevention. 2013;22:2161-2181. DOI: 10.1158/1055-9965.EPI-13-0621
  126. 126. Konstadoulakis MM, Syrigos KN, Albanopoulos C, Mayers G, Golematis B. The presence of anti-carcinoembryonic antigen (CEA) antibodies in the sera of patients with gastrointestinal malignancies. Journal of Clinical Immunology. 1994;14:310-313. DOI: 10.1007/BF01540984
  127. 127. Saif MW, Zalonis A, Syrigos K. The clinical significance of autoantibodies in gastrointestinal malignancies: An overview. Expert Opinion on Biological Therapy. 2007;7:493-507. DOI: 10.1517/14712598.7.4.493
  128. 128. Ura Y, Ochi Y, Hamazu M, Ishida M, Nakajima K, Watanabe T. Studies on circulating antibody against carcinoembryonic antigen (CEA) and CEA-like antigen in cancer patients. Cancer Letters. 1985;25:283-295. DOI: 10.1016/S0304-3835(15)30008-2
  129. 129. Albanopoulos K, Armakolas A, Konstadoulakis MM, Leandros E, Tsiompanou E, Katsaragakis S, et al. Prognostic significance of circulating antibodies against carcinoembryonic antigen (anti-CEA) in patients with colon cancer. The American Journal of Gastroenterology. 2000;95:1056-1061. DOI: 10.1111/j.1572-0241.2000.01982.x
  130. 130. Nakamura H, Hinoda Y, Nakagawa N, Makiguchi Y, Itoh F, Endo T, et al. Detection of circulating anti-MUC1 mucin core protein antibodies in patients with colorectal cancer. Journal of Gastroenterology. 1998;33:354-361. DOI: 10.1007/s005350050096
  131. 131. Yagihashi A, Asanuma K, Nakamura M, Araya J, Mano Y, Torigoe T, et al. Detection of anti-survivin antibody in gastrointestinal cancer patients. Clinical Chemistry. 2001;47:1729-1731
  132. 132. Flammann HT, Kuhn HM. P53 autoantibodies and cancer: Specificity, diagnosis and monitoring. In: Shoenfeld Y, Gershwin ME, editors. Cancer and Autoimmunity. Amsterdam, The Netherlands: Elsevier Science; 2000. pp. 181-188
  133. 133. Soussi T. p53 antibodies in the sera of patients with various types of cancer: A review. Cancer Research. 2000;60:1777-1788
  134. 134. Shimada H, Ochiai T, Nomura F. Japan p53 antibody research group. Titration of serum p53 antibodies in 1085 patients with various types of malignant tumors: A multiinstitutional analysis by the Japan p53 antibody research group. Cancer. 2003;97:682-689. DOI: 10.1002/cncr.11092
  135. 135. Cho-Chung YS. Autoantibody biomarkers in the detection of cancer. Biochimica et Biophysica Acta. 2006;1762:587-591. DOI: 10.1016/j.bbadis.2006.04.001
  136. 136. Qiu LL, Hua PY, Ye LL, Wang YC, Qiu T, Bao HZ, et al. The detection of serum anti-p53 antibodies from patients with gastric carcinoma in China. Cancer Detection and Prevention. 2007;31:45-49. DOI: 10.1016/j.cdp.2006.12.005
  137. 137. Zhou SL, Ku JW, Fan ZM, Yue WB, Du F, Zhou YF. Detection of autoantibodies to a panel of tumor-associated antigens for the diagnosis values of gastric cardia adenocarcinoma. Diseases of the Esophagus. 2015;28:371-379. DOI: 10.1111/dote.12206
  138. 138. Shimizu K, Ueda Y, Yamagishi H. Titration of serum p53 antibodies in patients with gastric cancer: A single-institute study of 40 patients. Gastric Cancer. 2005;8:214-219. DOI: 10.1007/s10120-005-0337-4
  139. 139. Wang P, Song C, Xie W, Ye H, Wang K, Dai L, et al. Evaluation of diagnostic value in using a panel of multiple tumor-associated antigens for immunodiagnosis of cancer. Journal of Immunology Research. 2014;2014:512540. DOI: 10.1155/2014/512540
  140. 140. Shimada H, Noie T, Ohashi M, Oba K, Takahashi Y. Clinical significance of serum tumor markers for gastric cancer: A systematic review of literature by the task force of the Japanese gastric cancer association. Gastric Cancer. 2014;17:26-33. DOI: 10.1007/s10120-013-0259-5
  141. 141. Werner S, Chen H, Butt J, Michel A, Knebel P, Holleczek B, et al. Evaluation of the diagnostic value of 64 simultaneously measured autoantibodies for early detection of gastric cancer. Scientific Reports. 2016;6:25467. DOI: 10.1038/srep25467
  142. 142. Di Mario F, Cavallaro LG. Non-invasive tests in gastric diseases. Digestive and Liver Disease. 2008;40:523-530. DOI: 10.1016/j.dld.2008.02.028
  143. 143. Majeed W, Iftikhar A, Khaliq T, Aslam B, Muzaffar H, Atta K, et al. Gastric carcinoma: Recent trends in diagnostic biomarkers and molecular targeted therapies. Asian Pacific Journal of Cancer Prevention. 2016;17:3053-3060
  144. 144. Zayakin P, Ancāns G, Siliņa K, Meistere I, Kalniņa Z, Andrejeva D, et al. Tumor-associated autoantibody signature for the early detection of gastric cancer. International Journal of Cancer. 2013;132:137-147. DOI: 10.1002/ijc.27667
  145. 145. Dinis-Ribeiro M et al. Management of precancerous conditions and lesions in the stomach (MAPS): Guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy. 2012;44(1):74-94
  146. 146. Andres E, Fothergill H, Mecili M. Efficacy of oral cobalamin (vitamin B12) therapy. Expert Opinion on Pharmacotherapy. 2010;11(2):249-256
  147. 147. Stolte M, Meier E, Meining A. Cure of autoimmune gastritis by helicobacter pylori eradication in a 21-year-old male. Zeitschrift für Gastroenterologie. 1998;36(8):641-643
  148. 148. Faller G, Winter M, Steininger H, et al. Decrease of antigastric autoantibodies in helicobacter pylori gastritis after cure of infection. Pathology, Research and Practice. 1999;195(4):243-246
  149. 149. Dockray GJ. Clinical endocrinology and metabolism. Gastrin. Best Practice & Research Clinical Endocrinology & Metabolism. 2004;18(4):555-568
  150. 150. Moore AR, Boyce M, Steele IA, Campbell F, Varro A, Pritchard DM. Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis. PLoS One. 2013;8(10):e76462
  151. 151. Kwekkeboom DJ, Krenning EP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematology/Oncology Clinics of North America. 2016;30(1):179-191
  152. 152. Fossmark R, Sordal O, Jianu CS, et al. Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A. Alimentary Pharmacology & Therapeutics. 2012;36(11-12):1067-1075
  153. 153. Massironi S, Zilli A, Fanetti I, Ciafardini C, Conte D, Peracchi M. Intermittent treatment of recurrent type-1 gastric carcinoids with somatostatin analogues in patients with chronic autoimmune atrophic gastritis. Digestive and Liver Disease. 2015;47(11):978-983

Written By

Mila Dimitrova Kovacheva-Slavova, Todor Asenov Angelov, Hristo Yankov Valkov, Hristo Ilianov Iliev and Borislav Georgiev Vladimirov

Submitted: 26 January 2019 Reviewed: 22 May 2019 Published: 14 August 2019