Autoimmune Gastritis: Historical Antecedents, Outstanding Discoveries, and Unresolved Problems

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
International Reviews Of Immunology (Impact Factor: 4.1). 08/2009; 24(1-2):1-29. DOI: 10.1080/08830180590884413
Source: PubMed


The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious (fatal) anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis, the discovery of the megaloblast that characterized the anemia, the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), and a gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The link between PA and gastritis and atrophy was first confirmed histologically after immediate fixation of the stomach postmortem and later, in the 1940s, by peroral tube biopsy. The causes of gastritis remained enigmatic until the era of autoimmunity, when autoantibodies were detected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomy in pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Autoimmune) and Type B (later, Bacterial) gastritis. Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase, and by the highly informative experimental murine model of postneonatal thymectomy autoimmune gastritis, and in Type B of the causative role of gastric infection with Helicobacter pylori (H. pylori). A denouement will require a full understanding of (1) the origin and pathogenetic contribution of antibody to intrinsic factor; (2) the connection, if any, between H. pylori infection and Type A autoimmune gastritis; and (3) the genetic contributions to gastritis, whether due to autoimmunity or to H. pylori infection.

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    • "Pernicious anaemia is a form of anaemia that is undeniably associated with vitamin B12 deficiency. Finding the cure for pernicious anaemia even led to the discovery of vitamin B12 [1-7]. Nowadays, vitamin B12 deficiency is not only associated with (pernicious) anaemia, but is also linked with other conditions such as dementia, neuropathy and subacute combined degeneration of the spinal cord [8-11]. "
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    ABSTRACT: Pernicious anaemia is undeniably associated with vitamin B12 deficiency, but the association between subnormal vitamin B12 concentrations and anaemia in older people is unclear. The aim of this systematic review was to evaluate the association between subnormal vitamin B12 concentrations and anaemia in older people. Clinical queries for aetiology and treatment in bibliographic databases (PubMed [01/1949-10/2009]; EMBASE [01/1980-10/2009]) were used. Reference lists were checked for additional relevant studies. Observational studies (> or =50 participants) and randomized placebo-controlled intervention trials (RCTs) were considered. 25 studies met the inclusion criteria. Twenty-one observational cross-sectional studies (total number of participants n = 16185) showed inconsistent results. In one longitudinal observational study, low vitamin B12 concentrations were not associated with an increased risk of anaemia (total n = 423). The 3 RCTs (total n = 210) were well-designed and showed no effect of vitamin B12 supplementation on haemoglobin concentrations during follow-up in subjects with subnormal vitamin B12 concentrations at the start of the study. Due to large clinical and methodological heterogeneity, statistical pooling of data was not performed. Evidence of a positive association between a subnormal serum vitamin B12 concentration and anaemia in older people is limited and inconclusive. Further well-designed studies are needed to determine whether subnormal vitamin B12 is a risk factor for anaemia in older people.
    BMC Geriatrics 06/2010; 10(1):42. DOI:10.1186/1471-2318-10-42 · 1.68 Impact Factor
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    • "Iodine-related [64] Guillain-Barre' syndrome Accepted Myelin GM gangliosides – – 1.5/10 5 1.25/1 – Y Arabs [65] Hashimoto's disease Accepted Thyroid Thyroid peroxidase, thyroglobulin 50–60 3–4% 22/10 5 1/5–18 0.55 Unknown [66] Idiopathic thrombocytopenic purpura Accepted Platelets Glycoprotein IIb/IIIg and Ib/IX – 1.6–6.6/ 10 5 – 1/3 Unknown [67] Multiple sclerosis Accepted CNS Myelin-basic protein, myelin oligodendrocyte glycoprotein (MOG) 25–45 58/10 5 3/10 5 1/2 0.25–0.31 [ Northern Europe, Y Asia [68] Myasthenia gravis Accepted Neuromuscular plaque Acetylcholine receptor <40, 50–60 5–20/10 5 0.4/10 5 1/3 44% [ Western countries [65] Myositis Accepted Derma and muscle DNA-dependent nucleosidestimulated ATPase, aminoacyl-tRNA synthetase, signal recognition protein (SRP54) 5–15, 45–65 0.5–5/10 5 1–2/10 5 1/2 Concordant pair [ Western Australia [65] Pemphigus vulgaris Accepted Derma Desmoglein 3 40–60 – 0.1/10 5 1/1 – [ Northern Africa [59] Pernicious anemia Accepted Gastric mucosa Intrinsic factor type 1 60–70 151/10 5 – 1/2 – [ African–Americans, Latin-Americans [69] Polymyalgia rheumatica Suspected Musculoskeletal Unknown >50 751/10 5 13–110/10 5 1/1.7 – [ Northern Europe [70] Primary biliary cirrhosis Accepted Bile ducts Pyruvate dehydrogenase complex-E2 (PDC-E2) 50–60 40/10 5 1–49/10 5 1/10 0.63 [ Northern Europe, Northern US [71] Primary sclerosing cholangitis Suspected Bile ducts Tubulin b isoform 5 40 3.9–10/10 5 0.4/10 5 1.5/1 Concordant pair [ Northern Europe [72] Primary systemic vasculitis Accepted Small and medium vessels Proteinase-3, myeloperoxidase 45–55 (F), 55– 65 (M) 10–53/10 5 1–10/10 5 1/1 – [ Rural areas [62] Rheumatoid arthritis Accepted Articulation Rheumatoid factor, keratin, CCP, collagen, fibronectin 45–55 1% 41/10 5 1/2 0.12–0.20 [ Native Americans [73] "
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    ABSTRACT: There are currently over 100 human diseases that are considered to be autoimmune or chronic inflammatory affecting 5-10% of the world population and spanning through all medical specialties. As a result, health care costs are enormous and the clinical management is often challenging, particularly considering the comorbidity rates and the multi-organ involvement of each condition. We herein propose the creation of a new specialist, coined the autoimmunologist, to overcome the current limitations in the diagnostic process and clinical follow-up of patients with autoimmune diseases. More importantly, we also propose the creation of regional centers of excellence in autoimmunity where clinical research and management, as well as basic research may be united and interact in ideal synergy to ultimately create real translational research and provide better health care.
    Journal of Autoimmunity 11/2008; 31(4):325-30. DOI:10.1016/j.jaut.2008.08.004 · 8.41 Impact Factor
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    • "In 50 to 70% of patients with PA there are antibodies against gastric secreted intrinsic factor, a product of parietal cells, which enhances the absorption of vitamin B 12 (Whittingham and Mackay, 2005). "
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    ABSTRACT: Aims: Helicobacter pylori infection, although the prevalence is declining in Western world, is still responsible for several clinically important diseases. None of the diagnostic tests is perfect and in this study, the performance of three stool antigen tests was assessed. In areas of high H. pylori prevalence, the definition of patients with the greatest benefit from eradication therapy may be a problem; the role of duodenal gastric metaplasia in categorizing patients at risk for duodenal ulcer was evaluated in this respect. Whether persistent chronic inflammation and elevated H. pylori antibodies after successful eradication are associated with each other or with atrophic gastritis, a long term sequelae of H. pylori infection, were also studied. Patients and methods: The three stool antigen tests were assessed in pre- and post-eradication settings among 364 subjects in two studies as compared to the rapid urease test (RUT), histology, culture, the 13C-urea breath test (UBT) and enzyme immunoassay (EIA) based H. pylori serology. The association between duodenal gastric metaplasia with duodenal ulcer was evaluated in a retrospective study including 1054 patients gastroscopied due to clinical indications and 154 patients previously operated for duodenal ulcer. The extent of duodenal gastric metaplasia was assessed from histological specimens in different patient groups formed on the basis of gastroscopy findings and H. pylori infection. Chronic gastric inflammation (108 patients) and H. pylori antibodies and serum markers for atrophy (77 patients) were assessed in patients earlier treated for H. pylori. Results: Of the stool antigen tests studied, the monoclonal antibody-based EIA-test showed the highest sensitivity and specificity both in the pre-treatment setting (96.9% and 95.9%) and after therapy (96.9% and 97.8%). The polyclonal stool antigen test and the in-office test had at baseline a sensitivity of 91% and 94%, and a specificity of 96% and 89%, respectively and in a post-treatment setting, a sensitivity of 78% and 91%, and a specificity of 97%, respectively. Duodenal gastric metaplasia was strongly associated with H. pylori positive duodenal ulcer (odds ratio 42). Although common still five years after eradication, persistent chronic gastric inflammation (21%) and elevated H. pylori antibodies (33%) were neither associated with each other nor with atrophic gastritis. Conclusions: Current H. pylori infection can feasibly be diagnosed by a monoclonal antibody-based EIA test with the accuracy comparable to that of reference methods. The performance of the polyclonal test as compared to the monoclonal test was inferior especially in the post-treatment setting. The in-office test had a low specificity for primary diagnosis and hence positive test results should probably be confirmed with another test before eradication therapy is prescribed. The presence of widespread duodenal gastric metaplasia showed promising results in detecting patients who should be treated for H. pylori due to an increased risk of duodenal ulcer. If serology is used later on in patients with earlier successfully treated for H. pylori, it should be taken into account that H. pylori antibodies may persist elevated for years for unknown reason. However, this phenomenon was not found to be associated with persistent chronic inflammation or atrophic changes. H. pylori-infektio liitetään maha- ja pohjukaissuolihaavoihin ja mahalaukun syöpään. Syöpäriskiä lisäävät krooniseen H. pylori-infektioon liittyvät mahalaukun limakalvomuutokset, atrofia ja intestinaalinen metaplasia. Häätöä on suositeltu haavan sairastaneille potilaille estämään haavan uusiutumista sekä niille, joilla on mahalaukun syöpää lähisuvussa. Infektion häätämisestä hyötyy myös osa ylävatsavaivoja potevista, vaikkei haavatautia olisi koskaan todettukaan. Näiden häätöhoidosta hyötyvien potilaiden löytäminen on tarpeen erikoisesti alueilla, joissa helikobakteeri-infektio väestössä on vielä hyvin tavallinen eikä häätöhoidon antaminen siten ole mahdollista kaikille infektoituneille. Infektion toteamiseksi on ollut kliinisessä käytössä useita testejä, joista osaan tarvitaan mahalaukun tähystyksessä otettava koepala (pikatesti, histologinen tutkimus ja viljely) ja lisäksi ilman mahalaukun tähystystä infektio voidaan todeta verinäytteestä (serologia) tai hengitystestillä. Mahalaukun tähystys on kajoavana tutkimuksena potilaalle epämiellyttävä, se on kallis, eikä sitä ole syytä tehdä ilman muita indikaatioita pelkästään helikobakteeri-infektion toteamiseksi. Serologinen testi ei erota jatkuvaa infektiota aiemmin sairastetusta infektiosta, ja hengitystesti taas vie runsaasti sekä potilaan että henkilökunnan aikaa laboratoriossa. Tässä väitöstutkimuksessa selvitimme kolmen eri ulosteesta tehtävän helikobakteeri-testin soveltuvuutta infektion osoittamiseksi ennen ja jälkeen häätöhoidon. Luotettavimmat tulokset tulivat molemmissa yllä olevissa tilanteissa monoklonaalisiin vasta-aineisiin perustuvalla EIA menetelmällä tehtävällä uloste-antigeeni testillä, joka sittemmin on otettu kliiniseen käyttöön. Etsittäessa häätöhoidosta mahdollisesti hyötyviä potilasryhmiä totesimme, että pohjukaissuolen alkuosan limakalvomuutokset (gastrinen metaplasia) liittyvät voimakkaasti pohjukaissuolihaavaan ja vaikka tähystystutkimuksen tekohetkellä ei potilaalla todeta haavatautia, niin niille, joilla todetaan laaja-alaiset gastrisen metaplasian alueet, kannattaisi harkita helikobakteerin häätöä pohjukaissuolihaavan ehkäisemiseksi. Totesimme, että osalle potilaista onnistuneen helikobakteerin häädön jälkeen jää vuosiksi koholle veren helikobakteeri vasta-aineet ja pysyvä lievä tulehdus mahalaukun limakalvolle. Nämä ilmiöt eivät liittyneet toisiinsa emmekä havainneet, että ne olisivat yhteydessä autoimmuuniprosessiin, joka voisi johtaa mahalaukun limakalvon tuhoutumiseen vielä häädön jälkeenkin. Liittyykö mahalaukun limakalvolla pysyvä tulehdus lisääntyneeseen syöpäriskiin, jää selvitettäväksi jatkotutkimuksilla.
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