autoimmune atrophic gastritis—pathogenesis, pathology ... · autoimmune gastritis.38–45 the...

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 10 | SEPTEMBER 2013 | 529

Miraca Life Sciences Research Institute, 6655 North MacArthur Boulevard, Irving, TX 75039, USA (W. L. Neumann, R. M. Genta). Department of Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center at Dallas, VAMC, 4500 South Lancaster Boulevard, Dallas, TX 75216, USA (E. Coss). Department of Medicine (DIMED), Pathology & Cytopathology Unit, University of Padua, Via Giustiniani 2, 35128 Padova, Italy (M. Rugge)

Correspondence to: R. M. Genta [email protected]

Autoimmune atrophic gastritis —pathogenesis, pathology and managementWilliam L. Neumann, Elizabeth Coss, Massimo Rugge and Robert M. Genta

Abstract | Autoimmune gastritis is a chronic progressive inflammatory condition that results in the replacement of the parietal cell mass by atrophic and metaplastic mucosa. A complex interaction of autoantibodies against the parietal cell proton pump and sensitized T cells progressively destroy the parietal cells, inducing hypochlorhydria and then achlorhydria, while autoantibodies against the intrinsic factor impair the absorption of vitamin B12. The resulting cobalamin deficiency manifests with megaloblastic anaemia and neurological and systemic signs and symptoms collectively known as pernicious anaemia. Previously believed to be predominantly a disease of elderly women of Northern European ancestry, autoimmune gastritis has now been recognized in all populations and ethnic groups, but because of the complexity of the diagnosis no reliable prevalence data are available. For similar reasons, as well as the frequent and often unknown overlap with Helicobacter pylori infection, the risk of gastric cancer has not been adequately assessed in these patients. This Review summarizes the epidemiology, pathogenesis and pathological aspects of autoimmune metaplastic atrophic gastritis. We also provide practical advice for the diagnosis and management of patients with this disease.

Neumann, W. L. et al. Nat. Rev. Gastroenterol. Hepatol. 10, 529–541 (2013); published online 18 June 2013; doi:10.1038/nrgastro.2013.101

Introduction Atrophy, derived from the Greek words α and τροφή (liter-ally meaning “not fed”), is used as a synonym for wasting (as, for example, in atrophy of muscles). When applied to the gastric mucosa, atrophy is defined as the reduction or disappearance of the native gastric glands, irrespective of whether they have been replaced by nothing, fibrosis, or a type of epithelium that should normally not be there (metaplasia).1 Both the antrum and corpus might be involved, but evident functional and clinical consequences occur only when atrophy affects the latter. The decrease or disappearance of parietal cells results in reduced or absent acid production (hypochlorhydria or achlorhydria) and loss of intrinsic factor. An increased gastric pH enables the colonization of the stomach by bacteria (normally deterred by the low physiological pH) that might produce nitrites and promote carcinogenesis; it interferes with the absorption of certain indispensable substances (such as iron and vitamin B12); and by continuously stimulating the gastrin-secreting cells of the antrum it induces the proliferation of endocrine-like cells in the corpus, which might give rise to neuroendocrine tumours (previously known as carcinoids).

The progressive depletion of native gastric structures in scattered patches throughout the stomach, one of the results of long-standing Helicobacter pylori infection,

is known as multifocal atrophic gastritis (Figure 1). In another set of patients, selective loss of the parietal cell mass occurs, which is replaced by atrophic and meta plastic mucosa, with preservation of the antrum (Figure 1b). Although the ultimate aetiology of this con-dition is unclear, we know that it results from a constel-lation of autoimmune phenomena (some of which might be triggered by yet unknown environmental factors) and is often associated with other primary autoimmune conditions. Hence, it is referred to as autoimmune meta-plastic atrophic gastritis, a condition that progresses at an unknown pace from a mild chronic inflammation of the gastric corpus to an advanced stage associated with a severe form of vitamin B12 deficiency anaemia known as pernicious anaemia. The clinical description of pernicious anaemia preceded the discovery of its cause (atrophic gastritis) by several decades and the two terms are often, if incorrectly, used synonymously.2–5 In the past three decades, the perceived relevance of auto-immune atrophic gastritis has been somewhat obfus-cated by the overwhelming attention given to H. pylori infection. Consequently, both gastroenterologists and pathologists might have lost some familiarity with this entity. Now that the prevalence of H. pylori is declining, particularly in the Western world,6–12 neglected condi-tions are resurfacing and we should be ready to recog-nize and treat them. Furthermore, some researchers believe that the improving sanitation and the resulting decreased childhood exposure to both infectious and non infectious antigens might contribute to the observed increase in certain autoimmune and allergic conditions such as coeliac disease, eosinophilic oesophagitis, asthma

Competing interestsW. L. Neumann declares associations with the following companies: Pathologists Bio-Medical Labs, Miraca Life Sciences. R. M. Genta declares associations with the following company: Miraca Life Sciences. Please see the article online for full details of the relationships. The other authors declare no competing interests.

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and IBD.13–16 The incidence of autoimmune gastritis might also be on the increase, possibly influenced by similar mechanisms.17

The purpose of this Review is to provide gastro-enterologists with up-to-date practical information they can use when receiving a histopathological diagnosis of atrophic gastritis in a set of gastric biopsy samples. We discuss the epidemiology, pathogenesis and pathological aspects of autoimmune metaplastic atrophic gastritis. We then guide clinicians through the additional tests that are often needed to confirm the histopathological findings, and provide suggestions for treatment and follow up.

Key points

■ Atrophic gastritis can be associated with long-standing Helicobacter pylori infection (multifocal atrophic gastritis) and with an autoimmune process that progressively destroys the oxyntic mucosa (autoimmune atrophic gastritis)

■ Both types of atrophic gastritis are underdiagnosed, in part because of inadequate biopsy sampling

■ Autoimmune atrophic gastritis progresses from a mild chronic inflammation of the gastric corpus to an advanced stage associated with a severe form of vitamin B12 deficiency anaemia known as pernicious anaemia

■ Traditionally, autoimmune atrophic gastritis has been viewed as a disease affecting predominantly elderly women of Northern European descent, but growing evidence suggests that there might be no racial specificity

■ The diagnosis of autoimmune gastritis rests on the demonstration of its characteristic histopathological features and the demonstration of autoantibodies against intrinsic factor and parietal cells

■ Management of the early stages of autoimmune atrophic gastritis is focused on the prevention of vitamin B12, folate and iron deficiencies

EpidemiologyTraditionally, pernicious anaemia (and, consequently, advanced autoimmune gastritis) has been viewed as an uncommon disease affecting predominantly elderly women of Northern European descent.18,19 Although numerous studies confirm the female proclivity, growing evidence suggests that there might be no racial speci-ficity.17,20–26 Indeed, some US studies indicate a higher prevalence of pernicious anaemia in nonwhite women, and also suggest an earlier age of onset in these ethnic groups when compared with white women.20,24,26,27 Epidemiological studies and case series support the concept that autoimmune gastritis and pernicious anaemia exist—and might be underdiagnosed—in all parts of the world.27–36 Several factors converge to make this condition underdiagnosed. As most patients in the community present with either microcytic or macrocytic anaemia, it seems that they are often treated with iron, folate and cobalamin, without a thorough investigation of the underlying cause of anaemia. General pathologists not conversant with the specific criteria tend to make generic diagnoses such as ‘chronic gastritis with intesti-nal metaplasia’, thus failing to alert clinicians to the pos-sibility of atrophic gastritis. Finally, gastroenterologists who do not take topographically well-defined biopsy samples of the gastric mucosa hamper pathologists’ ability even to suspect the diagnosis. For these and other reasons, it is difficult to carry out studies to specifically evaluate the prevalence of autoimmune gastritis in the general population. The most recent targeted survey esti-mated an overall prevalence of 2%, with peaks of 4–5% among elderly women.24

Relationship with H. pylori infectionIn 1998, an article on the relationship between gastric H+,K+ATPase (the proton pump responsible for acid secretion, highly expressed in the parietal cell c analiculi), H. pylori infection and corpus-restricted atrophic gastritis, ended with the statement that “it is quite likely that the study of anti-gastric autoimmunity, its specificit y, and the time of its development before and after eradication will become an important research issue for the evaluation and understanding of the long-term outcome of H. pylori infection”.37 15 years later, in spite of the continuing interest and considerable pro-gress made in this area, particularly in animal models, the aetiology and pathogenesis of human autoimmune gastritis remain elusive.

At the risk of oversimplifying this highly complex issue, the population of patients with atrophic gastritis can be considered as consisting of three groups. One group will have ‘pure’ H. pylori infection, characterized by pangastri-tis, multifocal metaplastic atrophy and no autoantibodies. A second group will have ‘pure’ autoimmune gastritis, with corpus-restricted metaplastic atrophy, a normal or reactive antrum, and no evidence of past or present H. pylori infection. A third group includes patients with a spectrum of corpus atrophic metaplastic gastritis ranging from minimal (‘pre-atrophic’) to severe, a normal or inflamed antrum, evidence of current or past H. pylori

Much lessin�ammation

Antral gastritis

A1

a b

A1

B1

B2

A2

Normal antrum

Atrophy

Multifocal atrophic (H. pylori) Autoimmune corpus-restricted

Biopsy sitesIntestinal metaplasia

A2

B1

B2

Figure 1 | Atrophic gastritis. a | Multifocal atrophic gastritis is caused by long-standing Helicobacter pylori infection and is characterized by antrum-predominant or pangastritis and various degrees of metaplastic atrophy (blue patches) that invariably involve the antrum and might extend into the corpus. b | In autoimmune gastritis, the inflammatory atrophic process involves exclusively the corpus (grey discoloration) and patches of intestinal, pseudopyloric and pancreatic metaplasia are found throughout the gastric body and fundus. The locations of the four biopsy samples recommended by the Sydney System are represented. The Updated Sydney System also recommends a sample from the incisura angularis, but in practice this is rarely taken.

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infection, and autoantibodies reactive to gastric tissue (specifically H+,K+ATPase). Although the first and second group of patients provide no clues as to the aetiology or pathogenesis of autoimmune atrophic gastritis, the third group has been the major focus of attention in the search for a causal connection between H. pylori infection and autoimmune gastritis.38–45 The plausibility of an auto-immune pathway in a subgroup of patients with H. pylori gastritis is supported by numerous lines of evidence, including: first, increased influx of B cells and/or T cells around glands and into the epithelium of the corpus mucosa;37second, the predominant severity of inflam-matory and atrophic changes in the oxyntic compart-ment;17,39 third, increased apoptosis in oxyntic glands;41 and fourth, decreased gastric acid secretion coexisting with increased gastrin levels.46 Furthermore, claims that eradication of H. pylori infection could arrest or reverse the early phases of autoimmune gastritis (the ‘pre-atrophic’ stage) have been invoked to further support the plausibility of a causal relationship between H. pylori and gastric autoimmunity.47–49

In spite of these pieces of largely circumstantial evi-dence, however, consistent proof that molecular mimicry contributes to autoreactivity is lacking, and the iden-tity of the epitopes recognized by human antigastric autoantibodies remains to be determined. Studies using cloned T cells from patients infected with H. pylori and patients with autoimmune atrophic gastritis have iden-tified molecular mimicry between H. pylori, hydrogen and potassium receptors and ATPase, suggesting that the infection might stimulate T cells that target parietal cells.50 These studies provide support for the concept of a cross-reactive mechanism between H. pylori organisms and gastric epithelial antigens that might be responsible for, or at least participate in, the pathogenesis of auto-immune gastritis.51–53 The concurrent presence of present or past (documented by serology) H. pylori infection is sometimes invoked as proof that H. pylori is involved in the pathogenesis of a large spectrum of immune-mediated diseases, including autoimmune gastritis.54,55 This argument is fallacious, as association does not prove causation. Other mechanisms for the patho genesis of autoimmune gastritis have also been sporadically studied, including the role of IgG4, shown to participate in the pathogenesis of autoimmune pancreatitis; IgG4 immunoreactive plasma cells in gastric biopsies were found to be 100% specific for autoimmune atrophic gas-tritis,56 although the low sensitivity of this finding makes it unsuitable for diagnostic purposes.

In conclusion, many of the processes involved in the pathogenesis of autoimmune gastritis remain poorly understood and at this time it is best to think of this con-dition as one resulting from a ‘mosaic of autoimmunity’. This term indicates the overlapping influences of genetic, environmental and hormonal factors that, combined with selective and nonselective immune defects, contri-bute to the emergence of autoimmune conditions.57,58 We have not discussed animal studies in this article as most mouse models consist of genetically modified animals in whom gastric autoimmunity is induced by exposure

to splenocytes from neonatally thymectomized mice59 or other highly contrived manipulations of the animals’ immune system. Although important information on pathogenetic mechanisms is generated by studying such models, their immediate relevance to human disease remains unclear.

Associations with other autoimmune diseasesAutoimmune gastritis has been associated with other autoimmune diseases, particularly thyroiditis, since the early 1960s;60–65 the expression ‘thyrogastric a utoimmunity’ was used to describe the presence of thyroid auto antibodies or autoimmune thyroid disease in patients with pernicious anaemia.60,66–68 Other auto-immune diseases with an increased incidence amongst those with autoimmune gastritis include type 1 dia-betes, vitiligo and Addison disease.69,70 Pernicious anaemia has also been described in patients with various immuno deficiency syndromes such as IgA deficiency, chromosome 18q deletion syndrome and X-linked hypogammaglobulinaemia, Good syndrome and common variable immunodeficiency.71–74 Familial clustering of pernicious anaemia has long been recog-nized, and a few reported cases involving monozygotic twins and triplets further support a heritable compo-nent to this disease.75–78 However, the genetic aspect of autoimmune gastritis remains poorly understood, and additional studies aimed at unravelling the molecular aspects of this disease are arguably overdue.58

PathologyThroughout its long course, autoimmune gastritis exhib-its a spectrum of histopathological changes, starting with chronic inflammation in the gastric corpus and ulti-mately culminating with the replacement of the oxyntic glands by metaplastic mucosa. As structural atrophy leads to functional impairment, acid production pro-gressively decreases and increasing gastrin levels fuel neuroendocrine hyperplasia.

Macroscopic appearanceKnowledge of the macroscopic appearance of the stomach of patients with autoimmune atrophic gastri-tis has been largely based on autopsy findings, as few patients with atrophy undergo gastrectomy. With both gastrectomies and autopsies fading into obsolescence, the current generation of pathologists might well go through their professional life without ever having seen the stomach of a patient with pernicious anaemia. Gastroenterologists, who need to know the endo-scopic appearance of the atrophic stomach, will find a d escription below.

From the pathologist’s perspective, it will suffice to say that in the early inflammatory stages there are no dis-tinctive gross mucosal changes. As atrophy progresses, however, the mucosa becomes thinner and the rugal folds flatten. When the whole stomach is examined, the corpus appears like a thin flat sack, on which small nodules (pseudopolyps, hyperplastic or adenomatous polyps and neuroendocrine tumours) might be seen (Figure 2).

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Microscopic featuresHistopathologically, autoimmune gastritis is character-ized by diffuse corpus-restricted atrophic gastritis with variable proportions of intestinal metaplasia, pseudo-pyloric metaplasia (now referred to as spasmolytic p olypeptide-expressing metaplasia),79,80 pancreatic acinar metaplasia,81,82 and hyperplasia of the endocrine-like cells.83,84 In the absence of concurrent or past H. pylori infection, the antrum is either normal or shows reactive gastropathy (Figure 3a).

The histopathological changes of autoimmune atrophic gastritis can be divided into three evolving phases.25,85 The early phase is characterized by a multi-focal, dense lymphocytic and plasma cell infiltration of the oxyntic mucosa involving the entire thickness of the lamina propria with an accentuation in the deeper, glandular portion,47 and often mixed with eosinophils and mast cells. Patchy destruction of individual oxyntic glands by lymphocytes might occur, and the parietal cells exhibit pseudohypertrophic changes with ‘snout-ing’ (luminal cytoplasmic projections) reminiscent of PPI-induced effects.25,47,86 As these histological features are nonspecific, the pathology report should raise the possibility of early autoimmune gastritis and recom-mend appropriate serologic tests for antiparietal cell and anti-intrinsic factor autoantibodies.87 The second phase (florid) is characterized by diffuse lympho plasmacytic infiltration of the lamina propria, marked atrophy of oxyntic glands and normal or reduced thickness of the mucosa with a relative increase in the thickness of the foveolar component. Pseudopyloric metaplasia is often extensive, and intestinal metaplasia becomes increasingly prominent (Figure 3b).88,89 These features are sufficiently distinctive to make a strong case for a diagnosis of autoimmune atrophic gastritis, particu-larly if the antrum is neither inflamed nor atrophic. Confirmation of diagnosis, however, still rests on the demonstration of antibodies directed against parietal cell and intrinsic factor antigens.

The end stage is characterized by a marked reduction in oxyntic glands, which might be completely absent from biopsy specimens, foveolar hyperplasia with underlying microcystic change, and the formation of hyperplastic and inflammatory polyps. Pseudopyloric, pancreatic and intestinal metaplasia becomes wide-spread and the muscularis mucosae might be consider-ably thickened. Although scattered lymphoid aggregates are often present, inflammation is usually minimal and the atrophic mucosa has an empty look. Endocrine-like cell hyperplasia, sometimes detectable in the florid phase, is almost invariably present in the advanced form

Figure 2 | Resected stomach from a patient with end-stage autoimmune atrophic gastritis. The gastrectomy was performed in error after the endoscopic biopsy from a benign neuroendocrine tumour was mistakenly interpreted as an adenocarcinoma. Note the complete absence of gastric rugae in the completely flattened mucosa of the corpus.

a b

Oxy

*

Figure 3 | Typical histopathological features of autoimmune atrophic gastritis. a | The antral mucosa shows moderate foveolar hyperplasia (reactive gastropathy) with neither inflammation nor metaplasia. b | The mucosa of the corpus shows absence of parietal cells, intestinal metaplasia (arrows) and pseudopyloric metaplasia (asterisk). A small cluster of surviving oxyntic glands (Oxy) is seen in the lower portion of the mucosa.

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of atrophic gastritis.88,89 The advanced phase is usually seen only in patients with pernicious anaemia. The vast majority of gastric biopsy specimens from patients with autoimmune gastritis will show the changes of the florid phase, with substantial intestinal and pseudo-pyloric metaplasia and mononuclear inflammation of the remaining oxyntic glands. Pathologists, often faced with limited clinical history and gastric biopsy speci-mens devoid of precise topographical origins, need a high index of suspicion to make the correct diagnosis in advanced cases as it is not uncommon for a section of atrophic corpus mucosa with extensive pseudo pyloric and focal intestinal metaplasia and sparse parietal cells to be erroneously interpreted as a fragment of transi-tional zone (with or without coexisting intestinal meta-plasia). Immunohistochemical stains for pepsinogens and the rarity or absence of G cells will confirm the origin from the corpus (and, consequently, the atrophy) and chromogranin staining will probably reveal parietal e ndocrine-like cell hyperplasia (see below).

The gastric antrum in autoimmune gastritisThe sparing of the antrum is part of the definition of autoimmune ‘corpus-restricted’ atrophic gastritis. However, two important exceptions exist. When auto-immune gastritis occurs concurrently with H. pylori infection, the antrum might show the entire spectrum of H. pylori gastritis, including atrophy and metaplasia in long-standing infections; active inflammation, not a prominent feature of pure autoimmune gastritis, will often be found in the corpus of these patients.55 In these cases, a diagnosis of autoimmune gastritis can only be made if corroborated by positive antiparietal cell and anti-intrinsic factor antibodies. OLGA (operative link for gastritis assessment) staging, a system for the assessment of gastric cancer risk,90,91 has been tested in a series of patients with autoimmune gastritis.17 Similar to a series of patients with H. pylori gastritis,92,93 low atrophy stages largely prevailed. Incidental gastric neoplasia (both intraepithelial and invasive) only occurred when atrophy also involved the gastric antrum, and was associated with coexisting H. pylori infection.17

A second situation, possibly rare and certainly uncommonly recognized, involves a distinctive form of atrophic gastritis that differs markedly from both multi-focal and autoimmune atrophic gastritis. In a detailed report of eight patients,94 the authors described intense mucosal inflammatory infiltrates persisting even into the phase of severe glandular atrophy with a pan gastric distribution involving the body and antrum of the stomach equally. None of the eight patients had evidence of present or previous H. pylori infection, and neuro-endocrine hyperplasia was not observed. All patients had systemic autoimmune or connective tissue dis-eases, including four cases of autoimmune entero colitis. The authors proposed that the distinctive histology of this form of atrophic pangastritis and its association with systemic autoimmune disease suggests an auto-immune process directed against multiple cell lineages in the stomach.94

Associated lesions The chronic inflammatory state that persists through the early and florid phases of autoimmune gastritis and the resulting impairment of gastric acid secretion create a fertile background for the development of in flammatory and neoplastic proliferations in the gastric mucosa.

Neuroendocrine hyperplasia and tumours When the parietal cell mass is reduced to the point that acid production becomes impaired and hypo chlorhydria or achlorhydria occurs, a chronic state of sustained hypergastrinaemia results. In chronic hypergastrinaemic states, gastrin stimulates endocrine-like cells to prolif-erate. The proliferations run the spectrum from simple hyperplasia to neuroendocrine tumours.95,96

In simple endocrine-like cell hyperplasia (defined as an endocrine-like cell density >2 SDs of the normal density in matched controls), cells are hyper trophied and arranged singly or in clusters of fewer than five cells, usually in the lower third of the gastric pits. Linear hyperplasia consists of groups of five consecu-tive neuro endocrine cells lining the base of the pits or in the glandular neck region (Figure 4). Micronodular hyperplasia is defined as clusters of five or more neuro-endocrine cells, bounded by basement membrane, that do not exceed the diameter of a gastric gland (<150 μm). Aggregates of five or more micronodules are referred to as adenomatoid hyperplasia.96 Several studies have concluded that linear, micronodular and adeno matoid hyperplasia have low potential for pro-gression to neuro endocrine tumours.84,95 By contrast, individual nodules >150 μm in diameter, particularly when they seem to result from the fusion of several micronodules with loss of the basement membrane,

a b

Figure 4 | Atrophic corpus mucosa. a | Hematoxylin and eosin staining. No oxyntic glands are seen but endocrine-like-cell hyperplasia is evident throughout the lower half of the mucosa. b | Staining with anti-chromogranin antibodies to highlight (dark brown) the endocrine-like cells. Endocrine-like cells are lining the entire circumference or long portions of gastric pits (linear hyperplasia) and form small clusters of packed cells (nodular hyperplasia).

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might progress to become microinvasive with depo-sition of newly formed stroma in the lamina propria (Figure 5). These lesions are s ometimes referred to as endocrine-like-cell dysplasia.84,96

Nodules of endocrine-like cells with a diameter ranging from 0.5–5 mm that are not specifically identi-fied at endoscopy have been referred to as microneuro-endocrine tumours (or microcarcinoids), whereas neuroendocrine proliferations that are >500 μm and are endoscopically identified are classified as neuro-endocrine tumours.97 We find this distinction petty and, because it is tied to an endoscopist’s individual skills, it lacks wide reproducibility. Therefore, we prefer to use the term neuroendocrine tumour for any endocrine-like cell proliferation >500 μm, irrespective of its endoscopic appearance (or lack thereof).96 Figure 6 shows a typical small carcinoid arising in the atrophic mucosa of the gastric corpus.

Neuroendocrine tumours associated with auto-immune atrophic gastritis are typically small (<1 cm), tend to be multiple, and almost invariably coexist with multifocal enterochromaffin-like-cell hyper plasia. Histologically, they consist of nests or ribbons of endo-crine cells with the characteristic ‘salt and pepper’ chromatin, and have very low mitotic and prolifera-tion indexes.95,96 These carcinoids have essentially no malignant potential.

Hyperplastic polyps Hyperplastic polyps are found in 1.3% of all US out-patients who undergo upper endoscopies in community-based endoscopy or surgery centres, and these polyps represent between 15–20% of all gastric polyps.98,99 Hyperplastic polyps can occur in normal gastric mucosa or might be associated with various forms of gastritis. An association between hyperplastic polyps and atrophic autoimmune gastritis is well established.100–105 In these patients, the polyps tend to be located more proximally and are more numerous than in patients with other forms of gastritis.100 Therefore, when multiple proximal hyper-plastic polyps are found, the possibility of autoimmune gastritis should be considered.

Pseudopolyps of the parietal mucosa When its destruction is almost complete, the remnants of preserved oxyntic mucosa protrude into the gastric lumen as scattered islands in a sea of atrophy. These areas of surviving, intact, albeit inflamed, native p arietal tissue are known as pseudopolyps and are similar to their intestinal counterparts found in the setting of IBD.20,106 Histologically, they consist of oxyntic mucosa mainly spared from chronic inflammatory infiltrates and atrophy.20,106 However, the oxyntic glands often demon-strate the pseudohypertrophic changes associated with early autoimmune gastritis. Endocrine-like-cell hyper-plasia is not a typical feature.20 These pseudopolyps are under-recognized in clinical practice because biopsy samples of the polyps alone, as might often be the case, will not demonstrate definitive features of atrophic gastritis and will shed little light on the pathology of the adjacent, atrophic mucosa. Thus, proper diagnosis by the pathologist requires communication from the endoscopist regarding the polypoid endoscopic impres-sion of the biopsied mucosa and appropriate sampling from the surrounding background.

Pyloric gland adenoma Pyloric gland adenoma, an entity described in 2002,107 is one of the many neoplasms that might arise in a back-ground of autoimmune gastritis. In two large series including a total of 131 pyloric gland adenomas, roughly one-third were reported to be from patients with auto-immune gastritis.107,108 However, even in the setting of autoimmune gastritis, these neoplasms are infrequently encountered.20 Nonetheless, practicing pathologists should be aware of this lesion: some authors, but not all, have reported that pyloric gland adenomas frequently contain high-grade dysplasia and might transition to car-cinoma in up to 30% of cases.107–109 Interested patholo-gists can find a detailed histopathological description of these polyps in Chen’s and Vieth’s series,107,108 and in a study detailing the GNAS and KRAS mutations in these polyps.110

Adenocarcinoma The histopathological spectrum of advanced stages of autoimmune atrophic gastritis includes corpus atrophy, intestinal metaplasia and spasmolytic

Figure 5 | Endocrine-like-cell dysplasia. Staining with anti-chromogranin antibodies demonstrates several clusters of endocrine-like cells arranged in a disorderly fashion with the appearance of an infiltrating pattern, in contrast to the round micronodules seen in the upper portion of the image. These irregular clusters, which result from the fusion of several micronodules, might lose their basement membrane and progress to deposit newly formed stroma in the lamina propria. These lesions, sometimes referred to as endocrine-like-cell dysplasia, are associated with an increased risk of the development of carcinoids.

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polypeptide-expressing metaplasia. As these features are recognized as preneoplastic lesions, autoimmune atrophic gastritis has traditionally been listed amongst the precancerous states of the stomach.111–113 The actual risk of gastric adenocarcinoma, however, remains con-troversial, with conflicting data resulting from small, often inadequately controlled studies. Thus, in 2012, publication of the first meta-analysis performed by using the calculated annual incidence rates of gastric adenocarcin oma in patients with documented perni-cious anaemia was particularly welcome.114 These authors analysed six European studies that included follow-up data in 453 patients and showed an annual incidence of gastric adeno carcinoma of 0.27% per person-year with an overall relative risk of 6.8 (95% CI 2.6–18.1).112,114–119 In the same study, the authors performed a wider analysis of 21 publications that had not been included in the origi-nal analysis because of lack of adequate follow-up data or endoscopic information, and the results were essentially similar.114 The authors conclude that there was a remark-able similarity of the incidence rates of gastric cancer amongst all studies, in spite of major hetero geneity of design, location, selection of patients, sample size, type and methods of follow-up, and methods for diagnosis of gastric cancer. By the authors’ own admission, however, this meta-analysis could not define the ‘general popu-lation’ to which incidence rates would have to be com-pared. Furthermore, given that many of the included studies spanned the pre-Helicobacter period, the addi-tional influence of this crucial risk factor could not be evaluated. This issue is highly problematic, particularly in light of the observation, made by one of the same authors a little over a decade ago, that one-third of patients with corpus atrophy have evidence of H. pylori infection.120 Even more relevant, data indicate that in a series of 562 patients with autoimmune atrophic gastritis only those with concurrent H. pylori infection had an increased risk of epithelial neoplasia.17 In the absence of solid evidence it would be inopportune to make any type of recommen-dations at this time. Thus, the follow-up of patients with autoimmune atrophic gastritis must be left in each case to the clinical judgment of the treating physician.121

Diagnosis The diagnosis of autoimmune gastritis rests on the dem-onstration of its characteristic histopathological fea-tures and the demonstration of autoantibodies against intrinsi c factor and parietal cells.

Biopsy sampling strategies Gastric mucosal atrophy, defined as a decrease of the structures present in the normal stomach,1,122 is simply a histopathological finding.123 To make a reliable and aetiologically specific diagnosis of atrophic gastritis, the pathologist should examine at the very least two topo-graphically identified biopsy specimens from the antrum and two from the corpus (Figure 1). The rationale for this separate sampling is detailed in the guidelines of the Updated Sydney System.124 Briefly, when foci of atrophy (metaplastic or not) are present in both gastric com-partments, the diagnosis is almost certainly multifocal atrophic gastritis, probably related to long-standing (and possibly no longer detectable) H. pylori infection.43,123 By contrast, if the antrum is either normal or shows reac-tive gastropathy with mild or moderate chronic inflam-mation only, and specimens from the corpus show atrophy, particularly with intestinal, pancreatic acinar and pseudo pyloric metaplasia, then a diagnosis of auto-immune atrophic gastritis is extremely likely.17,124 As autoimmune gastritis is often associated with endocrine-like-cell proliferations and neuroendocrine tumours, histopathol ogists should stain the corpus samples with chromogranin or synaptophysin.1,21,113,114,122,124–126

Although this practice should be discouraged, many clinicians submit multiple gastric biopsy fragments in a single formalin container. If they are all normal or at least no obvious atrophy of the oxyntic mucosa is present, no further workup is necessary. However, if features sug-gestive of a drop out of oxyntic glands are present, an immunohistochemical stain for gastrin-producing cells (G cells) will establish the origin of each fragment (G cells, abundant in the antrum, are rare or absent from the oxyntic mucosa) and determine whether corpus atrophy is present. Pepsinogen I staining, although not widely available in nonspecialized laboratories, is

a b

Figure 6 | A small neuroendocrine tumour (carcinoid) in the stomach of a patient with autoimmune atrophic gastritis. The tumour is circumscribed, and although it expands into the submucosa, the growth pattern is not infiltrative. a | Staining with hematoxylin and eosin. b | Staining with anti-chromogranin antibodies.

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also a very specific tool to identify the atrophic corpus by highlighting the native oxyntic commitment of the p seudopyloric metaplastic glands (Figure 7).127,128

Laboratory investigations Two laboratory analyses are helpful for the diagno-sis of autoimmune gastritis and indispensable for the diagnosis of pernicious anaemia: the demonstration of macrocytic anaemia (defined as a haemoglobin concen-tration <130 g/l for men and <120 g/l for women and a mean corpuscular volume >100 fl), and levels of cobala-min <350 pg/ml.129,130 Although it is recommended that serum vitamin B12 levels be obtained, the results are often unreliable.131 Thus, in the right clinical setting, if the clinical suspicion for vitamin B12 deficiency exists despite normal serum levels, further confirmatory testing measuring levels of methylmalonic acid, total homocysteine, or both might be helpful in making the diagnosis in patients who have not received vitamin B12 supplementation. Other serological studies helpful for diagnosis include the presence of intrinsic factor anti-bodies and parietal cell antibodies. Intrinsic factor deficiency used to be demonstrated using the Schilling test, a cumbersome multistep study that involves the ingestion of radiolabelled vitamin B12, followed by an injection of nonlabelled vitamin B12. Levels of labelled vitamin B12 are measured in the patient’s urine 24 h later. If low absorption is detected, the test is repeated after the oral administration of intrinsic factor, which will normalize absorption in patients with pernicious anaemia.132,133 The demonstration of autoantibodies against intrinsic factor, present in up to 80% of patients with pernicious anaemia, has now effectively replaced the Shilling test.130

The ‘virtual’ or ‘serological’ biopsy In the past decade, several studies have evaluated the value of combining various serological tests to assess the morphological and functional status of the gastric mucosa without actually visualizing it. These panels have become informally known as the ‘virtual’ or the ‘sero-logical’ biopsy. For example, a serological panel including anti-Helicobacter IgG antibodies, pepsin ogens I and II and gastrin-17 (available commercially as GastroPanel® [Biohit Oy, Finland]) has been shown to have a fair cor-relation with the presence of atrophy in gastric biop-sies.134–139 Antico et al.140 report the results of a study designed to evaluate the usefulness of a panel for the diagnosis of autoimmune atrophic gastritis by compar-ing serological and histopathological findings. The panel used included antibodies against parietal cells, intrinsic factor and H. pylori, and measured serum gastrin levels. The 181 patients tested included those with refractory iron deficiency anaemia or with macro cytic anaemia associated with vitamin B12 deficiency. Although the phenotypes of gastritis chosen to stratify patients (auto-immune gastritis, gastric atrophy, multifocal atrophic gastritis and nonspecific lymphocytic gastritis) prob-ably have considerable overlap (particularly the category gastric atrophy, which could be part of both auto immune and multifocal atrophic gastritis), the authors found that different patterns of serological responses were reliably associated with different histopathological fea-tures. For example, patients with multi focal atrophic gastritis (a consequence of H. pylori infection) had anti-bodies against H. pylori, but had normal gastrin levels and no antibodies against intrinsic factor or parietal cells, whereas those with the broad category gastric atrophy had elevated gastrin levels, antibodies against both intrinsic factor and parietal cells, and negative test results for H. pylori infection. The authors sensibly suggest that these serological panels could be useful to select patients who might benefit from an endoscopy with gastric biopsies.140

Clinical manifestations The distinction between autoimmune atrophic gastritis and its most dramatic outcome, pernicious anaemia, is crucial when addressing the clinical features of this con-dition. Atrophic gastritis, irrespective of its aetiology, does not cause specific signs or symptoms unless the degree of atrophy impairs the absorption of vitamin B12 and possibly other substances, including folate and iron. The development of vitamin deficiencies is a long process, and patients might have vague symptoms for many years before all reserves are depleted. Thus, it seems helpful to consider the following three different scenarios.

A patient with upper gastrointestinal symptoms In this scenario, routine gastric biopsy specimens are taken from a patient with one of the complaints that com-monly lead to an oesophagogastroduodenoscopy (EGD; for example, dyspepsia, bloating or heartburn). If the biopsy set is sufficient for the evaluation of both antrum and corpus, or the pathologist performs appropriate

a b

Figure 7 | Autoimmune gastritis in a biopsy sample obtained from the corpus mucosa. Serial histology sections of the same biopsy specimen are stained by a | hematoxylin and eosin and b | immunohistochemistry for pepsinogen I. Native oxyntic glands are replaced by a metaplastic population of glandular structures; goblet cells are the hallmark of metaplastic intestinalized glands (arrows). Few nonintestinalized glands stain positive for pepsinogen I (circle). The immunohistochemical stain reveals the native oxyntic commitment of the pseudopyloric metaplastic glands.

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staining and determines the origin of each specimen, a diagnosis of atrophic gastritis is possible (Figure 8). In the absence of H. pylori infection it is appropriate to indi-cate in a comment that, although autoimmune gastritis is likely, the diagnosis cannot be specific and it is i ncumbent upon the clinician to perform confirmatory tests.

The patient with vague systemic symptoms Patients who present with weakness, asthenia or cardiac symptoms (such as palpitations or chest pain) related to iron deficiency anaemia are usually referred to gastro-enterologists by general practitioners or other special-ists. Given that most of these patients are >50 years, the most common reason for the gastroenterology consultation is to exclude a gastrointestinal cancer, and both colonoscopy and EGD are commonly performed. Notably, however, iron deficiency anaemia is a common finding at presentation of autoimmune atrophic gastritis and might precede the onset of pernicious anaemia by several years. Building on observations made by Faber more than a century ago,141 Hershko et al.142 conducted a series of prospective studies in patients with refrac-tory iron deficiency anaemia and demonstrated that 40 of 150 patients (27%) had autoimmune atrophic gastri-tis (as evidenced by the presence of hypergastrinaemia and strongly positive antiparietal serum antibodies). More recently, these authors found that iron deficiency anaemia was the presenting feature in 83 of 160 patients (52%) with autoimmune atrophic gastritis, which sug-gests that iron deficiency anaemia might be the most common haemato logical presentation of this condi-tion.22 However, those patients presenting with iron defi-ciency anaemia were predominantly women, were about 20 years younger, and had a much greater prevalence of active H. pylori infection than those who presented with classic cobalamin deficiency and macrocytic anaemia. As a consequence, the patients with iron deficiency anaemia also had a much higher rate of chronic active inflammation than those without anaemia.

In these cases, the gastroenterologist should consider the possibility of atrophic gastritis, obtain appropriate biopsy samples, and be particularly attentive for small polyps in the corpus, which might represent neuroendo-crine tumours. If atrophy is detected histologically, the same steps outlined above (Figure 8) are recommended, including the performance of specific laboratory tests. Once the diagnosis of autoimmune gastritis is estab-lished, the patient should be evaluated for concurrent autoimmune conditions, especially thyroid disease.

The patient with pernicious anaemia Most patients in whom the diagnosis of pernicious anaemia is made by general practitioners, haematol-ogists or neurologists are not referred to a gastro-enterologist. Vitamin B12 supplements, to which iron and folate supplements are almost invariably added, resolve the anaemia and the other manifestations of cobalamin deficiency irrespective of the cause. When a patient with an established diagnosis reaches the gastro-enterologist, the first step is a gastroscopy. The purpose

is to confirm the diagnosis of corpus-restricted atrophic gastritis by obtaining topographically defined biopsy samples from the antrum, corpus and fundus, and to inspect for polyps. During the first gastroscopy, all polyps should be removed and submitted for histo-pathological examination in individual, topographically labelled containers.98,99 If concurrent H. pylori infection is detected, it should be treated. At this stage, nearly all patients will have endocrine-like-cell hyperplasia. If only simple, linear or micronodular hyperplasia is found and no epithelial dysplasia is present, a 3–5 year interval before the next gastroscopic evaluation has been sug-gested.130 Patients with endocrine-like-cell dys plasia are at increased risk of developing neuroendocrine tumours.126,143 Therefore, if such lesions are detected, more frequent evaluation would be appropriate. Patients with extensive metaplastic atrophy (OLGA stages III or IV), gastric epithelial dysplasia, adenomas, or foci of dys-plasia in hyperplastic polyps, should have a yearly EGD as part of a cancer surveillance programme.

Endoscopy The initial pre-atrophic stages of autoimmune gastritis are not associated with substantial macroscopic changes; therefore, the diagnosis cannot even be suspected endo-scopically. When atrophy is more extensive, gastric folds in the body and fundus might be flattened or absent, but the endoscopic assessment of atrophy suffers from low sensitivity and even lower specificity (Figure 9). Thus, irrespective of the stage, the role of endoscopy in

Corpus-predominantatrophic gastritis with

H. pylori infection

Treat H. pylori infection

No anaemiaAnti-IF Ab (–), anti-PC Ab (–)

Diagnosis: multifocalatrophic gastritis

Diagnosis:autoimmune gastritis

Macrocytic anaemiaAnti-IF Ab (+), anti-PC Ab (+)

Corpus-restrictedatrophic gastritis

No H. pylori infection

Measure vitamin B12 levels

Methylmalonic acid andtotal homocysteine levels

Normal Low

Normal Low

Diagnosis:autoimmune gastritis

Diagnosis:autoimmune gastritis with

pernicious anaemia

CBCAnti-IF Ab, anti-PC Ab

Figure 8 | Algorithm to be followed when the unexpected diagnosis of autoimmune gastritis is suggested in the histopathology report. Abbreviations: Ab, antibody; Anti-IF Ab, anti-intrinsic factor antibody; Anti-PC Ab, anti-parietal cell antibody; CBC, complete blood count.

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autoimmune gastritis is largely limited to the acquisition of mucosal samples and the removal of polyps.

Management Management of the early stages of autoimmune atrophic gastritis is focused on the prevention of vitamin B12, folate and iron deficiencies. Adequate supplementation of these substances will effectively prevent cobalamin depletion and the development of anaemia. When per-nicious anaemia, with or without extrahaemato logical manifestations of cobalamin deficiency, is already present, the initial strategy involves the parenteral repletion of the vitamin B12 reserves followed by life-long maintenance on oral cyanocobalamin, and oral iron supplementation as needed for full haemoglobin response. After an initial endoscopic evaluation, sur-veillance programs might be implemented as indicated above.131 Owing to the frequent association with other autoimmune disorders, particularly thyroiditis and

type 1 diabetes, the diagnosis of autoimmune gastritis at any stage should prompt a clinical and laboratory i nvestigation for these conditions.67,68,144–147

ConclusionsGastritis is a condition of changing fortunes. Hailed by François Broussais in 1822 as the central lesion at the origin of most diseases148 and vilified by Jean Cruveilhier as a nonexisting myth less than 20 years later,149 it attracted sporadic interest from clinical researchers during the following century, when Addison,3 Flint4 and Biermer5 described the atrophic gastric changes at the core of pernicious anaemia. Although research on other types of gastritis has benefitted from some reflected attention, the uncontested focus of the past 30 years has been H. pylori, a hitherto disregarded bacterium cultured in 1982 and quickly recognized as the indirect cause of peptic ulcer disease and most gastric malignancies. Improved sanitation and antibiotics have now begun to slowly displace H. pylori (as well as other pathogens) from much of the world, opening a pathway for the surge of allergic and auto immune diseases. The next generation of gastro enterologists might have to adjust to new nosological patterns, and the ability to recog-nize and treat a utoimmune g astritis might acquire increased importance.

Figure 9 | Endoscopic appearance of the gastric corpus in a patient with end-stage autoimmune gastritis. Courtesy of Professor I. Maguilnik, University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

Review criteria

The MEDLINE and PubMed databases were searched in July 2012 and in January 2013 for articles in English, French and German. The terms “atrophy”, “atrophic”, “autoimmune”, “multifocal”, “anemia”, “pernicious”, “megaloblastic”, “iron-deficiency”, “intrinsic factor”, “autoantibody”, “neuroendocrine” and “carcinoid” were combined with “stomach” and “gastric” to locate articles. Historical articles published prior to 1950 were retrieved from reference lists, which were also checked for additional relevant papers. Because these searches yielded a combined total in excess of 5,000 articles, inclusion was determined by the authors’ subjective evaluation of relevance.

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Author contributionsR. M. Genta and W. L. Neumann contributed to researching data for the article, discussion of content, writing, and reviewing/editing the manuscript before submission. E. Coss and M. Rugge researched data for the article, made substantial contributions to discussion of content and reviewed/edited the manuscript before submission.

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