자가면역에 의한 위축성 위염 2013 네이처!!

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multifocal atrophic gastritis and autoimmune atrophic gastritis

Autoimmune atrophic gastritis 2013 nature.pdf

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위축성 위염. a | 다발성 위축성 위염은 장기간의 헬리코박터 파일로리 감염에 의해 발생하며, 위저부 우세형 또는 전위염을 특징으로 하며, 다양한 정도의 대사성 위축(파란 반점)이 위저부를 반드시 포함하며, 위체부로 확장될 수 있습니다. b | 자가면역성 위염에서는 염증성 위축 과정이 위체부에만 국한되며(회색 변색), 위체부와 위저부 전체에 장상피, 가짜 위문부, 췌장 상피 변성 반점이 관찰됩니다. 시드니 시스템에서 권장하는 4개의 생검 샘플 위치가 표시되어 있습니다. 업데이트된 시드니 시스템은 각도각 부위에서 샘플을 채취하도록 권장하지만, 실제로는 거의 채취되지 않습니다.

1. nature  
2. nature reviews gastroenterology & hepatology  
3. review articles  
4. article

• Review Article
• Published: 18 June 2013

Autoimmune atrophic gastritis—pathogenesis, pathology and management

• William L. Neumann, 
• Elizabeth Coss, 
• Massimo Rugge & 
• Robert M. Genta 

Nature Reviews Gastroenterology & Hepatology volume 10, pages529–541 (2013)Cite this article

• 9787 Accesses

• 343 Citations

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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.

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

초록

자가면역 위염은

위 점막의 벽세포 조직이

위축 및 대사성 점막으로 대체되는 만성 진행성 염증성 질환입니다.

벽세포의 프로톤 펌프에 대한 자가항체와

감작된 T 세포의 복잡한 상호작용이

벽세포를 점차적으로 파괴하여 저염산증 및 무염산증을 유발하며,

내인성 인자에 대한 자가항체는 비타민 B12의 흡수를 방해합니다.

이로 인한 코발라민 결핍은

거대적혈구성 빈혈과 신경학적 및 전신적 증상 및 증후군으로 나타나는

악성 빈혈로 알려져 있습니다.

과거에는 주로 북유럽계 노인 여성에서 주로 발생하는 질환으로 여겨졌지만,

현재는 모든 인구 집단과 인종에서 발생함이 인정되었으나,

진단 복잡성으로 인해 신뢰할 수 있는 유병률 데이터는 없습니다.

유사한 이유와 헬리코박터 파일로리 감염과의 빈번하고 종종 알려지지 않은 중복으로 인해,

이 환자들에서 위암의 위험은 충분히 평가되지 않았습니다.

이 리뷰는

자가면역성 대사성 위축성 위염의 역학, 병인 및 병리학적 측면을 요약합니다.

또한 이 질환을 가진 환자의 진단 및 관리에 대한 실용적인 조언을 제공합니다.

핵심 포인트

• 위축성 위염은 장기간 지속된 Helicobacter pylori 감염(다발성 위축성 위염)과 위 점막을 점차적으로 파괴하는 자가면역 과정(자가면역성 위축성 위염)과 연관될 수 있습니다.
• 두 유형의 위축성 위염은 생검 샘플링이 불충분하기 때문에 진단이 미흡한 경우가 많습니다
• 자가면역성 위축성 위염은 위 체부의 경증 만성 염증에서 시작되어 비타민 B12 결핍성 빈혈의 심각한 형태인 악성 빈혈과 연관된 진행 단계로 발전합니다
• 전통적으로 자가면역성 위축성 위염은 북유럽계 노인 여성에서 주로 발생하는 질환으로 여겨져 왔지만, 최근 증거는 인종적 특이성이 없을 수 있음을 시사합니다
• 자가면역 위염의 진단은 특징적인 조직병리학적 소견과 내인성 인자 및 위벽 세포에 대한 자가항체의 검출을 기반으로 합니다
• 자가면역 위축성 위염의 초기 단계 관리에는 비타민 B12, 엽산 및 철분 결핍 예방에 초점을 맞춥니다

Introduction

Atrophy, derived from the Greek words α and τροφή (literally 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).

위축(atrophy)은 

그리스어 ‘α'와 'τροφή’(직역하면 ‘영양을 받지 않는’)에서 유래한 용어로, 

소모(예: 근육 위축)와 동의어로 사용됩니다. 

위 점막에 적용될 때 위축은 

원시 위샘의 감소 또는 소실로 정의되며, 

이들이 아무것도 대체되지 않았는지, 

섬유화로 대체되었는지, 

또는 정상적으로 존재하지 않아야 할 상피 유형(metaplasia)으로 대체되었는지 여부와 무관합니다.1 

위의 항문부와 체부 모두 영향을 받을 수 있지만, 

기능적 및 임상적 증상이 명확히 나타나는 것은 후자가 영향을 받을 때입니다.

 벽세포의 감소 또는 소실은 

산 생산의 감소 또는 소실(hypochlorhydria 또는 achlorhydria)과

 내인성 인자(intrinsic factor)의 상실을 초래합니다. 

위 pH의 상승은 

정상적으로 낮은 생리적 pH에 의해 억제되는 세균의 위 내 식민화를 가능하게 하며, 

이 세균은 질산염을 생성하고 발암을 촉진할 수 있습니다; 

필수 물질(철분과 비타민 B12 등)의 흡수를 방해하며; 

그리고 위체부의 가스트린 분비 세포를 지속적으로 자극하여 

위체부에서 내분비 유사 세포의 증식을 유도할 수 있으며, 

이는 신경내분비 종양(이전에는 카르시노이드로 알려져 있음)을 유발할 수 있습니다.

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 metaplastic mucosa, with preservation of the antrum (Figure 1b). Although the ultimate aetiology of this condition is unclear, we know that it results from a constellation 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 metaplastic 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 autoimmune atrophic gastritis has been somewhat obfuscated 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 conditions are resurfacing and we should be ready to recognize and treat them. Furthermore, some researchers believe that the improving sanitation and the resulting decreased childhood exposure to both infectious and noninfectious antigens might contribute to the observed increase in certain autoimmune and allergic conditions such as coeliac disease, eosinophilic oesophagitis, asthma 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 gastroenterologists 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. 

장기간 헬리코박터 파일로리 감염의 결과로 

위 전체에 산재한 패치 형태로 원시 위 구조의 점진적 소실은 

다발성 위축성 위염(그림 1)으로 알려져 있습니다. 

다른 환자군에서는 위벽 세포의 선택적 손실이 발생하며, 

이는 위체부의 보존과 함께 위벽 세포의 위축 및 대사성 변화로 대체됩니다(그림 1b). 

이 질환의 최종 원인은 명확하지 않지만, 

자가면역 현상의 복합체(일부는 아직 알려지지 않은 환경 요인에 의해 유발될 수 있음)에서 기인하며, 

다른 주요 자가면역 질환과 자주 동반됩니다. 

따라서 

이 질환은 자가면역 변성 위축성 위염으로 불리며, 

위체부의 경증 만성 염증에서 시작해 

비타민 B12 결핍성 빈혈의 심각한 형태인 악성 빈혈과 연관된 진행 단계로 발전하는 질환입니다. 

악성 빈혈의 임상적 묘사는 

그 원인(위체 위축성 위염)의 발견보다 수십 년 앞서 이루어졌으며, 

두 용어는 종종 잘못된 방식으로 동의어로 사용됩니다.2–5 

지난 30년간 

헬리코박터 파일로리 감염에 대한 과도한 주목으로 인해 

자가면역성 위체 위축성 위염의 중요성이 다소 흐려졌습니다. 

이로 인해 소화기 내과 의사 및 병리학자들은 

이 질환에 대한 친숙함을 잃었을 수 있습니다. 

현재 헬리코박터 파일로리 감염의 유병률이 감소하고 있으며, 

특히 서구 세계에서 이 현상이 두드러지고 있습니다.6–12 

이에 따라 

소홀히 다루어졌던 질환들이 다시 등장하고 있으며, 

우리는 이를 인식하고 치료할 준비가 되어 있어야 합니다. 

또한 일부 연구자들은 

위생 상태의 개선과 그에 따른 어린 시절의 감염성 및 비감염성 항원 노출의 감소가 

셀리악 병, 호산구 식도염, 천식 및 IBD와 같은 

특정 자가 면역 및 알레르기 질환의 증가에 기여할 수 있다고 생각합니다.13–16 

자가면역성 위염의 발생률도 증가 추세에 있을 수 있으며, 

이는 유사한 메커니즘에 의해 영향을 받을 수 있습니다.17 

이 리뷰의 목적은 

위 생검 샘플에서 위축성 위염의 조직병리학적 진단을 받은 경우, 

소화기 내과 의사들이 활용할 수 있는 최신 실용적 정보를 제공하는 것입니다. 

우리는 

자가면역성 대사성 위축성 위염의 역학, 병인, 병리학적 측면을 논의합니다. 

이어 임상 의사들이 

조직병리학적 소견을 확인하기 위해 필요한 추가 검사를 안내하며, 

치료 및 추적 관찰에 대한 제안을 제공합니다.

Epidemiology

Traditionally, 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 specificity.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 intestinal metaplasia’, thus failing to alert clinicians to the possibility 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 estimated an overall preval‎ence of 2%, with peaks of 4–5% among elderly women.24

역학 

전통적으로 악성 빈혈(그리고 이에 따른 진행성 자가면역성 위염)은 주

로 북유럽계 노인 여성에서 발생하는 드문 질환으로 여겨져 왔습니다.18,19 

여성의 발병 경향이 확인되었지만, 

최근 연구들은 인종적 특이성이 없을 수 있음을 시사합니다.17,20–26 

실제로, 일부 미국 연구에서는 

비백인 여성에서 악성 빈혈의 유병률이 더 높으며, 

백인 여성에 비해 발병 연령이 더 이른 것으로 나타났습니다.20,24,26,27 

역학 연구와 사례 보고서는 

자가면역성 위염과 악성 빈혈이 전 세계 모든 지역에서 존재하며, 

진단이 미흡할 수 있다는 개념을 지지합니다.27–36 

이 질환이 진단되지 않는 데는 여러 요인이 복합적으로 작용합니다. 

지역사회에서 대부분의 환자가 소구체성 또는 대구체성 빈혈로 증상을 보이기 때문에, 

빈혈의 근본 원인을 철저히 조사하지 않고 

철분, 엽산, 코발라민으로 치료하는 경우가 많습니다. 

일반 병리학자들은 

특정 기준에 익숙하지 않아 '장상피화성 만성 위염'과 같은 일반적인 진단을 내리기 쉽고, 

이로 인해 위축성 위염의 가능성을 임상 의사에게 알리지 못합니다. 

마지막으로, 

위 점막의 해부학적으로 명확히 정의된 생검 샘플을 채취하지 않는 소화기 내과 의사들은 

병리학자들이 진단을 의심하는 것조차 어렵게 만듭니다. 

이러한 이유와 다른 요인들로 인해 

일반 인구에서 자가면역성 위염의 유병률을 구체적으로 평가하는 연구를 수행하기 어렵습니다. 

가장 최근의 표적 조사에서는 

전체 유병률이 2%로 추정되었으며, 

노인 여성에서 4–5%의 피크를 보였습니다.24

Relationship with H. pylori infection

In 1998, an article on the relationship between gastric H+,K+ATPase (the proton pump responsible for acid secretion, highly expressed in the parietal cell canaliculi), 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 specificity, and the time of its development before and after eradication will become an important research issue for the eval‎uation and understanding of the longterm outcome of H. pylori infection”.37 15 years later, in spite of the continuing interest and considerable progress made in this area, particularly in animal models, the aetiology and pathogenesis of human autoimmune gastritis remain elusive.

헬리코박터 파일로리 감염과의 관계

1998년, 

위 H+,K+ATPase(산 분비에 관여하는 프로톤 펌프, 위벽 세포의 관상 구조에서 고도로 발현됨) 

H. pylori 감염 및 체부 제한성 위축성 위염에 대한 논문이 발표되었으며, 

이 논문은 “위장관 자가면역 반응의 연구, 그 특이성, 

그리고 H. pylori 박멸 전후의 발생 시기가 

H. pylori 감염의 장기적 결과 평가 및 이해를 위한 중요한 연구 주제로 부상할 가능성이 높다”는 

결론으로 마무리되었습니다.37 

15년 후, 

이 분야에 대한 지속적인 관심과 특히 동물 모델에서 이루어진 상당한 진전에도 불구하고, 

인간 자가면역성 위염의 병인 및 병리 메커니즘은 여전히 미해결 상태입니다.

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 pangastritis, 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 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 autoimmune 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 inflammatory and atrophic changes in the oxyntic compartment;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 ‘preatrophic’ stage) have been invoked to further support the plausibility of a causal relationship between H. pylori and gastric autoimmunity.47–49

이 매우 복잡한 문제를 과도하게 단순화할 위험을 감수하고, 

위축성 위염 환자의 인구를 세 그룹으로 나눌 수 있습니다.

첫 번째 그룹은

‘순수한’ H. pylori 감염을 특징으로 하며,

전위염, 다발성 변성 위축, 자가항체 음성을 보입니다.

두 번째 그룹은

‘순수한’ 자가면역성 위염을 특징으로 하며,

체부 제한성 변성 위축, 정상 또는 반응성 항문부,

과거 또는 현재 H. pylori 감염의 증거가 없습니다.

세 번째 그룹은

최소(‘전위축성’)에서 중증까지의 체부 위축성 대사성 위염을 보이는 환자들로,

정상 또는 염증성 위저부,

현재 또는 과거 H. pylori 감염의 증거,

위 조직(특히 H+,K+ATPase)에 반응하는 자가항체를 포함합니다.

첫 번째 및 두 번째 그룹의 환자는

자가면역 위축성 위염의 병인 또는 병리 메커니즘에 대한 단서를 제공하지 않지만,

세 번째 그룹은 H. pylori 감염과 자가면역 위염 간의 인과 관계 탐색에서

주요 연구 대상이 되어 왔습니다.38–45

H. pylori 위염을 가진 환자 하위 그룹에서

자가면역 경로의 가능성은 다음과 같은 다양한 증거로 뒷받침됩니다:

첫째, 선체 점막의 상피층 주변 및 내부에 B 세포와/또는 T 세포의 유입 증가;37

둘째, 산성 부위에서 염증 및 위축 변화의 주된 심각성;17,39

셋째, 산성 선체에서의 세포 사멸 증가;41

넷째, 위산 분비 감소와 동시에 가스트린 수치 증가.46

또한, H. pylori 감염 제거가 자가면역 위염의 초기 단계(‘전위축기’)를 중단하거나 역전시킬 수 있다는 주장은

H. pylori와 위 자가면역 사이의 인과 관계 가능성을 추가로 뒷받침합니다.47–49

In spite of these pieces of largely circumstantial evidence, however, consistent proof that molecular mimicry contributes to autoreactivity is lacking, and the identity 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 identified 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 autoimmune 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 immunemediated diseases, including autoimmune gastritis.54,55 This argument is fallacious, as association does not prove causation. Other mechanisms for the pathogenesis 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 gastritis,56 although the low sensitivity of this finding makes it unsuitable for diagnostic purposes. In spite of these pieces of largely circumstantial evidence, however, consistent proof that molecular mimicry contributes to autoreactivity is lacking, and the identity 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 identified 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 autoimmune 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 immunemediated diseases, including autoimmune gastritis.54,55 This argument is fallacious, as association does not prove causation. Other mechanisms for the pathogenesis 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 gastritis,56 although the low sensitivity of this finding makes it unsuitable for diagnostic purposes. 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.

그러나 이러한 주로 간접적인 증거에도 불구하고, 

분자 모방이 자가반응성에 기여한다는 일관된 증거는 부족하며, 

인간 항위액 자가항체가 인식하는 에피토프의 정체는 아직 밝혀지지 않았습니다. 

H. pylori에 감염된 환자 및 

자가면역 위축성 위염 환자로부터 분리된 클론화된 T 세포를 사용한 연구는 

H. pylori, 수소 및 칼륨 수용체, ATPase 사이의 분자 모방 현상을 확인했으며, 

이는 감염이 위벽 세포를 표적으로 하는 T 세포를 자극할 수 있음을 시사합니다.50 

이러한 연구는 

H. pylori와 위 상피 항원 사이의 교차 반응 메커니즘이 

자가면역 위염의 병인에 책임이 있거나 적어도 참여할 수 있다는 개념을 지지합니다. 51–53 

H. pylori 감염의 현재 또는 과거(혈청학적으로 확인된) 동시 존재는 

H. pylori가 자가면역 위염을 포함한 광범위한 면역매개 질환의 병인에 관여한다는 

증거로 제시되기도 합니다.54,55 

그러나 이 주장은 오류입니다. 

연관성은 인과 관계를 증명하지 않기 때문입니다. 

자가면역 위염의 병인에 대한 다른 메커니즘도 간헐적으로 연구되어 왔으며, 이 중 IgG4의 역할이 포함됩니다. IgG4는 자가면역 췌장염의 병인에 참여하는 것으로 알려져 있으며, 위 생검에서 발견된 IgG4 면역반응성 플라즈마 세포는 자가면역 위축성 위염에 100% 특이적이었지만, 이 발견의 낮은 민감도로 인해 진단 목적으로는 부적합합니다. 그러나 이러한 주로 간접적인 증거에도 불구하고, 분자 모방이 자가반응성에 기여한다는 일관된 증거는 부족하며, 인간 항위장 자동항체가 인식하는 에피토프의 정체는 아직 밝혀지지 않았습니다. H. pylori에 감염된 환자 및 자가면역 위축성 위염 환자로부터 분리된 클론화된 T 세포를 사용한 연구는 H. pylori, 수소 및 칼륨 수용체, ATPase 사이의 분자 모방 현상을 확인했으며, 이는 감염이 위벽 세포를 표적으로 하는 T 세포를 자극할 수 있음을 시사합니다.50 이러한 연구는 H. pylori와 위 상피 항원 사이의 교차 반응 메커니즘이 자가면역 위염의 병인에 기여하거나 적어도 참여할 수 있다는 개념을 지지합니다. 51–53 H. pylori 감염의 현재 또는 과거(혈청학적으로 확인된) 동시 존재는 H. pylori가 자가면역성 위염을 포함한 광범위한 면역매개 질환의 병인에 관여한다는 증거로 제시되기도 합니다.54,55 그러나 이 주장은 오류입니다. 연관성은 인과 관계를 증명하지 않기 때문입니다. 자가면역 위염의 병인에 대한 다른 메커니즘도 간헐적으로 연구되어 왔으며, 이 중 IgG4의 역할이 포함됩니다. IgG4는 자가면역 췌장염의 병인에 참여하는 것으로 알려져 있습니다; 위 생검에서 발견된 IgG4 면역반응성 플라즈마 세포는 자가면역 위축성 위염에 대해 100% 특이적이었지만,56 이 결과의 낮은 민감도는 진단 목적으로 적합하지 않습니다. 신생아 시기에 흉선 제거된 쥐의 비장 세포59 또는 동물 면역 체계의 고도로 조작된 실험과 같은 다른 복잡한 조작에서도 유사한 결과가 관찰되었습니다. 이러한 모델을 연구함으로써 병리학적 메커니즘에 대한 중요한 정보가 생성되지만, 인간 질환에 대한 직접적인 관련성은 여전히 불분명합니다.

Associations with other autoimmune diseases

Autoimmune gastritis has been associated with other autoimmune diseases, particularly thyroiditis, since the early 1960s;60–65 the expression‎ ‘thyrogastric autoimmunity’ was used to describe the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anaemia.60,66–68 Other autoimmune diseases with an increased incidence amongst those with autoimmune gastritis include type 1 diabetes, vitiligo and Addison disease.69,70 Pernicious anaemia has also been described in patients with various immunodeficiency 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 recognized, and a few reported cases involving monozygotic twins and triplets further support a heritable component 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

다른 자가면역 질환과의 연관성 

자가면역 위염은 1960년대 초반부터 다른 자가면역 질환, 

특히 갑상선염과 연관되어 왔으며;60–65 

'갑상선-위장관 자가면역' ‘thyrogastric autoimmunity 이라는 용어가 

악성 빈혈 환자에게서 갑상선 자가항체나 자가면역 갑상선 질환이 존재하는 경우를 

설명하기 위해 사용되었습니다.60,66–68 

배경 위체 위축성 위염(ABG)은 자가면역 갑상선 질환(AITD) 환자에서 조직학적으로 특성화되지 않았으며, 그 유병률은 간접적 증거에만 의존해 이전에 평가된 것과 크게 다를 수 있습니다.

목적 AITD 환자에서 ABG의 존재를 검출하고 특성화하는 것입니다.

방법 AITD 환자 62명(남성 5명, 여성 57명, 연령 21~74세)을 대상으로 혈청 가스트린 수치를 측정하여 ABG의 존재를 스크리닝했습니다. 고가스트린혈증을 보이는 환자는 위내시경 검사를 받은 후 다중 생검 표본의 조직학적 검사를 진행했습니다. ABG의 진단은 고가스트린혈증과 펜타가스트린 저항성 무산증으로 정의되었으며, 조직학적 검사로 확인되었습니다.

결과 62명 중 22명(35%)이 고가스트린혈증을 나타냈으며(평균 ± SEM 가스트린 수치: 1070 ± 288 pmol/L). 22명 모두에서 ABG 진단이 조직학적 검사로 확인되었으며, 위축 정도는 중등도에서 중증에 해당했습니다. 그룹 A(20-40세; n=21)에서는 6명(29%)이 ABG를 보였으며, 그룹 B(41-60세; n=30)에서는 11명(37%), 그룹 C(61-80세; n=11)에서는 5명(45%)이 ABG를 보였습니다. 위벽 세포 항체는 ABG를 가진 환자 중 68% (15/22)에서만 검출되었습니다. AITD와 ABG를 가진 환자 중 82% (18/22)에서 빈혈이 관찰되었지만, ABG가 없는 환자 중에서는 22% (9/40)에서만 관찰되었습니다 (P<.0001).

결론 본 연구에서 AITD를 가진 환자 중 약 1/3이 ABG를 가지고 있었으며, 이는 젊은 환자에서도 진단되었습니다. 가스트린 수치 측정은 ABG 진단에 가장 신뢰할 수 있는 도구로 나타났으며, 빈혈(미세적혈구성 포함)의 존재는 진단되지 않은 ABG를 시사했습니다.

자가면역 위염 환자에게서 발생률이 높은 다른 자가면역 질환에는 

제1형 당뇨병, 백반증 및 아디슨 병이 포함됩니다.69,70 

악성 빈혈은 

IgA 결핍, 18q 염색체 결손 증후군 및 X-연관 저감마글로불린혈증과 같은 

다양한 면역결핍 증후군 환자에서도 보고되었습니다. 

굿 증후군 및 일반 변이성 면역결핍증과 같은 면역결핍 증후군에서 보고되었습니다.71–74 악성 빈혈의 가족 내 집적 현상은 오래전부터 인정되어 왔으며, 일란성 쌍둥이와 삼둥이를 포함한 몇 가지 보고된 사례는 이 질환의 유전적 요소를 추가로 뒷받침합니다.75–78 그러나 자가면역성 위염의 유전적 측면은 여전히 잘 이해되지 않고 있으며, 이 질환의 분자적 메커니즘을 규명하기 위한 추가 연구는 시급히 필요하다고 주장됩니다.58

Pathology

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

병리학
자가면역성 위염은 장기간에 걸쳐 위체부에서 만성 염증으로 시작되어 최종적으로 산성 분비선(oxyntic glands)이 대사성 점막으로 대체되는 조직병리학적 변화의 스펙트럼을 나타냅니다. 구조적 위축이 기능적 장애로 이어지면서 산 분비량이 점차 감소하며, 증가한 가스트린 수치가 신경내분비 과형성을 촉진합니다.

Macroscopic appearance

Knowledge of the macroscopic appearance of the stomach of patients with autoimmune atrophic gastritis 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 endoscopic appearance of the atrophic stomach, will find a description below. From the pathologist’s perspective, it will suffice to say that in the early inflammatory stages there are no distinctive 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).

거시적 소견
자가면역 위축성 위염 환자의 위의 거시적 소견은 주로 부검 소견에 기반해 왔습니다. 위축을 보이는 환자가 위절제술을 받는 경우가 드물기 때문입니다. 위절제술과 부검이 점차 사라지면서 현재 세대의 병리학자들은 악성 빈혈 환자의 위를 직접 관찰하지 않고도 전문직 생활을 마칠 수 있을 것입니다. 위내시경적 소견을 알아야 하는 소화기 내과 의사들은 아래 설명을 참고할 수 있습니다. 병리학자의 관점에서 보면, 초기 염증 단계에서는 특이적인 거시적 점막 변화가 없습니다. 위축이 진행됨에 따라 점막은 얇아지고 주름이 평평해집니다. 위 전체를 검사할 때 위체는 얇고 평평한 주머니처럼 보이며, 그 위에 작은 결절(가성 폴립, 과형성 또는 선종성 폴립 및 신경내분비 종양)이 관찰될 수 있습니다(그림 2).

Microscopic features

Histopathologically, autoimmune gastritis is characterized by diffuse corpus-restricted atrophic gastritis with variable proportions of intestinal metaplasia, pseudopyloric metaplasia (now referred to as spasmolytic polypeptide-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 multifocal, 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 ‘snouting’ (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 recommend appropriate serologic tests for antiparietal cell and anti-intrinsic factor autoantibodies.87 The second phase (florid) is characterized by diffuse lymphoplasmacytic 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, particularly 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 widespread and the muscularis mucosae might be considerably thickened. Although scattered lymphoid aggregates are often present, inflammation is usually minimal and the atrophic mucosa has an empty look. Endocrinelike cell hyperplasia, sometimes detectable in the florid phase, is almost invariably present in the advanced form 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 pseudopyloric metaplasia and mononuclear inflammation of the remaining oxyntic glands. Pathologists, often faced with limited clinical history and gastric biopsy specimens 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 pseudopyloric and focal intestinal metaplasia and sparse parietal cells to be erroneously interpreted as a fragment of transitional zone (with or without coexisting intestinal metaplasia). 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 endocrine-like cell hyperplasia (see below). 

The gastric antrum in autoimmune gastritis

The sparing of the antrum is part of the definition of autoimmune ‘corpus-restricted’ atrophic gastritis. However, two important exceptions exist. When autoimmune 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

자가면역성 위염에서의 위 항문부
위 항문부의 보존은 자가면역성 ‘체부 제한성’ 위축성 위염의 정의에 포함됩니다. 그러나 두 가지 중요한 예외가 존재합니다. 자가면역성 위염이 헬리코박터 파일로리(H. pylori) 감염과 동시에 발생할 경우, 위 항문부는 H. pylori 위염의 전체 스펙트럼을 나타낼 수 있으며, 장기 감염 시 위축과 대사성 변화가 포함될 수 있습니다; 순수한 자가면역성 위염에서 두드러지지 않는 특징인 활성 염증이 이러한 환자의 체부에서 자주 발견됩니다.55 이러한 경우, 자가면역성 위염 진단을 내리기 위해서는 위벽 세포 항체와 내인성 인자 항체 양성 결과가 확인되어야 합니다. 위암 위험 평가를 위한 시스템인 OLGA(위염 평가를 위한 수술적 링크) 단계 분류는 자가면역성 위염 환자를 대상으로 한 연구에서 테스트되었습니다.90,91 H. pylori 위염 환자를 대상으로 한 연구와 유사하게,92,93 위축 단계가 낮은 단계가 주로 관찰되었습니다. 우연히 발견된 위 종양(상피내 및 침윤성 모두)은 위 antrum 부위의 위축이 동반된 경우에만 발생했으며, H. pylori 감염과 동반되었습니다.17

A second situation, possibly rare and certainly uncommonly recognized, involves a distinctive form of atrophic gastritis that differs markedly from both multifocal 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 pangastric 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 neuroendocrine hyperplasia was not observed. All patients had systemic autoimmune or connective tissue diseases, including four cases of autoimmune enterocolitis. The authors proposed that the distinctive histology of this form of atrophic pangastritis and its association with systemic autoimmune disease suggests an autoimmune process directed against multiple cell lineages in the stomach.94

두 번째 상황은 드물고 확실히 드물게 인식되는 것으로, 다발성 및 자가면역 위 위축성 위염과 현저히 다른 독특한 형태의 위 위축성 위염을 포함합니다. 8명의 환자에 대한 상세한 보고에서,94 저자들은 심한 선상 위축 단계까지 지속되는 강한 점막 염증 침윤이 위의 몸통과 위저부 모두에 균일하게 분포하는 전위성 분포를 보였다고 설명했습니다. 8명의 환자 중 누구도 현재 또는 과거 H. pylori 감염의 증거가 없었으며, 신경내분비 과형성은 관찰되지 않았습니다. 모든 환자는 전신성 자가면역 질환 또는 결합 조직 질환을 동반했으며, 이 중 4명은 자가면역성 장염을 포함했습니다. 저자들은 이 형태의 전위성 위염의 독특한 조직학적 소견과 전신성 자가면역 질환과의 연관성이 위의 다중 세포 계통을 대상으로 한 자가면역 과정을 시사한다고 제안했습니다.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 inflammatory 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 hypochlorhydria or achlorhydria occurs, a chronic state of sustained hypergastrinaemia results. In chronic hypergastrinaemic states, gastrin stimulates endocrine-like cells to proliferate. 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 hypertrophied 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 consecutive neuroendocrine 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 neuroendocrine 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 adenomatoid hyperplasia have low potential for progression to neuroendocrine 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, might progress to become microinvasive with deposition of newly formed stroma in the lamina propria (Figure 5).

These lesions are sometimes 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 identified at endoscopy have been referred to as microneuroendocrine tumours (or microcarcinoids), whereas neuroendocrine proliferations that are >500 μm and are endoscopically identified are classified as neuroendocrine 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 >500μm, 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 autoimmune atrophic gastritis are typically small (<1 cm), tend to be multiple, and almost invariably coexist with multifocal enterochromaffin-like-cell hyperplasia. Histologically, they consist of nests or ribbons of endocrine cells with the characteristic ‘salt and pepper’ chromatin, and have very low mitotic and proliferation indexes.95,96 These carcinoids have essentially no malignant potential.

Hyperplastic polyps

Hyperplastic polyps are found in 1.3% of all US outpatients who undergo upper endoscopies in communitybased 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 hyperplastic 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 parietal 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 demonstrate the pseudohypertrophic changes associated with early autoimmune gastritis. Endocrine-like-cell hyperplasia 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 impression 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 background 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 autoimmune 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 carcinoma in up to 30% of cases.107–109 Interested pathologists 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 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 controversial, 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 adenocarcinoma in patients with documented pernicious 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 adenocarcinoma 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 original 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 remarkable similarity of the incidence rates of gastric cancer amongst all studies, in spite of major heterogeneity 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 population’ to which incidence rates would have to be compared. Furthermore, given that many of the included studies spanned the pre-Helicobacter period, the additional 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 recommendations 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 demonstration of its characteristic histopathological features and the demonstration of autoantibodies against intrinsic 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 topographically 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 compartments, 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 reactive gastropathy with mild or moderate chronic inflammation only, and specimens from the corpus show atrophy, particularly with intestinal, pancreatic acinar and pseudopyloric metaplasia, then a diagnosis of autoimmune atrophic gastritis is extremely likely.17,124 As autoimmune gastritis is often associated with endocrinelike-cell proliferations and neuroendocrine tumours, histopathologists 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 suggestive 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 also a very specific tool to identify the atrophic corpus by highlighting the native oxyntic commitment of the pseudopyloric metaplastic glands (Figure 7).127,128

Laboratory investigations

Two laboratory analyses are helpful for the diagnosis of autoimmune gastritis and indispensable for the diagnosis of pernicious anaemia: the demonstration of macrocytic anaemia (defined as a haemoglobin concentration <130 g/l for men and <120 g/l for women and a mean corpuscular volume >100 fl), and levels of cobalamin <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 antibodies 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 ‘serological’ biopsy. For example, a serological panel including anti-Helicobacter IgG antibodies, pepsinogens I and II and gastrin-17 (available commercially as GastroPanel® [Biohit Oy, Finland]) has been shown to have a fair correlation with the presence of atrophy in gastric biopsies.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 comparing 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 macrocytic anaemia associated with vitamin B12 deficiency. Although the phenotypes of gastritis chosen to stratify patients (autoimmune gastritis, gastric atrophy, multifocal atrophic gastritis and nonspecific lymphocytic gastritis) probably have considerable overlap (particularly the category gastric atrophy, which could be part of both autoimmune and multifocal atrophic gastritis), the authors found that different patterns of serological responses were reliably associated with different histopathological features. For example, patients with multifocal atrophic gastritis (a consequence of H. pylori infection) had antibodies 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 condition. 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 commonly 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 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 indicate in a comment that, although autoimmune gastritis is likely, the diagnosis cannot be specific and it is incumbent 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 gastroenterologists by general practitioners or other specialists. 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 refractory iron deficiency anaemia and demonstrated that 40 of 150 patients (27%) had autoimmune atrophic gastritis (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 suggests that iron deficiency anaemia might be the most common haematological presentation of this condition.22 However, those patients presenting with iron deficiency 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 neuroendocrine 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 established, 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, haematologists or neurologists are not referred to a gastroenterologist. 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 gastroenterologist, 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 histopathological 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 suggested.130 Patients with endocrine-like-cell dysplasia 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 dysplasia 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 endoscopically. 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 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 pernicious anaemia, with or without extrahaematological manifestations of cobalamin deficiency, is already present, the initial strategy involves the parenteral repletion of the vitamin B12 reserves followed by lifelong maintenance on oral cyanocobalamin, and oral iron supplementation as needed for full haemoglobin response. After an initial endoscopic eval‎uation, surveillance 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 investigation for these conditions.67,68,144–147

Conclusions

Gastritis 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 autoimmune diseases. The next generation of gastroenterologists might have to adjust to new nosological patterns, and the ability to recognize and treat autoimmune gastritis might acquire increased importance.