Atrophic Gastritis

Etiology

Although the etiology of atrophic gastritis is still being debated, we know H. pylori bacteria are the main culprit for chronic atrophic gastritis. Over time, this can lead to progressive loss and destruction of gastric glands described as multifocal atrophic gastritis. The prevalence of the infection is almost 50% of the world population. H. pylori were initially found to be the cause of gastric and duodenal ulcers in the early 1980s. The difficulty arises in the management of individuals infected with the pathogen that can then adversely affect the management of esophageal disease.[3][5]

Autoimmune gastritis is due to the destruction of oxyntic mucosa cells from autoantibodies against the H+/K+ ATPase antigen protein resulting in mucosal atrophy. This autoimmune reaction predominantly attacks the body and fundus of the stomach where the oxyntic cells are located (parietal and chief cells), sparing the antrum.[6][7]

Epidemiology

Chronic atrophic gastritis is more prevalent in the older population, although it is variable in different regions of the world. The difficulty arises due to the asymptomatic nature of the condition in most individuals.[8]

Age

In a population-based cohort study in Germany diagnosed on the serological assessment of pepsinogen 1 and H. pylori testing, the prevalence increased from 4.8% in the 50 to 54 age group to 8.7% in the 70 to 74 age group. This difference was observed to be higher in Japan, rising from 2.7 to 9.1%.[9][10]

Autoimmune atrophic gastritis is prevalent in the older women of Northern European and Scandinavian origin but has now been found to exist in every ethnicity, region, and age.[11]

Age and Helicobacter Pylori

There is a higher prevalence of CAG in older individuals with H. pylori infection and slightly more common in men. Prevalence was observed in serological pepsinogen and endoscopic biopsy testing. In higher incidence areas like Japan and China, this varies to as high as 33% to 84%.[12][9]

Overall there is a wide variation in the risk of gastric adenocarcinoma developing in individuals with premalignant conditions like CAG (GA/IM) with a <1% annual incidence (person-year) irrespective of whether the individual is from a low risk or high-risk group.[13]

There are two different types of malignancies associated with CAG, gastric adenocarcinoma linked to H pylori infection and a neuroendocrine gastrin dependent tumor (type 1 gastric carcinoid) secondary to hyperplasia of the enterochromaffin-like cells.[2]

Atrophic Gastritis and Cancer Risk

Endoscopic surveillance was performed in another cohort study for individuals with H pylori AG to identify the risks of gastric cancer. The mean duration of follow-up endoscopy was 6.2 +/- 4.8 years. The cumulative 5-year incidence of gastric adenocarcinoma ranged between 0.7% in no or mild AG to 10% in severe AG.[14][15]

Pathophysiology

The risk of gastric cancer in individuals is related to a combination of three different sets of etiologies: the primary H. pylori infection and the host’s ability of an immune response, the host’s susceptibility to atrophic gastritis from chronic inflammation, and environmental factors like cigarette smoking and high salt intake.

H. pylori may cause non-atrophic gastritis (NAG) initially that may be susceptible to cure by clearing the infection; however, severe NAG might lead to atrophy of the mucosa and pseudopyloric metaplasia. At this stage, progression to atrophy depends on the virulence of the bacteria like the presence of cag-positive vacA s1m1 strains vs. cag-negative vacA s2m2 strains in non-atrophic gastritis (NAG).[16]

Multifocal Atrophic Gastritis (MAG) or Type B Gastritis

A prolonged inflammatory process, mostly due to H. pylori, leads to a gradual loss of glandular oxyntic mucosa. This starts in the body and antrum and then spreads throughout the stomach, and it is called multifocal atrophic gastritis (MAG). The reducing levels of pepsinogen 1 are an indicator of the degree of atrophy of the oxyntic cells. Pepsinogen 2 levels rise due to their contrasting stimulation by the inflammation by H. pylori and hyperplasia of the foveolar cells. Pepsinogen levels and pepsinogen 1/pepsinogen 2 ratio can predict extensive atrophic gastritis.[17]

Autoimmune Metaplastic Atrophic Gastritis (AMAG) or Type A Gastritis

This elusive syndrome is uncommon and may also have concomitant H pylori infection. It is largely asymptomatic in the early stages. It involves severe diffuse atrophy of the oxyntic cells (parietal cells) in the body and fundus but not in the antrum due to an autoimmune reaction from anti-parietal cell antibodies. This causes hypochlorhydria raising the pH in the stomach. The intrinsic factor, which is essential for vitamin B12 absorption, is secreted from the parietal cells. Lack of intrinsic factor leads to pernicious anemia, the hematological manifestation of this autoimmune process.[18][6][19]

Intestinal Metaplasia

The lost gastric epithelial mucosa is eventually replaced by intestinal-type mucosa, which may be small intestinal or colonic type depending on the morphology and immunohistochemistry. There may be small intestinal goblet cells amongst enterocytes and may have microvilli giving a ‘brush border’ appearance.[20]

The colonic type of intestinal metaplasia shows a large bowel phenotype and mucin expression. The digestive enzymes are not detectable all the time and hence are termed ‘incomplete.’ This mucosa does not have microvilli and has a variety of mucin cells. Incomplete mucosa and a large area of involvement of this type of intestinal metaplasia carry a higher risk of being pre-malignant.[10]

Histopathology

H. pylori are the most frequent cause of gastritis with the infiltration of polymorphonuclear neutrophils and mononuclear leukocytes in the mucosa and lamina propria. The severity of the inflammation depends on the strain of H. pylori, and marked acute inflammation can predispose to microabscesses. In chronic gastritis, there is an accumulation of mononuclear leukocytes in the lamina propria and the presence of lymphoid aggregates with germinal centers.[21]

The histological features include pallor, loss of gastric folds, prominent vessels, and an atrophic border (demarcation of pale atrophy where normal pink border ends).[22]

It is suggested that the extent of the atrophic border with the normal pink mucosa is directly related to the prediction of CAG progression to GC risk. In certain circumstances, corpus biopsies can provide valuable information as prolonged proton pump inhibitor use can have almost no infiltration of H. pylori, and the oxyntic mucosa affected is more proximal to the antrum.[23]

On standard white light endoscopy, IM appears as small grey-white slightly elevated plaques with surrounded uneven patchy pale and pink mucosa.[24] When IM spreads, straight glands become elongated and in a groove pattern like those in the antrum.[25]

Metaplasia is defined as the replacement of the differentiated mucosa type into another differentiated cell type, not normal for the organ. Intestinal metaplasia involves the replacement of gastric mucosa with intestinal mucosa characteristically, goblets cells, enterocytes, and colonocytes.[26]

History and Physical

The classical presentation would suggest individuals presenting with epigastric pain, nausea, and occasionally vomiting; however, this is rare. The most common presentation is anemia. This can manifest as generalized weakness, tiredness, headaches, and palpitations.[27]

We know that most of the individuals with H. pylori-induced multifocal atrophic gastritis are asymptomatic.  The symptoms, if present, like nausea and vomiting, are short-lived and recurrent.[28]

Similarly, autoimmune metaplastic atrophic gastritis usually has nonspecific signs and symptoms in mostly females over 60 years of age.[29]

Pernicious anemia can develop in AMAG with an overall prevalence of 0.1%. It can present with fatigue, dizziness, irritability, depression, insomnia, and mood swings. Occasionally, it can present with normal vitamin B12 levels.[30]

Most individuals are already treated for their iron, folate, or vitamin B12 deficiency without a confirmed underlying diagnosis.[11]

The presentation can be variable and can lead to diagnostic difficulty when individuals have associated autoimmune conditions such as hypothyroidism, myelodysplastic syndromes, sideroblastic anemia, or coexisting iron deficiency anemia and thalassemia.[30]

The physical examination is of limited use and is usually nonspecific with rare evidence of pallor, anemia, and emaciation due to poor appetite, but these are uncommon.

In AMAG, there may be stigmata of associated autoimmune disease with jaundice, tachycardia, and a systolic murmur.[30]

Evaluation

It is evident from all guidelines worldwide that chronic atrophic gastritis or intestinal metaplasia patients are at risk of gastric adenocarcinoma. The aim is to identify advanced stages of gastritis with atrophy and intestinal metaplasia in the antrum and the corpus mucosa to prevent progression to high-grade dysplasia and invasive carcinoma. High-quality endoscopy is the gold standard.

Pepsinogen Levels

Low pepsinogen 1 levels and a low pepsinogen 1/pepsinogen 2 ratio can predict advanced atrophic gastritis and should be followed by endoscopy. It was concluded that a combination of pepsinogen, H. pylori status, and gastrin-17 levels is a good diagnostic test for the diagnosis of atrophic gastritis in populations at high risk of GC.[31]

In a meta-analysis of a study population of more than 32000 individuals to identify individuals at risk of GC and CAG, the risk of development of GC from a positive pepsinogen test 

A value of .3+ had a sensitivity of 57% and specificity of 76%.[32]

Endoscopy

The recent update in guidance on the investigation and management of gastric precancerous lesions (GPL) relate to publications from the European Society of Gastroenterological Endoscopy in association with European Societies (management of epithelial precancerous conditions and lesions in the stomach (MAPS II) and the American Gastroenterological Association (AGA).[17]

The European and British guidelines focus on the diagnosis, treatment, and surveillance of atrophic gastritis, IM, and dysplasia, whereas the American guidelines focus on the management of individuals with IM.

First-time biopsies should be followed by mapping biopsies according to the Sydney protocol for gastritis from at least two topographic sites, antrum x2 (A1 lesser curve of the antrum & A2 greater curve of the antrum), incisura angularis (A3), anterior and posterior corpus x2 and for H. pylori. This is because of the irregular spread of gastritis. Also, any morphologically abnormal lesion like an ulcer, raised surface, or polyp adjacent to the atrophic areas should be biopsied separately and sent for histological assessment in a separate vial.[33]

Endoscopy Techniques

Conventional chromoendoscopy (CE) with the application of dyes like indigo carmine, methylene blue, acetic acid, and hematoxylin is highly accurate in the detection of preneoplastic gastric lesions.[34]

High definition chromo-endoscopy is better than high definition white light endoscopy for the diagnosis and the mapping of the extent of gastric precancerous lesions (GPLs).

White light endoscopy (WLE) is not good enough, but HD WLE has shown promising results but not reliable enough to offer as protocol.[35]

Narrowband imaging is shown to be more sensitive for detecting AG and IM compared to HD white light endoscopy and also the better visual diagnostic ability for detecting early cancer. Some centers are using a combined HD WLE with narrowband imaging to achieve a better yield of targeted biopsies.[36][37]

The Updated Sydney protocol showed the incisura angularis region has the highest incidence and severity of IM. Incisura increased the high-risk stages of OLGA/OLGIM stages. Incisura and more extensive biopsies could be useful where CE is not available.[38][39]

Low-Grade and High-Grade Dysplasia

High-quality chromo-endoscopy is recommended if biopsies show low-grade or high-grade dysplasia. The individual may need intensive surveillance endoscopy or referral for endoscopic resection.[17]

It is important to note that the OLGA system evaluates the whole spectrum from gastric atrophy, fibrosis, pseudo-pyloric metaplasia, and intestinal metaplasia in contrast to the OLGIM system that only evaluates IM.

OLGA and OLGIM both advise testing for and treating H. pylori in patients with GPL. This also applies after the endoscopic excision of GPLs. Both assessment systems also agree IM, whether it is extensive/ colonic (incomplete) type or IM with a family history of GC, are considered high risk for GC. In both assessment techniques, IM subtyping is also not essential but would be useful for surveillance.

European guidelines advise short interval repeat endoscopy with Sydney Protocol of biopsies in those accidentally found to have CAG. In contrast, the American Gastroenterological Association (AGA) does not recommend a short interval endoscopy. This should be high-quality guide-targeted biopsies and virtual chromo-endoscopy.[40]

The guidance by the AGA is based on shared decision making between clinician and patient for routine surveillance endoscopy of 'high risk for GC' patients and takes into consideration race/ethnicity as a risk factor. The rationale by AGA is that none of the randomized controlled trials suggest endoscopic surveillance reduces the risk of GC in individuals with GPL. The rationale of European Societies is that there is sufficient data from observational cohort studies to justify more stringent surveillance.[41][42]

Treatment / Management

Helicobacter Pylori Eradication

There have been numerous studies assessing the role of eradication therapy on chronic atrophic and non-atrophic gastritis and gastric cancer. In one meta-analysis, eradication therapy significantly improved the histological (OLGA/OLGIM) grading of gastric atrophy in the corpus and antrum and intestinal metaplasia in the antrum (but not corpus).[43](A1)

There may be a significant improvement in the risk of developing intestinal GC by H. pylori eradication. In two other meta-analyses, H. pylori eradication significantly reduced the risk of GC but not chronic atrophic gastritis and IM.[44][45] H. pylori eradication therapy is recommended in individuals endoscopically treated for superficial gastric neoplasia. This reduces the metachronous recurrence of GC by almost half.[4](A1)

In summary, H. pylori eradication has an essential role in histological downstaging and may have a role in the reduction of progression to GC.

COX Inhibitors

Even though cyclo-oxygenase inhibitors (COX-1 or COX-2) have been shown to slow down the progression of precancerous gastric conditions, and in theory, reduce the risk of GC, there is not enough statistical evidence from trials to recommend them for prevention.[46](A1)

Non-steroidal Anti-inflammatory Drugs

There is some evidence of the beneficial effect of NSAIDs and aspirin in slowing down the progression of gastric precancerous lesions after H. pylori eradiation from previous trials. Still, the effect is small to recommend it as a guideline. Further research is required to study the effects of NSAIDs on GPLs. Low dose aspirin may be safer to use and provide other systemic benefits, for example, in cardiovascular disease, but any benefit should be reviewed against the known gastrointestinal effects.[47](A1)

Other Drugs

Moluodan, a Chinese herbal medicine, reported in an RCT in individuals with dysplasia downgraded to non-dysplastic tissue by 24.6% on histological testing after six months of treatment.[48] Rebamipide reduced inflammation and the incidence of atrophic gastritis and intestinal metaplasia in an RCT from China.[49](A1)

Vitamin A, C, and E have been shown to reduce the risk of gastric cancer by a third in the general population when ingested in low supplemental doses.[50](A1)

Endoscopic Treatment

The treatment of chronic atrophic gastritis and intestinal metaplasia is surveillance to reduce progression to more advanced GPLs like dysplasia. The frequency of surveillance depends on histological findings.

Endoscopic resection is recommended for dysplastic lesions and early gastric adenocarcinoma. Endoscopic mucosal resection (EMR) technique is required for en-bloc excision of less than 10 mm lesions. Endoscopic submucosal dissection (ESD) may be required for lesions larger than 10 mm.[51][52](B2)

The protocols for more advanced intestinal gastric adenocarcinoma lesions are beyond the scope of this article and should follow gastric cancer protocols to ensure R0 resections.

Differential Diagnosis

Based on the clinical presentation, the following conditions can present with upper gastrointestinal symptoms and signs, making diagnosis reliant on invasive investigations like endoscopy:

Esophageal

Inflammatory

• Reflux esophagitis
• Eosinophilic esophagitis
• Esophageal stricture

Infective

• Bacterial/fungal/viral esophagitis
• Chagas disease
• Candidiasis

Motility Disorders

• Achalasia of the esophagus
• Diffuse esophageal spasm
• Nutcracker esophagus 

Neoplastic

• Adenocarcinoma
• Squamous cell carcinoma
• Lymphoma
• Gastrointestinal stromal tumor
• Neuroendocrine tumor

Stomach

Inflammatory

• Gastric ulcer (H. pylori, corticosteroids, stress, anastomotic ulcers)
• Acute erosive gastritis (NSAIDs, aspirin)
• Chemo toxic
• Crohn disease
• Biliary reflux gastritis
• Menetrier gastritis
• Radiation-induced
• Foreign body (trichobezoar, swallowed objects)

Infective

• Bacterial gastroenteritis
• Viral gastroenteritis
• Fungal gastroenteritis

Neoplastic

• Gastric adenocarcinoma
• Gastric lymphoma, Non-Hodgkin
• Gastrointestinal stromal tumor
• Neuroendocrine tumor

Duodenum

Inflammatory

• Duodenitis
• Duodenal ulcers
• Infective
• Bacterial gastroenteritis
• Viral gastroenteritis
• Fungal gastroenteritis

Neoplastic

• Malignant neoplasm of the small intestine
• Gastrointestinal stromal tumor
• Neuroendocrine tumor

Pancreas

• Pancreatitis

Gallbladder

• Cholelithiasis

Staging

The progressive changes in the gastric mucosa can lead to the development of the intestinal type of gastric adenocarcinomas. The histological changes from superficial gastritis to malignant mucosal transformation are described below:

• Helicobacter pylori gastritis
• Non-atrophic gastritis (NAG)
• Duodenal ulcer or multi-focal atrophic gastritis (MAG) without metaplasia
• MAG with metaplasia (small intestinal type) or intestinal metaplasia of the incomplete colonic type
• Low-grade dysplasia
• High-grade dysplasia
• Intraepithelial mucosal carcinoma
• Invasive intestinal adenocarcinoma

Staging of Chronic Atrophic Gastritis/Intestinal Metaplasia

It was the success of hepatitis severity staging that encouraged a group of pathologists and gastroenterologists 'The Operative Link on Gastritis Assessment (OLGA)' to organize a similar reporting system. This is based on cancer risk from lowest (Stage 0) to highest (Stage IV) based on the severity of atrophy and the extent of the spread of the atrophy in the stomach.[53]

The abnormal mucosal areas identified using a visual analog scale are compared with standardized biopsy samples of at least five different topographic areas. The staging is based on the combined scoring of the severity of atrophy and the location and extent of CAG in the stomach. The extent of mucosal atrophy is calculated on histological specimens as the percentage proportion of atrophic/metaplastic mucosa compared to normal mucosa in the antrum and corpus. Separate 'mean' atrophy severity scores are calculated of the antrum and corpus and then compared with the topographic areas involved resulting in stages 1, 2, 3, and 4 of the OLGA classification.

Atrophy Severity (antrum and corpus)

• No atrophy 0% - score 0
• Mild 0-30% - score 1
• Moderate 30-60% - score 2
• Severe >60% - score 3

Location

Antral Atrophy Score

• A1 (lesser curve of antrum)
• A2 (greater curve of the antrum)
• A3 (incisura angularis)

Corpus Atrophy Score

• C1 (lesser curve of the corpus)
• C2 (greater curve of the corpus)

The mean antral score will be calculated as A1+A2+A3 and the mean corpus score C1+ C2. The overall OLGA score is classified between stages 1 to 4 based on a combination of the severity of atrophy and the location of spread in the antrum and/or corpus. Stages 0, 1, and 2 are considered low risk and stage 3 and 4, high risk. In summary, advanced stage 3 and 4 have more extensive mucosal atrophy and more widespread topographic involvement of the stomach mucosa of the antrum and corpus and warrant definitive surveillance. It is of note that an individual can have stage 3 gastritis with severe atrophy scoring 3 that only involves the antrum but will be stage 2 if it only involves the corpus.   

GA and GIM have higher risks for progression to gastric cancer when involving corpus, antrum, and incisura (pan gastritis stage 3 or 4).

The Operative Link on Gastric Intestinal Metaplasia uses the same configuration of biopsies at five regions in individuals with intestinal metaplasia and classifies low-risk OLGIM stage 0, 1, 2, and high-risk OLGIM stage 3, 4 based on the severity and extent of spread of IM in the stomach. This system is recommended by the American Gastroenterological Association (AGA), whereas European and British centers follow the OLGA classification for mapping and surveillance. The severity of metaplasia is graded as mild, moderate, and severe intestinal metaplasia in the antrum and the corpus. More advanced stages (3/4) have a progressive spread of moderate to severe intestinal metaplasia in the corpus and the antrum.[54]

The OLGA system of histological classification evaluates all chronic atrophic changes, including intestinal metaplasia, whereas, in OLGIM, only intestinal metaplasia is considered. The proponents of OLGIM suggest a higher likelihood of progression to gastric cancer in high stage OLGIM vs. high stage OLGA cases.[55]

A recent meta-analysis of studies comprising more than 2700 subjects showed a strong association between OLGA/OLGIM stages 3/4 and gastric adenocarcinoma vs. stage 1/2. It is essential that individuals with OLGA/OLGIM stages 3/4 have more intensive surveillance to reduce the risk of GC.[56]

Gastric dysplasia is the turning point in the progression of gastric carcinogenesis. Dysplasia should, without a doubt, be treated as a malignant lesion with endoscopic or surgical resection.[57]

The staging of gastric adenocarcinoma is based on the Lauren classification into diffuse and intestinal-type gastric adenocarcinoma.[58]

Prognosis

Gastric adenocarcinoma is the fifth most common cancer in the world.[1]

Chronic atrophic gastritis is often diagnosed late, as many individuals can be asymptomatic for years and diagnosed incidentally. It is essential to investigate those with risk factors, such as the new onset of upper gastrointestinal symptoms in those over 50 years of age, pernicious anemia, or with a family history.[27]

According to one of the largest meta-analysis of numerous studies carried out worldwide, the incidence of gastric cancer in individuals with gastric atrophy varies widely from 0.53 percent to 15.24 per 1000 person-years depending on region and ethnicity, with the highest numbers in Asian countries. The incidence of GC in individuals with intestinal metaplasia was even more varied from 0.38 to 17.08 per 1000 person-years. The highest incidence rate, which was above 15 per 1000 person-years, was in Asia and the United States of America.[13]

In terms of prognosis, the cumulative five-year incidence of gastric adenocarcinoma increases from 0.7% in mild to 10% in severe atrophic gastritis in H. pylori-associated gastritis in a more recent Japanese cohort study.[14]

It is essential to identify individuals from certain ethnic minorities at risk and investigate them. In another study, Americans of Hispanic and Asian heritage had a higher prevalence of H. pylori infection and gastric precancerous lesions (GPLs). Patient ethnicity should be taken into consideration as a risk factor in the detection of GPLs.[3][59]

Complications

Complications associated with gastric mucosal atrophy can typically be:

• Achlorhydria (loss of acid production results in hypergastrinemia)
• Macrocytic anemia (intrinsic factor in autoimmune gastritis)
• Chronic iron deficiency anemia (due to loss of iron absorption)
• Duodenal/gastric ulcer
• Benign strictures of the pylorus
• Hemorrhagic gastritis
• Gastric adenocarcinoma
• Mucosa-associated lymphoid tissue (MALT)
• Gastric carcinoid tumor (enterochromaffin cell hyperplasia)