Atrophic gastritis

Atrophic gastritis is a histopathologic entity characterized by chronic inflammation of the gastric mucosa with loss of the gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue as a response to chronic injury ¹. Atrophy of the gastric mucosa is the endpoint of chronic processes, such as chronic gastritis associated with Helicobacter pylori infection, other unidentified environmental factors, and autoimmunity directed against gastric glandular cells (autoimmune gastritis) ¹.

Atrophic gastritis represents the end stage of chronic gastritis, both infectious and autoimmune. In both cases, the clinical manifestations of atrophic gastritis are those of chronic gastritis, but pernicious anemia is observed specifically in patients with autoimmune gastritis and not in those with Helicobacter pylori–associated atrophic gastritis.

The 2 main causes of atrophic gastritis result in distinct topographic types of gastritis, which can be distinguished histologically. Helicobacter pylori–associated atrophic gastritis is usually a multifocal process that involves both the antrum and the oxyntic mucosa of the gastric corpus and fundus, whereas autoimmune gastritis essentially is restricted to the gastric corpus and fundus. Individuals with autoimmune gastritis may develop pernicious anemia because of extensive loss of parietal cell mass and anti-intrinsic factor antibodies ².

Helicobacter pylori–associated atrophic gastritis is frequently asymptomatic, but individuals with this disease are at increased risk of developing gastric carcinoma, which may decrease following Helicobacter pylori eradication ³. Patients with chronic atrophic gastritis develop low gastric acid output and hypergastrinemia, which may lead to enterochromaffin-like cell hyperplasia and carcinoid tumors ⁴.

Atrophic gastritis causes

Atrophic gastritis usually is associated with either chronic Helicobacter pylori infection or with autoimmune gastritis. The environmental subtype of atrophic gastritis corresponds mostly with Helicobacter pylori–associated atrophic gastritis, although other unidentified environmental factors may play a role in the development of gastric atrophy. Yagi et al ⁵ used magnifying endoscopy to distinguish atrophic gastritis caused by Helicobacter pylori from autoimmune gastritis.

Chronic atrophic gastritis caused by Helicobacter pylori infection of the stomach

Helicobacter pylori infection of the stomach is by far the most common cause of chronic atrophic gastritis.

The risk of atrophic gastritis is increased by 10-fold if an Helicobacter pylori infection is present.

Whether Helicobacter pylori infection follows the multifocal atrophic gastritis pathway or the nonatrophic antral gastritis pathway may be related to genetic susceptibility factors, environmental factors that modulate the host-bacterial interaction, or bacterial strains.

Although Helicobacter pylori possessing the CAG gene (cytotoxin-associated gene) pathogenicity island have been shown to have increased virulence, to cause higher levels of mucosal inflammation, and to be present more frequently in individuals infected with Helicobacter pylori who develop gastric cancer, no specific virulence factors have been identified that might be useful to predict specific Helicobacter pylori disease outcome.

Host factors or the effects of other environmental agents are likely to be the determinant elements modulating patterns of disease progression. For example, family relatives of individuals with gastric cancer develop pangastritis more frequently in response to Helicobacter pylori infection and they also develop multifocal intestinal metaplasia more often, a preneoplastic lesion of the stomach and a component of Helicobacter pylori–associated atrophic gastritis.

Chronic atrophic gastritis with intestinal metaplasia is recognized to be a precancerous lesion that can evolve toward low- and high-grade intraepithelial lesions and gastric cancer, particularly those involving Helicobacter pylori infection ¹.

Autoimmune atrophic gastritis

Autoimmune atrophic gastritis is a type of chronic atrophic gastritis limited to the corpus-fundus mucosa and characterized by marked diffuse atrophy of the parietal and chief cells.

Autoimmune gastritis is associated with serum antiparietal and anti-intrinsic factor (IF) antibodies that cause intrinsic factor deficiency, which, in turn, causes decreased availability of vitamin B12 (cobalamin) and, eventually, pernicious anemia in some patients.

In some families, the disease appears to be transmitted with an autosomal dominant pattern of inheritance.

A large population-based study by Zhang et al ⁶ suggested that the presence of antigastric parietal cell antibodies may contribute to the development of chronic atrophic gastritis even in the absence of Helicobacter pylori infection. The study, which included 9684 persons aged 50-74 years, reported an overall seroprevalence of antigastric parietal cell antibody in this population of 19.5%, with a strong association found between the existence of antigastric parietal cell antibodies and the presence of chronic atrophic gastritis. The more severe the disease, the greater the association with antigastric parietal cell antibody was found. However, the link between antigastric parietal cell antibodies and the severity of chronic atrophic gastritis was greatest in persons who were negative for Helicobacter pylori ⁶.

Autoimmune atrophic gastritis has been associated with thyroid diseases, type 1 diabetes mellitus, Addison disease, chronic spontaneous urticaria, myasthenia gravis, vitiligo, and perioral cutaneous autoimmune conditions (eg, erosive oral lichen planus) ². Thus, in the setting of any autoimmune condition and increased autoimmune disease clustering, clinicians should rule out concomitant autoimmune conditions ².

Atrophic gastritis prevention

Experts don’t know it is possible to stop gastritis from happening. But you may lower your risk of getting the disease by:

• Having good hygiene habits, especially washing your hands. This can keep you from getting the Helicobacter pylori bacteria.
• Not eating or drinking things that can irritate your stomach lining. This includes alcohol, caffeine, and spicy foods.
• Not taking medicines such as aspirin and over-the-counter pain and fever medicines (nonsteroidal anti-inflammatory drugs or NSAIDS).

Atrophic gastritis symptoms

Atrophic gastritis represents the end stage of chronic gastritis, both infectious and autoimmune. In both cases, the clinical manifestations of atrophic gastritis are those of chronic gastritis, but pernicious anemia is observed specifically in patients with autoimmune gastritis and not in those with Helicobacter pylori–associated atrophic gastritis.

Helicobacter pylori-associated atrophic gastritis

Acute Helicobacter pylori infection usually is not detected clinically, but experimental infection results in a clinical syndrome characterized by epigastric pain, fullness, nausea, vomiting, flatulence, malaise, and, sometimes, fever. The symptoms resolve in approximately a week, regardless of whether or not Helicobacter pylori organisms are eliminated.

Persistence of the organism causes Helicobacter pylori chronic gastritis, which usually is asymptomatic or may manifest as epigastric pain and, rarely, nausea, vomiting, anorexia, or significant weight loss. Symptoms associated with complications of chronic Helicobacter pylori–associated atrophic gastritis may develop, including gastric ulcers and gastric adenocarcinoma.

Autoimmune atrophic gastritis

The clinical manifestations of autoimmune atrophic gastritis primarily are related to the deficiency of cobalamin, which is not absorbed adequately because of intrinsic factor (IF) deficiency resulting from severe gastric parietal cell atrophy. The disease has an insidious onset and progresses slowly. Cobalamin (vitamin B12) deficiency affects the hematological, gastrointestinal, and neurologic systems.

Hematologic manifestations

The most significant manifestation is megaloblastic anemia, but, rarely, purpura due to thrombocytopenia may develop. Symptoms of anemia include weakness, light-headedness, vertigo and tinnitus, palpitations, angina, and symptoms of congestive heart failure.

Gastrointestinal manifestations

The lack of cobalamin is associated with megaloblastosis of the gastrointestinal tract epithelium. Patients sometimes complain of a sore tongue. Anorexia with moderate weight loss, occasionally associated with diarrhea may result from the malabsorption associated with megaloblastic changes in the epithelium of the small intestine.

Neurologic manifestations

These result from demyelination, followed by axonal degeneration and neuronal death. The affected sites include peripheral nerves, posterior and lateral columns of the spinal cord, and the cerebrum. Signs and symptoms include numbness and paresthesias in the extremities, weakness, and ataxia. Sphincter disturbances may be present. Mental function disturbances vary from mild irritability to severe dementia or psychosis. Neurologic disease may occur in patients with normal hematocrit and normal red cell parameters.

Anemia

Patients with pernicious anemia have an increased frequency of gastric polyps and have a 2.9-fold increase in gastric cancer.

Additionally, patients with autoimmune atrophic gastritis and Helicobacter pylori infection may manifest iron deficient anemia that may be refractory to oral iron treatment. Helicobacter pylori eradication in combination with continued oral iron therapy has been shown to result in a significant increase in hemoglobin levels.

Primary hyperparathyroidism

Massironi et al ⁷ found evidence of a noncausal association between chronic autoimmune atrophic gastritis and primary hyperparathyroidism. In a prospective study, they evaluated the prevalence of primary hyperparathyroidism in 107 patients with chronic autoimmune atrophic gastritis and the prevalence of chronic autoimmune atrophic gastritis in 149 patients with sporadic primary hyperparathyroidism. The results indicate that primary hyperparathyroidism is about three-fold more prevalent in patients with chronic autoimmune atrophic gastritis than in the general population and that chronic autoimmune atrophic gastritis is about four-fold more prevalent in patients with primary hyperparathyroidism than in the general population.

Atrophic gastritis complications

The multifocal atrophic gastritis that develops in some individuals with Helicobacter pylori infection is associated with increased risk of the following:

• Gastric ulcers
• Gastric adenocarcinoma

The corpus-restricted atrophic gastritis that develops in patients with autoimmune gastritis is associated with an increased risk of the following:

• Pernicious anemia
• Gastric polyps
• Gastric adenocarcinoma

Atrophic gastritis diagnosis

Physical examination is of little contributory value in atrophic gastritis; however, some findings are associated specifically with the complications of Helicobacter pylori–associated atrophic gastritis and autoimmune atrophic gastritis.

In uncomplicated Helicobacter pylori–associated atrophic gastritis, clinical findings are few and nonspecific. Epigastric tenderness may be present. If gastric ulcers coexist, guaiac-positive stool may result from occult blood loss.

Findings in a patient with autoimmune atrophic gastritis result from the development of pernicious anemia and neurologic complications.

With severe cobalamin (vitamin B12) deficiency, the patient is pale and has slightly icteric skin and eyes. The pulse is rapid, and the heart may be enlarged. Auscultation usually reveals a systolic flow murmur.

Upper gastrointestinal endoscopy is essential to establish a diagnosis of atrophic gastritis. Areas of intestinal metaplasia may be recognized with endoscopy; perform sampling of multiple biopsy specimens.

Tissue sampling from both the gastric antrum and corpus is essential to establish the topography of gastritis and to identify atrophy and intestinal metaplasia, which may be patchy.

The diagnosis of atrophic gastritis can only be ascertained histologically. The endoscopic findings are not helpful for diagnosis, but endoscopy is essential to perform multiple gastric biopsy sampling. Obtain at least 2 biopsy samples from the gastric antrum, 2 from the corpus and 1 from the incisura, and submit to pathology in separate vials.

Decreased serum pepsinogen I levels and the ratio of pepsinogen I to pepsinogen II in the serum can be used to assess gastric atrophy. The finding of low pepsinogen I levels (< 20 ng/mL) has a sensitivity of approximately 96.2% and a specificity of 97% for detection of fundus atrophy. The reported best cut-off pepsinogen I value for patients with atrophic gastritis appears to be 40 mcg/L, with a 90% sensitivity, 67% specificity, 69% accuracy, and 92% negative predictive value, whereas the reported best cut-off value for the ratio of pepsinogen I to pepsinogen II appears to be 8, with a 71% sensitivity, specificity, and accuracy each, and an 86% negative predictive value ⁸.

The combination of pepsinogen, gastrin-17 and anti- Helicobacter pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis ⁹. In a systematic review and meta-analysis of data from 20 studies (1995-2016) comprising 4241 subjects, investigators found a 27% prevalence of atrophic gastritis, a 74.7% summary sensitivity, a 95.6% sensitivity, and a 91% negative predictive value ⁹.

Other laboratory findings may include the following ¹⁰:

• Elevated serum gastrin levels
• Microcytic, hypochromic anemia (which may precede the development of megaloblastic, vitamin B12-associated anemia)
• Vitamin B12 deficiency (which may elevated homocysteine levels)

Identifying the underlying cause of atrophic gastritis and assessing specific complications can require several laboratory tests.

Diagnosis of Helicobacter pylori–associated atrophic gastritis is made as follows:

• Histologic examination of gastric biopsy with Helicobacter pylori special stains: Histologic identification of Helicobacter pylori is the standard method to assess if the organism is the underlying cause of atrophic gastritis. Histologic examination also helps evaluate the degree and distribution of atrophy, which helps identify the type of atrophic gastritis. Although histologic identification of Helicobacter pylori is the standard approach to identify the infection, at late stages of extensive atrophic gastritis, the number of Helicobacter pylori organisms is decreased markedly because intestinal metaplasia creates an unfavorable environment for Helicobacter pylori. In these cases, other tests, such as the urea breath test (ie, with nonradioactive isotope 13C or with radioactive isotope 14C), and serologic evidence of infection may provide evidence for Helicobacter pylori infection.
• Rapid urease test from gastric biopsy tissue
• Bacterial culture of gastric biopsy specimens: This usually is performed in the research setting or to assess antibiotic susceptibility in patients in whom first-line eradication therapy fails.
• Serologic detection of anti-Helicobacter pylori antibodies

Diagnosis of autoimmune gastritis is made as follows:

• Antiparietal and anti-intrinsic factor antibodies in the serum
• Achlorhydria, both basal and stimulated, and hypergastrinemia
• Low serum cobalamin (B-12) levels (< 100 pg/mL)
• Shilling test: Results may be abnormal and can be corrected by intrinsic factor.

Atrophic gastritis treatment

Once atrophic gastritis is diagnosed, treatment can be directed (1) to eliminate the causal agent, which is a possibility in cases of Helicobacter pylori–associated atrophic gastritis; (2) to correct complications of the disease, especially in patients with autoimmune atrophic gastritis who develop pernicious anemia (in whom vitamin B-12 replacement therapy is indicated); or (3) to attempt to reverse the atrophic process.

No consensus from different studies exists regarding the reversibility of atrophic gastritis; however, removal of Helicobacter pylori from the already atrophic stomach may block further progression of the disease. Until recently, specific recommendations for Helicobacter pylori eradication were limited to peptic ulcer disease. At the Digestive Health Initiative International Update Conference on Helicobacter pylori held in the United States, the recommendations for Helicobacter pylori testing and treatment were broadened. Helicobacter pylori testing and eradication of the infection also were recommended after resection of early gastric cancer and for low-grade mucosa-associated lymphoid tissue lymphoma.

If Helicobacter pylori is identified as the underlying cause of gastritis, subsequent eradication now is almost generally an accepted practice. Protocols for Helicobacter pylori eradication require a combination of antimicrobial agents and antisecretory agents, such as a proton pump inhibitors (PPIs), ranitidine bismuth citrate (RBC), or bismuth subsalicylate. Despite the combinatorial effect of drugs in regimens used to treat Helicobacter pylori infection, cure rates remain, at best, 80-95%.

Lack of patient compliance and antimicrobial resistance are the most important factors influencing poor outcome. Currently, the most widely used and efficient therapies to eradicate Helicobacter pylori are triple therapies (recommended as first-line treatments) and quadruple therapies (recommended as second-line treatment when triple therapies fail to eradicate Helicobacter pylori). In both cases, the best results are achieved by administering therapy for 10-14 days, although some studies have recommended the duration of treatment of 7 days. The accepted definition of cure is no evidence of Helicobacter pylori 4 or more weeks after ending the antimicrobial therapy.

Triple therapy for Helicobacter pylori infection

Twice-a-day (bid) proton pump inhibitor or ranitidine-bismuth-citrate (Tritec) triple therapies include lansoprazole (Prevacid), 30 mg oral twice daily; omeprazole (Prilosec), 20 mg oral twice daily; or ranitidine-bismuth-citrate (Tritec), 400 mg bid. Antibiotic therapy includes clarithromycin (Biaxin), 500 mg oral twice daily; amoxicillin, 1000 mg oral twice daily; or metronidazole, 500 mg oral twice daily.

Pack kits containing combination triple therapies are available as combinations of lansoprazole, amoxicillin, and clarithromycin (PrevPac) and bismuth subsalicylate, tetracycline, and metronidazole (Helidac). PrevPac contains drug combinations in the dosage recommended as first-line treatment by the Maastricht 2-2000 Consensus report from Europe. Note the following:

• PrevPac components include lansoprazole (Prevacid), 30 mg oral twice daily; clarithromycin (Biaxin), 500 mg oral twice daily; and amoxicillin, 1000 mg oral twice daily.
• Helidac triple-therapy components include bismuth subsalicylate, 525 mg (two 262.4-mg chewable tabs)  oral 4 times per day (qid); metronidazole, 250 mg oral 4 times per day; and tetracycline HCL, 500 mg oral 4 times per day.

Quadruple therapy for Helicobacter pylori infection

Quadruple therapy, with indicated adult dose is a proton pump inhibitor oral twice daily, including lansoprazole (Prevacid), 30 mg oral twice daily or omeprazole (Prilosec), 20 mg oral twice daily, and antibiotics, including tetracycline HCl, 500 mg oral 4 times per day; bismuth subsalicylate, 120 mg oral 4 times per day; and metronidazole, 500 mg oral 3 times per day (tid).

Guidelines for follow-up care for cases of atrophic gastritis are not established. Handle subsequent Helicobacter pylori eradication failures on a case-by-case basis.

If the patient was treated for Helicobacter pylori infection, confirm eradication. Perform evaluation of eradication at least 4 weeks after the end of treatment. Eradication may be assessed by noninvasive methods, such as the urea breath test.

Follow-up care may be individualized depending on the findings during endoscopy. For example, if dysplasia is found at endoscopy, increased surveillance is necessary.

Atrophic gastritis prognosis

Atrophic gastritis is a progressive condition with increasing loss of gastric glands and replacement by foci of intestinal metaplasia over years.

Results from studies evaluating the evolution of atrophic gastritis after eradication of Helicobacter pylori have been conflicting. Follow-up for up to several years after Helicobacter pylori eradication has not shown regression of gastric atrophy in most studies, whereas other studies report improvement in the extent of atrophy.

Whether Helicobacter pylori eradication in a patient with atrophic gastritis reduces the risk of development of gastric cancer is another important question. Available data are limited, but a prospective study in a Japanese population reported that Helicobacter pylori eradication in patients with endoscopically-resected early gastric cancer resulted in decreased appearance of new early cancers, while intestinal-type gastric cancers developed in the control group without Helicobacter pylori eradication.

These findings support an interventional approach, with eradication of Helicobacter pylori if the organisms are detected in patients with atrophic gastritis, aiming at prevention of development of gastric cancer.

Morbidity and mortality

Mortality and morbidity associated with atrophic gastritis are related to specific clinicopathologic complications that may develop during the course of the underlying disease.

Similar to other individuals infected with Helicobacter pylori, patients who develop atrophic gastritis may complain of dyspeptic symptoms. Individuals with either Helicobacter pylori–associated atrophic gastritis or autoimmune atrophic gastritis carry an increased risk of developing gastric carcinoid tumors and gastric carcinoma. More recently, there is a case report from New York Mount Sinai Hospital involving synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis in the absence of Helicobacter pylori infection ¹¹. The patient underwent transduodenal resection of the duodenal neuroendocrine tumor s, and subsequent followup over 2 years revealed no recurrence or metastasis from the gastric or duodenal disease.

The major effects of autoimmune gastritis are consequences of the loss of parietal and chief cells and include achlorhydria, hypergastrinemia, loss of pepsin and pepsinogen, anemia, and an increased risk of gastric neoplasms.

Autoimmune atrophic gastritis represents the most frequent cause of pernicious anemia in temperate climates. The risk of gastric adenocarcinoma appears to be at least 2.9 times higher in patients with pernicious anemia than in the general population. A recent study also reported an increased frequency of esophageal squamous carcinomas in patients with pernicious anemia.

Autoimmune atrophic gastritis and Helicobacter pylori gastritis may also have a significant role in the development of unexplained or refractory iron deficient anemia.

References

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