Continuing Education Activity

The current classification of gastritis is based on time course (acute versus chronic), histological features, anatomic distribution, and underlying pathological mechanisms. Acute gastritis will evolve into chronic if not treated. Helicobacter pylori (H. pylori) is the most common cause of gastritis worldwide. However, 60 to 70% of H. pylori-negative subjects with functional dyspepsia or non-erosive gastroesophageal reflux were also found to have gastritis. This activity describes the etiology, epidemiology, pathophysiology, histopathology, evaluation, differential diagnosis, and gastritis management. It also explores the role of collaboration amongst the professional team to enhance care delivery for patients with gastritis.

Objectives:

• Identify the etiology of gastritis.
• Describe clinical approaches for the diagnosis of gastritis.
• Review current treatment and management options used in gastritis.
• Outline the importance of collaboration and communication among the professional team to enhance care delivery in patients with gastritis, leading to successful patient outcomes.

Introduction

The definition of gastritis has its basis in histological features of the gastric mucosa. It is not erythema observed during gastroscopy, and no specific clinical presentations or symptoms define it. The current classification of gastritis centers on time course (acute versus chronic), histological features, anatomic distribution, and underlying pathological mechanisms.

Acute gastritis will evolve into chronic if not treated. Helicobacter pylori (H. pylori) is the most common cause of gastritis worldwide. However, 60 to 70% of H. pylori-negative subjects with functional dyspepsia or non-erosive gastroesophageal reflux were also found to have gastritis. H. pylori-negative gastritis is a consideration when an individual fulfills all four of these criteria (i) A negative triple staining of gastric mucosal biopsies (hematoxylin and eosin, Alcian blue stain and a modified silver stain), (ii) A negative H pylori culture, (iii) A negative IgG H. pylori serology, and (iv) no self-reported history of H. pylori treatment. In these patients, the cause of gastritis may relate to tobacco smoking, consumption of alcohol, and/or the use of non-steroidal anti-inflammatory drugs (NSAIDs) or steroids.

Other causes of gastritis include:

1. Autoimmune gastritis associated with serum anti-parietal and anti-intrinsic factor antibodies; characterized by chronic atrophic gastritis limited to the corpus and fundus of the stomach that is causing marked diffuse atrophy of parietal and chief cells.
2. Gastritis causes include organisms other than H. pylori, such as Mycobacterium avium intracellulare, Herpes simplex, and Cytomegalovirus.
3. Gastritis is caused by acid reflux. Rare causes of gastritis include collagenous gastritis, sarcoidosis, eosinophilic gastritis, and lymphocytic gastritis.

Clinical presentation, laboratory investigations, gastroscopy, and the histological and microbiological examination of tissue biopsies are essential for diagnosing gastritis and its causes. Treatment of H. pylori-associated gastritis results in the rapid disappearance of polymorphonuclear infiltration and a reduction of chronic inflammatory infiltrate with the gradual normalization of the mucosa. Mucosal atrophy and metaplastic changes may resolve shortly, but it is not necessarily the outcome of the treatment of H. pylori in all treated patients. Other types of gastritis should be treated based on their causative etiology. 

Etiology

Gastritis can be acute or chronic with various causes.[1][2][3][4][5] The causes of gastritis can be summarized as follows:

1. H. pylori-associated gastritis: This is the most common cause of gastritis worldwide. 
2. H. pylori-negative gastritis: The patients should fulfill all four of these criteria (i) A negative triple staining of gastric mucosal biopsies (hematoxylin and eosin, the Alcian blue stain and a modified silver stain), (ii) A negative H. pylori culture, (iii) A negative IgG H. pylori serology, and (iv) No self-reported history of H. pylori treatment. In these patients, the cause of gastritis may relate to tobacco smoking, consumption of alcohol, and/or the use of NSAIDs or steroids.
3. Autoimmune gastritis: This is a chronic inflammatory disease characterized by chronic atrophic gastritis and associated with raised serum anti-parietal and anti-intrinsic factor antibodies. The loss of parietal cells results in a reduction of gastric acid secretion, which is necessary for the absorption of inorganic iron. Therefore, iron deficiency is commonly a finding in patients with autoimmune gastritis. Iron deficiency in these patients usually precedes vitamin B12 deficiency. The disease is common in young women.
4. Gastritis may result from infection by organisms other than H. pylori, such as Mycobacterium avium-intracellulare, enterococcal infection, Herpes simplex, and cytomegalovirus. Parasitic gastritis may result from cryptosporidium, Strongyloides stercoralis, or anisakiasis infection.
5. Gastritis may result from bile acid reflux.
6. Radiation gastritis.
7. Crohn disease-associated gastritis: This is an uncommon cause of gastritis.
8. Collagenous gastritis: This is a rare cause of gastritis. The disease characteristically presents with marked subepithelial collagen deposition accompanied by mucosal inflammatory infiltrate. The exact etiology and pathogenesis of collagenous gastritis are still unclear.
9. Eosinophilic gastritis: This is another rare cause of gastritis. The disease could be part of the eosinophilic gastrointestinal disorders, characterized by the absence of known causes of eosinophilia (not secondary to an infection, systematic inflammatory disease, or any other causes to explain the eosinophilia).
10. Sarcoidosis-associated gastritis: Sarcoidosis is a multisystemic disorder characterized by the presence of non-caseating granulomas. Although sarcoidosis can affect any body organ, the gastrointestinal tract, including the stomach, is rarely affected.
11. Lymphocytic gastritis: This is a rare cause of gastritis. The etiology of lymphocytic gastritis remains unestablished, but an association with H. pylori infection or celiac disease has been suggested.
12. Ischemic gastritis: This is rare and associated with high mortality.
13. Vasculitis-associated gastritis: Diseases causing systemic vasculitis can cause granulomatous infiltration of the stomach. An example is Granulomatosis with polyangiitis, formerly known as Wegner granulomatosis. 
14. Ménétrier disease: This disease is characterized by (i) the presence of large gastric mucosal folds in the body and fundus of the stomach, (ii) Massive foveolar hyperplasia of surface and glandular mucous cells, (iii) Protein-losing gastropathy, hypoalbuminemia, and edema in 20 to 100% of patients, and (iv) reduced gastric acid secretion because of loss of parietal cells [6]. 

Epidemiology

In the Western population, there is evidence of a declining incidence of infectious gastritis caused by H. pylori with an increasing prevalence of autoimmune gastritis.[7] Autoimmune gastritis is more common in women and older people. The prevalence is estimated to be approximately 2% to 5%. However, available data do not have high reliability.[7][8]

Chronic gastritis remains a relatively common disease in developing countries. The prevalence of H. pylori infection in children in the Western population is approximately 10%, but about 50% in developing countries.[9][10] In developing countries, the overall prevalence of H. pylori varies depending on geographical region and socioeconomic conditions. It is approximately 69% in Africa, 78% in South America, and 51% in Asia.   

Socioeconomic and environmental hygiene are the essential factors in transmitting H. pylori infection worldwide. These factors include family-bound hygiene, household density, and cooking habits. The pediatric origin of H. pylori infection is currently considered the primary determinant of H. pylori-associated gastritis in a community.[11]

Pathophysiology

H.pylori-associated gastritis transmission is via the fecal-oral route. H. pylori possess several virulence factors which facilitate cell adhesion (e.g., BabA/B, sabA, OipA), cell damage and disruption of tight junctions (e.g., Ure A/B), and evasion from the immune response (e.g., LPS). In particular, the cytotoxin-associated gene a (CagA) is considered a potent inducer of inflammation and correlates with gastric cancer development.[12]

Another factor influencing H. pylori's pathogenic effects is host factors—the host susceptible factors such as polymorphism in genes coding for tall receptors or specific cytokines. The infection with H. pylori triggers IL-8, which attracts neutrophils that release oxyradicals leading to cell damage. Lymphocyte infiltration is also present in H. pylori infection.

Chronic gastritis mostly results from H. pylori infection and appears either in a non-atrophic or atrophic form. These two forms are phenotypes of gastritis at different stages of the same life-long disease.[13]

The progression from acute to chronic gastritis begins in childhood as a simple chronic superficial mononuclear inflammation of gastric mucosa which progress in years or decades to atrophic gastritis characterized by loss of normal mucosal glands in the antrum, corpus, fundus, or all. 

Factors that determine progression to atrophic gastritis and sequelae, such as a peptic ulcer or gastric cancer, are not clearly understood and are unpredictable. However, Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) have been identified in gastric tumors, and DNA from H. pylori, EBV, and PCR determined the presence of HCMV in biopsies from patients with gastric cancer complicating chronic gastritis.[14] Some researchers have confirmed the involvement of EBV and H. pylori in the development of gastric cancer in patients with chronic gastritis. They found no role for human papillomavirus (HPV) in gastric tumorigenesis.[15]

NSAIDs cause gastritis through the inhibition of prostaglandin synthesis. Prostaglandins are responsible for maintaining the protective mechanisms of gastric mucosa from injuries caused by hydrochloric acid.

The pathogenesis of autoimmune gastritis focuses on two theories. According to the first theory, an immune response against superimposed H. pylori antigen gets triggered, antigen cross-reacting with antigens within the proton-pump protein or the intrinsic factor, leading to a cascade of cellular changes and causing damage to the parietal cells and stopping hydrochloric acid secretion and thus these cells gradually become atrophic and not functioning.

The second theory assumes that the autoimmune disorder develops irrespective of H. pylori infection, and it directs itself against the proteins of the proton pump. As per both theories, autoimmune gastritis results from a complex interaction between genetic susceptibility and environmental factors resulting in immunological dysregulation involving sensitized T lymphocytes and autoantibodies directed against parietal cells and the intrinsic factor.[16]

Histopathology

Histologically, gastritis definitively demonstrates by the presence of at least grade 2 neutrophils or mononuclear cells in at least one gastric biopsy site or grade 1 neutrophils or mononuclear cells in at least two sites.[17] Sampling comes from five gastric biopsy specimens from the following locations: antrum with greater and lesser curvature, incisura, and corpus with greater and lesser curvature. Specimens must be put into separate vials and grouped for each site of the lesion. The aim is to maximize the opportunity to identify H. pylori and not miss the diagnosis.

The first appearance of H. pylori infection in gastritis tends to be antral. The inflammation, composed mainly of mononuclear inflammatory cells and plasma cells, is superficial and mostly in the upper layers of the mucosa of the corpus (body of the stomach).

The chronic inflammation of gastric mucosa is associated with neutrophilic inflammation; the effects are dependent on the cytotoxicity of the H. pylori strain. The most cytotoxic strains will result in the development of atrophic gastritis. The lost mucosal glands in atrophic gastritis become replaced with new immature glandular and epithelial cells resembling glands of intestinal tissues.

In the early phases of autoimmune gastritis, lymphocytic and plasma cell infiltration of oxyntic mucosa is present with accentuation in the deeper glandular portion. Hyperplasia of endocrine cells in gastric mucosa is an early feature in autoimmune gastritis. Oxyntic glands may undergo destruction, and parietal cells show pseudohypertrophy as the disease progress. In advanced disease, marked atrophy of the oxyntic glands and diffuse lymphoblastic infiltration of the lamina propria are present. Intestinal metaplasia is present in end-stage disease.[18]

History and Physical

There are no typical clinical manifestations of gastritis. Sudden onset of epigastric pain, nausea, and vomiting have been described to accompany acute gastritis. Many people are asymptomatic or develop minimal dyspeptic symptoms. If not treated, the picture may evolve into chronic gastritis. History of smoking, consumption of alcohol, intake of NSAIDs or steroids, allergies, radiotherapy, or gall bladder disorders should all be considerations. A history of treatment for inflammatory bowel disease, vasculitic disorders, or eosinophilic gastrointestinal disorders might require exploration if no cause of gastritis is apparent. 

The most common initial findings for chronic and autoimmune gastritis are (1) hematological disorders such as anemia (iron deficiency) detected on routine check-ups, (2) positive histological examination of gastric biopsies, (3) clinical suspect based on the presence of other autoimmune disorders, neurological symptoms (related to vitamin B12 deficiency) or positive family history.[19]

Iron-deficiency anemia (based on blood film showing microscopic hypochromic changes and iron studies) commonly presents in the early stages of autoimmune gastritis. Achlorhydria causing impairment of iron absorption in the duodenum and early jejunum is the leading cause.[20] Iron-deficiency anemia could also occur in other types of chronic gastritis. 

Autoimmune gastritis is associated with other autoimmune disorders (mainly thyroid diseases), including Hashimoto thyroiditis, Addison disease, chronic spontaneous urticaria, myasthenia gravis, Diabetes type 1, vitiligo, and perioral cutaneous autoimmune disorders, especially erosive oral lichen planus.[18] The association between chronic atrophic autoimmune gastritis and autoimmune thyroid disease earned the name in the early 60s of “thyrogastric syndrome.”

Evaluation

•  The diagnosis of gastritis has its basis in histopathological examination of gastric biopsy tissues. While medical history and laboratory tests are helpful, endoscopy and biopsy are the gold standard in diagnosing and identifying its distribution, severity, and cause. 
• The tests used for the diagnosis of H. pylori-associated gastritis fall into two main groups: (1) Invasive methods (requiring gastroscopy and biopsies): These include histological staining (hematoxylin and eosin, the Alcian blue stain and a modified silver stain), cultures, rapid urease test, and molecular detection (PCR DNA). (2) Non-invasive methods (not requiring gastroscopy and biopsies): These include urease breath test (13C-UBT), fecal antigen test, and serology. However, simultaneous treatment with proton-pump inhibitors leads to false-negative results in both invasive and non-invasive tests.[21] Also, patients treated with proton-pump inhibitors usually have negative histological staining for H. pylori. Staining of gastric mucosal biopsies by immunohistochemistry is recommended to detect H. pylori. 
• Serological tests for detecting antibodies against H. pylori cannot differentiate between active and past infection. 
• The diagnosis of autoimmune gastritis centers on laboratory and histological examination. These include: (1) atrophic gastritis of gastric corpus (body) and fundus of the stomach, (2) autoantibodies against the intrinsic factor and the parietal cells, (3) raised serum gastrin levels, (4) serum pepsinogen 1 level and (5) pepsinogen 1 to pepsinogen 2 ratios.[22][23]
• The most sensitive serum biomarker in autoimmune gastritis is parietal cell antibodies (compared to intrinsic factor antibodies). 
• The determination of the risk of gastric cancer in autoimmune gastritis is by (1) low levels of pepsinogen 1, (2) low pepsinogen 1/pepsinogen 2 ratios, (3) high fasting serum gastrin, (4) atrophic gastritis of the corpus and fundus. In these patients, the risk of cancer is high irrespective of whether they have or do not have ongoing H. pylori infection. 
• Pernicious anemia is a condition of macrocytic anemia associated with low cobalamin levels and atrophic corpus-fundus gastritis associated with parietal cell antibodies or intrinsic factor autoantibodies.
• Other tests that may be necessary for autoimmune gastritis are gastrin-17, IgG, and anti-H. pylori antibodies, cytokines (such as IL-8), and ghrelin (a growth hormone-releasing peptide produced mainly by the gastric fundus mucosa).[24]

Treatment / Management

Treatment regimens differ from antibiotics (in H. pylori gastritis) to vitamin supplementation (in autoimmune metaplastic atrophic gastritis) to immunomodulatory therapy (in autoimmune enteropathy) to dietary modifications (in eosinophilic gastritis).

H. pylori-associated gastritis: A triple-therapy of clarithromycin/proton-pump inhibitor/amoxicillin for 14 to 21 days is considered the first line of treatment. Clarithromycin is preferred over metronidazole because the recurrence rates with clarithromycin are far less compared to a triple therapy using metronidazole. However, metronidazole is the option of choice in areas where clarithromycin resistance is known. Quadruple bismuth-containing therapy would be of benefit, particularly if using metronidazole.[25]

After two eradication failures, H. pylori culture and antibiotic resistance tests should be considered. 

Autoimmune gastritis: Substitution of deficient iron and vitamin B12 (parenteral 1000 micrograms or oral 1000 to 2000 micrograms) is needed. Monitor Iron and folate levels, and eradicate any co-infection with H. pylori. Endoscopic surveillance for cancer risk and gastric neuroendocrine tumors (NET) is required.[26][27]

Other forms of treatment for gastritis include cessation of alcohol, smoking, anti-inflammatory drugs, and spicy food, as well as managing stress, immunomodulatory therapy in autoimmune enteropathy, and dietary modification in eosinophilic gastritis.

Differential Diagnosis

• Infectious gastritis
• Non-infectious gastritis
• Peptic ulcer disease
• Gastric cancer
• Cholecystitis
• Zollinger-Ellison syndrome
• Dyspepsia
• Gallstone disease
• Pancreatitis
• Autoimmune gastritis
• Myocardial ischemia
• Gastric involvement with inflammatory bowel disease, particularly Crohn disease
• Menetrier disease
• Lymphoma
• Celiac disease
• Multiple endocrine neoplasias

Prognosis

The prognosis depends on the cause. The symptoms do decrease for most people who undertake treatment, but recurrences are common. Patients with H.pylori-induced gastritis also have a small risk of developing gastric cancer in the future.

Complications

• Peptic ulcer
• Chronic atrophic gastritis (loss of appropriate glands resulting mainly from long-standing H. pylori infection)
• Gastric metaplasia/dysplasia
• Gastric cancer (adenocarcinoma)
• Iron-deficiency anemia (chronic gastritis and early stages of gastric autoimmunity)
• Vitamin B12 deficiency (autoimmune gastritis)
• Gastric bleeding
• Achlorhydria (autoimmune gastritis, chronic gastritis)
• Gastric perforation
• Mucosa-associated lymphoid tissue (MALT) lymphoma
• Neuroendocrine tumors (NET) (previously referred to as gastric carcinoid; complicates autoimmune gastritis)
  • Autoimmune gastritis predisposes to the development of both gastric adenocarcinoma and gastric type 1 NET
  • The development of NET in these patients is related to mucosal atrophy and hyperplasia of immature mucus neck cells
  • The enhanced differentiation of immature precursor neck cells into histamine-producing enterochromaffin-like (ECL) cells secondary to hypergastrinemia is the process
• Vitamin C, vitamin D, folic acid, zinc, magnesium, and calcium deficiency (atrophic autoimmune gastritis)

Pearls and Other Issues

Diagnosis of gastritis depends on the histological features of gastric biopsies. While history and laboratory tests are helpful, gastric mucosal biopsies are the gold standard in diagnosing and identifying its distribution, severity, and etiologic cause.

Enhancing Healthcare Team Outcomes

Infection with H. pylori represents the common cause of chronic gastritis. Most patients may present to the general practitioner, mid-level practitioner, pharmacist, or emergency department because of complications. Because of the difficulty in diagnosis and varied presentation of gastritis, the condition is best managed by an interprofessional team. The key is to cure the patient of the disorder.

Successful eradication therapy should heal chronic non-atrophic gastritis and prevent patients from complications. Clinicians should provide the public and patients with information about the transmission of infection via the fecal-oral route, the importance of handwashing habits, and hygiene practices to prevent infection with H. pylori. However, it is not known how to help the general population maintain handwashing habits and hygiene practices in the long run.

The presentation and symptoms of gastritis are poorly defined in terms of the clinical picture. Therefore the definite diagnosis is only based on a histological examination of the gastric mucosa. Since that is an invasive procedure, the diagnosis is often estimated and suspected but not confirmed. Healthcare workers, including doctors, nurses, and pharmacists, need to be aware of this fact when suspecting the disease and be aware of the diagnosis, sequelae, and complications. The pharmacist should assist the team by educating the patient on the importance of medication compliance if a cure is to be achieved.

Patients with autoimmune gastritis need regular surveillance for early cancer detection since the risk of gastric neuroendocrine tumors and gastric carcinoma increases. The risk of gastric cancer is also high in patients whose H. pylori is not eradicated. Thus, regular endoscopy is required in high-risk patients.

Finally, the nurse and pharmacist should assist the team by educating the patient on the avoidance of alcohol and the discontinuation of smoking and informing the clinicians of any failure in therapy or changes in patient status.

Gastritis diagnosis and treatment require an interprofessional team approach, including clinicians, specialists, specialty-trained nurses, and pharmacists collaborating across disciplines to achieve optimal patient results. [Level 5]