Atrophic gastritis

Atrophic gastritis is a condition characterized by chronic inflammation of the gastric mucosa with atrophy, gland loss, and metaplastic changes. It is classified into autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis (EMAG). Chronic infection with Helicobacter pylori (H. pylori) is the most common cause. Patients suffering from atrophic gastritis often do not display any symptoms or may only experience nonspecific discomfort in the epigastric region. Important diagnostic steps include gastroscopy with biopsy and laboratory studies (e.g., gastrin). Therapeutic emphasis depends on the underlying etiology: substitution of vitamin B₁₂ (AMAG) or H. pylori eradication therapy (helicobacter-associated atrophic gastritis). If left untreated, atrophic gastritis may lead to peptic ulcer disease or result in the development of various cancers.

• AMAG
  • Associated with major histocompatibility haplotypes HLA-B8 and HLA-DR3
  • Associated with other autoimmune diseases (e.g., autoimmune thyroiditis)
• EMAG
  • Helicobacter pylori infection (most important risk factor of atrophic gastritis overall)
  • Dietary factors (e.g., N-nitroso compounds , alcohol intake, high salt intake)

References:^[1][3]

AMAG

• Autoimmune destruction of the parietal cells
  • → Achlorhydria → increased release of gastrin (due to loss of negative feedback) → G cell hyperplasia → hypergastrinemia
    • Hypergastrinemia; may lead to hyperplasia of enterochromaffin-like cells and, consequently, to an increased risk of carcinoid tumors.
• Autoantibodies against intrinsic factor → vitamin B₁₂ deficiency → pernicious anemia

EMAG

• Helicobacter-associated: colonization by H. pylori → decreased production of mucins → increased production of gastric acids → inflammation primarily of the antrum→ ascending propagation; → shift of the corpus-antrum border → in case of chronification: atrophy of the gastric glands → hypochlorhydria (not achlorhydria) and epithelial metaplasia → increased risk of gastric cancers
• Diet: bacteria in the stomach metabolize nitrates present in food → formation of N-nitroso compounds (carcinogenic) → epithelial metaplasia → increased risk of gastric cancers

References:^[1][3]

• Intensity of symptoms may be inconsistent and vary widely
  • Hematemesis; (coffee-ground appearance or bright red in color), possibly melena
  • Epigastric pain is possible
  • Nausea, vomiting
  • Abdominal paresthesia and dyspepsia
    • Bloating, increased frequency of belching
    • Strong, boring sensation of hunger combined with decreased appetite
    • Hunger pain, but postprandial pain is possible as well
    • Rapid sensation of satiety after food intake
• Additionally in AMAG
  • Anemia: iron deficiency (early) and pernicious anemia (late)
    • Achlorhydria impairs the intestinal absorption of inorganic iron → iron deficiency anemia
    • Lack of intrinsic factor → vitamin B₁₂ deficiency → pernicious anemia
      • Features of Vitamin B12 deficiency: triad of hematologic, neurologic, and gastrointestinal disorders (see vitamin B₁₂ deficiency)
  • Evidence of other autoimmune diseases (e.g., Hashimoto's thyroiditis)
• Additionally in EMAG
  • Asymptomatic progression is common
  • Symptoms often a consequence of gastric or duodenal ulcer bleeding

References:^[1][3][4]

Esophagogastroduodenoscopy and biopsy

• Diagnostic test of choice
• To evaluate the gastric mucosa and collect biopsy samples from the gastric antrum and corpus, possibly also from the fundus
• Number and localization of necessary biopsy samples depend on the issue
  • For detection of H. pylori: 2× antrum, 2× corpus; if the urease test is applied: 1× antrum and corpus each
  • In case of vitamin B₁₂ deficiency and suspected type A gastritis: 2× dome of fundus, 2× corpus
  • In case of unspecific complaints in the epigastric region, visually inconspicuous endoscopy results and protracted course: diagnosis by exclusion via biopsy samples from distal duodenum (2×), antrum (2×), corpus (2×) and fundus (2×)

Helicobacter pylori diagnostics

• Collection of biopsies
  • For histology: 2 biopsy samples from the antrum (peripyloric and angular incisure) and corpus (lesser curvature and greater curvature) each
  • For the urease test: 1 biopsy sample from antrum and corpus each
• Applied methods: As a rule, there should always be a combination of two methods.
  • Histology (gold standard) including staining and direct microscopic identification
    • Curved, flagellated gram-negative rod
  • Rapid urease test: detection of ammonia production by the urease of H. pylori
  • Culture and resistogram : culture of H. pylori requires a special nutrient broth and takes about 14 days. It may be conducted to test resistances (in exceptional cases!)
  • Detection of H. pylori DNA by PCR: very sensitive and specific, but almost never used in daily clinical practice
  • Interfering factors in H. pylori diagnostics (especially in the rapid urease test)
    • Preexisting medication with PPIs: PPIs should preferably be discontinued two weeks prior to the test.
    • Upper gastrointestinal bleeding: Verification methods are prone to interference if biopsies are taken in the context of bleeding or in the immediate vicinity of ulcerations
    • Pre- and peripyloric biopsies: especially prone to interference in the case of bile reflux
    • Preceding partial gastrectomy
    • Gastric cancer and MALToma
    • Mucosal atrophy and intestinal metaplasia revealed by histology
• Non-invasive methods
  • H. pylori antigen detection in stool specimens
    • On the basis of ELISA testing, involving monoclonal antibodies
    • Suitable option as initial test (cost-effective)
  • Positive Urea breath test: detection of a labeled carbon isotope in breath samples
  • Serum IgG antibodies against H. pylori: H. pylori antibodies may be detected even after eradication → test indicates (past) exposure, not necessarily current infection (lower specificity)
• Diagnostic confidence:
  • Diagnosis is generally confirmed if two tests are positive.
  • Exceptions:
    • Duodenal ulcer: one positive result is sufficient
    • Chronic active gastritis: if H. pylori is detected and signs of chronic active gastritis are observed simultaneously (infiltration of neutrophil granulocytes is characteristic), diagnosis is considered confirmed without further positive results.
    • Positive culture: Detection by culture is sufficient for diagnosis in itself.

Additional tests

• Hematology
  • In case of chronic bleeding (any type): possibly microcytic anemia
  • In AMAG: possibly macrocytic anemia
• Serum pepsinogen isoforms
  • Pepsinogen I is only secreted by oxyntic glands of the gastric fundus and body, but pepsinogen II is secreted by all gastric glands (as well as by Brunner's glands of the duodenum)
  • → Therefore, if gastritis (primarily) affects the gastric fundus, the ratio of the two isoforms in the serum changes.
  • → Measurement of pepsinogen isoforms may provide a clue towards localization of gastric inflammation (AMAG: confined to gastric body and fundus; EMAG: distributed, but predominantly antrum)
• Vitamin B₁₂ levels: decreased in AMAG
• Serum gastrin levels: increased in AMAG
• Serology : anti-intrinsic factor and anti-parietal cell antibodies

References:^[1][3][5][6]

• Chemical gastritis
  • Etiology: various substances cause reactive gastritis
    • Drugs, particularly NSAIDs (additional intake of glucocorticoids and/or SSRIs further increases the risk)
    • Alcohol (especially high-proof and if consumed regularly)
    • Nicotine
  • Pathophysiology: interaction of direct noxae,NSAIDs, smoking, alcohol, and increased duodenogastric reflux → scattered infiltration of the gastric mucosa by lymphocytes and plasma cells → edema of the gastric mucosa → if and when the regenerative potential of the gastric mucosa is exceeded, erosions and ulcers develop. Also, glands in the corpus may atrophy, leading to decreased secretion of gastric acids and pepsinogen → hypochlorhydria, possibly leading to metaplasia and dysplasia
  • Clinical features
    • General symptoms of chronic gastritis (epigastric pain; , nausea; , vomiting, hematemesis, melena, dyspepsia)
    • Complaints of varying intensity are common
  • Therapy
    • Avoid noxae (e.g., discontinue NSAIDs, abstaining from smoking and alcohol)
    • Proton pump inhibitor (PPI) therapy
      • In case of erosions and ulcerations administer high doses for 1–2 weeks
      • Gradually discontinue PPIs to avoid rebound (PPI therapy leads to reactive hypergastrinemia).
    • Other substances: sucralfate, ursodeoxycholic acid, cholestyramine, prokinetic drugs
    • If H. pylori is detected → Helicobacter pylori eradication therapy
  • Complications: gastric ulcers → bleeding, perforation
• Noninfectious granulomatous gastritis
  • Crohn disease
    • Localization: most commonly in the duodenum, thereafter in descending frequency in the gastric antrum and gastric corpus
    • Diagnosis
      • Endoscopy: normal findings are frequent
      • Biopsy samples from duodenum (4), gastric antrum (4) and gastric corpus (2) to unambiguously differentiate between Crohn's disease and ulcerative colitis.
  • Other: e.g., sarcoidosis, vasculitis
• Eosinophilic gastritis
  • Etiology: obscure, frequently associated with allergic diseases
  • Clinical signs
    • Dyspepsia, bloating, diarrhea, vomiting, and epigastric discomfort
    • Possibly signs of bleeding due to mucosal lesions of higher degrees (erosions, ulcerations) and stenoses due to incomplete healing of ulcerations
  • Diagnosis
    • Confirmation: deep biopsies (or macro-biopsies) from stomach and duodenum
    • Additional possible results: blood eosinophilia, serum ↑ IgE
  • Differential diagnosis: If symptoms of bronchial asthma, vasculitis, or eosinophilic myocarditis are observed: see eosinophilic granulomatosis with polyangiitis → swift immunosuppression is necessary!
  • Therapy
    • If allergic diathesis has been confirmed: reduction diet eliminating milk, soy, eggs, wheat, and meat on a trial basis; thereafter selectively reestablish normal diet
    • In symptomatic patients with predominant affliction of the mucosa: cromoglicic acid
    • In case of stenoses, bleeding, or other complications:
      • Immunosuppression with glucocorticoids should be considered: e.g., prednisone
      • Especially if there is bleeding, PPIs should be administered as primary medication to inhibit gastric acid production: e.g., pantoprazole.
  • Prognosis
    • Full remission in most cases
    • Chronic recurrent progression with low tendency for healing and high tendency for complications is possible.
• Lymphocytic gastritis
  • Etiology: obscure
  • Clinical signs: epigastric pain, bleeding from the upper gastrointestinal tract, iron deficiency anemia
  • Diagnostics: gastroscopy including biopsy samples from gastric corpus, gastric antrum, and duodenum
    • H. pylori can almost never be detected histologically. However, corresponding antibodies are frequently found in serum of affected patients.
    • Lymphocytic infiltration of the mucosa, as is also observed in celiac disease
  • Therapy: H. pylori eradication often leads to healing (even if H. pylori is not detectable)
• Ménétrier's disease
  • Definition: gastritis featuring massive enlargement of the mucosal folds
  • Clinical features: dyspeptic symptoms (i.e., abdominal pain, nausea, vomiting, diarrhea, weight loss)
  • Diagnostics
    • Endoscopy: prominent rugae in the gastric fundus
    • Biopsy: foveolar hyperplasia and parietal cell atrophy
  • Complications:
    • Loss of protein → edema
    • Malignant degeneration
  • Therapy: if H. pylori is detected → eradication, otherwise symptomatic treatment and regular gastroscopic check-ups

References:^[7][8]

The differential diagnoses listed here are not exhaustive.

General

• Avoid intake of substances that may exacerbate ongoing inflammation (e.g., alcohol, NSAIDs)
• Symptomatic treatment with proton pump inhibitors (PPIs), antacids, sucralfate, or H₂-receptor blockers

AMAG

• Vitamin B12 replacement therapy (parenteral)
• If H. pylori is detected: attempt to eradicate → may lead to healing
• Risk of malignant degeneration requires regular endoscopic check-ups

Helicobacter-associated atrophic gastritis

Helicobacter pylori eradication therapy with proton pump inhibitors (PPIs) at twice the standard dose + 2 antibiotics (+ possibly bismuth) for a minimum of 7 (possibly 10) days , thereafter continue one PPI at standard dose

• Indications ;
  • Test-and-treat strategy; : for patients that are < 55 years old; , suffer from uninvestigated dyspepsia; , and have no record of "alarm features" (e.g., bleeding)
  • Active peptic ulcer disease
  • History of peptic ulcer disease
  • MALT lymphoma: disease may be cured by sole H. pylori eradication in stage I (success rate of 80%), in stage II eradication therapy as part of a therapeutic framework)
  • Additionally, there are optional indications, which do not necessarily require eradication therapy (e.g.,if long-term NSAID administration is intended and H. pylori has been detected)
• First-line therapies
  • Triple therapy: PPI + clarithromycin + amoxicillin or metronidazole
  • Bismuth-containing quadruple therapy: PPI or an H₂-receptor antagonist + bismuth + tetracycline + metronidazole
  • In case of therapy failure or resistance to clarithromycin:
    • Alternative 1: fluoroquinolone triple therapy involving PPI + levofloxacin or moxifloxacin + amoxicillin
    • Alternative 2: penicillin-free fluoroquinolone triple therapy involving PPI + levofloxacin or moxifloxacin + rifabutin
• Alternative: sequential therapy
  1. PPI + amoxicillin (for 5 days)
  2. PPI + clarithromycin + tinidazole (for additional 5 days)

References:^[4][9][6]

AMAG

• Vitamin B₁₂ deficiency (→ pernicious anemia, funicular myelosis)
• Gastric adenocarcinoma
• Gastric neuroendocrine tumors: particularly carcinoid tumors (commonly featuring polypoid precursors)
• Esophageal squamous cell carcinoma

EMAG

• Ulcerations in the stomach/duodenum (peptic ulcer disease) → upper gastrointestinal bleeding or perforation
• AMAG
• Gastric adenocarcinoma
• Gastric MALT lymphoma
• Extraintestinal manifestations (chronic urticaria, Parkinson's disease, migraine, immune thrombocytopenic purpura, iron deficiency anemia, rosacea)

Helicobacter-associated atrophic gastritis frequently presents with ulcerations. Atrophic gastritis of autoimmune origin does not!
References:^{[1][3][10][11]}

We list the most important complications. The selection is not exhaustive.