Atrophic gastritis

Atrophic gastritis is a condition characterized by chronic inflammation of the gastric mucosa with atrophy, gland loss, and metaplastic changes. There are two types: autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis (EMAG), which is commonly caused by Helicobacter pylori (H. pylori). Patients with atrophic gastritis are often asymptomatic or may only experience nonspecific discomfort in the epigastric region. Important diagnostic steps include gastroscopy with biopsy and laboratory studies (e.g., gastrin). The therapeutic approach depends on the underlying etiology. AMAG is treated with vitamin B12 substitution, whereas individuals with EMAG will receive H. pylori eradication therapy. If left untreated, atrophic gastritis may lead to peptic ulcer disease or result in the development of various cancers.

• Prevalence ^[1]
  • AMAG: ∼ 2–5%
  • EMAG: prevalence strongly correlates with level of endemic H. pylori infection → increase in prevalence with advancing age → affects the majority of elderly patients

Epidemiological data refers to the US, unless otherwise specified.

Autoimmune metaplastic atrophic gastritis (AMAG)

• Associated with major histocompatibility haplotypes HLA-B8 and HLA-DR3
• Associated with other autoimmune diseases (e.g., autoimmune thyroiditis)

Environmental metaplastic atrophic gastritis (EMAG)

• Helicobacter pylori infection
  • Most important risk factor for chronic gastritis, including atrophic gastritis ^[2]
  • Colonizes mainly antrum of stomach
• Dietary factors
  • N-nitroso compounds
  • Alcohol intake
  • High salt intake

AMAG

• Autoimmune destruction of the parietal cells in the gastric corpus and fundus (autoantibodies against H⁺/K⁺ ATPase) → achlorhydria → increased release of gastrin (due to loss of negative feedback) → G cell hyperplasia → hypergastrinemia → hyperplasia of enterochromaffin-like cells → ↑ risk of carcinoid tumors.
• Achlorhydria impairs the intestinal absorption of inorganic iron → iron deficiency anemia (early manifestation)
• Autoantibodies against intrinsic factor → vitamin B12 deficiency → pernicious anemia

EMAG

• Colonization by H. pylori
  • Inflammation of the antrum → destruction of D cells → ↓ somatostatin → ↑ gastrin → ↑ production of gastric acids → duodenal ulcers ^[3][4]
  • Inflammation of the gastric body → local destruction of mucosa (via cytotoxins such as ammonia) → ↓ production of mucins and atrophy of the gastric glands → hypochlorhydria → hypergastrinemia and epithelial dysplasia → epithelial metaplasia → ↑ risk of gastric cancers ^[5]
• Diet: bacteria in the stomach metabolize nitrates present in food → formation of carcinogenic N-nitroso compounds → epithelial metaplasia → ↑ risk of gastric cancers

.

General symptoms

• Hematemesis; (coffee-ground appearance or bright red), possibly melena
• Epigastric pain is possible.
• Nausea, vomiting
• Abdominal paresthesia and dyspepsia

Specific symptoms in AMAG

• Signs of anemia
  • E.g., pallor, fatigue (caused by iron deficiency anemia and/or pernicious anemia)
  • Features of vitamin B12 deficiency: triad of hematologic, neurologic, and gastrointestinal disorders
• Symptoms of other autoimmune diseases (e.g., goiter in Hashimoto thyroiditis)

Specific symptoms in EMAG

• Asymptomatic progression is common.
• Patients often have recurring ulcers (abdominal pain, dyspepsia)
• Symptoms often occur as a result of gastric or duodenal ulcer bleeding (see “Signs of GI bleeding”).

Helicobacter-associated atrophic gastritis frequently manifests with ulcerations. Atrophic gastritis of autoimmune origin does not.

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

Helicobacter pylori diagnostics

Indications ^[6]

• Dyspepsia (method depends on patient characteristics)
  • H. pylori test-and-treat strategy: urea breath test (in patients ≤ 60 years of age without alarm features of gastritis) ^[6][7]
  • EGD with biopsies or rapid urease testing (in patients > 60 years of age or with ≥ 1 alarm feature of gastritis)
• Low-grade MALT lymphoma
• Peptic ulcer disease (active or positive history without prior eradication)
• Endoscopically resected early gastric cancer

PPIs should be discontinued at least 2 weeks prior to testing for H. pylori to minimize false-negative rates. ^[8]

Modalities

As a rule, at least two methods should be employed. The diagnosis is generally confirmed if two tests are positive.

• Invasive methods
  • Collection of biopsy samples
    • For histology: 2 biopsy samples from the antrum (peripyloric and angular incisure) and 2 samples from the corpus (lesser curvature and greater curvature)
    • For the urease test: 1 biopsy sample from the antrum and 1 sample from the corpus
  • Histology (gold standard) including staining and direct microscopic identification shows curved, flagellated gram-negative rods
  • 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
  • Detection of H. pylori DNA by PCR: very sensitive and specific, but almost never used in daily clinical practice
• Non-invasive methods
  • H. pylori stool antigen test: detects the presence of H. pylori antigens in a stool sample
    • Can be used for diagnosis of H. pylori infection and proof of eradication after treatment
    • Suitable option as initial test (cost-effective)
  • 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)

Additional tests

• Hematology
  • In cases of chronic bleeding (any type): possibly microcytic anemia
  • In AMAG: possibly macrocytic anemia
• Serum pepsinogen isoforms
• Vitamin B12 levels: ↓ in AMAG
• Serum gastrin levels: ↑ in AMAG
• Serology
  • Anti-intrinsic factor
  • Anti-parietal cell antibodies

Microscopy findings

The following microscopic findings may be seen in both types of atrophic gastritis.

• Chronic inflammation → granulocytic infiltrations in the mucosa, lymphocytic infiltrations in the submucosa
• Mucosal thinning
• Loss of glands
• Epithelial metaplasia
  • (Pseudo)pyloric: replacement of parietal and chief cells in oxyntic glands by mucus-secreting cells, which are usually present in the pyloric region
  • Intestinal: replacement of epithelial cells in the oxyntic or antral mucosa by intestinal epithelium cells (e.g., goblet cells)
• Possible detection of H. pylori (gram-negative, rod-shaped bacteria)
• G-cell hyperplasia (common in AMAG)

Patterns of affliction

• AMAG: Lesions are confined to the gastric body and fundus.
• EMAG: Lesions first manifest in the gastric antrum (predominant), then spread to body and fundus.

• Chemical gastritis
• Sarcoidosis
• Vasculitis
• Granulomatous gastritis
• Eosinophilic gastritis
• Lymphocytic gastritis
• Ménétrier disease

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

Sucralfate should not be given simultaneously with PPIs and/or H2 antagonists because it is activated by an acidic environment.

AMAG

• Vitamin B12 replacement therapy (parenteral)
• If H. pylori is detected: attempt to eradicate (may lead to healing)
• Because there is a risk of malignant degeneration, regular endoscopic check-ups are required.

Helicobacter-associated atrophic gastritis

• See “H. pylori eradication therapy” below.

Consider treatment in any patient testing positive for H. pylori infection.

First-line treatment options ^[6][9]

PPIs twice daily PLUS 2 antibiotics with/without bismuth for 10–14 days ^[6]

• Clarithromycin triple therapy: in areas of low (< 15%) clarithromycin resistance
  • PPIs at standard or double dose twice daily (e.g., omeprazole ) ^[6]
  • PLUS clarithromycin ^[6]
  • PLUS amoxicillin OR metronidazole ^[6]
  • Duration: 14 days
• Clarithromycin-based concomitant therapy
  • PPIs at standard dose twice daily (e.g., omeprazole ) ^[6]
  • PLUS clarithromycin ^[6]
  • PLUS amoxicillin ^[6]
  • PLUS Metronidazole OR tinidazole ^[6]
  • Duration: 10–14 days
• Bismuth quadruple therapy: in areas of high (> 15%) clarithromycin resistance
  • PPIs at standard dose twice daily (e.g., omeprazole ) ^[6]
  • PLUS bismuth (e.g., bismuth subcitrate OR bismuth subsalicylate ^[6]
    • Mechanism of action: binds to the surface of an ulcer → physical protection from acids → gastric HCO₃^- secretion restores mucosal pH gradient
    • Indications (other than quadruple therapy): ulcer therapy, traveler's diarrhea caused by ETEC
  • PLUS tetracycline ^[6]
  • PLUS metronidazole ^[6]
  • Duration: 10–14 days

“Three days of C(AM)Ping:” the triple therapy consists of Clarithromycin, Amoxicillin OR Metronidazole, and PPI.

Follow-up

• Confirm eradication after each therapy regimen ^[8][10]
  • Urea breath test, stool antigen test, or biopsy 4–6 weeks after completion of therapy.
  • Serology is not preferred to confirm eradication, as it remains positive for weeks/months after eradication.
• Antisecretory therapy can be discontinued once eradication is confirmed. ^[10]

AMAG

• Vitamin B12 deficiency; (leading to pernicious anemia, which potentially causes 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
• Gastric adenocarcinoma
• Gastric MALT lymphoma
• Extraintestinal manifestations (e.g., chronic urticaria, Parkinson disease, migraine, immune thrombocytopenic purpura, iron deficiency anemia, rosacea) ^[11]

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

1. Coati I, Fassan M, Farinati F, Graham DY, Genta RM, Rugge M. Autoimmune gastritis: Pathologist's viewpoint. World J Gastroenterol. 2015; 21 (42): p.12179-12189. doi: 10.3748/wjg.v21.i42.12179 . | Open in Read by QxMD
2. Hilzenrat N, Lamoureux E, Weintrub I, Alpert E, Lichter M, Alpert L. Helicobacter heilmannii-like spiral bacteria in gastric mucosal biopsies. Prevalence and clinical significance.. Arch Pathol Lab Med. 1995; 119 (12): p.1149-53.
3. Kaneko H, Nakada K, Mitsuma T, et al. Helicobacter pylori infection induces a decrease in immunoreactive-somatostatin concentrations of human stomach.. Dig Dis Sci. 1992; 37 (3): p.409-16. doi: 10.1007/BF01307736 . | Open in Read by QxMD
4. Sumii M, Sumii K, Tari A, et al. Expression of antral gastrin and somatostatin mRNA in Helicobacter pylori-infected subjects.. Am J Gastroenterol. 1994; 89 (9): p.1515-9.
5. Smoot DT, Mobley HL, Chippendale GR, Lewison JF, Resau JH. Helicobacter pylori urease activity is toxic to human gastric epithelial cells.. Infect Immun. 1990; 58 (6): p.1992-4. doi: 10.1128/IAI.58.6.1992-1994.1990 . | Open in Read by QxMD
6. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017; 112 : p.212-238. doi: 10.1038/ajg.2016.563 . | Open in Read by QxMD
7. Moayyedi PM, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol. 2017; 112 (7): p.988-1013. doi: 10.1038/ajg.2017.154 . | Open in Read by QxMD
8. Fashner J, Gitu AC. Diagnosis and Treatment of Peptic Ulcer Disease and H. pylori Infection. Am Fam Physician.. 2015; 91 (4): p.236-242.
9. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Blood. 2006; 107 (4): p.1673-1679. doi: 10.1182/blood-2005-09-3534 . | Open in Read by QxMD
10. Wong F, Rayner-hartley E, Byrne MF. Extraintestinal manifestations of Helicobacter pylori: a concise review. World J Gastroenterol. 2014; 20 (34): p.11950-11961. doi: 10.3748/wjg.v20.i34.11950 . | Open in Read by QxMD
11. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut. 2016; 66 (1): p.6-30. doi: 10.1136/gutjnl-2016-312288 . | Open in Read by QxMD
12. Ables AZ, Simon I, Melton ER. Update on Helicobacter pylori treatment.. Am Fam Physician. 2007; 75 (3): p.351-8.
13. Herold G. Internal Medicine. Herold G ; 2014