Optimizing the Management of Helicobacter PyloriInfections

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Optimizing the Management of Helicobacter PyloriInfections

Prevalence and Consequences of H. pylori Infection

How Common Is Helicobacter Pylori Infection?

H. pylori is one of the most common chronic bacterial infections worldwide, affecting an estimated 4.4 billion people. Incidence and prevalence of infection vary widely, with the highest rates of infection reported in Latin and South America, Russia, and Asia. Where data are available, rates are generally lower in high-income countries (HICs) than low- and middle-income countries (LMICs). However, H. pylori infection remains reasonably common in HICs, with prevalence rates of up to 30% to 50%.Geographical variability also occurs within countries. For example, within the US, prevalence rates vary substantially by state, from 12% in Washington up to 34% in Mississippi. Variation in prevalence among states is, at least partly, due to sociodemographic factors

Why Is There This Geographic Variability in Rates of H. Pylori Infection?

  • Rates of H. pylori infection have been linked to socioeconomic and hygiene conditions, which vary both between and within countries. Within HICs such as the US, infection rates also vary with ethnicity/race and age, with the lowest prevalence in non-Hispanic whites, and higher prevalence in blacks, Hispanics, and older individuals. Additionally, since the infection is usually acquired during childhood, infection rates are higher in immigrants from regions with high prevalence (such as Asia and Latin America) compared with individuals who were born in regions with lower infection rates (such as Europe and North America). In one study, seroprevalence of H. pylori was 70% in immigrants to the US from East Asia and up to 81% in the Fujianese population.
  • Regional variation in prevalence is also seen within high prevalence countries such as China and Korea. The prevalence of H. pylori infection is higher in rural areas than urban areas; trends of decreasing incidence of the infection have been observed in recent years with increasing urbanization.

What Are the Risk Factors for H. Pylori Infection?

  • Low socioeconomic status and poor hygiene in early childhood are the two major risk factors that have been identified for H. pylori infection.
  • Most H. pylori infection occurs during childhood, as infected family members (particularly infected mothers) are a key reservoir for infection.
  • Crowded living conditions, attending daycare facilities from a young age, insanitary living conditions, lack of access to clean drinking water, and large family size (high number of siblings) are among the factors that have been associated with higher rates of acquisition of the infection.
  • Lifestyle factors, such as smoking, alcohol consumption, and a diet high in cholesterol and saturated fat, have also been associated with an increased risk of H. pylori infection, although the impact of these is relatively unimportant.
  • Breastfeeding may provide some natural protection against the acquisition of H. pylori, although results from studies vary.
  • Other factors such as hygiene and family transmission play more important roles, particularly in regions with high prevalence and in low socioeconomic conditions
  • Genetic predisposition may also be a risk factor for H. pylori infection.
  • The variation in prevalence that has been observed across races and ethnicities remains even when controlling for differences in confounders such as living conditions, socioeconomic status, income, and immigration.
  • Family history of gastric cancer can also be an important predictive risk factor; most gastric cancers are due to H. pylori infection, and therefore the likelihood of transmission from a close family member is increased.

What Are the Potential Consequences of Untreated H. Pylori Infection?

  • The rate of progression and severity of gastric inflammation (gastritis) produced by H. pylori varies among individuals.
  • The rate of gastritis progression is unpredictable, and many infected individuals are asymptomatic.
  • Chronic active gastritis develops at some point in nearly all individuals with ongoing H. pylori infection.
  • H. pylori-induced gastritis is a major risk factor for other conditions including gastric and duodenal ulcers, gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma.
  • While most infected individuals do not develop symptoms, approximately 10% to 20% may develop peptic ulcer disease, while a separate and smaller proportion (~1%) of infected individuals will go on to develop gastric adenocarcinoma, or gastric MALT lymphoma
  • Almost all gastric cancers arise from chronic gastritis that is usually due to H. pylori infection.
  • The International Agency for Research on Cancer (IARC) has classified H. pylori as a Group 1 (or “definite”) carcinogen and approximately 78% of all gastric cancers are estimated to be attributable to H. pylori infection.
  • The risk of development of gastric cancer depends on the severity and extent of gastric atrophy and intestinal metaplasia caused by H. pylori.
  • Eradication of H. pylori lowers the risk of development of gastric cancer in patients where precancerous lesions have not already formed, but may not stop further progression in those with lesions. Therefore, timely eradication of infection is key in preventing progression to more serious outcomes.
  • In addition to severe gastric diseases, H. pylori has also been associated with unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura (ITP), and vitamin B12 deficiency.
  • In a multicenter study of children with iron deficiency and iron-deficiency anemia, H. pylori infection was a significant predictor of low ferritin and low hemoglobin concentrations.
  • n adults with ITP, increased platelet counts have been observed in patients treated for H. pylori, and in general, response rates were higher in patients living in regions with a high prevalence of H. pylori.
  • However, similar findings have not always been observed in pediatric patients. Finally, there is some evidence of malabsorption of vitamin B12 in patients with chronic H. pylori infection. However, most of the evidence linking vitamin B12 deficiency and H. pylori infection suggests association rather than causation.

What Are the Additional Risk Factors Associated With Development of Peptic Ulcers and Gastric Cancer in Patients With H. Pylori Infection?

In addition to the identified risk factors for the acquisition of H. pylori infection, a number of additional factors increase the risk of severe outcomes from infection, including peptic ulcer and gastric cancer. Since the risk of development of gastric cancer increases with the severity and extent of atrophic gastritis and intestinal metaplasia, timely eradication of the underlying H. pylori infection is important for limiting the risk. Eradication reduces the risk of gastric cancer in individuals who have not already developed severe or extensive atrophy or intestinal metaplasia.

The virulence of the H. pylori strain can also affect the risk of development of more serious outcomes.

H. pylori produces a number of virulence factors depending on the strain.

H. pylori cytotoxin-associated gene A (cagA)-positive strains have been identified as the strongest risk factor for gastric cancer.

After adherence to gastric epithelial cells, H. pylori cagA-positive strains deliver CagA into the host cytoplasm via a pilus-like type IV secretion system (TFSS) syringe.

CagA disrupts a number of signal transduction pathways, as well as inhibiting normal epithelial differentiation, by altering cell adhesion, migration, and polarity.

Among the other virulence factors associated with gastric cancer development are vacuolating cytotoxin A (VacA) and blood group antigen-binding adhesin (BabA).

VacA induces vacuole formation; strains of H. pylori that carry the s1 or m1 genotypes, which are associated with high vacuolation, have been associated with an increased risk of gastric cancer in Western populations.

BabA is an adhesin that binds to Lewis b blood group antigens and determines the colonization density of H. pylori. Both BabA high- and low-producing strains are associated with an increased risk of gastric cancer, compared with BabA-negative strains.

All three of these virulence factors have also been associated with an increased risk of peptic ulcer disease.

Genetic factors and environmental factors also play a key role in H. pylori infection outcome.

Risk of development of peptic ulcer disease is higher in patients with a family history of peptic ulcers.

Furthermore, a number of genetic polymorphisms have been identified as potentially predisposing to the development of gastric atrophy and increased risk of gastric cancer.

Many of these polymorphisms have been identified in genes involved in the immune response, including those encoding interleukins and pro-inflammatory cytokines, such as TNF-α.

Dietary influences have also been noted in the risk of the development of peptic ulcers and gastric cancer from H. pylori infection. Diets high in salt, saturated fat, cholesterol, and refined carbohydrates, and low in vitamin C have been associated with a higher odds of developing gastric cancer.

When To Test for H. PyloriInfections

Testing for H. pylori infection generally recommended:

  • Unexplained dyspepsia
  • Active peptic ulcer disease
  • Previous history of peptic ulcer disease which was not treated for H. pylori infection
  • Low-grade gastric MALT lymphoma
  • History of endoscopy resection of early gastric cancer
  • First-degree relatives of gastric cancer patients
  • ITP
  • Unexplained iron deficiency anemia
  • Vitamin B12 deficiency
  • Initiating NSAID treatment

Testing for H. pylori infection not generally recommended:

  • Asymptomatic individuals in areas with low prevalence
  • GERD
  • Hyperplastic gastric polyps
  • Hyperemesis gravidarum

In regions of the world with a high prevalence of H. pylori and associated diseases, such as the Western Pacific, universal or population screening is being considered, mainly to lower the high burden of gastric cancer cases. As an example, the Chinese National Consensus Report recommends screening and treatment in regions with a high risk of gastric cancer.

Given the relative low prevalence of H. pylori infection in the US, the ACG recommends against universal or population-based screening.

However, there are specific populations within the US, principally immigrants from high gastric cancer risk areas (Western Pacific, Central and South America, Eastern Europe), who might benefit from targeted H. pylori screening efforts.

Which Tests Should Be Used for Identification of H. Pylori Infection?

  • National guidelines vary in their recommendations for testing strategies, based on the availability of resources and the risk of development of more severe diseases, such as gastric cancer.
  • ACG guidelines advise the use of tests that identify an active infection, such as a urea breath test, fecal antigen test, or endoscopic biopsy.
  • Urea breath tests detect the presence of urease in the stomach by measuring exhaled isotope-labeled carbon dioxide, indicating that urea was metabolized by H. pylori.
  • C urea breath tests have been identified as the best diagnostic method in the Maastricht V/Florence consensus report, as they have both high sensitivity and specificity.
  • C urea breath tests can also be used and often have lower costs but are not suitable for use in children or pregnant women due to exposure to radiation.
  • Fecal antigen tests are generally cheaper than urea breath tests and do not require supervision from medical ancillary staff.
  • The tests are based on enzyme immunoassays or immunochromatography, and the monoclonal tests have high sensitivities and specificities.
  • Serology tests have a sensitivity level ranging from 85% to 100%, and a specificity of 76% to 96%; however, higher specificities are seen with urea breath tests and fecal antigen tests, and therefore they are preferred as part of the "test-and-treat" approach in patients with unexplained dyspepsia and in most other clinical scenarios. However, serology tests may be helpful in cases of bleeding peptic ulcers where tests of active infection performed at the time of bleeding can give false-negative results.
  • Non-invasive tests are less helpful in older adults and, therefore, should be reserved for patients younger than 60 years who do not have any red flag symptoms, such as weight loss, dysphagia, overt gastrointestinal (GI) bleeding, abdominal mass, or iron deficiency anemia.
  • An esophagogastroduodenoscopy should be performed in older patients and any patients who have red flag symptoms or a high risk of gastric cancer.
  • In regions with high rates of gastric cancer, such as China, endoscopy may be used as the first-choice testing procedure, to avoid missing a diagnosis of upper gastrointestinal malignancy.
  • Endoscopies should be performed in conjunction with biopsies for pathology and/or a rapid urease test (RUT).
  • In the presence of urease, which is produced by H. pylori, urea is hydrolyzed to ammonia, which raises the pH of the medium in the test, resulting in a color change. RUT allows immediate identification and treatment, but is not recommended as a post-eradication assessment test due to reduced sensitivity.
  • H. pylori preferentially live in the antrum but migrate to the corpus in states of low acid secretion. For this reason, if the patient is taking a PPI at the time of endoscopy (as is common), biopsies should be taken from both antrum and corpus for H. pylori detection.

When Should Patients Be Tested?

  • Patients should be tested both for initial diagnosis and after eradication treatment, to establish whether the eradication attempt was successful. With current first-line therapies only being successful about 80% of the time in trials, testing after an eradication attempt is important so that additional regimens can be given for refractory cases.
  • After eradication treatment, PPIs should be discontinued at least 2 weeks before post-treatment testing, and at least 4 weeks should be allowed between discontinuing antibiotics and bismuth compounds before testing.
  • PPIs, antibiotics, and bismuth can lead to false-negative urea breath and fecal antigen tests, as they inhibit the growth of H. pylori, and the bactericidal activity of antibiotics may disguise the fact that the bacteria have not been fully eradicated.

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