Helicobacter pylori-Associated Iron Deficiency Anemia in Childhood and Adolescence-Pathogenesis and Clinical Management Strategy.

Many epidemiological studies and meta-analyses show that persistent Helicobacter pylori infection in the gastric mucosa can lead to iron deficiency or iron deficiency anemia (IDA), particularly in certain populations of children and adolescents. Moreover, it has been demonstrated that H. pylori infection can lead to and be closely associated with recurrent and/or refractory iron deficiency and IDA. However, the pathogenesis and specific risk factors leading to this clinical outcome in H. pylori-infected children remain poorly understood. In general, most of pediatric patients with H. pylori-associated IDA do not show evidence of overt blood loss due to gastrointestinal hemorrhagic lesions. In adult populations, H. pylori atrophic gastritis is reported to cause impaired iron absorption due to impaired gastric acid secretion, which, subsequently, results in IDA. However, significant gastric atrophy, and the resultant substantial reduction in gastric acid secretion, has not been shown in H. pylori-infected children. Recently, it has been hypothesized that competition between H. pylori and humans for iron availability in the upper gastrointestinal tract could lead to IDA. Many genes, including those encoding major outer membrane proteins (OMPs), are known to be involved in iron-uptake mechanisms in H. pylori. Recent studies have been published that describe H. pylori virulence factors, including specific OMP genes that may be associated with the pathogenesis of IDA. Daily iron demand substantively increases in children as they begin pubertal development starting with the associated growth spurt, and this important physiological mechanism may play a synergistic role for the microorganisms as a host pathogenetic factor of IDA. Like in the most recent pediatric guidelines, a test-and-treat strategy in H. pylori infection should be considered, especially for children and adolescents in whom IDA is recurrent or refractory to iron supplementation and other definitive causes have not been identified. This review will focus on providing the evidence that supports a clear biological plausibility for H. pylori infection and iron deficiency, as well as IDA.

The Resolution of Severe Iron-Deficiency Anemia After Successful Eradication of Helicobacter pylori in Teenagers.

Long-term follow-up studies with Helicobacter pylori eradication therapy in children with H. pylori-associated iron-deficiency anemia (IDA) are scarce. We investigated whether successful H. pylori eradication would result in maintaining resolution of recurrent and/or refractory IDA in a cohort of teenagers in Japan. Methods: In this case series, 7 H. pylori-infected patients with recurrent and/or refractory IDA (12-16 y old) received successful eradication therapy and were then followed for a median of 20 months (range, 9-76 mo) after oral iron supplementation therapy (1-4 mo) was discontinued. Five patients of our study cohort participated in rigorous sports activities. Results: No visual appearance of ulcerations or erosions was found by esophagogastroduodenoscopy. In all patients studied, the gastric biopsies showed histological evidence of chronic gastritis without significant atrophy and intestinal metaplasia. Compared with the baseline (median values: hemoglobin, 6.3 g/dL; serum iron, 9 µg/dL; serum ferritin, 1.5 ng/mL), values of hemoglobin (P < 0.001), serum iron (P < 0.005), and ferritin (P < 0.001) significantly increased, on average, 2-3 months after eradication therapy and these iron indices were maintained at the same or higher levels at the endpoint of follow-up (median values: 14.2 g/dL, 102 µg/dL, and 29.3 ng/mL, respectively). No patient had recurrence of IDA at the time of final follow-up. Conclusions: H. pylori infection can be closely associated with recurrent or refractory IDA in teenage children. It is speculated that increased iron demands as a result of growth spurt in adolescents may play a synergistic role in combination with H. pylori in the pathogenesis of IDA.

The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood.

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first-line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test-and-treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test-and-treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first-line therapy against H. pylori-associated diseases. The guidelines recommend against a "test-and-treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy.

Folate concentrations in pediatric patients with newly diagnosed inflammatory bowel disease.

BACKGROUND: Folate is postulated to protect against cell injury and long-term risk of cancer. Folate deficiency has been shown to be associated with inflammatory bowel disease (IBD). However, folate concentrations are poorly delineated in children with IBD. OBJECTIVE: The objective was to compare folate concentrations between children with newly diagnosed IBD and healthy controls. DESIGN: Red blood cell folate (RBCF) and whole-blood folate (WBF) concentrations were measured in 78 children (mean age: 12.8 +/- 2.7 y): 22 patients with newly diagnosed untreated Crohn disease, 11 patients with ulcerative colitis, 4 patients with indeterminate colitis, and 41 controls. Vitamin supplementation and dietary intakes determined by food-frequency questionnaire were recorded for 20 IBD patients and 28 controls. RESULTS: RBCF concentrations were 19.4% lower in controls (587.0 +/- 148.6 ng/mL) than in patients (728.7 +/- 185.8 ng/mL; P = 0.0004), and WBF concentrations were 11.1% lower in controls (218.2 +/- 49.7 ng/mL) than in patients (245.3 +/- 59.1 ng/mL; P = 0.031). Total folate intake was 18.8% higher in controls (444.7 +/- 266.7 microg/d) than in IBD patients (361.1 +/- 230.6 microg/d), but this difference was not statistically significant (P = 0.264). Folate intakes were below the Recommended Dietary Allowance (200-400 microg/d), adjusted for age and sex, in 35.4% of study subjects. CONCLUSIONS: In contrast with previous evidence of folate deficiency in adult IBD patients, our data indicate higher folate concentrations in children with newly diagnosed untreated IBD than in controls. This finding was unexpected, especially in light of the higher dietary folate intakes and hematocrit values in children without IBD. The influence of IBD therapy on folate metabolism and the long-term clinical implications of high RBCF and WBF concentrations at the time of IBD diagnosis should be explored further.

A controlled, household-randomized, open-label trial of the effect that treatment of Helicobacter pylori infection has on iron deficiency in children in rural Alaska.

BACKGROUND: Helicobacter pylori infection and iron deficiency are prevalent in disadvantaged populations worldwide. Previous small or uncontrolled studies have reported that successful treatment of H. pylori infection may resolve iron deficiency or anemia. METHODS: We screened 68% of children 7-11 years old living in 10 western Alaska villages. The 219 children with iron deficiency (serum ferritin level, <22.5 pmol/L [<10 microg/L]) and H. pylori infection (diagnosed on the basis of (13)C-labeled urea breath tests) were enrolled in a household-randomized, unblinded trial. All children received iron supplementation for 6 weeks; children in the intervention group also received a 2-week course of treatment for H. pylori infection plus another 2-week course of treatment if the infection had not resolved at 2 months after treatment initiation. RESULTS: At 2 months after treatment initiation, 32% of children in the intervention group and 39% of children in the control group had iron deficiency. At 14 months after treatment initiation, 65% of children in the intervention group and 72% of children in the control group had iron deficiency (adjusted relative risk [ARR], 0.90 [95% confidence interval [CI], 0.74-1.1]); in addition, 22% of children in the intervention group and 14% of children in the control group had anemia (ARR, 1.6 [95% CI, 0.86-2.9]). Results were similar when children were compared by H. pylori infection status. CONCLUSIONS: In a high-prevalence population, treatment and resolution of H. pylori infection did not improve isolated iron deficiency or mild anemia up to 14 months after treatment initiation.

Gastroesophageal reflux disease: could intervention in childhood reduce the risk of later complications?

Gastroesophageal reflux (GER) is a ubiquitous disorder in infants. Whereas infants typically outgrow regurgitation by 1 year of age, the prevalence of gastroesophageal reflux disease (GERD) symptoms in those aged 3 to >18 years ranges from 1.8% to 22%. The pathophysiology of GERD in children is similar to that in adults. However, children may present with gastroesophageal and extraesophageal symptoms distinct from classic heartburn. In addition to a growing awareness of the high prevalence of the disorder, increasing evidence supports GERD being a lifelong condition in some individuals that begins in childhood. Although the diagnostic workup in children compared with adults may differ, studies suggest that the early detection and treatment of GERD in childhood may result in better adult disease outcomes, improved quality of life, and decreased overall healthcare burden. Studies of proton pump inhibitor therapy in children confirm high rates of mucosal healing and GER symptom resolution, even in children whose symptoms did not respond to H2-receptor therapy or fundoplication procedures. Omeprazole, lansoprazole, and esomeprazole are formulated as capsules containing enteric-coated granules that can be sprinkled onto applesauce or other soft foods. Lansoprazole is also formulated as strawberry-flavored granules for suspension. These as well as other alternative dosing formulations expand the ability to administer these agents to children. Moreover, long-term studies in adults and in children demonstrate that these agents are safe and well tolerated, even at the higher milligram per kilogram doses that are often required in pediatric patients because of their greater hepatic metabolic capacity.

Gastroesophageal reflux in children: pathogenesis, prevalence, diagnosis, and role of proton pump inhibitors in treatment.

A substantial percentage of infants, children and adolescents experience gastroesophageal reflux disease (GERD) and its accompanying symptoms, as well as disease complications. The diagnosis of GERD in children is made based upon the child's history, and data derived primarily from pH monitoring tests and endoscopy. In those children with confirmed reflux disease, the options for management parallel those recommended in adult patients, with the first step consisting of lifestyle changes. Surgical procedures may also be performed; however, these are rarely recommended prior to an adequate course of pharmacologic therapy, and appropriate case selection is important. Among the current pharmacotherapeutic options available in the US, the prokinetic agents and the acid-inhibitory agents (histamine-2 receptor antagonists, proton pump inhibitors) are the most widely used. The clinical utility of the prokinetic agents has been limited by the recent withdrawal of cisapride from the US marketplace and the potential for irreversible central nervous system complications with metoclopramide. Numerous clinical studies performed in adults, and several studies involving children, have demonstrated that the proton pump inhibitors are more effective than the histamine-2 receptor antagonists in the relief of GERD symptoms and healing of erosive esophagitis. In children, omeprazole and lansoprazole may be administered as the intact oral capsule, or in those who are unable or unwilling to swallow, the granule contents of the capsule may be mixed with soft foods (e.g. apple sauce) or fruit drinks/liquid dietary supplements prior to oral administration with no detrimental effects on pharmacokinetics, bioavailability, or pharmacodynamics. Studies performed with omeprazole and lansoprazole in children have shown pharmacokinetic parameters that closely resemble those observed in adults. In over a decade of use in adults, the proton pump inhibitor class of agents has been found to have a good safety profile. Studies involving children have also shown these agents to be well tolerated. In numerous drug-drug interaction studies performed with these two proton pump inhibitors, relatively few clinically significant interactions have been observed.