Resolution of Unexplained Iron Deficiency Following Successful Eradication of Helicobacter Pylori in Children

doi:10.21203/rs.3.rs-708094/v1

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Resolution of Unexplained Iron Deficiency Following Successful Eradication of Helicobacter Pylori in Children

https://doi.org/10.21203/rs.3.rs-708094/v1

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Background: Evidence is needed to inform whether Helicobacter pylori (HP) treatment is beneficial in children with refractory iron deficiency. We aimed to assess association between successful HP eradication and resolution of unexplained iron deficiency.

Methods: Medical records of children diagnosed with HP infection (based on histopathology) and without significant upper gastrointestinal source of blood loss, were retrospectively reviewed for presence of iron deficiency. Among those with non-anemic iron deficiency (NAID) or iron deficiency anemia (IDA), hemoglobin, ferritin and C-reactive protein (CRP) levels were compared prior and 6-9 months’ post successful HP eradication. Patients with overt bleeding or subsequent iron supplement therapy post HP diagnosis were excluded. Predictors of resolution of iron deficiency following HP eradication were assessed.

Results: Among 60 included children (median age 14.8, IQR12.3-16; 62% males), symptoms of anemia were observed in 20%. A total of 21 (35%) had IDA while the remainder 65% had NAID. Following successful HP eradication, 60% of these 60 patients normalized their iron status. There were significant improvements in both hemoglobin and ferritin following HP eradication with hemoglobin increasing from 12.3g/dL to 13.0 g/dL (P<0.001), and ferritin increasing from 6.3μg/l to 15.1 μg/l (P<0.001). In multivariate logistic regression that assessed sex, ethnicity, baseline hemoglobin, anemia or GI symptoms, previous iron therapy, and time from diagnosis to eradication, older age was the only factor associated with resolution of anemia following HP eradication: (OR 1.65, 95% CI 1.16-2.35, P = 0.005).

Conclusion: Successful HP eradication could be helpful in improving iron status among children with refractory NAID or IDA. Older age may predict this outcome. Screening for HP should be considered in the workup of refractory IDA or NAID.

Nutrition & Dietetics

Helicobacter Pylori

iron deficiency

anemia

children

Iron deficiency anemia (IDA) and non-anemic iron deficiency (NAID) are among the most common micronutrient deficiencies globally. They are particularly worrisome in children due to their harmful effect on growth, motor and cognitive functions (1). Helicobacter pylori (HP) is a major gastric pathogen infecting approximately half of the world population (2, 3), It is predominantly acquired during childhood and persists throughout life, unless therapeutically eradicated (4). HP infection causes chronic gastritis which remains asymptomatic in most infected children. Only about 15% of infected persons develop peptic ulcer disease (5–7). The association between HP infection and IDA has been a focus of attention for more than a decade (8, 9). HP seroprevalence is more common in children with refractory IDA (10). Children infected with HP are considered to be at a higher risk of IDA and NAID (11, 12). The mechanism by which HP contributes to iron deficiency (ID), in absence of gastric bleeding remains unclear; however, Several mechanisms have been postulated including the alteration of gastric acidity (10, 13–16), the induction of atrophic gastritis, reduction in ascorbic acid in gastric secretions (17), the development of gastric microerosions, inflammation and an up-regulation of hepcidin levels (17–22). However, ID and IDA does not develop in all HP infected patients, only in approximately 25% of them (23, 24). Unexplained and refractory IDA is considered as one of the indications for testing for HP infection in children and for eradication if the patient is found to be positive (24). Despite this clinical practice, evidence for the association between HP eradication therapy and resolution of childhood IDA is still matter of debate (23, 25–29). Ethnic dissimilarities as well as differences in diagnostic criteria may possibly explain differences in those studies. Regardless, the Joint ESPGHAN/NASPGHAN guidelines and the British society of gastroenterology recommend considering eradication of HP infection in patients with IDA and unremarkable esophagogastroscopy (19, 30). The primary aim of this study was to assess the resolution of NAID and IDA in pediatric patients after the successful eradication of HP. The secondary aim was to explore the contribution of inflammation, measured as CRP levels, to the change of ferritin and Hgb concentration with HP eradication.

Study population:

The study was conducted at Emek Medical Center, Israel. Patients were included if they were aged 2–18 years and fulfilled all of the following criteria: (1) confirmed diagnosis of HP infection (30), (2) presence of NAID or IDA based on ferritin and hemoglobin (Hgb) levels and using age and sex-specific cutoffs (31, 32), (3) lack of overt gastrointestinal (GI) bleeding, (4) successful subsequent HP eradication, and (5) without iron supplement therapy following the diagnosis of HP infection. Electronic medical records from one year prior to and one year following the performance of endoscopy were reviewed.

Exclusion criteria included patients with significant source of chronic and/or acute GI blood loss identified on upper and/or lower endoscopy, clinical or histological diagnosis of celiac disease, inflammatory bowel disease, eosinophilic gastroenteritis, malabsorption disorders, obvious cause of non-GI loss (e.g., epistaxis, significant menstrual bleed), known inherited blood disorder (e.g., thalassemia minor), malignancy or those without accessible iron status measurements following eradication or those receiving ongoing iron therapy.

Study design

This retrospective cohort study included the medical records of children diagnosed with HP infection, without overt upper gastrointestinal source of blood loss, from 2005 to 2020. Demographic, clinical, laboratory, endoscopic and histological findings were collected. Hgb, ferritin and C-Reactive Protein (CRP) levels were assessed before and after the eradication of HP. Our primary outcome was the resolution of IDA or NAID following HP eradication, without iron supplementation, defined by normalization of ferritin and Hgb levels adjusted for age and sex (31–33). Baseline Hgb and ferritin were obtained at least 3 months prior to HP eradication trial. Post treatment Hgb and ferritin were obtained within 6–9 months’ post successful HP eradication.

Determination of HP status

HP status was determined by presence of HP organisms on histological evaluation of gastric biopsies, positive rapid urease test or positive gastric culture for HP. In patients with discordant results by positive rapid urease and/or histology, positive HP serology or presence of chronic active gastritis on biopsy were used to determine the presence of active HP infection (30, 34). Patients with discordant histology results, who were on proton pump inhibitors (PPIs) and had no serology tests, were not included. Patients in whom diagnosis was based on non-invasive methods (urea breath test, HP fecal antigen or serology tests) without upper gastrointestinal endoscopy were not included.

Determination of NAID and IDA

In this study, we followed the guidelines of WHO and American Academy of pediatrics (AAP), which have defined ID as ferritin levels below 12 µg/L and 15 µg/L in otherwise healthy children under and above 5 years, respectively (31, 32). Anemia was defined based on age and sex according to the WHO criteria (33). Altitude correction was not needed as all patients lived below 1000m above sea level altitude. Although WHO recommends adjusting ferritin based on CRP levels(35), there was a very weak and non-significant correlation between ferritin and CRP at baseline (r = -0.03, P = 0.8157) and after the therapy (r = -0.03, P = 0.8571) in our study. Therefore, we did not apply the BRINDA method to adjust serum ferritin concentration based on inflammation status(36, 37).

Statistical analysis

Data were analyzed using SPSS (version 21.0, SPSS, Inc., Chicago, IL, USA). Continuous variables were presented as either mean ± SD or median with interquartile range (IQR) depending on the data approximation to normal distribution. In order to analyze the factors predictive of ID resolution, Fisher's exact test was used to explore univariate associations between primary outcomes and categorical variables. Association between variables at triple therapy initiation and resolution of ID was evaluated using univariate and multivariate logistic regression. Multiple logistic regression analysis was then performed using variables that were statistically significant on univariate analysis. The difference in ferritin before and after the therapy were compared between patients with elevated and non-elevated CRP levels at the baseline (elevated CRP level is defined as CRP > 5 mg/L) to determine whether inflammation may modify the association between HP eradication and improvement in iron status. All reported P-values are two-sided. P-values < 0.05 were considered significant.

Patients' characteristics

Between January 2005 and December 2019, 293 children were diagnosed with HP. As shown in Fig. 1, 99 of them had IDA/NAID at diagnosis. After exclusion of patients who did not fulfil the inclusion criteria, 60 children and adolescents (median age 14.8, IQR12.3-16; 62% males) were included. Their demographic and phenotypic characteristics are presented in Table 1. Self-reported symptoms of anemia (Headache, dizziness or weakness) were observed in twelve patients (20%). Forty% received iron supplement therapy prior to HP diagnosis. Eight patients (13%) did not have any GI symptoms and were evaluated for HP solely on the basis of IDA/NAID. Triple therapy included Amoxicillin (Amx) + Clarithromycin (Clr) + PPIs in 63%, Amx + Metronidazole (Mtz) + PPIs in 35% and Clr + Mtz + PPI in 1 patient only (2%), this triple therapy was given for 1–2 weeks and followed by 2–4 weeks of PPI therapy. The median time from HP diagnosis to initiation of triple therapy was 1.5 months, (IQR, 0.9–2.9); median time between successful HP eradication and iron status reassessment was 7.4 months (IQR, 6.7–8.2 months).

Table 1

Patient characteristics
Covariate	All Cohort (n = 60)
Male, N (%)	37 (62)
Age at diagnosis, years, Median (IQR)	14.8 (12.3–16)
Ethnicity, N (%) Jews Arabs	35 (58) 25 (42)
Clinical symptoms, N (%) Abdominal / epigastric pain Weight loss Heartburn Decreased appetite Weakness Headache Dizziness	54 (90) 11 (18) 8 (13) 36 (60) 15 (25) 14 (23) 10 (17)
Endoscopic findings, N (%) Antral nodularity Antral gastropathy Gastric erosions Duodenal erosions	57 (95) 50 (83) 10 (17) 21 (35)
Diagnostic method for HP identification, N (%) Histological evaluation Gastric culture Rapid Urease test	58 (97) 22 (37) 19 (32)
Baseline laboratory findings Hemoglobin, g/dl Mean (SD) Ferritin, ug/l Mean (SD) CRP, mg/l Mean (SD)	12.3 (1.2) 6.3 (3.6) 3.7 (2.6)
Type of iron deficiency, N (%) IDA NAID	21 (35) 39 (65)
Duration between diagnosis and HP treatment initiation, months, Median (IQR)	6.3 (2.2–14.9)
Previous Iron supplements therapy, N (%)	24 (40)
Triple therapy, N (%) Clr + Amx + PPI Mtz + Amx + PPI Mtz + Clr + PPI	38 (63) 21 (35) 1 (2)
Test of eradication's approval, N (%) Urea breath test HP fecal antigen	48 (80) 12 (20)
Post treatment laboratory findings Hemoglobin, g/dl Mean (SD) Ferritin, ug/l Mean (SD) CRP, mg/l Mean (SD)	13 (1.2) 15.1 (7.8) 1.6 (1.4)

Effect on Iron status

Prior to HP eradication, mean Hgb and ferritin levels were 12.3 g/dl and 6.3 µg/l respectively. When including only 21 patients with IDA, mean Hgb and ferritin were much lower 11.1 g/dl and 3.9 µg/l respectively. Post HP eradication, Hgb levels increased significantly in the whole group to a mean Hgb of 13 as well as among IDA patients to a mean of 12.5 as shown in Fig. 2a and 2b (P < 0.001). In addition, ferritin levels were significantly higher following successful HP eradication (Fig. 2c) (P < 0.001). Prior to HP eradication, of 60 patients, 21 (35%) had IDA while the remainder 65% had NAID. Post successful eradication 60% of the total 60 patients normalized their iron status as shown in Fig. 3.

Predictors of resolution of IDA/NAID

In univariate logistic regression, older age, higher baseline Hgb levels and being NAID rather than IDA prior to triple therapy initiation were associated with resolution of ID at end of follow-up: (OR 1.4, 95% CI 1.11–1.77, P = 0.004), (OR 2.49, 95% CI 1.37–4.55, P = 0.003) and (OR 4.13, 95% CI 1.34–12.66, P = 0.013) respectively. Multivariate logistic regression demonstrated that only older age was an independent, predictive factor for resolution of ID at end of follow-up: (OR 1.65, 95% CI 1.16–2.35, P = 0.005). Sex, ethnicity, presence of self-reported anemia symptoms, previous iron therapy, time from diagnosis to eradication and the presence of GI symptoms were not found to be associated with the resolution of ID (data not shown)

Correlation between inflammation and the iron status

After the treatment, the mean serum ferritin concentration increased by 8.64 (CI: 4.48–12.8) µg/l among children who had elevated CRP (defined as CRP > 5.0 mg/L), compared to 8.68 (CI: 6.27–11.1) µg/l among children with normal CRP level as shown in Fig. 4.

In this study, we have found that the eradication of HP in children was associated with a significant increase in Hgb and ferritin levels. The increase in iron stores was much higher in older children and those with pre-eradication higher Hgb. Older age was the sole independent predictive factor associated with the resolution if ID.

The treatment of IDA in children is a public health priority due to its harmful long-term effects and relative ease and availability of diagnosis and treatment (38). For decades, researchers have been concerned with the relationship between HP and IDA and the importance of HP eradication in IDA treatment. This issue has major implications especially in low resource settings where both conditions are prevalent (39) and HP diagnostic tools are not always accessible (40). Also in affluent settings, concerns over antibiotic resistance are alarming (41).

Our results are an important contribution to the growing body of literature exploring the correlation between HP eradication in children and the resolution of NAID and ID (42–44). Our study is unique in that it has studied patients not treated with supplementary iron and can thus focus on the sole effect of HP eradication on iron absorption without dietary changes. Kurekci et al (45) have also previously demonstrated an improvement in Hgb and iron stores after the eradication of HP in children, but unlike their study, ours have relied on a histological evidence of HP infection.

HP infection is usually acquired in childhood and its significance as a colonizing pathogen is still debateable. NAID and IDA are also very common in childhood. Several risk factors such as lower socio-economic status, poor nutrition, household crowdedness and being a minority group or from a developing country are common between HP and IDA (25)^,(29)^,(46)^,(47) making exploring the causation a harder task. Nevertheless, several large studies have managed to show a correlation between NAID / IDA and HP infection and an improvement in the iron stores after the eradication of HP (48). It is still unknown how lasting this effect is. In a randomized controlled trial in rural Alaska, Gessner et al did not demonstrate any improvement in Hgb or iron stores 14 months after the eradication of HP (29). When the same cohort was examined at 40 months post eradication, a modest improvement in iron stores was noticed in the HP negative group (49). Sarker et al found that HP was not related to IDA or iron treatment failure in Bengali children (25). Our results suggest that HP eradication without iron supplement is associated with the resolution of ID/IDA at 6 months’ post eradication.

Older age as a predictive factor of the resolution of IDA was observed in several studies, Duque et al have observed that Mexican children with HP infection and IDA were older than their schoolmates with IDA without HP infection (27). Baggett et al also observed that in Alaskan children, the relationship between HP infection and IDA was age dependent and reached significance in older children. This was explained by a longer duration of infection causing a larger loss in iron stores (29). This might explain the finding that in our cohort older children had a better improvement in iron stores compared to younger children, since longer duration of HP infection in those cases might have contributed initially to their anemia.

CRP is an accurate marker of inflammation. It has been found to be higher in adult patients with HP infection, also those with peptic ulcer disease and asymptomatic carriers compared to healthy adult controls (50). In children on the other hand, the findings in the literature are unequivocal. Azab et al have found a significantly higher CRP level in HP infected children with IDA, compared to HP noninfected children with IDA and a healthy control (18). Ozkasab et al also found prohepcidin, but not CRP, to be elevated in children with HP infection and IDA compared to HP infected children with NAID or those without ID, these results were explained by a possible role of inflammation in HP induced IDA (20). On the other hand, other studies have argued that the inflammatory response to HP colonization in children, compared to adults, seems to be neglectable. Harris et al have demonstrated the role of T regulatory cells in down-regulating HP induced inflammation (51). Soares et al have also demonstrated the role of CD4 and CD8 cells in creating a more regulated immune response to HP in children compared to adults (52). These results align well with our results, for in our cohort there was no correlation between CRP and the iron status in all children before and after HP eradication. This finding contributes to the growing debate regarding the role of systemic inflammation in HP induced IDA in children.

Limitation of our study include those inherent to retrospective studies like the absence of randomization and of a control group. Other limitations include being a single centre study. Though our sample is similar in Hgb levels to larger samples and can be considered representative. Some of the strengths of our study is the use of biopsy and gastric culture and not serological testing as an indicator of HP infection.

In conclusion, we have found a clear correlation between HP eradication and improvement in Hgb levels and iron stores in children 6 months’ post eradication. The improvement was much more significant in older children. Larger prospective studies are needed in order to better understand the complex relationship between HP and ID/IDA and the potential benefit compared to the harms of HP eradication in children.

AAP – American academy of pediatrics

Amx - Amoxicillin

Clr - Clarithromycin

CRP - C-reactive protein

ESPGHAN– European society of pediatric gastroenterology, hepatology and nutrition

Hgb - Hemoglobin

HP - Helicobacter pylori

IDA - iron deficiency anemia

Mtz - Metronidazole

NAID - non-anemic iron deficiency

NASPGHAN – North America society of pediatric gastroenterology, hepatology and nutrition

PPI – protein pump inhibitor

WHO – world health organization

Funding: The authors declare receiving no funding for this research.

Conflicts of interest/Competing interests : The authors declare no conflict of interests.

Availability of data and material : N/A

Code availability : N/A

Authors' contributions : OT and CL contributed equally to writing the manuscript. PS and HL helped writing and editing the manuscript, analyzed data and created figures. FR initiated the research article, collected and analyzed the data, contributed to the writing and editing.

Ethics approval : The research was approved by the ethical committee at Emek Medical Center, Afula, Israel.

Consent to participate : N/A

Consent for publication : The authors transfers to the Nutrition Journal publication rights and they warrant that the contribution is original. The author signs for and accepts responsibility for releasing this material on behalf of any and all co-authors.

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Resolution of Unexplained Iron Deficiency Following Successful Eradication of Helicobacter Pylori in Children

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Abstract

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Introduction

Patients And Methods

Study population:

Study design

Determination of HP status

Determination of NAID and IDA

Statistical analysis

Results

Patients' characteristics

Effect on Iron status

Predictors of resolution of IDA/NAID

Correlation between inflammation and the iron status

Discussion

Conclusion

Abbreviations

Declarations

References

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