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Helicobacter pylori–associated iron-deficiency anemia in adolescent female athletes
Helicobacter pylori–associated iron-deficiency anemia in adolescent female athletes Yon Ho Choe, MD, Young Se Kwon, MD, Min Kyung Jung, MD, Sung Kil Kang, MD, Tae Sook Hwang, MD, PhD, and Yun Chul Hong, MD, PhD Objective: The objective was to investigate the role of Helicobacter pylori infection in iron-deficiency anemia (IDA) of pubescent athletes. Study design: Blood sampling and a questionnaire survey were performed on 440 regular high school students and 220 athletes of a physical education high school. Hemoglobin, serum iron, total iron-binding capacity, ferritin, and immunoglobulin G antibody to H pylori were measured to compare the prevalence of IDA and H pylori infection in the groups. Nutritional analysis and a questionnaire survey for socioeconomic status were undertaken to compare and control for other risk factors that might influence IDA and H pylori infection in the groups. In those with IDA coexistent with H pylori infection, we also determined whether IDA can be managed by H pylori eradication. Results: The prevalence rates of IDA, H pylori infection, and H pylori– associated IDA in female athletes were higher than in the control group. The relative risk of IDA was 2.9 (95% CI, 1.5 to 5.6) for those with H pylori infection. Athletes who exhibited H pylori–associated IDA showed significant increases in hemoglobin, iron, and ferritin levels after H pylori eradication. The subjects in the control group who were treated orally with iron alone showed no significant changes. Conclusion: Adolescent female athletes may have development of H pylori–associated IDA, which can be managed by H pylori eradication. (J Pediatr 2001;139:100-4)
From the Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Samsung Medical Center, Seoul, Korea; the Department of Pediatrics, Inha University Hospital, Inchon, Korea; the Department of Pathology, Inha University Hospital, Inchon, Korea; and the Department of Preventive Medicine, Inha University, College of Medicine, Inchon, Korea.
Supported by a grant from the Korea Research Foundation (KRF-99-003-F00181). Submitted for publication July 26, 2000; revision received Oct 26, 2000; accepted Jan 25, 2001. Reprint requests: Yon Ho Choe, MD, Department of Pediatrics, Samsung Medical Center, 50 Ilwon-dong, Kangnam-ku, Seoul, 135-710, Korea. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/114700 doi:10.1067/mpd.2001.114700
100
Helicobacter pylori infection has been associated with iron-deficiency anemia in children.1-5 In 1997, we conducted a double-blinded, placebo-controlled trial in pubescent children with IDA and coexisting H pylori infection.6 We found that H pylori infection can contribute to IDA, and that the infection should be suspected when IDA is refractory to iron administration. We obtained similar results in another open therapeutic trial.7 During the course of those 2 studies, we found that a considerable number of adolescent athletes had IDA coupled with H pylori infection. Adolescents are particularly susceptible to iron deficiency because of their
high iron requirements.8 Sports anemia, reported for the first time in 1970, 9 is multifactorial: dilutional pseudoanemia, intravascular hemolysis, starvation anemia, and IDA.10-15 In Korea, most adolescent athletes live together in training camps for 6 months per year, usually between middle school and college. These athletes would seem to be at risk for H pylori infection because of environmental factors such as bed sharing, absence of a fixed hot water supply, and poor sanitation.16-18 We investigated the role of H pylori infection in the IDA of pubescent athletes.
IDA Ig TIBC
Iron-deficiency anemia Immunoglobulin Total iron-binding capacity
METHODS Study Population We selected 2 coeducational schools: a general high school and a physical education high school. Blood sampling and a questionnaire survey were performed; 660 subjects who met the study requirements were enrolled. Criteria for enrollment included no history of significant diseases such as infectious or gastrointestinal bleeding disorders, and menorrhagia in girls. Of these, 440 (228 boys and 212 girls) were regular high school students and nonathletes, and 220 (148 boys and 72 girls) were athletes at the physical education high school. The Ethical Committee of Inha University Hospital approved this study. All of the subjects have written consent.
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THE JOURNAL OF PEDIATRICS VOLUME 139, NUMBER 1
Study Design MEASUREMENT OF IDA PARAMETERS AND SERUM H PYLORI IGG ANTIBODY. Hemoglobin, serum iron, total ironbinding capacity, serum ferritin, and serum immunoglobulin G antibody to H pylori were measured. The hemoglobin level was measured with a Coulter S-PLUS IV (Coulter Electronics Inc, Miami, Fla). Serum was separated and stored at –20°C for iron deficiency analysis. Serum iron and TIBC were determined with spectrophotometry (Hitachi 747, Hitachi, Tokyo, Japan), and transferrin saturation was calculated by dividing the concentration of serum iron by the TIBC. The serum ferritin assay was performed with a radioimmunoassay kit, Ferritin-Iron II (Ramco Laboratories Inc, Houston, Tex). Serum IgG antibody to H pylori was measured by an enzyme-linked immunosorbent assay, GAP test IgG kit (Bio-Rad Laboratories Inc, Hercules, Calif). IDA was defined as a low serum ferritin level (<12 ng/mL), a low level of transferrin saturation (<15%), and a low hemoglobin level (<12 g/dL).19 H pylori infection was defined as a positive enzyme-linked immunosorbent assay result. NUTRITIONAL ANALYSIS AND THE QUESTIONNAIRE ON SOCIOECONOMIC STATUS. We assessed risk factors that might influence the IDA and H pylori infection of the 2 groups. First, daily intakes of total calorie, carbohydrate, protein, fat, and iron were measured by nutritionists with a 24-hour recall method. These data were analyzed with the Computer Aided Nutritional analysis program for Professionals (CAN-Pro, Seoul, Korea). Second, a structured questionnaire was sent to the children’s parents to obtain parental information on occupation and educational level and environmental information such as the house type and number of rooms and the number of people accommodated. The Hollingshead index,20 type of house,
Table I. Comparisons of the prevalence rates of anemia, IDA, H pylori infection, and H pylori-associated IDA in athletes and control group
Number (% positive)
Anemia IDA H pylori infection H pylori–associated IDA
Athletes (n = 220)
Control group (n = 440)
P value
32 (14.6) 18 (8.2) 95 (43.2) 12 (5.5)
42 (9.6) 24 (5.5) 100 (22.7) 10 (2.3)
.05 .176 .001 .032
IDA, Iron-deficiency anemia.
and household crowding were included as variables indicative of socioeconomic status. The Hollingshead index is based on the parents’ occupation and education; a score of 0 was given to the lowest level of education and occupation, and a score of 4 was given to the highest. Four socioeconomic classes were identified ranging from lowest (I) to highest (IV) on the basis of the sum of the scores. Household crowding was shown by a crowding index, which was defined as the number of persons living in the house divided by the number of rooms. In addition, we measured the serum levels of vitamin B12 and folic acid with a Radioassay Kit Vitamin B12[57Co]/Folate[125I] (ICN) in those subjects who were found to have IDA, to exclude any influence of vitamin B12 and folic acid on IDA.21 H PYLORI ERADICATION TO MANAGE IDA. To gain insight into whether H pylori infection contributes to IDA, we identified and recruited subjects who exhibited IDA in combination with H pylori infection (12 athletes and 10 control nonathletes) and conducted an open therapeutic trial. All of the subjects underwent gastroduodenal endoscopy. Evidence of H pylori infection was obtained with 2 biopsy-related methods, urease activity assay and histologic examination. H pylori positivity was defined as a positive CLO test (Delta West, Perth, Australia) and
identification of the microorganisms by Giemsa stain. CLO testing and Giemsa staining of endoscopy samples showed all of the subjects to be positive for H pylori. One of the 10 members of the control group had a duodenal ulcer, and he was excluded from the trial. No other sample revealed evidence of hemorrhage in the gastric and duodenal mucosa. Stool examinations for occult blood (monoclonal antibody to human hemoglobin, Kit OC Haemodia; Eiken Chemical Co, Tokyo, Japan) were negative in the 21 remaining subjects. Twelve athletes received a 2-week course of triple therapy without iron supplementation with a combination of bismuth subcitrate (8 mg of bismuth/kg/d), amoxicillin (50 mg/kg/d), and metronidazole (20 mg/kg/d). Nine members of the control group were given oral ferrous sulfate at an elemental iron dosage of 6 mg/kg/d for 10 weeks. Follow-up assessment of iron status was conducted 8 weeks after the 2-week regimen ended and included measurements of hemoglobin, iron, TIBC, and ferritin.6
Statistical Analyses Statistical tests used included χ2 test to identify prevalence differences between the groups, Student’s t test and Wilcoxon signed rank test to assess differences in group means, and multivariate regression analysis to study the relative importance of H pylori infection, after controlling for the other 101
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CHOE ET AL
Table II. Comparisons of the prevalence rates of anemia, IDA, H pylori infection, and H pylori–associated IDA in athletes and control group, by sex
Boys
Anemia IDA H pylori infection H pylori–associated IDA
Girls
Athletes (n = 148)
Control group (n = 228)
P value
Athletes (n = 72)
Control group (n = 212)
P value
5 (3.4) 3 (2.0) 63 (42.6) 2 (1.4)
5 (2.2) 4 (1.8) 57 (25.0) 3 (1.3)
.485 .848 .001 .977
27 (37.5) 15 (20.8) 32 (44.4) 10 (13.9)
37 (17.5) 20 (9.4) 43 (20.3) 7 (3.3)
.001 .011 .001 .001
Values are expressed as numbers with percent positive in parentheses. IDA, Iron-deficiency anemia.
RESULTS
Table III. Comparisons between the socioeconomic status of groups
Athletes (%) Hollingshead index Housing tenure Crowding index
I + II III + IV Owned Rented <1.5 ≥1.5
38.0 62.0 43.8 56.2 53.5 46.5
Control subjects (%)
P value
31.9 68.1 34.1 65.9 50.0 50.0
.375 .156 .577
Hollingshead index I: lowest class, IV: highest class.
Table IV. Changes in the hematologic parameters of groups after treatment
The ages of the 660 subjects ranged from 15 to 17 years (mean age, 15.9 years). The prevalence rates of anemia, IDA, and H pylori infection in athletes were higher than those of the control group (Table I). When the data for boys and girls were analyzed separately, significant differences in the prevalence rates of anemia, IDA, H pylori infection, and H pylori–associated IDA were found only in girls (Table II). In the boys there was a significant difference in the H pylori infection rate between the athletes and members of the control group.
Athletes (n = 12)
Control subjects (n = 9)
H pylori eradication
Oral iron therapy
10.3 ± 0.8 12.5 ± 1.0
10.0 ± 0.6 10.2 ± 0.6
.0005
40.1 ± 20.3 85.3 ± 31.9
38.9 ± 12.9 41.2 ± 14.5
Nutritional Analysis and the Questionnaire on Socioeconomic Status
.0011
399.9 ± 47.4 362.0 ± 27.4
406.1 ± 25.5 394.7 ± 19.7
.0357
6.6 ± 1.8 11.0 ± 3.0
6.5 ± 2.1 7.2 ± 3.1
.0088
No differences in the daily intakes of total calorie (P = .7762), protein (P = .0747), or carbohydrate (P = .2066) between the groups were found. Iron (P = .0001) and lipid (P = .012) intakes were higher in athletes than in the control group. No significant differences in socioeconomic status such as the Hollingshead index, type of house, or crowding index were found between the groups (Table III). None of the subjects who exhibited IDA had folic acid or vitamin B12 deficiency. The risk factors that were significant by univariate analysis were H pylori
Hemoglobin (g/dL) Baseline 8 weeks after therapy Iron (µg/dL) Baseline 8 weeks after therapy TIBC (µg/dL) Baseline 8 weeks after therapy Ferritin (ng/mL) Baseline 8 weeks after therapy
P value
TIBC, Total iron-binding capacity.
factors. A multivariate logistic regression model was used to assess the relative risk of IDA for H pylori infection and different school types after adjustment was done for height and 102
Measurement of IDA Parameters and Serum H pylori IgG Antibody
weight. Unless stated otherwise, a P value of <.05 was taken to be significant. All statistical analyses were performed with SAS statistics software (version 6.12).
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THE JOURNAL OF PEDIATRICS VOLUME 139, NUMBER 1 infection and school type. These were reanalyzed with a multivariate logistic regression model to prevent any confounding effect after adjustment was done for height and weight. The odds ratio of IDA for those with H pylori infection was 2.9 (95% CI, 1.5 to 5.6) and was 7.7 (95% CI, 1.2 to 50) for boys and 2.9 (95% CI, 1.3 to 6.4) for girls.
H pylori Eradication to Manage IDA Measurements of hemoglobin, iron, TIBC, and ferritin were performed at baseline and 8 weeks after the 2-week regimen ended. Follow-up endoscopy was performed 4 weeks after the eradication therapy in athletes. H pylori was eradicated in 11 (91.7%) of 12 athletes (Table IV). The Wilcoxon signed rank test indicated that athletes showed significant increases in hemoglobin, iron, and ferritin levels after H pylori eradication. Members of the control group treated with oral iron alone showed no significant changes in hematologic parameters.
DISCUSSION Our results show that pubescent female athletes are likely to have H pylori-associated IDA. Their environments, involving extended stays at training camps, overcrowding, and poor hygiene, expose them to H pylori infection. In other words, H pylori infection exacerbates the iron deficit in adolescent female athletes whose iron supply is marginal. H pylori is acquired primarily early in life. Although there is debate as to whether residency in an institution or a nursing home beginning at an advanced age is associated with an increased prevalence of H pylori infection, some studies have shown that living in institutions continues to be a significant risk factor for H pylori infection even in adults.22-24 In Korea, as in other countries that encourage athletic participation, most outstand-
ing athletes are cultivated in units such as dedicated physical education high schools. Students are obliged to live together in training camps for more than half a year. This study reveals that the prevalence rate of H pylori infection was higher in athletes than in nonathletes. The diagnosis of H pylori infection was made with specific serum IgG antibodies only.25 In this study a serologic examination with the GAP test IgG kit showed a sensitivity of 94.9%, a specificity of 92.4%, a positive predictive value of 74.7%, and a negative predictive value of 98.7% in Korean children. It is also known that serologic assays appear to have the necessary sensitivity or specificity to screen pediatric patient populations over the age of 12 years.26 The most common type of true anemia that affects athletes is IDA. The frequent sources of iron deficiency are blood loss from the gastrointestinal tract and menstruation, poor dietary intake, and iron loss through profuse sweating.14 Gastrointestinal blood loss caused by ischemia or mechanical trauma is particularly widespread in long-distance runners. In our study the IDA prevalence in athletes was 8.2% and in the control group 5.5%, although athletes had greater iron intakes. These findings suggest that a component of the IDA involves iron loss. Although the mechanisms by which H pylori infection may lead to iron-deficiency anemia remain unclear, a recent study ruled out gastrointestinal bleeding or iron malabsorption and suggested that H pylori gastritis could act as a sequestering focus for iron.4 There is no good evidence that low or marginal iron stores alone hinder athletic performance; however, even mild degrees of IDA have been shown to impair athletic performance.27 Iron treatment alone cannot correct the anemia of those with IDA coexistent with H pylori infection,3-7 and these patients need H pylori eradication to manage their anemia.
In conclusion, the prevalence rate of H pylori–associated IDA was higher in adolescent female athletes than in male athletes and nonathletes. We speculate that this is because female athletes are more vulnerable to iron deficiency than other groups; the high prevalence of H pylori infection in athletes increases the risk of IDA more than twofold. When pubescent girls, including athletes, are found to have IDA, and their anemia is refractory to iron administration, they should be evaluated for H pylori infection. We are indebted to the parents for allowing their sons and daughters to participate in this study, to the schoolteachers for helping us execute our study, and to Ji Sun Lee for nutritional analysis.
REFERENCES 1. Dufour C, Brisigotti M, Fabretti G, Luxardo P, Mori PG, Barabino A. Helicobacter pylori gastric infection and sideropenic refractory anemia. J Pediatr Gastroenterol Nutr 1993;17:225-7. 2. Yip R, Limburg PJ, Ahlquist DA, Carpenter HA, O Neill A, Kruse D, et al. Pervasive occult gastrointestinal bleeding in an Alaska native population with prevalent iron deficiency. JAMA 1997;277:1135-9. 3. Marignani M, Angeletti S, Bordi C, Malagnino F, Mancino C, Fave GD, et al. Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol 1997;32:617-22. 4. Barabino A, Dufour C, Marino CE, Claudiani F, Alessandri AD. Unexplained refractory iron-deficiency anemia associated with Helicobacter pylori gastric infection in children: further clinical evidence. J Pediatr Gastroenterol Nutr 1999;28:116-9. 5. Annibale B, Marignani M, Monarca B, Antonelli G, Marcheggiano A, Martino G, et al. Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis. Ann Intern Med 1999;131:668-72. 6. Choe YH, Kim SK, Son BK, Lee DH, Hong YC, Pai SH. Randomized placebo-controlled trial of Helicobacter pylori eradication for irondeficiency anemia in preadolescent 103
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children and adolescents. Helicobacter 1999;4:135-9. Choe YH, Lee JE, Kim SK. Effect of Helicobacter pylori eradication on sideropenic refractory anaemia in adolescent girls with Helicobacter pylori infection. Acta Paediatr 2000;89:154-7. Hallberg L, Hulten L, Lindstedt G, Lundberg PA, Mark A, Purens J, et al. Prevalence of iron deficiency in Swedish adolescents. Pediatr Res 1993;34:680-7. Yoshimura H. Anemia during physical training (sports anemia). Nutr Rev 1970;28:251-3. Clement DB, Sawchuk LL. Iron status and sports performance. Sports Med 1984;1:65-74. Eichner ER. Sports anemia, iron supplements, and blood doping. Med Sci Sports Exerc 1992;24(suppl 9): S315-8. Newhouse IJ, Clement DB. Iron status in athletes: an update. Sports Med 1988;5:337-52. Weaber CM, Rajaram S. Exercise and iron status. J Nutr 1992;122(suppl 3):782-7. Nichols AW. Nonorthopedic problems in the aquatic athlete. Clin Sports Med 1999;18:395-411. Escanero JF, Villanueva J, Rojo A, Herrera A, Diego CD, Guerra M. Iron stores in professional athletes
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throughout the sports season. Physiol Behav 1997;62:811-4. Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, et al. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet 1992;339:896-7. Malaty HM, Graham DY. Effect of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut 1994;35: 742-5. Webb PM, Knight T, Greaves S, Wilson A, Newell DG, Elder J, et al. Relation between infection with Helicobacter pylori and living conditions in childhood: evidence for person-toperson transmission in early life. BMJ 1994;308:750-3. Looker AC, Dallman PR, Carrol MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997;277:973-6. Hollingshead A. Two factor index of social position. New Haven, CT: Yale University Press; 1957. Vossough P, Leikin S, Purugganan G, Gautier G. Evaluation of parameters of folic acid and vitamin B12 deficiency in patients with iron deficiency anemia. Pediatr Res 1968;2:179-86. Regev A, Fraser GM, Braun M, Maoz E, Leibovici L, Niv Y. Seroprevalence of Helicobacter pylori and length of
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stay in a nursing home. Helicobacter 1999;4:89-93. Megraud F, Brassens RMP, Denis F, Belbouri A, Hoa DQ. Seroepidemiology of Campylobacter pylori infection in various populations. J Clin Microbiol 1989;27:1870-3. Bohmer CJ, Klinkenberg-Knol EC, Kuipers EJ. Niezen-de Boer MC, Schreuder H, Schuckink-Kool F, et al. The prevalence of Helicobacter pylori infection among inhabitants and health employees of institutes for the intellectually disabled. Am J Gastroenterol 1997;92:1000-4. Sim JG, Kim EC, Seo JK. The role of serology in the diagnosis of H. pylori infection in children. Clin Pediatr 1995;34:458-62. Oliveira AMR, Rocha GA, Queiroz DMM, Mendes EN, Carvalho AST, Ferrari TCA, et al. Evaluation of enzyme-linked immunosorbent assay for the diagnosis of Helicobacter pylori infection in children from different age groups with and without duodenal ulcer. J Pediatr Gastroenterol Nutr 1999;28:157-61. Schoene RB, Escourrou P, Robertson HT, Nilson KL, Parsons JR, Smith NJ. Iron repletion decreases maximal exercise lactate concentration in female athletes with minimal iron-deficiency anemia. J Lab Clin Med 1983;102:306-12.
From the Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Samsung Medical Center, Seoul, Korea; the Department of Pediatrics, Inha University Hospital, Inchon, Korea; the Department of Pathology, Inha University Hospital, Inchon, Korea; and the Department of Preventive Medicine, Inha University, College of Medicine, Inchon, Korea.
Supported by a grant from the Korea Research Foundation (KRF-99-003-F00181). Submitted for publication July 26, 2000; revision received Oct 26, 2000; accepted Jan 25, 2001. Reprint requests: Yon Ho Choe, MD, Department of Pediatrics, Samsung Medical Center, 50 Ilwon-dong, Kangnam-ku, Seoul, 135-710, Korea. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/114700 doi:10.1067/mpd.2001.114700
100
Helicobacter pylori infection has been associated with iron-deficiency anemia in children.1-5 In 1997, we conducted a double-blinded, placebo-controlled trial in pubescent children with IDA and coexisting H pylori infection.6 We found that H pylori infection can contribute to IDA, and that the infection should be suspected when IDA is refractory to iron administration. We obtained similar results in another open therapeutic trial.7 During the course of those 2 studies, we found that a considerable number of adolescent athletes had IDA coupled with H pylori infection. Adolescents are particularly susceptible to iron deficiency because of their
high iron requirements.8 Sports anemia, reported for the first time in 1970, 9 is multifactorial: dilutional pseudoanemia, intravascular hemolysis, starvation anemia, and IDA.10-15 In Korea, most adolescent athletes live together in training camps for 6 months per year, usually between middle school and college. These athletes would seem to be at risk for H pylori infection because of environmental factors such as bed sharing, absence of a fixed hot water supply, and poor sanitation.16-18 We investigated the role of H pylori infection in the IDA of pubescent athletes.
IDA Ig TIBC
Iron-deficiency anemia Immunoglobulin Total iron-binding capacity
METHODS Study Population We selected 2 coeducational schools: a general high school and a physical education high school. Blood sampling and a questionnaire survey were performed; 660 subjects who met the study requirements were enrolled. Criteria for enrollment included no history of significant diseases such as infectious or gastrointestinal bleeding disorders, and menorrhagia in girls. Of these, 440 (228 boys and 212 girls) were regular high school students and nonathletes, and 220 (148 boys and 72 girls) were athletes at the physical education high school. The Ethical Committee of Inha University Hospital approved this study. All of the subjects have written consent.
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THE JOURNAL OF PEDIATRICS VOLUME 139, NUMBER 1
Study Design MEASUREMENT OF IDA PARAMETERS AND SERUM H PYLORI IGG ANTIBODY. Hemoglobin, serum iron, total ironbinding capacity, serum ferritin, and serum immunoglobulin G antibody to H pylori were measured. The hemoglobin level was measured with a Coulter S-PLUS IV (Coulter Electronics Inc, Miami, Fla). Serum was separated and stored at –20°C for iron deficiency analysis. Serum iron and TIBC were determined with spectrophotometry (Hitachi 747, Hitachi, Tokyo, Japan), and transferrin saturation was calculated by dividing the concentration of serum iron by the TIBC. The serum ferritin assay was performed with a radioimmunoassay kit, Ferritin-Iron II (Ramco Laboratories Inc, Houston, Tex). Serum IgG antibody to H pylori was measured by an enzyme-linked immunosorbent assay, GAP test IgG kit (Bio-Rad Laboratories Inc, Hercules, Calif). IDA was defined as a low serum ferritin level (<12 ng/mL), a low level of transferrin saturation (<15%), and a low hemoglobin level (<12 g/dL).19 H pylori infection was defined as a positive enzyme-linked immunosorbent assay result. NUTRITIONAL ANALYSIS AND THE QUESTIONNAIRE ON SOCIOECONOMIC STATUS. We assessed risk factors that might influence the IDA and H pylori infection of the 2 groups. First, daily intakes of total calorie, carbohydrate, protein, fat, and iron were measured by nutritionists with a 24-hour recall method. These data were analyzed with the Computer Aided Nutritional analysis program for Professionals (CAN-Pro, Seoul, Korea). Second, a structured questionnaire was sent to the children’s parents to obtain parental information on occupation and educational level and environmental information such as the house type and number of rooms and the number of people accommodated. The Hollingshead index,20 type of house,
Table I. Comparisons of the prevalence rates of anemia, IDA, H pylori infection, and H pylori-associated IDA in athletes and control group
Number (% positive)
Anemia IDA H pylori infection H pylori–associated IDA
Athletes (n = 220)
Control group (n = 440)
P value
32 (14.6) 18 (8.2) 95 (43.2) 12 (5.5)
42 (9.6) 24 (5.5) 100 (22.7) 10 (2.3)
.05 .176 .001 .032
IDA, Iron-deficiency anemia.
and household crowding were included as variables indicative of socioeconomic status. The Hollingshead index is based on the parents’ occupation and education; a score of 0 was given to the lowest level of education and occupation, and a score of 4 was given to the highest. Four socioeconomic classes were identified ranging from lowest (I) to highest (IV) on the basis of the sum of the scores. Household crowding was shown by a crowding index, which was defined as the number of persons living in the house divided by the number of rooms. In addition, we measured the serum levels of vitamin B12 and folic acid with a Radioassay Kit Vitamin B12[57Co]/Folate[125I] (ICN) in those subjects who were found to have IDA, to exclude any influence of vitamin B12 and folic acid on IDA.21 H PYLORI ERADICATION TO MANAGE IDA. To gain insight into whether H pylori infection contributes to IDA, we identified and recruited subjects who exhibited IDA in combination with H pylori infection (12 athletes and 10 control nonathletes) and conducted an open therapeutic trial. All of the subjects underwent gastroduodenal endoscopy. Evidence of H pylori infection was obtained with 2 biopsy-related methods, urease activity assay and histologic examination. H pylori positivity was defined as a positive CLO test (Delta West, Perth, Australia) and
identification of the microorganisms by Giemsa stain. CLO testing and Giemsa staining of endoscopy samples showed all of the subjects to be positive for H pylori. One of the 10 members of the control group had a duodenal ulcer, and he was excluded from the trial. No other sample revealed evidence of hemorrhage in the gastric and duodenal mucosa. Stool examinations for occult blood (monoclonal antibody to human hemoglobin, Kit OC Haemodia; Eiken Chemical Co, Tokyo, Japan) were negative in the 21 remaining subjects. Twelve athletes received a 2-week course of triple therapy without iron supplementation with a combination of bismuth subcitrate (8 mg of bismuth/kg/d), amoxicillin (50 mg/kg/d), and metronidazole (20 mg/kg/d). Nine members of the control group were given oral ferrous sulfate at an elemental iron dosage of 6 mg/kg/d for 10 weeks. Follow-up assessment of iron status was conducted 8 weeks after the 2-week regimen ended and included measurements of hemoglobin, iron, TIBC, and ferritin.6
Statistical Analyses Statistical tests used included χ2 test to identify prevalence differences between the groups, Student’s t test and Wilcoxon signed rank test to assess differences in group means, and multivariate regression analysis to study the relative importance of H pylori infection, after controlling for the other 101
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Table II. Comparisons of the prevalence rates of anemia, IDA, H pylori infection, and H pylori–associated IDA in athletes and control group, by sex
Boys
Anemia IDA H pylori infection H pylori–associated IDA
Girls
Athletes (n = 148)
Control group (n = 228)
P value
Athletes (n = 72)
Control group (n = 212)
P value
5 (3.4) 3 (2.0) 63 (42.6) 2 (1.4)
5 (2.2) 4 (1.8) 57 (25.0) 3 (1.3)
.485 .848 .001 .977
27 (37.5) 15 (20.8) 32 (44.4) 10 (13.9)
37 (17.5) 20 (9.4) 43 (20.3) 7 (3.3)
.001 .011 .001 .001
Values are expressed as numbers with percent positive in parentheses. IDA, Iron-deficiency anemia.
RESULTS
Table III. Comparisons between the socioeconomic status of groups
Athletes (%) Hollingshead index Housing tenure Crowding index
I + II III + IV Owned Rented <1.5 ≥1.5
38.0 62.0 43.8 56.2 53.5 46.5
Control subjects (%)
P value
31.9 68.1 34.1 65.9 50.0 50.0
.375 .156 .577
Hollingshead index I: lowest class, IV: highest class.
Table IV. Changes in the hematologic parameters of groups after treatment
The ages of the 660 subjects ranged from 15 to 17 years (mean age, 15.9 years). The prevalence rates of anemia, IDA, and H pylori infection in athletes were higher than those of the control group (Table I). When the data for boys and girls were analyzed separately, significant differences in the prevalence rates of anemia, IDA, H pylori infection, and H pylori–associated IDA were found only in girls (Table II). In the boys there was a significant difference in the H pylori infection rate between the athletes and members of the control group.
Athletes (n = 12)
Control subjects (n = 9)
H pylori eradication
Oral iron therapy
10.3 ± 0.8 12.5 ± 1.0
10.0 ± 0.6 10.2 ± 0.6
.0005
40.1 ± 20.3 85.3 ± 31.9
38.9 ± 12.9 41.2 ± 14.5
Nutritional Analysis and the Questionnaire on Socioeconomic Status
.0011
399.9 ± 47.4 362.0 ± 27.4
406.1 ± 25.5 394.7 ± 19.7
.0357
6.6 ± 1.8 11.0 ± 3.0
6.5 ± 2.1 7.2 ± 3.1
.0088
No differences in the daily intakes of total calorie (P = .7762), protein (P = .0747), or carbohydrate (P = .2066) between the groups were found. Iron (P = .0001) and lipid (P = .012) intakes were higher in athletes than in the control group. No significant differences in socioeconomic status such as the Hollingshead index, type of house, or crowding index were found between the groups (Table III). None of the subjects who exhibited IDA had folic acid or vitamin B12 deficiency. The risk factors that were significant by univariate analysis were H pylori
Hemoglobin (g/dL) Baseline 8 weeks after therapy Iron (µg/dL) Baseline 8 weeks after therapy TIBC (µg/dL) Baseline 8 weeks after therapy Ferritin (ng/mL) Baseline 8 weeks after therapy
P value
TIBC, Total iron-binding capacity.
factors. A multivariate logistic regression model was used to assess the relative risk of IDA for H pylori infection and different school types after adjustment was done for height and 102
Measurement of IDA Parameters and Serum H pylori IgG Antibody
weight. Unless stated otherwise, a P value of <.05 was taken to be significant. All statistical analyses were performed with SAS statistics software (version 6.12).
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THE JOURNAL OF PEDIATRICS VOLUME 139, NUMBER 1 infection and school type. These were reanalyzed with a multivariate logistic regression model to prevent any confounding effect after adjustment was done for height and weight. The odds ratio of IDA for those with H pylori infection was 2.9 (95% CI, 1.5 to 5.6) and was 7.7 (95% CI, 1.2 to 50) for boys and 2.9 (95% CI, 1.3 to 6.4) for girls.
H pylori Eradication to Manage IDA Measurements of hemoglobin, iron, TIBC, and ferritin were performed at baseline and 8 weeks after the 2-week regimen ended. Follow-up endoscopy was performed 4 weeks after the eradication therapy in athletes. H pylori was eradicated in 11 (91.7%) of 12 athletes (Table IV). The Wilcoxon signed rank test indicated that athletes showed significant increases in hemoglobin, iron, and ferritin levels after H pylori eradication. Members of the control group treated with oral iron alone showed no significant changes in hematologic parameters.
DISCUSSION Our results show that pubescent female athletes are likely to have H pylori-associated IDA. Their environments, involving extended stays at training camps, overcrowding, and poor hygiene, expose them to H pylori infection. In other words, H pylori infection exacerbates the iron deficit in adolescent female athletes whose iron supply is marginal. H pylori is acquired primarily early in life. Although there is debate as to whether residency in an institution or a nursing home beginning at an advanced age is associated with an increased prevalence of H pylori infection, some studies have shown that living in institutions continues to be a significant risk factor for H pylori infection even in adults.22-24 In Korea, as in other countries that encourage athletic participation, most outstand-
ing athletes are cultivated in units such as dedicated physical education high schools. Students are obliged to live together in training camps for more than half a year. This study reveals that the prevalence rate of H pylori infection was higher in athletes than in nonathletes. The diagnosis of H pylori infection was made with specific serum IgG antibodies only.25 In this study a serologic examination with the GAP test IgG kit showed a sensitivity of 94.9%, a specificity of 92.4%, a positive predictive value of 74.7%, and a negative predictive value of 98.7% in Korean children. It is also known that serologic assays appear to have the necessary sensitivity or specificity to screen pediatric patient populations over the age of 12 years.26 The most common type of true anemia that affects athletes is IDA. The frequent sources of iron deficiency are blood loss from the gastrointestinal tract and menstruation, poor dietary intake, and iron loss through profuse sweating.14 Gastrointestinal blood loss caused by ischemia or mechanical trauma is particularly widespread in long-distance runners. In our study the IDA prevalence in athletes was 8.2% and in the control group 5.5%, although athletes had greater iron intakes. These findings suggest that a component of the IDA involves iron loss. Although the mechanisms by which H pylori infection may lead to iron-deficiency anemia remain unclear, a recent study ruled out gastrointestinal bleeding or iron malabsorption and suggested that H pylori gastritis could act as a sequestering focus for iron.4 There is no good evidence that low or marginal iron stores alone hinder athletic performance; however, even mild degrees of IDA have been shown to impair athletic performance.27 Iron treatment alone cannot correct the anemia of those with IDA coexistent with H pylori infection,3-7 and these patients need H pylori eradication to manage their anemia.
In conclusion, the prevalence rate of H pylori–associated IDA was higher in adolescent female athletes than in male athletes and nonathletes. We speculate that this is because female athletes are more vulnerable to iron deficiency than other groups; the high prevalence of H pylori infection in athletes increases the risk of IDA more than twofold. When pubescent girls, including athletes, are found to have IDA, and their anemia is refractory to iron administration, they should be evaluated for H pylori infection. We are indebted to the parents for allowing their sons and daughters to participate in this study, to the schoolteachers for helping us execute our study, and to Ji Sun Lee for nutritional analysis.
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