Folate concentrations in pediatric patients with newly diagnosed
inflammatory bowel disease1–4
Melvin B Heyman, Elizabeth A Garnett, Nishat Shaikh, Karen Huen, Folashade A Jose, Paul Harmatz, Harland S Winter,
Robert N Baldassano, Stanley A Cohen, Benjamin D Gold, Barbara S Kirschner, George D Ferry, Erin Stege, and
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 be-
tween children with newly diagnosed IBD and healthy controls.
concentrations were measured in 78 children (mean age: 12.8 6
2.7 y): 22 patients with newly diagnosed untreated Crohn disease,
11 patients with ulcerative colitis, 4 patients with indeterminate co-
litis, 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 6 148.6 ng/mL) than in patients (728.7 6 185.8 ng/mL; P ¼
0.0004), and WBF concentrations were 11.1% lower in controls
(218.2 6 49.7 ng/mL) than in patients (245.3 6 59.1 ng/mL; P ¼
0.031). Total folate intake was 18.8% higher in controls (444.7 6
266.7 lg/d) than in IBD patients (361.1 6 230.6 lg/d), but this dif-
ference was not statistically significant (P ¼ 0.264). Folate intakes
were below the Recommended Dietary Allowance (200–400 lg/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 di-
etary 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.
Am J Clin
Inflammatory bowel disease (IBD) occurs in children of all
ages (1). Pediatric patients with IBD are a distinctly different
group compared with adult subjects with IBD, allowing for in-
vestigation of initial host immune responses and characterization
of genotype-phenotype relations, environmental influences, and
natural history of the disease (2). Folate, a water-soluble B vita-
min, has been shown to prevent DNA damage and cell injury,
which can lead to different types of cancer, including those as-
sociated with IBD (3–6).
Folate deficiency may be also associated with tumor growth in
IBD (7). Folate concentrations in adult patients with IBD have
been reported to be normal or low compared with those in non-
IBD controls (8, 9). Evidence of folate deficiency in IBD may
have multiple causes, including low dietary intake, malabsorp-
tion, and medication interactions (10, 3). Some studies have
indicated that adult patients with Crohn Disease (CD) may have
abnormal folate absorption (11). Other studies indicate a high
prevalence of inadequate nutrient intakes (9). Sulfasalazine and
other IBD medications can decrease folate concentrations (12,
13). Folate supplementation, therefore, is generally recom-
mended for patients with IBD. However, recent studies suggest
that folate supplementation may actually predispose to the de-
velopment of certain tumors, including colorectal cancer—a
major concern for patients with IBD (14–16).
1From the Department of Pediatrics, University of California, San Francisco,
San Francisco, CA (MBH, EAG, and FAJ); the School of Public Health, Uni-
versity of California, Berkeley, Berkeley, CA (NS, KH, and NH); the Child-
ren’sHospitaland ResearchCenter,Oakland,CA(PHandES);the Children’s
Center for Digestive Health Care, Atlanta, GA (SAH); the Pediatrics, Emory
University School of Medicine, Atlanta, GA (SAC and BDG); Pediatrics,
MassGeneral Hospital for Children, Boston, MA (HSW); Pediatrics, Child-
ren’s Hospital of Philadelphia, Philadelphia, PA (RNB); the University of
ren’s Hospital, Baylor College of Medicine, Houston, TX (GDF).
2The contents are solely the responsibility of the authors and do not neces-
of the National Institutes of Health. Information on the National Center for
Research Resources is available at http://www.ncrr.nih.gov/. Information on
Re-engineering the Clinical Research Enterprise can be obtained from http://
3Supported in part by NIH grants R03 DK063187 (to MBH, NH, and PH),
M01 RR01271, and UL1 RR024131 (Pediatric Clinical Research Centers at
UCSF and Children’s Hospital Oakland); K24 DK060617 (to MBH); T32
DK007762-31S1 (to FAJ); the family of Joel Barnett (to BSK); and the
family of John Fullerton (to MBH).
4Reprints not available. Address correspondence to MB Heyman, 500 Par-
San Francisco, CA 94143-0136. E-mail: email@example.com.
Received June 22, 2008. Accepted for publication November 18, 2008.
First published online December 30, 2008; doi: 10.3945/ajcn.2008.26576.
Am J Clin Nutr 2009;89:545–50. Printed in USA. ? 2009 American Society for Nutrition
Folate concentrations are poorly delineated in children with
IBD. A few studies have reported that children with IBD may
have equivalent or slightly higher red blood cell folate (RBCF)
concentrations (17, 18). However, it remains unclear whether
children with newly diagnosed IBD typically have a folate
deficiency or elevated concentrations of folate. Furthermore,
whether folate concentrations are associated with dietary intake,
host factors (eg, age, ethnicity, and sex), or clinical character-
istics (eg, hematocrit level, location of disease, and disease ac-
tivity index) is similarly unclear. We describe our observations
of RBCF and whole-blood folate (WBCF) concentrations in
pediatric patients with untreated, recently diagnosed IBD com-
pared with observations in non-IBD controls.
SUBJECTS AND METHODS
Children aged 5–17 y were recruited from May 2005 to
November 2006 from 8 major clinical centers: UCSF Children’s
Hospital, University of California, San Francisco; The University
of Chicago Children’s Hospital, Chicago, IL; Children’s Center
for Digestive Health Care and Emory University School of
Medicine, Atlanta, GA; Texas Children’s Hospital, Baylor
College of Medicine, Houston, TX; Children’s Hospital of Phil-
adelphia, Philadelphia, PA; MassGeneral Hospital for Children,
Boston, MA; and Children’s Hospital, Oakland, CA. Blood
samples were sent to the Holland Laboratory at the University of
California, Berkeley (UCB) for processing, analysis, and storage.
Patients were enrolled at the time of initial IBD diagnoses and
included children with ulcerative colitis (UC), CD, and indeter-
minate colitis (IC). The diagnoses were confirmed by clinical,
histologic, and/or radiologic features. Patients were excluded
if they were taking any medications for IBD treatment (includ-
ing 5-aminosalicyclic acids, antibiotics, steroids, and immuno-
Controls were similarly recruited from children referred to
the gastroenterology clinics for evaluation of abdominal pain,
constipation, and/or diarrhea and with diagnoses (eg, chronic
functional constipation, chronic recurrent abdominal pain, and
irritable bowel syndrome) that excluded inflammatory conditions
(ie, eosinophilic esophagitis and celiac disease).
for the study, and all procedures complied with the approved
protocol and the Health Insurance Portability and Accountability
Act. Patients and parents provided assents and consents before
entry into the study.
Blood samples were collected from 78 pediatric patients for
the measurement of hematocrit, RBCF, and WBF concentrations
byelectrochemiluminescence immunoassay (ECLIA)at a central
laboratory (ARUP Laboratories, Salt Lake City, UT). RBCF
concentrations were calculated from WBF concentrations
[RBCF ¼ (WBF 3 100)/hematocrit]. Clinical information, in-
cluding body mass index (BMI; in kg/m2), history of recent
illness, medication use, family history of IBD, and medical
history, was collected. Dietary intake was determined for 20
IBD patients and 28 controls at the California sites by using
a detailed food-recall questionnaire (Block questionnaire) and
reported vitamin supplement use (19, 20).
used to compare IBD patients with controls by demographic
factors (ie, age, sex, and ethnicity) and clinical measurements (ie,
hematocrit, WBF, and RBCF). Because WBF concentrations did
not differ significantly between the 3 IBD subtypes, the UC, CD,
and IC patients were combined into one group for subsequent
analyses. Multiple linear regression models were used to assess
the effect of IBD on folate concentrations after adjustment for
potential confounders, including age and ethnicity. We used
several indicator variables for each ethnic group (African Amer-
icans, Asians, and others) in the model and compared them with
those for whites (reference group). To identify which clinical
characteristics may be predictive of folate concentrations in IBD
patients, we used a stepwise regression procedure (SAS PROC
Reg; SAS Institute Inc, Cary, NC). The full model included
dummy variables for disease location, Pediatric Crohn’s Disease
Activity Index (PCDAI; 21), time to diagnosis, and demographic
the model as a preliminary screening technique to determine
potential predictors. All statistical analyses were performed in
STATA 9.0 (Statacorp, College Station, TX) and SAS version 9.1
Folate concentrations were measured in 78 children: 37 with
newly diagnosed, untreated IBD (22 with CD, 11 with UC, and 4
with IC) and 41 healthy controls (Table 1). These 2 groups
differed slightly by age (P ¼ 0.042) and ethnicity (P ¼ 0.048),
but not by sex (P ¼ 0.370). Thus, subsequent multiple linear
regression models adjusted for both age and ethnicity. BMI
ranged from 12.4 to 41.9 in controls and from 13.9 to 26.3 in
IBD patients. The mean values were not significantly different
between cases and controls (20.1 and 18.7, respectively; P ¼
0.189). The controls enrolled were most often referred for
Characteristics of patients with inflammatory bowel disease (IBD)
PatientsControls (n ¼ 41)
11.4 6 3.22
20.1 6 5.2
IBD (n ¼ 37)
12.8 6 2.7
18.7 6 3.4
1Two-tailed t test or chi-square test.
2Mean 6 SD (all such values).
3Number with percentage in parentheses (all such values).
4Pacific Islander, Native American, or unknown.
HEYMAN ET AL
evaluation of abdominal pain (55.8%), constipation (34.9%),
and/or diarrhea (14%) but had no diagnosed underlying in-
flammatory conditions. The IBD patients had a variable pre-
sentation at diagnosis (Table 2). There were no statistically
significant differences in age, hematocrit, or erythrocyte sedi-
mentation rate (ESR) in patients with different subtypes of IBD.
The most common presenting symptom in the CD group was
abdominal pain (50%). In UC and IC patients, the most common
presenting symptom was blood in the stool (63.6% and 100%,
respectively). Other symptoms and disease locations varied be-
tween the 3 subtypes as described in detail in Table 2.
Mean RBCF concentrations in pediatric patients with newly
diagnosed, untreated UC and CD were similar (776.6 6 202.4
and 735.3 6 167.1 ng/mL, respectively; P ¼ 0.537) and notice-
0.084). Thus, the comparison of RBCF concentrations between
cases and controls only included UC and CD patients in the
‘‘case’’ group. None of our patients or controls was folate
deficient on the basis of blood measurements, and 6 subjects (2
controls, 4 IBD patients) had elevated concentrations on the basis
of minimum and maximum values provided by ARUP Labora-
tories (280–903ng/mL). Higher WBF and RBCF concentrations
were found independent of hematocrit concentrations, which
were slightly lower in IBD patients (P ¼ 0.030) than in controls
In the multiple linear regression model (Table 4), mean folate
concentrations remained significantly associated with disease
status after adjustment for age and ethnicity (P ¼ 0.001 and P ,
0.0005 for WBF and RBCF, respectively). WBF concentrations
on average were 41.8 ng/mL higher in IBD patients (95% CI:
17.0, 66.7 ng/mL) than in controls after adjusting for age and
ethnicity. Similar results were found for RBCF (P , 0.001). We
identified a trend of lower folate RBCF and WBF concentrations
in older children, but it was not statistically significant (P ¼ 0.13
and P ¼ 0.08, respectively). In addition, higher folate concen-
trations were observed in whites than in all other ethnic groups.
However, only the difference from African American IBD pa-
tients was significant (P ¼ 0.046 for RBCF). No significant
differences in folate concentrations were found by sex in either
IBD patients or controls (P ¼ 0.469 and P ¼ 0.776 for RBCF
and WBF, respectively).
267 lg/d; n ¼ 28) than in IBD patients (361 6 231 lg/d for IBD;
n ¼ 20), but this difference was not statistically significant (P ¼
0.264) (Table 5). RBCFand WBF concentrations in patients with
dietary folate intake data were not significantly different from
those in subjects lacking these data (P . 0.05). The Recom-
mended Dietary Allowance (RDA) of folic acid is 200 lg/d for
4–8-y-olds, 300 lg/d for 9–13-y-olds, and 400 lg/d for 14–18-
y-olds. Of 48 subjects with dietary intake data, 17 (35.4%) had
intakes below the RDA (10 IBD and 7 control), adjusted for age
and sex. Although dietary intake below the RDA was more fre-
quent in patients than in controls, the difference was not statisti-
cally significant (P ¼ 0.074). Dietary folate intake did not
correlate with either RBCF or WBF concentrations. Despite
having a slightly lower dietary folate intake, IBD patients had
higher WBF and RBCF concentrations than did controls. Using
a multiple linear regression model, we found an association be-
tween lower ratios of dietary folate intake to blood folate con-
centrations (RBCF and WBF) in cases but not in controls (P ¼
0.041 and P ¼ 0.045, respectively) after adjustment for BMI and
ratios of dietary folate to blood folate concentrations for RBCF
and WBF with increasing BMI after adjustment for age and dis-
ease status (P ¼ 0.11 and P ¼ 0.18, respectively). The interaction
between disease status and BMI was not statistically significant.
Characteristics of the patients with inflammatory bowel disease (IBD), by subtype1
Crohn disease (n ¼ 22)
12.8 6 2.02
36.2 6 19.5
35.1 6 3.4
Abdominal pain: 11 (50%)
Weight loss: 7 (3.18%)
Diarrhea: 8 (13.6%)
Blood in stool: 2 (9.1%)
Other (eg, poor growth, fever,
fatigue, anemia, perianal
problems): 4 (18.2%)
Ileal involvement: 4
Colonic involvement: 8 (4 with
Ileocolonic involvement: 8 (4 with
upper disease and 1 with perianal
Two with isolated upper disease
Ulcerative colitis (n ¼ 11)
12.5 6 3.6
34 6 19.4
32.4 6 4.4
Blood in stool: 7 (63.6%)
Abdominal pain: 5 (45.5%)
Diarrhea: 4 (36.4%)
Weight loss: 2 (18.2%)
Other (eg, anemia, vomiting,
fatigue, constipation, perianal
problems): 1 (9.1%)
Left-sided ulcerative colitis: 1
Indeterminate colitis (n ¼ 4)
13.5 6 4.0
18.5 6 17.7
36.8 6 3.0
Blood in stool: 4 (100%)
Abdominal pain: 2 (50%)
Diarrhea: 1 (25%)
Age at diagnosis (y)
Disease locationColonic involvement: 2
Ileocolonic involvement: 2
1There were no significant differences in age (P ¼ 0.81), erythrocyte sedimentation rate (ESR; P ¼ 0.25), or hematocrit (P ¼ 0.11) between the IBD
subtypes as determined by ANOVA.
2Mean 6 SD (all such values).
FOLATE CONCENTRATIONS IN CHILDREN WITH IBD
Folate concentrations did not correlate significantly with multi-
vitamin use (P ¼ 0.206 and P ¼ 0.071 for RBCF and WBF, re-
spectively). In addition, folate supplementation, measured by
dietary questionnaire, was not associated with RBCF or WBF
(P ¼ 0.478 and P ¼ 0.658, respectively).
The mean PCDAI score in CD patients (30.9 6 16.8) ranged
from 5 to 57.5. Elevated PCDAI scores were associated with
higher RBCF concentrations (Figure 1). The mean PCDAI score
increase in RBCF. The results for WBF were similar (P ¼ 0.047).
Length of time from onset of symptoms to date of diagnosis did
not correlate with blood folate concentrations. Symptoms at pre-
sentation, specifically abdominal pain, bloody stool, or diarrhea,
were also not related to folate concentrations (P ¼ 0.484, 0.606,
and 0.287, respectively). Stepwise regression analyses identified
several potential predictors of folate concentrations in IBD pa-
tients, including location of disease, age, and ethnicity (Table 6).
Upper gastrointestinal tract involvement was associated with
lower WBF concentrations (P ¼ 0.013), and disease in the colon
adjustment for age and ethnicity. Similar associations were ob-
served with RBCF (P ¼ 0.021 and P ¼ 0.019, respectively). We
also analyzed the disease locations according to the Montreal
classification system. However, this did not affect any of our
conclusions (data not shown).
In contrast with previous studies reporting folate deficiencies
in adult IBD patients (8, 10), we observed higher WBF and
RBCF concentrations in pediatric patients with newly diagnosed
IBD than in controls. This is particularly interesting because we
observed lower hematocrit levels and folate intakes in IBD pa-
tients. This substantiates our previous report of higher blood
folate concentrations in pediatric IBD patients (18). Further-
more, RBCF was positively correlated with PCDAI in CD pa-
tients. Additionally, several other factors were associated with
blood folate concentrations, including age, location of disease,
The clinical impact of these findings may be important to the
therapeutic management of patients with IBD. Our data suggest
that anemia in patients with IBD at presentation is independent of
folate status. However, consideration of additional nutrients (eg,
iron, vitamin B-6, vitamin B-12, zinc, selenium, and copper) in
be addressed. Furthermore, differences in metabolic pathways or
intestinal flora in patients with IBD can inherently affect folate
absorption and intestinal metabolism, which can alter folate
concentrations in patients with IBD.
To date, many clinicians have recommend folate supple-
mentation for all IBD patients. However, recent studies have
reported a potential increased risk of colon cancer and other
cancers in patients with an underlying predisposition to these
tumors who are supplemented with folate (14, 15, 22, 16). Be-
cause we found normal folate concentrations in pediatric pa-
tients with newly diagnosed IBD, further evaluation of current
folate supplementation recommendations is necessary. Addi-
tionally, the effects of subsequent IBD treatments on folate
Hematocrit and whole-blood folate (WBF) and red blood cell folate (RBCF) concentrations in patients with inflammatory
bowel disease (IBD) and controls
Controls (n ¼ 41)
35.9 6 4.9 (23.5–48.1)2
218.2 6 49.7 (136.0–335.8)
587.0 6 148.6 (314.0–982.0)
IBD (n ¼ 37)P value1
33.6 6 3.9 (26.9–43.0)
245.3 6 59.1 (131.1–396.0)
728.7 6 185.8 (405.0–1211.0)
1Two tailed t test.
2Mean 6 SD; range in parentheses (all such values).
Multiple linear regression analysis of the differences in red blood cell folate
(RBCF) concentrations between patients with inflammatory bowel disease
(IBD) and controls (n ¼ 80)1
b Coefficient (95% CI)P valueR2
181.0 (102.8, 259.1)
29.8 (222.4, 2.8)
2147.1 (2291.4, 22.9)
2133.3 (2283.6, 17.1)
2117.6 (2307.6, 72.4)
1Multiple linear regression analysis was used to determine the effects
of disease status, age, and ethnicity on RBCF. RBCF concentrations were
significantly greater in patients with IBD than in controls (P , 0.001) after
adjustment for age and ethnicity and were significantly lower in African
American than in white patients.
Folate intakes in patients with inflammatory bowel disease (IBD) and
(n ¼ 28)
142.4 6 63.12
142.7 6 57.6
159.6 6 241.2
444.7 6 266.7
(n ¼ 20)
119.2 6 57.8
135.0 6 76.0
106.87 6 186.2
361.1 6 230.6
Folic acid, fortified
Folic acid, supplemental
Folate intake, total
(dietary 1 supplemental)
1Two-tailed t test.
2Mean 6 SD (all such values).
HEYMAN ET AL
concentrations also warrant further investigation because it is
known that sulfasalazine and other IBD medications can de-
crease folate concentrations (12, 13).
We found that folate concentrations did not differ significantly
sample size, this observation still remains to be verified in larger
studies. Because CD patients are more likely to experience small
intestinal malabsorption, anorexia, and weight loss than are UC
patients, we expected to observe lower folate concentrations in
these patients. However, it is possible that small intestinal bac-
terial overgrowth in patients with CD compared with UC con-
tribute to higher folate concentrations in this group of patients.
We also found that younger children with IBD tended to have
higher folate concentrations than did older patients. Higher
concentrations of RBCF and WBF concentrations in whites than
in other ethnic groups, particularly African Americans, were also
observed in our study. These differences may be related to some
unknown nutrient intake factor or possibly to the length of time
that the underlying disease may be developing undiagnosed.
African American children often experience a delayed diagnosis
and present at an older age than do white children (1). Genetic
background may further explain some of the variation in folate
concentrations in children with comparable dietary folate
intakes. Further studies are underway to investigate func-
tionally significant polymorphisms, including those in the 5,10-
methylenetetrahydrofolate reductase gene, which may help to
explain why children with similar dietary folate intakes have
significantly different RBCF and WBF concentrations (23).
Limitations in our study include the lack of precise dietary
intake data, because retrospective food recall is sometimes in-
accurate when assessing nutritional status. However, the Block
food-frequency questionnaire used in our study was previously
thoroughly validated for adults (19) and children (20). Another
limitation was the slight difference in age and race-ethnicity
composition between the 2 groups. However, multiple regres-
sion techniques enabled us to adjust for these differences in
statistical models. Despite these limitations, we identified sig-
nificantly higher blood folate concentrations in pediatric patients
with newly diagnosed IBD than in controls, even though the
latter group appeared to have higher dietary folate intakes.
The findings of the present study suggest that folate deficiency
is uncommon in pediatric patients with newly diagnosed IBD.
The effects of genetic polymorphisms and the ultimate influences
of IBD therapies on folate status and metabolism remain to be
determined. The long-term implications of folate supplementa-
tion on growth and development, the natural history of disease,
and the eventual potential for development of intestinal cancers
remain to be systematically investigated.
The study coordinators at each clinical center were essential to the collec-
tion of the data, including, but not limited to, Erin DeMicco and Ann L Clark.
The authors’responsibilities were as follows—MBH, EAG, NS, KH, FAJ,
and NH: worked directly to recruit patients, process the samples, analyze and
interpret the data, and draft the final manuscript; and PH, HSW, RNB, SAC,
provide the samples and clinical data, and complete the final manuscript. All
authors had a significant role in this project and approved the final version of
the manuscript. None of the authors had a conflict of interest to report.
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Location: not upper GI2
Location: upper GI
Location: not colon2
2147.1 (2269.8, 224.3)
136.5 (24.1, 248.9)
24.8 (225.8, 16.1)
2277.9 (2443.2, 2112.6)
2162.4 (2357.4, 32.6)
2227.0 (2570.6, 116.7)
1Multiple linear regression analysis was used to determine the effects
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adjustment for age and ethnicity, upper gastrointestinal (GI) tract involve-
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