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Inadequate Riboflavin Intake and Anemia Risk in a Chinese Population: Five-Year Follow Up of the Jiangsu Nutrition Study

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Riboflavin (vitamin B2) has been shown in animal studies to affect the absorption and metabolism of iron. Cross-sectional population studies show a relationship between riboflavin intake and anemia but prospective population studies are limited. The aim of the study was to determine the relationship between riboflavin intake and the risk of anemia in a Chinese cohort. The study used data from 1253 Chinese men and women who participated in two waves of the Jiangsu Nutrition Study (JIN), five years apart, in 2002 and 2007. Riboflavin intake and hemoglobin (Hb) were quantitatively assessed together with dietary patterns, lifestyle, socio-demographic and health-related factors. At baseline, 97.2% of participants had inadequate riboflavin intake (below the estimate average requirement). Riboflavin intake was positively associated with anemia at baseline, but low riboflavin intake was associated with an increased risk of anemia at follow-up among those anemic at baseline. In the multivariate model, adjusting for demographic and lifestyle factors and dietary patterns, the relative risk and 95% confidence interval for anemia at follow-up, across quartiles of riboflavin intake were: 1, 0.82(0.54-1.23), 0.56(0.34-0.93), 0.52(0.28-0.98) (p for trend 0.021). There was a significant interaction between riboflavin and iron intake; when riboflavin intake was low, a high iron intake was associated with a lower probability of anemia at follow-up. This association disappeared when riboflavin intake was high. Inadequate riboflavin intake is common and increases the risk of anemia in Chinese adults. Given the interaction with iron intake correcting inadequate riboflavin intake may be a priority in the prevention of anemia, and population based measurement and intervention trials are required.
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Inadequate Riboflavin Intake and Anemia Risk in a
Chinese Population: Five-Year Follow Up of the Jiangsu
Nutrition Study
Zumin Shi
1,2
*, Shiqi Zhen
1
, Gary A. Wittert
2
, Baojun Yuan
1
, Hui Zuo
1
, Anne W. Taylor
2
1Department of Nutrition and Foodborne Disease Prevention, Jiangsu Provincial Centre for Disease Control and Prevention, Nanjing, China, 2Discipline of Medicine,
University of Adelaide, Adelaide, Australia
Abstract
Objectives:
Riboflavin (vitamin B2) has been shown in animal studies to affect the absorption and metabolism of iron. Cross-
sectional population studies show a relationship between riboflavin intake and anemia but prospective population studies
are limited. The aim of the study was to determine the relationship between riboflavin intake and the risk of anemia in a
Chinese cohort.
Method:
The study used data from 1253 Chinese men and women who participated in two waves of the Jiangsu Nutrition
Study (JIN), five years apart, in 2002 and 2007. Riboflavin intake and hemoglobin (Hb) were quantitatively assessed together
with dietary patterns, lifestyle, socio-demographic and health-related factors.
Results:
At baseline, 97.2% of participants had inadequate riboflavin intake (below the estimate average requirement).
Riboflavin intake was positively associated with anemia at baseline, but low riboflavin intake was associated with an
increased risk of anemia at follow-up among those anemic at baseline. In the multivariate model, adjusting for demographic
and lifestyle factors and dietary patterns, the relative risk and 95% confidence interval for anemia at follow-up, across
quartiles of riboflavin intake were: 1, 0.82(0.54–1.23), 0.56(0.34–0.93), 0.52(0.28–0.98) (p for trend 0.021). There was a
significant interaction between riboflavin and iron intake; when riboflavin intake was low, a high iron intake was associated
with a lower probability of anemia at follow-up. This association disappeared when riboflavin intake was high.
Conclusion:
Inadequate riboflavin intake is common and increases the risk of anemia in Chinese adults. Given the
interaction with iron intake correcting inadequate riboflavin intake may be a priority in the prevention of anemia, and
population based measurement and intervention trials are required.
Citation: Shi Z, Zhen S, Wittert GA, Yuan B, Zuo H, et al. (2014) Inadequate Riboflavin Intake and Anemia Risk in a Chinese Population: Five-Year Follow Up of the
Jiangsu Nutrition Study. PLoS ONE 9(2): e88862. doi:10.1371/journal.pone.0088862
Editor: Keitaro Matsuo, Kyushu University Faculty of Medical Science, Japan
Received July 12, 2013; Accepted January 13, 2014; Published February 12, 2014
Copyright: ß2014 Shi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study is supported by Jiangsu Provincial Natural Science Foundation (BK2008464) and the Jiangsu Provincial Health Bureau, China. The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: zumin.shi@adelaide.edu.au
Introduction
Despite the nutrition transition and improved nutritional status
in many developing countries, anemia remains a major public
health problem. In China, according to data from a national
nutrition survey, more than 15% of the population were anemic in
2002, [1]. While iron deficiency is the main cause of anemia in
developing countries [2], other nutritional factors, for example
vitamins (vitamin A, vitamin C and vitamin B2) [3], are also
important but have received considerably less attention. Ribofla-
vin (vitamin B2) deficiency is one of the most common vitamin
deficiencies in developing countries especially those with rice as
the staple food coupled with insufficient milk and meat intake [4].
In animal studies, riboflavin has been shown to increase iron
absorption [3], and riboflavin deficiency can significantly increase
the rate of gastrointestinal iron loss as well as decrease the
mobilization of iron from stores [5]. In humans riboflavin
deficiency has been shown to negatively affect iron utilization [6].
In China the mean intake of riboflavin is around 0.8 mg/d,
which is below the estimated average requirement (EAR, 1.4 mg/
d for men aged 18 and above, 1.2 mg/d for women aged 18–49
years, 1.4 mg/d for women aged 50 years and above) [7]. In
contrast, the iron intake in the population is over 23 mg/d [8],
which is above the RNI (15 mg/d for men aged 18–49 years,
20 mg/d for women aged 18–49 years) [7].
The association between riboflavin intake and anemia in China
has been inconsistent in cross-sectional studies. One case-control
study in South-west China found that as compared to non-anemic
elderly women, anemic elderly women had lower riboflavin intake
[9]. Another Chinese study showed that there was no significant
difference in riboflavin intake between anemic and non-anemic
pregnant women [10]. The relationship between riboflavin intake
and anemia has not, as far as we can determine, been
prospectively investigated in a representative cohort study in
China, or indeed elsewhere. The aim of the current study was to
assess the association between riboflavin intake and the risk of
PLOS ONE | www.plosone.org 1 February 2014 | Volume 9 | Issue 2 | e88862
anemia using the five year longitudinal data from the Jiangsu
Nutrition Study. The second aim of the study was to assess the
interaction between riboflavin intake and iron intake in relation to
anemia.
Subjects and Methods
Study design
The methodologies of the Jiangsu Nutrition (JIN) Cohort Study
have been described previously [11–13]. The baseline of the
cohort was based on a subsample of the Chinese National
Nutrition and Health Survey representing Jiangsu province in
2002. The rural sample was selected from six counties (Jiangyin,
Taichang, Shuining, Jurong, Sihong and Haimen). From each of
the six counties, three smaller towns were randomly selected. The
urban sample was selected from the capital cities of the two
prefectures, Nanjing and Xuzhou; and from each capital city three
streets were randomly selected. In each town/street, two villages/
neighbourhoods were randomly selected, and 90 households were
further selected randomly from each village/neighbourhood. All
the members in the households were invited to take part in the
study. In addition, one third of the households were interviewed
on dietary intake.
At baseline, 2813 adults aged 20 and above had detailed dietary
information and blood hemoglobin measurement. At follow-up in
2007, 1668 participants were identified through household visits,
and 1481 of them participated in the follow-up interview. After
excluding 228 participants without hemoglobin values at follow-
up, the final sample size examined for anemia status change
consisted of 520 men and 733 women (total n = 1253) (Figure 1).
The study was conducted according to the guidelines in the
Declaration of Helsinki and all procedures involving human
subjects/patients were approved by Jiangsu Provincial Centre for
Disease Control and Prevention. Written consent to participate
was obtained from all the participants.
Data collection and measurements
Participants were interviewed at their homes by intensively
trained health workers using a standard questionnaire [11].
Outcome variables. An overnight fasting blood sample
(capillary and venous) was collected at baseline and follow-up.
The capillary blood samples were analyzed for hemoglobin (Hb)
by the cyanmethemoglobin method [14] in the local Centers for
Disease Control and Prevention. The venous blood plasma was
separated by centrifugation at 3,200 rpm for 10–15 min within
1 h of collection, kept at room temperature without sunshine and
sent to central laboratory for biochemical tests. Serum ferritin was
analyzed only at baseline in a laboratory in the National Centre
for Disease Control and Prevention in Beijing using a commer-
cially available radioimmunoassay kit (Beijing North Institute of
Biological Technology). Anemia was defined as a Hb level below
13 g/dL for men and 12 g/dL for women [15]. Iron deficiency
anemia (IDA) was defined as the presence of both anemia and a
serum ferritin level ,15 mg/l.
Dietary intake. In 2002 and 2007, dietary intake patterns
during the previous year were investigated by a series of detailed
questions about the usual frequency and quantity of intake of 33
food groups and beverages using a food frequency questionnaire
(FFQ) administered by a trained health care worker. The FFQ
administered in this manner has been validated with weighted
food records [16–18]. Baseline riboflavin intake (exposure variable)
and other nutrients (e.g. vitamin C, protein), alcohol and vegetable
oil intakes were assessed using a 3-day weighed food diary which
recorded all foods consumed by each individual, on three
consecutive days (including one weekend); this 3-day weighed
food diary was not undertaken at follow-up due to its high cost and
time needed. At the beginning and end of the 3-day survey, health
workers weighed all the food stocked in the household. Each day,
all purchases, home production, and processed snack foods were
weighed and recorded. Food intakes of each individual in the
household were recorded in detail each day.
During the interview, the health workers would check any
intake value for a particular food that fell below or above the usual
intake value by the population in the region. Food consumption
data were analyzed using the Chinese Food Composition Table
[19]. Inadequate riboflavin intake was defined as the usual
riboflavin intake below the Chinese EAR (1.4 mg/d for men aged
18 and above, 1.2 mg/d for women aged 18–49 years, 1.4 mg/d
for women aged 50 years and above) [7]. To estimate the
prevalence of inadequate riboflavin intake, we used the EAR cut
point method [20]. We used the National Cancer Institute (NCI)
method to estimate the distribution of usual riboflavin intake [21].
Dietary patterns. Baseline dietary patterns were identified
by factor analysis based on food intake estimated by the FFQ,
using standard principal component analysis as described
elsewhere [22]. Four food patterns were obtained: Factor 1
(‘macho’) included various kinds of animal foods and alcohol;
Factor 2 (the ‘traditional’ pattern) loaded heavily on rice, fresh
vegetables and inversely on wheat flour; Factor 3 (‘sweet tooth’)
contained cake, milk, yoghurt and drinks; and, Factor 4 (‘vegetable
rich’ pattern) was characterized whole grains, fruits, root
vegetables, fresh and pickled vegetables, milk, eggs and fish. The
four factors explained 28.5% of the variance in intake. Similarly
four dietary patterns were identified at follow up. The correlation
coefficient for corresponding dietary patterns between baseline
and follow up ranged from 0.139 (‘vegetable rich’ pattern),
0.241(‘macho’ pattern, p,0.001), 0.254(‘sweet tooth’ pattern, p,
0.001) to 0.593 (‘traditional’ pattern, p,0.001).
Covariates. Cigarette smoking was assessed by asking the
frequency of daily cigarette smoking in the past 30 days. Education
was recoded into either ‘Low’ (illiteracy, primary school);
‘Medium’ (junior middle school); or, ‘High’ (high middle school
or higher), based on six categories of education levels in the
questionnaire. Occupation was recoded into ‘Manual’ or ‘Non-
manual’ based on a question with 12 occupational categories.
Figure 1. Sample description.
doi:10.1371/journal.pone.0088862.g001
Riboflavin and Anemia
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Hypertension medication use (yes/no) was asked at baseline and
follow-up.
In both baseline and follow-up, anthropometric measurements
were obtained using standard protocols and techniques [18,23],
including body weight, height, and blood pressure. Body weight
was measured in light indoor clothing to the nearest 100 grams,
and height to the nearest mm. Using the Chinese classification,
BMI is categorized as normal (BMI,24 kg/m
2
), overweight (BMI
24–27.9 kg/m
2
), and obese (BMI$28 kg/m
2
)[24]. Blood pressure
was measured twice by mercury sphygmomanometer on the right
upper arm of the subject, who was seated for 5 min before the
measurement. The mean of these two measurements was used in
the analyses. The cuff size was selected on the basis of the upper
arm circumference to ensure that the cuff did not overlap [23].
Hypertension was defined as systolic blood pressure above
140 mmHg and/or diastolic blood pressure above 90 mmHg, or
use of antihypertensive medications.
Statistics
Riboflavin intake was coded into quartiles. Chi square test was
used to compare differences between categorical variables, and
ANOVA was used to compare differences in continuous variables
between groups. Poisson regression with robust variance models
were also used to assess the association between riboflavin intake
quartiles and anemia at follow up [25]. Prevalence rate ratio was
calculated and adjusted for age, sex, energy intake, iron intake
(model 1), and further adjustment for education, occupation,
smoking, hypertension, overweight (yes/no) at baseline, energy,
iron and vitamin C intake (as continuous variables), baseline
dietary patterns (model 2), and follow up dietary patterns (model
3). Tests of linear trends across riboflavin quartiles were computed
using ordinal scoring. Food patterns were also put into the
multivariate models to control for residual confounding, as
suggested by Imamura et al [26]. To assess the interaction between
riboflavin intake and iron intake, we treated both variables as
continuous and put the product term of the variables in a logistic
regression adjusting for potential confounding variables (variables
adjusted in above model 2). After the logistic regression, we used
the margins command to determine the adjusted probability
(marginal effect) of anemia at follow up according to riboflavin
intake and iron intake at baseline. For graphical visualization of
the predicted probability of anemia at follow up, we used the
‘‘marginsplot’’ command, and the median of each quartile of iron
intake was used. In the provinces, a distinct definition of urban/
rural dwelling is difficult due to ongoing economic development.
Since we have adjusted for education and job status as well as
dietary patterns, the decision was made not to adjust for urban/
rural. All the analyses were performed using STATA 12 (Stata
Corporation, College Station). Statistical significance was consid-
ered to be when p,0.05 (two sided).
Results
At baseline, among 1253 participants, there were 124 (23.9%)
men and 261 (35.6%) women with anemia. The prevalence of iron
deficiency anemia at baseline was 3.8% (0.8% in men, 5.9% in
women). Of the 1253 participants followed up for five years,
13.1% developed anemia, while anemia resolved in 21.5% for the
total sample. Only 9.3% of the participants had persistent anemia
at the 5-year follow-up.
Individuals lost to follow up were younger (45.2 vs 49.4 years),
were more likely to have high education (20.8% vs 10.9%, p,
0.001), had higher Hb (13.6 vs 13.2 g/dl, p,0.001) and a lower
prevalence of anemia (21.5% vs 30.7%, p,0.001), but there were
no differences in mean BMI (p = 0.324), or energy (p = 0.246) and
riboflavin intake (p = 0.358).
The mean intake of riboflavin at baseline was 0.80 (SD 0.33)
mg/d. Overall 97.2% (98.0% women and 96.2% men) of the
sample had usual riboflavin intake below Chinese EAR. The mean
intake of iron was 24.9 mg/d (26.9 mg/d in men, 23.4 mg/d in
women). Income and education were positively associated with
riboflavin intake (Table 1). There were significant differences in
energy, fat, protein, iron, vitamin C, and fiber intakes across
quartiles of riboflavin intake. Riboflavin intake was positively
associated with ferritin and association remained after adjusting
for age and gender (data not shown).
At baseline, there was a positive association between riboflavin
intake and anemia in women but not in men (Table 2). Across
quartiles of riboflavin intake, the prevalence rate ratio (model 2)
was 1.15(0.69–1.90), 0.97(0.53–1.75), and 1.01(0.50–2.05) in men
(p for trend 0.821); 1.13(0.87–1.48), 1.40(1.04–1.89), and
1.32(0.93–1.88) in women (p for trend 0.046). There was a
significant interaction between age and riboflavin intake in
women: the positive association between riboflavin intake and
anemia was only significant in women below age of 50 years (p for
interaction 0.029) (data not shown).
The risk of anemia at follow-up in relation to riboflavin intake
and anemic status at baseline is shown in Table 3. In the absence
of anemia at baseline riboflavin intake had no association with
anemia at follow-up. However, among those anemic at baseline,
there was a clear inverse association between riboflavin intake and
likelihood of anemia at follow-up. The relative risk and 95%
confidence intervals for anemia at follow-up across quartiles of
riboflavin intake were (model 3): 1, 0.82(0.54–1.23), 0.56(0.34–
0.93), 0.52(0.28–0.98) (p for trend 0.021). Additional adjustment
for other B vitamins and folate intake did not change the
association between riboflavin intake and anemia (data not
shown).
There was an interaction between riboflavin intake and iron
intake at baseline according to the presence or absence of anemia
(riboflavin and iron intake interaction, P = 0.008) (Figure 2).
Among those non-anemic at baseline, when riboflavin intake was
low, there was a strong inverse association between iron intake and
the risk of anemia at follow up. However, the association between
iron intake and anemia was weak when riboflavin intake was high.
Among those anemic at baseline, a high riboflavin intake at
baseline was associated with lower risk of persistent anemia,
independent of iron intake.
The interaction between riboflavin and iron intake at baseline
was similar in men and women (Figure 3). The predicted
probability of anemia at follow up was 0.30(95%CI, 0.18–0.41) in
men with riboflavin intake of 0.4 mg/d and iron intake of 16 mg/
d. The corresponding figure was 0.12(0.07–0.16) for men with
riboflavin intake of 1.2 mg/d and iron intake of 37 mg/d. When
riboflavin intake reached 1.4 mg/d, iron intake was not related to
the probability of anemia in the sample.
Discussion
In this prospective study, we found that inadequate riboflavin
intake was common, and associated with an increased risk of
persistent anemia. There was a significant interaction between
riboflavin intake and iron intake in relation to anemia risk.
Riboflavin deficiency, based on either intake of riboflavin or
measurement of a serum biomarker (erythrocyte glutathione
reductase activation coefficient, EGRAC) is common in many
populations. For example, in Taiwan, it has been shown that
about one in four elderly had marginal riboflavin deficiency based
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on riboflavin biomarker EGRAC [27]. Data from the China
Nutrition and Health Survey (CHNS) showed that there was a
persistent low intake of riboflavin in the Chinese population: the
mean intake was around 0.7–0.9 mg/d among adults aged 18–45
years in six surveys between 1989 and 2004 [8]. This low intake of
riboflavin may partly be due to the low consumption of milk. The
mean intake of milk was only 2 g/d in 1989 and 12 g/d in 2004
[8]. In our study, only 6.5% of participants had an adequate intake
of riboflavin.
There was a positive association between riboflavin intake and
anemia among women, particularly in those below 50 years. In the
same study population, we have previously reported that at
baseline there was a positive association between total meat
consumption and anemia: OR for anemia across quartiles of meat
consumption were 1.00, 1.20, 1.39, 1.37(1.09–1.73), respectively
[28]. Accordingly the apparent inconsistency may be the result of
reverse causation in some of the study population. Women with
anemia may have changed their diet and consequently increased
riboflavin intake but had persistent anemia because of ongoing
menstrual related blood loss.
In contrast to some cross sectional studies [10,29], but consistent
with a prior case control study [9], this longitudinal study shows
that inadequate riboflavin intake is an important risk factor for
anemia in China. The findings are in keeping with the known
biological role of riboflavin in enhancing iron absorption and
utilization [5,30] (when riboflavin intake is high, the ability to
mobilise iron from ferritin to and utilise it for the synthesis Hb will
be high), and beneficial effects of riboflavin supplementation in the
prevention of anemia in some [3,31], but not all studies [3]. Three
of 7 riboflavin supplementation trials undertaken before 1990 and
reviewed in 2000 by Fishman et al showed beneficial effects [3].
However, these supplementation studies were mainly performed in
developing countries and with short term (six weeks to three
months) and small sample sizes (between 27 and 200). A recently
Table 1. Baseline sample characteristics according to quartiles of riboflavin intake (n = 1253).
a
Q1 Q2 Q3 Q4 p
b
(n = 313) (n = 313) (n = 313) (n = 314)
Age 51.3(14.0) 49.9(13.0) 48.9(12.7) 47.4(12.6) 0.002
BMI (kg/m
2
) 23.3(3.7) 23.5(3.5) 23.6(3.4) 23.3(2.9) 0.671
Overweight/obesity (%) (BMI$24 kg/m
2
) 38.2 40.3 44.4 37.8 0.314
Hemoglobin (g/dL) 13.0(1.7) 13.0(1.7) 13.3(1.7) 13.5(1.9) ,0.001
Ferritin (mg/l) 81.1(66) 93.4(78.7) 104.3(81.8) 111.1(89.7) ,0.001
Ferritin ,15 mg/l (%) 10.0 8.7 8.4 6.8 0.001
Nutrient intake
Energy (kcal) 1841.9(460.4) 2210.5(458.6) 2512.8(575.2) 2766.2(677.7) ,0.001
Fat (g/d) 59.8(24.5) 74.4(28.2) 90.3(35.2) 101.7(39.6) ,0.001
Protein (g/d) 53(12.2) 66.5(12.7) 78.1(15.4) 92.1(23.3) ,0.001
Total iron (mg/d) 19.3(7.6) 21.9(6.2) 25.9(7.3) 32.5(11.1) ,0.001
Non-heme iron (mg/d) 18.2(7.9) 20.1(6.5) 23.3(7.4) 27.8(11.5) ,0.001
Heme iron (mg/d) 1.1(1.2) 1.8(1.9) 2.6(3) 4.7(5.7) ,0.001
Vitamin C (mg/d) 45.3(22.9) 63.4(33.3) 66.5(33.5) 84.8(45.5) ,0.001
Riboflavin (mg/d) 0.5(0.1) 0.7(0) 0.8(0.1) 1.3(0.3) ,0.001
Fiber (g/d) 10.3(9.6) 10.5(7.9) 11.2(6.5) 14.4(12.1) ,0.001
Alcohol intake (g/d) 0.7(3.7) 1.4(4.9) 2(5.6) 3.1(6.1) ,0.001
Women (%) 77.7 63.9 49.5 42.8 ,0.001
Anemia (baseline) (%) 30.9 32.6 31.0 28.4 0.730
Hypertension (%) 31.8 28.1 33.5 29.7 0.475
Smoker (%) 16.9 21.4 30.4 39.6 ,0.001
Alcohol drinker (%) 12.4 18.2 30.0 38.3 ,0.001
Education
Low (%) 64.3 57.5 53.7 39.6
Medium (%) 28.0 32.6 35.8 44.7 ,0.001
High (%) 7.6 9.9 10.5 15.7
Manual job (%) 51.6 48.6 53 50.2 0.710
Income
Low (%) 34.7 27.3 19.6 18.8
Medium (%) 33.4 38.6 36.9 25.2 ,0.001
High (%) 31.8 34.1 43.6 56.0
a
Values are presented as mean(SD) or percentage.
b
p values were generated by chi-squared test for categorical variables and ANOVA test for continuous exposures.
doi:10.1371/journal.pone.0088862.t001
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published trial, undertaken in China, showed that retinol and
riboflavin supplements decreased the prevalence of anemia in
pregnant women also taking iron and folic acid supplements [32].
In addition a recent clinical trial in United Kingdom found that
riboflavin supplementation can improve hematologic status among
women aged 19–25 years with moderate riboflavin-deficiency
[31].
The mean intake of iron (27 mg/d in men, 23 mg/d in women)
exceeds the Chinese recommendation, suggesting there is
adequate intake of iron. The majority of iron intake is in the
form of non-heme iron. As the traditional Chinese diet is low in
meat and milk and high in vegetable and other plant foods, the
iron bioavailability is low [33]. The substantial decrease in
prevalence of anemia in China over the past few decades may
partly be due to the overall improvement of living condition and
access to health service as well as the control of infectious diseases,
and improvements in diet. The fact that the consumption of
animal food has increased (75 g/d in 1989; 122 g/d in 2004) while
the intake of cereals and starchy roots has declined [8], may
increase in the bioavailability of iron in some degree. However,
there was no substantial increase in the riboflavin intake over the
past decades [8], probably due to the low intake of milk in the
population. Despite the high prevalence of anemia in the sample,
the level of ferritin is relatively normal. Among the anemic, only a
Table 2. Baseline association between riboflavin intake (quartiles) and anemia.
a
Riboflavin intake quartiles in 2002
P
for trend
Q1 Q2 Q3 Q4
(0.5 mg/d)
b
(0.7 mg/d) (0.8 mg/d) (1.3 mg/d)
All participants (n = 1253)
Model 1
c
1 1.20(0.94–1.52) 1.28(0.99–1.67) 1.36(1.02–1.83) 0.033
Model 2
d
1 1.13(0.89–1.43) 1.19(0.91–1.56) 1.22(0.89–1.69) 0.201
Men (n = 520)
Model 1
c
1 1.23(0.73–2.04) 1.08(0.61–1.90) 1.34(0.73–2.45) 0.465
Model 2
d
1 1.15(0.69–1.90) 0.97(0.53–1.75) 1.01(0.50–2.05) 0.821
Women (n = 733)
Model 1
c
1 1.17(0.90–1.53) 1.48(1.11–1.97) 1.50(1.08–2.09) 0.004
Model 2
d
1 1.13(0.87–1.48) 1.40(1.04–1.89) 1.32(0.93–1.88) 0.046
a
Values are prevalence rate ratio (95% CI) from Poisson regression.
b
mean riboflavin intake with quartile.
c
Model 1 adjusted for age (years, as continuous), sex (not adjusted in sex specific model), energy and iron intake.
d
Model 2 adjusted for age, sex (not adjusted in sex specific model), smoking (0, 1–19, $20 cigarettes/day), alcohol drinking (g/day), education (low, medium, high), and
occupation (manual/non-manual), overweight (BMI$24 kg/m
2
, yes/no), hypertension (yes/no), intake of energy (kcal/day), iron (mg/day), and vitamin C (mg/day) (as
continuous variables), for baseline dietary patterns.
doi:10.1371/journal.pone.0088862.t002
Table 3. Relative risk (95% CI) for anemia at follow-up derived from Poisson regression according to quartiles of baseline riboflavin
intake among Chinese adults by anemic status at baseline in Jiangsu Nutrition Study.
a
Riboflavin intake quartiles in 2002 P for trend
Q1 Q2 Q3 Q4
(0.5 mg/d)
b
(0.7 mg/d) (0.8 mg/d) (1.3 mg/d)
Non-anemic at baseline (n = 868)
Model 1
c
1 1.16(0.80–1.68) 0.83(0.53–1.31) 0.97(0.61–1.54) 0.571
Model 2
d
1 1.17(0.81–1.68) 0.84(0.53–1.33) 1.00(0.59–1.68) 0.663
Model 3
e
1 1.17(0.81–1.68) 0.80(0.50–1.28) 1.00(0.59–1.69) 0.621
Anemic at baseline (n = 385)
Model 1
c
1 0.89(0.60–1.32) 0.61(0.38–0.97) 0.61(0.37–1.00) 0.020
Model 2
d
1 0.82(0.54–1.23) 0.57(0.35–0.93) 0.52(0.28–0.97) 0.017
Model 3
e
1 0.82(0.54–1.23) 0.56(0.34–0.93) 0.52(0.28–0.98) 0.021
a
Values are prevalence rate ratio (95% CI) from Poisson regression.
b
mean riboflavin intake with quartile.
c
Model 1 adjusted for age (years, as continuous), sex, and energy intake.
d
Model 2 adjusted for age, sex, smoking (0, 1–19, $20 cigarettes/day), alcohol drinking (g/day), education (low, medium, high), and occupation (manual/non-manual),
overweight (BMI$24 kg/m
2
, yes/no), hypertension (yes/no), intake of energy (kcal/day), iron (mg/day), and vitamin C (mg/day) (as continuous variables), and baseline
dietary patterns.
e
Model 3 additional adjusted for dietary patterns (continuous) at follow-up.
doi:10.1371/journal.pone.0088862.t003
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Figure 2. Interaction between riboflavin intake and iron intake at baseline in relation to anemia at follow up stratified by anemia status
at baseline. Marginsplot syntax was used to make the plot after logistic regression adjusting for age, gender, smoking, energy intake, dietary patterns
(continuous), education, income, BMI, and hypertension at baseline. The values represent the adjusted probability of anemia at follow-up. The values of
iron intake represent the median intake in each quartile of iron intake. P value for interaction between riboflavin intake and iron intake was 0.008.
doi:10.1371/journal.pone.0088862.g002
Figure 3. Interaction between riboflavin intake and iron intake at baseline in relation to anemia at follow up stratified by gender.
Marginsplot syntax was used to make the plot after logistic regression adjusting for age, smoking, energy intake, dietary patterns, education, income,
BMI, and hypertension at baseline. Anemia status at baseline was also adjusted in the model. The values of iron intake represent the median intake in
each quartile of iron intake. The values represent the adjusted probability of anemia at follow-up. P for interaction between riboflavin and iron intake
was 0.016.
doi:10.1371/journal.pone.0088862.g003
Riboflavin and Anemia
PLOS ONE | www.plosone.org 6 February 2014 | Volume 9 | Issue 2 | e88862
small proportion of the participants had ferritin ,15 mg/l. This
may be due to the fact that when riboflavin is inadequate, the
mobilization of iron from ferritin is limited [34].
The study raises questions about the current anemia prevention
strategy of using iron fortified soy sauce, which started in 2004
after a substantial drop of the prevalence of anemia between 1982
and 2002. Iron supplementation may not be the best way to
prevent anemia in the population when riboflavin intake is
inadequate. In the short term, riboflavin supplement is required.
Riboflavin alone without additional iron supplement has been
shown to improve hematologic status in young women in the
United Kingdom [31]. Riboflavin may have a role in the
prevention of cancer and cardiovascular disease [35], and iron
overload has been implicated in the etiology of type 2 diabetes
mellitus [36], accordingly increasing dietary riboflavin may have
significant overall public health benefits for the Chinese popula-
tion where non communicable chronic disease is becoming
epidemic.
A limitation of the study is the large number of individuals lost
to follow up. Those lost to follow-up were younger (better
educated and with lower prevalence of anemia) and as compared
to the individuals who remained in the cohort they would have
been at a lower risk of nutritionally-related anemia. The study
included more women than men (possibly due to the fact that men
in the rural area were more likely to migrate to urban area for
work). This may limit the ability to generalize our findings to the
general population. A further limitation is that absence of a
biomarker for riboflavin status (e.g. EGRAC) and the use of
ferritin levels to assess iron status in the absence of a marker of
inflammation. We did not measure serum ferritin at follow-up.
Finally, information on medical conditions (e.g. gastrointestinal
bleeding) which may cause blood loss is not available. The strength
of the study is its relatively large sample and detailed information
on dietary intake at baseline. We were able to adjust for a range of
confounding factors including dietary patterns at both time points.
In conclusion, riboflavin intake was largely inadequate in the
Chinese population. Low intake of riboflavin is associated with
increased risk of anemia. When riboflavin intake is adequate, there
is no association between iron intake and anemia in the
population. Correcting riboflavin deficiency may therefore be
one of the components in the prevention of anemia, and
population based measurement and intervention trials are
required.
Author Contributions
Conceived and designed the experiments: ZS. Performed the experiments:
ZS BY. Analyzed the data: ZS. Contributed reagents/materials/analysis
tools: BY. Wrote the paper: ZS SZ GAW BY HZ AWT.
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... 15,101 Few researchers have examined the effect of riboflavin supplementation on improving hematological status in humans (Table 5). 41,44,[102][103][104][105][106][107][108][109][110][111][112] Most of these studies have been conducted in low-and middle-income countries, including Gambia, Nigeria, China, Côte d'Ivoire, and Thailand, whose populations have endemic riboflavin deficiency and inadequate intake. A prospective survey carried out in China (2002)(2003)(2004)(2005)(2006)(2007) reported a positive association between inadequate riboflavin intake (less than the Chinese EAR; assessed by a 3-d weighed-food record) and anemia (hemoglobin < 120 g/L). ...
... A prospective survey carried out in China (2002)(2003)(2004)(2005)(2006)(2007) reported a positive association between inadequate riboflavin intake (less than the Chinese EAR; assessed by a 3-d weighed-food record) and anemia (hemoglobin < 120 g/L). 111 The Chinese EARs used in this survey were 1.4 mg/d for men aged !18 years, 1.2 mg/d for women aged 18-49 years, and 1.4 mg/d for women aged !50 years. At baseline, the P for trend across quartiles (Q) of riboflavin intake (Q1, 0.5 mg/d; Q2, 0.7 mg/d; Q3, 0.8 mg/d; and Q4,1.3 mg/d) and anemia among women was 0.004 when controlling for age, energy intake, and iron intake, but this value dropped to 0.046 with additional adjustments (eg, for smoking, alcohol drinking, education, overweight). ...
... compared with those with anemia and riboflavin intakes at Q1 at baseline. 111 However, no biochemical indicators of riboflavin status were measured in this survey. ...
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... Riboflavin is an important precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) (Balasubramaniam et al., 2019;Andreieva et al., 2020). Riboflavin insufficiency manifests as persistent anemia (Shi et al., 2014). The biosynthesis of riboflavin begins with guanosine triphosphate and ribose-5-phosphate, followed by six enzymatic steps (Fischer and Bacher, 2005). ...
... By deregulating the rib operon and purine pathway of B. subtilis, riboflavin production was greatly improved. The specific genetic engineering steps included overexpression of the ribA gene and deletion of the purR gene, after which maximum output of riboflavin reached more than 826.52 mg/L ( Figure 1B; Shi et al., 2014). In Candida famata overexpression of sef1 and imh3 was combined with classic mutagenesis methods to construct the high riboflavin-producing strain AF-4. ...
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... By deregulating the rib operon and purine pathway of B. subtilis, riboflavin production was greatly improved. The specific genetic engineering steps included overexpression of the ribA gene and deletion of the purR gene, after which maximum output of riboflavin reached more than 826.52 mg/L ( Figure 1B; Shi et al., 2014). In Candida famata overexpression of sef1 and imh3 was combined with classic mutagenesis methods to construct the high riboflavin-producing strain AF-4. ...
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