Received: 23 February 2020 Revised: 20 May 2020 Accepted: 21 May 2020

DOI: 10.1111/obr.13080

ETIOLOGY AND PATHOPHYSIOLOGY

Can diet-induced weight loss improve iron homoeostasis in

patients with obesity: A systematic review and meta-analysis

I-Chun Teng1 | Sung-Hui Tseng2,3 | Bianda Aulia4 | Chun-Kuang Shih5 |

Chyi-Huey Bai6,7 | Jung-Su Chang1,5,8,9

1
Graduate Institute of Metabolism and
Obesity Sciences, College of Nutrition, Taipei Summary
Medical University, Taipei, Taiwan Despite the increasing worldwide prevalence of obesity and iron deficiency (ID),
2
Department of Physical Medicine and
there are still no guidelines on how to treat and manage obesity-related ID. The aim
Rehabilitation, Taipei Medical University
Hospital, Taipei, Taiwan of this systematic review and meta-analysis was to investigate whether weight loss
3
Department of Physical Medicine and can re-establish iron homoeostasis among subjects with unhealthy weight (over-
Rehabilitation, School of Medicine, College of
Medicine, Taipei Medical University, Taipei, weight [OW] or obesity). PubMed, Medline, Embase, Web of Science, and the
Taiwan Cochrane Library were systemically searched for studies that compared the iron sta-
4
Department of Nutrition and Health, Faculty
tus before and after a weight-loss intervention. A random-effects model was used to
of Medicine, Public Health, and Nursing,
Universitas Gadjah Mada, Yogyakarta, calculate the pooled and subgroup weighted mean differences (WMDs) of iron bio-
Indonesia
markers. In total, 879 subjects were pooled across 14 studies. Improved haemoglobin
5
School of Nutrition and Health Sciences,
College of Nutrition, Taipei Medical University,
was found in longitudinal studies (WMD = 2.50 g/dl, 95% confidence interval [CI]:
Taipei, Taiwan 0.88, 4.12 g/dl, I2 = 14%) but not in randomized controlled trials or after being strati-
6
Department of Public Health, College of fied by dietary programmes. Significantly increased transferrin saturation was
Medicine, Taipei Medical University, Taipei,
Taiwan observed in pooled (WMD = 1.68%, 95% CI: 0.97%, 2.39%, I2 = 44%) and subgroup
7
Department of Public Health, College of analyses. A meta-regression showed that changes in the iron status were positively
Public Health, Taipei Medical University,
correlated with changes in the body mass index (BMI) and the intervention duration
Taipei, Taiwan
8
Nutrition Research Center, Taipei Medical but negatively correlated with the baseline body weight/BMI, age, gender and a stan-
University Hospital, Taipei, Taiwan dard hypocaloric diet. Our data suggested that in spite of energy restrictions, weight
9
Chinese Taipei Society for the Study of
loss may help re-establish iron homoeostasis in people who are OW or obese.
Obesity (CTSSO), Taipei, Taiwan

Correspondence KEYWORDS
Dr. Jung-Su Chang, School of Nutrition and haemoglobin, iron, transferrin saturation, weight loss
Health Sciences, College of Nutrition, Taipei
Medical University, 250 Wu-Xing Street,
Taipei 11031, Taiwan.
Email: susanchang@tmu.edu.tw

Funding information
Ministry of Science and Technology, Taiwan,
Grant/Award Number: MOST107-2320-B-
038-010-MY3; Ministry of Education, Taiwan;
Taipei Medical University Hospital, Grant/
Award Number: 109TMU-TMUH-13

I-Chun Teng and Sung-Hui Tseng contributed equally to this work.

Obesity Reviews. 2020;1–16. wileyonlinelibrary.com/journal/obr © 2020 World Obesity Federation 1

2 TENG ET AL.
1 | I N T RO D UC TI O N
The double burden of obesity and iron deficiency (ID) are among the
1,2
most common nutritional disorders in the world. A systematic review
and meta-analysis showed that people who were overweight (OW) or
obese had lower circulating iron concentrations (weighted mean differ-
ence [WMD]: iron: −8.37 μg/dl; 95% confidence interval [CI]: −11.38,
−5.36 μg/dl; percentage transferrin saturation [%TS]: −2.34%, 95% CI:
−3.29%, −1.4%) and a 1.31-fold (95% CI: 1.01, 1.68) higher risk of
developing ID compared with normal weight.3 This is in line with the
4,5
current view that obesity is an emerging risk factor for ID.
ID may progress to anaemia if iron stores are depleted.6 Multiple
aetiologies may coexist in an individual patient, and different types or
stages of ID or iron-deficiency anaemia (IDA) have been reported.7
First, absolute or true ID refers to a decreased level of total body iron
stores (indicated as serum ferritin of <30 ng/ml) in the absence of
inflammation.7 A diagnosis of absolute ID/IDA is relatively easy, as it
is commonly linked to an inadequate iron intake, increased iron
requirements, malabsorption or malnutrition.8 In contrast, functional
ID or IDA (also referred to as iron-restricted erythropoiesis)9 indicates
insufficient mobilization of iron from iron stores (e.g., the liver and
macrophages) to the circulation, causing the supply of iron for meet-
7
ing daily bone marrow requirements to become limiting. This condi-
tion is commonly seen in patients with chronic inflammation such as
obesity or obesity-related co-morbidities. Hence, functional IDA is
also termed anaemia of inflammation (AI) (also known as anaemia of
6,10
chronic disease [ACD]).
The subclinical syndrome of functional IDA differs from absolute
IDA by which functional IDA is characterized by low circulating iron
despite adequate iron stores (indicated by elevated serum ferritin or
liver iron) together with mild to moderate anaemia (haemoglobin
[Hb] rarely <8 g/dl).6 The hallmark of obesity-related ID is an alteration
of the tissue iron efflux (e.g., decreased intestinal iron absorption and
inhibition of the release of stored iron to peripheral areas) due to the
inflammation-driven upregulation of hepcidin, which causes degrada-
tion of the iron exporter membrane protein, ferroportin.11 Hence,
patients with obesity may progress from functional ID to AI/ACD as
the disease progresses and inflammation becomes more severe. In
addition, decreasing the delivery of iron from macrophages might not
only cause hypoferremia, but the trapped iron may also precipitate in
tissue-resident macrophages leading to an iron overload in tissues.12,13
Overall, iron dysregulation in obesity may result in two distinct patho-
physiological effects on the body's iron status, with high-iron-demand
organs like bone marrow being deprived of systemic iron; on the other
hand, iron-storage organs like the liver may be overloaded with trapped
iron leading to an increased risk of tissue iron overload.
For several decades, a hypocaloric diet or the combination of a
hypocaloric diet and exercise/physical activity has been used in
practice to induce weight loss, and >5% of initial body weight
(BW) loss is known to improve cardiometabolic profiles and reduce
14–17
proinflammatory cytokines and hepcidin. It was suggested that
a healthy mode of weight loss is accompanied by reductions in
inflammatory biomarkers and hepcidin levels, which, in turn, may
help re-establish physiological iron homoeostasis in patients who
were OW or obese through improving intestinal iron absorption and
intracellular iron efflux.4 Currently, data on the effects of
hypocaloric diet-induced weight loss on the body's iron status are
scarce, and results are inconsistent. Some studies showed that
energy restrictions decreased serum iron levels,18–21 while others
showed increased circulating iron in response to a hypocaloric
diet16,22,23 or exercise/physical activity.17,24 The broad aim of this
systematic review and meta-analysis was to investigate whether
diet-induced weight loss has beneficial effects on the systemic iron
status (indicated by Hb, iron, ferritin and %TS) in patients with obe-
sity. We also performed a meta-regression analysis to identify con-
founding factors (e.g., age, gender, intervention duration, type of
dietary programme and study design, and changes in the body mass
index [BMI] and BW) that may affect outcomes.
2 | METHODS
This systematic review and meta-analysis were conducted according
to guidelines of Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) recommendations.25 The review was
registered in the PROSPERO International Prospective Register of
Systematic Reviews as #CRD42020158026 (https://www.crd.york.ac.
uk/prospero), and confirmation should be forthcoming soon.
2.1 | Search question
This study posed the question: in children, adolescents, and adults
with unhealthy weight (OW or obesity), does weight loss induced by a
‘hypocaloric diet’ or the combination of a ‘hypocaloric diet and life-
style modification’ or ‘exercise/physical activity’ result in changes in
the body's iron status (indicated by Hb, iron, ferritin and %TS) in ran-
domized controlled trials (RCTs) or longitudinal studies?
2.2 | Data sources and search strategy
A systematic literature search was performed in March to July 2019
using PubMed, Medline, Embase, Web of Science and the Cochrane
Library. An additional literature search was performed using refer-
ences of retrieved papers. The search was restricted to the English
language and human subjects. No restriction on the publication date
was applied. The search was conducted using the keywords: ‘iron’ OR
‘hepatic iron’ OR ‘transferrin saturation’ OR ‘ferritin’ OR ‘hemoglobin’
OR ‘hepcidin’ OR ‘interleukin-6’ AND ‘weight loss’ OR ‘weight reduc-
tion’ OR ‘change in body weight’ AND ‘hypocaloric diet’ OR ‘diet’ OR
‘lifestyle modification’ OR ‘physical activity’ OR ‘exercise’ AND ‘ran-
domized control trial’ OR ‘longitudinal study’.
2.3 | Inclusion and exclusion criteria
Search questions were based on the PICO framework listed below.
Briefly, studies were included if they met the following criteria.
TENG ET AL.
1. An original research article published in a peer-reviewed journal.
2. Population: children, adolescents or adults who were OW or obese
and who participated in a weight-reduction programme. Being OW
or obese was reported by the authors according to World Health
Organization (WHO) guidelines1 or the National Cholesterol Edu-
cation Program-Third Adult Treatment Panel (NCEP:ATPIII) criteria
for metabolic syndrome (MetS).26 Briefly, adults aged 18 years or
older who were OW (BMI 25–29.9 kg/m2 or BMI 24–26.9 kg/m2)
or obese (BMI ≥30 kg/m2 or BMI ≥27 kg/m2) or with a mean BMI
of ≥25 kg/m2 were included in the meta-analysis. For children and
adolescents, being OW (BMI ≥85th–94th percentile or BMI for
age Z score [BAZ] of >1 to ≤2 standard deviations [SDs]) and
obese (BMI ≥95th percentile or BAZ of >2 SDs) were defined in
age- and sex-specific manners.27
3. Intervention: weight-reduction programmes involving a
‘hypocaloric diet’ or ‘lifestyle modification (a combination of nutri-
tional education and physical activity or exercise)’ over a period of
at least 1 month in an RCT or longitudinal study.
4. Comparison: the effects of a ‘hypocaloric diet’ or ‘a combination of
physical activity and nutritional education’ or ‘exercise and nutri-
tional education’ on changes in the body's iron status. In the sub-
group analysis, we also compared types of programmes (standard
hypocaloric diet vs. alternative hypocaloric diet [e.g., a high-protein
diet, high-fat and low-carbohydrate diet, a diet high in cereals or
vegetables and a calorie-restricted meal replacement with fish-oil
supplementation] vs. physical activity/exercise), and study design
(longitudinal vs. RCT) on changes in iron biomarkers (Hb, serum
iron, ferritin, %TS and hepcidin), and the proinflammatory cytokine,
interleukin (IL)-6. The ‘standard hypocaloric diet’ was defined as
45%–65% carbohydrates, 10%–20% protein and <30% fat,28 with
23
the exception of a study by Kaner et al. which had a high protein
ratio (macronutrient ratio: 55%–60% carbohydrates, 25%–30%
protein and 12%–15% fat) based on the Dietary Guidelines of Tur-
key for adults. Details of the study characteristics and dietary
intervention programmes are presented in Table S1.
5. Outcomes: intervention outcomes included changes in BW or the
BMI and iron indices.
Articles were excluded if they did not meet the predefined inclu-
sion criteria, were not a human study, the full-text was unavailable
(e.g., only a protocol or an abstract), were duplicate studies, used
drugs or vitamin and mineral supplementation or lacked information
on iron parameters before and after the intervention.
2.4 | Data extraction and study quality assessment
Data extraction was performed by one author (ICT) and checked by
another (BA). Retrieved records were sent to Endnote® (vers. 9.3; ©
2019 Clarivate), where duplicates were removed. Data extracted
included baseline characteristics, changes in BW/BMI, iron indices
and IL-6. Study characteristics included the name of the first author,
year of the study, sample size, percentage of females, participants'
3
ages (mean and range), mean BW, mean BMI, the duration of weight
loss, type of hypocaloric diet (standard or alternative), study design
(longitudinal or RCT), and mean changes in BW and iron biomarkers
before and after the intervention.
Study quality was evaluated by three independent researchers
(SHT, CHB and CKS) using the Effective Public Health Practice Project
(EPHPP) Quality Assessment Tool for Quantitative Studies. The
EPHPP, originally created in 1999 by Helen Thomas and Dr. Donna
Ciliska, consists of six domains: study bias, study design, confounders,
blinding, data collection methods, and withdrawals and dropouts.29
Each domain is rated as strong (3 points), moderate (2 points) and
weak (1 point), and domain scores are averaged to provide a total
score. The overall quality of a study can be rated as strong, moderate
or low.30
2.5 | Data analysis
A meta-analysis was conducted using R Studio (vers. 1.0, RStudio,
Boston, MA, USA). A DerSimonian-Laird random-effects model was
used to calculate pooled and subgroup effects (within group) of
weight loss on iron parameters before and after the intervention.
Random-effects models were shown to yield more accurate results
compared with fixed-effects models because they do not assume zero
variability across studies.31 Between-study heterogeneity was evalu-
ated using the Cochrane Q-test, and data were reported as tau2, Chi2
and I2. An I2 value of 0% indicates no observed heterogeneity, and
larger values suggest increasing heterogeneity between studies, with
25%, 50% and 75%, respectively, indicating low, moderate and high
heterogeneity.32 A meta-regression analysis was performed to iden-
tify potential confounders (e.g., baseline BMI, BMI changes, gender,
age, type of programme and intervention duration) that may have
affected the primary outcome (changes in the iron status).
Mean changes (SD) of BW, BMI and iron indices (Hb, iron, ferritin
and %TS) from the baseline to the endpoint were calculated as ‘the
end of intervention value minus the baseline value’. The primary out-
comes (changes in the iron status) and secondary outcomes (changes
in BW, hepcidin and IL-6) were reported as WMDs with 95% CIs. For
the pooled analysis, if an examined study contained multiple dietary
intervention programmes, the mean and SD estimates for weight
change (kilogramme) and iron changes (Hb, iron, %TS and ferritin) for
those intervention arms were pooled to yield one mean and SD esti-
mate. A subgroup analysis was performed to determine the impact of
the dietary design (e.g., standard vs. alternative hypocaloric diet) and
trial design (e.g., RCT vs. longitudinal study) on changes in the iron sta-
tus. When a study contributed more than one arm of a dietary inter-
vention, the actual population number for that arm was used for the
subgroup meta-analysis to avoid double counting. We also excluded
those who did not complete the intervention (e.g., dropouts or with-
drawals). So the actual population numbers also indicated those par-
ticipants who successfully completed the intervention. Sensitivity
analyses were conducted in relation to all outcomes by omitting one
study at a time to evaluate potential sources of heterogeneity across
4 TENG ET AL.
studies. Outliers were defined as studies outside the pseudo 95% CI
of a funnel plot. Publication bias was examined by visually inspecting
the funnel plot, and Egger's test p values of <0.1 were considered sta-
tistically significant.
3 | RESULTS
A PRISMA flow diagram demonstrates how studies were identified
and selected (Figure 1). The initial search identified 7581 electronic
papers through online databases. After removing duplicates
(n = 1253) and irrelevant topics (n = 5364), we screened 964 studies
by title and abstract; 825 articles were excluded for various reasons,
such as patients with other diseases or treatments (e.g., cancer, sar-
copenia, celiac disease, osteoarthritis and bariatric surgery), preg-
nancy, animal study or use of vitamin and mineral supplements or
drugs. We next retrieved 139 potentially eligible articles for full-text
screening, among which 125 studies were further excluded as they
did not fulfil our predefined criteria, such as subjects were not
FIGURE 1 Plasma flowchart illustrating the study selection process
OW/obese, not a weight-loss study, not a human study, not an RCT
or longitudinal trial, no information on changes of iron biomarkers, a
review article, or the full text was unavailable. Overall, 14 studies
were selected for the systematic review and meta-analysis, of which
six were longitudinal studies and eight were RCTs.
3.1 | Quality assessment
The methodological quality of all the included studies (n = 14) were
evaluated using the EPHPP tool. The overall quality of the 14 studies
ranged from strong to weak with three studies rated as strong, six as
moderate and five as weak (Table 1). The strongest ratings were found
for the components of selection bias (13 strong and one weak22), con-
founders, study design (11 strong, one moderate19 and two weak20,23)
and data collection methods (14 strong). However, bias was fre-
quently assessed as unclear for blinding, intervention integrity, and
withdrawals and dropouts, as those were often not described in the
text, or a study had a low follow-up rate.
TENG ET AL. 5

TABLE 1 Quality assessment of the included 14 studies using the Effective Public Health Practice Project (EPHPP) tool

Selection Study Data collection Withdrawals and Global

Study bias design Confounders Blinding methods dropouts score
Moreno-Navarrete et al. Strong Moderate Strong Moderate Strong Strong Strong
(2016)14
Kaner et al. (2019)23 Strong Moderate Weak Weak Strong Strong Weak
Guglielmi et al. (2015)19 Strong Weak Moderate Weak Strong Weak Weak
Noakes et al. (2005)21 Strong Strong Strong Weak Strong Strong Moderate
Griffin et al. (2012)22 Weak Strong Strong Moderate Strong Weak Weak
Cheng et al. (2013)33 Strong Strong Strong Moderate Strong Weak Moderate
Huang et al. (2018)15 Strong Strong Strong Moderate Strong Strong Strong
20
Kretsch et al. (1998) Strong Moderate Weak Weak Strong Weak Weak
Rodriguez et al. (2007)34 Strong Strong Strong Weak Strong Strong Moderate
35
Lim et al. (2011) Strong Strong Strong Strong Strong Weak Moderate
Bijeh et al. (2012)36 Strong Strong Strong Weak Strong Weak Weak
Amato et al. (2010)16 Strong Moderate Strong Weak Strong Strong Moderate
Gong et al. (2014)24 Strong Strong Strong Moderate Strong Strong Strong
17
Coimbra et al. (2017) Strong Moderate Strong Weak Strong Strong Moderate

3.2 | Characteristics of included studies
Table 2 describes the general characteristics of study participants
from the 14 studies. In total, 879 subjects who were OW or obese
(mean BMI: 31.8 ± 4.17 kg/m2, 82% females) were included, of which
660 were adults (mean BMI: 32.9 ± 4.23 kg/m2) and 219 were chil-
dren and adolescents (mean BMI: 25.2 ± 3.83 kg/m2). Eight
studies15,21,22,24,33–36 (57.1%) were RCTs and six studies14,16,17,19,20,23
14,16,17,19,20,23
(42.9%) were longitudinal studies. In adults, 10 studies
(10/11) employed hypocaloric diet-induced weight loss, with the
exception of one study that used exercise as a stand-alone weight-
loss programme.36 In children and adolescents, two studies used life-
style modifications (a combination of nutritional education and physi-
cal activity or exercise),17,24 and one study used a standard
hypocaloric diet (60% energy of the recommended dietary allowance
for age and sex: 50% carbohydrates, 20% protein and 21% fat).16
36
However, subjects enrolled in exercise or a combination of
exercise/physical activity and lifestyle modification17,24 did not have
restricted energy intake.
The majority of studies reported baseline and endpoint values of
serum ferritin (14/14), serum iron (12/14), %TS (11/14), Hb (11/14),
BW (13/14) and BMI (11/14). However, only four studies reported
serum hepcidin (4/14) and IL-6 (4/14) concentrations.15–17,24 The
range of the intervention duration was 1.5–24 months (adults: 1.5 to
24 months, children: 6 to 12 months), and the ranges of reductions in
BW and BMI were −14.9 to 4.7 kg (adults: −14.9 to −0.15 kg, chil-
dren: −3.8 to 4.7 kg) and −4.5 to 0.4 kg/m2 (adults: −4.5 to
−0.51 kg/m2, children: −3.4 to 0.4 kg/m2), respectively. The range of
changes in iron biomarkers were Hb: 6 to −4 g/dl (adults: 4 to
−4 g/dl, children: 6–1 g/dl), %TS: 4.7% to −0.59% (adults: 4% to
−0.59%, children: 4.7%–2.25%), iron: 3.34 to −3.12 μmol/L (adults:
2.01 to −3.12 μmol/L, children: 3.34–1.52 μmol/L) and serum ferritin:
22 to −106.1 μg/L (adults: 22 to −106.1 μg/L, children: −2.5 to
−3.5 μg/L).
3.3 | Meta-analysis of the WMDs of BW and iron
biomarkers
A meta-analysis of the overall WMDs for BW and BMI showed a sig-
nificant reduction in BW (WMD = −4.60 kg, 95% CI: −6.74, −2.47 kg;
I2 = 86%) and BMI (WMD = −1.32 kg/m2, 95% CI: −2.14,
−0.50 kg/m2; I2 = 82%) (pooled analysis; Figure S1). Heterogeneity
was high, but no publication bias was detected as Egger's regression
test remained nonsignificant (all p > 0.1; Figure S1). We did not per-
form a meta-analysis on changes in hepcidin and IL-6 due to the lim-
ited study number (n = 4) and diverse study designs and populations.
3.3.1 | Haemoglobin
A meta-analysis of the overall WMD in Hb showed a nonsignificant
trend towards increased Hb levels (WMD = 0.82 g/dl, 95% CI: −0.59,
2.22 g/dl) (pooled analysis; Figure 2). Heterogeneity was very high
(I2 = 91%), indicating variability across the studies. We next performed
a subgroup analysis according to the type of study design (longitudinal
vs. RCT) and dietary programme. A significant increase in the Hb level
was found in longitudinal studies with low heterogeneity
(WMD = 2.50 g/dl, 95% CI: 0.88, 4.12 g/dl; I2 = 14%) but not in RCTs
(WMD = 0.31 g/dl, 95% CI: −1.42, 2.03 g/dl; I2 = 93%) (Figure 2A). A
univariate meta-regression analysis found that in RCTs, the WMD of
Hb was positively correlated with the mean BW change (ß = 0.287,
 6

TABLE 2 Characteristics and outcomes of the iron biomarkers of weight-reduction studies according to the age group of study participants (N = 879)

Mean age n (%, Mean weight change, kg

Authors (year) (years) female) Study design (duration) Programme Group (95% CI)
Adults (N = 660)
Moreno-Navarrete et al. 54.4 16 (69%) Longitudinal (24 Mon) Standard hypocaloric diet + exercise - -
(2016)14
Kaner et al. (2019)23 - 147 (100%) Longitudinal (3 Mon) Standard hypocaloric diet - −9 (−12.84, −5.16)
19
Guglielmi et al. (2015) 35.0 91 x(66%) Longitudinal (3, 6, 12 Standard hypocaloric diet + exercise Premenopausal −6.7 (−15.22, 1.82)
Mon) women
60.7 Postmenopausal 6.5 (−2.56, 15.56)
women
49.2 Men −14.9 (−23.32, −6.48)
Noakes et al. (2005)21 - 100 (100%) RCT (3 Mon) Standard hypocaloric diet (control) Control −5.4 (−9.01, −1.79)
Alternative hypocaloric diet (high-protein diet) High protein −6.8 (−10.23, −3.37)
Griffin et al. (2012)22 22.4 36 (100%) RCT (6, 12 Mon) Standard hypocaloric diet (control) Control −4.1 (−6.49, −1.71)
22.1 Alternative hypocaloric diet (high protein diet) High protein −9.6 (−12.42, −6.78)
Cheng et al. (2013)33 22.4 36 (100%) RCT (6, 12 mon) Standard hypocaloric diet (control) Control −4.3 (−11.05, 2.45)
22.1 Alternative hypocaloric diet (high-protein diet) High protein −9.4 (−15.96, −2.84)
Huang et al. (2018)15 48.3 93 (73%) RCT (3 Mon) Standard hypocaloric diet (CRMR) CRMR −5.9 (−11.93, 0.13)
49.7 Alternative hypocaloric diet (CRMRF) CRMRF −4.4 (−11.2, 2.4)
Kretsch et al. (1998)20 - 14 (100%) Longitudinal (5, 10, Alternative hypocaloric diet (high fat and low - −12.3 (−19.12, −5.48)
15 weeks) carbohydrates)
Rodriguez et al. (2007)34 - 57 (100%) RCT (2, 6 weeks) Alternative hypocaloric diet (high cereal) High cereal −2.78 (−8.3, 2.74)
Alternative hypocaloric diet (high vegetable) High vegetable −2.01 (−5.81, 1.79)
Lim et al. (2011)35 28.0 59 (100%) RCT (3 Mon) Alternative hypocaloric diet (high protein) + exercise - −5.1 (−5.79, −4.41)
36
Bijeh et al. (2012) 41.2 11 (%) RCT (6 Mon) Exercise programme - −0.15 (−4.99, 4.69)
Children and adolescents (N = 219)
Amato et al. (2010)16 12.4 15 (53%) Longitudinal (6 Mon) Standard hypocaloric diet - −3.8 (−13.86, 6.26)
Gong et al. (2014)24 9.3 160 (40%) RCT (12 Mon) Lifestyle modification + increased physical activity - 4.7 (2.73, 6.67)
17
Coimbra et al. (2017) 9.1 44 (45%) Longitudinal (8 Mon) Exercise + lifestyle modification - 0.9 (−4.7, 6.5)

Abbreviations: CI, confidence interval; CRMR, calorie-restricted meal replacement; CRMRF, calorie-restricted meal replacement with fish-oil supplementation; IL, interleukin; RCT, randomized control trial.
TENG ET AL.
TABLE 2 (Continued)
Authors (year)
TABLE 2 Continued
Authors (year)
Adults (N = 660)
Moreno-Navarrete et al.
(2016)14
Kaner et al. (2019)23
19
Guglielmi et al. (2015)
Noakes et al. (2005)21
Griffin et al. (2012)22
Cheng et al. (2013)33
Huang et al. (2018)15
Kretsch et al. (1998)20
34
Rodriguez et al. (2007)
Lim et al. (2011)35
Bijeh et al. (2012)36
Children and adolescents (N = 219)
Amato et al. (2010)16
24
Gong et al. (2014)
Coimbra et al. (2017)17
Abbreviations: CI, confidence interval; CRMR, calorie-restricted meal replacement; CRMRF, calorie-restricted meal replacement with fish-oil supplementation; IL, interleukin; RCT, randomized control trial.
Mean age n (%, Mean weight change, kg
TENG ET AL.
(years) female) Study design (duration) Programme Group (95% CI)
Mean transferrin saturation change, Mean serum ferritin change, Mean haemoglobin change, g/L Mean hepcidin change, ng/ml Mean IL-6 change, pg/ml
% (95% CI) μg/L (95% CI) (95% CI) (95% CI) (95% CI)
- −8 (−46.11, 30.11) 1 (−8.11, 10.11) −66 (−127.58, −4.42) -
2.6 (0.3, 4.9) 2.6 (0.08, 5.12) 4 (2.16, 5.84) - -
- 1 (−10.31, 12.31) - - -
- 19.5 (−26.29, 65.29) - - -
- −106.1 (−149.27, −62.93) - - -
0.9 (0.4, 1.4) 7 (2.76, 11.24) 0 (−0.4, 0.4) - -
0.7 (0.2, 1.2) 15 (7.23, 22.77) 0 (−0.4, 0.4) - -
0 (−4.21, 4.21) −4 (−10.65, 2.65) −4 (−6.26, −1.74) - -
4 (1.94, 6.06) 13 (6.31, 19.69) 0 (−1.97, 1.97) - -
−0.4 (−9.69, 8.89) −2.25 (−17.53, 13.03) −4 (−9.59, 1.59) - -
3.2 (−1.94, 8.34) 22 (−0.55, 44.55) 0 (−6.17, 6.17) - -
−0.59 (−4.92, 3.74) −8.4 (−49.67, 32.87) 0.7 (−9.06, 10.46) −3.7 (−9.73, 2.33) −1.14 (−1.77, −0.51)
0.91 (−3.49, 5.31) 0.5 (−52.22, 53.22) −0.7 (−6.9, 5.5) −11.3 (−16.21, −6.39) −2.04 (−2.84, −1.24)
1.9 (−4.23, 8.03) 4.2 (−14.4, 22.8) 0 (−4.22, 4.22) - -
1.2 (−7.68, 10.08) −1.3 (−16.08, 13.48) 1 (−4.69, 6.69) - -
3.2 (−5.92, 12.32) −2 (−19.79, 15.79) −1 (−5.71, 3.71) - -
- −4.99 (−5.01, −4.97) - - -
- −3.36 (−7.89, 1.17) - - -
4.5 (−1.34, 10.34) −2.5 (−9.73, 4.73) 2 (−1.65, 5.65) −279 (−478.6, −79.4) −0.5 (−1.37, 0.37)
4.7 (1.72, 7.68) −3 (−7.13, 1.13) 6 (2.68, 9.32) - −0.3 (−0.61, 0.01)
2.25 (1.09, 3.41) −3.5 (−12.83, 5.83) 1 (−2.56, 4.56) −5 (−9.72, −0.28) −0.23 (−0.43, −0.03)
7
8 TENG ET AL.

F I G U R E 2 Forest plot of weighted mean differences (WMDs) of changes in haemoglobin stratified by the (A) study design and (B) type of
weight-reduction programme

p = 0.030) but was negatively correlated with the baseline mean BMI
(ß = −0.5109, p = 0.030) and percent females (ß = −0.0956,
p = 0.039) (Table S2B).
We also assessed the effects of dietary programmes on the Hb
status after weight loss. Despite a trend towards the right-hand side
of the forest plot (indicating an increased WMD of Hb), no differences
were found according to the type of dietary programme: alternative
hypocaloric diet (WMD = 0.87 g/dl, 95% CI: −1.01, 2.74 g/dl;
I2 = 61%), exercise/physical activity and lifestyle modification
(WMD = 3.54 g/dl, 95% CI: −1.36, 8.44 g/dl; I2 = 75%) or standard
TENG ET AL. 9

hypocaloric diet (WMD = 0.03 g/dl, 95% CI: −2.34, 2.40 g/dl;
I2 = 82%) (Figure 2B). The univariate meta-regression analysis found
that compared with a standard hypocaloric diet, exercise/physical
activity (ß = 7.86, p = 0.007) and, to a lesser extent, the alternative
hypocaloric diet (ß = 2.8, p = 0.06) were positively correlated with the
WMD in Hb levels (Table S2B).
3.3.2 | Transferrin saturation (%TS)
A meta-analysis of the overall WMD for %TS showed a significant
increase (WMD = 1.68%, 95% CI: 0.97%, 2.39%; I2 = 44%), with mod-
erate heterogeneity (pooled analysis; Figure 3). An increase in circulat-
ing TS after weight loss was also observed in all subgroup analyses:

F I G U R E 3 Forest plot of weighted mean differences (WMDs) of changes in transferrin saturation stratified by the (A) study design and
(B) type of weight-reduction programme
10 TENG ET AL.

longitudinal studies (WMD = 2.37%, 95% CI: 1.37%, 3.38%; I2 = 0%)
(Figure 3A), RCTs (WMD = 1.37%, 95% CI: 0.59%, 2.15%; I2 = 42%)
(Figure 3A), an alternative hypocaloric diet (WMD = 1.96%, 95% CI:
2
0.31%, 3.62%; I = 43%) (Figure 3B), exercise/physical activity and
lifestyle modification (WMD = 3.07%, 95% CI: 0.81%, 5.34%;
I2 = 56%) (Figure 3B) or a standard hypocaloric diet (WMD = 0.96%,
95% CI: 0.48%, 1.45%; I2 = 0%) (Figure 3B). A univariate meta-
regression analysis of RCTs found significant positive correlations

F I G U R E 4 Forest plot of weighted mean differences (WMDs) of changes in serum iron stratified by the (A) study design and (B) type of
weight-reduction programme
TENG ET AL.
between the WMD of %TS and the intervention duration (ß = 0.0745,
p = 0.0015) and changes in the mean BMI (ß = 1.965, p = 0.0012) (-
Table S2). A multivariate meta-regression analysis showed that after
adjusting for the intervention duration, a change in the BMI was an
independent predictor of %TS (ß = 2.169, p = 0.048) (Table S2C).
3.3.3 | Serum iron
No significant differences were found in the pooled WMD of serum
iron levels (WMD = 0.06 μmol/L, 95% CI: −0.69, 0.81 μmol/L;
I2 = 85%) (pooled analysis; Figure 4A,B) or in the subgroup analysis,
except exercise/physical activity and lifestyle modification, which
showed increased serum iron levels after weight
(WMD = 1.58 μmol/L, 95% CI: 0.84, 2.31 μmol/L; I = 0%) (Figure 4B).
2
A pooled univariate meta-regression analysis found that age
(ß = −0.0582, p = 0.0046) and, to a lesser extent, the mean baseline
BMI (ß = −0.1246, p = 0.071) were negatively correlated with the
WMD of serum iron (Table S2A). A subgroup analysis found signifi-
cant positive correlations in RCTs between the WMDs of serum iron
and the intervention duration (ß = 0.077, p = 0.001) and mean BMI
change (ß = 0.901, p = 0.046), and a weak correlation with age
(ß = −0.052, p = 0.068) (Table S2B).
3.3.4 | Serum ferritin
No significant differences were found in the overall WMD of serum
ferritin levels (WMD = 0.90 g/L, 95% CI: −2.74, 4.55 g/L; I2 = 86%)
(pooled analysis; Figure 5) or in the subgroup analysis (Figure 5A,B).
3.4 | Publication bias and sensitivity analysis
To evaluate publication bias, we examined the presence of funnel
plot asymmetry and performed Egger's regression test for each iron
index. Egger's test showed nonsignificant publication bias for (A) Hb
(t = −0.544, p = 0.595) and significant bias for (B) %TS (t = 1.995,
p = 0.067), (C) serum iron (t = 2.67, p = 0.016), and (D) serum ferri-
tin (t = 2.566, p = 0.019) (Figure 6). A visual inspection of the fun-
nel plot of the WMD of %TS indicated that Gong et al.'s24 and
Griffin et al.'s22 studies were outside the pseudo 95% CI of the fun-
nel plot (Figure 6B). We next conducted a sensitivity analysis to
evaluate the overall impact of outliers on %TS. After excluding Gong
et al.'s study,24 the pooled WMD of %TS remained significant
(WMD = 1.43, 95% CI: 0.81, 2.04) with low heterogeneity
2
(I = 32%), and Egger's test was nonsignificant (t = 1.65, p = 0.1248)
(Figure S2A–C). A very similar result was found after excluding Grif-
fin et al.'s22 study19 (WMD = 1.29, 95% CI: 0.73, 1.85; I2 = 23%)
(D–F) or both Gong et al.'s24 and Griffin et al.'s22 studies19
2
(WMD = 0.97, 95% CI: 0.64, 1.30; I = 0%), and Egger's test indi-
cated nonsignificant publication bias (G–I) (Figure S2).
11
A visual inspection of the funnel plots of the WMD of serum iron
(Figure 6C) and ferritin (Figure 6D) showed asymmetry, which was
also confirmed by Egger's test, suggesting the presence of publication
bias. A sensitivity analysis of the WMD of serum iron showed that
after excluding all outliers (iron: n = 6 and ferritin: n = 5 arms of stud-
ies), the WMDs of iron (WMD = −1.32, 95% CI: −1.56, −1.08;
I2 = 0%) (Figure S3) and ferritin (WMD = −4.99, 95% CI: −5.01,
−4.97; I2 = 0%) were significantly reduced after weight loss (Figure S4).
However, Egger's test remained significant, suggesting strong publica-
tion bias affecting serum iron and ferritin levels even after the exclu-
sion of outliers.
loss 4 | DISCUSSION
Over the past few decades, only 14 papers have investigated the
effects of hypocaloric diet-induced weight loss on the iron status,
highlighting limited research in this field. The current meta-analysis of
14 articles suggested that weight loss, specifically diet-induced weight
loss, has beneficial effects of raising bioavailable iron (as indicated by
%TS) and to a lesser extent, Hb. Specifically, we found that, after
weight loss, %TS had increased by 1.68% (95% CI: 0.97%, 2.39%),
with the greatest effects found in longitudinal studies (WMD: 2.37%,
95% CI: 1.37%, 3.38%) and with an alternative hypocaloric diet
(WMD: 1.96%, 95% CI: 0.31%, 3.62%). This has important clinical
implications as %TS not only indicates the body's iron status but also
reflects the erythropoiesis balance between iron release by the reticu-
loendothelial system and iron uptake by bone marrow. In adults with
normal iron homoeostasis, the transferrin-bound iron pool in plasma is
approximately 3 mg, and this pool has >8- to 10-fold turnover rate
per day, resulting in approximately 20–30 mg of transferrin-bound
iron being delivered to developing erythroblasts or iron-demanding
tissues.37,38 Our study found that weight loss resulted in a 1.68%
increase in transferrin iron-binding sites being occupied by iron. With
a total of the transferrin-bound iron pool of 30 mg and one third of
transferrin (20%–40%) being saturated with iron,39 this suggests that
an additional 1–3 mg of transferrin-bound iron may become bioavail-
able for the body after weight loss. Our finding is in agreement with
Zhao et al.'s meta-analysis,3 which showed that patients who were
OW or obese had a 2.34% decrease in %TS (WMD: −2.34%, 95% CI:
−3.29%, −1.40%) compared with normal-weight individuals. Based on
this result, it is tempting to suggest that diet-induced weight loss may
improve bioavailable iron to levels that are similar to people who are
normal weight. However, it is difficult to estimate the clinical signifi-
cance of a 1.68% increase in %TS after weight loss as iron has diverse
biological functions. Emerging evidence suggests that ID alone can
cause symptoms in the absence of anaemia. This observation is
supported by recent evidence-based studies that showed that iron
supplementation was associated with reduced self-reported fatigue in
nonanaemic ID patients.40–42 Overall, our data suggested that in spite
of energy restrictions, weight loss may help re-establish physiological
iron homoeostasis in people who are OW or obese.
12 TENG ET AL.

F I G U R E 5 Forest plot of weighted mean differences (WMDs) of changes in serum ferritin stratified by the (A) study design and (B) type of
weight-reduction programme

Despite the increasing worldwide prevalence of obesity and ID,
there are still no guidelines on how to treat and manage obesity-
related ID or AI/ACD. Currently, iron supplementation remains the
standard treatment method despite numerous studies having shown
that people who are OW or obese have a diminished response to oral
iron therapy.43–45 Furthermore, patients with metabolic dysfunction
are frequently associated with tissue iron overload, and oral iron ther-
apy may further increase the risk of tissue iron overload.46,47 For clini-
cians who treat patients with obesity and ID, our meta-analytical
results suggest that an effective weight loss programme to re-
establish iron homoeostasis in patients who are OW or obese may
require (1) ≥5 months of a weight-management intervention (range
TENG ET AL.
F I G U R E 6 Funnel plot of mean differences in
(A) haemoglobin, (B) transferrin saturation, (C) serum iron,
and (D) ferritin, and standard errors of studies included in
the meta-analysis
for the alternative hypocaloric diet was 12–1.5 months and that for
longitudinal studies was 24–3 months), (2) achieving greater than 6 kg
of weight loss or a reduction in BMI of ≥−1.76 kg/m2 and, to a lesser
extent, (3) use of an alternative hypocaloric diet for adults or
exercise/physical activity for children. Both the length of the interven-
tion and effective weight loss may act as the most important modula-
tors for re-establishing iron homoeostasis among patients with
unhealthy weight. Because the number of studies with an alternative
hypocaloric diet was quite small with diverse designs, it was difficult
to draw firm conclusions as to which alternative hypocaloric diet was
more advantageous compared with a standard hypocaloric diet in
improving iron homoeostasis. Exercise/physical activity also had a
beneficial effect on the iron status, but those studies did not control
for energy intake because subjects were children.17,24
13
Another challenge for clinicians and dieticians is the lack of con-
sensus on the diagnosis of functional ID or AI/ACD for patients with
obesity or obesity-related co-morbidities. Currently, most of the liter-
ature follows guidelines of the WHO, which defines absolute ID/IDA
as serum ferritin of <12 or <15 ng/ml, %TS of <16% and Hb of <13
and <12 g/dl for adult men and women, respectively.48 However, this
definition is inadequate for patients with chronic inflammation, as
serum ferritin concentrations tend to increase in that situation. The
international consensus statement on the perioperative management
of anaemia and ID proposed that (1) anaemia be defined as Hb of
<13 g/dl, (2) absolute ID as serum ferritin of <30 ng/ml, (3) AI/ACD
with functional ID as serum ferritin of 30–100 ng/ml, %TS of <20% or
C-reactive protein of >5 mg/ml and (4) AI/ACD as serum ferritin of
>100 ng/ml, %TS of <20% or C-reactive protein of >5 mg/ml.49
14
Although serum iron, ferritin and %TS are standard iron biomarkers
for diagnosing ID, each of them has different physiological functions.
Our results also suggest that compared with TS, serum iron and ferri-
tin were less sensitive to weight loss, but the reason for this remains
unclear. For normal-weight subjects, serum ferritin is regarded as a
reliable indicator of body iron stores. However, serum ferritin may be
viewed as an acute-phase reactant for patients with obesity. It is well
known that inflammation upregulates ferritin synthesis, which raises
concerns about ferritin-based diagnoses of ID among patients with
obesity3 or inflammatory diseases.50 The serum iron concentration
3+
indicates the amount of ferric iron (Fe ) bound to serum transferrin,
but it is not a sensitive measure of ID, partly because of daily fluctua-
tions. Transferrin is the major iron transfer protein in the plasma, and
TS is the ratio of serum iron to the total iron-binding capacity (TIBC).
TS normally indicates the bioavailability of iron in the body, and a low-
level TS indicates an inadequate iron supply for erythropoiesis.
Although TS accounts for less than 0.1% of total body iron, it is very
dynamic and has a very high turnover rate to supply the iron demand
for erythropoiesis. Kamei et al. also showed that interassay variability
was small for TS (10%) and large for ferritin (60%).51
Results of this meta-analysis suggest that diet-induced weight
loss may improve iron delivery to the bone marrow to maintain effec-
tive erythropoiesis; however, results were heterogeneous, and caution
is needed when interpreting these results. High heterogeneity sug-
gests that the effects of diet-induced weight loss on the iron status
varied across studies. We were unable to explore causes of the het-
erogeneity due to the limited number of studies. However, the meta-
regression analysis identified several key factors that may affect over-
all outcomes. Factors such as a longitudinal study, changes in
BW/BMI and, to a lesser extent, an alternative hypocaloric diet or
exercise may have beneficial effects; in contrast, the baseline
BMI/BW, a female gender and age may reduce treatment effects. In
the pooled analysis, Hb had the highest heterogeneity (I2 = 91%),
followed by ferritin (I2 = 86%) and serum iron (I2 = 85%). In contrast,
2
%TS had the least heterogeneity (I = 44%). The subgroup analysis
showed substantially decreased heterogeneity, which suggests that
the study design is a potential confounder of the variation in treat-
ment outcomes. For example, longitudinal studies had the lowest het-
2 2
erogeneity across all iron parameters (Hb: I = 14%; %TS: I = 0%;
serum iron: I2 = 61%; serum ferritin: I2 = 66%) compared with RCTs
(Hb: I2 = 93%; %TS: I2 = 42%; serum iron: I2 = 81%; serum ferritin:
I2 = 87%). Publication bias may also have affected the heterogeneity
and overall outcomes. Egger's regression analysis suggested the pres-
ence of publication bias for %TS, serum iron and ferritin. The removal
of outliers by the sensitivity analysis substantially decreased the het-
erogeneity in %TS (I2 = 0%), serum iron (I2 = 0%) and ferritin (I2 = 0%),
but Egger's test remained significant for serum iron and ferritin.
There are several limitations and strengths in the current study.
The 14 studies included in our meta-analysis were heterogeneous
with respect to clinical heterogeneity (e.g., age, gender, BMI, trial
design, intervention programmes and duration) and statistical het-
erogeneity, which indicates variations in intervention effects. We
tried to minimize these effects by performing independent study
TENG ET AL.
quality assessments, stratifying data according to the type of study
design and intervention programmes and using a random-effects
model to assume heterogeneity. In addition, a meta-regression anal-
ysis was also employed to identify sources of heterogeneity.
Another limitation is that none of the selected studies was double-
blinded, as it was impossible to blind subjects and research staff to
the intervention. The wide range of weight loss (−14.9 to 4.7 kg), in
particular among children (adults: −14.9 to −0.15 kg, children: −3.8
to 4.7 kg), also contributed to the high heterogeneity and overall
effects. Strengths included this being the first meta-analysis to
investigate the effects of diet-induced weight loss on the iron sta-
tus, use of well-accepted iron biomarkers and inclusion of different
types of study designs (RCT: five study arms; longitudinal: 11 study
arms) and hypocaloric dietary programmes (standard: six study arms;
alternative: seven study arms). By presenting haematological iron
results as WMDs and not standardized mean differences, our study
provides a clearer estimation of systemic iron changes in response
to weight loss.
In conclusion, results of our meta-analysis support the idea that
diet-induced weight loss can produce beneficial effects on physiologi-
cal iron homoeostasis in patients with obesity. Several marginal or sig-
nificant modulators were also identified in this study. In particular,
effective weight loss and the intervention duration emerged as key
modulators for re-establishing bioavailable iron in patients who are
OW or obese. We also found that the baseline BW/BMI, age, female
gender and a standard hypocaloric diet may have adverse effects on
the iron status during weight loss. Given the high prevalence rate of
being OW/obese and the concomitant presence of ID and tissue iron
overload among patients with obesity, the current findings may help
clinicians and dieticians design effective weight-loss programmes that
not only aim for weight loss but also to re-establish bioavailable iron
in patients with obesity.
AC KNOWLEDG EME NT S
Dr. Jung-Su Chang was supported by grants from the Taipei Medical
University Hospital (109TMU-TMUH-13), the Ministry of Education,
Taiwan and the Ministry of Science and Technology, Taiwan
(MOST107-2320-B-038-010-MY3).
CONFLIC T OF INT ER E ST
No potential conflicts of interest are reported by any authors.
AUT HOR S' CONT R IBUT IONS
JSC conceived the topic and designed the review questions. SHT and
YCC designed the search strategy and interpreted the results. ICT per-
formed the literature search, data extraction and data analysis. ICT,
SHT, CHB and YCC performed the quality assessment. ICT performed
the data analysis. JSC drafted the paper, and all authors approved the
submitted paper.
OR CID
Jung-Su Chang https://orcid.org/0000-0001-8608-9349
TENG ET AL.
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SUPPORTING INF ORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Teng I-C, Tseng S-H, Aulia B,
Shih C-K, Bai C-H, Chang J-S. Can diet-induced weight loss
improve iron homoeostasis in patients with obesity: A
systematic review and meta-analysis. Obesity Reviews. 2020;
1–16. https://doi.org/10.1111/obr.13080