http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 854Gender Differences in the Association of Ferritin and 25-hydroxyvitamin D ANCA… [602643]

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 854Gender Differences in the Association of Ferritin and
25-hydroxyvitamin D
ANCA PANTEA STOIAN1*, CORNELIA BALA2, ADRIANA RUSU2, ANDRA SUCEVEANU3, DUMITRU CRISTINEL BADIU4,6,
CORNELIA NITIPIR4, GEORGIANA DITU5, CRISTINA BICA1, DAN NICOLAE PADURARU4, CRISTIAN SERAFINCEANU1
1Carol Davila, University of Medicine and Pharmacy, Department of Diabetes and Nutrition, 37 Dionisie Lupu, 030167, Bucharest,
Romania
2Iuliu Hatieganu, University of Medicine and Pharmacy, Department of Diabetes and Nutrition, 4 Louis Pasteur, 400349,
Cluj Napoca, Romania
3Ovidius University, Faculty of Medicine, 124 Mamaia Blvd., 900527, Constanta, Romania
4Carol Davila, University of Medicine and Pharmacy, 37 Dionisie Lupu, 030167, Bucharest, Romania
5Prof. Dr. Nicolae Paulescu, National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
6 Bagdasar Arseni, Clinical Emergency Hospital, Department of Surgery, 12 Berceni Road, 041915, Bucharest, Romania
This study aimed to investigate gender differences in the relationship between ferritin levels and 25(OH)vitamin
D deficiency in overweight persons and whether this relationship is mediated by total and visceral adiposity
and fatty liver index (FLI), a marker of non-alcoholic fatty liver disease.Our study was a retrospective one in
which were collecting data from 92 patients seen in an outpatient clinical centre between January 2011
and October 2017. Patients were classified with vitamin D deficiency if 25(OH)vitamin D levels were < 20.0
ng/mL. Univariate linear regression analysis assessed the association between ferritin levels and
25(OH)vitamin D deficiency, with and without correction for age, body composition (total fat mass and
visceral fat mass) and FLI. In men, a statistically significant positive association between 25(OH)vitamin D
deficiency and ferritin levels were found ( β=0.424, p=0.008) in univariate and model adjusted for age. After
adjustment for age and total fat mass and for age and visceral fat mass the association became non-
significant in men ( β=0.327, p=0.067 and β=0.295, p=0.106, respectively) and maintained non-significant
after further adjustment for FLI (p <0.05). In women, ferritin level was negatively associated with
25(OH)vitamin deficiency in the model adjusted for age, visceral fat mass and FLI ( β=-0.335, p=0.026). In
this study, we showed that serum ferritin levels were negatively associated with the presence of
25(OH)vitamin D deficiency in women and this association was independent of age, body composition and
FLI. No association was observed in men.
Keywords: gender differences; vitamin D; ferritin; body composition; fatty liver index
Traditionally vitamin D is associated with bone
metabolism and calcium homeostasis, and its deficiencyis linked to rickets in children and also osteoporosis in adults
[1]. New roles have been attributed to vitamin D, and its
pleiotropic effects have been shown to be attributable toimmunomodulatory qualities of vitamin D receptor
agonists [2]. Thus, it is not surprising that its deficiency has
been linked to various conditions that have inflammationas a pathogenetic mechanism, such as autoimmune
diseases, cardiovascular diseases, insulin resistance and
diabetes mellitus [2-4].Accordingly, vitamin D levels areregulated by several factors, including UV exposure, dietary
intake, gender and obesity [5,6].
Iron is an essential trace element for most of the
physiologic processes, with a critical role in energy
homeostasis, from oxygen transport to energy metabolism,
* email: ancastoian@yahoo.com; Phone: 0723684855 All authors have contributed equally to this manuscriptbut also in DNA replication and transcriptional regulation
[8-10].Due to its involvement in hepatic and adipose tissueinsulin resistance and oxidative stress, iron also interferes
with the primary pathogenetic mechanisms of obesity-
related diseases, including non-alcoholic fatty liver disease(NAFLD). Ferritin acts as the primary form of storage of
iron in most cells, and small quantities are released in
circulation reflecting body iron stores.Serum ferritin levelsare regulated by hepcidin, which is the chief regulator of
iron homeostasis [11].Hepatocytes mainly produce
hepcidin, but small quantities are also provided by adiposetissue, macrophages and pancreatic cells [12-15], and its
production appears to be influenced by oestrogens by
regulation of ferroportin expression [16].
Researchers on the relation between ferritin and vitamin
D levels are limited, and results are conflicting, with studies
showing either a positive association [18] or no association[19,20]. Furthermore, insufficient data are available on the
gender influence on this association, with one study
Fig. 1. Chemical formula of
25-hydroxycholecalciferol [7]
Fig. 2. The
Crystallographic
structure of
mitochondrial
ferritin [17]

REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 http://www.revistadechimie.ro 865showing a positive correlation in women and but not in
men [21] and a second one showing an inverse association
of ferritin levels with vitamin D levels in men and a positiveassociation in premenopausal women [22].
Our study proposed to investigate gender differences in
the relationship between ferritin levels and 25(OH)vitaminD deficiency in overweight persons and whether this
relationship is mediated by total and visceral adiposity and
fatty liver index (FLI), a marker of NAFLD.
Experimental part
Materials and methods
Study participants
This was a retrospective study in which were collected
data from charts of patients seen in an outpatient clinicalcentre in Bucharest, Romania between January 2011 and
October 2017. Were included adults below 79 years of age,
with overweight or obesity as defined by a body mass (BMI)≥
25 kg/m2, with 25(OH)vitamin D levels available and
which had not undergone a nutritional intervention in the
previous 12 months. Patients were excluded if they hadparathyroid pathology, had used vitamin D supplements in
the last six months, were using hepatoprotective drugs,
had a previous diagnosis of osteoporosis, gastrointestinalor autoimmune diseases, kidney or hepatic failure. Also,
were excluded pregnant or lactating women and patients
of non-Caucasian race.
The research was conducted following Good Clinical
Practice Guidelines and the Declaration of Helsinki, and
the Institutional Review Board approved the study protocol.Due to retrospective design, according to local regulations,
the signature of the informed consent was not required
[23].
Data collected
Detailed medical history, age, gender, results of
anthropometrical measurements (weight, height, waist
circumference), clinical assessments (blood pressurevalues and body fat composition), and results of
investigations were collected from patients’ files.
According to local procedures, height and weight weremeasured in the morning, in fasting condition, with patients
wearing light clothes and no shoes. BMI was calculated as
weight (kg)/height
2 (m). The waist circumference was
measured in standing position at a half distance between
the lowest rib and the iliac crest using a soft tape. Blood
pressure was measured in sitting position after 5 minutesof rest. Visceral fat mass (VFM) and body fat mass (BFM)
were measured by bioelectric impedance, using Omron
body composition monitor (Omron Healthcare Europe BV).Diabetes was diagnosed if fasting plasma glucose ≥126
mg/dL on two different occasions and/or HbA1c was ≥6.5%
or patients had a previous diagnosis of diabetes or werefollowing therapy with hypoglycaemiant drugs.
Hypertension was defined as a systolic blood pressure of
≥140 mmHg, a diastolic blood pressure ≥ 90 mmHg, and/
or use of antihypertensive therapy. Fatty liver index (FLI)
[24] assessing liver steatosis was calculated with the
following formula: FLI=[e
0.953×loge (TG)+0.139×BMI+0.718×loge (GGT)
+0.053×waist circumference–15.745)]/[1+e 0.953×loge (TG)+0.139×BMI+0.718×loge
(GGT)+0.053×waist circumference–15.745]×100.
Laboratory assessments
Laboratory investigations on which data were collected
included: fasting blood glucose, glycated haemoglobin
(HbA1c), triglycerides, total cholesterol, HDL-cholesterol,ferritin, 25(OH)vitamin D, total calcium, magnesium,
haemoglobin, haematocrit, mean corpuscular volume, iron
and full iron binding capacity. As per institutionalprocedures, all blood samples were collected in the
morning, in fasting condition and assessed in an
institutional laboratory in the day of collection. HbA1c wasdetermined using ion-exchange chromatography. Fasting
plasma glucose, triglycerides, total and HDL-cholesterol
were determined by routine enzymatic methods. LDL-cholesterol was calculated using the Friedewald formula
[25]: LDL-cholesterol= total cholesterol – HDL-cholesterol
– triglycerides/5. Haemoglobin, haematocrit and meancorpuscular volume were assessed using flow cytometry
methods and iron and total iron binding capacity (TIBC) by
colourimetric methods. Serum ferritin and 25(OH)vitaminD levels were measured using an electrochemi-
luminescence method. Patients were classified as having
vitamin D deficiency if 25(OH)vitamin D levels were <20.0ng/mL [23].
Statistical analysis
Statistical analysis was performed using SPSS-PC 20.0
(SPSS Inc., Chicago, IL, USA). Kolmogorov-Smirnov tests,
skewness and kurtosis, were used to evaluate thedistribution of all quantitative variables. Data are presented
as number (percentage, %) for categorical variables and
mean ± standard deviation (SD) or median (quartile 1;quartile 3) for continuous variables. Comparing variables
between groups with and without 25(OH) vitamin D
deficiency and gender were performed by Student t-test,Mann-Whitney U test and chi-square test. Univariate linear
regression analysis assessed the association between
ferritin levels and 25(OH)vitamin D deficiency, with andwithout correction for age, body composition (total fat mass
and visceral fat mass) and FLI. Because ferritin had a non-
Gaussian distribution, for the inclusion in the regressionanalysis as a dependent variable, it was logarithmically
transformed. The presence of collinearity among predictors
was tested in all regression models employing more than
one predictor. Due to collinearity issues, total fat mass and
visceral fat mass were included in separate regressionmodels.
Results and discussions
Data of 148 patients fulfilling the inclusion criteria and
without exclusion criteria admitted between January 2011
and October 2017 were collected. Of these, 56 had noferritin evaluation and were excluded from the analysis.
Thus, here we present data from 92 patients with
overweight or obesity and with age ranging between 20and 69 years. The characteristics of the analysed
population are presented in table 1.BMI ranged between
25.5 kg/m2and 56.0 kg/m
2, with a mean value of 32.8 kg/
m2. Of the patients analysed, 21 (22.8%) had arterial
hypertension, and 9 (9.8%) had type 2 diabetes. Median
levels of ferritin were 82.5 µg/L, and median 25(OH)vitamin
D levels were 22.5 ng/mL. Mean haemoglobin levels were
14.2 mg/dL, median iron levels 16.9 µg/L and TIBC 66.2
µg/dL. According to 25(OH)vitamin D levels, 35 patients
(38.0% of the sample included in the analysis) had
25(OH)vitamin D deficiency. No statistically significant
difference between groups with and without25(OH)vitamin D deficiency was observed for any
parameters analysed. Median ferritin levels were100.0 µg/
L in those with 25(OH)vitamin D deficiency and 68.4 µg/L
in those without (p=0.088).
54 patients, representing 58.7%, were women.
Compared to women, men had significantly higher levelsof ferritin: 174.5 µg/L
vs 48.1 µg/L, p <0.001. Also, weight
(p <0.001), BMI (p=0.048), waist circumference
(p=0.002), visceral fat mass (p <0.001), diastolic bloodpressure (p=0.039), fasting plasma glucose (p=0.018),

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 866haemoglobin (p <0.001) and haematocrit (p <0.001) were
higher in men than in women. BMI was 34.3 kg/m2 in men
and 31.8 kg/m2 in women; visceral fat mass was 17.4 kg
in men and 9.1 kg in women. FLI score was also
significantly higher in men than in women: 88.4 vs 63.2, p<0.001. Total fat mass was higher in women than in men
(43.5 kg vs 36.0 kg, p <0.001). No difference was observed
in the 25(OH)vitamin D levels and the frequency of25(OH)vitamin D deficiency between the genders. The
frequency of 25(OH), vitamin D deficiency, was 39.5% in
men and 37% in women (p=0.813, table 2).
In men, serum ferritin levels were significantly higher in
those with 25(OH)vitamin D deficiency compared to those
without 261.7 (159.5; 415.0) vs 146.8 (63.7; 192.8),p=0.006. In women, the difference observed between
those with and without 25(OH)vitamin D deficiency was
not statistically significant: 56.6 (25.3; 112.1) in those with25(OH)vitamin D deficiency and 46.7 (27.4; 96.9) in those
without 25(OH)vitamin D deficiency, p=0.788.
A univariate linear regression analysis was performed
with Log ferritin as dependent variable and presence of
25(OH)vitamin D deficiency as an independent variable.
Statistically significant positive association between25(OH)vitamin D deficiency and ferritin levels was found
only in men ( β=0.424, p=0.008) for this model. The
adjustment for age did not change the significance of the
association. After adjustment for age and total fat mass(Model 1) and for age and visceral fat mass (Model 2) the
association between ferritin and 25(OH)vitamin D
deficiency become non-significant in men ( β=0.327,
p=0.067 and β=0.295, p=0.106, respectively) and
maintained non-significant after further adjustment for FLI
(p <0.05). In women, no association was observed neitherin the unadjusted model nor after the adjustment for age
and total fat mass or age and visceral fat mass. However,
in women, Log ferritin level was negatively associated with25(OH)vitamin deficiency in the model adjusted for age,
visceral fat mass and FLI ( β=-0.335, p=0.026, table 3).
For all adjusted models V ariance Inflation Factor was <10and correlation coefficients <0.80, showing no
multicollinearity in the data.
In this retrospective research, we evaluated the gender
differences in the relationship between ferritin levels and
25(OH)vitamin D deficiency in overweight men and
women and whether body composition and FLI mediated
Table 1
CLINICAL CHARACTERISTICS OF PATIENTS ENROLLED (WHOLE SAMPLE AND ACCORDING TO 25(OH)VITAMIN D STATUS)
BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; FPG = fasting plasma glucose; HbA1c = gly cated
haemoglobin; HBP = high blood pressure; MCV = mean corpuscular volume; TIBC = total iron binding capacity; FLI = fatty liver in dex

REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 http://www.revistadechimie.ro 867this relationship. After adjustment for age, body composition
parameters and FLI score, serum ferritin levels were
negatively associated with the presence of 25(OH)vitaminD deficiency in women; no association was observed in
men.
Data on the gender differences in the relationship
between ferritin levels and vitamin D levels are limited.
We were able to identify only two publications investigating
these differences and both emerged from researchersperformed in Korean populations [21,22] and reported
results are contradictory. In an analysis of data of 695
persons Jeong et al. [21] reported no correlation betweenferritin and 25(OH)vitamin D levels in men and a positive
relation between ferritin and 25(OH)vitamin D levels in
women, with higher ferritin levels in those with highervitamin D levels [21]. The second study, enrolling
participants from the 2012 Korean National Health and
Nutrition Examination Survey (KNHANES) showed aninverse association between ferritin and 25(OH)vitamin D
levels in men and a positive association in premenopausal
women, with lower ferritin levels in those with25(OH)vitamin D deficiency and insufficiency as compared
BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; FPG
= fasting plasma glucose; HbA1c = glycated haemoglobin; HBP = high blood pressure; MCV
= mean corpuscular volume; TIBC = total iron binding capacity; FLI = fatty liver indexTable 2
CLINICAL CHARACTERISTICS OF PATIENTS
ENROLLED ACCORDING TO THEIR GENDER
Table 3
ASSOCIATION OF SERUM FERRITIN LEVELS WITH 25(OH)VITAMIN D
DEFICIENCY BY GENDER
Unadjusted model included only ferritin as dependent variable and
25(OH)vitamin D deficiency as predictor. Normal 25(OH)vitamin D
levels were used as reference. Model 1: adjusted for age, Model 2:
adjusted for age and total fat mass, Model 3: adjusted for age and
visceral fat mass, Model 5: adjusted for age, total fat mass and fatty
liver index, Model 5: adjusted for age, visceral fat mass and fatty liver
index

http://www.revistadechimie.ro REV.CHIM.(Bucharest) ♦69♦No. 4 ♦2018 868to those with normal levels of this vitamin [22]. Our results
are in line with the former study with regards to lack of
relationship in men; we also observed similar results tothe latter study in women, showing that in women the
presence of 25(OH)vitamin D deficiency was associated
with lower serum ferritin levels[26] The differencesobserved in the direction of the association among the
studies may be due to the variables used for the adjustment
– only age in the article of Jeong at al. [21] (positiveassociation also seen in our results when the correction
for made just for age) and multiple parameters, some of
which are also included in the FLI score we used in thearticle of Seong et al. [22].
The observed gender differences in the associations
may be due to the oestrogen and testosterone levels whichhave been associated with both ferritin and vitamin D
[5,16].Pregnancy and ovulation, conditions in which
oestrogen production increases, were shown to beassociated with higher 25(OH)vitamin D levels
[27,28].Vitamin D stimulates 17 β-oestradiol synthesis,
consequent vitamin D receptors expression and thusoestrogen signalling [29]. In men vitamin D metabolising
enzymes (CYP2R1, CYP27B1, and CYP24A1) and the
vitamin D receptors are expressed in the male reproductivesystem, including Leydig cells, thus suggesting a link
between sex steroid productions and vitamin D
[30].Oestrogen shave recently emerged as factors involvedin iron metabolisms. In a cohort from 1990-2000 NHANES,
it was shown that hormonal replacement therapy was
associated with lower ferritin levels ( β=-34.13, p=0.0002),
independent of other potential confounders such as
breakthrough bleeding and hysterectomy [31]. The link
hypothesised is the influence of oestrogens on the hepcidinsynthesis, the primary regulator of iron homeostasis [32].
In men, ferritin levels were positively associated with
the presence of 25(OH)vitamin D deficiency in the
unadjusted model. After adjustment for total and visceral
fat mass the association lost its statistical significance,suggesting that body composition mediated the
relationship. Obesity has been shown to be influenced both
vitamin D and ferritin levels [21,33,34].A metanalysisincluding 34 cross-sectional studies showed a significant
but weak correlation between BMI and 25(OH)vitamin D
levels, with a 4% reduction in 25(OH)vitamin D with each10 % increase in BMI [6].Among conditions hypothesised
in the association between obesity and vitamin D levels
are 25(OH)vitamin D sequestration in the adipose tissue[35] and volumetric dilution of vitamin D [36]. Also, obesity
is a state of subclinical chronic inflammation associated
with increased production of pro-inflammatory cytokines.In this context of chronic inflammation vitamin D may act
as an acute phase reactant and with consequent decreased
circulating levels of 25(OH)vitamin D [33].Visceral andsubcutaneous adipose tissue has also been associated
with ferritin levels [37] and, as both adiposity and increased
hepatic iron stores have been linked with states of insulinresistance and increased fasting insulin and glucose levels,
one of the hypothesised mechanisms is increased insulin
resistance [38]. These mechanisms may explain ourresults observed in men.
In women, we found that the association between
ferritin and 25(OH)vitamin D was not mediated by the totalor visceral adiposity. After adjustment for FLI score, the
association become statistically significant with lower
ferritin levels in those with vitamin D deficiency. Previouslyit was showed that one-third of the patients with NAFLD,
the hepatic expression of metabolic syndrome, have higher
ferritin levels, with hepatic iron deposition [11].Also, it wasshowed that iron stores were associated with higher levels
of sex hormone binding globulin and lower testosterone
levels in men [39] and women with PCOS [40].We did notassess testosterone and oestrogen levels in our group of
patients.Thus we can only speculate that the potential
causes of our observations just in women may berepresented by the endocrinological effect of iron stores in
NAFLD, which were linked to sex binding globulin
hormones level [41] and with consecutive lower availabilityof oestrogen levels [40,42]. Additionally, while in men
obesity was associated with lower testosterone levels, in
women obesity was associated with lower oestrogenlevels in fertile women and higher oestrogen levels in
postmenopausal women [43-45].
Our research has several limitations that should be
discussed.[46,47]. First, due to its retrospective design, we
cannot evaluate the causality – we cannot assess whether
25(OH)vitamin D deficiency causes lower ferritin levels ofvice versa. Secondly, we enrolled a small sample size of
overweight and obese patients; thus, our findings are
limited to this population. Although our study has theselimitations, this is the first reported study assessing gender
differences in the relationship between ferritin and vitamin
D in a Caucasian population.
In conclusion, in this study, we showed that serum ferritin
levels were negatively associated with the presence of
25(OH)vitamin D deficiency in women and this associationwas independent of age, body composition and FLI. No
association was observed in men. Further studies on larger
samples, also evaluating oestrogen and testosterone levelsare warranted to confirm our findings.
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Manuscript received: 6.09.2017