European Journal of Internal Medicine 22 (2011) 355–362

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European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Review article

Novel roles of vitamin D in disease: What is new in 2011?

Stefania Makariou a, b, Evangelos N. Liberopoulos a, Moses Elisaf a, Anna Challa b,⁎
a
Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
b
Department of Child Health, Medical School, University of Ioannina, Ioannina, Greece

a r t i c l e i n f o a b s t r a c t

Article history: Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of
Received 8 March 2011 genes. Until recently its main known role was to control bone metabolism and calcium and phosphorus
Received in revised form 21 April 2011 homeostasis. During the last 2 decades it has been realized that vitamin D deficiency, which is really common
Accepted 28 April 2011
worldwide, could be a new risk factor for many chronic diseases, such as the metabolic syndrome and its
Available online 31 May 2011
components, the whole spectrum of cardiovascular diseases, several auto-immune conditions, and many
Keywords:
types of cancer as well as all-cause mortality. Except for the great number of epidemiological studies that
Vitamin D support the above presumptions, vitamin D receptors (VDRs) have been identified in many tissues and cells.
Mortality The effect of vitamin D supplementation remains controversial and the need for more persuasive study
Metabolic syndrome outcomes is intense.
Cardiovascular disease © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Immune system
Cancer

1. Introduction and background 1.2. Sources and metabolism of vitamin D

In recent years emphasis has been given on the role of vitamin D in
areas beyond bone metabolism and calcium homeostasis [1]. In this
context, vitamin D deficiency has been associated with risk factors for
cardiovascular disease, the metabolic syndrome and its components
(i.e. hypertension, atherogenic dyslipidemia, diabetes mellitus, im-
paired glucose tolerance, central obesity), and even with cancer,
autoimmune diseases, infections and overall mortality [2,3].
The aims of this review are to summarize the most recent data
regarding these associations and try to clarify whether and to what
extent oral vitamin D supplementation could be used as a beneficial
intervention in such diseases.
1.1. Search methods
We searched the PubMed up to 15 January 2011 using combina-
tions of the following keywords: vitamin D deficiency/insufficiency
and mortality, metabolic syndrome, cardiovascular disease, immune
system and cancer.
Randomized controlled trials, original papers and review articles
are included in the present review. Also the references of those
reviews were scanned for relevant articles.
⁎ Corresponding author at: Department of Child Health, School of Medicine,
University of Ioannina, Ioannina 45 110, Greece. Tel.: + 30 2651009271; fax: + 30
2651007882.
E-mail addresses: achalla@cc.uoi.gr, makarioustefania@yahoo.com (A. Challa).
Fig. 1 summarizes the sources and metabolism of vitamin D as well
as its main sites of action [4–6].
1.3. Definition, prevalence and risk factors for vitamin D deficiency
The most commonly used cut-points for serum 25(OH) Vit D levels in
adults are: N75 nmol/L (N30 ng/mL) for vitamin D sufficiency, 50–
70 nmol/L (20–28 ng/mL) for insufficiency and b50 nmol/L (b20 ng/mL)
for deficiency. It has been estimated that 1 billion people worldwide
have vitamin D deficiency or insufficiency [7,8]. The Third National
Health and Nutrition Examination Survey (NHANES III) reported the
prevalence of vitamin D deficiency in United States adults to be 25–57%
[9].
Furthermore, 40–100% of U.S. and European non institutionalized
elderly people are vitamin D deficient, mainly because aging is
associated with decreased concentrations of 7-dehydrocholesterol
in the skin [2,10]. Obesity is another strong risk factor for vitamin D
deficiency, because fat cells sequester vitamin D. Lower vitamin D
levels among older and obese people may also stem from reduced
outdoor activity and sunlight exposure [10,11]. Additionally, at par-
ticular risk are race/ethnic groups with darker skin coloring living
in the Northern hemisphere, since melanin skin pigmentation absorbs
UVB light, thus reducing vitamin D synthesis [10,12]. In addition,
children and young adults, as well as pregnant and lactating women
and their infants, especially when there is multiparity, short spacing
between pregnancies, non-white maternal skin and exclusive breast
feeding, are also potentially at risk for vitamin D deficiency [13].

0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2011.04.012
356 S. Makariou et al. / European Journal of Internal Medicine 22 (2011) 355–362

Ultraviolet light Dietary intake

Exposed skin Vitamin D3 Vitamin D2

7-dehydrocholesterol (cholecalciferol) (ergocalciferol)

Liver

25-hydrohyvitamin D 3
(calcidiol)

Parathyroid Kidneys Other organs

Hormone Via 1-alpha- Via 1-alpha- Cytokines
(PTH) hydroxylase hydroxylase

1,25-dihydroxyvitamin D3 CYP24
(calcitriol)

Calcitroic
Increased bone reabsorption (mediated via PTH)
acid
Increased intestinal absorption of calcium and phosphate
Decreased renal excretion of calcium
Regulates cellular growth, function, and differentiation

Fig. 1. Synthesis and effects of vitamin D. The majority of body's vitamin D (80–90%) comes from endogenous production in the skin through ultraviolet irradiation of the precursor,
7-dehydrocholesterol. Other main sources of vitamin D are fatty fish, eggs and dairy products, as well as dietary supplements [4]. Both endogenous and ingested vitamin D is stored in
fat tissue, since it is a fat-soluble molecule, and then it is released into circulation, bound to a vitamin D-binding protein. Vitamin D undergoes first a hepatic 25-hydroxylation, and
then a renal 1-α-hydroxylation to produce the active hormone 1,25(OH)2Vit D. The second hydroxylation is tightly regulated by serum parathyroid hormone (PTH), calcium and
phosphorus levels. 1,25(OH)2Vit D itself induces the expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24), which catabolizes both 25(OH)Vit D and 1,25(OH)2Vit D into
biologically inactive, water-soluble calcitroic acid. The biological functions of vitamin D are exerted through the interaction of the steroid hormone 1,25(OH)2Vit D with a single
vitamin D receptor (VDR) in the cell nucleus that functions as a ligand-dependent transcription factor. Subsequently it regulates the expression of many target genes for the
production of several molecules such as osteocalcin, osteopontin, calbindin-D28K, calbindin-D9K, TGF-β2 and vitamin D 24-hydrohylase. Therefore, it was hypothesized that the
vitamin D endocrine system has additional physiological functions [4–6].
 S. Makariou et al. / European Journal of Internal Medicine 22 (2011) 355–362
2. Vitamin D and all-cause mortality
Several studies and meta-analyses suggest that vitamin D
deficiency has a negative association with survival, while supple-
mentation may decrease overall mortality [5,14]. A recent meta-
analysis of 18 randomized controlled trials (n = 57,000) showed that
supplementation with vitamin D (300 to 2000 IU/day) resulted in
significant reduction in mortality from any cause [relative risk (RR)
0.93, 95% confidence interval (CI) 0.92 to 1.18] [2,15]. In addition,
among 13,331 US adults participating in NHANES III study, those in
the lowest quartile of 25(OH)Vit D (b18 ng/mL; b45 nmol/L) had a
26% increased risk of all-cause death during a follow-up period of
8.7 years compared with those in the highest quartile [3,10].
3. Vitamin D and the metabolic syndrome
The metabolic syndrome (MetS), describing the cluster of
abdominal obesity, hypertension, dyslipidemia and hyperglycemia,
is a constellation of vascular risk factors associated with increased risk
for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM)
[16,17]. NHANES III and NHANES 2003–2004 studies have shown a
significant inverse association between serum vitamin D concentra-
tions and MetS as a whole, as well as with each one of its diagnostic
criteria [6,18,19]. So far, there is no data on the effects of vitamin D
supplementation on the prevalence of MetS in vitamin D deficient
patients [6].
4. Vitamin D and hypertension
Epidemiological observations, like the incidence of hypertension
increasing with higher latitude, higher recordings of blood pressure
(BP) in winter months [2,20] and racial/ethnic differences in 25(OH)
Vit D levels explaining approximately half of the increased hyperten-
sion prevalence in non-Hispanic blacks compared with whites,
support an association between vitamin D and blood pressure (BP)
[10]. Furthermore, the cross-sectional study NHANES III showed that
participants in the highest 25(OH)Vit D quartile (N85.7 nmol/L) had
systolic BP (SBP) and diastolic BP (DBP) 3.0 and 1.6 mm Hg lower,
respectively, compared with those in the lowest 25(OH)Vit D quartile
(b40.4 nmol/L) [21]. In the large prospective cohort studies of the
Health Professionals' Follow up (HPFS) (n = 613) and the Nurses'
Health Study (NHS) (n = 1198 women), an increased risk of incident
hypertension was demonstrated in subjects with vitamin D insuffi-
ciency (b37.5 nmol/L) compared with vitamin D sufficient people
(N75 nmol/L) [22].
Several potential mechanisms have been proposed to explain the
vitamin D's implication in the regulation of BP. In rodents 1,25
(OH)2Vit D was proved a negative regulator of the renin-angiotensin
system [23]. Also, vitamin D may have a direct vascular effect, as
implied by the presence of 1α-hydroxylase activity in vascular
smooth muscle and endothelial cells, and by the presence of VDRs
in endothelial cells [6]. To date, only a small number of randomized
control trials have reported data on BP with vitamin D supplemen-
tation. In Pfeifer's et al. study, there was a 7 mm Hg reduction in SBP in
the vitamin D group compared with controls (p = 0.02) [24]. A recent
meta-analysis comparing vitamin D with placebo found a small but
significant drop in DBP (3 mm Hg) among those taking vitamin D, but
only in contestants who were hypertensive at baseline [25]. Yet, the
largest trial to date, the Women's Health Initiative (WHI), failed to
show any significant impact of a small dose of vitamin D (400 IU) plus
1000 mg calcium/day on SBP or DBP after a mean follow-up of 7 years
in post-menopausal women [26]. However, the lack of effect may
have been due to the low doses of vitamin D and poor adherence
(59%) to the medication, in a population not hypertensive at baseline
[26]. Overall, the current evidence to support the role of vitamin D
357
supplementation in reducing BP is weak, and further randomized
trials are needed to explore this possibility.
5. Vitamin D and glucose metabolism
Vitamin D may play a role in maintaining insulin function. Several
studies have found a cross-sectional association between low 25(OH)
Vit D levels and obesity, glucose intolerance, hyperinsulinemia
and type 2 diabetes [3,10,18,27]. Although fat cells sequester vitamin
D, the cross-sectional association of 25(OH)Vit D deficiency with
diabetes remains even after body mass index, physical activity, and
other potential confounding factors are taken into account [3].
Vitamin D seems to affect the glucose-induced insulin secretion,
both directly and indirectly [28,29]. The direct effects are probably
mediated by the binding of circulating or locally, within the β-cell,
produced 1,25(OH)2Vit D to β-cell VDRs [30–32]. The indirect effects
may be associated with the regulation of calcium flux through β-cells
[32,33], as insulin secretion is calcium dependent [34]. Also, in
peripheral insulin target tissues, vitamin D may enhance insulin
sensitivity by stimulating the expression of insulin receptors [35], or
by the regulation of free fatty acid metabolism in skeletal muscles
and adipose tissue [36] via the vitamin D-induced expression of the
nuclear peroxisome proliferators-activated receptor (PPAR)-δ [37].
Replenishing vitamin D in patients with type 2 diabetes was found
to improve insulin secretion, peripheral insulin sensitivity and
glycosylated hemoglobin levels [38–40]. However, the expected
benefit from vitamin D repletion on fasting blood glucose, glucose
tolerance, or insulin sensitivity was not observed in some studies
[41,42]. This inconsistency may be due to ethnic differences or VDR
polymorphisms [43]. For example, among women in the Nurses'
Health Study (NHS), over a 20-year follow up, there was no asso-
ciation between total vitamin D intake and type 2 diabetes, but the
combined calcium (N1200 mg/day) and vitamin D (N800 IU/day)
intake was associated with a 33% lower risk compared with intakes
b600 mg and 400 IU, respectively [44]. Also, a post-hoc analysis of
the large Women's Health Initiative (WHI) randomized placebo-
controlled trial (n = 33,951) showed that calcium supplementation
(1000 mg) plus 400 IU of vitamin D/day did not reduce the risk of
incident diabetes over a 7-year follow-up, while no changes in fasting
glucose, insulin, and homeostasis model assessment of insulin
resistance (HOMA-IR) were observed [45]. However, there were
limitations in this study including the low vitamin D dose,
concomitant therapy with calcium and cross-contamination with
controls also taking vitamin D supplementation.
In another study with healthy volunteers who were not vitamin D
deficient at baseline, high-dose of calcitriol (1.5 μg/day for 7 days) did
not increase insulin sensitivity, as measured by euglycemic clamp,
compared with placebo subjects [42]. On the contrary, high-dose
(4000 IU/day) vitamin D supplementation improved insulin sensi-
tivity in South Asians with insulin resistance [46]. Similarly, in another
study, the combination of vitamin D with calcium over a 3-year time
attenuated the rise of fasting plasma glucose (FPG) only in subjects
with impaired FPG at baseline [47]. Thus, vitamin D supplementation
may be effective mainly in patients with impaired glucose metabolism
and low levels of circulating vitamin D [38,48–50].
Clinical studies designed specifically to assess the effect of vitamin
D supplementation with large doses of vitamin D (2000–7000 IU) in
high-risk populations with both vitamin D deficiency and impaired
glucose metabolism are currently underway [51].
6. Vitamin D and lipid metabolism
Some studies reported an association between vitamin D status
and/or supplementation with lipids. Specifically, another analysis of
the NHANES III examining several CVD risk factors, including lipids, in
US adults (n = 15,088) found the adjusted prevalence of high serum
358 S. Makariou et al. / European Journal of Internal Medicine 22 (2011) 355–362
triglyceride levels (OR 1.47) to be higher in the first compared to the
fourth quartile of serum 25(OH)Vit D levels (p b 0.001) [12]. However,
these findings are not in accordance with a study using data from
NHANES 2003–2004 (n = 1654) which showed a positive relation-
ship between vitamin D and high density lipoprotein cholesterol
(HDL-C) (p = 0.004) but not with triglycerides [19]. On the contrary,
in a European large cohort (n = 6810) serum 25(OH)Vit D was
inversely associated with triglyceride levels (p b 0.004) after adjust-
ment for insulin growth factor (IGF)-1, obesity, social and lifestyle
variations [52]. Moreover, 25(OH)Vit D was positively correlated
with HDL-C levels (p b 0.01) in 381 young adults and inversely related
with low density lipoprotein cholesterol (LDL-C) only in males
(n = 201) (p = 0.007) [53]. Furthermore, 25(OH)Vit D was positively
associated with apolipoprotein A-I (p b 0.03), and negatively corre-
lated with the LDL-C to HDL-C ratio (p b 0.044) in 51 healthy subjects
[54]. Others report inverse correlations of serum 1,25(OH)2Vit D
with very low density lipoprotein cholesterol (VLDL-C) and triglyc-
eride levels [55]. Overall, vitamin D deficiency seems to alter the lipid
profile by increasing peripheral insulin resistance [5].
Oral supplements of vitamin D in postmenopausal women did
not improve total cholesterol, LDL-C or HDL-C over 12 months [56].
In contrast, calcium plus vitamin D supplementation (600 mg and
200 IU/day, respectively) along with a 15-week weight-loss inter-
vention program resulted in pronounced reductions in total choles-
terol to LDL-C and LDL-C to HDL-C ratios (p b 0.01 for both) as well as
LDL-C levels (p b 0.05) compared with placebo in overweight/obese
women (n = 63). The decrease in lipid and lipoprotein concentrat-
ions could partly be attributed to calcium intake through various
mechanisms [57]. In another study, when vitamin D was added to a
weight loss program, led to greater reduction in triglycerides than
weight loss alone, but paradoxically led to an increase in LDL-C levels
compared with placebo [58]. Overall, the data from these studies are
not sufficient to either confirm or refute any benefit from vitamin D
and/or calcium supplementation on lipids and future prospective
studies are needed to address this issue.
7. Vitamin D and cardiovascular effects
Many coronary risk factors, including hypertension, diabetes
mellitus, and dyslipidemia as well as endothelial cell function [59]
and vascular calcification [60] may be affected by vitamin D. Vitamin D
deficiency is currently regarded as an independent cardiovascular
disease (CVD) risk factor [51], based on earlier observations of
geographic and seasonal differences in mortality from ischemic heart
disease [61] and results from large, cross-sectional studies using the
NHANES databases (n = 16,603), where the frequency of ischemic
heart disease and stroke was related to 25(OH)Vit D deficiency
(p b 0.0001) [62]. Also, an analysis involving 8351 adults showed a
high prevalence of vitamin D deficiency (74%) in patients with
coronary artery disease and heart failure [63].
Many studies evaluated prospectively the relation of vitamin D
with long-term cardiovascular outcomes in subjects with no history
of cardiovascular disease. Vitamin D deficiency (b15 ng/mL) was
associated with a 2-fold increased rate of myocardial infarction over a
10-year period in healthy male professionals (n = 18,225) [64], or
with increased risk of myocardial infarction, coronary insufficiency,
cerebrovascular events, claudication, or heart failure in the Framing-
ham Offspring study compared with those with levels N15 ng/mL,
after adjustment for age and conventional risk factors [65]. Also, a
recent meta-analysis report was in support of an overall association
of 25(OH)Vit D baseline levels in the lowest compared with the
highest categories with cardiovascular events [pooled hazard ratio
(HR) = 1.54, 95% CI 1.22–1.95]. This association did not differ
significantly across studies. A significant association of low 25(OH)
Vit D levels with cardiovascular mortality (HR = 1.38, 95% CI 1.19–
2.80) was also seen in this meta-analysis [64].
In addition to the effect on classical cardiovascular risk factors,
vitamin D may influence cardiac function and atherosclerosis through
multiple other mechanisms. Vitamin D deficiency is related to
increased activity of the renin-angiotensin-aldosterone system [66],
cardiac contractility, vascular tone, cardiac collagen content, and
cardiac tissue maturation [67] and has direct effects on vascular
smooth muscle cell calcification and proliferation [68]. Furthermore,
hypovitaminosis D may correlate with chronic subacute inflamma-
tion, NF-κB activation [69], and loss of suppression of foam cell
formation [70], thereby promoting atherosclerotic lesions.
Vitamin D and calcium supplementation has not been shown to
alter either coronary or cerebrovascular risk over a 7-year period in
the WHI study [71,72]. One should cautiously interpret these results
due to the small dose and poor compliance with vitamin D as well as
the fact that some data suggest that calcium supplementation may
lead to an increase in myocardial infarction rates [73]. Despite this,
resent data point out that women who consistently received
supplementation with calcium and vitamin D did not experience
more cardiovascular events or deaths than women who received
minimal supplementation [74].
Conclusively, it is suggested that vitamin D deficiency represents
an important new cardiovascular (CV) risk factor. More clinical trials
are urgently needed to determine whether there is a causal
association and whether vitamin D replenishment could reduce the
increase in CV risk. Unfortunately, the Thiazolidinedione Intervention
with vitamin D Evaluation (TIDE) trial was recently postponed due to
rosiglitazone withdrawal. This study aimed to compare the effect
of rosiglitazone vs placebo and vitamin D vs placebo on CV events.
Consequently, the Vitamin D and Omega-3 Trial (VITAL), a 5-year,
randomized, placebo-controlled trial involving 20,000 U.S. people, is
the only project to date aiming to examine whether vitamin D
supplementation (2000 IU/d) with or without addition of omega-3
fatty acids, could play a role in the primary prevention of cancer and
cardiovascular disease [75].
8. Vitamin D and heart failure
Observational studies have shown that low serum 25(OH)Vit D
levels are common in patients with congestive heart failure [76]. The
NHANES III showed that adults with very low vitamin D serum levels
(n = 13,131) had more than triple the risk of death from heart failure
over 8 years compared with those with normal levels [77]. Moreover,
in the German Ludwigshafen Risk and Cardiovascular Health (LURIC)
cohort study, which prospectively followed individuals referred for
coronary angiography, low levels of 25(OH)Vit D and 1,25(OH)2Vit D
were associated with increased risk of death from heart failure or
sudden cardiac death [78]. Also, 25(OH)Vit D levels were negatively
correlated with pro-B-natriuretic peptide and inversely associated
with impaired left ventricular function [78]. Of note, reverse causation
(i.e. the sickest patients having the lowest vitamin D levels) could still
in part account for the above described association. Supplementation
with 2000 IU/d of vitamin D reduced inflammatory markers in
patients with heart failure and improved serum parathyroid hormone
levels in one study without any significant direct survival benefit [79].
Further studies are needed to ascertain whether vitamin D supple-
mentation can improve symptoms and prognosis in heart failure.
9. Vitamin D and stroke
The Ludwigshafen Risk and Cardiovascular Health (LURIC)
prospective study showed that low levels of both 25(OH)Vit D and
1,25(OH)2Vit D were independently predictive for fatal strokes,
during a median of 8 years follow-up [80]. The most recent data
coming from NHANES (n ~ 8000) show that over a median of 14 years,
whites with levels of 25(OH)Vit D b15 ng/mL had double the risk of
dying from stroke compared with those having higher levels [81].
 S. Makariou et al. / European Journal of Internal Medicine 22 (2011) 355–362
However, no such association was found in black NHANES partici-
pants despite their lower overall vitamin D levels and greater fatal
stroke risk compared with whites. This quite surprising finding could
possibly be attributed to adaptive resistance to the adverse effects
of hypovitaminosis D probably developed in African Americans [81].
10. Vitamin D and renal disease
Low levels of 25(OH)Vit D were associated with albuminuria in a
cross sectional analysis of NHANES [82]. Furthermore, observational
data show that the use of activated vitamin D analogs in patients
with end-stage renal disease may lower mortality [83]. Also,
treatment with such analogs decreased proteinuria in two random-
ized clinical trials [84,85]. The Selective vitamin D receptor activation
with paricalcitol for reduction of albuminuria in patients with type 2
diabetes (VITAL) study has shown that the addition of a vitamin D-
receptor activator, paricalcitol (Zemplar, Abbot Laboratories) to
therapy in patients with diabetic nephropathy reduces albuminuria
without risking hypercalcemia or hyperphosphatemia and calcifica-
tion of diabetic vessels [86,87].
11. Vitamin D and immune system effects
In the 1980s, researchers observed high expression of VDRs in
lymphocytes and macrophages, sparking interest for a potential role
of vitamin D in immunity [88]. It has been shown that the overall
effect of 1,25(OH)2Vit D is the enhancement of protective innate
immune responses, while maintaining self-tolerance by dampening
over-zealous adaptive immune responses [89].
Many studies have shown that the majority of patients with
systemic lupus erythematosus (SLE) have insufficient levels of 25
(OH)Vit D, even when taking vitamin D supplementation [90].
The two largest studies to date both report a significant correlation
between higher disease activity and lower 25(OH)VitD [91,92].
Interestingly, in another study anti-vitamin D antibodies were found
in 4% of patients with SLE, possibly contributing to increased vitamin
D clearance [93].
Recent clinical studies have shown that vitamin D levels are
lower among patients with multiple sclerosis (MS) and that exposure
to ultraviolet (UV) light or calcitriol administration reduce disease
symptoms [94]. Also, low serum vitamin D at the time of a first
demyelinating event increases the risk of subsequent multiple
sclerosis in children, strengthening the argument that vitamin D
deficiency plays a causal role in MS by placing the deficiency so close
to onset [95].
Vitamin D deficiency has been associated with type 1 diabetes
mellitus (T1DM) as well. Interestingly, T1DM incidence was reported
to increase when vitamin D deficiency was present in the first month
of life [94], whereas increasing vitamin D intake during pregnancy
reduced the development of islet auto-antibodies in offspring [39].
Possibly VDR gene polymorphisms may be associated with the risk
of developing T1DM, but the data available up to now have been
conflicting [96].
Continued research will help us to better understand the key role
of vitamin D as immunomodulatory agent, and the way we could
probably use it as a disease-suppressing intervention for auto-
immune diseases.
12. Vitamin D and cancer
Both prospective and retrospective epidemiological studies indi-
cate that people living at higher latitudes are at increased risk for
colon, breast, prostate, pancreatic, ovarian and other cancers as
well as Hodgkin's lymphoma, and are more likely to die from them
as compared with people living at lower latitudes [7,97,98]. One
likely hypothesis is that since those specific tissues express 25-
359
hydroxyvitamin D-1α-hydroxylase they can produce 1,25(OH)2Vit D
locally, and then control more than 200 genes, including those
responsible for the regulation of cellular proliferation, differentiation,
apoptosis, and angiogenesis [7,99,100].
Meta-analyses for the 2008 IARC (International Agency for
Research on Cancer) report revealed inverse relationships between
25(OH)Vit D levels and carcinoma or adenoma of the bowel [101,102].
Moreover, an analysis from the NHS cohort (n = 32,826) showed that
the odd ratios for colorectal cancer were inversely associated with
median serum levels of 25(OH)Vit D, whereas serum 1,25(OH)2Vit D
had no association [103]. On the other hand, the WHI study showed
that daily supplementation of calcium (1000 mg) plus vitamin D
(400 IU) for 7 years had no effect on the incidence of colorectal cancer
among postmenopausal women [104]. However, participants in
the same study who at baseline had a 25(OH)Vit D concentration
b12 ng/mL had a 253% increase in the incidence of colorectal cancer
relative to those in the highest quartile (N23 ng/mL) over a follow-up
period of 8 years [105]. Also, an intake of 2000 IU/day of vitamin D
was estimated to reduce by 27% the incidence of colorectal cancer
in some studies [104,106].
Furthermore, the 2008 IARC report for breast cancer stated that
vitamin D has a protective effect with a RR of 0.85 (95% CI 0.71–1.02)
for each 25 nmol/L rise in the serum vitamin D level [102]. Also, a
meta-analysis regarding vitamin D and the prevention of breast
cancer demonstrated a 45% decrease in breast cancer risk for those
in the highest quartile of circulating 25(OH)Vit D (N60 nmol/L)
compared with those at the lowest, but no relationship was found
between circulating 1,25(OH)2Vit D and breast cancer [107]. Recently,
a clinical trial (n = 1179) showed that the incidence of breast cancer
was lowered by daily supplementation with 1000 IU of vitamin D plus
calcium in postmenopausal women [108].
Epidemiological studies have shown that increased exposure to UV
light may be protective against prostate cancer [109]. Also, in vitro
studies have demonstrated that 1,25(OH)2Vit D and its synthetic
analogs inhibit the proliferation of prostate cancer cell lines [99]. On
the other hand, in the 2008 IARC report for prostate cancer no
protective effect could be determined [102]. Furthermore, poly-
morphisms of the VDR gene may modify vitamin's D biological activity
and confer different susceptibility to prostate cancer as well as the
local metabolism of hormonal vitamin D, which seems to play an
important role in the development and progression of prostate cancer
[110].
Also, epidemiological studies show that children and young adults
who are exposed to the most sunlight have reduced risk of non-
Hodgkin's lymphoma [111]. Despite that, clinical trials up to now have
failed to obtain good results in clinical management of myelodys-
plastic syndromes and myeloid leukemia by using 1,25(OH)2Vit D or
analogs [112].
Conclusively, although there is already some evidence for a
protective effect of vitamin D against some types of cancer, much
research still needs to be done.
13. Vitamin D supplementation and safety issues
Supplementation of up to 2000 IU vitamin D daily has been
deemed by the U.S. Food and Drug Administration's nutritional
guidelines to be generally recognized as more effective and safe [113].
On the contrary higher levels have not definitely been shown to
confer greater benefits and sometimes they have been linked with
health problems.
The most common symptoms of vitamin D intoxication are those
related with hypercalcemia (i.e. thirst, itchiness, diarrhea, malaise,
wasting, polyuria and diminished appetite) resulting from primary
renal failure. Also, calcification especially in the kidney, aorta, heart,
lung and subcutaneous tissue can occur [114]. All the reports show
that hypercalcemia results only when 25(OH)VitD levels have
360 S. Makariou et al. / European Journal of Internal Medicine 22 (2011) 355–362
Table 1
Non-skeletal diseases associated with hypovitaminosis D.
All cause mortality
Metabolic syndrome
Hypertension
Impaired glucose metabolism and type 2 diabetes
Dyslipidemia
Cardiovascular diseases (myocardial infarction, coronary insufficiency,
coronary calcification, increased carotid intima median thickness)
Heart failure
Peripheral arterial disease
Stroke
Renal disease
Autoimmune diseases (lupus erythematosus, multiple sclerosis, type 1 diabetes)
Cancer (bowel, breast, prostate, non-Hodgkin lymphoma)
Respiratory diseases (wheezing illness, autoimmune interstitial lung diseases)
Liver fibrosis
Psychiatric diseases (depression, autism, schizophrenia)
Loss of gait performance and falls in the elderly
Lower androgen levels
consistently been above 375–500 nmol/L [115], which requires a daily
intake of 40.000 IU [116]. A recent review concluded that the safe
upper limit for vitamin D consumption is 10,000 IU/day [113]. Doses
above this limit increase the risk of renal calculi formation, especially
in patients with absorptive hypercalciuria and end-stage renal disease
on dialysis [117].
It is noteworthy that in both the Framingham cohort study [65]
and in the overall NHANES-III study [3] there was a suggestion of a
U-shaped curve with a trend towards increased risk for CVD and
mortality also at high levels of 25(OH)VitD, which did not meet
statistical significance, as few individuals had very high 25(OH)VitD
levels. What is more, Bolland et al. presented evidence coming from a
new analysis of the WHI and two other studies, pointing to a roughly
20% increased risk of both myocardial infarction and stroke in people
taking both calcium and vitamin D [118]. Also, a small case–control
study in patients with ischemic heart disease found that very elevated
25(OH)VitD levels (N89 ng/mL) were actually harmful (adjusted
OR = 3.18) [119]. Moreover, some individuals may be adversely
affected by elevated 25(OH)Vit D concentrations with respect to risk
of cancers of the prostate [120,121], breast [122], pancreas [123,124]
and esophagus [125,126].
In fact, continued investigation is necessary to ensure that vitamin
D intake recommendations are targeted to individuals who are more
likely to benefit most, while simultaneously protecting vulnerable
subgroups from risk of overexposure to high vitamin D serum
concentrations.
14. Conclusion
During the last 20 years, vitamin D and its non-classical actions
have taken an important place in the clinical scenario. Indeed, many
epidemiological and interventional studies have proved the benefits
of vitamin D sufficiency status in improving health. Yet, as already
mentioned, there is still demand for further research to clarify the
promising clinical use of vitamin D in the prevention and treatment of
various chronic diseases.
Learning points
• 1 billion people worldwide are vitamin D deficient
• the metabolic syndrome and its components are inversely related to
serum 25(OH)VitD levels
• vitamin D deficient people may have increased risk for hyperten-
sion, impaired glucose tolerance or diabetes mellitus and dyslipi-
demia, but there is still not enough evidence that vitamin D
supplementation could ameliorate these diseases
• vitamin D deficiency is regarded a new cardiovascular risk factor
• low vitamin D is associated with albuminuria, which is decreased by
the use of activated vitamin D analogs
• vitamin D deficiency may be a risk factor for auto-immune diseases
and for some types of cancer
• Table 1 summarizes the diseases possibly associated with vitamin D
deficiency
Conflict of interest
We state herein that this review was conducted independently; no
company or institution supported it financially. Some of the authors
have given talks, attended conferences and participated in trials and
advisory boards sponsored by various pharmaceutical companies. We
have had no involvements that might raise the question of bias in the
work reported or in the conclusions, implications, or opinions stated.
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