treatment of vitamin d deficiency as a primary prevention for cardiovascular disease
TRANSCRIPT
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Treatment of Vitamin D Deficiency as a Primary Prevention for Cardiovascular
Disease
Monica Raharjo
Faculty of Medicine Universitas Trisakti
Jakarta 2012
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Validation Page
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Table of Contents
1. Abstract..52. Introduction........53. Defining Vitamin D Deficiency5-10
3.1.Vitamin D Metabolism6-73.2.Measure of Vitamin D Status..........................83.3.Prevalence of Hypovitaminosis D in Indonesia.......8-93.4.Risk Factors for Hypovitaminosis D.9-10
4. Vitamin D and Cardiovascular Disease..10-164.1.Studies Linking Vitamin D Deficiency with Cardiovascular Risk..11-144.2.Vitamin D and Hypertension144.3.Vitamin D and Coronary Heart Disease..14-154.4.Vitamin D and Heart Failure...15-16
5. Treatment of Vitamin D Deficiency.......16-215.1.Screening for Vitamin D Deficiency...18-195.2.Vitamin D Supplementation20-21
6. Conclusion..21-227. References...22-24
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AbstractVitamin D refers to a collection of fat-soluble steroid responsible for calcium
regulation and musculoskeletal health. Recent studies have shown that vitamin D
also plays a role in maintaining cardiovascular health. Low vitamin D levels,
reflected by measurements of 25-hydroxyvitamin D, have been related with ahigher risk of cardiovascular disease and cardiovascular mortality. Low vitamin D
levels are also risk factors for coronary heart disease and heart failure, because of
its role in the development of hypertension, atherosclerosis, endothelial
dysfunction, and vascular calcification. With the relatively high prevalence of
hypovitaminosis D found in Indonesia, treatment of vitamin D deficiency,
including use of vitamin D supplementations, may be proposed as a primary
prevention method for cardiovascular disease.
Key Words: cardiovascular disease, vitamin D, hypovitaminosis D, primary
prevention, vitamin D supplementation
Introduction
A growing body of evidence has found that low vitamin D levels are
related to an increase in the risk of cardiovascular disease (CVD). CVD linked
with low vitamin D levels includes peripheral vascular disease, coronary artery
disease, heart failure, and stroke.1
Evidence also suggests that vitamin D
deficiency also plays a role in the development of atherosclerosis, endothelial
dysfunction, and vascular calcification.2
All these data suggest that vitamin D
plays a role in maintaining cardiovascular health. Therefore, the issue of whether
correcting vitamin D levels in individuals with vitamin D deficiency may lead to a
reduction in CVD risk should be explored.
The objectives of this paper is to define vitamin D deficiency, discuss the
relationship between low vitamin D levels and CVD, and elaborate on treatment
of vitamin D deficient individuals, which includes the use of vitamin D
supplements, as a possible means of primary prevention for CVD, all based on
available evidences and data. All data were collected by searching PubMed for
recent English-language articles related to vitamin D and CVD. The goal of this
paper is to propose a possible primary prevention method of CVD that may
hopefully benefit the public and those in the medical field in fighting CVD.
Defining Vitamin D Deficiency
Vitamin D refers to a collection of fat-soluble steroid which comes in five
different forms vitamin D1-D5 (Table-1), vitamin D2 (ergocalciferol) and vitamin
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D3 (cholecalciferol) being the most studied forms of vitamin D.1
Vitamin D2 is
made by invertebrates and plants after being exposed to ultraviolet radiation and
can be found in certain mushrooms. Vitamin D3 is made endogenously in the skin
after being exposed to ultraviolet B (UVB) light that comes from the sunlight.
UVB light converts cutaneous 7-dehydrocholesterol to vitamin D3. Vitamin D3
produced by the skin is variable depending on skin pigmentation, latitude, season,
clothing, age, sunscreen use, and local weather conditions. Vitamin D3 can also
be derived from food such as cod liver oil, salmon, mackerel, tuna, and also
fortified foods. Dietary intakes of vitamin D only comprise 10-20% of circulating
vitamin D levels. Both vitamin D2 and vitamin D3 can be found in multivitamins
and supplements and have the same ability to increase circulating vitamin D
levels.2-4
Table-1. Five Different Forms of Vitamin D1
Vitamin D Metabolism
Vitamin D is biologically inactive and must be converted into its active
form, 1,25(OH)2D or calcitriol (Figure-1). Vitamin D, produced in the skin or
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ingested in food, multivitamins, or supplements, is either stored in adipose tissue
or brought to the liver where it is converted to 25-hydroxyvitamin D or 25(OH)D
by the enzyme D-25-hydroxylase.4
25(OH)D is the standard measure of a persons
vitamin D status. 25(OH)D is used as a measurement because it is the form of
vitamin D that circulates in blood in the highest concentration (1000x higher in
circulation compared to calcitriol), because it reflects total vitamin D from solar
and dietary exposure as well as conversion from adipose stores, and because of its
long half-life (3 weeks as compared to short 8 hours half-life of calcitriol).5
25(OH)D is then converted into its active form calcitriol in the proximal tubule of
the kidney by the enzyme 25(OH)D-1-hydroxylase. Calcitriol levels are
regulated primarily by the parathyroid hormone (PTH), which will stimulate
calcitriol synthesis when there is a decrease in calcitriol levels. Therefore,
calcitriol levels are a poor measure ofa persons vitamin D status because it may
be normal in deficient states due to the regulatory control of calcitriol levels by
PTH.2-4, 6
Figure-1. Process of vitamin D activation2
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Measure of Vitamin D Status
As stated above, 25(OH)D is the standard measure of a persons vitamin D
status and therefore an important parameter in defining vitamin D deficiency. The
World Health Organization (WHO) and current International Osteoporosis
Foundation guidelines defined vitamin D deficiency as 25(OH)D serum levels
below 10 ng/mL and vitamin D insufficiency as 25(OH)D serum levels below 20
ng/mL. This differs with normal laboratory reference range which is 30-76 ng/mL.
Reasons for setting the low end of 25(OH)D serum normal range at 30 ng/mL are
as follows. Firstly, several studies suggest that levels of PTH rise when levels of
25(OH)D fall below 30 ng/mL. Secondly, several studies suggest that active
calcium absorption is optimal when levels of 25(OH)D is 30 ng/mL. However,
these two reasons are now being questioned as it is found that there is no absolute
threshold level of serum 25(OH)D at which PTH levels rise. Also, peak
absorption of calcium occurs at levels of 25(OH)D between 20 and 30 ng/mL.
Osteoporosis Canada also issued a report defining vitamin D insufficiency as
25(OH)D levels between 10 and 29 ng/mL and suggests that 25(OH)D levels
should be at least 30 ng/mL. Even though definitions of vitamin D insufficiency/
deficiency and interpretation of 25(OH)D levels still varies, it is agreed that serum
25(OH)D levels below 20 ng/mL are considered inadequate.2, 4
Prevalence of Hypovitaminosis D in Indonesia
Hypovitaminosis D can be found in developing countries in East Asia and
the Pacific, including Indonesia (Table-2), despite the fact that most developing
countries lie in the zones that have sufficient sunlight for vitamin D synthesis. The
distance that sunlight travels to the earths atmosphere is the least in regionsnearest the equator, like Indonesia. UVB rays in regions near the equator are most
intense and thus vitamin D synthesis is possible all year long. In developing
countries, hypovitaminosis D is found to be one of the most prevalent childhood
disorders, in addition to infectious disease and malnutrition. Hypovitaminosis D
has also been reported in women of all age groups living in the Philippines,
Malaysia, and Indonesia. A study done in postmenopausal women living in
Jakarta, Indonesia showed that 73% of study participants had a serum 25(OH)D
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level < 50 nmol/l (equivalent to 20 ng/mL). Another study found that over 60% of
504 women 18-40 year old living in Kuala Lumpur or Jakarta, Indonesia were
reported in 2008 to have serum 25(OH)D levels below 50 nmol/l or 20 ng/mL. A
study also done in 2008 reported that 35% of 74 Indonesian elderly women living
in institutionalized care units in Jakarta or Bekasi, Indonesia had serum 25(OH)D
levels below 75 nmol/l (equivalent to 30 ng/mL).7
More studies to assess
prevalence of hypovitaminosis D in Indonesia should be done.
Table-2. Prevalence of Hypovitaminosis D in Developing Countries in East Asian
and the Pacific7
Risk Factors for Hypovitaminosis D
Risk factors associated with hypovitaminosis D includes age, female sex,
obesity, dark skin pigmentation, clothing style, socioeconomic status, nutritional
status, pollution in the atmosphere, and various medical conditions especially
malabsorption syndromes. These risk factors are similar to risk factors for
hypovitaminosis D in Western countries and are therefore not unique to
developing countries. Individuals at the extremes of age (elderly persons,
preschool children, and neonates) are prone to hypovitaminosis D. Aging has been
shown to reduce by half the capacity of the skin to produce cutaneous 7-
dehydrocholesterol that will be converted to vitamin D3. This occurs because of
structural changes in the dermis when a person ages. Furthermore, people of older
age usually spend less time outdoors and have a relatively lower dietary intake.
Obesity also increases a persons susceptibility to hypovitaminosis D. Vitamin D
levels negatively correlates with BMI and fat because vitamin D is stored in
excess adipose tissue. Vitamin D deficiency is twice as likely to be found among
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individuals with obesity compared to non-obese individuals. Skin pigmentation
greatly affects vitamin D synthesis, in which it acts as a natural sunscreen. The
use of sunscreen with a sun protection factor (SPF) greater than 15 also affects
vitamin D synthesis, reducing it by 99%. Clothing style which conceals skin
exposure will also reduce vitamin D synthesis. Socioeconomic status and
nutritional status also affect vitamin D levels. Individuals of low socioeconomic
status are usually malnourished in protein. This may cause a decrease in vitamin
D binding protein in blood, thus diminishing the bodys ability to conserve
25(OH)D. Air or atmospheric pollution has also been associated with lower
vitamin D synthesis. High atmospheric pollution diminishes the amount of UVB
light reaching ground level thus reducing cutaneous vitamin D synthesis.2, 6-7
Vitamin D and Cardiovascular Disease
It has been long known that vitamin D in its active form is responsible for
regulating calcium metabolism and thus affects bone health if insufficient.
Recently, it has been found that hypovitaminosis D not only affects bone health
but also cardiovascular health. Vitamin D receptors have been found on most
tissues in the body including cardiomyocytes, endothelium, and vascular smooth
muscle cells. Circulating calcitriol enters target cell (in its free form or facilitated
by megalin) and binds to vitamin D receptor in the cytoplasm causing
transcription of vitamin D-regulated genes which includes genes important for
innate immunity, muscle function, and endothelial cell proliferation.5-6
Furthermore, extra-renal 25(OH)D-1-hydroxylase (the enzyme that converts
25(OH)D to calcitriol) has also been found in vascular smooth muscle cells.3
Locally produced calcitriol is thought to have an important paracrine orautocrine function in regulating the cardiovascular system.
5First, calcitriol
inhibits proliferation of vascular smooth muscle cells, a process which contributes
to vascular proliferation. Calcitriol also increases synthesis of matrix G1A protein,
a substance which inhibits vascular calcification. Next, calcitriol suppresses levels
of proinflammatory cytokines tumor necrosis factor- and interleukin-6 and
upregulates the level of interleukin-10, an anti-inflammatory cytokine.3
Lastly, in
mice, calcitriol is found to be a negative regulator of the renin-angiotensin system
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(by suppressing renin gene expression) thus affecting an individuals blood
pressure.8
As mentioned previously, in individuals with inadequate vitamin D,
serum 25(OH)D will fall below normal levels but calcitriol levels will remain
normal as it is regulated by PTH. This statement is only true for calcitriol
produced by renal 25(OH)D-1-hydroxylase, but does not apply to locally
produced calcitriol by extra-renal 25(OH)D-1-hydroxylase. Locally produced
calcitriol level is dependent on serum levels of 25(OH)D. Thus, a person with low
levels of serum 25(OH)D will also have low levels of locally produced calcitriol,
and is more prone to CVD.3
Decreased 25(OH)D levels also correlates with elevated PTH serum
levels. Elevated PTH levels may contribute to CVD because PTH promotes
myocyte hypertrophy and vascular remodeling and also stimulates secretion of
proinflammatory cytokines by vascular smooth muscle cells. High levels of PTH
are known to induce the synthesis of interleukin-6. Hyperparathyroidism is also
found to be associated with left ventricular hypertrophy, cardiomyopathy, and
increased mortality.1, 3, 9-10
Studies Linking Vitamin D Deficiency with Cardiovascular Risk
Various studies have been done linking vitamin D deficiency with a risk of
CVD and cardiovascular death. A cohort study was done by Kilkkinen et al on
6,219 Finnish men and women who participated in the Mini-Finland Health
Survey (2,817 men and 3,402 women, mean age 49.4 years old) without history or
findings of CVD at baseline. Blood samples were taken at baseline and levels of
25(OH)D determined by radioimmunoassay. Follow-up was done until death by
CVD or other causes (640 coronary heart disease deaths and 293 cerebrovasculardisease deaths) were identified through linkage with Statistics Finland or until end
of follow-up (maximum 28.9 years, median 27.1 years). Results show that there
was an inverse association between serum 25(OH)D levels and total CVD
mortality. Age-and-sex-adjusted hazard ratio for total CVD death was 0.71 (95%
confidence interval [CI], 0.58 to 0.87, P for trend
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index, alcohol consumption, smoking, physical activity, and season, hazard ratio
for total CVD death was 0.76 (95% CI, 0.61 to 0.95, P=0.005). An inverse
association was also found between serum 25(OH)D levels and the risk of
coronary heart disease in which hazard ratio was 0.83 (95% CI, 0.65-1.06,
P=0.037) for the highest quintile of 25(OH)D serum levels versus the lowest. This
study concludes that a low circulating level of vitamin D may predict a higher risk
of CVD death.11
Another cohort study was conducted by Wang et al on 1,739 Framingham
Offspring Study participants (mean age 59 years old, 947 women, all white)
without previous CVD. Measurement of 25(OH)D serum was done on all 1,739
participants by radioimmunoassay. Only 10% of total participants had 25(OH)D
levels above 30 ng/mL, 28% had 25(OH)D levels below 15 ng/mL, and 9% had
25(OH)D levels below 10 ng/mL. In this study, vitamin D deficiency was defined
as 25(OH)D levels below 15 ng/mL. During the follow up of participants
(maximum 7.6 years, mean 5.4 years), 120 participants among them 57 women
developed a first cardiovascular event (65 coronary heart disease events, 28
cerebrovascular events, 8 occurrences of claudication, and 19 occurrences of heart
failure). Cardiovascular disease was approximately twice as high in participants
with 25(OH)D levels < 15 ng/mL compared to participants with 25(OH)D levels
15 ng/mL. The highest rate of CVD was observed in participants with
hypertension and vitamin D deficiency. Levels of 25(OH)D < 15 ng/mL were
associated with an age-and-sex-adjusted hazard ratio of 2.04 (95% CI, 1.42 to
2.94, P < 0.001) for cardiovascular events compared to levels of 25(OH)D 15
ng/mL. After adjustment for conventional cardiovascular risk factors and renal
function, levels of 25(OH)D < 15 ng/mL were associated with a multivariable-adjusted hazard ratio 1.62 (95% CI, 1.11 to 2.63, P=0.01) for cardiovascular
events compared to levels of 25(OH)D 15 ng/mL. This shows that there is a
significant association between low 25(OH)D levels and risk of cardiovascular
events. Participants with hypertension and low 25(OH)D levels had a greater risk
of cardiovascular events, in which levels of 25(OH)D < 15 ng/mL in hypertensive
participants were associated with a multivariable-adjusted hazard ratio of 2.13
(95% CI, 1.30 to 3.48, P=0.003) for cardiovascular events. This study concludes
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that moderate to severe vitamin D deficiency is associated with an increased
cardiovascular risk, with higher risk in individuals with hypertension.9
Analysis of an electronic medical record database of the integrated
Intermountain Healthcare system identified 41,497 subjects with vitamin D
measurements (mean age 55 years, 74.8% women). Vitamin D levels were
divided into three categories: normal > 30 ng/mL found in 36% of patients, low
16-30 ng/mL found in 47% of patients, and very low 15 ng/mL found in 17% of
patients. Follow-up of patients after vitamin D determination was done for an
average of 1.3 years (maximum 9.3 years). Results of this study showed an
increased prevalence of hypertension (30% relative and 12% absolute) in very low
versus normal categories. There was also an increase in incident hypertension by
62% (P < 0.0001) in low versus normal categories. Increases in prevalence of
heart failure (90% relative and 9% absolute), myocardial infarction (MI) (81%
relative and 2.6% absolute), and stroke (51% relative and 2% absolute) were also
observed in very low versus normal vitamin D categories in subjects 50 years old
(P < 0.0001). Greater hazard ratio for CVD was found in those with very low to
low levels as compared to normal levels.12
Findings from a study presented at the American Heart Associations
scientific conference in 2009 held in Orlando, Florida also reported that low
vitamin D levels is associated with a higher mortality and CVD risk. Patients with
very low levels of serum 25(OH)D were 77% more likely to die, 45% more likely
to develop coronary artery disease, and 78% more likely to suffer from stroke than
patients with normal levels of serum 25(OH)D. Patients with low levels of
25(OH)D were also twice as likely to develop heart failure compared with those
having normal values of 25(OH)D.
13
Examination of 8,351 adult patients with CVDs using data from the
National Health and Nutrition Examination Survey (NHANES) shows that
hypovitaminosis D was highly prevalent in these patients. The CVDs examined
were coronary heart disease (CHD) which includes angina and MI, heart failure,
stroke, and peripheral arterial disease. Results show that hypovitaminosis D was
especially more common in patients with CHD and heart failure. It is still
uncertain whether hypovitaminosis D precedes CVDs in these patients or
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hypovitaminosis D is due to limited physical activity and sunlight exposure as a
result of CVDs.14
Vitamin D and Hypertension
Vitamin D deficiency has been linked with hypertension, a major risk
factor for CVD. The Framingheart Offspring Study found that CVD risk was
greater in participants with hypertension and vitamin D deficiency as compared to
vitamin D deficiency alone.9
Vitamin D is related to blood pressure control
because of the effect it has on the renin-angiotensin system, in which vitamin D in
its active form (calcitriol) suppresses renin gene expression.3, 8
Suppression of
renin activities may be due to increased intracellular calcium levels. Vitamin D
also alters the sensitivity of vascular smooth muscle cells, causing vasodilatation
and thus improved blood flow and lower blood pressure. Serum levels of
25(OH)D inversely correlates with blood pressure.1
A study has been done to examine the associations of serum 25(OH)D
with heart rate, systolic blood pressure, and rate-pressure product (heart rate times
systolic blood pressure). Analysis was done on 27,153 participants 20 years
with measured 25(OH)D determined by radioimmunoassay, heart rate, and
systolic blood pressure in the NHANES. Results of the study showed that pulse
rate and systolic blood pressure increased with decreasing vitamin D levels.
Consequently, rate-pressure product also increased as vitamin D decreased.
Participants with 25(OH)D levels < 10 ng/mL had consistently higher rate-
pressure product than those with 25(OH)D levels 35 ng/mL. This suggests that
vitamin D deficiency may increase cardiac work and cardiac oxygen demand, and
also may affect myocardial blood flow.
15
Vitamin D and Coronary Heart Disease
In addition to its effect on the renin-angiotensin system, vitamin D also
affects endothelial function, vascular compliance, and lipid profile. Low levels of
25(OH)D is associated with endothelial dysfunction (change in endothelium
properties toward decreased vasodilatation and proinflammatory state),2
vascular
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calcification, and higher levels of very low density lipoprotein and triglyceride,1
all contributing to atherosclerosis and may cause CHD.
A nested case-control study was done by Giovannucci et al to assess
whether plasma 25(OH)D levels are associated with risk of CHD. Participants
included 18,225 men health care professionals in the Health Professionals Follow-
up Study (aged 40 to 75 years) who were free of diagnosed CVD at blood
collection. Blood samples were collected at baseline and plasma 25(OH)D levels
were determined by using the radioimmunoassay technique. Plasma 25(OH)D
levels were divided into 4 categories: deficient defined as 25(OH)D levels 15
ng/mL; insufficient defined as 25(OH)D levels between 15.1 to 29.9 ng/mL,
further divided into two different categories at its midpoint; and sufficient defined
as 25(OH)D levels 30 ng/mL. During 10 years of follow-up, 454 participants
were identified with incident non-fatal MI or fatal CHD (352 participants had
non-fatal MI and 102 had fatal CHD). Nine hundred men were randomly selected
as controls. Results of the study showed that plasma 25(OH)D levels were lower
in cases than in controls. Men with lower 25(OH)D concentrations were more
likely to be smokers, less physically active, weigh heavier, and have a parental
history of MI. Risk of MI was significantly elevated in men with deficient levels
of 25(OH)D (relative risk [RR] was 2.42 after adjustment for matching factors,
95% CI, 1.53-3.84, P
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failure and sudden cardiac death. Participants of this study were 3,299 patients of
the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred to
coronary angiography at a single tertiary care center in southwest Germany.
Serum 25(OH)D concentrations of these patients were determined at baseline.
Vitamin D status was classified into four categories based on 25(OH)D
concentrations: severe vitamin D deficiency for 25(OH)D concentrations less than
10 ng/mL, moderate vitamin D deficiency for 25(OH)D concentrations between
10 to 19.99 ng/mL, vitamin D insufficiency for 25(OH)D concentrations between
20 to 29.99 ng/mL, and vitamin D of optimal range for 25(OH)D concentrations
more than 30 ng/mL. Results of this study are as follows. Patients with lower
25(OH)D concentrations were observed to have arterial hypertension, higher New
York Heart Association (NYHA) classes, and impaired left ventricle function.
Levels of N-terminal pro-B-type natriuretic peptide was inversely associated with
25(OH)D concentrations (R= -0.253, P < 0.001). After a median follow-up time of
7.7 years, 188 patients died from sudden cardiac death and 116 patients died of
heart failure. The hazard ratio for death due to heart failure and sudden cardiac
death was 2.84 (95% CI, 1.20 to 6.74) for patients with severe vitamin D
deficiency compared to 5.05 (95% CI, 2.13 to 11.97) for patients with 25(OH)D
levels in the optimal range. These results showed that low levels of 25(OH)D are
associated with myocardial dysfunction, and deaths due to heart failure and
sudden cardiac death.17
Treatment of Vitamin D Deficiency
All these data, presented above, seem to suggest that vitamin D deficiency
is an important risk factor of CVD apart from known conventional risk factors ofCVD. The clinical implication is that vitamin D deficiency should be identified
and corrected to prevent cardiovascular events. Correction of vitamin D
deficiency can be achieved by two different means: first, by increasing
endogenous synthesis of vitamin D; and second, by increasing dietary intakes of
vitamin D (exogenous source of vitamin D).
Endogenous synthesis of vitamin D is related to sunlight exposure and risk
factors for hypovitaminosis D, whereby increasing sunlight exposure and
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eliminating risk factors will lead to an increase in cutaneous vitamin D synthesis.
However, this cannot always be done for every individual. For example, in elderly
persons with changes in the dermis and in individuals living in places with air
pollution which reduces UVB light exposure, risk factors (aging and pollution, in
this case) cannot be eliminated. Hence, individuals with vitamin D deficiency
whose risk factors cannot be eliminated can correct their vitamin D status by
increasing dietary intakes of vitamin D.
Individuals with vitamin D deficiency should first attempt to increase
sunlight exposure and modify risk factors because 95% of the bodys vitamin D
requirement comes from the synthesis of vitamin D in the epidermis. Further,
excessive sunlight exposure cannot cause vitamin D toxicity because UVB will
convert excess vitamin D3 into inert isomers, in contrast to excessive oral vitamin
D intake which can cause vitamin D toxicity if taken at very high doses.18
Increasing dietary intakes of vitamin D may come from three sources
which are: natural foods containing vitamin D such as oily fish (Table-3), fortified
foods, and last vitamin D supplementation. For adults, every 100 IU vitamin
ingested daily increases serum 25(OH)D levels by about 1 ng/mL.4, 18-19
Table-3. Food Sources of Vitamin D
18
Treatment recommendation by Lee at al (Figure-2) for vitamin D
deficiency starts with initiation of 50,000 IU vitamin D2 or D3 weekly for a
period of 8 to 12 weeks (initial repletion phase). Initial repletion phase is followed
by maintenance therapy that can be done in 3 different ways: 1.administration of
50,000 IU vitamin D2 or D3 every two weeks, 2.administration of 1,000 to 2,000
IU vitamin D3 daily, and 3.sunlight exposure for 5 to 10 minutes in Caucasians
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(individuals with darker skin should be exposed to sunlight at longer times)
between 10 in the morning to 3 oclock in the evening. Serum levels of 25(OH)D
should be assessed after 3 to 6 months of treatment.18
Schwalfenberg recommends
the use of vitamin D3 over vitamin D2 because vitamin D2 is associated with
higher risk of toxicity. If prescribed, vitamin D2 therapy should be monitored well
to prevent overdose.20
A maintenance or prevention daily dose of 800-2000 IU or
more will be needed to avoid recurrent deficiency.21
Figure-2.Treatment Recommendation for Vitamin D Deficiency
18
Treatment of vitamin D deficiency is expected to prevent CVDs related
with low levels of vitamin D including CHD and heart failure, taking into
considerations the role of vitamin D in maintaining cardiovascular health. This
includes slowing down atherosclerosis, endothelial dysfunction, and vascular
calcification. Treatment of vitamin D deficiency is also related with a reduction of
hypertension, a major risk factor of CVD, by suppressing the renin-angiotensin
system. Thus, treating vitamin D deficiency in otherwise healthy individuals
should be explored further as a primary prevention method for CVD.
Screening for Vitamin D Deficiency
Although vitamin D deficiency is prevalent even in people living in
regions exposed to the sun (like Indonesia), measurement of serum 25(OH)D
levels is expensive and is therefore not supported as a universal screening method.
Measurement of serum 25(OH)D is generally recommended for those at risk for
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severe deficiency of vitamin D, that is people with decreased intake of vitamin D,
malabsorption of vitamin D due to gastrointestinal problems, or alterations in
renal function (Table-4).21
Measurement of 25(OH)D serum levels should also be
done in patients with musculoskeletal symptoms, such as bone pain, myalgias,
and generalized weakness because these symptoms are often the first sign of
hypovitaminosis D.18, 21
Table-4. Individuals to be Screened for Vitamin D Deficiency 21
Holick argued that with the recognition of widespread vitamin D
deficiency or insufficiency, there is no need to measure everybodys blood
25(OH)D levels. He added that it will be much more cost-effective to implement a
vitamin D supplementation program until there is higher fortification of vitamin D
in more foods. Patients who should be screened for hypovitaminosis D includes
patients with inflammatory bowel disease, cystic fibrosis, liver and kidneydisease, gastric-bypass patients, patients taking antiseizure/ glucocorticoids/ AIDS
medication, patients with primary hyperparathyroidism, and patients with chronic
granulomatous disorders. These patients are at high-risk for vitamin D
deficiency.19
However, these recommendations are made for hypovitaminosis D in
general and it is still unclear who to screen for vitamin D deficiency in relation to
primary prevention of CVD.
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Vitamin D Supplementation
In light of vitamin Ds protective effects on cardiovascular health, several
studies have been done to evaluate the effects of vitamin D supplementations on
risk of CVD. Apart from consistent results of studies confirming a link between
vitamin D and CVDs, results of studies on vitamin D supplementation were not
consistent.
A meta-analysis of 18 randomized controlled trials was done to examine
effect of vitamin D supplementation on any health condition and mortality.
Outcome of analysis was total mortality and the supplementation evaluated was
vitamin D2 and vitamin D3, excluding calcitriol and other vitamin D analogues.
Data related to groups receiving vitamin D were considered from the intervention
group, while data related to groups not receiving vitamin D were considered from
the control group. Mean daily dose of vitamin D used in the trials varied from 300
IU to 2000 IU, but most of the daily doses were between 400 IU and 833 IU.
Difference in serum 25(OH)D levels between intervention groups and control
groups was 1.4 to 5.2-fold greater in intervention groups. The summary RR (=
0.93) of the 18 trials shows a significant decrease in the risk of all-cause mortality
with the use of vitamin D supplementation (95% CI, 0.87-0.99). Results of this
meta-analysis suggest that intake of vitamin D supplements may decease total
mortality, independent of the dose of vitamin D supplements.22
The result of this
meta-analysis is consistent with the result of a cohort study done on 3,285 patients
scheduled for coronary angiography at a single tertiary center which found that
low 25(OH)D and calcitriol levels are independently associated with all-cause and
cardiovascular mortality.
23
Johnson et al studied 36,282 postmenopausal women who joined the
Womens Health Initiative (WHI) 50 to 79 year old at 40 clinical sites, evaluating
the risk of coronary and cerebrovascular events in women given supplementation
of calcium carbonate 500 mg with vitamin D 200 IU twice daily as compared to
women who received placebo. A follow-up of 7 years was done in which 499
women assigned to active calcium/vitamin D and 475 women assigned to placebo
died of MI or CHD. 362 women assigned to calcium/vitamin D and 377 assigned
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21
to placebo were diagnosed with stroke. Risks of coronary revascularization,
angina, heart failure, transient ischemic attack, and outcomes were similar in
women who received calcium/vitamin D and in women who received placebo.
The study concludes that calcium/vitamin D supplementation neither increased
nor decreased the risk for CHD or stroke in participants of the 7-year randomized
trial.24
Several explanations as to why the WHI study was inconsistent with
previous results were because the dose of vitamin D used in the trial was
inadequate and placebo-treated women were allowed to take calcium or vitamin D
supplementation. Experts argue that current recommended daily allowance
recommendations (which is 200 IU for adults 20-50 years old, 400 IU for adults
51-70 year old, and 600 IU for adults >70 years old) are inadequate. The average
older adult needs at least 800 IU vitamin D daily to achieve serum 25(OH)D
concentration sufficient to suppress PTH levels maximally. Further, older adults
with dark skin and limited sun exposure may require 2000 IU daily because ful l
body sun exposure provides 10,000 IU of vitamin D in a day. The prevalence of
vitamin D deficiency in WHI patients is unknown because measurements of
serum 25(OH)D were not done at baseline. This explains why benefits from
vitamin D supplementation were not found because only patients with vitamin D
deficiency would benefit from vitamin D supplementation.25
Inconsistency found in studies done to assess effectiveness of vitamin D
supplementation warrants that large clinical trials be conducted. The vitamin D
and omega-3 trial (VITAL), the first large-scale randomized clinical trial studying
vitamin D and omega-3 for the primary prevention of cancer and CVD should
resolve the issue of whether vitamin D supplementation is effective for primaryprevention of CVD.
3, 9
Conclusion
As discussed above, various studies and reviews have shown that vitamin
D plays a role in maintaining cardiovascular health. Low levels of vitamin D
(reflected by circulating levels of 25(OH)D) are associated with an increased risk
of CVD and also an increased cardiovascular mortality. It is also associated with
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22
an increase in the prevalence of hypertension, a major risk factor for CVD, and
CVDs like CHD and heart failure. Treatment of vitamin D deficiency either by
increasing endogenous or exogenous source of vitamin D in otherwise healthy
individuals may be a primary prevention method for CVD that can be
implemented in various countries with prevalent vitamin D deficiency. However,
who to screen for vitamin D deficiency and effectiveness of vitamin D
supplementation in regards to cardiovascular health are still unclear. The use of
supplementation in treatment of vitamin D deficiency for cardiovascular health
has been studied but results are inconsistent. Ongoing clinical trials studying
vitamin D for the primary prevention of CVD should be able to provide more
answers.
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Curriculum Vitae
Name : Monica Raharjo
Student Number : 030.09.157
Place/ Date of Birth : Jakarta/ 04 March 1992
Gender : Female
Address : Green Garden Blok D3/11-12, Jakarta Barat 11520
Nationality : Indonesian
Phone Number : 0818777019
E-mail Address :[email protected]
Education Background :
1995-1998: TK Kristen XI PBK KPS, Jakarta, Indonesia 1998-2003: Telok Kurau Primary School, Singapore 2003-2009: Morning Star Academy, Jakarta, Indonesia 2009-now: Faculty of Medicine Universitas Trisakti, Jakarta, Indonesia
mailto:[email protected]:[email protected]:[email protected]:[email protected]