LITHUANIAN UNIVERISTY OF HEALTH SCIENCES
FACULTY OF MEDICINE
Department of Health and Research
Title of master thesis
LITERATURE REVIEW: THE ROLE OF VITAMIN D IN
AUTOIMMUNE DISEASES
2
TABLE OF CONTENTS
1. Summary 3 2. Acknowledgements 5 3. Conflicts of interest 5 4. Abbreviations 6 5. Introduction 76. Aim and objectives 10
3
SUMMARY
Author- Afnan Ahmed
Scientific Supervisor -Dr Egle Vaitkaitiene MD,Professor Research title – The role of vitamin D in autoimmune disease
Aim. To analyze and review the role of vitamin D in autoimmune diseases.
Objectives
1. Assessing the metabolism of vitamin D in the human organism. 2. The analyze the role vitamin D has on the immune system. 3. To evaluate the role of vitamin D in autoimmune diseases.
Methodology
This was a Systematic Literature review where research was conducted using different databases (PubMed, Science direct, BMJ,Journal of Rheumatology). Articles from the year 2000 were chosen with keywords ‘vitamin D’, ‘vitamin D metabolism’, ‘Importance of vitamin D’ and ‘autoimmune diseases’. Articles which filled these criteria were chosen for this review.
Results
Out of the 42 studies, eight found that those with autoimmune disease are more likely to be vitamin deficient. Two studies showed that lower levels of vitamin D is a risk factor for developing autoimmune diseases and three studies showed that that decreased sun exposure in childhood is a risk factor for developing autoimmune diseases. Two studies showed that in adults there was also a higher rate of autoimmune diseases in countries with less sun exposure. Fifteen studies showed there was inverse relationship between disease activity and vitamin D levels. Two studies discovered that vitamin D levels can be used as a prognostic factor if it can be used to assess adequate response to a treatment .Interestingly two other studies proposed an inverse relationship between quality of life with autoimmune diseases and vitamin D levels. However one study did not find any association between vitamin D levels and the risk for developing autoimmune disease.
Conclusion
4 1.There is an inverse relationship between vitamin D and disease activity. The higher the level of Vitamin D the less likelihood of relapses or disease exacerbations. It has been proven that supplementation of Vitamin D improve symptoms in autoimmune diseases.
2.Vitamin D can be used as a prognostic factor in autoimmune diseases. The higher the level of vitamin D the better the patients response to treatment and outcome.
5
ACKNOWLEDGEMENTS
I would like to express my deepest appreciation to Dr Egle Vaitkaitiene for her guidance who enabled me through my final year project
CONFLICT OF INTEREST
6
ABBREVIATIONS
SLE- systemic Lupus Erythematosus
IBD- Inflammatory Bowel Disease
MS-Multiple Sclerosis
DM- Diabetes Mellitus
SLEDAI- Systemic Lupus Erythematous Activity
AI- Autoimmune disease
UC- Ulcerative Colitis
CD- Crohn s Disease
PTH- parathyroid hormone
ESCEO- European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
VDBP- vitamin D binding protein
7
INTRODUCTION
Vitamin D deficiency is a world-wide problem with over a billion people with vitamin D inadequacy [1]. The main source of vitamin D is the sun, therefore the highest rate of vitamin D deficiency can be found in the United states and Europe, especially in countries of low latitude [2,3]. Vitamin D deficiency is also prevalent in those countries which have adequate sunshine throughout the year. This may be due to many factors like high skin melanin content, coverage of skin which are both common in Asia and the Middle East [2]. It is also important to know what the cut-off for vitamin D deficiency and insufficiency is. In recent guideline’s it has been defined that vitamin D levels:
1. Below 50nmol/l is deficiency, 2. 50-74nmol/l is insufficiency
3. Sufficient levels are defined as above 75nmol/l [4,5].
The measurement of vitamin D levels is measured by using serum 25(OH)D even though it is not the active form of vitamin D. 1,25 dihydroxyvitamin D has a half-life of less than 4 hours while 25(OH) has a half-life of 2 days. It is therefore a more reliable marker for Vitamin D level in the body. Also the levels of 1. 25 dihydroxyvitamin D are normal when a person becomes vitamin D deficient due to the compensatory mechanism of PTH. This can therefore be misleading when a person is vitamin D deficient [6,7]
There are three main sources of vitamin D – the sun, diet and vitamin D supplements. The sun being the main source with over 90% of our requirements coming from the sun [8].
Metabolism of vitamin D
Vitamin D is a fat-soluble vitamin. There are two forms of vitamin D in which both are inactive- Vitamin D2 and Vitamin D3. Vitamin D2 also called ergocalciferol is obtained through ones diet eg fish and dairy products( Image 1).Vitamin D3 also called cholecalciferol is synthesized in the skin from -7-dehydrocholesterol.[8]Both vitamin D2 and D3 are metabolized in the liver by cholecalciferol 25-hydrxylase to 25-hydroxyvitamin D ( calcifediol). Calcifediol is then converted to its active metabolite calcitriol in the kidney[8] This conversion is aided by the enzyme 25(OH) D-1alpha –hydroxylase to produce the active metabolite 1,25-(OH) 2D3. Vitamin D is transported around the body bound to vitamin D binding globulin [9]. Calcitriol is also metabolized by 24-OHase which converts calcitriol into calcitriol acid(inactive metabolite) which is excreted in bile.[10]
8 A) Intestine – calcitriol acts on the intestine to increase the synthesis of calcium binding protein which
as a result increases the intestinal absorption of calcium [11].
B) Bone – Calcitriol increases calcification of bone by activating chondrocyte differentiation and also increase resorption of bone to increase serum calcium levels [12].
C) Kidney- Calcitriol acts on the distal tubule of the kidney to reabsorb calcium to increase serum calcium [13].
Regulation of Calcitriol
9
10
AIM
To analyze and literature review on the role of vitamin D in autoimmune diseases.
OBJECTIVES
1. To assessing the metabolism of vitamin D in the human organism. 2. To analyse the role vitamin D has on the immune system.
11
LITERATURE REVIEW
Importance of vitamin D
Bone health is important in gaining a well-balanced lifestyle, one of the many vitamins that contribute to this is vitamin D. This can be best seen, when there is a deficiency in vitamin D, this leads to the development of rickets in children and osteomalcia in adults. The way in which this occurs is, low levels of vitamin D leads to a low calcium levels resulting in excess release of PTH. This Excess in PTH causes secondary hyperparathyroidism and thus reducing the phosphorus reabsorption from the kidney. This hypophosphatemia subsequently causes the release of calcium from bone in order to restore the serum calcium concentrations . As a result of this cascade there is an impairment in bone mineralization and bone weakness[14] leading to bone pain skeletal deformity, fractures and muscle weakness[15].Vitamin D supplementation has also been found to reduce the risk of fractures in people with osteoporosis. In a double blinded study on pregnant women with a history of hip fractures Hitz et al showed that supplementation with 1550 mg of elemental calcium 1400 IU of vitamin D there was decrease in bone turnover, and increase bone mineral density.[16] Pfeifer et al carried out a randomized control trial in which they found there was a 27% decrease in falls in those over the age of 77 when given 1000 mg of calcium plus 800 IU of vitamin D per day. In recent recommendation by the ESCEO recommends 50 nmol/L is the minimal level of vitamin D required to prevent fractures in those with osteoporosis [17].
Effect of vitamin D in the immune system
Manolagas was the first to discover that almost all the immune cells Vitamin D Receptors[18]. This has an effect on different cells in the immune system.
Macrophages: by enhancing their anti-microbial effect, enhancing their chemotactic, phagocytic effects .Enhancement of the chemotactic effect and phagocytic actions and also upregulates cathelicidin results in destabilization of the microbial membrane [19,20].
Dendritic cells: Normal function of dendritic cells is an antigen presenting cells so therefore present antigens to the T cells and B cells and are responsible for the intitation of the adaptive immunity Vitamin D makes them more tolerogenic and in an immature state which leads to the following
12 Inhibition the production of pro-inflammatory molecules eg. IL-12 and IL-23 and increasing the production of anti- inflammatory molecules eg. IL-10[21,22].
T cells: Decrease in the pro-inflammatory effect and having a more of anti-inflammatory by having an effect by the following mechanism; decrease in the production of Th1(INF alpha and 1L-2) and Th17 cytokines (IL17 and IL-21) and an increase in the production of anti-inflammatory TH2 cytokines(IL3, IL4, IL5, IL10). So therefore a skewing the T cell towards a Th2 phenotype .It also has an effect on the T regulator cells in which their normal function
is to supress and inhibit the proliferation of immune cells and help in the prevention of autoimmune disease .Vitamin D inhibits dendritic cells therefore increasing in the proliferation of the regulatory cell[(23,24].
B cells: Vitamin D causes anti-proliferative effects which leads to a decrease in differention, proliferation and ignition of apoptosis and lower levels of immunoglobulins, inhibition of memory and plasma cells and also apoptosis of immunoglobulin producing cells [25]
Image 2. The effect of vitamin D on the immune system [26]
Multiple Sclerosis
13 MS patients, when vitamin D levels were greater than 10ng/l were firstly related to a 15% decrease in the developing new T2 lesions, secondly 33.33% decrease risk of developing contrast enhancing lesions on a brain MRI ,and finally related with a 0.94% decrease in chance of a relapse. The same relationship was proven by Mowry et al in a pediatric group of patients [28]. He found that 85% of his study population had an abnormal vitamin D levels. In this study he revealed an even more significate correlation between vitamin D levels and MS. He discovered there was a 34% drop in the rate of remissions with a 19ng/ml increase in serum 25(OH)D levels. Low vitamin D levels have been proposed as being a risk factor for developing MS [29]. Munger et al measured the serum 25(OH) of 7 millions US soldiers before the onset of MS each of the participants had a minimum of two serum levels for vitamin D measured . He found there was a decrease in the risk of developing MS with an increase in serum 25(OH) levels by 50nmol/l which resulted in an 41% decrease in the risk for developing MS. Furthermore they found there was a significant drop in vitamin D levels in those diagnosed with MS when compared to their levels 6 years prior .There have been two small studies done to evaluate the effectiveness of vitamin D supplementation in MS patients. A total of 18 patients took part in this one year open label study in which they were given 0.5 ng/d oral calcitriol. At the start of the study 1/3 of the patients had gadolinium enhancing lesion on MRI however after evaluating these lesions 48 weeks later this number dropped to 29%. During the study four patients had an exacerbation of their MS. This number increased to nine after the end of the study, and they were no longer taking vitamin D supplements . Although though this difference is not significant in this study, it may be of greater significance if it was done in a bigger population and over a longer period of time [30]. The sun is the main source of vitamin D and studies have shown greater sun exposure results in a decreased risk in developing MS.[31,32]. Kampman et al concluded that there was a 25% decrease in the risk of developing MS with an increase of every unit in the sun exposure [31]. Another study on larger population group showed that there was a 45% decrease in the risk of developing MS with every one unit increase in the sun exposure [32].The same conclusion was reached by some studies in Australia [33]
Rheumatoid arthritis
Merlino et al carried out a population‐based prospective cohort study on a total of 29,368 women
14 insufficient . In a cross-sectional study carried out by Azzeh et al revealed that vitamin D could be used as a predictor for disease activity in RA [36].He found that there was a much higher chance of increased disease activity in those people who had serum 25(OH) levels that was less than 12.3 ng/mL, resulted in a greater chance of increased disease activity in RA. On the other hand there was a lower chance of increase disease activity in those with serum 25(OH) levels more than 17.9 ng/mL meant t a lower chance of disease activity. He also found that across the three disease groups(high, medium and low) the higher the serum level of vitamin D the lower the group. Vitamin D levels have also been associated with disease activity in RA patients. In a study conducted by Elbassiony et al it was demonstrated that low levels of vitamin D was linked to increased disease activity when using DAS- 28-CRP to measure the disease activity[37]. Fakharan et al also came to the same conclusion. They compared three different disease activity groups- low, moderate and high. Those with high disease activity were found to have the lowest vitamin D levels (17.06 mg/ml) when compared to the moderate and low activity group (30.5 and 36.7 mg/ml respectively) [38]. Many studies that have demonstrated the inverse relationship between vitamin D levels and the disease activity, Blaney et al showed that vitamin D can be used amongst other RA markers to evaluate the disease activity [39]. Low vitamin D levels have also been found to have an effect on the quality of life of RA patients[40]. Vojinovic et al carried out a large multicentre study in 13 European countries in which he found a higher rate of vitamin D deficiency and insufficiency in RA patients. This study takes into consideration different types of weather and sun exposure to eliminate bias. Franco et al found that vitamin D levels can be used as a prognostic factor for the response of treatment[41]. In a longitudinal observation retrospective study he concluded those patients that had serum 25(OH ) levels less than < 20 ng/ml at the time of their diagnosis of RA had a higher disease activity [41].In this 12 month follow up when evaluating their response to treatment, they concluded that once again hypovitaminosis was inversely related to response to treatment. Lastly there was a correlation found between exacerbation of RA and levels of vitamin D. It is clear from these studies that vitamin D levels have an effect on the disease activity and the response to treatment. This led Gopinath et al to perform a randomized control trial to evaluate the effectiveness of vitamin D supplementation in RA patients. A total of 121 people took part in this study in which he found a decrease in their pain scale using the VAS analog. Although this is a randomized control trial there are some limitations to this study- It was over a short period of time, VAS analog is a subjective measure of pain and the participants were also taking calcium supplements so the pain relief could be due to the calcium rather than the vitamin D[42].
Systemic lupus erythematosus
16
Diabetes Mellitus
An interesting study that was done to evaluate the serum level of vitamin D binding protein(VDBP )in people with DM type 1. In this study they compared the VDBP levels in three different groups- DM group, control group, those who have a family history of DM. When comparing these groups it was concluded that the lowest level was in the DM group followed by those with a family history of DM and lastly the control group 385.3 µg/mL, 402 µg/mL, 423.5 µg/mL respectively[51]. It has also been found that those with DM type 1 are more likely to be vitamin D deficient. In a study that was carried out in Bern they found that out of the 129 people in the study more than half (60.5%) had serum levels less than 50nmol/l.In this study they took the serum vitamin D levels at different times of the year thereby taking into account the decrease in sun exposure in winter [52]. Another study that was done in Italy, compared a group of 88 newly diagnosed DM type 1 patients with a control group that consisted 57 healthy individulas. The study showed DM patients had a lower serum 25(OH) compared to the control group[53].
A study performed in Saudia Arabia further supported the latter findings. Saudia Arabia is a country in which they have sun exposure all year round. They also concluded that DM patients were vitamin D deficient as compared to the control group. 84% of DM patients were Vitamin D deficient and only 59% of the control group were deficient [54]. As previously mentioned the main source of vitamin D is the sun[8], therefore it is important to determine if the rate of DM is higher in those countries with lower sun exposure when compared to those with higher sun exposure. A study that was done across 51 countries over a 4 year period concluded that there was an increase in the cases of DM type 1 in countries of higher latitudes[55]. All the studies previously discussed have showed a correlation between vitamin D deficiency and DM type 1. However a study conducted in Finland did not find any relationship between the two. A total of 3723 children born between 1997 and 2002 who were considered high risk were included in the study. In this study the mothers were asked to fill out a questionnaire about their vitamin D intake from food and supplements. This study did not show any association between the amount of vitamin D taking during pregnancy and the development of DM. There are some limitations to the latter study. This conclusion was reached after performing a questionnaire which could be unreliable and subjective[56].
Inflammatory bowel Disease
18
METHODS
19
RESULTS
Table 1. Summary of the effects of vitamin D on autoimmune diseases.
No Author Disease Age Gender Type of
Disease Conclusion 1. Mowry et al [27] Multiple sclerosis 18-70 Male and Female Longitudinal cohort study An Increase of 10ng/ml vitamin D levels was associated with a decrease in new T2 lesions by 15% 2. Mowry et al [28] Multiple sclerosis <18 Male and Female longitudinal cohort study An increase of 10ng/ml vitamin D resulted in an 34% decrease in chance in relapse 3. Munger et al [29] Multiple sclerosis 18-48 Male prospective study
Low vitamin D is a risk factor for MS. An increase of 50nmol/l related to a 41% decrease in the risk of developing MS 4. Wingerchuk et al [30] Multiple sclerosis 18-65 Male and Female open label study Supplementation with 2.5ug/d of calcitriol results in a decrease in gandolium enhancing lesions 5. Kampman et al [31] Multiple sclerosis 24-73 Male and Female Retrospective recall questionnaire
Decrease exposure of the sun in childhood is associate with an increase in the risk for Ms
6. Islam at al [32] Multiple sclerosis 15-50 Male and Female
Cohort Study Increase in the risk of developing MS with decrease in sun exposure in childhood 7. van der Mei
et al [33] Multiple sclerosis <60 Male and female Population based case-control study.
20 8. Merlino et al[34] Rheumatoid
Arthritis
55-69 female a population‐
based prospective cohort study
Increase in the risk in developing RA with a decrease in vitamin D intake from diet and supplements
9. Craig et al [35] Rheumatoid Arthritis 51 years Male and Female Longitudinal Study
High rate of vitamin D deficiency and insufficiency in RA patients 10 Azzeh et al [36] Rheumatoid Arthritis 22-75 Male and gender cross-sectional study
Lower levels of vitamin D is a risk factor for RA
11 Elbassiony et al [37] Rheumatoid Arthritis 27–67 Male and Female cross sectional study
Increase in disease activity with low vitamin D levels
12 Fakharan et al [38] Rheumatoid Arthritis 49-52 Male and Female Longitudinal, retrospective study
Vitamin D levels associated with disease activity
13 Blaney et al [39] Rheumatoid Arthritis 20-67 Male and Female
- Vitamin D levels can be used as a disease marker for RA
14 Franco et al [40] Rheumatoid Arthritis 30 and 65 year s Male and Female longitudinal, retrospective study
Vitamin D can used as a prognostic factor for the response of treatment 15 Gopinath et al [41] . Rheumatoid Arthritis Male and Female randomized control trial Supplmentation with s 500 IU/day of 1,25 dihydroxy vitamin D3
21 16 Elbassiony et al [42] Rheumatoid Arthritis 27–67 Male and Female cross sectional study
Increase in disease activity with low vitamin D levels
17 Borba et al[43] SLE cross-sectional
case-control study
Vitamin D deficiency is more common in people with SLE
18 Gado et al[44] SLE 40 Male and
Female
cross-sectional case-control study
Vitamin d deficiency and insuffiency in SLE patients and higher ds-DNA levels in people with vitamin D deficiency
19 Lauren L
Ritterhouse et al [45]
SLE Male and
Female
case control study
Lower levels with people who are ANA positive
20 Amital et al [46]
SLE 13–77 Male and
Female
cohort study Higher disease activity with lower levels of vitamin D
21 Lima et al [47]
SLE <25 Male and
Female
randomized double blinded trial
Decrease in inflammatory markers with vitamin D supplementation 22 Abou-Raya et al [48] SLE 38 y Male And Female randomized double blinded trial
Low vitamin D levels is related to increase in inflammatory markers and increase in disease activity
23 Petri et al [49]
SLE 49-63 Male and
Female
longitudinal observational study
22 24 Quine et al
[50]
SLE Male and
Female
Cohort study Increase in the number of flares with low vitamin D levels 25 Blanton et al [51] Diabetes Mellitus 22 Male and Female retrospective, cross-sectional analysis Decrease in VDBP in DM with vitamin D deficiency
26 Janner et al [52] Diabetes Mellitus 6- 18 Male and Female
cross-sectional High rate of vitamin D deficiency in DM type I 27 Pozzilli1 et al [53] Diabetes Mellitus 14 Male and Female retrospective study Newly diagnosed DM patients have a higher rate of vitamin D deficiency 28 Abbas BS et al [54] Diabetes Mellitus Male and Female prospective cross-sectional study
High rate of vitamin D deficiency in DM 1 29 Mohr et al [55] Diabetes Mellitus <14 Male and Female
Higher rates of DM type 1 in countries in high latitudes
30 Marjamäki et al [56] Diabetes Mellitus 8- 13 Male and Female prospective, population-based cohort No association between maternal vitamin D intake from diet and the risk of developing DM type 1 31 Ananthakrishnan et al [57] Inflammatory Bowel Disease 40–73 Female prospective cohort study
Correlation between vitamin D levels and the risk of devolving UC and Crohns disease and the decrease risk of developing DM with every 100 IU increase in vitamin D 32 Ananthakrishnan et al [58] Inflammatory Bowel Disease 41-49 Male and Female
23 Out of the 42 studies, eight found that those with AI disease are more likely to be vitamin deficient. Two studies showed that lower levels of vitamin D is a risk factor for developing AI diseases and three studies showed that that decreased sun exposure in childhood is a risk factor for developing AI diseases. Two studies showed that in adults there was also a higher rate of AI diseases in countries with less sun exposure. Fifteen studies showed there was inverse relationship between disease activity and vitamin D levels. Two studies discovered that vitamin D levels can be used as a prognostic factor i.e. it can be used to assess adequate response to a treatment. Interestingly two other studies proposed an inverse relationship between quality of life with AI diseases and vitamin D levels. However one study did not find any association between vitamin D levels and the risk for developing AI disease.
33 Blanck et al [59] Inflammatory Bowel Disease >18 Male and Female cross-sectional study
Increase in disease activity with low levels of vitamin
34 Ulitsky et al[60] Inflammatory Bowel Disease 18–88 Male and Female retrospective, observational stud
Low levels of vitamin D related to increase in disease activity and a lower quality of life 35 Alkhouri et al[61] Inflammatory Bowel Disease 1 -18 Male and Female retrospective study
Paediatric group with IBD are more likely to be vitamin D deficient when compared to other minerals
36 Pappa et al[62] Inflammatory Bowel Disease 8-22 Male and Female cross-sectional study
High rate of vitamin D deficiency in
37 Khalili et al[63] Inflammatory Bowel
Disease
30–55 Female prospective study
24
DISCUSSION
From the results it is evident that there are many different roles which vitamin D plays in the above autoimmune diseases. Firstly eight out of the 42 studies found that those with autoimmune disease are more likely to be vitamin D deficient. Some studies found, at the time of diagnosis, there were a high percentage of patient with autoimmune diseases that were vitamin d deficient.
There are 5 different minerals that the human body needs. One study found that out of the 5 minerals vitamin D was the lowest in people with autoimmune diseases. This study thereby concluded that low levels of vitamin D is a risk factor for developing the above autoimmune diseases. One paper highlighted the absolute need for vitamin D in patients with Crohn’s diseases. Its showed there was a decreased risk for needing a Crohn’s related surgery with adequate levels of vitamin D. There were several studies that found with adequate supplementation of Vitamin D there was a decrease in the disease activity in many different ways. For example in MS, there was a decrease in the number of T2 lesions and a decrease in the number of relapses with an increase in the level of vitamin D. The main source of vitamin D is the sun. Studies have been done to evaluate the relationship between sun exposure and developing autoimmune diseases. Three studies found that the likely hood of developing MS is greatly reduced with increased sun exposure in childhood. Two studies found that there was an increase in the rate of IBD and type 2 DM in those places with a decrease in sun exposure . Inflammatory markers are affected with a levels of vitamin D. The lower the vitamin D the higher the inflammatory markers and vice versa.
25
CONCLUSION
In summary, there are many different studies which demonstrate the role vitamin D has on autoimmune disease.
1. There is an inverse relationship between vitamin D and disease activity. The higher the level of Vitamin D the less likelihood of relapses or disease exacerbations. It has been proven that supplementation of Vitamin D improve symptoms in autoimmune diseases.
2. Vitamin D can be used as a prognostic factor in autoimmune diseases. The higher the level of vitamin D the better the patients response to treatment and outcome
26
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