thanks Professor Giovannonni, I’m sharing your blog post here from www.http://multiple-sclerosis-research.blogspot.co.uk/
Commentary is in italics. Keep taking the tablets! ( and going on the sunbed, without changing colour)
- Doubt cast on vitamin D’s role against disease
- Vitamin D in the MS media
- T reg problems in MS
- Advent Calendar 12
Posted: 12 Dec 2013 01:53 AM PST
Vitamin controversy is not such a controversy if you ask the experts. #MSBlog #MSResearch“Some of you may have seen the BBC news from last week that covered the meta-analysis below. The press release and article is worth reading. They both question the health benefits of vD supplements and clinical outcome for a host of diseases including MS.”
“The difference between so called observational and intervention studies suggests that low vD levels are a marker of ill health, in our case MS. According this hypothesis inflammatory processes involved in pre-symptomatic MS and the clinical course of MS would reduce vD levels, which would then explain why low vD status is associated with MS. I have a problem with these conclusions regarding MS as they ignore the strong epidemiological data linking vD and/or sunshine to MS, for example latitude, migration studies, month of birth effect, parent-of-origin effects, difference in MS concordance rates between non-identical twins and siblings.”
“As I am not a vD expert I asked Bruce Hollis, one of the world’s preeminent vD experts for an opinion. This is what Bruce said:
‘Same old story, not enough vitamin D and wrong dosing schedules. Please read my recent paper in JCEM online as it discusses these issues. Happy Holidays all.’
The abstract from Bruce Hollis’ review is below. He is simply making the point if you review a large number of studies that use the incorrect dose and dosing schedules of vD you get a result that suggest vD supplementation does not make a difference. In other words if you put crap in you get crap out. What Bruce and his colleagues are suggesting is that we need to properly designed vD intervention studies with adequate vD supplementation schedules that essentially keep your blood vD levels above 100 nmol/L all year round. Why this level? If you study populations that still live a hunter-gather existence in Africa, or people who work outdoor such as farmers and lifeguards, they all have blood levels above 100nmol/L.”
“Therefore this meta-analysis does not change our advice regarding levels of vD supplementation. We still support the vD Council’s recommendations of 5,000U of vD3 per day.”
Conversion units of vD:
This blogs recommendations for levels of vD supplementation:
“Please note that this is an average recommendation and some people may need more than this and other less than this to maintain a blood level between 100 and 200 nmol/L. In an ideal world you would start vD supplementation at this level and after 6-8 weeks you would have your levels checked and adjusted accordingly. There are many factors that control blood levels in an individual apart from the dose of vD. It is also important to note that you should not be taking any calcium supplements with vD. Calcium supplements are only necessary for bone health or if you have thin bones.”
Background: Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known.
Methods: We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality.
Results: High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality.
Conclusions: The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.Hollis and Wagner. The role of the parent compound vitamin d with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013 Dec;98(12):4619-28.
Context: There is no doubt that vitamin D must be activated to the hormonal form 1,25-dihydroxyvitamin D to achieve full biological activity or that many tissues participate in this activation process-be it endocrine or autocrine. We believe that not only is 25-hydroxyvitamin D important to tissue delivery for this activation process, but also that intact vitamin D has a pivotal role in this process.
Objective: In this review, evidence on the vitamin D endocrine/autocrine system is presented and discussed in relation to vitamin D-binding protein affinity, circulating half-lives, and enzymatic transformations of vitamin D metabolites, and how these affect biological action in any given tissue.
Conclusions: Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, as a substrate in many tissues, not originally thought to be important. Based on emerging data from the laboratory, clinical trials, and data on circulating 25-hydroxyvitamin D amassed during many decades, it is likely that for the optimal functioning of these systems, significant vitamin D should be available on a daily basis to ensure stable circulating concentrations, implying that variation in vitamin D dosing schedules could have profound effects on the outcomes of clinical trials because of the short circulating half-life of intact vitamin D.
Posted: 12 Dec 2013 01:54 AM PST
Grishkan IV, Fairchild AN, Calabresi PA, Gocke AR. 1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization. Proc Natl Acad Sci U S A. 2013 Dec. [Epub ahead of print]
Pharmacologic targeting of T helper (TH) cell trafficking poses an attractive opportunity for amelioration of autoimmune diseases such as multiple sclerosis (MS). MS risk is associated with vitamin D deficiency, and its bioactive form, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to prevent experimental autoimmune encephalomyelitis, a mouse model of MS, via an incompletely understood mechanism. Herein, we systematically examined 1,25(OH)2D3 effects on TH cells during their migration from the lymph nodes to the CNS. Our data demonstrate that myelin-reactive TH cells are successfully generated in the presence of 1,25(OH)2D3, secrete proinflammatory cytokines, and do not preferentially differentiate into suppressor T cells. These cells are able to leave the lymph node, enter the peripheral circulation, and migrate to the s.c. immunization sites. However, TH cells from 1,25(OH)2D3-treated mice are unable to enter the CNS parenchyma but are instead maintained in the periphery. Upon treatment cessation, mice rapidly develop experimental autoimmune encephalomyelitis, demonstrating that 1,25(OH)2D3 prevents the disease only temporarily likely by halting TH cell migration into the CNS.
We have had a topsy turvy week in the world of media and vitamin D. Last week the media was saying it is all a load of tosh following studies in non-MS cases published in the Lancet questioning whether vitamin D is all a myth and that vitamin D had marginal effect on autoimmunity in humans and this week it is the bees knees. Is there any wonder why we do not really know what is going on.
Vitamin D is vital for bone health and can influence immune function and is made in humans following sun exposure. This study was in mice, furry animals who prefer to live in the dark. In this study they gave lots of vitamin D and it stops the development of EAE.
That EAE returns after you stop delivering drug is no big shakes and should be expected to happen.
If you have a decent disease induction protocol (as the antigen depot is there) and the natural regulation that occurs with disease development has not been generated, then disease comes back after a few days or weeks following stopping drug treatment. Unfortunately, this can come as a shock to the people not experienced in the world of EAE. This has led to cancelled clinical trial because of the risk of MS rebound.
A logical extreme extension of this idea is that vitamin D works in a way similar to Tysabr to block white cells getting in the brain. So it there evidence that sunshine causes PML? (The brain disease that can occur due to stopping white blood cells getting into the CNS)……….Well No.
So the treatment effect is not going to be in the same league as Tysabri. However, to take another extreme with high dose statins we showed that they could inhibit EAE development and could block migration of cells through brain blood vessels because it could inhibit rearrangement of their cellular skeleton. Within two days of stopping drug disease returned (See D below). So what happened in MS? Despite some influence on lesion load in a few studies in MS as shown in EAE studies….the clinical effect has yet to be shown to be earth shattering at the doses used as found in a few studies. So we can go from something ace to it being a damp squib.
In the study they find apparently that it works by blocking a chemokine receptor called CXCR3 (CD182) is reduced, which is a molecule a bit like a stamp that helps it find the brain postcode (ZIP code) by being attracted to molecules that can be produced in MS lesions. Now, what happens in mice were CXCR3 has been removed, well maybe not a lot in some people’s hands and EAE can develop just fine in the absence of CXCR3 following inhibition.
This study suggests that vitamin D works by stopping white blood cells from entering the brain because it reduces a homing receptor. If this is the actual case if should be easy to test. Giving vitamin D to cells in the test tube in humans suggests that there may be an immune modulatory effect, so not quite the same as found in this mouse study. However, you could for example take bloods from any Northern European/American in winter (who will be vitamin D deficient, particularly if they are non-VD supplementing non-whites) show the cells migrate in test-tube assays, now give the person vitamin D to make them vitamin D replete and you should see a major change.
If vitamin D had such a dramatic impact, there are enough MSers now supplementing with vitamin D for MSers to see a dramatic impact. I personally think that neutriceuticals will have incremental effects, because otherwise they would also come with big side-effects. You may need pharmaceuticals to have major impact. ProfG may think otherwise.
The suggestions that Vitamin D is a risk factor are clear but it maybe has more practical impact in determining whether you will get MS.
Therefore, we should all be ensuring are children are vitamin D replete. This is to my mind where studies should focus. I will be surprised if some clinical trials ongoing will provide useful answers but we will see.
So another bit of Vitamin D in the media last week was questioning whether vitamin D was influencing autoimmunity (in diabetes) in humans. But if you are not doing the right studies are you going to get a useful answer?
You need to ensure you have good bone health to deal with falls and if it limits autoimmunity this is a plus point.