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I don't have a copy of the article. However I recall reading that with good vitamin d levels survival rate of many illnesses are higherShaulPSC UCSent via BlackBerry by AT&TFrom: athan Date: Mon, 29 Dec 2008 09:50:22 -0500To: < >Subject: Article on Vitamin D http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf This is a a somewhat contrarian article about vitamin D... it seems to be saying that vitamin D suppresses the immune system, among a lot of other things that run counter to current thought about vitamin D (such as that sunlight isn't necessary for adequate vitamin D levels, and neither are supplements, and that low vitamin D levels are the result of disease, not a cause and that supplements just make things worse!) I tend to think that I'll need to see a lot more evidence to convince me that he's right, since there seems to be a lot of evidence to the contrary, but I would be be interested in any thoughts about it (especially from , who can probably understand it much better than I can! athan

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I don't have a copy of the article. However I recall reading that with good vitamin d levels survival rate of many illnesses are higherShaulPSC UCSent via BlackBerry by AT&TFrom: athan Date: Mon, 29 Dec 2008 09:50:22 -0500To: < >Subject: Article on Vitamin D http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf This is a a somewhat contrarian article about vitamin D... it seems to be saying that vitamin D suppresses the immune system, among a lot of other things that run counter to current thought about vitamin D (such as that sunlight isn't necessary for adequate vitamin D levels, and neither are supplements, and that low vitamin D levels are the result of disease, not a cause and that supplements just make things worse!) I tend to think that I'll need to see a lot more evidence to convince me that he's right, since there seems to be a lot of evidence to the contrary, but I would be be interested in any thoughts about it (especially from , who can probably understand it much better than I can! athan

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CholangitisSuprt@... wrote:

>

> I don't have a copy of the article. However I recall reading that with

> good vitamin d levels survival rate of many illnesses are higher

>

Yes, that's what most researchers seem to be saying. The article I

linked to was saying that the low vitamin D was caused by the disease,

rather than the other way round, and that supplementation probably

wouldn't help, and might cause more problems. That doesn't agree with

most articles I've read , nor am I knowledgeable enough to evaluate his

argument...

For now I'll go on taking my vitamin D!

athan

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CholangitisSuprt@... wrote:

>

> I don't have a copy of the article. However I recall reading that with

> good vitamin d levels survival rate of many illnesses are higher

>

Yes, that's what most researchers seem to be saying. The article I

linked to was saying that the low vitamin D was caused by the disease,

rather than the other way round, and that supplementation probably

wouldn't help, and might cause more problems. That doesn't agree with

most articles I've read , nor am I knowledgeable enough to evaluate his

argument...

For now I'll go on taking my vitamin D!

athan

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CholangitisSuprt@... wrote:

>

> I don't have a copy of the article. However I recall reading that with

> good vitamin d levels survival rate of many illnesses are higher

>

Yes, that's what most researchers seem to be saying. The article I

linked to was saying that the low vitamin D was caused by the disease,

rather than the other way round, and that supplementation probably

wouldn't help, and might cause more problems. That doesn't agree with

most articles I've read , nor am I knowledgeable enough to evaluate his

argument...

For now I'll go on taking my vitamin D!

athan

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I am having trouble with Adobe right now, so I can't read it yet.

However, after breastfeeding 4 kids I have done a fair amount of

research on how to get vitamin D, and why we are lacking in it in

recent years. One major cause is the American diet, as well as the

dangers of sunlight and the avoidance of exposure. It's true that a

well balanced diet, complete with all nutritional requirements, should

not leave one lacking in Vit D, but how many of us really get that? As

for suppressing my immune system, I have Crohn's which is caused by an

over active immune system. Logic seems to say this would noet be so

detrimental to me. In fact, my CD went into overdrive several years

back when I was taking supplements to *boost* my immune system (before

I knew I had CD). And if Vit D deficiencies are the result of disease,

not the cause, well then what the author propose we do for that? It

would be nice if we could just erase PSC huh? :)

ee

>

> http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

>

> This is a a somewhat contrarian article about vitamin D... it seems to

> be saying that vitamin D suppresses the immune system, among a lot of

> other things that run counter to current thought about vitamin D (such

> as that sunlight isn't necessary for adequate vitamin D levels, and

> neither are supplements, and that low vitamin D levels are the

result of

> disease, not a cause and that supplements just make things worse!)

>

> I tend to think that I'll need to see a lot more evidence to

convince me

> that he's right, since there seems to be a lot of evidence to the

> contrary, but I would be be interested in any thoughts about it

> (especially from , who can probably understand it much

> better than I can!

>

> athan

>

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Thanks for all the infoSent via BlackBerry by AT&TFrom: athan Date: Mon, 29 Dec 2008 11:06:07 -0500To: < >Subject: Re: Article on Vitamin D CholangitisSuprt (AT) aol (DOT) com wrote: > > I don't have a copy of the article. However I recall reading that with > good vitamin d levels survival rate of many illnesses are higher > Yes, that's what most researchers seem to be saying. The article I linked to was saying that the low vitamin D was caused by the disease, rather than the other way round, and that supplementation probably wouldn't help, and might cause more problems. That doesn't agree with most articles I've read , nor am I knowledgeable enough to evaluate his argument... For now I'll go on taking my vitamin D! athan

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I am still trying to pick a side. :)

>

> There are conflicting arguments on both sides of a lot of things

(drinking

> coffee, drinking wine, political parties, religion, evolution, global

> warming, etc.), One tends to pick your side and figure the other side is

> manipulating facts, manufacturing fake facts or ignoring the facts.

>

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I am still trying to pick a side. :)

>

> There are conflicting arguments on both sides of a lot of things

(drinking

> coffee, drinking wine, political parties, religion, evolution, global

> warming, etc.), One tends to pick your side and figure the other side is

> manipulating facts, manufacturing fake facts or ignoring the facts.

>

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I am still trying to pick a side. :)

>

> There are conflicting arguments on both sides of a lot of things

(drinking

> coffee, drinking wine, political parties, religion, evolution, global

> warming, etc.), One tends to pick your side and figure the other side is

> manipulating facts, manufacturing fake facts or ignoring the facts.

>

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If you believe the internet (http://en.wikipedia.org/wiki/Vitamin_D

is one of many examples), you only need 10-15 minutes/day of sunlight in the

spring/summer in temperate latitudes to achieve “normal” levels of

vitamin D. This is for fair skinned people – the only difference

for darker skinned individuals is a little more exposure. There are

numerous examples of this type of article (gone too far with sun protection),

even to the point of the Australian Ministry of Health backing down on previous

recommendations of keeping out of the sun (Australia has the highest incidence

of skin cancer in the world). “International Journal of

Epidemiology .

Her finding: Far more lives are lost to diseases caused by a lack of sunlight

than to those caused by too much.”

For me (Nordic background), 10-15 minutes/day will NOT give me a

tan, but it sure helps my eczema!

As Ian points out, stick around, the conventional wisdom will

change again (e.g., coffee is bad/good/bad/good for you).

Arne

UC 1977, PSC 2000

Alive and well in Minnesota

From:

[mailto: ] On Behalf Of athan

http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

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If you believe the internet (http://en.wikipedia.org/wiki/Vitamin_D

is one of many examples), you only need 10-15 minutes/day of sunlight in the

spring/summer in temperate latitudes to achieve “normal” levels of

vitamin D. This is for fair skinned people – the only difference

for darker skinned individuals is a little more exposure. There are

numerous examples of this type of article (gone too far with sun protection),

even to the point of the Australian Ministry of Health backing down on previous

recommendations of keeping out of the sun (Australia has the highest incidence

of skin cancer in the world). “International Journal of

Epidemiology .

Her finding: Far more lives are lost to diseases caused by a lack of sunlight

than to those caused by too much.”

For me (Nordic background), 10-15 minutes/day will NOT give me a

tan, but it sure helps my eczema!

As Ian points out, stick around, the conventional wisdom will

change again (e.g., coffee is bad/good/bad/good for you).

Arne

UC 1977, PSC 2000

Alive and well in Minnesota

From:

[mailto: ] On Behalf Of athan

http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

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Share on other sites

If you believe the internet (http://en.wikipedia.org/wiki/Vitamin_D

is one of many examples), you only need 10-15 minutes/day of sunlight in the

spring/summer in temperate latitudes to achieve “normal” levels of

vitamin D. This is for fair skinned people – the only difference

for darker skinned individuals is a little more exposure. There are

numerous examples of this type of article (gone too far with sun protection),

even to the point of the Australian Ministry of Health backing down on previous

recommendations of keeping out of the sun (Australia has the highest incidence

of skin cancer in the world). “International Journal of

Epidemiology .

Her finding: Far more lives are lost to diseases caused by a lack of sunlight

than to those caused by too much.”

For me (Nordic background), 10-15 minutes/day will NOT give me a

tan, but it sure helps my eczema!

As Ian points out, stick around, the conventional wisdom will

change again (e.g., coffee is bad/good/bad/good for you).

Arne

UC 1977, PSC 2000

Alive and well in Minnesota

From:

[mailto: ] On Behalf Of athan

http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

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Hi athan;

Thanks for posting this article. Before adding my own personal

comments [it's a very controversial issue!!], I thought it would be

good to share some of the correspondence that this article generated

in " BioEssays " earlier this year. There were 2 letters followed by a

reply by Marshall:

____________________________________

BioEssays 30:506-507, 2008 Wiley Periodicals, Inc.

B. Grant

Sunlight, Nutrition, and Health Research Center (SUNARC)

P.O. Box 641603, San Francisco, CA 94164-1603.

E-mail: wbgrant@...

Cedric F. Garland

Department of Family and Preventive Medicine 0631C

University of California San Diego, La Jolla, CA.

For readers wishing additional supporting references please contact

Dr Grant

The health benefits of vitamin D greatly outweigh the health risks

Sir,

In his recent essay, Trevor G. Marshall explores how vitamin D

supplementation may be contributing to the current epidemics of

obesity and chronic disease.(1) Unfortunately, he has overlooked many

important papers that disagree with his hypothesis. This letter

points out some of the omissions.

The health benefits of vitamin D3 have been reviewed recently.(2) The

benefits for bone health have been known for nearly a century.

Benefits for cancer, infectious diseases, autoimmune diseases and

metabolic diseases have been identified in the past three decades.

Starting in the 1980s, largely observational evidence mounted that

solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of

many types of cancer.(3) Based on observational studies, it is

estimated that 2500 and 3600 International Units (IU) of vitamin D3

are required daily for a 30-50% reduction in risk of colorectal and

breast cancer, respectively.(4,5) A recent randomized, double-blind,

placebo controlled clinical trial that studied post-menopausal women

in Nebraska found a 77% reduction in all-cancer incidence between the

ends of the first and fourth years,(5) adding strong support to the

observational studies.

Vitamin D enhances innate immunity through induction of human

cathelicidin, LL-37.(1) LL-37 helps control both bacterial and viral

infections. A recent post-hoc analysis of vitamin D3 supplementation

for post-menopausal women living in New York State found substantial

benefits in reducing the common cold and influenza for 800 IU/day,

and very strong benefits for 2000 IU/day.(6) Benefits also appear to

be strong for septicaemia (Grant, submitted).

Many autoimmune diseases appear to arise from an improper immune

response to viral infections. Since LL-37 reduces the risk of viral

infections, it may also influence the risk of autoimmune diseases

such as multiple sclerosis. The well-known increase in prevalence of

multiple sclerosis with increasing latitude is consistent with this

hypothesis.

There is also a growing body of literature that low vitamin D status

is a risk factor for many metabolic diseases, including hypertension,

type 2 diabetes, and cardiovascular disease.(2) A recent

observational study found that vitamin D deficiency is associated

with incident cardiovascular disease.(7)

There are some diseases where vitamin D supplementation may be

contraindicated. These include granulomatous diseases such as

sarcoidosis where local production of 1,25-dihydroxyvitamin D

(calcitriol) in response to the disease can leak into the serum and

dysregulate calcium metabolism.(8)

The current vitamin D3 fortification of food in the United States

contributes an average of 250-300 IU/day to the American diet. This

amount is too low to have a substantial beneficial effect on risk of

cancer. Intake or production of vitamin D3 of 1000-2000 IU/day seems

now to be required for optimal health, and typically will raise serum

25-hydroxyvitamin D (calcidiol) levels to 40-60 ng/mL.(4,6,9)

It is possible that the reason that there have not been more clinical

trials of vitamin D supplementation clinical trials is that there is

little income in selling vitamin D3 (a year's supply of 1500 IU/day

costs less than $20 U.S.), and such trials are expensive.

The rising prevalence of obesity in the United States has been

attributed to over consumption of popular energy-dense foods compared

to energy output.(10) Until obesity is eliminated, increased vitamin

D3 supplementation and fortification of foods could provide

substantial health benefits, including reduced incidence of several

serious diseases.

Disclosure

WBGreceives funding from the UV Foundation (McLean, VA), the Vitamin

D Society (Canada), and the European Sunlight Association.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. Bioessays 30:173-182.

2. Holick MF. 2007. Vitamin D deficiency. N Engl J Med 357:266-281.

3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H et al.

2006. The role of vitamin D in cancer prevention. Am J Public Health

96:252-261.

4. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. 2007. What

is the dose-response relationship between vitamin D and cancer risk?

Nutr Rev 65:S91-95.

5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.

2007. Vitamin D and calcium supplementation reduces cancer risk:

results of a randomized trial. Am J Clin Nutr 85:1586-1591.

6. Aloia JF, Li-Ng M. 2007. Re: epidemic influenza and vitamin D.

Epidemiol Infect 135:1095-1096; author reply 1097-1098.

7. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al.

2008. Vitamin D Deficiency and Risk of Cardiovascular Disease.

Circulation [Epub ahead of print].

8. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

9. Cannell J, Hollis B, Zasloff M, Heaney R. 2008. Diagnosis and

treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107-118.

10. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. New York: Penguin Press. 430

____________________________________

BioEssays 30:508-509, 2008 Wiley Periodicals,

Barbara J. Boucher

Centre for Diabetes & Metabolic Medicine

Barts & the London Medical & Dental School, London, UK

E-mail: bboucher@...

DOI 10.1002/bies.20751

Published online in Wiley InterScience (www.interscience.wiley.com).

Comment on " Vitamin D discovery outpaces FDA decision making "

" Before you let the sun in, make sure it wipes its shoes "

Dylan , Under Milk Wood. 1954

Sir,

It is always wise to consider evidence from points of view other than

those that are current `received wisdom' so that we can see clearly

what we are really looking at. Thus, the above review is of

considerable interest.(1) The author postulates that circulating

hormonal [activated] vitamin D (calcitriol) concentration is more

important than circulating 25-hydroxyvitamin D [25-(OH)D] in the

determination of tissue functions that are modulated by vitamin D. He

also appears to suggest that changes in circulating 25-hydroxy

vitamin D reflect changes in calcitriol formation and uptake rather

than availability of vitamin D and that circulating calcitriol

concentration tells us about vitamin D effectiveness. This would

indeed be the case if all tissues depended on uptake of calcitriol

from the circulation for their supplies of hormonal vitamin D.

However, many tissues express the hydroxylase activating vitamin D

and several have been confirmed as producers of calcitriol in situ.(2-

4) Such tissues must use circulating 25-(OH)D, the substrate for

activation by 25-hydroxyvitamin D 1-alphahydroxylase. Thus, for

example, in the placenta, calcitriol is produced in large amounts

from early in pregnancy with increases in circulating maternal

calcitriol and reductions in maternal circulating 25-(OH)D.(4)

However, to suggest that all variation on serum 25-(OH)D

concentrations in different disease processes reflects changes in

local tissue vitamin D activation to the exclusion of variations due

to the amount of vitamin D in the body would be to ignore the massive

changes in serum 25-(OH)D seen within hours of exposure to UVB,

without any changes in circulating calcitriol(5) and would not

explain the remarkable seasonal variations in serum 25-(OH)D seen

with variation in available effective UVB from sunlight, with

variations in dietary intake of vitamin D and with supplement use. In

Sweden for example, in a group of 116 women in the winter, an average

serum 25(OH)D of 69 nmol/l was accounted for by the following: (1)

daily intake of normally fortified Swedish foods, 6.2 nmol/l, (2)

three fish meals/week, 25.5 nmol/l, (3) regular vitamin supplement

use, 11.0 nmol/l and (4) a vacation in the sun within the last 6

months, 14.5 nmol/l, which leaves 11.8 nmol/l of 25-(OH)D to be

accounted for the balance between incoming vitamin D and the amount

of 25-(OH)D being consumed by local vitamin D activating tissues.

(6,7) In addition, however much ultraviolet B effective for induction

of vitamin D synthesis [effUVb] one is exposed to, vitamin D toxicity

does not develop because of feed-back mechanisms in the skin itself.

(8) Similarly, feedback mechanisms ensure that circulating calcitriol

is virtually unchanged in the face of reductions in serum 25-(OH)D in

the circulation until there is clinically obvious vitamin D

deficiency with bone disease such as rickets or osteomalacia when

calcitriol does eventually fall, though even then, in some case,

serum calcitriol is found to be increased.(9) These findings

challenge the argument that vitamin D modulation of tissue function

depends predominantly on circulating calcitriol and explain why

vitamin D repletion continues to be judged at present by circulating

concentrations of the storage adduct, 25-(OH)D, acting as it does as

the substrate for local tissue activation throughout the body and not

just in the kidney. In support of this position, it is well known

that measurement of circulating calcitriol [hormonally active

1,25dihydroxyvitamin D] is unhelpful in the assessment of vitamin D

repletion since its concentrations are normally so tightly regulated

across a wide range of concentrations of 25-(OH)D.(10) Finally, the

fact that vitamin D activation has been demonstrated in several of

the extrarenal human tissues known to express specific vitamin D

activating 1-alpha hydroxylase supports the view that assessment of

substrate availability of vitamin D, as reflected by serum 25-(OH)D,

is likely to be of importance in the assessment of vitamin D

repletion in humans.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

2. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin Da-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

3. Merke J, Milde P, Lewicka S, Hugel U, Mangelsdorf DJ, et al. 1989.

J Clin Invest. 83:1903-1915.

4. KN, Bulmer JN, Kilby MD, Hewison M. 2004. Vitamin D and

placental-decidual function. J Soc Gynecol Investig 11:263-271.

5. Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosen T, et

al. 1995. Sunlight increases serum 25(OH) vitamin D concentration

whereas 1,25(OH)2D3 is unaffected. Results from a general population

study in Goteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr

49: 44-407.

6. Engelsen O, Brustad M, Aksnes L, Lund E. 2005. Daily duration of

vitamin D synthesis in human skin with relation to latitude, total

ozone, altitude, ground cover, aerosols and cloud thickness.

Photochem Photobiol 81:1287-1290.

7. Burgaa A, Akesson A, Oster A, sson K, Wolk A. 2007.

Associations of diet, supplement use and ultraviolet B radiation

exposure with vitamin D status in Swedish women during winter. Am J

Clin Nutr 86: 404.

8. Bickle DD. 1997. Vitamin D and Skin. Chapter 25 in Vitamin D. Ed.

Feldman D, Glorieux FH, Wesley Pike J. 379-394.

9. Pettifor JM, s ED. 1997. Vitamin D deficiency and

nutritional rickets in children. Chapter 42 in Vitamin D. Ed. Feldman

D, Glorieux FH, Wesley Pike J. 663-678.

10. Hollis B. 1997. Detection of vitamin D and its major metabolites.

Chapter 38 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J.

587-606.

____________________________________

BioEssays 30:510-511, 2008 Wiley Periodicals, Inc.

Trevor G. Marshall

School of Biological Sciences

and Biotechnology

c/o 3423 Hill Canyon Avenue

Murdoch University

Western Australia

E-mail: trevor.m@...

Author's reply to correspondence from Drs Grant, Garland, and Boucher

Sir,

The primary function of calcitriol, 1,25-dihydroxyvitamin-D (1,25-D),

is to activate the Vitamin D Nuclear Receptor (VDR), enabling

transcription and transrepression of genes. Even pathways previously

thought to be 'non-genomic' have been shown to rely upon gene

transcription.(1) Thus, the measured level of 25-hydroxyvitamin-D (25-

D) is not sufficient to determine " Vitamin D deficiency " or " Vitamin

D status " . Only the 1,25-D form of Vitamin D has the ability to

activate the VDR to transcribe genes, and therefore only measurements

including this metabolite can accurately describe the overall

homeostasis of the Vitamin D metabolism in man [see Ref. 2, Fig. 1].

Dr Boucher has highlighted many of the difficulties confronting

clinical medicine as it expands its knowledge base from the level of

tissues, as seen under the microscope, to that of individual genes

and proteins, interacting at the submicroscopic scale of the

molecule. Even though there are decades of clinical studies

attempting to delineate the association between health, disease and

the Vitamin D metabolites, any study conducted without reference to

genes, or transcription, must necessarily lead to an incomplete

characterization.

Drs. Grant and Garland correctly note that low levels of 25-D are

associated with many diseases. Yet they extrapolate that observation

to imply that a causal relationship should be expected between this

(largely inactive) metabolite, and those disease states. This is a

non sequitur, as our article shows there is not a first-order mass-

action relationship between the dosage of exogenous Vitamin D and the

measured level of the 25-D metabolite (see Ref. 2, Fig. 1). Not only

are there multiple metabolic feedback control mechanisms, there are

control inputs via Protein Kinase A (PKA), in addition to the steroid

and xenobiotic ligands of PXR. Our article explains why the observed

lower level of 25-D metabolite is a symptom of Vitamin D

dysregulation resulting from the disease state, an attempt by the

body to bring the level of the active metabolite back into its

control range.

Exploring the cause of the obesity epidemic, we took the rhetorical

question from Bajzer and Seeley,(3) " are gut bacteria a factor in the

obesity epidemic " , and built a detailed putative pathogenesis, based

on our molecular, and clinical, knowledge. Specifically cited were

two carefully controlled studies,(4,5) which had failed to show a

causal relationship between lifestyle, nutritional choices and

obesity. It would have been helpful if Grant and Garland could have

addressed any specific failings they might have seen in those

controlled studies, rather than give the citation they chose(6) as

the basis for their argument.

They suggest that deficiencies in the available clinical trials can

be blamed on the low profit potential from sales of the secosteroid

itself. Although the direct cost of Vitamin D supplements may not be

great, there is money to be made from market positioning, enough to

attract the interest of a large multinational. Our article explains

how the Coca-Cola Company has petitioned the FDA to be allowed to add

a high level of Vitamin D to their brands of orange juice, so that

they can claim that it reduces the risk of osteoporosis.(7) There is

clearly money available for higher quality studies. However, because

this secosteroid is still classified as a vitamin, rather than as a

drug, the FDA has not yet begun insisting that a more rigorous

understanding of the underlying biology be brought to bear upon

Vitamin D trial design.

Grant and Garland accept that sarcoidosis is a chronic inflammatory

diagnosis in which Vitamin D supplementation might do harm, but we

feel they need to address why other autoimmune diagnoses might not be

similarly exacerbated by supplementation. Our 2004 paper " Sarcoidosis

succumbs to antibiotics - implications for autoimmune disease " (8)

canvassed a homogeneity of inflammatory pathogeneses, a hypothesis

that has subsequently been supported by the emerging clinical

evidence.(9-11)

We do not disagree with the primary premise of Grant and Garland,

that Vitamin D supplementation of the food supply is one of the most

important public health issues of our time. Our article is arguing

that more sophisticated study designs will be needed if one is to

definitively evaluate the metabolism responsible for expression of at

least 913 genes. Only then can we determine if, and to what degree,

addition of Vitamin D to the food chain might be beneficial to the

public's health.

References

1. Bravo S, Paredes R, Izaurieta P, Lian JB, Stein JL, et al. 2006.

The classic receptor for 1alpha,25-dihydroxy vitamin D3 is required

for non-genomic actions of 1alpha,25-dihydroxy vitamin D3 in

osteosarcoma cells. J Cell Biochem 99:995-1000.

2. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

3. Bajzer M, Seeley RJ. 2006. Physiology: obesity and gut flora.

Nature 444: 1009-1010.

4. Caballero B, Clay T, SM, Ethelbah B, Rock BH, et al. 2003.

Pathways Study Research Group. Pathways: a school-based, randomized

controlled trial for the prevention of obesity in American Indian

schoolchildren. Am J Clin Nutr 78:904-905.

5. Reilly JJ, L, Montgomery C, on A, Fisher A, et al.

2006. Physical activity to prevent obesity in young children: cluster

randomised controlled trial. BMJ 333:1041.

6. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. Penguin Press, New York. 430 pp.

7. DHHS Food and Drug Administration. 2007. Food Labeling; Health

Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and

Osteoporosis. 21 CFR Part 101 [Docket No. 2004P-0464] Federal

Register/Vol. 72, No. 3/Friday, January 5, 2007.

8. Marshall TG, Marshall FE. 2004. Sarcoidosis succumbs to

antibiotics - implications for autoimmune disease. Autoimmunity

Reviews 3:295-3001.

9. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. 2006.

High levels of active 1,25-dihydroxyvitamin D despite low levels of

the 25-hydroxyvitamin D precursor - Implications of dysregulated

vitamin D for diagnosis and treatment of Chronic Disease. In: Stoltz

VD, editor. Vitamin D: New Research, Vol. 1. New York: Nova Science

Publishers.

10. Arnson Y, Amital H, Shoenfeld Y. 2007. Vitamin D and

autoimmunity: New aetiological and therapeutic considerations. Ann

Rheum Dis 66(9):1137-1142.

11. Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to

Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract

presentation, Days of Molecular Medicine 2006. Copy available from

URL http://autoimmunityresearch.org/karolinska-handout.pdf.

____________________________________

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

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Share on other sites

Hi athan;

Thanks for posting this article. Before adding my own personal

comments [it's a very controversial issue!!], I thought it would be

good to share some of the correspondence that this article generated

in " BioEssays " earlier this year. There were 2 letters followed by a

reply by Marshall:

____________________________________

BioEssays 30:506-507, 2008 Wiley Periodicals, Inc.

B. Grant

Sunlight, Nutrition, and Health Research Center (SUNARC)

P.O. Box 641603, San Francisco, CA 94164-1603.

E-mail: wbgrant@...

Cedric F. Garland

Department of Family and Preventive Medicine 0631C

University of California San Diego, La Jolla, CA.

For readers wishing additional supporting references please contact

Dr Grant

The health benefits of vitamin D greatly outweigh the health risks

Sir,

In his recent essay, Trevor G. Marshall explores how vitamin D

supplementation may be contributing to the current epidemics of

obesity and chronic disease.(1) Unfortunately, he has overlooked many

important papers that disagree with his hypothesis. This letter

points out some of the omissions.

The health benefits of vitamin D3 have been reviewed recently.(2) The

benefits for bone health have been known for nearly a century.

Benefits for cancer, infectious diseases, autoimmune diseases and

metabolic diseases have been identified in the past three decades.

Starting in the 1980s, largely observational evidence mounted that

solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of

many types of cancer.(3) Based on observational studies, it is

estimated that 2500 and 3600 International Units (IU) of vitamin D3

are required daily for a 30-50% reduction in risk of colorectal and

breast cancer, respectively.(4,5) A recent randomized, double-blind,

placebo controlled clinical trial that studied post-menopausal women

in Nebraska found a 77% reduction in all-cancer incidence between the

ends of the first and fourth years,(5) adding strong support to the

observational studies.

Vitamin D enhances innate immunity through induction of human

cathelicidin, LL-37.(1) LL-37 helps control both bacterial and viral

infections. A recent post-hoc analysis of vitamin D3 supplementation

for post-menopausal women living in New York State found substantial

benefits in reducing the common cold and influenza for 800 IU/day,

and very strong benefits for 2000 IU/day.(6) Benefits also appear to

be strong for septicaemia (Grant, submitted).

Many autoimmune diseases appear to arise from an improper immune

response to viral infections. Since LL-37 reduces the risk of viral

infections, it may also influence the risk of autoimmune diseases

such as multiple sclerosis. The well-known increase in prevalence of

multiple sclerosis with increasing latitude is consistent with this

hypothesis.

There is also a growing body of literature that low vitamin D status

is a risk factor for many metabolic diseases, including hypertension,

type 2 diabetes, and cardiovascular disease.(2) A recent

observational study found that vitamin D deficiency is associated

with incident cardiovascular disease.(7)

There are some diseases where vitamin D supplementation may be

contraindicated. These include granulomatous diseases such as

sarcoidosis where local production of 1,25-dihydroxyvitamin D

(calcitriol) in response to the disease can leak into the serum and

dysregulate calcium metabolism.(8)

The current vitamin D3 fortification of food in the United States

contributes an average of 250-300 IU/day to the American diet. This

amount is too low to have a substantial beneficial effect on risk of

cancer. Intake or production of vitamin D3 of 1000-2000 IU/day seems

now to be required for optimal health, and typically will raise serum

25-hydroxyvitamin D (calcidiol) levels to 40-60 ng/mL.(4,6,9)

It is possible that the reason that there have not been more clinical

trials of vitamin D supplementation clinical trials is that there is

little income in selling vitamin D3 (a year's supply of 1500 IU/day

costs less than $20 U.S.), and such trials are expensive.

The rising prevalence of obesity in the United States has been

attributed to over consumption of popular energy-dense foods compared

to energy output.(10) Until obesity is eliminated, increased vitamin

D3 supplementation and fortification of foods could provide

substantial health benefits, including reduced incidence of several

serious diseases.

Disclosure

WBGreceives funding from the UV Foundation (McLean, VA), the Vitamin

D Society (Canada), and the European Sunlight Association.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. Bioessays 30:173-182.

2. Holick MF. 2007. Vitamin D deficiency. N Engl J Med 357:266-281.

3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H et al.

2006. The role of vitamin D in cancer prevention. Am J Public Health

96:252-261.

4. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. 2007. What

is the dose-response relationship between vitamin D and cancer risk?

Nutr Rev 65:S91-95.

5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.

2007. Vitamin D and calcium supplementation reduces cancer risk:

results of a randomized trial. Am J Clin Nutr 85:1586-1591.

6. Aloia JF, Li-Ng M. 2007. Re: epidemic influenza and vitamin D.

Epidemiol Infect 135:1095-1096; author reply 1097-1098.

7. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al.

2008. Vitamin D Deficiency and Risk of Cardiovascular Disease.

Circulation [Epub ahead of print].

8. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

9. Cannell J, Hollis B, Zasloff M, Heaney R. 2008. Diagnosis and

treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107-118.

10. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. New York: Penguin Press. 430

____________________________________

BioEssays 30:508-509, 2008 Wiley Periodicals,

Barbara J. Boucher

Centre for Diabetes & Metabolic Medicine

Barts & the London Medical & Dental School, London, UK

E-mail: bboucher@...

DOI 10.1002/bies.20751

Published online in Wiley InterScience (www.interscience.wiley.com).

Comment on " Vitamin D discovery outpaces FDA decision making "

" Before you let the sun in, make sure it wipes its shoes "

Dylan , Under Milk Wood. 1954

Sir,

It is always wise to consider evidence from points of view other than

those that are current `received wisdom' so that we can see clearly

what we are really looking at. Thus, the above review is of

considerable interest.(1) The author postulates that circulating

hormonal [activated] vitamin D (calcitriol) concentration is more

important than circulating 25-hydroxyvitamin D [25-(OH)D] in the

determination of tissue functions that are modulated by vitamin D. He

also appears to suggest that changes in circulating 25-hydroxy

vitamin D reflect changes in calcitriol formation and uptake rather

than availability of vitamin D and that circulating calcitriol

concentration tells us about vitamin D effectiveness. This would

indeed be the case if all tissues depended on uptake of calcitriol

from the circulation for their supplies of hormonal vitamin D.

However, many tissues express the hydroxylase activating vitamin D

and several have been confirmed as producers of calcitriol in situ.(2-

4) Such tissues must use circulating 25-(OH)D, the substrate for

activation by 25-hydroxyvitamin D 1-alphahydroxylase. Thus, for

example, in the placenta, calcitriol is produced in large amounts

from early in pregnancy with increases in circulating maternal

calcitriol and reductions in maternal circulating 25-(OH)D.(4)

However, to suggest that all variation on serum 25-(OH)D

concentrations in different disease processes reflects changes in

local tissue vitamin D activation to the exclusion of variations due

to the amount of vitamin D in the body would be to ignore the massive

changes in serum 25-(OH)D seen within hours of exposure to UVB,

without any changes in circulating calcitriol(5) and would not

explain the remarkable seasonal variations in serum 25-(OH)D seen

with variation in available effective UVB from sunlight, with

variations in dietary intake of vitamin D and with supplement use. In

Sweden for example, in a group of 116 women in the winter, an average

serum 25(OH)D of 69 nmol/l was accounted for by the following: (1)

daily intake of normally fortified Swedish foods, 6.2 nmol/l, (2)

three fish meals/week, 25.5 nmol/l, (3) regular vitamin supplement

use, 11.0 nmol/l and (4) a vacation in the sun within the last 6

months, 14.5 nmol/l, which leaves 11.8 nmol/l of 25-(OH)D to be

accounted for the balance between incoming vitamin D and the amount

of 25-(OH)D being consumed by local vitamin D activating tissues.

(6,7) In addition, however much ultraviolet B effective for induction

of vitamin D synthesis [effUVb] one is exposed to, vitamin D toxicity

does not develop because of feed-back mechanisms in the skin itself.

(8) Similarly, feedback mechanisms ensure that circulating calcitriol

is virtually unchanged in the face of reductions in serum 25-(OH)D in

the circulation until there is clinically obvious vitamin D

deficiency with bone disease such as rickets or osteomalacia when

calcitriol does eventually fall, though even then, in some case,

serum calcitriol is found to be increased.(9) These findings

challenge the argument that vitamin D modulation of tissue function

depends predominantly on circulating calcitriol and explain why

vitamin D repletion continues to be judged at present by circulating

concentrations of the storage adduct, 25-(OH)D, acting as it does as

the substrate for local tissue activation throughout the body and not

just in the kidney. In support of this position, it is well known

that measurement of circulating calcitriol [hormonally active

1,25dihydroxyvitamin D] is unhelpful in the assessment of vitamin D

repletion since its concentrations are normally so tightly regulated

across a wide range of concentrations of 25-(OH)D.(10) Finally, the

fact that vitamin D activation has been demonstrated in several of

the extrarenal human tissues known to express specific vitamin D

activating 1-alpha hydroxylase supports the view that assessment of

substrate availability of vitamin D, as reflected by serum 25-(OH)D,

is likely to be of importance in the assessment of vitamin D

repletion in humans.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

2. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin Da-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

3. Merke J, Milde P, Lewicka S, Hugel U, Mangelsdorf DJ, et al. 1989.

J Clin Invest. 83:1903-1915.

4. KN, Bulmer JN, Kilby MD, Hewison M. 2004. Vitamin D and

placental-decidual function. J Soc Gynecol Investig 11:263-271.

5. Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosen T, et

al. 1995. Sunlight increases serum 25(OH) vitamin D concentration

whereas 1,25(OH)2D3 is unaffected. Results from a general population

study in Goteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr

49: 44-407.

6. Engelsen O, Brustad M, Aksnes L, Lund E. 2005. Daily duration of

vitamin D synthesis in human skin with relation to latitude, total

ozone, altitude, ground cover, aerosols and cloud thickness.

Photochem Photobiol 81:1287-1290.

7. Burgaa A, Akesson A, Oster A, sson K, Wolk A. 2007.

Associations of diet, supplement use and ultraviolet B radiation

exposure with vitamin D status in Swedish women during winter. Am J

Clin Nutr 86: 404.

8. Bickle DD. 1997. Vitamin D and Skin. Chapter 25 in Vitamin D. Ed.

Feldman D, Glorieux FH, Wesley Pike J. 379-394.

9. Pettifor JM, s ED. 1997. Vitamin D deficiency and

nutritional rickets in children. Chapter 42 in Vitamin D. Ed. Feldman

D, Glorieux FH, Wesley Pike J. 663-678.

10. Hollis B. 1997. Detection of vitamin D and its major metabolites.

Chapter 38 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J.

587-606.

____________________________________

BioEssays 30:510-511, 2008 Wiley Periodicals, Inc.

Trevor G. Marshall

School of Biological Sciences

and Biotechnology

c/o 3423 Hill Canyon Avenue

Murdoch University

Western Australia

E-mail: trevor.m@...

Author's reply to correspondence from Drs Grant, Garland, and Boucher

Sir,

The primary function of calcitriol, 1,25-dihydroxyvitamin-D (1,25-D),

is to activate the Vitamin D Nuclear Receptor (VDR), enabling

transcription and transrepression of genes. Even pathways previously

thought to be 'non-genomic' have been shown to rely upon gene

transcription.(1) Thus, the measured level of 25-hydroxyvitamin-D (25-

D) is not sufficient to determine " Vitamin D deficiency " or " Vitamin

D status " . Only the 1,25-D form of Vitamin D has the ability to

activate the VDR to transcribe genes, and therefore only measurements

including this metabolite can accurately describe the overall

homeostasis of the Vitamin D metabolism in man [see Ref. 2, Fig. 1].

Dr Boucher has highlighted many of the difficulties confronting

clinical medicine as it expands its knowledge base from the level of

tissues, as seen under the microscope, to that of individual genes

and proteins, interacting at the submicroscopic scale of the

molecule. Even though there are decades of clinical studies

attempting to delineate the association between health, disease and

the Vitamin D metabolites, any study conducted without reference to

genes, or transcription, must necessarily lead to an incomplete

characterization.

Drs. Grant and Garland correctly note that low levels of 25-D are

associated with many diseases. Yet they extrapolate that observation

to imply that a causal relationship should be expected between this

(largely inactive) metabolite, and those disease states. This is a

non sequitur, as our article shows there is not a first-order mass-

action relationship between the dosage of exogenous Vitamin D and the

measured level of the 25-D metabolite (see Ref. 2, Fig. 1). Not only

are there multiple metabolic feedback control mechanisms, there are

control inputs via Protein Kinase A (PKA), in addition to the steroid

and xenobiotic ligands of PXR. Our article explains why the observed

lower level of 25-D metabolite is a symptom of Vitamin D

dysregulation resulting from the disease state, an attempt by the

body to bring the level of the active metabolite back into its

control range.

Exploring the cause of the obesity epidemic, we took the rhetorical

question from Bajzer and Seeley,(3) " are gut bacteria a factor in the

obesity epidemic " , and built a detailed putative pathogenesis, based

on our molecular, and clinical, knowledge. Specifically cited were

two carefully controlled studies,(4,5) which had failed to show a

causal relationship between lifestyle, nutritional choices and

obesity. It would have been helpful if Grant and Garland could have

addressed any specific failings they might have seen in those

controlled studies, rather than give the citation they chose(6) as

the basis for their argument.

They suggest that deficiencies in the available clinical trials can

be blamed on the low profit potential from sales of the secosteroid

itself. Although the direct cost of Vitamin D supplements may not be

great, there is money to be made from market positioning, enough to

attract the interest of a large multinational. Our article explains

how the Coca-Cola Company has petitioned the FDA to be allowed to add

a high level of Vitamin D to their brands of orange juice, so that

they can claim that it reduces the risk of osteoporosis.(7) There is

clearly money available for higher quality studies. However, because

this secosteroid is still classified as a vitamin, rather than as a

drug, the FDA has not yet begun insisting that a more rigorous

understanding of the underlying biology be brought to bear upon

Vitamin D trial design.

Grant and Garland accept that sarcoidosis is a chronic inflammatory

diagnosis in which Vitamin D supplementation might do harm, but we

feel they need to address why other autoimmune diagnoses might not be

similarly exacerbated by supplementation. Our 2004 paper " Sarcoidosis

succumbs to antibiotics - implications for autoimmune disease " (8)

canvassed a homogeneity of inflammatory pathogeneses, a hypothesis

that has subsequently been supported by the emerging clinical

evidence.(9-11)

We do not disagree with the primary premise of Grant and Garland,

that Vitamin D supplementation of the food supply is one of the most

important public health issues of our time. Our article is arguing

that more sophisticated study designs will be needed if one is to

definitively evaluate the metabolism responsible for expression of at

least 913 genes. Only then can we determine if, and to what degree,

addition of Vitamin D to the food chain might be beneficial to the

public's health.

References

1. Bravo S, Paredes R, Izaurieta P, Lian JB, Stein JL, et al. 2006.

The classic receptor for 1alpha,25-dihydroxy vitamin D3 is required

for non-genomic actions of 1alpha,25-dihydroxy vitamin D3 in

osteosarcoma cells. J Cell Biochem 99:995-1000.

2. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

3. Bajzer M, Seeley RJ. 2006. Physiology: obesity and gut flora.

Nature 444: 1009-1010.

4. Caballero B, Clay T, SM, Ethelbah B, Rock BH, et al. 2003.

Pathways Study Research Group. Pathways: a school-based, randomized

controlled trial for the prevention of obesity in American Indian

schoolchildren. Am J Clin Nutr 78:904-905.

5. Reilly JJ, L, Montgomery C, on A, Fisher A, et al.

2006. Physical activity to prevent obesity in young children: cluster

randomised controlled trial. BMJ 333:1041.

6. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. Penguin Press, New York. 430 pp.

7. DHHS Food and Drug Administration. 2007. Food Labeling; Health

Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and

Osteoporosis. 21 CFR Part 101 [Docket No. 2004P-0464] Federal

Register/Vol. 72, No. 3/Friday, January 5, 2007.

8. Marshall TG, Marshall FE. 2004. Sarcoidosis succumbs to

antibiotics - implications for autoimmune disease. Autoimmunity

Reviews 3:295-3001.

9. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. 2006.

High levels of active 1,25-dihydroxyvitamin D despite low levels of

the 25-hydroxyvitamin D precursor - Implications of dysregulated

vitamin D for diagnosis and treatment of Chronic Disease. In: Stoltz

VD, editor. Vitamin D: New Research, Vol. 1. New York: Nova Science

Publishers.

10. Arnson Y, Amital H, Shoenfeld Y. 2007. Vitamin D and

autoimmunity: New aetiological and therapeutic considerations. Ann

Rheum Dis 66(9):1137-1142.

11. Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to

Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract

presentation, Days of Molecular Medicine 2006. Copy available from

URL http://autoimmunityresearch.org/karolinska-handout.pdf.

____________________________________

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

Link to comment
Share on other sites

Hi athan;

Thanks for posting this article. Before adding my own personal

comments [it's a very controversial issue!!], I thought it would be

good to share some of the correspondence that this article generated

in " BioEssays " earlier this year. There were 2 letters followed by a

reply by Marshall:

____________________________________

BioEssays 30:506-507, 2008 Wiley Periodicals, Inc.

B. Grant

Sunlight, Nutrition, and Health Research Center (SUNARC)

P.O. Box 641603, San Francisco, CA 94164-1603.

E-mail: wbgrant@...

Cedric F. Garland

Department of Family and Preventive Medicine 0631C

University of California San Diego, La Jolla, CA.

For readers wishing additional supporting references please contact

Dr Grant

The health benefits of vitamin D greatly outweigh the health risks

Sir,

In his recent essay, Trevor G. Marshall explores how vitamin D

supplementation may be contributing to the current epidemics of

obesity and chronic disease.(1) Unfortunately, he has overlooked many

important papers that disagree with his hypothesis. This letter

points out some of the omissions.

The health benefits of vitamin D3 have been reviewed recently.(2) The

benefits for bone health have been known for nearly a century.

Benefits for cancer, infectious diseases, autoimmune diseases and

metabolic diseases have been identified in the past three decades.

Starting in the 1980s, largely observational evidence mounted that

solar ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of

many types of cancer.(3) Based on observational studies, it is

estimated that 2500 and 3600 International Units (IU) of vitamin D3

are required daily for a 30-50% reduction in risk of colorectal and

breast cancer, respectively.(4,5) A recent randomized, double-blind,

placebo controlled clinical trial that studied post-menopausal women

in Nebraska found a 77% reduction in all-cancer incidence between the

ends of the first and fourth years,(5) adding strong support to the

observational studies.

Vitamin D enhances innate immunity through induction of human

cathelicidin, LL-37.(1) LL-37 helps control both bacterial and viral

infections. A recent post-hoc analysis of vitamin D3 supplementation

for post-menopausal women living in New York State found substantial

benefits in reducing the common cold and influenza for 800 IU/day,

and very strong benefits for 2000 IU/day.(6) Benefits also appear to

be strong for septicaemia (Grant, submitted).

Many autoimmune diseases appear to arise from an improper immune

response to viral infections. Since LL-37 reduces the risk of viral

infections, it may also influence the risk of autoimmune diseases

such as multiple sclerosis. The well-known increase in prevalence of

multiple sclerosis with increasing latitude is consistent with this

hypothesis.

There is also a growing body of literature that low vitamin D status

is a risk factor for many metabolic diseases, including hypertension,

type 2 diabetes, and cardiovascular disease.(2) A recent

observational study found that vitamin D deficiency is associated

with incident cardiovascular disease.(7)

There are some diseases where vitamin D supplementation may be

contraindicated. These include granulomatous diseases such as

sarcoidosis where local production of 1,25-dihydroxyvitamin D

(calcitriol) in response to the disease can leak into the serum and

dysregulate calcium metabolism.(8)

The current vitamin D3 fortification of food in the United States

contributes an average of 250-300 IU/day to the American diet. This

amount is too low to have a substantial beneficial effect on risk of

cancer. Intake or production of vitamin D3 of 1000-2000 IU/day seems

now to be required for optimal health, and typically will raise serum

25-hydroxyvitamin D (calcidiol) levels to 40-60 ng/mL.(4,6,9)

It is possible that the reason that there have not been more clinical

trials of vitamin D supplementation clinical trials is that there is

little income in selling vitamin D3 (a year's supply of 1500 IU/day

costs less than $20 U.S.), and such trials are expensive.

The rising prevalence of obesity in the United States has been

attributed to over consumption of popular energy-dense foods compared

to energy output.(10) Until obesity is eliminated, increased vitamin

D3 supplementation and fortification of foods could provide

substantial health benefits, including reduced incidence of several

serious diseases.

Disclosure

WBGreceives funding from the UV Foundation (McLean, VA), the Vitamin

D Society (Canada), and the European Sunlight Association.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. Bioessays 30:173-182.

2. Holick MF. 2007. Vitamin D deficiency. N Engl J Med 357:266-281.

3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H et al.

2006. The role of vitamin D in cancer prevention. Am J Public Health

96:252-261.

4. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. 2007. What

is the dose-response relationship between vitamin D and cancer risk?

Nutr Rev 65:S91-95.

5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.

2007. Vitamin D and calcium supplementation reduces cancer risk:

results of a randomized trial. Am J Clin Nutr 85:1586-1591.

6. Aloia JF, Li-Ng M. 2007. Re: epidemic influenza and vitamin D.

Epidemiol Infect 135:1095-1096; author reply 1097-1098.

7. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, et al.

2008. Vitamin D Deficiency and Risk of Cardiovascular Disease.

Circulation [Epub ahead of print].

8. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

9. Cannell J, Hollis B, Zasloff M, Heaney R. 2008. Diagnosis and

treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107-118.

10. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. New York: Penguin Press. 430

____________________________________

BioEssays 30:508-509, 2008 Wiley Periodicals,

Barbara J. Boucher

Centre for Diabetes & Metabolic Medicine

Barts & the London Medical & Dental School, London, UK

E-mail: bboucher@...

DOI 10.1002/bies.20751

Published online in Wiley InterScience (www.interscience.wiley.com).

Comment on " Vitamin D discovery outpaces FDA decision making "

" Before you let the sun in, make sure it wipes its shoes "

Dylan , Under Milk Wood. 1954

Sir,

It is always wise to consider evidence from points of view other than

those that are current `received wisdom' so that we can see clearly

what we are really looking at. Thus, the above review is of

considerable interest.(1) The author postulates that circulating

hormonal [activated] vitamin D (calcitriol) concentration is more

important than circulating 25-hydroxyvitamin D [25-(OH)D] in the

determination of tissue functions that are modulated by vitamin D. He

also appears to suggest that changes in circulating 25-hydroxy

vitamin D reflect changes in calcitriol formation and uptake rather

than availability of vitamin D and that circulating calcitriol

concentration tells us about vitamin D effectiveness. This would

indeed be the case if all tissues depended on uptake of calcitriol

from the circulation for their supplies of hormonal vitamin D.

However, many tissues express the hydroxylase activating vitamin D

and several have been confirmed as producers of calcitriol in situ.(2-

4) Such tissues must use circulating 25-(OH)D, the substrate for

activation by 25-hydroxyvitamin D 1-alphahydroxylase. Thus, for

example, in the placenta, calcitriol is produced in large amounts

from early in pregnancy with increases in circulating maternal

calcitriol and reductions in maternal circulating 25-(OH)D.(4)

However, to suggest that all variation on serum 25-(OH)D

concentrations in different disease processes reflects changes in

local tissue vitamin D activation to the exclusion of variations due

to the amount of vitamin D in the body would be to ignore the massive

changes in serum 25-(OH)D seen within hours of exposure to UVB,

without any changes in circulating calcitriol(5) and would not

explain the remarkable seasonal variations in serum 25-(OH)D seen

with variation in available effective UVB from sunlight, with

variations in dietary intake of vitamin D and with supplement use. In

Sweden for example, in a group of 116 women in the winter, an average

serum 25(OH)D of 69 nmol/l was accounted for by the following: (1)

daily intake of normally fortified Swedish foods, 6.2 nmol/l, (2)

three fish meals/week, 25.5 nmol/l, (3) regular vitamin supplement

use, 11.0 nmol/l and (4) a vacation in the sun within the last 6

months, 14.5 nmol/l, which leaves 11.8 nmol/l of 25-(OH)D to be

accounted for the balance between incoming vitamin D and the amount

of 25-(OH)D being consumed by local vitamin D activating tissues.

(6,7) In addition, however much ultraviolet B effective for induction

of vitamin D synthesis [effUVb] one is exposed to, vitamin D toxicity

does not develop because of feed-back mechanisms in the skin itself.

(8) Similarly, feedback mechanisms ensure that circulating calcitriol

is virtually unchanged in the face of reductions in serum 25-(OH)D in

the circulation until there is clinically obvious vitamin D

deficiency with bone disease such as rickets or osteomalacia when

calcitriol does eventually fall, though even then, in some case,

serum calcitriol is found to be increased.(9) These findings

challenge the argument that vitamin D modulation of tissue function

depends predominantly on circulating calcitriol and explain why

vitamin D repletion continues to be judged at present by circulating

concentrations of the storage adduct, 25-(OH)D, acting as it does as

the substrate for local tissue activation throughout the body and not

just in the kidney. In support of this position, it is well known

that measurement of circulating calcitriol [hormonally active

1,25dihydroxyvitamin D] is unhelpful in the assessment of vitamin D

repletion since its concentrations are normally so tightly regulated

across a wide range of concentrations of 25-(OH)D.(10) Finally, the

fact that vitamin D activation has been demonstrated in several of

the extrarenal human tissues known to express specific vitamin D

activating 1-alpha hydroxylase supports the view that assessment of

substrate availability of vitamin D, as reflected by serum 25-(OH)D,

is likely to be of importance in the assessment of vitamin D

repletion in humans.

References

1. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

2. Hewison M, Burke F, KN, Lammas DA, Sansom DM, et al. 2007.

Extra-renal 25-hydroxyvitamin Da-1alpha-hydroxylase in human health

and disease. J Steroid Biochem Mol Biol 103:316-321.

3. Merke J, Milde P, Lewicka S, Hugel U, Mangelsdorf DJ, et al. 1989.

J Clin Invest. 83:1903-1915.

4. KN, Bulmer JN, Kilby MD, Hewison M. 2004. Vitamin D and

placental-decidual function. J Soc Gynecol Investig 11:263-271.

5. Landin-Wilhelmsen K, Wilhelmsen L, Wilske J, Lappas G, Rosen T, et

al. 1995. Sunlight increases serum 25(OH) vitamin D concentration

whereas 1,25(OH)2D3 is unaffected. Results from a general population

study in Goteborg, Sweden (The WHO MONICA Project). Eur J Clin Nutr

49: 44-407.

6. Engelsen O, Brustad M, Aksnes L, Lund E. 2005. Daily duration of

vitamin D synthesis in human skin with relation to latitude, total

ozone, altitude, ground cover, aerosols and cloud thickness.

Photochem Photobiol 81:1287-1290.

7. Burgaa A, Akesson A, Oster A, sson K, Wolk A. 2007.

Associations of diet, supplement use and ultraviolet B radiation

exposure with vitamin D status in Swedish women during winter. Am J

Clin Nutr 86: 404.

8. Bickle DD. 1997. Vitamin D and Skin. Chapter 25 in Vitamin D. Ed.

Feldman D, Glorieux FH, Wesley Pike J. 379-394.

9. Pettifor JM, s ED. 1997. Vitamin D deficiency and

nutritional rickets in children. Chapter 42 in Vitamin D. Ed. Feldman

D, Glorieux FH, Wesley Pike J. 663-678.

10. Hollis B. 1997. Detection of vitamin D and its major metabolites.

Chapter 38 in Vitamin D. Ed. Feldman D, Glorieux FH, Wesley Pike J.

587-606.

____________________________________

BioEssays 30:510-511, 2008 Wiley Periodicals, Inc.

Trevor G. Marshall

School of Biological Sciences

and Biotechnology

c/o 3423 Hill Canyon Avenue

Murdoch University

Western Australia

E-mail: trevor.m@...

Author's reply to correspondence from Drs Grant, Garland, and Boucher

Sir,

The primary function of calcitriol, 1,25-dihydroxyvitamin-D (1,25-D),

is to activate the Vitamin D Nuclear Receptor (VDR), enabling

transcription and transrepression of genes. Even pathways previously

thought to be 'non-genomic' have been shown to rely upon gene

transcription.(1) Thus, the measured level of 25-hydroxyvitamin-D (25-

D) is not sufficient to determine " Vitamin D deficiency " or " Vitamin

D status " . Only the 1,25-D form of Vitamin D has the ability to

activate the VDR to transcribe genes, and therefore only measurements

including this metabolite can accurately describe the overall

homeostasis of the Vitamin D metabolism in man [see Ref. 2, Fig. 1].

Dr Boucher has highlighted many of the difficulties confronting

clinical medicine as it expands its knowledge base from the level of

tissues, as seen under the microscope, to that of individual genes

and proteins, interacting at the submicroscopic scale of the

molecule. Even though there are decades of clinical studies

attempting to delineate the association between health, disease and

the Vitamin D metabolites, any study conducted without reference to

genes, or transcription, must necessarily lead to an incomplete

characterization.

Drs. Grant and Garland correctly note that low levels of 25-D are

associated with many diseases. Yet they extrapolate that observation

to imply that a causal relationship should be expected between this

(largely inactive) metabolite, and those disease states. This is a

non sequitur, as our article shows there is not a first-order mass-

action relationship between the dosage of exogenous Vitamin D and the

measured level of the 25-D metabolite (see Ref. 2, Fig. 1). Not only

are there multiple metabolic feedback control mechanisms, there are

control inputs via Protein Kinase A (PKA), in addition to the steroid

and xenobiotic ligands of PXR. Our article explains why the observed

lower level of 25-D metabolite is a symptom of Vitamin D

dysregulation resulting from the disease state, an attempt by the

body to bring the level of the active metabolite back into its

control range.

Exploring the cause of the obesity epidemic, we took the rhetorical

question from Bajzer and Seeley,(3) " are gut bacteria a factor in the

obesity epidemic " , and built a detailed putative pathogenesis, based

on our molecular, and clinical, knowledge. Specifically cited were

two carefully controlled studies,(4,5) which had failed to show a

causal relationship between lifestyle, nutritional choices and

obesity. It would have been helpful if Grant and Garland could have

addressed any specific failings they might have seen in those

controlled studies, rather than give the citation they chose(6) as

the basis for their argument.

They suggest that deficiencies in the available clinical trials can

be blamed on the low profit potential from sales of the secosteroid

itself. Although the direct cost of Vitamin D supplements may not be

great, there is money to be made from market positioning, enough to

attract the interest of a large multinational. Our article explains

how the Coca-Cola Company has petitioned the FDA to be allowed to add

a high level of Vitamin D to their brands of orange juice, so that

they can claim that it reduces the risk of osteoporosis.(7) There is

clearly money available for higher quality studies. However, because

this secosteroid is still classified as a vitamin, rather than as a

drug, the FDA has not yet begun insisting that a more rigorous

understanding of the underlying biology be brought to bear upon

Vitamin D trial design.

Grant and Garland accept that sarcoidosis is a chronic inflammatory

diagnosis in which Vitamin D supplementation might do harm, but we

feel they need to address why other autoimmune diagnoses might not be

similarly exacerbated by supplementation. Our 2004 paper " Sarcoidosis

succumbs to antibiotics - implications for autoimmune disease " (8)

canvassed a homogeneity of inflammatory pathogeneses, a hypothesis

that has subsequently been supported by the emerging clinical

evidence.(9-11)

We do not disagree with the primary premise of Grant and Garland,

that Vitamin D supplementation of the food supply is one of the most

important public health issues of our time. Our article is arguing

that more sophisticated study designs will be needed if one is to

definitively evaluate the metabolism responsible for expression of at

least 913 genes. Only then can we determine if, and to what degree,

addition of Vitamin D to the food chain might be beneficial to the

public's health.

References

1. Bravo S, Paredes R, Izaurieta P, Lian JB, Stein JL, et al. 2006.

The classic receptor for 1alpha,25-dihydroxy vitamin D3 is required

for non-genomic actions of 1alpha,25-dihydroxy vitamin D3 in

osteosarcoma cells. J Cell Biochem 99:995-1000.

2. Marshall TG. 2008. Vitamin D discovery outpaces FDA decision

making. BioEssays 30:173-182.

3. Bajzer M, Seeley RJ. 2006. Physiology: obesity and gut flora.

Nature 444: 1009-1010.

4. Caballero B, Clay T, SM, Ethelbah B, Rock BH, et al. 2003.

Pathways Study Research Group. Pathways: a school-based, randomized

controlled trial for the prevention of obesity in American Indian

schoolchildren. Am J Clin Nutr 78:904-905.

5. Reilly JJ, L, Montgomery C, on A, Fisher A, et al.

2006. Physical activity to prevent obesity in young children: cluster

randomised controlled trial. BMJ 333:1041.

6. Pollan M. 2006. The Omnivore's Dilemma; Natural History of Four

Meals. Penguin Press, New York. 430 pp.

7. DHHS Food and Drug Administration. 2007. Food Labeling; Health

Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and

Osteoporosis. 21 CFR Part 101 [Docket No. 2004P-0464] Federal

Register/Vol. 72, No. 3/Friday, January 5, 2007.

8. Marshall TG, Marshall FE. 2004. Sarcoidosis succumbs to

antibiotics - implications for autoimmune disease. Autoimmunity

Reviews 3:295-3001.

9. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. 2006.

High levels of active 1,25-dihydroxyvitamin D despite low levels of

the 25-hydroxyvitamin D precursor - Implications of dysregulated

vitamin D for diagnosis and treatment of Chronic Disease. In: Stoltz

VD, editor. Vitamin D: New Research, Vol. 1. New York: Nova Science

Publishers.

10. Arnson Y, Amital H, Shoenfeld Y. 2007. Vitamin D and

autoimmunity: New aetiological and therapeutic considerations. Ann

Rheum Dis 66(9):1137-1142.

11. Marshall TG. 2006. VDR Nuclear Receptor Competence is the Key to

Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract

presentation, Days of Molecular Medicine 2006. Copy available from

URL http://autoimmunityresearch.org/karolinska-handout.pdf.

____________________________________

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

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Oh no controversy there Arne, coffee is not going anywhere in this

house! LOL

>

>

> As Ian points out, stick around, the conventional wisdom will change

again

> (e.g., coffee is bad/good/bad/good for you).

>

>

>

>

>

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Share on other sites

Oh no controversy there Arne, coffee is not going anywhere in this

house! LOL

>

>

> As Ian points out, stick around, the conventional wisdom will change

again

> (e.g., coffee is bad/good/bad/good for you).

>

>

>

>

>

Link to comment
Share on other sites

Oh no controversy there Arne, coffee is not going anywhere in this

house! LOL

>

>

> As Ian points out, stick around, the conventional wisdom will change

again

> (e.g., coffee is bad/good/bad/good for you).

>

>

>

>

>

Link to comment
Share on other sites

>

> http://trevormarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

>

> I would be be interested in any thoughts about it

Hi athan;

There are some things in the article by Trevor Marshall that I do

agree with, and others that I don't. I'll try to explain as best as I

can, and I hope that I don't loose you (and other readers) in the

process.

First, I do agree that vitamin D is not only a vitamin, but also an

important hormone with lots of biological effects, including causing

changes in the expression of a huge number of genes. The number of

changes in gene expression regulated by the active metabolite (1,25-

dihydroxyvitamin D) binding to the vitamin D receptor (VDR) is much

too large for the human brain to comprehend .... we need a computer

model of all the interactions to begin to accurately predict all the

biological responses.

Because vitamin A (retinol) does something similar ... i.e. is

metabolized in two steps to compounds (retinoic acids) that bind to

receptors (retinoic acid receptor (RAR) and retinoid X receptor

(RXR)) that then bind to a whole bunch of other receptors (including

VDR, PXR, LXR, PPAR) that affect expression of a multitude of

genes .... shouldn't we also call vitamin A a hormone? And why stop

there, since beta-carotene is metabolized in 2 steps to retinoic

acid, should we call carrots a hormone? And since docosahexaenoic

acid (DHA) (found in fish oil) binds to RXR and PPAR, causing a large

number of changes in gene expression, should we call DHA a hormone?

Shouldn't FDA also be regulating how many carrots we eat or how much

fish we eat, or fish oil supplements we take? The bottom line is that

a lot of nutrients have a marked effect on gene expression, and there

is not really a need to single-out vitamin D.

Second, I do agree that low values of 25-hydroxyvitamin D (the form

of vitamin D that is usually measured) CAN be the result of the

disease process. In the case of inflammatory bowel disease and

cholestatic liver diseases like PSC and PBC, there is good evidence

that absorption of vitamin D from the digestive system is impaired.

In the case of inflammatory bowel disease the level of 25-

hydroxyvitamin D (the main storage form of vitamin D) tends to be

reduced, and this level correlates with bone mineral density

(especially in males). Not surprisingly, then, supplementation with

vitamin D (and calcium) tends to rectify the metabolic bone disease

associated with IBD. This would not be expected if you believe

everything said in the Marshall article!

Could vitamin D deficiency tend to make the disease worse? Sure!

Because vitamin D plays an important role not only in bone metabolism

and the immune system (including how T cells migrate to various sites

in the body, and how much anti-bacterial peptides are produced, and

how strong the epithelial barrier is in the gut, and how much of the

inflammatory cytokine tumor necrosis factor alpha is produced),

deficiency of vitamin D would not be good for you in the long run.

Similarly, prolonged vitamin A deficiency would not be good for you

because vitamin A also regulates how and where T cells migrate, how

strong the epithelial barrier is in the gut, and how much IgA is

produced in the gut. The best way to rectify any deficiencies is

through supplementation .... and I am certainly all for this except

that this has to be done with caution to avoid potential toxicity

from over-doses.

The article by Trevor Marshall has some strong points. I like his

Figure 1, showing that the pregnane X receptor (PXR) is involved in

regulating not only 25-hydroxyvitamin D synthesis, but also 1,25-

hydroxyvitamin D catabolism. Because PXR is markedly down-regulated

in ulcerative colitis, this probably means that in ulcerative colitis

there would be impaired conversion of dietary vitamin D (or sunshine

generated vitamin D) to 25-hydroxyvitamin D. In principle, this

metabolism could be restored by taking rifampin, which is a PXR

activator (and used to control pruritus in PSC and PBC patients).

However, the long-term effects of rifampin therapy on 1,25-

hydroxyvitamin D catabolism are a concern to me [my son is taking

rifampin]. Will long-term treatment with rifampin require higher

vitamin D intakes to prevent depletion of vitamin D reserves? ... I

don't know.

While the article by Marshall is a bit controversial, it does get us

all thinking about what differences we might make to our long-term

health if we make sure we don't become nutrient/vitamin/hormone

deficient, and avoid taking too much of any one

nutrient/vitamin/hormone. Something that Marshall did not really

elaborate on was that the VDR actually pairs up with RXR to effect

changes in gene expression. What's the activator of RXR? Many suggest

that it is 9-cis retinoic acid, a metabolite of vitamin A. But others

point out that this metabolite cannot be reproducibly measured, and

that the best candidate 'natural' ligand for RXR is actually

docosahexaenoic acid (DHA). Regardless of who is right on this

specific point, does this mean that in order for VDR to function

properly, you also need either DHA of vitamin A? It's not just one

hormone/vitamin/nutrient that matters, but rather it's best to have a

good balance for everything to work properly!

I love Marshall's idea that certain bacteria might actually be

producing compounds that bind to VDR and prevent it from working. In

fact that's essentially the same idea that I have had about PSC,

namely that some as yet unidentified bacteria in the gut produces a

retinoic acid derivative that binds to RXR and prevents it from

working properly, disrupting bile, lipid, xenobiotic and bone

metabolism, bile transport, and the immune system.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

P.S. I tried to avoid using references this time, but would be glad

to provide any if anyone is interested in more detail.

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